CA2272584C - Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases - Google Patents
Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases Download PDFInfo
- Publication number
- CA2272584C CA2272584C CA002272584A CA2272584A CA2272584C CA 2272584 C CA2272584 C CA 2272584C CA 002272584 A CA002272584 A CA 002272584A CA 2272584 A CA2272584 A CA 2272584A CA 2272584 C CA2272584 C CA 2272584C
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- straight
- chain
- formula
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 14
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical class C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 238000011282 treatment Methods 0.000 title claims description 18
- 230000002425 cardiocirculatory effect Effects 0.000 title abstract 2
- 201000010099 disease Diseases 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 103
- 150000001875 compounds Chemical class 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 125000002252 acyl group Chemical group 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 37
- -1 azido, formyl Chemical group 0.000 claims description 36
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 125000004414 alkyl thio group Chemical group 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical group CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 12
- 230000009471 action Effects 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 claims description 11
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 230000009467 reduction Effects 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 208000028867 ischemia Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 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 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 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 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- AJXWEJAGUZJGRI-UHFFFAOYSA-N fluorine azide Chemical compound FN=[N+]=[N-] AJXWEJAGUZJGRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 230000009424 thromboembolic effect Effects 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 229940015043 glyoxal Drugs 0.000 claims description 3
- 239000002840 nitric oxide donor Substances 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical class NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000005256 alkoxyacyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- CPPKAGUPTKIMNP-UHFFFAOYSA-N cyanogen fluoride Chemical compound FC#N CPPKAGUPTKIMNP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002081 enamines Chemical class 0.000 claims description 2
- 150000002084 enol ethers Chemical class 0.000 claims description 2
- 150000003948 formamides Chemical class 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 230000009935 nitrosation Effects 0.000 claims description 2
- 238000007034 nitrosation reaction Methods 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 230000015556 catabolic process Effects 0.000 claims 1
- 238000006731 degradation reaction Methods 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 150000003254 radicals Chemical class 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 229960000443 hydrochloric acid Drugs 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- YPWYWSHQWNOAGP-UHFFFAOYSA-N pyrazolo[3,4-b]pyridine Chemical compound N1=CC=C[C]2C=NN=C21 YPWYWSHQWNOAGP-UHFFFAOYSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000002537 thrombolytic effect Effects 0.000 description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 3
