CN109384727A - 酞嗪酮类化合物、其制备方法、药物组合物及用途 - Google Patents
酞嗪酮类化合物、其制备方法、药物组合物及用途 Download PDFInfo
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- CN109384727A CN109384727A CN201710682388.1A CN201710682388A CN109384727A CN 109384727 A CN109384727 A CN 109384727A CN 201710682388 A CN201710682388 A CN 201710682388A CN 109384727 A CN109384727 A CN 109384727A
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- Prior art keywords
- acid
- compound
- formula
- pharmaceutically acceptable
- alkyl
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- -1 Phthalazines ketone compounds Chemical class 0.000 title claims abstract description 52
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 239000012453 solvate Substances 0.000 claims abstract description 22
- 150000002148 esters Chemical class 0.000 claims abstract description 20
- 239000000651 prodrug Substances 0.000 claims abstract description 20
- 229940002612 prodrug Drugs 0.000 claims abstract description 20
- 206010012310 Dengue fever Diseases 0.000 claims abstract description 17
- 208000025729 dengue disease Diseases 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- 241000725619 Dengue virus Species 0.000 claims description 16
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 235000011054 acetic acid Nutrition 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- 125000005916 2-methylpentyl group Chemical group 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-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
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 4
- 230000003287 optical effect Effects 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 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 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005270 trialkylamine group Chemical group 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 claims description 2
- 125000004338 2,2,3-trimethylbutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 2
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 claims description 2
- 125000005925 3-methylpentyloxy group Chemical group 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000007818 Grignard reagent Substances 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 125000002091 cationic group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
一种式I所示的酞嗪酮类化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其制备方法,药物组合物及其在制备登革热病毒抑制剂中的用途。所述酞嗪酮类化合物结构如式I所示。该类化合物或其药物组合物具有抗登革病毒活性以及较好的选择性,可用于预防和/或治疗登革热病毒感染。
Description
技术领域
本发明涉及酞嗪酮类化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其制备方法,药物组合物及用途。
背景技术
登革热已成为热带和亚热带地区主要的公共健康问题。据研究报道每年有3.9亿人感染登革热病毒,有9600万人表现出疾病症状。全球大概有1/2的人口面临登革热病毒的威胁。在中国,广东、广西、福建、云南是主要的登革热的流行区。
登革病毒(Dengue virus,DV)属于黄病毒科的主要成员之一,感染人类所称的疾病为登革病毒病,根据疾病严重程度不同临床上分为登革热(dengue fever)、登革出血热(dengue hemorrhagic fever)和登革休克综合征(dengue shock syndrome),主要由埃及伊蚊和白纹伊蚊叮咬传播。登革病毒存在四种亚型且变异性强,目前尚无疫苗可同时预防四种亚型,而单独预防一种亚型可能会导致依赖抗体增强。
目前一种潜在治疗登革的α-葡萄糖甘酶抑制剂Celgosivir已经处于临床二期研究,另外UV-4B、60-P-004、Modipafant这三个药物已经进入临床一期,尚未有上市药物。因此,研究和开发更多作用于新靶点、新机制及全新母核结构的非核苷类小分子抗登革病毒药物日益迫切,是目前药物化学领域研究的热点,且具有十分重要的理论、经济和社会意义。
发明内容
本发明的一个目的是提供一种式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,具有抗登革病毒活性以及较好的选择性,是一类新型抗登革病毒抑制剂。
本发明提供以下技术方案:
一种式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物:
其中,
A选自芳基或杂芳基;
R1、R2各自独立地为H、烷基,或R1和R2一起表示(CH2)x,x为选自2、3、4或5,优选选自4或5;其中1-3个CH2基团可以被NH、O代替;优选地,其中1-2个CH2基团可以被NH、O代替;
R3表示一个或多个取代基,其各自独立地选自H、卤素、氰基、羟基、烷基、卤代烷基、环烷基、杂环基、烷氧基、杂链烃基、烷基磺酰基、-N(Q1)(Q2)、
R4选自-NHCOLR7或-COLR7;优选R4为-NHCOOL’R7、-NHCOL’R7、-NHCONHL’R7或-CONHL’R7;
R5表示一个或多个取代基,其各自独立地选自H、卤素、氰基、羟基、烷基、卤代烷基、烷氧基;
各个R6各自独立地选自H、羟基、烷基、环烷基、烷氧基、杂环基、-N(Q1)(Q2);
各个L为任选被卤素取代的亚烷基或任选被卤素取代的亚杂链烃基;
各个L’为任选被卤素取代的亚烷基;
各个R7各自独立地选自H、羟基、烷基、环烷基、烷氧基、卤素、任选取代的杂环基、-N(Q1)(Q2);所述“任选取代的杂环基”中的取代基为烷基;
各个Q1、Q2各自独立地为H或烷基;
n为选自0至10的整数;优选地,为选自0至7的整数,优选地,为选自0至5的整数;
优选地,
所述“芳基”为5-10元芳基;优选地,所述芳基为苯基、萘基;
所述“杂芳基”为含有1-3个选自N、O和S中的杂原子的5-10元杂芳基;优选地,为含有1-2个选自N、O和S中的杂原子的5-10元杂芳基;优选地,所述杂芳基选自吡啶基、吡咯基、嘧啶基、吡嗪基、哒嗪基、噻吩基、呋喃基、 2,4-二甲基吡唑基、N-甲基吡唑基、咪唑基、噁唑基、噻唑基、吲哚基、氮杂吲哚基、萘啶基、喹啉基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-a]嘧啶基;
R3表示1个、2个或3个取代基;
R5表示1个或2个取代基;
所述“卤素”选自氟、氯、溴或碘;
所述“烷基”、“卤代烷基”“烷基磺酰基”中的烷基为C1-C10直链或支链烷基,优选地,为C1-C7直链或支链烷基,优选地,为C1-C5直链或支链烷基,优选地,选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基,1-甲基丁基、2-甲基丁基、3-甲基丁基、异戊基、1-乙基丙基、新戊基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、正庚基、2-甲基己基、3-甲基己基、2,2-二甲基戊基、3,3-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3-乙基戊基或2,2,3-三甲基丁基;优选地,选自甲基、乙基、丙基、异丙基、丁基或异丁基;
所述“亚烷基”为C1-C10直链或支链亚烷基,优选为C1-C6直链或支链亚烷基,更优选为C1-C4直链或支链亚烷基,更优选亚正丁基;
优选地,所述“卤代烷基”选自三氟甲基;
所述“烷氧基”为C1-C6直链或支链烷氧基,优选地,所述烷氧基为C1-C5直链或支链烷氧基;优选地,所述烷氧基选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基、异己氧基或3-甲基戊氧基;
所述“环烷基”为C3-C6环烷基,优选地,所述环烷基选自环丙基、环丁基、环戊基或环己基;
所述“杂环基”中的杂环为环上含有1个、2个或3个选自N、O、S的杂原子的3-7元非芳香环,优选地,所述杂环基为环上含有1个或2个选自N、O的杂原子的3-6元非芳香环;
所述“杂链烃基”、“亚杂链烃基”中的杂链烃结构为C1-C7饱和或不饱和的、链上含1-5个选自N、O的杂原子的直链或支链的杂链结构,可选地,所述杂链烃结构为C1-C5饱和或不饱和的、链上含1个、2个或3个选自N、O的杂原子的直链或支链杂链烃结构,可选地,所述杂链烃结构为C1-C5饱和或不饱和的、链上含1个、2个或3个O的直链或支链杂链烃结构;
优选地,上述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其中,
A为苯基、N-甲基吡唑基、吡啶基、嘧啶基、吲哚基、吡嗪基、氮杂吲哚基、喹啉基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-a]嘧啶基;
R1、R2各自独立地选自H或甲基;
R3表示1个、2个或3个取代基,其各自独立地选自H、氟、氯、氰基、羟基、甲基、异丙基、甲氧基、甲磺酰基、三氟甲基、氮杂环丁基、甲氨基、N,N-二甲氨基、
n为选自0、1或2;
各个R6各自独立地选自H、甲基、羟基、环丙基或吗啉基;
R4选自-NHCOOL’R7、-NHCOL’R7、-NHCONHL’R7或-CONHL’R7;
各个L’为亚正丁基;
各个R7各自独立地选自H、羟基、氯、甲氧基、吗啉基、4-甲基哌啶基、N,N-二甲氨基;
R5表示1个或2个取代基,其各自独立地选自H、氟、甲基、氰基、三氟甲基、甲氧基。
优选地,上述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其中,
所述异构体包括一种或多种光学异构体、对映异构体、非对映异构体或消旋体混合物;
所述药学上可接受的盐包括式I化合物的阴离子盐和阳离子盐;
优选地,所述药学上可接受的盐包括式I化合物的碱金属的盐、碱土金属的盐、铵盐;优选地,所述碱金属包括钠、钾、锂、铯,所述碱土金属包括镁、钙、锶;
优选地,所述药学上可接受的盐包括式I化合物与有机碱形成的盐;优选地,所述有机碱包括三烷基胺、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲氨基吡啶、二甲基苯胺、N-烷基吗啉、1,5-二氮杂双环[4.3.0]壬烯-5(DBN)、1,8-二氮杂双环[5.4.0]十一碳烯-7(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO);优选地,所述三烷基胺包括三甲胺、三乙胺、N-乙基二异丙胺;优选地,所述N-烷基吗啉包括N-甲基吗啉;
优选地,所述药学上可接受的盐包括式I化合物与酸形成的盐;优选地,所述酸包括无机酸、有机酸;优选地,所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸;优选地,所述有机酸包括甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、谷氨酸、双羟萘酸;
所述溶剂化物为式I化合物与药学上可接受的溶剂形成的配合物;优选地,所述药学上可接受的溶剂包括水,乙醇,乙酸,N,N-二甲基甲酰胺,二甲基亚砜;优选地,所述药学上可接受的溶剂为水。
优选地,上述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其中,所述式I化合物为下列化合物之一:
本发明还提供一种制备上述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物的方法,通过以下线路1或线路2进行制备:
路线1:
化合物a-1通过Suzuki偶联反应制得化合物I,
其中,R1、R2、R3、R4、R5、A的定义如上所述;
路线2:
化合物b-1和化合物b-2通过亲核取代反应制得化合物I,
其中,R1、R2、R3、R4、R5、A的定义如上所述。
优选地,上述式I化合物为化合物5或化合物11,分别通过以下线路a或线路b进行制备:
路线a:
通式H1所示的化合物,水解后得到通式H2所示的化合物,通式H2所示的化合物与卤代物H3进行亲核取代反应得到通式H4所示的化合物,然后在金属催化剂或者碱的作用下,通过Suzuki偶联反应,得到通式H5所示的酞嗪酮类化合物,最后与各类胺或者酸发生缩合反应得到通式H6所示的化合物;
其中,R为氨基或羧基;A、R1、R2、R3、R4的定义与权利要求1-4中任一项的定义相同;
路线b:
通式H7所示的化合物先被制备成通式H8所示的格式试剂后,与邻苯二甲酸酐加成反应得到通式H9所示的化合物,通式H9所示的化合物与水合肼关环得到通式H10所示的化合物,最后通式H10所示的化合物与对卤代物进行亲核取代反应得到通式H11所示的酞嗪酮类化合物,最后H11所示的酞嗪酮类化合物与各类胺或者酸发生缩合反应得到通式H12所示的化合物;
其中,R为氨基或羧基;R1、R2、R3、R4、R5的定义如上所述;
优选地,所述的水解反应在酸性或碱性条件下在溶剂中进行;所述酸性条件所采用的酸为选自醋酸、盐酸、硫酸、三氟乙酸中的一种或多种;所述碱性条件所采用的碱为选自氢氧化钾、氢氧化钠、乙酸钾、乙酸钠、叔丁醇钾、叔丁醇钠中的一种或多种;所述溶剂为选自乙醇、甲醇、水、乙酸中的一种或多种;
优选地,所述的亲核取代反应在碱存在下在溶剂中进行;所述碱为选自碳酸钾、碳酸铯、氢化钠、氢化钾、叔丁醇钾、叔丁醇钠或氢氧化钠中的一种或多种;所述溶剂为选自乙腈、N,N-二甲基甲酰胺或四氢呋喃中的一种或多种;
优选地,所述的Suzuki偶联反应在溶剂中,在金属催化剂、碱及配体存在下在加热条件下进行;所述溶剂选自N,N-二甲基甲酰胺、甲苯或1,4-二氧六环;所述碱为选自碳酸铯、碳酸钾、叔丁醇钾和叔丁醇钠中的一种或多种;所述金属催化剂为选自醋酸钯、Pd(PPh3)4或Pd(dppf)2Cl2中的一种或多种;所述配体为选自三苯基膦、1,1'-双(二苯基膦)二茂铁、联萘二苯基膦、2-二环己基膦-2′,6′-二甲氧基-联苯和2-二环己膦基-2'-(N,N-二甲胺)-联苯中的一种或多种;
优选地,上述制备的格式试剂为镁盐、铁盐、铜盐、锌盐或锂盐。
本发明还提供一种药物组合物,其包含上述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物中的一种或多种以及任选存在的药学上可接受的载体。
所述药学上可接受的载体是指药学领域常规的药物载体,例如:稀释剂,如水等;填充剂,如淀粉、蔗糖等;粘合剂,如纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮;湿润剂,如甘油;崩解剂,如琼脂、碳酸钙和碳酸氢钠;吸收促进剂,如季铵化合物;表面活性剂,如十六烷醇;吸附载体,如高岭土和皂粘土;润滑剂,如滑石粉、硬脂酸钙和硬脂酸镁、和聚乙二醇等。另外,还可以在上述药物组合物中加入其它辅剂,如香味剂和甜味剂等。
优选地,所述药物组合物的剂型为片剂、粉剂、颗粒剂、胶囊剂、糖浆、注射用剂。
本发明还提供一种上述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,或者上述药物组合物在制备预防和/或治疗登革热病毒感染的药物中的用途。
本发明还提供一种上述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,或者上述的药物组合物在制备登革热病毒抑制剂中的用途。
本发明还提供一种预防和/或治疗疗登革热病毒感染及其相关疾病的方法,包括向患者给予有效量的上述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,或者上述的药物组合物。
本发明的式I化合物具有抗登革病毒活性,对感染登革病毒的细胞的毒性小,选择性好,是一类新型抗登革病毒抑制剂。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于示例性地对本发明进行说明,并不用于限制本发明。
以下实施例中:核磁共振氢谱采用BrukerAMX-400型、Gemini-300型或AMX–600型核磁共振仪记录,化学位移δ的单位为ppm。比旋光度由Perkin-Elmer241型自动旋光仪测定,所用微波为CEM-discovery微波反应器。所有反应溶剂均按照常规方法进行纯化。柱层析用硅胶(200-300目)为青岛海洋化工分厂生产。薄层层析使用GF254高效板,为烟台化工研究所生产。固定相采用GF254(HG/T2354-92)硅胶和羧甲基纤维素钠(800-1200)制备,分别为青岛海洋化工有限公司和中国医药(集团)上海化学试剂公司生产。所有溶剂均为分析纯试剂,所用试剂均购自国药集团化学试剂有限公司。采用碘、紫外荧光等方法显色。减压蒸除有机溶剂在旋转蒸发仪中进行。
实施例1:化合物I-1的制备
步骤1:将10g 1,4-二氯酞嗪(化合物1)加入200mL醋酸中,120℃下搅拌5h后,冷却至室温浓缩,用水洗涤, 抽滤得8.5g白色晶体(化合物2)(收率94%)。1H NMR(400MHz,CDCl3)δ9.94–9.87(m,1H),8.48(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),8.00–7.87(m,2H)。
步骤2:将8.5g化合物2溶于200ml二氧六环和40ml水,依次加入7.21g对氟苯硼酸,1.71g邻苯二茂铁二氯化钯,30g碳酸铯,氮气置换3次,100℃下反应过夜,TLC示底物完全消失,停止反应冷却至室温,反应用乙酸乙酯萃取,有机层水洗3次后无水硫酸钠干燥,浓缩,柱层析得3.6g黄色晶体(化合物3)(收率30%)。1H NMR(400MHz,CDCl3)δ8.46(dd,J=7.7,1.1Hz,1H),8.02–7.96(m,1H),7.86(dtd,J=17.7,7.3,1.4Hz,2H),7.36(d,J=8.4Hz,2H),6.66(d,J=8.5Hz,2H),5.27(s,2H)。
步骤3:将300mg中间体化合物3溶于50ml N,N-二甲基甲酰胺(DMF)中,再加入326mg对硝基苄溴和492mg碳酸铯,反应液在50℃下反应5-6小时,TLC示底物完全消失,停止反应并将反应液冷却至室温,反应液用乙酸乙酯萃取,有机层水洗3次后用无水硫酸钠干燥,浓缩,柱层析得455mg黄色晶体(化合物4)(收率80%)。1H NMR(400MHz,CDCl3)δ8.55(dd,J=6.8,2.4Hz,1H),8.22(s,1H),7.85–7.81(m,2H),7.75(t,J=2.8Hz,1H),7.67(d,J=8.7Hz,2H),7.61–7.55(m,3H),7.24(d,J=8.6Hz,2H),5.56(s,2H)。
步骤4:将377mg中间体化合物4溶于30ml异丙醇,依次加入1.01g硼酸频哪醇酯,280mg叔丁醇钾,110℃下反应过夜,TLC示底物完全消失,停止反应冷却至室温,反应用乙酸乙酯萃取,有机层水洗3次后无水硫酸钠干燥,浓缩,柱层析得312mg黄色晶体(化合物5)(收率90%)。
步骤5:将100mg中间体化合物5和86mg三光气溶于10ml无水二氯甲烷,氮气置换3次,冰浴下加入0.12ml三乙胺,5分钟后将0.12ml N,N-二甲基丁醇溶于10ml无水二氯甲烷,加入到反应液中,室温下过夜反应,TLC示底物完全消失,停止反应并将反应液冷却至室温,反应液用乙酸乙酯萃取,有机层水洗3次后用无水硫酸钠干燥,浓缩,柱层析得90mg黄色晶体(化合物I-1)(收率64%)。1H NMR(400MHz,CDCl3)δ8.56–8.52(m,1H),7.77(tt,J=8.6,3.6Hz,2H),7.72–7.68(m,1H),7.61–7.55(m,2H),7.49(d,J=8.5Hz,2H),7.37(d,J=7.7Hz,2H),7.24(t,J=8.6Hz,2H),5.43(s,2H),4.17(t,J=6.3Hz,2H),2.39(d,J=7.5Hz,2H),2.29(s,6H),1.69(dd,J=13.4,6.8Hz,2H),1.61(dd,J=10.2,5.2Hz,2H)。
以与实施例1相同的方法制备化合物I-2至化合物I-34:
实施例2:化合物II-1的制备
步骤1:采用实施例1相同的方法制备得到中间体化合物5;
步骤2:将70mgN,N-二甲基丁酸溶于20ml无水二氯甲烷中,再加入0.15ml草酰氯和一滴DMF,反应液在0℃下反应5-6小时,停止反应浓缩,将反应液溶于无水THF,滴入到143mg实施例1制备得到的中间体化合物5与0.118ml三乙胺THF溶液中,反应液在0℃下过夜反应,TLC监测反应完毕,浓缩柱层析得90mg黄色晶体(II-1)(收率47%)。 1H NMR(400MHz,CDCl3)δ9.86(s,1H),8.51(dd,J=6.8,2.5Hz,1H),7.76(ddt,J=9.8,7.1,3.4Hz,2H),7.69(dt,J=6.5,3.2Hz,1H),7.56(ddd,J=17.4,8.7,5.3Hz,4H),7.47(d,J=8.5Hz,2H),7.26–7.19(m,2H),5.42(s,2H),2.51(dd,J=14.2,7.3Hz,4H),2.37(s,6H),1.94–1.86(m,2H).
以与实施例2相同的方法制备化合物II-2至II-9:
实施例3:化合物III-48的制备
步骤1:将220mg一氯酞嗪酮溶于20ml N,N-二甲基甲酰胺(DMF)中,再加入252mg溴甲基苯甲酸甲酯和359mg碳酸铯,反应液在50℃下反应5-6小时,TLC示底物完全消失,停止反应并将反应液冷却至室温,反应液用乙酸乙酯萃取,有机层水洗3次后用无水硫酸钠干燥,浓缩,柱层析得300mg黄色晶体(化合物9)(收率84.2%)
步骤2:将:300mg中间体化合物9溶于30ml THF/H2O(5:1)中,再加入97mg水合氢氧化锂,反应液在室温下过夜反应,TLC示底物完全消失,反应液浓缩,柱层析得150mg黄色晶体(化合物10)(收率52%)
步骤3:将:150mg中间体化合物10溶于20ml无水二氯甲烷中,再加入0.12ml草酰氯和一滴DMF,反应液在0℃下反应5-6小时,停止反应浓缩,将反应液溶于无水THF,滴入到0.081ml N,N-二甲基丁胺与0.104ml三乙胺THF溶液中,反应液在0℃下过夜反应,TLC监测反应完毕,浓缩柱层析得90mg黄色晶体(化合物11)(收率46%)。
步骤4:将90mg化合物11溶于20ml二氧六环和4ml水,依次加入40mg对氟苯硼酸,9mg邻苯二茂铁二氯化钯,79mg碳酸铯,氮气置换3次,100℃下反应过夜,TLC示底物完全消失,停止反应冷却至室温,反应用乙酸乙酯萃取,有机层水洗3次后无水硫酸钠干燥,浓缩,柱层析得黄色晶体III-48(收率30%)。1H NMR(400MHz,CDCl3)δ8.46(dd,J=7.7,1.1Hz,1H),8.02–7.96(m,1H),7.86(dtd,J=17.7,7.3,1.4Hz,2H),7.36(d,J=8.4Hz,2H),6.66(d,J=8.5Hz,2H),5.27(s,2H)。
以与实施例3相同的方法制备化合物III-1至III-14以及III-21至III-47:
实施例4:化合物III-15的制备
步骤1:在氮气保护下将1g对溴氟苯溶于20ml无水THF,在零下20℃下缓慢滴加5.71ml 1M异丙基溴化镁的THF溶液,室温下搅拌1h,将948mg 2-氟邻苯二甲酸酐在氮气保护下溶于10ml无水THF,在零下40℃下将前一步的反应液缓慢滴入,室温过夜反应。TLC监测反应完毕,用NH4Cl饱和溶液淬灭反应,EA/H2O萃取,无水硫酸钠干燥,有机层旋干,将残留物溶于20ml乙醇,加入571mg水合肼(50%),回流3h,浓缩柱层析得730mg黄色晶体(化合物12)(收率49%)。
步骤2:其它步骤参考实施例3,得III-15。(H NMR(400MHz,CDCl3)δ8.33(dd,J=8.4,5.0Hz,1H),7.95–7.83(m,4H),7.64(dd,J=8.0,2.7Hz,1H),7.49(dt,J=8.4,1.0Hz,2H),7.38(td,J=8.2,2.7Hz,1H),5.42(t,J=1.0Hz,2H),3.45–3.38(m,2H),2.61(d,J=0.7Hz,3H),2.49–2.42(m,2H),2.24(s,6H),1.59–1.49(m,4H)).
以与实施例4相同的方法制备化合物III-16至III-20:
测试例1:用于测试本发明实施例中制得的化合物对登革热病毒RNA复制能力的影响
1.实验材料:
1.1细胞株:
Huh7细胞株(中科院上海药物研究所提供);
1.2病毒株:
登革病毒Ⅱ型D2Y98PT病毒株(Dengue 2virus D2Y98PT Strain)储存液,中科院上海药物研究所实验室保存,PBS缓冲液,保存于-80℃。病毒储存液滴度为2×107PFU/mL(BHK细胞测定)。
1.3细胞培养试剂及耗材:
FBS(Hyclone);DMEM高糖培养基(Gibco);96-well Cell Culture Plate(Corning);MTT(Sigma);MTT检测裂解液(中科院上海药物研究所配制);二甲亚砜(DMSO,国药);
1.4培养上清中病毒RNA提取和检测相关试剂和仪器:
Qiasymphony SP/AS instructment(Qiagen);Quantitect Virus One-step qRT-PCR Kit(Qiagen);DMSO(Sigma);Ⅱ型登革病毒特异性引物及Taqman探针(Invitrogen);Optical 96-well Reaction Plate(ABI);ABI Fast-7500Real-TimePCR Systems(ABI);
2.实验流程及方法:
2.1化合物的配制:
2.1.1阳性对照化合物的配制:
阳性对照化合物为2'-C-methyladenosine(CAS No.:818374-78-6,以下简称为2MeA),中科院药物研究所合成。HPLC纯度≧98%。
取2MeA粉末并精密称量其质量,使用DMSO为溶剂,将化合物按下述公式计算得到的溶剂体积溶解至40mM。
溶解后的阳性对照化合物2MeA置于4℃保存。
2.1.2送检化合物的配制:
取送检化合物粉末2~5mg并精密称量其质量(mg),使用DMSO为溶剂,按前述公式将化合物溶解至40mM。溶解后的化合物置于4℃保存。
2.2化合物的稀释:
2.2.1首次送检化合物的稀释:
取溶解后化合物1.6μL加入至198.4μL含2%FBS的DMEM培养液中,作为第一个稀释浓度,随后从第一个稀释浓度中取出50μL加入至150μL 2%FBS DMEM培养液中,并以此梯度稀释,稀释至所需浓度梯度。同时,预留一个无化合物的稀释浓度作为对照。
2.2.2复测化合物的稀释:
复测化合物根据所需浓度范围,取40mM浓度的化合物储备液,加入DMSO稀释至所需起始浓度,并取1.6μL加入至198.4μL含2%FBS的DMEM培养液中,建立实验所需的第一个稀释浓度,并按前述方法继续建立浓度梯度。同时预留一个无化合物对照。
2.3.Huh7细胞的铺种、感染及化合物加样:
2.3.1Huh7细胞的铺种:
取健康传代的体外培养Huh7细胞,弃培养液,用PBS润洗培养皿细胞两遍并弃去PBS溶液。加入1mL胰酶溶液,37℃消化至轻叩培养皿细胞即脱落。向培养皿中加入1mL 10%FBS DMEM培养液,并温柔吹吸细胞悬液至细胞悬液均匀分散。收取所有细胞悬液至10mLDMEM培养液中,300×g离心沉淀细胞。离心后弃去上清培养液,重新加入适量2%FBS DMEM培养液并悬浮细胞沉淀至均匀分散的细胞悬液。取适量细胞悬液于显微镜下计数。计数后,细 胞浓度调整至4×105个/mL,悬于2%FBS DMEM培养液中,以100μL/well铺种于96孔培养板中,于37℃,5%CO2培养箱中过夜培养。
2.3.2登革病毒的感染:
次日,取铺种的Huh7细胞,加入50μL登革病毒感染Huh7细胞(MOI=0.1),于培养箱中孵育2小时,建立病毒感染。
病毒感染后,用新鲜2%FBS DMEM洗涤细胞两遍,并最终置换为150μL 2%FBSDMEM培养液。
2.3.3受检化合物的加样:
将化合物梯度稀释液(及每个化合物对应的无化合物对照梯度)按适当的排布方式,每孔50μL加入至96孔细胞培养板中。
若按照前述章节2.2.1中所述首次送检化合物的稀释方法,最终化合物与细胞相互作用浓度梯度分别为:80,20,5,1.25,0.3125,0μM。
加入化合物后,96孔培养板继续置于培养箱中培养48小时。
2.4化合物抗病毒活性检测及细胞毒性检测
2.4.1化合物的细胞毒性检测
预先配置1%(w/v)MTT溶液于PBS溶液中。
Huh7细胞培养48小时后从培养箱中取出,吸取所有细胞培养上清,合并复孔样品,向培养孔中加入100μL MTT溶液,于培养箱中孵育1小时。
一小时后每孔加入100μL MTT溶解液,于37℃培养箱中裂解过夜以释放MTT代谢产物,次日于酶标仪上测定570nM吸光度,以无细胞培养基孔做空白对照,以无化合物对照孔OD@570度数为100%基准,计算各孔细胞相对存活率。并以此计算CC50数值。
2.4.2化合物的抗病毒活性检测
细胞培养上清合并复孔后,使用Qiasymphony SP/AS核酸自动纯化工作站提取上清中病毒核酸,并建立一步法qRT-PCR反应体系,设置已知浓度的登革病毒基因组RNA标准品建立定量标准曲线,于ABI 7900HT实时定量荧光PCR仪上定量检测培养上清中病毒核酸含量。
通过标准曲线对培养上清中病毒RNA含量进行绝对定量。以无化合物的病毒阳性对照孔RNA拷贝数为100%基准,计算各化合物剂量下的病毒复制抑制率,并以此计算IC50数值。
实验结果的质量控制
本试验质量控制以同步实验的参考化合物2MeA的IC50数值及培养上清中病毒RNA的qRT-PCR实验结果参数为主要质量控制依据。其中:参考化合物2MeA在本实验室的最近一年的IC50(μM)为:1.2819±0.5598(Mean±SD);病毒RNA之qRT-PCR实验结果中,标准曲线回归系数R2≥0.990;满足以上条件则视为实验成功。
实验结果:实验结果如表1所示。
表1:实施例的化合物对Huh7细胞的毒性和抑制登革热病毒活性
注:CC50为实施例的化合物对Huh7细胞的生长的影响,半数(50%)致死浓度。IC50为实施例的化合物对登革热病毒RNA复制的抑制达半数(50%)时的浓度。
从测试例1的测试结果可以看出,实施例化合物的IC50均小于10μM,都具有抑制登革热病毒RNA复制的活性,CC50较高,对Huh7细胞的毒性较小,选择性好。
Claims (10)
1.一种式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物:
其中,
A选自芳基或杂芳基;
R1、R2各自独立地为H、烷基,或R1和R2一起表示(CH2)x,x为选自2、3、4或5,优选选自4或5;其中1-3个CH2基团可以被NH、O代替;优选地,其中1-2个CH2基团可以被NH、O代替;
R3表示一个或多个取代基,其各自独立地选自H、卤素、氰基、羟基、烷基、卤代烷基、环烷基、杂环基、烷氧基、杂链烃基、烷基磺酰基、-N(Q1)(Q2)、
R4选自-NHCOLR7或-COLR7;优选R4为-NHCOOL’R7、-NHCOL’R7、-NHCONHL’R7或-CONHL’R7;
R5表示一个或多个取代基,其各自独立地选自H、卤素、氰基、羟基、烷基、卤代烷基、烷氧基;
各个R6各自独立地选自H、羟基、烷基、环烷基、烷氧基、杂环基、-N(Q1)(Q2);
各个L为任选被卤素取代的亚烷基或任选被卤素取代的亚杂链烃基;
各个L’为任选被卤素取代的亚烷基;
各个R7各自独立地选自H、羟基、烷基、环烷基、烷氧基、卤素、任选取代的杂环基、-N(Q1)(Q2);所述“任选取代的杂环基”中的取代基为烷基;
各个Q1、Q2各自独立地为H或烷基;
n为选自0至10的整数;优选地,为选自0至7的整数,优选地,为选自0至5的整数;
优选地,
所述“芳基”为5-10元芳基;优选地,所述芳基为苯基、萘基;
所述“杂芳基”为含有1-3个选自N、O和S中的杂原子的5-10元杂芳基;优选地,为含有1-2个选自N、O和S中的杂原子的5-10元杂芳基;优选地,所述杂芳基选自吡啶基、吡咯基、嘧啶基、吡嗪基、哒嗪基、噻吩基、呋喃基、2,4-二甲基吡唑基、N-甲基吡唑基、咪唑基、噁唑基、噻唑基、吲哚基、氮杂吲哚基、萘啶基、喹啉基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-a]嘧啶基;
R3表示1个、2个或3个取代基;
R5表示1个或2个取代基;
所述“卤素”选自氟、氯、溴或碘;
所述“烷基”、“卤代烷基”“烷基磺酰基”中的烷基为C1-C10直链或支链烷基,优选地,为C1-C7直链或支链烷基,优选地,为C1-C5直链或支链烷基,优选地,选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基,1-甲基丁基、2-甲基丁基、3-甲基丁基、异戊基、1-乙基丙基、新戊基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、正庚基、2-甲基己基、3-甲基己基、2,2-二甲基戊基、3,3-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3-乙基戊基或2,2,3-三甲基丁基;优选地,选自甲基、乙基、丙基、异丙基、丁基或异丁基;
所述“亚烷基”为C1-C10直链或支链亚烷基,优选为C1-C6直链或支链亚烷基,更优选为C1-C4直链或支链亚烷基,更优选亚正丁基;
优选地,所述“卤代烷基”选自三氟甲基;
所述“烷氧基”为C1-C6直链或支链烷氧基,优选地,所述烷氧基为C1-C5直链或支链烷氧基;优选地,所述烷氧基选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基、异己氧基或3-甲基戊氧基;
所述“环烷基”为C3-C6环烷基,优选地,所述环烷基选自环丙基、环丁基、环戊基或环己基;
所述“杂环基”中的杂环为环上含有1个、2个或3个选自N、O、S的杂原子的3-7元非芳香环,优选地,所述杂环基为环上含有1个或2个选自N、O的杂原子的3-6元非芳香环;
所述“杂链烃基”、“亚杂链烃基”中的杂链烃结构为C1-C7饱和或不饱和的、链上含1-5个选自N、O的杂原子的直链或支链的杂链结构,可选地,所述杂链烃结构为C1-C5饱和或不饱和的、链上含1个、2个或3个选自N、O的杂原子的直链或支链杂链烃结构,可选地,所述杂链烃结构为C1-C5饱和或不饱和的、链上含1个、2个或3个O的直链或支链杂链烃结构。
2.根据权利要求1所述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其中,
A为苯基、N-甲基吡唑基、吡啶基、嘧啶基、吲哚基、吡嗪基、氮杂吲哚基、喹啉基、咪唑并[1,2-a]吡啶基、咪唑并[1,2-a]嘧啶基;
R1、R2各自独立地选自H或甲基;
R3表示1个、2个或3个取代基,其各自独立地选自H、氟、氯、氰基、羟基、甲基、异丙基、甲氧基、甲磺酰基、三氟甲基、氮杂环丁基、甲氨基、N,N-二甲氨基、
n为选自0、1或2;
各个R6各自独立地选自H、甲基、羟基、环丙基或吗啉基;
R4选自-NHCOOL’R7、-NHCOL’R7、-NHCONHL’R7或-CONHL’R7;
各个L’为亚正丁基;
各个R7各自独立地选自H、羟基、氯、甲氧基、吗啉基、4-甲基哌啶基、N,N-二甲氨基;
R5表示1个或2个取代基,其各自独立地选自H、氟、甲基、氰基、三氟甲基、甲氧基。
3.根据权利要求1或2所述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其中,
所述异构体包括一种或多种光学异构体、对映异构体、非对映异构体或消旋体混合物;
所述药学上可接受的盐包括式I化合物的阴离子盐和阳离子盐;
优选地,所述药学上可接受的盐包括式I化合物的碱金属的盐、碱土金属的盐、铵盐;优选地,所述碱金属包括钠、钾、锂、铯,所述碱土金属包括镁、钙、锶;
优选地,所述药学上可接受的盐包括式I化合物与有机碱形成的盐;优选地,所述有机碱包括三烷基胺、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲氨基吡啶、二甲基苯胺、N-烷基吗啉、1,5-二氮杂双环[4.3.0]壬烯-5(DBN)、1,8-二氮杂双环[5.4.0]十一碳烯-7(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO);优选地,所述三烷基胺包括三甲胺、三乙胺、N-乙基二异丙胺;优选地,所述N-烷基吗啉包括N-甲基吗啉;
优选地,所述药学上可接受的盐包括式I化合物与酸形成的盐;优选地,所述酸包括无机酸、有机酸;优选地,所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸;优选地,所述有机酸包括甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、谷氨酸、双羟萘酸;
所述溶剂化物为式I化合物与药学上可接受的溶剂形成的配合物;优选地,所述药学上可接受的溶剂包括水,乙醇,乙酸,N,N-二甲基甲酰胺,二甲基亚砜;优选地,所述药学上可接受的溶剂为水。
4.根据权利要求1-3任一项所述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,其中,所述式I化合物为下列化合物之一:
5.制备权利要求1-4中任一项所述式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物的方法,通过以下线路1或线路2进行制备:
路线1:
化合物a-1通过Suzuki偶联反应制得化合物I,
其中,R1、R2、R3、R4、R5、A的定义与权利要求1-4中任一项的定义相同;
路线2:
化合物b-1和化合物b-2通过亲核取代反应制得化合物I,
其中,R1、R2、R3、R4、R5、A的定义与权利要求1-4中任一项的定义相同。
6.根据权利要求5所述的方法,其中,所述式I化合物为化合物5或化合物11,分别通过以下线路a或线路b进行制备:
路线a:
通式H1所示的化合物,水解后得到通式H2所示的化合物,通式H2所示的化合物与卤代物H3进行亲核取代反应得到通式H4所示的化合物,然后在金属催化剂或者碱的作用下,通过Suzuki偶联反应,得到通式H5所示的酞嗪酮类化合物,最后与各类胺或者酸发生缩合反应得到通式H6所示的化合物;
其中,R为氨基或羧基;A、R1、R2、R3、R4的定义与权利要求1-4中任一项的定义相同;
路线b:
通式H7所示的化合物先被制备成通式H8所示的格式试剂后,与邻苯二甲酸酐加成反应得到通式H9所示的化合物,通式H9所示的化合物与水合肼关环得到通式H10所示的化合物,通式H10所示的化合物与对卤代物进行亲核取代反应得到通式H11所示的酞嗪酮类化合物,最后H11所示的酞嗪酮类化合物与各类胺或者酸发生缩合反应得到通式H12所示的化合物;
其中,R为氨基或羧基;R1、R2、R3、R4、R5的定义与权利要求1-4中任一项的定义相同;
优选地,所述的水解反应在酸性或碱性条件下在溶剂中进行;所述酸性条件所采用的酸为选自醋酸、盐酸、硫酸、三氟乙酸中的一种或多种;所述碱性条件所采用的碱为选自氢氧化钾、氢氧化钠、乙酸钾、乙酸钠、叔丁醇钾、叔丁醇钠中的一种或多种;所述溶剂为选自乙醇、甲醇、水、乙酸中的一种或多种;
优选地,所述的亲核取代反应在碱存在下在溶剂中进行;所述碱为选自碳酸钾、碳酸铯、氢化钠、氢化钾、叔丁醇钾、叔丁醇钠或氢氧化钠中的一种或多种;所述溶剂为选自乙腈、N,N-二甲基甲酰胺或四氢呋喃中的一种或多种;
优选地,所述的Suzuki偶联反应在溶剂中,在金属催化剂、碱及配体存在下在加热条件下进行;所述溶剂选自N,N-二甲基甲酰胺、甲苯或1,4-二氧六环;所述碱为选自碳酸铯、碳酸钾、叔丁醇钾和叔丁醇钠中的一种或多种;所述金属催化剂为选自醋酸钯、Pd(PPh3)4或Pd(dppf)2Cl2中的一种或多种;所述配体为选自三苯基膦、1,1'-双(二苯基膦)二茂铁、联萘二苯基膦、2-二环己基膦-2′,6′-二甲氧基-联苯和2-二环己膦基-2'-(N,N-二甲胺)-联苯中的一种或多种;
优选地,上述制备的格式试剂为镁盐、铁盐、铜盐、锌盐或锂盐。
7.一种药物组合物,其包含权利要求1-4中任一项所述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物中的一种或多种以及任选存在的药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其中,所述药物组合物的剂型为片剂、粉剂、颗粒剂、胶囊剂、糖浆、注射用剂。
9.权利要求1-4中任一项所述的中任一项所述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,或者权利要求7或8所述的药物组合物在制备预防和/或治疗登革热病毒感染的药物中的用途。
10.权利要求1-4中任一项所述的中任一项所述的式I化合物或其异构体或其药学上可接受的盐、酯、前药或溶剂合物,或者权利要求7或8所述的药物组合物在制备登革热病毒抑制剂中的用途。
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WO2020259539A1 (zh) * | 2019-06-25 | 2020-12-30 | 中国科学院上海药物研究所 | 4-吡啶取代酞嗪酮类化合物、其制备方法、药物组合物及用途 |
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