ES2505290T3 - Derivados de 3,4,4A,10B-tetrahidro-1H-tiopirano[4,3-c]isoquinolina - Google Patents
Derivados de 3,4,4A,10B-tetrahidro-1H-tiopirano[4,3-c]isoquinolina Download PDFInfo
- Publication number
- ES2505290T3 ES2505290T3 ES10790569.7T ES10790569T ES2505290T3 ES 2505290 T3 ES2505290 T3 ES 2505290T3 ES 10790569 T ES10790569 T ES 10790569T ES 2505290 T3 ES2505290 T3 ES 2505290T3
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- Prior art keywords
- methyl
- ethyl
- oxadiazol
- compound
- tetrazol
- Prior art date
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title description 18
- -1 pyrazol-4-yl Chemical group 0.000 claims abstract description 1080
- 150000001875 compounds Chemical class 0.000 claims abstract description 704
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 167
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 123
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims abstract description 34
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 30
- 239000011737 fluorine Substances 0.000 claims abstract description 28
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 28
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 23
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 12
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims abstract description 6
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims abstract description 5
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims abstract description 4
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims abstract description 4
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims abstract description 4
- 125000004515 1,2,4-thiadiazol-3-yl group Chemical group S1N=C(N=C1)* 0.000 claims abstract description 4
- 125000004516 1,2,4-thiadiazol-5-yl group Chemical group S1N=CN=C1* 0.000 claims abstract description 4
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims abstract description 4
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims abstract description 4
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims abstract description 4
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims abstract description 4
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims abstract description 4
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims abstract description 3
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 300
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 160
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 48
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 46
- 238000011282 treatment Methods 0.000 claims description 46
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 37
- 201000010099 disease Diseases 0.000 claims description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- 238000011321 prophylaxis Methods 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 23
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 21
- 230000001684 chronic effect Effects 0.000 claims description 17
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 17
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 15
- 230000001154 acute effect Effects 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 208000006673 asthma Diseases 0.000 claims description 12
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 10
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 10
- 206010014561 Emphysema Diseases 0.000 claims description 9
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 9
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 8
- 206010006451 bronchitis Diseases 0.000 claims description 8
- 208000030090 Acute Disease Diseases 0.000 claims description 7
- 208000014085 Chronic respiratory disease Diseases 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
- 208000007451 chronic bronchitis Diseases 0.000 claims description 7
- 208000023504 respiratory system disease Diseases 0.000 claims description 7
- 230000002685 pulmonary effect Effects 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 3
- 230000000414 obstructive effect Effects 0.000 claims 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 361
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 194
- 239000000243 solution Substances 0.000 description 188
- 239000007787 solid Substances 0.000 description 177
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 137
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 132
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 107
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 102
- 238000000034 method Methods 0.000 description 102
- 239000000741 silica gel Substances 0.000 description 98
- 229910002027 silica gel Inorganic materials 0.000 description 98
- 235000019439 ethyl acetate Nutrition 0.000 description 96
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- 239000000203 mixture Substances 0.000 description 84
- 238000003818 flash chromatography Methods 0.000 description 80
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 73
- 238000006243 chemical reaction Methods 0.000 description 71
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 69
- 238000010828 elution Methods 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 63
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 56
- 239000012071 phase Substances 0.000 description 56