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 210000000709 aorta Anatomy 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 238000004587 chromatography analysis Methods 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
- 230000008602 contraction Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- SDRAQDOOQWFHLN-UHFFFAOYSA-N 1-benzyl-3-(furan-2-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound N1=C(C=2OC=CC=2)C=2C(O)=NC=NC=2N1CC1=CC=CC=C1 SDRAQDOOQWFHLN-UHFFFAOYSA-N 0.000 description 2
- FAWKBOJEHYLCLI-UHFFFAOYSA-N 2-[(2-fluorophenyl)methyl]pyrazol-3-amine Chemical compound NC1=CC=NN1CC1=CC=CC=C1F FAWKBOJEHYLCLI-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- FTAPDGOLMPBGEE-UHFFFAOYSA-N 5-(1-benzylpyrazolo[3,4-d]pyrimidin-3-yl)furan-2-carbaldehyde Chemical compound O1C(C=O)=CC=C1C(C1=CN=CN=C11)=NN1CC1=CC=CC=C1 FTAPDGOLMPBGEE-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- 101000790711 Chlamydomonas reinhardtii Uncharacterized membrane protein ycf78 Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010078321 Guanylate Cyclase Proteins 0.000 description 2
- 102000014469 Guanylate cyclase Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000012891 Ringer solution Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- FTIJEMFXCSOMJI-UHFFFAOYSA-N [5-(5-amino-1-benzylpyrazol-3-yl)furan-2-yl]methanol Chemical compound NC1=CC(C=2OC(CO)=CC=2)=NN1CC1=CC=CC=C1 FTIJEMFXCSOMJI-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 238000009530 blood pressure measurement Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229950005499 carbon tetrachloride Drugs 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- XEYBHCRIKKKOSS-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide Chemical compound [Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N XEYBHCRIKKKOSS-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 239000000066 endothelium dependent relaxing factor Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052987 metal hydride Inorganic materials 0.000 description 2
- 150000004681 metal hydrides Chemical class 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 2
- 229960001802 phenylephrine Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229940083618 sodium nitroprusside Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-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
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- 230000002883 vasorelaxation effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- QVCUKHQDEZNNOC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1NC2 QVCUKHQDEZNNOC-UHFFFAOYSA-N 0.000 description 1
- KQKJGGWWURFJGL-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-(5-piperidin-1-ylsulfinylfuran-2-yl)pyrazolo[3,4-b]pyridine Chemical compound FC1=CC=CC=C1CN1C2=NC=CC=C2C(C=2OC(=CC=2)S(=O)N2CCCCC2)=N1 KQKJGGWWURFJGL-UHFFFAOYSA-N 0.000 description 1
- NEVFXACCFBNHFG-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-(furan-2-yl)-7H-pyrazolo[3,4-b]pyridin-6-one Chemical compound C12=NC(O)=CC=C2C(C=2OC=CC=2)=NN1CC1=CC=CC=C1F NEVFXACCFBNHFG-UHFFFAOYSA-N 0.000 description 1
