WO1997019919A1 - Derives de sulfamides - Google Patents
Derives de sulfamides Download PDFInfo
- Publication number
- WO1997019919A1 WO1997019919A1 PCT/JP1996/003520 JP9603520W WO9719919A1 WO 1997019919 A1 WO1997019919 A1 WO 1997019919A1 JP 9603520 W JP9603520 W JP 9603520W WO 9719919 A1 WO9719919 A1 WO 9719919A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- optionally substituted
- acceptable salt
- pharmaceutically acceptable
- hydrate
- Prior art date
Links
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 78
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 48
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 36
- 125000001424 substituent group Chemical group 0.000 claims abstract description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 26
- 125000002252 acyl group Chemical group 0.000 claims abstract description 22
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 21
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
- 239000004019 antithrombin Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims abstract description 6
- -1 1-naphthylmethylaminosulfonyl Chemical group 0.000 claims description 225
- 150000001875 compounds Chemical class 0.000 claims description 79
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000003277 amino group Chemical group 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004434 sulfur atom Chemical group 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 239000003146 anticoagulant agent Substances 0.000 claims description 4
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 229940122388 Thrombin inhibitor Drugs 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 239000003245 coal Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 6
- 230000036571 hydration Effects 0.000 claims 2
- 238000006703 hydration reaction Methods 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 230000002785 anti-thrombosis Effects 0.000 claims 1
- 229960004251 hydroquinine Drugs 0.000 claims 1
- 125000005182 hydroxyalkylcarbonyl group Chemical group 0.000 claims 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 12
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 208000007536 Thrombosis Diseases 0.000 abstract description 3
- 150000004677 hydrates Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000003786 synthesis reaction Methods 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 239000002904 solvent Substances 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 8
- 125000004149 thio group Chemical group *S* 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 235000010724 Wisteria floribunda Nutrition 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- PBLNHHSDYFYZNC-UHFFFAOYSA-N (1-naphthyl)methanol Chemical compound C1=CC=C2C(CO)=CC=CC2=C1 PBLNHHSDYFYZNC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 229940127218 antiplatelet drug Drugs 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000023555 blood coagulation Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 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
- 238000006482 condensation reaction Methods 0.000 description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 description 3
- 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940126701 oral medication Drugs 0.000 description 3
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
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- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 108090000166 Thrombin receptors Proteins 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000005138 alkoxysulfonyl group Chemical group 0.000 description 2
- 125000005210 alkyl ammonium group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 2
- 229960003856 argatroban Drugs 0.000 description 2
- 125000005604 azodicarboxylate group Chemical group 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
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- 125000005144 cycloalkylsulfonyl group Chemical group 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
- 235000019425 dextrin Nutrition 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
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- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
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- 238000010992 reflux Methods 0.000 description 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 2
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
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- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
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- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- MNQDKWZEUULFPX-UHFFFAOYSA-M dithiazanine iodide Chemical group [I-].S1C2=CC=CC=C2[N+](CC)=C1C=CC=CC=C1N(CC)C2=CC=CC=C2S1 MNQDKWZEUULFPX-UHFFFAOYSA-M 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000006005 fluoroethoxy group Chemical group 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical group C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical group C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 125000000346 malonyl group Chemical group C(CC(=O)*)(=O)* 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- HPXIKMBHOXLFOR-LICLKQGHSA-N n-[(e)-(3,4-dimethoxyphenyl)methylideneamino]pyridine-4-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1\C=N\NC(=O)C1=CC=NC=C1 HPXIKMBHOXLFOR-LICLKQGHSA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940127216 oral anticoagulant drug Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- WEYVCQFUGFRXOM-UHFFFAOYSA-N perazine Chemical group C1CN(C)CCN1CCCN1C2=CC=CC=C2SC2=CC=CC=C21 WEYVCQFUGFRXOM-UHFFFAOYSA-N 0.000 description 1
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical group C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical group O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001166 thiolanyl group Chemical group 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical class C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000002753 trypsin inhibitor Substances 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
- 229950004348 verazide Drugs 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention has the general formula (1)
- R t represents a hydrogen atom, a lower alkyl group or an amino protecting group
- R 2 represents a nitrogen-containing heterocyclic ring which may have a substituent or may be condensed.
- R 3 represents a group A— (CH 2 ) m —, a hydrogen atom or an optionally substituted lower alkyl group, wherein A represents an optionally substituted aryl group, an optionally substituted And m represents an integer of 0 to 6.
- An optionally condensed heterocyclic ring or an optionally substituted lower cycloalkyl group, and m represents an integer of 0 to 6.
- One (CH 2 ) ra — moiety is substituted with one or more substituents.
- R 4 represents a hydrogen atom, a lower alkyl group or an amino protecting group
- one (CH 2 ) n — represents one or more Which may be substituted with a substituent), more specifically, a sulfamide derivative having an antithrombin inhibitory activity, or a pharmaceutically acceptable salt or hydrate thereof;
- the present invention relates to a pharmaceutical composition characterized by containing them as an active ingredient.
- Thrombus is composed of aggregated platelets and fibrin, ischemic heart disease such as angina pectoris and myocardial infarction, cerebrovascular disorder such as cerebral infarction, venous thrombosis such as arterial thromboembolism, pulmonary embolism and generalized blood vessels It is involved in the occurrence and exacerbation of blood coagulation syndrome (DIC).
- ischemic heart disease such as angina pectoris and myocardial infarction
- cerebrovascular disorder such as cerebral infarction
- venous thrombosis such as arterial thromboembolism
- pulmonary embolism pulmonary embolism and generalized blood vessels It is involved in the occurrence and exacerbation of blood coagulation syndrome (DIC).
