CN1299280A - 具有抗肿瘤作用的吲哚基-3-乙醛酸衍生物 - Google Patents
具有抗肿瘤作用的吲哚基-3-乙醛酸衍生物 Download PDFInfo
- Publication number
- CN1299280A CN1299280A CN99805923A CN99805923A CN1299280A CN 1299280 A CN1299280 A CN 1299280A CN 99805923 A CN99805923 A CN 99805923A CN 99805923 A CN99805923 A CN 99805923A CN 1299280 A CN1299280 A CN 1299280A
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- Prior art keywords
- acid
- alkyl
- amino
- group
- acetaldehyde amide
- Prior art date
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- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000002253 acid Substances 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000003085 diluting agent Substances 0.000 claims abstract description 9
- 239000000725 suspension Substances 0.000 claims abstract description 9
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 8
- 239000000843 powder Substances 0.000 claims abstract description 7
- 238000002360 preparation method Methods 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
- 239000000829 suppository Substances 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- -1 indole-3-acetaldehyde amide Chemical class 0.000 claims description 97
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Natural products CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 40
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 25
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 239000002246 antineoplastic agent Substances 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- WHOOUMGHGSPMGR-UHFFFAOYSA-N Tryptaldehyde Natural products C1=CC=C2C(CC=O)=CNC2=C1 WHOOUMGHGSPMGR-UHFFFAOYSA-N 0.000 claims description 9
- 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
- 239000013543 active substance Substances 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
- 230000032050 esterification Effects 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 229940073608 benzyl chloride Drugs 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-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
- 125000002252 acyl group Chemical group 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
- 125000004193 piperazinyl group Chemical group 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
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 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
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000003708 ampul Substances 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- 229960000846 camphor Drugs 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000009472 formulation Methods 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
