CN114761025A - PDIA4抑制剂及其用于抑制β细胞病变及治疗糖尿病的用途 - Google Patents
PDIA4抑制剂及其用于抑制β细胞病变及治疗糖尿病的用途 Download PDFInfo
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- CN114761025A CN114761025A CN202080082502.7A CN202080082502A CN114761025A CN 114761025 A CN114761025 A CN 114761025A CN 202080082502 A CN202080082502 A CN 202080082502A CN 114761025 A CN114761025 A CN 114761025A
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 17
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- 102100037089 Protein disulfide-isomerase A4 Human genes 0.000 title abstract description 47
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- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical compound [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- FNIHKDRPXSKDKE-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[[2-(3-methoxyphenyl)acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC(OC)=CC=C2)=O)=C1N)=O FNIHKDRPXSKDKE-UHFFFAOYSA-N 0.000 description 3
- HDAKGFRYQHEJLO-UHFFFAOYSA-N methyl 2-amino-5-(3-benzamidopropoxy)-4-methoxybenzoate Chemical compound COC(C(C(N)=C1)=CC(OCCCNC(C2=CC=CC=C2)=O)=C1OC)=O HDAKGFRYQHEJLO-UHFFFAOYSA-N 0.000 description 3
- YWHYVIRVBFAGCS-UHFFFAOYSA-N methyl 2-amino-5-[2-(1,3-dioxoisoindol-2-yl)ethoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCN(C(C2=CC=CC=C22)=O)C2=O)=C1N)=O YWHYVIRVBFAGCS-UHFFFAOYSA-N 0.000 description 3
- HIIVYKSUHGLXNL-UHFFFAOYSA-N methyl 2-amino-5-[3-(1,3-dioxoisoindol-2-yl)propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCN(C(C2=CC=CC=C22)=O)C2=O)=C1N)=O HIIVYKSUHGLXNL-UHFFFAOYSA-N 0.000 description 3
- CBBHNQRBCKOCLX-UHFFFAOYSA-N methyl 2-amino-5-[3-[(2,6-difluorobenzoyl)amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C(F)=CC=C2)=C2F)=O)=C1N)=O CBBHNQRBCKOCLX-UHFFFAOYSA-N 0.000 description 3
- CWLHXSNGKHIDSJ-UHFFFAOYSA-N methyl 2-amino-5-[3-[(2,6-dimethoxybenzoyl)amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C(OC)=CC=C2)=C2OC)=O)=C1N)=O CWLHXSNGKHIDSJ-UHFFFAOYSA-N 0.000 description 3
- LBHFHBJOXRGBIY-UHFFFAOYSA-N methyl 2-amino-5-[3-[(2-fluorobenzoyl)amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C=CC=C2)=C2F)=O)=C1N)=O LBHFHBJOXRGBIY-UHFFFAOYSA-N 0.000 description 3
- PEXNOYDTBICPEX-UHFFFAOYSA-N methyl 2-amino-5-[3-[(3-fluorobenzoyl)amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C2=CC(F)=CC=C2)=O)=C1N)=O PEXNOYDTBICPEX-UHFFFAOYSA-N 0.000 description 3
- QAMNGACIDYXTFJ-UHFFFAOYSA-N methyl 2-amino-5-[3-[[2-(2-chlorophenyl)acetyl]amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=CC=C2)=C2Cl)=O)=C1N)=O QAMNGACIDYXTFJ-UHFFFAOYSA-N 0.000 description 3
- CUFYWRFLPKKCSE-UHFFFAOYSA-N methyl 2-amino-5-[3-[[2-(2-fluorophenyl)acetyl]amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=CC=C2)=C2F)=O)=C1N)=O CUFYWRFLPKKCSE-UHFFFAOYSA-N 0.000 description 3
- HVNRJMLOYDRLJA-UHFFFAOYSA-N methyl 2-amino-5-[4-(1,3-dioxoisoindol-2-yl)butoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCCN(C(C2=CC=CC=C22)=O)C2=O)=C1N)=O HVNRJMLOYDRLJA-UHFFFAOYSA-N 0.000 description 3
- MFBPGQHSZJXVBE-UHFFFAOYSA-N methyl 4-methoxy-2-nitro-5-[3-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC=C(C(F)(F)F)C=C2)=O)=C1[N+]([O-])=O)=O MFBPGQHSZJXVBE-UHFFFAOYSA-N 0.000 description 3
- GCINJZKBBZPKMT-UHFFFAOYSA-N methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OCCCCl)=C(OC)C=C1[N+]([O-])=O GCINJZKBBZPKMT-UHFFFAOYSA-N 0.000 description 3
- ZSEDOLHIPVJGSN-UHFFFAOYSA-N methyl 5-[2-(1,3-dioxoisoindol-2-yl)ethoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCN(C(C2=CC=CC=C22)=O)C2=O)=C1[N+]([O-])=O)=O ZSEDOLHIPVJGSN-UHFFFAOYSA-N 0.000 description 3
- BAVDFKQPUFZRAX-UHFFFAOYSA-N methyl 5-[3-(1,3-dioxoisoindol-2-yl)propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCN(C(C2=CC=CC=C22)=O)C2=O)=C1[N+]([O-])=O)=O BAVDFKQPUFZRAX-UHFFFAOYSA-N 0.000 description 3
- RKKDKGAHYOVUAQ-UHFFFAOYSA-N methyl 5-[3-[(2,6-dimethoxybenzoyl)amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C(OC)=CC=C2)=C2OC)=O)=C1[N+]([O-])=O)=O RKKDKGAHYOVUAQ-UHFFFAOYSA-N 0.000 description 3
- SCFUBGMXBZQVEG-UHFFFAOYSA-N methyl 5-[4-(1,3-dioxoisoindol-2-yl)butoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCCN(C(C2=CC=CC=C22)=O)C2=O)=C1[N+]([O-])=O)=O SCFUBGMXBZQVEG-UHFFFAOYSA-N 0.000 description 3
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- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 3
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
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- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- UPVUQELOASQBMY-UHFFFAOYSA-N methyl 2-amino-3,4,5-trimethoxybenzoate Chemical compound COC(=O)C1=CC(OC)=C(OC)C(OC)=C1N UPVUQELOASQBMY-UHFFFAOYSA-N 0.000 description 2
- QQFHCCQSCQBKBG-UHFFFAOYSA-N methyl 2-amino-4,5-dimethoxybenzoate Chemical compound COC(=O)C1=CC(OC)=C(OC)C=C1N QQFHCCQSCQBKBG-UHFFFAOYSA-N 0.000 description 2
- OTDAWMYBEJWVQV-UHFFFAOYSA-N methyl 2-amino-4,5-dipropoxybenzoate Chemical compound CCCOC(C(OCCC)=C1)=CC(C(OC)=O)=C1N OTDAWMYBEJWVQV-UHFFFAOYSA-N 0.000 description 2
- MIEGAZWFLDCDKN-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propoxy]benzoate Chemical compound CC(C)(C)OC(NCCCOC(C(OC)=C1)=CC(C(OC)=O)=C1N)=O MIEGAZWFLDCDKN-UHFFFAOYSA-N 0.000 description 2
- RITWQRJWGZJPDO-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[(4-methoxybenzoyl)amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C=C2)=CC=C2OC)=O)=C1N)=O RITWQRJWGZJPDO-UHFFFAOYSA-N 0.000 description 2
- WVCSSXNQWLLVPW-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[[2-(4-methoxyphenyl)acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=C2)=CC=C2OC)=O)=C1N)=O WVCSSXNQWLLVPW-UHFFFAOYSA-N 0.000 description 2
- IPHZYVDYUULSHQ-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=C(C(F)(F)F)C=CC=C2)=O)=C1N)=O IPHZYVDYUULSHQ-UHFFFAOYSA-N 0.000 description 2
- IHKUCKGJXMDXKJ-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC(C(F)(F)F)=CC=C2)=O)=C1N)=O IHKUCKGJXMDXKJ-UHFFFAOYSA-N 0.000 description 2
- HJHNYUUHGDHWNV-UHFFFAOYSA-N methyl 2-amino-4-methoxy-5-[3-[[2-[4-(trifluoromethyl)phenyl]acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC=C(C(F)(F)F)C=C2)=O)=C1N)=O HJHNYUUHGDHWNV-UHFFFAOYSA-N 0.000 description 2
- IURBKQKPIFBPIF-UHFFFAOYSA-N methyl 2-amino-5-(2-benzamidoethoxy)-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCNC(C2=CC=CC=C2)=O)=C1N)=O IURBKQKPIFBPIF-UHFFFAOYSA-N 0.000 description 2
- MHLMKUNIQFGHRC-UHFFFAOYSA-N methyl 2-amino-5-[3-[(4-fluorobenzoyl)amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C=C2)=CC=C2F)=O)=C1N)=O MHLMKUNIQFGHRC-UHFFFAOYSA-N 0.000 description 2
- QTPMCIFTGJHDKC-UHFFFAOYSA-N methyl 2-amino-5-[3-[[2-(3-chlorophenyl)acetyl]amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC(Cl)=CC=C2)=O)=C1N)=O QTPMCIFTGJHDKC-UHFFFAOYSA-N 0.000 description 2
- BSSULYLDVNIXIF-UHFFFAOYSA-N methyl 2-amino-5-[3-[[2-(3-fluorophenyl)acetyl]amino]propoxy]-4-methoxybenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC(F)=CC=C2)=O)=C1N)=O BSSULYLDVNIXIF-UHFFFAOYSA-N 0.000 description 2
- HCEIEWYPDCDNNU-UHFFFAOYSA-N methyl 3,4,5-trimethoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=C(OC)C(OC)=C1[N+]([O-])=O HCEIEWYPDCDNNU-UHFFFAOYSA-N 0.000 description 2
- SYYKLKHBZGFKOC-UHFFFAOYSA-N methyl 4,5-dimethoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O SYYKLKHBZGFKOC-UHFFFAOYSA-N 0.000 description 2
- OYUOEQIUQQLQET-UHFFFAOYSA-N methyl 4-methoxy-2-nitro-5-[3-[[2-(3,4,5-trimethoxyphenyl)acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=C2OC)=CC(OC)=C2OC)=O)=C1[N+]([O-])=O)=O OYUOEQIUQQLQET-UHFFFAOYSA-N 0.000 description 2
- WIKZGOSHUOMNBX-UHFFFAOYSA-N methyl 4-methoxy-2-nitro-5-[3-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=C(C(F)(F)F)C=CC=C2)=O)=C1[N+]([O-])=O)=O WIKZGOSHUOMNBX-UHFFFAOYSA-N 0.000 description 2
- WXFLBRJWBKQJRU-UHFFFAOYSA-N methyl 4-methoxy-2-nitro-5-[3-[[2-[3-(trifluoromethyl)phenyl]acetyl]amino]propoxy]benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC(C(F)(F)F)=CC=C2)=O)=C1[N+]([O-])=O)=O WXFLBRJWBKQJRU-UHFFFAOYSA-N 0.000 description 2
- PFLKOVYPMSEQER-UHFFFAOYSA-N methyl 4-methoxy-5-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propoxy]-2-nitrobenzoate Chemical compound CC(C)(C)OC(NCCCOC(C(OC)=C1)=CC(C(OC)=O)=C1[N+]([O-])=O)=O PFLKOVYPMSEQER-UHFFFAOYSA-N 0.000 description 2
- ZRVMCAHKKICNEQ-UHFFFAOYSA-N methyl 4-methoxy-5-[3-[(4-methoxybenzoyl)amino]propoxy]-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C=C2)=CC=C2OC)=O)=C1[N+]([O-])=O)=O ZRVMCAHKKICNEQ-UHFFFAOYSA-N 0.000 description 2
- UFGWFZYHDQEAEZ-UHFFFAOYSA-N methyl 4-methoxy-5-[3-[[2-(3-methoxyphenyl)acetyl]amino]propoxy]-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC2=CC(OC)=CC=C2)=O)=C1[N+]([O-])=O)=O UFGWFZYHDQEAEZ-UHFFFAOYSA-N 0.000 description 2
- NOYGHSBICSYLPQ-UHFFFAOYSA-N methyl 4-methoxy-5-[3-[[2-(4-methoxyphenyl)acetyl]amino]propoxy]-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=C2)=CC=C2OC)=O)=C1[N+]([O-])=O)=O NOYGHSBICSYLPQ-UHFFFAOYSA-N 0.000 description 2
- IBMHYZWSCBAQSZ-UHFFFAOYSA-N methyl 5-(2-aminoethoxy)-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCN)=C1[N+]([O-])=O)=O IBMHYZWSCBAQSZ-UHFFFAOYSA-N 0.000 description 2
- PDBUGLHBGTVQHG-UHFFFAOYSA-N methyl 5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OCCCl)=C(OC)C=C1[N+]([O-])=O PDBUGLHBGTVQHG-UHFFFAOYSA-N 0.000 description 2
- AIQQUBOJMCQDDN-UHFFFAOYSA-N methyl 5-(3-aminopropoxy)-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCN)=C1[N+]([O-])=O)=O AIQQUBOJMCQDDN-UHFFFAOYSA-N 0.000 description 2
- POOHALPQYUWVTK-UHFFFAOYSA-N methyl 5-(3-benzamidopropoxy)-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C([N+]([O-])=O)=C1)=CC(OCCCNC(C2=CC=CC=C2)=O)=C1OC)=O POOHALPQYUWVTK-UHFFFAOYSA-N 0.000 description 2
- YQDWJXFMWYORHL-UHFFFAOYSA-N methyl 5-[3-[(2,6-difluorobenzoyl)amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C(F)=CC=C2)=C2F)=O)=C1[N+]([O-])=O)=O YQDWJXFMWYORHL-UHFFFAOYSA-N 0.000 description 2
