AU2004238500B2 - Azaindole-derivatives as factor Xa inhibitors - Google Patents
Azaindole-derivatives as factor Xa inhibitors Download PDFInfo
- Publication number
- AU2004238500B2 AU2004238500B2 AU2004238500A AU2004238500A AU2004238500B2 AU 2004238500 B2 AU2004238500 B2 AU 2004238500B2 AU 2004238500 A AU2004238500 A AU 2004238500A AU 2004238500 A AU2004238500 A AU 2004238500A AU 2004238500 B2 AU2004238500 B2 AU 2004238500B2
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- pyridine
- unsubstituted
- pyrrolo
- formula
- 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
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- 229940123583 Factor Xa inhibitor Drugs 0.000 title description 2
- -1 -(C2-C 4 )-alkyl Chemical group 0.000 claims description 235
- 150000001875 compounds Chemical class 0.000 claims description 143
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 90
- 125000000623 heterocyclic group Chemical group 0.000 claims description 85
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 61
- 239000000203 mixture Substances 0.000 claims description 59
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 40
- 239000000460 chlorine Substances 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 125000004076 pyridyl group Chemical group 0.000 claims description 33
- 125000001544 thienyl group Chemical group 0.000 claims description 30
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 29
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 24
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 239000011737 fluorine Substances 0.000 claims description 22
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 20
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000000335 thiazolyl group Chemical group 0.000 claims description 19
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- ZRQQXFMGYSOKDF-UHFFFAOYSA-N 1-propan-2-ylpiperidin-4-amine Chemical compound CC(C)N1CCC(N)CC1 ZRQQXFMGYSOKDF-UHFFFAOYSA-N 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000000524 functional group Chemical group 0.000 claims description 14
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 14
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 12
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 239000002243 precursor Substances 0.000 claims description 9
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 5
- STPAJSBKCQJVQQ-UHFFFAOYSA-N 1,4-oxazepane;piperazine Chemical compound C1CNCCN1.C1CNCCOC1 STPAJSBKCQJVQQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- RUSUSNUQHGLRLN-UHFFFAOYSA-N 1-[(6-chloro-1-benzothiophen-2-yl)methyl]-5-(2-hydroxyethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrrolo[2,3-c]pyridine-2-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC2=CC(OCCO)=NC=C2N1CC1=CC2=CC=C(Cl)C=C2S1 RUSUSNUQHGLRLN-UHFFFAOYSA-N 0.000 claims description 3
- BGJDEGLGOREKMO-UHFFFAOYSA-N 1-[(6-chloro-1-benzothiophen-2-yl)methyl]-5-(2-methoxyethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrrolo[2,3-c]pyridine-2-carboxamide Chemical compound C=1C2=CC=C(Cl)C=C2SC=1CN1C=2C=NC(OCCOC)=CC=2C=C1C(=O)NC1CCN(C(C)C)CC1 BGJDEGLGOREKMO-UHFFFAOYSA-N 0.000 claims description 3
- COWWBSWHWVBSOT-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-hydroxyethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrrolo[2,3-c]pyridine-2-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC2=CC(OCCO)=NC=C2N1CC1=NOC(C=2SC(Cl)=CC=2)=C1 COWWBSWHWVBSOT-UHFFFAOYSA-N 0.000 claims description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- IFFHYPWKJWLMRH-UHFFFAOYSA-N methyl 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-2-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC2=CC(C(=O)OC)=CN=C2N1CC(=NO1)C=C1C1=CC=C(Cl)S1 IFFHYPWKJWLMRH-UHFFFAOYSA-N 0.000 claims description 3
- IRELEWXEFDQBIO-UHFFFAOYSA-N methyl 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-2-[(1-pyridin-4-ylpiperidin-4-yl)carbamoyl]pyrrolo[3,2-b]pyridine-5-carboxylate Chemical compound C1CN(C=2C=CN=CC=2)CCC1NC(=O)C1=CC2=NC(C(=O)OC)=CC=C2N1CC(=NO1)C=C1C1=CC=C(Cl)S1 IRELEWXEFDQBIO-UHFFFAOYSA-N 0.000 claims description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims 1
- PQFUKMHLKFDJKO-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-2-[(1-pyridin-4-ylpiperidin-4-yl)carbamoyl]pyrrolo[3,2-b]pyridine-5-carboxylic acid Chemical compound C1CN(C=2C=CN=CC=2)CCC1NC(=O)C1=CC2=NC(C(=O)O)=CC=C2N1CC(=NO1)C=C1C1=CC=C(Cl)S1 PQFUKMHLKFDJKO-UHFFFAOYSA-N 0.000 claims 1
