RU2131876C1 - Бициклические тетрагидропиразолпиридины или их фармацевтически приемлемые соли, фармацевтическая композиция, способ ингибирования фосфодиэстеразы, способ лечения - Google Patents

Бициклические тетрагидропиразолпиридины или их фармацевтически приемлемые соли, фармацевтическая композиция, способ ингибирования фосфодиэстеразы, способ лечения Download PDF

Info

Publication number: RU2131876C1
Authority: RU; Russia
Prior art keywords: oxo; ethyl; pyridine; pyrazolo; tetrahydro
Prior art date: 1993-07-06

Application number

RU96103653A

Other languages

English (en)

Russian (ru)

Other versions

RU96103653A (ru

Inventor

Джекоб Дюплантье Аллен

Original Assignee

Пфайзер Инк.

Priority date (The priority date 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 date listed.)

1993-07-06

Filing date

1994-06-16

Publication date

1999-06-20

1994-06-16 Application filed by Пфайзер Инк. filed Critical Пфайзер Инк.

1998-05-10 Publication of RU96103653A publication Critical patent/RU96103653A/ru

1999-06-20 Application granted granted Critical

1999-06-20 Publication of RU2131876C1 publication Critical patent/RU2131876C1/ru

Links

150000001875 compounds Chemical class 0.000 description 69
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
238000006243 chemical reaction Methods 0.000 description 31
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
108060008682 Tumor Necrosis Factor Proteins 0.000 description 23
102000003390 tumor necrosis factor Human genes 0.000 description 23
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
239000000203 mixture Substances 0.000 description 22
239000000243 solution Substances 0.000 description 22
102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 21
108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 21
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
239000011541 reaction mixture Substances 0.000 description 17
238000010992 reflux Methods 0.000 description 17
238000003756 stirring Methods 0.000 description 17
-1 bicyclic tetrahydropyrazolopyridines Chemical class 0.000 description 16
YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 16
210000004027 cell Anatomy 0.000 description 15
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
238000000034 method Methods 0.000 description 14
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
239000007787 solid Substances 0.000 description 13
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
150000003839 salts Chemical class 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 11
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 11
229910052739 hydrogen Inorganic materials 0.000 description 11
239000000523 sample Substances 0.000 description 11
238000004458 analytical method Methods 0.000 description 10
239000001257 hydrogen Substances 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
238000004519 manufacturing process Methods 0.000 description 9
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
239000007983 Tris buffer Substances 0.000 description 8
239000012267 brine Substances 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 8
208000027866 inflammatory disease Diseases 0.000 description 7
239000003921 oil Substances 0.000 description 7
239000002904 solvent Substances 0.000 description 7
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
102000004190 Enzymes Human genes 0.000 description 6
108090000790 Enzymes Proteins 0.000 description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
125000000217 alkyl group Chemical group 0.000 description 6
239000000872 buffer Substances 0.000 description 6
201000010099 disease Diseases 0.000 description 6
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
229940079593 drug Drugs 0.000 description 6
239000003814 drug Substances 0.000 description 6
238000010438 heat treatment Methods 0.000 description 6
230000007062 hydrolysis Effects 0.000 description 6
238000006460 hydrolysis reaction Methods 0.000 description 6
239000011777 magnesium Substances 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
239000003880 polar aprotic solvent Substances 0.000 description 6
239000003586 protic polar solvent Substances 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
239000011534 wash buffer Substances 0.000 description 6
238000005406 washing Methods 0.000 description 6
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 5
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 5
WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 5
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
238000009835 boiling Methods 0.000 description 5
239000000499 gel Substances 0.000 description 5
229910052736 halogen Inorganic materials 0.000 description 5
150000002367 halogens Chemical class 0.000 description 5
239000010410 layer Substances 0.000 description 5
210000004072 lung Anatomy 0.000 description 5
229910052749 magnesium Inorganic materials 0.000 description 5
229910052757 nitrogen Inorganic materials 0.000 description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
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 4
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
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 4
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
229910005965 SO 2 Inorganic materials 0.000 description 4
206010040070 Septic Shock Diseases 0.000 description 4
125000003342 alkenyl group Chemical group 0.000 description 4
125000003545 alkoxy group Chemical group 0.000 description 4
BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 4
206010003246 arthritis Diseases 0.000 description 4
208000006673 asthma Diseases 0.000 description 4
206010006451 bronchitis Diseases 0.000 description 4
239000003937 drug carrier Substances 0.000 description 4
239000003480 eluent Substances 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
239000000284 extract Substances 0.000 description 4
150000002431 hydrogen Chemical class 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