- DIC blood coagulation syndrome
- Antithrombotic drugs are classified into antiplatelet drugs such as aspirin, diviridamol, and abrostadil, and anticoagulants such as perfaline, heparin, and argatroban.Of these, most antiplatelet drugs are oral drugs, Has many questions.
- anticoagulants which are oral drugs only, include pafarin, which inhibits the production of coagulation factors by antagonizing vitamin K, but has side effects such as skin necrosis and teratogenic effects. There are many. Therefore, the emergence of oral anticoagulants having a different mechanism of action from monophalin is desired in clinical settings.
- Thrombin is the last step in blood coagulation and acts on fibrinogen to produce fibrin.
- Thrombin inhibitors include argatroban, tripeptide (a synthetic derivative of D-Phe-Pro-Arg-II), and hirudin, all of which are injections and are used to treat or prevent thrombosis.
- Oral drugs that can be administered for a long period of time are desirable.
- platelet aggregation is considered to be important for thrombogenicity, and antiplatelet drugs have been widely used.
- thrombin potently induces platelet aggregation via its receptor
- antithrombin drugs have been reported to inhibit platelet aggregation by inhibiting thrombin receptor activation.
- the inventors of the present invention have conducted intensive studies on an orally available anti-tombin drug with few side effects, and as a result, have found that a specific sulfamide derivative shows an excellent effect. Reached.
- the present invention relates to the general formula (1)
- R 2 represents a nitrogen-containing heterocyclic ring which may have a substituent and may be condensed
- 3 represents a group A— (CH 2 ) m —, a hydrogen atom or an optionally substituted lower alkyl group, wherein A is an optionally substituted aryl group, an optionally substituted
- m represents an integer of 0 to 6.
- the heterocyclic ring which may be substituted or the lower cycloalkyl group which may be substituted is an integer of 0 to 6.
- one (CH 2 ) m — moiety is substituted with one or more substituents.
- R 4 represents a hydrogen atom, a lower alkyl group or an amino protecting group
- the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. , N-butyl group, tributyl group, s-butyl group, t-butyl group and the like.
- the lower alkoxy group means a linear or branched alkyloxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, an n-broboxine group, and an i-propoquine group.
- the amino protecting group may be any group that can protect the amino group to which R i is bonded in the synthesis process of the general formula (1), and a commonly used amino protecting group is used.
- Such amino protecting groups include, for example, formyl, acetyl, benzoyl, trifluoroacetyl, benzyloxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, phthaloyl, benzyl, tosyl And a t-butoxycarbonyl group.
- the optionally substituted amino group means, in addition to the above-mentioned amino protecting group, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted acryl group, for example, a substituted A lower alkoxycarbonyl group or an optionally substituted lower alkylaminocarbonyl group, an optionally substituted aryl group, an optionally substituted sulfonyl group, an optionally substituted or condensed An optionally substituted heterocyclic group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted aryloxy group, 1 or more substituted or unsubstituted heterocyclic oxy group, optionally substituted silyl group, etc.
- An amino group which may be substituted for example, a methylamino group, an ethylamino group, an acetylamino group, a dimethylaminocarbonylamino group, a phenylamino group, p-Toluenesulfonylamino group, methanesulfonylamino group, 4-piberidinylamino group, cyclohexylamino group, cyclopentylamino group, cyclobromoamino group, etc., preferably methylamino group, ethylamino group, acetylamino group , P-toluenesulfonylamino group, methanesulfonylamino group, cyclobutyrylamino group and the like.
- the lower alkyl group which may be substituted means a halogen atom, a hydroxyl group, a thiol group, an amino group which may be substituted, an aryl group which may be substituted, for example, A lower alkoxycarbonyl group or an optionally substituted lower alkylaminocarbonyl group, a nitro group, a cyano group, an optionally substituted aryl group, an optionally substituted sulfonyl group, or an optionally substituted A heterocyclic group which may be fused, a carboxyl group which may be substituted, a lower alkoxy group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkyl which may be substituted Alkyloxy group, optionally substituted aryloxy group, optionally substituted lower alkylthio group, substituted A heterocyclic oxy group which may be condensed, a cycloalkylthio group which may be substituted, a
- the optionally substituted lower alkoxy group means a lower alkoxy group in which the same group as the above-mentioned lower alkyl group is substituted, for example, a fluoromethoxy group, a fluoroethoxy group. And a benzyloxy group.
- An aryl group is a group in which one hydrogen atom has been removed from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, a xylyl group, a biphenyl group, an anthryl group, and a phenylamine group.
- Preferable examples include a phenyl group and a naphthyl group.
- the aryl group which may be substituted means that any hydrogen atom of the above aryl group is
- optionally substituted lower alkyl groups optionally substituted lower alkoxy groups, halogen atoms, hydroxyl groups, thiol groups, optionally substituted amino groups, optionally substituted acyl groups
- 2-ethoxyphenyl group 2-benzylphenyl group, 3-bromo-11-naphthyl group, 6-methoxy-11-naphthyl group, 1-1-naphthyl group, 2-naphthyl group, etc., and preferably 2-phenylethyl group Enyl group, 6-hydroquinone-naphthyl group,
- the optionally substituted cycloalkyl group refers to a coal number of 3 to 4, preferably 4 to
- any hydrogen atom of the cycloalkyl group 6 is substituted with one or more substituents
- substituents include the same groups as the above aryl groups.
- Such examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-fluorocyclopropyl, 2-benzylcyclohexyl, 2-aminocyclopentyl, 2-aminocyclopentyl and 2-aminocyclopentyl.