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 230000021603 oncosis Effects 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- RLLPVAHGXHCWKJ-UHFFFAOYSA-N permethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 RLLPVAHGXHCWKJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 claims description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)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
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- 239000002552 dosage form Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 20
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 239000004480 active ingredient Substances 0.000 abstract 1
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- 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 37
- 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 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 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
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- 238000000034 method Methods 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 238000007912 intraperitoneal administration Methods 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 235000012489 doughnuts Nutrition 0.000 description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 8
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- 239000002585 base Substances 0.000 description 7
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
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- 206010028980 Neoplasm Diseases 0.000 description 6
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- 125000003710 aryl alkyl group Chemical group 0.000 description 6
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- 125000004446 heteroarylalkyl group Chemical group 0.000 description 6
- 208000035126 Facies Diseases 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 5
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- 210000004881 tumor cell Anatomy 0.000 description 5
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- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
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- 230000015572 biosynthetic process Effects 0.000 description 4
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- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 4
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- 150000003141 primary amines Chemical class 0.000 description 4
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- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
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- IZXWCDITFDNEBY-UHFFFAOYSA-N 1-(chloromethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CCl)C=C1 IZXWCDITFDNEBY-UHFFFAOYSA-N 0.000 description 2
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 2
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
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- 229910052794 bromium Inorganic materials 0.000 description 1
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- 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
- 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
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- 235000010446 mineral oil Nutrition 0.000 description 1
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- 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
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- CBFZWGRQXZYRRR-UHFFFAOYSA-N pyridin-4-amine;hydrochloride Chemical compound Cl.NC1=CC=NC=C1 CBFZWGRQXZYRRR-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及通式(1)的N-取代的吲哚-3-乙醛酰胺作为抗肿瘤剂的用途和具有抗肿瘤作用的药物组合物,其特征是含有一定量的至少一种通式(1)的化合物,可选为它们的生理学上可耐受的酸加成盐或其N-氧化物。本发明还包括抗肿瘤剂,包含根据通式1的一种或多种N-取代的吲哚-3-乙醛酰胺作为活性试剂,和可选它们的生理学上可耐受的酸加成盐,如果可能的话,和其N-氧化物,还包含药学上可利用的赋形剂和/或稀释剂或助剂,剂型为片剂、包衣片、胶囊、输注或安瓿溶液、栓剂、贴剂、可以吸入的粉末制剂、悬浮液、霜剂和软膏。
Description
吲哚-3-乙醛酰胺具有多种用途,可作为药效学上的活性化合物和药物化学中的合成原料。
荷兰专利申请6502481描述了具有抗炎与退热活性和止痛活性的化合物。
英国申请GB-B1028812使用吲哚基-3-乙醛酸及其酰胺的衍生物作为止痛剂、抗惊厥剂和β-肾上腺素能化合物。
G.Domschke等(Ber.94,2353(1961))描述了3-吲哚基乙醛酰胺(原文如此),它们不具有药理学特征。
E.Walton在《医药化学杂志》11,1252(1968)中报道了吲哚-3-基乙醛酸衍生物,它们对磷酸甘油脱氢酶和乳酸脱氢酶具有抑制作用。
欧洲专利说明书EP675110描述了1H-吲哚-3-乙醛酰胺,它们是sPLA2抑制剂,用于脓毒性休克、胰腺炎的治疗和变应性鼻炎、类风湿性关节炎的治疗。
本发明的目的是提供具有有效抗肿瘤作用的N-取代的吲哚-3-乙醛酰胺,从而赋予有效的药物价值。
所述化合物作为药物已经公开在DE-A19636150 A1中,具有平喘、抗变态反应和免疫抑制/免疫调节作用。
本发明因此涉及通式1的N-取代的吲哚-3-乙醛酰胺(原文如此)在抗肿瘤剂制备中的用途,具有根据式1的活性物质成分的抗肿瘤剂,还涉及它们在肿瘤病治疗中的用途。式1
其中各原子团R、R1、R2、R3、R4和Z具有下列含义:
R=氢、(C1-C6)烷基,其中的烷基可以被苯环单取代或多取代,就该苯环来说,它可以被卤素、(C1-C6)烷基、(C3-C7)环烷基、羧基、用C1-C6链烷醇酯化的羧基、三氟甲基、羟基、甲氧基、乙氧基、苄氧基和苄基单取代或多取代,该苄基在苯基部分被(C1-C6)烷基、卤原子或三氟甲基单取代或多取代,
R进一步是苄氧羰基(Z基)和叔丁氧羰基(BOC原子团),进而是乙酰基。
R1可以是苯环,该苯环被(C1-C6)烷基、(C1-C6)烷氧基、氰基、卤素、三氟甲基、羟基、苄氧基、硝基、氨基、(C1-C6)烷基氨基、(C1-C6)烷氧羰基氨基和羧基或用C1-C6链烷醇酯化的羧基单取代或多取代,或者可以是式2的吡啶结构及其N-氧化物(原文如此)
及其N-氧化物,其中的吡啶结构选择性地键合到环碳原子2、3和4上,并且可以被取代基R5和R6取代。原子团R5和R6可以是相同或不同的,具有(C1-C6)烷基的含义和(C3-C7)环烷基、(C1-C6)烷氧基、硝基、氨基、羟基、卤素和三氟甲基的含义,进一步是乙氧羰基氨基和羧基烷氧基,其中的烷基可以具有1-4个C原子。
R1进一步可以是2-或4-嘧啶基杂环,其中的2-嘧啶基杂环可以被甲基单取代或多取代,进而是被(C1-C6)烷基、卤素、硝基、氨基和(C1-C6)烷基氨基取代的2-、3-、4-和8-喹啉基结构,是(原文如此)2-、3-和4-喹啉甲基,其中喹啉基和喹啉甲基的吡啶甲基部分的环碳原子可以被(C1-C6)烷基、(C1-C6)烷氧基、硝基、氨基和(C1-C6)烷氧羰基氨基取代。
R1在R=氢、甲基或苄基和苄氧羰基(Z原子团)、叔丁氧羰基(BOC原子团)和乙酰基的情况下,进而可以是下列原子团:-CH2COOH;-CH(CH3)-COOH;-(CH3)2-CH-(CH2)2-CH-COO-;H3C-H2C-CH(CH3)-CH(COOH)-;HO-H2C-CH(COOH)-;phenyl-CH2-CH(COOH)-;(4-imidazolyl)-CH2-CH-(COOH)-;HN=C(NH2)-NH-(CH2)3-CH(COOH)-;H2N-(CH2)4-CH(COOH)-;H2N-CO-CH2-CH-(COOH)-;HOOC-(CH2)2-CH(COOH)-;
R1在R是氢、Z基、BOC原子团、乙酰基或苄基的情况下,进而可以是天然或非天然氨基酸的酸根,例如α-甘氨酰、α-肌氨酰、α-丙氨酰、α-亮氨酰、α-异亮氨酰、α-丝氨酰、α-苯丙氨酰、α-组氨酰、α-脯氨酰、α-精氨酰、α-赖氨酰、α-天冬酰和α-谷氨酰,其中各氨基酸的氨基可以是未保护的或被保护的。氨基官能的可能的保护基团是苄酯基(Z原子团)和叔丁氧羰基(BOC原子团)以及乙酰基。在R1要求保护天冬酰和谷氨酰的情况下,第二、未键合的羧基以游离羧基或C1-C6链烷醇酯的形式存在,例如甲基、乙基或叔丁基的酯。