- OZJLBVYQJXVQCZ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-methoxyethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrrolo[2,3-c]pyridine-2-carboxamide Chemical compound C1=C(C=2SC(Cl)=CC=2)ON=C1CN1C=2C=NC(OCCOC)=CC=2C=C1C(=O)NC1CCN(C(C)C)CC1 OZJLBVYQJXVQCZ-UHFFFAOYSA-N 0.000 claims 1
- CKIPRHGVOKOYCY-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-oxo-n-(1-propan-2-ylpiperidin-4-yl)-4h-pyrrolo[3,2-b]pyridine-2-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(N1CC2=NOC(=C2)C=2SC(Cl)=CC=2)=CC2=C1C=CC(=O)N2 CKIPRHGVOKOYCY-UHFFFAOYSA-N 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 239000000243 solution Substances 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 56
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 54
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 54
- 125000003118 aryl group Chemical group 0.000 description 50
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 41
- 239000000047 product Substances 0.000 description 41
- 239000002904 solvent Substances 0.000 description 41
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 35
- 108010074860 Factor Xa Proteins 0.000 description 35
- 229910052736 halogen Inorganic materials 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 33
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 description 33
- 230000015572 biosynthetic process Effects 0.000 description 32
- 150000002367 halogens Chemical class 0.000 description 32
- 125000004122 cyclic group Chemical group 0.000 description 31
- 230000002829 reductive effect Effects 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- 239000000651 prodrug Substances 0.000 description 29
- 229940002612 prodrug Drugs 0.000 description 29
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 28
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 24
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 23
- 125000004093 cyano group Chemical group *C#N 0.000 description 23
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 22
- 125000002950 monocyclic group Chemical group 0.000 description 22
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 21
- MSRJJSCOWHWGGX-UHFFFAOYSA-N 2h-1,3-diazepine Chemical compound C1N=CC=CC=N1 MSRJJSCOWHWGGX-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 description 21
- 230000005764 inhibitory process Effects 0.000 description 21
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 21
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 21
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 20
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 20
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 20
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 20
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 20
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 20
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 20
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 20
- 125000001309 chloro group Chemical group Cl* 0.000 description 20
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 20
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 20
- 150000003536 tetrazoles Chemical class 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- 125000002619 bicyclic group Chemical group 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 18
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 17
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 description 17
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 125000005842 heteroatom Chemical group 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 16
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 16
- 125000002883 imidazolyl group Chemical group 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- 125000003373 pyrazinyl group Chemical group 0.000 description 16
- 125000003226 pyrazolyl group Chemical group 0.000 description 16
- 125000002098 pyridazinyl group Chemical group 0.000 description 16
- 125000000714 pyrimidinyl group Chemical group 0.000 description 16
- 229910052717 sulfur Inorganic materials 0.000 description 16
- 239000011593 sulfur Substances 0.000 description 16
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 15
- GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 description 15