- Examples thereof include a carboxycyclopentyl group and 2- (6-methoxy-1,4-benzoquinone), and preferably a cyclohexyl group.
- a nitrogen-containing heterocyclic ring which may be substituted or condensed, contains at least one nitrogen atom as a hetero atom and further contains a hetero atom such as an oxygen atom or a zeo atom.
- nitrogen-containing heterocyclic ring examples include, for example, an aziridine ring, an azetidine ring, a piar ring, a piar phosphorus ring, a piar lysine ring, an indole ring, an indoline ring, an isindole ring, an octahydroindole ring, Carbazole ring, pyridine ring, biperidine ring, quinoline ring, dihydroquinoline ring, tetrahydroquinoline ring, decahydroquinoline ring, isoquinoline ring, tetrahydroisoquinoline ring, decahydroisoquinoline ring, quinoline ring, acridine ring, phenanthridine ring Ring, benzoquinoline ring, pyrazole ring, imidazole ring, imidazoline ring, imidazolidine ring, benzimidazole ring,
- the peridine ring, the perazine ring, and the Preferred are a soquinoline ring and a tetrahydroisoquinoline ring.
- Preferred examples of the substituent include a N-acetylbiperazine ring, an N-p-toluenesulfonylbiberazine ring, a 4-methylbiveridine ring, and the like.
- a heterocyclic ring which may be substituted or condensed is a saturated or unsaturated 3- to 7-membered ring containing one or more nitrogen, oxygen or iodo atoms as a hetero atom. It means a saturated heterocycle, and one or more aromatic rings, heterocycles and cycloalkyl rings other than a 3- to 7-membered ring may be condensed. Any hydrogen atom bonded to a carbon atom on the ring may be substituted with one or more substituents. Examples of such substituents are the same as those described above for the aryl group. No.
- heterocyclic ring examples include, in addition to the aforementioned nitrogen-containing heterocyclic ring, for example, a pyran ring, a furan ring, a tetrahydrofuran ring, a tetrahydrofuran ring, a thiophene ring, a benzothiophene ring, a dihydrobenzothiophene ring, and a benzofuran.
- An acryl group is a group obtained by removing OH of a carboxyl group of a carboxylic acid, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, oxalyl group, malonyl group, succinyl group, benzoyl group, Examples include a toluolyl group, a naphthoyl group, a phthaloyl group, a pyrrolidinecarbonyl group, a pyridinecarbonyl group and the like, and preferably an acetyl group and a benzoyl group.
- the optionally substituted acyl group means a lower alkyl group as a substituent, or an acyl group substituted with another group similar to the above-mentioned lower alkyl group.
- Preferred examples include a lower alkylcarbonyl group, an optionally substituted lower alkylaminocarbonyl group, an optionally substituted lower alkyloxycarbonyl group, and an aminocarbonylcarbonyl group.
- the acryloxy group means a group in which an oxygen atom is bonded to the acryl group, and examples thereof include an acetyloxy group and a benzoyloxy group.
- the lower alkoxycarbonyl group means a group in which a carbonyl group is bonded to a lower alkoxy group, and represents a group having 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy moiety.
- methoxyquincarbonyl ethoxycarboxy, ⁇ -propoxycarbonyl, i-propoxycarbonyl, n-butynecarbonyl, ibutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl And the like, preferably a methoxycarbonyl group, an ethoxyquincarbonyl group and the like.
- the lower alkoxycarbonyloxy group is a group in which an oxygen atom is bonded to a lower alkoxycarbonyl group, and represents an alkoxy moiety having 1 to 6, preferably 1 to 4 carbon atoms.
- Examples include a carbonyloxy group and a t-butoxycarbonyloxy group, and preferably, a methoxycarbonyloxy group, an ethoxyquincarbonyloxy group, and the like.
- the hydroxyalkylcarbonyloxy group is a group in which a carbonyloxy group (COO) is bonded to a group obtained by substituting one or more hydroxyl groups with the above-mentioned lower alkyl group, for example, a hydroxymethylcarbonyloxy group, Examples thereof include groups having 1 to 6, preferably 1 to 4 carbon atoms in the alkyl moiety such as a 2-hydroxyxylcarbonyloxy group and a 2,3-dihydroxypropylcarbonyloxy group.
- the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom
- the lower alkylsulfonyl group is a group in which a sulfonyl group is bonded to the lower alkyl group, and has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, and a A propylsulfonyl group, an i-propylsulfonyl group and the like.
- the arylsulfonyl group means a group in which a sulfonyl group is bonded to the above aryl group, and examples thereof include a phenylsulfonyl group and a naphthylsulfonyl group.
- the lower alkylsulfonyl group which may be substituted and the arylsulfonyl group which may be substituted have one arbitrary hydrogen atom bonded to a carbon atom of the lower alkylsulfonyl group and the arylsulfonyl group.
- T represents a group which may be substituted with the above substituents, and examples of the substituent include the same ones as those described as the substituent of the aryl group. Examples of such a group include a p-toluenesulfonyl group and a trifluoromethanesulfonyl group.
- the optionally substituted aminosulfonyl group is a group in which a sulfonyl group is bonded to the above-mentioned optionally substituted amino group, and examples thereof include a methylaminosulfonyl group and a benzylaminosulfonyl group.
- the optionally substituted lower alkoxysulfonyl group means a group in which a sulfonyl group is bonded to the above-mentioned optionally substituted lower alkoxy group, such as a methoxysulfonyl group or a benzyloxysulfonyl group.