- YGUKECOAPNQYPJ-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-(furan-2-yl)pyrazolo[3,4-b]pyridine Chemical compound FC1=CC=CC=C1CN1C2=NC=CC=C2C(C=2OC=CC=2)=N1 YGUKECOAPNQYPJ-UHFFFAOYSA-N 0.000 description 1
- KMSSQBUEYJOECZ-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-(furan-2-yl)pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound N1=C(C=2OC=CC=2)C=2C(N)=NC=NC=2N1CC1=CC=CC=C1F KMSSQBUEYJOECZ-UHFFFAOYSA-N 0.000 description 1
- QOMRCMAKWINLAN-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridine-3-carboxylic acid Chemical compound C12=NC=CC=C2C(C(=O)O)=NN1CC1=CC=CC=C1F QOMRCMAKWINLAN-UHFFFAOYSA-N 0.000 description 1
- OFNYURYXPSSFBX-UHFFFAOYSA-N 1-benzyl-3-(furan-2-yl)pyrazolo[3,4-d]pyrimidine Chemical compound N1=C(C=2OC=CC=2)C2=CN=CN=C2N1CC1=CC=CC=C1 OFNYURYXPSSFBX-UHFFFAOYSA-N 0.000 description 1
- JEQJKIADCIASBN-UHFFFAOYSA-N 1-benzyl-4-chloro-3-(furan-2-yl)pyrazolo[3,4-d]pyrimidine Chemical compound N1=C(C=2OC=CC=2)C=2C(Cl)=NC=NC=2N1CC1=CC=CC=C1 JEQJKIADCIASBN-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- DBQFXQNGQUPVER-UHFFFAOYSA-N 2-chloro-4,5-dimethylpyrimidine Chemical compound CC1=CN=C(Cl)N=C1C DBQFXQNGQUPVER-UHFFFAOYSA-N 0.000 description 1
- XKEWXLRCWAMRIU-UHFFFAOYSA-N 3-[5-(hydroxymethyl)furan-2-yl]-3-oxopropanenitrile Chemical compound OCC1=CC=C(C(=O)CC#N)O1 XKEWXLRCWAMRIU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NCGICGYLBXGBGN-UHFFFAOYSA-N 3-morpholin-4-yl-1-oxa-3-azonia-2-azanidacyclopent-3-en-5-imine;hydrochloride Chemical compound Cl.[N-]1OC(=N)C=[N+]1N1CCOCC1 NCGICGYLBXGBGN-UHFFFAOYSA-N 0.000 description 1
- SYPSQMYDLWXIBL-UHFFFAOYSA-N 4,4-dichlorobut-3-en-2-amine Chemical compound CC(N)C=C(Cl)Cl SYPSQMYDLWXIBL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GHLWOVMNJMFHOQ-UHFFFAOYSA-N 5-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]furan-2-sulfinyl chloride Chemical compound FC1=CC=CC=C1CN1C2=NC=CC=C2C(C=2OC(=CC=2)S(Cl)=O)=N1 GHLWOVMNJMFHOQ-UHFFFAOYSA-N 0.000 description 1
- ZUMWLTDLJCUETE-UHFFFAOYSA-N 5-amino-1-[(2-fluorophenyl)methyl]-3-(furan-2-yl)pyrazole-4-carbonitrile Chemical compound NC1=C(C#N)C(C=2OC=CC=2)=NN1CC1=CC=CC=C1F ZUMWLTDLJCUETE-UHFFFAOYSA-N 0.000 description 1
- WKJJBZGBSPQRFP-UHFFFAOYSA-N 5-amino-1-benzyl-3-(furan-2-yl)pyrazole-4-carbonitrile Chemical compound NC1=C(C#N)C(C=2OC=CC=2)=NN1CC1=CC=CC=C1 WKJJBZGBSPQRFP-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 101100520660 Drosophila melanogaster Poc1 gene Proteins 0.000 description 1
- QQZWEECEMNQSTG-UHFFFAOYSA-N Ethyl nitrite Chemical compound CCON=O QQZWEECEMNQSTG-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical class O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101100520662 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PBA1 gene Proteins 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 229910004738 SiO1 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 1
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- FJKCHOGJZJQUKM-UHFFFAOYSA-N [2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyrazin-3-yl]-3h-furan-2-yl]methanol Chemical compound N=1N(CC=2C(=CC=CC=2)F)C2=NC=CN=C2C=1C1(CO)CC=CO1 FJKCHOGJZJQUKM-UHFFFAOYSA-N 0.000 description 1
- FMKIZPPNOUDGSG-UHFFFAOYSA-N [5-(1-benzylpyrazolo[3,4-b]pyridin-3-yl)furan-2-yl]methanol Chemical compound O1C(CO)=CC=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1 FMKIZPPNOUDGSG-UHFFFAOYSA-N 0.000 description 1
