WO2008037783A1 - Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles - Google Patents
Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles Download PDFInfo
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- WO2008037783A1 WO2008037783A1 PCT/EP2007/060288 EP2007060288W WO2008037783A1 WO 2008037783 A1 WO2008037783 A1 WO 2008037783A1 EP 2007060288 W EP2007060288 W EP 2007060288W WO 2008037783 A1 WO2008037783 A1 WO 2008037783A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- substituted
- alkyl
- indole
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- -1 1-substituted indole-2-carboxaldehyde Chemical class 0.000 claims abstract description 34
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 7
- MLIREBYILWEBDM-UHFFFAOYSA-N anhydrous cyanoacetic acid Natural products OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- AYWCZPUGHPFELW-UHFFFAOYSA-N 2-methanimidoyl-1H-indol-3-amine Chemical compound Nc1c(C=N)[nH]c2ccccc12 AYWCZPUGHPFELW-UHFFFAOYSA-N 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 3
- 239000000543 intermediate Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 241000725303 Human immunodeficiency virus Species 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 150000001299 aldehydes Chemical class 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 4
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 0 *c1c(C=O)[n](*)c2ccccc12 Chemical compound *c1c(C=O)[n](*)c2ccccc12 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical class [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- SBNOTUDDIXOFSN-UHFFFAOYSA-N 1h-indole-2-carbaldehyde Chemical compound C1=CC=C2NC(C=O)=CC2=C1 SBNOTUDDIXOFSN-UHFFFAOYSA-N 0.000 description 2
- CHIFTAQVXHNVRW-UHFFFAOYSA-N 1h-indole-3-carbonitrile Chemical compound C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical group ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000011260 aqueous acid Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000006170 formylation reaction Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 150000002940 palladium Chemical class 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002577 pseudohalo group Chemical group 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- BJYNPOMFNPNCHZ-UHFFFAOYSA-N 3-bromo-1h-indole-2-carbaldehyde Chemical compound C1=CC=C2C(Br)=C(C=O)NC2=C1 BJYNPOMFNPNCHZ-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- OCJMNSVWIYIHRK-UHFFFAOYSA-N CCCCCOC(CC#N)=O Chemical compound CCCCCOC(CC#N)=O OCJMNSVWIYIHRK-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- UBRZYIWZTSPGJV-UHFFFAOYSA-N N#CC1=Cc([n](CCN2CCCC2)c2ccccc22)c2N(c(cc2)ccc2[N+]([OH2+])=O)C1=O Chemical compound N#CC1=Cc([n](CCN2CCCC2)c2ccccc22)c2N(c(cc2)ccc2[N+]([OH2+])=O)C1=O UBRZYIWZTSPGJV-UHFFFAOYSA-N 0.000 description 1
- NNJXIAOPPYUVAX-UHFFFAOYSA-N N-acetylindoxyl Chemical compound C1=CC=C2N(C(=O)C)C=C(O)C2=C1 NNJXIAOPPYUVAX-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VCVPCTIEVKHAIQ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1Nc1c(C=O)[n](CCN2CCCC2)c2ccccc12)=O Chemical compound [O-][N+](c(cc1)ccc1Nc1c(C=O)[n](CCN2CCCC2)c2ccccc12)=O VCVPCTIEVKHAIQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000012084 conversion product Substances 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000012011 nucleophilic catalyst Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- ZOUWOGOTHLRRLS-UHFFFAOYSA-N palladium;phosphane Chemical class P.[Pd] ZOUWOGOTHLRRLS-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- This invention relates to a process for preparing 2-oxo-2,5-dihydro-lH-pyrido[3,2-b]- indole-3-carbonitriles starting from 1 -substituted indole-2-carboxaldehydes with an aromatic amine and reacting the thus obtained intermediates with a cyanoacetic acid ester.
- HIV human immunodeficiency virus
- HIV inhibitors which comprises the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs).
- NRTIs nucleoside reverse transcriptase inhibitors
- NRTIs non-nucleoside reverse transcriptase inhibitors
- NRTIs nucleoside reverse transcriptase inhibitors
- NcRTIs nucleotide competitive RT inhibitors
- NcRTI compounds involve multi-step procedures of four or more steps.
- WO 2005/111047 at p. 73 describes a procedure for preparing 2-oxo-2,5-dihydro-lH-pyrido[3,2-b]indole-3- carbonitriles starting from N-acetyl-3 -hydroxy- indole wherein the 3 -hydroxy group is substituted by an arylamino group, then the acetyl group is removed and the resulting indole derivative is formylated in a Vilsmeier-Haack procedure using POCI3 and DMF to a 2-formyl-3-arylamino-indole.
- the latter is cyclized with ethyl cyanoacetate to a 2-0X0-2, 5-dihydro-lH-pyrido[3,2-b]indole-3-carbonitrile, which is alkylated in its 5-position with an alkyl iodide.
