AP609A - Tricyclic 5,6-dihydro-9H-pyrazolo[3,4c]-1,2,4-triazolo[4,3-A]pyridines. - Google Patents
Tricyclic 5,6-dihydro-9H-pyrazolo[3,4c]-1,2,4-triazolo[4,3-A]pyridines. Download PDFInfo
- Publication number
- AP609A AP609A APAP/P/1996/000806A AP9600806A AP609A AP 609 A AP609 A AP 609A AP 9600806 A AP9600806 A AP 9600806A AP 609 A AP609 A AP 609A
- Authority
- AP
- ARIPO
- Prior art keywords
- alkyl
- pyrazolo
- ethyl
- dihydro
- pyridine
- Prior art date
Links
- 150000003222 pyridines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims abstract description 32
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims abstract description 32
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims abstract description 25
- 102000003390 tumor necrosis factor Human genes 0.000 claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
- 206010006895 Cachexia Diseases 0.000 claims abstract description 8
- 206010040070 Septic Shock Diseases 0.000 claims abstract description 8
- 230000036303 septic shock Effects 0.000 claims abstract description 8
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 7
- 206010012434 Dermatitis allergic Diseases 0.000 claims abstract description 7
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 7
- 201000010105 allergic rhinitis 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
- 201000008937 atopic dermatitis Diseases 0.000 claims abstract description 7
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 7
- 206010006451 bronchitis Diseases 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 7
- 206010040047 Sepsis Diseases 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 31
- -1 (C2CJalkenyl Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052684 Cerium Inorganic materials 0.000 claims description 7
- 208000030507 AIDS Diseases 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 230000004968 inflammatory condition Effects 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
- CZSOESDMMFWTJY-UHFFFAOYSA-N 12-cyclopentyl-10-ethyl-5-(2-iodophenyl)-3,4,6,11,12-pentazatricyclo[7.3.0.02,6]dodeca-1(9),2,4,10-tetraene Chemical compound C1CN(C(=NN=2)C=3C(=CC=CC=3)I)C=2C2=C1C(CC)=NN2C1CCCC1 CZSOESDMMFWTJY-UHFFFAOYSA-N 0.000 claims 1
- 229910014585 C2-Ce Inorganic materials 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000010 aprotic solvent Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000003880 polar aprotic solvent Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 210000003979 eosinophil Anatomy 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000003586 protic polar solvent Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 241000282412 Homo Species 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-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
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-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
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 210000005091 airway smooth muscle Anatomy 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000099 in vitro assay Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 210000000440 neutrophil Anatomy 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- SYSZENVIJHPFNL-UHFFFAOYSA-N (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyl-L-asparagine, isoform B (protein) Chemical compound COC1=CC=C(I)C=C1 SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- SWACGCLWAODPJN-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-7-methylsulfanyl-4,5-dihydropyrazolo[3,4-c]pyridine Chemical compound C1CN=C(SC)C2=C1C(CC)=NN2C1CCCC1 SWACGCLWAODPJN-UHFFFAOYSA-N 0.000 description 1
- STPXIOFWKOIYHX-UHFFFAOYSA-N 1-methylcyclohexane-1-carbonyl chloride Chemical compound ClC(=O)C1(C)CCCCC1 STPXIOFWKOIYHX-UHFFFAOYSA-N 0.000 description 1
- XONUSAAXQLCRGJ-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-pyrazolo[3,4-c]pyridine Chemical compound N1=CCC2CNNC2=C1 XONUSAAXQLCRGJ-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
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- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 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 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 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
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Abstract
A compound of the formula wherein r1, r2, r3, r9 and r10 are as defined above. The compound of formula i and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (pde)type iv and the production of tumor necrosis factor (tnf)and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases charactrized by phosphodiesterase (pde)type iv activity as well as aids, sepsis, septic shock and other diseases, such as cachexia, involving the production of tnf.
Description
TRICYCLIC 5,6-DlHYDRO-9H-PYRAZOLOr3,4-c1-1.2,4-TRIAZOLQf4,3-o1PYRIDINES
Background of the Invention
Thisinventionrelatestotricyclic5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3ff]pyridines which are selective inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases as well as AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF. Compounds of the present invention may have combined PDE IV and TNF inhibitory ( activity.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans and to pharmaceutical compositions useful therefor.
Since the recognition that cyclic AMP is an intracellular second messenger (E.W. Sutherland, and T. W. Rail, Pharmacol. Rev.. 1960, 12, 265), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J.A. Beavo and D. H. Reifsnyder, TiPS. 1990,11,150), and their selective inhibition has led to improved drug therapy (C.D. Nicholson, R. A. Challiss and M. Shahid, TiPS, 1991,12, 19). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M.W. Verghese O et al,, J, Mol. Cell Cardiol.. 1989, 12 (Suppl. II), S 61) and airway smooth muscle θ relaxation (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
TNF is recognized to be involved in many infectious and auto-immune diseases, including cachexia (W. Friers, FEBS Letters. 1991,285, 199). Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C.E. Spooner et al., Clinical Immunology and Immunopathology. 1992,
62, S11).
AP/P/ 9 6 / 0 0 8 0 6
AP.00609
-2Summary of the Invention
The present invention relates to a compound of the formula
C 'θ c
© o
and the pharmaceutically acceptable salts thereof; wherein
R1 is hydrogen, (C,-C6)alkyl, (C,-Cs)alkoxy, (C2-C4)alkenyl, phenyl, dimethylamino, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl (C,-C3)alkyl or (C,-C6)acyl wherein the alkyl, phenyl or alkenyl groups may be substituted with up to two hydroxy, (C,C3)alkyl, or trifluoromethyl groups, or up to three halogens;
R2 and R3 are each independently selected from the group consisting of hydrogen, (C,-C,4)alkyl, (C,-C7)alkoxy(C1-C7)alkyl, (C2-C,4)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C,-C2)alkyl, a saturated or unsaturated (C4-C7)heterocyclic(CH2)„ group wherein n is 0, 1 or 2, containing as the heteroatom one or two of the group consisting of oxygen, sulphur, sulphonyl, nitrogen and NR4 wherein R4 is hydrogen or (C,-C4)alkyl; or a group of the formula
AP/P/ 9 6 / 0 0 8 0 6 wherein a is an integer from 1 to 5; b and c are 0 or 1; R5 is hydrogen, hydroxy, (C,C5)alkyl, (C2-C5)alkenyl, (C,-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, CO2R6, CONR6R7, NR6R7, NO2 or SO2NR6R7 wherein R® and R7 are each independently hydrogen or (C,-C4)alkyl; wherein Z is oxygen, sulphur, SO2, CO or NR8 wherein R8 is hydrogen or (C,-C4)alkyl; and Y is (C,-C5)alkylene or (C2-C6)alkenyl optionally substituted with up to two (C,-C7)alkyl or (C3-C7)cycloalkyl groups; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups may be substituted with one to fourteen, preferably one to five, of the group consisting of (C, -C2)alkyl, trifluoromethyl or halogen; and
AP.00609
C 10 r c
G
-3R9 and R10 are each independently selected from the group consisting of hydrogen, (C,-C6)alkyl, (C,-Ce)aikoxy, (Ce-C,0)aryl and (Ce-C,0)aryloxy.