- the optionally substituted cycloalkyloxysulfonyl group means a group in which a sulfonyl group is bonded to an optionally substituted cycloalkyl group via an oxygen atom, for example, cyclohexyloxysulfonyl. And cyclopentyloxysulfonyl groups.
- the optionally substituted cycloalkylsulfonyl group is a group in which a sulfonyl group is bonded to the optionally substituted cycloalkyl group, and examples thereof include a cyclohexylsulfonyl group and a cyclopentylsulfonyl group.
- An optionally substituted or optionally fused heterocyclic sulfonyl group means a group in which a sulfonyl group is bonded to an optionally substituted heterocyclic group, for example, a 4-quinolylsulfonyl group, 8 —Tetrahydroquinolylsulfonyl group and the like are preferred.
- the optionally substituted sulfonyl group includes an optionally substituted lower alkylsulfonyl group, an optionally substituted cycloalkylsulfonyl group, an optionally substituted cycloalkyloxysulfonyl group, a substituted An optionally substituted aminosulfonyl group, an optionally substituted or condensed heterocyclic sulfonyl group, an optionally substituted lower alkoxysulfonyl group or And represents an arylsulfonyl group which may be substituted.
- the optionally substituted carboxyl group means a group in which an oxy group is bonded to the aforementioned optionally substituted acyl group, for example, a methylcarbonyloxy group, an ethylcarponyloxy group, an isopropyl group.
- the lower alkoxyalkyl group means a group in which a lower alkyl group is bonded to the lower alkoxy group, for example, a methoxymethyl group, a methoxethyl group, a t-butoxymethyl group, a 1-ethoxyl group, or a 1- (isopropoxy) ethyl group. And the like. Further, the part of the alkoxy group or the alkyl group of the lower alkoxyalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
- the lower hydroquinalkyl group means a group in which one or more hydroxyl groups are substituted on the lower alkyl group, for example, a hydroxymethyl group, a 2-hydroquinethyl group, a 1-hydroxyxethyl group, and a 3-hydroxy-1-n group.
- a hydroxymethyl group for example, a 2-hydroquinethyl group, a 1-hydroxyxethyl group, and a 3-hydroxy-1-n group.
- the alkyl group portion of the lower hydroxyalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
- lower aminoalkyl group means a group in which the lower alkyl group is bonded to the above-mentioned optionally substituted amino group, for example, t-butylaminomethyl group, aminomethyl group, 2-aminoethyl group, benzyl group. Examples include a minomethyl group, a methylaminomethyl group, and a 2-methylaminoethyl group. Further, the alkyl group portion of the lower aminoalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
- the lower-potential ruboxylalkyl group is a group in which the above-mentioned lower alkyl group is bonded to the above-mentioned optionally substituted carboxyl group, for example, acetyloquinmethyl group, 2-acetyloxetyl group, ethyl Examples include a carbonyloxymethyl group, a cyclohexylcarbonyloxymethyl group, a cyclopropylcarbonylcarbonylmethyl group, and an isobutyrylcarbonylcarbonylmethyl group.
- the alkyl group portion of the lower carboxyl alkyl group is substituted with the same substituent as the above-mentioned alkyl group. It may be.
- the lower carbonylaminoalkyl group means a group in which the lower aminoalkyl group is bonded to the optionally substituted sacyl group, for example, an acetylaminoamino group, a t-butyloxycarbonylaminomethyl group.
- sacyl group for example, an acetylaminoamino group, a t-butyloxycarbonylaminomethyl group.
- the amino group or the alkyl group of the lower carbonylaminoalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
- the optionally substituted lower alkylthio group is a group in which a thio group is bonded to the aforementioned optionally substituted lower alkyl group, and examples thereof include a methylthio group, an ethylthio group, an isopropylpropyl group, and a t-butylthio group. .
- the optionally substituted cycloalkylthio group means a group in which a thio group is bonded to the above-mentioned optionally substituted cycloalkyl group, for example, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, Examples include a cyclohexylthio group.
- the optionally substituted arylthio group is a group in which a thio group is bonded to the above-mentioned optionally substituted aryl group, for example, X-Xylthio, 11-naphthylthio,
- the heterocyclic thio group which may be substituted or optionally condensed means a group in which a thio group is bonded to the above-mentioned optionally substituted or optionally condensed heterocyclic group,
- a 4-quinolylthio group, an 8-tetrahydroquinolylthio group and the like can be mentioned.
- the optionally substituted sulfonyloxy group is a group in which an oxy group is bonded to the above-mentioned optionally substituted sulfonyl group, and examples thereof include a p-toluenesulfonyloxy group and a methanesulfonyloxy group. .
- the optionally substituted cycloalkyloxy group is a group in which the above-mentioned optionally substituted cycloalkyl group is bonded to an oxy group, for example, a cyclopropyloxy group, a cyclobenzyloxy group, a 4-amino group. Cyclohexyloxy group and the like. You.
- the optionally substituted or optionally condensed heterocyclic oxy group means a group in which the above-mentioned optionally substituted or optionally condensed heterocyclic group is bonded to an oxy group, Examples thereof include a 4-quinolyloxy group and an 8-tetrahydroquinolyloxy group.
- the optionally substituted silyl group means a silyl group in which the above-mentioned optionally substituted lower alkyl group or an optionally substituted aryl group is bonded to the same or different 1 to 3 silyl groups, for example, trimethylsilyl.
- silyl group triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group and the like.
- Examples of the substituents which may be substituted with one (CH 2 ) ra — moiety and one (CH 2 ) — moiety include those similar to the substituents described for the aryl group.
- the compound of the present invention can form pharmaceutically acceptable salts.