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 15
- PPSZHCXTGRHULJ-UHFFFAOYSA-N dioxazine Chemical compound O1ON=CC=C1 PPSZHCXTGRHULJ-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 15
- 125000002971 oxazolyl group Chemical group 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 15
- 125000000168 pyrrolyl group Chemical group 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 14
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 14
- BWCDLEQTELFBAW-UHFFFAOYSA-N 3h-dioxazole Chemical compound N1OOC=C1 BWCDLEQTELFBAW-UHFFFAOYSA-N 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 125000001786 isothiazolyl group Chemical group 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 14
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 13
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 13
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 12
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 12
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 12
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- 238000005809 transesterification reaction Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 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
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000007891 venous angioplasty Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03011304.7 | 2003-05-19 | ||
| EP03011304A EP1479680A1 (en) | 2003-05-19 | 2003-05-19 | Azaindole derivatives as Factor Xa inhibitors |
| PCT/EP2004/004754 WO2004101563A1 (en) | 2003-05-19 | 2004-05-05 | AZAINDOLE-DERIVATIVES AS FACTOR Xa INHIBITORS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2004238500A1 AU2004238500A1 (en) | 2004-11-25 |
| AU2004238500B2 true AU2004238500B2 (en) | 2010-07-22 |
Family
ID=33040951
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004238500A Expired - Fee Related AU2004238500B2 (en) | 2003-05-19 | 2004-05-05 | Azaindole-derivatives as factor Xa inhibitors |
Country Status (24)
| Country | Link |
|---|---|
| EP (2) | EP1479680A1 (https=) |
| JP (1) | JP4733642B2 (https=) |
| KR (1) | KR20060012636A (https=) |
| CN (1) | CN100347172C (https=) |
| AR (1) | AR045682A1 (https=) |
| AU (1) | AU2004238500B2 (https=) |
| BR (1) | BRPI0410429A (https=) |
| CA (1) | CA2526084A1 (https=) |
| CL (1) | CL2004001079A1 (https=) |
| CR (1) | CR8088A (https=) |
| EC (1) | ECSP056179A (https=) |
| MA (1) | MA27799A1 (https=) |
| MX (1) | MXPA05012156A (https=) |
| NO (1) | NO20055911L (https=) |
| NZ (1) | NZ543669A (https=) |
| OA (1) | OA13169A (https=) |
| PE (1) | PE20050554A1 (https=) |
| RS (1) | RS20050857A (https=) |
| RU (1) | RU2330853C2 (https=) |
| TN (1) | TNSN05296A1 (https=) |
| TW (1) | TW200510411A (https=) |
| UA (1) | UA86767C2 (https=) |
| WO (1) | WO2004101563A1 (https=) |
| ZA (1) | ZA200508150B (https=) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2351940T3 (es) * | 2005-11-18 | 2011-02-14 | F. Hoffmann-La Roche Ag | Derivados de azaindol-2-carboxamida. |
| US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
| IN2015DN01061A (https=) | 2012-08-17 | 2015-06-26 | Bayer Cropscience Ag | |
| US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
| CN111834531B (zh) * | 2019-04-15 | 2022-04-19 | 天津大学 | 一种有机半导体材料、制备方法及应用 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1241472B (it) | 1990-07-06 | 1994-01-17 | Olivier Linda | Dispositivo elettromeccanico per la cattura continua in particolare di topi e ratti. |
| US5788965A (en) | 1991-02-28 | 1998-08-04 | Novo Nordisk A/S | Modified factor VII |
| US5833982A (en) | 1991-02-28 | 1998-11-10 | Zymogenetics, Inc. | Modified factor VII |
| SI9520044B (sl) | 1994-04-26 | 2004-08-31 | Aventis Pharmaceuticals Inc. | Inhibitorji Xa faktorja |
| ZA964008B (en) * | 1995-06-02 | 1997-07-11 | Akzo Nobel Nv | Imidazo[1,5a]pyridine derived serine protease inhibitors |
| EP1040108B1 (en) * | 1997-12-19 | 2004-02-25 | Schering Aktiengesellschaft | Ortho-anthranilamide derivatives as anti-coagulants |
| HU227568B1 (en) * | 1997-12-24 | 2011-08-29 | Sanofi Aventis Deutschland | Indole derivatives, as inhibitors os factor xa |
| EP0987274A1 (en) | 1998-09-15 | 2000-03-22 | Hoechst Marion Roussel Deutschland GmbH | Factor VIIa Inhibitors |
| JP4241970B2 (ja) * | 1998-10-30 | 2009-03-18 | 中外製薬株式会社 | アミド結合を有するインドール誘導体、及びモノ又はジアザインドール誘導体 |
| US6632815B2 (en) * | 1999-09-17 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
