CA2309332C - 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors - Google Patents
2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors Download PDFInfo
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- CA2309332C CA2309332C CA002309332A CA2309332A CA2309332C CA 2309332 C CA2309332 C CA 2309332C CA 002309332 A CA002309332 A CA 002309332A CA 2309332 A CA2309332 A CA 2309332A CA 2309332 C CA2309332 C CA 2309332C
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- carbon atoms
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- hydroxyl
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- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 title description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 title description 3
- IJYHVZICHKCLMQ-UHFFFAOYSA-N imidazo[4,5-d]triazin-4-one Chemical class O=C1N=NN=C2N=CN=C12 IJYHVZICHKCLMQ-UHFFFAOYSA-N 0.000 title description 2
- -1 2-phenyl-substituted imidazotriazinones Chemical class 0.000 claims abstract description 94
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 150000001412 amines Chemical class 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 8
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 8
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 8
- 201000001881 impotence Diseases 0.000 claims abstract description 8
- 210000002229 urogenital system Anatomy 0.000 claims abstract description 8
- 208000010228 Erectile Dysfunction Diseases 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 320
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 238
- 125000000217 alkyl group Chemical group 0.000 claims description 170
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 132
- 229910052739 hydrogen Inorganic materials 0.000 claims description 121
- 239000001257 hydrogen Substances 0.000 claims description 120
- 125000003545 alkoxy group Chemical group 0.000 claims description 109
- 238000000034 method Methods 0.000 claims description 81
- 125000001424 substituent group Chemical group 0.000 claims description 78
- 239000000203 mixture Substances 0.000 claims description 76
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 66
- 125000000623 heterocyclic group Chemical group 0.000 claims description 66
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 150000002431 hydrogen Chemical class 0.000 claims description 58
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 54
- 229910052757 nitrogen Inorganic materials 0.000 claims description 51
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 51
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 49
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 40
- 239000000460 chlorine Chemical group 0.000 claims description 40
- 229910052801 chlorine Inorganic materials 0.000 claims description 40
- 125000003386 piperidinyl group Chemical group 0.000 claims description 39
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 239000011737 fluorine Chemical group 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000002757 morpholinyl group Chemical group 0.000 claims description 31
- 125000002252 acyl group Chemical group 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 29
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 28
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 28
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000004076 pyridyl group Chemical group 0.000 claims description 27
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 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 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical group 0.000 claims description 21
- 125000004122 cyclic group Chemical group 0.000 claims description 20
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 125000001425 triazolyl group Chemical group 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 18
- ITOAVBRRRCBWLU-UHFFFAOYSA-N 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride Chemical compound CCCC1=NC(C)=C(C(N2)=O)N1N=C2C1=CC(S(Cl)(=O)=O)=CC=C1OCC ITOAVBRRRCBWLU-UHFFFAOYSA-N 0.000 claims description 17
- 125000002541 furyl group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 13
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 12
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Chemical group O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 150000001204 N-oxides Chemical class 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical group [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- LFMFPKKYRXFHHZ-UHFFFAOYSA-N R24 Chemical compound C1=C(Cl)C(C)=CC=C1NC1=NC(N)=C(C=CC=C2)C2=N1 LFMFPKKYRXFHHZ-UHFFFAOYSA-N 0.000 claims description 4
