CA2342230A1 - 2-oxo-2h-quinoline derivatives - Google Patents
2-oxo-2h-quinoline derivatives Download PDFInfo
- Publication number
- CA2342230A1 CA2342230A1 CA002342230A CA2342230A CA2342230A1 CA 2342230 A1 CA2342230 A1 CA 2342230A1 CA 002342230 A CA002342230 A CA 002342230A CA 2342230 A CA2342230 A CA 2342230A CA 2342230 A1 CA2342230 A1 CA 2342230A1
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- oxo
- quinoline
- amidino
- 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.)
- Abandoned
Links
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 108010074860 Factor Xa Proteins 0.000 claims abstract description 13
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- -1 COOA Chemical group 0.000 claims description 83
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 15
- 239000004305 biphenyl Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 235000010290 biphenyl Nutrition 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 208000007536 Thrombosis Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 125000000565 sulfonamide group Chemical group 0.000 claims description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 5
- 206010022562 Intermittent claudication Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 238000002399 angioplasty Methods 0.000 claims description 5
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 150000004866 oxadiazoles Chemical class 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000003797 solvolysis reaction Methods 0.000 claims description 3
- GLCWMNBUQIWUNH-UHFFFAOYSA-N 3-[[6-(3-carbamimidoylphenoxy)-4-methyl-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound C12=CC=C(OC=3C=C(C=CC=3)C(N)=N)C=C2C(C)=CC(=O)N1CC1=CC=CC(C(N)=N)=C1 GLCWMNBUQIWUNH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims 1
- NGWIOCRFKUBPBG-UHFFFAOYSA-N 7-[[6-(3-carbamimidoylphenoxy)-4-methyl-2-oxoquinolin-1-yl]methyl]naphthalene-2-carboximidamide Chemical compound C1=C2C(C)=CC(=O)N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C2=CC=C1OC1=CC=CC(C(N)=N)=C1 NGWIOCRFKUBPBG-UHFFFAOYSA-N 0.000 claims 1
- 208000001435 Thromboembolism Diseases 0.000 abstract description 6
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000005984 hydrogenation reaction Methods 0.000 description 15
- 150000003254 radicals Chemical class 0.000 description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 239000007868 Raney catalyst Substances 0.000 description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 9
- 229910000564 Raney nickel Inorganic materials 0.000 description 9
- 108090000190 Thrombin Proteins 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229960004072 thrombin Drugs 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 238000010265 fast atom bombardment Methods 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 7
- 238000010931 ester hydrolysis Methods 0.000 description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N hydroxylamine hydrochloride Substances Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 7
- WCYJQVALWQMJGE-UHFFFAOYSA-M hydroxylammonium chloride Chemical compound [Cl-].O[NH3+] WCYJQVALWQMJGE-UHFFFAOYSA-M 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- CERZNQPNTHWEAD-UHFFFAOYSA-N 3-[3-(bromomethyl)phenyl]-5-methyl-1,2,4-oxadiazole Chemical compound O1C(C)=NC(C=2C=C(CBr)C=CC=2)=N1 CERZNQPNTHWEAD-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- STXAVEHFKAXGOX-UHFFFAOYSA-N 3-bromobenzonitrile Chemical compound BrC1=CC=CC(C#N)=C1 STXAVEHFKAXGOX-UHFFFAOYSA-N 0.000 description 5
- 108010054265 Factor VIIa Proteins 0.000 description 5
- 230000002785 anti-thrombosis Effects 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 108010048049 Factor IXa Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229940012414 factor viia Drugs 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 108010014173 Factor X Proteins 0.000 description 3
- 239000004280 Sodium formate Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001409 amidines Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000001735 carboxylic acids Chemical class 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
- 239000012153 distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- AQLYZDRHNHZHIS-UHFFFAOYSA-N quinoline-2,6-diol Chemical compound N1C(=O)C=CC2=CC(O)=CC=C21 AQLYZDRHNHZHIS-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 3
- 235000019254 sodium formate Nutrition 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- FWIROFMBWVMWLB-UHFFFAOYSA-N 1-bromo-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1 FWIROFMBWVMWLB-UHFFFAOYSA-N 0.000 description 2
- XFRBXZCBOYNMJP-UHFFFAOYSA-N 2,2,6-trimethyl-1,3-dioxin-4-one Chemical compound CC1=CC(=O)OC(C)(C)O1 XFRBXZCBOYNMJP-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical group COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- PRNMVFNRQVCJSP-UHFFFAOYSA-N 3-(3-nitrophenoxy)benzonitrile Chemical compound [O-][N+](=O)C1=CC=CC(OC=2C=C(C=CC=2)C#N)=C1 PRNMVFNRQVCJSP-UHFFFAOYSA-N 0.000 description 2
- DANOKUDOZKTSKV-UHFFFAOYSA-N 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl chloride Chemical compound O1C(C)=NC(C=2C=C(C=CC=2)C(Cl)=O)=N1 DANOKUDOZKTSKV-UHFFFAOYSA-N 0.000 description 2
- OLTGNKSLMVBVEQ-UHFFFAOYSA-N 3-[7-(bromomethyl)naphthalen-2-yl]-5-methyl-1,2,4-oxadiazole Chemical compound O1C(C)=NC(C=2C=C3C=C(CBr)C=CC3=CC=2)=N1 OLTGNKSLMVBVEQ-UHFFFAOYSA-N 0.000 description 2
- JERDUVBTEFKKFN-UHFFFAOYSA-N 3-[[6-(3-carbamimidoylphenoxy)-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(CN2C(C=CC3=CC(OC=4C=C(C=CC=4)C(N)=N)=CC=C32)=O)=C1 JERDUVBTEFKKFN-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- SGHBRHKBCLLVCI-UHFFFAOYSA-N 3-hydroxybenzonitrile Chemical compound OC1=CC=CC(C#N)=C1 SGHBRHKBCLLVCI-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- BQEXDUKMTVYBRK-UHFFFAOYSA-N 4-methyl-3-nitrophenol Chemical compound CC1=CC=C(O)C=C1[N+]([O-])=O BQEXDUKMTVYBRK-UHFFFAOYSA-N 0.000 description 2
- PIIZYNQECPTVEO-UHFFFAOYSA-N 4-nitro-m-cresol Chemical compound CC1=CC(O)=CC=C1[N+]([O-])=O PIIZYNQECPTVEO-UHFFFAOYSA-N 0.000 description 2
- DGWKXFQUTJHBMC-UHFFFAOYSA-N 6-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(COC=3C=C4C=CC(=O)N(CC=5C=C(C=CC=5)C=5N=C(C)ON=5)C4=CC=3)C=CC=2)=N1 DGWKXFQUTJHBMC-UHFFFAOYSA-N 0.000 description 2
- RSAWRLGKANTYHC-UHFFFAOYSA-N 6-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-1h-quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(COC=3C=C4C=CC(=O)NC4=CC=3)C=CC=2)=N1 RSAWRLGKANTYHC-UHFFFAOYSA-N 0.000 description 2
- DBSPUDKBNOZFMX-UHFFFAOYSA-N 7-hydroxyquinolin-2(1H)-one Chemical compound C1=CC(=O)NC2=CC(O)=CC=C21 DBSPUDKBNOZFMX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 2
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 238000010934 O-alkylation reaction Methods 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000002429 anti-coagulating effect Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 239000003114 blood coagulation factor Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 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 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000011146 sterile filtration Methods 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- HBOKLJQDSNMDNY-UHFFFAOYSA-N (2-oxo-1h-quinolin-6-yl) acetate Chemical compound N1C(=O)C=CC2=CC(OC(=O)C)=CC=C21 HBOKLJQDSNMDNY-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- JUSWZYFYLXTMLJ-JTQLQIEISA-N (2s)-1-(benzenesulfonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1S(=O)(=O)C1=CC=CC=C1 JUSWZYFYLXTMLJ-JTQLQIEISA-N 0.000 description 1
- RQYKQWFHJOBBAO-JTQLQIEISA-N (2s)-1-benzoylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)C1=CC=CC=C1 RQYKQWFHJOBBAO-JTQLQIEISA-N 0.000 description 1
- XDBHWPLGGBLUHH-UHFFFAOYSA-N (3-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C#N)=C1 XDBHWPLGGBLUHH-UHFFFAOYSA-N 0.000 description 1
- ZANBTPPDVPZODR-UHFFFAOYSA-N (3-methyl-4-nitrophenyl) acetate Chemical compound CC(=O)OC1=CC=C([N+]([O-])=O)C(C)=C1 ZANBTPPDVPZODR-UHFFFAOYSA-N 0.000 description 1
- LOJOZDZXVXMUTE-UHFFFAOYSA-N (4-methyl-3-nitrophenyl) acetate Chemical compound CC(=O)OC1=CC=C(C)C([N+]([O-])=O)=C1 LOJOZDZXVXMUTE-UHFFFAOYSA-N 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- GXMSDZNGYASWKF-UHFFFAOYSA-N 1-[(3-carbamimidoylphenyl)methyl]-2-oxo-6-phenylmethoxyquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(CN2C(C(C(O)=O)=CC3=CC(OCC=4C=CC=CC=4)=CC=C32)=O)=C1 GXMSDZNGYASWKF-UHFFFAOYSA-N 0.000 description 1
- FKRCKWYWZDUQOV-UHFFFAOYSA-N 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-2-oxo-6-phenylmethoxyquinoline-3-carboxylic acid Chemical compound C=1C2=CC(C(=N)N)=CC=C2C=CC=1CN(C(C(C(O)=O)=CC1=C2)=O)C1=CC=C2OCC1=CC=CC=C1 FKRCKWYWZDUQOV-UHFFFAOYSA-N 0.000 description 1
- BDUPEXVUYKVYRX-UHFFFAOYSA-N 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-6-(3-carbamimidoylphenoxy)-2-oxoquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(OC=2C=C3C=C(C(=O)N(CC=4C=C5C=C(C=CC5=CC=4)C(N)=N)C3=CC=2)C(O)=O)=C1 BDUPEXVUYKVYRX-UHFFFAOYSA-N 0.000 description 1
- IQPHTJYQHLFCRN-UHFFFAOYSA-N 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-6-(3-carbamimidoylphenoxy)-2-oxoquinoline-4-carboxylic acid Chemical compound NC(=N)C1=CC=CC(OC=2C=C3C(C(O)=O)=CC(=O)N(CC=4C=C5C=C(C=CC5=CC=4)C(N)=N)C3=CC=2)=C1 IQPHTJYQHLFCRN-UHFFFAOYSA-N 0.000 description 1
- RDOPLFRGQKVQDC-UHFFFAOYSA-N 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-6-[(3-carbamimidoylphenyl)methoxy]-2-oxoquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(COC=2C=C3C=C(C(=O)N(CC=4C=C5C=C(C=CC5=CC=4)C(N)=N)C3=CC=2)C(O)=O)=C1 RDOPLFRGQKVQDC-UHFFFAOYSA-N 0.000 description 1
- ASRKPCZZRVTEHY-UHFFFAOYSA-N 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-7-(3-carbamimidoylphenoxy)-2-oxoquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(OC=2C=C3N(CC=4C=C5C=C(C=CC5=CC=4)C(N)=N)C(=O)C(C(O)=O)=CC3=CC=2)=C1 ASRKPCZZRVTEHY-UHFFFAOYSA-N 0.000 description 1
- YGDTXKYCAOIPBF-UHFFFAOYSA-N 1-[[7-[(e)-n'-hydroxycarbamimidoyl]naphthalen-2-yl]methyl]-7-[3-[(e)-n'-hydroxycarbamimidoyl]phenoxy]-2-oxoquinoline-3-carboxylic acid Chemical compound O/N=C(/N)C1=CC=CC(OC=2C=C3N(CC=4C=C5C=C(C=CC5=CC=4)C(\N)=N/O)C(=O)C(C(O)=O)=CC3=CC=2)=C1 YGDTXKYCAOIPBF-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006219 1-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- UZYQSNQJLWTICD-UHFFFAOYSA-N 2-(n-benzoylanilino)-2,2-dinitroacetic acid Chemical compound C=1C=CC=CC=1N(C(C(=O)O)([N+]([O-])=O)[N+]([O-])=O)C(=O)C1=CC=CC=C1 UZYQSNQJLWTICD-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- QQHOQYUZXLYLDX-UHFFFAOYSA-N 2-[1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-7-(3-carbamimidoylphenoxy)-4-methyl-2-oxoquinolin-3-yl]acetic acid Chemical compound C=1C=C2C(C)=C(CC(O)=O)C(=O)N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C2=CC=1OC1=CC=CC(C(N)=N)=C1 QQHOQYUZXLYLDX-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- OUCGHPCPXCFQCS-UHFFFAOYSA-N 2-[7-(3-carbamimidoylphenoxy)-1-[(3-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-3-yl]acetamide Chemical compound C12=CC(OC=3C=C(C=CC=3)C(N)=N)=CC=C2C(C)=C(CC(N)=O)C(=O)N1CC1=CC=CC(C(N)=N)=C1 OUCGHPCPXCFQCS-UHFFFAOYSA-N 0.000 description 1
- YYXYSVBKNGODHV-UHFFFAOYSA-N 2-[7-(3-carbamimidoylphenoxy)-1-[(3-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-3-yl]acetic acid Chemical compound C12=CC(OC=3C=C(C=CC=3)C(N)=N)=CC=C2C(C)=C(CC(O)=O)C(=O)N1CC1=CC=CC(C(N)=N)=C1 YYXYSVBKNGODHV-UHFFFAOYSA-N 0.000 description 1
- MPWPINAAYNBHQO-UHFFFAOYSA-N 2-[7-(3-carbamimidoylphenoxy)-1-[(4-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-3-yl]acetamide Chemical compound C12=CC(OC=3C=C(C=CC=3)C(N)=N)=CC=C2C(C)=C(CC(N)=O)C(=O)N1CC1=CC=C(C(N)=N)C=C1 MPWPINAAYNBHQO-UHFFFAOYSA-N 0.000 description 1
- XXHUFZKXHZGLRU-UHFFFAOYSA-N 2-[7-(3-carbamimidoylphenoxy)-1-[(4-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-3-yl]acetic acid Chemical compound C12=CC(OC=3C=C(C=CC=3)C(N)=N)=CC=C2C(C)=C(CC(O)=O)C(=O)N1CC1=CC=C(C(N)=N)C=C1 XXHUFZKXHZGLRU-UHFFFAOYSA-N 0.000 description 1
- FUOINKPUNLXBBC-UHFFFAOYSA-N 2-amino-4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]benzaldehyde Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C(N)C(C=O)=CC=3)C=CC=2)=N1 FUOINKPUNLXBBC-UHFFFAOYSA-N 0.000 description 1
- RJDZUIZJGROKFB-UHFFFAOYSA-N 2-amino-4-[tert-butyl(dimethyl)silyl]oxybenzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C(C=O)C(N)=C1 RJDZUIZJGROKFB-UHFFFAOYSA-N 0.000 description 1
- QJKMVTUYBNPARL-UHFFFAOYSA-N 2-amino-5-phenylmethoxybenzaldehyde Chemical compound C1=C(C=O)C(N)=CC=C1OCC1=CC=CC=C1 QJKMVTUYBNPARL-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- LILVVZJBGYMAKS-UHFFFAOYSA-N 2-nitro-5-phenylmethoxybenzaldehyde Chemical compound C1=C(C=O)C([N+](=O)[O-])=CC=C1OCC1=CC=CC=C1 LILVVZJBGYMAKS-UHFFFAOYSA-N 0.000 description 1
- 125000004362 3,4,5-trichlorophenyl group Chemical group [H]C1=C(Cl)C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 1
- LYIBNRJWCHARHF-UHFFFAOYSA-N 3-(4-methyl-3-nitrophenoxy)benzonitrile Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1OC1=CC=CC(C#N)=C1 LYIBNRJWCHARHF-UHFFFAOYSA-N 0.000 description 1
- ICUJVTKZUNIFAB-UHFFFAOYSA-N 3-(4-nitrophenoxy)benzonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=CC(C#N)=C1 ICUJVTKZUNIFAB-UHFFFAOYSA-N 0.000 description 1