The term “alkyl·, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term alkoxy’, as used herein, includes O-alkyl groups wherein alkyl is defined above.
The term thenyl, as used herein, unless otherwise indicated, is defined by thiophene-CH2-.
The term aryl, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C^CgJalkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C^CgJalkyl.
The term aryloxy, as used herein, includes O-aryl groups wherein aryl is defined above.
The term acyl, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms alkyl or aryl are as defined above.
Preferred compounds of formula I include those wherein R1 is methyl, ethyl or isopropyl.
Other preferred compounds of formula I include those wherein R3 is (C,-C6)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C,-Cs)alkyl or phenyl optionally substituted with 1 or 2 of the group consisting of hydrogen, hydroxy, (C,-C5)alkyl, (C2C5)alkenyl, (C,-C5)alkoxy, halogen, trifluoromethyl, CO2R®, CONR®R7, NR®R7, NO2 or SO2NR®R7 wherein R® and R7 are each independently hydrogen or (C^CJalkyl.
Specific preferred compounds of formula I include the following:
9-cyclopentyl-5,6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3ojpyridine;
9-cyclopenyl-5,6-dihydro-7-ethyl-3-(furan-2-yl)-9H-pyrazolo[3,4-c]-1,2,4triazolo [4,3-σ] pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-pyridyl)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-a]pyridine;
90800/96 /d/dV
AP.00609
C 10 r
c c
-49-cyclopentyl-5,6-dihydro-7-ethyl-3-(4-pyridyl)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(3-thenyl)-9tf-pyrazolo[3,4-c]-1,2,4-triazolo[4,3ojpyridine;
3-benzyl-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-propyl-9H-pyrazolo(3,4-c]-1,2,4-triazolo(4,3o]pyridine;
3,9-dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3ojpyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(1-methylcyclohex-1-yl)-9H-pyrazolo[3,4-c]1.2.4- triazolo[4,3-o]pyridine;
3-(fer/-butyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9/7-pyrazolo[3,4-c]-1,2,4triazolo[4,3-o]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-methylphenyl)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-o]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-methoxyphenyi)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-o]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9W-pyrazolo[3,4-c]1,2,4triazolo[4,3-o]pyridine;
3-(2-chlorophenyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-a]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-iodophenyl)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-o]pyridine;
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-trifluoromethylphenyl)-9H-pyrazolo[3,4-c]1.2.4- triazolo[4,3-a]pyridine; and
5,6-dihydro-7-ethyl-9-(4-fluorophenyl)-3-(1-methylcyclohex-1-yl)-9H-pyrazolo[3,4c]-1,2,4-triazolo[4,3-o]pyridine.
The present invention also relates to a method for the inhibition of phosphodiesterase (PDE) type IV and the production of TNF comprising administering to a patient an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating an inflammatory condition in mammals which comprises administering to said mammal an
AP/P/ 9 6 / 0 0 8 0 6
AP. ο οβ
9
-5antiinflammatory amount of a compound of the formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition for the (a) treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by phosphodiesterase (PDE) Type IV activity, AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF, or (b) the inhibition of phosphodiesterase (PDE) type IV and the production of TNF comprising an effective amount of a compound according to formula I or a pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable carrier.
This invention also relates to a method of treating or preventing a condition selected from the group consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases, such as cachexia, involving the production of
TNF comprising administering to a patient an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.
AP/P/ 9 6 / 0 0 8 0 6
AP.00609
-6Detailed Description of the Invention
The following reaction schemes illustrate, but are not limiting to, the preparation of the compounds of the present invention. Unless otherwise indicated R’, R2, R3, R9 and R10 in the reaction schemes and the discussion that follow are defined as above.
vi
AP/P/ 9 6 / 0 0 8 0 6
AP.00609
-7Preparation 2
I X
AP/P/ 9 6 / 0 0 8 0 6
AP.00609 c 10 c
-8Preparation 3
Preparation 4
VII I —
IX
AP/P/ 9 6 / 0 0 8 0 6
AP . 0 0 6 0 9
0 8 0 0 / 96 /d/dV
C _ Scheme 2
Ο -
XI
AP.00609
-10Scheme 3
XIV r
r c
c
XV
XVI
I
AP/P/ 96/00806
AP . 0 0 6 0 9 r , 10 <
c o
-11In Reaction 1 of Preparation 1, the 2-pyrrolidinone compound of formula III is converted to the corresponding N-(4-methoxyphenyl)-2-pyrrolidone compound of formula IV by reacting III with 4-iodoanisole or 4-bromoanisole neat in the presence of copper power and potassium carbonate. The reaction mixture is heated to a temperature between about 110°Cto about 170°C, preferably about 150°C, for a time period between about 14 hours to about 22 hours, preferably about 18 hours, under inert reaction conditions.
In Reaction 2 of Preparation 1, R1 halide, wherein R1 is (C,-C6)alkyl, is added to a suspension of magnesium in an anhydrous aprotic solvent. The reaction mixture is heated to reflux until all the magnesium is consumed and thereafter cooled to a temperature between about -15°C to about 15°C, preferably about 0°C. The N-(4methoxyphenyl)-2-pyrrolidone compound of formula IV is then added and the reaction mixture is warmed to room temperature while being stirred for a time period between about 1.5 hours to about 2.5 hours, preferably about 2 hours. Suitable alkyl halides include bromomethane, bromoethane or bromopropane. The preferred anhydrous aprotic solvent is anhydrous ether.
The desired intermediate is isolated and converted to the corresponding 1,2,5,6tetrahydropyridine compound of formula V by dispersing the precipitate in a mixture of a non-polar aprotic solvent and base. Ethyl oxalyl chloride is added and the reaction mixture is heated to reflux for a time period between about 1.5 hours to about 4.5 hours, preferably about 3.0 hours. The preferred non-polar aprotic solvent is benzene and the preferred base is sodium hydroxide. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in ethanol. After heating at reflux for a time period between about 1 hour and about 3 hours, preferably about 1.5 hours, the mixture is concentrated under reduced pressure and acidified to a pH of about 3 with hydrochloric acid.
In Reaction 3 of Preparation 1, the compound of formula V is converted to the corresponding 3-methoxy-1,2,5,6-tetrahydropyridine compound of formula VI by heating to reflux a reaction mixture of V and 3-methyl-1-p-tolyltriazene in an aprotic solvent, preferably 1,2-dichloroethane, for a time period between about 30 minutes to about 2 hours, preferably about 45 minutes.
In Reaction 1 of Preparation 2, the 1,2,5,6-tetrahydropyridine compound of formula VII, wherein R11 is hydrogen or methyl, is converted to the corresponding
0 8 0 0 / 96 /d/dV
AP.00609
-124,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine compound of formula VIII by reacting VII with a hydrazine compound of the formula R3HNNH2, wherein R3 is as defined above. Both derivatives of the compound of formula VII, 3-hydroxy and 3methoxy, may be used as starting materials under one of three different sets of reaction conditions.
Under one set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VII is converted to the corresponding compound of formula VIII by reacting VII with a hydrazine hydrochloride and sodium alkoxide in an anhydrous polar protic solvent. The preferred sodium alkoxide is sodium methoxide and the preferred anhydrous polar protic solvent is anhydrous ethanol. The reaction mixture is heated to reflux for a time period between about 9 hours to about 15 hours, preferably about
C 12 hours.
Under a second set of reaction conditions, the 1,2,5,6-tetrahydro-pyridine compound VII is converted to the corresponding compound of formula VIII by reacting
VII with a hydrazine in an anhydrous polar protic solvent, preferably ethanol. The reaction mixture is heated to reflux for a time period between about 16 hours to about 24 hours, preferably about 20 hours.
Under a third set of reaction conditions, the 1,2,5,6-tetrahydropyridine compound of formula VII is converted to the corresponding compound of formula VIII by reacting VII with either a hydrazine or hydrazine hydrochloride in a polar protic solvent, preferably methanol. The reaction mixture is heated to a temperature between
O about 70°C to about 110°C, preferably about 90°C, under a gentle stream of nitrogen until all of the solvent is removed. The neat mixture is then heated to a temperature c
between about 120°C to about 180°C, preferably about 150°C, for a time period between about 30 minutes to about 90 minutes, preferably 60 minutes.
in Reaction 2 of Preparation 2, the compound of formula VIII is converted to the corresponding 6-H-4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-c]pyridine compound of formula IX by reacting a solution of VIII in a polar aprotic solvent, preferably acetonitrile, with a solution of cerium (IV) ammonium nitrate in water at a temperature between about -15°C to about 15°C, preferably about 0°C, for a time period between about 20 minutes to about 50 minutes, preferably about 35 minutes. Upon completion of the reaction, the mixture is diluted with water and extracted with ethyl acetate. The
AP/P/ 9 6 / 0 0 8 0 6
AP.00609
-13combined organics are then washed with saturated sodium bicarbonate followed by sodium sulfite.
In Reaction 1 of Preparation 3, the compound of formula XII, prepared as described in United States Patent 3,423,414, is converted to the corresponding compound of formula VIII, wherein R1 is dimethylamino, by treating XII with sodium hydride in a polar aprotic solvent, such as tetrahydrofuran, at a temperature between about O°C to about 62°C, preferably about 25°C, for a time period between about 1 hour to about 6 hours, preferably about 1 hour. An excess amount of methyl iodide is then added to the reaction mixture at room temperature and the reaction mixture is allowed to stir for a time period between about 1 hour to about 24 hours, preferably about 2 hours.
In Reaction 2 of Preparation 3, the compound of formula VIII is further reacted to give the corresponding 6-H-4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine compound of formula IX, wherein R1 is dialkylamino, according to the procedure described above in Reaction 2 of Preparation 2.
In Reaction 1 of Preparation 4, the compound of formula XII is converted to the corresponding compound of formula XIII by reacting XII with bromotrimethylsilane and sodium nitrite in an aprotic solvent, such as carbon tetrachloride, at a temperature between about 0°C to about 25°C, preferably about 25°C, for a time period between about 6 hours to about 48 hours, preferably about 24 hours.
In Reaction 2 of Preparation 4, the compound of formula XIII is converted to the corresponding compound of formula VIII, wherein R1 is vinyl, by reacting XIII with vinyltributyltin and a catalytic amount of tetrakis(triphenylphosphine)palladium(0) in a non-polar aprotic solvent, such as benzene, at a temperature between about 80° C to about 120°C, preferably about 100°C, for a time period between about 24 hours to about 72 hours, preferably about 48 hours.
In Reaction 3 of Preparation 3, the compound of formula VIII is further reacted to give the corresponding 6-H-4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo[3,4-c]pyridine compound of formula IX, wherein R1 is alkenyl, according to the procedure described above in Reaction 2 of Preparation 2.
In Reaction 1 of Scheme I, the lactam compound of formula IX is converted to the corresponding thiolactam compound of formula X by reacting IX with phosphorus pentasulfide in a polar aprotic solvent, such as 1,4-dioxane or pyridine. The reaction
AP/P/ 9 6 / 0 0 8 0 6
AP .00609
-14mixture is heated to reflux for a time period between about 12 hours to about 48 hours, preferably about 18 hours.
In Reaction 2 of Scheme 2, the thiolactam X is converted to the corresponding tricyclic 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine compound of formula
I by treating X with anhydrous hydrazine in the presence of an anhydrous aprotic solvent, such as pyridine, under inert reaction conditions. The reaction mixture is heated to a temperature between about 50°C to about 100°C, preferably about 70°C, for a time period between about 5 minutes to about 30 minutes, preferably about 5 minutes. The volatile materials are then removed under reduced pressure and fresh anhydrous aprotic solvent, preferably pyridine, is added followed by the addition of an appropriate acid chloride of the formula R2COCI, wherein R2 is as defined above. The resulting reaction mixture is stirred for a time period between about 1 hour to about 4 hours, preferably about 2 hours. The volatile materials are once again removed under reduced pressure. The residue is dissolved in an aprotic solvent, such as dimethylformamide, and heated to reflux for a time period between about 1 hour to about 4 hours, preferably about 2 hours.
In Reaction 1 of Scheme 2, the thiolactam compound of formula X is converted to the corresponding methylthio compound of formula XI by treating a mixture of X and silica gel in an aprotic solvent, such as ether, with a solution of diazomethane in ether.
The reaction temperature will generally be in the range of about -5°C to about 10°C, preferably about 0°C, for a time period between about 30 minutes to about 5 hours, preferably about 1 hour.
In Reaction 2 of Scheme 2, the methyfthiol compound of formula XI is converted to the corresponding tricyclic 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-o] pyridine compound of formula I by reacting XI with a hydrazide compound of the formula R2CONHNH2, or the corresponding hydrochloride salt form, in an aprotic solvent, such as pyridine, under inert reaction conditions. The reaction mixture is heated to a temperature between about 120°C to about 150°C, preferably about 135°C, for a time period between about 2 hours to about 6 hours, preferably about 4 hours. The volatile materials are then removed under reduced pressure and the resulting oil is heated further to a temperature between about 135°C to about 165°C, preferably about 150°C, for a time period between about 2 hours to about 6 hours, preferably about 4 hours.
AP/P/ 9 6 / 0 0 8 0 6
AP.00609
Ο 10
O o
o
-15In Reaction 1 of Scheme 3, the compound of formula XIV is converted to the corresponding compound of formula XV according to the procedure described in Canadian Journal of Chemistry, 33. 1714 (1955).
In Reaction 2 of Scheme 3, the compound of formula XV is converted to the corresponding compound of formula XVI, wherein R’2 is (C,-Ce)alkyl, by reacting XV with alkyl lithium in a polar aprotic solvent, such as ether, at a temperature between about -50°C to about -80°C, preferably about -78°C, for a time period between about 15 minutes to about 2 hours, preferably about 30 minutes.
In Reaction 3 of Scheme 3, the compound of formula XVI is converted to the corresponding 5,6-dihydro-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine compound of formula I, wherein R1 is (C,-Ce)acyl, by treating XVI with pyridinium chlorochromate in a non-polar aprotic solvent, such as methylene chloride, at room temperature for a time period between about 6 hours to about 24 hours, preferably about 12 hours.
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit phosphodiesterase IV (PDE4) and, consequently, demonstrate their effectiveness for treating inflammatory diseases is shown by the following in vitro assay.
BIOLOGICAL ASSAY Human Eosinophil PDE,
Human peripheral blood is collected in ethylenediaminetetraacetic acid, diluted 1:2 in piperazine-N,N'-bis-2-ethanesulfonic acid (PIPES) buffer and then layered over percoll solution. Gradients are formed by centrifugation for 30 minutes at 2000 rpm at 4°C. The remainder of the isolation procedure, which is based on the procedure of Kita et al., J. Immunol., 152. 5457 (1994), is carried out at 4°C. The neutrophil/eosinophil layer is collected from the percoll gradient and the red blood cells are lysed. Remaining cells are washed in PIPES (1% FCS), incubated with anti-CD16 microbeads (MACS) for 1 hour, and passed over a magnetic column to remove the neutrophils. Eosinophils are collected in the eluate and analyzed for viability by trypan blue and purity by diff-quick stain. Eosinophil purity is routinely greater than 99% using this method.
Purified eosinophils are resuspended in 750pL of PDE lysis buffer (20 mM triethylamine, 1 mM ethylenediaminetetraacetic acid, 100 pg/ml bacitracin, 2mM benzamidine, 50 μΜ leupeptin, 50μΜ PMSF, 100 pg/ml soybean trypsin inhibitor) and quick frozen in liquid nitrogen. Cells are thawed slowly and sonicated. Membranes are
AP/P/ 9 6 / 0 0 8 0 6
AP.00609
C 10 r co
-16vortexed (disruption is confirmed by Trypan blue staining of fragments). Disrupted cells are centrifuged at 45k rpm for 30 minutes at 4°C to isolate membranes. Cytosol is decanted, and membrane resuspended to 200 /yg/ml for use as PDE source in the hydrolysis assay yielding a window from 3000 to 5000 counts.
Compounds are dissolved in dimethyl sulfoxide at 10-2M, then diluted 1:25 in water to 4 χ 104 M. This suspension is serially diluted 1:10 in 4% dimethyl sulfoxide, for a final dimethyl sulfoxide concentration in the assay of 1%.
PHOSPHODIESTERASE INHIBITION ASSAY
To 12 x 75 mm glass tubes add:
μ\ PDE assay buffer (200 mM Tris/40 mM MgC12) /yl 4 nM/ml cAMP stock /yl test compound /yl PDE source (membrane)
Background control = membrane boiled 10'
Positive control = 25 /yl unboiled membrane Incubate 25 minutes in 37°C water bath.
Reaction is stopped by boiling samples 5 minutes. Samples are applied to Affigel column (1 ml bed volume) previously equilibrated with 0.25 M acetic acid followed by 0.1 mMN-[2-hydroxyethyl]piperazine-N'-2-ethanesulfonicacid (HEPES)/0.1 mMNaCI wash buffer (pH 8.5). cAMP is washed off column with HEPES/NaCI, 5'-AMP is eluted in 4 ml volumes with 0.25 M acetic acid. 1 ml of eluate is counted in 3 ml scintillation fluid for 1 minute ([3H].
Substrate conversion = (cpm positive control x 4)/total activity. Conversion rate must be between 3 and 15% for experiment to be valid.