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 55
- 238000000746 purification Methods 0.000 description 55
- 239000002904 solvent Substances 0.000 description 55
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- 239000000725 suspension Substances 0.000 description 51
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 50
- 229910000027 potassium carbonate Inorganic materials 0.000 description 48
- 235000011181 potassium carbonates Nutrition 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 239000003480 eluent Substances 0.000 description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 40
- 230000002829 reductive effect Effects 0.000 description 40
- 239000002253 acid Substances 0.000 description 39
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- 239000007864 aqueous solution Substances 0.000 description 38
- 238000002953 preparative HPLC Methods 0.000 description 31
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 25
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 238000003795 desorption Methods 0.000 description 20
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 238000004440 column chromatography Methods 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 17
- 238000007792 addition Methods 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 239000000463 material Substances 0.000 description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- 239000005711 Benzoic acid Substances 0.000 description 14
- 235000010233 benzoic acid Nutrition 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- VUYVXCJTTQJVKJ-UHFFFAOYSA-N palladium(2+);tricyclohexylphosphanium;dichloride Chemical compound Cl[Pd]Cl.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 VUYVXCJTTQJVKJ-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 229940095102 methyl benzoate Drugs 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 208000010668 atopic eczema Diseases 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
- QAFVXBQPQCSSLI-UHFFFAOYSA-N 1h-thieno[3,2-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1SC=C2 QAFVXBQPQCSSLI-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 10
- 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 10
- 239000002585 base Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 8
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 7
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 7
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 7
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 7
- 208000002205 allergic conjunctivitis Diseases 0.000 description 7
- 208000024998 atopic conjunctivitis Diseases 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000000460 chlorine Chemical group 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000000172 allergic effect Effects 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 208000033679 diabetic kidney disease Diseases 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 6
- SCEIUVCRLMZRRY-UHFFFAOYSA-N thieno[3,2-d]pyrimidine hydrochloride Chemical compound Cl.N1=CN=CC2=C1C=CS2 SCEIUVCRLMZRRY-UHFFFAOYSA-N 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- VLXVPDOWMACDNZ-UHFFFAOYSA-N 5-(chloromethyl)-3-(methoxymethyl)-1,2,4-oxadiazole Chemical compound COCC1=NOC(CCl)=N1 VLXVPDOWMACDNZ-UHFFFAOYSA-N 0.000 description 5
- 206010009900 Colitis ulcerative Diseases 0.000 description 5
- 206010010741 Conjunctivitis Diseases 0.000 description 5
- 208000011231 Crohn disease Diseases 0.000 description 5
- 206010012438 Dermatitis atopic Diseases 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 201000004681 Psoriasis Diseases 0.000 description 5
- 201000001949 Retinal Vasculitis Diseases 0.000 description 5
- 206010039705 Scleritis Diseases 0.000 description 5
- 206010040070 Septic Shock Diseases 0.000 description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 description 5
- ICMGLRUYEQNHPF-UHFFFAOYSA-N Uraprene Chemical compound COC1=CC=CC=C1N1CCN(CCCNC=2N(C(=O)N(C)C(=O)C=2)C)CC1 ICMGLRUYEQNHPF-UHFFFAOYSA-N 0.000 description 5
- 206010046851 Uveitis Diseases 0.000 description 5
- 201000008937 atopic dermatitis Diseases 0.000 description 5
- 201000005547 chronic conjunctivitis Diseases 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 208000030533 eye disease Diseases 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
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- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09179982 | 2009-12-18 | ||
| EP09179982 | 2009-12-18 | ||
| US31555210P | 2010-03-19 | 2010-03-19 | |
| US315552P | 2010-03-19 | ||
| PCT/EP2010/069704 WO2011073231A1 (en) | 2009-12-18 | 2010-12-15 | 3,4,4A,10B-TETRAHYDRO-1H-THIOPYRANO-[4, 3-c] ISOQUINOLINE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2505290T3 true ES2505290T3 (es) | 2014-10-09 |
Family
ID=41718903
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10790569.7T Active ES2505290T3 (es) | 2009-12-18 | 2010-12-15 | Derivados de 3,4,4A,10B-tetrahidro-1H-tiopirano[4,3-c]isoquinolina |
| ES14164018.5T Active ES2621291T3 (es) | 2009-12-18 | 2010-12-15 | Derivados de 3,4,4a,10b-tetrahidro-1h-tiopirano-[4,3-c]isoquinolina |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES14164018.5T Active ES2621291T3 (es) | 2009-12-18 | 2010-12-15 | Derivados de 3,4,4a,10b-tetrahidro-1h-tiopirano-[4,3-c]isoquinolina |
Country Status (29)
| Country | Link |
|---|---|