- This alkylation has to be postponed until after the formylation reaction because when using 1 -alkyl- indoles as starting materials, the formylation reaction gives rise to side reactions resulting in lower yields and complex purification procedures.
- the Vilsmeier-Haack formylation reaction in the procedure of WO 2005/111047 runs in low yield (25% in the example that is referred to) so that the described procedure is inappropriate for scaling up due to its low overall yield.
- the present invention is aimed at providing new synthesis processes for preparing
- NcRTI compounds that comprise less steps, that can be scaled up for the production of multi-kilogram or larger quantities, that are reproducible, economical and through which the end product is obtained in high yield and with a high degree of purity.
- the present invention concerns a process for preparing a compound of formula:
- R 1 is Ci_ 6 alkyl optionally substituted with diCi_ 6 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl;
- R 2 is hydrogen or Ci_6alkyloxy
- Ar is phenyl or pyridyl, both optionally substituted with one, two or three substituents selected from Chalky!, halo, nitro, cyano and Ci_6alkoxy; wherein the process comprises condensing a 1 -substituted indole-2-carboxaldehyde of formula (II) with an aromatic amine Ar-NH 2 (III), thus obtaining a (2-iminomethyl-lH-indol-3-yl)- amine (IV-a), which is optionally converted to an aldehyde (IV-b), and reacting the (2-imino methyl- lH-indo 1-3 -yl)-amine (IV-a) or the aldehyde (IV-b), or a mixture thereof, with a cyanoacetic acid ester (V) as represented in the following reaction scheme, wherein R 1 , R 2 and Ar are as specified above, Lg is a leaving group and R is Ci_ 4 alky
- this invention concerns a process for preparing a compound of formula (IV-a) or (IV-b), or a mixture thereof, wherein the compound of formula (IV-a) or (IV-b) is as specified above, wherein said process comprises condensing a 1 -substituted indole-2-carboxaldehyde of formula (II) with an aromatic amine Ar-NH 2 (III), thus obtaining a (2-iminomethyl-lH-indol-3-yl)-amine (IV-a), which is optionally converted to an aldehyde (IV-b) as represented in the following reaction scheme, wherein R 1 , R 2 and Ar are as specified above, Lg is a leaving group:
- the invention concerns a process for preparing a compound of formula (I), as specified above, wherein the compound of formula (I) is prepared by condensing a 1 -substituted indole-2-carboxaldehyde of formula (II) with an aromatic amine Ar-NH 2 (III), and with a cyanoacetic acid ester (V), without isolation of the condensation product of the reaction between (II) and (III), to obtain the desired end product of formula (I), as outlined in the following reaction scheme wherein R 1 , R 2 , Ar, Lg and R are as specified above:
- Ci_ 4 alkyl defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methyl-l -propyl, 2-methyl-2-propyl.
- Ci_4alkyl may be a linear Ci_ 4 alkyl (i.e. n.Ci_ 4 alkyl, i.e. methyl, ethyl, n.propyl or n.butyl).
- Ci_ 6 alkyl encompasses Ci_4alkyl and the homologues having 5 or 6 carbon atoms such as, e.g., pentyl, 2-methylbutyl, 3-methylbutyl, 2-ethylpropyl, hexyl, 2-methylpentyl, 3-methyl- pentyl, 2-ethylbutyl, and the like.
- Particular subgroups of the compounds of formula (I) or of the intermediates used in the processes described herein are those wherein R 1 is Ci_ 4 alkyl, in particular methyl; or wherein R 1 is linear Ci_ 4 alkyl, in particular n.propyl or n.butyl, substituted in with diCi_ 6 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl.
- Particular subgroups of the compounds of formula (I) or of the intermediates used in the processes described herein are those wherein Ar is phenyl substituted with nitro or halo, in particular Ar is phenyl substituted with nitro, more in particular Ar is 4-nitrophenyl.
- Ar is pyridyl substituted with halo, in particular with chloro, more in particular Ar is a group which can be designated as 2-chloro-pyridin-5-yl or 6-chloro-3-pyridinyl.
- Lg is halo, in particular chloro, bromo, iodo, or Lg is a triflate (or trifluoromethanesulfonate) group.
- the conversion from (II) with (III) to (IV-a) is an aryl animation reaction in which an aromatic halide or pseudohalide (such as a triflate) is reacted with an amine.
- this aryl amination reaction is a Buchwald-Hartwig type of reaction, which comprises reacting an aromatic halide or pseudohalide with the amine in the presence of a catalyst, in particular a palladium catalyst.
- Suitable palladium catalysts are palladium phosphine complexes, such as the palladium Xantphos complexes, in particular Pd(Xantphos)2 (Xantphos being 9,9'-dimethyl-4,5-bis(diphenylphosphino)- xanthene), the DPPF complexes of palladium such as (DPPF)PdCl 2 (DPPF being l,l '-bis(diphenylphosphino)ferrocene), the palladium complexes of l,l'-binaphthalene- 2,2'-diylbis(diphenylphosphine) (BINAP), which can be used as such or can be prepared in situ such as by reaction of a palladium salt or palladium complex such as e.g.
- BINAP palladium (II) acetate (Pd(OAc) 2 ) or (palladium)2(dibenzylideneacetone)3 (Pd 2 (dba) 3 ), with BINAP.
- the BINAP ligand may be used in its racemic form.
- This reaction may be conducted in a suitable solvent such as an aromatic hydrocarbon, e.g. toluene, or an ether, e.g. tetrahydrofuran (THF), methylTHF, dioxane and the like, in the presence of a base such as an alkali metal carbonate or phosphate, e.g.
- an alkoxide base in particular an alkali metal Ci_ 6 alkoxide such as sodium or potassium t.butoxide (NaOtBu or KOtBu), or an organic bases such as l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) or a tertiary amine (e.g. triethylamine), and in particular in the presence of cesium carbonate.
- Ci_ 6 alkoxide such as sodium or potassium t.butoxide (NaOtBu or KOtBu)
- organic bases such as l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) or a tertiary amine (e.g. triethylamine), and in particular in the presence of cesium carbonate.
- DBU l,8-diazabicyclo(5.4.0)undec-7-ene
- a tertiary amine e.g. triethyl
- the intermediates of formula (IV-a) may be converted to the corresponding aldehydes of formula (IV-b) by treatment of the former with aqueous acid, e.g. aqueous HCl or HBr.
- aqueous acid e.g. aqueous HCl or HBr.
- the intermediates of formula (IV-a) will be transformed to those of formula (IV-b) during the work-up of the reaction of (II) with (III).
- Washing with aqueous acid, for example with aqueous HCl, of the reaction mixture of the reaction of (II) with (III) may be done to remove basic components such as unreacted Ar-NH 2 (III). This washing step may cause the hydrolysis of the enamine (IV-a) to the aldehyde (IV-b).
- an alcohol such as methanol, ethanol, n.propanol, isopropanol
- an ether such as THF
- a dipolar aprotic solvent such as DMA, DMF, DMSO, NMP
- a halogenated hydrocarbon such as dichloromethane, chloroform
- an aromatic hydrocarbon such as toluene
- a glycol such as ethylene glycol
- a base e.g. an amine such as piperidine, pyrrolidine, morpholine, triethylamine, diisopropylethylamine (DIPE), and the like.
- the intermediates of formula (II) wherein Lg is halo may be prepared by halogenating an indole derivative of formula (VI).
- Suitable halogenating agents are the halogens themselves or halogenating reagents such as the halogenated succinimides, e.g. N-chloro or N-bromosuccinimide.
- This halogenating reaction may be conducted in a suitable solvent, such as, for example, an aromatic hydrocarbon, e.g. toluene, or an ether, e.g. tetrahydrofuran (THF), methylTHF, dioxane, and the like.
- Other derivatives of formula (II) can be prepared by exchanging the halo group by other leaving groups.
- the intermediates of formula (II) may also be prepared by first preparing 3-bromo- indole-2-carboxaldehyde and subsequent N-alkylation of the latter with a reagent R 1 -Lg, wherein R 1 and Lg are as specified above and Lg in particular is a halo group such as chloro or bromo.
- the N-alkylation may be conducted in a suitable solvent, e.g. a dipolar aprotic solvent such as DMA, DMF, DMSO and the like in the presence of a base such as an alkali metal hydride, e.g. NaH or LiH.
- a nucleophilic catalyst may be added to the reaction mixture, e.g. tetrabutylammonium iodide (TBAI).
- the process for preparing the compound of formula (I) of the invention starts from intermediates (II) and (III) to obtain the intermediate (IV) and subsequent condensation of (IV) with (V) to obtain compound (I). In one embodiment, all of the steps of this process may be conducted in the same solvent or solvent mixture.
- this process is conducted in a one-pot procedure, without isolation of intermediate (IV).
- the reaction of (II) with (III) is conducted in the solvent described above for this reaction, in particular a hydrocarbon such as toluene, which is removed partially or completely after which the solvent described above for the reaction of (IV) with (V), in particular an alcohol such as glycol, is added.
- This process variant offers the possibility to synthesize compound (I) in a quick, simple and straightforward manner.
- An additional feature of the present invention comprises the fact that the intermediates of formula
- Particular intermediates of formula (IV) are those wherein the radicals Ar, R 1 , and R 2 have the specific meanings defined above.
- a subclass of the intermediates of formula (IV) is that wherein X is N-Ar, i.e. intermediates (IV-a).
