CA2563401C - Imidazole derivatives used as tafia inhibitors - Google Patents
Imidazole derivatives used as tafia inhibitors Download PDFInfo
- Publication number
- CA2563401C CA2563401C CA2563401A CA2563401A CA2563401C CA 2563401 C CA2563401 C CA 2563401C CA 2563401 A CA2563401 A CA 2563401A CA 2563401 A CA2563401 A CA 2563401A CA 2563401 C CA2563401 C CA 2563401C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- twice
- unsubstituted
- imidazol
- aminopyridin
- 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 - Fee Related
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 18
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title description 2
- 150000002460 imidazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 175
- -1 aminopyridyl Chemical group 0.000 claims description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 30
- 125000004076 pyridyl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- IQZKZQSOVLMDRA-UHFFFAOYSA-N 3-(6-aminopyridin-3-yl)-2-(1-cyclopentylimidazol-4-yl)propanoic acid Chemical compound C1=NC(N)=CC=C1CC(C(O)=O)C1=CN(C2CCCC2)C=N1 IQZKZQSOVLMDRA-UHFFFAOYSA-N 0.000 claims description 4
- UMNZFTZTLPYOTD-UHFFFAOYSA-N ethyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C=1N(C2CCCCC2)C=NC=1C(C(=O)OCC)CC1=CC=C(N)N=C1 UMNZFTZTLPYOTD-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- WJBQXBVLVFMKCZ-UHFFFAOYSA-N 2-hydroxyethyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C1=NC(N)=CC=C1CC(C(=O)OCCO)C1=CN(C2CCCCC2)C=N1 WJBQXBVLVFMKCZ-UHFFFAOYSA-N 0.000 claims description 3
- XHKJBNCTUYFLDC-UHFFFAOYSA-N 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoic acid Chemical compound C1=NC(N)=CC=C1CC(C(O)=O)C1=CN(C2CCCCC2)C=N1 XHKJBNCTUYFLDC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- IRLIYIPUIDRSIO-UHFFFAOYSA-N methyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C=1N(C2CCCCC2)C=NC=1C(C(=O)OC)CC1=CC=C(N)N=C1 IRLIYIPUIDRSIO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- CRPVPLLSDAUWRU-UHFFFAOYSA-N 1-cyclohexyloxycarbonyloxyethyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C=1C=C(N)N=CC=1CC(C=1N=CN(C=1)C1CCCCC1)C(=O)OC(C)OC(=O)OC1CCCCC1 CRPVPLLSDAUWRU-UHFFFAOYSA-N 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- MUHISURTDGVAGF-UHFFFAOYSA-N cyclopropylmethyl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C1=NC(N)=CC=C1CC(C=1N=CN(C=1)C1CCCCC1)C(=O)OCC1CC1 MUHISURTDGVAGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- WIQPBDWLVQXSNI-UHFFFAOYSA-N propan-2-yl 3-(6-aminopyridin-3-yl)-2-(1-cyclohexylimidazol-4-yl)propanoate Chemical compound C=1N(C2CCCCC2)C=NC=1C(C(=O)OC(C)C)CC1=CC=C(N)N=C1 WIQPBDWLVQXSNI-UHFFFAOYSA-N 0.000 claims description 2
- WEGXHKRQVOAGFJ-UHFFFAOYSA-N 3-(6-aminopyridin-3-yl)-2-[1-(4,4-dimethylcyclohexyl)imidazol-4-yl]propanoic acid Chemical compound C1CC(C)(C)CCC1N1C=C(C(CC=2C=NC(N)=CC=2)C(O)=O)N=C1 WEGXHKRQVOAGFJ-UHFFFAOYSA-N 0.000 claims 1
- 108090000201 Carboxypeptidase B2 Proteins 0.000 abstract description 11
- 208000007536 Thrombosis Diseases 0.000 abstract description 10
- 238000011282 treatment Methods 0.000 abstract description 7
- 102000003847 Carboxypeptidase B2 Human genes 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 208000005189 Embolism Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 230000003176 fibrotic effect Effects 0.000 abstract description 4
- 201000005665 thrombophilia Diseases 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 104
- 238000000034 method Methods 0.000 description 102
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 71
- 125000000217 alkyl group Chemical group 0.000 description 63
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- 150000003254 radicals Chemical class 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 125000003118 aryl group Chemical group 0.000 description 37
