CA2192643C - Derives phenyle tri-substitues utilises comme inhibiteurs de pde iv - Google Patents
Derives phenyle tri-substitues utilises comme inhibiteurs de pde iv Download PDFInfo
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- CA2192643C CA2192643C CA002192643A CA2192643A CA2192643C CA 2192643 C CA2192643 C CA 2192643C CA 002192643 A CA002192643 A CA 002192643A CA 2192643 A CA2192643 A CA 2192643A CA 2192643 C CA2192643 C CA 2192643C
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- Prior art keywords
- group
- formula
- groups
- pyridine
- optionally substituted
- Prior art date
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- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title abstract description 6
- -1 Tri-substituted phenyl Chemical class 0.000 title description 123
- 150000001875 compounds Chemical class 0.000 claims abstract description 210
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 39
- 125000005843 halogen group Chemical group 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 9
- 150000004677 hydrates Chemical class 0.000 claims abstract description 6
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 90
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 50
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 239000005864 Sulphur Chemical group 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 101150101604 ACVR1B gene Proteins 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Chemical group 0.000 claims description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- RYVZYACBVYKUHD-UHFFFAOYSA-N Alk5 Natural products CC#CC#CCCCCC=CC(=O)NCC(C)C RYVZYACBVYKUHD-UHFFFAOYSA-N 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 53
- 125000000217 alkyl group Chemical group 0.000 abstract description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 25
- 229910052731 fluorine Chemical group 0.000 abstract description 22
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 15
- 125000000547 substituted alkyl group Chemical group 0.000 abstract description 15
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 12
- 239000001257 hydrogen Substances 0.000 abstract description 12
- 238000011282 treatment Methods 0.000 abstract description 12
- 125000003342 alkenyl group Chemical group 0.000 abstract description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 abstract description 9
- 125000003118 aryl group Chemical group 0.000 abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 125000005518 carboxamido group Chemical group 0.000 abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- 208000006673 asthma Diseases 0.000 abstract description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract description 5
- 239000000651 prodrug Substances 0.000 abstract description 5
- 229940002612 prodrug Drugs 0.000 abstract description 5
- 125000000304 alkynyl group Chemical group 0.000 abstract description 4
- 238000011321 prophylaxis Methods 0.000 abstract description 4
- 125000004414 alkyl thio group Chemical group 0.000 abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 2
- 125000001589 carboacyl group Chemical group 0.000 abstract description 2
- 208000007101 Muscle Cramp Diseases 0.000 abstract 1
- 208000005392 Spasm Diseases 0.000 abstract 1
- 230000028709 inflammatory response Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- 239000000543 intermediate Substances 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000002904 solvent Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 239000002585 base Substances 0.000 description 33
- 239000000203 mixture Substances 0.000 description 32
- 239000003153 chemical reaction reagent Substances 0.000 description 31
- 239000002253 acid Substances 0.000 description 28
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 238000000034 method Methods 0.000 description 26
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 25
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 21
- 238000004587 chromatography analysis Methods 0.000 description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 17
- 229910052799 carbon Inorganic materials 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 15
- 229910052681 coesite Inorganic materials 0.000 description 15
- 229910052906 cristobalite Inorganic materials 0.000 description 15
- 229910052682 stishovite Inorganic materials 0.000 description 15
- 229910052905 tridymite Inorganic materials 0.000 description 15
- 229910052801 chlorine Inorganic materials 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 229910052794 bromium Inorganic materials 0.000 description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000011737 fluorine Substances 0.000 description 11
- 125000002524 organometallic group Chemical group 0.000 description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 108010044467 Isoenzymes Proteins 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 210000003979 eosinophil Anatomy 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 102000004127 Cytokines Human genes 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 150000004292 cyclic ethers Chemical class 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000007800 oxidant agent Substances 0.000 description 5