- NJCUIQGXTMNHCC-UHFFFAOYSA-N [5-(1-benzylpyrazolo[3,4-d]pyrimidin-3-yl)furan-2-yl]methanol Chemical compound O1C(CO)=CC=C1C(C1=CN=CN=C11)=NN1CC1=CC=CC=C1 NJCUIQGXTMNHCC-UHFFFAOYSA-N 0.000 description 1
- BABCBGUFCZUZCC-UHFFFAOYSA-N [5-[5-amino-1-[(2-fluorophenyl)methyl]pyrazol-3-yl]furan-2-yl]methanol Chemical compound NC1=CC(C=2OC(CO)=CC=2)=NN1CC1=CC=CC=C1F BABCBGUFCZUZCC-UHFFFAOYSA-N 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- NHOWLEZFTHYCTP-UHFFFAOYSA-N benzylhydrazine Chemical compound NNCC1=CC=CC=C1 NHOWLEZFTHYCTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- UBAZGMLMVVQSCD-UHFFFAOYSA-N carbon dioxide;molecular oxygen Chemical compound O=O.O=C=O UBAZGMLMVVQSCD-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- KMSRVXJGTIRNNK-UHFFFAOYSA-N diaminomethylideneazanium;hydrogen carbonate Chemical compound NC(N)=N.OC(O)=O KMSRVXJGTIRNNK-UHFFFAOYSA-N 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical group CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- ITQFPVUDTFABDH-AATRIKPKSA-N ethyl (e)-3-ethoxyprop-2-enoate Chemical compound CCO\C=C\C(=O)OCC ITQFPVUDTFABDH-AATRIKPKSA-N 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- ATADHKWKHYVBTJ-UHFFFAOYSA-N hydron;4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol;chloride Chemical compound Cl.CNCC(O)C1=CC=C(O)C(O)=C1 ATADHKWKHYVBTJ-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 229960003827 isosorbide mononitrate Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 description 1
- 229960004027 molsidomine Drugs 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 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
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- VQZBWXREWZZOQJ-UHFFFAOYSA-N propanedial;sodium;hydrate Chemical compound O.[Na].O=CCC=O VQZBWXREWZZOQJ-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 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
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003279 thiopental Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical group OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- 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
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Reproductive Health (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Gynecology & Obstetrics (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19649460.5 | 1996-11-26 | ||
| DE19649460A DE19649460A1 (de) | 1996-11-26 | 1996-11-26 | Neue substituierte Pyrazolderivate |
| PCT/EP1997/006366 WO1998023619A1 (de) | 1996-11-26 | 1997-11-14 | Neue substituierte pyrazolderivate zur behandlung von herzkreislauferkrankungen |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2272584A1 CA2272584A1 (en) | 1998-06-04 |
| CA2272584C true CA2272584C (en) | 2007-10-16 |
Family
ID=7813100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002272584A Expired - Fee Related CA2272584C (en) | 1996-11-26 | 1997-11-14 | Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0944631B1 (enExample) |
| JP (2) | JP4422800B2 (enExample) |
| CN (1) | CN1122032C (enExample) |
| AR (1) | AR010310A1 (enExample) |
| AT (1) | ATE259812T1 (enExample) |
| AU (1) | AU729642B2 (enExample) |
| BR (1) | BR9714363A (enExample) |
| CA (1) | CA2272584C (enExample) |
| CZ (1) | CZ185099A3 (enExample) |
| DE (2) | DE19649460A1 (enExample) |
| DK (1) | DK0944631T3 (enExample) |
| EE (1) | EE9900211A (enExample) |
| ES (1) | ES2214646T3 (enExample) |