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- 239000012071 phase Substances 0.000 description 28
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 24
- 239000007832 Na2SO4 Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 230000008569 process Effects 0.000 description 23
- 235000019260 propionic acid Nutrition 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 238000000746 purification Methods 0.000 description 17
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000006413 ring segment Chemical group 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 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 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- RFEBDZANCVHDLP-UHFFFAOYSA-N 3-[(4-cyanophenyl)methylamino]-6-(trifluoromethyl)quinoxaline-2-carboxylic acid Chemical compound OC(=O)C1=NC2=CC=C(C(F)(F)F)C=C2N=C1NCC1=CC=C(C#N)C=C1 RFEBDZANCVHDLP-UHFFFAOYSA-N 0.000 description 8
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 150000001537 azepanes Chemical class 0.000 description 6
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 6
- 150000004051 azocanes Chemical class 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 4
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 4
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 4
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 4
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 4
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 4
- MSRJJSCOWHWGGX-UHFFFAOYSA-N 2h-1,3-diazepine Chemical compound C1N=CC=CC=N1 MSRJJSCOWHWGGX-UHFFFAOYSA-N 0.000 description 4
- GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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- 102000009123 Fibrin Human genes 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 4
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
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- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- PPSZHCXTGRHULJ-UHFFFAOYSA-N dioxazine Chemical compound O1ON=CC=C1 PPSZHCXTGRHULJ-UHFFFAOYSA-N 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 4
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 4
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- MIKDAPXBFKPUPI-UHFFFAOYSA-N ethyl 3-(6-aminopyridin-3-yl)-2-(1-but-2-ynylimidazol-4-yl)propanoate Chemical compound C=1N(CC#CC)C=NC=1C(C(=O)OCC)CC1=CC=C(N)N=C1 MIKDAPXBFKPUPI-UHFFFAOYSA-N 0.000 description 1
- XUHQQQWQROOXCV-UHFFFAOYSA-N ethyl 3-(6-aminopyridin-3-yl)-2-[1-[2-(benzhydrylamino)-2-oxoethyl]imidazol-4-yl]propanoate Chemical compound C=1N(CC(=O)NC(C=2C=CC=CC=2)C=2C=CC=CC=2)C=NC=1C(C(=O)OCC)CC1=CC=C(N)N=C1 XUHQQQWQROOXCV-UHFFFAOYSA-N 0.000 description 1
- XUNPOHHZCBFCDS-UHFFFAOYSA-N ethyl 3-(6-aminopyridin-3-yl)-2-[1-[[4-(1,2,4-triazol-1-yl)phenyl]methyl]imidazol-4-yl]propanoate Chemical compound C=1N(CC=2C=CC(=CC=2)N2N=CN=C2)C=NC=1C(C(=O)OCC)CC1=CC=C(N)N=C1 XUNPOHHZCBFCDS-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
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- MWHLCFYPFGFBQO-UHFFFAOYSA-N hydron;2-(1h-imidazol-5-yl)acetic acid;chloride Chemical compound Cl.OC(=O)CC1=CN=CN1 MWHLCFYPFGFBQO-UHFFFAOYSA-N 0.000 description 1
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
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- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102004020186A DE102004020186A1 (de) | 2004-04-22 | 2004-04-22 | Heterocyclylessigsäuren als Inhibitoren von TAFla |
| DE102004020186.2 | 2004-04-22 | ||
| PCT/EP2005/003630 WO2005105781A1 (de) | 2004-04-22 | 2005-04-07 | Imidazol-derivate als tafia-inhibitoren |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2563401A1 CA2563401A1 (en) | 2005-11-10 |
| CA2563401C true CA2563401C (en) | 2012-08-07 |
Family