- such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like.
- Organic acids such as inorganic acid salt, succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate Salts and the like can be mentioned.
- the compound of the present invention and a pharmaceutically acceptable salt thereof can also form a hydrate.
- the compound of the present invention can have various steric structures.
- the asymmetric carbon atom when considering the asymmetric carbon atom as its center, its absolute configuration may be any of D-form, L-form and DL-form. Included in the invention.
- the absolute configuration of the asymmetric carbon atom in the substituted phenylalanine residue in the general formula (1) is desirably L-form.
- Compounds that are a phenethylbenzyl group, a 3-bromonaphthyl group, a 1-isoquinolyl group, a 2,3-dimethoxybenzyl group, or a 6-hydroxynaphthyl group show particularly excellent effects as a medicament.
- N In the general formula (1), R 2 represents a group (2) to (6)
- R 7 is an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted low-valued alkoxy group, an optionally substituted or condensed Good heterocyclic ring, oxygen atom, hydroxyl group, optionally substituted acyl group, optionally substituted amino group, optionally substituted carboxyl group, optionally substituted acyloxy group, halogen atom, substituted Lower alkylsulfonyl group which may be substituted, arylsulfonyl group which may be substituted, low-handling alkoxyalkyl group, lower hydroxyalkyl group, lower aminoalkyl group, lower carboxyalkyl Group, a lower carbonyl ⁇ amino alkyl group.
- B is TanShu atom, SansoHara child, a sulfur atom or NR 8, wherein R 8 is a hydrogen atom, a lower alkyl group but it may also be substituted, Amino protecting A, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted and optionally condensed heterocyclic ring, p and q is the same or different and represents an integer of 0 to 5, provided that + is any one of 1, 2.3, 4 or 5, and r and s are the same or different and represent an integer of 0 to 5 Where r + s Is any of 0, 1.
- R 2 is particularly a group (2), particularly an optionally substituted piperazinyl group Or a compound which is a piperidinyl group which may be substituted, more preferably, R 2 is N-acetylbiperazinyl group, 4-methylbiperidinyl group, N- (N, N-dimethylaminocarbonyl)
- R 2 is N-acetylbiperazinyl group, 4-methylbiperidinyl group, N- (N, N-dimethylaminocarbonyl)
- Compounds that are a piperazinyl group, a methanesulfonylbiperazinyl group, a benzenesulfonylbiperazinyl group, or a p-toluenesulfonylbiverazinyl group also show excellent effects as pharmaceuticals and are included in the present invention.
- the compounds having two or three preferable substituents of R 2 , R 3 and R 5 at the same time are particularly preferable compounds.
- the compound of the present invention can be produced by a combination of reactions suitable for a target compound.
- the following shows a typical reaction scheme, but the present invention is not limited to only the following method.
- R 2 is a hydrogen atom or lower alkyl.
- R 5 represents a lower alkyl group, and X represents a leaving group such as a halogen atom, a hydroxyl group, an alkanesulfonyl group, an arylsulfonyl group, etc.).
- the compound of the general formula (10) is obtained by performing a condensation reaction of the compound of the general formula (9) and the compound of the general formula (19).
- the condensation reaction used here includes, for example, the commonly used active ester method, acid anhydride method, azide method, acid chloride method, various condensing agents, etc., in basic and experimental peptide synthesis (1985, published by Maruzen, 1985). Examples include the methods shown.
- the condensing agents used include N, N 'dicyclohexyl carbodiimide (DCC), water-soluble carbodiimide (WS CI), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), Bop reagent, Py reagent Commonly used reagents such as the bop reagent are mentioned.
- the compound of the general formula (19) is usually used in an amount of 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, relative to the compound of the general formula (9).
- the compound of the general formula (11) can be prepared by reacting a compound of the general formula (9) with a suitable alcohol and an isocyanate such as chlorosulfonyl isocyanate in a suitable solvent in the presence or absence of a base.
- a suitable solvent such as tetrahydrofuran, dioxane, dichloromethane, ethyl acetate and the like
- examples of the base include organic bases such as triethylamine and pyridine.
- alcohols, t-butyl alcohol, benzyl alcohol and the like are used, and the reaction can be carried out using phosgene or the like instead of chlorosulfonyl isocyanate.
- This reaction can be usually carried out at -80 to 30 ° C for 0.1 to 24 hours.
- the isocyanates used are usually of the general formula
- the compound of (9) is used in an amount of 1.0 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents, and the alcohol is used in an amount of 1.0 to 5.0 equivalents, 1.0 to 1.0 equivalent. Two equivalents are used.
- the obtained carbamate compound can be converted to an amine compound by performing deprotection.
- the compound of the general formula (12) can be obtained by performing the same reaction as in obtaining the compound of the general formula (11) from the compound of the general formula (10), or obtaining the compound of the general formula (10). Can be obtained by performing the same condensation reaction as described above from the compound of the general formula (11).
- the compound of the general formula (13) can be obtained from the compound of the general formula (11) by a commonly used alkylation or arylation reaction. That is, in an appropriate solvent, an alcohol represented by the general formula (20) (when X is a hydroxyl group) activated by ethoxyazadicarboxylate (DEAD) -triphenylphosphine or the like, or a base Halide compound represented by the general formula (20) in the presence or absence of
- Examples of compounds of the general formula (20), which are alcohols, include methanol, ethanol, phenol, benzyl alcohol, 2,3-dimethylbenzyl alcohol, 1-naphthalenemethanol, 3-bromo-1-naphthalenemethanol, and 2-phenylene.