- Another subclass of the intermediates of formula (IV) is that wherein X is O, i.e. intermediates (IV-b).
- the process of the present invention runs in relatively high yield making it suitable for scaling up for the production of multi-kilogram and larger quantities.
- the process is well-suited for preparing end products having Ar groups with various substitutions, whereas the process described in WO 2005/111047 gave poor results, for example for Ar being chloropyridine.
- the process moreover is reproducible and economical. Further advantages that may be mentioned are the availability of starting materials and reagents that can be purchased or are easy to prepare.
- N-Bromosuccinimide (1.05 equiv., 290 mmol, 51.7 g) was added to a solution of l-methylindole-2-carboxaldehyde (1) (1.0 equiv., 276 mmol, 44.0 g) in Me-THF
- N-Bromosuccinimide (1.2 equiv., 69.4 mmol, 12.4 g) was added to a solution of indole-2-carboxaldehyde (12) [Agnusdei, M.; Bandini, M.; Melloni, A., Alfonso; Umani-Ronchi, A. J. Org. Chem. 2003, 68, 7126-7129] (1.0 equiv., 57.9 mmol, 8.4 g) in Me-THF (500 ml). The reaction mixture was stirred at room temperature for 2 h.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
l'invention concerne un processus de préparation de 2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitriles commençant par indole-2-carboxaldehyde substitué en 1 avec une amine aromatique et qui consiste ensuite à faire réagir l'intermédiaire ainsi obtenu avec un ester d'acide cyanoacétique.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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EP06121584 | 2006-09-29 | ||
EP06121584.4 | 2006-09-29 |
Publications (1)
Publication Number | Publication Date |
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WO2008037783A1 true WO2008037783A1 (fr) | 2008-04-03 |
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PCT/EP2007/060288 WO2008037783A1 (fr) | 2006-09-29 | 2007-09-28 | Processus de préparation de 2-oxo-2,5-dihydro-1h-pyrido[3,2-b]indole-3-carbonitriles |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8349839B2 (en) | 2009-04-09 | 2013-01-08 | Boehringer Ingelheim International Gmbh | Inhibitors of HIV replication |
WO2016054491A1 (fr) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Composés hétérocycliques et leurs utilisations |
WO2017214269A1 (fr) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Composés hétérocycliques et leurs utilisations |
Citations (6)
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WO2002059123A2 (fr) * | 2000-12-18 | 2002-08-01 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Composes benzoylalkylindolepyridinium et compositions pharmaceutiques comprenant ces composes |
WO2004046143A1 (fr) * | 2002-11-15 | 2004-06-03 | Tibotec Pharmaceuticals Ltd. | Indolepyridinium substitue utilise comme composes anti-infection |
WO2005111044A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | 1,5-dihydropyrido[3,2-b]indol-2-ones substituees en position 4 |
WO2005111047A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | 1-heterocyclyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones |
WO2005111035A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | 6,7,8,9-substitue 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones convenant comme agents pharmaceutiques anti-infectieux |
WO2005110411A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | Combinaison de substitue 1-phenyl-1,5-dihydro-pyrido- [3,2-b] indol-2-ones et autres inhibiteurs du vih |
-
2007
- 2007-09-28 WO PCT/EP2007/060288 patent/WO2008037783A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002059123A2 (fr) * | 2000-12-18 | 2002-08-01 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Composes benzoylalkylindolepyridinium et compositions pharmaceutiques comprenant ces composes |
WO2004046143A1 (fr) * | 2002-11-15 | 2004-06-03 | Tibotec Pharmaceuticals Ltd. | Indolepyridinium substitue utilise comme composes anti-infection |
WO2005111044A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | 1,5-dihydropyrido[3,2-b]indol-2-ones substituees en position 4 |
WO2005111047A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | 1-heterocyclyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones |
WO2005111035A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | 6,7,8,9-substitue 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones convenant comme agents pharmaceutiques anti-infectieux |
WO2005110411A1 (fr) * | 2004-05-17 | 2005-11-24 | Tibotec Pharmaceuticals Ltd. | Combinaison de substitue 1-phenyl-1,5-dihydro-pyrido- [3,2-b] indol-2-ones et autres inhibiteurs du vih |
Non-Patent Citations (1)
Title |
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N.Z.TUGUSHEVA ET AL: "Investigation of the reaction of N-acetylinindoxyl with substituted anilines - synthesis of derivatives of indolo[3,2-b]quinolines", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 37, no. 7, 2001, pages 885 - 893, XP002421863 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8349839B2 (en) | 2009-04-09 | 2013-01-08 | Boehringer Ingelheim International Gmbh | Inhibitors of HIV replication |
WO2016054491A1 (fr) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Composés hétérocycliques et leurs utilisations |
WO2017214269A1 (fr) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Composés hétérocycliques et leurs utilisations |
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