DE69829879T2 - Indolderivate als faktor xa inhibitoren - Google Patents
Indolderivate als faktor xa inhibitoren Download PDFInfo
- Publication number
- DE69829879T2 DE69829879T2 DE69829879T DE69829879T DE69829879T2 DE 69829879 T2 DE69829879 T2 DE 69829879T2 DE 69829879 T DE69829879 T DE 69829879T DE 69829879 T DE69829879 T DE 69829879T DE 69829879 T2 DE69829879 T2 DE 69829879T2
- Authority
- DE
- Germany
- Prior art keywords
- indole
- alkyl
- phenyl
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 37
- 229940123583 Factor Xa inhibitor Drugs 0.000 title description 13
- 229940054051 antipsychotic indole derivative Drugs 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 313
- 239000000203 mixture Substances 0.000 claims description 114
- -1 (C 1 -C 10 ) - Alkyl radical Chemical class 0.000 claims description 91
- 108010074860 Factor Xa Proteins 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 53
- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 45
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 23
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 17
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 239000003112 inhibitor Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 230000023555 blood coagulation Effects 0.000 claims description 13
- 125000000524 functional group Chemical group 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 13
- 208000007536 Thrombosis Diseases 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- 239000002243 precursor Substances 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 10
- 150000001450 anions Chemical class 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 238000011321 prophylaxis Methods 0.000 claims description 10
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000000369 oxido group Chemical group [*]=O 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Chemical group 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 229910004013 NO 2 Inorganic materials 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 230000009424 thromboembolic effect Effects 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 150000001204 N-oxides Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 249
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 240
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 174
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 165
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 134
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 107
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- 239000000047 product Substances 0.000 description 90
- 238000001819 mass spectrum Methods 0.000 description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 75
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- 239000011347 resin Substances 0.000 description 50
- 229920005989 resin Polymers 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- 235000019441 ethanol Nutrition 0.000 description 48
- 229960004756 ethanol Drugs 0.000 description 44
- 230000000694 effects Effects 0.000 description 40
- 239000002904 solvent Substances 0.000 description 40
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 238000003818 flash chromatography Methods 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 37
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 125000001424 substituent group Chemical group 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000000463 material Substances 0.000 description 33
- 239000013058 crude material Substances 0.000 description 32
- 239000013078 crystal Substances 0.000 description 30
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 29
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 28
- 230000014759 maintenance of location Effects 0.000 description 28
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 27
- 239000005695 Ammonium acetate Substances 0.000 description 27
- 235000019257 ammonium acetate Nutrition 0.000 description 27
- 229940043376 ammonium acetate Drugs 0.000 description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 25
- 238000003556 assay Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 25
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 25
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 25
- 239000007858 starting material Substances 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 238000003786 synthesis reaction Methods 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 23
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 23
- 230000015271 coagulation Effects 0.000 description 21
- 238000005345 coagulation Methods 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 20
- PDJZOFLRRJQYBF-UHFFFAOYSA-N 4-(aminomethyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(CN)C=C1 PDJZOFLRRJQYBF-UHFFFAOYSA-N 0.000 description 19
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 19
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 19
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 108090000190 Thrombin Proteins 0.000 description 18
- 108010000499 Thromboplastin Proteins 0.000 description 18
- 102000002262 Thromboplastin Human genes 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 229960004072 thrombin Drugs 0.000 description 18
- 125000004093 cyano group Chemical group *C#N 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 229940088598 enzyme Drugs 0.000 description 16
- 150000002475 indoles Chemical class 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 239000000758 substrate Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
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- GETOHMIIRHERDB-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]indole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC=CC=C2N1CC1=CC=CC(C#N)=C1 GETOHMIIRHERDB-UHFFFAOYSA-N 0.000 description 11
- LRXFKKPEBXIPMW-UHFFFAOYSA-N 2-(9h-fluoren-2-yl)propanoic acid Chemical compound C1=CC=C2C3=CC=C(C(C(O)=O)C)C=C3CC2=C1 LRXFKKPEBXIPMW-UHFFFAOYSA-N 0.000 description 11
- 239000003146 anticoagulant agent Substances 0.000 description 11
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- 238000002953 preparative HPLC Methods 0.000 description 10
- CMBGGZQNJYMKRZ-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]-5-fluoroindole-2-carboxylic acid Chemical compound OC(=O)C1=CC2=CC(F)=CC=C2N1CC1=CC=CC(C#N)=C1 CMBGGZQNJYMKRZ-UHFFFAOYSA-N 0.000 description 9
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 125000001041 indolyl group Chemical group 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
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- 239000012312 sodium hydride Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 238000010561 standard procedure Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 208000032843 Hemorrhage Diseases 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
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- DNIOUOCUBMTIDC-UHFFFAOYSA-N phenyl(pyridin-4-yl)methanamine Chemical compound C=1C=NC=CC=1C(N)C1=CC=CC=C1 DNIOUOCUBMTIDC-UHFFFAOYSA-N 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- LEEZUCJXPOWXPB-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]-4-methoxyindole-2-carboxylic acid Chemical compound OC(=O)C1=CC=2C(OC)=CC=CC=2N1CC1=CC=CC(C#N)=C1 LEEZUCJXPOWXPB-UHFFFAOYSA-N 0.000 description 7
- VWGUDGOGNMZVSS-UHFFFAOYSA-N 1-[(3-cyanophenyl)methyl]-4-methylindole-2-carboxylic acid Chemical compound OC(=O)C1=CC=2C(C)=CC=CC=2N1CC1=CC=CC(C#N)=C1 VWGUDGOGNMZVSS-UHFFFAOYSA-N 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 101710163968 Antistasin Proteins 0.000 description 7
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 108010094028 Prothrombin Proteins 0.000 description 7
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- IWRRRCZSVINKHU-UHFFFAOYSA-N pyrazol-3-ylidenemethanone Chemical class O=C=C1C=CN=N1 IWRRRCZSVINKHU-UHFFFAOYSA-N 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
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- 150000003568 thioethers Chemical class 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 108010065972 tick anticoagulant peptide Proteins 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
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- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
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Classifications
-
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97122901 | 1997-12-24 | ||
| EP97122901 | 1997-12-24 | ||
| PCT/EP1998/008030 WO1999033800A1 (en) | 1997-12-24 | 1998-12-10 | Indole derivatives as inhibitors or factor xa |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69829879D1 DE69829879D1 (de) | 2005-05-25 |
| DE69829879T2 true DE69829879T2 (de) | 2006-03-02 |
Family
ID=8227884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69829879T Expired - Lifetime DE69829879T2 (de) | 1997-12-24 | 1998-12-10 | Indolderivate als faktor xa inhibitoren |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US6337344B1 (https=) |
| EP (1) | EP1042287B1 (https=) |
| JP (1) | JP4589529B2 (https=) |