- 2,3-dimethoxybenzyl alcohol, 1-naphthalenemethanol, 2-phenethylbenzyl alcohol, etc. are exemplified.
- Solvents used in this step include dichloromethane, chloroform, tetrahydrofuran, benzene and the like.
- Bases that may be used in the reaction of halide compounds and the like include sodium hydride and lithium carbonate. And sodium hydrogencarbonate.
- the reaction can be carried out at a temperature of 180 to 100 ° C and a reaction time of 1 to 240 hours.
- the compound of the general formula (20) is usually
- the compound of the general formula (14) is obtained by converting the compound of the general formula (11) into the general formula (13)
- the same reaction as when the compound of the general formula (12) is obtained is performed from the compound of the general formula (12), or the same condensation as when the compound of the general formula (10) is obtained from the compound of the general formula (9).
- the reaction can be produced by carrying out the reaction from the general formula (13).
- the compound of the general formula (15) can be obtained by reacting a compound of the general formula (14) with hydrogen sulfide in a suitable solvent in the presence or absence of a base.
- the solvent used here includes pyridine, methanol, ethanol, n-propanol, i-propanol, and the like.
- the base includes pyridine, triethylamine, getylamine, and the like.
- the reaction can be performed at a reaction temperature of 0 to 100 ° C and a reaction time of 1 to 2 hours.
- the compound of the general formula (16) can be produced from the compound of the general formula (15) by reacting an alkyl halide in a suitable solvent in the presence or absence of a base.
- the alkyl halides include, for example, methyl iodide, methyl iodide and the like, preferably methyl iodide and the like.
- Solvents that can be used in this step include acetone, methanol, acetonitrile, tetrahydrofuran, and the like.
- a base such as pyridine, triethylamine, or getylamine can be used.
- the reaction can be performed at a temperature of 0 to 100 ° C for 0.1 to 10 hours.
- the alkyl halides used here can be used in the range of 1.0 to 20.0 equivalents to the compound of the general formula (9).
- the compound of the general formula (17) can be obtained by adding a strong acid to a compound of the general formula (14) in a lower alcohol solvent.
- the lower alcohol solvent used here includes methanol, ethanol, n-propanol, i-propanol and the like.
- As the strong acid hydrochloric acid, sulfuric acid, nitric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, or a mixed acid thereof can be used.
- the strong acid can be used in an amount of 1 to 1000 equivalents, preferably 100 to 300 equivalents, relative to the compound of the general formula (14).
- the reaction can be performed at a temperature of 30 to 30 ° (reaction time of 1 to 48 hours).
- the compound of the general formula (1) can be prepared by reacting the compound of the general formula (16) with an ammonium salt or an alkylammonium salt in a suitable solvent, or by converting the compound of the general formula (17) It is obtained by reacting the compound with ammonia.
- ammonium salts used herein include, for example, hydroxyammonium acetate and the like, which is usually used in an amount of 1.0 to 2.0 equivalents to the compound of the general formula (16).
- Examples of the alkylammonium salts include methylammonium acetate and the like, which can be used usually in a range of 1.0 to 2.0 equivalents to the compound of the general formula (16).
- the reaction temperature in this step can be in the range of 0 to 100 ° C., and the reaction time can be in the range of 1 to 72 hours.
- the compound of the general formula (18) constituting a part of the compound of the present invention can be produced by subjecting the compound of the general formula (14) to a reduction reaction usually carried out.
- the reduction reaction used here may be, for example, a method of adding hydrogen in the presence of a catalyst such as platinum, palladium, carbon-palladium, carbon-platinum, Raneynigel, or tin chloride, zinc, sodium sulfide, aluminum amalgam, chlorinated aluminum.
- a reduction method using a commonly used reducing agent such as chromium, sodium thiosulfate, sodium borohydride, and lithium aluminum hydride may be mentioned.
- the reaction temperature in this step is 180 to 100 ° C.
- the reaction time can be 1 to 72 hours.
- the compound of general formula (1) thus obtained can be purified in a simple manner by ordinary chemical operations such as extraction, crystallization, recrystallization and various types of chromatography.
- the compounds of the present invention can be formulated together with suitable excipients, diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc. .
- suitable excipients diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc.
- suitable excipients diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc.
- suitable excipients diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors,
- liquid preparations for oral administration i.e., emulsions, syrups, suspensions, solutions, etc. should contain commonly used inert diluents, such as water or vegetable oils. Can be. In the case of liquid preparations, they may be contained in capsules of an absorbable substance such as gelatin.
- preparations for parenteral administration that is, solvents or suspensions used in the production of injections, suppositories, etc.
- the preparation method of the preparation may be a conventional method.
- the dose may be administered in the range of 180 mg, preferably in the range of 1 to 60 mg, once or twice or three times at appropriate intervals, or may be administered intermittently.
- Ncr- (benzyl (tert-butyloxycarbonyl) aminosulfonyl) -13-cyanophenylalanine-14-acetylbiperazide 0.8 g (1.4 mmo 1 ⁇ yield 50) %).
- N- (tert-butyloxycarbonyl (3-phenyl-2-n-propyl) aminosulfonyl) -13-cyanophenylanilanine-14-acetylbiperazide 250 mg ( 0.42 mmo 1: 99% yield).
- N- (tert-butyloxycarbonyl (2-methoxyethoxybenzyl) aminosulfonyl) 1-3-cyanophenylalanine 4-acetylbiperazide 39 Omg (0, 62 mmol) of pyridine 3 ml Bubble hydrogen gas at room temperature into a mixed solution of 6 ml of triethylamine for 30 minutes, and then leave for 3 days. 40 ml of water and 40 ml of ethyl acetate are added to the reaction solution, and 2N HCl is added to adjust the aqueous layer to pH 4, and then the layers are separated.