- DSYDIXQOVPFWJN-UHFFFAOYSA-N 3-[(2-oxo-1H-quinolin-6-yl)oxy]benzonitrile Chemical compound C(#N)C=1C=C(OC=2C=C3C=CC(NC3=CC=2)=O)C=CC=1 DSYDIXQOVPFWJN-UHFFFAOYSA-N 0.000 description 1
- PVIJBFQBUFKGQF-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylphenyl)methyl]-2-oxoquinolin-6-yl]oxybenzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1CN1C(=O)C=CC2=CC(OC=3C=C(C=CC=3)C(N)=N)=CC=C21 PVIJBFQBUFKGQF-UHFFFAOYSA-N 0.000 description 1
- LSUVTFBYUJLEMX-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylphenyl)methyl]-2-oxoquinolin-7-yl]oxybenzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1CN1C(=O)C=CC2=CC=C(OC=3C=C(C=CC=3)C(N)=N)C=C21 LSUVTFBYUJLEMX-UHFFFAOYSA-N 0.000 description 1
- FKNTYBNNTKOADM-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylphenyl)methyl]-3-ethyl-4-methyl-2-oxoquinolin-7-yl]oxybenzenecarboximidamide Chemical compound C1=C2N(CC=3C=CC(=CC=3)C(N)=N)C(=O)C(CC)=C(C)C2=CC=C1OC1=CC=CC(C(N)=N)=C1 FKNTYBNNTKOADM-UHFFFAOYSA-N 0.000 description 1
- AFYMFIMULTVDKA-UHFFFAOYSA-N 3-[1-[(4-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-6-yl]oxybenzenecarboximidamide Chemical compound C12=CC=C(OC=3C=C(C=CC=3)C(N)=N)C=C2C(C)=CC(=O)N1CC1=CC=C(C(N)=N)C=C1 AFYMFIMULTVDKA-UHFFFAOYSA-N 0.000 description 1
- QHYWTFHIYFMVAK-UHFFFAOYSA-N 3-[1-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-2-oxoquinolin-6-yl]oxybenzonitrile Chemical compound O1C(C)=NC(C=2C=CC(CN3C(C=CC4=CC(OC=5C=C(C=CC=5)C#N)=CC=C43)=O)=CC=2)=N1 QHYWTFHIYFMVAK-UHFFFAOYSA-N 0.000 description 1
- CPMJGJMFWDXRIO-UHFFFAOYSA-N 3-[1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-2-oxoquinolin-6-yl]oxybenzonitrile Chemical compound O1C(C)=NC(C=2C=C3C=C(CN4C(C=CC5=CC(OC=6C=C(C=CC=6)C#N)=CC=C54)=O)C=CC3=CC=2)=N1 CPMJGJMFWDXRIO-UHFFFAOYSA-N 0.000 description 1
- BMXSEDLZMUPKSH-UHFFFAOYSA-N 3-[4-(bromomethyl)phenyl]-5-methyl-1,2,4-oxadiazole Chemical compound O1C(C)=NC(C=2C=CC(CBr)=CC=2)=N1 BMXSEDLZMUPKSH-UHFFFAOYSA-N 0.000 description 1
- QYDTXRDZSNFSGU-UHFFFAOYSA-N 3-[6-(3-carbamimidoylphenoxy)-2-oxoquinolin-1-yl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(OC=2C=C3C=CC(=O)N(C=4C=C(C=CC=4)C(N)=N)C3=CC=2)=C1 QYDTXRDZSNFSGU-UHFFFAOYSA-N 0.000 description 1
- SKNPBXZZSZBPSD-UHFFFAOYSA-N 3-[6-(3-cyanophenoxy)-2-oxoquinolin-1-yl]benzonitrile Chemical compound C=1C=C2N(C=3C=C(C=CC=3)C#N)C(=O)C=CC2=CC=1OC1=CC=CC(C#N)=C1 SKNPBXZZSZBPSD-UHFFFAOYSA-N 0.000 description 1
- FNGJXGVNJSUYIM-UHFFFAOYSA-N 3-[6-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-2-oxoquinolin-1-yl]benzonitrile Chemical compound O1C(C)=NC(C=2C=C(COC=3C=C4C=CC(=O)N(C=5C=C(C=CC=5)C#N)C4=CC=3)C=CC=2)=N1 FNGJXGVNJSUYIM-UHFFFAOYSA-N 0.000 description 1
- PKZVVSLQFZRWIN-UHFFFAOYSA-N 3-[7-(3-carbamimidoylphenoxy)-2-oxoquinolin-1-yl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(OC=2C=C3N(C=4C=C(C=CC=4)C(N)=N)C(=O)C=CC3=CC=2)=C1 PKZVVSLQFZRWIN-UHFFFAOYSA-N 0.000 description 1
- ZGQGRPYHCXFMBH-UHFFFAOYSA-N 3-[[1-(3-carbamimidoylphenyl)-2-oxoquinolin-6-yl]oxymethyl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(COC=2C=C3C=CC(=O)N(C=4C=C(C=CC=4)C(N)=N)C3=CC=2)=C1 ZGQGRPYHCXFMBH-UHFFFAOYSA-N 0.000 description 1
- DTZFXKBBFPOZND-UHFFFAOYSA-N 3-[[1-(3-carbamimidoylphenyl)-2-oxoquinolin-7-yl]oxymethyl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(COC=2C=C3N(C=4C=C(C=CC=4)C(N)=N)C(=O)C=CC3=CC=2)=C1 DTZFXKBBFPOZND-UHFFFAOYSA-N 0.000 description 1
- CCJIYAAVHIKULX-UHFFFAOYSA-N 3-[[1-[(4-carbamimidoylphenyl)methyl]-2-oxoquinolin-6-yl]oxymethyl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1CN1C(=O)C=CC2=CC(OCC=3C=C(C=CC=3)C(N)=N)=CC=C21 CCJIYAAVHIKULX-UHFFFAOYSA-N 0.000 description 1
- GUQFARGAHKXFPK-UHFFFAOYSA-N 3-[[1-[(4-carbamimidoylphenyl)methyl]-2-oxoquinolin-7-yl]oxymethyl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1CN1C(=O)C=CC2=CC=C(OCC=3C=C(C=CC=3)C(N)=N)C=C21 GUQFARGAHKXFPK-UHFFFAOYSA-N 0.000 description 1
- RMVVDYJWOJJHBI-UHFFFAOYSA-N 3-[[6-[(3-carbamimidoylphenyl)methoxy]-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(COC=2C=C3C=CC(=O)N(CC=4C=C(C=CC=4)C(N)=N)C3=CC=2)=C1 RMVVDYJWOJJHBI-UHFFFAOYSA-N 0.000 description 1
- BDLDAWZFSQSEDB-UHFFFAOYSA-N 3-[[7-(3-carbamimidoylphenoxy)-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(CN2C(C=CC3=CC=C(OC=4C=C(C=CC=4)C(N)=N)C=C32)=O)=C1 BDLDAWZFSQSEDB-UHFFFAOYSA-N 0.000 description 1
- QQTKQLOCVMXQMM-UHFFFAOYSA-N 3-[[7-(3-carbamimidoylphenoxy)-3-ethyl-4-methyl-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound C1=C2N(CC=3C=C(C=CC=3)C(N)=N)C(=O)C(CC)=C(C)C2=CC=C1OC1=CC=CC(C(N)=N)=C1 QQTKQLOCVMXQMM-UHFFFAOYSA-N 0.000 description 1
- ALMXUQNHMOIDSC-UHFFFAOYSA-N 3-[[7-(3-carbamimidoylphenoxy)-4-methyl-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound C12=CC(OC=3C=C(C=CC=3)C(N)=N)=CC=C2C(C)=CC(=O)N1CC1=CC=CC(C(N)=N)=C1 ALMXUQNHMOIDSC-UHFFFAOYSA-N 0.000 description 1
- LLKLUTPIPLGLSW-UHFFFAOYSA-N 3-[[7-[(3-carbamimidoylphenyl)methoxy]-2-oxoquinolin-1-yl]methyl]benzenecarboximidamide Chemical compound NC(=N)C1=CC=CC(COC=2C=C3N(CC=4C=C(C=CC=4)C(N)=N)C(=O)C=CC3=CC=2)=C1 LLKLUTPIPLGLSW-UHFFFAOYSA-N 0.000 description 1
- NFYVSBBZWOIZDU-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxybenzonitrile Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(C#N)=C1 NFYVSBBZWOIZDU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- OVDAMAMRYHAQOB-UHFFFAOYSA-N 3-ethyl-4-methyl-1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]quinolin-2-one Chemical compound C1=C2N(CC=3C=C4C=C(C=CC4=CC=3)C=3N=C(C)ON=3)C(=O)C(CC)=C(C)C2=CC=C1OC(C=1)=CC=CC=1C1=NOC(C)=N1 OVDAMAMRYHAQOB-UHFFFAOYSA-N 0.000 description 1
- ZZZSLMFADGXEHR-UHFFFAOYSA-N 3-ethyl-4-methyl-7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound C1=C2N(CC=3C=C(C=CC=3)C=3N=C(C)ON=3)C(=O)C(CC)=C(C)C2=CC=C1OC(C=1)=CC=CC=1C1=NOC(C)=N1 ZZZSLMFADGXEHR-UHFFFAOYSA-N 0.000 description 1
- FRYZFQJJVUCDFY-UHFFFAOYSA-N 3-ethyl-4-methyl-7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1h-quinolin-2-one Chemical compound C1=C2NC(=O)C(CC)=C(C)C2=CC=C1OC(C=1)=CC=CC=1C1=NOC(C)=N1 FRYZFQJJVUCDFY-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- HFBSGJKKDGGAIX-UHFFFAOYSA-N 4-(dibromomethyl)-6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1h-quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C4C(C(Br)Br)=CC(=O)NC4=CC=3)C=CC=2)=N1 HFBSGJKKDGGAIX-UHFFFAOYSA-N 0.000 description 1
- ZBUHMWBLSYGWMX-UHFFFAOYSA-N 4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]aniline Chemical compound O1C(C)=NC(C=2C=C(OC=3C=CC(N)=CC=3)C=CC=2)=N1 ZBUHMWBLSYGWMX-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- PTVFUHTYJLKEDZ-UHFFFAOYSA-N 4-hydroxy-2-nitrobenzaldehyde Chemical compound OC1=CC=C(C=O)C([N+]([O-])=O)=C1 PTVFUHTYJLKEDZ-UHFFFAOYSA-N 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- KVHNYSIGANDRKA-UHFFFAOYSA-N 4-methyl-1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C4C(C)=CC(=O)N(CC=5C=C6C=C(C=CC6=CC=5)C=5N=C(C)ON=5)C4=CC=3)C=CC=2)=N1 KVHNYSIGANDRKA-UHFFFAOYSA-N 0.000 description 1
- BIUKXZDWKZGTJK-UHFFFAOYSA-N 4-methyl-1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C4N(CC=5C=C6C=C(C=CC6=CC=5)C=5N=C(C)ON=5)C(=O)C=C(C)C4=CC=3)C=CC=2)=N1 BIUKXZDWKZGTJK-UHFFFAOYSA-N 0.000 description 1
- YKZOEIXTNIWYSD-UHFFFAOYSA-N 4-methyl-6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1h-quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C4C(C)=CC(=O)NC4=CC=3)C=CC=2)=N1 YKZOEIXTNIWYSD-UHFFFAOYSA-N 0.000 description 1
- QCLYRWZWNVZQTM-UHFFFAOYSA-N 4-methyl-7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound Cc1nc(no1)-c1cccc(Cn2c3cc(Oc4cccc(c4)-c4noc(C)n4)ccc3c(C)cc2=O)c1 QCLYRWZWNVZQTM-UHFFFAOYSA-N 0.000 description 1
- SKNUTYIILSBRRO-UHFFFAOYSA-N 4-methyl-7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1h-quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C4NC(=O)C=C(C)C4=CC=3)C=CC=2)=N1 SKNUTYIILSBRRO-UHFFFAOYSA-N 0.000 description 1
- ZYILMIXAVLPPRF-UHFFFAOYSA-N 5-ethyl-2,2,6-trimethyl-1,3-dioxin-4-one Chemical compound CCC1=C(C)OC(C)(C)OC1=O ZYILMIXAVLPPRF-UHFFFAOYSA-N 0.000 description 1
- XLYPHUGUKGMURE-UHFFFAOYSA-N 5-hydroxy-2-nitrobenzaldehyde Chemical compound OC1=CC=C([N+]([O-])=O)C(C=O)=C1 XLYPHUGUKGMURE-UHFFFAOYSA-N 0.000 description 1
- KDEHRIZWKZILNT-UHFFFAOYSA-N 5-methyl-3-[3-(4-methyl-3-nitrophenoxy)phenyl]-1,2,4-oxadiazole Chemical compound O1C(C)=NC(C=2C=C(OC=3C=C(C(C)=CC=3)[N+]([O-])=O)C=CC=2)=N1 KDEHRIZWKZILNT-UHFFFAOYSA-N 0.000 description 1
- UZEQSRHAOUKWNG-UHFFFAOYSA-N 5-methyl-3-[3-(4-nitrophenoxy)phenyl]-1,2,4-oxadiazole Chemical compound O1C(C)=NC(C=2C=C(OC=3C=CC(=CC=3)[N+]([O-])=O)C=CC=2)=N1 UZEQSRHAOUKWNG-UHFFFAOYSA-N 0.000 description 1
- WBZYDYUZNFEQJR-UHFFFAOYSA-N 6-(3-carbamimidoylbenzoyl)oxy-1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-2-oxoquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(C(=O)OC=2C=C3C=C(C(=O)N(CC=4C=C5C=C(C=CC5=CC=4)C(N)=N)C3=CC=2)C(O)=O)=C1 WBZYDYUZNFEQJR-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- BDOIGZFLOINEMG-UHFFFAOYSA-N 6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-2-oxoquinoline-4-carboxylic acid Chemical compound O1C(C)=NC(C=2C=CC(CN3C(C=C(C4=CC(OC=5C=C(C=CC=5)C=5N=C(C)ON=5)=CC=C43)C(O)=O)=O)=CC=2)=N1 BDOIGZFLOINEMG-UHFFFAOYSA-N 0.000 description 1
- SMJVTQQHMCNIQG-UHFFFAOYSA-N 6-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-1-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=CC(CN3C(C=CC4=CC(OCC=5C=C(C=CC=5)C=5N=C(C)ON=5)=CC=C43)=O)=CC=2)=N1 SMJVTQQHMCNIQG-UHFFFAOYSA-N 0.000 description 1
- QGGBILVKQSMQEM-UHFFFAOYSA-N 6-hydroxy-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(CN3C(C=CC4=CC(O)=CC=C43)=O)C=CC=2)=N1 QGGBILVKQSMQEM-UHFFFAOYSA-N 0.000 description 1
- JXWUJANNOWHWLU-UHFFFAOYSA-N 7-(3-carbamimidoylphenoxy)-1-[(3-carbamimidoylphenyl)methyl]-2-oxoquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(CN2C(C(C(O)=O)=CC3=CC=C(OC=4C=C(C=CC=4)C(N)=N)C=C32)=O)=C1 JXWUJANNOWHWLU-UHFFFAOYSA-N 0.000 description 1
- MKDCIXJCKXFFKE-UHFFFAOYSA-N 7-(3-carbamimidoylphenoxy)-1-[(3-carbamimidoylphenyl)methyl]-2-oxoquinoline-4-carboxylic acid Chemical compound NC(=N)C1=CC=CC(CN2C(C=C(C3=CC=C(OC=4C=C(C=CC=4)C(N)=N)C=C32)C(O)=O)=O)=C1 MKDCIXJCKXFFKE-UHFFFAOYSA-N 0.000 description 1
- QUQJASLDBYJXSN-UHFFFAOYSA-N 7-(3-carbamimidoylphenoxy)-1-[[4-(2-carbamimidoylphenyl)phenyl]methyl]-2-oxoquinoline-3-carboxylic acid Chemical compound NC(=N)C1=CC=CC(OC=2C=C3N(CC=4C=CC(=CC=4)C=4C(=CC=CC=4)C(N)=N)C(=O)C(C(O)=O)=CC3=CC=2)=C1 QUQJASLDBYJXSN-UHFFFAOYSA-N 0.000 description 1
- NEHLPJYONMQKCH-UHFFFAOYSA-N 7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-2-oxoquinoline-4-carboxylic acid Chemical compound O1C(C)=NC(C=2C=C(CN3C(C=C(C4=CC=C(OC=5C=C(C=CC=5)C=5N=C(C)ON=5)C=C43)C(O)=O)=O)C=CC=2)=N1 NEHLPJYONMQKCH-UHFFFAOYSA-N 0.000 description 1
- IDQBMHXYHVHRQV-UHFFFAOYSA-N 7-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(COC=3C=C4N(CC=5C=C(C=CC=5)C=5N=C(C)ON=5)C(=O)C=CC4=CC=3)C=CC=2)=N1 IDQBMHXYHVHRQV-UHFFFAOYSA-N 0.000 description 1
- KFUASLRKDWDSRI-UHFFFAOYSA-N 7-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-1-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]quinolin-2-one Chemical compound O1C(C)=NC(C=2C=CC(CN3C(C=CC4=CC=C(OCC=5C=C(C=CC=5)C=5N=C(C)ON=5)C=C43)=O)=CC=2)=N1 KFUASLRKDWDSRI-UHFFFAOYSA-N 0.000 description 1
- GTUFBYYGZCFMKI-UHFFFAOYSA-N 7-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-1h-quinolin-2-one Chemical compound O1C(C)=NC(C=2C=C(COC=3C=C4NC(=O)C=CC4=CC=3)C=CC=2)=N1 GTUFBYYGZCFMKI-UHFFFAOYSA-N 0.000 description 1
- WOPRABODDPZIGG-UHFFFAOYSA-N 7-[[6-[(3-carbamimidoylphenyl)methoxy]-2-oxoquinolin-1-yl]methyl]naphthalene-2-carboximidamide Chemical compound NC(=N)C1=CC=CC(COC=2C=C3C=CC(=O)N(CC=4C=C5C=C(C=CC5=CC=4)C(N)=N)C3=CC=2)=C1 WOPRABODDPZIGG-UHFFFAOYSA-N 0.000 description 1
- XZDQEVZJLSACJT-UHFFFAOYSA-N 7-[[7-(3-carbamimidoylphenoxy)-3-ethyl-4-methyl-2-oxoquinolin-1-yl]methyl]naphthalene-2-carboximidamide Chemical compound C1=C2N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C(=O)C(CC)=C(C)C2=CC=C1OC1=CC=CC(C(N)=N)=C1 XZDQEVZJLSACJT-UHFFFAOYSA-N 0.000 description 1
- FVJNRIOLAFARNJ-UHFFFAOYSA-N 7-[[7-(3-carbamimidoylphenoxy)-4-methyl-2-oxoquinolin-1-yl]methyl]naphthalene-2-carboximidamide Chemical compound C=1C=C2C(C)=CC(=O)N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C2=CC=1OC1=CC=CC(C(N)=N)=C1 FVJNRIOLAFARNJ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- ZDZODEPZDLVCCG-UHFFFAOYSA-N C(N)(=N)C1=CC=C(CN2C(C(=CC3=CC=C(C=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)OCC)=O)C=C1 Chemical compound C(N)(=N)C1=CC=C(CN2C(C(=CC3=CC=C(C=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)OCC)=O)C=C1 ZDZODEPZDLVCCG-UHFFFAOYSA-N 0.000 description 1
- WFTBYSXTZWHWAI-UHFFFAOYSA-N C(N)(=N)C1=CC=C(CN2C(C=C(C3=CC(=CC=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)O)=O)C=C1 Chemical compound C(N)(=N)C1=CC=C(CN2C(C=C(C3=CC(=CC=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)O)=O)C=C1 WFTBYSXTZWHWAI-UHFFFAOYSA-N 0.000 description 1
- UPURINNGUGJJPA-UHFFFAOYSA-N C(N)(=N)C1=CC=C(CN2C(C=C(C3=CC=C(C=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)O)=O)C=C1 Chemical compound C(N)(=N)C1=CC=C(CN2C(C=C(C3=CC=C(C=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)O)=O)C=C1 UPURINNGUGJJPA-UHFFFAOYSA-N 0.000 description 1
- IMEFYKVBYNFLGN-UHFFFAOYSA-N C(N)(=N)C1=CC=C(CN2C(C=C(C3=CC=C(C=C23)OC2=CC(=CC=C2)C(N)=N)C)=O)C=C1 Chemical compound C(N)(=N)C1=CC=C(CN2C(C=C(C3=CC=C(C=C23)OC2=CC(=CC=C2)C(N)=N)C)=O)C=C1 IMEFYKVBYNFLGN-UHFFFAOYSA-N 0.000 description 1