进而,R1可以是烯丙基氨基羰基-2-甲基丙-1-基。
R7是烷基、苯环,该苯环可以被(C1-C6)烷基、(C1-C6)烷氧基、卤素、硝基、氨基官能和(C1-C6)烷基氨基单取代或多取代。R7进而是二苯甲基和双对氟二苯甲基(原文如此)。
R2可以是氢和(C2-C6)烷基,其中的烷基被卤素和苯基单取代或多取代,就该苯基来说,它可以被卤素、(C1-C6)烷基、(C3-C7)环烷基、羧基、用C1-C6链烷醇酯化的羧基、三氟甲基、羟基、甲氧基、乙氧基或苄氧基单取代或多取代。视为R2的(C1-C6)烷基可以进一步被2-喹啉基和2-、3-和4-吡啶基结构取代,它们又都可以被卤素、(C1-C4)烷基或(C1-C4)烷氧基单取代或多取代。R2进一步是芳酰基,其中该原子团上的芳基部分是苯环,它可以被卤素、(C1-C6)烷基、(C3-C7)环烷基、羧基、用C1-C6链烷醇酯化的羧基、三氟甲基、羟基、甲氧基、乙氧基或苄氧基单取代或多取代。
R3和R4可以是相同或不同的,是氢、(C1-C6)烷基、(C3-C7)环烷基、(C1-C6)烷酰基、(C1-C6)烷氧基、卤素和苄氧基。R3和R4进而可以是硝基、氨基、(C1-C4)单或二烷基取代的氨基和(C1-C6)烷氧羰基氨基官能或(C1-C6)烷氧羰基氨基-(C1-C6)烷基官能。
Z是0和S。
关于原子团R、R1、R2、R3、R4、R5、R6、R7的定义烷基、烷酰基、烷氧基或烷基氨基在正常情况下被理解为既有“直链”、也有“支链”烷基的含义,其中的“直链烷基”例如可以是甲基、乙基、正丙基、正丁基、正戊基、正己基,“支链烷基”例如定义了异丙基或叔丁基。“环烷基”被理解为例如是环丙基、环丁基、环戊基、环己基或环庚基等原子团。
定义“卤素”代表氟、氯、溴或碘。定义“烷氧基”代表例如甲氧基、乙氧基、丙氧基、丁氧基、异丙氧基、异丁氧基或戊氧基等原子团。
化合物也可以使用酸加成盐的形式,例如无机酸的盐,酸例如盐酸、硫酸、磷酸,有机酸的盐,酸例如乙酸、乳酸、丙二酸、马来酸、富马酸、葡糖酸、葡糖醛酸、柠檬酸、扑酸、甲磺酸、三氟乙酸、琥珀酸和2-羟基乙磺酸。
式1化合物和它们的盐都是生物学上有活性的。
式1化合物可以以游离形式或生理学上可耐受的酸的形式给药。
给药可以通过口服、肠胃外、静脉内、透皮或吸入进行。
本发明进而涉及药物制剂,含有至少一种式1化合物或它们与生理学上可耐受的无机或有机酸的盐,适当情况下还含有药学上可利用的赋形剂和/或稀释剂或助剂。
适当的给药剂型例如片剂、包衣片、胶囊、输注或安瓿溶液、栓剂、贴剂、可以吸入的粉末制剂、悬浮液、霜剂和软膏。
下列反应流程1和2和一般操作描述根据本发明的化合物的制备方法。所有化合物都是按照所述方法或相似方法制备的。
按照下列流程1可以得到这样的通式1化合物,其中Z=0,R1=芳基、芳烷基、杂芳基和杂芳烷基,R2=烷基、芳烷基和杂芳烷基:流程1
第1阶段:
吲哚衍生物可以是未取代的,或者在C-2上或苯基结构中可以是单取代或多取代的,将其溶于一种质子、两极性非质子传递或非极性有机溶剂,例如异丙醇、四氢呋喃、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二噁烷、甲苯或二氯甲烷,滴加到一种碱在适当溶剂中的悬浮液中,该悬浮液是在三颈烧瓶中、在N2气氛下制得的或者以摩尔量或过量使用的,碱例如氢化钠、氢氧化钾粉末、叔丁醇钾、二甲氨基吡啶或氨基钠。然后,加入所需的烷基、芳烷基或杂芳烷基卤化物,适当时候加入一种催化剂,例如铜,使混合物反应一定时间,例如30分钟至12小时,使温度保持在0℃与120℃之间的范围内,优选为30℃至80℃,特别是在50℃与65℃之间。反应完成后,将反应混合物加入到水中,溶液例如用二乙醚、二氯甲烷、氯仿、甲基叔丁基醚或四氢呋喃萃取,在每种情况下所得有机相用无水硫酸钠干燥。有机相在真空中浓缩,残余物通过研制法结晶,或者油性残余物通过重结晶法、蒸馏法或硅胶或矾土的柱色谱法或快速色谱法纯化。所用洗脱剂例如二氯甲烷与二乙醚的8∶2(vol/vol)混合物或二氯甲烷与乙醇的9∶1(vol/vol)混合物。
第2阶段:
将按照上述第1阶段操作得到的N-取代的吲哚在氮气氛下溶于一种非质子传递或非极性有机溶剂,例如二乙醚、甲基叔丁基醚、四氢呋喃、二噁烷、甲苯、二甲苯、二氯甲烷或氯仿,加入到单摩尔高达60%过量的草酰氯在非质子传递或非极性溶剂中的溶液中,该溶液是在氮气氛下制得的,溶剂例如二乙醚、甲基叔丁基醚、四氢呋喃、二噁烷、甲苯、二甲苯、二氯甲烷,温度保持在-5℃与20℃之间。反应溶液然后在10℃与130℃之间的温度下加热30分钟至5小时,优选在20℃与80℃之间,特别是在30℃与50℃之间,溶剂然后蒸发。将以这种方式生成的“吲哚基-3-乙醛酰氯”残余物溶于一种非质子传递溶剂,例如四氢呋喃、二噁烷、二乙醚、甲苯,或者溶于一种两极性非质子传递溶剂,例如二甲基甲酰胺、二甲基乙酰胺或二甲基亚砜,冷却至10℃与-15℃之间的温度,优选在-5℃与0℃之间,在一种酸清除剂的存在下,用伯胺或仲胺在一种稀释剂中的溶液处理。可行的稀释剂是上面用于溶解吲哚基-3-乙醛酰氯的溶剂。所用酸清除剂是三乙胺、吡啶、二甲氨基吡啶、碱性离子交换剂、碳酸钠、碳酸钾、氢氧化钾粉末和过量的反应所用伯胺或仲胺。反应发生在0℃至120℃的温度下,优选在20-80℃下,特别是在40℃与60℃之间。反应1-3小时并在室温下放置24小时后,过滤酸清除剂的盐酸盐,滤液在真空中浓缩,残余物从有机溶剂中重结晶或者通过硅胶或矾土柱色谱法纯化。所用洗脱剂例如二氯甲烷与乙醇的混合物(95∶5,vo1/vol)。
操作例
按照基于流程1的第1和第2阶段的一般操作,合成了下列化合物,下表详细给出了各自的化学名称。在第A-J页上的表1a-j中,这些化合物的结构和熔点可以从通式1和取代基R1-R4及Z找到。
实施例1
N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺(D24241)
第1阶段
1-(4-氟苄基)吲哚
向2.64g氢化钠(0.11mol,矿物油悬浮液)在100ml二甲基亚砜中的混合物中加入11.72g(0.1mol)吲哚的50ml二甲基亚砜溶液。混合物在60℃下加热1.5小时,然后冷却,滴加15.9g(0.11mol)4-氟苄基氯。溶液加热至60℃,放置过夜,然后倒入400ml水中,搅拌。混合物用总量为150ml的二氯甲烷萃取几次,有机相用无水硫酸钠干燥,过滤,滤液在真空中浓缩。残余物在高真空中蒸馏:21.0g(理论产率96%)熔点(0.5mm):140℃
第2阶段
N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺(D24241)
在0℃和N2下,向2.25ml草酰氯的25ml乙醚溶液中滴加4.75g(21.1mmol)1-(4-氟苄基)吲哚的25ml乙醚溶液。混合物加热回流2小时,然后蒸发溶剂。然后向残余物中加入50ml四氢呋喃,溶液冷却至-5℃,滴加4.66g(49.5mmol)4-氨基吡啶的200ml THF溶液进行处理。混合物加热回流3小时,在室温下放置过夜。用吸滤法滤出盐酸4-氨基吡啶,沉淀用THF洗涤,滤液在真空中浓缩,残余物从乙酸乙酯中重结晶。
产量:7.09g(理论产率90%)
熔点:225-226℃
元素分析:
计算值C 70.77 H4.32 N11.25
实测值C 71.09 H 4.36 N 11.26
实施例2,D24242 N-(吡啶-4-基)-(1-甲基吲哚-3-基)乙醛酰胺
实施例3,D24834 N-(吡啶-3-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例4,D24835 N-(吡啶-3-基)-(1-苄基吲哚-3-基)乙醛酰胺
实施例5,D24836 N-(吡啶-3-基)-[1-(2-氯苄基)吲哚-3-基]乙醛酰胺
实施例6,D24840 N-(4-氟苯基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例7,D24841 N-(4-硝基苯基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例8,D24842 N-(2-氯吡啶-3-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例9,D24843 N-(吡啶-4-基)-(1-苄基吲哚-3-基)乙醛酰胺
实施例10,D24848 N-(吡啶-4-基)-[1-(3-吡啶甲基)吲哚-3-基]乙醛酰胺
实施例11,D24849 N-(4-氟苯基)-[1-(2-吡啶甲基)吲哚-3-基]乙醛酰胺
实施例12,D24850 N-(4-氟苯基)-[1-(3-吡啶甲基)吲哚-3-基]乙醛酰胺
实施例13,D24851 N-(吡啶-4-基)-[1-(4-氯苄基)吲哚-3-基]乙醛酰胺
实施例14,D24852 N-(吡啶-4-基)-[1-(2-氯苄基)吲哚-3-基]乙醛酰胺
实施例15,D24853 N-(吡啶-2-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例16,D24847 N-(吡啶-4-基)-[1-(2-吡啶甲基)吲哚-3-基]乙醛酰胺
实施例17,D24858(4-苯基哌嗪-1-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例18,D24854 N-(吡啶-2-基)-(1-苄基吲哚-3-基)乙醛酰胺
实施例19,D25421 N-(吡啶-4-基)-[1-(4-氟苄基)-6-乙氧羰基氨基吲哚-3-基]乙醛酰胺
实施例20,D25422 N-(吡啶-4-基)-[1-(4-氟苄基)-5-乙氧羰基氨基吲哚-3-基]乙醛酰胺
实施例21,D25423 N-(吡啶-4-基)-[1-(4-氟苄基)-6-环戊氧羰基氨基吲哚-3-基]乙醛酰胺
实施例22,D25420 4-(吡啶-4-基)哌嗪-1-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例23,D24866 N-(3,4,5-三甲氧基苄基)-N-(烯丙氨基羰基-2-甲基丙-1-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
实施例24 N-(吡啶-4-基)-[1-(4-氟苄基)-5-甲氧基吲哚-3-基]乙醛酰胺
实施例25 N-(吡啶-4-基)-[1-(4-氟苄基)-5-乙氧羰基氨基甲基吲哚-3-基]乙醛酰胺
按照合成流程1制备的通式1化合物的原料详见表1。
用于合成最终产物D24241、D24242、D24834、D24835、D24836、D24840、D24841、D24842、D24843、D24848、D24849、D24850、D24851、D24852、D24853、D24847、D24858、D24854、D25420、D25422、D25421、D25423的全部前体都是商业上可得到的。
进而,其中Z=0、R1=芳基、芳烷基、杂芳基、杂芳烷基和烯丙氨基羰基-2-甲基丙-1-基,R2=烷基、芳烷基和杂芳烷基的通式1化合物也是可以按照流程2的合成途径得到的:
流程2
化合物D24241、D24841、D24840和D24834(反应流程2的第2阶段,另见表1)和它们的反应性前体D24825、D24831、D24832和D24833(反应流程2的第1阶段,另见第K页上的表2)是按照目前的流程2得到的。
N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺(D24241)
第1阶段
N-(吡啶-4-基)-(吲哚-3-基)乙醛酰胺
在0℃下,向9ml草酰氯的100ml无水乙醚溶液中滴加10g(85.3mmol)吲哚的100ml乙醚溶液。混合物在回流下保持3小时。然后在-5℃下加入12g(127.9mmol)4-氨基吡啶的500ml四氢呋喃悬浮液,反应混合物在搅拌下加热回流3小时,在室温下放置过夜。过滤,沉淀用水处理,干燥后的化合物在硅胶柱(硅胶60,Merck AG,Darmstadt)上纯化,所用洗脱剂为二氯甲烷/乙醇(10∶1,v/v)。
产量:9.8g(理论产率43.3%)
熔点:250℃以上
第2阶段N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺(D24241)使按照第1阶段得到的N-(吡啶-4-基)-(吲哚-3-基)乙醛酰胺与4-氟苄基氯按照“苄基化操作”(第5页)反应,分离所得化合物D24241。
产率:理论上的41%
熔点:224-225℃
元素分析:
计算C70.77 H4.32 N11.25
实测C70.98 H4.40 N11.49
通式1化合物按照流程2制备的一般操作
第1阶段:
吲哚衍生物可以是未取代的,或者在C-2上或苯环中可以是取代的,将其溶于一种溶剂,例如上述用于溶解草酰氯的溶剂,在-5℃与+5℃之间的温度下滴加到单摩尔高达60%过量的草酰氯在一种非质子传递或非极性溶剂中的溶液中,该溶液是在氮气氛下制备的,溶剂例如二乙醚、甲基叔丁基醚、四氢呋喃、二噁烷或二氯甲烷。反应溶液然后在10℃与120℃之间的温度下加热1至5小时,优选为20℃与80℃之间,特别是在30℃与60℃之间,然后蒸发溶剂。将(吲哚-3-基)乙醛酰氯残余物溶解或悬浮在一种非质子传递溶剂中,例如四氢呋喃、二噁烷、二乙醚、甲苯,或者是一种两极性非质子传递溶剂,例如二甲基甲酰胺、二甲基乙酰胺或二甲基亚砜,冷却至-10℃与+10℃之间的温度,优选为-5℃至0℃,在一种酸清除剂的存在下,用伯胺或仲胺在一种稀释剂中的溶液处理。可行的稀释剂是上面用于溶解“吲哚基-3-乙醛酰氯”的溶剂。所用酸清除剂是三乙胺、吡啶、二甲氨基吡啶、碱性离子交换剂、碳酸钠、碳酸钾、氢氧化钾粉末和过量的反应所用伯胺或仲胺。反应发生在0℃至120℃的温度下,优选在20-80℃下,特别是在40℃与60℃之间。反应1-4小时并在室温下放置24小时后,混合物过滤,沉淀用水消化,用吸滤法滤出,在真空中干燥。所需化合物通过有机溶剂重结晶法或者通过硅胶或矾土柱色谱法纯化。所用洗脱剂例如二氯甲烷与乙醇的混合物(10∶1,vol/vol)。
第2阶段:
将按照上述第1阶段操作得到的“吲哚-3-基乙醛酰胺”溶于一种质子、两极性非质子传递或非极性有机溶剂,例如异丙醇、四氢呋喃、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二噁烷、甲苯或二氯甲烷,滴加到一种碱在适当溶剂中的悬浮液中,该悬浮液是在三颈烧瓶中、在N2气氛下制得的或者以摩尔量或过量使用的,碱例如氢化钠、氢氧化钾粉末、叔丁醇钾、二甲氨基吡啶或氨基钠。然后,加入所需的烷基、芳烷基或杂芳烷基卤化物,该卤化物是未经稀释的或用一种稀释剂稀释过,该稀释剂例如也用于溶解“吲哚-3-基乙醛酰胺”,适当时候加入一种催化剂,例如铜,使混合物反应一定时间,例如30分钟至12小时,使温度保持在0℃与120℃之间的范围内,优选在30℃与80℃之间,特别是在50℃与70℃之间。反应完成后,将反应混合物加入到水中,溶液例如用二乙醚、二氯甲烷、氯仿、甲基叔丁基醚、四氢呋喃或正丁醇萃取,在每种情况下所得有机相用无水硫酸钠干燥。有机相在真空中浓缩,残余物通过研制法结晶,或者油性残余物通过蒸馏法或硅胶或矾土的柱色谱法或快速色谱法纯化。所用洗脱剂例如二氯甲烷与二乙醚的8∶2(vol/vol)混合物或二氯甲烷与乙醇的9∶1(v/v)混合物。
按照基于合成流程2的第1和第2阶段的这种一般操作,合成了化合物D24241、D24841、D24840和D24834,它们也已经按照反应流程1的合成操作制备过,详见表1。这些化合物的有关前体可以从第K和L页上的表2找到。
化合物在下列药理模型中显示出良好的、依赖于剂量的抗肿瘤作用:
吲哚、特别是D-24851和D-24241首先在XTT增殖试验/细胞毒性试验中是清晰可见的(表3和表3a)。在该试验系统中,研究了物质对肿瘤细胞系增殖行为的作用。在此过程中,测定了这些物质的细胞毒性。试验方法描述在Scudiero等1988《癌症研究》48,4827中。
研究当中使用下列肿瘤细胞系:
KB细胞系:口腔上皮癌,
L1210细胞系:小鼠淋巴性白血病,
LNCAP细胞系:前列腺癌,和
SK-0V-3细胞系:卵巢癌。
大量不同的吲哚在全部四种肿瘤细胞系中都是活性的。D-24851和D-24241显示出最强的作用,D-24851更强于D-24241(表3和4)。
利用D-24851和D-24241在裸鼠中空纤维和L1210(小鼠)测定中进行了进一步的对比研究,两种化合物都观察到了依赖于剂量的强抗肿瘤作用(表3和5)。在中空纤维测定中,两种化合物的活性几乎是同样强的,而对于L1210,D-24851的活性在口服和腹膜内给药后明显强于D-24241。与市场上可得到的抗肿瘤物质相比,D-24851在多数情况下,在白血病模型中的活性都明显强于已知的对比物(表5)。
D-24851与市场上可得到的抗肿瘤物质相比更大的优点是化合物的低毒性(表3和5)。LD50值为1000mg/kg p.o.和>1000mg/kg i.p.,因此化合物具有更宽的治疗范围。进而,在D-24851给药后,没有观察到DNA的断裂。在血细胞生成试验中,D-24851的腹膜内给药也没有改变任何所研究的血液指标。
在大鼠Dunning肿瘤的进一步的化疗模型中,在D-24851反复口服给药后,观察到肿瘤生长的停滞,在某些动物中甚至观察到肿瘤消退。
在裸鼠的KB试验中,在两种吲哚D-24851和D-24241给药后同样观察到了抗肿瘤作用(表3、3a和4)。
在利用肿瘤细胞系L1210、即小鼠淋巴性白血病所进行的研究中,在D-24851腹膜内或口服给药后,见到存活时间明显地、依赖于剂量地延长了,剂量为100和147mg/kg多次(图1a和图1b)。
实验证明治疗范围更宽,因此,活性物质可以以高于商业上可得到的肿瘤药物的剂量给药。
本发明的范围不希望受到下列细节的限制,不过据说,每日大约20mg至500mg的剂量是口服可行的。在以注射剂或输液方式静脉内给药的情况下,可以给以250mg/天或以上,这因患者的体重和各自的耐受性而异。
表3
根据实施例13的组合物D-24851
D-24851:N-(吡啶-4-基)-[1-(4-氯苄基)吲哚-3-基]乙醛酰胺
模型 | Result. | SK-OV-3 | KB | L1210 | LNCap | MCF-7 | Tox |
XTT(μg/ml) | EC50 | ≈0.03 | ≈0.017 | ≈0.017 | ≈0.03 | ||
1×ip(mg/kg) | LD50 | =1000 | |||||
1×per os (mg/kg) | LD50 | >1000 | |||||
腹膜内中空纤维4×46mg/kg ip | %INH | 无作用 | 56 | 38 | |||
腹膜内中空纤维4×147mg/kg ip | %INH | 12 | 60 | 68 | |||
皮下中空纤维4×46mg/kg ip | %INH | 44 | 无作用 | 47 | |||
皮下中空纤维4×147 mg/kg ip | %INH | 3 5 | 67 | 68 | |||
体内 | |||||||
1×681mg/kg ip1×464mg/kg ip | %ILS | 018 | |||||
4×215mg/kg ip4×147mg/kg ip | %ILS | 1394 | |||||
7×100mg/kg ip7×147mg/kg ip | %ILS | 3559 | |||||
1×681mg/kg po4×215mg/kg po7×100mg/kg po7×147mg/kg po | %ILS | 22316375 | |||||
7×46mg/kg ip2×215mg/kg po | %WHI | 3318 |
表3a
实施例物质 | 肿瘤细胞XTT | |||
(D-数字) | KB | L 1210 | LNCAP | SK-OV-3 |
EC50[μg/ml] | EC50[μg/ml] | EC50[μg/ml] | EC50[μg/ml] | |
1(D 24241) | 0.020 | 0.170 | >31.600 | 0.170 |
3(D 24834) | 1.75 | 1.75 | 9.250 | 1.750 |
4(D 24835) | 17.5 | 1.750 | >31.6 | 9.200 |
6(D 24840) | 3.100 | 1.750 | >31.6 | 17.5 |
9(D 24843) | 0.050 | 0.090 | 3.240 | 1.750 |
10(D 24848) | 4.060 | 1.75 | >31.6 | 7.220 |
11(D 24849) | 4.590 | 1.750 | 17.500 | 4.250 |
12(D 24850) | >31.6 | 0.017 | >31.6 | >31.6 |
13(D 24851) | 0.017 | 0.017 | 0.030 | 0.030 |
14(D 24852) | 1.75 | 1.75 | 17.5 | 2.58 |
15(D 24853) | >31.6 | 3.1 | >31.6 | >31.6 |
16(D 24847) | 4.59 | 1.75 | 17.500 | 4.250 |
表2(D 24831) | 17.5 | 17.5 | 17.5 | 17.5 |
进一步的动物实验结果:
在D-24851以7×100mg/kg和7×147mg/kg p.o.给药后,观察到肿瘤生长停滞,在某些动物中甚至观察到肿瘤消退。
结晶形式经过试验与原始形式相比没有差异。
D-24851不导致DNA的断裂。
在血细胞生成试验中,D-24851的腹膜内给药没有改变任何所研究的血液指标。
表4
根据实施例1的D-24241:N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
模型 | Result. | SK-OV-3 | KB | L1210 | LNCap | MCF-7 | Tox |
XTT(μg/ml) | EC50 | ≈0.17 | ≈0.02 | ≈0.17 | >31.6 | ||
1×ip(mg/kg) | LD50 | ≈158 | |||||
1×per os (mg/kg) | LD50 | >1000 | |||||
腹膜内中空纤维4×15.8mg/kg ip | %INH | 46 | 43 | 无作用 | |||
皮下中空纤维4×15.8mg/kg ip | %INH | 81 | 68 | 33 | |||
In vivo: | |||||||
1×14.7mg/kg ip | %ILS | 无作用 | |||||
1×30mg/kg per os | %ILS | 无作用 | |||||
1×464mg/kg per os | %ILS | 44 | |||||
4×30mg/kg per os | %ILS | 无作用 | |||||
6×30mg/kg per os | %ILS | 无作用 | |||||
14×30mg/kg per os | %ILS | 无作用 | |||||
19×50mg/kg per os | %ILS | 50 | |||||
2×46.4mg/kg ip | %WHI | 22 | |||||
4×21.5mg/kg ip | %WHI | 无作用 | |||||
2×215mg/kg po | %WHI | 47 |
Claims (10)
其中各原子团R、R1、R2、R3、R4和Z具有下列含义:
R=氢、(C1-C6)烷基,其中的烷基可以被苯环单取代或多取代,就该苯环来说,它可以被卤素、(C1-C6)烷基、(C3-C7)环烷基、羧基、用C1-C6链烷醇酯化的羧基、三氟甲基、羟基、甲氧基、乙氧基、苄氧基和苄基单取代或多取代,该苄基在苯基部分被(C1-C6)烷基、卤原子或三氟甲基单取代或多取代,
R进一步是苄氧羰基(Z基)和叔丁氧羰基(BOC原子团),进而是乙酰基。
R1可以是苯环,该苯环被(C1-C6)烷基、(C1-C6)烷氧基、氰基、卤素、三氟甲基、羟基、苄氧基、硝基、氨基、(C1-C6)烷基氨基、(C1-C6)烷氧羰基氨基和羧基或用C1-C6链烷醇酯化的羧基单取代或多取代,或者可以是式2的吡啶结构及其N-氧化物
及其N-氧化物,其中的吡啶结构选择性地键合到环碳原子2、3和4上,并且可以被取代基R5和R6取代;原子团R5和R6可以是相同或不同的,具有(C1-C6)烷基的含义和(C3-C7)环烷基、(C1-C6)烷氧基、硝基、氨基、羟基、卤素和三氟甲基的含义,进一步是乙氧羰基氨基和羧基烷氧基,其中的烷基可以具有1-4个C原子;
R1进一步可以是2-或4-嘧啶基杂环,其中的2-嘧啶基杂环可以被甲基单取代或多取代,进而是被(C1-C6)烷基、卤素、硝基、氨基和(C1-C6)烷基氨基取代的2-、3-、4-和8-喹啉基结构,是2-、3-和4-喹啉甲基,其中喹啉基和喹啉甲基的吡啶甲基部分的环碳原子可以被(C1-C6)烷基、(C1-C6)烷氧基、硝基、氨基和(C1-C6)烷氧羰基氨基取代;
