TW201617318A - 先驅藥 - Google Patents
先驅藥 Download PDFInfo
- Publication number
- TW201617318A TW201617318A TW104134887A TW104134887A TW201617318A TW 201617318 A TW201617318 A TW 201617318A TW 104134887 A TW104134887 A TW 104134887A TW 104134887 A TW104134887 A TW 104134887A TW 201617318 A TW201617318 A TW 201617318A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- compound
- pharmaceutically acceptable
- acceptable salt
- mmol
- Prior art date
Links
- 239000000651 prodrug Substances 0.000 title description 2
- 229940002612 prodrug Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 208000024891 symptom Diseases 0.000 claims description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 7
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims description 5
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 5
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 33
- 229960002586 roflumilast Drugs 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 14
- 230000035515 penetration Effects 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- -1 2-pentyl Chemical group 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001641 gel filtration chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 2
- PHMVKACGFNRCJR-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2-hydroxyethyl)benzamide Chemical compound ClC=1C=NC=C(C=1N(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)CCO)Cl PHMVKACGFNRCJR-UHFFFAOYSA-N 0.000 description 2
- AGLXHGXBTKDTJN-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-n-methylbenzamide Chemical compound ClC=1C=NC=C(Cl)C=1N(C)C(=O)C(C=1)=CC=C(OC(F)F)C=1OCC1CC1 AGLXHGXBTKDTJN-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- VRCNZZNIJOVFAS-UHFFFAOYSA-N N-(cyanomethyl)-3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide Chemical compound C(#N)CN(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)C1=C(C=NC=C1Cl)Cl VRCNZZNIJOVFAS-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000037323 metabolic rate Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- IANXAXNUNBAWBA-UHFFFAOYSA-N 2,2,3-trimethylundecane Chemical compound CCCCCCCCC(C)C(C)(C)C IANXAXNUNBAWBA-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- XMATUFGYDKBPRT-UHFFFAOYSA-N 2-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl]-(3,5-dichloropyridin-4-yl)amino]acetic acid Chemical compound C(=O)(O)CN(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)C1=C(C=NC=C1Cl)Cl XMATUFGYDKBPRT-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- QCLQPRNCQQNPSV-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2,2-dimethyl-1,3-dioxolan-4-yl)benzamide Chemical compound ClC=1C=NC=C(C=1N(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)C1OC(OC1)(C)C)Cl QCLQPRNCQQNPSV-UHFFFAOYSA-N 0.000 description 1
- FFPKMHUVXXRDJI-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2,3-dihydroxypropyl)benzamide Chemical compound ClC=1C=NC=C(C=1N(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)CC(CO)O)Cl FFPKMHUVXXRDJI-UHFFFAOYSA-N 0.000 description 1
- ZDXXRGSNAUHLDJ-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(3-hydroxypropyl)benzamide Chemical compound ClC=1C=NC=C(C=1N(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)CCCO)Cl ZDXXRGSNAUHLDJ-UHFFFAOYSA-N 0.000 description 1
- OGJGEQGRTOXYJQ-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(methoxymethyl)benzamide Chemical compound ClC=1C=NC=C(C=1N(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)COC)Cl OGJGEQGRTOXYJQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BBKBPYFNBFEICG-UHFFFAOYSA-N 4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane Chemical compound CC1(C)OCC(CI)O1 BBKBPYFNBFEICG-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- NVEAPQDQUDMGNE-UHFFFAOYSA-N C(CCCCCCCCC)OCCCBr Chemical compound C(CCCCCCCCC)OCCCBr NVEAPQDQUDMGNE-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- PKAUVIXBZJUYRV-UHFFFAOYSA-N methane;hydroiodide Chemical compound C.I PKAUVIXBZJUYRV-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- VTDIUAGLMHTEMI-UHFFFAOYSA-N methyl 2-[[3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoyl]-(3,5-dichloropyridin-4-yl)amino]acetate Chemical compound ClC=1C=NC=C(C=1N(C(C1=CC(=C(C=C1)OC(F)F)OCC1CC1)=O)CC(=O)OC)Cl VTDIUAGLMHTEMI-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 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
- 238000009210 therapy by ultrasound Methods 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
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本發明係提供式(I)所示之化合物或其藥學上可容許之鹽：
□
〔式中，R為氫原子、可經羥基取代之C1-6烷基、C1-6烷氧基或氰基〕。
Description
本發明係關於先驅藥。
已知磷酸二酯酶(PDE)阻害劑係有效用於治療炎症性疾患。特定而言，PDE4阻害劑係有效於治療氣喘或呼吸道閉塞(例如，COPD=慢性閉塞性肺疾患)等呼吸道之炎症性疾患(專利文獻1)。該等之中，屬於PDE4阻害劑之N-(3,5-二氯吡啶-4-基)-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺(亦稱為羅氟司特(roflumilast))係作為經口劑(商品名：迪開舒(Daxas)(註冊商標))在歐美市售(專利文獻2)，近年來亦正在檢討其於水性醫藥製劑或經皮吸收製劑之應用(專利文獻3~5)。
[專利文獻1]美國專利第5712298號說明書
[專利文獻2]美國專利申請案公開第2013/0131123號說明書
[專利文獻3]日本專利特表2008-513416號公報
[專利文獻4]日本專利特表2005-529930號公報
[專利文獻5]日本專利特開2011-219364號公報
由於羅氟司特係非常不易溶於水中之化合物，因而為了使製劑中高濃度地含有羅氟司特，便需要特別的工夫。此外，由於羅氟司特係皮膚穿透性亦較低之化合物，因而其係屬於非常難以作為經皮吸收製劑之化合物。
於是，本發明之目的係提供水溶性及皮膚穿透性優異，且在體內迅速地代謝而產生羅氟司特之化合物或其鹽。
本發明者等人進行深入檢討之結果，發現若在構成羅氟司特的苯甲醯胺之氮原子中導入取代基，則化合物的物性會顯著地變化，水溶性及皮膚穿透性係提升，遂完成本發明。
即，本發明係提供以下之(1)~(15)。
(1)一種式(I)所示之化合物或其藥學上可容許之
鹽：
[式中，R為氫原子、可經羥基取代之C1-6烷基、C1-6烷氧基或氰基〕。
(2)如(1)所記載之化合物或其藥學上可容許之鹽，其中，R為氫原子、可經羥基取代之C1-6烷基或氰基。
(3)如(1)所記載之化合物或其藥學上可容許之鹽，其中，R為氫原子、羥甲基、甲氧基或氰基。
(4)如(1)所記載之化合物或其藥學上可容許之鹽，其中，R為氫原子、羥甲基或氰基。
(5)一種醫藥組成物，其係含有如(1)~(4)中任一項所記載之化合物或其藥學上可容許之鹽。
(6)如(5)所記載之醫藥組成物，其係PDE4阻害劑。
(7)如(5)所記載之醫藥組成物，其係對阻害PDE4有效的疾患或症狀之治療劑。
(8)如(7)所記載之醫藥組成物，其中，上述疾患或症狀為慢性閉塞性肺疾患。
(9)一種阻害PDE4屬有效的疾患或症狀之治療方法，其係包含將如(1)~(4)中任一項所記載之化合物
或其藥學上可容許之鹽投予至有所需要的對象。
(10)如(9)所記載之治療方法，其中，上述疾患或症狀為慢性閉塞性肺疾患。
(11)一種如(1)~(4)中任一項所記載之化合物或其藥學上可容許之鹽之用途，其係用於製造用於治療阻害PDE4屬有效的疾患或症狀之醫藥組成物。
(12)如(11)所記載之用途，其中，上述疾患或症狀為慢性閉塞性肺疾患。
(13)如(1)~(4)中任一項所記載之化合物或其藥學上可容許之鹽，其係用於使用為醫藥組成物之有效成分。
(14)如(13)所記載之化合物或其藥學上可容許之鹽，其中，上述醫藥組成物為PDE4阻害劑。
(15)如(13)所記載之化合物或其藥學上可容許之鹽，其中，上述醫藥組成物為用於治療對阻害PDE4有效的疾患或症狀之醫藥組成物。
(16)如(15)所記載之化合物或其藥學上可容許之鹽，其中，上述疾患或症狀為慢性閉塞性肺疾患。
根據本發明所涉及之式(I)所示之化合物或其藥學上可容許之鹽，水溶性及皮膚穿透性係優異，且可在體內迅速地代謝而產生羅氟司特。從而，本發明所涉及之化合物或其藥學上可容許之鹽可在水性製劑等廣泛種類
的製劑中使用為有效成分，且由於被吸收至體內後會迅速地產生羅氟司特，因而有易於管理羅氟司特的血中濃度之優點。即，本發明所涉及之式(I)所示之化合物或其藥學上可容許之鹽係有用於作為羅氟司特之先驅藥。
再者，本發明所涉及之式(I)所示之化合物或其藥學上可容許之鹽可由羅氟司特以短步驟且高產率進行製造。
圖1係顯示實施例1~3及5、以及比較例1之皮膚穿透性之圖。
以下係針對本發明之一實施形態進行說明。
本實施形態係式(I)所示之化合物(以下亦稱為化合物(I))或其藥學上可容許之鹽。
式中，R為氫原子、可經羥基取代之C1-6烷基、C1-6烷氧基或氰基。
C1-6烷基係意味碳數為1~6之烷基，作為
C1-6烷基，可列舉例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、正戊基、2-戊基、3-戊基、正己基、2-己基、3-己基。
此外，C1-6烷基可任意經羥基取代。作為經羥基取代之C1-6烷基，可列舉例如羥甲基、1-羥乙基、2-羥乙基、2,3-二羥丙-1-基等。
C1-6烷氧基係意味碳數為1~6之烷氧基，作為C1-6烷氧基，可列舉例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第三丁氧基、正戊氧基、2-戊氧基、3-戊氧基、正己氧基、2-己氧基、3-己氧基。
作為藥學上可容許之鹽，只要是無機酸或有機酸之鹽，且為醫藥品領域中能夠使用之酸，則無特別限制。作為無機酸，可列舉例如鹽酸、氫溴酸、磷酸、硫酸、硝酸等。此外，作為有機酸，可列舉例如醋酸、檸檬酸、富馬酸、馬來酸、酒石酸、安息香酸、雙羥萘酸等羧酸、甲磺酸、苯磺酸、甲苯磺酸等磺酸、麩胺酸、天冬胺酸等酸性胺基酸、碳酸、重碳酸等。
在化合物(I)中，R為氫原子、可經羥基取代之C1-6烷基、C1-6烷氧基或氰基，較佳為氫原子、經羥基取代之C1-3烷基、C1-3烷氧基或氰基，更佳為氫原子、羥甲基、2,3-二羥丙-1-基、3-羥丙-1-基、甲氧基或氰基，特佳為氫原子、羥甲基、甲氧基或氰基。
作為特佳的化合物(I)，可列舉
N-氰基甲基-N-(3,5-二氯吡啶-4-基)-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺、N-(3,5-二氯吡啶-4-基)-N-(2-羥乙基)-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺、N-(3,5-二氯吡啶-4-基)-N-甲基-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺、N-(3,5-二氯吡啶-4-基)-N-(2,3-二羥丙-1-基)-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺、N-(3,5-二氯吡啶-4-基)-N-(3-羥丙-1-基)-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺、以及N-(3,5-二氯吡啶-4-基)-N-甲氧基甲基-3-環丙基甲氧基-4-二氟甲氧基苯甲醯胺。
其次，針對本發明之化合物(I)之製造方法進行說明。
化合物(I)可藉由於鹼之存在下使化合物(II)對羅氟司特進行反應而予以製造。
作為上述反應中所使用之鹼，只要是可使苯甲醯胺之氮原子上之質子進行脫質子化，則無特別限制。作為鹼，可列舉氫氧化鈉、氫氧化鉀等金屬氫氧化物；甲氧鈉、第三丁氧鉀等金屬烷氧化物；氫化鈉、氫化鉀等金
屬氫化物；六甲基二矽胺化鈉、六甲基二矽胺化鋰等金屬胺化物；丁基鋰、溴化異丙基鎂等烷基金屬化合物。作為較佳的鹼，係氫化鈉。
在化合物(II)中，R係與化合物(I)中所定義者同義，X為脫離基。作為X，只要是作用為脫離基者，則無特別限制，可列舉氟原子、氯原子、溴原子、碘原子等鹵素原子；甲磺醯氧基等烷基磺醯氧基；三氟甲磺醯氧基、九氟丁磺醯氧基等氟烷基磺醯氧基；甲苯磺醯氧基等芳基磺醯氧基。
此外，在化合物(I)中，R為經羥基取代之C1-6烷基之情況，亦可使用R為經可轉換成羥基之基取代之C1-6烷基的化合物作為化合物(II)而施行反應。作為可轉換成羥基之基，可列舉例如對羥基進行保護而成之衍生物或酯。在此情況，可藉由在上述反應之後，利用熟習該項技術者所週知的方法，適宜地施行脫保護或還原而轉換成羥基。
此外，上述反應可在溶媒中施行，亦可在無溶媒下施行。
上述反應中所使用之溶媒，只要是對反應不會造成影響者，則無特別限制。作為溶媒，可列舉例如二乙醚、二異丙醚、四氫呋喃(THF)等醚系溶媒、苯、甲苯、二甲苯等烴系溶媒、二氯甲烷、氯仿等含有鹵素之烴系溶媒、N,N-二甲基甲醯胺(DMF)、二甲基亞碸(DMSO)等非質子性極性有機溶媒。
上述反應可藉由在反應混合物中添加水而停止。亦可使用氯化銨水溶液等代替所添加之水。
上述反應中所獲得之化合物(I)可藉由熟習該項技術者所週知的方法予以精製。作為精製方法，可列舉例如管柱層析、凝膠過濾層析、晶析等。
本發明之其他實施形態係含有化合物(I)之醫藥組成物。
醫藥組成物係除了化合物(I)以外，尚可配合作為目標之劑型，含有能夠作為醫藥品而添加的添加劑。作為添加劑，可列舉賦形劑、等張化劑、安定化劑、溶解輔助劑、緩衝劑、pH調整劑、填充劑、黏合劑、崩解劑、潤滑劑、著色劑、香料。
由於本實施形態之化合物或其藥學上可容許之鹽具有優異的水溶性，因而在將含有該化合物或其藥學上可容許之鹽之醫藥組成物予以製劑化為錠劑、膠囊劑、顆粒劑、散劑、液劑等經口劑、注射劑(投予至靜脈內、肌肉內、皮下、腹腔內者皆可)之情況，相較於含有羅氟司特之製劑而言，製劑化係較容易，藥理作用的可靠性亦較高。此外，由於本實施形態之化合物或其藥學上可容許之鹽具有優異的皮膚穿透性，因而在將含有該化合物或其藥學上可容許之鹽之醫藥組成物予以製劑化為貼附劑、糊劑、貼布劑、軟膏劑、凝膠劑、洗劑、乳霜劑、氣霧劑等經皮吸收製劑之情況，相較於含有羅氟司特之製劑而言，製劑化係較容易，藥理作用的可靠性亦較高。再者，含有
本實施形態之化合物或其藥學上可容許之鹽之醫藥組成物亦可作為吸入劑、點鼻劑、點眼劑、栓劑等。
以下，藉由實施例、製造例及試驗例詳細說明本發明。另外，在實施例中所使用之簡寫係熟習該項技術者所週知慣用的簡寫。
DMF：N,N-二甲基甲醯胺
DMI：N,N-二甲基咪唑啶酮
DMSO：二甲基亞碸
n：正
ODS：十八基矽膠
TBS：第三丁基二甲基矽烷基
tert：第三
THF：四氫呋喃
質子核磁共振譜(1H-NMR)之化學位移係以相對於四甲基矽烷(內部標準)而言之δ單位(ppm)記載，偶合常數係以赫茲(Hz)記載。分裂圖案係意味s：單峰、d：二重峰、t：三重峰、q：四重峰、m：多重峰、br：寬峰。
於氮氣流下，在羅氟司特0.5g(1.24mmol)之乾燥DMF溶液(5mL)中加入氫化鈉56.4mg(60%油中分散，1.41mmol)，於室溫攪拌約15分鐘。在反應混合物中加入氯乙腈0.172mL(2.73mmol)及碘化鈉0.4g(0.269mmol)，於室溫維持2小時。反應終了後，在混合物中加入水5mL，以氯仿5mL萃取3次，將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，於減壓下餾去溶媒。將殘渣以矽膠管柱層析(醋酸乙酯/正己烷)予以精製，並將所獲得之粗生成物進一步以凝膠過濾層析予以精製，而以淡黃色油狀物之形式獲得標題化合物213mg(0.481mmol，產率48%)。
熔點：196℃
1H-NMR(500MHz,CDCl3)δ 0.35(m,2H),0.65(m,2H),1.21(m,1H),3.78(d,2H),4.65(s,2H),6.61(t,1H),6.87(dd,1H),6.96(d,1H),7.15(d,1H),8.57(s,2H).
於氮氣流下，在羅氟司特0.5g(1.24mmol)之乾燥DMF溶液(5mL)加入氫化鈉56.5mg(60%油中分散，1.41mmol)，於室溫攪拌約15分鐘後，加入溴醋酸甲酯0.25mL(2.73mmol)，進一步於室溫攪拌2.5小時後，於60℃攪拌4.5小時。將反應混合物放冷至室溫，加入水3mL，以氯仿9mL萃取3次。將有機層以無水硫酸鈉乾燥，於減壓下餾去溶媒，而以橙色油狀物之形式獲得標題合物649mg(1.37mmol)。
將製造例1中所獲得之化合物0.257g(0.541mmol)、硼氫化鈉0.111g(2.93mmol)於氮氣流下溶解於甲醇5mL、THF 1.5mL中，於室溫攪拌24小時。反應終了後，於減壓下餾去溶媒，在殘渣中加入水5mL，以氯仿5mL萃取3次。將有機層以無水硫酸鈉乾燥後，於
減壓下餾去溶媒。將殘渣以矽膠管柱層析(氯仿)予以精製，並將所獲得之粗生成物進一步以凝膠過濾層析予以精製，而以油狀物之形式獲得標題化合物50.3mg(0.481mmol，產率21%)。
熔點：97℃
1H-NMR(400MHz,CDCl3)δ 0.32(m,2H),0.64(m,2H),1.20(m,1H),2.91(brs,1H),3.76(d,2H),3.95(dd,2H),4.01(d,2H),6.59(t,1H),6.89(dd,1H),6.93(dd,1H),7.08(d,1H),8.49(s,2H).
於氮氣流下，在羅氟司特0.25g(0.60mmol)之乾燥DMF溶液(5ml)中，於0℃加入氫化鈉72mg(60%油中分散，3.0mmol)及碘化甲烷0.19mL(3.0mmol)，於室溫攪拌12小時。在反應混合物中加入水3mL，以醋酸乙酯萃取3次。將有機層以無水硫酸鈉乾燥，於減壓下餾去溶媒。將殘渣以ODS管柱(乙腈/水/THF)予以精製，進一步進行脫鹽處理(NH濾匣，二
氯甲烷/甲醇)並餾去溶媒，而以茶褐色油狀物之形式獲得標題化合物0.16g(0.38mmol)。
熔點：68℃
1H-NMR(400MHz,CDCl3)δ 0.32(m,2H),0.63(m,2H),1.20(m,1H),3.31(s,3H),3.76(d,2H),6.57(t,1H),6.90(dd,1H),6.94(d,1H),7.08(d,1H),8.48(s,2H).
使2,2-二甲基-1,3-二氧雜環戊烷-4-甲醇0.935mL(7.57mmol)、三苯基膦2.39g(9.11mmol)、咪唑1.54g(22.7mmol)、碘2.30g(18.1mmol)溶解於乾燥甲苯20mL中，於90℃攪拌2小時。將反應液冷卻至室溫，加入飽和硫代硫酸鈉水溶液，而停止反應。將所獲得之反應混合物以二氯甲烷萃取，將有機層以飽和食鹽水洗淨，以無水硫酸鈉乾燥後，於減壓下餾去溶媒而獲得白色固體5.54g。將所獲得之固體依序以二乙醚、己烷分散洗淨後，以矽膠管柱層析予以精製，而以無色油狀物之形式獲得標題化合物1.04g(4.28mmol)。
於氮氣流下，將羅氟司特0.32g(0.8mmol)、製造例2-1中所獲得之化合物0.29g(1.21mmol)、氫氧化鉀92mg(1.64mmol)之乾燥DMSO溶液(5mL)於100℃攪拌1日。放冷後，在反應混合物中加入氯仿，進一步進行攪拌，濾去所析出之固體。於減壓下餾去濾液，將殘渣以矽膠管柱層析(醋酸乙酯/正己烷)予以精製，而以油狀物之形式獲得標題化合物56.5mg(0.11mmol，產率14%)。
在製造例2-2中所獲得之化合物47mg(0.092
mmol)之THF溶液(1.0mL)中加入1M鹽酸2mL，於室溫攪拌12小時。在反應混合物中加入飽和碳酸氫鈉水溶液，使其成為pH 7~8後，以氯仿萃取3次，將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，於減壓下餾去溶媒。將所獲得之殘渣以矽膠管柱層析予以精製，而獲得標題化合物28.2mg(0.059mmol，產率64%)。
1H-NMR(500MHz,CDCl3)δ 0.33(m,2H),0.64(m,2H),1.20(m,1H),1.26(m,2H),2.55(brs,1H),3.47(brs,1H),3.75(d,2H),3.95(m,3H),6.59(t,1H),6.89(dd,1H),6.95(d,1H),7.06(d,1H),8.50(s,2H).
於氮氣流下，在羅氟司特0.5g(1.2mmol)之DMI溶液(5mL)中，於室溫加入氫化鈉139mg(60%油中分散，3.5mmol)及3-第三丁基二甲基矽烷基氧基丙基溴化物0.25mL(2.9mmol)，加熱至70℃，攪拌12小時。在反應混合物中加入水3mL，以醋酸乙酯萃取3
次。將所獲得之有機層以飽和氯化鈉水溶液洗淨後，以無水硫酸鈉乾燥，於減壓下餾去溶媒。將殘渣以矽膠管柱層析(庚烷/醋酸乙酯)予以精製，而以白色固體之形式獲得標題化合物212mg(0.368mmol，產率31%)。
使製造例3-1中所獲得之化合物180mg(0.31mmol)溶解於甲醇及濃鹽酸(體積比97：3)之混合液3mL中，於室溫攪拌1小時。於減壓下濃縮反應混合物，並使用矽膠管柱層析(庚烷/醋酸乙酯)進行精製。使所獲得之殘渣溶解於醋酸乙酯中，以飽和碳酸氫鈉水溶液洗淨，而以白色固體之形式獲得標題化合物86mg(0.186mmol，產率60%)。
1H-NMR(400MHz,CDCl3)δ 0.32(m,2H),0.63(m,2H),1.20(m,1H),1.84(m,2H),3.75(d,2H),3.78(t,2H),3.98(t,2H),6.58(t,1H),6.88(dd,1H),6.94(d,1H),7.05(d,1H),8.49(s,2H).
於氮氣流下，在羅氟司特505mg(1.25mmol)之乾燥DMF溶液(5mL)中，加入氫化鈉69mg(60%油中分散，1.73mmol)後，加入溴甲基甲基醚0.3mL(3.67mmol)，於室溫攪拌2小時。在反應混合物中加入水5mL，以氯仿萃取3次，而獲得有機層。將有機層以無水硫酸鈉乾燥後，於減壓下餾去溶媒，而獲得油狀的粗生成物。將粗生成物以矽膠管柱層析(正己烷/二氯甲烷)予以精製，並將所獲得之淡黃色固體由二氯甲烷/正己烷進行再結晶，而以白色固體之形式獲得標題化合物188mg(0.42mmol，產率34%)。
1H-NMR(500MHz,CDCl3)δ 0.32(m,2H),0.64(m,2H),1.20(m,1H),3.60(s,3H),3.75(d,2H),5.26(s,2H),6.57(t,1H),6.92(dd,1H),6.95(d,1H),7.10(d,1H),8.50(s,2H).
於氮氣流下，在羅氟司特0.5g(1.24mmol)之乾燥DMF溶液(5mL)中加入氫化鈉55.3mg(60%油中分散，1.38mmol)，於室溫攪拌約15分鐘。在反應混合物加入氯乙醯胺0.25g(1.63mmol)及碘化鈉0.41g(2.74mmol)，於室溫攪拌12小時。在反應混合物加入水5mL，以氯仿5mL萃取3次，將有機層以飽和食鹽水洗淨後，以無水硫酸鈉乾燥，於減壓下餾去溶媒。將殘渣以矽膠管柱層析(甲醇/二氯甲烷)予以精製，並進一步以凝膠過濾層析予以精製，而以淡黃色固體之形式獲得標題化合物94mg(0.204mmol，產率16%)。
熔點：90.99℃
1H-NMR(500MHz,DMSO-d6)δ 0.38(m,2H),0.56(m,2H),1.23(m,1H),3.91(d,2H),4.75(s,2H),7.15(t,1H),7.19(d,1H),7.48(s,1H),7.49(dd,1H),7.59(d,1H),7.78(s,1H),8.28(s,2H).
使製造例1中所獲得之化合物0.65g(1.37mmol)溶解於甲醇14mL中，於室溫加入1N氫氧化鈉水溶液14mL，攪拌5分鐘。於減壓下濃縮反應混合物，加入1N鹽酸直至水層的pH值成為1，以氯仿10mL萃取3次。合併所獲得之有機層，並以無水硫酸鈉乾燥，於減壓下餾去溶媒，而獲得淡黃色的殘渣。在所獲得之殘渣中加入1N氫氧化鈉5mL，以氯仿5mL洗淨2次後，加入1N鹽酸直至水層的pH值成為1，以氯仿5mL萃取3次。將所獲得之有機層以無水硫酸鈉乾燥，於減壓下餾去溶媒。將所獲得之殘渣以矽膠管柱層析(氯仿/甲醇)予以精製，而以淡黃色非晶質之形式獲得標題化合物0.342mg(0.740mmol，產率54%)。
熔點：182℃
1H-NMR(500MHz,CDCl3)δ 0.32(m,2H),0.64(m,2H),1.20(m,1H),3.76(d,2H),4.45(s,2H),6.61(t,1H),6.92(dd,1H),6.96(d,1H),7.15(d,1H),8.50(s,2H).
在包含輔酵素(NADPH生成系統)之100mmol/L Tris-HCl緩衝液中，以成為0.5mg蛋白/mL的濃度之方式
加入人類肝臟酵素部分，於37℃預培養5分鐘。在此溶液中以成為0.1μmol/L的濃度之方式加入各化合物，於37℃培養1小時後，添加經水冷之乙腈而停止反應。將所獲得之溶液進行過濾後，以LC-MS/MS施行定量並算出成為羅氟司特之代謝率(%)。另外，表1中，「有加熱處理」係意味在將人類肝臟酵素部分進行添加之前，藉由預先進行加熱處理，而使代謝酵素去活化。
將結果示於表1。表1中之數值係意味成為羅氟司特之代謝率(%)。實施例1~6之化合物係因源自人類肝臟之酵素而進行代謝，並生成羅氟司特。此外，在藉由將人類肝臟酵素部分於使用前進行加熱處理而使代謝酵素失活之情況，則不會生成羅氟司特。另一方面，參考例1及2之化合物係即便經人類肝臟酵素部分處理，亦不會生成羅氟司特。
在磷酸緩衝液(pH 7)10mL中過量加入各化合物，施行30分鐘超音波處理。將所獲得之懸浮液進行過濾，在濾液0.5mL中加入乙腈0.5mL，作為試驗溶液，藉由高速液體層析法測定試驗溶液中之各化合物的濃度，並就飽和溶解度進行算出。另外，使用羅氟司特作為比較例1。
將結果示於表2。明顯可知實施例1~3及參考例1、2之化合物相較於羅氟司特而言，係具有4倍以上的較高水溶性。
摘取無毛小鼠的背部皮膚，以該皮膚片之表皮側(應用面積：1cm2)接觸被驗化合物(實施例、比較例或參考例之化合物)之溶液之方式設於Franz型擴散槽(玻璃
槽)中。此外，使用PBS(磷酸緩衝生理食鹽水)作為流通液，將流量設為5mL/小時，恆溫槽溫度係設定為32℃。其次，以各被驗化合物的濃度成為1w/w%之方式加入二甲基亞碸後，進行充分攪拌而調製被驗化合物之溶液。將所獲得之被驗化合物之溶液100μL導入至上述Franz型擴散槽之供體室。導入被驗化合物之溶液之後，每2小時對流通液進行取樣，直至24小時後。在每2小時所取樣之流通液中加入乙腈並稀釋成2倍，離心分離後，獲得其上清液作為HPLC分析用試料。將所獲得之分析用試料分別藉由高速液體層析法進行分析，算出Jmax(最大皮膚穿透速度)及24小時之累積穿透量。另外，使用羅氟司特作為比較例1。
將結果示於表3。比較例1之化合物(羅氟司特)係即便在24小時後，亦不會顯示出皮膚穿透，相對於此，實施例及參考例之化合物則顯示出充分的皮膚穿透性。此外，將被驗化合物之累積穿透量(μg/cm2)的經時變化示於圖1。實施例1~3、5及6之化合物相較於比較例1之化合物(羅氟司特)而言係顯示出較高的皮膚穿透性。
Claims (8)
- 一種式(I)所示之化合物或其藥學上可容許之鹽：
- 如請求項1之化合物或其藥學上可容許之鹽，其中，R為氫原子、可經羥基取代之C1-6烷基或氰基。
- 如請求項1之化合物或其藥學上可容許之鹽，其中，R為氫原子、羥甲基、甲氧基或氰基。
- 如請求項1之化合物或其藥學上可容許之鹽，其中，R為氫原子、羥甲基或氰基。
- 一種醫藥組成物，其係含有如請求項1至4中任一項之化合物或其藥學上可容許之鹽。
- 如請求項5之醫藥組成物，其係PDE4阻害劑。
- 如請求項5之醫藥組成物，其係對阻害PDE4有效的疾患或症狀之治療劑。
- 如請求項7之醫藥組成物，其中，前述疾患或症狀為慢性閉塞性肺疾患。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014-217205 | 2014-10-24 | ||
| JP2014217205 | 2014-10-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201617318A true TW201617318A (zh) | 2016-05-16 |
| TWI648264B TWI648264B (zh) | 2019-01-21 |
Family
ID=55760938
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW104134887A TWI648264B (zh) | 2014-10-24 | 2015-10-23 | Pioneer drug |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US9969688B2 (zh) |
| EP (1) | EP3210974B1 (zh) |
| JP (1) | JP5938537B1 (zh) |
| KR (1) | KR101878621B1 (zh) |
| CN (1) | CN106573889B (zh) |
| ES (1) | ES2777550T3 (zh) |
| TW (1) | TWI648264B (zh) |
| WO (1) | WO2016063906A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6727302B2 (ja) * | 2016-07-01 | 2020-07-22 | 久光製薬株式会社 | Ｎ−（３，５−ジクロロピリド−４−イル）−ｎ−メチル−３−シクロプロピルメトキシ−４−ジフルオロメトキシベンズアミドの製造方法 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0706513T3 (da) | 1993-07-02 | 2002-09-09 | Altana Pharma Ag | Fluoralkoxysubstituerede benzamider og anvendelse deraf som cyklisk-nukleotid phosphodiesteraseinhibitorer |
| JP3571511B2 (ja) * | 1997-11-11 | 2004-09-29 | トーアエイヨー株式会社 | 経皮吸収製剤 |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| JP2005529928A (ja) * | 2002-05-28 | 2005-10-06 | アルタナ ファルマ アクチエンゲゼルシャフト | 眼の病気を治療するためのロフルミラストの眼科的使用 |
| DE102004046235A1 (de) | 2004-09-22 | 2006-03-30 | Altana Pharma Ag | Arzneimittelzubereitung |
| JP5576693B2 (ja) * | 2010-04-02 | 2014-08-20 | 久光製薬株式会社 | 経皮吸収促進剤、および該経皮吸収促進剤を含有する経皮製剤 |
| US8592427B2 (en) | 2010-06-24 | 2013-11-26 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives |
| CN103073490A (zh) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | 罗氟司特活性代谢物的制备方法 |
| WO2015013715A2 (en) * | 2013-07-26 | 2015-01-29 | Thr Regents Of The University Of California | C-h fluorination of heterocycles with silver (ii) fluoride |
| CN104107173B (zh) * | 2014-06-27 | 2017-06-27 | 山东泰田新药开发有限公司 | 一种罗氟司特片剂及其制备方法 |
-
2015
- 2015-10-21 JP JP2016510876A patent/JP5938537B1/ja active Active
- 2015-10-21 US US15/502,793 patent/US9969688B2/en active Active
- 2015-10-21 ES ES15852038T patent/ES2777550T3/es active Active
- 2015-10-21 EP EP15852038.7A patent/EP3210974B1/en active Active
- 2015-10-21 KR KR1020177003343A patent/KR101878621B1/ko active IP Right Grant
- 2015-10-21 CN CN201580042766.9A patent/CN106573889B/zh active Active
- 2015-10-21 WO PCT/JP2015/079689 patent/WO2016063906A1/ja active Application Filing
- 2015-10-23 TW TW104134887A patent/TWI648264B/zh active
Also Published As
| Publication number | Publication date |
|---|---|
| ES2777550T3 (es) | 2020-08-05 |
| WO2016063906A1 (ja) | 2016-04-28 |
| US9969688B2 (en) | 2018-05-15 |
| EP3210974B1 (en) | 2020-01-29 |
| JPWO2016063906A1 (ja) | 2017-04-27 |
| JP5938537B1 (ja) | 2016-06-22 |
| CN106573889B (zh) | 2019-01-01 |
| KR20170047224A (ko) | 2017-05-04 |
| US20170233343A1 (en) | 2017-08-17 |
| EP3210974A1 (en) | 2017-08-30 |
| EP3210974A4 (en) | 2018-04-11 |
| CN106573889A (zh) | 2017-04-19 |
| KR101878621B1 (ko) | 2018-07-13 |
| TWI648264B (zh) | 2019-01-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6800872B2 (ja) | リシルオキシダーゼ様２阻害剤とその使用 | |
| JP6090801B2 (ja) | キナーゼ阻害剤としてのアミノキナゾリン | |
| TWI510451B (zh) | 具有ｈｉｖ接合酶抑制活性的化合物之製造方法 | |
| AU2009225869B2 (en) | Substituted 4-hydroxypyrimidine-5-carboxamides | |
| CN1251097B (zh) | 具有血管生成抑制活性的酞嗪类化合物 | |
| EP0816340B1 (en) | Process for preparing 4-(2-(2-pyridyl)ethoxy)benzaldehyde derivatives | |
| US20080058383A1 (en) | Androgen Receptor Modulators | |
| JP2003522761A (ja) | Ｃｏｘ−２の選択的阻害剤としてのピリミジン誘導体 | |
| JP7113900B2 (ja) | ソマトスタチンモジュレーターを製造するプロセス | |
| TW202024095A (zh) | 生長抑制素(somatostatin)調節劑及其用途 | |
| US20170273961A1 (en) | Novel iminonitrile derivatives | |
| CN111484481A (zh) | 哒嗪酮类衍生物、其制备方法及其在医药上的用途 | |
| JP5346337B2 (ja) | ７−アルキニル−１，８−ナフチリドンの誘導体、これらの調製方法および治療におけるこれらの使用 | |
| RU2444515C2 (ru) | Производное амида индазолакриловой кислоты | |
| CN100379742C (zh) | 用作ltd4拮抗剂的新型三环衍生物 | |
| JP2005511602A (ja) | アントラニル酸アミドおよびｖｅｇｆ受容体チロシンキナーゼ阻害剤としてのその使用 | |
| TW201617318A (zh) | 先驅藥 | |
| WO2006093253A1 (ja) | キノリルアルキルチオ基を有する新規環式化合物 | |
| CN114269720A (zh) | 乙酰辅酶a合成酶短链2(acss2)的小分子抑制剂 | |
| JPH05331164A (ja) | アンジオテンシンｉｉ拮抗性イソインドール誘導体 | |
| WO2016128905A1 (en) | Thienopyrrole compounds as s-nitrosoglutathione reductase inhibitors | |
| JPH10506095A (ja) | 平滑筋弛緩薬としての（３，４−ジオキソシクロブテン−１−イル）クロメン、インデンおよびジヒドロナフタレノン誘導体 | |
| TW202237581A (zh) | 用作激酶抑制劑的化合物及其用途 | |
| CN117417297A (zh) | 一种新型杂环化合物 | |
| TW201713631A (zh) | 作為trpm8拮抗劑之咪唑啉酮衍生物 |