% Inhibition = 1 -(eluted cpm - background cpm/control cpm - bkgd cpm) x 100.
IC50s are generated by linear regression of inhibition titer curve (linear portion): and are expressed in μΜ.
TNF
The ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating diseases involving the production of TNF is shown by the following in vitro assay:
AP/P/ 9 6 / 0 0 8 0 6
AP .0 0 6 0 9 r . 10
P c
c
-17Peripheral blood (100 mis) from human volunteers is collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolated by Ficoll/Hypaque and washed three times in incomplete Hanks' balanced salt solution (HBSS). Cells are resuspended in a final concentration of 1 x 10” cells per ml in prewarmed RPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 10® cells in 1.0 ml in 24-well plates. The cells are incubated at 37°C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours, after which time nonadherent cells are removed by gentle washing. Test compounds (10//1) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. Lipopolysaccharide (LPS) (10//1) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37°C. At the end of the incubation period TNF was analyzed by a sandwich EUSA (R&D Quanfikine Kit). IC50 determinations are made for each compound based on linear regression analysis.
Pharmaceutically-acceptable acid addition salts of the compounds of this invention include, but are not limited to, those formed with HCI, HBr, HNO3, H2SO4, H3PO4, CH3SO3H, p-CH3C6H4SO3H, CH3CO2H, gluconic acid, tartaric acid, maleic acid and succinic acid. Pharmaceutically-acceptable cationic salts of the compounds of this invention of formula I wherein R5 is CO2R® and R® is hydrogen include, but are not limited to, those of sodium, potassium, calcium, magnesium, ammonium, N,N'dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine and diethanolamine.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of the compounds of formula I and the pharmaceutically acceptable salts thereof (hereinafter also referred to as the active compounds of the present invention) are generally in the range of from 0.1-400 mg daily for an average adult patient (70 kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.1 to 50 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 40 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but
AP/P/ 9 6 / 0 0 8 0 6
AP.00609 ζ*\ 10 ο
Ο ο
-18there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For administration to humans for the inhibition of TNF, a variety of conventional routes may be used including orally, parenterally and topically. In general, the active compound will be administered orally or parenterally at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg. The compound of formula I can also be administered topically in an ointment or cream in concentrations of about 0.5% to about 1%, generally applied 2 or 3 times per day to the affected area. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovales either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic.
The present invention is illustrated by the following examples, but it is not limited to the details thereof. The starting materials used in Preparations 1 -4 are prepared as described in PCT Publication WO 95/01980.
Preparation 1
1-Cyclopentvl-4,5-dihvdro-3-ethvl-7-methylthio-1 H-pyrazolof3.4-clpyridine
A magnetically stirred mixture of 1-cyclopentyl-3-ethyi-7-thio-4,5,6,7-tetrahydro1H-pyrazolo[3,4-c]pyridine (0.322 grams), neutral silica gel (10 grams) and ether (100 ml) in a 500 ml erlenmeyer flask was cooled to 0°C. To this mixture was slowly added an excess solution of diazomethane in ether. Evolution of gas occurred and after 1 hour the reaction was quenched with acetic acid (1 drop), filtered and concentrated
AP/P/ 9 6 / 0 0 8 0 6
AP .0 0 6 0 9
-19C
r.
under reduced pressure to give a yellow oil. The oil was purified by chromatography on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give 0.232 grams of a yellow oil. Anal, calcd. for C,4H21N3S: C, 63.85; H, 8.04; N, 15.94. Found: C, 64,01; H, 8.37; N, 15.71.
Preparation 2
1-Cvclopentyl-3-ethvl-7-thio-4.5.6.7-tetrahvdro-1 H-pyrazolof3,4-c1pyridine
A solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4cjpyridine (10.0 grams) in anhydrous 1,4-dioxane was treated with phosphorus pentasulfide (3.9 grams). After stirring at reflux for 12 hours the mixture was cooled to ambient temperature and concentrated under reduced pressure. The resulting yellow oil was dissolved in methylene chloride and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The orange residue was purified by chromatography on a silica gel column using a gradient mixture of hexanes in methylene chloride as eluent to give 9.3 grams of a yellow solid. Melting Point 15215 3°C; Anal, calcd. for C13H)9N3S: C, 62.63; H, 7.68; N, 16.86. Found: C, 62.14; H,
7.51; N, 16.35.
Preparation 3
1-cvclopentyl-3-ethyl-6-(4-methoxvphenvl)-7-oxo-4.5.6,7-tetrahydro-1H-pvrazolof3,4clpyridine
A stirred mixture of 3-methoxy-1-(3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6tetrahydro-pyridine (0.49 grams, 1.7 mmole), cyclopentylhydrazine hydrochloride (0.40 grams) and sodium methoxide (46 mg, 0.85 mmole) in anhydrous ethanol was heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1:4 ethyl acetate/hexane as eluent to give a white solid. Recrystallization from ether gave white needles. M.P. 64-65°C; MS m/z [M+] 340.2025; HRMS [M+] 340.2046.
Preparation 4
1-Cyclopentvl-3-ethvl-7-oxo-4.5.6.7-tetrahvdro-1 H-pyrazoloF3.4-clpyridine
A stirred solution of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenyl)-7-oxo-4,5,6,730 tetrahydro-1 H-pyrazolo[3,4-c]pyridine (2.58 grams, 7.60 mmoles) in acetonitrile (90 ml) at 0°C is treated with a solution of ceric ammonium nitrate (12.5 grams, 22.8 mmoles) in water (110 ml). After stirring for 35 minutes the mixture is diluted with water (550 ml) and extracted with ethyl acetate (100 ml x 4). The combined organics are washed with
0 8 0 0 / 96 /d/dV
AP.00609
-2050% saturated sodium bicarbonate (250 ml) followed by 10% sodium sulfite until the aqueous wash becomes pale yellow. The organic layer is then washed further with saturated bicarbonate and brine, and treated with decolorizing charcoal. After stirring for 30 minutes the mixture is dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The brown residue is recrystallized from ether to give .814 grams of a tan solid. M.P. 143-145°C; MS (M/Z) 234; Ή NMR (250 MHz, CDClj) 1.21 (t, J = 7.6 Hz, 3H), 1.62-2.13 (m, 8H), 2.62 (q, J = 7.6 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 3.51 (dt, J = 2.7 and 6.8 Hz, 2H), 5.47 (s, 1H), 5.61 (pentet, J = 7.7 Hz, 1H).
