CA2166721C - Bicyclic tetrahydro pyrazolopyridines - Google Patents
Bicyclic tetrahydro pyrazolopyridinesInfo
- Publication number
- CA2166721C CA2166721C CA002166721A CA2166721A CA2166721C CA 2166721 C CA2166721 C CA 2166721C CA 002166721 A CA002166721 A CA 002166721A CA 2166721 A CA2166721 A CA 2166721A CA 2166721 C CA2166721 C CA 2166721C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- ethyl
- compound
- phenyl
- hydrogen
- 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
- -1 Bicyclic tetrahydro pyrazolopyridines Chemical class 0.000 title claims description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims abstract description 25
- 102000003390 tumor necrosis factor Human genes 0.000 claims abstract description 25
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 21
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 7
- 206010040070 Septic Shock Diseases 0.000 claims abstract description 7
- 206010003246 arthritis Diseases 0.000 claims abstract description 7
- 208000006673 asthma Diseases 0.000 claims abstract description 7
- 206010006451 bronchitis Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 230000036303 septic shock Effects 0.000 claims abstract description 7
- 208000030507 AIDS Diseases 0.000 claims abstract description 6
- 206010012434 Dermatitis allergic Diseases 0.000 claims abstract description 6
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 6
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 6
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 6
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 6
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 230000005764 inhibitory process Effects 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 2
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 2
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 2
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
- LSARSGAQJQDEIH-UHFFFAOYSA-N 1-(1,1-dioxothiolan-3-yl)-3-ethyl-6-(3-methoxyphenyl)-4,5-dihydropyrazolo[3,4-c]pyridin-7-one Chemical compound C1CN(C=2C=C(OC)C=CC=2)C(=O)C2=C1C(CC)=NN2C1CCS(=O)(=O)C1 LSARSGAQJQDEIH-UHFFFAOYSA-N 0.000 claims description 2
- WZYGDFRYVJMFLK-UHFFFAOYSA-N 1-(1,1-dioxothiolan-3-yl)-3-ethyl-6-(3-methylphenyl)-4,5-dihydropyrazolo[3,4-c]pyridin-7-one Chemical compound CCc1nn(C2CCS(=O)(=O)C2)c2c1CCN(C2=O)c1cccc(C)c1 WZYGDFRYVJMFLK-UHFFFAOYSA-N 0.000 claims description 2
- ZAKZEXHBGMZAQI-UHFFFAOYSA-N 1-(1,1-dioxothiolan-3-yl)-3-ethyl-6-[3-(trifluoromethyl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridin-7-one Chemical compound C1CN(C=2C=C(C=CC=2)C(F)(F)F)C(=O)C2=C1C(CC)=NN2C1CCS(=O)(=O)C1 ZAKZEXHBGMZAQI-UHFFFAOYSA-N 0.000 claims description 2
- JRJZYRLMEKTVEZ-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)-3-ethyl-6-(3-methoxyphenyl)-4,5-dihydropyrazolo[3,4-c]pyridin-7-one Chemical compound CCC1=NN(C=2C=C(Cl)C(Cl)=CC=2)C(C2=O)=C1CCN2C1=CC=CC(OC)=C1 JRJZYRLMEKTVEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000006383 alkylpyridyl group Chemical group 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 4
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
- YYQGUWHFXVXQOO-GFCCVEGCSA-N 2-chloro-4-[[3-[(2R)-2-hydroxybutyl]-1-methyl-2-oxobenzimidazol-5-yl]amino]pyridine-3-carbonitrile Chemical compound ClC1=C(C#N)C(=CC=N1)NC1=CC2=C(N(C(N2C[C@@H](CC)O)=O)C)C=C1 YYQGUWHFXVXQOO-GFCCVEGCSA-N 0.000 claims 1
- BGCPLWWYPZAURQ-UHFFFAOYSA-N 5-[[5-chloro-2-(2,2,6,6-tetramethylmorpholin-4-yl)pyrimidin-4-yl]amino]-3-(3-hydroxy-3-methylbutyl)-1-methylbenzimidazol-2-one Chemical compound ClC=1C(=NC(=NC=1)N1CC(OC(C1)(C)C)(C)C)NC1=CC2=C(N(C(N2CCC(C)(C)O)=O)C)C=C1 BGCPLWWYPZAURQ-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 239000003921 oil Substances 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 14