- DDFGDPVPWHUQTO-UHFFFAOYSA-N C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C(=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C(N)=N)C)CC(=O)N)=O Chemical compound C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C(=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C(N)=N)C)CC(=O)N)=O DDFGDPVPWHUQTO-UHFFFAOYSA-N 0.000 description 1
- VWBDCOCNHDPUPS-UHFFFAOYSA-N C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C(=CC2=CC(=CC=C12)OC1=CC(=CC=C1)C(N)=N)C(=O)OC)=O Chemical compound C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C(=CC2=CC(=CC=C12)OC1=CC(=CC=C1)C(N)=N)C(=O)OC)=O VWBDCOCNHDPUPS-UHFFFAOYSA-N 0.000 description 1
- OOHJTNZXDNLNOZ-UHFFFAOYSA-N C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C(=CC2=CC(=CC=C12)OCC1=CC(=CC=C1)C(N)=N)C(=O)OC)=O Chemical compound C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C(=CC2=CC(=CC=C12)OCC1=CC(=CC=C1)C(N)=N)C(=O)OC)=O OOHJTNZXDNLNOZ-UHFFFAOYSA-N 0.000 description 1
- LFSRUEQBBPLHHN-UHFFFAOYSA-N C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C(N)=N)C(=O)O)=O Chemical compound C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C(N)=N)C(=O)O)=O LFSRUEQBBPLHHN-UHFFFAOYSA-N 0.000 description 1
- RYYGRQUGQKUFLU-UHFFFAOYSA-N C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC(=CC=C12)OC1=CC(=CC=C1)C(N)=N)=O Chemical compound C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC(=CC=C12)OC1=CC(=CC=C1)C(N)=N)=O RYYGRQUGQKUFLU-UHFFFAOYSA-N 0.000 description 1
- KXUOPVBEEXLSLA-UHFFFAOYSA-N C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC=C(C=C12)OCC1=CC(=CC=C1)C(N)=N)=O Chemical compound C(N)(=N)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC=C(C=C12)OCC1=CC(=CC=C1)C(N)=N)=O KXUOPVBEEXLSLA-UHFFFAOYSA-N 0.000 description 1
- WERAPVVNGQVNIM-UHFFFAOYSA-N C(N)(=N)C=1C=C(CN2C(C=C(C3=CC(=CC=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)O)=O)C=CC1 Chemical compound C(N)(=N)C=1C=C(CN2C(C=C(C3=CC(=CC=C23)OC2=CC(=CC=C2)C(N)=N)C(=O)O)=O)C=CC1 WERAPVVNGQVNIM-UHFFFAOYSA-N 0.000 description 1
- GFZRRGJFXUPIMY-UHFFFAOYSA-N CC1=NC(=NO1)C1=CC=C(CN2C(C=C(C3=CC(=CC=C23)OC2=CC(=CC=C2)C2=NOC(=N2)C)C)=O)C=C1.BrCC1=CC=C(C=C1)C1=NOC(=N1)C Chemical compound CC1=NC(=NO1)C1=CC=C(CN2C(C=C(C3=CC(=CC=C23)OC2=CC(=CC=C2)C2=NOC(=N2)C)C)=O)C=C1.BrCC1=CC=C(C=C1)C1=NOC(=N1)C GFZRRGJFXUPIMY-UHFFFAOYSA-N 0.000 description 1
- BJTQPICLRBRIFC-UHFFFAOYSA-N CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C1=NOC(=N1)C)C(=O)O)=O Chemical compound CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C1=NOC(=N1)C)C(=O)O)=O BJTQPICLRBRIFC-UHFFFAOYSA-N 0.000 description 1
- UOBOPMUVPPBUKT-UHFFFAOYSA-N CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C1=NOC(=N1)C)C(=O)OC)=O Chemical compound CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=C(C2=CC=C(C=C12)OC1=CC(=CC=C1)C1=NOC(=N1)C)C(=O)OC)=O UOBOPMUVPPBUKT-UHFFFAOYSA-N 0.000 description 1
- OBOXUPPMRGFJOU-UHFFFAOYSA-N CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC(=CC=C12)OCC1=CC(=CC=C1)C1=NOC(=N1)C)=O Chemical compound CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC(=CC=C12)OCC1=CC(=CC=C1)C1=NOC(=N1)C)=O OBOXUPPMRGFJOU-UHFFFAOYSA-N 0.000 description 1
- CAYMSTKJNDVUKG-UHFFFAOYSA-N CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC=C(C=C12)OCC1=CC(=CC=C1)C1=NOC(=N1)C)=O Chemical compound CC1=NC(=NO1)C1=CC=C2C=CC(=CC2=C1)CN1C(C=CC2=CC=C(C=C12)OCC1=CC(=CC=C1)C1=NOC(=N1)C)=O CAYMSTKJNDVUKG-UHFFFAOYSA-N 0.000 description 1
- WTAHNLNTZKUGKL-UHFFFAOYSA-N CC1=NC(=NO1)C=1C=C(CN2C(C=CC3=CC(=CC=C23)OC2=CC(=CC=C2)C#N)=O)C=CC1 Chemical compound CC1=NC(=NO1)C=1C=C(CN2C(C=CC3=CC(=CC=C23)OC2=CC(=CC=C2)C#N)=O)C=CC1 WTAHNLNTZKUGKL-UHFFFAOYSA-N 0.000 description 1
- ILHLAMHDWVDQBU-UHFFFAOYSA-N CC1=NC(=NO1)C=1C=C(CN2C(C=CC3=CC(=CC=C23)OC2=CC(=CC=C2)C2=NOC(=N2)C)=O)C=CC1 Chemical compound CC1=NC(=NO1)C=1C=C(CN2C(C=CC3=CC(=CC=C23)OC2=CC(=CC=C2)C2=NOC(=N2)C)=O)C=CC1 ILHLAMHDWVDQBU-UHFFFAOYSA-N 0.000 description 1
- QYSJLMMPNQEIIY-UHFFFAOYSA-N CC1=NC(=NO1)C=1C=C(OC2=CC=C3C(=CC(NC3=C2)=O)C(=O)OC)C=CC1 Chemical compound CC1=NC(=NO1)C=1C=C(OC2=CC=C3C(=CC(NC3=C2)=O)C(=O)OC)C=CC1 QYSJLMMPNQEIIY-UHFFFAOYSA-N 0.000 description 1
- BGCYBADHMUIIML-UHFFFAOYSA-N COC(=O)c1cc(=O)[nH]c2ccc(Oc3cccc(c3)-c3noc(C)n3)cc12 Chemical compound COC(=O)c1cc(=O)[nH]c2ccc(Oc3cccc(c3)-c3noc(C)n3)cc12 BGCYBADHMUIIML-UHFFFAOYSA-N 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- WRFGDVXYBXOOBW-UHFFFAOYSA-N O([Si](C)(C)C(C)(C)C)C1=CC(=C(C=C1)C=O)[N+](=O)[O-] Chemical compound O([Si](C)(C)C(C)(C)C)C1=CC(=C(C=C1)C=O)[N+](=O)[O-] WRFGDVXYBXOOBW-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- KVUASKRUUOTZQN-UHFFFAOYSA-N [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]boronic acid Chemical compound O1C(C)=NC(C=2C=C(C=CC=2)B(O)O)=N1 KVUASKRUUOTZQN-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- XETRDYSPPPDVAB-UHFFFAOYSA-N butan-1-ol;propan-1-ol Chemical compound CCCO.CCCCO XETRDYSPPPDVAB-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- HUXULLJDEXUMOP-UHFFFAOYSA-N carbamimidoyl fluoride Chemical compound NC(F)=N HUXULLJDEXUMOP-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- GLDJZEPVNOJOJY-UHFFFAOYSA-N disodium sulfide octahydrate Chemical compound O.O.O.O.O.O.O.O.[Na+].[Na+].[S-2] GLDJZEPVNOJOJY-UHFFFAOYSA-N 0.000 description 1
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- IAPKEAZIMVCGSS-UHFFFAOYSA-N ethyl 1,7-bis[(7-cyanonaphthalen-2-yl)methyl]-2-oxoquinoline-3-carboxylate Chemical compound C1=CC(C#N)=CC2=CC(CN3C4=CC(CC=5C=C6C=C(C=CC6=CC=5)C#N)=CC=C4C=C(C3=O)C(=O)OCC)=CC=C21 IAPKEAZIMVCGSS-UHFFFAOYSA-N 0.000 description 1
- MEFDJEYTBGLLFT-UHFFFAOYSA-N ethyl 1-[(3-carbamimidoylphenyl)methyl]-2-oxo-6-phenylmethoxyquinoline-3-carboxylate Chemical compound C=1C=C2N(CC=3C=C(C=CC=3)C(N)=N)C(=O)C(C(=O)OCC)=CC2=CC=1OCC1=CC=CC=C1 MEFDJEYTBGLLFT-UHFFFAOYSA-N 0.000 description 1
- KAPRLQCKVSIYNM-UHFFFAOYSA-N ethyl 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-2-oxo-6-phenylmethoxyquinoline-3-carboxylate Chemical compound C=1C=C2N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C(=O)C(C(=O)OCC)=CC2=CC=1OCC1=CC=CC=C1 KAPRLQCKVSIYNM-UHFFFAOYSA-N 0.000 description 1
- NFOFBVDBLLLPFO-UHFFFAOYSA-N ethyl 1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-7-(3-carbamimidoylphenoxy)-2-oxoquinoline-3-carboxylate Chemical compound C1=C2N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C(=O)C(C(=O)OCC)=CC2=CC=C1OC1=CC=CC(C(N)=N)=C1 NFOFBVDBLLLPFO-UHFFFAOYSA-N 0.000 description 1
- PQIOLJMPIIMXCZ-UHFFFAOYSA-N ethyl 2-oxo-6-phenylmethoxy-1h-quinoline-3-carboxylate Chemical compound C=1C=C2NC(=O)C(C(=O)OCC)=CC2=CC=1OCC1=CC=CC=C1 PQIOLJMPIIMXCZ-UHFFFAOYSA-N 0.000 description 1
- WUPPSORTBSLEFR-UHFFFAOYSA-N ethyl 7-(3-carbamimidoylphenoxy)-1-[(3-carbamimidoylphenyl)methyl]-2-oxoquinoline-3-carboxylate Chemical compound C1=C2N(CC=3C=C(C=CC=3)C(N)=N)C(=O)C(C(=O)OCC)=CC2=CC=C1OC1=CC=CC(C(N)=N)=C1 WUPPSORTBSLEFR-UHFFFAOYSA-N 0.000 description 1
- CRSVTCDZPRVJPI-UHFFFAOYSA-N ethyl 7-(3-carbamimidoylphenoxy)-1-[[4-(2-carbamimidoylphenyl)phenyl]methyl]-2-oxoquinoline-3-carboxylate Chemical compound C1=C2N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C(N)=N)C(=O)C(C(=O)OCC)=CC2=CC=C1OC1=CC=CC(C(N)=N)=C1 CRSVTCDZPRVJPI-UHFFFAOYSA-N 0.000 description 1
- FWLUHPVEAUVWQM-UHFFFAOYSA-N ethyl 7-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C2NC(=O)C(C(=O)OCC)=CC2=CC=C1OC(C=1)=CC=CC=1C1=NOC(C)=N1 FWLUHPVEAUVWQM-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012433 hydrogen halide Chemical class 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 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 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- XPVLGBMOZZAHSS-UHFFFAOYSA-N methyl 1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-2-oxoquinoline-3-carboxylate Chemical compound C=1C=C2N(CC=3C=C4C=C(C=CC4=CC=3)C=3N=C(C)ON=3)C(=O)C(C(=O)OC)=CC2=CC=1OC(C=1)=CC=CC=1C1=NOC(C)=N1 XPVLGBMOZZAHSS-UHFFFAOYSA-N 0.000 description 1
- NGSLRYSMEYSGOZ-UHFFFAOYSA-N methyl 1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-6-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methoxy]-2-oxoquinoline-3-carboxylate Chemical compound C=1C=C2N(CC=3C=C4C=C(C=CC4=CC=3)C=3N=C(C)ON=3)C(=O)C(C(=O)OC)=CC2=CC=1OCC(C=1)=CC=CC=1C1=NOC(C)=N1 NGSLRYSMEYSGOZ-UHFFFAOYSA-N 0.000 description 1
- PUUVETCRWRLXMA-UHFFFAOYSA-N methyl 2-[7-(3-carbamimidoylphenoxy)-1-[(3-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-3-yl]acetate Chemical compound C1=C2N(CC=3C=C(C=CC=3)C(N)=N)C(=O)C(CC(=O)OC)=C(C)C2=CC=C1OC1=CC=CC(C(N)=N)=C1 PUUVETCRWRLXMA-UHFFFAOYSA-N 0.000 description 1
- JAUPJJKTZAISQE-UHFFFAOYSA-N methyl 2-[7-(3-carbamimidoylphenoxy)-1-[(4-carbamimidoylphenyl)methyl]-4-methyl-2-oxoquinolin-3-yl]acetate Chemical compound C1=C2N(CC=3C=CC(=CC=3)C(N)=N)C(=O)C(CC(=O)OC)=C(C)C2=CC=C1OC1=CC=CC(C(N)=N)=C1 JAUPJJKTZAISQE-UHFFFAOYSA-N 0.000 description 1
- FPVXMBACNGQBJL-UHFFFAOYSA-N methyl 6-(3-carbamimidoylbenzoyl)oxy-1-[(7-carbamimidoylnaphthalen-2-yl)methyl]-2-oxoquinoline-3-carboxylate Chemical compound C=1C=C2N(CC=3C=C4C=C(C=CC4=CC=3)C(N)=N)C(=O)C(C(=O)OC)=CC2=CC=1OC(=O)C1=CC=CC(C(N)=N)=C1 FPVXMBACNGQBJL-UHFFFAOYSA-N 0.000 description 1
- MOFQFRGBLARXCX-UHFFFAOYSA-N methyl 6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoyl]oxy-1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-2-oxoquinoline-3-carboxylate Chemical compound C=1C=C2N(CC=3C=C4C=C(C=CC4=CC=3)C=3N=C(C)ON=3)C(=O)C(C(=O)OC)=CC2=CC=1OC(=O)C(C=1)=CC=CC=1C1=NOC(C)=N1 MOFQFRGBLARXCX-UHFFFAOYSA-N 0.000 description 1
- SCQBFOCRSMBJEX-UHFFFAOYSA-N methyl 6-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-1-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl]-2-oxoquinoline-4-carboxylate Chemical compound C12=CC=C(OC=3C=C(C=CC=3)C=3N=C(C)ON=3)C=C2C(C(=O)OC)=CC(=O)N1CC(C=C1)=CC=C1C1=NOC(C)=N1 SCQBFOCRSMBJEX-UHFFFAOYSA-N 0.000 description 1
- XCDIFBJMNRCCNN-UHFFFAOYSA-N methyl 7-[tert-butyl(dimethyl)silyl]oxy-1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-2-oxoquinoline-3-carboxylate Chemical compound O=C1C(C(=O)OC)=CC2=CC=C(O[Si](C)(C)C(C)(C)C)C=C2N1CC(C=C1C=2)=CC=C1C=CC=2C1=NOC(C)=N1 XCDIFBJMNRCCNN-UHFFFAOYSA-N 0.000 description 1
- BLWJXCFYMIQWFX-UHFFFAOYSA-N methyl 7-[tert-butyl(dimethyl)silyl]oxy-2-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(O[Si](C)(C)C(C)(C)C)C=C2NC(=O)C(C(=O)OC)=CC2=C1 BLWJXCFYMIQWFX-UHFFFAOYSA-N 0.000 description 1
- RMODSCHKKZEXCM-UHFFFAOYSA-N methyl 7-hydroxy-1-[[7-(5-methyl-1,2,4-oxadiazol-3-yl)naphthalen-2-yl]methyl]-2-oxoquinoline-3-carboxylate Chemical compound O=C1C(C(=O)OC)=CC2=CC=C(O)C=C2N1CC(C=C1C=2)=CC=C1C=CC=2C1=NOC(C)=N1 RMODSCHKKZEXCM-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- GMKZNVDDACSDKS-UHFFFAOYSA-N n'-hydroxy-3-(4-nitrophenoxy)benzenecarboximidamide Chemical compound O\N=C(/N)C1=CC=CC(OC=2C=CC(=CC=2)[N+]([O-])=O)=C1 GMKZNVDDACSDKS-UHFFFAOYSA-N 0.000 description 1
- GCKFGHRWFAPHMR-UHFFFAOYSA-N n-[4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]phenyl]-3-oxobutanamide Chemical compound C1=CC(NC(=O)CC(=O)C)=CC=C1OC1=CC=CC(C=2N=C(C)ON=2)=C1 GCKFGHRWFAPHMR-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003354 serine derivatives Chemical class 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention relates to novel compounds of formula (I), wherein X, Y, R, R1, R2, R3 and n have the meaning cited in patent claim 1. Said compounds are inhibitors of coagulation factor Xa and can be used in the prophylaxis and/or therapy of thromboembolic diseases.
Description
2-Oxo-2H-quinoline derivatives The invention relates to compounds of the formula I
R' R
\ \
p I
~CH2)"
Rs wherein R and Rlin each case independently of one another are H, A, - ( CHZ ) m-R4, - ( CHz ) m-OA or - ( CHI ) m-Ar , NH NH
Ar, ~ \N ~ ~ N , RZ is Rs or Rs R3 is Ar, R4 is CN, COOH, COOA, CONH2, CONHA, CONAZ oz C (=NH) -NHz, RS i s -C ( =NH ) -NH2, -NH-C ( =NH ) -NHS
or -C(=0)-N=C(NHZ)2, which are unsubstituted or monosubstituted by -COA, -COOA, -OH~ or by a conventional amino-protective group, ~~ N.O ~~ N.O
HN--~ N , O or CHs R6 is H, A or NH2, Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO2, CF3, NH2, NHA, NA2, pyrrolidin-FEB-26-O1 OB:34 496151727191 P.02 R-512 Job-133 ~28. FEB. 2001 14:35 0049 6151 727191 NR. 255 S. 2/4 - a -Iial, CN, NO=, CF3, NHz, NF~a. NAz, pyrrolidin-1-yl , pip~eridin-1-yl , benzyloxy, SOzNHz , S'OZNHA, SOZNA2. - ~ CHZ ) a-~2 . - ( CHa ) a-NHA, -- (CHa) a-NAz. -O- (CHz) a-NHz, -0- (CHz) a-NHA, -O- (CH2)n-NAz, -O- (CHz)~,-O- oz' R5, A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, O ar S, Hal is F, Cl, Br or I, m is 0, 1 or 2 and n is 0, 'z, 2 ox 3 and salts thereof.
The invention also relates to the optically active foams, the racemates, the diastereomers and the hydrates and solvates of these compounds.
The invention was based on the object of discovering new compounds with valuable propex'tzes, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I
and their salts have vex-y valuable pharmacological properties, coupled with a good tolerability. In particular, they show Factor Xa-inhibiting properties and can therefore be used for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis follawing angioplasty and claudicatio intermittens.
Compounds of the formula I acCOrding to the ixxve~ctt~.on can furthermore be inhibitors of the clotting factors Factor VIIa, Factor IXa and thrombin of the blood clotting cascade.