| HU (1) | HUP0000562A3 (enExample) |
| ID (1) | ID21881A (enExample) |
| IL (1) | IL129998A0 (enExample) |
| MX (1) | MXPA99004826A (enExample) |
| NO (1) | NO992400D0 (enExample) |
| NZ (1) | NZ335890A (enExample) |
| PT (1) | PT944631E (enExample) |
| SK (1) | SK67699A3 (enExample) |
| TR (1) | TR199901172T2 (enExample) |
| TW (1) | TW403746B (enExample) |
| WO (1) | WO1998023619A1 (enExample) |
| ZA (1) | ZA9710573B (enExample) |
Families Citing this family (62)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19744026A1 (de) | 1997-10-06 | 1999-04-08 | Hoechst Marion Roussel De Gmbh | Pyrazol-Derivate, ihre Herstellung und ihre Verwendung in Arzneimitteln |
| DE19827679A1 (de) * | 1998-06-22 | 1999-12-23 | Dresden Arzneimittel | Adenosinrezeptoraffine, antikonvulsiv und antiallergisch/antiasthmatisch wirkende Pyrazolo[3,4-d]pyrimidine und Verfahren zu deren Herstellung |
| DE19834045A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin |
| DE19834044A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
| DE19834047A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
| GB9824310D0 (en) * | 1998-11-05 | 1998-12-30 | Univ London | Activators of soluble guanylate cyclase |
| DE19920352A1 (de) * | 1999-05-04 | 2000-11-09 | Bayer Ag | Substituiertes Pyrazolderivat |
| DE19943634A1 (de) | 1999-09-13 | 2001-04-12 | Bayer Ag | Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften |
| DE19943636A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften |
| DE19943635A1 (de) * | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
| DE10021069A1 (de) * | 2000-04-28 | 2001-10-31 | Bayer Ag | Substituiertes Pyrazolderivat |
| AR031176A1 (es) | 2000-11-22 | 2003-09-10 | Bayer Ag | Nuevos derivados de pirazolpiridina sustituidos con piridina |
| EP1339716B1 (de) | 2000-11-22 | 2004-11-03 | Bayer HealthCare AG | lactam-substituierte pyrazolopyridinderivate |
| DE10057751A1 (de) | 2000-11-22 | 2002-05-23 | Bayer Ag | Neue Carbamat-substituierte Pyrazolopyridinderivate |
| DE10057754A1 (de) | 2000-11-22 | 2002-05-23 | Bayer Ag | Neue Sulfonamid-substituierte Pyrazolopyridinderivate |
| DE10109858A1 (de) | 2001-03-01 | 2002-09-05 | Bayer Ag | Neuartige halogensubstituierte Aminodicarbonsäurederivate |
| DE10109861A1 (de) | 2001-03-01 | 2002-09-05 | Bayer Ag | Neuartige seitenkettenhalogenierte Aminodicarbonsäurederivate |
| DE10110749A1 (de) * | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte Aminodicarbonsäurederivate |
| DE10122894A1 (de) | 2001-05-11 | 2002-11-14 | Bayer Ag | Neue Sulfonat-substituierte Pyrazolopyridinderivate |
| DE10132416A1 (de) * | 2001-07-04 | 2003-01-16 | Bayer Ag | Neue Morpholin-überbrückte Pyrazolopyridinderivate |
| DE10220570A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
| DE10232572A1 (de) | 2002-07-18 | 2004-02-05 | Bayer Ag | Neue 2,5-disubstituierte Pyrimidinderivate |
| DE10244810A1 (de) * | 2002-09-26 | 2004-04-08 | Bayer Ag | Neue Morpholin-überbrückte Indazolderivate |
| AU2004275694B2 (en) * | 2003-06-30 | 2008-03-06 | Bizbiotech Co., Ltd. | Compounds, compositions and methods |
| DE102005050375A1 (de) | 2005-10-21 | 2007-04-26 | Bayer Healthcare Ag | Tetrazol-Derivate und ihre Verwendung |
| DE102005050498A1 (de) | 2005-10-21 | 2007-06-06 | Bayer Healthcare Aktiengesellschaft | Cyclopropylessigsäure-Derivate und ihre Verwendung |
| DE102005050377A1 (de) | 2005-10-21 | 2007-04-26 | Bayer Healthcare Ag | Heterocyclische Verbindungen und ihre Verwendung |
| DE102005050497A1 (de) | 2005-10-21 | 2007-04-26 | Bayer Healthcare Ag | Difluorphenol-Derivate und ihre Verwendung |
| DE102005050376A1 (de) | 2005-10-21 | 2007-05-31 | Bayer Healthcare Ag | Dicarbonsäure-Derivate und ihre Verwendung |
| DE102006020327A1 (de) * | 2006-04-27 | 2007-12-27 | Bayer Healthcare Ag | Heterocyclisch substituierte, anellierte Pyrazol-Derivate und ihre Verwendung |
| DE102006043443A1 (de) | 2006-09-15 | 2008-03-27 | Bayer Healthcare Ag | Neue aza-bicyclische Verbindungen und ihre Verwendung |
| DE102007015035A1 (de) | 2007-03-29 | 2008-10-02 | Bayer Healthcare Ag | Substituierte Dibenzoesäure-Derivate und ihre Verwendung |
| DE102007015034A1 (de) | 2007-03-29 | 2008-10-02 | Bayer Healthcare Ag | Lactam-substituierte Dicarbonsäuren und ihre Verwendung |
| DE102007026392A1 (de) | 2007-06-06 | 2008-12-11 | Bayer Healthcare Ag | Lösungen für die Perfusion und Konservierung von Organen und Geweben |
| DE102007028320A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
| DE102007028407A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
| DE102007028406A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
| DE102007028319A1 (de) | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituierte Oxazolidinone und ihre Verwendung |
| WO2009134750A1 (en) | 2008-04-28 | 2009-11-05 | Janssen Pharmaceutica Nv | Benzoimidazoles as prolyl hydroxylase inhibitors |
| EP2138178A1 (en) | 2008-06-28 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidninones for the treatment fo chronic obstructive pulmonary disease (COPD) and/or asthma |
| DE102008063992A1 (de) | 2008-12-19 | 2010-09-02 | Lerner, Zinoviy, Dipl.-Ing. | Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung |
| DE102009004245A1 (de) | 2009-01-09 | 2010-07-15 | Bayer Schering Pharma Aktiengesellschaft | Neue anellierte, Heteroatom-verbrückte Pyrazol- und Imidazol-Derivate und ihre Verwendung |
| UY33041A (es) | 2009-11-27 | 2011-06-30 | Bayer Schering Pharma Aktienegesellschaft | Procedimiento para la preparaciòn de {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5-il}carbamato de metilo y su purificaciòn para el uso como principio activo farmacèutico |
| GB201004311D0 (en) | 2010-03-15 | 2010-04-28 | Proximagen Ltd | New enzyme inhibitor compounds |
| JP5860459B2 (ja) | 2010-06-30 | 2016-02-16 | アイアンウッド ファーマシューティカルズ インコーポレイテッド | ｓＧＣ刺激薬 |
| ES2572803T3 (es) | 2010-11-09 | 2016-06-02 | Ironwood Pharmaceuticals, Inc. | Estimuladores de GCs |
| CN103619845B (zh) * | 2011-04-21 | 2016-08-17 | 拜耳知识产权有限责任公司 | 氟烷基取代的吡唑并吡啶及其用途 |
| IN2014DN01883A (enExample) | 2011-09-14 | 2015-05-15 | Proximagen Ltd | |
| US9139564B2 (en) | 2011-12-27 | 2015-09-22 | Ironwood Pharmaceuticals, Inc. | 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators |
| SI2847228T1 (sl) | 2012-05-10 | 2018-11-30 | Bayer Pharma Aktiengesellschaft | Protitelesa zmožna vezave na faktor koagulacije XI in/ali njeno aktivirano obliko faktor XIa in njihove uporabe |
| US20160324856A1 (en) | 2014-01-13 | 2016-11-10 | Ironwood Pharmaceuticals, Inc. | Use of sgc stimulators for the treatment of neuromuscular disorders |
| BR112017023855A2 (pt) | 2015-05-06 | 2018-07-17 | Bayer Pharma Aktiengesellschaft | o uso de estimulantes de sgc, ativadores de scg, em separado e combinações com inibidores de pde5 para o tratamento de úlceras digitais (du) concomitantes à esclerose múltipla (ssc) |