R1在R=氢、甲基或苄基和苄氧羰基(Z原子团)、叔丁氧羰基(BOC原子团)和乙酰基的情况下,进而可以是下列原子团:-CH2COOH;-CH(CH3)-COOH;-(CH3)2-CH-(CH2)2-CH-COO-;H3C-H2C-CH(CH3)-CH(COOH)-;HO-H2C-CH(COOH)-;phenyl-CH2-CH(COOH)-;(4-imidazolyl)-CH2-CH-(COOH)-;HN=C(NH2)-NH-(CH2)3-CH(COOH)-;H2N-(CH2)4-CH(COOH)-;H2N-CO-CH2-CH-(COOH)-;HOOC-(CH2)2-CH(COOH)-;
R1在R是氢、Z基、BOC原子团、乙酰基或苄基的情况下,进而可以是天然或非天然氨基酸的酸根,例如α-甘氨酰、α-肌氨酰、α-丙氨酰、α-亮氨酰、α-异亮氨酰、α-丝氨酰、α-苯丙氨酰、α-组氨酰、α-脯氨酰、α-精氨酰、α-赖氨酰、α-天冬酰和α-谷氨酰,其中各氨基酸的氨基可以是未保护的或被保护的;氨基官能的可能的保护基团是苄酯基(Z原子团)和叔丁氧羰基(BOC原子团)以及乙酰基;在R1要求保护天冬酰和谷氨酰的情况下,第二、未键合的羧基以游离羧基或C1-C6链烷醇酯的形式存在,例如甲基、乙基或叔丁基的酯;
进而,R1可以是烯丙基氨基羰基-2-甲基丙-1-基;
R和R1进一步可以与它们所键合的氮原子共同形成式3的哌嗪环或高哌嗪环,只要R1是氨基亚烷基,其中式3
R7是烷基、苯环,该苯环可以被(C1-C6)烷基、(C1-C6)烷氧基、卤素、硝基、氨基官能和(C1-C6)烷基氨基单取代或多取代,R7进而是二苯甲基和双对氟二苯甲基;
R2可以是氢和(C1-C6)烷基,其中的烷基被卤素和苯基单取代或多取代,就该苯基来说,它可以被卤素、(C1-C6)烷基、(C3-C7)环烷基、羧基、用C1-C6链烷醇酯化的羧基、三氟甲基、羟基、甲氧基、乙氧基或苄氧基单取代或多取代,视为R2的(C1-C6)烷基可以进一步被2-喹啉基和2-、3-和4-吡啶基结构取代,它们又都可以被卤素、(C1-C4)烷基或(C1-C4)烷氧基单取代或多取代;R2进一步是芳酰基,其中该原子团上的芳基部分是苯环,它可以被卤素、(C1-C6)烷基、(C3-C7)环烷基、羧基、用C1-C6链烷醇酯化的羧基、三氟甲基、羟基、甲氧基、乙氧基或苄氧基单取代或多取代;
R3和R4可以是相同或不同的,是氢、(C1-C6)烷基、(C3-C7)环烷基、(C1-C6)烷酰基、(C1-C6)烷氧基、卤素和苄氧基;R3和R4进而可以是硝基、氨基、(C1-C4)单或二烷基取代的氨基和(C1-C6)烷氧羰基氨基官能或(C1-C6)烷氧羰基氨基-(C1-C6)烷基官能;
Z是O和S。
3、具有抗肿瘤作用的药物组合物,其特征在于它含有至少一种通式1或1a化合物,也可选为它们的酸加成盐,例如无机酸的盐,酸例如盐酸、硫酸、磷酸,有机酸的盐,酸例如乙酸、乳酸、丙二酸、马来酸、富马酸、葡糖酸、葡糖醛酸、柠檬酸、扑酸、甲磺酸、三氟乙酸、琥珀酸和2-羟基乙磺酸,以及可能的N-氧化物。
4、通式1或1a的N-取代的吲哚-3-乙醛酰胺及其生理学上可耐受的酸加成盐在抗肿瘤剂制备中的用途,该抗肿瘤剂在用于肿瘤病的治疗时使用这些试剂、具体也就是下列化合物或其与生理学上可耐受的酸的盐,或者如果可能的话,是它们的N-氧化物:
D24241 N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺
D24843 N-(吡啶-4-基)-(1-苄基吲哚-3-基)乙醛酰胺
D24850 N-(4-氟苯基)-[1-(3-吡啶甲基)吲哚-3-基]乙醛酰胺
D24851 N-(吡啶-4-基)-[1-(4-氯苄基)吲哚-3-基]乙醛酰胺
D25505 N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺HC1。
5、抗肿瘤剂,包含根据通式1或1a的一种或多种N-取代的吲哚-3-乙醛酰胺和可选的它们的生理学上可耐受的酸加成盐作为活性试剂,特别是根据权利要求4的一种或多种化合物。
6、抗肿瘤剂,包含D 24241 N-(吡啶-4-基)-[1-(4-氟苄基)吲哚-3-基]乙醛酰胺或其盐酸盐作为活性试剂。
7、抗肿瘤剂,包含D24843 N-(吡啶-4-基)-(1-苄基吲哚-3-基)乙醛酰胺作为活性试剂。
8、抗肿瘤剂,包含D24850 N-(4-氟苯基)-[1-(3-吡啶甲基)吲哚-3-基]乙醛酰胺作为活性试剂。
9、抗肿瘤剂,包含D24851 N-(吡啶-4-基)-[1-(4-氯苄基)吲哚-3-基]乙醛酰胺作为活性试剂。
10、抗肿瘤剂,包含根据通式1或1a的一种或多种N-取代的吲哚-3-乙醛酰胺作为活性试剂,可选为它们的生理学上可耐受的酸加成盐,如果可能的话,是N-氧化物,特别是根据权利要求4和6至8的一种或多种化合物,还包含药学上可利用的赋形剂和/或稀释剂或助剂,剂型为片剂、包衣片、胶囊、输注或安瓿溶液、栓剂、贴剂、可以吸入的粉末制剂、悬浮液、霜剂和软膏。
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WO2009006839A1 (fr) * | 2007-07-11 | 2009-01-15 | Medical College Of Chinese People`S Armed Police Force | Dérivés d'indol-3-yl oxalylpodophyllotoxine substitués, leurs sels et leur application |
CN102942516A (zh) * | 2012-11-05 | 2013-02-27 | 宁波大学 | 一种生物碱类化合物及其制备方法和应用 |
CN102942516B (zh) * | 2012-11-05 | 2015-02-25 | 宁波大学 | 一种生物碱类化合物及其制备方法和应用 |
CN105198788A (zh) * | 2015-09-30 | 2015-12-30 | 蒋军荣 | 一种吲哚氧代乙酰(n-二芳甲基)哌嗪衍生物及其制备方法和应用 |
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