ITMI991740A1 - DERIVATIVES OF 1H-PYRID 3,4-B INDOL-1-ONE - Google Patents
DERIVATIVES OF 1H-PYRID 3,4-B INDOL-1-ONE Download PDFInfo
- Publication number
- ITMI991740A1 ITMI991740A1 IT1999MI001740A ITMI991740A ITMI991740A1 IT MI991740 A1 ITMI991740 A1 IT MI991740A1 IT 1999MI001740 A IT1999MI001740 A IT 1999MI001740A IT MI991740 A ITMI991740 A IT MI991740A IT MI991740 A1 ITMI991740 A1 IT MI991740A1
- Authority
- IT
- Italy
- Prior art keywords
- pyrido
- indole
- methyl
- compounds
- benzyloxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- AIVGLMHJGRETPC-UHFFFAOYSA-N pyrido[3,4-b]indol-1-one Chemical compound C1=CC=C2C3=CC=NC(=O)C3=NC2=C1 AIVGLMHJGRETPC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 230000002195 synergetic effect Effects 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- -1 aminopropoxy residue Chemical group 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 description 3
- HUMIEJNVCICTPJ-UHFFFAOYSA-N 2,2-dimethoxy-n-methylethanamine Chemical compound CNCC(OC)OC HUMIEJNVCICTPJ-UHFFFAOYSA-N 0.000 description 3
- RALOWUUARKEBPP-UHFFFAOYSA-N 2-methyl-5-phenylmethoxy-9h-pyrido[3,4-b]indol-1-one Chemical compound C1=CC=C2NC=3C(=O)N(C)C=CC=3C2=C1OCC1=CC=CC=C1 RALOWUUARKEBPP-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LYIIBVSRGJSHAV-UHFFFAOYSA-N 2-aminoacetaldehyde Chemical class NCC=O LYIIBVSRGJSHAV-UHFFFAOYSA-N 0.000 description 2
- IGQODMNCFGIAGL-UHFFFAOYSA-N 5-methoxy-2,9-dimethylpyrido[3,4-b]indol-1-one Chemical compound C1=2C(OC)=CC=CC=2N(C)C2=C1C=CN(C)C2=O IGQODMNCFGIAGL-UHFFFAOYSA-N 0.000 description 2
- GAJVTYXGDDNRDB-UHFFFAOYSA-N 5-methoxy-2-methyl-9h-pyrido[3,4-b]indol-1-one Chemical compound C1=2C(OC)=CC=CC=2NC2=C1C=CN(C)C2=O GAJVTYXGDDNRDB-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 2
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000010902 straw Substances 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 125000001302 tertiary amino group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZZKVJQSZAKCMQC-UHFFFAOYSA-N 2-(2-phenylethyl)-5-phenylmethoxy-9H-pyrido[3,4-b]indol-1-one Chemical compound O=c1n(CCc2ccccc2)ccc2c3c(OCc4ccccc4)cccc3[nH]c12 ZZKVJQSZAKCMQC-UHFFFAOYSA-N 0.000 description 1
- WWGXOBZZHDHVHB-UHFFFAOYSA-N 2-(4-methylphenyl)-5-phenylmethoxy-9H-pyrido[3,4-b]indol-1-one Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(NC2=CC=C1)C(N(C=C3)C1=CC=C(C=C1)C)=O WWGXOBZZHDHVHB-UHFFFAOYSA-N 0.000 description 1
- AWLNUVABXJGOMK-UHFFFAOYSA-N 2-[(2-hydroxy-3-methoxyphenyl)methyl]-5-phenylmethoxy-9H-pyrido[3,4-b]indol-1-one Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(NC2=CC=C1)C(N(C=C3)CC1=C(C(=CC=C1)OC)O)=O AWLNUVABXJGOMK-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- OARHOMYAESGRDC-UHFFFAOYSA-N 2-benzyl-5-phenylmethoxy-9H-pyrido[3,4-b]indol-1-one Chemical compound O=c1n(Cc2ccccc2)ccc2c3c(OCc4ccccc4)cccc3[nH]c12 OARHOMYAESGRDC-UHFFFAOYSA-N 0.000 description 1
- PMYLOWCDBKUIHJ-UHFFFAOYSA-N 2-chloro-6-(1-oxo-5-phenylmethoxy-9H-pyrido[3,4-b]indol-2-yl)benzonitrile Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(NC2=CC=C1)C(N(C=C3)C1=C(C(=CC=C1)Cl)C#N)=O PMYLOWCDBKUIHJ-UHFFFAOYSA-N 0.000 description 1
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- FGGARIKATUQZBE-UHFFFAOYSA-N 2-fluoro-6-(1-oxo-5-phenylmethoxy-9H-pyrido[3,4-b]indol-2-yl)benzonitrile Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(NC2=CC=C1)C(N(C=C3)C1=C(C(=CC=C1)F)C#N)=O FGGARIKATUQZBE-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- HFCFJYRLBAANKN-UHFFFAOYSA-N 2-methyl-3-nitroaniline Chemical compound CC1=C(N)C=CC=C1[N+]([O-])=O HFCFJYRLBAANKN-UHFFFAOYSA-N 0.000 description 1
- QSKHTPCGSIEKKP-UHFFFAOYSA-N 2-phenyl-5-phenylmethoxy-9H-pyrido[3,4-b]indol-1-one Chemical compound O=c1n(ccc2c3c(OCc4ccccc4)cccc3[nH]c12)-c1ccccc1 QSKHTPCGSIEKKP-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- QIBATEGCNKHWAL-UHFFFAOYSA-N 5-[(4-methoxyphenyl)methoxy]-2-methyl-9H-pyrido[3,4-b]indol-1-one Chemical compound COC1=CC=C(COC2=C3C4=C(NC3=CC=C2)C(N(C=C4)C)=O)C=C1 QIBATEGCNKHWAL-UHFFFAOYSA-N 0.000 description 1
- NDVFFNSAWLLMLP-UHFFFAOYSA-N 5-hydroxy-2-methyl-9h-pyrido[3,4-b]indol-1-one Chemical compound C12=C(O)C=CC=C2NC2=C1C=CN(C)C2=O NDVFFNSAWLLMLP-UHFFFAOYSA-N 0.000 description 1
- OQQAXSFKCHWSIX-UHFFFAOYSA-N 5-phenylmethoxy-2-(pyridin-2-ylmethyl)-9H-pyrido[3,4-b]indol-1-one Chemical compound O=c1n(Cc2ccccn2)ccc2c3c(OCc4ccccc4)cccc3[nH]c12 OQQAXSFKCHWSIX-UHFFFAOYSA-N 0.000 description 1
- MZQDSTRSEWEOTF-UHFFFAOYSA-N 5-phenylmethoxy-2-(pyridin-3-ylmethyl)-9H-pyrido[3,4-b]indol-1-one Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(NC2=CC=C1)C(N(C=C3)CC=1C=NC=CC=1)=O MZQDSTRSEWEOTF-UHFFFAOYSA-N 0.000 description 1
- CRQUXIDIHNXLHO-UHFFFAOYSA-N 5-phenylmethoxy-2-(pyridin-4-ylmethyl)-9H-pyrido[3,4-b]indol-1-one Chemical compound O=c1n(Cc2ccncc2)ccc2c3c(OCc4ccccc4)cccc3[nH]c12 CRQUXIDIHNXLHO-UHFFFAOYSA-N 0.000 description 1
- URUKVYJJUDAOHY-UHFFFAOYSA-N 5-phenylmethoxy-2-(thiophen-2-ylmethyl)-9H-pyrido[3,4-b]indol-1-one Chemical compound O=c1n(Cc2cccs2)ccc2c1[nH]c1cccc(OCc3ccccc3)c21 URUKVYJJUDAOHY-UHFFFAOYSA-N 0.000 description 1
- YGOZEPRGGWCKRT-UHFFFAOYSA-N 5-phenylmethoxy-2-thiophen-2-yl-9H-pyrido[3,4-b]indol-1-one Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(NC2=CC=C1)C(N(C=C3)C=1SC=CC=1)=O YGOZEPRGGWCKRT-UHFFFAOYSA-N 0.000 description 1
- RPILFBNJODYZDV-UHFFFAOYSA-N 5-phenylmethoxypyrido[3,4-b]indol-1-one Chemical compound O=C1N=CC=C(C=23)C1=NC3=CC=CC=2OCC1=CC=CC=C1 RPILFBNJODYZDV-UHFFFAOYSA-N 0.000 description 1
- YNOWOIHZZBGWTD-UHFFFAOYSA-N 6-bromo-2-methyl-9H-pyrido[3,4-b]indol-1-one Chemical compound Cn1ccc2c3cc(Br)ccc3[nH]c2c1=O YNOWOIHZZBGWTD-UHFFFAOYSA-N 0.000 description 1
- JNFBSHTWNCJILP-UHFFFAOYSA-N 6-ethyl-2-methyl-9H-pyrido[3,4-b]indol-1-one Chemical compound CCc1ccc2[nH]c3c(ccn(C)c3=O)c2c1 JNFBSHTWNCJILP-UHFFFAOYSA-N 0.000 description 1