| ES2839248T5 (es) | 2015-07-23 | 2024-02-22 | Bayer Pharma AG | Estimuladores y/o activadores de la guanilatociclasa soluble (sGC) en combinación con un inhibidor de la endopeptidasa neutra (inhibidor de NEP) y/o un antagonista de angiotensina AII y su uso |
| WO2017106175A2 (en) | 2015-12-14 | 2017-06-22 | Ironwood Pharmaceuticals, Inc. | USE OF sGC STIMULATORS FOR THE TREATMENT OF GASTROINTESTINAL SPHINCTER DYSFUNCTION |
| WO2017121700A1 (de) * | 2016-01-15 | 2017-07-20 | Bayer Pharma Aktiengesellschaft | 1,3-disubstituierte 1h-pyrazolo[3,4-b]pyridin- derivate und ihre verwendung als stimulatoren der löslichen guanylatcyclase |
| CN110022871A (zh) | 2016-10-11 | 2019-07-16 | 拜耳制药股份公司 | 包含sGC刺激物和盐皮质激素受体拮抗剂的组合产品 |
| EP3525778A1 (de) | 2016-10-11 | 2019-08-21 | Bayer Pharma Aktiengesellschaft | Kombination enthaltend sgc aktivatoren und mineralocorticoid-rezeptor-antagonisten |
| EP3554488A2 (en) | 2016-12-13 | 2019-10-23 | Cyclerion Therapeutics, Inc. | Use of sgc stimulators for the treatment of esophageal motility disorders |
| ES2924359T3 (es) | 2017-04-11 | 2022-10-06 | Sunshine Lake Pharma Co Ltd | Compuestos de indazol sustituidos con flúor y usos de los mismos |
| BR112020022340A2 (pt) | 2018-05-15 | 2021-02-02 | Bayer Aktiengesellschaft | benzamidas substituídas por 1,3-tiazol-2-il para o tratamento de doenças associadas com sensibilização de fibras nervosas |
| MX2021000363A (es) | 2018-07-11 | 2021-04-29 | Cyclerion Therapeutics Inc | Uso de estimuladores de la guanilato ciclasa soluble (sgc) para el tratamiento de trastornos mitocondriales. |
| WO2020164008A1 (en) | 2019-02-13 | 2020-08-20 | Bayer Aktiengesellschaft | Process for the preparation of porous microparticles |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0615542B2 (ja) * | 1986-07-22 | 1994-03-02 | 吉富製薬株式会社 | ピラゾロピリジン化合物 |
| US4994482A (en) * | 1989-07-31 | 1991-02-19 | Bristol-Myers Squibb Company | Arylpyrazol derivatives as anti-platelet agents, compositions and use |
| WO1993023036A1 (fr) * | 1992-05-21 | 1993-11-25 | Yoshitomi Pharmaceutical Industries, Ltd. | Compose de pyrazole condense optiquement actif, pour le traitement de la thrombocytopenie et de l'erythropenie |
| JP2928079B2 (ja) * | 1994-02-14 | 1999-07-28 | 永信薬品工業股▲ふん▼有限公司 | １−（置換ベンジル）−３−（置換アリール）縮合ピラゾール類、その製造法及びその用途 |
| CN1039536C (zh) * | 1994-02-28 | 1998-08-19 | 永信药品工业股份有限公司 | 1,3取代缩合吡唑类化合物及其应用和制备方法 |
-
1996
- 1996-11-26 DE DE19649460A patent/DE19649460A1/de not_active Withdrawn
-
1997
- 1997-11-14 CN CN97180065A patent/CN1122032C/zh not_active Expired - Fee Related
- 1997-11-14 EP EP97951204A patent/EP0944631B1/de not_active Expired - Lifetime
- 1997-11-14 EE EEP199900211A patent/EE9900211A/xx unknown
- 1997-11-14 DE DE59711321T patent/DE59711321D1/de not_active Expired - Lifetime
- 1997-11-14 CA CA002272584A patent/CA2272584C/en not_active Expired - Fee Related
- 1997-11-14 NZ NZ335890A patent/NZ335890A/en unknown
- 1997-11-14 JP JP52421898A patent/JP4422800B2/ja not_active Expired - Fee Related
- 1997-11-14 ID IDW990388A patent/ID21881A/id unknown
- 1997-11-14 HU HU0000562A patent/HUP0000562A3/hu unknown
- 1997-11-14 AT AT97951204T patent/ATE259812T1/de active
- 1997-11-14 PT PT97951204T patent/PT944631E/pt unknown
- 1997-11-14 IL IL12999897A patent/IL129998A0/xx unknown
