CN108003153A - 含氮五元杂环并喹啉类化合物及其盐、制法、药物组合物和用途 - Google Patents
含氮五元杂环并喹啉类化合物及其盐、制法、药物组合物和用途 Download PDFInfo
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- CN108003153A CN108003153A CN201711279295.0A CN201711279295A CN108003153A CN 108003153 A CN108003153 A CN 108003153A CN 201711279295 A CN201711279295 A CN 201711279295A CN 108003153 A CN108003153 A CN 108003153A
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- nitrogen
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 229940111121 antirheumatic drug quinolines Drugs 0.000 title 1
- 125000000623 heterocyclic group Chemical group 0.000 title 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title 1
- -1 heterocyclic quinoline compound Chemical class 0.000 claims abstract description 64
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims abstract description 29
- 210000003780 hair follicle Anatomy 0.000 claims abstract description 29
- 201000004384 Alopecia Diseases 0.000 claims abstract description 24
- 238000002512 chemotherapy Methods 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 12
- 231100000360 alopecia Toxicity 0.000 claims abstract description 11
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 230000006378 damage Effects 0.000 claims abstract description 7
- 238000005576 amination reaction Methods 0.000 claims abstract description 4
- 238000006396 nitration reaction Methods 0.000 claims abstract description 4
- 238000001959 radiotherapy Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 7
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910002651 NO3 Inorganic materials 0.000 claims description 6
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 229910017604 nitric acid Inorganic materials 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 230000000802 nitrating effect Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- 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 4
