CN110087729A - 一类具有季铵盐结构的双功能化合物 - Google Patents
一类具有季铵盐结构的双功能化合物 Download PDFInfo
- Publication number
- CN110087729A CN110087729A CN201780076957.6A CN201780076957A CN110087729A CN 110087729 A CN110087729 A CN 110087729A CN 201780076957 A CN201780076957 A CN 201780076957A CN 110087729 A CN110087729 A CN 110087729A
- Authority
- CN
- China
- Prior art keywords
- hydroxy
- phenyl
- ethoxy
- salt
- azabicyclo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 284
- 150000003242 quaternary ammonium salts Chemical group 0.000 title claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 275
- -1 quaternary ammonium salt structure compound Chemical class 0.000 claims abstract description 201
- 238000000034 method Methods 0.000 claims abstract description 85
- 239000012453 solvate Substances 0.000 claims abstract description 35
- 230000003287 optical effect Effects 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 242
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 193
- 238000002360 preparation method Methods 0.000 claims description 143
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 112
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 92
- 239000000543 intermediate Substances 0.000 claims description 63
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 27
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 22
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
- 125000000732 arylene group Chemical group 0.000 claims description 10
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 239000007858 starting material Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000005529 alkyleneoxy group Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 8
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 239000005977 Ethylene Substances 0.000 claims description 6
- 239000003957 anion exchange resin Substances 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 150000004820 halides Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005002 aryl methyl group Chemical group 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 229940124630 bronchodilator Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000005549 heteroarylene group Chemical group 0.000 claims description 4
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 4
- 229910001923 silver oxide Inorganic materials 0.000 claims description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 150000002430 hydrocarbons Chemical group 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 238000011260 co-administration Methods 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229940097042 glucuronate Drugs 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 230000003637 steroidlike Effects 0.000 claims description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 4
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims 3
- CHMYWZIKRSMHFB-UHFFFAOYSA-N 1-propyl-1-azoniabicyclo[2.2.2]octane Chemical class C1CC2CC[N+]1(CCC)CC2 CHMYWZIKRSMHFB-UHFFFAOYSA-N 0.000 claims 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N alpha-methyl toluene Natural products CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 150000003842 bromide salts Chemical class 0.000 claims 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims 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 claims 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 21
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 17
- 229940044551 receptor antagonist Drugs 0.000 abstract description 13
- 239000002464 receptor antagonist Substances 0.000 abstract description 13
- 208000006673 asthma Diseases 0.000 abstract description 9
- 208000019693 Lung disease Diseases 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000000556 agonist Substances 0.000 abstract description 3
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract description 2
- 230000006838 adverse reaction Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 240
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 218
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 204
- 230000002829 reductive effect Effects 0.000 description 141
- 239000002904 solvent Substances 0.000 description 120
- 239000007787 solid Substances 0.000 description 119
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- 239000000047 product Substances 0.000 description 110
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- 239000000243 solution Substances 0.000 description 78
- 238000003756 stirring Methods 0.000 description 78
- 235000019441 ethanol Nutrition 0.000 description 77
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 71
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
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- 238000001914 filtration Methods 0.000 description 56
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 46
- 239000002274 desiccant Substances 0.000 description 46
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- 125000001246 bromo group Chemical group Br* 0.000 description 38
- 229910000027 potassium carbonate Inorganic materials 0.000 description 37
- 235000011181 potassium carbonates Nutrition 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 34
- 102000005962 receptors Human genes 0.000 description 33
- 108020003175 receptors Proteins 0.000 description 33
- 239000003054 catalyst Substances 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- 238000004090 dissolution Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 238000005984 hydrogenation reaction Methods 0.000 description 25
- 241000700199 Cavia porcellus Species 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 238000012360 testing method Methods 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 239000004480 active ingredient Substances 0.000 description 20
- 239000002198 insoluble material Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007810 chemical reaction solvent Substances 0.000 description 18
- 238000001816 cooling Methods 0.000 description 18
- 230000005764 inhibitory process Effects 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
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- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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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
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- Otolaryngology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供一类式I所示的具有β2肾上腺受体激动剂和M受体拮抗剂双功能活性季铵盐类结构的化合物、其药学上可接受的盐、溶剂化物、光学异构体，以及包含这类季铵盐结构化合物的药物组合物，制备这类季铵盐结构化合物和中其间体的方法，及其在治疗肺部疾病方面的应用。本发明的化合物对M受体亚型选择性高，在治疗COPD和哮喘等肺部疾病中具有不良反应少、毒副作用低的特点。
Description
PCT国内申请，说明书已公开。
Claims (18)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611150752 | 2016-12-14 | ||
| CN2016111507521 | 2016-12-14 | ||
| PCT/CN2017/115807 WO2018108089A1 (zh) | 2016-12-14 | 2017-12-13 | 一类具有季铵盐结构的双功能化合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
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| JP (1) | JP6963616B2 (zh) |
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| CN110003025A (zh) * | 2019-04-29 | 2019-07-12 | 天津华津制药有限公司 | 1-[2-羟基-3-氨基-5-(苄氧基)苯基]-乙酮的制备方法 |
| KR20230004640A (ko) * | 2020-04-26 | 2023-01-06 | 베이징 서우바이 파마슈티컬 컴퍼니 리미티드 | M 수용체 길항제의 결정 및 이의 제조 방법 및 이의 응용 |
| CN111704912A (zh) * | 2020-06-29 | 2020-09-25 | 烟台丰蓬液晶材料有限公司 | 一种3-烯基苯炔液晶化合物的制备新方法 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1088582A (zh) * | 1992-09-30 | 1994-06-29 | 艾尔夫·萨诺费股份有限公司 | 碱式季酰胺，其制备方法及其药物组合物 |
| WO1998016200A1 (en) * | 1996-10-15 | 1998-04-23 | The Liposome Company, Inc. | Carriers containing an etherlipid/complementarily shape lipid combination and therapeutic uses thereof |
| CN1784400A (zh) * | 2003-05-02 | 2006-06-07 | 诺瓦提斯公司 | 与毒蕈碱性m3受体结合的奎宁环衍生物 |
| CN102459231A (zh) * | 2009-04-30 | 2012-05-16 | 帝人制药株式会社 | 季铵盐化合物 |
| WO2016128456A1 (en) * | 2015-02-12 | 2016-08-18 | Chiesi Farmaceutici S.P.A. | Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity |
Family Cites Families (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5679693A (en) * | 1992-09-30 | 1997-10-21 | Sanofi | 1-azoniabicyclo 2.2.1!heptanes, method of preparing them and pharmaceutical compositions in which they are present |
| GB9617730D0 (en) * | 1996-08-23 | 1996-10-02 | Pfizer Ltd | Quarternary ammonium compounds |
| EP1056740A1 (en) | 1998-02-20 | 2000-12-06 | Fine Chemicals Corporation (Proprietary) Limited | Process for the production of optically enriched (r)- or (s)-albuterol |
| DE19921693A1 (de) | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Neuartige Arzneimittelkompositionen auf der Basis von anticholinergisch wirksamen Verbindungen und ß-Mimetika |
| PE20040950A1 (es) | 2003-02-14 | 2005-01-01 | Theravance Inc | DERIVADOS DE BIFENILO COMO AGONISTAS DE LOS RECEPTORES ADRENERGICOS ß2 Y COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS |
| ES2329133T3 (es) | 2003-05-28 | 2009-11-23 | Theravance, Inc. | Compuestos azabicicloalcanicos como antagonistas de receptores de muscarinicos. |
| CA2543858C (en) | 2003-11-21 | 2014-04-15 | Theravance, Inc. | Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity |
| DE102004024453A1 (de) | 2004-05-14 | 2006-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue langwirksame Bronchodilatoren zur Behandlung von Atemwegserkrankungen |
| DE602004027555D1 (de) * | 2004-09-15 | 2010-07-15 | Shuqiang Zhao | Chinuclidinverbindungen mit quaternärer ammoniumgruppe, verfahren zu ihrer herstellung und ihre verwendung als acetylcholinblockierende mittel |
| CN100408549C (zh) | 2005-09-08 | 2008-08-06 | 上海医药工业研究院 | 左旋沙丁胺醇盐酸盐的合成方法 |
| WO2008017827A2 (en) | 2006-08-08 | 2008-02-14 | Argenta Discovery Limited | Azole and thiazole derivatives and their uses |
| JP2010505810A (ja) | 2006-10-04 | 2010-02-25 | ファイザー・リミテッド | アドレナリン作動薬およびムスカリン拮抗薬としてのスルホンアミド誘導体 |
| GB0702413D0 (en) | 2007-02-07 | 2007-03-21 | Argenta Discovery Ltd | New chemical compounds |
| WO2008149110A1 (en) | 2007-06-08 | 2008-12-11 | Argenta Discovery Limited | Bicyclor [2.2.1] hept-7-ylamine derivatives and their use in the treatment of diseases and conditions in which m3 muscarinic receptor activity and beta-adrenergic activity are implicated |
| JP4934223B2 (ja) | 2008-02-06 | 2012-05-16 | アストラゼネカ・アクチエボラーグ | 化合物 |
| US8263623B2 (en) | 2008-07-11 | 2012-09-11 | Pfizer Inc. | Triazol derivatives useful for the treatment of diseases |
| WO2010015792A1 (en) | 2008-08-06 | 2010-02-11 | Argenta Discovery Limited | Nitrogen containing heterocyclic compounds useful as bifunctional modulators of m3 receptors and beta-2 receptors |
| HUE035049T2 (en) | 2009-04-23 | 2018-05-02 | Theravance Respiratory Co Llc | Diamide Compounds having Muscarinic Receptor Antagonist and Beta 2 Adrenergic Receptor Agonist Activity |
| GB0913342D0 (en) | 2009-07-31 | 2009-09-16 | Astrazeneca Ab | Compounds - 801 |
| BR112013031493B1 (pt) | 2011-06-10 | 2022-04-19 | Chiesi Farmaceutici S.P.A | Composto, composição farmacêutica, uso de um composto, combinação de um composto, dispositivo e processo de preparação de um composto |
| JP6072920B2 (ja) | 2012-09-24 | 2017-02-01 | 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 | 複素環化合物、前記化合物を含む薬物、これらの使用及びこれらの調製方法 |
| CA2893627C (en) * | 2012-12-06 | 2021-09-14 | Chiesi Farmaceutici S.P.A. | Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity |
| RU2641285C2 (ru) | 2013-07-13 | 2018-01-17 | Бэйцзин Фсвэлкам Текнолоджи Девелопмент Ко., Лтд | Соединения хинина, способ их получения и их медицинское применение |
-
2017
- 2017-12-13 RU RU2019121119A patent/RU2722720C1/ru active
- 2017-12-13 JP JP2019533093A patent/JP6963616B2/ja active Active
- 2017-12-13 AU AU2017376363A patent/AU2017376363B2/en active Active
- 2017-12-13 ES ES17880998T patent/ES2836113T3/es active Active
- 2017-12-13 MY MYPI2019003398A patent/MY196804A/en unknown
- 2017-12-13 EP EP17880998.4A patent/EP3556435B1/en active Active
- 2017-12-13 CN CN201780076957.6A patent/CN110087729B/zh active Active
- 2017-12-13 KR KR1020197017003A patent/KR102278197B1/ko active Active
- 2017-12-13 WO PCT/CN2017/115807 patent/WO2018108089A1/zh unknown
- 2017-12-13 US US16/469,457 patent/US11447485B2/en active Active
- 2017-12-13 CA CA3047023A patent/CA3047023C/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1088582A (zh) * | 1992-09-30 | 1994-06-29 | 艾尔夫·萨诺费股份有限公司 | 碱式季酰胺，其制备方法及其药物组合物 |
| WO1998016200A1 (en) * | 1996-10-15 | 1998-04-23 | The Liposome Company, Inc. | Carriers containing an etherlipid/complementarily shape lipid combination and therapeutic uses thereof |
| CN1784400A (zh) * | 2003-05-02 | 2006-06-07 | 诺瓦提斯公司 | 与毒蕈碱性m3受体结合的奎宁环衍生物 |
| CN102459231A (zh) * | 2009-04-30 | 2012-05-16 | 帝人制药株式会社 | 季铵盐化合物 |
| WO2016128456A1 (en) * | 2015-02-12 | 2016-08-18 | Chiesi Farmaceutici S.P.A. | Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3556435A4 (en) | 2019-10-23 |
| KR102278197B1 (ko) | 2021-07-15 |
| EP3556435A1 (en) | 2019-10-23 |
| US11447485B2 (en) | 2022-09-20 |
| KR20190082902A (ko) | 2019-07-10 |
| MY196804A (en) | 2023-05-03 |
| EP3556435B1 (en) | 2020-10-28 |
| RU2722720C1 (ru) | 2020-06-03 |
| JP2020504724A (ja) | 2020-02-13 |
| AU2017376363B2 (en) | 2020-02-06 |
| CN110087729B (zh) | 2022-04-05 |
| WO2018108089A1 (zh) | 2018-06-21 |
| CA3047023C (en) | 2022-05-31 |
| CA3047023A1 (en) | 2018-06-21 |
| AU2017376363A1 (en) | 2019-10-17 |
| US20200002329A1 (en) | 2020-01-02 |
| ES2836113T3 (es) | 2021-06-24 |
| JP6963616B2 (ja) | 2021-11-10 |
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