- 1997-11-14 DK DK97951204T patent/DK0944631T3/da active
- 1997-11-14 AU AU54823/98A patent/AU729642B2/en not_active Ceased
- 1997-11-14 WO PCT/EP1997/006366 patent/WO1998023619A1/de not_active Ceased
- 1997-11-14 CZ CZ991850A patent/CZ185099A3/cs unknown
- 1997-11-14 TR TR1999/01172T patent/TR199901172T2/xx unknown
- 1997-11-14 MX MXPA99004826A patent/MXPA99004826A/es not_active IP Right Cessation
- 1997-11-14 SK SK676-99A patent/SK67699A3/sk unknown
- 1997-11-14 BR BR9714363A patent/BR9714363A/pt active Search and Examination
- 1997-11-14 ES ES97951204T patent/ES2214646T3/es not_active Expired - Lifetime
- 1997-11-21 TW TW086117406A patent/TW403746B/zh not_active IP Right Cessation
- 1997-11-25 ZA ZA9710573A patent/ZA9710573B/xx unknown
- 1997-11-26 AR ARP970105563A patent/AR010310A1/es active IP Right Grant
-
1999
- 1999-05-19 NO NO992400A patent/NO992400D0/no unknown
-
2009
- 2009-09-11 JP JP2009210476A patent/JP2010013475A/ja not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| EP0944631A1 (de) | 1999-09-29 |
| CN1238773A (zh) | 1999-12-15 |
| DE19649460A1 (de) | 1998-05-28 |
| NZ335890A (en) | 2001-02-23 |
| EE9900211A (et) | 1999-12-15 |
| BR9714363A (pt) | 2000-03-21 |
| HUP0000562A2 (hu) | 2000-10-28 |
| CN1122032C (zh) | 2003-09-24 |
| CZ185099A3 (cs) | 1999-08-11 |
| JP4422800B2 (ja) | 2010-02-24 |
| HUP0000562A3 (en) | 2001-12-28 |
| SK67699A3 (en) | 2000-02-14 |
| ES2214646T3 (es) | 2004-09-16 |
| WO1998023619A1 (de) | 1998-06-04 |
| MXPA99004826A (es) | 2008-02-19 |
| PT944631E (pt) | 2004-06-30 |
| AU729642B2 (en) | 2001-02-08 |
| JP2001505567A (ja) | 2001-04-24 |
| ZA9710573B (en) | 1998-06-10 |
| ID21881A (id) | 1999-08-05 |
| AU5482398A (en) | 1998-06-22 |
| DK0944631T3 (da) | 2004-06-07 |
| NO992400L (no) | 1999-05-19 |
| JP2010013475A (ja) | 2010-01-21 |
| EP0944631B1 (de) | 2004-02-18 |
| HK1023119A1 (en) | 2000-09-01 |
| TR199901172T2 (xx) | 1999-08-23 |
| TW403746B (en) | 2000-09-01 |
| IL129998A0 (en) | 2000-02-29 |
| CA2272584A1 (en) | 1998-06-04 |
| DE59711321D1 (de) | 2004-03-25 |
| AR010310A1 (es) | 2000-06-07 |
| ATE259812T1 (de) | 2004-03-15 |
| NO992400D0 (no) | 1999-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2272584C (en) | Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases | |
| US6451805B1 (en) | Substituted pyrazole derivatives for the treatment of cardiocirculatory diseases | |
| AU746586B2 (en) | Quinazolinone inhibitors of cGMP phosphodiesterase | |
| AU751316B2 (en) | Substituted pyrazole derivatives condensed with six-membered heterocyclic rings | |
| CA2429308C (en) | Novel lactam-substituted pyrazolopyridine derivatives | |
| JP5014551B2 (ja) | ホスホジエステラーゼ阻害剤として有効なβ−カルボリン誘導体 | |
| CA2409743C (en) | Substituted pyrrolopyridinone derivatives useful as phosphodiesterase inhibitors | |
| AU736303B2 (en) | New heterocyclylmethyl-substituted pyrazol derivates | |
| JP5501369B2 (ja) | 可溶性グアニレートシクラーゼ活性化剤 | |
| JP2012509877A5 (enExample) | ||
| CA2368023A1 (en) | Fused pyridopyridazine inhibitors of cgmp phosphodiesterase | |
| JP2004517828A (ja) | 新規なスルホンアミド置換ピラゾロピリジン誘導体 | |
| CA2870062A1 (en) | Pyrrolopyrazone inhibitors of tankyrase | |
| JP2001220390A (ja) | 縮合ピラゾール誘導体 | |
| JP2006516144A (ja) | インテグリン受容体アンタゴニスト誘導体としてのチアゾール化合物 | |
| CA2507958A1 (en) | Pyrazole compounds as integrin receptor antagonists derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20121114 |