- GQCCELVKMBHZFC-UHFFFAOYSA-N methyl 5-[3-[(2-fluorobenzoyl)amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C=CC=C2)=C2F)=O)=C1[N+]([O-])=O)=O GQCCELVKMBHZFC-UHFFFAOYSA-N 0.000 description 2
- JLRMMBCARUDMBL-UHFFFAOYSA-N methyl 5-[3-[(3-fluorobenzoyl)amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C2=CC(F)=CC=C2)=O)=C1[N+]([O-])=O)=O JLRMMBCARUDMBL-UHFFFAOYSA-N 0.000 description 2
- HIQQFEDMGPKSIG-UHFFFAOYSA-N methyl 5-[3-[(4-fluorobenzoyl)amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(C(C=C2)=CC=C2F)=O)=C1[N+]([O-])=O)=O HIQQFEDMGPKSIG-UHFFFAOYSA-N 0.000 description 2
- GVZKMVMJYISDIR-UHFFFAOYSA-N methyl 5-[3-[[2-(2-chlorophenyl)acetyl]amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=CC=C2)=C2Cl)=O)=C1[N+]([O-])=O)=O GVZKMVMJYISDIR-UHFFFAOYSA-N 0.000 description 2
- SLNDAJVBISCTKC-UHFFFAOYSA-N methyl 5-[3-[[2-(2-fluorophenyl)acetyl]amino]propoxy]-4-methoxy-2-nitrobenzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCNC(CC(C=CC=C2)=C2F)=O)=C1[N+]([O-])=O)=O SLNDAJVBISCTKC-UHFFFAOYSA-N 0.000 description 2
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- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
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Images
Classifications
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- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/34—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having amino groups and esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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- A61K31/13—Amines
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
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Abstract
本发明揭示蛋白质二硫键异构酶A4(PDIA4)抑制剂及其用于抑制胰脏β细胞病变及治疗糖尿病的用途。鉴别出抑制PDIA4的IC50值在4μM至300nM范围内的候选药物。该等化合物在增强胰脏β细胞分泌胰岛素方面具有高活性。代表性化合物第8号(4,5‑二甲氧基‑2‑丙炔酰胺基苯甲酸)单独或与二甲双胍的复合治疗可有效地保留胰脏β细胞功能、治疗及/或逆转糖尿病,将糖尿病患者的血糖浓度恢复至正常水平。
Description
【技术领域】
本发明大体上涉及PDIA4抑制剂。
【背景技术】
2型糖尿病(T2D)的特征在于周边胰岛素抗性、胰岛素分泌不足及β细胞渐进性损失。β细胞功能及质量衰减为T2D的中心标志。积累的数据表明,在早期阶段保持功能β细胞质量可延迟且逆转T2D。因此,鉴别出对β细胞功能异常及死亡起关键作用的因素可更好地了解β细胞病变及T2D发展且获得新的T2D治疗策略。
蛋白质二硫键异构酶(PDI)家族(21个成员)对细胞功能具有多种作用且据报导牵涉到感染、生育、凝血、免疫、肿瘤转移或细胞存活率/生长。蛋白质二硫键异构酶(PDI)家族对健康及疾病的作用未得到充分研究。蛋白质二硫键异构酶A3(PDIA3)及蛋白质二硫键异构酶A4(PDIA4)为此家族的两个成员。由于缺乏Pdia3、但不缺乏PDIA4的小鼠显示在胚胎阶段死亡,因此其功能可能并非冗余的。迄今为止,尚未开发出基于PDI的药物。
高度需要用于在早期糖尿病阶段保持β细胞功能及质量、从而可逆转T2D的方法。
【发明内容】
在一个方面中,本发明涉及一种式(I)化合物或其医药学上可接受的盐,
R1为-C(=O)OR6;
R2为H、(C1-C6)烷基、苯甲基,或-L-R11,其中L为一键或(C1-C6)亚烷基,且R11为苯基、卤基、二氧代异吲哚啉、-NR7R8,或-NR7-CO-R8;
R3为H、(C1-C6)烷基,或苯甲基;
R4为H或(C1-C6)烷氧基;
R5为H、(C1-C6)胺、硝基、-NR7R8,或-NR7-CO-R8;
X1及X2各自独立地为-O-、-S-或共价键;
R6为H、卤素、(C1-C6)烷基、(C1-C6)芳基、苯甲基、卤基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烃,其中n为1至6;
R7及R8各自独立地为H、(C1-C6)烷氧基、苯基、苯甲酰基、卤基苯甲酰基、苯甲基、羰基(C1-C6)炔烃、(C1-C6)炔烃、噁唑、噻唑或咪唑;其中(C1-C6)烷氧基、苯基、苯甲酰基及苯甲基中的每一者视情况独立地经一或多个选自F、Cl、Br、I、(C1-C6)烷氧基、(C1-C6)烷基或卤基(C1-C6)烷基的取代基取代;或R7及R8连同N原子一起形成苯甲酰亚胺酸。
在本发明的一个实施方式中,R6为H或(C1-C6)烷基、苯甲基、卤基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烃。
在本发明的另一个实施方式中,R2为(C1-C6)烷基,或-L-R11,其中L为(C1-C6)亚烷基,且R11为二氧代异吲哚啉、-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H、苯基、苯甲酰基、卤基苯甲酰基、苯甲基、羰基(C1-C6)炔烃,或噁唑。
在另一个实施方式中,L为(C1-C6)亚烷基,且R11为-NR7-CO-R8。
在另一个实施方式中,L为(C1-C6)亚烷基,且R11为-NR7-CO-R8,其中R7为羰基(C1-C6)炔烃,R8为噁唑、噻唑或咪唑。
在另一个实施方式中,R11为1,3-二氧代异吲哚啉。
在本发明的另一个实施方式中,苯基、苯甲酰基及/或苯甲基各自独立地经一或多个选自F、Cl、Br、I或卤基(C1-C6)烷基的取代基取代。
在本发明的另一个实施方式中,R5为-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H或羰基(C1-C6)炔烃。
在本发明的另一个实施方式中,R5为硝基。
在本发明的另一个实施方式中,R6为羰基(C1-C6)炔烃。
在本发明的另一个实施方式中,R2为-L-R11,其中L为(C1-C6)亚烷基,且R11为-NR7R8,其中R7及R8连同N原子一起形成苯甲酰亚胺酸。
在本发明的另一个实施方式中,R7及R8连同N原子一起形成苯甲酰亚胺酸。
在本发明的另一个实施方式中,R2为-L-R11,其中L为(C1-C6)亚烷基,R11为-NR7R8,或-NR7-CO-R8;R7为羰基(C1-C6)炔烃且R8为苯甲酰基。
在本发明的另一个实施方式中,R2为(C1-C6)烷基;R3为(C1-C6)烷基,R4为H;R5为-NR7-CO-R8,其中R7为H且R8为(C2)炔烃。
在本发明的另一个实施方式中,R5为-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H、羰基(C1-C6)炔烃,或(C1-C6)炔烃。
在本发明的另一个实施方式中,R2为-L-R11,其中L为(C1-C6)亚烷基,且R11为二氧代异吲哚啉或-NR7R8,其中R7及R8各自独立地为苯甲酰基,或羰基(C1-C6)炔烃。
在另一个实施方式中,本发明所述的化合物或其医药学上可接受的盐选自由表6中所列的化合物组成的群。
在另一方面中,本发明涉及一种医药组合物,其包含:本发明的化合物或其医药学上可接受的盐;及医药学上可接受的载剂或赋形剂。所述医药组合物可以进一步包含二甲双胍。
在另一方面中,本发明涉及一种医药组合物,其包含:(a)本发明的化合物或其医药学上可接受的盐;及(b)二甲双胍。
另外,在另一方面中,本发明涉及本发明的化合物或其医药学上可接受的盐或医药组合物的用途,其用于制造供在有需要的个体中增强胰脏β细胞分泌胰岛素、治疗糖尿病及/或逆转及恢复血糖浓度至正常水平的药剂。
本发明亦涉及本发明的化合物或其医药学上可接受的盐或医药组合物,其用于有需要的个体增强胰脏β细胞分泌胰岛素、治疗糖尿病及/或逆转及恢复血糖浓度至正常水平。
在一个实施方式中,本发明的化合物或其医药学上可接受的盐或医药组合物用于在有需要的个体中抑制PDIA4活性、抑制胰脏β细胞病变、治疗糖尿病及/或逆转及恢复血糖浓度至正常水平。
本发明亦涉及一种在有需要的个体中抑制胰脏β细胞病变、增强胰脏β细胞分泌胰岛素、治疗糖尿病及/或逆转及恢复血糖浓度至正常水平的方法,该方法包含向有需要的个体投与治疗有效量的本发明化合物或其医药学上可接受的盐或医药组合物。
又在另一方面中,本发明涉及一种抑制PDIA4活性的方法,该方法包含促使本发明的化合物或其医药学上可接受的盐与PDIA4接触且藉此抑制PDIA4活性。
此等及其他方面由以下较佳实施例的描述结合以下附图而将变得显而易见,但其中可进行变化及润饰而不悖离本发明的新颖构思的精神及范畴。
附图说明本发明的一或多个实施例,且与书面说明书一起用于解释本发明的原理。只要可能,则整个附图中使用相同的组件符号指示实施例的相同或类似组件。
【附图说明】
图1为流程图,其描述自苗头化合物至先导化合物及候选药物中筛选出PDIA4抑制剂。(A)流程,其描述使用分子对接、PDIA4生物分析及总体合成的组合,自苗头化合物至先导化合物及候选药物中筛选出PDIA4抑制剂的策略。(B)针对葡萄糖诱导的胰岛素分泌(GSIS)及细胞存活率进行的基于Min6胰岛细胞株的分析。(C)对于PDIA4抑制剂而言,使用糖尿病db/db小鼠。
图2显示了分子对接,表明所选PDIA4抑制剂与PDIA4活性模体(AM)之间存在相互作用。(A)AM 1、2及3表示第一、第二及第三CGHC域。硫、氮及氧原子分别以黄色、蓝色及红色显示。分别显示了CPD P1与PDIA4模型的氨基酸残基之间的氢键及疏水性相互作用。(B):类似于(A),分子对接表明所选CPD 8与PDIA4的活性模体(AM)之间存在相互作用。
图3显示候选药物对释放胰岛素的影响及细胞毒性。(A)候选药物对β细胞分泌胰岛素的影响。Min6细胞在氧饱和无血清克雷布斯-林格氏碳酸氢盐(Krebs-Ringerbicarbonate,KRB)缓冲液中培育30分钟,该缓冲液含有高葡萄糖(16.7mM)、CCF642及候选药物。收集上清液用于胰岛素ELISA分析。(B)将Min6细胞分别与PBS、CCF642及候选药物一起培育24小时。PBS洗涤之后,将WST-1添加至各孔中再培育20分钟。
图4显示CPD8本身及与二甲双胍的组合可治疗及逆转Leprdb/db小鼠的糖尿病。(A-B)将新发糖尿病Leprdb/db小鼠分组且用PBS媒剂(CTR)、西格列汀(sitagliptin)(STG,30mg/kg)、CPD8(2.5mg/kg)及CPD8(2.5mg/kg)与二甲双胍(960mg/kg)组合(CPD8+Met)治疗指定的时间。监测小鼠的空腹血糖(FBG(A))及餐后血糖(PBG(B))。值(n)为括号中所示的小鼠数目。
【具体实施方式】
代表性酰基包括乙酰基、丙酰基、丁酰基及苯甲酰基。
不介于两个字母或符号之间的破折号(“-”)用于指示部分或取代基的连接点。举例而言,部分-CONH2是经由碳原子连接的。
如本文所用,术语“酯”意谓含有经取代的羧酸的化合物(例如-COO-烷基)。
如本文所用,术语“磺酰基”表示具有式:-S(O)2-的基团。
术语“亚烷基”是指1至18个碳原子的饱和、分支链或直链或环状烃基团,其具有两个单价基团中心,该等中心由母体烷烃的相同或不同碳原子上移除两个氢原子而衍生。典型的亚烷基包括(但不限于)亚甲基(-CH2-)、1,2-亚乙基(-CH2CH2-)、1,3-亚丙基(-CH2CH2CH2-)、1,4-亚丁基(-CH2CH2CH2CH2-)及其类似基团。
术语“(Cm-Cn)”(其中m、n为整数且n>m)意谓特定地揭示m至n范围内的所有整数单元量作为本发明的一部分。因此,“(Cm-Cn)”意谓Cm、Cm+1、Cm+2、...、Cn-2、Cn-1、Cn、(Cm-Cm+1)、(Cm-Cm+2)、(Cm-Cm+3)、...、(Cm-Cn-2)、(Cm-Cn-1)、(Cm-Cn);(Cm+1-Cm+2)、(Cm+1-Cm+3)、(Cm+1-Cm+4)、...、(Cm+1-Cn-2)、(Cm+1-Cn-1)、(Cm+1-Cn)、...、(Cn-2-Cn-1)、(Cn-2-Cn);及(Cn-1-Cn)作为本发明的实施方式包括在内。
“(C1-C6)”意谓特定地揭示1至6范围内的所有整数单元量作为本发明的一部分。因此,C1、C2、C3、C4、C5、C6;(C1-C2)、(C1-C3)、(C1-C4)、(C1-C5)、(C1-C6);(C2-C3)、(C2-C4)、(C2-C5)、(C2-C6);(C3-C4)、(C3-C5)、(C3-C6);(C4-C5)、(C4-C6)及(C5-C6)单元量作为本发明的实施方式包括在内。
术语“治疗(treating/treatment)”是指向患有疾病或具有此类疾病的症状或有患此类疾病的倾向性的个体投与有效量的治疗剂,目的在于治愈、缓解、减轻、医治、改善或预防疾病、其症状或其倾向性。
由美国健康与人群服务部食品及药物管理局(U.S.Department of Health andHuman Services Food and Drug Administration)发布的“估计治疗剂在临床试验中在成年健康自愿者中的安全初始剂量的行业及审查者导引(Guidance for Industry andReviewers Estimating the Safe Starting Dose in Clinical Trials forTherapeutics in Adult Healthy Volunteers)”揭示“人类等效剂量”可藉由下式计算得到:
HED=动物剂量(mg/kg)×(动物体重(kg)/人体重(kg))0.33。
缩写:PDIA4:蛋白质二硫键异构酶家族成员A4;CCTB:碳/碳三键;IC50:半数最大抑制浓度。
本发明涉及发现用于治疗2型糖尿病的PDIA4抑制剂。将分子对接与PDIA4生物分析组合用于鉴别出基于PDIA4的苗头化合物。对先导化合物进行优化以改良其生物活性,直至候选药物的IC50值在nM范围内。
实施例
材料及方法
虚拟筛选
为了获得可靠的PDIA4作用模型,对来自蛋白质数据库的3IDV(人类PDIA4的催化域(残基53-284))、3EC3(大鼠PDIA4的非催化域(残基283-523))及3F8U(人类PDIA3的残基25-501)的A链进行多重序列比对。三种蛋白质序列与人类PDIA4分别共享100%、88%及42%同源性。PDIA4的同源模型使用Discovery Studio v.4.1产生且基于PDIA4的3IDV、3EC3及3F8U的A链的结晶学结构,其用作结构模板。使用CHARMM力场将来自内部工厂化学库的两百六十一种化合物转变成3D坐标以藉由Discovery Studio中的Prepare Ligand模块将化合物最小化。在pH 7.5下,将残基中的质子化状态调节成显性离子形式。使用PDIA4的第二CGHC模体的周围残基作为对接包,该第二CGHC模体由第一与第二活性域之间的结合包构成。使用GOLD v.5.1程序(CCDC Software Limited,Cambridge,UK)内的Goldscore执行化合物与PDIA4的第二活性域之间的分子对接。最后,在化合物的100种对接验证中,选择最佳候选物(具有较高的GOLD适合度分数)来探究PDIA4的第二活性域的“抑制键”验证。
化学方法
使用Bruker Fourier 300及AVIII 500频谱仪、使用标准plus程序获得NMR频谱(1H及13C NMR)。使用TMS作为内标,用百万分的分率(ppm,δ)列举化学位移。在Finnigan MatTSQ-7000质谱仪(ESIMS及HRESIMS)上量测MS资料。在Fisher-Johns设备(未校正)上记录熔点。藉由L-2130泵浦(Hitachi,Ibaraki,Japan)在C18管柱(150mm×4.6mm)上执行HPLC。在硅胶(70-230目,Merck,Darmstadt,Germany)上进行管柱层析。在硅胶盘(KG60-F254,Merck)上进行TLC分析。除非另外提及,否则所有化学品及材料依自市售供货商接收到的原样使用而不进行任何纯化。在N2下,自氢化钙中蒸馏出无水二氯甲烷。
流程1
试剂及条件:(i)HCl、MeOH、60℃;(ii)10%Pd-C、EtOAc、RT;(iii)丙炔酸、DCC、CH2Cl2、0℃。
4,5-二甲氧基-2-硝基苯甲酸甲酯(2)
向1(5.00g,22.00mmol)及K2CO3(12.17g,88.04mmol)于DMF(50mL)中的混合物中逐滴添加CH3I(5.48mL,88.04mmol)。所得溶液在N2下加热至100℃维持15小时。将反应混合物悬浮于H2O(150mL)中且接着用EtOAc(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩,得到固体。用MeOH洗涤该固体,得到2(5.22g,98%)。1H NMR(500MHz,CDCl3)δ7.43(s,1H),7.06(s,1H),3.96(s,3H),3.95(s,3H),3.89(s,3H)。
2-氨基-4,5-二甲氧基苯甲酸甲酯(3)
向2(5.22g,21.66mmol)于EtOAc(10mL)中的溶液中添加催化量的10%Pd/C(1g)。在室温下、在H2氛围下搅拌混合物8小时。用硅藻土过滤反应混合物且真空浓缩滤液。藉由硅胶层析(EtOAc/正己烷=1:9)纯化残余物,得到呈黄色固体状的3(3.00g,66%)。1H NMR(500MHz,CDCl3)δ7.27(s,1H),6.12(s,1H),5.55(s,2H),3.84(s,3H),3.83(s,3H),3.80(s,3H)。
4,5-二甲氧基-2-丙炔酰胺基苯甲酸甲酯(4)
在冰浴中,向3(50mg,0.24mmol)于无水CH2Cl2(10mL)中的溶液中逐滴添加含有丙炔酸(0.022mL,0.36mmol)及N,N'-二环己基碳二亚胺(73mg,0.36mmol)的无水CH2Cl2(5mL)。所得溶液在N2下搅拌2小时。将反应混合物悬浮于H2O(50mL)中且接着用CH2Cl2(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。过滤混合物且用EtOAc/正己烷=1:1(10mL)洗涤。藉由硅胶层析(EtOAc/正己烷=1:5)纯化残余物,得到4(57mg,91%)。1H NMR(500MHz,CDCl3)δ11.56(s,1H),8.31(s,1H),7.44(s,1H),3.93(s,3H),3.90(s,3H),3.87(s,3H),2.92(s,1H)。
流程2
试剂及条件:(i)DMAP、DCC、(CH3)3Si(CH2)2OH、THF、RT;(ii)10%Pd-C、EtOAc、H2、RT;(iii)丙炔酸、DCC、CH2CI2、0℃;(iv)TBAF、THF、RT。
4,5-二甲氧基-2-硝基苯甲酸2-(三甲基硅烷基)乙酯(5)
依循针对化合物4所述的程序,向1(100mg,0.44mmol)、N,N'-二环己基碳二亚胺(109mg,0.528mmol)及DMAP(5mg,0.04mmol)于无水THF(10mL)中的反应物中逐滴添加2-(三甲基硅烷基)乙醇(0.094mL,0.66mmol),得到5(59mg,41%)。1H NMR(300MHz,CDCl3)δ7.43(s,1H),7.05(s,1H),4.38(m,2H),3.06(s,3H),3.95(s,3H),1.08(m,2H),0.04(s,9H)。
2-氨基-4,5-二甲氧基苯甲酸2-(三甲基硅烷基)乙酯(6)
依循针对化合物3所述的程序,向5(100mg,0.31mmol)于EtOAc(10mL)中的反应物中添加催化量的10%Pd/C(10mg),得到6(41mg,45%)。1H NMR(300MHz,CDCl3)δ7.29(s,1H),6.12(s,1H),4.34(m,2H),3.84(s,3H),3.80(s,3H),1.10(m,2H),0.07(s,9H)。
4,5-二甲氧基-2-丙炔酰胺基苯甲酸2-(三甲基硅烷基)乙酯(7)
依循针对化合物4所述的程序,在冰浴中,向6(100mg,0.34mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.031mL,0.50mmol)及N,N'-二环己基碳二亚胺(104mg,0.50mmol)的无水CH2Cl2(5mL),得到7(108mg,92%)。1H NMR(300MHz,CDCl3)δ11.65(s,1H),8.32(s,1H),7.45(s,1H),4.41(m,2H),3.94(s,3H),3.87(s,3H),1.14(m,2H),0.08(s,9H)。
4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)
在室温下,向7(50mg,0.14mmol)于无水THF(4mL)中的溶液中逐滴添加TBAF(1M于THF中,0.43mL,0.43mmol)。所得溶液在N2下搅拌24小时。反应混合物用1N HCl(aq)(50mL)及EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(MeOH/CH2Cl2=3:97)纯化,得到8(30mg,84%)。1H NMR(500MHz,DMSO)δ11.87(s,1H),8.06(s,1H),7.45(s,1H),4.45(s,1H),3.80(s,3H),3.77(s,3H)。