| US (1) | US9018175B2 (OSRAM) |
| EP (2) | EP2813509B1 (OSRAM) |
| JP (1) | JP5645961B2 (OSRAM) |
| KR (1) | KR20120123313A (OSRAM) |
| CN (1) | CN102652136B (OSRAM) |
| AR (1) | AR079451A1 (OSRAM) |
| AU (1) | AU2010332955B8 (OSRAM) |
| BR (1) | BR112012014058A8 (OSRAM) |
| CA (1) | CA2784013A1 (OSRAM) |
| CO (1) | CO6551705A2 (OSRAM) |
| DK (1) | DK2513119T3 (OSRAM) |
| EA (1) | EA023212B1 (OSRAM) |
| ES (2) | ES2505290T3 (OSRAM) |
| GE (1) | GEP20146105B (OSRAM) |
| HR (1) | HRP20140893T1 (OSRAM) |
| ME (1) | ME01914B (OSRAM) |
| MX (1) | MX2012006696A (OSRAM) |
| NZ (1) | NZ601115A (OSRAM) |
| PH (1) | PH12012501125A1 (OSRAM) |
| PL (1) | PL2513119T3 (OSRAM) |
| PT (1) | PT2513119E (OSRAM) |
| RS (1) | RS53544B1 (OSRAM) |
| SG (2) | SG180824A1 (OSRAM) |
| SI (1) | SI2513119T1 (OSRAM) |
| SM (1) | SMT201400185B (OSRAM) |
| TW (1) | TWI468411B (OSRAM) |
| UA (1) | UA107689C2 (OSRAM) |
| WO (1) | WO2011073231A1 (OSRAM) |
| ZA (1) | ZA201204135B (OSRAM) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110300432A1 (en) | 2010-06-07 | 2011-12-08 | Snyder Shawn W | Rechargeable, High-Density Electrochemical Device |
| RU2013142268A (ru) * | 2011-02-17 | 2015-03-27 | Сипла Лимитед | Фармацевтическая композиция |
| WO2012171903A1 (en) | 2011-06-15 | 2012-12-20 | Nycomed Gmbh | Novel 3,4,4a,10b-tetrahydro-1h-thiopyrano[4,3-c]isoquinoline compounds |
| WO2014016548A2 (en) * | 2012-07-27 | 2014-01-30 | Cipla Limited | Pharmaceutical composition |
| US20150322049A1 (en) * | 2012-12-13 | 2015-11-12 | Ludwig Aigner | Leukotriene pathway antagonists for the treatment of dementia, cognitive deficits in parkinson's disease and/or learning and memory deficiencies in parkinson's disease |
| EP2951161A1 (en) | 2013-02-04 | 2015-12-09 | Grünenthal GmbH | 4-amino substituted condensed pyrimidine compounds as pde4 inhibitors |
| BR112015019276A2 (pt) | 2013-02-19 | 2017-07-18 | Pfizer | compostos de azabenzimidazol como inibidores de isoenzimas de pde4 para o tratamento de distúrbios do snc e outros distúrbios |
| US10131669B2 (en) | 2014-07-24 | 2018-11-20 | Pfizer Inc. | Pyrazolopyrimidine compounds |
| EA031201B1 (ru) | 2014-08-06 | 2018-11-30 | Пфайзер Инк. | Соединения имидазопиридазина |
| WO2017089347A1 (en) | 2015-11-25 | 2017-06-01 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas |
| WO2022006470A1 (en) | 2020-07-01 | 2022-01-06 | Vanderbilt University | Methods of treatment for a kidney disease |
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| AU2001281965A1 (en) | 2000-07-14 | 2002-01-30 | Byk Gulden Lomberg Chemische Fabrik G.M.B.H. | Novel 6-phenylphenanthridines |
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| JP2008532980A (ja) * | 2005-03-09 | 2008-08-21 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | アミド置換された６−フェニルフェナントリジン |
| MX2009011089A (es) * | 2007-04-23 | 2009-10-30 | Sanofi Aventis | Derivados de quinolina-carboxamida en calidad de antagonistas de p2y12. |
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-
2010
- 2010-12-14 AR ARP100104617A patent/AR079451A1/es unknown
- 2010-12-15 AU AU2010332955A patent/AU2010332955B8/en not_active Ceased
- 2010-12-15 BR BR112012014058A patent/BR112012014058A8/pt not_active IP Right Cessation
- 2010-12-15 PH PH1/2012/501125A patent/PH12012501125A1/en unknown
- 2010-12-15 ES ES10790569.7T patent/ES2505290T3/es active Active
- 2010-12-15 MX MX2012006696A patent/MX2012006696A/es active IP Right Grant
- 2010-12-15 RS RSP20140499 patent/RS53544B1/sr unknown
- 2010-12-15 CA CA2784013A patent/CA2784013A1/en not_active Abandoned
- 2010-12-15 GE GEAP201012783A patent/GEP20146105B/en unknown
- 2010-12-15 KR KR1020127017957A patent/KR20120123313A/ko not_active Withdrawn
- 2010-12-15 PT PT107905697T patent/PT2513119E/pt unknown
- 2010-12-15 JP JP2012543701A patent/JP5645961B2/ja not_active Expired - Fee Related
- 2010-12-15 ME MEP-2014-114A patent/ME01914B/me unknown
- 2010-12-15 EA EA201200891A patent/EA023212B1/ru not_active IP Right Cessation
- 2010-12-15 CN CN201080057293.7A patent/CN102652136B/zh not_active Expired - Fee Related
- 2010-12-15 SI SI201030746T patent/SI2513119T1/sl unknown
- 2010-12-15 EP EP14164018.5A patent/EP2813509B1/en active Active
- 2010-12-15 ES ES14164018.5T patent/ES2621291T3/es active Active
- 2010-12-15 PL PL10790569T patent/PL2513119T3/pl unknown
- 2010-12-15 SG SG2012034732A patent/SG180824A1/en unknown
- 2010-12-15 UA UAA201208482A patent/UA107689C2/ru unknown
- 2010-12-15 US US13/515,214 patent/US9018175B2/en not_active Expired - Fee Related
- 2010-12-15 SG SG2014000335A patent/SG196785A1/en unknown
- 2010-12-15 NZ NZ601115A patent/NZ601115A/en not_active IP Right Cessation
- 2010-12-15 DK DK10790569.7T patent/DK2513119T3/da active
- 2010-12-15 WO PCT/EP2010/069704 patent/WO2011073231A1/en not_active Ceased
- 2010-12-15 HR HRP20140893AT patent/HRP20140893T1/hr unknown
- 2010-12-15 EP EP10790569.7A patent/EP2513119B1/en active Active
- 2010-12-17 TW TW99144591A patent/TWI468411B/zh not_active IP Right Cessation
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2012
- 2012-05-24 CO CO12085785A patent/CO6551705A2/es active IP Right Grant
- 2012-06-06 ZA ZA2012/04135A patent/ZA201204135B/en unknown
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2014
- 2014-12-11 SM SM201400185T patent/SMT201400185B/xx unknown
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