- MLZCBRRJYGVWLU-UHFFFAOYSA-N 6-ethylpyrido[3,4-b]indol-1-one Chemical compound CCc1ccc2N=C3C(=CC=NC3=O)c2c1 MLZCBRRJYGVWLU-UHFFFAOYSA-N 0.000 description 1
- JGWPATQLHSWLPD-UHFFFAOYSA-N 6-hydroxy-2-methyl-9H-pyrido[3,4-b]indol-1-one Chemical compound Cn1ccc2c3cc(O)ccc3[nH]c2c1=O JGWPATQLHSWLPD-UHFFFAOYSA-N 0.000 description 1
- RMAJCKFXCZQPEW-UHFFFAOYSA-N 6-methoxy-2-methyl-7-phenylmethoxy-9H-pyrido[3,4-b]indol-1-one Chemical compound COc1cc2c(cc1OCc1ccccc1)[nH]c1c2ccn(C)c1=O RMAJCKFXCZQPEW-UHFFFAOYSA-N 0.000 description 1
- JHFYNVWNPCZOIF-UHFFFAOYSA-N 6-methoxy-2-methyl-9H-pyrido[3,4-b]indol-1-one Chemical compound COc1ccc2[nH]c3c(ccn(C)c3=O)c2c1 JHFYNVWNPCZOIF-UHFFFAOYSA-N 0.000 description 1
- TVGCPUCACMCTJT-UHFFFAOYSA-N 6-methoxy-7-phenylmethoxypyrido[3,4-b]indol-1-one Chemical compound COc1cc2C3=CC=NC(=O)C3=Nc2cc1OCc1ccccc1 TVGCPUCACMCTJT-UHFFFAOYSA-N 0.000 description 1
- SFRGSUXVDNQQMP-UHFFFAOYSA-N 7-methoxy-2-methyl-9H-pyrido[3,4-b]indol-1-one Chemical compound COC1=CC=C2C3=C(NC2=C1)C(N(C=C3)C)=O SFRGSUXVDNQQMP-UHFFFAOYSA-N 0.000 description 1
- SUFVHERYXLPQPG-UHFFFAOYSA-N 9-[(4-chlorophenyl)methyl]-2-methyl-5-phenylmethoxypyrido[3,4-b]indol-1-one Chemical compound Cn1ccc2c3c(OCc4ccccc4)cccc3n(Cc3ccc(Cl)cc3)c2c1=O SUFVHERYXLPQPG-UHFFFAOYSA-N 0.000 description 1
- NDISVRDXKDIION-UHFFFAOYSA-N 9-[(4-methoxyphenyl)methyl]-2-methyl-5-phenylmethoxypyrido[3,4-b]indol-1-one Chemical compound C(C1=CC=CC=C1)OC1=C2C3=C(N(C2=CC=C1)CC1=CC=C(C=C1)OC)C(N(C=C3)C)=O NDISVRDXKDIION-UHFFFAOYSA-N 0.000 description 1
- PESMEDRWVDLQHL-UHFFFAOYSA-N 9-[2-(dimethylamino)ethyl]-2-methyl-5-phenylmethoxypyrido[3,4-b]indol-1-one Chemical compound CN(C)CCn1c2cccc(OCc3ccccc3)c2c2ccn(C)c(=O)c12 PESMEDRWVDLQHL-UHFFFAOYSA-N 0.000 description 1
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- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: Description of the industrial invention entitled:
"DERIVATI DI lH-PIRIDO[3,4-B]INDOL-l-ONE" "DERIVATIVES OF 1H-PYRIDO [3,4-B] INDOL-1-ONE"
La presente invenzione riguarda derivati di lH-pirido[3,4-b]indol-lone e le composizioni farmaceutiche che li contengono. The present invention relates to derivatives of 1H-pyrido [3,4-b] indolone and the pharmaceutical compositions containing them.
Derivati IH — pirido[3,4b]indol-l -onici sostituiti sull’anello fenilico da almeno un gruppo OH, OCH3 o da un residuo amminopropossi, quali ad esempio i composti 5-idrossi-2-metil-lH-pirido[3,4-b]indoI-l-one, 5-metossi-2-metil- 1 H-pirido[3 ,4-b] indol- 1 -one, 6-metossi-2-metil- lH-pirido-[3,4-b]indol-l-one, 7-metossi-2-metil-lH-pirido[3,4-b]indol-l-one e 5-[3-[(lJl-dimetiletil)ammino]-2-idrossipropossi]-2-metil-lH-pirido[3,4-b]indol-1-one sono descritti nei seguenti documenti: EP 7Ó5831, DE2626889, Synthesis 1980, (5), 372-274 e J. Chromatography, 1967, 31(2), 446-454. IH - pyrid [3,4b] indole-1 -one derivatives substituted on the phenyl ring by at least one OH group, OCH3 or by an aminopropoxy residue, such as for example 5-hydroxy-2-methyl-1H-pyrido [3 , 4-b] IndoI-1-one, 5-methoxy-2-methyl- 1 H-pyrido [3, 4-b] indole- 1 -one, 6-methoxy-2-methyl- 1H-pyrido- [3 , 4-b] indole-1-one, 7-methoxy-2-methyl-1H-pyrido [3,4-b] indole-1-one and 5- [3 - [(1-dimethylethyl) amino] -2 -hydroxypropoxy] -2-methyl-1H-pyrido [3,4-b] indole-1-one are described in the following documents: EP 7Ó5831, DE2626889, Synthesis 1980, (5), 372-274 and J. Chromatography, 1967 , 31 (2), 446-454.
Per nessuno di questi composti viene riportata attività antitumorale. Si è ora trovato che certi lH-pirido[3,4-b]indol-l-oni sono dotati di attività antitumorale, particolarmente nei confronti di tumori del colon e del polmone. For none of these compounds antitumor activity is reported. It has now been found that certain 1H-pyrido [3,4-b] indol-1-oni are endowed with antitumor activity, particularly against colon and lung cancers.
I composti dell'invenzione hanno la seguente formula I: The compounds of the invention have the following formula I:
in cui: in which:
R rappresenta idrogeno; alchile C1C6 eventualmente sostituito da uno o più gruppi amminici primari, secondari o terziari, gruppi idrossi o carbossi; cicloalchile C5-C6; aralchile; eteroaralchile; arile; eteroarile; R1 rappresenta idrogeno; alchile CrC6 eventualmente sostituito da uno o più gruppi amminici primari, secondari o terziari, gruppi idrossi o carbossi; cicloalchile C5-C6; aralchile; eteroaralchile; R represents hydrogen; C1C6 alkyl optionally substituted by one or more primary, secondary or tertiary amino groups, hydroxy or carboxy groups; C5-C6 cycloalkyl; aralkyl; heteroaralkyl; aryl; heteroaryl; R1 represents hydrogen; CrC6 alkyl optionally substituted by one or more primary, secondary or tertiary amino groups, hydroxy or carboxy groups; C5-C6 cycloalkyl; aralkyl; heteroaralkyl;
R2 è idrogeno; alchile C1C6 eventualmente sostituito da uno o più gruppi amminici primari, secondari p terziari, gruppi idrossi o carbossi; cicloalchile C5-C6; aralchile; arile; eteroarile; eteroarilalchile; C1C8 acile; R2 is hydrogen; C1C6 alkyl optionally substituted by one or more primary, secondary p-tertiary amino groups, hydroxy or carboxy groups; C5-C6 cycloalkyl; aralkyl; aryl; heteroaryl; heteroarylalkyl; C1C8 acyl;
X rappresenta uno o più gruppi scelti indipendentemente tra idrogeno, alchile C1-C6, idrossi, alcossi C1C4, alogenoalcossi C1-C3, ammino, C1-C3 alchilammino, C1-C3- acilammino, C1-C3- alchilsolfonilammino alogeno, nitro, ciano, carbossi, CrC3 alcossicarbonile, solfonile, C1-C3-alchilsolfonile, amminosolfonile, C1C3- alchilamminosolfonile, trifluorometile. X represents one or more groups independently selected from hydrogen, C1-C6 alkyl, hydroxy, C1C4 alkoxy, C1-C3 haloalkoxy, amino, C1-C3 alkylamino, C1-C3- acylamino, C1-C3- alkylsulfonylamino halogen, nitro, cyano, carboxy, CrC3 alkoxycarbonyl, sulfonyl, C1-C3-alkylsulfonyl, aminosulfonyl, C1C3- alkylaminosulfonyl, trifluoromethyl.