- 238000001819 mass spectrum Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 8
- 125000004346 phenylpentyl group Chemical group C1(=CC=CC=C1)CCCCC* 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003880 polar aprotic solvent Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 125000003944 tolyl group Chemical group 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- ZPTVZXFLKDHHPE-UHFFFAOYSA-N 3-methyl-1-(4-methylphenyl)-2,4-dihydrotriazine Chemical compound N1N(C)CC=CN1C1=CC=C(C)C=C1 ZPTVZXFLKDHHPE-UHFFFAOYSA-N 0.000 description 2
- DLAHXRUKBPTZHD-UHFFFAOYSA-N 5-hydroxy-1-phenyl-4-propanoyl-2,3-dihydropyridin-6-one Chemical compound C1CC(C(=O)CC)=C(O)C(=O)N1C1=CC=CC=C1 DLAHXRUKBPTZHD-UHFFFAOYSA-N 0.000 description 2
- AEOBEOJCBAYXBA-UHFFFAOYSA-N A2P5P Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1OP(O)(O)=O AEOBEOJCBAYXBA-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000124008 Mammalia Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000005091 airway smooth muscle Anatomy 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
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- 238000000746 purification Methods 0.000 description 1
- 150000005229 pyrazolopyridines Chemical class 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
- 238000003260 vortexing Methods 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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8829293A | 1993-07-06 | 1993-07-06 | |
| US08/088,292 | 1993-07-06 | ||
| PCT/IB1994/000156 WO1995001980A1 (en) | 1993-07-06 | 1994-06-16 | Bicyclic tetrahydro pyrazolopyridines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2166721A1 CA2166721A1 (en) | 1995-01-19 |
| CA2166721C true CA2166721C (en) | 1999-07-27 |
Family
ID=22210524
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166721A Expired - Fee Related CA2166721C (en) | 1993-07-06 | 1994-06-16 | Bicyclic tetrahydro pyrazolopyridines |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0707585A1 (index.php) |
| JP (1) | JP2944048B2 (index.php) |
| KR (1) | KR100228949B1 (index.php) |
| CN (1) | CN1048015C (index.php) |
| AU (1) | AU695301B2 (index.php) |
| BR (1) | BR9406946A (index.php) |
| CA (1) | CA2166721C (index.php) |
| CZ (1) | CZ3696A3 (index.php) |
| EG (1) | EG20513A (index.php) |
| FI (1) | FI943208A7 (index.php) |
| HU (1) | HUT74170A (index.php) |
| IL (1) | IL110175A (index.php) |
| MX (1) | MX9405132A (index.php) |
| NO (1) | NO305029B1 (index.php) |
| NZ (1) | NZ266525A (index.php) |
| PL (1) | PL312426A1 (index.php) |
| RU (1) | RU2131876C1 (index.php) |
| TW (1) | TW316904B (index.php) |
| WO (1) | WO1995001980A1 (index.php) |
| ZA (1) | ZA944844B (index.php) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL319758A1 (en) * | 1994-10-20 | 1997-08-18 | Pfizer | Bicyclic tetrahydropyrasole pyridines and their application as medicines |
| JP3107827B2 (ja) * | 1995-06-06 | 2000-11-13 | ファイザー・インコーポレーテッド | トリサイクリック５，６−ジヒドロ−９Ｈ−ピラゾロ［３，４−ｃ］−１，２，４−トリアゾロ［４，３−ａ］ピリジン類 |
| AP932A (en) * | 1996-08-26 | 2001-02-02 | Pfizer | Tricyclic 5,6-dihydro-9H-pyrazolo (3,4c)-1,2,4,-triazolo (4,3-a) pyridines. |
| AU724549B2 (en) * | 1996-09-04 | 2000-09-28 | Pfizer Inc. | Indazole derivatives and their use as inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF) |
| EP1017384B1 (en) * | 1997-09-26 | 2004-11-10 | Zentaris GmbH | Azabenzimidazole-based compounds for modulating serine/threonine protein kinase function |