R' R
\ \
p I
~CH2)"
Rs wherein R and Rlin each case independently of one another are H, A, - ( CHZ ) m-R4, - ( CHz ) m-OA or - ( CHI ) m-Ar , NH NH
Ar, ~ \N ~ ~ N , RZ is Rs or Rs R3 is Ar, R4 is CN, COOH, COOA, CONH2, CONHA, CONAZ oz C (=NH) -NHz, RS i s -C ( =NH ) -NH2, -NH-C ( =NH ) -NHS
or -C(=0)-N=C(NHZ)2, which are unsubstituted or monosubstituted by -COA, -COOA, -OH~ or by a conventional amino-protective group, ~~ N.O ~~ N.O
HN--~ N , O or CHs R6 is H, A or NH2, Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO2, CF3, NH2, NHA, NA2, pyrrolidin-FEB-26-O1 OB:34 496151727191 P.02 R-512 Job-133 ~28. FEB. 2001 14:35 0049 6151 727191 NR. 255 S. 2/4 - a -Iial, CN, NO=, CF3, NHz, NF~a. NAz, pyrrolidin-1-yl , pip~eridin-1-yl , benzyloxy, SOzNHz , S'OZNHA, SOZNA2. - ~ CHZ ) a-~2 . - ( CHa ) a-NHA, -- (CHa) a-NAz. -O- (CHz) a-NHz, -0- (CHz) a-NHA, -O- (CH2)n-NAz, -O- (CHz)~,-O- oz' R5, A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, O ar S, Hal is F, Cl, Br or I, m is 0, 1 or 2 and n is 0, 'z, 2 ox 3 and salts thereof.
The invention also relates to the optically active foams, the racemates, the diastereomers and the hydrates and solvates of these compounds.
The invention was based on the object of discovering new compounds with valuable propex'tzes, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I
and their salts have vex-y valuable pharmacological properties, coupled with a good tolerability. In particular, they show Factor Xa-inhibiting properties and can therefore be used for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis follawing angioplasty and claudicatio intermittens.
Compounds of the formula I acCOrding to the ixxve~ctt~.on can furthermore be inhibitors of the clotting factors Factor VIIa, Factor IXa and thrombin of the blood clotting cascade.
Aromatic amidine derivatives having an antithrombotic action are known, for example, from EP 0 540 051 Bl.
Cyclic guanidines for treatment of thromboembolic diseases are described, for example, in WO 97/08165.
Aromatic heterocyclic compounds having a Factor Xa-inhibitory activity are known, for example, from WO 96/10022. Substituted N-[(aminoiminomethyl)phenyl-alkyl]-azaheterocyclylamides as Factor Xa inhibitors are described in WO 96/40679.
The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibiting action against the activated clotting protease, known by the name Factor Xa, or to the inhibition of other activated serine proteases, such as Factor VIIa, Factor IXa or thrombin.
Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyses the conversion of prothrombin into thrombin. Thrombin splits fibrinogen into fibrin monomers which, after crosslinking, make an elemental contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic diseases. However, an inhibition of thrombin can inhibit the fibrin formation involved in thrombus formation.
The inhibition of thrombin can be measured, for example, by the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.
An inhibition of Factor Xa can thus prevent thrombin being formed.
The compounds of the formula I according to the invention and their salts intervene in the blood clotting process by inhibiting Factor X and thus inhibit the formation of thrombi.
The inhibition of Factor Xa by the compounds according to the invention and the measurement of the FEB-26-O1 06:34 496151727191 P.03 R-512 Job-133 ~28. FEB. 2001 14:35 0049 6151 727191 NR. 255 S. 3/4 anticoaguJ.ating and antithrombotic activity can be determined by customary in vitro or in v~.vo methods_ A
suitable method is described, for example, by J. Hauptmann et al. in. Thrombosis aad Haemostasis x.990, 63, 220-223.
The inhibition of Factor Xa can be measured, for example, by the method of T. Hara et a1. in Thromb.
Haemostas. 1994, 71., 314-319.
After binding to tissue factor, clotting Factor vrla inj_tiates the extrinsic part of the czotting cascade and contributes towards activation of Factor X to Factor Xa. Inhibition of Factor VIIa thus prevents the formation o~ Factor Xa and therefore a subsequent formation of thrombin.
The inhibition of Factor VIIa by the compounds according to the invention and the measurement of the anticoagulating and the antithrombotic activity can be determined by customary in vitro or in vivo methods. A
customary method for measuring the inhibition of Factor VIIa is described, for example, by H.F. Ronning Ea al_ in Thrombosis Research 1996, 84, 73-S1.
Clotting Factor IXa is generated in the intrinsic clotting cascade and likewise participates in the activation of Factor X to Factor Xa. An inhibition of Factor IXa can therefore prevent formation of Factor Xa in another manner.
The inhibition of Factor IXa by the compounds according to the invention and the measurement of the anticoagul.ating and antithrombotic activity can be determined by customary in vitro or in vivo methods . A
suitable method is described, for example, by T. Chang et al. in Jouz-rsal of .Bio.Zogical Chemistry 1998, 273, 12089-12094_ The compounds of the formula I can be employed as medicament active compounds in human and veterinary FEB-28-01 08:34 496151127191 P.04 R-512 Job-133 ~28. FEB. 2001 14:36 0049 6151 727191 NR. 25S S. 4/4 medicine, ire particular for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammatiozis, apoplexy, angina pectoris, restenosis fol3owing angioplasty and claudicatio intermittens_ The invention relates to the compouzlds of the formu~.a T
and their saxts and to a process for the preparation of compounds of the formula 1 according to Claim 1 and their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolyszng or hydrogenolysing agent in that i) an amidino group is liberated from its oxadiazole derivative or oxazolidimone derivative by hydrogenolyszs or solvolysis, ii) a conventiozzal amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or an amino group protected by a conventional protective group is liberated, or b) in a compound of the formula I, one or more radical (s) R, R1, Ra and/or R3 is or are converted into one or more radical (s) R, Rl, R2 and/or R3, in that, for exampJ_e, i) an ester group is hydrolysed to a carboxyl group, ii) a vitro group is reduced, iii) an amino group is acylat~d, iv) a cyano group is converted into an amidino group and/or c) a base or acid of the formula I is converted into one of its salts.
For all the radicals which occur more than once, such as, for example, Ar, the meanings thereof are independent of one another.
Unless expressly stated otherwise, the radicals and parameters R, X, Y, Ri, R2, R3 and n above and below have the meanings given in the case of formula I.
A is alkyl, is linear or branched and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 C atoms. A is preferably methyl, and moreover ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl or 1,1,2- or 1,2,2-trimethylpropyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Alkylene is preferably methylene, ethylene, propylene or butylene, or furthermore branched alkylene.
COA is acyl and is preferably formyl, acetyl or propionyl, or furthermore also butyryl, pentanoyl or hexanoyl.
Hal is preferably F, C1 or Br, or also I.
R 1 S H , A, - ( CH2 ) m-R4 , - ( CH2 ) m-OA Or - ( CH2 ) m-Ar , preferably H, A, -CH2-R4 or R4, and R is particularly preferably H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COOH
or COOA.
R1 is H, A, -(CH2)m-R4, -(CH2)m-OA Or -(CH )m-Ar, preferably H, A, -CH2-R4 or R4, and Rl particularly preferably is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COON or CODA, and especially preferably H, A or COOH.
R2 is preferably Ar, particularly preferably phenyl which is monosubstituted by R5, and especially preferably phenyl which is monosubstituted by amidino.
R3 is Ar, preferably phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, Hal, CN or CF3, or phenyl, benzodioxol-5-yl, naphthyl or biphenyl, which are unsubstituted or mono- or disubstituted by cycloalkyl having 3-6 C atoms, OH, NH2, NHA, NA2, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHA, SO2NA2 , - ( CH2 ) n-NH2 . - ( CH2 ) n-NHA, - ( CH2 ) n-NA2 , -0- ( CH2 ) n-NH2 , -0- ( CH2 ) n-NHA, -0- ( CH2 ) n-NA2 , Or R5 , naphthyl or biphenyl monosubstituted by amidino being preferred. Preferred substituents for biphenyl are amidino, fluorine, SO2NH2 or SO2NHA.
Ar is phenyl, naphthyl of biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO2, CF3, NH2, NHA, NA2, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHA, SO2NA2, phenylsulfonamido, - ( CH2 ) n-NH2 , - ( CH2 ) n-NHA, - ( CH2 ) n-NA2 , -0- ( CH2 ) n-NH2 .
-0- ( CH2 ) n-NHA, -0- ( CH2 ) n-NA2 , -0- ( CH2 ) m-0- Or R5 .
Ar is preferably unsubstituted phenyl, naphthyl or biphenyl, and moreover preferably phenyl, naphthyl or biphenyl, which are mono-, di- or trisubstituted, for example by A, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, _ g _ propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, sulfonamido, methyl-sulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenyl sulfonamido, aminomethyl, aminoethyl, N-methylaminomethyl, N-ethylaminomethyl, N,N-dimethyl aminomethyl, aminomethyloxy, aminoethyloxy or R5, and furthermore benzodioxolyl.
Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)-phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)-phenyl, o-, m- or p-(N-ethylamino)-phenyl, o-, m- or p-(N,N-diethyl-amino)-phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-(methylsulfonamido)-phenyl, o-, m- or p-amidino-phenyl, 7-amidino-2-naphthyl, 3-fluoro-2'-sulfamoyl-biphenyl-4-yl, 3-fluoro-2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, o-, m- or p-(pyrrolidin-1-yl)-phenyl, o-, m- or p-(piperidin-1-yl)-phenyl, o-, m- or p-{5-methyl-[1,2,4Joxadiazol-3-yl)}-phenyl, 7-{5-methyl-[1,2,4-oxadiazol-3-yl)}-napth-2-yl, o-, m- or p-{5-oxo-[1,2,4]-oxadiazol-3-yl)}-phenyl or 7-{5-oxo-[1,2,4]-oxadiazol-3-yl)}-naphth-2-yl, and also preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-_ g _ dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
R4 is preferably, for example, COOH, COOA or CONH2.
RS is preferably, for example, unsubstituted -C ( =NH ) -NH2 , -NH-C ( =NH ) -NHz , -C ( =0 ) -N=C ( NHZ ) 2 , whi ch can also be monosubstituted by OH, ~~N.O ~~N.O
HN--~ N=
or especially preferably unsubstituted -C(=NH)-NHZ or {~N~O
N =C
CH3.
X is preferably, for example, absent, or is carbonyl or alkylene, in particular methylene or -CH(CH3)-.
Y is preferably 0.
m is preferably 0 or 1, and furthermore also 2.
n is preferably 0 or 1, and furthermore also 2 or 3.
The compounds of the formula I can have one or more chiral centres and can therefore occur in various stereoisomeric forms. Formula I includes all these forms.
' - 10 -The invention accordingly particularly relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to Ih, which correspond to the formula I and wherein the radicals not described in more detail have the meaning given in the case of formula I, but wherein in Ia R is H, A, -CHZ-COOA, -CH2-COOH, -CH2-CONHz, COOH or CODA;
in Ib R is H, A, -CHz-COOA, -CH2-COOH, -CHZ-CONH2, COOH or COOA, R1 is H, A, -CHZ-COOA, -CH2-COOH, -CHZ-CONHZ, COOH or COOA;
in Ic R is H, A, -CH2-COOA, -CHz-COOH, -CH2-CONH2, COOH or CODA
R1 is H, A, -CHZ-COOA, -CH2-COOH, -CH2-CONH2, COOH or CODA, Rz is phenyl which is monosubstituted by R5;
in Id R is H, A, -CHz-COOA, -CH2-COOH, -CH2-CONHz, COOH or COOA, R1 is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COOH or CODA, RZ is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, or by phenyl which is mono- or disubstituted by R5, S02NH2, S02NHA or F;
in Ie R is H, A, -CHz-COOA, -CH2-COOH, -CH2-CONHz, COOH or COOA, R1 is H, A, -CHZ-COOA, -CHZ-COOH, -CH2-CONHz, COOH or COOA, Rz is phenyl which is monosubstituted by R5, ' - 11 -R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, or biphenyl which is mono- or disubstituted by R5, SOZNH2, S02NHA or F, R5 i s -C ( =NH ) -NH2 or {~N~O
N =-~
in If R is H, A, -CH2-COOA, -CHZ-COOH, -CHZ-CONH2, COOH or COOA, R1 is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COOH or COOA, R2 is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, biphenyl which is mono- or disubstituted by R5 , SOzNH2 , SOzNHA or F , R5 is -C (=NH) -NHz or ~~N'o N =
n is 0 or 1;
in Ig R is H, A, -CH2-COOA, -CHZ-COOH, -CH2-CONHz, COOH or COOA, R1 is H, A, -CH2-COOA, -CHz-COOH, -CHz-CONH2, COOH or CODA, Rz is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, or biphenyl which is mono- or disubstituted by R5, SOzNH2, S02NHA or F, RS is -C (=NH) -NH2 or {~N~O
N =
n is 0 or 1, X is absent or is alkylene or carbonyl, Y is absent or is 0;
in Ih R is H, A, -CHZ-COOA, -CHZ-COOH, -CH2-CONH2, COOH or CODA, R1 is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONHz, COOH or COOA, R2 is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are mono substituted by CN or R5, or biphenyl which is mono- or disubstituted by R5, S02NH2 , S02NHA or F , R5 is -C (=NH) -NH2, which can also be monosubstituted by OH, or {~N~O
N =C
n is 0 or 1, X is absent, Y is 0.
The compounds of the formula I and also the starting substances for their preparation are moreover prepared by methods which are known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the reactions mentioned. It is also possible here to make use of variants which are known per se and are not mentioned in more detail here.
If desired, the starting substances can also be fornled in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protective group instead o'f an H atom bonded to an N atom, in particular those which carry an R'-N group, wherein R' is an amino-protective group, instead of an HN group, and/or those which carry a hydroxyl-protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I but carry a group -COOR", wherein R" is a hydroxyl-protective group, instead of a group -COOH.
Preferred starting substances are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
The liberation of the amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example Raney nickely. Suitable solvents are those mentioned below, in particular alcohols, such as methanol or ethanol, organic acids, such as acetic acid or propionic acid, or mixtures thereof. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100° under pressures between about 1 and 200 bar, preferably at 20-30° (room temperature) under 1-10 bar.
The oxadiazole group is introduced, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic acid ester, N,N'-carbonyldiimidazole or acetic anhydride.
Several - identical or different - protected amino and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective groups present differ from one another, they can in many cases be split off selectively.
The term "amino-protective group" is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but can easily be removed after the desired chemical reaction has been carried out at other points of the molecule. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protective groups are removed after the desired reaction (or reaction sequence), their nature and size is moreover not critical; preferably, however, those having 1-20, in particular 1-8 C atoms are preferred. The term "acyl group" is to be interpreted in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl, and above all aralkoxy carbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA;
alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC
(tert-butyloxycarbonyl) and 2-iodoethoxycarbonyl;
aralkyloxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protective groups are BOC
and Mtr, and furthermore CBZ, Fmoc, benzyl and acetyl.
The term "hydroxyl-protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out at other points of the molecule. Typical such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore also alkyl groups. The nature and size of the hydroxyl-protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms are preferred.
Examples of hydroxyl-protective groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluene-sulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is effected - depending on the protective group used - with, for example, strong acids, expediently with TFA or perchloric acid, or also with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as methylene chloride, and furthermore also alcohols, such as methanol, ethanol or isopropanol, as well as water. Mixtures of the abovementioned solvents are furthermore possible. TFA is preferably used in excess without addition of a further solvent, and perchloric acid in the form of a mixture of acetic acid and 70~ perchloric acid in a ratio of 9:1. The reaction temperatures for the cleavage are expediently between about 0 and about 50°, and the reaction is preferably carried out at between 15 and 30° (room temperature).
The groups BOC, OBut and Mtr can preferably be split off, for example, with TFA in methylene chloride or with about 3 to 5n HC1 in dioxane at 15-30°, and the FMOC group with an approximately 5 to 50~ solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.
Protective groups which can be removed by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be split off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst, such as palladium, expediently on a support, such as charcoal). Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100°
under pressures between about 1 and 200 bar, preferably at 20-30° under 1-10 bar. A hydrogenolysis of the CBZ
group is effected particularly well, for example, on 5 to 10~ Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°.
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetra-chloride, trifluoromethylbenzene, chloroform or methylene chloride; alcohols, such as methanol, ethanol, isopropanol, n-propanol n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF);
nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene;
esters, such as ethyl, acetate, or mixtures of the solvents mentioned.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst, such as, for example, Pd/C.
For the preparation of an amidine of the formula I (for example Ar = phenyl which is monosubstituted by C(=NH)-NH~) , it is also possible to add ammonia onto a nitrile. The addition reaction is preferably carried out in several stages, by, in a manner known per se, a) converting the nitrile into a thioamide with H2S, which is converted with an alkylating agent, for example CH3I, into the corresponding S-alkylimido-thioester, which in turn reacts with NH3 to give the amidine, b) converting the nitrite with an alcohol, for example ethanol, in the presence of HC1 into the corresponding imido-ester and treating this with ammonia, or c) reacting the nitrite with lithium bis-(trimethylsilyl)-amide and subsequently hydrolysing the product.
It is furthermore possible to convert a compound of the formula I into another compound of the formula I by converting one or more radical ( s ) R, R1 RZ and/or R3 into one or more radical ( s ) R, R1, RZ and/or R3, for example by acylating an amino group or reducing nitro ' groups (for example by hydrogenation on Raney nickel or Pd-charcoal in an inert solvent, such as methanol or ethanol) to amino groups.
Esters can be hydrolysed, for example, with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100°.
Free amino groups can furthermore be acylated in the customary manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, expediently i~ an inert solvent, such as methylene chloride or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60 and +30°.
A base of the formula I can be converted into the associated acid addition salt with an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, and subsequent evaporation. Acids which are particularly suitable for this reaction are those which give physiologically acceptable salts. It is thus possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malefic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids and lauryl-sulfuric acid. Salts with acids which are not physiologically acceptable, for example picrates, can be used for isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted with bases (for example sodium hydroxide or carbonate or potassium hydroxide or carbonate) into the corresponding metal salt, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts .
Physiologically acceptable organic bases, such as, for example, ethanolamine, can also be used.
Because of their molecular structure, compounds of the formula I according to the invention can be chiral and may accordingly occur in various enantiomeric forms.
They can therefore be present in a racemic or in an optically active form.
Since the pharmaceutical activity of the racemates and of the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product, or already the intermediate product, can be separated into enantiomeric compounds by chemical or physical measures known to the expert or can be already employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids, such as the R and S
forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
Chromatographic separation of enantiomers with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates, or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous. Suitable mobile phases for this are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in a ratio of 82:15:3.
The invention furthermore relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by a non-chemical route.
For this use, they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and optionally in combination with one or more further active compounds.
The invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These formulations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc and Vaseline. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants for parenteral use and ointments, creams or powders for topical use. The new compounds can also be lyophilized and the lyophilisates obtained can be used, for example, for the preparation of injection preparations. The formulations mentioned can be sterilized and/or comprise auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavourings and/or several further active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be used in combating and preventing thromboembolic diseases, such as thrombosis, miocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.
The substances according to the invention are as a rule preferably administered here in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg/kg of bodyweight. However, the specific dose for each patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, bodyweight, general state of health, sex, on the diet, on the administration time and route, and on the rate of excretion, medicament combination and severity of the particular disease to which the treatment applies. Oral administration is preferred.
All temperatures above and below are stated in °C. In the following examples, "customary working up" means:
water is added, if necessary, the pH is adjusted to between 2 and 10, if necessary, depending on the structure of the end product, the mixture is extracted with ethyl acetate or methylene chloride, the organic phase is separated off, dried over sodium sulfate and ' evaporated and the residue is purified by chromatography over silica gel and/or by crystallization. Rf values on silica gel; mobile phase:
ethyl acetate/methanol 9:1.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (Fast Atom Bombardment) (M+H)+
Example 1 By reaction of 3-(tert-butyldimethylsilyloxy)-benzonitrile and .1-fluoro-4-nitrobenzene with tetrabutylammonium fluoride in THF analogously to Synthesis 1988, 378-379, the compound 3-(4-nitro-phenoxy)-benzonitrile ("AB"), m.p. 113-114°, is obtained.
90.4 g of sodium bicarbonate and 350 ml of water are added to a suspension of 78.4 g of "AB" and 68.0 g of hydroxylammonium chloride in 1 1 of methanol. The mixture is heated under reflux for 6 hours, while stirring. After cooling, water is added and the crystals which have precipitated out are separated off.
After drying, 87.5 g of pale yellow needle-shaped crystals of 3-(4-nitrophenoxy)-N-hydroxybenzamidine ("B"), m.p. 176-177°, EI273 are obtained.
A solution of 87.5 g of "B" in 250 ml of acetic anhydride is heated under reflux for 3 hours. After cooling, the mixture is poured onto ice-water and the precipitate is worked up in the customary manner to give 76.8 g of 5-methyl-3-[3-(4-nitrophenoxy)-phenyl]-[1,2,4]-oxadiazole ("C"), m.p. 134-135°, EI297.
A solution of 58.3 g of "C" in 500 ml of 1,4-dioxane is heated to 80° . 97 . 1 g of sodium sulfide octahydrate in 500 ml of water are then added (Yang-i Lin et al., J. Heterocycl. Chem. 1980, 17, 1273). After the mixture has been stirred for 2 hours, it is worked up in the customary manner to give 50.6 g of 5-methyl-3-[3-(4-aminophenoxy)-phenyl]-[1,2,4]-oxadiazole ("D"), m.p.
88-89°, EI267.
' 7.1 ml of 2,2,6-trimethyl-1,3-dioxin-4-one are added dropwise at 120° to a solution of 14.4 g of "D" in 130 ml of xylene and the mixture is subsequently stirred for 3 hours. After cooling, it is worked up in the customary manner to give 16.5 g of N-{4-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-phenyl}-3-oxo-butyramide ("E"), m.p. 104-105°, EI351.
~'~ N
--~~ ~ o N I ~ I \ 0 0 "E".
N
H
A solution of 8.2 g of "E" in 23 ml of concentrated sulfuric acid is stirred at 80° for 3 hours. After cooling and customary working up, 7.1 g of 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("F"), m.p. 234-235°, EI333 are obtained.
O"N
--~' ~ o N \
O
0.81 g of potassium tert-butylate and then 2.28 g of 3-(3-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole are added to a solution of 2.0 g of "F" in 50 ml of DMF and the mixture is subsequently stirred for 2 hours. After customary working up, in addition to 0.7 g of 0-alkylation product, 1.66 g of 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("G"), m.p. 167-168°, FAB 506 are obtained.
~"N
i o N I \ I \ \
N O N-~
l \ ' N "G", Analogously, reaction of "F" gives with 3-(2-bromomethyl-naphthalene-7-yl)-5-methyl-[1,2,4]oxadiazole, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline, m.p. 103-104°;
with 3-(4-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline, m.p. 204-205°.
Example 2 1 drop of acetic acid and water-moist Raney nickel are added to a solution of 0.37 g of "G" in 30 ml of methanol and the mixture is stirred under an HZ
atmosphere for 24 hours. After removal of the catalyst and customary working up, 0.12 g of 1-(3-amidinobenzyl)-6-(3-amidinophenoxy)-4-methyl-2-oxo-2H-quinoline, FAB 426 is obtained.
NH
H2N \ O \ \
N o NH
\ 'NH2 The following amidine derivatives are obtained analogously by hydrogenation with Raney nickel 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, m.p. 281-282°, FAB 476;
1-(4-amidinobenzyl)-6-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, m.p. 141-145°, FAB 426.
Example 3 2 eq. of N-bromosuccinimide and benzoyl peroxide are added to a solution of "F" in methanol and the mixture is stirred under reflux for 16 hours. After customary working up, 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-dibromomethyl-2-oxo-2H-quinoline are obtained.
The compound is then reacted with sodium formate and the product is subsequently oxidized by known methods to give 6-[3-(5-methyl[1,2,4]oxadiazol-3-yl)-phenoxy]
4-methoxycarbonyl-2-oxo-2H-quinoline ("H").
Reaction of "H" analogously to Example 1 gives, with 3-(3-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole ("1") with 3-(2-bromomethylnaphthalene-7-yl)-5-methyl-[1,2,4]oxadiazole ("2"), with 3-(4-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole ("3") with 3-(4'-bromomethylbiphenyl)-2-yl-5-methyl-[1,2,4]-oxadiazole ("4"), in addition to the 0-alkylation products, the following compounds ' - 26 -1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalene]-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4'-ylmethyl-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, from which the following carboxylic acid derivatives are obtained by customary ester hydrolysis 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalene]-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4'-ylmethyl-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline.
The following amidino derivatives are obtained therefrom by hydrogenation analogously to Example 2 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-6-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl[4'-ylmethyl)-6-(3 amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline.
Alternatively, the carboxylic acid esters can first be alkylated, then hydrogenated to the amidino derivatives and finally hydrolysed.
Example 4 2.13 mol of potassium carbonate are added to a solution of 0.425 mol of 4-methyl-3-nitro-phenol in 2 1 of pyridine. 0.425 mol of hopper (I) chloride is added and the mixture is heated under reflux for 0.5 hour.
0.5 mol of 3-bromobenzonitrile is then added and the mixture is heated under reflux for 3 days. After customary working up 3-(4-methyl-3-nitrophenoxy)-benzonitrile is obtained. Analogously to Example 1, the compound 5-methyl-3-[3-(4-methyl-3-nitro-phenoxy)-phenyl]-[1,2,4]-oxadiazole is obtained therefrom with hydroxylammonium chloride and by heating in acetic anhydride. By reduction of the nitro group analogously to Example 1 and oxidation of the methyl group analogously to Example 3, the compound 5-methyl-3-[3-(4-formyl-3-amino-phenoxy)-phenyl]-[1,2,4]-oxadiazole is obtained therefrom. By Friedlander condensation analogously to the method of del mar Blanco et al., Heterocycles, 1993, 1397 et seq., the compound 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethoxycarbonyl-2-oxo-2H-quinoline ("I") is obtained therefrom.
Analogously to Example 3, by reaction of "I" with compounds "1", "2", "3" and "4" and subsequent hydrogenation, the following compounds are obtained 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl-4'-ylmethyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline.
Ester hydrolysis gives therefrom the compounds 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-ber~zyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl-4'-ylmethyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline.
Example 5 By reaction of 3-hydroxybenzonitrile with 3-bromo-nitrobenzene analogously to Example 4, the compound 3-(3-nitro-phenoxy)-benzonitrile is obtained.
Analogously to Example 1, the compound 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("K") is obtained by reduction of the nitro group, formation of the oxadiazole ring, reaction with 2,2,6-trimethyl-1,3-dioxin-4-one and cyclization with concentrated sulfuric acid. Analogously to Example 3, 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline ("L") is obtained therefrom by oxidation of the 4-methyl group.
By reaction of "L" analogously to Example 1 gives, with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-(3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]
oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H
quinoline.
1-[4-(5-methyl-(1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, from which the followirig carboxylic acid derivatives are obtained by customary ester hydrolysis 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-(1,2,4]oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline.
By hydrogenation analogously to Example 2, the following amidino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline.
By reaction of "K" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline.
1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline.
By hydrogenation analogously to Example 2, the following amino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, Example 6 By reaction of 3-hydroxybenzonitrile with 3-bromo-nitrobenzene analogously to Example 4, the compound 3-(3-nitro-phenoxy)-benzonitrile is obtained.
Analogously to Example l, the compound 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline ("M") is obtained by reduction of the nitro group, formation of the oxadiazole ring, reaction with 2,2,6-trimethyl-5-ethyl-1,3-dioxin-4-one and cyclization with concentrated sulfuric acid. By reaction of "M" with "1", "2" and "3", in addition to the O-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline.
By hydrogenation analogously to Example 2, the following amidino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H-quinoline.
The following compounds are obtained analogously 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidinonaphthalene)-2-ylmethyl)-7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline.
Example 7 4.3 g of potassium carbonate are added to a suspension of 1.0 g of 6-hydroxyquinolin-2-one in 25 ml of DMF and the mixture is subsequently stirred at room temperature for 0.5 hour. 0.6 g o~ copper (I) chloride is then added and the mixture is heated under reflux for 0.5 hour. After addition of 3-bromobenzonitrile in 25 ml of pyridine, the reaction mixture is heated under reflux for 18 hours. It is worked up in the customary manner to give, after chromatography over silica gel, the two compounds 6-(3-cyanophenoxy)-2-oxo-2H-quinoline ("N"), m.p.
221-222°, EI 262 and 1-(3-cyanophenyl)-6-(3-cyanophenoxy)-2-oxo-2H-quinoline ("O"), m.p. 82-84°, EI 363.
By reaction of "N" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-cyanophenoxy]-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-cyanophenoxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-cyanophenoxy]-2-oxo-2H-quinoline.
By reaction with hydroxylammonium chloride and subsequent reduction with Hz and Raney nickel, the following compounds are obtained therefrom 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline, FAB 413; m.p. 160-162°, 1-(7-amidinonaphthalen-2-ylmethyl) 6-(3-amidino-phenoxy)-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline.
An analogous procedure, starting from 7-hydroxyquinoline-2-one, gives the compounds 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline, 1-(7-amidinonaphthalene)-2-ylmethyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline, 1-(4-amidinobenzyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline.
0.19 g of hydroxylammonium chloride and 0.22 g of sodium bicarbonate is added to a suspension of 0.12 g of "0" in 5 ml of ethanol. After further addition of 0.5 ml of water, the mixture is boiled under reflux for 2 hours. After customary working up, 1-(3-N-hydroxyamidino-phenyl)-6-(3-N-hydroxyamidino-phenoxy)-2-oxo-2H-quinoline, EI 429 is obtained.
By oxadiazole formation and hydrogenation, 1-(3-amidino-phenyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline, FAB 398; m.p. 62-64° is obtained therefrom.
1-(3-Amidino-phenyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline is obtained analogously.
Example 8 A suspension of 1 g of 6-hydroxy-2-oxo-2H-quinoline in 30 ml of DMF is cooled to about 10° and 0.84 g of potassium tert-butylate is then added. 2.0 g of 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]oxadiazol (m. p. 54-55°) are added and the mixture is subsequently stirred for 2 hours and worked up in the customary manner. 6-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-benzyl-oxy]-2-oxo-2H-quinoline ("P"), m.p. 208-209°, EI333 is obtained.
By reaction of "P" with 3-bromobenzonitrile analogously to Example 7, the compound 1-(3-cyanophenyl)-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline.
By reaction with hydroxylammonium chloride and subsequent reduction with H2 and Raney nickel, 1-(3-amidino-phenyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline is obtained therefrom.
By reaction of "P" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline.
By subsequent reduction with H2 and Raney nickel, the following compounds are obtained therefrom 1-(3-amidinobenzyl)-6-(3-amidinobenzyloxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 1-(4-amidinobenzyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline.
' Example 9 Analogously to Example 8, by reaction of 7-hydroxy-2-oxo-2H-quinoline with 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]oxadiazole, the compound 7-[3-(5-methyl[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline ("Q"), m.p. 168-170°, EI 333 is obtained.
By reaction of "Q" with 3-bromobenzonitrile analogously to Example 7, the compound 1-(3-(cyanophenyl)-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline is obtained.
By reaction with hydroxylammonium chloride and subsequent reduction with HZ and Raney nickel, 1-(3-amidino-phenyl)-7-(3-amidinobenzyloxy)-2-oxo-2H
quinoline is obtained therefrom.
By reaction of "Q" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline.
By subsequent reduction with HZ and Raney nickel, the following compounds are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 1-(4-amidinobenzyl)-7-(3-amidinobenzyloxy)-2-oxo-2H-quinoline.
Example 10 By reaction of 6-hydroxy-2-oxo-2H-quinoline with acetic anhydride in pyridine in a known manner, 6-acetoxy-2-oxo-2H-quinoline, m.p. 221-222° is obtained. By subsequent alkylation with "1", in addition to the O-alkylation product, the compound 1-(3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-acetoxy-2-oxo-2H-quinoline, m.p. 157-158° is obtained. By deacetylation in a known manner, 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-hydroxy-2-oxo-2H-quinoline, m.p. 271-273°
("R") is obtained.
By reaction of "R" with 3-[5-methyl-[1,2,4]oxadiazol-3-yl]-benzoyl chloride with the addition of caesium carbonate in DMF, after customary working up the compound 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline is obtained.
By subsequent hydrogenation analogously to Example 2, 1-(3-amidinobenzyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline is obtained therefrom.
By reaction of "R" with 1-(3-[5-methyl-[1,2,4]-oxadiazol-3-yl]-phenyl}methyl bromide and subsequent hydrogenation, the compound 1-(3-amidinobenzyl)-6-[1-(3-amidinophenyl)methoxy)-2-oxo-2H-quinoline, m.p.
125-127° is obtained analogously.
NH \ I O
I
NH2 ~ N O NH
I \ _NHZ
. - - 37 -The compound 1-(3-amidinobenzyl)-7-[1-(3-amidino-phenyl)methyloxy)-2-oxo-2H-quinoline, m.p. 146-150° is obtained analogously.
Example 11 By reaction of "R" with 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylboronic acid, 1-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-2-oxo-2H-quinoline and therefrom, by hydrogenation, 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline are obtained.
The other compounds mentioned in Example 7 are also obtained analogously.
Example 12 By reaction of 3-methyl-4-nitro-phenol with acetic anhydride and sulfuric acid, 1-acetoxy-3-methyl-4-nitro-benzene is obtained. Subsequent bromination with NBS with irradiation gives 1-acetoxy-3-dibromo-methyl-4-nitro-benzene, m.p. 130-131°, EI 353. By reaction with sodium formate in water and ethanol, 3-formyl-4-nitro-phenol, m.p. 145-146°, EI 167 is obtained, and is converted by reaction with benzyl bromide with addition of potassium carbonate in DMF
into 1-benzyloxy-3-formyl-4-nitro-benzene, m.p.
120-121°, EI 257. By reduction of the nitro group with Na2S in dioxane and water at 80°, 1-benzyloxy-3-formyl 4-amino-benzene, EI 245 is obtained. By reaction with diethyl malonate in piperidine and heating, the compound 6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H
quinoline ("S"), m.p. 155-156°, EI 323 is obtained therefrom.
By reaction of "S" with "2", 1-[7-(5-methyl]-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H-quinoline is . . _ 38 -obtained, and is converted by hydrogenation with Raney nickel into 1-[7-amidino-naphthalen-2-ylmethyl]-6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H-quinoline.
By ester hydrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-benzyloxy-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
Example 13 The regio-isomeric carboxylic acid derivatives (3-carboxy-...) from Example 3 are obtained as follows:
a) By reaction of 4-methyl-3-nitro-phenol with acetic anhydride and sulfuric acid, 1-acetoxy-4-methyl-3-nitro-benzene is obtained. Subsequent bromination with NBS with irradiation gives 1-acetoxy-4-dibromo-methyl-3-nitro-benzene. By reaction with sodium formate in water and ethanol, 4-formyl-3-nitro-phenol is obtained therefrom, and is converted by reaction with tert-butyl-dimethylsilyl chloride with the addition of imidazole in methylene chloride into 1-tert-butyl-dimethylsiloxy-4-formyl-3-nitro-benzene. By reduction of the nitro group with NazS in dioxane and water at 80°, 1-tert-butyl-dimethylsilyloxy-4-formyl-3-amino-benzene is obtained. By reaction with dimethyl malonate with addition of piperidine, the compound 7-tert-butyl-dimethylsilyloxy-3-methoxycarbonyl-2-oxo-2H-quinoline ("T") is obtained therefrom.
By reaction of "T" with "2", 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-tert-butyl-dimethylsilyloxy-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained, which is converted into 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-hydroxy-3-methoxycarbonyl-2-oxo-2H-quinoline ("U") by splitting off of the silyl group.
. . _ 39 _ By reaction of "U" with 3-bromobenzonitrile and further reaction analogously to Example 1, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained therefrom, and 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained therefrom by hydrogenation.
By ester hydrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
b) By reaction of "U" with 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]-oxadiazole analogously to Example 8, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-3-methoxycarbonyl-2-oxo-2H-quinoline is obtained, and is converted by hydrogenation into 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzyloxy)-3-methoxy-carbonyl-2-oxo-2H-quinoline.
By ester hyrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzyloxy)-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
c) By reaction of "U" with 3-[5-methyl-[1,2,4]-oxadiazol-3-yl]-benzoyl chloride analogously to Example 10, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoyloxy]-3-methoxycarbonyl-2-oxo-2H-quinoline is obtained, and is converted by hydrogenation into 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzoyloxy)-3-methoxycarbonyl-2-oxo-2H-quinoline.
By ester hydrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzoyloxy)-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
- ' - 40 -The regio-isomeric 7-isomers are obtained analogously starting from 3-methyl-4-nitro-phenol.
Example 14 The following compounds are obtained analogously to Example 12 1-(3-amidino-benzyl)-6-benzyloxy-3-ethoxycarbonyl 2-oxo-2H-quinoline, m.p. 176.9°, and 1-(3-amidino benzyl)-6-benzyloxy-3-carboxy-2-oxo-2H-quinoline, m.p.
>300° therefrom by ester hydrolysis, and the compound 1-(7-cyano-naphthalen-2-ylmethyl)-7-(7-cyano-naphthalen-2-ylmethyl)-3-ethoxycarbonyl-2-oxo-2H-quinoline, m.p. 216.4°.