< 10 Example 1
9-Cvclopentyl-5.6-dihvdro-7-ethyl-3-(3-pvridyl)-9//-pvrazolof3.4-cl1.2.4-triazolof4.3-o1pyridine
-Cyclopentyl-4,5-dihydro-3-ethyl-7-methylthio-1H-pyrazolo[3,4-c]pyridine (0.036 grams, 0.14 mmoles) and nicotinic acid hydrazide (0.021 grams, 0.15 mmoles) was dissolved in anhydrous pyridine (5 ml) in a flame dried flask. An oven-dried condenser was added, which was septa sealed and had an outlet to a bubbler. A long stainless steel needle was pierced through the septa and condenser center into the magnetically stirred solution. Nitrogen was bubbled through the long needle. The flask was heated to 135°C for 4 hours. The pyridine was then removed under nitrogen purge. The resulting oil was heated to 150°C for 4 hours. The flask was cooled to ambient temperature and contained 0.045 grams of the crude title compound as a white ( solid. The crude product did not contain any impurities measurable by thin layer chromatography. The product can be purified by either column chromatography on a silica gel column using a gradient mixture of ethyl acetate/hexane as eluent or by recrystallization from a mixture of ethyl acetate in hexane. Melting Point 140-5°C (crude); Ή NMR (300 MHz, CDCI3) δ 1.24 (t, J=7.6 Hz, 3H), 1.72 (m, 2H), 1.94 (m, 2H), 2.16 (m, 4H), 2.66 (q, J=7.6 Hz, 2H), 2.98 (t, J=7.0 Hz, 2H), 4.25 (t, 1=7.0 Hz, 2H), 5.60 (quintet, J=7.7 Hz, 1H), 7.48 (dd, J=4.9 and 7.8 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.75 (dd, J=1.4 and 4.9 Hz, 1H), 8.9 (d, J=1.7 Hz, 1H); Anal, calcd. for C19H22N6: C,
68.23; H, 6.63; N, 25.13. Found: C, 67.39; H, 6.87; N, 24.00.
0 8 0 0 / 96 /d/dV
AP.00609
-21Examples 2-18
Reaction of the appropriate hydrazide with 1-cyclopentyl-4,5-dihydro-3-ethyl-7methylthio-1H-pyrazolo[3,4-c]pyridine, analogous to the procedure of Example 1, affords the following compounds of formula I wherein R’ is ethyl and R3 is cyclopentyl.
0 8 0 0 / 96 /d/dV
AP.0 0 6 0 9
APiVI 9 6 / 0 0 8 0 6
AP. Ο Ο 6 Ο 9
-23Example 19
9-Cvclopentvl-5.6-dihydro-7-ethyl-3-(thlen-2-yl)-9//-pvrazolof3,4-cl1.2,4-triazolof4.3-g1pyridine
-Cyclopentyl-3-ethyl-7-thio-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (0.35 5 grams, 1.4 mmole) was dissolved in 4 ml anhydrous pyridine in a flame dried flask under nitrogen. The flask was warmed to 70°C and 1.5 ml of anhydrous hydrazine was added. The yellow solution turned pink and was stirred for 5 minutes. The pyridine and excess hydrazine were then removed under reduced pressure to give a pink solid that turned light green after being placed under vacuum (approximately 0.1 mm) for 30 minutes. Next, anhydrous pyridine (4 ml) followed by 2-thiophene carbonyl chloride (0.69 grams, 4.7 mmoles) was added to the flask and the mixture was stirred for 2 hours. The pyridine was removed under reduced pressure, and the residue was dissolved in dimethylformamide (4 ml) and heated at reflux for 2 hours. The mixture was then cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The aqueous layer was basified to pH=12 with 1N sodium hydroxide and extracted with ethyl acetate three times. The combined organics were washed with 1N sodium hydroxide, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by chromatography on a silica gel column using a gradient mixture of ethyl acetate and hexane as eluent to give 304 mg of the title compound as a white solid. Melting Point 125-6°C; Ή NMR (300 MHz, CDCI3) δ 1.25 (t, J=7.5 Hz, 3H), 1.60-1.74 (m, 2H), 1.9-2.0 (m, 2H), 2.11-2.21 (m, 4H), 2.67 (q, J=7.6 Hz, 2H), 3.00 (t, J=7.1 Hz, 2H), 4.30 (t, J=7.1 Hz, 2H), 5.60 (quintet, J=7.7 Hz, 1H), 7.20 (dd, J=3.9 and 5.1 Hz, 1H), 7.49-7.54 (m, 2H); Anal, calcd. for C18H21N5S: C, 63.68; H, 6.24, N, 20.63. Found: C, 63.66; H, 6.19; N, 21.00.
Examples 20-30
Reaction of the appropriate acid chloride with hydrazine and 1 -cyclopentyl-3ethyl-7-thio-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, analogous to the procedure of Example 19, affords the following compounds of formula I wherein R1 is ethyl and R3 is cyclopentyl.
AP/P/ 9 6 / 0 0 8 0 6
AP.00609 c
r.