Alchile C1-C6 è preferibilmente metile, etile, n-propile, isopropile, isobutile, in particolare metile. C1-C6 alkyl is preferably methyl, ethyl, n-propyl, isopropyl, isobutyl, in particular methyl.
Alchile sostituito è preferibilmente 2- idrossietile, 2-amminoetile, 2-dimetilamminoetile, carbossimetile. Substituted alkyl is preferably 2-hydroxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, carboxymethyl.
Cicloalchile C5-C6 è preferibilmente cicloesile o ciclopentile. C5-C6 cycloalkyl is preferably cyclohexyl or cyclopentyl.
Aralchile è preferibilmente benzile o fenetile. Aralkyl is preferably benzyl or phenethyl.
Arile è preferibilmente fenile, naftile o fenile sostituito da uno o due sostituenti scelti fra alchile C1-C6, idrossi, alcossi C1-C4, alogenoalcossi C1C3, ammino, C1-C3 alchilammino, C1C3 acilammino, C1C3-alchilsolfonilammino alogeno, nitro, ciano, carbossi, C1-C3 alcossicarbonile, solfonile, C1-C3- alchilsolfonile, amminosolfonile, C1-C3- alchilamminosolfonile, trifluorometile. Aryl is preferably phenyl, naphthyl or phenyl substituted by one or two substituents selected from C1-C6 alkyl, hydroxy, C1-C4 alkoxy, C1C3 halogenalkoxy, amino, C1-C3 alkylamino, C1C3 acylamino, C1C3-alkylsulfonylamino halogen, nitro carboxy, C1-C3 alkoxycarbonyl, sulfonyl, C1-C3- alkylsulfonyl, aminosulfonyl, C1-C3- alkylaminosulfonyl, trifluoromethyl.
Eteroarile è preferibilmente furile, tienile, imidazolile, benzotienile, benzofiirile, piridile, indolile, pirimidile, tiazolile. Heteroaryl is preferably furyl, thienyl, imidazolyl, benzothienyl, benzophyryl, pyridyl, indolyl, pyrimidyl, thiazolyl.
Eteroarilalchile è preferibilmente piridilmetile, tienilmetile, furilmetile. Alcossi C1-C4 è preferibilmente metossi o etossi. Heteroarylalkyl is preferably pyridylmethyl, thienylmethyl, furylmethyl. Alkoxy C1-C4 is preferably methoxy or ethoxy.
Alogenoalcossi C,-C3 è preferibilmente difluorometossi, triclorometossi, trifluorometossi. Halogenalkoxy C, -C3 is preferably difluoromethoxy, trichloromethoxy, trifluoromethoxy.
Alogeno è preferibilmente cloro. Halogen is preferably chlorine.
C1-C3 alcbilammino è preferibilmente metilammino, acilammino è preferibilmente acetilammino, C1C3- alchilsolfonilammino è preferibilmente metilsolfonilammino, C1C3-alchilsolfonile è preferibilmente metilsolfonile, C1-C3- alchilamminosolfonile è preferibilmente metilamminosolfonile e dimetilamminosolfoniie. C1-C3 alkylamino is preferably methylamino, acylamino is preferably acetylamino, C1C3-alkylsulfonylamino is preferably methylsulfonylamino, C1C3-alkylsulfonyl is preferably methylsulfonyl, C1-C3-alkylamino sulphonyl is preferably methylsulfonylamine and preferably methylsulfonylamine.
Esempi di composti preferiti di formula I sono quelli in cui R è alchile C1-C6, R, è idrogeno, X è idrogeno e R2 è alchile C1-C6, aralchile o arile. R2-O è preferibilmente nella posizione 5 del sistema eterociclico dell'lH-pirido[3,4-b]indol-l-one, come rappresentato nella seguente formula la Examples of preferred compounds of formula I are those in which R is C1-C6 alkyl, R, is hydrogen, X is hydrogen and R2 is C1-C6 alkyl, aralkyl or aryl. R2-O is preferably in position 5 of the heterocyclic system of 1H-pyrido [3,4-b] indole-1-one, as represented in the following formula
I composti di Formula I sono preparatali secondo il processo illustrato nello schema 1 seguente. The compounds of Formula I are prepared according to the process illustrated in the following scheme 1.
I composti di formula II, noti o preparatili secondo metodi noti, sono fatti reagire con pentacloruro di fosforo in un solvente aprotico e quindi con un derivato di amminoacetaldeide, quale ad esempio la 2-metilamminoacetaldeide dimetilacetale, a dare i composti di formula III che sono quindi ciclizzati in presenza di acidi quali ad esempio HCI gas in diossano o acido trifluoroacetico in cloruro di metilene a composti di formula I . The compounds of formula II, known or prepared according to known methods, are reacted with phosphorus pentachloride in an aprotic solvent and then with an aminoacetaldehyde derivative, such as for example 2-methylaminoacetaldehyde dimethylacetal, to give the compounds of formula III which are then cyclized in the presence of acids such as for example HCI gas in dioxane or trifluoroacetic acid in methylene chloride to compounds of formula I.
I composti di formula II possono essere preparati secondo lo schema 2 The compounds of formula II can be prepared according to scheme 2
Le aniline di formula IV, note o preparabili con metodi noti, sono trasformate nei fenoli corrispondenti di formula V per reazione con nitriti alcalini in presenza di acidi forti seguita da idrolisi con urea e sali di rame (II). I fenoli V sono quindi fatti reagire con alogenuri di formula R2Hal dove Hai è preferibilmente cloro o bromo, in presenza di accettori di acidità a dare i composti VI. La reazione con diesteri deiracido ossalico, in particolare dietil ossalato, in presenza di basi forti quali idruri metallici o alcossidi alcalini in solventi anidri e atmosfera inerte, fornisce i composti VII che sono ciclizzati a indoli VIII per riduzione del gruppo nitro, ad esempio con zinco in acidi. I composti II sono quindi ottenuti dai composti Vili per semplice idrolisi del gruppo estere, eventualmente preceduta dall’introduzione del sostituente Rj con metodi noti, ad esempio di N-alchilazione. The anilines of formula IV, known or preparable with known methods, are transformed into the corresponding phenols of formula V by reaction with alkaline nitrites in the presence of strong acids followed by hydrolysis with urea and copper (II) salts. The phenols V are then reacted with halides of formula R2Hal where Hai is preferably chlorine or bromine, in the presence of acidity acceptors to give compounds VI. The reaction with oxalic acid diesters, in particular diethyl oxalate, in the presence of strong bases such as metal hydrides or alkaline alkoxides in anhydrous solvents and inert atmosphere, gives compounds VII which are cyclized to indoles VIII by reduction of the nitro group, for example with zinc in acids. Compounds II are then obtained from compounds VIII by simple hydrolysis of the ester group, possibly preceded by the introduction of the substituent Rj with known methods, for example by N-alkylation.
Qualora i gruppi R, R1 R2 e X contengano sostituenti che interferiscono con le reazioni utilizzate, si ricorrerà a opportuni gruppi protettivi che saranno poi rimossi secondo metodi convenzionali. If the groups R, R1, R2 and X contain substituents that interfere with the reactions used, appropriate protective groups will be used which will then be removed according to conventional methods.
Un procedimento alternativo per la preparazione dei composti di formula I prevede la reazione dei composti di formula I in cui almeno uno tra R1 ed R2 è idrogeno, ed R è diverso da idrogeno, con alogenuri di formula R’2-Hal, in cui R’2 ha gli stessi significati di R2 con P eccezione di idrogeno e Hai è preferibilmente cloro e bromo, in presenza di idruri, idrossidi o alcossidi di metalli alcalini, quali ad esempio NaH, KOH, t-BuOK. Si opera generalmente in solventi quali DMSO, DMF a temperature comprese tra 0°C ed 80°C, preferibilmente 25-50°C. An alternative procedure for the preparation of the compounds of formula I provides for the reaction of the compounds of formula I in which at least one of R1 and R2 is hydrogen, and R is different from hydrogen, with halides of formula R'2-Hal, in which R '2 has the same meanings as R2 with the exception of hydrogen and Hai is preferably chlorine and bromine, in the presence of hydrides, hydroxides or alkoxides of alkali metals, such as for example NaH, KOH, t-BuOK. It generally operates in solvents such as DMSO, DMF at temperatures between 0 ° C and 80 ° C, preferably 25-50 ° C.
I composti di formula I in cui R2 è idrogeno possono essere ottenuti, oltre che dal processo illustrato nello schema 1, anche per idrogenazione catalitica di composti di formula I in cui R2 è un arilmetile, quale ad esempio benzile. Si opera in solventi quali THF, MeOH, o loro miscele, in presenza di un catalizzatore metallico quale platino o palladio, operando generalmente a pressione e temperatura ambiente. The compounds of formula I in which R2 is hydrogen can be obtained, in addition to the process illustrated in scheme 1, also by catalytic hydrogenation of compounds of formula I in which R2 is an arylmethyl, such as benzyl for example. One operates in solvents such as THF, MeOH, or their mixtures, in the presence of a metal catalyst such as platinum or palladium, generally operating at ambient pressure and temperature.
I composti secondo l’invenzione sono stati saggiati farmacologicamente contro quattro linee di cellule tumorali umane: HT 29 (carcinoma del colon), PC 3 (carcinoma della prostata), H 460M (carcinoma del polmone), MCF-7 (carcinoma della mammella). Dopo 144 ore di incubazione delle cellule con il composto da saggiare, è stata determinata la citotossicità, utilizzando il saggio MTT (Mosman, T. “Rapid Colorimetrie Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay”; J. Immunolog. Methods, (1983), 65., 66; Green, L.M., Rapid Colorimetrie Assay for Celi Viability; Application to thè Quantitation of Cytotoxic and Growth Inhibitory Lymphokines”, J. Immunol. Methods, (1984), 70, 257-268). The compounds according to the invention were pharmacologically tested against four human tumor cell lines: HT 29 (colon cancer), PC 3 (prostate cancer), H 460M (lung cancer), MCF-7 (breast cancer) . After 144 hours of cell incubation with the compound to be tested, cytotoxicity was determined using the MTT assay (Mosman, T. "Rapid Colorimetrie Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay"; J. Immunolog. Methods, (1983), 65., 66; Green, L.M., Rapid Colorimetrie Assay for Celi Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines ", J. Immunol. Methods, (1984), 70, 257-268) .
Dai dati ottenuti è emerso che i composti secondo la presente invenzione sono dotati di una marcata attività nei confronti di tumori solidi, in particolare dei tumori del colon e del polmone. From the data obtained it emerged that the compounds according to the present invention are endowed with a marked activity against solid tumors, in particular colon and lung tumors.
I composti secondo la presente invenzione possono essere somministrati in dosi variabili da 0,01 mg a 1 g per Kg di peso corporeo al giorno. Una modalità di somministrazione preferita è quella che utilizza un dosaggio da circa 1 mg a circa 500 mg per Kg di peso corporeo al giorno, impiegando dosi unitarie tali da somministrare in 24 ore da circa 70 mg a circa 3,5 g della sostanza attiva ad un paziente con un peso di circa 70 Kg. Una tale modalità di somministrazione può essere aggiustata per ottenere un miglior effetto terapeutico. Ad esempio, le dosi possono essere aggiustate in considerazione della situazione terapeutica del paziente. I composti attivi secondo rinvenzione possono essere somministrati per via orale, endovenosa, intramuscolare o sottocutanea. The compounds according to the present invention can be administered in doses ranging from 0.01 mg to 1 g per kg of body weight per day. A preferred method of administration is that which uses a dosage from about 1 mg to about 500 mg per kg of body weight per day, using unit doses such as to be administered in 24 hours from about 70 mg to about 3.5 g of the active substance. a patient with a weight of about 70 kg. Such a mode of administration can be adjusted to obtain a better therapeutic effect. For example, the doses can be adjusted in consideration of the patient's therapeutic situation. The active compounds according to the invention can be administered orally, intravenously, intramuscularly or subcutaneously.
I composti dell’invenzione, quando somministrati, secondo modalità terapeutiche ben note, in combinazione con altri agenti utilizzati per indurre la regressione di tumori, aumentano gli effetti antitumorali di detti composti in maniera sinergica. Esempi dei composti che possono essere utilizzati in combinazione con i composti dell’invenzione sono rappresentati da cisplatino, carboplatino, doxorubicina, topotecan, taxolo, taxotere, vincristna, 5-fluorouracile. The compounds of the invention, when administered, according to well-known therapeutic methods, in combination with other agents used to induce the regression of tumors, increase the antitumor effects of said compounds in a synergistic way. Examples of the compounds that can be used in combination with the compounds of the invention are represented by cisplatin, carboplatin, doxorubicin, topotecan, taxol, taxotere, vincristna, 5-fluorouracil.
Le composizioni farmaceutiche secondo la presente invenzione contengono quantità terapeuticamente efficaci di almeno un composto secondo l’invenzione in miscela con eccipienti compatibili con l’uso farmaceutico. The pharmaceutical compositions according to the present invention contain therapeutically effective amounts of at least one compound according to the invention mixed with excipients compatible with pharmaceutical use.
Le composizioni per via orale comprendono generalmente un diluente inerte o un supporto edibile e possono essere racchiuse in capsule di gelatina o ridotte in compresse. Altre possibili forme di somministrazione per via orale sono rappresentate da capsule, pillole, elisir, sospensioni o sciroppi. The oral compositions generally comprise an inert diluent or an edible carrier and can be enclosed in gelatin capsules or reduced into tablets. Other possible forms of oral administration are represented by capsules, pills, elixirs, suspensions or syrups.
Le compresse, le pillole, le capsule e composizioni similari possono contenere i seguenti ingredienti (in aggiunta al composto attivo): un legante, quale cellulosa microcristallina, gomma adragante o gelatina; un supporto quale amido o lattosio, un disgregante quale acido alginico, primogel, amido di mais e simili; un lubrificante quale magnesio stearato; un fluidificante quale biossido di silicio colloidale; un dolcificante quale saccarosio o saccarina o un aromatizzante quale aroma di menta, salicilato di metile o aroma d’arancia. Quando la composizione selezionata è in forma di capsule, essa può contenere in aggiunta un veicolo liquido quale un olio grasso. Altre composizioni possono contenere vari materiali, per esempio agenti di rivestimento (per compresse e pillole) quali zucchero o shellac. Il materiale usato nella preparazione delle composizioni dovrebbe essere farmaceuticamente puro e non tossico ai dosaggi impiegati. Tablets, pills, capsules and similar compositions may contain the following ingredients (in addition to the active compound): a binder, such as microcrystalline cellulose, tragacanth or gelatin; a carrier such as starch or lactose, a disintegrant such as alginic acid, primogel, corn starch and the like; a lubricant such as magnesium stearate; a fluidifier such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin or a flavoring such as mint flavor, methyl salicylate or orange flavor. When the selected composition is in capsule form, it may additionally contain a liquid carrier such as a fatty oil. Other compositions may contain various materials, for example coating agents (for tablets and pills) such as sugar or shellac. The material used in the preparation of the compositions should be pharmaceutically pure and non-toxic at the dosages employed.