- N- (tert-Butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 1-3-Carbothioamidophenylalanine 1-4-Acetylbiperazide Add 353 mg of methyl and reflux under heating for 50 minutes. The reaction mixture was evaporated under reduced pressure, 2 ml of methanol and 29 mg of ammonium acetate were added to the obtained residue, and the mixture was heated and refluxed for 4 hours. After that, the reaction mixture was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography (Fuji).
- Plasma thrombin time is measured by an automatic blood coagulation analyzer KC-1OA (Ame
- a single dose of 100 mg / kg S for test compound is orally administered to the rat.
- Blood samples (0.45 ml) were collected from the left ventricle before and 0.5, 1, 2, and 4 hours after administration, and plasma TT was measured. From the measured TT values, the ratio of the TT values before and after the administration of the test compound (TT ratio) was calculated. Table 2 shows the results. Table 2
- the sulfamide derivative of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof exhibits excellent antithrombin activity and is orally administrable and has few side effects. It is valid.
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Description
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019980703942A KR19990071666A (ko) | 1995-11-30 | 1996-12-02 | 술파미드 유도체 |
AU76557/96A AU7655796A (en) | 1995-11-30 | 1996-12-02 | Sulfamide derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP31240795 | 1995-11-30 | ||
JP7/312407 | 1995-11-30 |
Publications (1)
Publication Number | Publication Date |
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WO1997019919A1 true WO1997019919A1 (fr) | 1997-06-05 |
Family
ID=18028868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1996/003520 WO1997019919A1 (fr) | 1995-11-30 | 1996-12-02 | Derives de sulfamides |
Country Status (3)
Country | Link |
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KR (1) | KR19990071666A (ja) |
AU (1) | AU7655796A (ja) |
WO (1) | WO1997019919A1 (ja) |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054164A1 (en) * | 1997-05-30 | 1998-12-03 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
US5998412A (en) * | 1997-01-23 | 1999-12-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
US6130220A (en) * | 1997-10-16 | 2000-10-10 | Syntex (Usa) Inc. | Sulfamide-metalloprotease inhibitors |
US6376506B1 (en) | 1997-01-23 | 2002-04-23 | Syntex (U.S.A.) Llc | Sulfamide-metalloprotease inhibitors |
US6538017B2 (en) | 2001-03-09 | 2003-03-25 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
WO2003033024A1 (fr) * | 2001-10-16 | 2003-04-24 | Chugai Seiyaku Kabushiki Kaisha | Inhibiteur de proliferation cellulaire |
US6680312B2 (en) | 1998-02-05 | 2004-01-20 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
US6710061B2 (en) | 2001-03-09 | 2004-03-23 | Ortho-Mcneil Pharamceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
ES2219177A1 (es) * | 2003-05-05 | 2004-11-16 | Almirall Prodesfarma, S.A. | Derivados de n-(2-feniletil) sufalmida como antagonistas de la integrina alfa4. |
US7115607B2 (en) | 2001-07-25 | 2006-10-03 | Amgen Inc. | Substituted piperazinyl amides and methods of use |
US7666610B2 (en) | 2002-03-29 | 2010-02-23 | Chugai Seiyaku Kabushiki Kaisha | Expressing transporters on viral envelopes |
US7666998B2 (en) | 2001-12-04 | 2010-02-23 | Chugai Seiyaku Kabushiki Kaisha | Cell growth inhibitor containing anti-PepT antibody |
US7731960B2 (en) | 2003-03-28 | 2010-06-08 | Chugai Seiyaku Kabushiki Kaisha | Antibodies that inhibit transport activity of peptide transporters |
US7750204B2 (en) | 2002-06-05 | 2010-07-06 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing antibody |
US7964767B2 (en) | 2004-03-31 | 2011-06-21 | Chugai Seiyaku Kabushiki Kaisha | Transgenic mice expressing baculovirus soluble GP64 and methods of using such mice to make antibodies |
US8084490B2 (en) | 2004-06-16 | 2011-12-27 | Janssen Pharmaceutica N.V. | Sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
US8492431B2 (en) | 2005-12-19 | 2013-07-23 | Janssen Pharmaceutica, N.V. | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity |
US8497298B2 (en) | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US8691867B2 (en) | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US8716231B2 (en) | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
US8853263B2 (en) | 2006-05-19 | 2014-10-07 | Janssen Pharmaceutica Nv | Co-therapy for the treatment of epilepsy and related disorders |
US8937096B2 (en) | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
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JPS6056919A (ja) * | 1983-08-10 | 1985-04-02 | ソシエテ・デチユードウ・シヤンテイフイツク・エ・アンデユストリエル・ドウ・リールドウフランス | N‐(1‐アリル‐2‐ピロリジニルメチル)‐2‐メトキシ‐4‐アミノ‐5‐メチルスルフアモイルベンズアミドを有効成分とする心臓血管障害および血小板機能不全等の治療剤 |
JPH06312973A (ja) * | 1993-04-30 | 1994-11-08 | Yamanouchi Pharmaceut Co Ltd | 新規なフェニルスルファミド誘導体 |