流程3
试剂及条件:(i)10%Pd-C、EtOAc、H2、MeOH、RT;(ii)丙炔酸、DCC、CH2Cl2、0℃。
2-氨基-4,5-二甲氧基苯甲酸(9)
向1(5.00g,22.00mmol)于MeOH(20mL)中的溶液中添加催化量的10%Pd/C(1.5g)且在H2氛围下、在室温下搅拌混合物24小时。反应混合物用硅藻土过滤且真空浓缩,得到9(4.00g,92%)。1H NMR(500MHz,DMSO)δ7.14(s,1H),6.33(s,1H),3.73(s,3H),3.63(s,3H)。
2-氨基-4,5-二甲氧基苯甲酸丙炔酸酐(10)
依循针对化合物4所述的程序,在冰浴中,向9(500mg,2.54mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.234mL,3.81mmol)及N,N'-二环己基碳二亚胺(466mg,2.26mmol)的无水CH2Cl2(5mL),得到10(15mg,2%)。1H NMR(300MHz,CDCl3)δ7.50(s,1H),7.02(s,1H),3.97(s,3H),3.96(s,3H)。
流程4
试剂及条件:(i)BnBr、K2CO3、DMF、110℃;(ii)Zn、AcOH、50℃;(iii)丙炔酰氯、K2CO3、CH2Cl2、0℃。
5-(苯甲氧基)-4-甲氧基-2-硝基苯甲酸苯甲酯(12)
依循针对化合物2所述的程序,向11(439mg,2.00mmol)及K2CO3(710mg,5.15mmol)于DMF(20mL)中的反应物中添加苯甲基溴(0.61mL,5.15mmol)。所得溶液在N2下加热至110℃,得到12(807mg,99%)。1H NMR(500MHz,CDCl3)δ7.43(s,1H),7.34(m,10H),7.13(s,1H),5.30(s,2H),5.18(s,2H),3.96(s,3H)。
2-氨基-5-(苯甲氧基)-4-甲氧基苯甲酸苯甲酯(13)
向12(1.00g,2.54mmol)于HOAc(20mL)中的溶液中添加Zn(1.66g,25.44mmol)且在N2下将混合物加热至50℃维持24小时。利用硅藻土过滤反应混合物。将残余物溶解于EtOAc(50mL)中且接着用NaHCO3(3×50mL)洗涤。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:3)纯化,得到13(330mg,36%)。1H NMR(500MHz,CDCl3)δ7.37(m,11H),6.15(s,1H),5.64(s,2H),5.28(s,2H),5.04(s,2H),3.87(s,3H)。
5-(苯甲氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸苯甲酯(14)
在冰浴中,向13(500mg,1.37mmol)于无水CH2Cl2(30mL)中的溶液中逐滴添加丙炔酰氯(1.00g,11.36mmol)及K2CO3(475mg,3.44mmol)。所得溶液在0℃下、在N2下搅拌0.5小时。将反应混合物悬浮于H2O(50mL)中且接着用CH2Cl2(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:4)纯化,得到14(76mg,13%)。1H NMR(500MHz,CDCl3)δ11.52(s,1H),8.36(s,1H),7.56(s,1H),7.37(m,10H),5.33(s,2H),5.13(s,2H),4.71(s,1H),3.97(s,3H)。
流程5
试剂及条件:(i)LiOH、MeOH、80℃;(ii)丙炔酸、DCC、CH2Cl2、0℃。
2-氨基-5-(苯甲氧基)-4-甲氧基苯甲酸(15)
13(150mg,0.41mmol)及LiOH(100mg,2.30mmol)于MeOH(10mL)中的溶液在N2下加热至70℃维持18小时。将所得溶液酸化至pH 2且用1N HCl(50mL)及EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。使残余物再结晶,得到15(100mg,89%)。1HNMR(500MHz,CDCl3)δ7.43(s,1H),7.41(s,2H),7.35(t,J=7.4Hz,2H),7.28(t,J=7.3Hz,1H),6.12(s,1H),5.02(s,2H),3.85(s,3H)。
2-氨基-5-(苯甲氧基)-4-甲氧基苯甲酸丙炔酸酸酐(16)
依循针对化合物4所述的程序,在冰浴中,向15(250mg,0.92mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.084mL,0.92mmol)及N,N'-二环己基碳二亚胺(246mg,1.19mmol)的无水CH2Cl2(5mL),得到16(36mg,12%)。1H NMR(500MHz,CDCl3)δ7.57(s,1H),7.44(d,J=7.3Hz,2H),7.37(t,J=7.5Hz,2H),7.32(t,J=7.3Hz,1H),7.04(s,1H),5.21(s,2H),3.97(s,3H),3.20(s,1H)。
流程6
试剂及条件:(i)HNO3、AcOH、50℃;(ii)Zn、AcOH、50℃;(iii)丙炔酰氯、K2CO3、CH2Cl2、0℃。
3,4,5-三甲氧基-2-硝基苯甲酸甲酯(18)
向17(500mg,2.21mmol)于HOAc(4mL)中的溶液中添加HNO3(2mL)且在N2下加热至50℃维持1.5小时。将反应混合物悬浮于H2O(50mL)中且接着用EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:4)纯化,得到18(231mg,38%)。1H NMR(500MHz,CDCl3)δ7.25(s,1H),3.94(s,3H),3.93(s,3H),3.92(s,3H),3.85(s,3H)。
2-氨基-3,4,5-三甲氧基苯甲酸甲酯(19)
依循针对化合物13所述的程序,向18(1.00g,3.69mmol)于HOAc(20mL)中的反应物中添加Zn(2.41g,36.90mmol)且在N2下将混合物加热至50℃维持24小时。利用硅藻土过滤反应混合物。残余物用EtOAc(50mL)及NaHCO3(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:4)纯化,得到19(590mg,66%)。1HNMR(500MHz,CDCl3)δ7.13(s,3H),3.93(s,3H),3.84(s,6H),3.79(s,3H)。
3,4,5-三甲氧基-2-丙炔酰胺基苯甲酸甲酯(20)
依循针对化合物14所述的程序,在冰浴中,向19(1.36g,5.68mmol)于无水CH2Cl2(30mL)中的反应物中逐滴添加丙炔酰氯(1.00g,11.36mmol)及K2CO3(1.57g,3.11.36mmol),得到20(148mg,9%)。1H NMR(500MHz,CDCl3)δ7.20(s,1H),3.92(s,3H),3.91(s,3H),3.88(s,3H),3.87(s,3H),2.88(s,1H)。
流程7
试剂及条件:(i)LiOH、MeOH、80℃;(ii)丙炔酸、DCC、CH2Cl2、0℃。
2-氨基-3,4,5-三甲氧基苯甲酸(21)
依循针对化合物15所述的程序,在N2下将19(560mg,2.32mmol)及LiOH(240mg,5.72mmol)于MeOH(10mL)中的反应物加热至70℃维持18小时,得到21(380mg,73%)。1H NMR(500MHz,CDCl3)δ7.19(s,1H),3.95(s,3H),3.86(s,3H),3.80(s,3H)。
2-氨基-3,4,5-三甲氧基苯甲酸丙炔酸酸酐(22)
依循针对化合物4所述的程序,在冰浴中,向21(320mg,1.41mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.130mL,2.11mmol)及N,N'-二环己基碳二亚胺(435mg,2.11mmol)的无水CH2Cl2(5mL),得到22(6mg,2%)。1H NMR(500MHz,CDCl3)δ7.39(s,1H),4.05(s,3H),4.01(s,3H),3.95(s,3H),3.19(s,1H)。
流程8
试剂及条件:(i)10%Pd-C、MeOH、H2、RT;(ii)丙炔酸、DCC、CH2Cl2、0℃。
2-氨基-5-羟基-4-甲氧基苯甲酸(23)
向11(500mg,2.35mmol)于MeOH(30mL)中的溶液中添加催化量的10%Pd/C(200mg)且在H2氛围下、在室温下搅拌混合物9小时。利用硅藻土过滤反应混合物且真空浓缩滤液。残余物藉由硅胶层析(MeOH/CH2Cl2=1:9)纯化,得到23(350mg,82%)。1H NMR(300MHz,CDCl3)δ8.30(s,1H),7.18(s,1H),6.38(S,1H),3.83(s,3H),3.27(s,1H)。
流程9
试剂及条件:(i)溴化丙烷、K2CO3、DMF、100℃;(ii)HNO3、AcOH、50℃;(iii)Zn、AcOH、50℃;(iv)LiOH、MeOH、80℃;(v)丙炔酸、DCC、CH2Cl2、0℃。
3,4-二丙氧基苯甲酸丙酯(25)
依循针对化合物2所述的程序,向24(5g,32.47mmol)及K2CO3(22.36g,162mmol)于DMF(50mL)中的反应物中添加1-溴丙烷(13.2mL,145mmol)。所得溶液在N2下加热至110℃,得到25(8.5g,89%)。1H NMR(300MHz,CDCl3)δ7.62(dd,J=8.4,2.0Hz,1H),7.53(d,J=2.0Hz,1H),6.85(d,J=8.4Hz,1H),4.22(t,J=6.7Hz,2H),3.99(t,J=6.6Hz,4H),1.80(m,6H),1.02(m,9H)。
2-硝基-4,5-二丙氧基苯甲酸丙酯(26)
依循针对化合物18所述的程序,向25(8.10g,28.93mmol)于HOAc(20mL)中的反应物中添加HNO3(5mL)且在N2下加热至50℃,得到26(8.50g,90%)。1HNMR(300MHz,CDCl3)δ7.40(s,1H),7.04(s,1H),4.24(t,J=6.7Hz,2H),4.02(m,4H),1.86(sxt,J=7.1Hz,4H),1.72(m,2H),1.04(td,J=7.4,1.5Hz,6H),0.95(t,J=7.4Hz,3H)。
2-氨基-4,5-二丙氧基苯甲酸丙酯(27)
向26(8.50g,26.15mmol)于HOAc(20mL)中的溶液中添加Zn(17.00g,261.54mmol)且在N2下、在室温下搅拌混合物2小时。用硅藻土过滤反应混合物。残余物用EtOAc(150mL)及NaHCO3(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:7)纯化,得到27(4.90g,64%)。1H NMR(300MHz,CDCl3)δ7.36(s,1H),6.10(s,1H),4.18(t,J=6.7Hz,2H),3.88(m,4H),1.79(m,6H),1.01(m,9H)。
2-氨基-4,5-二丙氧基苯甲酸甲酯(28)
在N2下,将27(1g,3.86mmol)及LiOH(810mg,19.30mmol)于MeOH(20mL)中的溶液加热至70℃维持24小时。将所得溶液酸化至pH 2且用1N HCl(50mL)及EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。使残余物再结晶,得到28(450mg,46%)。1HNMR(300MHz,CDCl3)δ7.32(s,1H),6.10(s,1H),3.89(m,2H),3.81(s,3H),1.80(m,4H),1.01(m,6H)。
2-丙炔酰胺基-4,5-二丙氧基苯甲酸甲酯(29)
依循针对化合物4所述的程序,在冰浴中,向28(440mg,1.74mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.183mL,2.61mmol)及N,N'-二环己基碳二亚胺(466mg,2.26mmol)的无水CH2Cl2(5mL),得到29(66mg,12%)。1H NMR(300MHz,CDCl3)δ11.52(s,1H),8.27(s,1H),7.46(s,1H),4.03(t,J=6.6Hz,2H),3.94(t,J=6.6Hz,2H),3.89(s,3H),2.91(s,1H),1.83(m,4H),1.02(t,J=7.4Hz,6H)。
流程10
试剂及条件:(i)丙炔酸、DCC、CH2Cl2、0℃。
2-丙炔酰胺基-4,5-二丙氧基苯甲酸丙酯(30)
依循针对化合物4所述的程序,在冰浴中,向27(590mg,2.00mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.184mL,3.00mmol)及N,N'-二环己基碳二亚胺(453mg,2.19mmol)的无水CH2Cl2(5mL),得到30(342mg,49%)。1H NMR(300MHz,CDCl3)δ11.56(s,1H),8.27(s,1H),7.48(s,1H),4.25(t,J=6.7Hz,2H),4.03(t,J=6.6Hz,2H),3.94(t,J=6.6Hz,2H),2.90(s,1H),1.82(m,6H),1.02(m,9H)。
流程11
试剂及条件:(i)溴化丙烷、K2CO3、DMF、100℃;(ii)HNO3、AcOH、50℃。
3,4-双(苯甲氧基)苯甲酸苯甲酯(31)
依循针对化合物2所述的程序,向24(10.00g,64.94mmol)及K2CO3(44.00g,318.23mmol)于DMF(100mL)中的反应物中添加苯甲基溴(27mL,227.3mmol)。所得溶液在N2下加热至110℃,得到31(27.10g,98%)。1H NMR(300MHz,CDCl3)δ7.53(s,1H),7.35(m,15H),7.18(s,1H),5.33(s,2H),5.23(s,4H)。
4,5-双(苯甲氧基)-2-硝基苯甲酸苯甲酯(32)
依循针对化合物18所述的程序,向31(16.00g,37.69mmol)于HOAc(30mL)中的反应物中添加HNO3(15mL)且在室温下、在N2下搅拌,得到32(16.44g,95%)。1H NMR(300MHz,CDCl3)δ7.50(s,1H),7.36(m,15H),7.15(s,1H),5.30(s,2H),5.20(s,4H)。
流程12
试剂及条件:(i)(CH3)3Si(CH2)2OH、Ph3P、DIAD、THF、RT;(ii)1-溴-3-氯丙烷、K2CO3、DMF、100℃;(iii)邻苯二甲酰亚胺钾、K2CO3、DMF、100℃;(iv)NH2NH2-H2O、MeOH、60℃;(v)苯甲酰氯、吡啶、CH2CI2;(vi)Zn、AcOH、THF、RT;(vii)丙炔酸、DCC、CH2Cl2、0℃;(viii)TBAF、THF、RT。
5-羟基-4-甲氧基-2-硝基苯甲酸2-(三甲基硅烷基)乙酯(33)
在冰浴中,向11(5000mg,23.46mmol)及三苯膦(12.31g,46.92mmol)于无水THF(150mL)中的溶液中逐滴添加2-(三甲基硅烷基)乙醇(5.04mL,35.19mmol)及偶氮二甲酸二异丙酯(6.93mL,35.19mmol)。所得溶液在室温下、在N2下搅拌7小时。将反应混合物悬浮于H2O(150mL)中且接着用EtOAc(3×150mL)萃取。收集有机层且经无水MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:9)纯化,得到33(2.03g,29%)。1H NMR(300MHz,CDCl3)δ7.49(s,1H),7.11(s,1H),4.38(m,2H),3.99(s,3H),1.07(m,2H),0.03(s,9H)。
5-(3-氯丙氧基)-4-甲氧基-2-硝基苯甲酸2-(三甲基硅烷基)乙酯(34)
依循针对化合物2所述的程序,向33(2.43g,7.76mmol)及K2CO3(2.15g,15.53mmol)于DMF(150mL)中的反应物中添加1-溴-3-氯丙烷(0.921mL,9.32mmol)。所得溶液在N2下加热至100℃,得到34(2.88g,95%)。1H NMR(300MHz,CDCl3)δ7.42(s,1H),7.08(s,1H),4.38(m,2H),4.24(m,2H),3.67(m,2H),2.34(m,2H),1.08(m,2H),0.04(s,9H)。
5-(3-(1,3-二氧代异吲哚啉-2-基)丙氧基)-4-甲氧基-2-硝基苯甲酸2-(三甲基硅烷基)乙酯(35)
依循针对化合物2所述的程序,向34(2.88g,7.37mmol)及K2CO3(2.04g,14.75mmol)于DMF(100mL)中的反应物中添加邻苯二甲酰亚胺钾盐(1.64g,8.85mmol)。所得溶液在N2下加热至100℃,得到35(3.42g,93%)。1H NMR(300MHz,CDCl3)δ7.81(m,2H),7.70(m,2H),7.32(s,1H),6.99(s,1H),4.36(m,2H),4.14(q,J=5.5Hz,2H),3.90(t,J=6.4Hz,2H),3.66(s,3H),2.25(m,2H),1.06(m,2H),0.03(s,9H)。
5-(3-氨基丙氧基)-4-甲氧基-2-硝基苯甲酸2-(三甲基硅烷基)乙酯(36)
向35(1.50g,3.00mmol)于MeOH(150mL)中的溶液中逐滴添加单水合肼(1.45mL,29.97mmol)。所得溶液在N2下回流且搅拌24小时。真空浓缩反应混合物且悬浮于H2O(150mL)中且接着用EtOAc(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(MeOH/CH2Cl2=1:99)纯化,得到36(140mg,13%)。1H NMR(300MHz,CDCl3)δ7.45(s,1H),6.52(s,1H),5.38(s,2H),4.39(m,2H),3.91(s,3H),3.79(t,J=5.8Hz,2H),3.37(m,2H),1.90(m,2H),1.08(m,2H),0.03(s,9H)。
5-(3-苯甲酰胺基丙氧基)-4-甲氧基-2-硝基苯甲酸2-(三甲基硅烷基)乙酯(37)
向36(140mg,0.38mmol)于无水CH2Cl2(10mL)中的溶液中逐滴添加吡啶(0.122mL,1.51mmol)及苯甲酰氯(0.131mL,1.13mmol)。所得溶液在N2下、在室温下搅拌12小时。将反应混合物悬浮于H2O(50mL)中且接着用CH2Cl2(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:4)纯化,得到37(177mg,99%)。1H NMR(300MHz,CDCl3)δ8.02(d,J=7.1Hz,2H),7.57(tt,J=7.4,1.2Hz,1H),7.45(m,3H),6.54(s,1H),5.24(s,1H),4.45(t,J=5.9Hz,2H),4.38(m,2H),3.85(s,3H),3.42(q,J=6.3Hz,2H),2.13(m,2H),1.08(m,2H),0.03(s,9H)。
2-氨基-5-(3-苯甲酰胺基丙氧基)-4-甲氧基苯甲酸2-(三甲基硅烷基)乙酯(38)
向37(180mg,0.38mmol)于HOAc/THF=1:4(20mL)中的溶液中添加Zn(248mg,3.79mmol)且在N2下、在室温下搅拌混合物24小时。利用硅藻土过滤反应混合物。残余物用EtOAc(50mL)及NaHCO3(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:3)纯化,得到38(158mg,94%)。1H NMR(300MHz,CDCl3)δ8.04(m,2H),7.55(m,1H),7.42(m,2H),7.06(s,1H),6.08(s,1H),4.45(t,J=6.2Hz,2H),4.32(m,2H),3.77(s,3H),3.26(t,J=6.8Hz,2H),2.11(tt,J=6.2,6.8Hz,2H),1.07(m,2H),0.05(s,9H)。
4-甲氧基-2-丙炔酰胺基-5-(3-(N-丙炔酰基苯甲酰胺基)丙氧基)苯甲酸2-(三甲基硅烷基)乙酯(39)
依循针对化合物4所述的程序,在冰浴中,向38(125mg,0.28mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.037mL,0.56mmol)及N,N'-二环己基碳二亚胺(116mg,0.56mmol)的无水CH2Cl2(5mL),得到39(149mg,97%)。1H NMR(300MHz,CDCl3)δ11.82(s,1H),8.38(s,1H),7.94(dd,J=8.4,1.4Hz,2H),7.87(s,1H),7.52(m,1H),7.40(m,2H),4.37(m,2H),3.93(m,4H),3.72(m,1H),2.97(s,1H),2.68(s,1H),1.99(m,2H),1.12(m,2H),0.06(s,9H)。
4-甲氧基-2-丙炔酰胺基-5-(3-(N-丙炔酰基苯甲酰胺基)丙氧基)苯甲酸(40)
在室温下,向39(75mg,0.14mmol)于无水THF(3mL)中的溶液中逐滴添加TBAF(1M于THF中,0.75mL,0.75mmol)。所得溶液在N2下搅拌5小时。将反应混合物悬浮于1N HCl(aq)(50mL)中且用EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(MeOH/CH2Cl2=3:97)纯化,得到40(46mg,75%)。1H NMR(300MHz,DMSO)δ11.57(s,1H),8.40(s,1H),7.94(m,2H),7.52(m,1H),7.40(m,2H),4.35(t,J=6.3Hz,2H),3.95(m,4H),3.72(m,1H),2.99(s,1H),2.71(s,1H),2.00(m,2H)。
流程13
试剂及条件:(i)溴化丙烷、K2CO3、DMF、RT;(ii)Zn、AcOH、50℃;(iii)丙炔酸、DCC、CH2Cl2、0℃。
4-甲氧基-2-硝基-5-丙氧基苯甲酸丙酯(41)
依循针对化合物2所述的程序,向11(2.13g,10.00mmol)及K2CO3(5.52g,39.92mmol)于DMF(50mL)中的反应物中添加1-溴丙烷(3.63mL,40.00mmol)。所得溶液在N2下加热至100℃,得到41(2.80g,94%)。1H NMR(500MHz,CDCl3)δ7.41(s,1H),7.04(s,1H),4.24(t,J=6.7Hz,2H),4.04(t,J=6.7Hz,2H),4.92(s,3H),1.87(dt,J=6.7,7.4Hz,2H),1.71(dt,J=6.7,7.4Hz,2H),1.03(t,J=7.4Hz,3H),0.95(t,J=7.4Hz,3H)。
2-氨基-4-甲氧基-5-丙氧基苯甲酸丙酯(42)
向41(2.70g,9.08mmol)于HOAc(20mL)中的溶液中添加Zn(5.94g,90.81mmol)且在N2下、在室温下搅拌混合物48小时。利用硅藻土过滤反应混合物。残余物用EtOAc(150mL)及NaHCO3(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:7)纯化,得到27(1.90g,78%)。1H NMR(500MHz,CDCl3)δ7.33(s,1H),6.11(s,1H),4.19(t,J=6.7Hz,2H),3.87(t,J=6.7Hz,2H),3.82(s,3H),1.77(m,4H),1.00(m,6H)。
4-甲氧基-2-丙炔酰胺基-5-丙氧基苯甲酸丙酯(43)
依循针对化合物4所述的程序,在冰浴中,向41(440mg,1.74mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.183mL,2.61mmol)及N,N'-二环己基碳二亚胺(466mg,2.26mmol)的无水CH2Cl2(5mL),得到43(202mg,38%)。1H NMR(300MHz,CDCl3)δ11.56(s,1H),8.30(s,1H),7.46(s,1H),4.26(t,J=6.7Hz,2H),3.95(t,J=6.8Hz,2H),3.91(s,3H),1.81(m,4H),1.02(m,6H)。
流程14
试剂及条件:(i)LiOH、MeOH、70℃;(ii)丙炔酸、DCC、CH2Cl2、0℃。
2-氨基-4-甲氧基-5-丙氧基苯甲酸(44)
依循针对化合物15所述的程序,在N2下将42(500mg,1.87mmol)及LiOH(790mg,18.70mmol)于MeOH(20mL)中的反应物加热至70℃,得到44(310mg,75%)。1H NMR(500MHz,CDCl3)δ7.35(s,1H),6.11(s,1H),3.89(t,J=6.8Hz,2H),3.84(s,3H),1.81(m,2H),1.01(t,J=7.5Hz,3H)。
2-氨基-4-甲氧基-5-丙氧基苯甲酸丙炔酸酸酐(45)
依循针对化合物4所述的程序,在冰浴中,向44(225mg,1.00mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.092mL,1.50mmol)及N,N'-二环己基碳二亚胺(267mg,1.29mmol)的无水CH2Cl2(5mL),得到45(5mg,2%)。1H NMR(300MHz,CDCl3)δ7.49(s,1H),7.02(s,1H),4.06(t,J=6.7Hz,2H),3.96(s,3H),3.20(s,1H),1.89(m,2H),1.05(t,J=7.4Hz,3H)。
流程15
试剂及条件:(i)HCl、MeOH、60℃;(ii)Cl(CH2)nBr、K2CO3、DMF、100℃;(iii)邻苯二甲酰亚胺钾、K2CO3、DMF、100℃;(iv)Zn、AcOH、THF、RT;(v)丙炔酸、DCC、CH2Cl2、0℃
5-羟基-4-甲氧基-2-硝基苯甲酸甲酯(46)
向11(20.00g,93.83mmol)于MeOH(300mL)中的溶液中逐滴添加12NHCl(aq)(30mL)。所得溶液在N2下回流72小时。真空浓缩反应混合物。残余物用H2O(100mL)洗涤且过滤,得到呈白色固体状的46(19.05g,89%)。1H NMR(300MHz,CDCl3)δ7.50(s,1H),7.12(s,1H),6.17(s,1H),3.99(s,3H),3.88(s,3H)。
5-(2-氯乙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(47a)
依循针对化合物2所述的程序,向46(1.00g,4.40mmol)及K2CO3(1.21g,8.80mmol)于DMF(50mL)中的反应物中添加1-溴-2-氯乙烷(0.44mL,5.28mmol)。所得溶液在N2下加热至100℃,得到47a(414mg,32%)。1H NMR(300MHz,CDCl3)δ7.24(s,1H),7.09(s,1H),4.34(t,J=5.9Hz,2H),3.95(s,3H),3.88(s,3H),3.86(t,J=5.9Hz,2H)。
5-(3-氯丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(47b)
依循针对化合物2所述的程序,在N2下,将11(19.05g,83.86mmol)、K2CO3(23.18g,167.71mmol)及1-溴-3-氯丙烷(12.44mL,125.79mmol)于DMF(350mL)中的反应物加热至100℃,得到47b(21.45g,84%)。1H NMR(300MHz,CDCl3)δ7.43(1,sH),7.09(s,1H),4.24(t,J=5.9Hz,2H),3.93(s,3H),3.89(s,3H),3.74(t,J=6.1Hz,2H),2.30(tt,J=5.9,6.1Hz,2H)。
5-(4-氯丁氧基)-4-甲氧基-2-硝基苯甲酸甲酯(47c)
依循针对化合物2所述的程序,在N2下,将11(1.00g,83.86mmol)、K2CO3(1.21g,8.80mmol)及1-溴-4-氯丁烷(0.61mL,5.28mmol)于DMF(50mL)中的反应物加热至100℃,得到47c(1.09g,78%)。1H NMR(300MHz,CDCl3)δ7.43(s,1H),7.04(s,1H),4.12(t,J=5.9Hz,2H),3.93(s,3H),3.88(s,3H),3.61(t,J=6.2Hz,3H),1.99(m,4H)。
5-(2-(1,3-二氧代异吲哚啉-2-基)乙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(48a)
依循针对化合物2所述的程序,在N2下,将47a(390mg,1.35mmol)、K2CO3(372mg,2.69mmol)及邻苯二甲酰亚胺钾盐(299mg,1.61mmol)于DMF(50mL)中的反应物加热至100℃,得到呈白色固体状的48a(463mg,86%)。1HNMR(300MHz,CDCl3)δ7.85(m,2H),7.72(m,2H),7.36(s,1H),7.10(s,1H),4.35(t,J=5.8Hz,2H),4.14(t,J=5.9Hz,2H),3.86(s,3H),3.85(s,3H)。
5-(3-(1,3-二氧代异吲哚啉-2-基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(48b)
依循针对化合物2所述的程序,在N2下,将47b(21.45g,70.63mmol)、K2CO3(19.52g,141.26mmol)及邻苯二甲酰亚胺钾盐(19.62g,105.95mmol)于DMF(300mL)中的反应物加热至100℃,得到呈白色固体状的48b(29.00g,99%)。1H NMR(300MHz,CDCl3)δ7.84(m,2H),7.72(m,2H),7.33(s,1H),7.00(s,1H),4.15(t,J=5.9Hz,2H),3.90(t,J=6.4Hz,2H),3.87(s,3H),3.67(s,3H),2.26(tt,J=5.9,6.4Hz,2H)。
5-(4-(1,3-二氧代异吲哚啉-2-基)丁氧基)-4-甲氧基-2-硝基苯甲酸甲酯(48c)
依循针对化合物2所述的程序,在N2下,将47c(950mg,2.99mmol)、K2CO3(826mg,5.98mmol)及邻苯二甲酰亚胺钾盐(665mg,3.59mmol)于DMF(50mL)中的反应物加热至100℃,得到呈白色固体状的48c(1064mg,83%)。1H NMR(300MHz,CDCl3)δ7.82(m,2H),7.70(m,2H),7.40(s,1H),7.03(s,1H),4.11(t,J=5.9Hz,2H),3.91(s,3H),3.88(s,3H),3.76(t,J=6.2Hz,3H),1.89(m,4H)。
2-氨基-5-(2-(1,3-二氧代异吲哚啉-2-基)乙氧基)-4-甲氧基苯甲酸甲酯(49a)
依循针对3所述的程序,48a(100mg,0.25mmol)、10%Pd/C(10mg)于EtOH/EtOAc=1:1(10mL)中、在H2下反应,得到49a(74mg,80%)。1H NMR(300MHz,CDCl3)δ7.84(m,2H),7.70(m,2H),7.35(s,1H),6.03(s,1H),5.55(s,2H),4.16(t,J=5.8Hz,2H),4.06(t,J=5.9Hz,2H),3.79(s,3H),3.67(s,3H)。
2-氨基-5-(3-(1,3-二氧代异吲哚啉-2-基)丙氧基)-4-甲氧基苯甲酸甲酯(49b)
依循针对3所述的程序,48b(100mg,0.24mmol)、10%Pd/C(10mg)于EtOH/EtOAc=1:1(10mL)中、在H2下反应,得到49b(76mg,82%)。1H NMR(300MHz,CDCl3)δ7.81(m,2H),7.68(m,2H),7.30(s,1H),6.05(s,1H),5.54(s,2H),3.99(t,J=6.2Hz,2H),3.88(t,J=6.9Hz,2H),3.80(s,3H),3.68(s,3H),2.16(tt,J=6.2,6.9Hz,2H)。
2-氨基-5-(4-(1,3-二氧代异吲哚啉-2-基)丁氧基)-4-甲氧基苯甲酸甲酯(49c)
依循针对3所述的程序,48c(100mg,0.23mmol)、10%Pd/C(10mg)于EtOH/EtOAc=1:1(10mL)中、在H2下反应,得到49c(74mg,80%)。1H NMR(300MHz,CDCl3)δ7.80(m,2H),7.68(m,2H),7.28(s,1H),6.08(s,1H),5.55(s,2H),3.93(t,J=6.0Hz,2H),3.80(s,3H),3.79(s,3H),3.74(t,J=6.7Hz,3H),1.83(m,4H)。
5-(2-(1,3-二氧代异吲哚啉-2-基)乙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(50a)
依循针对化合物4所述的程序,49a(50mg,0.14mmol)、丙炔酸(0.013mL,0.20mmol)及N,N'-二环己基碳二亚胺(42mg,0.20mmol)于CH2Cl2(15mL)中、在N2下反应,得到50a(57mg,99%)。1H NMR(500MHz,CDCl3)δ11.52(s,1H),8.25(s,1H),7.84(dd,J=5.5,3.1Hz,2H),7.71(dd,J=5.5,3.1Hz,2H),7.51(s,1H),4.25(t,J=5.9Hz,2H),4.10(t,J=5.9Hz,2H),3.88(s,3H),3.79(s,3H),2.90(s,2H)。
5-(3-(1,3-二氧代异吲哚啉-2-基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(50b)
依循针对化合物4所述的程序,49b(50mg,0.13mmol)、丙炔酸(0.012mL,0.20mmol)及N,N'-二环己基碳二亚胺(40mg,0.20mmol)于CH2Cl2(15mL)中、在N2下反应,得到50b(34mg,60%)。1H NMR(500MHz,CDCl3)δ11.53(s,1H),8.22(s,1H),7.80(dd,J=5.4,3.1Hz,2H),7.69(dd,J=5.4,3.0Hz,2H),7.43(s,1H),4.08(t,J=6.0Hz,2H),3.90(m,5H),3.68(s,3H),2.91(s,1H),2.21(tt,J=6.0,6.6Hz,2H)。
5-(4-(1,3-二氧代异吲哚啉-2-基)丁氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(50c)
依循针对化合物4所述的程序,49c(50mg,0.13mmol)、丙炔酸(0.012mL,0.19mmol)及N,N'-二环己基碳二亚胺(39mg,0.19mmol)于CH2Cl2(15mL)中、在N2下反应,得到50c(56mg,99%)。1H NMR(500MHz,CDCl3)δ11.52(s,1H),8.28(s,1H),7.81(dd,J=5.3,3.0Hz,2H),7.69(dd,J=5.5,3.0Hz,2H),7.43(s,1H),4.02(t,J=6.0Hz,2H),3.89(m,6H),3.75(t,J=6.6Hz,2H),2.91(s,1H),1.87(m,4H)。
流程16
试剂及条件:(i)NH2NH2-H2O、MeOH、60℃;(ii)RCOCl、吡啶、CH2Cl2、RT;(iii)Zn、AcOH、THF、RT;(iv)丙炔酸、DCC、CH2Cl2、0℃
5-(2-氨基乙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(51)
向48a(250mg,0.62mmol)于MeOH(25mL)中的溶液中逐滴添加单水合肼(0.303mL,6.24mmol)。所得溶液在N2下回流且搅拌4小时。真空浓缩反应混合物且悬浮于H2O(150mL)中且接着用EtOAc(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(MeOH/CH2Cl2=1:99)纯化,得到呈棕色油状的51(121mg,72%)。1H NMR(300MHz,CDCl3)δ7.47(s,1H),6.55(s,1H),5.36(s,2H),3.93(2,3H),3.89(m,5H),3.39(m,2H)。
5-(2-苯甲酰胺基乙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(52)
向51(50mg,0.19mmol)于无水CH2Cl2(10mL)中的溶液中逐滴添加吡啶(0.060mL,0.74mmol)及苯甲酰氯(0.065mL,0.56mmol)。所得溶液在N2下、在室温下搅拌2.5小时。将反应混合物悬浮于H2O(50mL)中且接着用CH2Cl2(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。藉由硅胶层析(EtOAc/正己烷=1:5)纯化残余物,得到52(65mg,94%)。1HNMR(300MHz,CDCl3)δ8.00(d,J=7.2Hz,2H),7.56(m,1H),7.44(m,3H),6.66(s,1H),5.34(s,1H),4.54(t,J=5.4Hz,2H),4.10(q,J=7.2Hz,2H),3.93(s,3H),3.89(s,3H),3.3.65(m,2H)。
2-氨基-5-(2-苯甲酰胺基乙氧基)-4-甲氧基苯甲酸甲酯(53)
依循针对化合物38所述的程序,向52(63mg,0.17mmol)于HOAc/THF=1:4(10mL)中的反应物中添加Zn(253mg,3.86mmol)且在N2下、在室温下搅拌混合物,得到53(45mg,78%)。1H NMR(300MHz,CDCl3)δ8.03(dd,J=8.3,1.4Hz,2H),7.53(tt,J=3.7,1.6Hz,1H),7.42(t,J=7.5Hz,2H),7.12(s,1H),6.09(s,1H),5.38(s,2H),4.52(t,J=5.2Hz,2H),3.81(s,3H),3.80(s,3H),3.50(t,J=5.4Hz,2H)。
4-甲氧基-2-丙炔酰胺基-5-(2-(N-丙炔酰基苯甲酰胺基)乙氧基)苯甲酸甲酯(54)
依循针对化合物4所述的程序,在冰浴中,向53(40mg,0.12mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.011mL,0.17mmol)及N,N'-二环己基碳二亚胺(36mg,0.17mmol)的无水CH2Cl2(5mL),得到54(49mg,94%)。1H NMR(300MHz,CDCl3)δ11.70(s,1H),8.34(s,1H),7.90(s,1H),7.83(m,2H),7.51(tt,J=7.4,1.6Hz,2H),7.35(m,2H),4.44(m,2H),4.25(m,1H),3.89(m,1H),3.83(s,3H),3.76(s,3H),2.98(s,1H),2.71(s,1H)。
流程17
试剂及条件:(i)NH2NH2-H2O、MeOH、60℃;(ii)RCOCl、吡啶、CH2Cl2、RT;(iii)RCO2HDMAP、DCC、CH2Cl2、RT;(iv)Zn、AcOH、THF、RT;(v)丙炔酸、DCC、CH2Cl2、0℃
5-(3-氨基丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(55)
向48b(29.00g,69.99mmol)于MeOH(500mL)中的溶液中逐滴添加单水合肼(33.95mL,699.86mmol)。所得溶液在N2下回流且搅拌24小时。真空浓缩反应混合物且悬浮于H2O(150mL)中且接着用EtOAc(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(MeOH/CH2Cl2=1:99)纯化,得到呈棕色油状的55(3.25g,16%)。1HNMR(300MHz,CDCl3)δ7.46(s,1H),6.53(s,1H),5.38(s,2H),3.92(2,3H),3.89(s,3H),3.80(t,J=5.7Hz,2H),3.38(dt,J=5.6,6.6Hz,2H),1.91(tt,J=5.7,6.5Hz,2H)。
5-(3-苯甲酰胺基丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56a)
向55(100mg,0.35mmol)于无水CH2Cl2(10mL)中的溶液中逐滴添加吡啶(0.113mL,1.41mmol)及苯甲酰氯(0.113mL,1.41mmol)。所得溶液在N2下、在室温下搅拌2.5小时。将反应混合物悬浮于H2O(50mL)中且接着用CH2Cl2(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:5)纯化,得到56a(124mg,91%)。1HNMR(300MHz,CDCl3)δ8.02(d,J=7.1Hz,2H),7.57(tt,J=7.4,1.2Hz,1H),7.45(m,3H),6.54(s,1H),5.26(s,1H),4.45(t,J=5.9Hz,2H),3.87(s,3H),3.85(s,3H),3.42(t,J=5.6Hz,2H),2.14(tt,J=5.9,5.6Hz,2H)。
5-(3-(2-氟苯甲酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56b)
依循针对56a所述的程序,使55(90mg,0.32mmol)、吡啶(0.102mL,1.27mmol)及2-氟苯甲酰氯(0.113mL,0.95mmol)于CH2Cl2(10mL)中、在N2下反应,得到56b(116mg,90%)。1HNMR(300MHz,CDCl3)δ7.93(td,J=7.5,1.8Hz,1H),7.53(m,1H),7.45(s,1H),7.23(m,1H),7.16(dd,J=11.1,2.8Hz,1H),6.55(s,1H),5.24(t,J=5.7Hz,1H),4.45(t,J=5.9Hz,2H),3.87(s,6H),3.44(dt,J=6.0,6.5Hz,2H),2.12(tt,J=5.9,6.5Hz,2H)。
5-(3-(3-氟苯甲酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56c)
在冰浴中,向55(100g,0.35mmol)、4-(二甲氨基)吡啶(43mg,0.35mmol)及3-氟苯甲酸(148mg,1.05mmol)于无水CH2Cl2(10mL)中的混合物中逐滴添加含有N,N'-二环己基碳二亚胺(363mg,1.76mmol)的无水CH2Cl2(5mL)。所得溶液在N2下、在室温下搅拌12小时。将反应混合物悬浮于H2O(50mL)中且接着用CH2Cl2(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。过滤混合物且用EtOAc/正己烷=1:1(10mL)洗涤。残余物藉由硅胶层析(EtOAc/正己烷=1:5)纯化,得到56c(129mg,90%)。1H NMR(300MHz,CDCl3)δ7.82(dt,J=7.6,1.3Hz,1H),7.69(m,1H),7.46(s,H),7.42(m,1H),7.28(m,1H),6.54(s,1H),5.22(s,1H),4.45(t,J=5.9Hz,2H),3.88(s,6H),3.42(dt,J=5.0,6.2Hz,2H),2.14(tt,J=6.2,5.9Hz,2H)。
5-(3-(4-氟苯甲酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56d)
依循针对56a所述的程序,使55(150mg,0.53mmol)、吡啶(0.171mL,2.11mmol)及4-氟苯甲酰氯(0.187mL,1.58mmol)于CH2Cl2(10mL)中、在N2下反应,得到56d(191mg,89%)。1HNMR(300MHz,CDCl3)δ8.04(m,2H),7.46(s,1H),7.11(m,2H),6.54(s,1H),5.21(s,1H),4.43(t,J=5.9Hz,2H),3.88(s,6H),3.41(dt,J=5.9,6.7Hz,2H),2.13(tt,J=6.7,5.9Hz,3H)。
5-(3-(2,6-二氟苯甲酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56e)
依循针对56c所述的程序,使55(100mg,0.35mmol)、2,6-二氟苯甲酸(167mg,1.05mmol)、4-(二甲氨基)吡啶(43mg,0.35mmol)及N,N'-二环己基碳二亚胺(363mg,1.76mmol)于CH2Cl2(15mL)中、在N2下反应,得到56e(147mg,98%)。1H NMR(300MHz,CDCl3)δ7.46(s,1H),7.38(m,1H),6.96(m,2H),6.54(s,1H),5.20(s,1H),4.47(t,J=5.9Hz,2H),3.88(s,3H),3.88(s,3H),3.42(t,J=6.8Hz,2H),2.10(tt,J=5.9,6.8Hz,3H)。
5-(3-(2,6-二甲氧基苯甲酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56f)
依循针对56a所述的程序,使55(120mg,0.42mmol)、吡啶(0.136mL,1.69mmol)及2,6-二甲氧基苯甲酰氯(254mg,1.27mmol)于CH2Cl2(10mL)中、在N2下反应,得到56f(189mg,99%)。1H NMR(300MHz,CDCl3)δ7.45(s,1H),7.29(t,J=8.5Hz,1H),6.56(d,J=8.5Hz,2H),6.52(s,1H),5.37(s,1H),4.45(t,J=5.8Hz,2H),3.86(s,3H),3.83(s,3H),3.78(s,6H),3.42(dt,J=6.1,6.4Hz,2H),2.07(tt,J=5.8,6.4Hz,3H)。
4-甲氧基-5-(3-(3-甲氧基苯甲酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56g)
依循针对56a所述的程序,使55(150mg,0.53mmol)、吡啶(0.171mL,2.11mmol)及3-甲氧基苯甲酰氯(222mL,1.58mmol)于CH2Cl2(10mL)中、在N2下反应,得到56g(218mg,99%)。1HNMR(300MHz,CDCl3)δ7.78(dt,J=7.8,1.2Hz,1H),7.69(m,1H),7.61(s,1H),7.51(t,J=7.9Hz,1H),7.27(ddd,J=8.3,2.7,0.9Hz,1H),6.69(s,1H),5.41(s,1H),4.60(t,J=5.9Hz,2H),4.04(s,3H),4.02(s,3H),4.00(s,3H),3.58(dt,J=6.0,6.5Hz,2H),2.11(tt,J=5.9,6.5Hz,2H)。
4-甲氧基-5-(3-(4-甲氧基苯甲酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56h)
依循针对56a所述的程序,使55(90mg,0.32mmol)、吡啶(0.102mL,1.27mmol)及4-甲氧基苯甲酰氯(0.128mL,0.95mmol)于CH2Cl2(10mL)中、在N2下反应,得到56h(131mg,99%)。1H NMR(300MHz,CDCl3)δ7.97(d,J=9.0Hz,2H),7.45(s,1H),6.91(d,J=9.0Hz,2H),6.54(s,1H),5.26(s,1H),4.41(t,J=5.9Hz,2H),3.88(s,3H),3.87(s,3H),3.85(s,3H),3.41(dt,J=6.0,6.5Hz,2H),2.11(tt,J=5.9,6.0Hz,2H)。
4-甲氧基-2-硝基-5-(3-(2-苯基乙酰胺基)丙氧基)苯甲酸甲酯(56i)
依循针对56c所述的程序,使55(50mg,0.18mmol)、苯乙酸(48mg,0.35mmol)、4-(二甲氨基)吡啶(21mg,0.18mmol)及N,N'-二环己基碳二亚胺(73mg,0.35mmol)于CH2Cl2(15mL)中、在N2下反应,得到56i(68mg,96%)。1H NMR(300MHz,CDCl3)δ7.47(s,1H),7.29(m,5H),6.47(s,1H),5.11(s,1H),4.20(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.63(s,2H),3.24(dt,J=6.0,6.5Hz,2H),1.96(tt,J=6.0,6.9Hz,2H)。
5-(3-(2-(2-氟苯基)乙酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56j)
依循针对56c所述的程序,使55(120mg,0.42mmol)、2-氟苯乙酸(195mg,1.27mmol)、4-(二甲氨基)吡啶(51mg,0.42mmol)及N,N'-二环己基碳二亚胺(435mg,2.11mmol)于CH2Cl2(15mL)中、在N2下反应,得到56j(176mg,99%)。1HNMR(300MHz,CDCl3)δ7.47(s,1H),7.24(m,2H),7.10(m,1H),7.06(m,1H),6.48(m,1H),5.14(s,1H),4.22(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.68(d,J=1.1Hz,2H),3.27(dt,J=5.9,6.7Hz,2H),1.97(tt,J=6.0,6.7Hz,2H)。
5-(3-(2-(3-氟苯基)乙酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56k)
依循针对56a所述的程序,使55(150mg,0.53mmol)、吡啶(0.170mL,2.11mmol)及3-氟苯基氯化物(109mg,0.63mmol)于CH2Cl2(10mL)中、在N2下反应,得到56k(210mg,95%)。1HNMR(300MHz,CDCl3)δ7.47(s,1H),7.27(m,1H),7.03(d,J=8.5Hz,1H),6.96(m,2H),6.48(s,1H),5.10(s,1H),4.21(t,J=6.1Hz,2H),3.92(s,3H),3.90(s,3H),3.62(s,2H),3.26(dt,J=5.9,6.6Hz,2H),1.98(tt,J=6.1,6.6Hz,2H)。
5-(3-(2-(4-氟苯基)乙酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56l)
依循针对56c所述的程序,使55(150mg,0.53mmol)、4-氟苯乙酸(244mg,1.58mmol)、4-(二甲氨基)吡啶(64mg,0.53mmol)及N,N'-二环己基碳二亚胺(544mg,2.64mmol)于CH2Cl2(15mL)中、在N2下反应,得到56l(219mg,99%)。1HNMR(300MHz,CDCl3)δ7.47(s,1H),7.22(m,2H),6.99(m,2H),6.49(s,1H),5.11(s,1H),4.20(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.60(s,2H),3.26(dt,J=5.9,6.6Hz,2H),1.97(tt,J=6.0,6.6Hz,2H)。
4-甲氧基-5-(3-(2-(2-甲氧苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56m)
依循针对56c所述的程序,使55(120mg,0.42mmol)、2-甲氧基苯乙酸(210mg,1.27mmol)、4-(二甲氨基)吡啶(51mg,0.42mmol)及N,N'-二环己基碳二亚胺(435mg,2.11mmol)于CH2Cl2(15mL)中、在N2下反应,得到56m(118mg,65%)。1H NMR(300MHz,CDCl3)δ7.46(s,1H),7.25(td,J=7.8,1.7Hz,1H),7.16(dd,J=7.4,1.7Hz,1H),6.89(td,J=7.4,1.1Hz,1H),6.86(d,J=8.2Hz,1H),6.47(s,1H),5.19(s,1H),4.21(t,J=6.0Hz,2H),3.91(s,3H),3.90(s,3H),3.77(s,3H),3.63(s,2H),3.26(dt,J=5.9,6.6Hz,2H),1.96(tt,J=6.0,6.6Hz,2H)。
4-甲氧基-5-(3-(2-(3-甲氧基苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56n)
依循针对56a所述的程序,使55(150mg,0.53mmol)、吡啶(0.128mL,1.58mmol)及3-甲氧基苯基氯化物(0.089mL,0.63mmol)于CH2Cl2(10mL)中、在N2下反应,得到56n(206mg,90%)。1H NMR(300MHz,CDCl3)δ7.46(s,1H),7.25(td,J=7.5,1.2Hz,1H),6.81(m,3H),6.48(s,1H),5.13(s,1H),4.20(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.77(s,3H),3.60(s,2H),3.25(dt,J=5.9,6.6Hz,2H),1.97(tt,J=6.0,6.6Hz,2H)。
4-甲氧基-5-(3-(2-(4-甲氧基苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56o)
依循针对56c所述的程序,使55(130mg,0.46mmol)、4-甲氧基苯乙酸(228mg,1.37mmol)、4-(二甲氨基)吡啶(51mg,0.46mmol)及N,N'-二环己基碳二亚胺(472mg,2.29mmol)于CH2Cl2(15mL)中、在N2下反应,得到56o(172mg,87%)。1H NMR(300MHz,CDCl3)δ7.47(s,1H),7.17(m,2H),6.84(m,2H),6.49(s,1H),5.48(t,J=5.5Hz,1H),4.19(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.77(s,3H),3.56(s,2H),3.26(dt,J=6.0,6.6Hz,2H),1.96(tt,J=6.0,6.6Hz,2H)。
4-甲氧基-5-(3-(2-(3,4,5-三甲氧基苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56p)
依循针对56c所述的程序,使55(120mg,0.42mmol)、3,4,5-三甲氧基苯乙酸(286mg,1.27mmol)、4-(二甲氨基)吡啶(52mg,0.42mmol)及N,N'-二环己基碳二亚胺(435mg,2.11mmol)于CH2Cl2(15mL)中、在N2下反应,得到56p(168mg,81%)。1H NMR(300MHz,CDCl3)δ7.47(s,1H),6.52(s,1H),6.48(s,2H),5.14(s,1H),4.21(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.82(s,6H),3.80(s,3H),3.56(s,2H),3.30(dt,J=5.9,6.7Hz,2H),1.99(tt,J=6.0,6.7Hz,2H)。
5-(3-(2-(2-氯苯基)乙酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56q)
依循针对56a所述的程序,使55(150mg,0.53mmol)、吡啶(0.128mL,1.58mmol)及2-氯苯基乙酰氯(0.092mL,0.63mmol)于CH2Cl2(10mL)中、在N2下反应,得到56q(207mg,90%)。1HNMR(300MHz,CDCl3)δ7.47(s,1H),7.37(m,1H),7.24(m,3H),6.47(s,1H),5.13(s,1H),4.23(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.78(s,2H),3.26(dt,J=6.0,6.6Hz,2H),1.97(tt,J=6.0,6.6Hz,2H)。
5-(3-(2-(3-氯苯基)乙酰胺基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(56r)
依循针对56c所述的程序,使55(120mg,0.42mmol)、3-氯苯乙酸(216mg,1.27mmol)、4-(二甲氨基)吡啶(51mg,0.42mmol)及N,N'-二环己基碳二亚胺(435mg,2.11mmol)于CH2Cl2(15mL)中、在N2下反应,得到56r(182mg,99%)。1HNMR(300MHz,CDCl3)δ7.47(s,1H),7.25(m,3H),7.15(m,1H),6.49(s,1H),5.10(t,J=5.3Hz,1H),4.21(t,J=6.1Hz,2H),3.92(s,3H),3.90(s,3H),3.60(s,2H),3.27(dt,J=5.9,6.7Hz,2H),1.98(tt,J=6.1,6.7Hz,2H)。
4-甲氧基-5-(3-(2-(2-(三氟甲基)苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56s)
依循针对56c所述的程序,使55(150mg,0.53mmol)、2-(三氟甲基)苯乙酸(323mg,1.58mmol)、4-(二甲氨基)吡啶(64mg,0.53mmol)及N,N'-二环己基碳二亚胺(544mg,2.64mmol)于CH2Cl2(15mL)中、在N2下反应,得到56s(230mg,93%)。1H NMR(300MHz,CDCl3)δ7.65(d,J=7.9Hz,1H),7.51(t,J=7.4Hz,1H),7.46(s,1H),7.38(t,J=6.1Hz,2H),6.47(s,1H),5.12(s,1H),4.21(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.84(d,J=1.1Hz,2H),3.26(dt,J=6.0,6.7Hz,2H),1.96(tt,J=6.0,6.7Hz,2H)。
4-甲氧基-5-(3-(2-(3-(三氟甲基)苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56t)
依循针对56c所述的程序,使55(150mg,0.53mmol)、3-(三氟甲基)苯乙酸(323mg,1.58mmol)、4-(二甲氨基)吡啶(64mg,0.53mmol)及N,N'-二环己基碳二亚胺(544mg,2.64mmol)于CH2Cl2(15mL)中、在N2下反应,得到56t(240mg,97%)。1H NMR(300MHz,CDCl3)δ7.53(m,2H),7.45(m,3H),6.49(s,1H),5.10(t,J=5.4Hz,1H),4.22(t,J=6.0Hz,2H),3.92(s,3H),3.90(s,3H),3.69(s,2H),3.27(dt,J=5.9,6.7Hz,2H),1.98(tt,J=6.0,6.7Hz,2H)。
4-甲氧基-5-(3-(2-(4-(三氟甲基)苯基)乙酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56u)
依循针对56a所述的程序,使55(150mg,0.53mmol)、吡啶(0.171mL,2.11mmol)及4-(三氟甲基)苯乙酰氯(141mg,0.63mmol)于CH2Cl2(10mL)中、在N2下反应,得到56u(223mg,90%)。1H NMR(300MHz,CDCl3)δ7.58(d,J=8.1Hz,2H),7.47(s,1H),7.39(d,J=8.1Hz,2H),6.51(s,1H),5.11(s,1H),4.21(t,J=6.1Hz,2H),3.92(s,3H),3.90(s,3H),3.69(s,2H),3.29(dt,J=5.9,6.5Hz,2H),1.98(tt,J=6.1,6.5Hz,2H)。
4-甲氧基-5-(3-(噁唑-5-甲酰胺基)丙氧基)-2-硝基苯甲酸甲酯(56v)
依循针对56c所述的程序,使55(150mg,0.53mmol)、噁唑-5-甲酸(179mg,1.58mmol)、4-(二甲氨基)吡啶(64mg,0.53mmol)及N,N'-二环己基碳二亚胺(544mg,2.64mmol)于CH2Cl2(15mL)中、在N2下反应,得到56v(185mg,92%)。1H NMR(300MHz,CDCl3)δ8.02(s,1H),7.79(s,1H),7.46(s,1H),6.54(s,1H),5.18(t,J=5.6Hz,1H),4.45(t,J=6.0Hz,2H),3.92(s,3H),3.88(s,3H),3.40(dt,J=6.0,6.6Hz,2H),2.11(tt,J=6.0,6.6Hz,2H)。
2-氨基-5-(3-苯甲酰胺基丙氧基)-4-甲氧基苯甲酸甲酯(57a)
依循针对化合物38所述的程序,向56a(150mg,0.39mmol)于HOAc/THF=1:4(10mL)中的反应物中添加Zn(253mg,3.86mmol)且在N2下、在室温下搅拌混合物,得到57a(113mg,82%)。1H NMR(300MHz,CDCl3)δ8.05(m,2H),7.54(tt,J=7.4,1.6Hz,1H),7.42(m,2H),7.04(s,1H),6.08(s,1H),4.44(t,J=6.1Hz,2H),3.79(s,3H),3.77(s,3H),3.27(t,J=5.8Hz,2H),2.11(tt,J=6.1,5.8Hz,2H)。
2-氨基-5-(3-(2-氟苯甲酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57b)
依循针对化合物38所述的程序,使56b(100mg,0.25mmol)、Zn(161mg,2.46mmol)于HOAc/THF=1:4(10mL)中、在N2下反应,得到57b(89mg,96%)。1H NMR(300MHz,CDCl3)δ7.93(td,J=7.5,1.9Hz,1H),7.51(m,1H),7.18(tt,J=7.6,1.1Hz,1H),7.12(ddd,J=10.8,8.3,1.0Hz,1H),7.04(s,1H),6.08(s,1H),4.45(t,J=6.1Hz,2H),3.79(s,3H),3.78(s,3H),3.28(t,J=6.7Hz,2H),2.10(tt,J=6.1,6.7Hz,2H)。
2-氨基-5-(3-(3-氟苯甲酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57c)
依循针对化合物38所述的程序,使56c(200mg,0.49mmol)、Zn(321mg,4.92mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57c(120mg,65%)。1H NMR(300MHz,CDCl3)δ7.82(d,J=7.7Hz,1H),7.72(m,1H),7.41(m,1H),7.25(m,1H),7.03(s,1H),6.09(s,1H),5.35(s,2H),4.45(t,J=6.1Hz,2H),3.80(s,3H),3.79(s,3H),3.27(t,J=6.7Hz,2H),2.11(tt,J=6.1,6.7Hz,2H)。
2-氨基-5-(3-(4-氟苯甲酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57d)
依循针对化合物38所述的程序,使56d(180mg,0.44mmol)、Zn(289mg,4.43mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57d(125mg,75%)。1H NMR(300MHz,CDCl3)δ8.06(m,2H),7.10(m,2H),7.03(s,1H),6.09(s,1H),5.02(s,2H),4.43(t,J=6.2Hz,2H),3.80(s,3H),3.78(s,3H),3.26(t,J=6.7Hz,2H),2.10(tt,J=6.2,6.7Hz,3H)。
2-氨基-5-(3-(2,6-二氟苯甲酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57e)
依循针对化合物38所述的程序,使56e(200mg,0.47mmol)、Zn(308mg,4.71mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57e(149mg,80%)。1H NMR(300MHz,CDCl3)δ7.40(m,1H),7.03(s,1H),6.94(t,J=8.2Hz,2H),6.08(s,1H),4.48(t,J=6.2Hz,2H),3.80(s,3H),3.79(s,3H),3.26(t,J=6.8Hz,2H),2.08(tt,J=6.2,6.8Hz,3H)。
2-氨基-5-(3-(2,6-二甲氧基苯甲酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57f)
依循针对化合物38所述的程序,使56f(150mg,0.34mmol)、Zn(218mg,3.35mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57f(70mg,50%)。1H NMR(300MHz,CDCl3)δ7.27(t,J=8.5Hz,1H),7.03(s,1H),6.54(d,J=8.3Hz,2H),6.08(s,1H),4.44(t,J=6.0Hz,2H),3.78(s,3H),3.77(s,9H),3.25(t,J=6.9Hz,2H),2.05(tt,J=6.0,6.9Hz,3H)。
2-氨基-4-甲氧基-5-(3-(3-甲氧基苯甲酰胺基)丙氧基)苯甲酸甲酯(57g)
依循针对化合物38所述的程序,使56g(200mg,0.48mmol)、Zn(313mg,4.79mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57g(166mg,89%)。1H NMR(300MHz,CDCl3)δ7.64(dt,J=7.6,1.2Hz,1H),7.56(dd,J=2.6,1.5Hz,1H),7.33(t,J=8.0Hz,1H),7.09(ddd,J=8.2,2.7,1.0Hz,1H),7.04(s,1H),6.08(s,1H),4.44(t,J=6.1Hz,2H),4.83(s,3H),3.79(s,3H),3.78(s,3H),3.27(t,J=6.7Hz,2H),2.10(tt,J=6.1,6.7Hz,2H)。
2-氨基-4-甲氧基-5-(3-(4-甲氧基苯甲酰胺基)丙氧基)苯甲酸甲酯(57h)
依循针对化合物38所述的程序,使56h(115mg,0.27mmol)、Zn(180mg,2.75mmol)于HOAc/THF=1:4(10mL)中、在N2下反应,得到57h(85mg,80%)。1H NMR(300MHz,CDCl3)δ8.00(m,2H),7.04(s,1H),6.90(m,2H),6.08(s,1H),4.41(t,J=6.1Hz,2H),3.84(s,3H),3.80(s,3H),3.78(s,3H),3.26(t,J=6.8Hz,2H),2.09(tt,J=6.1,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-苯基乙酰胺基)丙氧基)苯甲酸甲酯(57i)
依循针对化合物38所述的程序,使56i(81mg,0.20mmol)、Zn(132mg,2.01mmol)于HOAc/THF=1:4(10mL)中、在N2下反应,得到57i(69mg,92%)。1H NMR(300MHz,CDCl3)δ7.28(m,5H),7.00(s,1H),6.09(s,1H),4.21(t,J=6.2Hz,2H),3.83(s,3H),3.81(s,3H),3.62(s,2H),3.13(t,J=6.8Hz,2H),1.94(tt,J=6.2,6.8Hz,2H)。
2-氨基-5-(3-(2-(2-氟苯基)乙酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57j)
依循针对化合物38所述的程序,使56j(150mg,0.36mmol)、Zn(233mg,3.57mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57j(74mg,53%)。1H NMR(300MHz,CDCl3)δ7.24(m,2H),7.05(m,2H),7.00(s,1H),6.09(s,1H),4.23(t,J=6.2Hz,1H),3.83(s,3H),3.81(s,3H),3.68(s,2H),3.13(t,J=6.8Hz,2H),1.95(tt,J=6.2,6.8Hz,2H)。
2-氨基-5-(3-(2-(3-氟苯基)乙酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57k)
依循针对化合物38所述的程序,使56k(150mg,0.36mmol)、Zn(233mg,3.57mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57k(110mg,79%)。1H NMR(300MHz,CDCl3)δ7.26(m,1H),6.98(m,4H),6.09(s,1H),4.22(t,J=6.3Hz,2H),3.83(s,3H),3.81(s,3H),3.61(s,2H),3.13(t,J=6.8Hz,2H),1.95(tt,J=6.3,6.8Hz,2H)。
2-氨基-5-(3-(2-(4-氟苯基)乙酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57l)
依循针对化合物38所述的程序,使56l(175mg,0.42mmol)、Zn(272mg,4.16mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57l(120mg,74%)。1H NMR(300MHz,CDCl3)δ7.23(m,2H),6.98(m,3H),6.09(s,1H),4.21(t,J=6.2Hz,2H),3.83(s,3H),3.81(s,3H),3.59(s,2H),3.13(t,J=6.8Hz,2H),1.95(tt,J=6.2,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(2-甲氧苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57m)
依循针对化合物38所述的程序,使56m(100mg,0.23mmol)、Zn(151mg,2.31mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57m(73mg,78%)。1H NMR(300MHz,CDCl3)δ7.25(td,J=7.9,1.7Hz,1H),7.16(dd,J=7.5,1.7Hz,1H),7.00(s,1H),6.89(td,J=7.4,1.0Hz,1H),6.84(d,J=8.2Hz,1H),6.09(s,1H),4.21(t,J=6.2Hz,2H),3.83(s,3H),3.80(s,3H),3.77(s,3H),3.63(s,2H),3.12(t,J=6.8Hz,2H),1.94(tt,J=6.2,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(3-甲氧基苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57n)
依循针对化合物38所述的程序,使56n(150mg,0.35mmol)、Zn(227mg,3.47mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57n(97mg,69%)。1H NMR(300MHz,CDCl3)δ7.21(t,J=7.8Hz,1H),6.99(s,1H),6.85(m,1H),6.79(m,2H),6.09(s,1H),4.21(t,J=6.3Hz,2H),3.82(s,3H),3.81(s,3H),3.76(s,3H),3.59(s,2H),3.13(t,J=6.8Hz,2H),1.95(tt,J=6.3,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(4-甲氧基苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57o)
依循针对化合物38所述的程序,使56o(150mg,0.35mmol)、Zn(227mg,3.47mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57o(120mg,86%)。1H NMR(300MHz,CDCl3)δ7.18(m,2H),7.00(s,1H),6.83(m,2H),6.09(s,1H),4.20(t,J=6.3Hz,2H),3.83(s,3H),3.81(s,3H),3.76(s,3H),3.56(s,2H),3.13(t,J=6.8Hz,2H),1.94(tt,J=6.3,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(3,4,5-三甲氧基苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57p)
依循针对化合物38所述的程序,使56p(130mg,0.26mmol)、Zn(173mg,2.64mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57p(99mg,81%)。1H NMR(300MHz,CDCl3)δ7.00(s,1H),6.48(s,2H),6.09(s,1H),4.23(t,J=6.2Hz,2H),3.82(s,3H),3.81(s,9H),3.80(s,3H),3.55(s,2H),3.16(t,J=6.7Hz,2H),1.97(tt,J=6.2,6.7Hz,2H)。
2-氨基-5-(3-(2-(2-氯苯基)乙酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57q)
依循针对化合物38所述的程序,使56q(150mg,0.34mmol)、Zn(224mg,3.43mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57q(118mg,84%)。1H NMR(300MHz,CDCl3)δ7.36(m,1H),7.23(m,3H),7.00(s,1H),6.09(s,1H),4.24(t,J=6.2Hz,2H),3.83(s,3H),3.81(s,3H),3.78(s,2H),3.13(t,J=6.8Hz,2H),1.95(tt,J=6.2,6.8Hz,2H)。
2-氨基-5-(3-(2-(3-氯苯基)乙酰胺基)丙氧基)-4-甲氧基苯甲酸甲酯(57r)
依循针对化合物38所述的程序,使56r(150mg,0.34mmol)、Zn(224mg,3.43mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57r(100mg,72%)。1H NMR(300MHz,CDCl3)δ7.27(s,1H),7.22(m,2H),7.15(m,1H),7.00(s,1H),6.09(s,1H),4.22(t,J=6.2Hz,2H),3.83(s,3H),3.81(s,3H),3.59(s,2H),3.14(t,J=6.8Hz,2H),1.95(tt,J=6.2,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(2-(三氟甲基)苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57s)
依循针对化合物38所述的程序,使56s(175mg,0.37mmol)、Zn(243mg,3.72mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57s(151mg,92%)。1H NMR(300MHz,CDCl3)δ7.64(d,J=7.4Hz,1H),7.49(t,J=7.2Hz,1H),7.36(m,2H),6.99(s,1H),6.09(s,1H),4.23(t,J=6.2Hz,2H),3.83(s,6H),3.80(s,2H),3.12(t,J=6.8Hz,2H),1.94(tt,J=6.2,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(3-(三氟甲基)苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57t)
依循针对化合物38所述的程序,使56t(200mg,0.43mmol)、Zn(278mg,4.25mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57t(112mg,60%)。1H NMR(300MHz,CDCl3)δ7.46(m,4H),7.00(s,1H),6.09(s,1H),4.23(t,J=6.3Hz,2H),3.82(s,3H),3.81(s,3H),3.68(s,2H),3.14(t,J=6.8Hz,2H),1.96(tt,J=6.3,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(2-(4-(三氟甲基)苯基)乙酰胺基)丙氧基)苯甲酸甲酯(57u)
依循针对化合物38所述的程序,使56u(200mg,0.43mmol)、Zn(278mg,4.25mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57u(136mg,73%)。1H NMR(300MHz,CDCl3)δ7.56(d,J=8.2Hz,2H),7.39(d,J=8.2Hz,2H),7.01(s,1H),6.09(s,1H),4.23(t,J=6.3Hz,2H),3.82(s,3H),3.81(s,3H),3.68(s,2H),3.14(dt,J=6.8Hz,2H),1.96(tt,J=6.3,6.8Hz,2H)。
2-氨基-4-甲氧基-5-(3-(噁唑-5-甲酰胺基)丙氧基)苯甲酸甲酯(57v)
依循针对化合物38所述的程序,使56v(150mg,0.40mmol)、Zn(259mg,3.95mmol)于HOAc/THF=1:4(20mL)中、在N2下反应,得到57v(132mg,96%)。1H NMR(300MHz,CDCl3)δ8.00(s,1H),7.78(s,1H),7.02(s,1H),6.09(s,1H),4.46(t,J=6.2Hz,2H),3.81(s,3H),3.81(s,3H),3.24(t,J=6.7Hz,2H),2.09(tt,J=6.2,6.7Hz,2H)。
4-甲氧基-2-丙炔酰胺基-5-(3-(N-丙炔酰基苯甲酰胺基)丙氧基)苯甲酸甲酯(58a)
依循针对化合物4所述的程序,使57a(50mg,0.14mmol)、丙炔酸(0.018mL,0.28mmol)及N,N'-二环己基碳二亚胺(58mg,0.28mmol)于CH2Cl2(15mL)中、在N2下反应,得到58a(61mg,94%)。1H NMR(500MHz,CDCl3)δ11.71(s,1H),8.38(s,1H),7.95(d,J=7.9Hz,2H),7.88(s,1H),7.52(t,J=7.4Hz,1H),7.39(t,J=7.7Hz,2H),4.34(t,J=6.4Hz,2H),3.95(m,1H),3.90(s,3H),3.89(s,3H),3.71(m,1H),2.98(s,1H),2.69(s,1H),2.00(tt,J=6.4,6.7Hz,2H)。
5-(3-(2-氟-N-丙炔酰基苯甲酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58b)
依循针对化合物4所述的程序,使57b(50mg,0.13mmol)、丙炔酸(0.016mL,0.27mmol)及N,N'-二环己基碳二亚胺(55mg,0.27mmol)于CH2Cl2(15mL)中、在N2下反应,得到58b(57mg,89%)。1H NMR(500MHz,CDCl3)δ11.71(s,1H),8.38(s,1H),7.88(s,1H),7.86(td,J=7.6,1.8Hz,1H),7.48(m,1H),7.16(t,J=7.2Hz,1H),7.07(dd,J=10.5,8.4Hz,1H),4.35(t,J=6.5Hz,2H),3.94(m,1H),3.91(s,3H),3.90(s,3H),3.72(m,1H),2.98(s,1H),2.68(s,1H),2.00(tt,J=6.5,7.0Hz,2H)。
5-(3-(3-氟-N-丙炔酰基苯甲酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58c)
依循针对化合物4所述的程序,使57c(90mg,0.24mmol)、丙炔酸(0.029mL,0.48mmol)及N,N'-二环己基碳二亚胺(99mg,0.47mmol)于CH2Cl2(15mL)中、在N2下反应,得到58c(113mg,98%)。1H NMR(500MHz,CDCl3)δ11.71(s,1H),8.39(s,1H),7.75(d,J=7.8Hz,1H),7.61(ddd,J=9.3,2.4,1.5Hz,1H),7.37(m,1H),7.22(m,1H),4.35(t,J=6.3Hz,2H),3.93(m,1H),3.91(s,3H),3.90(s,3H),3.73(m,1H),2.98(s,1H),2.69(s,1H),1.99(tt,J=6.3,6.7Hz,2H)。
5-(3-(4-氟-N-丙炔酰基苯甲酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58d)
依循针对化合物4所述的程序,使57d(70mg,0.19mmol)、丙炔酸(0.023mL,0.37mmol)及N,N'-二环己基碳二亚胺(77mg,0.37mmol)于CH2Cl2(15mL)中、在N2下反应,得到58d(68mg,76%)。1H NMR(500MHz,CDCl3)δ11.71(s,1H),8.39(s,1H),7.98(m,2H),7.87(s,1H),7.06(m,1H),4.33(td,J=6.3,1.6Hz,2H),3.93(m,1H),3.91(s,3H),3.90(s,3H),3.72(m,1H),2.99(s,1H),2.69(s,1H),1.98(tt,J=6.3,6.9Hz,2H)。
5-(3-(2,6-二氟-N-丙炔酰基苯甲酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58e)
依循针对化合物4所述的程序,使57e(100mg,0.25mmol)、丙炔酸(0.031mL,0.51mmol)及N,N'-二环己基碳二亚胺(105mg,0.51mmol)于CH2Cl2(15mL)中、在N2下反应,得到58e(113mg,89%)。1H NMR(500MHz,CDCl3)δ11.73(s,1H),8.39(s,1H),7.89(s,1H),7.37(tt,J=8.5,6.2Hz,1H),6.90(t,J=8.2Hz,2H),4.38(t,J=6.3Hz,2H),3.91(s,6H),3.86(m,1H),3.70(m,1H),2.98(s,1H),2.69(s,1H),1.99(tt,J=6.3,6.9Hz,2H)。
5-(3-(2,6-二甲氧基-N-丙炔酰基苯甲酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58f)
依循针对化合物4所述的程序,使57f(50mg,0.12mmol)、丙炔酸(0.015mL,0.24mmol)及N,N'-二环己基碳二亚胺(49mg,0.24mmol)于CH2Cl2(15mL)中、在N2下反应,得到58f(61mg,98%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.39(s,1H),7.88(s,1H),7.24(m,1H),6.50(d,J=8.4Hz,2H),4.34(t,J=6.3Hz,2H),3.90(s,6H),3.88(m,1H),3.74(s,6H),3.68(m,1H),2.98(s,1H),2.67(s,1H),1.96(tt,J=6.9,7.2Hz,2H)。
4-甲氧基-5-(3-(3-甲氧基-N-丙炔酰基苯甲酰胺基)丙氧基)-2-丙炔酰胺基苯甲酸甲酯(58g)
依循针对化合物4所述的程序,使57g(130mg,0.33mmol)、丙炔酸(0.041mL,0.67mmol)及N,N'-二环己基碳二亚胺(138mg,0.67mmol)于CH2Cl2(15mL)中、在N2下反应,得到58g(127mg,77%)。1H NMR(500MHz,CDCl3)δ11.70(s,1H),8.37(s,1H),7.88(s,1H),7.53(d,J=7.6Hz,1H),7.45(dd,J=2.5,1.6Hz,1H),7.29(t,J=8.0Hz,1H),7.06(dd,J=8.6,2.2Hz,1H),4.33(t,J=6.4Hz,2H),3.94(m,1H),3.90(s,3H),3.89(s,3H),3.81(s,3H),3.72(m,1H),2.98(s,1H),2.69(s,1H),2.00(tt,J=6.4,6.8Hz,2H)。
4-甲氧基-5-(3-(4-甲氧基-N-丙炔酰基苯甲酰胺基)丙氧基)-2-丙炔酰胺基苯甲酸甲酯(58h)
依循针对化合物4所述的程序,使57h(60mg,0.15mmol)、丙炔酸(0.019mL,0.31mmol)及N,N'-二环己基碳二亚胺(64mg,0.31mmol)于CH2Cl2(15mL)中、在N2下反应,得到58h(72mg,95%)。1H NMR(500MHz,CDCl3)δ11.71(s,1H),8.37(s,1H),7.89(m,3H),6.86(d,J=8.8Hz,2H),4.30(t,J=6.0Hz,2H),3.93(m,1H),3.90(s,3H),3.89(s,3H),3.83(s,3H),3.70(m,1H),2.98(s,1H),2.69(s,1H),1.98(tt,J=6.0,6.8Hz,2H)。
4-甲氧基-5-(3-(N-(2-苯乙酰基)丙炔酰胺基)丙氧基)-2-丙炔酰胺基苯甲酸甲酯(58i)
依循针对化合物4所述的程序,使57i(50mg,0.13mmol)、丙炔酸(0.017mL,0.27mmol)及N,N'-二环己基碳二亚胺(55mg,0.27mmol)于CH2Cl2(15mL)中、在N2下反应,得到58i(63mg,98%)。1H NMR(500MHz,CDCl3)δ11.75(s,1H),8.39(s,1H),7.85(s,1H),7.26(m,5H),4.11(t,J=6.3Hz,2H),3.91(s,3H),3.88(s,3H),3.78(m,1H),3.56(s,2H),3.55(m,1H),3.00(s,1H),2.70(s,1H),1.83(tt,J=6.3,6.8Hz,2H)。
5-(3-(N-(2-(2-氟苯基)乙酰基)丙炔酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58j)
依循针对化合物4所述的程序,使57j(50mg,0.13mmol)、丙炔酸(0.018mL,0.26mmol)及N,N'-二环己基碳二亚胺(53mg,0.26mmol)于CH2Cl2(15mL)中、在N2下反应,得到58j(58mg,92%)。1H NMR(500MHz,CDCl3)δ11.75(s,1H),8.40(s,1H),7.86(s,1H),7.21(m,2H),7.05(m,1H),6.98(d,J=9.1Hz,1H),4.13(t,J=6.3,2.2Hz,2H),3.91(s,3H),3.89(s,3H),3.79(m,1H),3.61(s,2H),3.56(m,1H),2.99(s,1H),2.68(s,1H),1.84(tt,J=6.3,6.8Hz,2H)。
5-(3-(N-(2-(3-氟苯基)乙酰基)丙炔酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58k)
依循针对化合物4所述的程序,使57k(65mg,0.17mmol)、丙炔酸(0.020mL,0.33mmol)及N,N'-二环己基碳二亚胺(69mg,0.33mmol)于CH2Cl2(15mL)中、在N2下反应,得到58k(79mg,96%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.39(s,1H),7.85(s,1H),7.23(m,1H),6.99(d,J=7.5Hz,1H),6.92(m,2H),4.12(t,J=6.0Hz,2H),3.91(s,3H),3.89(s,3H),3.78(m,1H),3.56(m,3H),2.99(s,1H),2.68(s,1H),1.84(tt,J=6.0,6.9Hz,2H)。
5-(3-(N-(2-(4-氟苯基)乙酰基)丙炔酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58l)
依循针对化合物4所述的程序,使57l(90mg,0.23mmol)、丙炔酸(0.028mL,0.46mmol)及N,N'-二环己基碳二亚胺(95mg,0.46mmol)于CH2Cl2(15mL)中、在N2下反应,得到58l(112mg,98%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.40(s,1H),7.84(s,1H),7.18(dd,J=8.5,5.4Hz,2H),6.95(t,J=8.7Hz,2H),4.11(t,J=6.3Hz,2H),3.91(s,3H),3.89(s,3H),3.77(m,1H),3.57(m,1H),3.54(s,2H),2.99(s,1H),2.68(s,1H),1.83(tt,J=6.3,6.8Hz,2H)。
4-甲氧基-5-(3-(N-(2-(2-甲氧苯基)乙酰基)丙炔酰胺基)丙氧基)-2-丙炔酰胺基苯甲酸甲酯(58m)
依循针对化合物4所述的程序,使57m(50mg,0.12mmol)、丙炔酸(0.015mL,0.25mmol)及N,N'-二环己基碳二亚胺(51mg,0.25mmol)于CH2Cl2(15mL)中、在N2下反应,得到58m(49mg,78%)。1H NMR(500MHz,CDCl3)δ11.75(s,1H),8.39(s,1H),7.86(s,1H),7.20(td,J=3.9,1.5Hz,1H),7.11(dd,J=7.4,1.4Hz,1H),6.85(m,1H),6.81(d,J=8.3Hz,1H),4.11(td,J=6.3,2.1Hz,2H),3.90(s,3H),3.89(s,3H),3.80(m,1H),3.75(s,3H),3.56(s,2H),3.59(m,1H),2.99(s,1H),2.68(s,1H),1.83(tt,J=6.3,6.8Hz,2H)。
4-甲氧基-5-(3-(N-(2-(3-甲氧基苯基)乙酰基)丙炔酰胺基)丙氧基)-2-丙炔酰胺基苯甲酸甲酯(58n)
依循针对化合物4所述的程序,使57n(65mg,0.16mmol)、丙炔酸(0.020mL,0.32mmol)及N,N'-二环己基碳二亚胺(67mg,0.32mmol)于CH2Cl2(15mL)中、在N2下反应,得到58n(70mg,86%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.39(s,1H),7.84(s,1H),7.17(dd,J=8.9,7.7Hz,1H),6.78(m,3H),4.11(t,J=6.3Hz,2H),3.91(s,3H),3.89(s,3H),3.79(m,1H),3.76(s,3H),3.57(m,1H),3.53(s,2H),2.99(s,1H),2.68(s,1H),1.84(tt,J=6.3,6.8Hz,2H)。
4-甲氧基-5-(3-(N-(2-(4-甲氧基苯基)乙酰基)丙炔酰胺基)丙氧基)-2-丙炔酰胺基苯甲酸甲酯(58o)
依循针对化合物4所述的程序,使57o(90mg,0.22mmol)、丙炔酸(0.028mL,0.45mmol)及N,N'-二环己基碳二亚胺(92mg,0.45mmol)于CH2Cl2(15mL)中、在N2下反应,得到58o(80mg,71%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.39(s,1H),7.85(s,1H),7.12(d,J=8.6Hz,2H),6.79(m,2H),4.10(t,J=6.3Hz,2H),3.91(s,3H),3.89(s,3H),3.80(m,1H),3.76(s,3H),3.56(m,1H),3.49(s,2H),2.99(s,1H),2.68(s,1H),1.83(tt,J=6.3,6.7Hz,2H)。4-甲氧基-2-丙炔酰胺基-5-(3-(N-(2-(3,4,5-三甲氧基苯基)乙酰基)丙炔酰胺基)丙氧基)苯甲酸甲酯(58p)
依循针对化合物4所述的程序,使57p(75mg,0.16mmol)、丙炔酸(0.020mL,0.32mmol)及N,N'-二环己基碳二亚胺(67mg,0.32mmol)于CH2Cl2(15mL)中、在N2下反应,得到58p(80mg,87%)。1H NMR(500MHz,CDCl3)δ11.73(s,1H),8.40(s,1H),7.86(s,1H),6.47(s,2H),4.12(t,J=6.3Hz,2H),3.91(s,3H),3.90(s,3H),3.82(m,7H),3.80(s,3H),3.60(m,1H),3.51(s,2H),2.99(s,1H),2.68(s,1H),1.84(tt,J=6.3,6.7Hz,2H)。5-(3-(N-(2-(2-氯苯基)乙酰基)丙炔酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58q)
依循针对化合物4所述的程序,使57q(80mg,0.20mmol)、丙炔酸(0.024mL,0.39mmol)及N,N'-二环己基碳二亚胺(81mg,0.39mmol)于CH2Cl2(15mL)中、在N2下反应,得到58q(100mg,99%)。1H NMR(500MHz,CDCl3)δ11.75(s,1H),8.40(s,1H),7.85(s,1H),7.30(dd,J=5.6,3.6Hz,1H),7.22(m,1H),7.18(m,2H),4.13(t,J=6.1Hz,2H),3.91(s,3H),3.89(s,3H),3.78(m,1H),3.70(s,2H),3.56(m,1H),2.99(s,1H),2.68(s,1H),1.85(tt,J=6.1,6.7Hz,2H)。5-(3-(N-(2-(3-氯苯基)乙酰基)丙炔酰胺基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(58r)
依循针对化合物4所述的程序,使57r(75mg,0.18mmol)、丙炔酸(0.023mL,0.37mmol)及N,N'-二环己基碳二亚胺(76mg,0.37mmol)于CH2Cl2(15mL)中、在N2下反应,得到58r(84mg,89%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.39(s,1H),7.85(s,1H),7.21(s,1H),7.19(m,2H),7.10(m,1H),4.12(t,J=6.4Hz,2H),3.91(s,3H),3.89(s,3H),3.78(m,1H),3.57(m,1H),3.54(s,2H),2.99(s,1H),2.68(s,1H),1.84(tt,J=6.4,6.8Hz,2H)。4-甲氧基-2-丙炔酰胺基-5-(3-(N-(2-(2-(三氟甲基)苯基)乙酰基)丙炔酰胺基)丙氧基)苯甲酸甲酯(58s)
依循针对化合物4所述的程序,使57s(100mg,0.23mmol)、丙炔酸(0.028mL,0.45mmol)及N,N'-二环己基碳二亚胺(94mg,0.45mmol)于CH2Cl2(15mL)中、在N2下反应,得到58s(116mg,94%)。1H NMR(500MHz,CDCl3)δ11.75(s,1H),8.39(s,1H),7.85(s,1H),7.59(d,J=7.8Hz,1H),7.47(t,J=7.7Hz,1H),7.34(t,J=7.4Hz,2H),4.12(t,J=6.0Hz,2H),3.91(s,3H),3.89(s,3H),3.76(m,3H),3.55(m,1H),2.99(s,1H),2.68(s,1H),1.83(tt,J=6.0,6.8Hz,2H)。4-甲氧基-2-丙炔酰胺基-5-(3-(N-(2-(3-(三氟甲基)苯基)乙酰基)丙炔酰胺基)丙氧基)苯甲酸甲酯(58t)
依循针对化合物4所述的程序,使57t(75mg,0.17mmol)、丙炔酸(0.021mL,0.34mmol)及N,N'-二环己基碳二亚胺(70mg,0.34mmol)于CH2Cl2(15mL)中、在N2下反应,得到58t(92mg,99%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.40(s,1H),7.85(s,1H),7.49(m,2H),7.41(m,2H),7.34(t,J=7.4Hz,2H),4.13(t,J=6.3Hz,2H),3.91(s,3H),3.89(s,3H),3.78(m,1H),3.64(s,2H),3.59(m,1H),2.99(s,1H),2.68(s,1H),1.84(tt,J=6.3,6.8Hz,2H)。4-甲氧基-2-丙炔酰胺基-5-(3-(N-(2-(4-(三氟甲基)苯基)乙酰基)丙炔酰胺基)丙氧基)苯甲酸甲酯(58u)
依循针对化合物4所述的程序,使57u(102mg,0.23mmol)、丙炔酸(0.029mL,0.46mmol)及N,N'-二环己基碳二亚胺(96mg,0.46mmol)于CH2Cl2(15mL)中、在N2下反应,得到58u(115mg,91%)。1H NMR(500MHz,CDCl3)δ11.74(s,1H),8.41(s,1H),7.86(s,1H),7.54(d,J=8.2Hz,2H),7.35(d,J=8.0Hz,2H),4.13(t,J=6.3Hz,2H),3.91(s,3H),3.90(s,3H),3.79(m,1H),3.64(d,2H),3.60(m,1H),2.99(s,1H),2.69(s,1H),1.83(tt,J=6.3,6.8Hz,2H)。4-甲氧基-2-丙炔酰胺基-5-(3-(N-丙炔酰基噁唑-5-甲酰胺基)丙氧基)苯甲酸甲酯(58v)
依循针对化合物4所述的程序,使57v(100mg,0.29mmol)、丙炔酸(0.035mL,0.57mmol)及N,N'-二环己基碳二亚胺(118mg,0.57mmol)于CH2Cl2(15mL)中、在N2下反应,得到58v(118mg,91%)。1H NMR(500MHz,CDCl3)δ11.72(s,1H),8.40(s,1H),7.97(s,1H),7.89(s,1H),7.72(s,1H),4.37(t,J=6.4Hz,2H),3.91(s,6H),3.87(m,1H),3.70(m,1H),2.99(s,1H),2.69(s,1H),1.97(tt,J=6.3,6.8Hz,2H)。
流程18
试剂及条件:(i)3-(boc-氨基)-1-丙醇、DIAD、Ph3P、THF、RT;(ii)Zn、AcOH、THF、RT;(iii)丙炔酸、DCC、CH2Cl2、0℃
5-(3-((叔丁氧基羰基)氨基)丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯(59)
在冰浴中,向46(300mg,1.32mmol)及三苯膦(692mg,2.64mmol)于无水THF(30mL)中的溶液中逐滴添加3-(boc-氨基)-1-丙醇(0.270mL,1.58mmol)及偶氮二甲酸二异丙酯(6.93mL,35.19mmol)。所得溶液在N2下、在室温下搅拌6小时。将反应混合物悬浮于H2O(150mL)中且接着用EtOAc(3×150mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:3)纯化,得到59(500mg,99%)。1H NMR(300MHz,CDCl3)δ7.43(s,1H),7.04(s,1H),5.18(s,1H),4.16(t,J=5.9Hz,2H),3.95(s,3H),3.88(s,3H),3.34(m,2H),2.04(m,2H),1.43(m,9H)。
2-氨基-5-(3-((叔丁氧基羰基)氨基)丙氧基)-4-甲氧基苯甲酸甲酯(60)
依循针对化合物38所述的程序,向59(50mg,0.13mmol)于HOAc/THF=1:4(10mL)中的反应物中添加Zn(85mg,1.30mmol)且在N2下、在室温下搅拌混合物,得到60(33mg,72%)。1H NMR(300MHz,CDCl3)δ7.29(s,1H),7.11(s,1H),5.58(s,2H),5.45(s,1H),3.99(t,J=5.8Hz,2H),3.84(s,3H),3.82(s,3H),3.33(m,2H),1.94(m,2H),1.43(s,9H)。
5-(3-((叔丁氧基羰基)氨基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸甲酯(61)
依循针对化合物4所述的程序,在冰浴中,向60(33mg,0.09mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.009mL,0.14mmol)及N,N'-二环己基碳二亚胺(29mg,0.14mmol)的无水CH2Cl2(5mL),得到61(37mg,98%)。1H NMR(300MHz,CDCl3)δ11.56(s,1H),8.32(s,1H),7.44(s,1H),4.07(t,J=5.6Hz,2H),3.93(s,3H),3.90(s,3H),3.35(m,2H),1.99(m,2H),1.43(s,9H)。
流程19
试剂及条件:(i)苯甲酸、DCC、CH2Cl2、RT;(ii)K2CO3、DMF、100℃;(iii)Zn、AcOH、THF、RT;(iv)丙炔酸、DCC、CH2Cl2、0℃
(Z)-N-(3-氯丙基)苯甲酰亚胺酸(63)
在冰浴中,向62(100mg,0.77mmol)于无水CH2Cl2(10mL)中的溶液中逐滴添加含有苯甲酸(140mg,1.12mmol)及N,N'-二环己基碳二亚胺(238mg,1.15mmol)的无水CH2Cl2(5mL)。所得溶液在N2下、在室温下搅拌12小时。将反应混合物悬浮于H2O(50mL)中且接着用EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。过滤混合物且用EtOAc/正己烷=1:1(10mL)洗涤。残余物藉由硅胶层析(EtOAc/正己烷=1:3)纯化,得到63(142mg,93%)。1H NMR(300MHz,CDCl3)δ7.74(m,2H),7.45(m,3H),6.38(s,1H),3.62(m,4H),2.11(m,2H)。
(Z)-N-(3-(2-甲氧基-5-(甲氧基羰基)-4-硝基苯氧基)丙基)苯甲酰亚胺酸(64)
依循针对化合物2所述的程序,向46(1.72g,7.59mmol)及K2CO3(2.10g,15.17mmol)于DMF(150mL)中的反应物中添加63(1.50g,7.59mmol)。所得溶液在N2下加热至100℃,得到64(359mg,12%)。1H NMR(300MHz,CDCl3)δ7.78(m,2H),7.45(m,4H),7.08(s,1H),6.91(s,1H),4.25(t,J=5.7Hz,2H),3.88(s,3H),3.76(s,3H),3.70(m,2H),2.19(m,2H)。
(Z)-N-(3-(4-氨基-2-甲氧基-5-(甲氧基羰基)苯氧基)丙基)苯甲酰亚胺酸(65)
依循针对化合物38所述的程序,向64(80mg,0.21mmol)于HOAc/THF=1:4(10mL)中的反应物中添加Zn(134mg,2.06mmol)且在N2下、在室温下搅拌混合物,得到65(69mg,93%)。1H NMR(300MHz,CDCl3)δ7.80(m,2H),7.42(m,3H),7.33(s,1H),7.29(s,1H),6.10(s,1H),5.60(s,2H),4.10(t,J=5.5Hz,2H),3.82(s,3H),3.69(m,2H),3.62(s,3H),2.09(m,2H)。
(Z)-N-(3-(2-甲氧基-5-(甲氧基羰基)-4-丙炔酰胺基苯氧基)丙基)苯甲酰亚胺酸(66)
依循针对化合物4所述的程序,在冰浴中,向65(35mg,0.10mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.010mL,0.15mmol)及N,N'-二环己基碳二亚胺(30mg,0.15mmol)的无水CH2Cl2(5mL),得到66(26mg,65%)。1H NMR(300MHz,CDCl3)δ11.54(s,1H),8.30(s,1H),7.79(m,2H),7.44(m,4H),7.16(s,1H),4.17(t,J=5.5Hz,2H),3.90(s,3H),3.70(m,5H),2.92(s,1H),2.14(m,2H)。
流程20
试剂及条件:(i)NaOH、MeOH、THF、RT;(ii)(CH3)3Si(CH2)2OH、Ph3P、DIAD、THF、RT;(iii)Zn、AcOH、THF、RT;(iv)丙炔酸(propiolic acid)、DCC、CH2Cl2、0℃;(v)TBAF、THF、RT。
(Z)-5-(3-((羟基(苯基)亚甲基)氨基)丙氧基)-4-甲氧基-2-硝基苯甲酸(67)
在冰浴中,向64(229mg,0.59mmol)于MeOH(20mL)及THF(20mL)中的溶液中添加5NNaOH(2.5mL)。在室温下、在N2下搅拌反应混合物8小时。将所得溶液酸化至pH 2且用1N HCl(50mL)及EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。使残余物再结晶,得到67(220mg,99%)。1HNMR(300MHz,MeOD)δ7.84(m,2H),7.52(m,4H),7.31(s,1H),4.28(t,J=6.0Hz,2H),3.88(s,3H),3.64(t,J=6.6Hz,2H),2.19(m,2H)。
(Z)-N-(3-(2-甲氧基-4-硝基-5-((2-(三甲基硅烷基)乙氧基)羰基)苯氧基)丙基)苯甲酰亚胺酸(68)
在冰浴中,向67(210mg,0.56mmol)及三苯膦(294mg,1.12mmol)于无水THF(30mL)中的溶液中逐滴添加2-(三甲基硅烷基)乙醇(0.097mL,0.67mmol)及偶氮二甲酸二异丙酯(0.133mL,0.67mmol)。所得溶液在N2下搅拌3小时。将反应混合物悬浮于H2O(100mL)中且接着用EtOAc(3×100mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(EtOAc/正己烷=1:2)纯化,得到68(221mg,83%)。1H NMR(300MHz,CDCl3)δ7.78(m,2H),7.47(m,3H),7.39(s,1H),7.07(s,1H),6.91(s,1H),4.38(m,2H),4.25(t,J=5.7Hz,2H),3.75(s,3H),3.71(m,2H),2.19(m,2H),1.07(m,2H),0.04(s,9H)。
(Z)-N-(3-(4-氨基-2-甲氧基-5-((2-(三甲基硅烷基)乙氧基)羰基)苯氧基)丙基)苯甲酰亚胺酸(69)
依循针对化合物38所述的程序,向68(50mg,0.11mmol)于HOAc/THF=1:4(10mL)中的反应物中添加Zn(69mg,1.05mmol)且在N2下、在室温下搅拌混合物,得到69(40mg,85%)。1H NMR(300MHz,CDCl3)δ7.80(m,2H),7.42(m,3H),7.34(s,1H),7.31(s,1H),6.09(s,1H),5.60(s,2H),4.33(m,2H),4.09(t,J=7.1Hz,2H),3.69(m,2H),3.61(s,3H),2.09(m,2H),1.09(m,2H),0.06(m,9H)。
(Z)-N-(3-(2-甲氧基-4-丙炔酰胺基-5-((2-(三甲基硅烷基)乙氧基)羰基)苯氧基)丙基)苯甲酰亚胺酸(70)
依循针对化合物4所述的程序,在冰浴中,向69(170mg,0.38mmol)于无水CH2Cl2(10mL)中的反应物中逐滴添加含有丙炔酸(0.035mL,0.15mmol)及N,N'-二环己基碳二亚胺(118mg,0.57mmol)的无水CH2Cl2(5mL),得到70(180mg,95%)。1H NMR(300MHz,CDCl3)δ11.64(s,1H),8.31(s,1H),7.80(m,2H),7.43(m,4H),7.17(s,1H),4.40(m,2H),4.17(t,J=5.5Hz,2H),3.71(m,5H),2.91(s,1H),2.14(m,2H),1.13(m,2H),0.07(s,9H)。
(Z)-5-(3-((羟基(苯基)亚甲基)氨基)丙氧基)-4-甲氧基-2-丙炔酰胺基苯甲酸(71)
在室温下,向70(50mg,0.10mmol)于无水THF(2mL)中的溶液中逐滴添加TBAF(1M于THF中,0.50mL,0.50mmol)。所得溶液在N2下搅拌12小时。反应混合物用1N HCl(aq)(50mL)及EtOAc(3×50mL)萃取。合并的有机层经MgSO4干燥,过滤且真空浓缩。残余物藉由硅胶层析(MeOH/CH2Cl2=3:97)纯化,得到71(19mg,48%)。1H NMR(300MHz,DMSO)δ11.87(s,1H),8.52(t,J=5.5Hz,1H),8.08(s,1H),7.83(m,2H),7.48(m,3H),4.47(s,1H),4.04(t,J=6.2Hz,2H),3.80(s,3H),3.02(m,2H),1.98(m,2H)。
PDIA4分析
将重组PDI蛋白质PDIA4(23pM)与胰岛素(0.2mM)及DTT(0.1mM)一起在媒剂及指定剂量的化合物存在下、在25℃下培育30分钟。使用SpectraMax i3x读取器,基于制造商说明书(Molecular device,CA,USA),在595nm下量测混合物。依据如先前所公开的式:100%×(媒剂的OD595-CP的OD595)/(媒剂的OD595)来计算PDIA4酶活性的抑制。
葡萄糖刺激的胰岛素分泌
除非另外指明,否则使Min6细胞在含有10%胎牛血清、100个单位/毫升青霉素及100g/ml链霉素的杜尔贝科氏改良伊格尔氏培养基(Dulbecco's modified Eagle medium,DMEM)完全培养基中、在3.3mM葡萄糖存在下、在5%CO2培育箱中生长。使Min6细胞在含有3.3mM葡萄糖的氧饱和无血清克雷布斯-林格氏碳酸氢盐(KRB)缓冲液中、在37℃下预培育30分钟。接着将细胞(7.5×104)与含有高葡萄糖(16.7mM)或低葡萄糖(3.3mM)的KRB缓冲液一起再培育30分钟。收集上清液用于胰岛素ELISA分析。
细胞存活率测试
在37℃下,在完全培养基中培养Min6细胞。根据制造商指导原则,使用WST-1(4-[3-(4-碘苯基)-2-(4-硝基苯基)-2H-5-四唑]-1,3-苯二磺酸盐)测定细胞的细胞毒性。简言之,使细胞在含有完全培养基的96孔盘中、在指定的化合物存在下生长24小时。在PBS洗涤之后,将WST-1添加至各孔中再培育20分钟。移除培养基之后,使用SpectraMax i3x读取器,在450nm下量测培养盘中的细胞。
统计资料
来自三个或更多个独立实验的数据以平均值±标准偏差(SD)呈现。除非另外指明,否则使用ANOVA执行多组之间的比较。P<0.05(*)、<0.01(**)或<0.001(***)被认为是在对照组与治疗组之间具有统计显著性。
表1-表5显示PDIA4抑制剂的IC50值。
表1
表2
表3
表4
表5
结果
自苗头化合物至先导化合物中筛选出PDIA4抑制剂.
如图1中所述,应用虚拟筛选及PDIA4来搜寻苗头化合物、先导化合物及/或候选药物。虚拟筛选的细节描绘于实验程序(图1)。在261种植物化学成分中,鉴别出聚多炔糖苷(cytopiloyne)(CPD P1,表1)及聚多炔糖苷配基(CPD P2,表1)为两种最佳苗头化合物。图2显示CPD P1分子对接入具有3个活性模体的PDIA4中。建立PDIA4分析平台以量测CPD P2的半数最大抑制浓度(IC50)(167.9μM,表1)。
基于PDIA4的候选药物的表征.
接下来,基于CP/CPA的药效基团特征及PDIA4的结合袋,利用虚拟筛选自ZINC数据库中选出具有1至3个碳/碳三键(CCTB)的十种化合物,包括(E)-7-(己-2,4-二炔-1-亚基)-1,6-二氧杂螺[4.4]壬-2,8-二烯-4-基乙酸酯(C1)、(Z)-5-(己-2,4-二炔-1-亚基)呋喃-2(5H)-酮(C2)、1-苯基己-2,4-二炔-1,6-二醇(C3)、N-苯基丙炔酰胺(C4)、(2-(N-(2,4-二甲氧基苯基)丙炔酰胺基)-2-(噻吩-2-基)乙酰基)甘氨酸乙酯(C5)、3-甲基丁-2-烯酸(E)-7-(己-2,4-二炔-1-亚基)-1,6-二氧杂螺[4.4]壬-2,8-二烯-4-基酯(C6)、1-苯基丁-2-炔-1,4-二醇(C7)、N-(4-(丁-2-炔-1-基氨基)苯基)乙酰胺(C8)、己-2,4-二炔-1,6-二基双(2-苯基乙酸酯),及二苯甲酸己-2,4-二炔-1(C9)及6-二基酯(C10),且量测IC50值以试图确定先导化合物的核心结构(表1)。选择N-苯基丙炔酰胺(C4)(IC50=182.7μM,表1)作为活性核心结构,以针对先导化合物进行子结构搜寻。因此,选择含有N-苯基丙炔酰胺核心结构(C4)的(4-丙炔酰胺基苯甲酰基)甘氨酸(C11)、2-(4-丙炔酰胺基苯基)乙酸(C12)、4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)、4-丙炔酰胺基苯甲酸(C13)及2-羟基-5-丙炔酰胺基苯甲酸(C14)且测试其IC50值(表2)。结果,4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)作为潜在的先导化合物而突显出来,其IC50值为4μM,为苗头化合物CPD P1的53倍高(表2)。4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)由4,5-二甲氧基-2-硝基苯甲酸(1)基于流程2合成。
为了优化4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8),基于流程1及2将4,5-二甲氧基-2-硝基苯甲酸(1)化学修饰成化合物2-8。结果,4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)作为潜在的先导化合物而突显出来,其IC50值为4μM,为苗头化合物CPA的40倍高(表1及表2)。另外,基于流程3-20对4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)进行化学修饰。合成化合物9-58v且测试其对PDIA4的抑制(表1)。其IC50值显示于表3及表4中。关于CPD 1-58v的合成及结构说明的细节描述于材料及方法的化学处理章节中。因此,若干化合物8、58v、58s及58t具有低IC50值且可以用作候选药物。
所选PDIA4抑制剂对β细胞的胰岛素分泌及细胞存活率的药理学效应
接下来,我们检查所选PDIA4抑制剂CCF642(市售PDIA4抑制剂)及CPD P1、8、58v、58s及58t对Min6(小鼠β细胞)的胰岛素释放作用的影响。我们发现,CCF642及CPD P1、8、58v、58s及58t分别具有0.25μM、1.55μM、0.06μM、0.005μM、0.03μM及0.02μM的EC50值(图3及表2)。相比之下,对Min 6细胞释放胰岛素稍微具有影响。相应地,CCF642及CPD P1、8、58v、58s及58t分别具有23.9、>100、>100、>100、>100及64.9的CC50值(图3及表1-表4)。数据表明类似于CCF642,CPD P1、8、58v、58s及58t可以增强β细胞分泌胰岛素。图2中显示CPD8分子对接入具有3个活性模体的PDIA4。数据表明CPD 8与PDIA4的配合比CPD P1更佳(图2)。
所选PDIA4抑制剂对db/db小鼠糖尿病的药理学效应
此外,我们检查CPD 8(用于抑制Pdia4的候选药物之一)在db/db小鼠(2型糖尿病小鼠模型)中的活体内抗糖尿病作用。正如所预期,用作阳性对照物的30mg/kg西格列汀(sitagliptin,STG)使db/db小鼠的空腹血糖(FBG)显著降低(图4A)。2.5mg/kg剂量的CPD 8使db/db小鼠的FBG显著降低(图3A)。另外,CPD 8(2.5mg/kg)与二甲双胍(60mg/kg)的组合使db/db小鼠的FBG降低超过单独的CPD 8(图4A)。相应地,用作阳性对照物的30mg/kg西格列汀使db/db小鼠的餐后血糖(PBG)显著降低(图4B)。2.5mg/kg剂量的CPD 8使db/db小鼠的FBG显著降低(图4B)。另外,CPD 8(2.5mg/kg)与二甲双胍(60mg/kg)的组合使db/db小鼠的PBG降低超过单独的CPD8(图4B)。总体数据证明,CPD 8(基于PDIA4的候选药物之一)本身及组合可逆转db/db小鼠的2型糖尿病。
总之,胰脏β细胞衰竭为2型糖尿病(T2D)的标志。高度需要在早期糖尿病阶段保持β细胞功能/质量、从而可逆转T2D的策略。本发明涉及使用分子对接与PDIA4生物分析的组合自苗头化合物至先导化合物中筛选出基于PDIA4的抑制剂。N-苯基丙炔酰胺(C4)经鉴别为PDIA4抑制剂的活性核心结构。使用化学合成、分子对接及PDIA4生物分析的组合,鉴别出4,5-二甲氧基-2-丙炔酰胺基苯甲酸(8)为先导化合物。基于化合物与PDIA4的结构及之间的活性关系,合成48种化合物(表6)且表征。结果,鉴别出IC50值为4μM至300nM的若干候选药物,包括CPD P1、8、58v、58s及58t。针对β细胞功能及糖尿病治疗来测试这些化合物。类似于CCF642(市售PDIA4抑制剂),CPD P1、8、58v、58s及58t对β细胞的胰岛素分泌具有较高活性。相应地,单独及组合的CPD 8可以治疗及逆转db/db小鼠的T2D(糖尿病小鼠模型)。总体数据表明PDIA4为2型糖尿病(T2D)的新颖治疗标靶。表6说明本发明化合物。
表6
本说明书中引用及论述的所有参考文献均以全文引用的方式并入本文中,其引用程度如同各参考文献个别地以引用的方式并入一般。
权利要求书(按照条约第19条的修改)
1.一种式(I)化合物或其医药学上可接受的盐,
其中:
R1为-C(=O)OR6;
R2为H、(C1-C6)烷基、苯甲基,或-L-R11,其中L为键或(C1-C6)亚烷基,且R11为苯基、卤基、二氧代异吲哚啉、-NR7R8,或-NR7-CO-R8;
R3为H、(C1-C6)烷基,或苯甲基;
R4为H或(C1-C6)烷氧基;
R5为(C1-C6)胺、-NR7R8,或-NR7-CO-R8;
X1及X2各自独立地为-O-、-S-或共价键;
R6为H、卤素、(C1-C6)烷基、(C1-C6)芳基、苯甲基、卤基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烃,其中n为1至6;
R7及R8各自独立地为H、(C1-C6)烷氧基、苯基、苯甲酰基、卤基苯甲酰基、苯甲基、羰基(C1-C6)炔烃、(C1-C6)炔烃、噁唑、噻唑或咪唑;其中所述(C1-C6)烷氧基、苯基、苯甲酰基及/或苯甲基视情况各自独立地经一或多个选自F、Cl、Br、I、(C1-C6)烷氧基、(C1-C6)烷基或卤基(C1-C6)烷基的取代基取代;或R7及R8连同N原子一起形成苯甲酰亚胺酸。
2.如权利要求1所述的化合物或其医药学上可接受的盐,其中R6为H或(C1-C6)烷基、苯甲基、卤基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烃。
3.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中
R2为(C1-C6)烷基,或-L-R11,其中L为(C1-C6)亚烷基,且R11为二氧代异吲哚啉、-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H、苯基、苯甲酰基、卤基苯甲酰基、苯甲基、羰基(C1-C6)炔烃,或噁唑。
4.如权利要求3所述的化合物或其医药学上可接受的盐,其中所述苯基、苯甲酰基及/或苯甲基各自独立地经一或多个选自F、Cl、Br、I或卤基(C1-C6)烷基的取代基取代。
5.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中R5为-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H或羰基(C1-C6)炔烃。
6.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中R5为(C1-C6)胺。
7.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中R6为羰基(C1-C6)炔烃。
8.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为-L-R11,其中L为(C1-C6)亚烷基,且R11为-NR7R8,其中R7及R8连同N原子一起形成苯甲酰亚胺酸。
9.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为-L-R11,R11为-NR7R8或-NR7-CO-R8;R7为羰基(C1-C6)炔烃且R8为苯甲酰基。
10.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为(C1-C6)烷基;R3为(C1-C6)烷基,R4为H;R5为-NR7-CO-R8,其中R7为H且R8为(C2)炔烃。
11.如权利要求1所述的化合物或其医药学上可接受的盐,其中R5为-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H、羰基(C1-C6)炔烃,或(C1-C6)炔烃。
12.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为-L-R11,其中L为(C1-C6)亚烷基,且R11为二氧代异吲哚啉或-NR7R8,其中R7及R8各自独立地为苯甲酰基或羰基(C1-C6)炔烃。
13.如权利要求1所述的化合物或其医药学上可接受的盐,其选自由以下组成的群:
14.一种医药组合物,其包含:
(a)如权利要求1至13中任一项所述的化合物或其医药学上可接受的盐;及
(b)二甲双胍。
15.一种如权利要求1至13中任一项所述的化合物或其医药学上可接受的盐或如权利要求14的医药组合物的用途,其用于制造供在有需要的个体中增强胰脏β细胞所分泌的胰岛素、治疗糖尿病及/或逆转及恢复血糖浓度至正常水平的药剂。
Claims (15)
1.一种式(I)化合物或其医药学上可接受的盐,
其中:
R1为-C(=O)OR6;
R2为H、(C1-C6)烷基、苯甲基,或-L-R11,其中L为键或(C1-C6)亚烷基,且R11为苯基、卤基、二氧代异吲哚啉、-NR7R8,或-NR7-CO-R8;
R3为H、(C1-C6)烷基,或苯甲基;
R4为H或(C1-C6)烷氧基;
R5为H、(C1-C6)胺、硝基、-NR7R8,或-NR7-CO-R8;
X1及X2各自独立地为-O-、-S-或共价键;
R6为H、卤素、(C1-C6)烷基、(C1-C6)芳基、苯甲基、卤基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烃,其中n为1至6;
R7及R8各自独立地为H、(C1-C6)烷氧基、苯基、苯甲酰基、卤基苯甲酰基、苯甲基、羰基(C1-C6)炔烃、(C1-C6)炔烃、噁唑、噻唑或咪唑;其中所述(C1-C6)烷氧基、苯基、苯甲酰基及/或苯甲基视情况各自独立地经一或多个选自F、Cl、Br、I、(C1-C6)烷氧基、(C1-C6)烷基或卤基(C1-C6)烷基的取代基取代;或R7及R8连同N原子一起形成苯甲酰亚胺酸。
2.如权利要求1所述的化合物或其医药学上可接受的盐,其中R6为H或(C1-C6)烷基、苯甲基、卤基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烃。
3.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中
R2为(C1-C6)烷基,或-L-R11,其中L为(C1-C6)亚烷基,且R11为二氧代异吲哚啉、-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H、苯基、苯甲酰基、卤基苯甲酰基、苯甲基、羰基(C1-C6)炔烃,或噁唑。
4.如权利要求3所述的化合物或其医药学上可接受的盐,其中所述苯基、苯甲酰基及/或苯甲基各自独立地经一或多个选自F、Cl、Br、I或卤基(C1-C6)烷基的取代基取代。
5.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中R5为-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H或羰基(C1-C6)炔烃。
6.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中R5为硝基。
7.如权利要求1或2所述的化合物或其医药学上可接受的盐,其中R6为羰基(C1-C6)炔烃。
8.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为-L-R11,其中L为(C1-C6)亚烷基,且R11为-NR7R8,其中R7及R8连同N原子一起形成苯甲酰亚胺酸。
9.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为-L-R11,R11为-NR7R8或-NR7-CO-R8;R7为羰基(C1-C6)炔烃且R8为苯甲酰基。
10.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为(C1-C6)烷基;R3为(C1-C6)烷基,R4为H;R5为-NR7-CO-R8,其中R7为H且R8为(C2)炔烃。
11.如权利要求1所述的化合物或其医药学上可接受的盐,其中R5为-NR7R8或-NR7-CO-R8,其中R7及R8各自独立地为H、羰基(C1-C6)炔烃,或(C1-C6)炔烃。
12.如权利要求1所述的化合物或其医药学上可接受的盐,其中R2为-L-R11,其中L为(C1-C6)亚烷基,且R11为二氧代异吲哚啉或-NR7R8,其中R7及R8各自独立地为苯甲酰基或羰基(C1-C6)炔烃。
14.一种医药组合物,其包含:
(a)如权利要求1至13中任一项所述的化合物或其医药学上可接受的盐;及
(b)二甲双胍。
15.一种如权利要求1至13中任一项所述的化合物或其医药学上可接受的盐或如权利要求14的医药组合物的用途,其用于制造供在有需要的个体中增强胰脏β细胞所分泌的胰岛素、治疗糖尿病及/或逆转及恢复血糖浓度至正常水平的药剂。
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US201962942314P | 2019-12-02 | 2019-12-02 | |
US62/942,314 | 2019-12-02 | ||
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1229010A1 (en) * | 1999-10-01 | 2002-08-07 | Japan Energy Corporation | Novel diarylamide derivatives and use thereof as medicines |
US20080319194A1 (en) * | 2005-07-04 | 2008-12-25 | Albrecht Jacobi | Process for Preparing Quinazolinone Derivatives |
US20190119664A1 (en) * | 2016-03-28 | 2019-04-25 | Research Institute Of Innovative Technology For The Earth | Transformant, and method for producing protocatechuic acid or salt thereof using same |
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US9382330B2 (en) * | 2010-05-10 | 2016-07-05 | Academia Sinica | Pdia4, target of cytopiloyne derivatives, for tumor diagnosis and treatment |
CN106061261B (zh) * | 2013-11-01 | 2018-04-24 | 卡拉制药公司 | 治疗化合物的结晶形式及其用途 |
US9700042B2 (en) * | 2014-02-07 | 2017-07-11 | Shaker A. Mousa | Nanoformulation of musk-derived bioactive ingredients for nanocosmetic applications |
CN106535903A (zh) * | 2014-04-10 | 2017-03-22 | 中央研究院 | 以pdia4蛋白作为糖尿病的诊断、监测及治疗的目标 |
CN104725327B (zh) * | 2015-03-03 | 2017-08-25 | 山东大学 | 一种盐酸厄洛替尼的环保制备方法 |
CN105001168A (zh) * | 2015-08-25 | 2015-10-28 | 佛山市赛维斯医药科技有限公司 | 三烷氧基取代的苯并喹唑啉类酪氨酸激酶抑制剂及其用途 |
AU2019232437A1 (en) * | 2018-03-07 | 2020-10-08 | Bayer Aktiengesellschaft | Identification and use of ERK5 inhibitors |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1229010A1 (en) * | 1999-10-01 | 2002-08-07 | Japan Energy Corporation | Novel diarylamide derivatives and use thereof as medicines |
US20080319194A1 (en) * | 2005-07-04 | 2008-12-25 | Albrecht Jacobi | Process for Preparing Quinazolinone Derivatives |
US20190119664A1 (en) * | 2016-03-28 | 2019-04-25 | Research Institute Of Innovative Technology For The Earth | Transformant, and method for producing protocatechuic acid or salt thereof using same |
Non-Patent Citations (1)
Title |
---|
P. G. GEEGI ET AL.: "IN SILICO SCREENING OF PHYTOCHEMICALS IDENTIFIED FROM AEGICERAS CORNICULATUM (L.) BLANCO FOR ITS ANTI-DIABETIC ACTIVITY", 《 RJLBPCS》, vol. 5, no. 4, pages 81 - 91 * |
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CN114761025B (zh) | 2024-03-12 |
AU2020397821A1 (en) | 2022-06-23 |
WO2021113062A1 (en) | 2021-06-10 |
BR112022010783A2 (pt) | 2022-11-22 |
TW202136204A (zh) | 2021-10-01 |
KR20220110235A (ko) | 2022-08-05 |
IL292837A (en) | 2022-07-01 |
MX2022006397A (es) | 2022-06-24 |
EP4069252A1 (en) | 2022-10-12 |
EP4069252A4 (en) | 2024-01-10 |
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US20230046445A1 (en) | 2023-02-16 |
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