- 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 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 102000018594 Tumour necrosis factor Human genes 0.000 description 4
- 108050007852 Tumour necrosis factor Proteins 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 4
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 210000000440 neutrophil Anatomy 0.000 description 4
- 125000001979 organolithium group Chemical group 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 150000004756 silanes Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- DRTQHJPVMGBUCF-UCVXFZOQSA-N 1-[(2s,3s,4s,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@H]1[C@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UCVXFZOQSA-N 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 101000818522 Homo sapiens fMet-Leu-Phe receptor Proteins 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010040070 Septic Shock Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 125000004419 alkynylene group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003849 aromatic solvent Substances 0.000 description 3
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- GZKMGAXTHYGXEO-UHFFFAOYSA-M ruthenium(1+);triphenylphosphane;chloride Chemical compound [Ru]Cl.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 GZKMGAXTHYGXEO-UHFFFAOYSA-M 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000001044 sensory neuron Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
L'invention se rapporte à des composés de la formule générale (I) dans laquelle =W- représente (1) =C(Y)-, où Y représente un atome d'halogène ou un alkyle ou un groupe -Xr<a> dans lequel X représente -O-, -S(O)m- [m représentant zéro ou un nombre entier de valeur 1 ou 2], ou -N(R<b>)- [R<b> représentant un atome d'hydrogène ou un groupe alkyle éventuellement substitué] et R<a> représente un atome d'hydrogène ou un groupe alkyle éventuellement substitué ou (2) =N; L représente -XR, [R représentant un groupe alkyle, alcényle, cycloalkyle ou cycloalcényle éventuellement substitué], -C(R<11>)=C(R<1>)(R<2>) ou un groupe [-CH(R<11>)]nCH(R<1>)(R<2>)dans lequel R<11> représente un atome d'hydrogène ou de fluor ou un groupe méthyle, et R<1> et R<2>, qui peuvent être identiques ou différents, représentent chacun un atome d'hydrogène ou de fluor ou un alkyle, alcényle, alkynyle, alcoxy, alkylthio, éventuellement substitué, -CO2R<8>, [R<8> représentant un atome d'hydrogène ou un groupe alkyle, aralkyle ou aryle éventuellement substitué], -CONR<9>R<10> [ où R<9> et R<10>, qui peuvent être identiques ou différents sont tels que défini pour R<8>], le groupe -CSNR<9>R<10>, -CN ou -NO2 ou R<1> et R<2>, réunis à l'atome C auquel ils sont fixés, sont reliés pour former un groupe cycloalkyle ou cycloalcényle éventuellement substitué et n est zéro ou le nombre entier 1; Z représente un groupe (A) ou (B) dans lequel R<3> représente un atome d'hydrogène ou de fluor, un groupe alkyle à chaîne droite ou ramifiée, éventuellement substitué ou un groupe hydroxyle; R<4 >représente un atome d'hydrogène ou le groupe -(CH2)tAr ou -(CH2)t-Ar-(L<1>)n-Ar'; R<5> représente un groupe -(CH2)tAr ou -(CH2)t-Ar-(L<1>)n-Ar'; R<6> représente un atome d'hydrogène ou de fluor, un groupe alkyle à chaîne droite ou ramifiée; R<7> représente un atome d'hydrogène ou de fluor, un groupe alkyle à chaîne droite ou ramifiée, éventuellement substitué, ou un groupe Or<c> dans lequel R<c> représente un atome d'hydrogène ou un groupe alkyle ou alcényle éventuellement substitué, un groupe alcoxyalkyle, alcanoyle, formyle, carboxamido ou thiocarboxamoido. L'invention se rapporte également aux sels, solvates, hydrates, promédicaments et oxydes N de ces composés. Les composés de l'invention sont des inhibiteurs de la phosphodiestérase de type IV et sont utilisés dans la prophylaxie et le traitement de maladies telles que l'asthme dans lesquelles interviennent une réponse inflammatoire ou un spasme musculaire non désirés.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9412385.8 | 1994-06-21 | ||
| GB9412385A GB9412385D0 (en) | 1994-06-21 | 1994-06-21 | Chemical compounds |
| GB9412492.2 | 1994-06-22 | ||
| GB9412492A GB9412492D0 (en) | 1994-06-22 | 1994-06-22 | Chemical compounds |
| PCT/GB1995/001459 WO1995035281A1 (fr) | 1994-06-21 | 1995-06-21 | Derives phenyle tri-substitues utilises comme inhibiteurs de pde iv |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2192643A1 CA2192643A1 (fr) | 1995-12-28 |
| CA2192643C true CA2192643C (fr) | 2006-02-14 |
Family
ID=35892291
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002192643A Expired - Fee Related CA2192643C (fr) | 1994-06-21 | 1995-06-21 | Derives phenyle tri-substitues utilises comme inhibiteurs de pde iv |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2192643C (fr) |
-
1995
- 1995-06-21 CA CA002192643A patent/CA2192643C/fr not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2192643A1 (fr) | 1995-12-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |