EA021755B1 - ПИРАЗИНОВЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ENaC БЛОКАТОРОВ - Google Patents
ПИРАЗИНОВЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ENaC БЛОКАТОРОВ Download PDFInfo
- Publication number
- EA021755B1 EA021755B1 EA201390401A EA201390401A EA021755B1 EA 021755 B1 EA021755 B1 EA 021755B1 EA 201390401 A EA201390401 A EA 201390401A EA 201390401 A EA201390401 A EA 201390401A EA 021755 B1 EA021755 B1 EA 021755B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- alkyl
- optionally substituted
- triazaspiro
- diamino
- heterocyclic group
- Prior art date
Links
- 239000002713 epithelial sodium channel blocking agent Substances 0.000 title claims description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical class C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 248
- 238000000034 method Methods 0.000 claims abstract description 118
- 150000003839 salts Chemical class 0.000 claims abstract description 69
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 53
- 201000010099 disease Diseases 0.000 claims abstract description 46
- 102000003837 Epithelial Sodium Channels Human genes 0.000 claims abstract description 37
- 108090000140 Epithelial Sodium Channels Proteins 0.000 claims abstract description 37
- 239000012453 solvate Substances 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 104
- 125000000623 heterocyclic group Chemical group 0.000 claims description 99
- -1 [(2-hydroxyethyl) methylcarbamoyl] methyl Chemical group 0.000 claims description 94
- 229910052736 halogen Inorganic materials 0.000 claims description 55
- 150000002367 halogens Chemical class 0.000 claims description 54
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 50
- 125000005842 heteroatom Chemical group 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 239000003814 drug Substances 0.000 claims description 43
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 235000019260 propionic acid Nutrition 0.000 claims description 25
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- PTCAJYHERZZHQX-UHFFFAOYSA-N 1-[[[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-ene-8-carbonyl]phenyl]sulfonylamino]methyl]cyclobutane-1-carboxylic acid Chemical compound N1=C(Cl)C(N)=NC(N)=C1C(=O)\N=C/1NC2(CCN(CC2)C(=O)C=2C=C(C=CC=2)S(=O)(=O)NCC2(CCC2)C(O)=O)CN\1 PTCAJYHERZZHQX-UHFFFAOYSA-N 0.000 claims description 7
- YIJXODFVBVZSHM-UHFFFAOYSA-N 2-[2-chloro-4-[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-en-8-yl]-3-oxopropyl]phenoxy]acetic acid Chemical compound N1=C(Cl)C(N)=NC(N)=C1C(=O)\N=C/1NC2(CCN(CC2)C(=O)CCC=2C=C(Cl)C(OCC(O)=O)=CC=2)CN\1 YIJXODFVBVZSHM-UHFFFAOYSA-N 0.000 claims description 7
- XFJVQRJMKCBEIF-UHFFFAOYSA-N 2-[4-[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-en-8-yl]-3-oxopropyl]phenoxy]acetic acid Chemical compound N1=C(Cl)C(N)=NC(N)=C1C(=O)\N=C/1NC2(CCN(CC2)C(=O)CCC=2C=CC(OCC(O)=O)=CC=2)CN\1 XFJVQRJMKCBEIF-UHFFFAOYSA-N 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- QAKVHIKUNMGUOL-UHFFFAOYSA-N methyl n,n-dipropylcarbamate Chemical compound CCCN(CCC)C(=O)OC QAKVHIKUNMGUOL-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 5
- 239000000969 carrier Substances 0.000 claims description 5
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- VAGMFMWZIMXAGK-UHFFFAOYSA-N methyl n,n-diethylcarbamate Chemical compound CCN(CC)C(=O)OC VAGMFMWZIMXAGK-UHFFFAOYSA-N 0.000 claims description 3
- SELYJABLPLKXOY-UHFFFAOYSA-N methyl n,n-dimethylcarbamate Chemical compound COC(=O)N(C)C SELYJABLPLKXOY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 150000003890 succinate salts Chemical class 0.000 claims description 3
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims 2
- 230000001404 mediated effect Effects 0.000 abstract description 19
- 230000008569 process Effects 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 68
- 239000000243 solution Substances 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 40
- 239000000543 intermediate Substances 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- 239000003795 chemical substances by application Substances 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000000047 product Substances 0.000 description 26
- 208000006673 asthma Diseases 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000002253 acid Substances 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- 229940002612 prodrug Drugs 0.000 description 18
- 239000000651 prodrug Substances 0.000 description 18
- 229940124597 therapeutic agent Drugs 0.000 description 18
- 238000004587 chromatography analysis Methods 0.000 description 17
- 229940079593 drug Drugs 0.000 description 17
- 229910052805 deuterium Inorganic materials 0.000 description 16
- 229910052700 potassium Inorganic materials 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 238000007792 addition Methods 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 13
- 150000001721 carbon Chemical group 0.000 description 13
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 125000002837 carbocyclic group Chemical group 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 239000000443 aerosol Substances 0.000 description 9
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 9
- 229940011051 isopropyl acetate Drugs 0.000 description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 201000003883 Cystic fibrosis Diseases 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 8
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229940016681 dipropylacetamide Drugs 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QMPZTZLMYBJZOU-UHFFFAOYSA-N 3-[[3-[2-[(3,5-diamino-6-chloropyrazine-2-carbonyl)amino]-1,3,8-triazaspiro[4.5]dec-2-ene-8-carbonyl]phenyl]sulfonylamino]propanoic acid Chemical compound N1=C(Cl)C(N)=NC(N)=C1C(=O)\N=C/1NC2(CCN(CC2)C(=O)C=2C=C(C=CC=2)S(=O)(=O)NCCC(O)=O)CN\1 QMPZTZLMYBJZOU-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- ZTEJVXPWQMYTDA-UHFFFAOYSA-N 3-[[3-[2-(dipropylamino)-2-oxoethoxy]-3-oxopropyl]sulfamoyl]benzoic acid Chemical compound CCCN(CCC)C(=O)COC(=O)CCNS(=O)(=O)C1=CC=CC(C(O)=O)=C1 ZTEJVXPWQMYTDA-UHFFFAOYSA-N 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000000414 obstructive effect Effects 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 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 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 206010006451 bronchitis Diseases 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 208000023504 respiratory system disease Diseases 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- NLWICSZRQAVUQM-UHFFFAOYSA-N 2-hydroxy-1-[2-(trifluoromethyl)pyrrolidin-1-yl]ethanone Chemical compound OCC(=O)N1CCCC1C(F)(F)F NLWICSZRQAVUQM-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229940124630 bronchodilator Drugs 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229910052745 lead Inorganic materials 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 210000004877 mucosa Anatomy 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- PHDWRHJOTIANGT-UHFFFAOYSA-N 3-[3-chloro-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]phenyl]propanoic acid Chemical compound CC(C)(C)OC(=O)COC1=CC=C(CCC(O)=O)C=C1Cl PHDWRHJOTIANGT-UHFFFAOYSA-N 0.000 description 3
- GDZLXDPPCADDAZ-UHFFFAOYSA-N 3-[[1-[(2-methylpropan-2-yl)oxycarbonyl]cyclobutyl]methylsulfamoyl]benzoic acid Chemical compound C=1C=CC(C(O)=O)=CC=1S(=O)(=O)NCC1(C(=O)OC(C)(C)C)CCC1 GDZLXDPPCADDAZ-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Ophthalmology & Optometry (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Non-Adjustable Resistors (AREA)
Applications Claiming Priority (3)
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| US38398510P | 2010-09-17 | 2010-09-17 | |
| US201161524495P | 2011-08-17 | 2011-08-17 | |