| KR (1) | KR100608472B1 (https=) |
| CN (1) | CN1220681C (https=) |
| AR (1) | AR018031A1 (https=) |
| AT (1) | ATE293599T1 (https=) |
| AU (1) | AU743881B2 (https=) |
| BR (1) | BR9814340B1 (https=) |
| CA (1) | CA2316172C (https=) |
| CZ (1) | CZ298827B6 (https=) |
| DE (1) | DE69829879T2 (https=) |
| DK (1) | DK1042287T3 (https=) |
| ES (1) | ES2241194T3 (https=) |
| HU (1) | HU227568B1 (https=) |
| ID (1) | ID27044A (https=) |
| IL (1) | IL136954A0 (https=) |
| MY (1) | MY120064A (https=) |
| NO (1) | NO316912B1 (https=) |
| NZ (1) | NZ505370A (https=) |
| PL (1) | PL195682B1 (https=) |
| PT (1) | PT1042287E (https=) |
| RU (1) | RU2225397C2 (https=) |
| SI (1) | SI1042287T1 (https=) |
| TR (1) | TR200001954T2 (https=) |
| TW (1) | TWI241294B (https=) |
| WO (1) | WO1999033800A1 (https=) |
| ZA (1) | ZA9811759B (https=) |
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| GB9716657D0 (en) | 1997-08-07 | 1997-10-15 | Zeneca Ltd | Chemical compounds |
| HU227568B1 (en) * | 1997-12-24 | 2011-08-29 | Sanofi Aventis Deutschland | Indole derivatives, as inhibitors os factor xa |
| GB9803226D0 (en) | 1998-02-17 | 1998-04-08 | Zeneca Ltd | Chemical compounds |
| DE19917504A1 (de) * | 1999-04-17 | 2000-10-19 | Dresden Arzneimittel | Verwendung von Hydroxyindolen, die Inhibitoren der Phosphodiesterase 4 sind, zur Therapie chronisch obstruktiver Lungenerkrankungen |
| KR20010101355A (ko) | 1999-01-02 | 2001-11-14 | 로버트 흐라이탁, 미쉘 베스트 | 신규한 말론산 유도체, 이의 제조 방법, 이의 용도 및이를 함유하는 약제학적 조성물(인자 ｘａ 활성 억제) |
| JP2002534408A (ja) | 1999-01-02 | 2002-10-15 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | アリールアルカノイル誘導体、その調製のための方法、その使用およびそれらを含有する医薬組成物 |
| GB9902459D0 (en) * | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902455D0 (en) * | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902461D0 (en) * | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902453D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902452D0 (en) * | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| CO5370679A1 (es) * | 1999-06-01 | 2004-02-27 | Smithkline Beecham Corp | Inhibidores fab 1 |
| EP1095933A1 (en) | 1999-10-30 | 2001-05-02 | Aventis Pharma Deutschland GmbH | Novel N-guanidinoalkylamides, their preparation, their use, and pharmaceutical preparations comprising them |
| GB0000625D0 (en) | 2000-01-13 | 2000-03-01 | Zeneca Ltd | Chemical compounds |
| EP1127884A1 (en) | 2000-02-26 | 2001-08-29 | Aventis Pharma Deutschland GmbH | Novel malonic acid derivatives, processes for their preparation, their use as inhibitor of factor XA activity and pharmaceutical compositions containing them |
| GB0005366D0 (en) * | 2000-03-06 | 2000-04-26 | Xenova Ltd | Pharmaceutical compounds |
| US6548517B2 (en) | 2000-03-24 | 2003-04-15 | Millennium Pharmaceuticals, Inc. | Oxindole inhibitors of factor Xa |
| AU2001271531A1 (en) | 2000-06-27 | 2002-01-08 | Smith Kline Beecham Corporation | Fatty acid synthase inhibitors |
| WO2002026712A2 (en) * | 2000-09-29 | 2002-04-04 | Millennium Pharmaceuticals, Inc. | Quaternary amines and related inhibitors of factor xa |
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| DK1761519T3 (da) * | 2004-06-21 | 2008-07-21 | Hoffmann La Roche | Indolderivater som histaminreceptorantagonister |
| JP2008512364A (ja) * | 2004-09-06 | 2008-04-24 | エフ．ホフマン−ラ ロシュ アーゲー | ４−アミノメチルベンズアミジン誘導体及び第ＶＩＩａ因子阻害剤としてのその使用 |
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| GB0428173D0 (en) * | 2004-12-23 | 2005-01-26 | Astrazeneca Ab | Compounds |
| FR2880625B1 (fr) * | 2005-01-07 | 2007-03-09 | Sanofi Aventis Sa | Derives de n-(heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique |
| JP2008527028A (ja) * | 2005-01-19 | 2008-07-24 | バイオリポックス エービー | 炎症の治療に有用なインドール類 |
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| BRPI0519774A2 (pt) * | 2005-01-19 | 2009-02-10 | Biolipox Ab | composto ou um sal farmaceuticamente aceitÁvel do mesmo, formulaÇço farmacÊutica, uso de um composto ou um sal farmaceuticamente aceitÁvel do mesmo, mÉtodo de tratamento de uma doenÇa em que inibiÇço da atividade de um membro da famÍlia mapeg É desejada e/ou necessÁria, produto combinado, e, processo para a preparaÇço de um composto |
| JP2008527030A (ja) * | 2005-01-19 | 2008-07-24 | バイオリポックス エービー | 炎症の治療に有用なインドール類 |
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| HU227568B1 (en) * | 1997-12-24 | 2011-08-29 | Sanofi Aventis Deutschland | Indole derivatives, as inhibitors os factor xa |
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