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000470 constituent Substances 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- CUGZEDSDRBMZMY-UHFFFAOYSA-N trihydrate;hydrochloride Chemical compound O.O.O.Cl CUGZEDSDRBMZMY-UHFFFAOYSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 238000007039 two-step reaction Methods 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims 15
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 5
- FBCDRHDULQYRTB-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one;trihydrate;hydrochloride Chemical compound O.O.O.Cl.CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 FBCDRHDULQYRTB-UHFFFAOYSA-N 0.000 claims 4
- APJAEXGNDLFGPD-AWCRTANDSA-N 3-amino-n-{4-[2-(2,6-dimethyl-phenoxy)-acetylamino]-3-hydroxy-1-isobutyl-5-phenyl-pentyl}-benzamide Chemical compound C([C@@H]([C@@H](O)C[C@H](CC(C)C)NC(=O)C=1C=CC(N)=CC=1)NC(=O)COC=1C(=CC=CC=1C)C)C1=CC=CC=C1 APJAEXGNDLFGPD-AWCRTANDSA-N 0.000 claims 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- SCEVBRBKKQZTKM-UHFFFAOYSA-N 5-[[6-chloro-5-(1-methylindol-5-yl)-1H-benzimidazol-2-yl]oxy]-N-hydroxy-2-methylbenzamide Chemical group ClC=1C(=CC2=C(NC(=N2)OC=2C=CC(=C(C(=O)NO)C=2)C)C=1)C=1C=C2C=CN(C2=CC=1)C SCEVBRBKKQZTKM-UHFFFAOYSA-N 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 abstract description 13
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 7
- YQQHMYAEQTYRKO-UHFFFAOYSA-N 2-phenyl-3h-imidazo[4,5-d]triazin-4-one Chemical class N1=C2N=CN=C2C(=O)NN1C1=CC=CC=C1 YQQHMYAEQTYRKO-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 325
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
- 238000005160 1H NMR spectroscopy Methods 0.000 description 97
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 94
- 238000004128 high performance liquid chromatography Methods 0.000 description 94
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 150000003254 radicals Chemical class 0.000 description 48
- 101150041968 CDC13 gene Proteins 0.000 description 46
- 239000002904 solvent Substances 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- FVEZIIAYTYQUAL-UHFFFAOYSA-N 3-(5-methyl-4-oxo-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxybenzenesulfonyl chloride Chemical compound CCCOC1=CC=C(S(Cl)(=O)=O)C=C1C(NC1=O)=NN2C1=C(C)N=C2CCC FVEZIIAYTYQUAL-UHFFFAOYSA-N 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
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- UUBVXITYRLNELI-UHFFFAOYSA-N 3-(5,7-dimethyl-4-oxo-1h-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulfonyl chloride Chemical compound CCOC1=CC=C(S(Cl)(=O)=O)C=C1C(NC1=O)=NN2C1=C(C)N=C2C UUBVXITYRLNELI-UHFFFAOYSA-N 0.000 description 9
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- 238000004587 chromatography analysis Methods 0.000 description 7
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- 239000000047 product Substances 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
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- 238000002425 crystallisation Methods 0.000 description 6
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 5
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 5
- QAXDVKBGZRMSHF-UHFFFAOYSA-N 6-acetyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(C)=O QAXDVKBGZRMSHF-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- DTIMTCJMOWXMGT-UHFFFAOYSA-N 2-(butanoylamino)propanoic acid Chemical compound CCCC(=O)NC(C)C(O)=O DTIMTCJMOWXMGT-UHFFFAOYSA-N 0.000 description 4
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- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 description 1
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- APKXLNLSLLMQNI-UHFFFAOYSA-N n-[2-(3,4-dimethoxyphenyl)ethyl]-n-methyl-3-(5-methyl-4-oxo-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxybenzenesulfonamide Chemical compound C1=C(C=2NC(=O)C3=C(C)N=C(CCC)N3N=2)C(OCCC)=CC=C1S(=O)(=O)N(C)CCC1=CC=C(OC)C(OC)=C1 APKXLNLSLLMQNI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- JYHQZYYRXHKCJW-UHFFFAOYSA-N n-ethyl-n-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxybenzenesulfonamide Chemical compound CCCOC1=CC=C(S(=O)(=O)N(CC)CCO)C=C1C(NC1=O)=NN2C1=C(C)N=C2CCC JYHQZYYRXHKCJW-UHFFFAOYSA-N 0.000 description 1
- PUUULGNNRPBVBA-UHFFFAOYSA-N n-ethylprop-2-en-1-amine Chemical compound CCNCC=C PUUULGNNRPBVBA-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
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- 230000001537 neural effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
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- HZLFQUWNZMMHQM-UHFFFAOYSA-N piperazin-1-ylmethanol Chemical compound OCN1CCNCC1 HZLFQUWNZMMHQM-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical class N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
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- 210000000813 small intestine Anatomy 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
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- GGRAUDKKGGVZAD-UHFFFAOYSA-N tert-butyl 4-(5-hydroxy-2-methyl-1,2,5-oxadiazole-3-carbonyl)piperazine-1-carboxylate Chemical compound CN1ON(O)C=C1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1 GGRAUDKKGGVZAD-UHFFFAOYSA-N 0.000 description 1
- BAAKWZABPBXLSV-UHFFFAOYSA-N tert-butyl 4-(aminomethyl)morpholine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1CN(CN)CCO1 BAAKWZABPBXLSV-UHFFFAOYSA-N 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
- UJCKMNDBVWNFCA-UHFFFAOYSA-N tert-butyl n-[[4-[3-(5,7-dimethyl-4-oxo-1h-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonylmorpholin-2-yl]methyl]carbamate Chemical compound C1=C(C=2NC(=O)C3=C(C)N=C(C)N3N=2)C(OCC)=CC=C1S(=O)(=O)N1CCOC(CNC(=O)OC(C)(C)C)C1 UJCKMNDBVWNFCA-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Vascular Medicine (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002395558A CA2395558C (en) | 1997-11-12 | 1998-10-31 | Intermediates for 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19750085A DE19750085A1 (de) | 1997-11-12 | 1997-11-12 | 2-Phenyl-substituierte Imidazotriazinone |
| DE1998112462 DE19812462A1 (de) | 1998-03-23 | 1998-03-23 | 2-[2-Ethoxy-5(4-ethyl-piperazin-1-sulfonyl) -phenyl]-5-methyl-7-prophyl-3H-imidazo[5,1-f][1,2,4]triazin-4-on Dihydrochlorid |
| DE19840289.9 | 1998-09-04 | ||
| DE1998140289 DE19840289A1 (de) | 1998-09-04 | 1998-09-04 | 2-Phenyl-substituierte Imidazotriazinone |
| DE19812462.7 | 1998-09-04 | ||
| DE19750085.4 | 1998-09-04 | ||
| PCT/EP1998/006910 WO1999024433A1 (de) | 1997-11-12 | 1998-10-31 | 2-phenyl-substituierte imidazotriazinone als phosphodiesterase inhibitoren |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002395558A Division CA2395558C (en) | 1997-11-12 | 1998-10-31 | Intermediates for 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2309332A1 CA2309332A1 (en) | 1999-05-20 |
| CA2309332C true CA2309332C (en) | 2002-12-03 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002309332A Expired - Lifetime CA2309332C (en) | 1997-11-12 | 1998-10-31 | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
| CA002395558A Expired - Fee Related CA2395558C (en) | 1997-11-12 | 1998-10-31 | Intermediates for 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002395558A Expired - Fee Related CA2395558C (en) | 1997-11-12 | 1998-10-31 | Intermediates for 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
Country Status (43)
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| US (9) | US6362178B1 (h) |
| EP (3) | EP1049695B1 (h) |
| JP (2) | JP3356428B2 (h) |
| KR (2) | KR100430355B1 (h) |
| CN (2) | CN1123573C (h) |
| AR (2) | AR013759A1 (h) |
| AT (1) | ATE213246T1 (h) |
| AU (1) | AU738675B2 (h) |
| BG (1) | BG65257B1 (h) |
| BR (2) | BR9812785A (h) |
| CA (2) | CA2309332C (h) |
| CH (1) | CH693954A5 (h) |
| CO (1) | CO4980861A1 (h) |
| CU (1) | CU23063A3 (h) |
| CY (1) | CY1112949T1 (h) |
| CZ (1) | CZ301911B6 (h) |
| DE (3) | DE19881732C1 (h) |
| DK (3) | DK1049695T3 (h) |
| EE (1) | EE04781B1 (h) |
| ES (3) | ES2386420T3 (h) |
| FI (1) | FI113772B (h) |
| GB (1) | GB2346877B (h) |
| HN (1) | HN1998000175A (h) |
| HR (2) | HRP20020585B1 (h) |
| HU (3) | HU227841B1 (h) |
| ID (1) | ID25871A (h) |
| IL (3) | IL135462A0 (h) |
| IN (1) | IN188419B (h) |
| LU (1) | LU90561B1 (h) |
| MY (1) | MY138535A (h) |
| NO (2) | NO314940B1 (h) |
| NZ (1) | NZ504436A (h) |
| PE (1) | PE131799A1 (h) |
| PL (2) | PL194801B1 (h) |
| PT (2) | PT1174431E (h) |
| SE (1) | SE522809C2 (h) |
| SI (2) | SI1049695T1 (h) |
| SK (1) | SK287161B6 (h) |
| TR (1) | TR200001338T2 (h) |
| TW (2) | TW513431B (h) |
| UA (1) | UA46166C2 (h) |
| UY (2) | UY25246A1 (h) |
| WO (1) | WO1999024433A1 (h) |
Families Citing this family (176)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6403597B1 (en) * | 1997-10-28 | 2002-06-11 | Vivus, Inc. | Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation |
| US20040014761A1 (en) * | 1997-10-28 | 2004-01-22 | Place Virgil A. | Treatment of female sexual dysfunction with phosphodiesterase inhibitors |
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