ID=34964308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2563401A Expired - Fee Related CA2563401C (en) | 2004-04-22 | 2005-04-07 | Imidazole derivatives used as tafia inhibitors |
Country Status (34)
| Country | Link |
|---|---|
| EP (2) | EP1864979B1 (https=) |
| JP (1) | JP4939401B2 (https=) |
| KR (1) | KR101162047B1 (https=) |
| CN (1) | CN100572376C (https=) |
| AR (1) | AR053302A1 (https=) |
| AT (2) | ATE386737T1 (https=) |
| AU (1) | AU2005238144B2 (https=) |
| BR (1) | BRPI0510159A (https=) |
| CA (1) | CA2563401C (https=) |
| CR (1) | CR8650A (https=) |
| CY (1) | CY1108087T1 (https=) |
| DE (2) | DE102004020186A1 (https=) |
| DK (1) | DK1740569T3 (https=) |
| EC (1) | ECSP066941A (https=) |
| ES (1) | ES2299026T3 (https=) |
| HR (1) | HRP20080099T3 (https=) |
| IL (1) | IL178672A (https=) |
| MA (1) | MA28543B1 (https=) |
| MY (1) | MY140903A (https=) |
| NI (1) | NI200600217A (https=) |
| NO (1) | NO20065320L (https=) |
| NZ (1) | NZ550757A (https=) |
| PE (1) | PE20060172A1 (https=) |
| PL (1) | PL1740569T3 (https=) |
| PT (1) | PT1740569E (https=) |
| RS (1) | RS50553B (https=) |
| RU (1) | RU2375356C2 (https=) |
| SI (1) | SI1740569T1 (https=) |
| TN (1) | TNSN06341A1 (https=) |
| TW (1) | TWI359016B (https=) |
| UA (1) | UA87306C2 (https=) |
| UY (1) | UY28868A1 (https=) |
| WO (1) | WO2005105781A1 (https=) |
| ZA (1) | ZA200607668B (https=) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2009005516A (es) * | 2006-12-06 | 2009-06-04 | Sanofi Aventis | Derivados de urea y de sulfamida en calidad de inhibidores de tafia. |
| US7638541B2 (en) | 2006-12-28 | 2009-12-29 | Metabolex Inc. | 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine |
| WO2008100459A1 (en) * | 2007-02-13 | 2008-08-21 | Schering Corporation | Derivatives and analogs of chroman as functionally selective alpha2c adrenoreceptor agonists |
| AU2008279447A1 (en) * | 2007-07-19 | 2009-01-29 | Metabolex, Inc. | N-azacyclic substituted pyrrole, pyrazole, imidazole, triazole and tetrazole derivatives as agonists of the RUP3 or GPR119 receptor for the treatment of diabetes and metabolic disorders |
| WO2009103432A2 (en) * | 2008-02-21 | 2009-08-27 | Sanofi-Aventis | Covalently binding imaging probes |
| WO2009146802A1 (de) * | 2008-06-06 | 2009-12-10 | Sanofi-Aventis | Makrocyclische harnstoff- und sulfamidderivate als inhibitoren von tafia |
| WO2010050525A1 (ja) | 2008-10-29 | 2010-05-06 | 大正製薬株式会社 | ＴＡＦＩａ阻害活性を有する化合物 |
| RS52963B (sr) | 2009-05-15 | 2014-02-28 | Sanofi | Postupak za dobijanje jedinjenja koje je korisno kao inhibitor tafia |
| FR2947266B1 (fr) * | 2009-06-26 | 2011-06-17 | Servier Lab | Nouveaux derives d'acide 2-mercaptocyclopentanecarboxylique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| JP5909185B2 (ja) | 2009-10-01 | 2016-04-26 | シマベイ セラピューティクス， インコーポレーテッド | 置換テトラゾール−１−イルフェノキシメチルチアゾール−２−イルピペリジニルピリミジン塩 |
| BR112012023412A2 (pt) | 2010-03-18 | 2018-05-08 | Daiichi Sankyo Company, Limited | composto, drogra farmacêutica, inibidor de tafia, promotor de fibrinólise, droga preventiva ou terapêutica, composição farmacêutica, e, uso de um composto. |
| EP2548871B1 (en) * | 2010-03-18 | 2017-07-19 | Daiichi Sankyo Company, Limited | Cycloalkyl-substituted imidazole derivative |
| EP2638016B1 (en) * | 2010-11-11 | 2014-10-01 | Sanofi | Process for the preparation of 3-(6-amino-pyridin-3yl)-2-acrylic acid derivatives |
| EP2782575B1 (en) | 2011-11-25 | 2016-04-20 | Sanofi | Crystalline salts of r)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1h-imidazol-4-yl)-propionic acid |
| WO2013076179A1 (en) | 2011-11-25 | 2013-05-30 | Sanofi | Sodium salt of (r)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1h-imidazol-4-yl)-propionic acid |
| WO2013076177A1 (de) | 2011-11-25 | 2013-05-30 | Sanofi | Salz von (r)-3-(6-amino-pyridin-3-yl)-2-(1-cyclohexyl-1h-imidazol-4-yl)- propionsäureethylester |
| EP3184095A1 (en) | 2013-05-23 | 2017-06-28 | IP Gesellschaft für Management mbH | Administration units comprising polymorph 1 of 2-(2-methylamino-pyrimidin-4-yl]-1h-indole-5-carboxylic acid [(s)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide |
| KR20160018557A (ko) | 2013-06-10 | 2016-02-17 | 사노피 | TAFIa의 저해제로서의 마크로사이클릭 우레아 유도체, 이의 제법 및 의약품으로서의 이의 용도 |
| US20190117624A1 (en) | 2016-03-29 | 2019-04-25 | Daiichi Sankyo Company, Limited | Therapeutic agent for inflammatory bowel diseases |
| AU2017305392A1 (en) | 2016-08-03 | 2019-02-21 | Cymabay Therapeutics, Inc. | Oxymethylene aryl compounds for treating inflammatory gastrointestinal diseases or gastrointestinal conditions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2292262T3 (es) * | 1998-12-24 | 2008-03-01 | Astellas Pharma Inc. | Compuestos de imidazol y su uso medicinal. |
| WO2003013526A1 (en) * | 2001-08-08 | 2003-02-20 | Merck & Co. Inc. | Anticoagulant compounds |
| BR0307033A (pt) | 2002-01-22 | 2004-12-07 | Pfizer | ácidos 3-(imidazolil)-2-aminopropanóicos para o uso como inibidores tafi-a para o tratamento de doenças trombóticas |
-
2004
- 2004-04-22 DE DE102004020186A patent/DE102004020186A1/de not_active Withdrawn
-
2005
- 2005-04-06 PE PE2005000382A patent/PE20060172A1/es not_active Application Discontinuation
- 2005-04-07 DK DK05731221T patent/DK1740569T3/da active
- 2005-04-07 RU RU2006141246/04A patent/RU2375356C2/ru not_active IP Right Cessation
- 2005-04-07 DE DE502005002927T patent/DE502005002927D1/de not_active Expired - Lifetime
- 2005-04-07 PL PL05731221T patent/PL1740569T3/pl unknown
- 2005-04-07 NZ NZ550757A patent/NZ550757A/en not_active IP Right Cessation
- 2005-04-07 WO PCT/EP2005/003630 patent/WO2005105781A1/de not_active Ceased
- 2005-04-07 AU AU2005238144A patent/AU2005238144B2/en not_active Ceased
- 2005-04-07 SI SI200530185T patent/SI1740569T1/sl unknown
- 2005-04-07 ES ES05731221T patent/ES2299026T3/es not_active Expired - Lifetime
- 2005-04-07 RS RSP-2008/0107A patent/RS50553B/sr unknown
- 2005-04-07 HR HR20080099T patent/HRP20080099T3/xx unknown
- 2005-04-07 AT AT05731221T patent/ATE386737T1/de active
- 2005-04-07 BR BRPI0510159-0A patent/BRPI0510159A/pt not_active Application Discontinuation
- 2005-04-07 PT PT05731221T patent/PT1740569E/pt unknown
- 2005-04-07 CN CNB2005800115593A patent/CN100572376C/zh not_active Expired - Fee Related
- 2005-04-07 CA CA2563401A patent/CA2563401C/en not_active Expired - Fee Related
- 2005-04-07 EP EP07017340A patent/EP1864979B1/de not_active Expired - Lifetime
- 2005-04-07 EP EP05731221A patent/EP1740569B1/de not_active Expired - Lifetime
- 2005-04-07 AT AT07017340T patent/ATE523505T1/de active
- 2005-04-07 JP JP2007508756A patent/JP4939401B2/ja not_active Expired - Fee Related
- 2005-04-07 KR KR1020067021881A patent/KR101162047B1/ko not_active Expired - Fee Related
- 2005-04-20 AR ARP050101556A patent/AR053302A1/es not_active Application Discontinuation
- 2005-04-20 MY MYPI20051748A patent/MY140903A/en unknown
- 2005-04-20 TW TW094112493A patent/TWI359016B/zh not_active IP Right Cessation
- 2005-04-22 UY UY28868A patent/UY28868A1/es unknown
- 2005-07-04 UA UAA200612254A patent/UA87306C2/ru unknown
-
2006
- 2006-09-13 ZA ZA200607668A patent/ZA200607668B/en unknown
- 2006-09-20 NI NI200600217A patent/NI200600217A/es unknown
- 2006-09-22 CR CR8650A patent/CR8650A/es unknown
- 2006-10-17 IL IL178672A patent/IL178672A/en not_active IP Right Cessation
- 2006-10-19 MA MA29399A patent/MA28543B1/fr unknown
- 2006-10-20 EC EC2006006941A patent/ECSP066941A/es unknown
- 2006-10-20 TN TNP2006000341A patent/TNSN06341A1/en unknown
- 2006-11-20 NO NO20065320A patent/NO20065320L/no not_active Application Discontinuation
-
2008
- 2008-05-12 CY CY20081100491T patent/CY1108087T1/el unknown
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20190408 |