C>
C>
| HRMS or Analysis (found) %C, %H, %N | HRMS [M+H] 300.2188 | 66.56, 7.85, 25.44 | 65.24, 6.42, 18.83 | 65.26, 6.37, 19.03 | HRMS [M+H] 326.2345 | MS (m/z) 300 | HRMS [M+H] 354.2658 | 61.90, 5.94, 23.05 | 51.64, 5.00, 14.89 | 61.43, 5.53, 16.74 | 68.60, 8.88, 22.51 |
| HRMS or Analysis (calcd.) %C, %H, %N | [M + H] 300.2188 | 66.39, 7.80, 25.81 | 65.29, 6.03, 19.05 | 65.29, 6.03, 19.04 | [M+H] 326.2345 | [M+H] 354.2658 | 61.86, 5.74, 22.79 | 52.29, 4.83, 15.25 | -1 62.83, 5.53, 17.45 | 68.97, 8.68, 22.34 | |
| MW | 299.41 | 271-37 | 367.89 | 367.89 | 325.48 | 299.44 | 353.4 | 368.87 | 459.34 | 401.44 | 313.45 |
| MP°C | 88-92 | 174-5 | 132-4 | 158 | oily j | oily | oily | 161-3 | 145-7 | 154-5 | 144-5 |
| I'M tr | n-propyl | methyl | 2-chlorophenyl | 3-chlorophenyl | | cyclopentyl | isopropyl | 1 -methylcyclohex-1 -yl | 2-chloropyrid-3-yl | 2-iodophenyi | 2-trifluoromethyl phenyl | tert-butyl |
| Ex. # | 20 | V— OJ | 22 | 23 | 24 | 25 | 26 | 27 | 28 | 29 | 30 |
0 8 0 0 / 9 6 /d/dV in o
AP.00609
Example 31
5.6-dihydro-7-ethvl-9-(4-fluorophenvl)-3-(1-methvlcyclohex-1-vl)-9//pyrazolof3,4-d-1.2.4-triazoloi4.3-g1pyridine 3-Ethyl-1(4-fluorophenyl)-7-thio-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (0.092 grams) was dissolved in anhydrous pyridine (5 ml) and the solution was warmed to 70°C. Anhydrous hydrazine (2 ml) was added and the resulting yellow solution slowly turned beige. After 5 minutes the volatile materials were removed under reduced pressure to give a yellow solid. Next, anhydrous pyridine (5 ml) was added followed by 1-methyl cyclohexane carbonyl chloride (0.2 grams). After stirring for 2 hours at ambient temperature the pyridine was removed under reduced pressure and the residue was dissolved in dimethylformamide (5 ml). After stirring at reflux for 12 hours the solution was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, and then dried over sodium sulfate. Concentration under reduced pressure gave a light brown oil.
The oil was purified by chromatography on a silica gel column using 1:2 ethyl acetate/hexane as eluent to give 0.09 grams of a pale yellow solid. Melting Point 6061 °C; MS (m/z) 380.
Claims (9)
- A compound of the formula and the pharmaceutically acceptable salts thereof; whereinR1 is hydrogen, (C,-Ce)alkyl, (C,-Ce)alkoxy, (C2-C4)alkenyl, phenyl, dimethylamino, (C3-C6)cycloalkyl, (C3-Ce)cycloalkyl (C,-C3)alkyl or (C,-Ce)acyl wherein the alkyl, phenyl or alkenyl groups may be substituted with up to two hydroxy, (C,C3)alkyl, or trifluoromethyl groups, or up to three halogens;R2 and R3 are each independently selected from the group consisting of hydrogen, (C,-C,Jalkyl, (C1-C7)alkoxy(C1-C7)alkyl, (C
- 2-C14)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C,-C2)alkyl, a saturated or unsaturated (C4-C7)heterocyclic(CH2)n group wherein n is 0, 1 or 2, containing as the heteroatom one or two of the group consisting of oxygen, sulphur, sulphonyl, nitrogen and NR4 wherein R4 is hydrogen or (C,-C4)alkyl; or a group of the formula (Y)k-(Z) (R5)AP/P/ 96/00806 wherein a is an integer from 1 to 5; b and c are 0 or 1; R5 is hydrogen, hydroxy, (C,C5)alkyl, (C2-C5)alkenyl, (C,-C5)alkoxy, (C3-C6)cycloalkoxy, halogen, trifluoromethyl, CO2R8, CONR6R7, NR6R7, NO2 or SO2NR6R7 wherein R8 and R7 are each independently hydrogen or (C,-C4)alkyl; wherein Z is oxygen, sulphur, SO2, CO or NR8 wherein R8 is hydrogen or (C,-C4)alkyl; and Y is (C,-C5)alkylene or (C2-Ce)alkenyl optionally substituted with up to two (C,-C7)alkyl or (C3-C7)cycloalkyl groups; wherein each of the alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups may be substituted with one to fourteen, preferably one to five, of the group consisting of (C,-C2)alkyl, trifluoromethyl or halogen; andR9 and R10 are each independently selected from the group consisting of hydrogen, (C,-C6)alkyl, (C,-C6)alkoxy, (Ce-C10)aryl and (C6-C10)aryloxy.AP. Ο Ο 6 Ο 9-272. A compound according to claim 1, wherein R1 is methyl, ethyl or isopropyl.
- 3. A compound according to claim 1, wherein R3 is (C,-Ce)alkyl, (C2CJalkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C,-C2)allkyl or phenyl optionally5 substituted with 1 or 2 of the group consisting of hydrogen, hydroxy, (C,-C5)alkyl, (C2C5)a!kenyl, (C,-C5)alkoxy, halogen, trifluoromethyl, CO2R®, CONR®R7, NReR7, NO2 or SO2NR®R7 wherein R® and R7 are each independently hydrogen or (C,-C4)alkyl.
- 4. A compound according to claim 1 selected from the group consisting of: 9-cyclopentyl-5,6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,310 σ] pyridine;9-cyclopentyl-5,6-dihydro-7-ethyl-3-(4-pyridyl)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-o]pyridine;9-cyclopentyl-5,6-dihydro-7-ethyl-3-(3-thenyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3ojpyridine;15 3,9-dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3o]pyridine;9-cyclopentyl-5,6-dihydro-7-ethyl-3-(1-methylcyclohex-1-yl)-9W-pyrazolo[3,4-c]1,2,4-triazolo[4,3-o]pyridine;3-(ferf-butyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo[3,4-c]-1,2,420 triazolo[4,3-o]pyridine;9-cyclopentyl-5,6-dihydro-7-ethyl-3-(thien-2-yl)-9H-pyrazolo[3,4-c]1,2,4θ triazolo[4,3-o]pyridine;3-(2-chlorophenyl)-9-cyclopentyl-5,6-dihydro-7-ethyl-9/7-pyrazolo[3,4-c]-1,2,4o triazolo[4,3-o]pyridine;25 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-iodophenyl)-9H-pyrazolo[3,4-c]-1,2,4triazolo[4,3-a]pyridine; and
- 5,
- 6-dihydro-7-ethyl-9-(4-fluorophenyl)-3-(1-methylcyclohex-1-yl)-9/7-pyrazolo[3,4c]-1,2,4-triazolo[4,3-o]pyridine.5. A method for the inhibition of phosphodiesterase (PDE) type IV and the 30 production of tumor necrosis factor (TNF) comprising administering to a patient an effective amount of a compound according to claim 1.AP/P/ 9 6 / 0 0 8 0 6AP. Ο Ο 6 Ο 9-286. A method of treating an inflammatory condition in mammals which comprises administering to said mammal an antiinflammatory amount of a compound of the formula I and the pharmaceutically acceptable salts thereof.