210000001616 monocyte Anatomy 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
239000008194 pharmaceutical composition Substances 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
230000036303 septic shock Effects 0.000 description 4
239000000741 silica gel Substances 0.000 description 4
229910002027 silica gel Inorganic materials 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
230000001629 suppression Effects 0.000 description 4
239000000725 suspension Substances 0.000 description 4
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
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 3
208000030507 AIDS Diseases 0.000 description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
241000124008 Mammalia Species 0.000 description 3
201000004681 Psoriasis Diseases 0.000 description 3
206010039085 Rhinitis allergic Diseases 0.000 description 3
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 3
108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 3
201000010105 allergic rhinitis Diseases 0.000 description 3
239000000010 aprotic solvent Substances 0.000 description 3
125000003118 aryl group Chemical group 0.000 description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
239000003153 chemical reaction reagent Substances 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
230000000694 effects Effects 0.000 description 3
125000000623 heterocyclic group Chemical group 0.000 description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
238000012417 linear regression Methods 0.000 description 3
239000012280 lithium aluminium hydride Substances 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
239000012044 organic layer Substances 0.000 description 3
229910052760 oxygen Inorganic materials 0.000 description 3
239000001301 oxygen Substances 0.000 description 3
125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
239000000546 pharmaceutical excipient Substances 0.000 description 3
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
238000001953 recrystallisation Methods 0.000 description 3
239000000126 substance Substances 0.000 description 3
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
125000006526 (C1-C2) alkyl group Chemical group 0.000 description 2
125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
125000006701 (C1-C7) alkyl group Chemical group 0.000 description 2
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
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
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 description 2
HRVGXJYBJMMTEJ-UHFFFAOYSA-N 1-cyclohexyl-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)=NN2C1CCCCC1 HRVGXJYBJMMTEJ-UHFFFAOYSA-N 0.000 description 2
QJLZPHIDOKBEGS-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-5,6-dihydro-4h-pyrazolo[3,4-c]pyridin-7-one Chemical compound C1CNC(=O)C2=C1C(CC)=NN2C1CCCC1 QJLZPHIDOKBEGS-UHFFFAOYSA-N 0.000 description 2
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 2
HSUSROMNEDXTDQ-UHFFFAOYSA-N 3-ethyl-1-(4-methoxyphenyl)-6-phenyl-4,5-dihydropyrazolo[3,4-c]pyridin-7-one Chemical compound CCC1=NN(C=2C=CC(OC)=CC=2)C(C2=O)=C1CCN2C1=CC=CC=C1 HSUSROMNEDXTDQ-UHFFFAOYSA-N 0.000 description 2
125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 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
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
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
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
206010012434 Dermatitis allergic Diseases 0.000 description 2
229920001917 Ficoll Polymers 0.000 description 2
239000007995 HEPES buffer Substances 0.000 description 2
241000282412 Homo Species 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
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
239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
229930006000 Sucrose Natural products 0.000 description 2
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
230000001464 adherent effect Effects 0.000 description 2
230000032683 aging Effects 0.000 description 2
150000001350 alkyl halides Chemical class 0.000 description 2
239000000908 ammonium hydroxide Substances 0.000 description 2
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
150000001502 aryl halides Chemical class 0.000 description 2
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201000008937 atopic dermatitis Diseases 0.000 description 2
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QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
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230000000052 comparative effect Effects 0.000 description 2
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229910052740 iodine Inorganic materials 0.000 description 2
239000011630 iodine Substances 0.000 description 2
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
229910052943 magnesium sulfate Inorganic materials 0.000 description 2
235000019341 magnesium sulphate Nutrition 0.000 description 2
229960000988 nystatin Drugs 0.000 description 2
VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
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GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
239000007858 starting material Substances 0.000 description 2
KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
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229910052717 sulfur Inorganic materials 0.000 description 2
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WIKZRYSGQPZTMM-UHFFFAOYSA-N (3,4-dichlorophenyl)hydrazine;hydron;chloride Chemical compound [Cl-].[NH3+]NC1=CC=C(Cl)C(Cl)=C1 WIKZRYSGQPZTMM-UHFFFAOYSA-N 0.000 description 1
FQHCPFMTXFJZJS-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine;hydrochloride Chemical compound Cl.COC1=CC=C(NN)C=C1 FQHCPFMTXFJZJS-UHFFFAOYSA-N 0.000 description 1
125000006833 (C1-C5) alkylene group Chemical group 0.000 description 1
125000006592 (C2-C3) alkenyl group Chemical group 0.000 description 1
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- 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