Per la preparazione di composizioni farmaceutiche per somministrazione parenterale l’ingrediente attivo può essere incluso in soluzioni o sospensioni, che possono contenere in aggiunta i seguenti componenti: un diluente sterile quale acqua per iniezioni, soluzione salina, olio, polietilenglicol, glicerina, glicol propilenico o altri solventi sintetici; agenti antibatterici quali alcool benzilico; antiossidanti quali acido ascorbico o sodio bisolfito; agenti chelanti quali acido etilendiamminotetraacetico; tamponi quali acetati, citrati o fosfati e agenti per aggiustare la tonicità della soluzione, quali cloruro di sodio o destrosio. Le preparazioni parenterali possono essere racchiuse in ampolle, siringhe monodose, fiale di vetro o plastica. For the preparation of pharmaceutical compositions for parenteral administration the active ingredient can be included in solutions or suspensions, which may additionally contain the following components: a sterile diluent such as water for injections, saline, oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution, such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, single-dose syringes, glass or plastic ampoules.
La presente invenzione sarà ulteriormente descritta facendo riferimento agli esempi forniti qui di seguito a titolo illustrativo e non limitativo. The present invention will be further described with reference to the examples provided below for illustrative and non-limiting purposes.
Si sospendono in 15 mi di acqua 952,0 mg di 6-nitro-2-amminotoluene, successivamente si aggiungono 3 mi di H2S04 conc. e 10 mi di H2S04 al 10%. 952.0 mg of 6-nitro-2-aminotoluene are suspended in 15 ml of water, then 3 ml of conc. H2SO4 are added. and 10 ml of H2SO4 at 10%.
Una volta sciolta quasi tutta l'ammina si raffredda la soluzione a 0°C e si aggiungono 561,1 mg (8,132 mmoli) di NaN02 sciolti in 4 mi di H20. Once almost all the amine has been dissolved, the solution is cooled to 0 ° C and 561.1 mg (8.132 mmoles) of NaN02 dissolved in 4 ml of H20 are added.
Si lascia sotto agitazione per lh30’, quindi si aggiungono 468,8 mg (1,878 mmoli) di CuS04.5H20 e 364,5 mg (6,070 mmoli) di Urea. It is left under stirring for 30 ', then 468.8 mg (1.878 mmoles) of CuS04.5H20 and 364.5 mg (6.070 mmoles) of Urea are added.
Si scalda a 90°C per 2h30' e si lascia quindi la soluzione a temperatura ambiente per una notte. The mixture is heated to 90 ° C for 2h30 'and the solution is then left at room temperature for one night.
Si filtra il precipitato giallo paglierino e lo si scioglie in 35 mi di NaOH al 5%, si filtra e si acidifica fino a pH acido con HC1 al 5% (36 mi). The straw yellow precipitate is filtered and dissolved in 35 ml of 5% NaOH, filtered and acidified to acid pH with 5% HCl (36 ml).
Il precipitato viene filtrato ed asciugato sotto vuoto. The precipitate is filtered and dried under vacuum.
Dalla reazione si ottengono 680 mg di solido giallino. From the reaction 680 mg of yellowish solid are obtained.
La resa della reazione è del 71%. The reaction yield is 71%.
IH, IH,
In un pallone sotto atmosfera inerte per argon si sciolgono 13,41 g (0,0876 moli) del derivato della preparazione 1 in DMF anidra (88 mi), quindi si aggiungono 12,12 g (0,0877 moli) di K2C03 anidro e si lascia sotto agitazione a temperatura ambiente per 30 minuti. In a flask under an inert atmosphere for argon, 13.41 g (0.0876 moles) of the derivative of preparation 1 are dissolved in anhydrous DMF (88 ml), then 12.12 g (0.0877 moles) of anhydrous K2C03 are added and it is left under stirring at room temperature for 30 minutes.
Si aggiungono 11,2 mi (0,0943 moli) di Benzilbromuro e si scalda a 60°C per 4h. 11.2 ml (0.0943 moles) of Benzylbromide are added and the mixture is heated at 60 ° C for 4h.
La reazione viene controllata tramite TLC (Esano/Acetato d'etile 8:2). Si filtrano i sali inorganici, lavandoli con DMF (50 1) e si evapora il solvente fino a un volume di circa 40 mi. The reaction is controlled by TLC (hexane / ethyl acetate 8: 2). The inorganic salts are filtered, washing them with DMF (50 1) and the solvent is evaporated to a volume of about 40 ml.
Il residuo oleoso ottenuto viene filtrato su silice (impaccata con Esano/Acetato d’etile 9:1), ottenendo 14,62 g di prodotto solido giallo paglierino. The oily residue obtained is filtered on silica (packed with hexane / ethyl acetate 9: 1), obtaining 14.62 g of solid straw yellow product.
La resa della reazione è del 68,6%. The reaction yield is 68.6%.
In un pallone sotto atmosfera inerte per argon si miscelano 8,47 g (0,0755 moli) di Potassio ter-butossido e 70 mi di Dietilossalato, agitando finché il t-butilato non si è sciolto. In a flask under an inert atmosphere for argon, 8.47 g (0.0755 moles) of Potassium tert-butoxide and 70 ml of diethyloxalate are mixed, stirring until the t-butylate has dissolved.
Alla soluzione giallastra si aggiungono 14,62 g (0,060 moli) del derivato della preparazione 2 e si scalda a 60°C per 2h. 14.62 g (0.060 moles) of the derivative of preparation 2 are added to the yellowish solution and heated at 60 ° C for 2h.
La reazione viene controllata tramite TLC (Esano/Acetato d'etile 8:2). Si aggiungono alla soluzione viola 120 mi di Etere etilico e si porta a pH neutro con acido acetico (4,4 mi); si aggiunge acqua e si estrae con etere (80 mi *3). The reaction is controlled by TLC (hexane / ethyl acetate 8: 2). 120 ml of ethyl ether are added to the violet solution and it is brought to neutral pH with acetic acid (4.4 ml); water is added and extracted with ether (80 ml * 3).
La soluzione organica viene anidrificata con sodio solfato e si evapora il solvente. The organic solution is dried with sodium sulphate and the solvent is evaporated.
Il residuo ottenuto viene utilizzato tal quale per la reazione successiva. The residue obtained is used as such for the subsequent reaction.
In un pallone si sciolgono 21,0 g del derivato della preparazione 3 in 227 mi di Acido acetico al 98%, si aggiungono 10,1 mi di HzO e si scalda a riflusso. In a flask, 21.0 g of the derivative of preparation 3 are dissolved in 227 ml of 98% acetic acid, 10.1 ml of HzO are added and the mixture is refluxed.
Si aggiungono quindi 29,08 g (0,445 moli) di Zinco in polvere e si agita per 30 minuti. Then 29.08 g (0.445 moles) of powdered zinc are added and the mixture is stirred for 30 minutes.
La reazione viene controllata tramite TLC (Esano/ Acetato d'etile 8:2). Si filtrano i sali di zinco e si lavano con etanolo (30 mi *3) ed acido acetico (25 mi *2). The reaction is controlled by TLC (hexane / ethyl acetate 8: 2). The zinc salts are filtered and washed with ethanol (30 ml * 3) and acetic acid (25 ml * 2).
Si aggiunge acqua (250 mi) alla soluzione filtrata ottenendo la precipitazione del prodotto, si filtra e si lava con un po’ d'acqua. Water (250 ml) is added to the filtered solution obtaining the precipitation of the product, filtered and washed with a little water.
Il prodotto ottenuto non necessita di ulteriori purificazioni. The product obtained does not require further purification.
La resa della reazione è del 76,6% sui due passaggi. The reaction yield is 76.6% on the two steps.
In un pallone si sciolgono 13,55 g (0,0459 moli) del derivato della preparazione 4 in 68 mi di Etanolo, si scalda a 50°C e si aggiungono 2,31 g (0,0578 moli) di NaOH sciolti in 40 mi di acqua distillata. Si scalda a 80-90°C per 2h. In a flask, 13.55 g (0.0459 moles) of the derivative of preparation 4 are dissolved in 68 ml of Ethanol, heated to 50 ° C and 2.31 g (0.0578 moles) of NaOH dissolved in 40 are added. ml of distilled water. It is heated to 80-90 ° C for 2h.
La reazione viene controllata tramite TLC (Esano / Acetato d'etile 8:2 e CH2Cl2/MeOH 9:1). The reaction is controlled by TLC (hexane / ethyl acetate 8: 2 and CH2Cl2 / MeOH 9: 1).
Si acidifica a pH acido con HC1 5% (42,0 mi) e si filtra l'acido precipitato. It is acidified to acid pH with 5% HCl (42.0 ml) and the precipitated acid is filtered.
Il prodotto, solido bianco sporco, ottenuto non necessita di ulteriori purificazioni. La resa della reazione è quantitativa. The product, an off-white solid, obtained does not require further purification. The yield of the reaction is quantitative.
Preparazione 6 Preparation 6
In un pallone soto atmosfera inerte per argon si sciolgono 14,00 g (0,0524 moli) del derivato della preparazione 5 grezzo in 88 mi di 1,2-dimetossietano, si aggiungono 13,115 (0,0629 moli) di PC15 e si agita a temperatura ambiente per 3h; quindi si scalda a 40°C per Ih. In a flask under an inert atmosphere for argon, 14.00 g (0.0524 moles) of the derivative of crude preparation 5 are dissolved in 88 ml of 1,2-dimethoxyethane, 13.115 (0.0629 moles) of PC15 are added and the mixture is stirred. at room temperature for 3h; then it is heated to 40 ° C for 1 h.
Si evapora il solvente e si riprende il residuo con 30 mi di 1,2-dimetossietano e, sempre sotto atmosfera inerte si raffredda a 0°C e si aggiungono 19 mi (0,148 moli) di metilamminoacetaldeide dimetilacetale sciolta in 100 mi di etere etilico. The solvent is evaporated and the residue is taken up with 30 ml of 1,2-dimethoxyethane and, again under an inert atmosphere, it is cooled to 0 ° C and 19 ml (0.148 moles) of methylaminoacetaldehyde dimethylacetal dissolved in 100 ml of ethyl ether are added.
Si agita a 0°C per dieci minuti, quindi si porta a temperatura ambiente e si lascia sotto agitazione per una notte. La reazione viene controllata tramite TLC (Esano/Acetato d'etile 1:1 e CH2Cl2/MeOH 9:1). The mixture is stirred at 0 ° C for ten minutes, then brought to room temperature and left under stirring overnight. The reaction is controlled by TLC (hexane / ethyl acetate 1: 1 and CH2Cl2 / MeOH 9: 1).
Si filtra il prodotto precipitato lavandolo con abbondante etere. The precipitated product is filtered by washing it with abundant ether.
Il prodotto ottenuto risulta contenere anche tracce della metilamminoacetaldeide dimetilacetale di partenza. Tuttavia non si sottopone il prodotto ad ulteriori purificazioni. The product obtained also contains traces of the starting methylaminoacetaldehyde dimethylacetal. However, the product is not subjected to further purification.
In un pallone si saturano 3,8 mi di diossano con HCI gassoso, quindi si scalda a 40°C e si aggiungono 395 mg (0,991 mmoli) del derivato ottenuto in a). 3.8 ml of dioxane are saturated with gaseous HCl in a flask, then heated to 40 ° C and 395 mg (0.991 mmoles) of the derivative obtained in a) are added.
Si scalda a 50°C per 30 minuti, quindi si filtra il prodotto ottenuto. The mixture is heated to 50 ° C for 30 minutes, then the obtained product is filtered.
Si ottengono 333 mg di grezzo che, dopo purificazione tramite cromatografia flash (eluente Esano/ Acetato d'etile 2:8, con caricamento con polverino), fornisce 126,2 mg di 5-benzilossi-2-metil-lH-pirido[3,4-b]indol-1-one. 333 mg of crude product are obtained which, after purification by flash chromatography (eluent hexane / ethyl acetate 2: 8, with powder filling), gives 126.2 mg of 5-benzyloxy-2-methyl-1H-pyrido [3 , 4-b] indole-1-one.
Il prodotto ottenuto viene purificato ulteriormente facendolo bollire in MeOH, filtrando e lavandolo con etere etilico. The product obtained is further purified by boiling it in MeOH, filtering and washing it with ethyl ether.
Preparazione 7 Preparation 7
Utilizzando nelle procedure descritte nella preparazione 6 gli opportuni acidi indol-2-carbossilici e le opportune 2-amminoacetaldeidi dialchil acetali vengono preparati i seguenti lH-pirido[3,4-b]indol-l-oni: Using the suitable indole-2-carboxylic acids and the suitable 2-aminoacetaldehydes dialkyl acetals in the procedures described in preparation 6, the following 1H-pyrido [3,4-b] indol-1-oni are prepared:
5-benzilossi-lH-pirido[3,4-b]indol-l-one, p.f. 264-265°C; 5-benzyloxy-1H-pyrido [3,4-b] indole-1-one, m.p. 264-265 ° C;
5-benzilossi-2-(2-piridilmetil)-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2- (2-pyridylmethyl) -1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-(3-piridilmetil)- 1 H-pirido[3 ,4-b] indol- 1 -one; 5-benzyloxy-2- (3-pyridylmethyl) - 1 H-pyrido [3, 4-b] indole- 1 -one;
5-benzilossi-2-(4-piridilmetil)- 1 H-pirido[3 ,4-b]indol- 1 -one; 5-benzyloxy-2- (4-pyridylmethyl) - 1 H-pyrido [3, 4-b] indole-1 -one;
5-benzilossi-2-benzil-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2-benzyl-1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-(2-feniletil)-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2- (2-phenylethyl) -1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-fenil-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2-phenyl-1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-(3-cloro-2-cianofenil)-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2- (3-chloro-2-cyanophenyl) -1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-(3 -fluoro-2-cianofenil)- 1 H-pirido[3 ,4-b] indol- 1 -one; 5-benzyloxy-2- (3 -fluoro-2-cyanophenyl) - 1H-pyrido [3, 4-b] indole- 1 -one;
5-benzilossi-2-(3-cloro-5-trifluorometilpiridil)-lH-pirido[3,4-b]mdol-l-one; 5-benzilossi-2-(2-tienilmetil)-lH-pirido[3 ,4-b] indol- 1 -one; 5-benzyloxy-2- (3-chloro-5-trifluoromethylpyridyl) -1H-pyrido [3,4-b] mdol-1-one; 5-benzyloxy-2- (2-thienylmethyl) -1H-pyrido [3, 4-b] indole-1 -one;
5-benzilossi-2-(2-idrossi-3-metossibenzil)-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2- (2-hydroxy-3-methoxybenzyl) -1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-(2-tienil)-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2- (2-thienyl) -1H-pyrido [3,4-b] indole-1-one;
5-benzilossi-2-(4-metilfenil)-lH-pirido[3,4-b]indol-l-one; 5-benzyloxy-2- (4-methylphenyl) -1H-pyrido [3,4-b] indole-1-one;
5-(4-metossibenzilossi)-2-metil-lH-pirido[3,4-b]indol-l-one; 5- (4-methoxybenzyloxy) -2-methyl-1H-pyrido [3,4-b] indole-1-one;
5-(4-clorobenzilossi)-2-metil- 1 H-pirido[3,4-b]indol- 1 -one; 5- (4-chlorobenzyloxy) -2-methyl- 1 H-pyrido [3,4-b] indole-1 -one;
5-(4-trifluorometilbenzilossi)-2-metil- lH-pirido[3 ,4-b]indol- 1 -one; 5- (4-trifluoromethylbenzyloxy) -2-methyl-1H-pyrido [3, 4-b] indole-1 -one;
5-metossi-2-metil- 1 H-pirido[3 ,4-b]indol- 1 -one; 5-methoxy-2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one;
5-metossi- 1 H-pirido[3 ,4-b] indol- 1 -one; 5-methoxy- 1H-pyrid [3, 4-b] indole- 1 -one;
-benzilossi-2-metil-lH-pirido[3,4-b]indol-l-one; -benzyloxy-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-benzilossi-lH-pirido[3,4-b]indol-l-one; -benzyloxy-1H-pyrido [3,4-b] indole-1-one;
-metossi-2-metil-lH-pirido[3,4-b]indol-l-one; -methoxy-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-metossi- 1 H-pirido [3 ,4-b]indol- 1 -one; -methoxy- 1 H-pyrid [3, 4-b] indole- 1 -one;
-nitro-2-metil- 1 H-pirido[3 ,4-b]indol- 1 -one; -nitro-2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one;
-nitro- 1 H-pirido[3,4-b]indol- 1 -one; -nitro- 1 H-pyrid [3,4-b] indole- 1 -one;
-nitro-2-metil-lH-pirido[3,4-b]indol-l-one; -nitro-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-nitro- 1 H-pirido[3 ,4-b]indol- 1 -one; -nitro- 1 H-pyrid [3, 4-b] indole- 1 -one;