- 7. A method of treating or preventing a condition selected from the group 5 consisting of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases as well as AIDS, septic shock and other diseases, such as cachexia, involving the production of TNF comprising administering to a patient an effective amount of a compound according to claim 1.
- 10 8. A pharmaceutical composition for the (a) treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by phosphodiesterase (PDE) type IV activity,AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF, or (b) the inhibition of phosphodiesterase (PDE) type IV and the
- 15 production of tumor necrosis factor (TNF) comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.AP/P/ 9 6 / 0 0 8 0 6AP . Ο Ο 6 Ο 9-295 AbstractA compound of the formula wherein R1, R2, R3, R9 and R’° are as defined above. The compound of formula I and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase15 (PDE) type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by phosphodiesterase (PDE) Type IV activity as well as AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB1995/000429 WO1996039408A1 (en) | 1995-06-06 | 1995-06-06 | TRICYCLIC 5,6-DIHYDRO-9H-PYRAZOLO[3,4-c]-1,2,4-TRIAZOLO[4,3-α]PYRIDINES |
| CA002223624A CA2223624C (en) | 1995-06-06 | 1995-06-06 | Tricyclic 5,6-dihydro-9h-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-.alpha.]pyridines |
| HU9601541A HUP9601541A3 (en) | 1995-06-06 | 1996-06-05 | Tricyclic 5,6-dihydro-9h-pyrazolo[3,4-c]-1,2,4-triazolol[4,3-a]-pyridines and pharmaceutical compositions containing them |
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| Publication Number | Publication Date |
|---|---|
| AP9600806A0 AP9600806A0 (en) | 1996-07-31 |
| AP609A true AP609A (en) | 1997-09-03 |
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| APAP/P/1996/000806A AP609A (en) | 1995-06-06 | 1996-05-06 | Tricyclic 5,6-dihydro-9H-pyrazolo[3,4c]-1,2,4-triazolo[4,3-A]pyridines. |
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| FR2792938B1 (en) | 1999-04-28 | 2001-07-06 | Warner Lambert Co | NEWS 1-AMINO TRIAZOLO [4,3-a] QUINAZOLINE-5-ONES PHOSPHODIESTERASE IV INHIBITORS |
| EP1380585B1 (en) * | 1999-04-30 | 2004-11-10 | Pfizer Products Inc. | Pyrazolopyridinone as intermediate |
| 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 |
| PT1212089E (en) | 1999-08-21 | 2006-08-31 | Altana Pharma Ag | ROFLUMILAST AND SALMETEROL SYNERGY COMBINATION |
| EP1265861A2 (en) | 2000-03-16 | 2002-12-18 | Inflazyme Pharmaceuticals, Ltd. | Benzylated pde4 inhibitors |
| NZ529335A (en) * | 2001-05-25 | 2005-09-30 | Pfizer | A PDE 4 inhibitor and an anti-cholinergic agent in combination for treating obstructive airways diseases |
| EP1397135B1 (en) * | 2001-05-25 | 2006-12-06 | Boehringer Ingelheim Pharma GmbH & Co.KG | Combination of a pde4 inhibitor and tiotropium or derivative thereof for treating obstructive airways |
| GB0122031D0 (en) * | 2001-09-12 | 2001-10-31 | Pfizer Ltd | Use of pde4 inhibitors in a dry powder inhaler |
| GB0129395D0 (en) * | 2001-12-07 | 2002-01-30 | Pfizer Ltd | Pharmaceutical combination |
| US20050107420A1 (en) * | 2002-05-23 | 2005-05-19 | Boehringe Ingelheim Pharma Gmbh & Co. Kg | Combination of a PDE4 inhibitor and tiotropium or derivative thereof for treating obstructive airways and other inflammatory diseases |
| WO2006075748A1 (en) * | 2005-01-17 | 2006-07-20 | Santen Pharmaceutical Co., Ltd. | Therapeutic agent for allergic conjunctival disease |
| WO2007045979A1 (en) | 2005-10-19 | 2007-04-26 | Ranbaxy Laboratories Limited | Pharmaceutical compositions of muscarinic receptor antagonists |
| RS53461B (en) | 2006-07-05 | 2014-12-31 | Takeda Gmbh | Combination of hmg-coa reductase inhibitors atorvastatin or simvastatin with a phosphodiesterase 4 inhibitor, such as roflumilast for the treatment of inflammatory pulmonary diseases |
| JP5579724B2 (en) * | 2008-10-17 | 2014-08-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Tetra-aza-heterocycles as phosphatidylinositol-3-kinase (PI-3 kinase) inhibitors |
| EP2507244B1 (en) | 2009-12-04 | 2014-11-05 | Nerviano Medical Sciences S.r.l. | Tricyclopyrazole derivatives |
| WO2013084182A1 (en) | 2011-12-08 | 2013-06-13 | Glenmark Pharmaceuticals S.A. | Pharmaceutical composition that includes a pde4 enzyme inhibitor and an analgesic agent |
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| WO1995001980A1 (en) * | 1993-07-06 | 1995-01-19 | Pfizer Inc. | Bicyclic tetrahydro pyrazolopyridines |
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| US3697532A (en) * | 1970-08-12 | 1972-10-10 | Squibb & Sons Inc | 5-methyldipyrazolo {8 3,4-b;3{40 ,4{40 -d{9 {0 pyridin-3(2h)-ones |
| CA2143143A1 (en) * | 1994-03-08 | 1995-09-09 | Toshihiko Tanaka | 3-phenylpyrrolidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995001980A1 (en) * | 1993-07-06 | 1995-01-19 | Pfizer Inc. | Bicyclic tetrahydro pyrazolopyridines |
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