IL139406A - Heterocyclic derivatives inhibiting factor XA, pharmaceutical preparations containing them and their use as a drug in the treatment of diseases or conditions mediated by factor XA in warm-blooded animals - Google Patents
Heterocyclic derivatives inhibiting factor XA, pharmaceutical preparations containing them and their use as a drug in the treatment of diseases or conditions mediated by factor XA in warm-blooded animalsInfo
- Publication number
- IL139406A IL139406A IL13940699A IL13940699A IL139406A IL 139406 A IL139406 A IL 139406A IL 13940699 A IL13940699 A IL 13940699A IL 13940699 A IL13940699 A IL 13940699A IL 139406 A IL139406 A IL 139406A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- alkyl
- compound
- carboxy
- substituent
- Prior art date
Links
- 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 26
- 108010074860 Factor Xa Proteins 0.000 title claims description 23
- 239000003814 drug Substances 0.000 title claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 11
- 241001465754 Metazoa Species 0.000 title claims description 10
- 201000010099 disease Diseases 0.000 title claims description 7
- 230000001404 mediated effect Effects 0.000 title claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- -1 cyano, amino, hydroxy Chemical group 0.000 claims abstract description 147
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 125000001424 substituent group Chemical group 0.000 claims abstract description 41
- 125000005843 halogen group Chemical group 0.000 claims abstract description 22
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 17
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims abstract description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 6
- 239000005864 Sulphur Substances 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 4
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims abstract description 3
- 125000004429 atom Chemical group 0.000 claims abstract description 3
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 4
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000013160 medical therapy Methods 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- QUWXNGCXFLZUFK-UHFFFAOYSA-N [4-[(5-chloro-1h-indol-2-yl)sulfonyl]piperazin-1-yl]-(4-pyridin-4-ylphenyl)methanone Chemical compound C=1C2=CC(Cl)=CC=C2NC=1S(=O)(=O)N(CC1)CCN1C(=O)C(C=C1)=CC=C1C1=CC=NC=C1 QUWXNGCXFLZUFK-UHFFFAOYSA-N 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 6
- 125000005115 alkyl carbamoyl group Chemical group 0.000 abstract description 5
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 abstract 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 abstract 4
- 125000003302 alkenyloxy group Chemical group 0.000 abstract 3
- 125000005133 alkynyloxy group Chemical group 0.000 abstract 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 2
- 125000004414 alkyl thio group Chemical group 0.000 abstract 2
- 125000002947 alkylene group Chemical group 0.000 abstract 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 238000000034 method Methods 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000004949 mass spectrometry Methods 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 239000007858 starting material Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- 239000008280 blood Substances 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 6
- 230000002429 anti-coagulating effect Effects 0.000 description 6
- 230000002785 anti-thrombosis Effects 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- DZLGZIGLHCRIMF-UHFFFAOYSA-N 4-pyridin-4-ylbenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=NC=C1 DZLGZIGLHCRIMF-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 5
- 239000003146 anticoagulant agent Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 4
- 108010000499 Thromboplastin Proteins 0.000 description 4
- 102000002262 Thromboplastin Human genes 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010053567 Coagulopathies Diseases 0.000 description 3
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 3
- 108010049003 Fibrinogen Proteins 0.000 description 3
- 102000008946 Fibrinogen Human genes 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229940012952 fibrinogen Drugs 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- GJNUEXVAMWPNER-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-chloro-2-piperazin-1-ylsulfonylindole Chemical compound C=1C2=CC(Cl)=CC=C2N(S(=O)(=O)C=2C=CC=CC=2)C=1S(=O)(=O)N1CCNCC1 GJNUEXVAMWPNER-UHFFFAOYSA-N 0.000 description 2
- RAGCMVFLVAMVGB-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-chloroindole-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC2=CC(Cl)=CC=C2N1S(=O)(=O)C1=CC=CC=C1 RAGCMVFLVAMVGB-UHFFFAOYSA-N 0.000 description 2
- CBLNRPJMYRFUAL-UHFFFAOYSA-N 1-(benzenesulfonyl)-6-chloro-2-piperazin-1-ylsulfonylindole Chemical compound C12=CC(Cl)=CC=C2C=C(S(=O)(=O)N2CCNCC2)N1S(=O)(=O)C1=CC=CC=C1 CBLNRPJMYRFUAL-UHFFFAOYSA-N 0.000 description 2
- LXSUDBCGRSVSOS-UHFFFAOYSA-N 1-(benzenesulfonyl)-6-chloroindole-2-sulfonyl chloride Chemical compound C12=CC(Cl)=CC=C2C=C(S(Cl)(=O)=O)N1S(=O)(=O)C1=CC=CC=C1 LXSUDBCGRSVSOS-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- WVFHVTAOWAKGFT-UHFFFAOYSA-N 4-imidazol-1-ylbenzoic acid;hydrochloride Chemical compound Cl.C1=CC(C(=O)O)=CC=C1N1C=NC=C1 WVFHVTAOWAKGFT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010051508 Preconativ Proteins 0.000 description 2
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- 102100027378 Prothrombin Human genes 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
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- 125000001589 carboacyl group Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
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- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
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- 229960004592 isopropanol Drugs 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 238000004452 microanalysis Methods 0.000 description 2
- 230000014508 negative regulation of coagulation Effects 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940039716 prothrombin Drugs 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229960003766 thrombin (human) Drugs 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- VCQURUZYYSOUHP-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) 2,2,2-trifluoroacetate Chemical compound FC1=C(F)C(F)=C(OC(=O)C(F)(F)F)C(F)=C1F VCQURUZYYSOUHP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
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- 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
- C07D403/12—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 chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9809351.1A GB9809351D0 (en) | 1998-05-02 | 1998-05-02 | Heterocyclic derivatives |
| GBGB9903337.5A GB9903337D0 (en) | 1999-02-16 | 1999-02-16 | Heterocyclic derivatives |
| PCT/GB1999/001308 WO1999057113A1 (en) | 1998-05-02 | 1999-04-27 | Heterocyclic derivatives which inhibit factor xa |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL139406A0 IL139406A0 (en) | 2001-11-25 |
| IL139406A true IL139406A (en) | 2004-07-25 |
Family
ID=26313572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13940699A IL139406A (en) | 1998-05-02 | 1999-04-27 | Heterocyclic derivatives inhibiting factor XA, pharmaceutical preparations containing them and their use as a drug in the treatment of diseases or conditions mediated by factor XA in warm-blooded animals |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US6753331B1 (pt) |
| EP (2) | EP1528061A1 (pt) |
| JP (1) | JP2002513790A (pt) |
| KR (1) | KR20010043246A (pt) |
| CN (1) | CN1133634C (pt) |
| AT (1) | ATE282610T1 (pt) |
| AU (1) | AU754453B2 (pt) |
| BR (1) | BR9910179A (pt) |
| CA (1) | CA2331042A1 (pt) |
| DE (1) | DE69921994T2 (pt) |
| EE (1) | EE200000527A (pt) |
| ES (1) | ES2232131T3 (pt) |
| HK (1) | HK1034711A1 (pt) |
| HU (1) | HUP0101712A3 (pt) |
| IL (1) | IL139406A (pt) |
| NO (1) | NO320893B1 (pt) |
| NZ (1) | NZ507835A (pt) |
| PL (1) | PL343706A1 (pt) |
| PT (1) | PT1082321E (pt) |
| SI (1) | SI1082321T1 (pt) |
| SK (1) | SK16512000A3 (pt) |
| TR (1) | TR200003200T2 (pt) |
| WO (1) | WO1999057113A1 (pt) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL115420A0 (en) | 1994-09-26 | 1995-12-31 | Zeneca Ltd | Aminoheterocyclic derivatives |
| GB9902989D0 (en) * | 1999-02-11 | 1999-03-31 | Zeneca Ltd | Heterocyclic derivatives |
| GB9914342D0 (en) * | 1999-06-19 | 1999-08-18 | Zeneca Ltd | Compound |
| GB9917344D0 (en) * | 1999-07-24 | 1999-09-22 | Zeneca Ltd | Novel salt |
| TWI288745B (en) | 2000-04-05 | 2007-10-21 | Daiichi Seiyaku Co | Ethylenediamine derivatives |
| GB0012448D0 (en) | 2000-05-24 | 2000-07-12 | Astrazeneca Ab | New process |
| WO2002038184A1 (en) * | 2000-11-09 | 2002-05-16 | Astrazeneca Ab | Oral pharmaceutical composition containing a block copolymer |
| GB0104752D0 (en) * | 2001-02-27 | 2001-04-18 | Astrazeneca Ab | Pharmaceutical compositions |
| WO2003000657A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
| US7479502B2 (en) | 2002-12-03 | 2009-01-20 | Pharmacyclics, Inc. | 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors |
| WO2004108671A1 (en) * | 2003-06-06 | 2004-12-16 | Suven Life Sciences Limited | Substituted indoles with serotonin receptor affinity, process for their preparation and pharmaceutical compositions containing them |
| EP1650206A4 (en) * | 2003-08-01 | 2006-12-20 | Nippon Soda Co | PHENYLAZOLE COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND ANTIOXIDANTS |
| SE0400014D0 (sv) * | 2004-01-08 | 2004-01-08 | Astrazeneca Ab | Heterocyclic derivatives |
| CN101218227A (zh) * | 2005-07-08 | 2008-07-09 | 阿斯利康(瑞典)有限公司 | 作为因子Xa的抑制剂的杂环磺酰胺衍生物 |
| WO2007008144A1 (en) * | 2005-07-08 | 2007-01-18 | Astrazeneca Ab | Heterocyclic sulfonamide derivatives as inhibitors of factor xa |
| WO2007008145A1 (en) * | 2005-07-08 | 2007-01-18 | Astrazeneca Ab | Heterocyclic sulfonamide derivatives as inhibitors of factor xa |
| WO2007008143A1 (en) * | 2005-07-08 | 2007-01-18 | Astrazeneca Ab | Heterocyclic sulfonamide derivatives as inhibitors of factor xa |
| PL3762368T3 (pl) | 2018-03-08 | 2022-06-06 | Incyte Corporation | ZWIĄZKI AMINOPIRAZYNODIOLOWE JAKO INHIBITORY PI3K-γ |
| WO2020010003A1 (en) | 2018-07-02 | 2020-01-09 | Incyte Corporation | AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS |
| US20220380478A1 (en) | 2019-07-01 | 2022-12-01 | Tonix Pharma Holdings Limited | Anti-cd154 antibodies and uses thereof |
| EP4274587A1 (en) | 2021-01-06 | 2023-11-15 | Tonix Pharma Limited | Methods of inducing immune tolerance with modified anti-cd154 antibodies |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL115420A0 (en) * | 1994-09-26 | 1995-12-31 | Zeneca Ltd | Aminoheterocyclic derivatives |
| JP2001502655A (ja) * | 1995-12-21 | 2001-02-27 | デュポン ファーマシューティカルズ カンパニー | Ｘａ因子阻害薬であるイソオキサゾリン、イソチアゾリンおよびピラゾリン |
| GB9602166D0 (en) * | 1996-02-02 | 1996-04-03 | Zeneca Ltd | Aminoheterocyclic derivatives |
| GB9602294D0 (en) * | 1996-02-05 | 1996-04-03 | Zeneca Ltd | Heterocyclic compounds |
| UA56197C2 (uk) * | 1996-11-08 | 2003-05-15 | Зенека Лімітед | Гетероциклічні похідні |
| EP0986551B1 (en) | 1997-05-30 | 2006-08-02 | Takeda Pharmaceutical Company Limited | Sulfonamide derivatives, their production and use |
| GB9715894D0 (en) * | 1997-07-29 | 1997-10-01 | Zeneca Ltd | Heterocyclic derivatives |
| DE19743435A1 (de) * | 1997-10-01 | 1999-04-08 | Merck Patent Gmbh | Benzamidinderivate |
-
1999
- 1999-04-27 JP JP2000547083A patent/JP2002513790A/ja active Pending
- 1999-04-27 EP EP04022155A patent/EP1528061A1/en not_active Withdrawn
- 1999-04-27 DE DE69921994T patent/DE69921994T2/de not_active Expired - Lifetime
- 1999-04-27 EP EP99918178A patent/EP1082321B1/en not_active Expired - Lifetime
- 1999-04-27 WO PCT/GB1999/001308 patent/WO1999057113A1/en not_active Application Discontinuation
- 1999-04-27 CN CNB99808218XA patent/CN1133634C/zh not_active Expired - Fee Related
- 1999-04-27 TR TR2000/03200T patent/TR200003200T2/xx unknown
- 1999-04-27 SK SK1651-2000A patent/SK16512000A3/sk unknown
- 1999-04-27 US US09/674,559 patent/US6753331B1/en not_active Expired - Fee Related
- 1999-04-27 PL PL99343706A patent/PL343706A1/xx not_active Application Discontinuation
- 1999-04-27 EE EEP200000527A patent/EE200000527A/xx unknown
- 1999-04-27 IL IL13940699A patent/IL139406A/en not_active IP Right Cessation
- 1999-04-27 BR BR9910179-3A patent/BR9910179A/pt not_active Application Discontinuation
- 1999-04-27 KR KR1020007012193A patent/KR20010043246A/ko not_active Application Discontinuation
- 1999-04-27 ES ES99918178T patent/ES2232131T3/es not_active Expired - Lifetime
- 1999-04-27 HU HU0101712A patent/HUP0101712A3/hu unknown
- 1999-04-27 NZ NZ507835A patent/NZ507835A/xx unknown
- 1999-04-27 SI SI9930725T patent/SI1082321T1/xx unknown
- 1999-04-27 AU AU36206/99A patent/AU754453B2/en not_active Ceased
- 1999-04-27 AT AT99918178T patent/ATE282610T1/de not_active IP Right Cessation
- 1999-04-27 PT PT99918178T patent/PT1082321E/pt unknown
- 1999-04-27 CA CA002331042A patent/CA2331042A1/en not_active Abandoned
-
2000
- 2000-11-01 NO NO20005497A patent/NO320893B1/no unknown
-
2001
- 2001-07-26 HK HK01105226A patent/HK1034711A1/xx not_active IP Right Cessation
-
2004
- 2004-04-06 US US10/817,960 patent/US20040266759A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| HK1034711A1 (en) | 2001-11-02 |
| US6753331B1 (en) | 2004-06-22 |
| AU3620699A (en) | 1999-11-23 |
| HUP0101712A3 (en) | 2003-01-28 |
| EP1082321A1 (en) | 2001-03-14 |
| NZ507835A (en) | 2003-01-31 |
| IL139406A0 (en) | 2001-11-25 |
| NO20005497L (no) | 2000-12-21 |
| EP1082321B1 (en) | 2004-11-17 |
| ATE282610T1 (de) | 2004-12-15 |
| PT1082321E (pt) | 2005-03-31 |
| CN1133634C (zh) | 2004-01-07 |
| HUP0101712A2 (hu) | 2001-11-28 |
| ES2232131T3 (es) | 2005-05-16 |
| EE200000527A (et) | 2002-02-15 |
| SK16512000A3 (sk) | 2001-05-10 |
| BR9910179A (pt) | 2001-01-09 |
| KR20010043246A (ko) | 2001-05-25 |
| CN1308631A (zh) | 2001-08-15 |
| AU754453B2 (en) | 2002-11-14 |
| PL343706A1 (en) | 2001-08-27 |
| DE69921994T2 (de) | 2005-12-01 |
| CA2331042A1 (en) | 1999-11-11 |
| NO20005497D0 (no) | 2000-11-01 |
| TR200003200T2 (tr) | 2001-02-21 |
| JP2002513790A (ja) | 2002-05-14 |
| SI1082321T1 (en) | 2005-06-30 |
| US20040266759A1 (en) | 2004-12-30 |
| DE69921994D1 (de) | 2004-12-23 |
| WO1999057113A1 (en) | 1999-11-11 |
| NO320893B1 (no) | 2006-02-06 |
| EP1528061A1 (en) | 2005-05-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| MM9K | Patent not in force due to non-payment of renewal fees |