-metisolfonil-2-metil-lH-pirido[3,4-b]indol-l-one; -methysulfonyl-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-metisolfonil-lH-pirido[3,4-b]indol-l-one; -methysulfonyl-1H-pyrido [3,4-b] indole-1-one;
-metil-2-metil-lH-pirido[3,4-b]indol-l-one; -methyl-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-metil- 1 H-pirido[3,4-b]indol- 1 -one; -methyl- 1H-pyrido [3,4-b] indole- 1 -one;
-trifluorometossi-2-metil- 1 H-pirido[3 ,4-b]indol- 1 -one; -trifluorometossi-lH-pirido[3,4-b]mdol-l-one; -trifluoromethoxy-2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one; -trifluoromethoxy-1H-pyrido [3,4-b] mdol-1-one;
-fluoro-2-metil- 1 H-pirido[3 ,4-b] indol- 1 -one; -fluoro-2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one;
-fluoro- 1 H-pirido[3 ,4-b]indol- 1 -one; -fluoro- 1 H-pyrid [3, 4-b] indole- 1 -one;
-cloro-2-metil-lH-pirido[3,4-b]indol-l-one; -chloro-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-cloro- 1 H-pirido[3 ,4-b]indol- 1 -one; -chlor- 1 H-pyrid [3, 4-b] indole- 1 -one;
-idrossì-2-metil- 1 H-pirido[3,4-b]indol- 1 -one; -hydroxy-2-methyl- 1H-pyrido [3,4-b] indole- 1 -one;
-idrossi- 1 H-pirido[3,4-b]indol- 1 -one; -hydroxy- 1H-pyrido [3,4-b] indole- 1 -one;
-metossi-2-metil-lH-pirido[3,4-b]indol-l-one; -methoxy-2-methyl-1H-pyrido [3,4-b] indole-1-one;
-metossi- 1 H-pirido[3 ,4-b] indol- 1 -one; -methoxy- 1 H-pyrid [3, 4-b] indole- 1 -one;
.7-dimetossi-2-metil-lH-pirido[3,4-b]indol-l-one; .7-dimethoxy-2-methyl-1H-pyrido [3,4-b] indole-1-one;
.7-dimetossi-lH-piridot3,4-b]indol-l-one; .7-dimethoxy-1H-pyridot3,4-b] indole-1-one;
-metosi-2-metil- 1 H-pirido[3 ,4-b]indol- 1 -one; 6-metosi- 1 H-pirido[3 ,4-b]indol- 1 -one; -methosis-2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one; 6-methosis- 1 H-pyrido [3, 4-b] indole- 1 -one;
6-bromo-2-metil- 1 H-pirido[3 ,4-b] indol- 1 -one; 6-bromo-2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one;
6-bromo- 1 H-pirido[3 ,4-b]indol- 1 -one; 6-bromo- 1 H-pyrid [3, 4-b] indole- 1 -one;
6-metossi-7-benzilossi-2-metil- 1 H-pirido [3,4-b]indol- 1 -one; 6-methoxy-7-benzyloxy-2-methyl- 1H-pyrido [3,4-b] indole-1 -one;
6-metossi-7-benzilossi- 1 H-pirido [3, 4-b]indol- 1 -one; 6-methoxy-7-benzyloxy- 1H-pyrido [3, 4-b] indole- 1 -one;
6-etil-2-metil-lH-pirido[3,4-b]indol-l-one; 6-ethyl-2-methyl-1H-pyrido [3,4-b] indole-1-one;
6-etil- lH-pirido[3 ,4-b]indol- 1 -one; 6-ethyl-1H-pyrido [3, 4-b] indole-1 -one;
Preparazione 8 Preparation 8
Ad una sospensione di KOH (87,4 mg) in DMF anidra (3 mi) mantenuta in atmosfera di azoto, viene aggiunto il 5-benzilossi-2-metil-lH-pirido[3,4-b]indol-l-one della preparazione 6 (113,4 mg) e, successivamente, DMSO anidro (1 mi). Dopo 30 minuti viene aggiunto benzilbromuro (0,09 mi). La miscela di reazione viene agitata a temperatura ambiente per 50 minuti, quindi viene addizionata di HC1 IN (1,6 mi) fino a pH neutro e ripartita tra acqua ed acetato di etile. La fase organica viene anidrificata su Na2S04 anidro ed evaporata a secchezza. Il residuo ottenuto viene purificato per cromatografia su colonna eluendo inizialmente con n-esano/acetato di etile 7/3 e successivamente n-esano/acetato di etile 6/4. To a suspension of KOH (87.4 mg) in anhydrous DMF (3 ml) maintained in a nitrogen atmosphere, 5-benzyloxy-2-methyl-1H-pyrido [3,4-b] indol-1-one is added of preparation 6 (113.4 mg) and, subsequently, anhydrous DMSO (1 ml). After 30 minutes benzylbromide (0.09 ml) is added. The reaction mixture is stirred at room temperature for 50 minutes, then it is added with 1N HCl (1.6 ml) up to neutral pH and partitioned between water and ethyl acetate. The organic phase is dried on anhydrous Na2S04 and evaporated to dryness. The residue obtained is purified by column chromatography, eluting initially with n-hexane / ethyl acetate 7/3 and subsequently n-hexane / ethyl acetate 6/4.
Le frazioni cromatografiche contenenti il prodotto vengono riunite, concentrate a secchezza ed il residuo sottoposto a una seconda purificazione cromatografica eluendo con n-esano/acetato di etile 6/4. Le frazioni contenenti il prodotto vengono riunite, concentrate a secchezza ed il residuo sottoposto ad una purificazione mediante cromatografia flash, eluendo con nesano/acetato di etile 7/3. Per evaporazione delle frazioni contenenti il prodotto si ottiene un olio biancastro che viene cristallizzato con etere etilico bollente, per dare il 5-benzilossi-9-benzil-2-metil-lH-pirido[3„4-b]indol-lone come solido bianco (40,2 mg), The chromatographic fractions containing the product are combined, concentrated to dryness and the residue subjected to a second chromatographic purification eluting with n-hexane / ethyl acetate 6/4. The fractions containing the product are combined, concentrated to dryness and the residue subjected to purification by flash chromatography, eluting with nesane / ethyl acetate 7/3. By evaporation of the fractions containing the product, a whitish oil is obtained which is crystallized with boiling ethyl ether, to give 5-benzyloxy-9-benzyl-2-methyl-1H-pyrido [3 „4-b] indole as solid white (40.2 mg),
Preparazione 9 Preparation 9
I seguenti prodotti vengono preparati utilizzando nella procedura della preparazione 8 gli opportuni lH-pirido[3,4-b]indol-l-oni delle preparazioni 6 o 7 e gli opportuni agenti alchilanti: The following products are prepared using in the procedure of preparation 8 the suitable 1H-pyrid [3,4-b] indol-1-ones of preparations 6 or 7 and the appropriate alkylating agents:
5-benzilossi-9-(2-dimetilamminoetil)-2-metil-lH-pirido[3,4-b]indol-l-one; 5-(benzilossi)-9-(4-metossibenzil)-2-metil- 1 H-pirido[3 ,4-b]indol- 1 -one; 5-benzyloxy-9- (2-dimethylaminoethyl) -2-methyl-1H-pyrido [3,4-b] indole-1-one; 5- (benzyloxy) -9- (4-methoxybenzyl) -2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one;
5-(benzilossi)-9-(4-clorobenzil)-2-metil- 1 H-pirido[3 ,4-b]indol- 1 -one; 5- (benzyloxy) -9- (4-chlorobenzyl) -2-methyl- 1H-pyrido [3, 4-b] indole- 1 -one;
5-(benzilossi)-9-(4-trifluorometilbenzil)-2-metil-lH-pirido[3,4-b]indol-lone; 5- (benzyloxy) -9- (4-trifluoromethylbenzyl) -2-methyl-1H-pyrido [3,4-b] indole;
5-metossi-2,9-dimetil-lH-pirido[3,4-b]indol-l-one, 'H-NMR (DMSO-d6, 5-methoxy-2,9-dimethyl-1H-pyrido [3,4-b] indole-1-one, 'H-NMR (DMSO-d6,
Preparazione 10 Preparation 10
Una soluzione del 5-benzilossi-2-metil-lH-pirido[3,4-b]indol-l-one della preparazione 6 (199 mg) in THF/MeOH 3/1 (24 mi) viene idrogenata a pressione e temperatura ambiente in presenza di 10% palladio su carbone (198,2 mg). Dopo 30 minuti il consumo di idrogeno è terminato. Il catalizzatore viene allontanato per filtrazione e lavato sul filtro con THF (20 mi). Il filtrato riunito viene allontanato per evaporazione a pressione ridotta ed il residuo essiccato sotto vuoto a 30°C per 45’a dare il 5-idrossi-2-metillH-pirido[3,4-b]indol-l-one come un solido grigio. A solution of 5-benzyloxy-2-methyl-1H-pyrido [3,4-b] indol-1-one of preparation 6 (199 mg) in THF / MeOH 3/1 (24 ml) is hydrogenated at pressure and temperature environment in the presence of 10% palladium on carbon (198.2 mg). After 30 minutes, the hydrogen consumption is finished. The catalyst is removed by filtration and washed on the filter with THF (20 ml). The combined filtrate is removed by evaporation under reduced pressure and the residue dried under vacuum at 30 ° C for 45 minutes to give the 5-hydroxy-2-methylH-pyrido [3,4-b] indol-1-one as a solid grey.