| US6858616B2 (en) | 1998-12-23 | 2005-02-22 | Bristol-Myers Squibb Pharma Company | Nitrogen containing heterobicycles as factor Xa inhibitors |
| DE69921358T2 (de) | 1998-12-23 | 2006-03-09 | Bristol-Myers Squibb Pharma Co. | Stickstoffhaltige heterobicyclen als faktor-xa-hemmer |
| US6326495B2 (en) | 1999-04-30 | 2001-12-04 | Pfizer Inc. | Process for preparing 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes and intermediates useful therein |
| EA006685B1 (ru) | 1999-08-21 | 2006-02-24 | Алтана Фарма Аг | Синергетическая композиция |
| TWI243055B (en) * | 2000-04-13 | 2005-11-11 | Nippon Zoki Pharmaceutical Co | Pharmaceutical composition for use in treatment of dermatitis |
| US7541354B2 (en) * | 2000-08-10 | 2009-06-02 | Pfizer Italia S.R.L. | Bicyclo-pyrazoles |
| NZ524191A (en) * | 2000-08-14 | 2004-11-26 | Ortho Mcneil Pharm Inc | Substituted pyrazoles useful for treating autoimmune diseases mediated by cathepsin S |
| US6960595B2 (en) * | 2001-03-23 | 2005-11-01 | Bristol-Myers Squibb Pharma Company | 5-6 to 5-7 Heterobicycles as factor Xa inhibitors |
| WO2002085353A1 (en) | 2001-04-18 | 2002-10-31 | Bristol-Myers Squibb Company | 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones as factor xa inhibitors |
| WO2002085356A1 (en) | 2001-04-18 | 2002-10-31 | Bristol-Myers Squibb Company | 1, 4, 5, 6-tetrahydropyrazolo-[3, 4-c]-pyrid in-7-ones as factor xa inhibitors |
| JP4196678B2 (ja) | 2001-04-26 | 2008-12-17 | 味の素株式会社 | 複素環化合物 |
| CN102617567A (zh) * | 2001-09-21 | 2012-08-01 | 百时美施贵宝公司 | 含有内酰胺的化合物及其衍生物作为Xa因子的抑制剂 |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| NZ541836A (en) | 2003-02-27 | 2008-12-24 | Palau Pharma Sa | Pyrazolopyridine derivatives |
| US7135469B2 (en) * | 2003-03-18 | 2006-11-14 | Bristol Myers Squibb, Co. | Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors |
| EA200501548A1 (ru) | 2003-04-01 | 2006-02-24 | Апплайд Резеч Системз Арс Холдинг Н.В. | Ингибиторы фосфодиэстераз при бесплодии |
| US7145012B2 (en) | 2003-04-23 | 2006-12-05 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
| TW200618800A (en) * | 2004-08-03 | 2006-06-16 | Uriach Y Compania S A J | Heterocyclic compounds |
| DE102005031580A1 (de) * | 2005-07-06 | 2007-01-11 | Aicuris Gmbh & Co. Kg | Substituierte Sulfolanylpyrazole und ihre Verwendung |
| AR065804A1 (es) * | 2007-03-23 | 2009-07-01 | Smithkline Beecham Corp | Compuesto de indol carboxamida, composicion farmaceutica que lo comprende y uso de dicho compuesto para preparar un medicamento |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| US20100120694A1 (en) | 2008-06-04 | 2010-05-13 | Synergy Pharmaceuticals, Inc. | Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders |
| DK2170930T3 (da) | 2007-06-04 | 2012-11-05 | Synergy Pharmaceuticals Inc | Agonister af guanylatcyclase, anvendelige til behandlingen af gastrointestinale sygdomme, inflammation, cancer og andre sygdomme |
| CA2730603C (en) | 2008-07-16 | 2019-09-24 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| US9580471B2 (en) | 2011-03-01 | 2017-02-28 | Synergy Pharmaceuticals, Inc. | Process of preparing guanylate cyclase C agonists |
| WO2014131024A2 (en) | 2013-02-25 | 2014-08-28 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
| AU2014274812B2 (en) | 2013-06-05 | 2018-09-27 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase C, method of making and using same |
| MX375926B (es) | 2013-08-09 | 2025-03-07 | Ardelyx Inc | Compuestos y metodos para inhibir el transporte de fosfato. |
| CN110357888A (zh) * | 2018-04-09 | 2019-10-22 | 南京药捷安康生物科技有限公司 | 杂环磷酸二酯酶抑制剂及其用途 |