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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)

RU96103653A 1993-07-06 1994-06-16 Бициклические тетрагидропиразолпиридины или их фармацевтически приемлемые соли, фармацевтическая композиция, способ ингибирования фосфодиэстеразы, способ лечения RU2131876C1 (ru)

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
RU96103653A RU96103653A (ru)	1998-05-10
RU2131876C1 true RU2131876C1 (ru)	1999-06-20

Family

ID=22210524

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
RU96103653A RU2131876C1 (ru)	1993-07-06	1994-06-16	Бициклические тетрагидропиразолпиридины или их фармацевтически приемлемые соли, фармацевтическая композиция, способ ингибирования фосфодиэстеразы, способ лечения

Country Status (20)

Country	Link
EP (1)	EP0707585A1 (no)
JP (1)	JP2944048B2 (no)
KR (1)	KR100228949B1 (no)
CN (1)	CN1048015C (no)
AU (1)	AU695301B2 (no)
BR (1)	BR9406946A (no)
CA (1)	CA2166721C (no)
CZ (1)	CZ3696A3 (no)
EG (1)	EG20513A (no)
FI (1)	FI943208L (no)
HU (1)	HUT74170A (no)
IL (1)	IL110175A (no)
MX (1)	MX9405132A (no)
NO (1)	NO305029B1 (no)
NZ (1)	NZ266525A (no)
PL (1)	PL312426A1 (no)
RU (1)	RU2131876C1 (no)
TW (1)	TW316904B (no)
WO (1)	WO1995001980A1 (no)
ZA (1)	ZA944844B (no)

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RU2780338C2 (ru) *	2017-05-31	2022-09-21	Кемосентрикс, Инк.	6-5 КОНДЕНСИРОВАННЫЕ КОЛЬЦА КАК ИНГИБИТОРЫ С5а