- UTOMICFLROGMAE-UHFFFAOYSA-N quinoline-3,4-diamine Chemical compound C1=CC=CC2=C(N)C(N)=CN=C21 UTOMICFLROGMAE-UHFFFAOYSA-N 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical group [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- QEMBAAIUHZWKQO-UHFFFAOYSA-N amino azanylidynemethanesulfonate Chemical compound NOS(=O)(=O)C#N QEMBAAIUHZWKQO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 2
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- BLFRQYKZFKYQLO-UHFFFAOYSA-N 4-aminobutan-1-ol Chemical compound NCCCCO BLFRQYKZFKYQLO-UHFFFAOYSA-N 0.000 claims description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- 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 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 claims description 2
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 229940102253 isopropanolamine Drugs 0.000 claims description 2
- 229940001447 lactate Drugs 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-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
- 125000005341 metaphosphate group Chemical group 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 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
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 239000004323 potassium nitrate Substances 0.000 claims description 2
- 235000010333 potassium nitrate Nutrition 0.000 claims description 2
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000004317 sodium nitrate Substances 0.000 claims description 2
- 235000010344 sodium nitrate Nutrition 0.000 claims description 2
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 2
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 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
- 239000001384 succinic acid Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052718 tin Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 claims 1
- 230000002062 proliferating effect Effects 0.000 claims 1
- 239000001119 stannous chloride Substances 0.000 claims 1
- 239000011135 tin Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
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Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及含氮五元杂环并喹啉类化合物及其盐、制法、药物组合物和用途。所述含氮五元杂环并喹啉类化合物的结构式如I所示：
Description
本申请要求申请日为2017年11月24日的中国专利申请CN201711190023.3的优先权。上述中国专利申请以全文的形式引入本申请中。
技术领域
本发明属于医药化学领域，具体涉及含氮五元杂环并喹啉类化合物及其盐、制法、药物组合物和用途。
背景技术
脱发是一种常见的皮肤病，Mayo Clin Proc(IF＝5.71)报道，斑秃几乎与银屑病(俗称牛皮癣)一样普遍。脱发也是肿瘤病人化疗后的常见副作用，化疗脱发和斑秃一样也是毛囊受影响的脱发疾病，一般用药1-2周后即可发生脱发，其发生率仅次于恶心、呕吐，化疗引起的脱发(Chemotherapy-induced alopecia:CIA)可导致抗癌治疗最严重的心理不良反应。在美国，大约有85％的化疗患者会经历不同程度的脱发。47-85％的女性癌症患者认为CIA是化疗带来的最严重的外界伤害，甚至有8％的患者因此拒绝化疗。化疗结束用药后，1-2月头发可再生；一部分患者脱发无法完全恢复；在大部分患者中，再生头发的色泽、结构、质地以及生长速度都有所变化，头发的密度也较化疗前稀疏。
化疗脱发的可恢复性取决于毛囊干细胞受破坏的程度。化疗导致的脱发主要是因为化疗药物显著地影响了处于生长期的高分化的毛囊角质母细胞。此类细胞位于毛发下端的毛球部位，如果受到了破坏可由皮脂腺下端的毛囊干细胞进行补充。此种情况产生的结果仅是头发的暂时脱落。在另外一些化疗情况下，如果毛囊干细胞完全受到了破坏，那么导致的脱发将会是不可逆的。
目前应用于临床的药物和方法还实现不了有效治疗脱发的目的，且存在不同程度副作用，如雄激素受体竞争抑制剂对男性患者的副作用为女性化、性欲减退等等。到目前为止，除局部低温(戴冰帽)在临床上已证实具有一定的预防CIA外，其他各种方法均未在临床上证实有确切的疗效。
因此，提高药物对毛囊增殖的选择性和有效性是治疗脱发研究的重点和难点，迫切需要开发针对毛囊干细胞的化合物，减少对其他靶点导致的毒副作用，为治疗与之相关的疾病，如各类原因导致的脱发、肿瘤化疗、毛囊损伤等提供新的选择。
TLR7(Toll样受体7)在毛囊中分布较多，具有这种特殊的分布优势，与毛囊干细胞存在共表达；TLR7在小鼠表皮滤泡间上皮(IFE)角化细胞中与干细胞和祖细胞共表达；TLR7受体激动后可促进毛囊增殖。现有报道的小分子TLR7激动剂有Imiquimod、Gardiquimod、Resiquimod，但是这些激动剂尚未有关于治疗抗肿瘤药物导致脱发的研究。本申请发明人对现有多种小分子TLR7激动剂的结构进行了研究，根据药物设计原理进行了小分子化合物结构设计，并对合成的小分子化合物的毛囊增殖活性进行了筛选。
发明内容
本发明提供了通式I所示的含氮五元杂环并喹啉类化合物及其药学上可接受的盐：
其中：
R1选自氢、卤素、羟基、氰基、氨基、硝基、取代或非取代的C1-10烷基、取代或非取代的C2-10烯基、取代或非取代的C2-10炔基、取代或非取代的C1-10烷氧基、取代或非取代的C1-10烷硫基、取代或非取代的C3-10环烷基、取代或非取代的芳基、取代或非取代的含N和/或O的3-8元杂芳基；
其中，优选地，取代的C1-10烷基、取代的C1-10烷氧基、取代的C1-10烷硫基、取代的C2-10烯基、取代的C2-10炔基任选地被1、2或3个相同或不同取代基取代，所述取代基选自：卤素、羟基、氰基、氨基、硝基；
优选地，取代的C3-10环烷基任选地被1、2或3个相同或不同取代基取代，所述取代基选自：卤素、羟基、巯基、羧基、硝基；
优选地，取代或非取代的芳基任选地被1、2或3个相同或不同取代基取代，所述取代基选自卤素、羟基、硝基、氨基、氰基、磺酸基或羧基中的一种或多种，进一步优选的，芳基是苯基、苄基、萘基；
优选地，取代或非取代的含N和/或O的3-8元杂芳基选地被1、2或3个相同或不同取代基取代，所述取代基选自卤素、羟基、硝基、氨基、氰基、磺酸基或羧基中的一种或多种；
R2选自氢、卤素、羟基、氰基、氨基、硝基、取代或非取代的C1-10烷基、取代或非取代的C2-10烯基、取代或非取代的C2-10炔基、取代或非取代的C1-10烷氧基、取代或非取代的C1-10烷硫基、取代或非取代的C3-10环烷基、取代或非取代的芳基、取代或非取代的含N和/或O的3-8元杂芳基；
其中，优选地，，取代的C1-10烷基、取代的C1-10烷氧基、取代的C1-10烷硫基、取代的C2-10烯基、取代的C2-10炔基任选地被1、2或3个相同或不同取代基取代，所述取代基选自：卤素、羟基、氰基、氨基、硝基；
优选地，取代的C3-10环烷基任选地被1、2或3个相同或不同取代基取代，所述取代基选自：卤素、羟基、巯基、羧基、硝基；
优选地，取代或非取代的芳基任选地被1、2或3个相同或不同取代基取代，所述取代基选自卤素、羟基、硝基、氨基、氰基、磺酸基或羧基中的一种或多种，进一步优选的，芳基是苯基、苄基、萘基；
优选地，取代或非取代的含N和/或O的3-8元杂芳基选地被1、2或3个相同或不同取代基取代，所述取代基选自卤素、羟基、硝基、氨基、氰基、磺酸基或羧基中的一种或多种；
n是0、1、2、3；
A1、A2、A3分别独立地选自N、C、O，并且至少有一个选自N。
在另一个具体实施方案中，通式I所示的含氮五元杂环并喹啉类化合物及其药学上可接受的盐是通式II-1、通式II-2、通式II-3、通式II-4、通式II-5、通式II-6所示的化合物：
在另一个具体实施方案中，通式I所示的含氮五元杂环并喹啉类化合物及其药学上可接受的盐是如下式I-1所示的化合物：
在另一个具体实施方案中，通式I所示的含氮五元杂环并喹啉类化合物及其药学上可接受的盐，其药学上可接受的盐为无机盐和有机盐，选自盐酸盐、氢溴酸盐、硝酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、高氯酸盐以及甲酸盐、乙酸盐、丙酸盐、丙二酸盐、丙烯酸盐、丁二酸盐、草酸盐、D或L苹果酸盐、富马酸盐、马来酸盐、苯甲酸盐、羟基丁酸盐、邻苯二甲酸盐、甲磺酸盐、乙磺酸盐、磺酸盐、水杨酸盐、酒石酸盐、柠檬酸盐、乳酸盐、扁桃酸盐、琥珀酸中的一种或多种。
本发明还提供了通式I所示的含氮五元杂环并喹啉类化合物的制备方法，包括硝化、卤化、胺化、还原、环化反应，包括：
步骤1，以式VI的4-羟基喹啉化合物为起始原料，加入酸，然后加入硝化试剂进行硝化反应，得到式V的4-羟基-3-硝基喹啉化合物，反应式如下：
步骤2，将式V的4-羟基-3-硝基喹啉化合物溶于溶剂1中，加入卤化剂，反应得到式IV的4-氯-3-硝基喹啉化合物，反应式如下：
步骤3，将式IV的4-氯-3-硝基喹啉化合物溶于溶剂2中，加入碱和胺类化合物进行氨化反应，得到式III的4-氨基-3-硝基喹啉化合物，反应式如下：
步骤4，将式III的4-氨基-3-硝基喹啉化合物溶于溶剂3中，然后加入还原剂进行反应，得到式II的4-氨基-3-氨基喹啉化合物，反应式如下：
步骤5，将盐酸和溶剂4加入到式II的4-氨基-3-氨基喹啉化合物中，然后加入亚硝酸钠进行环化反应，调整反应液为碱性，所得沉淀物即为式I的含氮五元杂环并喹啉类化合物，反应式如下：
上述步骤1中所述酸选自甲酸、乙酸、丙酸、丁酸、硝酸中的一种或多种；
和/或，步骤1中所述硝化试剂选自硝酸、浓硫酸和硝酸盐混合物、乙酰基硝酸酯中的一种或多种；优选的，所述硝酸盐选自硝酸钠、硝酸钾中的一种；
和/或，步骤2中所述卤化剂选自五卤化磷、三氯氧磷、草酰氯、三苯基二氯化磷(Ph3PCl2)、五溴化磷、氧溴化磷、三苯基二溴化磷中的一种或多种；
和/或，步骤3中所述碱选自三乙胺、三甲胺、碳酸钠(Na2CO3)、碳酸氢钠(NaHCO3)、碳酸铯(Cs2CO3)、碳酸钾(K2CO3)、吡啶中的一种或多种；
和/或，步骤3中所述胺类化合物选自乙醇胺、丙醇胺、异丙醇胺、丁醇胺或丙炔胺；
和/或，步骤4中所述还原剂选自铁粉、氯化亚锡、锡、硫化钠、保险粉(连二硫酸钠)、亚硫酸盐、氢气、钯碳、雷尼镍(Raney Ni)、四氢铝锂、硼氢化钠、硫代硼氢化钠、一氧化碳中的一种或多种；
和/或，所述溶剂1、溶剂2、溶剂3和溶剂4选自水、甲醇、乙醇、丙三醇、二氯甲烷、丙酮、乙酸乙酯、二氧六环、甲苯、二甲苯、DMSO、DMF、四氢呋喃中的一种或多种。
本发明还提供了药物组合物，其包含式I的含氮五元杂环并喹啉类化合物及其药学上可接受的盐。
在另一个具体实施方案中，所述药物组合物还进一步包含一种或多种可药用赋形剂。
所述赋形剂可选自粘合剂、润滑剂、助流剂、崩解剂、成粒剂、包衣剂、润湿剂、溶剂、悬浮剂、调味剂中的一种或多种。
在另一个具体实施方案中，所述药物组合物可经口服给药、胃肠外给药、吸入喷雾给药、直肠给药、鼻内给药、舌下给药、颊内给药、透皮给药或植入给药。
在另一个具体实施方案中，所述药物组合物可制成适于通过所需的给药途径对患者给药的剂型，例如注射剂、胶囊剂、片剂、粉剂、颗粒剂、含片、糖浆、悬浮剂、溶液剂、乳剂、栓剂。
包含本发明式I的含氮五元杂环并喹啉类化合物及其药学上可接受的盐的药物组合物可以采用医学领域常规的方法进行制备，其中活性成分的含量为0.1重量％～99.5重量％，这取决于待治疗或者预防的病症以及给予所述化合物的受试者的特性。对于所给化合物的剂量方案可由本领域技术人员利用本文公开的内容容易地确定。
在另一个具体实施方案中，式I的含氮五元杂环并喹啉类化合物及其药学上可接受的盐可与一种或多种其他活性药物组分联用。该联用药物可以是包含本发明化合物或其药学上可接受的盐和一种或多种其他活性药物组合分的组合物的形式。
本发明还提供了式I的含氮五元杂环并喹啉类化合物及其药学上可接受的盐或其药物组合物用于制备具有毛囊增殖作用的药物的用途。
本发明还提供了式I的含氮五元杂环并喹啉类化合物及其药学上可接受的盐或其药物组合物用于制备治疗普通脱发、放化疗脱发、毛囊损伤的药物的用途。
本发明提供的式I的含氮五元杂环并喹啉类化合物具有促进毛囊增殖的作用。可将本发明的含氮五元杂环并喹啉类化合物制成乳膏剂，在头皮局部使用，一方面可以促进毛囊增殖，另一方面对肿瘤治疗的影响较少。
附图说明
图1是施含药乳膏剂和纯乳膏基质后小鼠毛囊切片HE染色对照图(第一只)。
图2是含药乳膏剂和纯乳膏基质后小鼠毛囊切片HE染色对照图(第二只)。
图3是含药乳膏剂和纯乳膏基质后小鼠毛囊切片HE染色对照图(第三只)。
图4是含药乳膏剂和不施药后小鼠毛囊切片HE染色对照图(第四只)。
图5是含药乳膏剂和纯乳膏基质后小鼠毛囊切片HE染色对照图(第五只)。
具体实施方式
下面对本发明的具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。
实施例1：1-羟乙基-1H-[1,2,3]三氮唑[4,5-c]喹啉的合成
第一步：
第二步：
第三步：
第四步：
第五步：
第一步：将5g的式VI-1的4-羟基喹啉(34.48mmol，购于九鼎化学)溶于丙酸中(40mL，纯度≥99.5％)加热至120℃；然后，将用丙酸稀释后的3.5mL的浓硝酸(41.38mmol，浓度为浓硝酸65-68％)在1.5h内缓缓滴入，约15min后，有黄色沉淀生成；补加丙酸20mL继续回流1h，TLC(薄层层析)显示并无反应物4-羟基喹啉，停止加热，冷却反应液至室温；过滤反应液，滤饼用石油醚洗涤，真空干燥，所得黄色固体即为式V-1的4-羟基-3-硝基喹啉(5.28g，平均产率80.7％)，熔点>300℃。
1HNMR(DMSO-d6,400MHz):σ(ppm)13.01(br,1H),9.20(d,1H,J＝6Hz),8.27(d,1H,J＝7.6Hz),7.81(td,1H,J1＝7.6Hz,J2＝1.4Hz),7.73(d,1H,J＝7.6Hz)7.53(t,1H,J＝7.6Hz).IR(KBr):3445,3161,3099,1618,1561,1438,1383,1340,1197,844,765 cm-1.MS(ES-)m/z:189(M-H+).HRMS m/s calculated for C9H6N2O3+Na+213.0271,found 213.0276.
第二步：将式V-1的4-羟基-3-硝基喹啉(2g，10.53mmol)溶解于二氯甲烷中，然后缓慢滴入草酰氯(4.5mL，52.65mmol)，当气泡生成缓和后，加热至40℃；半小时后浓缩反应液，所得白色固体即式VI-1的4-氯-3-硝基喹啉，熔点为116～118℃。
1HNMR(DMSO-d6,400MHz):σ(ppm)9.15(d,1H,J＝7.2Hz),8.25(d,1H,J＝8Hz),7.79(d,2H,J＝2.4Hz),7.54-7.50(m,1H).IR(KBr):3166,3100,1621,1599,1562,1443,1340,845,764cm-1.MS(ES-)m/z:207(M-H+)HRMS m/s calculated for C9H5ClN2O2-H+206.9967,found 206.9960.
第三步：将式VI-1的4-氯-3-硝基喹啉(1.37g，6.59mmol)溶解于20ml的甲醇中，冰水冷却；然后，加入三乙胺1.4ml(≥98％)和乙醇胺0.6ml(≥99％)，反应液搅拌过夜，次日过滤，所得固体即为式III-1的3-硝基-4-羟乙基氨基-喹啉(1.16g，两步平均产率：75.7％)，熔点为184～186℃。
1HNMR(CDCl3,400MHz):σ(ppm)9.89(br,1H),9.38(s,1H),8.31(d,1H,J＝8.4Hz),8.03(d,1H,J＝8.4Hz),7.78(t,1H,J＝7.6Hz),7.50(t,1H,J＝7.4Hz),4.13(quant,2H,J＝5.2Hz),4.0(t,2H,J＝5.2Hz).IR(KBr):3293,3159,1615,1593,1564,1536,1471,1417,1394,1337,1250,1200,1059,760cm-1.MS(EI+)m/z:234(M+H+).HRMS m/s calculated forC11H11N3O3+H+234.0873,found 234.0873.
第四步：将式III-1的化合物4(1g，4.29mmol)溶解于异丙醇中并加热至100℃；然后，滴入保险粉(连二硫酸钠)的水溶液(保险粉7.5g，水50ml)，让反应液100℃下搅拌0.5h；当TLC显示无反应物，停止加热，分出上层液体，浓缩反应液；浓缩后的固体用乙醇提取，浓缩乙醇液即得棕色油状物，即式II-1的3-氨基-4-羟乙基氨基-喹啉(896mg，平均产率：34.7％)。
1HNMR(CDCl3,400MHz):σ(ppm)8.42(s,1H),7.98-7.95(m,2H),7.52-7.39(m,2H),3.92(br,3H),3.73(t,2H,J＝4.4Hz),3.44(t,2H,J＝4.4Hz),1.26(s,1H).IR(KBr):3331,3216,2963,2852,1617,1571,1466,1439,1347,1261,799cm-1.MS(ES+)m/z:204(M+H+).HRMS m/s calculated for C11H13N3O+H+204.1131,found 204.1136.
第五步：将式II-1的化合物5(1.634g，8.04mmol)，盐酸1.5ml(12mol/l)，乙醇10ml，水10ml，置于单颈瓶中冷却至0℃；然后，分次加入亚硝酸钠833mg，反应液搅拌过夜；次日，过滤反应液，用NaOH碱化反应液至pH≈12，所得的沉淀即为式I-1的1-羟乙基-1H-[1,2,3]三氮唑[4,5-c]喹啉产物；若无沉淀，可用乙酸乙酯提取后，用柱层析的方法进行纯化，(806mg，平均产率：48.3％)，熔点为170～172℃。
1HNMR(CDCl3,400MHz):σ(ppm)9.44(s,1H),8.42(dd,1H,J1＝8.4Hz,J2＝0.8Hz),8.27(d,1H,J＝8.4Hz),7.83(td,1H,J1＝7.6Hz,J2＝1.2Hz),7.50(td,1H,J1＝7.8Hz,J2＝1.2Hz),5.17(t,2H,J＝5.2Hz),4.45(t,2H,J＝5Hz).IR(KBr):3292,3070,3007,2941,2851,1621,1586,1524,1454,1388,1323,1166,1069,761cm-1.MS(EI+)m/z:237(M+Na+).HRMS m/s calculated for C11H10N4O+Na+237.0747,found 237.0745.
生物学实施例
实验对象：6周龄C57雄性小鼠，分成A组和B组，其中A组为施用了含有实施例1制得的1-羟乙基-1H-[1,2,3]三氮唑[4,5-c]喹啉的乳膏剂，B组是仅施用了乳膏剂辅料的对照组，每组小鼠选取5只作为实验对象。
乳膏剂辅料配方：单硬脂酸甘油酯0.8g、硬脂酸0.8g、白凡士林2g、液体石蜡8g、甘油10g、水16g、十二烷基硫酸钠0.4g、冰片0.2g、二甲亚砜1.8g。主药：实施例1制得的1-羟乙基-1H-[1,2,3]三氮唑[4,5-c]喹啉的含量为10mg/10ml上述基质。
将所有原料置于80℃水浴中，顺时针搅拌30min，冷却至室温即可。
操作过程：C57小鼠用三溴乙醇麻醉后，在背部抹上熔化的石蜡；待石蜡凝固后撕去背部毛发，露出皮肤；拔毛后第九天，注射环磷酰胺(20μg/g)；从给药当天开始，在小鼠背部皮肤抹药1次/2日；左侧涂抹40μl纯乳膏基质，右侧涂抹含药乳膏40μl；第21天处死小鼠，背部取材，切片，HE染色，封片。
实验结果如下：对比同等高倍或低倍视野下A组和B组毛囊数量。小鼠背部皮肤毛囊被染色成蓝色，图中相同面积下，蓝色的小点A组比B组明显多，表明给予含有实施例1制得的1-羟乙基-1H-[1,2,3]三氮唑[4,5-c]喹啉的乳膏剂后对小鼠有明显的促进毛囊增殖作用(参见图1～图5)，对普通脱发、放化疗脱发、毛囊损伤有明显的改善效果。
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式，并且很显然，根据上述教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。
Claims (10)
1.通式I所示的含氮五元杂环并喹啉类化合物及其药学上可接受的盐：
其中：
R1选自氢、卤素、羟基、氰基、氨基、硝基、取代或非取代的C1-10烷基、取代或非取代的C2-10烯基、取代或非取代的C2-10炔基、取代或非取代的C1-10烷氧基、取代或非取代的C1-10烷硫基、取代或非取代的C3-10环烷基、取代或非取代的芳基、取代或非取代的含N和/或O的3-8元杂芳基；
R2选自氢、卤素、羟基、氰基、氨基、硝基、取代或非取代的C1-10烷基、取代或非取代的C2-10烯基、取代或非取代的C2-10炔基、取代或非取代的C1-10烷氧基、取代或非取代的C1-10烷硫基、取代或非取代的C3-10环烷基、取代或非取代的芳基、取代或非取代的含N和/或O的3-8元杂芳基；
n是0、1、2、3；
A1、A2、A3分别独立地选自N、C、O，并且至少有一个选自N；
其中，所述R1和R2中：
优选地，取代的C1-10烷基、取代的C1-10烷氧基、取代的C1-10烷硫基、取代的C2-10烯基、取代的C2-10炔基任选地被1、2或3个相同或不同取代基取代，所述取代基选自：卤素、羟基、氰基、氨基、硝基；
优选地，取代的C3-10环烷基任选地被1、2或3个相同或不同取代基取代，所述取代基选自：卤素、羟基、巯基、羧基、硝基；
优选地，取代或非取代的芳基任选地被1、2或3个相同或不同取代基取代，所述取代基选自卤素、羟基、硝基、氨基、氰基、磺酸基或羧基中的一种或多种，进一步优选的，芳基是苯基、苄基、萘基；
优选地，取代或非取代的含N和/或O的3-8元杂芳基选地被1、2或3个相同或不同取代基取代，所述取代基选自卤素、羟基、硝基、氨基、氰基、磺酸基或羧基中的一种或多种。
2.根据权利要求1所述的含氮五元杂环并喹啉类化合物及其药学上可接受的盐，其是通式II-1、通式II-2、通式II-3、通式II-4、通式II-5、通式II-6所示的化合物：
3.根据权利要求2所述的含氮五元杂环并喹啉类化合物及其药学上可接受的盐，其特征在于，所述含氮五元杂环并喹啉类化合物为下式I-1结构化合物：
4.根据权利要求1所述的含氮五元杂环并喹啉类化合物及其药学上可接受的盐，其特征在于：所述药学上可接受的盐为无机盐和有机盐，选自盐酸盐、氢溴酸盐、硝酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、高氯酸盐以及甲酸盐、乙酸盐、丙酸盐、丙二酸盐、丙烯酸盐、丁二酸盐、草酸盐、D或L苹果酸盐、富马酸盐、马来酸盐、苯甲酸盐、羟基丁酸盐、邻苯二甲酸盐、甲磺酸盐、乙磺酸盐、磺酸盐、水杨酸盐、酒石酸盐、柠檬酸盐、乳酸盐、扁桃酸盐、琥珀酸中的一种或多种。
5.权利要求1-4任意一项所述的含氮五元杂环并喹啉类化合物的制备方法，包括：
步骤1，以式VI的4-羟基喹啉化合物为起始原料，加入酸，然后加入硝化试剂进行硝化反应，得到式V的4-羟基-3-硝基喹啉化合物，反应式如下：
步骤2，将式V的4-羟基-3-硝基喹啉化合物溶于溶剂1中，加入卤化剂，反应得到式IV的4-氯-3-硝基喹啉化合物，反应式如下：
步骤3，将式IV的4-氯-3-硝基喹啉化合物溶于溶剂2中，加入碱和胺类化合物进行氨化反应，得到式III的4-氨基-3-硝基喹啉化合物，反应式如下：
步骤4，将式III的4-氨基-3-硝基喹啉化合物溶于溶剂3中，然后加入还原剂进行反应，得到式II的4-氨基-3-氨基喹啉化合物，反应式如下：
步骤5，将盐酸和溶剂4加入到式II的4-氨基-3-氨基喹啉化合物中，然后加入亚硝酸钠进行环化反应，调整反应液为碱性，所得沉淀物即为式I的含氮五元杂环并喹啉类化合物，反应式如下：
6.根据权利要求5所述的制备方法，其特征在于：
步骤1中所述酸选自甲酸、乙酸、丙酸、丁酸、硝酸中的一种或多种；
和/或，步骤1中所述硝化试剂选自硝酸、浓硫酸和硝酸盐混合物、乙酰基硝酸酯中的一种或多种；优选的，所述硝酸盐选自硝酸钠、硝酸钾中的一种；
和/或，步骤2中所述卤化剂选自五卤化磷、三氯氧磷、草酰氯、三苯基二氯化磷、五溴化磷、氧溴化磷、三苯基二溴化磷中的一种或多种；
和/或，步骤3中所述碱选自三乙胺、三甲胺、碳酸钠、碳酸氢钠、碳酸铯、碳酸钾、吡啶中的一种或多种；
和/或，步骤3中所述胺类化合物选自乙醇胺、丙醇胺、异丙醇胺、丁醇胺或丙炔胺；
和/或，步骤4中所述还原剂选自铁粉、氯化亚锡、锡、硫化钠、保险粉、亚硫酸盐、氢气、钯碳、雷尼镍、四氢铝锂、硼氢化钠、硫代硼氢化钠、一氧化碳中的一种或多种；
和/或，所述溶剂1、溶剂2、溶剂3和溶剂4选自水、甲醇、乙醇、丙三醇、二氯甲烷、丙酮、乙酸乙酯、二氧六环、甲苯、二甲苯、DMSO、DMF、乙醚、四氢呋喃中的一种或多种。
7.药物组合物，其包含权利要求1-4任意一项所述的含氮五元杂环并喹啉类化合物及其药学上可接受的盐。
8.根据权利要求7所述的药物组合物，其还进一步包含一种或多种可药用赋形剂。
9.权利要求1-4任意一项所述的含氮五元杂环并喹啉类化合物及其药学上可接受的盐或权利要求7-8任意一项所述的药物组合物用于制备具有毛囊增殖作用的药物的用途。
10.权利要求1-4任意一项所述的含氮五元杂环并喹啉类化合物及其药学上可接受的盐或权利要求7-8任意一项所述的药物组合物用于制备治疗普通脱发、放化疗脱发、毛囊损伤的药物的用途。
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| US11530218B2 (en) | 2020-01-20 | 2022-12-20 | Incyte Corporation | Spiro compounds as inhibitors of KRAS |
| US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
| US11767320B2 (en) | 2020-10-02 | 2023-09-26 | Incyte Corporation | Bicyclic dione compounds as inhibitors of KRAS |
| US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
| US11999752B2 (en) | 2020-08-28 | 2024-06-04 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of KRAS |
| US12030883B2 (en) | 2021-09-21 | 2024-07-09 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of KRAS |
| US12030884B2 (en) | 2021-10-01 | 2024-07-09 | Incyte Corporation | Pyrazoloquinoline KRAS inhibitors |
| US12077539B2 (en) | 2021-03-22 | 2024-09-03 | Incyte Corporation | Imidazole and triazole KRAS inhibitors |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11530218B2 (en) | 2020-01-20 | 2022-12-20 | Incyte Corporation | Spiro compounds as inhibitors of KRAS |
| US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
| US11999752B2 (en) | 2020-08-28 | 2024-06-04 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of KRAS |
| US11767320B2 (en) | 2020-10-02 | 2023-09-26 | Incyte Corporation | Bicyclic dione compounds as inhibitors of KRAS |
| US12077539B2 (en) | 2021-03-22 | 2024-09-03 | Incyte Corporation | Imidazole and triazole KRAS inhibitors |
| US12030883B2 (en) | 2021-09-21 | 2024-07-09 | Incyte Corporation | Hetero-tricyclic compounds as inhibitors of KRAS |
| US12030884B2 (en) | 2021-10-01 | 2024-07-09 | Incyte Corporation | Pyrazoloquinoline KRAS inhibitors |
| US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
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