| DE60040676D1 (de) * | 1999-09-17 | 2008-12-11 | Millennium Pharm Inc | BENZAMIDE UND ÄHNLICHE INHIBITOREN VON FAKTOR Xa |
| JP2001294572A (ja) * | 2000-02-09 | 2001-10-23 | Dai Ichi Seiyaku Co Ltd | 新規スルホニル誘導体 |
| US6436965B1 (en) * | 2000-03-02 | 2002-08-20 | Merck Frosst Canada & Co. | PDE IV inhibiting amides, compositions and methods of treatment |
| WO2002000651A2 (en) * | 2000-06-27 | 2002-01-03 | Bristol-Myers Squibb Pharma Company | Factor xa inhibitors |
| CA2440803A1 (en) * | 2001-03-07 | 2002-09-12 | Pfizer Products Inc. | Modulators of chemokine receptor activity |
| US6790845B2 (en) * | 2001-04-09 | 2004-09-14 | Bristol-Myers Squibb Pharma Company | Fused heterocyclic inhibitors of factor Xa |
| EP1314733A1 (en) * | 2001-11-22 | 2003-05-28 | Aventis Pharma Deutschland GmbH | Indole-2-carboxamides as factor Xa inhibitors |
| KR100960827B1 (ko) * | 2001-12-20 | 2010-06-08 | 오에스아이 파마슈티컬스, 인코포레이티드 | 피롤로피리미딘 Ａ₂ｂ 선택성 길항 화합물, 그의 합성방법 및 용도 |
| DE10214832A1 (de) * | 2002-04-04 | 2003-10-16 | Merck Patent Gmbh | Phenylderivate 4 |
| JP2004203791A (ja) * | 2002-12-25 | 2004-07-22 | Dai Ichi Seiyaku Co Ltd | 芳香族化合物 |
| JP2004210716A (ja) * | 2002-12-27 | 2004-07-29 | Dai Ichi Seiyaku Co Ltd | ジアミド誘導体 |
| US7135469B2 (en) * | 2003-03-18 | 2006-11-14 | Bristol Myers Squibb, Co. | Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors |
-
2003
- 2003-05-19 EP EP03011304A patent/EP1479680A1/en not_active Withdrawn
-
2004
- 2004-05-05 WO PCT/EP2004/004754 patent/WO2004101563A1/en not_active Ceased
- 2004-05-05 BR BRPI0410429-3A patent/BRPI0410429A/pt not_active IP Right Cessation
- 2004-05-05 AU AU2004238500A patent/AU2004238500B2/en not_active Expired - Fee Related
- 2004-05-05 CA CA002526084A patent/CA2526084A1/en not_active Abandoned
- 2004-05-05 EP EP04731161.8A patent/EP1636226B1/en not_active Expired - Lifetime
- 2004-05-05 RS YUP-2005/0857A patent/RS20050857A/sr unknown
- 2004-05-05 NZ NZ543669A patent/NZ543669A/en unknown
- 2004-05-05 JP JP2006529743A patent/JP4733642B2/ja not_active Expired - Fee Related
- 2004-05-05 MX MXPA05012156A patent/MXPA05012156A/es active IP Right Grant
- 2004-05-05 OA OA1200500323A patent/OA13169A/en unknown
- 2004-05-05 UA UAA200512133A patent/UA86767C2/ru unknown
- 2004-05-05 RU RU2005139557/04A patent/RU2330853C2/ru not_active IP Right Cessation
- 2004-05-05 KR KR1020057022131A patent/KR20060012636A/ko not_active Ceased
- 2004-05-05 CN CNB2004800139362A patent/CN100347172C/zh not_active Expired - Fee Related
- 2004-05-11 PE PE2004000481A patent/PE20050554A1/es not_active Application Discontinuation
- 2004-05-17 CL CL200401079A patent/CL2004001079A1/es unknown
- 2004-05-17 TW TW093113797A patent/TW200510411A/zh unknown
- 2004-05-17 AR ARP040101694A patent/AR045682A1/es unknown
-
2005
- 2005-10-10 ZA ZA200508150A patent/ZA200508150B/en unknown
- 2005-11-08 MA MA28588A patent/MA27799A1/fr unknown
- 2005-11-11 CR CR8088A patent/CR8088A/es not_active Application Discontinuation
- 2005-11-18 EC EC2005006179A patent/ECSP056179A/es unknown
- 2005-11-18 TN TNP2005000296A patent/TNSN05296A1/en unknown
- 2005-12-13 NO NO20055911A patent/NO20055911L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP4733642B2 (ja) | 2011-07-27 |
| OA13169A (en) | 2006-12-13 |
| JP2006528214A (ja) | 2006-12-14 |
| AU2004238500A1 (en) | 2004-11-25 |
| KR20060012636A (ko) | 2006-02-08 |
| EP1479680A1 (en) | 2004-11-24 |
| MXPA05012156A (es) | 2006-08-18 |
| MA27799A1 (fr) | 2006-03-01 |
| NO20055911L (no) | 2006-02-10 |
| TNSN05296A1 (en) | 2007-07-10 |
| ZA200508150B (en) | 2007-02-28 |
| HK1089175A1 (zh) | 2006-11-24 |
| RU2005139557A (ru) | 2007-06-27 |
| CA2526084A1 (en) | 2004-11-25 |
| CN100347172C (zh) | 2007-11-07 |
| BRPI0410429A (pt) | 2006-06-06 |
| CR8088A (es) | 2006-09-22 |
| CL2004001079A1 (es) | 2005-04-08 |
| UA86767C2 (ru) | 2009-05-25 |
| RS20050857A (sr) | 2007-11-15 |
| RU2330853C2 (ru) | 2008-08-10 |
| WO2004101563A1 (en) | 2004-11-25 |
| NZ543669A (en) | 2008-12-24 |
| EP1636226B1 (en) | 2014-10-15 |
| CN1791601A (zh) | 2006-06-21 |
| AR045682A1 (es) | 2005-11-09 |
| PE20050554A1 (es) | 2005-08-04 |
| ECSP056179A (es) | 2006-08-30 |
| EP1636226A1 (en) | 2006-03-22 |
| TW200510411A (en) | 2005-03-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK25 | Application lapsed reg. 22.2i(2) - failure to pay acceptance fee |