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EP0837860B1 (en) *	1995-06-06	2002-03-20	Pfizer Inc.	TRICYCLIC 5,6-DIHYDRO-9H-PYRAZOLO(3,4-c]-1,2,4-TRIAZOLO(4,3-ALPHA]PYRIDINES
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.
KR100338610B1 (ko) *	1996-09-04	2002-05-27	디. 제이. 우드, 스피겔 알렌 제이	인다졸 유도체 및 포스포디에스터라제 (pde) 유형 iv 및 종양괴사인자 (tnf) 생산의 억제제로서 그의 용도
EP1140941B1 (en) *	1998-12-23	2004-10-20	Bristol-Myers Squibb Pharma Company	Nitrogen containing heterobicycles as factor xa inhibitors
US6858616B2 (en)	1998-12-23	2005-02-22	Bristol-Myers Squibb Pharma Company	Nitrogen containing heterobicycles as factor Xa inhibitors
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
TR200909479T2 (tr)	1999-08-21	2012-02-21	Nycomed Gmbh	Sinerjistik kombinasyon.
TWI243055B (en) *	2000-04-13	2005-11-11	Nippon Zoki Pharmaceutical Co	Pharmaceutical composition for use in treatment of dermatitis
NZ524475A (en) *	2000-08-10	2004-11-26	Pharmacia Italia S	Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
US6960595B2 (en) *	2001-03-23	2005-11-01	Bristol-Myers Squibb Pharma Company	5-6 to 5-7 Heterobicycles as factor Xa inhibitors
US6706730B2 (en)	2001-04-18	2004-03-16	Bristol-Myers Squibb Pharma Company	1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones as factor Xa inhibitors
US6750225B2 (en)	2001-04-18	2004-06-15	Bristol-Myers Squibb Pharms Company	1,4,5,6-tetrahydropyrazolo-[3,4,-c]-pyridin-7-ones useful as factor Xa inhibitors
US7902179B2 (en)	2001-04-26	2011-03-08	Ajinomoto Co., Inc.	Heterocyclic compounds
US7772188B2 (en)	2003-01-28	2010-08-10	Ironwood Pharmaceuticals, Inc.	Methods and compositions for the treatment of gastrointestinal disorders
PT1611131E (pt)	2003-02-27	2010-12-20	Palau Pharma Sa	Derivados de pirazolopiridina
US7135469B2 (en) *	2003-03-18	2006-11-14	Bristol Myers Squibb, Co.	Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors
MXPA05010373A (es)	2003-04-01	2005-12-05	Applied Research Systems	Inhibidores de fosfodiesterasas en infertilidad.
US7145012B2 (en)	2003-04-23	2006-12-05	Pfizer Inc.	Cannabinoid receptor ligands and uses thereof
DE102005031580A1 (de) *	2005-07-06	2007-01-11	Aicuris Gmbh & Co. Kg	Substituierte Sulfolanylpyrazole und ihre Verwendung
PE20081889A1 (es) *	2007-03-23	2009-03-05	Smithkline Beecham Corp	Indol carboxamidas como inhibidores de ikk2
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
EP2998314B1 (en)	2007-06-04	2020-01-22	Bausch Health Ireland Limited	Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
WO2009149279A2 (en)	2008-06-04	2009-12-10	Synergy Pharmaceuticals Inc.	Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
ES2624828T3 (es)	2008-07-16	2017-07-17	Synergy Pharmaceuticals Inc.	Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros
US9616097B2 (en)	2010-09-15	2017-04-11	Synergy Pharmaceuticals, Inc.	Formulations of guanylate cyclase C agonists and methods of use
WO2012118972A2 (en)	2011-03-01	2012-09-07	Synegy Pharmaceuticals Inc.	Process of preparing guanylate cyclase c agonists
AU2014218599C1 (en)	2013-02-25	2018-09-06	Bausch Health Ireland Limited	Guanylate cyclase receptor agonists for use in colonic cleansing
AU2014235209B2 (en)	2013-03-15	2018-06-14	Bausch Health Ireland Limited	Guanylate cyclase receptor agonists combined with other drugs
WO2014151206A1 (en)	2013-03-15	2014-09-25	Synergy Pharmaceuticals Inc.	Agonists of guanylate cyclase and their uses
CN113388007A (zh)	2013-06-05	2021-09-14	博士医疗爱尔兰有限公司	鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法
KR20220147691A (ko)	2013-08-09	2022-11-03	알데릭스, 인코포레이티드	인산염 수송을 억제하기 위한 화합물 및 방법
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
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FR1463883A (fr) *	1964-09-08	1966-07-22	Ciba Geigy	Procédé de préparation de triaza-composés bicycliques
US3340269A (en) *	1964-09-08	1967-09-05	Ciba Geigy Corp	1-substituted 4-acyl-2, 3-dioxo-piperidine
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 JP JP7503938A patent/JP2944048B2/ja not_active Expired - Lifetime
- 1994-06-16 NZ NZ266525A patent/NZ266525A/en unknown
- 1994-06-16 PL PL94312426A patent/PL312426A1/xx unknown
- 1994-06-16 EP EP94916370A patent/EP0707585A1/en not_active Withdrawn
- 1994-06-16 BR BR9406946A patent/BR9406946A/pt not_active Application Discontinuation
- 1994-06-16 RU RU96103653A patent/RU2131876C1/ru active
- 1994-06-16 AU AU68057/94A patent/AU695301B2/en not_active Ceased
- 1994-06-16 HU HU9503934A patent/HUT74170A/hu unknown
- 1994-06-16 CZ CZ9636A patent/CZ3696A3/cs unknown
- 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 Application Discontinuation
- 1994-06-16 KR KR1019960700019A patent/KR100228949B1/ko not_active IP Right Cessation
- 1994-06-17 TW TW083105518A patent/TW316904B/zh active
- 1994-06-30 IL IL11017594A patent/IL110175A/xx active IP Right Grant
- 1994-07-05 EG EG40294A patent/EG20513A/xx active
- 1994-07-05 ZA ZA944844A patent/ZA944844B/xx unknown
- 1994-07-05 MX MX9405132A patent/MX9405132A/es unknown
- 1994-07-05 FI FI943208A patent/FI943208L/fi unknown
1996
- 1996-01-05 NO NO960056A patent/NO305029B1/no unknown

Non-Patent Citations (1)

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Title
Chemical Abstracts, 1977, vol. 86, N 5, nо 29, с.733. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
RU2780338C2 (ru) *	2017-05-31	2022-09-21	Кемосентрикс, Инк.	6-5 КОНДЕНСИРОВАННЫЕ КОЛЬЦА КАК ИНГИБИТОРЫ С5а

Also Published As

Publication number	Publication date
AU6805794A (en)	1995-02-06
CZ3696A3 (en)	1997-06-11
EG20513A (en)	1999-06-30
CA2166721C (en)	1999-07-27
IL110175A0 (en)	1994-10-07
BR9406946A (pt)	1996-08-06
NO960056L (no)	1996-01-05
KR960703852A (ko)	1996-08-31
IL110175A (en)	2000-01-31
HU9503934D0 (en)	1996-03-28
KR100228949B1 (ko)	1999-11-01
TW316904B (no)	1997-10-01
CN1048015C (zh)	2000-01-05
PL312426A1 (en)	1996-04-29
NO960056D0 (no)	1996-01-05
NZ266525A (en)	1997-10-24
MX9405132A (es)	1995-01-31
FI943208L (fi)	1995-01-07
FI943208A0 (fi)	1994-07-05
CA2166721A1 (en)	1995-01-19
JP2944048B2 (ja)	1999-08-30
JPH08507084A (ja)	1996-07-30
ZA944844B (en)	1996-01-05
EP0707585A1 (en)	1996-04-24
AU695301B2 (en)	1998-08-13
HUT74170A (en)	1996-11-28
CN1129940A (zh)	1996-08-28
NO305029B1 (no)	1999-03-22
WO1995001980A1 (en)	1995-01-19

Publication	Publication Date	Title
RU2131876C1 (ru)	1999-06-20	Бициклические тетрагидропиразолпиридины или их фармацевтически приемлемые соли, фармацевтическая композиция, способ ингибирования фосфодиэстеразы, способ лечения
JP3000674B2 (ja)	2000-01-17	ジヒドロピラゾロピロール類
AU702105B2 (en)	1999-02-11	Bicyclic tetrahydro pyrazolopyridines and their use as medicaments
EP0672031B1 (en)	2003-03-12	Catechol diethers as selective pde iv inhibitors
JP3554337B2 (ja)	2004-08-18	インダゾール誘導体、およびホスホジエステラーゼ（ｐｄｅ）タイプ４と腫瘍壊死因子（ｔｎｆ）産生の阻害剤としてのインダゾール誘導体の使用
RU2544011C2 (ru)	2015-03-10	Триазолопиридины в качестве ингибиторов фосфодиэстеразы для лечения кожных заболеваний
KR100339935B1 (ko)	2002-07-18	치환된 인다졸 유도체, 및 포스포디에스테라제 4형 및 종양괴사 인자 형성의 억제제로서의 그의 용도
AU2005278962A1 (en)	2006-03-09	Isoindolin-1-one derivatives
JP2011528372A (ja)	2011-11-17	α７ニコチン性アセチルコリンレセプターインヒビター
WO2012165399A1 (ja)	2012-12-06	イミダゾピリジン化合物
JP2010518026A (ja)	2010-05-27	ナトリウムチャネルが介在する疾患または状態の治療に有用なピリドピリミジノン化合物
US20030181472A1 (en)	2003-09-25	Inflammation modulators
BG99879A (bg)	1996-02-28	Инхибитори на нiv реверсивна транскриптаза
TWI659022B (zh)	2019-05-11	作為d-胺基酸氧化酶(daao)抑制劑之新穎經取代苯并咪唑衍生物
AU9240298A (en)	1999-01-21	Bicyclic tetrahydro pyrazolopyridines and their use as medicaments
CA2201728A1 (en)	1996-05-02	Bicyclic tetrahydro pyrazolopyridines and their use as medicaments

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Applications Claiming Priority (3)

Publications (2)

Family

ID=22210524

Family Applications (1)

Country Status (20)

Cited By (1)

Families Citing this family (34)

Family Cites Families (4)

Non-Patent Citations (1)

Cited By (1)

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