| JP2022533251A (ja) | 2019-05-21 | 2022-07-21 | アルデリックス， インコーポレイテッド | 患者において血清リン酸塩を低下させるための組み合わせ |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1463883A (fr) * | 1964-09-08 | 1966-07-22 | Ciba Geigy | Procédé de préparation de triaza-composés bicycliques |
| US3365459A (en) * | 1964-09-08 | 1968-01-23 | Ciba Geigy Corp | Certain tetrahydro pyrazolo-pyridine and pyrazolo-piperidine derivatives |
| US3340269A (en) * | 1964-09-08 | 1967-09-05 | Ciba Geigy Corp | 1-substituted 4-acyl-2, 3-dioxo-piperidine |
| HU183325B (en) * | 1981-02-11 | 1984-04-28 | Richter Gedeon Vegyeszet | Process for preparing new apovincaminol-3',4',5'-trimethoxy-benzoates substituted with a nitro group |
| EP0068378B1 (en) * | 1981-06-26 | 1986-03-05 | Schering Corporation | Novel imidazo(1,2-a)pyridines and pyrazines, processes for their preparation and pharmaceutical compositions containing them |
| FR2525602A1 (fr) * | 1982-04-21 | 1983-10-28 | Synthelabo | Imidazo(1,2-a)pyridines, leur preparation et leur application en therapeutique |
| US4668686A (en) * | 1985-04-25 | 1987-05-26 | Bristol-Myers Company | Imidazoquinoline antithrombrogenic cardiotonic agents |
| US5356897A (en) * | 1991-09-09 | 1994-10-18 | Fujisawa Pharmaceutical Co., Ltd. | 3-(heteroaryl)-pyrazololi[1,5-a]pyrimidines |
-
1994
- 1994-06-16 CN CN94193233A patent/CN1048015C/zh not_active Expired - Fee Related
- 1994-06-16 KR KR1019960700019A patent/KR100228949B1/ko not_active Expired - Fee Related
- 1994-06-16 BR BR9406946A patent/BR9406946A/pt not_active Application Discontinuation
- 1994-06-16 NZ NZ266525A patent/NZ266525A/en unknown
- 1994-06-16 JP JP7503938A patent/JP2944048B2/ja not_active Expired - Lifetime
- 1994-06-16 CA CA002166721A patent/CA2166721C/en not_active Expired - Fee Related
- 1994-06-16 WO PCT/IB1994/000156 patent/WO1995001980A1/en not_active Ceased
- 1994-06-16 CZ CZ9636A patent/CZ3696A3/cs unknown
- 1994-06-16 EP EP94916370A patent/EP0707585A1/en not_active Withdrawn
- 1994-06-16 HU HU9503934A patent/HUT74170A/hu unknown
- 1994-06-16 RU RU96103653A patent/RU2131876C1/ru active
- 1994-06-16 PL PL94312426A patent/PL312426A1/xx unknown
- 1994-06-16 AU AU68057/94A patent/AU695301B2/en not_active Ceased
- 1994-06-17 TW TW083105518A patent/TW316904B/zh active
- 1994-06-30 IL IL11017594A patent/IL110175A/xx active IP Right Grant
- 1994-07-05 FI FI943208A patent/FI943208A7/fi unknown
- 1994-07-05 MX MX9405132A patent/MX9405132A/es unknown
- 1994-07-05 EG EG40294A patent/EG20513A/xx active
- 1994-07-05 ZA ZA944844A patent/ZA944844B/xx unknown
-
1996
- 1996-01-05 NO NO960056A patent/NO305029B1/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW316904B (index.php) | 1997-10-01 |
| CN1129940A (zh) | 1996-08-28 |
| JP2944048B2 (ja) | 1999-08-30 |
| AU695301B2 (en) | 1998-08-13 |
| WO1995001980A1 (en) | 1995-01-19 |
| IL110175A0 (en) | 1994-10-07 |
| PL312426A1 (en) | 1996-04-29 |
| IL110175A (en) | 2000-01-31 |
| CZ3696A3 (en) | 1997-06-11 |
| FI943208L (fi) | 1995-01-07 |
| HU9503934D0 (en) | 1996-03-28 |
| EG20513A (en) | 1999-06-30 |
| NZ266525A (en) | 1997-10-24 |
| KR100228949B1 (ko) | 1999-11-01 |
| FI943208A0 (fi) | 1994-07-05 |
| CA2166721A1 (en) | 1995-01-19 |
| MX9405132A (es) | 1995-01-31 |
| NO960056D0 (no) | 1996-01-05 |
| NO305029B1 (no) | 1999-03-22 |
| NO960056L (no) | 1996-01-05 |
| FI943208A7 (fi) | 1995-01-07 |
| HUT74170A (en) | 1996-11-28 |
| EP0707585A1 (en) | 1996-04-24 |
| BR9406946A (pt) | 1996-08-06 |
| KR960703852A (ko) | 1996-08-31 |
| CN1048015C (zh) | 2000-01-05 |
| ZA944844B (en) | 1996-01-05 |
| RU2131876C1 (ru) | 1999-06-20 |
| AU6805794A (en) | 1995-02-06 |
| JPH08507084A (ja) | 1996-07-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |