TW200918056A - Nicotinamide derivatives, their preparation and their therapeutic application - Google Patents
Nicotinamide derivatives, their preparation and their therapeutic application Download PDFInfo
- Publication number
- TW200918056A TW200918056A TW097136703A TW97136703A TW200918056A TW 200918056 A TW200918056 A TW 200918056A TW 097136703 A TW097136703 A TW 097136703A TW 97136703 A TW97136703 A TW 97136703A TW 200918056 A TW200918056 A TW 200918056A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- phenyl
- ureido
- ethyl
- ethylamino
- Prior art date
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- 238000002360 preparation method Methods 0.000 title description 9
- 230000001225 therapeutic effect Effects 0.000 title description 3
- 150000005480 nicotinamides Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 108
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 61
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 45
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 22
- 125000001424 substituent group Chemical group 0.000 claims abstract description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
- 125000005843 halogen group Chemical group 0.000 claims abstract description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 8
- -1 2-tetrahydrofuranyl Chemical group 0.000 claims description 91
- 238000000034 method Methods 0.000 claims description 79
- 150000001412 amines Chemical class 0.000 claims description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 150000001408 amides Chemical class 0.000 claims description 49
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 43
- 239000011570 nicotinamide Substances 0.000 claims description 29
- 229960003966 nicotinamide Drugs 0.000 claims description 29
- 229960002715 nicotine Drugs 0.000 claims description 29
- 239000002253 acid Substances 0.000 claims description 27
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 27
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 24
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 22
- 238000012360 testing method Methods 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 13
- 125000003386 piperidinyl group Chemical group 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 235000005152 nicotinamide Nutrition 0.000 claims description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 11
- 239000007789 gas Substances 0.000 claims description 10
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012190 activator Substances 0.000 claims description 9
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 229910003827 NRaRb Inorganic materials 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 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 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 229910052731 fluorine Chemical group 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- LQJFSGNBNCOKTJ-UHFFFAOYSA-N N-(2-piperidin-1-ylethyl)decan-1-amine Chemical compound CCCCCCCCCCNCCN1CCCCC1 LQJFSGNBNCOKTJ-UHFFFAOYSA-N 0.000 claims description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000003725 azepanyl group Chemical group 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 150000002923 oximes Chemical group 0.000 claims description 4
- 239000000779 smoke Substances 0.000 claims description 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical group ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- 229910052796 boron Inorganic materials 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000052 vinegar Substances 0.000 claims description 3
- 235000021419 vinegar Nutrition 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 2
- 210000004907 gland Anatomy 0.000 claims description 2
- 125000003147 glycosyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000006525 methoxy ethyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])OC([H])([H])[H] 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 4
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- 238000007689 inspection Methods 0.000 claims 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims 2
- 125000005987 1-oxo-thiomorpholinyl group Chemical group 0.000 claims 1
- YNNUSGIPVFPVBX-UHFFFAOYSA-N 2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound CN1CCCC1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-UHFFFAOYSA-N 0.000 claims 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- HJCUTNIGJHJGCF-UHFFFAOYSA-N 9,10-dihydroacridine Chemical group C1=CC=C2CC3=CC=CC=C3NC2=C1 HJCUTNIGJHJGCF-UHFFFAOYSA-N 0.000 claims 1
- 101100042371 Caenorhabditis elegans set-3 gene Proteins 0.000 claims 1
- 206010012735 Diarrhoea Diseases 0.000 claims 1
- 244000061176 Nicotiana tabacum Species 0.000 claims 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims 1
- 125000005577 anthracene group Chemical group 0.000 claims 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims 1
- 125000003636 chemical group Chemical group 0.000 claims 1
- 125000004404 heteroalkyl group Chemical group 0.000 claims 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 1
- 125000002346 iodo group Chemical group I* 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 229960005181 morphine Drugs 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
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- 230000002265 prevention Effects 0.000 claims 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 229910052712 strontium Inorganic materials 0.000 claims 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims 1
- 229960002317 succinimide Drugs 0.000 claims 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 68
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 29
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
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- RJNJWHFSKNJCTB-UHFFFAOYSA-N benzylurea Chemical compound NC(=O)NCC1=CC=CC=C1 RJNJWHFSKNJCTB-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 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
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- GFAZHVHNLUBROE-UHFFFAOYSA-N hydroxymethyl propionaldehyde Natural products CCC(=O)CO GFAZHVHNLUBROE-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- NYIODHFKZFKMSU-UHFFFAOYSA-N n,n-bis(methylamino)ethanamine Chemical compound CCN(NC)NC NYIODHFKZFKMSU-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- LIQUIDFGSAJZBQ-UHFFFAOYSA-N n-methyl-2-(oxolan-2-ylmethylamino)-6-[4-(pyridin-3-ylmethylcarbamoylamino)phenyl]pyridine-3-carboxamide Chemical compound CNC(=O)C1=CC=C(C=2C=CC(NC(=O)NCC=3C=NC=CC=3)=CC=2)N=C1NCC1CCCO1 LIQUIDFGSAJZBQ-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DVCMYAIUSOSIQP-UHFFFAOYSA-N phenyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OC1=CC=CC=C1 DVCMYAIUSOSIQP-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 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
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- ZXYAAVBXHKCJJB-UHFFFAOYSA-N uracil-5-carboxylic acid Chemical compound OC(=O)C1=CNC(=O)NC1=O ZXYAAVBXHKCJJB-UHFFFAOYSA-N 0.000 description 1
- 239000004066 vascular targeting agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000010455 vermiculite Substances 0.000 description 1
- 235000019354 vermiculite Nutrition 0.000 description 1
- 229910052902 vermiculite Inorganic materials 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
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| FR0706799A FR2921657A1 (fr) | 2007-09-28 | 2007-09-28 | Derives de nicotinamide, leur preparation et leur application en therapeutique |
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| TW200918056A true TW200918056A (en) | 2009-05-01 |
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| EP (1) | EP2205566A2 (https=) |
| JP (1) | JP2010540504A (https=) |
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| AU (1) | AU2008334457A1 (https=) |
| BR (1) | BRPI0817973A2 (https=) |
| CA (1) | CA2700559A1 (https=) |
| CL (1) | CL2008002893A1 (https=) |
| FR (1) | FR2921657A1 (https=) |
| IL (1) | IL204663A0 (https=) |
| MX (1) | MX2010003445A (https=) |
| PA (1) | PA8797301A1 (https=) |
| PE (1) | PE20091033A1 (https=) |
| RU (1) | RU2010116765A (https=) |
| TW (1) | TW200918056A (https=) |
| UY (1) | UY31367A1 (https=) |
| WO (1) | WO2009074749A2 (https=) |
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| CN102775396B (zh) | 2005-11-08 | 2014-10-08 | 沃泰克斯药物股份有限公司 | Atp-结合弹夹转运蛋白的杂环调控剂 |
| CN104447716A (zh) | 2007-05-09 | 2015-03-25 | 沃泰克斯药物股份有限公司 | Cftr调节剂 |
| MX365732B (es) | 2007-12-07 | 2019-06-12 | Vertex Pharma | Procesos para producir acidos cicloalquilcarboxamido-piridin benzoicos. |
| EP3683218B1 (en) | 2007-12-07 | 2024-09-18 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid |
| NZ720282A (en) | 2008-02-28 | 2017-12-22 | Vertex Pharma | Heteroaryl derivatives as cftr modulators |
| FR2943675A1 (fr) * | 2009-03-24 | 2010-10-01 | Sanofi Aventis | Composes anticancereux, leur preparation et leur application en therapeutique |
| FR2943670B1 (fr) * | 2009-03-24 | 2011-05-06 | Sanofi Aventis | Derives anticancereux,leur preparation et leur application en therapeutique |
| FR2943669B1 (fr) * | 2009-03-24 | 2011-05-06 | Sanofi Aventis | Derives de nicotinamide,leur preparation et leur application en therapeutique |
| EP2440204B1 (en) * | 2009-06-12 | 2013-12-18 | Bristol-Myers Squibb Company | Nicotinamide compounds useful as kinase modulators |
| AU2011223790A1 (en) * | 2010-03-01 | 2012-08-30 | Myrexis, Inc. | Compounds and therapeutic uses thereof |
| US8912184B1 (en) | 2010-03-01 | 2014-12-16 | Alzheimer's Institute Of America, Inc. | Therapeutic and diagnostic methods |
| JP2013523833A (ja) | 2010-04-07 | 2013-06-17 | バーテックス ファーマシューティカルズ インコーポレイテッド | ３−（６−（１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）シクロプロパンカルボキサミド）−３−メチルピリジン−２−イル）安息香酸の医薬組成物およびその投与 |
| US8827372B2 (en) | 2010-07-07 | 2014-09-09 | Frontis Corp. | Blowing system |
| FR2965263A1 (fr) * | 2010-09-24 | 2012-03-30 | Sanofi Aventis | Derives de thienopyridine nicotinamide, leur preparation et leur application en therapeutique |
| US9169246B2 (en) | 2011-09-26 | 2015-10-27 | Sanofi | Pyrazoloquinolinone derivatives, preparation thereof and therapeutic use thereof |
| CN103012397B (zh) * | 2011-09-26 | 2017-03-01 | 赛诺菲 | 吡唑并喹啉酮衍生物、其制备方法及其治疗用途 |
| PT2573073E (pt) * | 2011-09-26 | 2015-02-05 | Sanofi Sa | Derivados de pirazoloquinolinona, sua preparação e sua utilização terapêutica |
| NZ727015A (en) | 2012-01-25 | 2017-12-22 | Vertex Pharma | Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
| AU2014349010C1 (en) | 2013-11-12 | 2020-08-06 | Vertex Pharmaceuticals Incorporated | Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases |
| CN103804270B (zh) * | 2014-01-23 | 2016-06-22 | 中国药科大学 | 5-(4-甲脒基苄氧基)色氨酸衍生物、其制法及应用 |
| RU2691136C2 (ru) | 2014-11-18 | 2019-06-11 | Вертекс Фармасьютикалз Инкорпорейтед | Способ проведения высокопроизводительной тестовой высокоэффективной жидкостной хроматографии |
| JP7092356B2 (ja) * | 2016-06-22 | 2022-06-28 | フーダン ユニヴァーシティ | ビアリール尿素誘導体またはそれらの塩、およびそれらの調製方法および使用 |
| CN107522641B (zh) * | 2016-06-22 | 2020-05-05 | 复旦大学 | 联芳基脲类衍生物或其盐及其制备方法和用途 |
| KR102831570B1 (ko) | 2018-05-04 | 2025-07-10 | 레미디 플랜, 인크. | 암 줄기 세포를 표적화하는 암 치료 |
| CN110396065A (zh) * | 2019-06-25 | 2019-11-01 | 南京普锐达医药科技有限公司 | 一种2,4-二氯-5-嘧啶甲酰氯的合成方法 |
| AU2020378067A1 (en) * | 2019-11-06 | 2022-05-26 | Remedy Plan, Inc. | Cancer treatments targeting cancer stem cells |
| WO2021219513A1 (en) | 2020-04-28 | 2021-11-04 | Basf Se | Pesticidal compounds |
| JP2024518089A (ja) * | 2021-05-13 | 2024-04-24 | リメディー プラン，インコーポレーテッド | Ｎａｍｐｔ阻害剤とその使用 |
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|---|---|---|---|---|
| DE4301110A1 (de) * | 1993-01-18 | 1994-07-21 | Bayer Ag | Verfahren zur Herstellung von 2-Amino-5-aminomethyl-pyridin |
| CZ20012185A3 (cs) * | 1998-12-16 | 2001-10-17 | Bayer Aktiengesellschaft | Nové bifenylové sloučeniny a sloučeniny analogické bifenylovým sloučeninám, způsob jejich přípravy, farmaceutické prostředky a pouľití těchto sloučenin a prostředků jako antagonistů integrinu |
| DE10063008A1 (de) * | 2000-12-16 | 2002-06-20 | Merck Patent Gmbh | Carbonsäureamidderivate |
| US20040067985A1 (en) * | 2002-10-04 | 2004-04-08 | Fortuna Haviv | Method of inhibiting angiogenesis |
| JP2007515400A (ja) * | 2003-11-28 | 2007-06-14 | ノバルティス アクチエンゲゼルシャフト | タンパク質キナーゼ依存性疾患の処置におけるジアリール尿素誘導体 |
| US20060216288A1 (en) * | 2005-03-22 | 2006-09-28 | Amgen Inc | Combinations for the treatment of cancer |
-
2007
- 2007-09-28 FR FR0706799A patent/FR2921657A1/fr not_active Withdrawn
-
2008
- 2008-09-24 TW TW097136703A patent/TW200918056A/zh unknown
- 2008-09-26 JP JP2010526335A patent/JP2010540504A/ja not_active Withdrawn
- 2008-09-26 KR KR1020107006595A patent/KR20100065165A/ko not_active Withdrawn
- 2008-09-26 EP EP08859496A patent/EP2205566A2/fr not_active Withdrawn
- 2008-09-26 BR BRPI0817973-5A patent/BRPI0817973A2/pt not_active IP Right Cessation
- 2008-09-26 CA CA2700559A patent/CA2700559A1/fr not_active Abandoned
- 2008-09-26 PE PE2008001687A patent/PE20091033A1/es not_active Application Discontinuation
- 2008-09-26 MX MX2010003445A patent/MX2010003445A/es not_active Application Discontinuation
- 2008-09-26 CN CN200880109332A patent/CN101808996A/zh active Pending
- 2008-09-26 CL CL2008002893A patent/CL2008002893A1/es unknown
- 2008-09-26 AU AU2008334457A patent/AU2008334457A1/en not_active Abandoned
- 2008-09-26 UY UY31367A patent/UY31367A1/es not_active Application Discontinuation
- 2008-09-26 RU RU2010116765/04A patent/RU2010116765A/ru not_active Application Discontinuation
- 2008-09-26 PA PA20088797301A patent/PA8797301A1/es unknown
- 2008-09-26 AR ARP080104193A patent/AR066171A1/es unknown
- 2008-09-26 WO PCT/FR2008/001338 patent/WO2009074749A2/fr not_active Ceased
-
2010
- 2010-03-22 IL IL204663A patent/IL204663A0/en unknown
- 2010-03-26 US US12/732,749 patent/US20100222319A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2008334457A1 (en) | 2009-06-18 |
| WO2009074749A2 (fr) | 2009-06-18 |
| WO2009074749A3 (fr) | 2009-08-20 |
| CN101808996A (zh) | 2010-08-18 |
| RU2010116765A (ru) | 2011-11-27 |
| PA8797301A1 (es) | 2009-05-15 |
| FR2921657A1 (fr) | 2009-04-03 |
| MX2010003445A (es) | 2010-04-27 |
| CA2700559A1 (fr) | 2009-06-18 |
| EP2205566A2 (fr) | 2010-07-14 |
| PE20091033A1 (es) | 2009-08-17 |
| US20100222319A1 (en) | 2010-09-02 |
| UY31367A1 (es) | 2009-04-30 |
| CL2008002893A1 (es) | 2009-10-16 |
| KR20100065165A (ko) | 2010-06-15 |
| IL204663A0 (en) | 2010-11-30 |
| AR066171A1 (es) | 2009-07-29 |
| JP2010540504A (ja) | 2010-12-24 |
| BRPI0817973A2 (pt) | 2019-04-09 |
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