| PCT/EP2011/066151 WO2012035158A1 (en) | 2010-09-17 | 2011-09-16 | Pyrazine derivatives as enac blockers |
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| EA201390401A1 EA201390401A1 (ru) | 2013-07-30 |
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| RS55940B1 (sr) | 2005-12-28 | 2017-09-29 | Vertex Pharma | Čvrsti oblici n-[2,4-bis(1,1-dimetiletil)-5-hidroksifenil]-1,4-dihidro-4-oksohinolin-3-karboksamida |
| US9050339B2 (en) | 2010-09-17 | 2015-06-09 | Novartis Ag | Pyrazine derivatives as ENaC blockers |
| AU2012331274B2 (en) | 2011-11-02 | 2017-06-08 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof |
| US8809340B2 (en) * | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
| FI2914248T4 (fi) | 2012-11-02 | 2023-12-19 | Vertex Pharma | Farmaseuttisia koostumuksia cftr-välitteisten tautien hoitamiseksi |
| EP2970468B1 (en) | 2013-03-13 | 2021-07-07 | Novartis AG | Notch2 binding molecules for treating respiratory diseases |
| UY36034A (es) | 2014-03-18 | 2015-09-30 | Astrazeneca Ab | Derivados de 3,5-diamino-6-cloro-pirazina-2-carboxamida y sales farmaceuticamente aceptables de estos |
| EP2932966A1 (en) | 2014-04-16 | 2015-10-21 | Novartis AG | Gamma secretase inhibitors for treating respiratory diseases |
| RU2749213C2 (ru) | 2014-10-07 | 2021-06-07 | Вертекс Фармасьютикалз Инкорпорейтед | Сокристаллы модуляторов регулятора трансмембранной проводимости при кистозном фиброзе |
| US20180002312A1 (en) * | 2015-01-12 | 2018-01-04 | Boehringer Ingelheim International Gmbh | Tetra- and pentasubstituted benzimidazolium compounds useful in the treatment of respiratory diseases |
| JP6667538B2 (ja) * | 2015-01-12 | 2020-03-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 呼吸器系疾患の治療に有用な置換ベンズイミダゾリウム化合物 |
| EP3245199B1 (en) * | 2015-01-12 | 2020-01-01 | Boehringer Ingelheim International GmbH | Substituted benzimidazolium compounds useful in the treatment of respiratory diseases |
| GB201610854D0 (en) | 2016-06-21 | 2016-08-03 | Entpr Therapeutics Ltd | Compounds |
| GB201619694D0 (en) | 2016-11-22 | 2017-01-04 | Entpr Therapeutics Ltd | Compounds |
| WO2018175340A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Reduced exposure conjugates modulating therapeutic targets |
| WO2018175302A1 (en) | 2017-03-20 | 2018-09-27 | Sienna Biopharmaceuticals, Inc. | Polymer conjugates targeting c-src with reduced exposure |
| GB201717051D0 (en) | 2017-10-17 | 2017-11-29 | Enterprise Therapeutics Ltd | Compounds |
| JP7197880B2 (ja) * | 2017-10-19 | 2022-12-28 | 学校法人 名城大学 | エステル化剤及びその利用 |
| GB201808093D0 (en) | 2018-05-18 | 2018-07-04 | Enterprise Therapeutics Ltd | Compounds |
| CN113929648A (zh) * | 2020-07-14 | 2022-01-14 | 浙江晖石药业有限公司 | 一种环丁烷-1,2-二甲酸酐及其中间体的制备方法 |
| IL301285A (en) | 2020-09-10 | 2023-05-01 | Precirix N V | Antibody fragment against fap |
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| WO2009074575A2 (en) * | 2007-12-10 | 2009-06-18 | Novartis Ag | Organic compounds |
| WO2009150137A2 (en) * | 2008-06-10 | 2009-12-17 | Novartis Ag | Organic compounds |
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| GB1219606A (en) | 1968-07-15 | 1971-01-20 | Rech S Et D Applic Scient Soge | Quinuclidinol derivatives and preparation thereof |
| IT1016489B (it) | 1974-03-18 | 1977-05-30 | Isf Spa | Inalatore |
| PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
| JPS6235216A (ja) | 1985-08-09 | 1987-02-16 | Noritoshi Nakabachi | 不均質物質層の層厚非破壊測定方法および装置 |
| GB8923590D0 (en) | 1989-10-19 | 1989-12-06 | Pfizer Ltd | Antimuscarinic bronchodilators |
| US6536427B2 (en) | 1990-03-02 | 2003-03-25 | Glaxo Group Limited | Inhalation device |
| PT100441A (pt) | 1991-05-02 | 1993-09-30 | Smithkline Beecham Corp | Pirrolidinonas, seu processo de preparacao, composicoes farmaceuticas que as contem e uso |
| WO1993018007A1 (fr) | 1992-03-13 | 1993-09-16 | Tokyo Tanabe Company Limited | Nouveau derive de carbostyrile |
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