Example 15 Analogously to Example 4, the compound 1-(7-cyano-naphthalen-2-ylmethyl)-7-(3-cyano-phenoxy]-3-ethoxycarbonyl-2-oxo-2H-quinoline, m.p. 183.5° is obtained, and 1-[7-(N-hydroxy-amidino)-naphthalen-2-ylmethyl]-7-[3-(N-hydroxy-amidino)-phenoxy]-3-carboxy-2-oxo-2H-quinoline m.p. >300° is obtained therefrom.
Example 16 800 mg of molecular sieve (0.4 nm) are added to a solution of 200 mg of 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 265 mg of 3-cyanophenylboronic acid and 220 mg of Cu(II) acetate in 15 ml of methylene chloride and the mixture is stirred under nitrogen at room temperature. After addition of 0.145 ml of pyridine and 0.25 ml of triethylamine, the mixture is subsequently stirred for 18 hours. After addition of 50 ml of water, the mixture is worked up in the customary manner and 190 mg of . ' - 41 -6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-1-(3-cyanophenyl)-2-oxo-2H-quinoline ("V"), EI 434 are obtained.
140 mg of "V" are suspended in 10 ml of ethanol, and 91 mg of hydroxylammonium chloride and 108 mg of sodium bicarbonate are added. 1 ml of water is then added and the mixture is heated under reflux for 8 hours. It is taken up in 20 ml of ice-water. The monohydroxyamidine is hydrogenated analogously to Example 2. 6-(3-amidino benzyloxy]-1-(3-amidinophenyl)-2-oxo-2H-quinoline is obtained.
The following examples relate to pharmaceutical formulations:
Example A: Injection glasses A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 with 2 N hydrochloric acid in 3 1 of doubly distilled water, subjected to sterile filtration, bottled in injection glasses, lyophilized under sterile conditions and closed under sterile conditions. Each injection glass contains 5 mg of active compound.
Example B: Suppositories A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter and the mixture is poured into moulds and allowed to cool. Each suppository comprises 20 mg of active compound.
Example C: Solution A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH2P04~2 H20, 28.48 g of NazHP04 ~ 12 H20 and 0 . 1 g of benzalkonium chloride in " - 42 -- 940 ml of doubly distilled water. The solution is adjusted to pH 6.8, topped up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
Example E: Tablets A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to tablets in the customary manner such that each tablet comprises 10 mg of active compound.
Example F: Coated tablets Tablets are pressed analogously to Example E and are then coated in the customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff.
Example G: Capsules 2 kg of active compound of the formula I are introduced into hard gelatine capsules in the customary manner such that each capsule contains 20 mg of the active compound.
Example H: Aafpoules A solution of 1 kg of active compound of the formula I
in 60 1 of doubly distilled water is subjected to sterile filtration, bottled into ampoules, lyophilized under sterile conditions and closed under sterile conditions. Each ampoule contains 10 mg of active compound.
Cyclic guanidines for treatment of thromboembolic diseases are described, for example, in WO 97/08165.
Aromatic heterocyclic compounds having a Factor Xa-inhibitory activity are known, for example, from WO 96/10022. Substituted N-[(aminoiminomethyl)phenyl-alkyl]-azaheterocyclylamides as Factor Xa inhibitors are described in WO 96/40679.
The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibiting action against the activated clotting protease, known by the name Factor Xa, or to the inhibition of other activated serine proteases, such as Factor VIIa, Factor IXa or thrombin.
Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyses the conversion of prothrombin into thrombin. Thrombin splits fibrinogen into fibrin monomers which, after crosslinking, make an elemental contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic diseases. However, an inhibition of thrombin can inhibit the fibrin formation involved in thrombus formation.
The inhibition of thrombin can be measured, for example, by the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.
An inhibition of Factor Xa can thus prevent thrombin being formed.
The compounds of the formula I according to the invention and their salts intervene in the blood clotting process by inhibiting Factor X and thus inhibit the formation of thrombi.
The inhibition of Factor Xa by the compounds according to the invention and the measurement of the FEB-26-O1 06:34 496151727191 P.03 R-512 Job-133 ~28. FEB. 2001 14:35 0049 6151 727191 NR. 255 S. 3/4 anticoaguJ.ating and antithrombotic activity can be determined by customary in vitro or in v~.vo methods_ A
suitable method is described, for example, by J. Hauptmann et al. in. Thrombosis aad Haemostasis x.990, 63, 220-223.
The inhibition of Factor Xa can be measured, for example, by the method of T. Hara et a1. in Thromb.
Haemostas. 1994, 71., 314-319.
After binding to tissue factor, clotting Factor vrla inj_tiates the extrinsic part of the czotting cascade and contributes towards activation of Factor X to Factor Xa. Inhibition of Factor VIIa thus prevents the formation o~ Factor Xa and therefore a subsequent formation of thrombin.
The inhibition of Factor VIIa by the compounds according to the invention and the measurement of the anticoagulating and the antithrombotic activity can be determined by customary in vitro or in vivo methods. A
customary method for measuring the inhibition of Factor VIIa is described, for example, by H.F. Ronning Ea al_ in Thrombosis Research 1996, 84, 73-S1.
Clotting Factor IXa is generated in the intrinsic clotting cascade and likewise participates in the activation of Factor X to Factor Xa. An inhibition of Factor IXa can therefore prevent formation of Factor Xa in another manner.
The inhibition of Factor IXa by the compounds according to the invention and the measurement of the anticoagul.ating and antithrombotic activity can be determined by customary in vitro or in vivo methods . A
suitable method is described, for example, by T. Chang et al. in Jouz-rsal of .Bio.Zogical Chemistry 1998, 273, 12089-12094_ The compounds of the formula I can be employed as medicament active compounds in human and veterinary FEB-28-01 08:34 496151127191 P.04 R-512 Job-133 ~28. FEB. 2001 14:36 0049 6151 727191 NR. 25S S. 4/4 medicine, ire particular for combating and preventing thromboembolic diseases, such as thrombosis, myocardial infarction, arteriosclerosis, inflammatiozis, apoplexy, angina pectoris, restenosis fol3owing angioplasty and claudicatio intermittens_ The invention relates to the compouzlds of the formu~.a T
and their saxts and to a process for the preparation of compounds of the formula 1 according to Claim 1 and their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolyszng or hydrogenolysing agent in that i) an amidino group is liberated from its oxadiazole derivative or oxazolidimone derivative by hydrogenolyszs or solvolysis, ii) a conventiozzal amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or an amino group protected by a conventional protective group is liberated, or b) in a compound of the formula I, one or more radical (s) R, R1, Ra and/or R3 is or are converted into one or more radical (s) R, Rl, R2 and/or R3, in that, for exampJ_e, i) an ester group is hydrolysed to a carboxyl group, ii) a vitro group is reduced, iii) an amino group is acylat~d, iv) a cyano group is converted into an amidino group and/or c) a base or acid of the formula I is converted into one of its salts.
For all the radicals which occur more than once, such as, for example, Ar, the meanings thereof are independent of one another.
Unless expressly stated otherwise, the radicals and parameters R, X, Y, Ri, R2, R3 and n above and below have the meanings given in the case of formula I.
A is alkyl, is linear or branched and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 C atoms. A is preferably methyl, and moreover ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl or 1,1,2- or 1,2,2-trimethylpropyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Alkylene is preferably methylene, ethylene, propylene or butylene, or furthermore branched alkylene.
COA is acyl and is preferably formyl, acetyl or propionyl, or furthermore also butyryl, pentanoyl or hexanoyl.
Hal is preferably F, C1 or Br, or also I.
R 1 S H , A, - ( CH2 ) m-R4 , - ( CH2 ) m-OA Or - ( CH2 ) m-Ar , preferably H, A, -CH2-R4 or R4, and R is particularly preferably H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COOH
or COOA.
R1 is H, A, -(CH2)m-R4, -(CH2)m-OA Or -(CH )m-Ar, preferably H, A, -CH2-R4 or R4, and Rl particularly preferably is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COON or CODA, and especially preferably H, A or COOH.
R2 is preferably Ar, particularly preferably phenyl which is monosubstituted by R5, and especially preferably phenyl which is monosubstituted by amidino.
R3 is Ar, preferably phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OA, Hal, CN or CF3, or phenyl, benzodioxol-5-yl, naphthyl or biphenyl, which are unsubstituted or mono- or disubstituted by cycloalkyl having 3-6 C atoms, OH, NH2, NHA, NA2, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHA, SO2NA2 , - ( CH2 ) n-NH2 . - ( CH2 ) n-NHA, - ( CH2 ) n-NA2 , -0- ( CH2 ) n-NH2 , -0- ( CH2 ) n-NHA, -0- ( CH2 ) n-NA2 , Or R5 , naphthyl or biphenyl monosubstituted by amidino being preferred. Preferred substituents for biphenyl are amidino, fluorine, SO2NH2 or SO2NHA.
Ar is phenyl, naphthyl of biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO2, CF3, NH2, NHA, NA2, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHA, SO2NA2, phenylsulfonamido, - ( CH2 ) n-NH2 , - ( CH2 ) n-NHA, - ( CH2 ) n-NA2 , -0- ( CH2 ) n-NH2 .
-0- ( CH2 ) n-NHA, -0- ( CH2 ) n-NA2 , -0- ( CH2 ) m-0- Or R5 .
Ar is preferably unsubstituted phenyl, naphthyl or biphenyl, and moreover preferably phenyl, naphthyl or biphenyl, which are mono-, di- or trisubstituted, for example by A, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, _ g _ propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, sulfonamido, methyl-sulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenyl sulfonamido, aminomethyl, aminoethyl, N-methylaminomethyl, N-ethylaminomethyl, N,N-dimethyl aminomethyl, aminomethyloxy, aminoethyloxy or R5, and furthermore benzodioxolyl.
Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)-phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)-phenyl, o-, m- or p-(N-ethylamino)-phenyl, o-, m- or p-(N,N-diethyl-amino)-phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-(methylsulfonamido)-phenyl, o-, m- or p-amidino-phenyl, 7-amidino-2-naphthyl, 3-fluoro-2'-sulfamoyl-biphenyl-4-yl, 3-fluoro-2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, o-, m- or p-(pyrrolidin-1-yl)-phenyl, o-, m- or p-(piperidin-1-yl)-phenyl, o-, m- or p-{5-methyl-[1,2,4Joxadiazol-3-yl)}-phenyl, 7-{5-methyl-[1,2,4-oxadiazol-3-yl)}-napth-2-yl, o-, m- or p-{5-oxo-[1,2,4]-oxadiazol-3-yl)}-phenyl or 7-{5-oxo-[1,2,4]-oxadiazol-3-yl)}-naphth-2-yl, and also preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-_ g _ dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
R4 is preferably, for example, COOH, COOA or CONH2.
RS is preferably, for example, unsubstituted -C ( =NH ) -NH2 , -NH-C ( =NH ) -NHz , -C ( =0 ) -N=C ( NHZ ) 2 , whi ch can also be monosubstituted by OH, ~~N.O ~~N.O
HN--~ N=
or especially preferably unsubstituted -C(=NH)-NHZ or {~N~O
N =C
CH3.
X is preferably, for example, absent, or is carbonyl or alkylene, in particular methylene or -CH(CH3)-.
Y is preferably 0.
m is preferably 0 or 1, and furthermore also 2.
n is preferably 0 or 1, and furthermore also 2 or 3.
The compounds of the formula I can have one or more chiral centres and can therefore occur in various stereoisomeric forms. Formula I includes all these forms.
' - 10 -The invention accordingly particularly relates to those compounds of the formula I in which at least one of the radicals mentioned has one of the abovementioned preferred meanings. Some preferred groups of compounds can be expressed by the following part formulae Ia to Ih, which correspond to the formula I and wherein the radicals not described in more detail have the meaning given in the case of formula I, but wherein in Ia R is H, A, -CHZ-COOA, -CH2-COOH, -CH2-CONHz, COOH or CODA;
in Ib R is H, A, -CHz-COOA, -CH2-COOH, -CHZ-CONH2, COOH or COOA, R1 is H, A, -CHZ-COOA, -CH2-COOH, -CHZ-CONHZ, COOH or COOA;
in Ic R is H, A, -CH2-COOA, -CHz-COOH, -CH2-CONH2, COOH or CODA
R1 is H, A, -CHZ-COOA, -CH2-COOH, -CH2-CONH2, COOH or CODA, Rz is phenyl which is monosubstituted by R5;
in Id R is H, A, -CHz-COOA, -CH2-COOH, -CH2-CONHz, COOH or COOA, R1 is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COOH or CODA, RZ is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, or by phenyl which is mono- or disubstituted by R5, S02NH2, S02NHA or F;
in Ie R is H, A, -CHz-COOA, -CH2-COOH, -CH2-CONHz, COOH or COOA, R1 is H, A, -CHZ-COOA, -CHZ-COOH, -CH2-CONHz, COOH or COOA, Rz is phenyl which is monosubstituted by R5, ' - 11 -R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, or biphenyl which is mono- or disubstituted by R5, SOZNH2, S02NHA or F, R5 i s -C ( =NH ) -NH2 or {~N~O
N =-~
in If R is H, A, -CH2-COOA, -CHZ-COOH, -CHZ-CONH2, COOH or COOA, R1 is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONH2, COOH or COOA, R2 is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, biphenyl which is mono- or disubstituted by R5 , SOzNH2 , SOzNHA or F , R5 is -C (=NH) -NHz or ~~N'o N =
n is 0 or 1;
in Ig R is H, A, -CH2-COOA, -CHZ-COOH, -CH2-CONHz, COOH or COOA, R1 is H, A, -CH2-COOA, -CHz-COOH, -CHz-CONH2, COOH or CODA, Rz is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are monosubstituted by CN or R5, or biphenyl which is mono- or disubstituted by R5, SOzNH2, S02NHA or F, RS is -C (=NH) -NH2 or {~N~O
N =
n is 0 or 1, X is absent or is alkylene or carbonyl, Y is absent or is 0;
in Ih R is H, A, -CHZ-COOA, -CHZ-COOH, -CH2-CONH2, COOH or CODA, R1 is H, A, -CH2-COOA, -CH2-COOH, -CH2-CONHz, COOH or COOA, R2 is phenyl which is monosubstituted by R5, R3 is phenyl or naphthyl, which are mono substituted by CN or R5, or biphenyl which is mono- or disubstituted by R5, S02NH2 , S02NHA or F , R5 is -C (=NH) -NH2, which can also be monosubstituted by OH, or {~N~O
N =C
n is 0 or 1, X is absent, Y is 0.
The compounds of the formula I and also the starting substances for their preparation are moreover prepared by methods which are known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), and in particular under reaction conditions which are known and suitable for the reactions mentioned. It is also possible here to make use of variants which are known per se and are not mentioned in more detail here.
If desired, the starting substances can also be fornled in situ, so that they are not isolated from the reaction mixture but are immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protective group instead o'f an H atom bonded to an N atom, in particular those which carry an R'-N group, wherein R' is an amino-protective group, instead of an HN group, and/or those which carry a hydroxyl-protective group instead of the H atom of a hydroxyl group, for example those which correspond to the formula I but carry a group -COOR", wherein R" is a hydroxyl-protective group, instead of a group -COOH.
Preferred starting substances are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
The liberation of the amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example Raney nickely. Suitable solvents are those mentioned below, in particular alcohols, such as methanol or ethanol, organic acids, such as acetic acid or propionic acid, or mixtures thereof. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100° under pressures between about 1 and 200 bar, preferably at 20-30° (room temperature) under 1-10 bar.
The oxadiazole group is introduced, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic acid ester, N,N'-carbonyldiimidazole or acetic anhydride.
Several - identical or different - protected amino and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective groups present differ from one another, they can in many cases be split off selectively.
The term "amino-protective group" is generally known and relates to groups which are suitable for protecting (blocking) an amino group from chemical reactions but can easily be removed after the desired chemical reaction has been carried out at other points of the molecule. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protective groups are removed after the desired reaction (or reaction sequence), their nature and size is moreover not critical; preferably, however, those having 1-20, in particular 1-8 C atoms are preferred. The term "acyl group" is to be interpreted in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl, and above all aralkoxy carbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA;
alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC
(tert-butyloxycarbonyl) and 2-iodoethoxycarbonyl;
aralkyloxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protective groups are BOC
and Mtr, and furthermore CBZ, Fmoc, benzyl and acetyl.
The term "hydroxyl-protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions but which can easily be removed after the desired chemical reaction has been carried out at other points of the molecule. Typical such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and furthermore also alkyl groups. The nature and size of the hydroxyl-protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms are preferred.
Examples of hydroxyl-protective groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluene-sulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is effected - depending on the protective group used - with, for example, strong acids, expediently with TFA or perchloric acid, or also with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, preferably, organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as methylene chloride, and furthermore also alcohols, such as methanol, ethanol or isopropanol, as well as water. Mixtures of the abovementioned solvents are furthermore possible. TFA is preferably used in excess without addition of a further solvent, and perchloric acid in the form of a mixture of acetic acid and 70~ perchloric acid in a ratio of 9:1. The reaction temperatures for the cleavage are expediently between about 0 and about 50°, and the reaction is preferably carried out at between 15 and 30° (room temperature).
The groups BOC, OBut and Mtr can preferably be split off, for example, with TFA in methylene chloride or with about 3 to 5n HC1 in dioxane at 15-30°, and the FMOC group with an approximately 5 to 50~ solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.
Protective groups which can be removed by hydrogenolysis (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be split off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst, such as palladium, expediently on a support, such as charcoal). Suitable solvents here are those mentioned above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is as a rule carried out at temperatures between about 0 and 100°
under pressures between about 1 and 200 bar, preferably at 20-30° under 1-10 bar. A hydrogenolysis of the CBZ
group is effected particularly well, for example, on 5 to 10~ Pd/C in methanol or with ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°.
Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetra-chloride, trifluoromethylbenzene, chloroform or methylene chloride; alcohols, such as methanol, ethanol, isopropanol, n-propanol n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF);
nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene;
esters, such as ethyl, acetate, or mixtures of the solvents mentioned.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst, such as, for example, Pd/C.
For the preparation of an amidine of the formula I (for example Ar = phenyl which is monosubstituted by C(=NH)-NH~) , it is also possible to add ammonia onto a nitrile. The addition reaction is preferably carried out in several stages, by, in a manner known per se, a) converting the nitrile into a thioamide with H2S, which is converted with an alkylating agent, for example CH3I, into the corresponding S-alkylimido-thioester, which in turn reacts with NH3 to give the amidine, b) converting the nitrite with an alcohol, for example ethanol, in the presence of HC1 into the corresponding imido-ester and treating this with ammonia, or c) reacting the nitrite with lithium bis-(trimethylsilyl)-amide and subsequently hydrolysing the product.