Preparazione 11 Preparation 11
Utilizzando la procedura descritta nella preparazione 10 vengono preparati i seguenti prodotti a partire dagli opportuni benzilossi-lH-pirido[3,4-b]indol-l-oni della preparazione 7: Using the procedure described in preparation 10, the following products are prepared starting from the appropriate benzyloxy-1H-pyrido [3,4-b] indol-1-oni of preparation 7:
5-idrossi- 1 H-pirido[3 ,4-b] indol- 1 -one; 5-hydroxy- 1 H-pyrid [3, 4-b] indole- 1 -one;
6-idrossi-2-metil-lH-pirido[3,4-b]indol-l-one 6-hydroxy-2-methyl-1H-pyrido [3,4-b] indole-1-one
Preparazione 12 Preparation 12
A una soluzione del 5-idrossi-2-metil-lH-pirido[3,4-b]indol-l-one della preparazione 10 (153,5 mg) in DMF anidra (1 mi), mantenuta sotto agitazione in atmosfera di azoto, viene aggiunto K2C03 (154,3 mg) e, dopo 30 minuti, ioduro di metile (0,19 mi). La miscela di reazione viene lasciata sotto agitazione a temperatura ambiente per 72 ore e successivamente viene ripresa con MeOH (2 mi) e concentrata a secchezza a pressione ridotta. Il residuo viene ripartito tra CH2C12 (8 mi) ed acqua (2 mi). La fase organica viene separata e quella acquosa viene ulteriormente estratta con CH2C12 (3 x 10 mi). Gli estratti organici riuniti vengono anidrificati ed evaporati a secchezza. Il residuo ottenuto viene purificato per cromatografia flash eludendo con acetato di etile/n-esano 8/2. To a solution of 5-hydroxy-2-methyl-1H-pyrido [3,4-b] indole-1-one of preparation 10 (153.5 mg) in anhydrous DMF (1 ml), kept under stirring in an atmosphere of nitrogen, K2C03 (154.3 mg) is added and, after 30 minutes, methyl iodide (0.19 ml). The reaction mixture is left under stirring at room temperature for 72 hours and is subsequently taken up with MeOH (2 ml) and concentrated to dryness at reduced pressure. The residue is partitioned between CH2C12 (8 ml) and water (2 ml). The organic phase is separated and the aqueous one is further extracted with CH2C12 (3 x 10 ml). The combined organic extracts are dried and evaporated to dryness. The obtained residue is purified by flash chromatography eluding with ethyl acetate / n-hexane 8/2.
Le frazioni cromatografiche contenenti il prodotto vengono riunite. Il residuo ottenuto per allontanamento del solvente viene ripreso con etere etilico e recuperato per filtrazione, a dare il 5-metossi-2,9-dimetil-lH-pirido[3,4-b]indol-l-one (42,1 mg). The chromatographic fractions containing the product are combined. The residue obtained by removing the solvent is taken up with ethyl ether and recovered by filtration, to give 5-methoxy-2,9-dimethyl-1H-pyrido [3,4-b] indole-1-one (42.1 mg ).
Preparazione 13 Preparation 13
Utilizzando la procedura descritta nella preparazione 12 vengono preparati i seguenti prodotti a partire dagli opportuni idrossi lH-pirido[3,4-b]indoI-l-oni della preparazione 11: Using the procedure described in preparation 12, the following products are prepared starting from the suitable hydroxy 1H-pyrido [3,4-b] indium-1-oni of preparation 11:
6-benzilossi-9-benzil-2-metil- lH-pirido[3 ,4-b]indol- 1 -one; 6-benzyloxy-9-benzyl-2-methyl-1H-pyrido [3, 4-b] indole-1 -one;
5-(4-bromobenzilossi)-9-(4-bromobenzil)-2-metil-lH-pirido[3,4-b]indol-lone; 5- (4-bromobenzyloxy) -9- (4-bromobenzyl) -2-methyl-1H-pyrido [3,4-b] indole;
6-metossi-7-benzilossi-9-benzil- 1 H-pirido[3 ,4-b] indol- 1 -one. 6-methoxy-7-benzyloxy-9-benzyl- 1H-pyrido [3, 4-b] indole- 1 -one.
Claims (6)
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IT1999MI001740A IT1313592B1 (en) | 1999-08-03 | 1999-08-03 | DERIVATIVES OF 1H-PYRID 3,4-B INDOL-1-ONE. |
PCT/EP2000/007279 WO2001009129A2 (en) | 1999-08-03 | 2000-07-28 | 1h-pirido[3, 4-b]indol-1-one derivatives |
AU68315/00A AU6831500A (en) | 1999-08-03 | 2000-07-28 | 1h-pirido[3, 4-b]indol-1-one derivatives |
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US7456193B2 (en) | 2002-10-23 | 2008-11-25 | Sanofi-Aventis | Pyridoindolone derivatives substituted in the 3-position by a heterocyclic group, their preparation and their application in therapeutics |
FR2846329B1 (en) * | 2002-10-23 | 2004-12-03 | Sanofi Synthelabo | PYRIDOINDOLONE DERIVATIVES SUBSTITUTED IN -3 BY A PHENYL, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
FR2869316B1 (en) | 2004-04-21 | 2006-06-02 | Sanofi Synthelabo | PYRIDOINDOLONE DERIVATIVES SUBSTITUTED IN -6, THEIR PREPARATION AND THEIR THERAPEUTIC USE. |
FR2892416B1 (en) | 2005-10-20 | 2008-06-27 | Sanofi Aventis Sa | 6-HETEROARYLPYRIDOINDOLONE DERIVATIVES, THEIR PREPARATION AND THERAPEUTIC USE THEREOF |
WO2010042867A2 (en) * | 2008-10-09 | 2010-04-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Activators of human pyruvate kinase |
CN102127074A (en) * | 2010-12-17 | 2011-07-20 | 中国药科大学 | 6-sulfamyl substituted-beta-carboline-1-ketone cell cycle protein dependent kinase 2 inhibitor and application thereof |
WO2012157744A1 (en) * | 2011-05-19 | 2012-11-22 | 国立大学法人 富山大学 | 1-THIOXO-1,2,3,4-TETRAHYDRO-β-CARBOLINE DERIVATIVE AND ANTI-CANCER AGENT COMPRISING SAME |
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