JPH06340619A (ja) * | 1993-05-03 | 1994-12-13 | Bristol Myers Squibb Co | グアニジニルまたはアミジニル置換メチルアミノ複素環トロンビン抑制剤 |
WO1995023809A1 (en) * | 1994-03-04 | 1995-09-08 | Eli Lilly And Company | Antithrombotic agents |
JPH07278095A (ja) * | 1994-03-04 | 1995-10-24 | Eli Lilly & Co | アルギニンアルデヒドの亜硫酸水素塩付加物 |
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1996
- 1996-12-02 KR KR1019980703942A patent/KR19990071666A/ko not_active Ceased
- 1996-12-02 AU AU76557/96A patent/AU7655796A/en not_active Abandoned
- 1996-12-02 WO PCT/JP1996/003520 patent/WO1997019919A1/ja not_active Application Discontinuation
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JPS6056919A (ja) * | 1983-08-10 | 1985-04-02 | ソシエテ・デチユードウ・シヤンテイフイツク・エ・アンデユストリエル・ドウ・リールドウフランス | N‐(1‐アリル‐2‐ピロリジニルメチル)‐2‐メトキシ‐4‐アミノ‐5‐メチルスルフアモイルベンズアミドを有効成分とする心臓血管障害および血小板機能不全等の治療剤 |
JPH06312973A (ja) * | 1993-04-30 | 1994-11-08 | Yamanouchi Pharmaceut Co Ltd | 新規なフェニルスルファミド誘導体 |
JPH06340619A (ja) * | 1993-05-03 | 1994-12-13 | Bristol Myers Squibb Co | グアニジニルまたはアミジニル置換メチルアミノ複素環トロンビン抑制剤 |
WO1995023809A1 (en) * | 1994-03-04 | 1995-09-08 | Eli Lilly And Company | Antithrombotic agents |
JPH07278095A (ja) * | 1994-03-04 | 1995-10-24 | Eli Lilly & Co | アルギニンアルデヒドの亜硫酸水素塩付加物 |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5998412A (en) * | 1997-01-23 | 1999-12-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
US6143744A (en) * | 1997-01-23 | 2000-11-07 | Syntex (U.S.A.) Inc. | Sulfamide-metalloprotease inhibitors |
US6376506B1 (en) | 1997-01-23 | 2002-04-23 | Syntex (U.S.A.) Llc | Sulfamide-metalloprotease inhibitors |
WO1998054164A1 (en) * | 1997-05-30 | 1998-12-03 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
US6359134B1 (en) | 1997-05-30 | 2002-03-19 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
US6130220A (en) * | 1997-10-16 | 2000-10-10 | Syntex (Usa) Inc. | Sulfamide-metalloprotease inhibitors |
US6680312B2 (en) | 1998-02-05 | 2004-01-20 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
US6630505B2 (en) | 2001-03-09 | 2003-10-07 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
US6890939B2 (en) | 2001-03-09 | 2005-05-10 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
US6710061B2 (en) | 2001-03-09 | 2004-03-23 | Ortho-Mcneil Pharamceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
US6538017B2 (en) | 2001-03-09 | 2003-03-25 | Ortho-Mcneil Pharmaceutical, Inc. | Aminopyrrolidine sulfonamides as serine protease inhibitors |
US7560460B2 (en) | 2001-07-25 | 2009-07-14 | Amgen Inc. | Substituted piperazines and methods of use |
US7115607B2 (en) | 2001-07-25 | 2006-10-03 | Amgen Inc. | Substituted piperazinyl amides and methods of use |
EP1437142A4 (en) * | 2001-10-16 | 2006-09-20 | Chugai Pharmaceutical Co Ltd | MEANS OF INHIBITING CELL GROWTH |
EP1437142A1 (en) * | 2001-10-16 | 2004-07-14 | Chugai Seiyaku Kabushiki Kaisha | Cell growth inhibitors |
WO2003033024A1 (fr) * | 2001-10-16 | 2003-04-24 | Chugai Seiyaku Kabushiki Kaisha | Inhibiteur de proliferation cellulaire |
US7666998B2 (en) | 2001-12-04 | 2010-02-23 | Chugai Seiyaku Kabushiki Kaisha | Cell growth inhibitor containing anti-PepT antibody |
US7666610B2 (en) | 2002-03-29 | 2010-02-23 | Chugai Seiyaku Kabushiki Kaisha | Expressing transporters on viral envelopes |
US8013208B2 (en) | 2002-06-05 | 2011-09-06 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing antibodies |
US7750204B2 (en) | 2002-06-05 | 2010-07-06 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing antibody |
US7731960B2 (en) | 2003-03-28 | 2010-06-08 | Chugai Seiyaku Kabushiki Kaisha | Antibodies that inhibit transport activity of peptide transporters |
ES2219177A1 (es) * | 2003-05-05 | 2004-11-16 | Almirall Prodesfarma, S.A. | Derivados de n-(2-feniletil) sufalmida como antagonistas de la integrina alfa4. |
US7964767B2 (en) | 2004-03-31 | 2011-06-21 | Chugai Seiyaku Kabushiki Kaisha | Transgenic mice expressing baculovirus soluble GP64 and methods of using such mice to make antibodies |
US8084490B2 (en) | 2004-06-16 | 2011-12-27 | Janssen Pharmaceutica N.V. | Sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
US8492431B2 (en) | 2005-12-19 | 2013-07-23 | Janssen Pharmaceutica, N.V. | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity |
US8497298B2 (en) | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
US8691867B2 (en) | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
US8716231B2 (en) | 2005-12-19 | 2014-05-06 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain |
US8937096B2 (en) | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
US8853263B2 (en) | 2006-05-19 | 2014-10-07 | Janssen Pharmaceutica Nv | Co-therapy for the treatment of epilepsy and related disorders |
Also Published As
Publication number | Publication date |
---|---|
KR19990071666A (ko) | 1999-09-27 |
AU7655796A (en) | 1997-06-19 |
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