It is furthermore possible to convert a compound of the formula I into another compound of the formula I by converting one or more radical ( s ) R, R1 RZ and/or R3 into one or more radical ( s ) R, R1, RZ and/or R3, for example by acylating an amino group or reducing nitro ' groups (for example by hydrogenation on Raney nickel or Pd-charcoal in an inert solvent, such as methanol or ethanol) to amino groups.
Esters can be hydrolysed, for example, with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100°.
Free amino groups can furthermore be acylated in the customary manner with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, expediently i~ an inert solvent, such as methylene chloride or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between -60 and +30°.
A base of the formula I can be converted into the associated acid addition salt with an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, and subsequent evaporation. Acids which are particularly suitable for this reaction are those which give physiologically acceptable salts. It is thus possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, and furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malefic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and -disulfonic acids and lauryl-sulfuric acid. Salts with acids which are not physiologically acceptable, for example picrates, can be used for isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted with bases (for example sodium hydroxide or carbonate or potassium hydroxide or carbonate) into the corresponding metal salt, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts .
Physiologically acceptable organic bases, such as, for example, ethanolamine, can also be used.
Because of their molecular structure, compounds of the formula I according to the invention can be chiral and may accordingly occur in various enantiomeric forms.
They can therefore be present in a racemic or in an optically active form.
Since the pharmaceutical activity of the racemates and of the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product, or already the intermediate product, can be separated into enantiomeric compounds by chemical or physical measures known to the expert or can be already employed as such in the synthesis.
In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids, such as the R and S
forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
Chromatographic separation of enantiomers with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates, or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous. Suitable mobile phases for this are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in a ratio of 82:15:3.
The invention furthermore relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical formulations, in particular by a non-chemical route.
For this use, they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and optionally in combination with one or more further active compounds.
The invention furthermore relates to pharmaceutical formulations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These formulations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc and Vaseline. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, and furthermore suspensions, emulsions or implants for parenteral use and ointments, creams or powders for topical use. The new compounds can also be lyophilized and the lyophilisates obtained can be used, for example, for the preparation of injection preparations. The formulations mentioned can be sterilized and/or comprise auxiliaries, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyestuffs, flavourings and/or several further active compounds, for example one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts can be used in combating and preventing thromboembolic diseases, such as thrombosis, miocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.
The substances according to the invention are as a rule preferably administered here in dosages of between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg/kg of bodyweight. However, the specific dose for each patient depends on the most diverse factors, for example on the activity of the specific compound employed, on the age, bodyweight, general state of health, sex, on the diet, on the administration time and route, and on the rate of excretion, medicament combination and severity of the particular disease to which the treatment applies. Oral administration is preferred.
All temperatures above and below are stated in °C. In the following examples, "customary working up" means:
water is added, if necessary, the pH is adjusted to between 2 and 10, if necessary, depending on the structure of the end product, the mixture is extracted with ethyl acetate or methylene chloride, the organic phase is separated off, dried over sodium sulfate and ' evaporated and the residue is purified by chromatography over silica gel and/or by crystallization. Rf values on silica gel; mobile phase:
ethyl acetate/methanol 9:1.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (Fast Atom Bombardment) (M+H)+
Example 1 By reaction of 3-(tert-butyldimethylsilyloxy)-benzonitrile and .1-fluoro-4-nitrobenzene with tetrabutylammonium fluoride in THF analogously to Synthesis 1988, 378-379, the compound 3-(4-nitro-phenoxy)-benzonitrile ("AB"), m.p. 113-114°, is obtained.
90.4 g of sodium bicarbonate and 350 ml of water are added to a suspension of 78.4 g of "AB" and 68.0 g of hydroxylammonium chloride in 1 1 of methanol. The mixture is heated under reflux for 6 hours, while stirring. After cooling, water is added and the crystals which have precipitated out are separated off.
After drying, 87.5 g of pale yellow needle-shaped crystals of 3-(4-nitrophenoxy)-N-hydroxybenzamidine ("B"), m.p. 176-177°, EI273 are obtained.
A solution of 87.5 g of "B" in 250 ml of acetic anhydride is heated under reflux for 3 hours. After cooling, the mixture is poured onto ice-water and the precipitate is worked up in the customary manner to give 76.8 g of 5-methyl-3-[3-(4-nitrophenoxy)-phenyl]-[1,2,4]-oxadiazole ("C"), m.p. 134-135°, EI297.
A solution of 58.3 g of "C" in 500 ml of 1,4-dioxane is heated to 80° . 97 . 1 g of sodium sulfide octahydrate in 500 ml of water are then added (Yang-i Lin et al., J. Heterocycl. Chem. 1980, 17, 1273). After the mixture has been stirred for 2 hours, it is worked up in the customary manner to give 50.6 g of 5-methyl-3-[3-(4-aminophenoxy)-phenyl]-[1,2,4]-oxadiazole ("D"), m.p.
88-89°, EI267.
' 7.1 ml of 2,2,6-trimethyl-1,3-dioxin-4-one are added dropwise at 120° to a solution of 14.4 g of "D" in 130 ml of xylene and the mixture is subsequently stirred for 3 hours. After cooling, it is worked up in the customary manner to give 16.5 g of N-{4-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-phenyl}-3-oxo-butyramide ("E"), m.p. 104-105°, EI351.
~'~ N
--~~ ~ o N I ~ I \ 0 0 "E".
N
H
A solution of 8.2 g of "E" in 23 ml of concentrated sulfuric acid is stirred at 80° for 3 hours. After cooling and customary working up, 7.1 g of 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("F"), m.p. 234-235°, EI333 are obtained.
O"N
--~' ~ o N \
O
0.81 g of potassium tert-butylate and then 2.28 g of 3-(3-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole are added to a solution of 2.0 g of "F" in 50 ml of DMF and the mixture is subsequently stirred for 2 hours. After customary working up, in addition to 0.7 g of 0-alkylation product, 1.66 g of 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("G"), m.p. 167-168°, FAB 506 are obtained.
~"N
i o N I \ I \ \
N O N-~
l \ ' N "G", Analogously, reaction of "F" gives with 3-(2-bromomethyl-naphthalene-7-yl)-5-methyl-[1,2,4]oxadiazole, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline, m.p. 103-104°;
with 3-(4-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline, m.p. 204-205°.
Example 2 1 drop of acetic acid and water-moist Raney nickel are added to a solution of 0.37 g of "G" in 30 ml of methanol and the mixture is stirred under an HZ
atmosphere for 24 hours. After removal of the catalyst and customary working up, 0.12 g of 1-(3-amidinobenzyl)-6-(3-amidinophenoxy)-4-methyl-2-oxo-2H-quinoline, FAB 426 is obtained.
NH
H2N \ O \ \
N o NH
\ 'NH2 The following amidine derivatives are obtained analogously by hydrogenation with Raney nickel 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, m.p. 281-282°, FAB 476;
1-(4-amidinobenzyl)-6-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, m.p. 141-145°, FAB 426.
Example 3 2 eq. of N-bromosuccinimide and benzoyl peroxide are added to a solution of "F" in methanol and the mixture is stirred under reflux for 16 hours. After customary working up, 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-dibromomethyl-2-oxo-2H-quinoline are obtained.
The compound is then reacted with sodium formate and the product is subsequently oxidized by known methods to give 6-[3-(5-methyl[1,2,4]oxadiazol-3-yl)-phenoxy]
4-methoxycarbonyl-2-oxo-2H-quinoline ("H").
Reaction of "H" analogously to Example 1 gives, with 3-(3-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole ("1") with 3-(2-bromomethylnaphthalene-7-yl)-5-methyl-[1,2,4]oxadiazole ("2"), with 3-(4-bromomethylphenyl)-5-methyl-[1,2,4]oxadiazole ("3") with 3-(4'-bromomethylbiphenyl)-2-yl-5-methyl-[1,2,4]-oxadiazole ("4"), in addition to the 0-alkylation products, the following compounds ' - 26 -1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalene]-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4'-ylmethyl-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, from which the following carboxylic acid derivatives are obtained by customary ester hydrolysis 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalene]-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[2-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4'-ylmethyl-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline.
The following amidino derivatives are obtained therefrom by hydrogenation analogously to Example 2 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-6-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl[4'-ylmethyl)-6-(3 amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline.
Alternatively, the carboxylic acid esters can first be alkylated, then hydrogenated to the amidino derivatives and finally hydrolysed.
Example 4 2.13 mol of potassium carbonate are added to a solution of 0.425 mol of 4-methyl-3-nitro-phenol in 2 1 of pyridine. 0.425 mol of hopper (I) chloride is added and the mixture is heated under reflux for 0.5 hour.
0.5 mol of 3-bromobenzonitrile is then added and the mixture is heated under reflux for 3 days. After customary working up 3-(4-methyl-3-nitrophenoxy)-benzonitrile is obtained. Analogously to Example 1, the compound 5-methyl-3-[3-(4-methyl-3-nitro-phenoxy)-phenyl]-[1,2,4]-oxadiazole is obtained therefrom with hydroxylammonium chloride and by heating in acetic anhydride. By reduction of the nitro group analogously to Example 1 and oxidation of the methyl group analogously to Example 3, the compound 5-methyl-3-[3-(4-formyl-3-amino-phenoxy)-phenyl]-[1,2,4]-oxadiazole is obtained therefrom. By Friedlander condensation analogously to the method of del mar Blanco et al., Heterocycles, 1993, 1397 et seq., the compound 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethoxycarbonyl-2-oxo-2H-quinoline ("I") is obtained therefrom.
Analogously to Example 3, by reaction of "I" with compounds "1", "2", "3" and "4" and subsequent hydrogenation, the following compounds are obtained 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl-4'-ylmethyl)-7-(3-amidino-phenoxy)-3-ethoxycarbonyl-2-oxo-2H-quinoline.
Ester hydrolysis gives therefrom the compounds 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-ber~zyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline, 1-(2-amidino-biphenyl-4'-ylmethyl)-7-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline.
Example 5 By reaction of 3-hydroxybenzonitrile with 3-bromo-nitrobenzene analogously to Example 4, the compound 3-(3-nitro-phenoxy)-benzonitrile is obtained.
Analogously to Example 1, the compound 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline ("K") is obtained by reduction of the nitro group, formation of the oxadiazole ring, reaction with 2,2,6-trimethyl-1,3-dioxin-4-one and cyclization with concentrated sulfuric acid. Analogously to Example 3, 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline ("L") is obtained therefrom by oxidation of the 4-methyl group.
By reaction of "L" analogously to Example 1 gives, with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-(3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl) naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]
oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H
quinoline.
1-[4-(5-methyl-(1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methoxycarbonyl-2-oxo-2H-quinoline, from which the followirig carboxylic acid derivatives are obtained by customary ester hydrolysis 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-(1,2,4]oxadiazol-3-yl)-phenoxy]-4-carboxy-2-oxo-2H-quinoline.
By hydrogenation analogously to Example 2, the following amidino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-4-carboxy-2-oxo-2H-quinoline.
By reaction of "K" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline.
1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-4-methyl-2-oxo-2H-quinoline.
By hydrogenation analogously to Example 2, the following amino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline, Example 6 By reaction of 3-hydroxybenzonitrile with 3-bromo-nitrobenzene analogously to Example 4, the compound 3-(3-nitro-phenoxy)-benzonitrile is obtained.
Analogously to Example l, the compound 7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline ("M") is obtained by reduction of the nitro group, formation of the oxadiazole ring, reaction with 2,2,6-trimethyl-5-ethyl-1,3-dioxin-4-one and cyclization with concentrated sulfuric acid. By reaction of "M" with "1", "2" and "3", in addition to the O-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-ethyl-4-methyl-2-oxo-2H-quinoline.
By hydrogenation analogously to Example 2, the following amidino derivatives are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-ethyl-4-methyl-2-oxo-2H-quinoline.
The following compounds are obtained analogously 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidinonaphthalene)-2-ylmethyl)-7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-methoxycarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-carboxymethyl-4-methyl-2-oxo-2H-quinoline, 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidino-phenoxy)-3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-7-(3-amidino-phenoxy)-3-aminocarbonylmethyl-4-methyl-2-oxo-2H-quinoline.
Example 7 4.3 g of potassium carbonate are added to a suspension of 1.0 g of 6-hydroxyquinolin-2-one in 25 ml of DMF and the mixture is subsequently stirred at room temperature for 0.5 hour. 0.6 g o~ copper (I) chloride is then added and the mixture is heated under reflux for 0.5 hour. After addition of 3-bromobenzonitrile in 25 ml of pyridine, the reaction mixture is heated under reflux for 18 hours. It is worked up in the customary manner to give, after chromatography over silica gel, the two compounds 6-(3-cyanophenoxy)-2-oxo-2H-quinoline ("N"), m.p.
221-222°, EI 262 and 1-(3-cyanophenyl)-6-(3-cyanophenoxy)-2-oxo-2H-quinoline ("O"), m.p. 82-84°, EI 363.
By reaction of "N" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-cyanophenoxy]-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-cyanophenoxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-cyanophenoxy]-2-oxo-2H-quinoline.
By reaction with hydroxylammonium chloride and subsequent reduction with Hz and Raney nickel, the following compounds are obtained therefrom 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline, FAB 413; m.p. 160-162°, 1-(7-amidinonaphthalen-2-ylmethyl) 6-(3-amidino-phenoxy)-2-oxo-2H-quinoline, 1-(4-amidino-benzyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline.
An analogous procedure, starting from 7-hydroxyquinoline-2-one, gives the compounds 1-(3-amidinobenzyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline, 1-(7-amidinonaphthalene)-2-ylmethyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline, 1-(4-amidinobenzyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline.
0.19 g of hydroxylammonium chloride and 0.22 g of sodium bicarbonate is added to a suspension of 0.12 g of "0" in 5 ml of ethanol. After further addition of 0.5 ml of water, the mixture is boiled under reflux for 2 hours. After customary working up, 1-(3-N-hydroxyamidino-phenyl)-6-(3-N-hydroxyamidino-phenoxy)-2-oxo-2H-quinoline, EI 429 is obtained.
By oxadiazole formation and hydrogenation, 1-(3-amidino-phenyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline, FAB 398; m.p. 62-64° is obtained therefrom.
1-(3-Amidino-phenyl)-7-(3-amidino-phenoxy)-2-oxo-2H-quinoline is obtained analogously.
Example 8 A suspension of 1 g of 6-hydroxy-2-oxo-2H-quinoline in 30 ml of DMF is cooled to about 10° and 0.84 g of potassium tert-butylate is then added. 2.0 g of 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]oxadiazol (m. p. 54-55°) are added and the mixture is subsequently stirred for 2 hours and worked up in the customary manner. 6-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-benzyl-oxy]-2-oxo-2H-quinoline ("P"), m.p. 208-209°, EI333 is obtained.
By reaction of "P" with 3-bromobenzonitrile analogously to Example 7, the compound 1-(3-cyanophenyl)-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline.
By reaction with hydroxylammonium chloride and subsequent reduction with H2 and Raney nickel, 1-(3-amidino-phenyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline is obtained therefrom.
By reaction of "P" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline.
By subsequent reduction with H2 and Raney nickel, the following compounds are obtained therefrom 1-(3-amidinobenzyl)-6-(3-amidinobenzyloxy-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 1-(4-amidinobenzyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline.
' Example 9 Analogously to Example 8, by reaction of 7-hydroxy-2-oxo-2H-quinoline with 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]oxadiazole, the compound 7-[3-(5-methyl[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline ("Q"), m.p. 168-170°, EI 333 is obtained.
By reaction of "Q" with 3-bromobenzonitrile analogously to Example 7, the compound 1-(3-(cyanophenyl)-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline is obtained.
By reaction with hydroxylammonium chloride and subsequent reduction with HZ and Raney nickel, 1-(3-amidino-phenyl)-7-(3-amidinobenzyloxy)-2-oxo-2H
quinoline is obtained therefrom.
By reaction of "Q" with "1", "2" and "3", in addition to the 0-alkylation products, the following compounds are obtained 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-7-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline.
By subsequent reduction with HZ and Raney nickel, the following compounds are obtained therefrom 1-(3-amidinobenzyl)-7-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 1-(7-amidino-naphthalen-2-ylmethyl)-7-(3-amidinobenzyloxy)-2-oxo-2H-quinoline, 1-(4-amidinobenzyl)-7-(3-amidinobenzyloxy)-2-oxo-2H-quinoline.
Example 10 By reaction of 6-hydroxy-2-oxo-2H-quinoline with acetic anhydride in pyridine in a known manner, 6-acetoxy-2-oxo-2H-quinoline, m.p. 221-222° is obtained. By subsequent alkylation with "1", in addition to the O-alkylation product, the compound 1-(3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-acetoxy-2-oxo-2H-quinoline, m.p. 157-158° is obtained. By deacetylation in a known manner, 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-hydroxy-2-oxo-2H-quinoline, m.p. 271-273°
("R") is obtained.
By reaction of "R" with 3-[5-methyl-[1,2,4]oxadiazol-3-yl]-benzoyl chloride with the addition of caesium carbonate in DMF, after customary working up the compound 1-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline is obtained.
By subsequent hydrogenation analogously to Example 2, 1-(3-amidinobenzyl)-6-(3-amidinobenzyloxy)-2-oxo-2H-quinoline is obtained therefrom.
By reaction of "R" with 1-(3-[5-methyl-[1,2,4]-oxadiazol-3-yl]-phenyl}methyl bromide and subsequent hydrogenation, the compound 1-(3-amidinobenzyl)-6-[1-(3-amidinophenyl)methoxy)-2-oxo-2H-quinoline, m.p.
125-127° is obtained analogously.
NH \ I O
I
NH2 ~ N O NH
I \ _NHZ
. - - 37 -The compound 1-(3-amidinobenzyl)-7-[1-(3-amidino-phenyl)methyloxy)-2-oxo-2H-quinoline, m.p. 146-150° is obtained analogously.
Example 11 By reaction of "R" with 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenylboronic acid, 1-[3-(5-methyl-[1,2,4]-oxadiazol-3-yl)-benzyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-2-oxo-2H-quinoline and therefrom, by hydrogenation, 1-(3-amidinobenzyl)-6-(3-amidino-phenoxy)-2-oxo-2H-quinoline are obtained.
The other compounds mentioned in Example 7 are also obtained analogously.
Example 12 By reaction of 3-methyl-4-nitro-phenol with acetic anhydride and sulfuric acid, 1-acetoxy-3-methyl-4-nitro-benzene is obtained. Subsequent bromination with NBS with irradiation gives 1-acetoxy-3-dibromo-methyl-4-nitro-benzene, m.p. 130-131°, EI 353. By reaction with sodium formate in water and ethanol, 3-formyl-4-nitro-phenol, m.p. 145-146°, EI 167 is obtained, and is converted by reaction with benzyl bromide with addition of potassium carbonate in DMF
into 1-benzyloxy-3-formyl-4-nitro-benzene, m.p.
120-121°, EI 257. By reduction of the nitro group with Na2S in dioxane and water at 80°, 1-benzyloxy-3-formyl 4-amino-benzene, EI 245 is obtained. By reaction with diethyl malonate in piperidine and heating, the compound 6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H
quinoline ("S"), m.p. 155-156°, EI 323 is obtained therefrom.
By reaction of "S" with "2", 1-[7-(5-methyl]-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H-quinoline is . . _ 38 -obtained, and is converted by hydrogenation with Raney nickel into 1-[7-amidino-naphthalen-2-ylmethyl]-6-benzyloxy-3-ethoxycarbonyl-2-oxo-2H-quinoline.
By ester hydrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-benzyloxy-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
Example 13 The regio-isomeric carboxylic acid derivatives (3-carboxy-...) from Example 3 are obtained as follows:
a) By reaction of 4-methyl-3-nitro-phenol with acetic anhydride and sulfuric acid, 1-acetoxy-4-methyl-3-nitro-benzene is obtained. Subsequent bromination with NBS with irradiation gives 1-acetoxy-4-dibromo-methyl-3-nitro-benzene. By reaction with sodium formate in water and ethanol, 4-formyl-3-nitro-phenol is obtained therefrom, and is converted by reaction with tert-butyl-dimethylsilyl chloride with the addition of imidazole in methylene chloride into 1-tert-butyl-dimethylsiloxy-4-formyl-3-nitro-benzene. By reduction of the nitro group with NazS in dioxane and water at 80°, 1-tert-butyl-dimethylsilyloxy-4-formyl-3-amino-benzene is obtained. By reaction with dimethyl malonate with addition of piperidine, the compound 7-tert-butyl-dimethylsilyloxy-3-methoxycarbonyl-2-oxo-2H-quinoline ("T") is obtained therefrom.
By reaction of "T" with "2", 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-tert-butyl-dimethylsilyloxy-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained, which is converted into 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-7-hydroxy-3-methoxycarbonyl-2-oxo-2H-quinoline ("U") by splitting off of the silyl group.
. . _ 39 _ By reaction of "U" with 3-bromobenzonitrile and further reaction analogously to Example 1, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained therefrom, and 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-3-methoxy-carbonyl-2-oxo-2H-quinoline is obtained therefrom by hydrogenation.
By ester hydrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
b) By reaction of "U" with 3-(3-bromomethyl-phenyl)-5-methyl-[1,2,4]-oxadiazole analogously to Example 8, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-3-methoxycarbonyl-2-oxo-2H-quinoline is obtained, and is converted by hydrogenation into 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzyloxy)-3-methoxy-carbonyl-2-oxo-2H-quinoline.
By ester hyrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzyloxy)-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
c) By reaction of "U" with 3-[5-methyl-[1,2,4]-oxadiazol-3-yl]-benzoyl chloride analogously to Example 10, 1-[7-(5-methyl-[1,2,4]oxadiazol-3-yl)-naphthalen-2-ylmethyl]-6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoyloxy]-3-methoxycarbonyl-2-oxo-2H-quinoline is obtained, and is converted by hydrogenation into 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzoyloxy)-3-methoxycarbonyl-2-oxo-2H-quinoline.
By ester hydrolysis, 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-benzoyloxy)-3-carboxy-2-oxo-2H-quinoline is obtained therefrom.
- ' - 40 -The regio-isomeric 7-isomers are obtained analogously starting from 3-methyl-4-nitro-phenol.
Example 14 The following compounds are obtained analogously to Example 12 1-(3-amidino-benzyl)-6-benzyloxy-3-ethoxycarbonyl 2-oxo-2H-quinoline, m.p. 176.9°, and 1-(3-amidino benzyl)-6-benzyloxy-3-carboxy-2-oxo-2H-quinoline, m.p.
>300° therefrom by ester hydrolysis, and the compound 1-(7-cyano-naphthalen-2-ylmethyl)-7-(7-cyano-naphthalen-2-ylmethyl)-3-ethoxycarbonyl-2-oxo-2H-quinoline, m.p. 216.4°.
Example 15 Analogously to Example 4, the compound 1-(7-cyano-naphthalen-2-ylmethyl)-7-(3-cyano-phenoxy]-3-ethoxycarbonyl-2-oxo-2H-quinoline, m.p. 183.5° is obtained, and 1-[7-(N-hydroxy-amidino)-naphthalen-2-ylmethyl]-7-[3-(N-hydroxy-amidino)-phenoxy]-3-carboxy-2-oxo-2H-quinoline m.p. >300° is obtained therefrom.
Example 16 800 mg of molecular sieve (0.4 nm) are added to a solution of 200 mg of 6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-2-oxo-2H-quinoline, 265 mg of 3-cyanophenylboronic acid and 220 mg of Cu(II) acetate in 15 ml of methylene chloride and the mixture is stirred under nitrogen at room temperature. After addition of 0.145 ml of pyridine and 0.25 ml of triethylamine, the mixture is subsequently stirred for 18 hours. After addition of 50 ml of water, the mixture is worked up in the customary manner and 190 mg of . ' - 41 -6-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyloxy]-1-(3-cyanophenyl)-2-oxo-2H-quinoline ("V"), EI 434 are obtained.
140 mg of "V" are suspended in 10 ml of ethanol, and 91 mg of hydroxylammonium chloride and 108 mg of sodium bicarbonate are added. 1 ml of water is then added and the mixture is heated under reflux for 8 hours. It is taken up in 20 ml of ice-water. The monohydroxyamidine is hydrogenated analogously to Example 2. 6-(3-amidino benzyloxy]-1-(3-amidinophenyl)-2-oxo-2H-quinoline is obtained.
The following examples relate to pharmaceutical formulations:
Example A: Injection glasses A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 with 2 N hydrochloric acid in 3 1 of doubly distilled water, subjected to sterile filtration, bottled in injection glasses, lyophilized under sterile conditions and closed under sterile conditions. Each injection glass contains 5 mg of active compound.
Example B: Suppositories A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter and the mixture is poured into moulds and allowed to cool. Each suppository comprises 20 mg of active compound.
Example C: Solution A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH2P04~2 H20, 28.48 g of NazHP04 ~ 12 H20 and 0 . 1 g of benzalkonium chloride in " - 42 -- 940 ml of doubly distilled water. The solution is adjusted to pH 6.8, topped up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment 500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
Example E: Tablets A mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to tablets in the customary manner such that each tablet comprises 10 mg of active compound.
Example F: Coated tablets Tablets are pressed analogously to Example E and are then coated in the customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff.
Example G: Capsules 2 kg of active compound of the formula I are introduced into hard gelatine capsules in the customary manner such that each capsule contains 20 mg of the active compound.
Example H: Aafpoules A solution of 1 kg of active compound of the formula I
in 60 1 of doubly distilled water is subjected to sterile filtration, bottled into ampoules, lyophilized under sterile conditions and closed under sterile conditions. Each ampoule contains 10 mg of active compound.
Claims (10)
1. Compounds of the formula I
wherein R and R1 in each case independently of one another are H, A, -(CH2)m-R4, -(CH2)m-OA or -(CH2)m-Ar, R2 is R3 is Ar, R4 is CN, COOH, COOA, CONH2, CONHA, CONA2 or C(=NH)-NH2, R5 is -C(=NH)-NH2, -NH-C(=NH)-NH2 or -C(=O)-N=C(NH2)2, which are unsubstituted or monosubstituted by -COA, -COOA, -OH
or by a conventional amino-protective group, R6 is H, A or NH2, Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO2, CF3, NH2, NHA, NA2, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHA, SO2NA2 , -(CH2)n-NH2, -(CH2)n-NHA, -(CH2)n-NA2, -0-(CH2)n-NH2, -0-(CH2)n-NHA, -0-(CH2)n-NA2 , -O-(CH2)m-O- Or R5, A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, O or S, Hal is F, C1, Br or I, m is 0, 1 or 2 and n is 0, '1, 2 or 3 and salts thereof.
wherein R and R1 in each case independently of one another are H, A, -(CH2)m-R4, -(CH2)m-OA or -(CH2)m-Ar, R2 is R3 is Ar, R4 is CN, COOH, COOA, CONH2, CONHA, CONA2 or C(=NH)-NH2, R5 is -C(=NH)-NH2, -NH-C(=NH)-NH2 or -C(=O)-N=C(NH2)2, which are unsubstituted or monosubstituted by -COA, -COOA, -OH
or by a conventional amino-protective group, R6 is H, A or NH2, Ar is phenyl, naphthyl or biphenyl, which are unsubstituted or mono-, di- or trisubstituted by A, cycloalkyl having 3-6 C atoms, OH, OA, Hal, CN, NO2, CF3, NH2, NHA, NA2, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHA, SO2NA2 , -(CH2)n-NH2, -(CH2)n-NHA, -(CH2)n-NA2, -0-(CH2)n-NH2, -0-(CH2)n-NHA, -0-(CH2)n-NA2 , -O-(CH2)m-O- Or R5, A is alkyl having 1-6 C atoms, X is absent or is alkylene having 1-4 C atoms or carbonyl, Y is absent or is NH, O or S, Hal is F, C1, Br or I, m is 0, 1 or 2 and n is 0, '1, 2 or 3 and salts thereof.
2. Compounds according to Claim 1, a) 1-(3-amidinobenzyl)-6-(3-amidinophenoxy)-4-methyl-2-oxo-2H-quinoline, b) 1-(7-amidino-naphthalen-2-ylmethyl)-6-(3-amidino-phenoxy)-4-methyl-2-oxo-2H-quinoline and salts thereof.
3. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent in that i) an amidino group is liberated from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis, ii) a conventional amino-protective group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or an amino group protected by a conventional protective group is liberated, or b) in a compound of the formula I, one or more radical(s) R, R1, R2 and/or R3 is or are converted into one or more radical(s) R, R1, R2 and/or R3, in that, for example, i) an ester group is hydrolysed to a carboxyl group, ii) a nitro group is reduced, iii) an amino group is acylated, iv) a cyano group is converted into an amidino group and/or c) a base or acid of the formula I is converted into one of its salts.
4. Process for the preparation of pharmaceutical formulations, characterized in that a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary.
5. Pharmaceutical formulation, characterized by a content of at least one compound of the formula I
according to Claim 1 and/or one of its physiologically acceptable salts.
according to Claim 1 and/or one of its physiologically acceptable salts.
6. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates as medicament active compounds.
7. Compounds of the formula I according to Claim 1 and their physiologically acceptable salts for combating thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.
8. Medicaments of the formula I according to Claim 1 and their physiologically acceptable salts as inhibitors of coagulation factor Xa.
9. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts for the preparation of a medicament.
10. Use of compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts in combating thromboses, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis following angioplasty and claudicatio intermittens.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19839499.3 | 1998-08-29 | ||
DE19839499A DE19839499A1 (en) | 1998-08-29 | 1998-08-29 | 2-oxo-2H-quinoline derivatives |
PCT/EP1999/005315 WO2000012479A1 (en) | 1998-08-29 | 1999-07-26 | 2-oxo-2h-quinoline derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2342230A1 true CA2342230A1 (en) | 2000-03-09 |
Family
ID=7879227
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002342230A Abandoned CA2342230A1 (en) | 1998-08-29 | 1999-07-26 | 2-oxo-2h-quinoline derivatives |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1107954A1 (en) |
JP (1) | JP2002523494A (en) |
KR (1) | KR20010072862A (en) |
CN (1) | CN1315942A (en) |
AR (1) | AR021782A1 (en) |
AU (1) | AU5164199A (en) |
BR (1) | BR9913140A (en) |
CA (1) | CA2342230A1 (en) |
DE (1) | DE19839499A1 (en) |
HK (1) | HK1042478A1 (en) |
HU (1) | HUP0103212A3 (en) |
ID (1) | ID27863A (en) |
NO (1) | NO20010996L (en) |
PL (1) | PL346045A1 (en) |
SK (1) | SK2652001A3 (en) |
WO (1) | WO2000012479A1 (en) |
ZA (1) | ZA200102565B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1569912T3 (en) | 2002-12-03 | 2015-06-29 | Pharmacyclics Inc | 2- (2-hydroxybiphenyl-3-yl) -1h-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors. |
DK3174868T3 (en) | 2014-08-01 | 2021-11-08 | Nuevolution As | COMPOUNDS ACTIVE AGAINST BROMODOMAINS |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4070470A (en) * | 1974-06-24 | 1978-01-24 | Otsuka Pharmaceutical Co., Ltd. | Platelet aggregation inhibiting carbostyrils, their compositions and method of use |
IE43079B1 (en) * | 1975-03-20 | 1980-12-17 | Ici Ltd | Quinolone derivatives |
JPS596858B2 (en) * | 1975-04-30 | 1984-02-15 | オオツカセイヤク カブシキガイシヤ | Method for producing 3,4-dihydrocarbostyryl derivative |
AT347956B (en) * | 1976-03-18 | 1979-01-25 | Ici Ltd | Process for the preparation of new quinol-2-on-4-yl-alkanoic acids and their base addition salts |
DE2651581A1 (en) * | 1976-11-12 | 1978-05-18 | Merck Patent Gmbh | CHINOLONE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
CA2091173A1 (en) * | 1990-09-07 | 1992-03-08 | Adriano Afonso | Antiviral compounds and antihypertensive compounds |
CA2091172C (en) * | 1990-09-07 | 1997-05-20 | Adriano Afonso | Antiviral compounds and antihypertensive compounds |
ZA928276B (en) * | 1991-10-31 | 1993-05-06 | Daiichi Seiyaku Co | Aromatic amidine derivates and salts thereof. |
DE4208304A1 (en) * | 1992-03-16 | 1993-09-23 | Merck Patent Gmbh | 2-OXOCHINOLINDERIVATE |
IL115420A0 (en) * | 1994-09-26 | 1995-12-31 | Zeneca Ltd | Aminoheterocyclic derivatives |
US5612353A (en) * | 1995-06-07 | 1997-03-18 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds |
DE19528418A1 (en) * | 1995-08-02 | 1997-02-06 | Merck Patent Gmbh | Endothelin receptor antagonists |
DE19530996A1 (en) * | 1995-08-23 | 1997-02-27 | Boehringer Mannheim Gmbh | Cyclic guanidines, process for their preparation and pharmaceuticals |
US5968959A (en) * | 1997-12-12 | 1999-10-19 | Orion Corporation | Method for the prevention and treatment of stunned myocardium |
-
1998
- 1998-08-29 DE DE19839499A patent/DE19839499A1/en not_active Withdrawn
-
1999
- 1999-07-26 KR KR1020017002261A patent/KR20010072862A/en not_active Application Discontinuation
- 1999-07-26 WO PCT/EP1999/005315 patent/WO2000012479A1/en not_active Application Discontinuation
- 1999-07-26 AU AU51641/99A patent/AU5164199A/en not_active Abandoned
- 1999-07-26 CN CN99810283A patent/CN1315942A/en active Pending
- 1999-07-26 JP JP2000567512A patent/JP2002523494A/en active Pending
- 1999-07-26 CA CA002342230A patent/CA2342230A1/en not_active Abandoned
- 1999-07-26 HU HU0103212A patent/HUP0103212A3/en unknown
- 1999-07-26 ID IDW20010680A patent/ID27863A/en unknown
- 1999-07-26 SK SK265-2001A patent/SK2652001A3/en unknown
- 1999-07-26 EP EP99936606A patent/EP1107954A1/en not_active Withdrawn
- 1999-07-26 BR BR9913140-4A patent/BR9913140A/en not_active Application Discontinuation
- 1999-07-26 PL PL99346045A patent/PL346045A1/en unknown
- 1999-08-27 AR ARP990104301A patent/AR021782A1/en unknown
-
2001
- 2001-02-27 NO NO20010996A patent/NO20010996L/en not_active Application Discontinuation
- 2001-03-28 ZA ZA200102565A patent/ZA200102565B/en unknown
-
2002
- 2002-03-25 HK HK02102249.3A patent/HK1042478A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
NO20010996D0 (en) | 2001-02-27 |
EP1107954A1 (en) | 2001-06-20 |
HUP0103212A3 (en) | 2002-06-28 |
KR20010072862A (en) | 2001-07-31 |
HUP0103212A2 (en) | 2002-05-29 |
SK2652001A3 (en) | 2001-09-11 |
CN1315942A (en) | 2001-10-03 |
WO2000012479A1 (en) | 2000-03-09 |
PL346045A1 (en) | 2002-01-14 |
DE19839499A1 (en) | 2000-03-02 |
HK1042478A1 (en) | 2002-08-16 |
AR021782A1 (en) | 2002-08-07 |
ID27863A (en) | 2001-04-26 |
AU5164199A (en) | 2000-03-21 |
NO20010996L (en) | 2001-02-27 |
BR9913140A (en) | 2001-05-08 |
ZA200102565B (en) | 2002-06-28 |
JP2002523494A (en) | 2002-07-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6492384B1 (en) | Imidazo (4,5-C) pyridine-4-one derivatives with factor XA inhibiting effect | |
US7557222B2 (en) | 1-[(4-Ethynylphenyl)]-2-[(phenyl)]-pyrrolidine-1,2-dicarboxamide derivatives as inhibitors of coagulation factors Xa and VIIa for the treatment of thrombosis | |
AU9540798A (en) | Benzamidine derivatives | |
EP3189053B1 (en) | An improved process for the preparation of apixaban and intermediates thereof | |
JP2002534429A (en) | Imidazo [4,5-c] pyridin-4-one derivatives | |
MXPA01008844A (en) | Pyrazole-3-on-derivative as factor xa inhibitors. | |
CA2342230A1 (en) | 2-oxo-2h-quinoline derivatives | |
US6380430B1 (en) | Biphenyl derivatives | |
US7598241B2 (en) | Carboxamide derivatives and their use as factor Xa inhibitors | |
US7183277B2 (en) | Carboxylic acid amides | |
CZ2001680A3 (en) | Derivative of 2-oxo-2H-quinoline, process of its preparation, use and pharmaceutical preparation in which it is comprised | |
US20050171102A1 (en) | Semicarbazide derivatives for combating thromboembolic diseases | |
MXPA01006942A (en) | Imidazo[4,5-c]-pyridine-4-on-derivatives | |
US20060135515A1 (en) | Heterocyclic amides and their use treating thromboembolic diseases and tumors | |
CA2417427A1 (en) | Acetamide derivatives and the use thereof as inhibitors of coagulation factors xa and viia | |
KR20040095256A (en) | Semicarbazide derivatives and the use thereof as antithrombotics |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |