TWI769600B - PDIA4抑制劑及其用於抑制β細胞致病機轉及治療糖尿病之用途 - Google Patents
PDIA4抑制劑及其用於抑制β細胞致病機轉及治療糖尿病之用途 Download PDFInfo
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- TWI769600B TWI769600B TW109142118A TW109142118A TWI769600B TW I769600 B TWI769600 B TW I769600B TW 109142118 A TW109142118 A TW 109142118A TW 109142118 A TW109142118 A TW 109142118A TW I769600 B TWI769600 B TW I769600B
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- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 16
- 102100037089 Protein disulfide-isomerase A4 Human genes 0.000 title abstract description 55
- 239000003112 inhibitor Substances 0.000 title abstract description 17
- 230000002401 inhibitory effect Effects 0.000 title abstract description 11
- 230000008506 pathogenesis Effects 0.000 title abstract description 5
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 title description 13
- 101001098824 Homo sapiens Protein disulfide-isomerase A4 Proteins 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 17
- 239000008103 glucose Substances 0.000 claims abstract description 17
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 claims abstract description 10
- 239000008280 blood Substances 0.000 claims abstract description 10
- 210000004369 blood Anatomy 0.000 claims abstract description 10
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960003105 metformin Drugs 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 31
- 150000001345 alkine derivatives Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 22
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 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 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 102000004877 Insulin Human genes 0.000 claims description 4
- 108090001061 Insulin Proteins 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229940125396 insulin Drugs 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000006277 halobenzyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 101710106226 Protein disulfide-isomerase A4 Proteins 0.000 abstract description 54
- NIEDTPAPBKLNRS-UHFFFAOYSA-N 4,5-dimethoxy-2-(prop-2-ynoylamino)benzoic acid Chemical compound COC1=CC(NC(=O)C#C)=C(C(O)=O)C=C1OC NIEDTPAPBKLNRS-UHFFFAOYSA-N 0.000 abstract description 48
- 229940000406 drug candidate Drugs 0.000 abstract description 13
- 230000003914 insulin secretion Effects 0.000 abstract description 11
- 230000003190 augmentative effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 203
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 142
- 238000000034 method Methods 0.000 description 135
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 97
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- -1 oxy Isoindoline Chemical compound 0.000 description 85
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 73
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 65
- 238000006243 chemical reaction Methods 0.000 description 62
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- RJZSMWCMFYBHTD-UHFFFAOYSA-N methyl 4,5-dimethoxy-2-(prop-2-ynoylamino)benzoate Chemical compound COC(C(C=C(C(OC)=C1)OC)=C1NC(C#C)=O)=O RJZSMWCMFYBHTD-UHFFFAOYSA-N 0.000 description 53
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 48
- 239000011701 zinc Substances 0.000 description 47
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- 229910004373 HOAc Inorganic materials 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
- 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 28
- 239000011541 reaction mixture Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 229940127573 compound 38 Drugs 0.000 description 26
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 26
- 235000019341 magnesium sulphate Nutrition 0.000 description 26
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 150000008064 anhydrides Chemical class 0.000 description 21
- 235000015320 potassium carbonate Nutrition 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- 230000008569 process Effects 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 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 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 17
- HJVAVGOPTDJYOJ-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1OC HJVAVGOPTDJYOJ-UHFFFAOYSA-N 0.000 description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 16
- WMSLCNCAJLLRKL-UHFFFAOYSA-N COC(C(C=C(C(OC)=C1)OCCCNCC2=CC(F)=CC=C2)=C1[N+]([O-])=O)=O Chemical compound COC(C(C=C(C(OC)=C1)OCCCNCC2=CC(F)=CC=C2)=C1[N+]([O-])=O)=O WMSLCNCAJLLRKL-UHFFFAOYSA-N 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 210000004027 cell Anatomy 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 150000002611 lead compounds Chemical class 0.000 description 10
- 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 10
- 229940095102 methyl benzoate Drugs 0.000 description 10
- XKJDYGVAWMETDI-UHFFFAOYSA-N 2-amino-4-methoxy-5-propoxybenzoic acid Chemical compound CCCOC1=CC(C(O)=O)=C(N)C=C1OC XKJDYGVAWMETDI-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 238000003032 molecular docking Methods 0.000 description 9
- SPYIETQLOVDJCF-XYOKQWHBSA-N (5e)-3-(4-methoxyphenyl)-5-[(5-nitrothiophen-2-yl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound C1=CC(OC)=CC=C1N(C(=S)S\1)C(=O)C/1=C\C1=CC=C([N+]([O-])=O)S1 SPYIETQLOVDJCF-XYOKQWHBSA-N 0.000 description 8
- 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 8
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical compound N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 8
- JSHSRQCOCMIIPA-UHFFFAOYSA-N 2-amino-3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=C(N)C(OC)=C1OC JSHSRQCOCMIIPA-UHFFFAOYSA-N 0.000 description 7
- PMZFPPTZSNLXJX-UHFFFAOYSA-N 2-amino-4-methoxy-5-phenylmethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1OCC1=CC=CC=C1 PMZFPPTZSNLXJX-UHFFFAOYSA-N 0.000 description 7
- DGLJJQQYCSTLKF-UHFFFAOYSA-N CCCOC1=C(C=C(C(=C1)C(=O)OCCC)NC(=O)C#C)OCCC Chemical compound CCCOC1=C(C=C(C(=C1)C(=O)OCCC)NC(=O)C#C)OCCC DGLJJQQYCSTLKF-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 102000006010 Protein Disulfide-Isomerase Human genes 0.000 description 7
- DNCRQMOLHOKOMK-UHFFFAOYSA-N benzyl 4-methoxy-5-phenylmethoxy-2-(prop-2-ynoylamino)benzoate Chemical compound COC(C(OCC1=CC=CC=C1)=C1)=CC(NC(C#C)=O)=C1C(OCC1=CC=CC=C1)=O DNCRQMOLHOKOMK-UHFFFAOYSA-N 0.000 description 7
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 7
- 108020003519 protein disulfide isomerase Proteins 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- NXDLXWPWCPKARL-UHFFFAOYSA-N CC#CNC(C=C(C(OCCCN(CC1=CC(F)=CC=C1)C#CC)=C1)OC)=C1C(OC)=O Chemical compound CC#CNC(C=C(C(OCCCN(CC1=CC(F)=CC=C1)C#CC)=C1)OC)=C1C(OC)=O NXDLXWPWCPKARL-UHFFFAOYSA-N 0.000 description 6
- PCXURHRRBGOIOU-UHFFFAOYSA-N CCCOC1=C(C=C(C(=C1)C(=O)OC)NC(=O)C#C)OCCC Chemical compound CCCOC1=C(C=C(C(=C1)C(=O)OC)NC(=O)C#C)OCCC PCXURHRRBGOIOU-UHFFFAOYSA-N 0.000 description 6
- BVCCRXDWPOVSHF-UHFFFAOYSA-N CCCOC1=C(C=C(C(=C1)C(=O)OCCC)NC(=O)C#C)OC Chemical compound CCCOC1=C(C=C(C(=C1)C(=O)OCCC)NC(=O)C#C)OC BVCCRXDWPOVSHF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- BZFWMRHSFWDVJI-UHFFFAOYSA-N benzyl 2-amino-4-methoxy-5-phenylmethoxybenzoate Chemical compound COC1=CC(N)=C(C(=O)OCC=2C=CC=CC=2)C=C1OCC1=CC=CC=C1 BZFWMRHSFWDVJI-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- OELQMDRRCQPISA-UHFFFAOYSA-N methyl 3,4,5-trimethoxy-2-(prop-2-ynoylamino)benzoate Chemical compound COC(C(C=C(C(OC)=C1OC)OC)=C1NC(C#C)=O)=O OELQMDRRCQPISA-UHFFFAOYSA-N 0.000 description 6
- ZKUUVVYMPUDTGJ-UHFFFAOYSA-N methyl 5-hydroxy-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C=C1[N+]([O-])=O ZKUUVVYMPUDTGJ-UHFFFAOYSA-N 0.000 description 6
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 6
- JANMDSADTGHPQB-UHFFFAOYSA-N propyl 2-amino-4,5-dipropoxybenzoate Chemical compound CCCOC(C(C=C(C(OCCC)=C1)OCCC)=C1N)=O JANMDSADTGHPQB-UHFFFAOYSA-N 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- HJESWRGJIPPLSR-UHFFFAOYSA-N COC(C(C(NC(C#C)=O)=C1)=CC(OCCCNC(C2=CC=CC=C2)=O)=C1OC)=O Chemical compound COC(C(C(NC(C#C)=O)=C1)=CC(OCCCNC(C2=CC=CC=C2)=O)=C1OC)=O HJESWRGJIPPLSR-UHFFFAOYSA-N 0.000 description 5
- PXUAXJHFNNPLTJ-UHFFFAOYSA-N COC1=C(C=C(C(=C1)NC(=O)C#C)C(=O)OC)OCCCN(C(=O)CC2=CC(=CC=C2)F)C(=O)C#C Chemical compound COC1=C(C=C(C(=C1)NC(=O)C#C)C(=O)OC)OCCCN(C(=O)CC2=CC(=CC=C2)F)C(=O)C#C PXUAXJHFNNPLTJ-UHFFFAOYSA-N 0.000 description 5
- YYGPLMNGGWCDTD-UHFFFAOYSA-N COC1=C(C=C(C(=C1)NC(=O)C#C)C(=O)OC)OCCCN(C(=O)CC2=CC=CC=C2F)C(=O)C#C Chemical compound COC1=C(C=C(C(=C1)NC(=O)C#C)C(=O)OC)OCCCN(C(=O)CC2=CC=CC=C2F)C(=O)C#C YYGPLMNGGWCDTD-UHFFFAOYSA-N 0.000 description 5
- PIGMVSQKERHIGF-UHFFFAOYSA-N benzyl 4-methoxy-2-nitro-5-phenylmethoxybenzoate Chemical compound COC1=CC([N+]([O-])=O)=C(C(=O)OCC=2C=CC=CC=2)C=C1OCC1=CC=CC=C1 PIGMVSQKERHIGF-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 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 5
- APWGOAKABZKZRS-UHFFFAOYSA-N methyl 4-methoxy-5-[3-[[2-(3-methoxyphenyl)acetyl]-prop-2-ynoylamino]propoxy]-2-(prop-2-ynoylamino)benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCN(C(CC2=CC(OC)=CC=C2)=O)C(C#C)=O)=C1NC(C#C)=O)=O APWGOAKABZKZRS-UHFFFAOYSA-N 0.000 description 5
- QMTQYZATMZMDDQ-UHFFFAOYSA-N methyl 4-methoxy-5-[3-[[2-(4-methoxyphenyl)acetyl]-prop-2-ynoylamino]propoxy]-2-(prop-2-ynoylamino)benzoate Chemical compound COC(C(C=C(C(OC)=C1)OCCCN(C(CC(C=C2)=CC=C2OC)=O)C(C#C)=O)=C1NC(C#C)=O)=O QMTQYZATMZMDDQ-UHFFFAOYSA-N 0.000 description 5
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 5
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- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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- C07C233/00—Carboxylic acid amides
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C233/55—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
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Abstract
本發明揭示蛋白質雙硫鍵異構酶A4 (PDIA4)抑制劑及其用於抑制胰臟β細胞致病機轉及治療糖尿病之用途。鑑別出抑制PDIA4的IC50
值在4 μM至300 nM範圍內之候選藥物。該等化合物在增強胰臟β細胞分泌胰島素方面具有高活性。代表性化合物第8
號(4,5-二甲氧基-2-丙炔醯胺基苯甲酸)單獨或與二甲雙胍的複合治療可有效地保留胰臟β細胞功能、治療及/或逆轉糖尿病,將糖尿病患者的血糖濃度恢復至正常水準。
Description
本發明大體上關於PDIA4抑制劑。
2型糖尿病(T2D)之特徵在於周邊胰島素抗性、胰島素分泌不足及β細胞漸進性損失。β細胞功能及質量衰減為T2D之中心標誌。積累的資料表明,在早期階段保持功能β細胞質量可延遲且逆轉T2D。因此,鑑別出對β細胞功能異常及死亡起關鍵作用的因素可更好地瞭解β細胞致病機轉及T2D發展且獲得新的T2D治療策略。
蛋白質雙硫鍵異構酶(PDI)家族(21個成員)對細胞功能具有多種作用且據報導牽涉到感染、生育、凝血、免疫、腫瘤轉移或細胞存活率/生長。蛋白質雙硫鍵異構酶(PDI)家族對健康及疾病的作用未得到充分研究。蛋白質雙硫鍵異構酶A3 (PDIA3)及蛋白質雙硫鍵異構酶A4 (PDIA4)為此家族之兩個成員。由於缺乏Pdia3、但不缺乏PDIA4的小鼠顯示在胚胎階段死亡,因此其功能可能並非冗餘的。迄今為止,尚未開發出基於PDI的藥物。
高度需要用於在早期糖尿病階段保持β細胞功能及質量、從而可逆轉T2D的方法。
在一個態樣中,本發明係關於一種式(I)化合物或其醫藥學上可接受之鹽,,其中:
R1
為-C(=O)OR6
;
R2
為H、(C1
-C6
)烷基、苯甲基,或-L-R11
,其中L為一鍵或(C1
-C6
)伸烷基,且R11
為苯基、鹵基、二側氧基異吲哚啉、-NR7
R8
,或-NR7
-CO-R8
;
R3
為H、(C1
-C6
)烷基,或苯甲基;
R4
為H或(C1
-C6
)烷氧基;
R5
為H、(C1
-C6
)胺、硝基、-NR7
R8
,或-NR7
-CO-R8
;
X1
及X2
各自獨立地為-O-、-S-或共價鍵;
R6
為H、鹵素、(C1
-C6
)烷基、(C1
-C6
)芳基、苯甲基、鹵基(C1
-C6
)烷基、-(CH2
)n
-Si(CH3
)3
,或羰基(C1
-C6
)炔烴,其中n為1至6;
R7
及R8
各自獨立地為H、(C1
-C6
)烷氧基、苯基、苯甲醯基、鹵基苯甲醯基、苯甲基、羰基(C1
-C6
)炔烴、(C1
-C6
)炔烴、㗁唑、噻唑或咪唑;其中(C1
-C6
)烷氧基、苯基、苯甲醯基及苯甲基中之每一者視情況獨立地經一或多個選自F、Cl、Br、I、(C1
-C6
)烷氧基、(C1
-C6
)烷基或鹵基(C1
-C6
)烷基的取代基取代;或R7
及R8
連同N原子一起形成苯甲醯亞胺酸。
在本發明的一個實施例中,R6
為H或(C1
-C6
)烷基、苯甲基、鹵基(C1
-C6
)烷基、-(CH2
)n
-Si(CH3
)3
,或羰基(C1
-C6
)炔烴。
在本發明之另一實施例中,R2
為(C1
-C6
)烷基,或-L-R11
,其中L為(C1
-C6
)伸烷基,且R11
為二側氧基異吲哚啉、-NR7
R8
或-NR7
-CO-R8
,其中R7
及R8
各自獨立地為H、苯基、苯甲醯基、鹵基苯甲醯基、苯甲基、羰基(C1
-C6
)炔烴,或㗁唑。
在另一個實施例中,L為(C1
-C6
)伸烷基,且R11
為-NR7
-CO-R8
。
在另一個實施例中,L為(C1
-C6
)伸烷基,且R11
為-NR7
-CO-R8
,其中R7
為羰基(C1
-C6
)炔烴,R8
為㗁唑、噻唑或咪唑。
在另一個實施例中,R11
為1,3-二側氧基異吲哚啉。
在本發明之另一實施例中,苯基、苯甲醯基及/或苯甲基各自獨立地經一或多個選自F、Cl、Br、I或鹵基(C1
-C6
)烷基之取代基取代。
在本發明之另一實施例中,R5
為-NR7
R8
或-NR7
-CO-R8
,其中R7
及R8
各自獨立地為H或羰基(C1
-C6
)炔烴。
在本發明之另一實施例中,R5
為硝基。
在本發明之另一實施例中,R6
為羰基(C1
-C6
)炔烴。
在本發明之另一實施例中,R2
為-L-R11
,其中L為(C1
-C6
)伸烷基,且R11
為-NR7
R8
,其中R7
及R8
連同N原子一起形成苯甲醯亞胺酸。
在本發明之另一實施例中,R7
及R8
連同N原子一起形成苯甲醯亞胺酸。
在本發明之另一實施例中,R2
為-L-R11
,其中L為(C1
-C6
)伸烷基,R11
為-NR7
R8
,或-NR7
-CO-R8
;R7
為羰基(C1
-C6
)炔烴且R8
為苯甲醯基。
在本發明之另一實施例中,R2
為(C1
-C6
)烷基;R3
為(C1
-C6
)烷基,R4
為H;R5
為-NR7
-CO-R8
,其中R7
為H且R8
為(C2
)炔烴。
在本發明之另一實施例中,R5
為-NR7
R8
或-NR7
-CO-R8
,其中R7
及R8
各自獨立地為H、羰基(C1
-C6
)炔烴,或(C1
-C6
)炔烴。
在本發明之另一實施例中,R2
為-L-R11
,其中L為(C1
-C6
)伸烷基,且R11
為二側氧基異吲哚啉或-NR7
R8
,其中R7
及R8
各自獨立地為苯甲醯基,或羰基(C1
-C6
)炔烴。
在另一實施例中,本發明之化合物或其醫藥學上可接受之鹽係選自由表6中所列之化合物組成之群。
在另一態樣中,本發明係關於一種醫藥組合物,其包含:本發明之化合物或其醫藥學上可接受之鹽;及醫藥學上可接受之載劑或賦形劑。該醫藥組合物可以進一步包含二甲雙胍。
在另一態樣中,本發明係關於一種醫藥組合物,其包含:(a)本發明之化合物或其醫藥學上可接受之鹽;及(b)二甲雙胍。
另外,在另一態樣中,本發明係關於本發明之化合物或其醫藥學上可接受之鹽或醫藥組合物的用途,其用於製造供在有需要之個體中增強胰臟β細胞分泌胰島素、治療糖尿病及/或逆轉及恢復血糖濃度至正常水準的藥劑。
本發明亦關於本發明之化合物或其醫藥學上可接受之鹽或醫藥組合物,其用於有需要之個體增強胰臟β細胞分泌胰島素、治療糖尿病及/或逆轉及恢復血糖濃度至正常水準。
在一個實施例中,本發明之化合物或其醫藥學上可接受之鹽或醫藥組合物係用於在有需要之個體中抑制PDIA4活性、抑制胰臟β細胞致病機轉、治療糖尿病及/或逆轉及恢復血糖濃度至正常水準。
本發明亦關於一種在有需要之個體中抑制胰臟β細胞致病機轉、增強胰臟β細胞分泌胰島素、治療糖尿病及/或逆轉及恢復血糖濃度至正常水準的方法,該方法包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽或醫藥組合物。
又在另一態樣中,本發明係關於一種抑制PDIA4活性的方法,該方法包含促使本發明的化合物或其醫藥學上可接受之鹽與PDIA4接觸且藉此抑制PDIA4活性。
此等及其他態樣由以下較佳實施例之描述結合以下附圖而將變得顯而易見,但其中可進行變化及潤飾而不悖離本發明之新穎構思的精神及範疇。
附圖說明本發明之一或多個實施例,且與書面說明書一起用於解釋本發明之原理。只要可能,則整個附圖中使用相同的元件符號指示實施例之相同或類似元件。
代表性醯基包括乙醯基、丙醯基、丁醯基及苯甲醯基。
不介於兩個字母或符號之間的虛線(「-」)用於指示部分或取代基之連接點。舉例而言,部分-CONH2
係經由碳原子連接。
如本文所用,術語「酯」意謂含有經取代之羧酸的化合物(例如-COO-烷基)。
如本文所用,術語「磺醯基」表示具有式:-S(O)2
-之基團。
術語「伸烷基」係指1至18個碳原子之飽和、分支鏈或直鏈或環狀烴基團,其具有兩個單價基團中心,該等中心係由母體烷烴之相同或不同碳原子上移除兩個氫原子而衍生。典型的伸烷基包括(但不限於)亞甲基(-CH2
-)、1,2-伸乙基(-CH2
CH2
-)、1,3-伸丙基(-CH2
CH2
CH2
-)、1,4-伸丁基(-CH2
CH2
CH2
CH2
-)及其類似基團。
術語「(Cm
-Cn
」(其中m、n為整數且n>m)意謂特定地揭示m至n範圍內之所有整數單元量作為本發明之一部分。因此,「(Cm
-Cn
)」意謂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
)作為本發明之實施例包括在內。
「(C1
-C6
)」意謂特定地揭示1至6範圍內之所有整數單元量作為本發明之一部分。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
)單元量作為本發明之實施例包括在內。
術語「治療(treating/treatment)」係指向患有疾病或具有此類疾病之症狀或有患此類疾病之傾向性的個體投與有效量之治療劑,目的在於治癒、緩解、減輕、醫治、改善或預防疾病、其症狀或其傾向性。
由美國健康與人群服務部食品及藥物管理局(U.S. Department of Health and Human Services Food and Drug Administration)發佈之「估計治療劑在臨床試驗中在成年健康自願者中之安全初始劑量的行業及審查者導引(Guidance for Industry and Reviewers Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers)」揭示「人類等效劑量」可藉由下式計算得到:
HED = 動物劑量(mg/kg)×(動物體重(kg)/人體重(kg))0.33
。
縮寫:
PDIA4:蛋白質雙硫鍵異構酶家族成員A4;CCTB:碳/碳參鍵;IC50
:半數最大抑制濃度。
本發明係關於發現用於治療2型糖尿病之PDIA4抑制劑。將分子對接與PDIA4生物分析組合用於鑑別出基於PDIA4的苗頭化合物。對先導化合物進行最佳化以改良其生物活性,直至候選藥物的IC50
值在nM範圍內。實例
材料及方法 虛擬篩選
為了獲得可靠的PDIA4作用模型,對來自蛋白質資料庫之3IDV (人類PDIA4之催化域(殘基53-284))、3EC3 (大鼠PDIA4之非催化域(殘基283-523))及3F8U (人類PDIA3之殘基25-501)之A鏈進行多重序列比對。三種蛋白質序列與人類PDIA4分別共享100%、88%及42%同源性。PDIA4之同源模型係使用Discovery Studio v.4.1產生且係基於PDIA4之3IDV、3EC3及3F8U之A鏈的結晶學結構,其用作結構模板。使用CHARMM力場將來自內部工廠化學庫的兩百六十一種化合物轉變成3D座標以藉由Discovery Studio中的Prepare Ligand模組將化合物最小化。在pH 7.5下,將殘基中的質子化狀態調節成顯性離子形式。使用PDIA4之第二CGHC模體的周圍殘基作為對接包,該第二CGHC模體係由第一與第二活性域之間的結合包構成。使用GOLD v.5.1程式(CCDC Software Limited, Cambridge, UK)內的Goldscore執行化合物與PDIA4之第二活性域之間的分子對接。最後,在化合物的100種對接驗證中,選擇最佳候選物(具有較高的GOLD適合度分數)來探究PDIA4之第二活性域的「抑制鍵」驗證。
化學方法
使用Bruker Fourier 300及AVIII 500頻譜儀、使用標準plus程式獲得NMR頻譜(1
H及13
C NMR)。使用TMS作為內標,用百萬分之分率(ppm,δ)列舉化學位移。在Finnigan Mat TSQ-7000質譜儀(ESIMS及HRESIMS)上量測MS資料。在Fisher-Johns設備(未校正)上記錄熔點。藉由L-2130泵浦(Hitachi, Ibaraki, Japan)在C18管柱(150 mm×4.6 mm)上執行HPLC。在矽膠(70-230目,Merck, Darmstadt, Germany)上進行管柱層析。在矽膠盤(KG60-F254, Merck)上進行TLC分析。除非另外提及,否則所有化學品及材料依自市售供應商接收到的原樣使用而不進行任何純化。在N2
下,自氫化鈣中蒸餾出無水二氯甲烷。
4,5- 二甲氧基 -2- 硝基苯甲酸甲酯 (2)
向1
(5.00 g,22.00 mmol)及K2
CO3
(12.17 g,88.04 mmol)於DMF (50 mL)中的混合物中逐滴添加CH3
I (5.48 mL,88.04 mmol)。所得溶液在N2
下加熱至100℃維持15小時。將反應混合物懸浮於H2
O (150 mL)中且接著用EtOAc (3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮,得到固體。用MeOH洗滌該固體,得到2
(5.22 g,98%)。1
H NMR (500 MHz, CDCl3
) δ 7.43 (s, 1H), 7.06 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.89 (s, 3H)。
2- 胺基 -4,5- 二甲氧基苯甲酸甲酯 (3)
向2
(5.22 g,21.66 mmol)於EtOAc (10 mL)中的溶液中添加催化量的10% Pd/C (1 g)。在室溫下、在H2
氛圍下攪拌混合物8小時。用矽藻土過濾反應混合物且真空濃縮濾液。藉由矽膠層析(EtOAc/正己烷=1:9)純化殘餘物,得到呈黃色固體狀之3
(3.00 g,66%)。1
H NMR (500 MHz, CDCl3
) δ 7.27 (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- 丙炔醯胺基苯甲酸甲酯 (4)
在冰浴中,向3
(50 mg,0.24 mmol)於無水CH2
Cl2
(10 mL)中之溶液中逐滴添加含有丙炔酸(0.022 mL,0.36 mmol)及N,N'-
二環己基碳二亞胺(73 mg,0.36 mmol)的無水CH2
Cl2
(5 mL)。所得溶液在N2
下攪拌2小時。將反應混合物懸浮於H2
O (50 mL)中且接著用CH2
Cl2
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。過濾混合物且用EtOAc/正己烷=1:1 (10 mL)洗滌。藉由矽膠層析(EtOAc/正己烷=1:5)純化殘餘物,得到4
(57 mg,91%)。1
H NMR (500 MHz, CDCl3
) δ 11.56 (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
試劑及條件:(i) DMAP、DCC、(CH3
)3
Si(CH2
)2
OH、THF、RT;(ii) 10% Pd-C、EtOAc、H2
、RT;(iii)丙炔酸、DCC、CH2
CI2
、0℃;(iv) TBAF、THF、RT。
4,5- 二甲氧基 -2- 硝基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (5)
依循針對化合物4
所述的程序,向1
(100 mg,0.44 mmol)、N,N'-
二環己基碳二亞胺(109 mg,0.528 mmol)及DMAP (5 mg,0.04 mmol)於無水THF (10 mL)中的反應物中逐滴添加2-(三甲基矽烷基)乙醇(0.094 mL,0.66 mmol),得到5
(59 mg,41%)。1
H NMR (300 MHz, CDCl3
) δ 7.43 (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- 胺基 -4,5- 二甲氧基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (6)
依循針對化合物3
所述的程序,向5
(100 mg,0.31 mmol)於EtOAc (10 mL)中的反應物中添加催化量的10% Pd/C (10 mg),得到6
(41 mg,45%)。1
H NMR (300 MHz, CDCl3
) δ 7.29 (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- 丙炔醯胺基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (7)
依循針對化合物4
所述的程序,在冰浴中,向6
(100 mg,0.34 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.031 mL,0.50 mmol)及N,N'-
二環己基碳二亞胺(104 mg,0.50 mmol)的無水CH2
Cl2
(5 mL),得到7
(108 mg,92%)。1
H NMR (300 MHz, CDCl3
) δ 11.65 (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- 丙炔醯胺基苯甲酸 (8)
在室溫下,向7
(50 mg,0.14 mmol)於無水THF (4 mL)中的溶液中逐滴添加TBAF (1 M於THF中,0.43 mL,0.43 mmol)。所得溶液在N2
下攪拌24小時。反應混合物用1 N HCl(aq)
(50 mL)及EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 3:97)純化,得到8
(30 mg,84%)。1
H NMR (500 MHz, DMSO) δ 11.87 (s, 1H), 8.06 (s, 1H), 7.45 (s, 1H), 4.45 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H)。
2- 胺基 -4,5- 二甲氧基苯甲酸 (9)
向1
(5.00 g,22.00 mmol)於MeOH (20 mL)中的溶液中添加催化量的10% Pd/C (1.5 g)且在H2
氛圍下、在室溫下攪拌混合物24小時。反應混合物用矽藻土過濾且真空濃縮,得到9
(4.00 g,92%)。1
H NMR (500 MHz, DMSO) δ 7.14 (s, 1H), 6.33 (s, 1H), 3.73 (s, 3H), 3.63 (s, 3H)。
2- 胺基 -4,5- 二甲氧基苯甲酸丙炔酸酐 (10)
依循針對化合物4
所述的程序,在冰浴中,向9
(500 mg,2.54 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.234 mL,3.81 mmol)及N,N'-
二環己基碳二亞胺(466 mg,2.26 mmol)的無水CH2
Cl2
(5 mL),得到10
(15 mg,2%)。1
H NMR (300 MHz, CDCl3
) δ 7.50 (s, 1H), 7.02 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H)。
5-( 苯甲氧基 )-4- 甲氧基 -2- 硝基苯甲酸苯甲酯 (12)
依循針對化合物2
所述的程序,向11
(439 mg,2.00 mmol)及K2
CO3
(710 mg,5.15 mmol)於DMF (20 mL)中的反應物中添加苯甲基溴(0.61 mL,5.15 mmol)。所得溶液在N2
下加熱至110℃,得到12
(807 mg,99%)。1
H NMR (500 MHz, CDCl3
) δ 7.43 (s, 1H), 7.34 (m, 10H), 7.13 (s, 1H), 5.30 (s, 2H), 5.18 (s, 2H), 3.96 (s, 3H)。
2- 胺基 -5-( 苯甲氧基 )-4- 甲氧基苯甲酸苯甲酯 (13)
向12
(1.00 g,2.54 mmol)於HOAc (20 mL)中的溶液中添加Zn (1.66 g,25.44 mmol)且在N2
下將混合物加熱至50℃維持24小時。利用矽藻土過濾反應混合物。將殘餘物溶解於EtOAc (50 mL)中且接著用NaHCO3
(3×50 mL)洗滌。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:3)純化,得到13
(330 mg,36%)。1
H NMR (500 MHz, CDCl3
) δ 7.37 (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- 丙炔醯胺基苯甲酸苯甲酯 (14)
在冰浴中,向13
(500 mg,1.37 mmol)於無水CH2
Cl2
(30 mL)中的溶液中逐滴添加丙炔醯氯(1.00 g,11.36 mmol)及K2
CO3
(475 mg,3.44 mmol)。所得溶液在0℃下、在N2
下攪拌0.5小時。將反應混合物懸浮於H2
O (50 mL)中且接著用CH2
Cl2
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:4)純化,得到14
(76 mg,13%)。1
H NMR (500 MHz, CDCl3
) δ 11.52 (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)。
2- 胺基 -5-( 苯甲氧基 )-4- 甲氧基苯甲酸 (15) 13
(150 mg,0.41 mmol)及LiOH (100 mg,2.30 mmol)於MeOH (10 mL)中的溶液在N2
下加熱至70℃維持18小時。將所得溶液酸化至pH 2且用1 N HCl (50 mL)及EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。使殘餘物再結晶,得到15
(100 mg,89%)。1
H NMR (500 MHz, CDCl3
) δ 7.43 (s, 1H), 7.41 (s, 2H), 7.35 (t,J
= 7.4 Hz, 2H), 7.28 (t,J
= 7.3 Hz, 1H), 6.12 (s, 1H), 5.02 (s, 2H), 3.85 (s, 3H)。
2- 胺基 -5-( 苯甲氧基 )-4- 甲氧基苯甲酸丙炔酸酸酐 (16)
依循針對化合物4
所述的程序,在冰浴中,向15
(250 mg,0.92 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.084 mL,0.92 mmol)及N,N'-
二環己基碳二亞胺(246 mg,1.19 mmol)的無水CH2
Cl2
(5 mL),得到16
(36 mg,12%)。1
H NMR (500 MHz, CDCl3
) δ 7.57 (s, 1H), 7.44 (d,J
= 7.3 Hz, 2H), 7.37 (t,J
= 7.5 Hz, 2H), 7.32 (t,J
= 7.3 Hz, 1H),7.04 (s, 1H), 5.21 (s, 2H), 3.97 (s, 3H), 3.20 (s, 1H)。
3,4,5- 三甲氧基 -2- 硝基苯甲酸甲酯 (18)
向17
(500 mg,2.21 mmol)於HOAc (4 mL)中的溶液中添加HNO3
(2 mL)且在N2
下加熱至50℃維持1.5小時。將反應混合物懸浮於H2
O (50 mL)中且接著用EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:4)純化,得到18
(231 mg,38%)。1
H NMR (500 MHz, CDCl3
) δ 7.25 (s, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H)。
2- 胺基 -3,4,5- 三甲氧基苯甲酸甲酯 (19)
依循針對化合物13
所述的程序,向18
(1.00 g,3.69 mmol)於HOAc (20 mL)中之反應物中添加Zn (2.41 g,36.90 mmol)且在N2
下將混合物加熱至50℃維持24小時。利用矽藻土過濾反應混合物。殘餘物用EtOAc (50 mL)及NaHCO3
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:4)純化,得到19
(590 mg,66%)。1
H NMR (500 MHz, CDCl3
) δ 7.13 (s, 3H), 3.93 (s, 3H), 3.84 (s, 6H), 3.79 (s, 3H)。
3,4,5- 三甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (20)
依循針對化合物14
所述的程序,在冰浴中,向19
(1.36 g,5.68 mmol)於無水CH2
Cl2
(30 mL)中的反應物中逐滴添加丙炔醯氯(1.00 g,11.36 mmol)及K2
CO3
(1.57 g,3.11.36 mmol),得到20
(148 mg,9%)。1
H NMR (500 MHz, CDCl3
) δ 7.20 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.87 (s, 3H), 2.88 (s, 1H)。
2- 胺基 -3,4,5- 三甲氧基苯甲酸 (21)
依循針對化合物15
所述的程序,在N2
下將19
(560 mg,2.32 mmol)及LiOH (240 mg,5.72 mmol)於MeOH (10 mL)中的反應物加熱至70℃維持18小時,得到21
(380 mg,73%)。1
H NMR (500 MHz, CDCl3
) δ 7.19 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.80 (s, 3H)。
2- 胺基 -3,4,5- 三甲氧基苯甲酸丙炔酸酸酐 (22)
依循針對化合物4
所述的程序,在冰浴中,向21
(320 mg,1.41 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.130 mL,2.11 mmol)及N,N'
-二環己基碳二亞胺(435 mg,2.11 mmol)的無水CH2
Cl2
(5 mL),得到22
(6 mg,2%)。1
H NMR (500 MHz, CDCl3
) δ 7.39 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.95 (s, 3H), 3.19 (s, 1H)。
2- 胺基 -5- 羥基 -4- 甲氧基苯甲酸 (23)
向11
(500 mg,2.35 mmol)於MeOH (30 mL)中的溶液中添加催化量的10% Pd/C (200 mg)且在H2
氛圍下、在室溫下攪拌混合物9小時。利用矽藻土過濾反應混合物且真空濃縮濾液。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 1:9)純化,得到23
(350 mg,82%)。1
H NMR (300 MHz, CDCl3
) δ 8.30 (s, 1H), 7.18 (s, 1H), 6.38 (S, 1H), 3.83 (s, 3H), 3.27 (s, 1H)。
流程 9
試劑及條件:(i)溴化丙烷、K2
CO3
、DMF、100℃;(ii) HNO3
、AcOH、50℃;(iii) Zn、AcOH、50℃;(iv) LiOH、MeOH、80℃;(v)丙炔酸、DCC、CH2
Cl2
、0℃。
3,4- 二丙氧基苯甲酸丙酯 (25)
依循針對化合物2所述的程序,向24
(5 g,32.47 mmol)及K2
CO3
(22.36 g,162 mmol)於DMF (50 mL)中的反應物中添加1-溴丙烷(13.2 mL,145 mmol)。所得溶液在N2
下加熱至110℃,得到25
(8.5 g,89%)。1
H NMR (300 MHz, CDCl3
) δ 7.62 (dd,J
= 8.4, 2.0 Hz, 1H), 7.53 (d,J
= 2.0 Hz, 1H), 6.85 (d,J
= 8.4 Hz, 1H), 4.22 (t,J
= 6.7 Hz, 2H), 3.99 (t,J
= 6.6 Hz, 4H), 1.80 (m, 6H), 1.02 (m, 9H)。
2- 硝基 -4,5- 二丙氧基苯甲酸丙酯 (26)
依循針對化合物18
所述的程序,向25
(8.10 g,28.93 mmol)於HOAc (20 mL)中的反應物中添加HNO3
(5 mL)且在N2
下加熱至50℃,得到26
(8.50 g,90%)。1
H NMR (300 MHz,CDCl3
) δ 7.40 (s, 1H), 7.04 (s, 1H), 4.24 (t,J
= 6.7 Hz, 2H), 4.02 (m, 4H), 1.86 (sxt,J
= 7.1 Hz, 4H), 1.72 (m, 2H), 1.04 (td,J
= 7.4, 1.5 Hz, 6H), 0.95 (t,J
= 7.4 Hz, 3H)。
2- 胺基 -4,5- 二丙氧基苯甲酸丙酯 (27)
向26
(8.50 g,26.15 mmol)於HOAc (20 mL)中的溶液中添加Zn (17.00 g,261.54 mmol)且在N2
下、在室溫下攪拌混合物2小時。用矽藻土過濾反應混合物。殘餘物用EtOAc (150 mL)及NaHCO3
(3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:7)純化,得到27
(4.90 g,64%)。1
H NMR (300 MHz, CDCl3
) δ 7.36 (s, 1H), 6.10 (s, 1H), 4.18 (t,J
= 6.7 Hz, 2H), 3.88 (m, 4H), 1.79 (m, 6H), 1.01 (m, 9H)。
2- 胺基 -4,5- 二丙氧基苯甲酸甲酯 (28)
在N2
下,將27
(1 g,3.86 mmol)及LiOH (810 mg,19.30 mmol)於MeOH (20 mL)中的溶液加熱至70℃維持24小時。將所得溶液酸化至pH 2且用1 N HCl (50 mL)及EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。使殘餘物再結晶,得到28
(450 mg,46%)。1
H NMR (300 MHz, CDCl3
) δ 7.32 (s, 1H), 6.10 (s, 1H), 3.89 (m, 2H), 3.81 (s, 3H), 1.80 (m, 4H), 1.01 (m, 6H)。
2- 丙炔醯胺基 -4,5- 二丙氧基苯甲酸甲酯 (29)
依循針對化合物4
所述的程序,在冰浴中,向28
(440 mg,1.74 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.183 mL,2.61 mmol)及N,N'
-二環己基碳二亞胺(466 mg,2.26 mmol)的無水CH2
Cl2
(5 mL),得到29
(66 mg,12%)。1
H NMR (300 MHz, CDCl3
) δ 11.52 (s, 1H), 8.27 (s, 1H), 7.46 (s, 1H), 4.03 (t,J
= 6.6 Hz, 2H), 3.94 (t,J
= 6.6 Hz, 2H), 3.89 (s, 3H), 2.91 (s, 1H), 1.83 (m, 4H), 1.02 (t,J
= 7.4 Hz, 6H)。
2- 丙炔醯胺基 -4,5- 二丙氧基苯甲酸丙酯 (30)
依循針對化合物4
所述的程序,在冰浴中,向27
(590 mg,2.00 mmol)於無水CH2
Cl2
(10 mL)中的反應物中添加逐滴含有丙炔酸(0.184 mL,3.00 mmol)及N,N'-
二環己基碳二亞胺(453 mg,2.19 mmol)的無水CH2
Cl2
(5 mL),得到30
(342 mg,49%)。1
H NMR (300 MHz, CDCl3
) δ 11.56 (s, 1H), 8.27 (s, 1H), 7.48 (s, 1H), 4.25 (t,J
= 6.7 Hz, 2H), 4.03 (t,J
= 6.6 Hz, 2H), 3.94 (t,J
= 6.6 Hz, 2H), 2.90 (s, 1H), 1.82 (m, 6H), 1.02 (m, 9H)。
3,4- 雙 ( 苯甲氧基 ) 苯甲酸苯甲酯 ( 31)
依循針對化合物2所述的程序,向24
(10.00 g,64.94 mmol)及K2
CO3
(44.00 g,318.23 mmol)於DMF (100 mL)中的反應物中添加苯甲基溴(27 mL,227.3 mmol)。所得溶液在N2
下加熱至110℃,得到31
(27.10 g,98%)。1
H NMR (300 MHz, CDCl3
) δ 7.53 (s, 1H), 7.35 (m, 15H), 7.18 (s, 1H), 5.33 (s, 2H), 5.23 (s, 4H)。
4,5- 雙 ( 苯甲氧基 )-2- 硝基苯甲酸苯甲酯 (32)
依循針對化合物18
所述的程序,向31
(16.00 g,37.69 mmol)於HOAc (30 mL)中之反應物中添加HNO3
(15 mL)且在室溫下、在N2
下攪拌,得到32
(16.44 g,95%)。1
H NMR (300 MHz, CDCl3
) δ 7.50 (s, 1H), 7.36 (m, 15H), 7.15 (s, 1H), 5.30 (s, 2H), 5.20 (s, 4H)。
流程 12
試劑及條件:(i) (CH3
)3
Si(CH2
)2
OH、Ph3
P、DIAD、THF、RT;(ii) 1-溴-3-氯丙烷、K2
CO3
、DMF、100℃;(iii)鄰苯二甲醯亞胺鉀、K2
CO3
、DMF、100℃;(iv) NH2
NH2
-H2
O、MeOH、60℃;(v)苯甲醯氯、吡啶、CH2
CI2
;(vi) Zn、AcOH、THF、RT;(vii)丙炔酸、DCC、CH2
Cl2
、0℃;(viii) TBAF、THF、RT。
5- 羥基 -4- 甲氧基 -2- 硝基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (33)
在冰浴中,向11
(5000 mg,23.46 mmol)及三苯膦(12.31 g,46.92 mmol)於無水THF (150 mL)中的溶液中逐滴添加2-(三甲基矽烷基)乙醇(5.04 mL,35.19 mmol)及偶氮二甲酸二異丙酯(6.93 mL,35.19 mmol)。所得溶液在室溫下、在N2
下攪拌7小時。將反應混合物懸浮於H2
O (150 mL)中且接著用EtOAc (3×150 mL)萃取。收集有機層且經無水MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:9)純化,得到33
(2.03 g,29%)。1
H NMR (300 MHz, CDCl3
) δ 7.49 (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-( 三甲基矽烷基 ) 乙酯 (34)
依循針對化合物2所述的程序,向33
(2.43 g,7.76 mmol)及K2
CO3
(2.15 g,15.53 mmol)於DMF (150 mL)中的反應物中添加1-溴-3-氯丙烷(0.921 mL,9.32 mmol)。所得溶液在N2
下加熱至100℃,得到34
(2.88 g,95%)。1
H NMR (300 MHz, CDCl3
) δ 7.42 (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- 二側氧基異吲哚啉 -2- 基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (35)
依循針對化合物2所述的程序,向34
(2.88 g,7.37 mmol)及K2
CO3
(2.04 g,14.75 mmol)於DMF (100 mL)中的反應物中添加鄰苯二甲醯亞胺鉀鹽(1.64 g,8.85 mmol)。所得溶液在N2
下加熱至100℃,得到35
(3.42 g,93%)。1
H NMR (300 MHz, CDCl3
) δ 7.81 (m, 2H), 7.70 (m, 2H), 7.32 (s, 1H), 6.99 (s, 1H), 4.36 (m, 2H), 4.14 (q,J
= 5.5 Hz, 2H), 3.90 (t,J
= 6.4 Hz, 2H), 3.66 (s, 3H), 2.25 (m, 2H), 1.06 (m, 2H), 0.03 (s, 9H)。
5-(3- 胺基丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (36)
向35
(1.50 g,3.00 mmol)於MeOH (150 mL)中的溶液中逐滴添加單水合肼(1.45 mL,29.97 mmol)。所得溶液在N2
下回流且攪拌24小時。真空濃縮反應混合物且懸浮於H2
O (150 mL)中且接著用EtOAc (3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 1:99)純化,得到36
(140 mg,13%)。1
H NMR (300 MHz, CDCl3
) δ 7.45 (s, 1H), 6.52 (s, 1H), 5.38 (s, 2H), 4.39 (m, 2H), 3.91 (s, 3H), 3.79 (t,J
= 5.8 Hz, 2H), 3.37 (m, 2H), 1.90 (m, 2H), 1.08 (m, 2H), 0.03 (s, 9H)。
5-(3- 苯甲醯胺基丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (37)
向36
(140 mg,0.38 mmol)於無水CH2
Cl2
(10 mL)中的溶液中逐滴添加吡啶(0.122 mL,1.51 mmol)及苯甲醯氯(0.131 mL,1.13 mmol)。所得溶液在N2
下、在室溫下攪拌12小時。將反應混合物懸浮於H2
O (50 mL)中且接著用CH2
Cl2
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:4)純化,得到37
(177 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 8.02 (d,J
= 7.1 Hz, 2H), 7.57 (tt,J
= 7.4, 1.2 Hz, 1H), 7.45 (m, 3H), 6.54 (s, 1H), 5.24 (s, 1H), 4.45 (t,J
= 5.9 Hz, 2H), 4.38 (m, 2H), 3.85 (s, 3H), 3.42 (q,J
= 6.3 Hz, 2H), 2.13 (m, 2H), 1.08 (m, 2H), 0.03 (s, 9H)。
2- 胺基 -5-(3- 苯甲醯胺基丙氧基 )-4- 甲氧基苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (38)
向37
(180 mg,0.38 mmol)於HOAc/THF = 1:4 (20 mL)中的溶液中添加Zn (248 mg,3.79 mmol)且在N2
下、在室溫下攪拌混合物24小時。利用矽藻土過濾反應混合物。殘餘物用EtOAc (50 mL)及NaHCO3
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:3)純化,得到38
(158 mg,94%)。1
H NMR (300 MHz, CDCl3
) δ 8.04 (m, 2H), 7.55 (m, 1H), 7.42 (m, 2H), 7.06 (s, 1H), 6.08 (s, 1H), 4.45 (t,J
= 6.2 Hz, 2H), 4.32 (m, 2H), 3.77 (s, 3H), 3.26 (t,J
= 6.8 Hz, 2H), 2.11 (tt,J
= 6.2, 6.8 Hz, 2H), 1.07 (m, 2H), 0.05 (s, 9H)。
4- 甲氧基 -2- 丙炔醯胺基 -5-(3-(N- 丙炔醯基苯甲醯胺基 ) 丙氧基 ) 苯甲酸 2-( 三甲基矽烷基 ) 乙酯 (39)
依循針對化合物4
所述的程序,在冰浴中,向38
(125 mg,0.28 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.037 mL,0.56 mmol)及N,N'-
二環己基碳二亞胺(116 mg,0.56 mmol)的無水CH2
Cl2
(5 mL),得到39
(149 mg,97%)。1
H NMR (300 MHz, CDCl3
) δ 11.82 (s, 1H), 8.38 (s, 1H), 7.94 (dd,J
= 8.4, 1.4 Hz, 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- 丙炔醯胺基 -5-(3-(N- 丙炔醯基苯甲醯胺基 ) 丙氧基 ) 苯甲酸 (40)
在室溫下,向39
(75 mg,0.14 mmol)於無水THF (3 mL)中的溶液中逐滴添加TBAF (1 M於THF中,0.75 mL,0.75 mmol)。所得溶液在N2
下攪拌5小時。將反應混合物懸浮於1 N HCl(aq)
(50 mL)中且用EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 3:97)純化,得到40
(46 mg,75%)。1
H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.40 (s, 1H), 7.94 (m, 2H), 7.52 (m, 1H), 7.40 (m, 2H), 4.35 (t,J
= 6.3 Hz, 2H), 3.95 (m, 4H), 3.72 (m, 1H), 2.99 (s, 1H), 2.71 (s, 1H),2.00 (m, 2H)。
4- 甲氧基 -2- 硝基 -5- 丙氧基苯甲酸丙酯 (41)
依循針對化合物2所述的程序,向11
(2.13 g,10.00 mmol)及K2
CO3
(5.52 g,39.92 mmol)於DMF (50 mL)中的反應物中添加1-溴丙烷(3.63 mL,40.00 mmol)。所得溶液在N2
下加熱至100℃,得到41
(2.80 g,94%)。1
H NMR (500 MHz, CDCl3
) δ 7.41 (s, 1H), 7.04 (s, 1H), 4.24 (t,J
= 6.7 Hz, 2H), 4.04 (t,J
= 6.7 Hz, 2H), 4.92 (s, 3H), 1.87 (dt,J
= 6.7, 7.4 Hz, 2H), 1.71 (dt,J
= 6.7, 7.4 Hz, 2H), 1.03 (t,J
= 7.4 Hz, 3H), 0.95 (t,J
= 7.4 Hz, 3H)。
2- 胺基 -4- 甲氧基 -5- 丙氧基苯甲酸丙酯 (42)
向41
(2.70 g,9.08 mmol)於HOAc (20 mL)中的溶液中添加Zn (5.94 g,90.81 mmol)且在N2
下、在室溫下攪拌混合物48小時。利用矽藻土過濾反應混合物。殘餘物用EtOAc (150 mL)及NaHCO3
(3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:7)純化,得到27
(1.90 g,78%)。1
H NMR (500 MHz, CDCl3
) δ 7.33 (s, 1H), 6.11 (s, 1H), 4.19 (t,J
= 6.7 Hz, 2H), 3.87 (t,J
= 6.7 Hz, 2H), 3.82 (s, 3H), 1.77 (m, 4H), 1.00 (m, 6H)。
4- 甲氧基 -2- 丙炔醯胺基 -5- 丙氧基苯甲酸丙酯 (43)
依循針對化合物4
所述的程序,在冰浴中,向41
(440 mg,1.74 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.183 mL,2.61 mmol)及N,N'
-二環己基碳二亞胺(466 mg,2.26 mmol)的無水CH2
Cl2
(5 mL),得到43
(202 mg,38%)。1
H NMR (300 MHz, CDCl3
) δ 11.56 (s, 1H), 8.30 (s, 1H), 7.46 (s, 1H), 4.26 (t,J
= 6.7 Hz, 2H), 3.95 (t,J
= 6.8 Hz, 2H), 3.91 (s, 3H), 1.81 (m, 4H), 1.02 (m, 6H)。
2- 胺基 -4- 甲氧基 -5- 丙氧基苯甲酸 (44)
依循針對化合物15
所述的程序,在N2
下將42
(500 mg,1.87 mmol)及LiOH (790 mg,18.70 mmol)於MeOH (20 mL)中的反應物加熱至70℃,得到44
(310 mg,75%)。1
H NMR (500 MHz, CDCl3
) δ 7.35 (s, 1H), 6.11 (s, 1H), 3.89 (t,J
= 6.8 Hz,2H), 3.84 (s, 3H), 1.81(m,2H), 1.01 (t,J
= 7.5 Hz,3H)。
2- 胺基 -4- 甲氧基 -5- 丙氧基苯甲酸丙炔酸酸酐 (45)
依循針對化合物4
所述的程序,在冰浴中,向44
(225 mg,1.00 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.092 mL,1.50 mmol)及N,N'
-二環己基碳二亞胺(267 mg,1.29 mmol)的無水CH2
Cl2
(5 mL),得到45
(5 mg,2%)。1
H NMR (300 MHz, CDCl3
) δ 7.49 (s, 1H), 7.02 (s, 1H), 4.06 (t,J
= 6.7 Hz, 2H), 3.96 (s, 3H), 3.20 (s, 1H), 1.89 (m, 2H), 1.05 (t,J
= 7.4 Hz, 3H)。
流程 15
試劑及條件:(i) HCl、MeOH、60℃;(ii) Cl(CH2
)nBr、K2
CO3
、DMF、100℃;(iii)鄰苯二甲醯亞胺鉀、K2
CO3
、DMF、100℃;(iv) Zn、AcOH、THF、RT;(v)丙炔酸、DCC、CH2
Cl2
、0℃
5- 羥基 -4- 甲氧基 -2- 硝基苯甲酸甲酯 (46)
向11
(20.00 g,93.83 mmol)於MeOH (300 mL)中的溶液中逐滴添加12 N HCl(aq)
(30 mL)。所得溶液在N2
下回流72小時。真空濃縮反應混合物。殘餘物用H2
O (100 mL)洗滌且過濾,得到呈白色固體狀的46
(19.05 g,89%)。1
H NMR (300 MHz, CDCl3
) δ 7.50 (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)
依循針對化合物2所述的程序,向46
(1.00 g,4.40 mmol)及K2
CO3
(1.21 g,8.80 mmol)於DMF (50 mL)中的反應物中添加1-溴-2-氯乙烷(0.44 mL,5.28 mmol)。所得溶液在N2
下加熱至100℃,得到47a
(414 mg,32%)。1
H NMR (300 MHz, CDCl3
) δ 7.24 (s, 1H), 7.09 (s, 1H), 4.34 (t,J
= 5.9 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.86 (t,J
= 5.9 Hz, 2H)。
5-(3- 氯丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (47b)
依循針對化合物2所述的程序,在N2
下,將11
(19.05g,83.86 mmol)、K2
CO3
(23.18 g,167.71 mmol)及1-溴-3-氯丙烷(12.44 mL,125.79 mmol)於DMF (350 mL)中的反應物加熱至100℃,得到47b
(21.45 g,84%)。1
H NMR (300 MHz, CDCl3
) δ 7.43 (1, sH), 7.09 (s, 1H), 4.24 (t,J
= 5.9 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.74 (t,J
= 6.1 Hz, 2H), 2.30 (tt,J
= 5.9, 6.1 Hz, 2H)。
5-(4- 氯丁氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (47c)
依循針對化合物2所述的程序,在N2
下,將11
(1.00 g,83.86 mmol)、K2
CO3
(1.21 g,8.80 mmol)及1-溴-4-氯丁烷(0.61 mL,5.28 mmol)於DMF (50 mL)中的反應物加熱至100℃,得到47c
(1.09 g,78%)。1
H NMR (300 MHz, CDCl3
) δ 7.43 (s, 1H), 7.04 (s, 1H), 4.12 (t,J
= 5.9 Hz, 2H), 3.93 (s, 3H),3.88 (s, 3H), 3.61 (t,J
= 6.2 Hz, 3H), 1.99 (m, 4H)。
5-(2-(1,3- 二側氧基異吲哚啉 -2- 基 ) 乙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (48a)
依循針對化合物2所述的程序,在N2
下,將47a
(390 mg,1.35 mmol)、K2
CO3
(372 mg,2.69 mmol)及鄰苯二甲醯亞胺鉀鹽(299 mg,1.61 mmol)於DMF (50 mL)中的反應物加熱至100℃,得到呈白色固體狀的48a
(463 mg,86%)。1
H NMR (300 MHz, CDCl3
) δ 7.85 (m, 2H), 7.72 (m, 2H), 7.36 (s, 1H), 7.10 (s, 1H), 4.35 (t,J
= 5.8 Hz, 2H), 4.14 (t,J
= 5.9 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H)。
5-(3-(1,3- 二側氧基異吲哚啉 -2- 基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (48b)
依循針對化合物2所述的程序,在N2
下,將47b
(21.45 g,70.63 mmol)、K2
CO3
(19.52 g,141.26 mmol)及鄰苯二甲醯亞胺鉀鹽(19.62 g,105.95 mmol)於DMF (300 mL)中的反應物加熱至100℃,得到呈白色固體狀的48b
(29.00 g,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.84 (m, 2H), 7.72 (m, 2H), 7.33 (s, 1H), 7.00 (s, 1H), 4.15 (t,J
= 5.9 Hz, 2H), 3.90 (t,J
= 6.4 Hz, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 2.26 (tt,J
= 5.9, 6.4 Hz, 2H)。
5-(4-(1,3- 二側氧基異吲哚啉 -2- 基 ) 丁氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (48c)
依循針對化合物2所述的程序,在N2
下,將47c
(950 mg,2.99 mmol)、K2
CO3
(826 mg,5.98 mmol)及鄰苯二甲醯亞胺鉀鹽(665 mg,3.59 mmol)於DMF (50 mL)中的反應物加熱至100℃,得到呈白色固體狀的48c
(1064 mg,83%)。1
H NMR (300 MHz, CDCl3
) δ 7.82 (m, 2H), 7.70 (m, 2H), 7.40 (s, 1H), 7.03 (s, 1H), 4.11 (t,J
= 5.9 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.76 (t,J
= 6.2 Hz, 3H), 1.89 (m, 4H)。
2- 胺基 -5-(2-(1,3- 二側氧基異吲哚啉 -2- 基 ) 乙氧基 )-4- 甲氧基苯甲酸甲酯 (49a)
依循針對3
所述的程序,48a
(100 mg,0.25 mmol)、10% Pd/C (10 mg)於EtOH/EtOAc = 1:1 (10 mL)中、在H2
下反應,得到49a
(74 mg,80%)。1
H NMR (300 MHz, CDCl3
) δ 7.84 (m, 2H), 7.70 (m, 2H), 7.35 (s, 1H), 6.03 (s, 1H), 5.55 (s, 2H), 4.16 (t,J
= 5.8 Hz, 2H), 4.06 (t,J
= 5.9 Hz, 2H), 3.79 (s, 3H), 3.67 (s, 3H)。
2- 胺基 -5-(3-(1,3- 二側氧基異吲哚啉 -2- 基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (49b)
依循針對3
所述的程序,48b
(100 mg,0.24 mmol)、10% Pd/C (10 mg)於EtOH/EtOAc = 1:1 (10 mL)中、在H2
下反應,得到49b
(76 mg,82%)。1
H NMR (300 MHz, CDCl3
) δ 7.81 (m, 2H), 7.68 (m, 2H), 7.30 (s, 1H), 6.05 (s, 1H), 5.54 (s, 2H), 3.99 (t,J
= 6.2 Hz, 2H), 3.88 (t,J
= 6.9 Hz, 2H), 3.80 (s, 3H), 3.68 (s, 3H), 2.16 (tt,J
= 6.2, 6.9 Hz, 2H)。
2- 胺基 -5-(4-(1,3- 二側氧基異吲哚啉 -2- 基 ) 丁氧基 )-4- 甲氧基苯甲酸甲酯 (49c)
依循針對3
所述的程序,48c
(100 mg,0.23 mmol)、10% Pd/C (10 mg)於EtOH/EtOAc = 1:1 (10 mL)中、在H2
下反應,得到49c
(74 mg,80%)。1
H NMR (300 MHz, CDCl3
) δ 7.80 (m, 2H), 7.68 (m, 2H), 7.28 (s, 1H), 6.08 (s, 1H), 5.55 (s, 2H), 3.93 (t,J
= 6.0 Hz, 2H), 3.80 (s, 3H),3.79 (s, 3H), 3.74 (t,J
= 6.7 Hz, 3H), 1.83 (m, 4H)。
5-(2-(1,3- 二側氧基異吲哚啉 -2- 基 ) 乙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (50a)
依循針對化合物4
所述的程序,49a
(50 mg,0.14 mmol)、丙炔酸(0.013 mL,0.20 mmol)及N,N'-
二環己基碳二亞胺(42 mg,0.20 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到50a
(57 mg,99%)。1
H NMR (500 MHz, CDCl3
) δ 11.52 (s, 1H), 8.25 (s, 1H), 7.84 (dd,J
= 5.5, 3.1 Hz, 2H), 7.71 (dd,J
= 5.5, 3.1 Hz, 2H), 7.51 (s, 1H), 4.25 (t,J
= 5.9 Hz, 2H), 4.10 (t,J
= 5.9 Hz, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 2.90 (s, 2H)。
5-(3-(1,3- 二側氧基異吲哚啉 -2- 基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (50b)
依循針對化合物4
所述的程序,49b
(50 mg,0.13 mmol)、丙炔酸(0.012 mL,0.20 mmol)及N,N'-
二環己基碳二亞胺(40 mg,0.20 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到50b
(34 mg,60%)。1
H NMR (500 MHz, CDCl3
) δ 11.53 (s, 1H), 8.22 (s, 1H), 7.80 (dd,J
= 5.4, 3.1 Hz, 2H), 7.69 (dd,J
= 5.4, 3.0 Hz, 2H), 7.43 (s, 1H), 4.08 (t,J
= 6.0 Hz, 2H), 3.90 (m, 5H), 3.68 (s, 3H), 2.91 (s, 1H), 2.21 (tt,J
= 6.0, 6.6 Hz, 2H)。
5-(4-(1,3- 二側氧基異吲哚啉 -2- 基 ) 丁氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (50c)
依循針對化合物4
所述的程序,49c
(50 mg,0.13 mmol)、丙炔酸(0.012 mL,0.19 mmol)及N,N'-
二環己基碳二亞胺(39 mg,0.19 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到50c
(56 mg,99%)。1
H NMR (500 MHz, CDCl3
) δ 11.52 (s, 1H), 8.28 (s, 1H), 7.81 (dd,J
= 5.3, 3.0 Hz, 2H), 7.69 (dd,J
= 5.5, 3.0 Hz, 2H), 7.43 (s, 1H), 4.02 (t,J
= 6.0 Hz, 2H), 3.89 (m, 6H), 3.75 (t,J
= 6.6 Hz, 2H), 2.91 (s, 1H), 1.87 (m, 4H)。
流程 16
試劑及條件:(i) NH2
NH2
-H2
O、MeOH、60℃;(ii) RCOCl、吡啶、CH2
Cl2
、RT;(iii) Zn、AcOH、THF、RT;(iv)丙炔酸、DCC、CH2
Cl2
、0℃
5-(2- 胺基乙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (51)
向48a
(250 mg,0.62 mmol)於MeOH (25 mL)中的溶液中逐滴添加單水合肼(0.303 mL,6.24 mmol)。所得溶液在N2
下回流且攪拌4小時。真空濃縮反應混合物且懸浮於H2
O (150 mL)中且接著用EtOAc (3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 1:99)純化,得到呈棕色油狀之51
(121 mg,72%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 6.55 (s, 1H), 5.36 (s, 2H), 3.93 (2, 3H), 3.89 (m, 5H), 3.39 (m, 2H)。
5-(2- 苯甲醯胺基乙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (52)
向51
(50 mg,0.19 mmol)於無水CH2
Cl2
(10 mL)中的溶液中逐滴添加吡啶(0.060 mL,0.74 mmol)及苯甲醯氯(0.065 mL,0.56 mmol)。所得溶液在N2
下、在室溫下攪拌2.5小時。將反應混合物懸浮於H2
O (50 mL)中且接著用CH2
Cl2
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。藉由矽膠層析(EtOAc/正己烷=1:5)純化殘餘物,得到52
(65 mg,94%)。1
H NMR (300 MHz, CDCl3
) δ 8.00 (d,J
= 7.2 Hz, 2H), 7.56 (m, 1H), 7.44 (m, 3H), 6.66 (s, 1H), 5.34 (s, 1H), 4.54 (t,J
= 5.4 Hz, 2H), 4.10 (q,J
= 7.2 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.3.65 (m, 2H)。
2- 胺基 -5-(2- 苯甲醯胺基乙氧基 )-4- 甲氧基苯甲酸甲酯 (53)
依循針對化合物38
所述的程序,向52
(63 mg,0.17 mmol)於HOAc/THF = 1:4 (10 mL)中的反應物中添加Zn (253 mg,3.86 mmol)且在N2
下、在室溫下攪拌混合物,得到53
(45 mg,78%)。1
H NMR (300 MHz, CDCl3
) δ 8.03 (dd,J
= 8.3, 1.4 Hz, 2H), 7.53 (tt,J
= 3.7, 1.6 Hz, 1H), 7.42 (t,J
= 7.5 Hz, 2H), 7.12 (s, 1H), 6.09 (s, 1H), 5.38 (s, 2H), 4.52 (t,J
= 5.2 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.50 (t,J
= 5.4 Hz, 2H)。
4- 甲氧基 -2- 丙炔醯胺基 -5-(2-(n- 丙炔醯基苯甲醯胺基 ) 乙氧基 ) 苯甲酸甲酯 (54)
依循針對化合物4
所述的程序,在冰浴中,向53
(40 mg,0.12 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.011 mL,0.17 mmol)及N,N'
-二環己基碳二亞胺(36 mg,0.17 mmol)的無水CH2
Cl2
(5 mL),得到54
(49 mg,94%)。1
H NMR (300 MHz, CDCl3
) δ 11.70 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.83 (m, 2H), 7.51 (tt,J
= 7.4, 1.6 Hz, 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
試劑及條件:(i)
NH2
NH2
-H2
O、MeOH、60℃;(ii)
RCOCl、吡啶、CH2
Cl2
、RT;(iii)
RCO2
H DMAP、DCC、CH2
Cl2
、RT;(iv)
Zn、AcOH、THF、RT;(v)
丙炔酸、DCC、CH2
Cl2
、0℃
a: R = Phenyl | g: R = 3-OMe-Phe | m: R = 2-OMe-Bn | s: R = 2-CF3 -Bn |
b: R = 2-F-Ph | h: R = 4-OMe-Ph | n: R = 3-OMe-Bn | t: R = 3-CF3 -Bn |
c: R = 3-F-Ph | i: R = Bn | o: R = 4-OMe-Bn | u: R = 4-CF3 -Bn |
d: R = 4-F-Ph | j: R = 2-F-Bn | p: R = 3,4,5-TriOMe-Bn | V: |
e: R = 2,6-二氟-Ph | k: R = 3-F-Bn | q: R = 2-CI-Bn | |
f: R = 2,6-DiOMe-Ph | 1: R = 4-F-Bn | r: R = 3-CI-Bn |
5-(3- 胺基丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (55)
向48b
(29.00 g,69.99 mmol)於MeOH (500 mL)中的溶液中逐滴添加單水合肼(33.95 mL,699.86 mmol)。所得溶液在N2
下回流且攪拌24小時。真空濃縮反應混合物且懸浮於H2
O (150 mL)中且接著用EtOAc (3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 1:99)純化,得到呈棕色油狀之55
(3.25 g,16%)。1
H NMR (300 MHz, CDCl3
) δ 7.46 (s, 1H), 6.53 (s, 1H), 5.38 (s, 2H), 3.92 (2, 3H), 3.89 (s, 3H), 3.80 (t,J
= 5.7 Hz, 2H), 3.38 (dt,J
= 5.6, 6.6 Hz, 2H), 1.91 (tt,J
= 5.7, 6.5 Hz, 2H)。
5-(3- 苯甲醯胺基丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56a)
向55
(100 mg,0.35 mmol)於無水CH2
Cl2
(10 mL)中的溶液中逐滴添加吡啶(0.113 mL,1.41 mmol)及苯甲醯氯(0.113 mL,1.41 mmol)。所得溶液在N2
下、在室溫下攪拌2.5小時。將反應混合物懸浮於H2
O (50 mL)中且接著用CH2
Cl2
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷=1:5)純化,得到56a
(124 mg,91%)。1
H NMR (300 MHz, CDCl3
) δ 8.02 (d,J
= 7.1 Hz, 2H), 7.57 (tt,J
= 7.4, 1.2 Hz, 1H), 7.45 (m, 3H), 6.54 (s, 1H), 5.26 (s, 1H), 4.45 (t,J
= 5.9 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.42 (t,J
= 5.6 Hz, 2H), 2.14 (tt,J
= 5.9, 5.6 Hz, 2H)。
5-(3-(2- 氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56b)
依循針對56a
所述的程序,使55
(90 mg,0.32 mmol)、吡啶(0.102 mL,1.27 mmol)及2-氟苯甲醯氯(0.113 mL,0.95 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56b
(116 mg,90%)。1
H NMR (300 MHz, CDCl3
) δ 7.93 (td,J
= 7.5, 1.8 Hz, 1H), 7.53 (m, 1H), 7.45 (s, 1H), 7.23 (m, 1H), 7.16 (dd,J
= 11.1, 2.8 Hz, 1H), 6.55 (s, 1H), 5.24 (t,J
= 5.7 Hz, 1H), 4.45 (t,J
= 5.9 Hz, 2H), 3.87 (s, 6H), 3.44 (dt,J
= 6.0, 6.5 Hz, 2H), 2.12 (tt,J
= 5.9, 6.5 Hz, 2H)。
5-(3-(3- 氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56c)
在冰浴中,向55
(100 g,0.35 mmol)、4-(二甲胺基)吡啶(43 mg,0.35 mmol)及3-氟苯甲酸(148 mg,1.05 mmol)於無水CH2
Cl2
(10 mL)中的混合物中逐滴添加含有N,N'-
二環己基碳二亞胺(363 mg,1.76 mmol)的無水CH2
Cl2
(5 mL)。所得溶液在N2
下、在室溫下攪拌12小時。將反應混合物懸浮於H2
O (50 mL)中且接著用CH2
Cl2
(3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。過濾混合物且用EtOAc/正己烷=1:1 (10 mL)洗滌。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:5)純化,得到56c
(129 mg,90%)。1
H NMR (300 MHz, CDCl3
) δ 7.82 (dt,J
= 7.6, 1.3 Hz, 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
= 5.9 Hz, 2H), 3.88 (s, 6H), 3.42 (dt,J
= 5.0, 6.2 Hz, 2H), 2.14 (tt,J
= 6.2, 5.9 Hz, 2H)。
5-(3-(4- 氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56d)
依循針對56a
所述的程序,使55
(150 mg,0.53 mmol)、吡啶(0.171 mL,2.11 mmol)及4-氟苯甲醯氯(0.187 mL,1.58 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56d
(191 mg,89%)。1
H NMR (300 MHz, CDCl3
) δ 8.04 (m, 2H), 7.46 (s, 1H), 7.11 (m, 2H), 6.54 (s, 1H), 5.21 (s, 1H), 4.43 (t,J
= 5.9 Hz, 2H), 3.88 (s, 6H), 3.41 (dt,J
= 5.9, 6.7 Hz, 2H), 2.13 (tt,J
= 6.7, 5.9 Hz, 3H)。
5-(3-(2,6- 二氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56e)
依循針對56c
所述的程序,使55
(100 mg,0.35 mmol)、2,6-二氟苯甲酸(167 mg,1.05 mmol)、4-(二甲胺基)吡啶(43 mg,0.35 mmol)及N,N'-
二環己基碳二亞胺(363 mg,1.76 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56e
(147 mg,98%)。1
H NMR (300 MHz, CDCl3
) δ 7.46 (s, 1H), 7.38 (m, 1H), 6.96 (m, 2H), 6.54 (s, 1H), 5.20 (s, 1H), 4.47 (t,J
= 5.9 Hz, 2H), 3.88 (s, 3H), 3.88 (s, 3H), 3.42 (t,J
= 6.8 Hz, 2H), 2.10 (tt,J
= 5.9, 6.8 Hz, 3H)。
5-(3-(2,6- 二甲氧基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56f)
依循針對56a
所述的程序,使55
(120 mg,0.42 mmol)、吡啶(0.136 mL,1.69 mmol)及2,6-二甲氧基苯甲醯氯(254 mg,1.27 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56f
(189 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.45 (s, 1H), 7.29 (t,J
= 8.5 Hz, 1H), 6.56 (d,J
= 8.5 Hz, 2H), 6.52 (s, 1H), 5.37 (s, 1H), 4.45 (t,J
= 5.8 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.78 (s, 6H), 3.42 (dt,J
= 6.1, 6.4 Hz, 2H), 2.07 (tt,J
= 5.8, 6.4 Hz, 3H)。
4- 甲氧基 -5-(3-(3- 甲氧基苯甲醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56g)
依循針對56a
所述的程序,使55
(150 mg,0.53 mmol)、吡啶(0.171 mL,2.11 mmol)及3-甲氧基苯甲醯氯(222 mL,1.58 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56g
(218 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.78 (dt,J
= 7.8, 1.2 Hz, 1H), 7.69 (m, 1H), 7.61 (s, 1H), 7.51 (t,J
= 7.9 Hz, 1H), 7.27 (ddd,J
= 8.3, 2.7, 0.9 Hz, 1H), 6.69 (s, 1H), 5.41 (s, 1H), 4.60 (t,J
= 5.9 Hz, 2H), 4.04 (s, 3H), 4.02 (s, 3H), 4.00 (s, 3H), 3.58 (dt,J
= 6.0, 6.5 Hz, 2H), 2.11 (tt,J
= 5.9, 6.5 Hz, 2H)。
4- 甲氧基 -5-(3-(4- 甲氧基苯甲醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56h)
依循針對56a
所述的程序,使55
(90 mg,0.32 mmol)、吡啶(0.102 mL,1.27 mmol)及4-甲氧基苯甲醯氯(0.128 mL,0.95 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56h
(131 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.97 (d,J
= 9.0 Hz, 2H), 7.45 (s, 1H), 6.91 (d,J
= 9.0 Hz, 2H), 6.54 (s, 1H), 5.26 (s, 1H), 4.41 (t,J
= 5.9 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.41 (dt,J
= 6.0, 6.5 Hz, 2H), 2.11 (tt,J
= 5.9, 6.0 Hz, 2H)。
4- 甲氧基 -2- 硝基 -5-(3-(2- 苯基乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (56i)
依循針對56c
所述的程序,使55
(50 mg,0.18 mmol)、苯乙酸(48 mg,0.35 mmol)、4-(二甲胺基)吡啶(21 mg,0.18 mmol)及N,N'-
二環己基碳二亞胺(73 mg,0.35 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56i
(68 mg,96%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 7.29 (m, 5H), 6.47 (s, 1H), 5.11 (s, 1H), 4.20 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.63 (s, 2H), 3.24 (dt,J
= 6.0, 6.5 Hz, 2H), 1.96 (tt,J
= 6.0, 6.9 Hz, 2H)。
5-(3-(2-(2- 氟苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56j)
依循針對56c
所述的程序,使55
(120 mg,0.42 mmol)、2-氟苯乙酸(195 mg,1.27 mmol)、4-(二甲胺基)吡啶(51 mg,0.42 mmol)及N,N'-
二環己基碳二亞胺(435 mg,2.11 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56j
(176 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (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
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.68 (d,J
= 1.1 Hz, 2H), 3.27 (dt,J
= 5.9, 6.7 Hz, 2H), 1.97 (tt,J
= 6.0, 6.7 Hz, 2H)。
5-(3-(2-(3- 氟苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56k)
依循針對56a
所述的程序,使55
(150 mg,0.53 mmol)、吡啶(0.170 mL,2.11 mmol)及3-氟苯基氯化物(109 mg,0.63 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56k
(210 mg,95%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 7.27 (m, 1H), 7.03 (d,J
= 8.5 Hz, 1H), 6.96 (m, 2H), 6.48 (s, 1H), 5.10 (s, 1H), 4.21 (t,J
= 6.1 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.62 (s, 2H), 3.26 (dt,J
= 5.9, 6.6 Hz, 2H), 1.98 (tt,J
= 6.1, 6.6 Hz, 2H)。
5-(3-(2-(4- 氟苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56l)
依循針對56c
所述的程序,使55
(150 mg,0.53 mmol)、4-氟苯乙酸(244 mg,1.58 mmol)、4-(二甲胺基)吡啶(64 mg,0.53 mmol)及N,N'-
二環己基碳二亞胺(544 mg,2.64 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56l
(219 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 7.22 (m, 2H), 6.99 (m, 2H), 6.49 (s, 1H), 5.11 (s, 1H), 4.20 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.60 (s, 2H), 3.26 (dt,J
= 5.9, 6.6 Hz, 2H), 1.97 (tt,J
= 6.0, 6.6 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(2- 甲氧苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56m)
依循針對56c
所述的程序,使55
(120 mg,0.42 mmol)、2-甲氧基苯乙酸(210 mg,1.27 mmol)、4-(二甲胺基)吡啶(51 mg,0.42 mmol)及N,N'
-二環己基碳二亞胺(435 mg,2.11 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56m
(118 mg,65%)。1
H NMR (300 MHz, CDCl3
) δ 7.46 (s, 1H), 7.25 (td,J
= 7.8, 1.7 Hz, 1H), 7.16 (dd,J
= 7.4, 1.7 Hz, 1H), 6.89 (td,J
= 7.4, 1.1 Hz, 1H), 6.86 (d,J
= 8.2 Hz, 1H), 6.47 (s, 1H),5.19 (s, 1H), 4.21 (t,J
= 6.0 Hz, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.77 (s, 3H), 3.63 (s, 2H), 3.26 (dt,J
= 5.9, 6.6 Hz, 2H), 1.96 (tt,J
= 6.0, 6.6 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(3- 甲氧基苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56n)
依循針對56a
所述的程序,使55
(150 mg,0.53 mmol)、吡啶(0.128 mL,1.58 mmol)及3-甲氧基苯基氯化物(0.089 mL,0.63 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56n
(206 mg,90%)。1
H NMR (300 MHz, CDCl3
) δ 7.46 (s, 1H), 7.25 (td,J
= 7.5, 1.2 Hz, 1H), 6.81 (m, 3H), 6.48 (s, 1H), 5.13 (s, 1H), 4.20 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.77 (s, 3H), 3.60 (s, 2H), 3.25 (dt,J
= 5.9, 6.6 Hz, 2H), 1.97 (tt,J
= 6.0, 6.6 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(4- 甲氧基苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56o)
依循針對56c
所述的程序,使55
(130 mg,0.46 mmol)、4-甲氧基苯乙酸(228 mg,1.37 mmol)、4-(二甲胺基)吡啶(51 mg,0.46 mmol)及N,N'-
二環己基碳二亞胺(472 mg,2.29 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56o
(172 mg,87%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 7.17 (m, 2H), 6.84 (m, 2H), 6.49 (s, 1H), 5.48 (t,J
= 5.5 Hz, 1H), 4.19 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.77 (s, 3H), 3.56 (s, 2H), 3.26 (dt,J
= 6.0, 6.6 Hz, 2H), 1.96 (tt,J
= 6.0, 6.6 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(3,4,5- 三甲氧基苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56p)
依循針對56c
所述的程序,使55
(120 mg,0.42 mmol)、3,4,5-三甲氧基苯乙酸(286 mg,1.27 mmol)、4-(二甲胺基)吡啶(52 mg,0.42 mmol)及N,N'
-二環己基碳二亞胺(435 mg,2.11 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56p
(168 mg,81%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 6.52 (s, 1H), 6.48 (s, 2H), 5.14 (s, 1H), 4.21 (t,J
= 6.0 Hz, 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, 6.7 Hz, 2H), 1.99 (tt,J
= 6.0, 6.7 Hz, 2H)。
5-(3-(2-(2- 氯苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56q)
依循針對56a
所述的程序,使55
(150 mg,0.53 mmol)、吡啶(0.128 mL,1.58 mmol)及2-氯苯基乙醯氯(0.092 mL,0.63 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56q
(207 mg,90%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 7.37 (m, 1H), 7.24 (m, 3H), 6.47 (s, 1H), 5.13 (s, 1H), 4.23 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.78 (s, 2H), 3.26 (dt,J
= 6.0, 6.6 Hz, 2H), 1.97 (tt,J
= 6.0, 6.6 Hz, 2H)。
5-(3-(2-(3- 氯苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (56r)
依循針對56c
所述的程序,使55
(120 mg,0.42 mmol)、3-氯苯乙酸(216 mg,1.27 mmol)、4-(二甲胺基)吡啶(51 mg,0.42 mmol)及N,N'
-二環己基碳二亞胺(435 mg,2.11 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56r
(182 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.47 (s, 1H), 7.25 (m, 3H), 7.15 (m, 1H), 6.49 (s, 1H), 5.10 (t,J
= 5.3 Hz, 1H), 4.21 (t,J
= 6.1 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.60 (s, 2H), 3.27 (dt,J
= 5.9, 6.7 Hz, 2H), 1.98 (tt,J
= 6.1, 6.7 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(2-( 三氟甲基 ) 苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56s)
依循針對56c
所述的程序,使55
(150 mg,0.53 mmol)、2-(三氟甲基)苯乙酸(323 mg,1.58 mmol)、4-(二甲胺基)吡啶(64 mg,0.53 mmol)及N,N'
-二環己基碳二亞胺(544 mg,2.64 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56s
(230 mg,93%)。1
H NMR (300 MHz, CDCl3
) δ 7.65 (d,J
= 7.9 Hz, 1H), 7.51 (t,J
= 7.4 Hz, 1H), 7.46 (s, 1H), 7.38 (t,J
= 6.1 Hz, 2H), 6.47 (s, 1H), 5.12 (s, 1H), 4.21 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.84 (d,J
= 1.1 Hz, 2H), 3.26 (dt,J
= 6.0, 6.7 Hz, 2H), 1.96 (tt,J
= 6.0, 6.7 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(3-( 三氟甲基 ) 苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56t)
依循針對56c
所述的程序,使55
(150 mg,0.53 mmol)、3-(三氟甲基)苯乙酸(323 mg,1.58 mmol)、4-(二甲胺基)吡啶(64 mg,0.53 mmol)及N,N'
-二環己基碳二亞胺(544 mg,2.64 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56t
(240 mg,97%)。1
H NMR (300 MHz, CDCl3
) δ 7.53 (m, 2H), 7.45 (m, 3H), 6.49 (s, 1H), 5.10 (t,J
= 5.4 Hz, 1H), 4.22 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.69 (s, 2H), 3.27 (dt,J
= 5.9, 6.7 Hz, 2H), 1.98 (tt,J
= 6.0, 6.7 Hz, 2H)。
4- 甲氧基 -5-(3-(2-(4-( 三氟甲基 ) 苯基 ) 乙醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56u)
依循針對56a
所述的程序,使55
(150 mg,0.53 mmol)、吡啶(0.171 mL,2.11 mmol)及4-(三氟甲基)苯乙醯氯(141 mg,0.63 mmol)於CH2
Cl2
(10 mL)中、在N2
下反應,得到56u
(223 mg,90%)。1
H NMR (300 MHz, CDCl3
) δ 7.58 (d,J
= 8.1 Hz, 2H), 7.47 (s, 1H), 7.39 (d,J
= 8.1 Hz, 2H), 6.51 (s, 1H), 5.11 (s, 1H), 4.21 (t,J
= 6.1 Hz, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.69 (s, 2H), 3.29 (dt,J
= 5.9, 6.5 Hz, 2H), 1.98 (tt,J
= 6.1, 6.5 Hz, 2H)。
4- 甲氧基 -5-(3-( 㗁唑 -5- 甲醯胺基 ) 丙氧基 )-2- 硝基苯甲酸甲酯 (56v)
依循針對56c
所述的程序,使55
(150 mg,0.53 mmol)、㗁唑-5-甲酸(179 mg,1.58 mmol)、4-(二甲胺基)吡啶(64 mg,0.53 mmol)及N,N'-
二環己基碳二亞胺(544 mg,2.64 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到56v
(185 mg,92%)。1
H NMR (300 MHz, CDCl3
) δ 8.02 (s, 1H), 7.79 (s, 1H), 7.46 (s, 1H), 6.54 (s, 1H), 5.18 (t,J
= 5.6 Hz, 1H), 4.45 (t,J
= 6.0 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.40 (dt,J
= 6.0, 6.6 Hz, 2H), 2.11 (tt,J
= 6.0, 6.6 Hz, 2H)。
2- 胺基 -5-(3- 苯甲醯胺基丙氧基 )-4- 甲氧基苯甲酸甲酯 (57a)
依循針對化合物38
所述的程序,向56a
(150 mg,0.39 mmol)於HOAc/THF = 1:4 (10 mL)中的反應物中添加Zn (253 mg,3.86 mmol)且在N2
下、在室溫下攪拌混合物,得到57a
(113 mg,82%)。1
H NMR (300 MHz, CDCl3
) δ 8.05 (m, 2H), 7.54 (tt,J
= 7.4, 1.6 Hz, 1H), 7.42 (m, 2H), 7.04 (s, 1H), 6.08 (s, 1H), 4.44 (t,J
= 6.1 Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.27 (t,J
= 5.8 Hz, 2H), 2.11 (tt,J
= 6.1, 5.8 Hz, 2H)。
2- 胺基 -5-(3-(2- 氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57b)
依循針對化合物38
所述的程序,使56b
(100 mg,0.25 mmol)、Zn (161 mg,2.46 mmol)於HOAc/THF = 1:4 (10 mL)中、在N2
下反應,得到57b
(89 mg,96%)。1
H NMR (300 MHz, CDCl3
) δ 7.93 (td,J
= 7.5, 1.9 Hz, 1H), 7.51 (m, 1H), 7.18 (tt,J
= 7.6, 1.1 Hz, 1H), 7.12 (ddd,J
= 10.8, 8.3, 1.0 Hz, 1H), 7.04 (s, 1H), 6.08 (s, 1H), 4.45 (t,J
= 6.1 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.28 (t,J
= 6.7 Hz, 2H), 2.10 (tt,J
= 6.1, 6.7 Hz, 2H)。
2- 胺基 -5-(3-(3- 氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57c)
依循針對化合物38
所述的程序,使56c
(200 mg,0.49 mmol)、Zn (321 mg,4.92 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57c
(120 mg,65%)。1
H NMR (300 MHz, CDCl3
) δ 7.82 (d,J
= 7.7 Hz, 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
= 6.1 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.27 (t,J
= 6.7 Hz, 2H), 2.11 (tt,J
= 6.1, 6.7 Hz, 2H)。
2- 胺基 -5-(3-(4- 氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57d)
依循針對化合物38
所述的程序,使56d
(180 mg,0.44 mmol)、Zn (289 mg,4.43 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57d
(125 mg,75%)。1
H NMR (300 MHz, CDCl3
) δ 8.06 (m, 2H), 7.10 (m, 2H), 7.03 (s, 1H), 6.09 (s, 1H), 5.02 (s, 2H), 4.43 (t,J
= 6.2 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.26 (t,J
= 6.7 Hz, 2H), 2.10 (tt,J
= 6.2, 6.7 Hz, 3H)。
2- 胺基 -5-(3-(2,6- 二氟苯甲醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57e)
依循針對化合物38
所述的程序,使56e
(200 mg,0.47 mmol)、Zn (308 mg,4.71 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57e
(149 mg,80%)。1
H NMR (300 MHz, CDCl3
) δ 7.40 (m, 1H), 7.03 (s, 1H), 6.94 (t,J
= 8.2 Hz, 2H), 6.08 (s, 1H), 4.48 (t,J
= 6.2 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.26 (t,J
= 6.8 Hz, 2H), 2.08 (tt,J
= 6.2, 6.8 Hz, 3H)。
2- 胺基 -5-(3-(2,6- 二甲氧基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57f)
依循針對化合物38
所述的程序,使56f
(150 mg,0.34 mmol)、Zn (218 mg,3.35 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57f
(70 mg,50%)。1
H NMR (300 MHz, CDCl3
) δ 7.27 (t,J
= 8.5 Hz, 1H), 7.03 (s, 1H), 6.54 (d,J
= 8.3 Hz, 2H), 6.08 (s, 1H), 4.44 (t,J
= 6.0 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 9H), 3.25 (t,J
= 6.9 Hz, 2H), 2.05 (tt,J
= 6.0, 6.9 Hz, 3H)。
2- 胺基 -4- 甲氧基 -5-(3-(3- 甲氧基苯甲醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57g)
依循針對化合物38
所述的程序,使56g
(200 mg,0.48 mmol)、Zn (313 mg,4.79 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57g
(166 mg,89%)。1
H NMR (300 MHz, CDCl3
) δ 7.64 (dt,J
= 7.6, 1.2 Hz, 1H), 7.56 (dd,J
= 2.6, 1.5 Hz, 1H), 7.33 (t,J
= 8.0 Hz, 1H), 7.09 (ddd,J
= 8.2, 2.7, 1.0 Hz, 1H), 7.04 (s, 1H), 6.08 (s, 1H), 4.44 (t,J
= 6.1 Hz, 2H), 4.83 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.27 (t,J
= 6.7 Hz, 2H), 2.10 (tt,J
= 6.1, 6.7 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(4- 甲氧基苯甲醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57h)
依循針對化合物38
所述的程序,使56h
(115 mg,0.27 mmol)、Zn (180 mg,2.75 mmol)於HOAc/THF = 1:4 (10 mL)中、在N2
下反應,得到57h
(85 mg,80%)。1
H NMR (300 MHz, CDCl3
) δ 8.00 (m, 2H), 7.04 (s, 1H), 6.90 (m, 2H), 6.08 (s, 1H), 4.41 (t,J
= 6.1 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.26 (t,J
= 6.8 Hz, 2H), 2.09 (tt,J
= 6.1, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2- 苯基乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57i)
依循針對化合物38
所述的程序,使56i
(81 mg,0.20 mmol)、Zn (132 mg,2.01 mmol)於HOAc/THF = 1:4 (10 mL)中、在N2
下反應,得到57i
(69 mg,92%)。1
H NMR (300 MHz, CDCl3
) δ 7.28 (m, 5H), 7.00 (s, 1H), 6.09 (s, 1H), 4.21 (t,J
= 6.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.62 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.94 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -5-(3-(2-(2- 氟苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57j)
依循針對化合物38
所述的程序,使56j
(150 mg,0.36 mmol)、Zn (233 mg,3.57 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57j
(74 mg,53%)。1
H NMR (300 MHz, CDCl3
) δ 7.24 (m, 2H), 7.05 (m, 2H), 7.00 (s, 1H), 6.09 (s, 1H), 4.23 (t,J
= 6.2 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.68 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.95 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -5-(3-(2-(3- 氟苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57k)
依循針對化合物38
所述的程序,使56k
(150 mg,0.36 mmol)、Zn (233 mg,3.57 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57k
(110 mg,79%)。1
H NMR (300 MHz, CDCl3
) δ 7.26 (m, 1H), 6.98 (m, 4H), 6.09 (s, 1H), 4.22 (t,J
= 6.3 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.61 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.95 (tt,J
= 6.3, 6.8 Hz, 2H)。
2- 胺基 -5-(3-(2-(4- 氟苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57l)
依循針對化合物38
所述的程序,使56l
(175 mg,0.42 mmol)、Zn (272 mg,4.16 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57l
(120 mg,74%)。1
H NMR (300 MHz, CDCl3
) δ 7.23 (m, 2H), 6.98 (m, 3H), 6.09 (s, 1H), 4.21 (t,J
= 6.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.59 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.95 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(2- 甲氧苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57m)
依循針對化合物38
所述的程序,使56m
(100 mg,0.23 mmol)、Zn (151 mg,2.31 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57m
(73 mg,78%)。1
H NMR (300 MHz, CDCl3
) δ7.25 (td,J
= 7.9, 1.7 Hz, 1H), 7.16 (dd,J
= 7.5, 1.7 Hz, 1H), 7.00 (s, 1H),6.89 (td,J
= 7.4, 1.0 Hz, 1H), 6.84 (d,J
= 8.2 Hz, 1H), 6.09 (s, 1H), 4.21 (t,J
= 6.2 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.63 (s, 2H), 3.12 (t,J
= 6.8 Hz, 2H), 1.94 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(3- 甲氧基苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57n)
依循針對化合物38
所述的程序,使56n
(150 mg,0.35 mmol)、Zn (227 mg,3.47 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57n
(97 mg,69%)。1
H NMR (300 MHz, CDCl3
) δ 7.21 (t,J
= 7.8 Hz, 1H), 6.99 (s, 1H), 6.85 (m, 1H), 6.79 (m, 2H), 6.09 (s, 1H), 4.21 (t,J
= 6.3 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H), 3.59 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.95 (tt,J
= 6.3, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(4- 甲氧基苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57o)
依循針對化合物38
所述的程序,使56o
(150 mg,0.35 mmol)、Zn (227 mg,3.47 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57o
(120 mg,86%)。1
H NMR (300 MHz, CDCl3
) δ 7.18 (m, 2H), 7.00 (s, 1H), 6.83 (m, 2H), 6.09 (s, 1H), 4.20 (t,J
= 6.3 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H), 3.56 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.94 (tt,J
= 6.3, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(3,4,5- 三甲氧基苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57p)
依循針對化合物38
所述的程序,使56p
(130 mg,0.26 mmol)、Zn (173 mg,2.64 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57p
(99 mg,81%)。1
H NMR (300 MHz, CDCl3
) δ 7.00 (s, 1H), 6.48 (s, 2H), 6.09 (s, 1H), 4.23 (t,J
= 6.2 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 9H), 3.80 (s, 3H), 3.55 (s, 2H), 3.16 (t,J
= 6.7 Hz, 2H), 1.97 (tt,J
= 6.2, 6.7 Hz, 2H)。
2- 胺基 -5-(3-(2-(2- 氯苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57q)
依循針對化合物38
所述的程序,使56q
(150 mg,0.34 mmol)、Zn (224 mg,3.43 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57q
(118 mg,84%)。1
H NMR (300 MHz, CDCl3
) δ 7.36 (m, 1H), 7.23 (m, 3H), 7.00 (s, 1H), 6.09 (s, 1H), 4.24 (t,J
= 6.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.78 (s, 2H), 3.13 (t,J
= 6.8 Hz, 2H), 1.95 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -5-(3-(2-(3- 氯苯基 ) 乙醯胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (57r)
依循針對化合物38
所述的程序,使56r
(150 mg,0.34 mmol)、Zn (224 mg,3.43 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57r
(100 mg,72%)。1
H NMR (300 MHz, CDCl3
) δ 7.27 (s, 1H), 7.22 (m, 2H), 7.15 (m, 1H), 7.00 (s, 1H), 6.09 (s, 1H), 4.22 (t,J
= 6.2 Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.59 (s, 2H), 3.14 (t,J
= 6.8 Hz, 2H), 1.95 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(2-( 三氟甲基 ) 苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57s)
依循針對化合物38
所述的程序,使56s
(175 mg,0.37 mmol)、Zn (243 mg,3.72 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57s
(151 mg,92%)。1
H NMR (300 MHz, CDCl3
) δ 7.64 (d,J
= 7.4 Hz, 1H), 7.49 (t,J
= 7.2 Hz, 1H), 7.36 (m, 2H), 6.99 (s, 1H), 6.09 (s, 1H), 4.23 (t,J
= 6.2 Hz, 2H), 3.83 (s, 6H), 3.80 (s, 2H), 3.12 (t,J
= 6.8 Hz, 2H), 1.94 (tt,J
= 6.2, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(3-( 三氟甲基 ) 苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57t)
依循針對化合物38
所述的程序,使56t
(200 mg,0.43 mmol)、Zn (278 mg,4.25 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57t
(112 mg,60%)。1
H NMR (300 MHz, CDCl3
) δ 7.46 (m, 4H), 7.00 (s, 1H), 6.09 (s, 1H), 4.23 (t,J
= 6.3 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.68 (s, 2H), 3.14 (t,J
= 6.8 Hz, 2H), 1.96 (tt,J
= 6.3, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-(2-(4-( 三氟甲基 ) 苯基 ) 乙醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57u)
依循針對化合物38
所述的程序,使56u
(200 mg,0.43 mmol)、Zn (278 mg,4.25 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57u
(136 mg,73%)。1
H NMR (300 MHz, CDCl3
) δ 7.56 (d,J
= 8.2 Hz, 2H), 7.39 (d,J
= 8.2 Hz, 2H), 7.01 (s, 1H), 6.09 (s, 1H), 4.23 (t,J
= 6.3 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.68 (s, 2H), 3.14 (dt,J
= 6.8 Hz, 2H), 1.96 (tt,J
= 6.3, 6.8 Hz, 2H)。
2- 胺基 -4- 甲氧基 -5-(3-( 㗁唑 -5- 甲醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (57v)
依循針對化合物38
所述的程序,使56v
(150 mg,0.40 mmol)、Zn (259 mg,3.95 mmol)於HOAc/THF = 1:4 (20 mL)中、在N2
下反應,得到57v
(132 mg,96%)。1
H NMR (300 MHz, CDCl3
) δ 8.00 (s, 1H), 7.78 (s, 1H), 7.02 (s, 1H), 6.09 (s, 1H), 4.46 (t,J
= 6.2 Hz, 2H), 3.81 (s, 3H), 3.81 (s, 3H), 3.24 (t,J
= 6.7 Hz, 2H), 2.09 (tt,J
= 6.2, 6.7 Hz, 2H)。
4- 甲氧基 -2- 丙炔醯胺基 -5-(3-( N - 丙炔醯基苯甲醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (58a)
依循針對化合物4
所述的程序,使57a
(50 mg,0.14 mmol)、丙炔酸(0.018 mL,0.28 mmol)及N,N'-
二環己基碳二亞胺(58 mg,0.28 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58a
(61 mg,94%)。1
H NMR (500 MHz, CDCl3
) δ 11.71 (s, 1H), 8.38 (s, 1H), 7.95 (d,J
= 7.9 Hz, 2H), 7.88 (s, 1H), 7.52 (t,J
= 7.4 Hz, 1H), 7.39 (t,J
= 7.7 Hz, 2H), 4.34 (t,J
= 6.4 Hz, 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, 6.7 Hz, 2H)。
5-(3-(2- 氟 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58b)
依循針對化合物4
所述的程序,使57b
(50 mg,0.13 mmol)、丙炔酸(0.016 mL,0.27 mmol)及N,N'-
二環己基碳二亞胺(55 mg,0.27 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58b
(57 mg,89%)。1
H NMR (500 MHz, CDCl3
) δ 11.71 (s, 1H), 8.38 (s, 1H), 7.88 (s, 1H), 7.86 (td,J
= 7.6, 1.8 Hz, 1H), 7.48 (m, 1H), 7.16 (t,J
= 7.2 Hz, 1H), 7.07 (dd,J
= 10.5, 8.4 Hz, 1H), 4.35 (t,J
= 6.5 Hz, 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, 7.0 Hz, 2H)。
5-(3-(3- 氟 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58c)
依循針對化合物4
所述的程序,使57c
(90 mg,0.24 mmol)、丙炔酸(0.029 mL,0.48 mmol)及N,N'-
二環己基碳二亞胺(99 mg,0.47 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58c
(113 mg,98%)。1
H NMR (500 MHz, CDCl3
) δ 11.71 (s, 1H), 8.39 (s, 1H), 7.75 (d,J
= 7.8 Hz, 1H), 7.61 (ddd,J
= 9.3, 2.4, 1.5 Hz, 1H), 7.37 (m, 1H), 7.22 (m, 1H), 4.35 (t,J
= 6.3 Hz, 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, 6.7 Hz, 2H)。
5-(3-(4- 氟 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58d)
依循針對化合物4
所述的程序,使57d
(70 mg,0.19 mmol)、丙炔酸(0.023 mL,0.37 mmol)及N,N'-
二環己基碳二亞胺(77 mg,0.37 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58d
(68 mg,76%)。1
H NMR (500 MHz, CDCl3
) δ 11.71 (s, 1H), 8.39 (s, 1H), 7.98 (m, 2H), 7.87 (s, 1H), 7.06 (m, 1H), 4.33 (td,J
= 6.3, 1.6 Hz, 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, 6.9 Hz, 2H)。
5-(3-(2,6- 二氟 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58e)
依循針對化合物4
所述的程序,使57e
(100 mg,0.25 mmol)、丙炔酸(0.031 mL,0.51 mmol)及N,N'-
二環己基碳二亞胺(105 mg,0.51 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58e
(113 mg,89%)。1
H NMR (500 MHz, CDCl3
) δ 11.73 (s, 1H), 8.39 (s, 1H), 7.89 (s, 1H), 7.37 (tt,J
= 8.5, 6.2 Hz, 1H), 6.90 (t,J
= 8.2 Hz, 2H), 4.38 (t,J
= 6.3 Hz, 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, 6.9 Hz, 2H)。
5-(3-(2,6- 二甲氧基 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58f)
依循針對化合物4
所述的程序,使57f
(50 mg,0.12 mmol)、丙炔酸(0.015 mL,0.24 mmol)及N,N'-
二環己基碳二亞胺(49 mg,0.24 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58f
(61 mg,98%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.24 (m, 1H), 6.50 (d,J
= 8.4 Hz, 2H), 4.34 (t,J
= 6.3 Hz, 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, 7.2 Hz, 2H)。
4- 甲氧基 -5-(3-(3- 甲氧基 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-2- 丙炔醯胺基苯甲酸甲酯 (58g)
依循針對化合物4
所述的程序,使57g
(130 mg,0.33 mmol)、丙炔酸(0.041 mL,0.67 mmol)及N,N'-
二環己基碳二亞胺(138 mg,0.67 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58g
(127 mg,77%)。1
H NMR (500 MHz, CDCl3
) δ 11.70 (s, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.53 (d,J
= 7.6 Hz, 1H), 7.45 (dd,J
= 2.5, 1.6 Hz, 1H), 7.29 (t,J
= 8.0 Hz, 1H), 7.06 (dd,J
= 8.6, 2.2 Hz, 1H), 4.33 (t,J
= 6.4 Hz, 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, 6.8 Hz, 2H)。
4- 甲氧基 -5-(3-(4- 甲氧基 -N- 丙炔醯基苯甲醯胺基 ) 丙氧基 )-2- 丙炔醯胺基苯甲酸甲酯 (58h)
依循針對化合物4
所述的程序,使57h
(60 mg,0.15 mmol)、丙炔酸(0.019 mL,0.31 mmol)及N,N'-
二環己基碳二亞胺(64 mg,0.31 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58h
(72 mg,95%)。1
H NMR (500 MHz, CDCl3
) δ 11.71 (s, 1H), 8.37 (s, 1H), 7.89 (m, 3H), 6.86 (d,J
= 8.8 Hz, 2H), 4.30 (t,J
= 6.0 Hz, 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, 6.8 Hz, 2H)。
4- 甲氧基 -5-(3-(N-(2- 苯乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-2- 丙炔醯胺基苯甲酸甲酯 (58i)
依循針對化合物4
所述的程序,使57i
(50 mg,0.13 mmol)、丙炔酸(0.017 mL,0.27 mmol)及N,N'
-二環己基碳二亞胺(55 mg,0.27 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58i
(63 mg,98%)。1
H NMR (500 MHz, CDCl3
) δ 11.75 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.26 (m, 5H), 4.11 (t,J
= 6.3 Hz, 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, 6.8 Hz, 2H)。
5-(3-(N-(2-(2- 氟苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58j)
依循針對化合物4
所述的程序,使57j
(50 mg,0.13 mmol)、丙炔酸(0.018 mL,0.26 mmol)及N,N'-
二環己基碳二亞胺(53 mg,0.26 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58j
(58 mg,92%)。1
H NMR (500 MHz, CDCl3
) δ 11.75 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 7.21 (m, 2H), 7.05 (m, 1H), 6.98 (d,J
= 9.1 Hz, 1H), 4.13 (t,J
= 6.3, 2.2 Hz, 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, 6.8 Hz, 2H)。
5-(3-(N-(2-(3- 氟苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58k)
依循針對化合物4
所述的程序,使57k
(65 mg,0.17 mmol)、丙炔酸(0.020 mL,0.33 mmol)及N,N'-
二環己基碳二亞胺(69 mg,0.33 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58k
(79 mg,96%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.23 (m, 1H), 6.99 (d,J
= 7.5 Hz, 1H), 6.92 (m, 2H), 4.12 (t,J
= 6.0 Hz, 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, 6.9 Hz, 2H)。
5-(3-(N-(2-(4- 氟苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58l)
依循針對化合物4
所述的程序,使57l
(90 mg,0.23 mmol)、丙炔酸(0.028 mL,0.46 mmol)及N,N'-
二環己基碳二亞胺(95 mg,0.46 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58l
(112 mg,98%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.18 (dd,J
= 8.5, 5.4 Hz, 2H), 6.95 (t,J
= 8.7 Hz, 2H), 4.11 (t,J
= 6.3 Hz, 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, 6.8 Hz, 2H)。
4- 甲氧基 -5-(3-(N-(2-(2- 甲氧苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-2- 丙炔醯胺基苯甲酸甲酯 (58m)
依循針對化合物4
所述的程序,使57m
(50 mg,0.12 mmol)、丙炔酸(0.015 mL,0.25 mmol)及N,N'
-二環己基碳二亞胺(51 mg,0.25 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58m
(49 mg,78%)。1
H NMR (500 MHz, CDCl3
) δ 11.75 (s, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.20 (td,J
= 3.9, 1.5 Hz, 1H), 7.11 (dd,J
= 7.4, 1.4 Hz, 1H), 6.85 (m, 1H), 6.81 (d,J
= 8.3 Hz, 1H), 4.11 (td,J
= 6.3, 2.1 Hz, 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, 6.8 Hz, 2H)。
4- 甲氧基 -5-(3-(N-(2-(3- 甲氧基苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-2- 丙炔醯胺基苯甲酸甲酯 (58n)
依循針對化合物4
所述的程序,使57n
(65 mg,0.16 mmol)、丙炔酸(0.020 mL,0.32 mmol)及N,N'-
二環己基碳二亞胺(67 mg,0.32 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58n
(70 mg,86%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.17 (dd,J
= 8.9, 7.7 Hz, 1H), 6.78 (m, 3H), 4.11 (t,J
= 6.3 Hz, 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, 6.8 Hz, 2H)。
依循針對化合物4
所述的程序,使57o
(90 mg,0.22 mmol)、丙炔酸(0.028 mL,0.45 mmol)及N,N'-
二環己基碳二亞胺(92 mg,0.45 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58o
(80 mg,71%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.12 (d,J
= 8.6 Hz, 2H), 6.79 (m, 2H), 4.10 (t,J
= 6.3 Hz, 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, 6.7 Hz, 2H)。 4- 甲氧基 -2- 丙炔醯胺基 -5-(3-(N-(2-(3,4,5- 三甲氧基苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (58p)
依循針對化合物4
所述的程序,使57p
(75 mg,0.16 mmol)、丙炔酸(0.020 mL,0.32 mmol)及N,N'
-二環己基碳二亞胺(67 mg,0.32 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58p
(80 mg,87%)。1
H NMR (500 MHz, CDCl3
) δ 11.73 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 6.47 (s, 2H), 4.12 (t,J
= 6.3 Hz, 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, 6.7 Hz, 2H)。 5-(3-(N-(2-(2- 氯苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58q)
依循針對化合物4
所述的程序,使57q
(80 mg,0.20 mmol)、丙炔酸(0.024 mL,0.39 mmol)及N,N'-
二環己基碳二亞胺(81 mg,0.39 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58q
(100 mg,99%)。1
H NMR (500 MHz, CDCl3
) δ 11.75 (s, 1H), 8.40 (s, 1H), 7.85 (s, 1H), 7.30 (dd,J
= 5.6, 3.6 Hz, 1H), 7.22 (m, 1H), 7.18 (m, 2H), 4.13 (t,J
= 6.1 Hz, 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, 6.7 Hz, 2H)。 5-(3-(N-(2-(3- 氯苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (58r)
依循針對化合物4
所述的程序,使57r
(75 mg,0.18 mmol)、丙炔酸(0.023 mL,0.37 mmol)及N,N'-
二環己基碳二亞胺(76 mg,0.37 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58r
(84 mg,89%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (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
= 6.4 Hz, 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, 6.8 Hz, 2H)。 4- 甲氧基 -2- 丙炔醯胺基 -5-(3-(N-(2-(2-( 三氟甲基 ) 苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (58s)
依循針對化合物4
所述的程序,使57s
(100 mg,0.23 mmol)、丙炔酸(0.028 mL,0.45 mmol)及N,N'
-二環己基碳二亞胺(94 mg,0.45 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58s
(116 mg,94%)。1
H NMR (500 MHz, CDCl3
) δ 11.75 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.59 (d,J
= 7.8 Hz, 1H), 7.47 (t,J
= 7.7 Hz, 1H), 7.34 (t,J
= 7.4 Hz, 2H), 4.12 (t,J
= 6.0 Hz, 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, 6.8 Hz, 2H)。 4- 甲氧基 -2- 丙炔醯胺基 -5-(3-(N-(2-(3-( 三氟甲基 ) 苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (58t)
依循針對化合物4
所述的程序,使57t
(75 mg,0.17 mmol)、丙炔酸(0.021 mL,0.34 mmol)及N,N'-
二環己基碳二亞胺(70 mg,0.34 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58t
(92 mg,99%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.40 (s, 1H), 7.85 (s, 1H), 7.49 (m, 2H), 7.41 (m, 2H), 7.34 (t,J
= 7.4 Hz, 2H), 4.13 (t,J
= 6.3 Hz, 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, 6.8 Hz, 2H)。 4- 甲氧基 -2- 丙炔醯胺基 -5-(3-(N-(2-(4-( 三氟甲基 ) 苯基 ) 乙醯基 ) 丙炔醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (58u)
依循針對化合物4
所述的程序,使57u
(102 mg,0.23 mmol)、丙炔酸(0.029 mL,0.46 mmol)及N,N'
-二環己基碳二亞胺(96 mg,0.46 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58u
(115 mg,91%)。1
H NMR (500 MHz, CDCl3
) δ 11.74 (s, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.54 (d,J
= 8.2 Hz, 2H), 7.35 (d,J
= 8.0 Hz, 2H), 4.13 (t,J
= 6.3 Hz, 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, 6.8 Hz, 2H)。 4- 甲氧基 -2- 丙炔醯胺基 -5-(3-(N- 丙炔醯基㗁唑 -5- 甲醯胺基 ) 丙氧基 ) 苯甲酸甲酯 (58v)
依循針對化合物4
所述的程序,使57v
(100 mg,0.29 mmol)、丙炔酸(0.035 mL,0.57 mmol)及N,N'-
二環己基碳二亞胺(118 mg,0.57 mmol)於CH2
Cl2
(15 mL)中、在N2
下反應,得到58v
(118 mg,91%)。1
H NMR (500 MHz, CDCl3
) δ 11.72 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 7.72 (s, 1H), 4.37 (t,J
= 6.4 Hz, 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, 6.8 Hz, 2H)。
5-(3-(( 第三丁氧基羰基 ) 胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸甲酯 (59)
在冰浴中,向46
(300 mg,1.32 mmol)及三苯膦(692 mg,2.64 mmol)於無水THF (30 mL)中之溶液中逐滴添加3-(boc-胺基)-1-丙醇(0.270 mL,1.58 mmol)及偶氮二甲酸二異丙酯(6.93 mL,35.19 mmol)。所得溶液在N2
下、在室溫下攪拌6小時。將反應混合物懸浮於H2
O (150 mL)中且接著用EtOAc (3×150 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:3)純化,得到59
(500 mg,99%)。1
H NMR (300 MHz, CDCl3
) δ 7.43 (s, 1H), 7.04 (s, 1H), 5.18 (s, 1H), 4.16 (t,J
= 5.9 Hz, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.34 (m, 2H), 2.04 (m, 2H), 1.43 (m, 9H)。
2- 胺基 -5-(3-(( 第三丁氧基羰基 ) 胺基 ) 丙氧基 )-4- 甲氧基苯甲酸甲酯 (60)
依循針對化合物38
所述的程序,向59
(50 mg,0.13 mmol)於HOAc/THF = 1:4 (10 mL)中的反應物中添加Zn (85 mg,1.30 mmol)且在N2
下、在室溫下攪拌混合物,得到60
(33 mg,72%)。1
H NMR (300 MHz, CDCl3
) δ 7.29 (s, 1H), 7.11 (s, 1H), 5.58 (s, 2H), 5.45 (s, 1H), 3.99 (t,J
= 5.8 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.33 (m, 2H), 1.94 (m, 2H), 1.43 (s, 9H)。
5-(3-(( 第三丁氧基羰基 ) 胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸甲酯 (61)
依循針對化合物4
所述的程序,在冰浴中,向60
(33 mg,0.09 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.009 mL,0.14 mmol)及N,N'-
二環己基碳二亞胺(29 mg,0.14 mmol)的無水CH2
Cl2
(5 mL),得到61
(37 mg,98%)。1
H NMR (300 MHz, CDCl3
) δ 11.56 (s, 1H), 8.32 (s, 1H), 7.44 (s, 1H), 4.07 (t,J
= 5.6 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.35 (m, 2H), 1.99 (m, 2H), 1.43 (s, 9H)。
流程 19
試劑及條件:(i)苯甲酸、DCC、CH2
Cl2
、RT;(ii) K2
CO3
、DMF、100℃;(iii) Zn、AcOH、THF、RT;(iv)丙炔酸、DCC、CH2
Cl2
、0℃
(Z)-N-(3- 氯丙基 ) 苯甲醯亞胺酸 (63)
在冰浴中,向62
(100 mg,0.77 mmol)於無水CH2
Cl2
(10 mL)中的溶液中逐滴添加含有苯甲酸(140 mg,1.12 mmol)及N,N'-
二環己基碳二亞胺(238 mg,1.15 mmol)的無水CH2
Cl2
(5 mL)。所得溶液在N2
下、在室溫下攪拌12小時。將反應混合物懸浮於H2
O (50 mL)中且接著用EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。過濾混合物且用EtOAc/正己烷=1:1 (10 mL)洗滌。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:3)純化,得到63
(142 mg,93%)。1
H NMR (300 MHz, CDCl3
) δ 7.74 (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 ) 苯甲醯亞胺酸 (64)
依循針對化合物2所述的程序,向46
(1.72 g,7.59 mmol)及K2
CO3
(2.10 g,15.17 mmol)於DMF (150 mL)中的反應物中添加63
(1.50 g,7.59 mmol)。所得溶液在N2
下加熱至100℃,得到64
(359 mg,12%)。1
H NMR (300 MHz, CDCl3
) δ 7.78 (m, 2H), 7.45 (m, 4H), 7.08 (s, 1H), 6.91 (s, 1H), 4.25 (t,J
= 5.7 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 3.70 (m, 2H), 2.19 (m, 2H)。
(Z)-N-(3-(4- 胺基 -2- 甲氧基 -5-( 甲氧基羰基 ) 苯氧基 ) 丙基 ) 苯甲醯亞胺酸 (65)
依循針對化合物38
所述的程序,向64
(80 mg,0.21 mmol)於HOAc/THF = 1:4 (10 mL)中的反應物中添加Zn (134 mg,2.06 mmol)且在N2
下、在室溫下攪拌混合物,得到65
(69 mg,93%)。1
H NMR (300 MHz, CDCl3
) δ 7.80 (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
= 5.5 Hz, 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- 丙炔醯胺基苯氧基 ) 丙基 ) 苯甲醯亞胺酸 (66)
依循針對化合物4
所述的程序,在冰浴中,向65
(35 mg,0.10 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.010 mL,0.15 mmol)及N,N'-
二環己基碳二亞胺(30 mg,0.15 mmol)的無水CH2
Cl2
(5 mL),得到66
(26 mg,65%)。1
H NMR (300 MHz, CDCl3
) δ 11.54 (s, 1H), 8.30 (s, 1H), 7.79 (m, 2H), 7.44 (m, 4H), 7.16 (s, 1H), 4.17 (t,J
= 5.5 Hz, 2H), 3.90 (s, 3H), 3.70 (m, 5H), 2.92 (s, 1H), 2.14 (m, 2H)。
流程 20
試劑及條件:(i) NaOH、MeOH、THF、RT;(ii) (CH3
)3
Si(CH2
)2
OH、Ph3
P、DIAD、THF、RT;(iii) Zn、AcOH、THF、RT;(iv)屈二醇酸(propiolic acid)、DCC、CH2
Cl2
、0℃;(v) TBAF、THF、RT。
(Z)-5-(3-(( 羥基 ( 苯基 ) 亞甲基 ) 胺基 ) 丙氧基 )-4- 甲氧基 -2- 硝基苯甲酸 (67)
在冰浴中,向64
(229 mg,0.59 mmol)於MeOH (20 mL)及THF (20 mL)中的溶液中添加5 N NaOH (2.5 mL)。在室溫下、在N2
下攪拌反應混合物8小時。將所得溶液酸化至pH 2且用1 N HCl (50 mL)及EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。使殘餘物再結晶,得到67
(220 mg,99%)。1
H NMR (300 MHz, MeOD) δ 7.84 (m, 2H), 7.52 (m, 4H), 7.31 (s, 1H), 4.28 (t,J
= 6.0 Hz,2H), 3.88 (s, 3H), 3.64 (t,J
= 6.6 Hz,2H), 2.19 (m, 2H)。
(Z)-N-(3-(2- 甲氧基 -4- 硝基 -5-((2-( 三甲基矽烷基 ) 乙氧基 ) 羰基 ) 苯氧基 ) 丙基 ) 苯甲醯亞胺酸 (68)
在冰浴中,向67
(210 mg,0.56 mmol)及三苯膦(294 mg,1.12 mmol )於無水THF (30 mL)中的溶液中逐滴添加2-(三甲基矽烷基)乙醇(0.097 mL,0.67 mmol)及偶氮二甲酸二異丙酯(0.133 mL,0.67 mmol)。所得溶液在N2
下攪拌3小時。將反應混合物懸浮於H2
O (100 mL)中且接著用EtOAc (3×100 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(EtOAc/正己烷 = 1:2)純化,得到68
(221 mg,83%)。1
H NMR (300 MHz, CDCl3
) δ 7.78 (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
= 5.7 Hz,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- 胺基 -2- 甲氧基 -5-((2-( 三甲基矽烷基 ) 乙氧基 ) 羰基 ) 苯氧基 ) 丙基 ) 苯甲醯亞胺酸 (69)
依循針對化合物38
所述的程序,向68
(50 mg,0.11 mmol)於HOAc/THF = 1:4 (10 mL)中的反應物中添加Zn (69 mg,1.05 mmol)且在N2
下、在室溫下攪拌混合物,得到69
(40 mg,85%)。1
H NMR (300 MHz, CDCl3
) δ 7.80 (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
= 7.1 Hz, 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- 丙炔醯胺基 -5-((2-( 三甲基矽烷基 ) 乙氧基 ) 羰基 ) 苯氧基 ) 丙基 ) 苯甲醯亞胺酸 (70)
依循針對化合物4
所述的程序,在冰浴中,向69
(170 mg,0.38 mmol)於無水CH2
Cl2
(10 mL)中的反應物中逐滴添加含有丙炔酸(0.035 mL,0.15 mmol)及N,N'
-二環己基碳二亞胺(118 mg,0.57 mmol)的無水CH2
Cl2
(5 mL),得到70
(180 mg,95%)。1
H NMR (300 MHz, CDCl3
) δ 11.64 (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
= 5.5 Hz, 2H), 3.71 (m, 5H), 2.91 (s, 1H), 2.14 (m, 2H), 1.13 (m, 2H), 0.07 (s, 9H)。
(Z)-5-(3-(( 羥基 ( 苯基 ) 亞甲基 ) 胺基 ) 丙氧基 )-4- 甲氧基 -2- 丙炔醯胺基苯甲酸 (71)
在室溫下,向70
(50 mg,0.10 mmol)於無水THF (2 mL)中的溶液中逐滴添加TBAF (1 M於THF中,0.50 mL,0.50 mmol)。所得溶液在N2
下攪拌12小時。反應混合物用1 N HCl(aq)
(50 mL)及EtOAc (3×50 mL)萃取。合併之有機層經MgSO4
乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析(MeOH/CH2
Cl2
= 3:97)純化,得到71
(19 mg,48%)。1
H NMR (300 MHz, DMSO) δ 11.87 (s, 1H), 8.52 (t,J
= 5.5 Hz, 1H), 8.08 (s, 1H), 7.83 (m, 2H), 7.48 (m, 3H), 4.47 (s, 1H), 4.04 (t,J
= 6.2 Hz, 2H), 3.80 (s, 3H), 3.02 (m, 2H), 1.98 (m, 2H)。
PDIA4 分析
將重組PDI蛋白質PDIA4 (23 pM)與胰島素(0.2 mM)及DTT (0.1 mM)一起在媒劑及指定劑量之化合物存在下、在25℃下培育30分鐘。使用SpectraMax i3x讀取器,基於製造商說明書(Molecular device, CA, USA),在595 nm下量測混合物。依據如先前所公開的式:100%×(媒劑之OD595
−CP之OD595
)/(媒劑之OD595
)來計算PDIA4酶活性的抑制。
葡萄糖刺激的胰島素分泌
除非另外指明,否則使Min6細胞在含有10%胎牛血清、100個單位/毫升青黴素及100 g/ml鏈黴素的杜爾貝科氏改良伊格爾氏培養基(Dulbecco's modified Eagle medium,DMEM)完全培養基中、在3.3 mM葡萄糖存在下、在5% CO2培育箱中生長。使Min6細胞在含有3.3 mM葡萄糖的氧飽和無血清克雷布斯-林格氏碳酸氫鹽(KRB)緩衝液中、在37℃下預培育30分鐘。接著將細胞(7.5×104
)與含有高葡萄糖(16.7 mM)或低葡萄糖(3.3 mM)的KRB緩衝液一起再培育30分鐘。收集上清液用於胰島素ELISA分析。
細胞存活率測試
在37℃下,在完全培養基中培養Min6細胞。根據製造商指導原則,使用WST-1 (4-[3-(4-碘苯基)-2-(4-硝基苯基)-2H-5-四唑]-1,3-苯二磺酸鹽)測定細胞的細胞毒性。簡言之,使細胞在含有完全培養基的96孔盤中、在指定的化合物存在下生長24小時。在PBS洗滌之後,將WST-1添加至各孔中再培育20分鐘。移除培養基之後,使用SpectraMax i3x讀取器,在450 nm下量測培養盤中的細胞。
統計資料
來自三個或更多個獨立實驗之資料係以平均值±標準差(SD)呈現。除非另外指明,否則使用ANOVA執行多組之間的比較。P
< 0.05 (*)、< 0.01 (**)或< 0.001(***)被認為是在對照組與治療組之間具有統計顯著性。
表1-表5顯示PDIA4抑制劑之IC50
值。表 1
表 2
表 3
表 4
表 5
CPD | MW | 結構 | IC50 (µM) | ||
P1 | 362.4 | 210.2 | |||
P2 | 200.2 | 167.9 | |||
C1 | 256.3 | 66.5 | |||
C2 | 158.2 | 96.5 | |||
C3 | 186.2 | 186.0 | |||
C4 | 145.2 | 182.7 | |||
C5 | 430.5 | 759.7 | |||
C6 | 296.3 | 753.1 | |||
C7 | 162.2 | >1000 | |||
C8 | 202.3 | >1000 | |||
C9 | 346.4 | >1000 | |||
C10 | 318.3 | >1000 | |||
CPD | MW | 結構 | IC50 (µM) |
C11 | 246.2 | 27.6 | |
C12 | 203.2 | 92.1 | |
8 | 249.2 | 4.0 | |
C13 | 189.2 | 57.3 | |
C14 | 205.2 | 55.7 |
CPD | MW | IC50 (µM) |
16 | 325.32 | 13.3 |
22 | 279.25 | 4.3 |
45 | 277.28 | 1.0 |
14 | 415.44 | 84.9 |
20 | 293.27 | 42.5 |
4 | 263.25 | 11.7 |
43 | 319.36 | 430.6 |
30 | 347.41 | >300 |
29 | 305.3 | >300 |
10 | 249.22 | 1.6 |
21 | 227.21 | >1000 |
44 | 225.24 | >1000 |
19 | 241.24 | >1000 |
3 | 211.22 | >1000 |
9 | 197.19 | >1000 |
55 | 284.27 | >1000 |
CPD | MW | IC50 (µM) |
50a | 422.39 | 48.8 |
50b | 436.42 | 4.3 |
50c | 450.45 | 5.6 |
54 | 448.43 | 3.3 |
58a | 462.46 | 4.7 |
40 | 448.43 | 3.9 |
58d | 480.45 | 2.4 |
58c | 480.45 | 2.7 |
58b | 480.45 | 4.2 |
58e | 498.44 | 2.4 |
58h | 492.48 | 3.7 |
58g | 492.48 | 3.3 |
58f | 522.5 | 2.6 |
61 | 406.4 | 4.7 |
58i | 476.5 | 1.9 |
58j | 494.5 | 1.8 |
58r | 510.9 | 1.6 |
58m | 506.5 | 1.3 |
58o | 506.5 | 2.1 |
7 | 349.5 | 78.7 |
66 | 410.4 | 4.4 |
70 | 496.6 | 7.5 |
71 | 396.4 | 6.2 |
58p | 566.6 | 3.3 |
58l | 494.5 | 1.4 |
58t | 544.5 | 0.8 |
58s | 544.5 | 1.0 |
58k | 494.5 | 1.2 |
58u | 544.5 | 2.4 |
58n | 506.5 | 1.4 |
58q | 510.9 | 1.6 |
58v | 453.4 | 0.3 |
CPD | EC50 (µM) | CC50 (µM) | SI (CC50/EC50) |
CCF642 | 0.25 | 23.9 | 95.6 |
P1 | 1.55 | > 100 | > 64.5 |
8 | 0.06 | > 100 | > 1666.7 |
58v | 0.005 | > 100 | > 20000 |
58t | 0.03 | > 100 | > 3333 |
58s | 0.02 | 64.9 | 3245 |
結果
自苗頭化合物至先導化合物中篩選出
PDIA4
抑制劑
.
如圖1中所述,應用虛擬篩選及PDIA4來搜尋苗頭化合物、先導化合物及/或候選藥物。虛擬篩選的細節描繪於實驗程序(圖1)。在261種植物化學成分中,鑑別出聚多炔糖苷(cytopiloyne)(CPDP1
,表1)及聚多炔糖苷配基(CPDP2
,表1)為兩種最佳苗頭化合物。圖2顯示CPDP1
分子對接入具有3個活性模體的PDIA4中。建立PDIA4分析平臺以量測CPDP2
的半數最大抑制濃度(IC50
)(167.9 μM,表1)。基於 PDIA4 之候選藥物的表徵 .
接下來,基於CP/CPA之藥效基團特徵及PDIA4之結合袋,利用虛擬篩選自ZINC資料庫中選出具有1至3個碳/碳參鍵(CCTB)的十種化合物,包括(E)-7-(己-2,4-二炔-1-亞基)-1,6-二氧雜螺[4.4]壬-2,8-二烯-4-基乙酸酯(C1)、(Z)-5-(己-2,4-二炔-1-亞基)呋喃-2(5H)-酮(C2
)、1-苯基己-2,4-二炔-1,6-二醇(C3
)、N-苯基丙炔醯胺(C4)、(2-(N-(2,4-二甲氧基苯基)丙炔醯胺基)-2-(噻吩-2-基)乙醯基)甘胺酸乙酯(C5)、3-甲基丁-2-烯酸(E)-7-(己-2,4-二炔-1-亞基)-1,6-二氧雜螺[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-基胺基)苯基)乙醯胺(C8
)、六-2,4-二炔-1,6-二基雙(2-苯基乙酸酯),及二苯甲酸己-2,4-二炔-1(C9
)及6-二基酯(C10
),且量測IC50
值以試圖確定先導化合物的核心結構(表1)。選擇N-苯基丙炔醯胺(C4
)(IC50
= 182.7 μM,表1)作為活性核心結構,以針對先導化合物進行子結構搜尋。因此,選擇含有N-苯基丙炔醯胺核心結構(C4
)的(4-丙炔醯胺基苯甲醯基)甘胺酸(C11
)、2-(4-丙炔醯胺基苯基)乙酸(C12
)、4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
)、4-丙炔醯胺基苯甲酸(C13
)及2-羥基-5-丙炔醯胺基苯甲酸(C14
)且測試其IC50
值(表2)。結果,4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
)作為潛在的先導化合物而突顯出來,其IC50
值為4 μM,為苗頭化合物CPDP1
的53倍高(表2)。4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
)係由4,5-二甲氧基-2-硝基苯甲酸(1
)基於流程2合成。
為了最佳化4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
),基於流程1及2將4,5-二甲氧基-2-硝基苯甲酸(1
)化學修飾成化合物2-8
。結果,4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
)作為潛在的先導化合物而突顯出來,其IC50
值為4 μM,為苗頭化合物CPA的40倍高(表1及表2)。另外,基於流程3-20對4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
)進行化學修飾。合成化合物9-58v且測試其對PDIA4的抑制(表1)。其IC50
值顯示於表3及表4中。關於CPD 1-58v之合成及結構說明之細節描述於材料及方法之化學處理章節中。因此,若干化合物8
、58v
、58s
及58t
具有低IC50值且可以用作候選藥物。
所選 PDIA4 抑制劑對 β 細胞之 胰島素分泌及細胞存活率的藥理學效應
接下來,吾人檢查所選PDIA4抑制劑CCF642 (市售PDIA4抑制劑)及CPDP1
、8
、58v
、58s
及58t
對Min6 (小鼠β細胞)之胰島素釋放作用的影響。吾人發現,CCF642及CPDP1
、8
、58v
、58s
及58t
分別具有0.25 μM、1.55 μM、0.06 μM、0.005 μM、0.03 μM及0.02 μM的EC50值(圖3及表2)。相比之下,對Min 6細胞釋放胰島素稍微具有影響。相應地,CCF642及CPDP1
、8
、58v
、58s
及58t
分別具有23.9、>100、>100、>100、>100及64.9的CC50值(圖3及表1-表4)。資料表明類似於CCF642,CPDP1
、8
、58v
、58s
及58t
可以增強β細胞分泌胰島素。圖2中顯示CPD8
分子對接入具有3個活性模體的PDIA4。資料表明CPD8
與PDIA4的配合比CPDP1
更佳(圖2)。
所選 PDIA4 抑制劑對 db/db 小鼠糖尿病的藥理學效應
此外,吾人檢查CPD8
(用於抑制Pdia4之候選藥物之一)在db/db小鼠(2型糖尿病小鼠模型)中的活體內抗糖尿病作用。正如所預期,用作陽性對照物的30 mg/kg西格列汀(sitagliptin,STG)使db/db小鼠的空腹血糖(FBG)顯著降低(圖4A)。2.5 mg/kg劑量的CPD8
使db/db小鼠的FBG顯著降低(圖3A)。另外,CPD8
(2.5 mg/kg)與二甲雙胍(60 mg/kg)之組合使db/db小鼠的FBG降低超過單獨的CPD8
(圖4A)。相應地,用作陽性對照物的30 mg/kg西格列汀使db/db小鼠的餐後血糖(PBG)顯著降低(圖4B)。2.5 mg/kg劑量的CPD8
使db/db小鼠的FBG顯著降低(圖4B)。另外,CPD8
(2.5 mg/kg)與二甲雙胍(60 mg/kg)之組合使db/db小鼠的PBG降低超過單獨的CPD8
(圖4B)。總體資料證明,CPD8
(基於PDIA4之候選藥物之一)本身及組合可逆轉db/db小鼠的2型糖尿病。
總之,胰臟β細胞衰竭為2型糖尿病(T2D)之標誌。高度需要在早期糖尿病階段保持β細胞功能/質量、從而可逆轉T2D的策略。本發明係關於使用分子對接與PDIA4生物分析之組合自苗頭化合物至先導化合物中篩選出基於PDIA4的抑制劑。N-苯基丙炔醯胺(C4
)經鑑別為PDIA4抑制劑之活性核心結構。使用化學合成、分子對接及PDIA4生物分析之組合,鑑別出4,5-二甲氧基-2-丙炔醯胺基苯甲酸(8
)為先導化合物。基於化合物與PDIA4的結構及之間的活性關係,合成48種化合物(表6)且表徵。結果,鑑別出IC50
值為4 μM至300 nM的若干候選藥物,包括CPDP1
、8
、58v
、58s
及58t
。針對β細胞功能及糖尿病治療來測試彼等化合物。類似於CCF642 (市售PDIA4抑制劑),CPDP1
、8
、58v
、58s
及58t
對β細胞的胰島素分泌具有較高活性。相應地,單獨及組合的CPD8
可以治療及逆轉db/db小鼠的T2D (糖尿病小鼠模型)。總體資料表明PDIA4為2型糖尿病(T2D)的新穎治療標靶。表6說明本發明化合物。
表6
3 : 2-胺基-4,5-二甲氧基苯甲酸甲酯; | R1=CH3O-CO- R2=CH3 R3= CH3; R4=H R5= 胺基(-NH2) X1=O; X2=O | |
4 : 4,5-二甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3O-CO- R2=CH3 R3= CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
7 : 4,5-二甲氧基-2-丙炔醯胺基苯甲酸2-(三甲基矽烷基)乙酯; | R1=(CH3)3 -Si-CH2-CH2-O-CO- R2=CH3 R3= CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
8 : 4,5-二甲氧基-2-丙炔醯胺基苯甲酸; | R1=HO-CO- R2=CH3 R3= CH3 R4=H R5= -NH-CO-CCH X1=O; X2=O | |
9 : 2-胺基-4,5-二甲氧基苯甲酸; | R1= HO-CO- R2=CH3 R3= CH3; R4=H R5= 胺基(-NH2) X1=O; X2=O | |
10 : 2-胺基-4,5-二甲氧基苯甲酸丙炔酸酸酐; | R1=HCC-CO-O-CO- R2=CH3 R3= CH3; R4=H R5= 胺基(-NH2) X1=O; X2=O | |
14 : 5-(苯甲氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸苯甲酯; 苯甲基=C6 H5 -CH2 - 苯基= C6 H5 | R1=苯甲基-O-CO- R2=-苯甲基(-CH2 -C6 H5 R3= CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
16 : 2-胺基-5-(苯甲氧基)-4-甲氧基苯甲酸丙炔酸酸酐 | R1=HCC-CO-O-CO- R2=苯甲基 R3= CH3; R4=H R5= 胺基(-NH2) X1=O; X2=O | |
19 : 2-胺基-3,4,5-三甲氧基苯甲酸甲酯; | R1=CH3O-CO- R2= -CH3 R3= -CH3 R4=CH3-O- R5= 胺基(-NH2) X1=O; X2=O | |
20 : 3,4,5-三甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=CH3 R3= CH3 R4=-O-CH3 R5=HCC-CO-NH- X1=O; X2=O | |
21 : 2-胺基-3,4,5-三甲氧基苯甲酸甲酯; | R1=HO-CO- R2=CH3 R3= CH3 R4=CH3-O- R5= 胺基(-NH2) X1=O; X2=O | |
22 : 2-胺基-3,4,5-三甲氧基苯甲酸丙炔酸酸酐; | R1=HCC-CO-O-CO- R2=CH3 R3= CH3 R4=CH3-O- R5= 胺基(-NH2) X1=O; X2=O | |
29 : 2-丙炔醯胺基-4,5-二丙氧基苯甲酸甲酯; | R1=CH3-O-CO- R2=CH3-(CH2)2- R3= CH3-(CH2)2- R4=-H R5=HCC-CO-NH- X1=O; X2=O | |
30 : 2-丙炔醯胺基-4,5-二丙氧基苯甲酸丙酯; | R1=CH3-(CH2)2 -O-CO- R2=CH3-(CH2)2- R3= CH3-(CH2)2- R4= H R5=HCC-CO-NH- X1=O; X2=O | |
40 : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -丙炔醯基苯甲醯胺基)丙氧基)苯甲酸; | R1=HO-CO- R2=CH2)3-N-(CO-CCH)-苯甲醯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
43 : 4-甲氧基-2-丙炔醯胺基-5-丙氧基苯甲酸丙酯; | R1=CH3-(CH2)2 -O-CO- R2=CH3-(CH2)2- R3= -CH3; R4= H R5= -NH-CO-CCH X1=O; X2=O | |
44 : 2-胺基-4-甲氧基-5-丙氧基苯甲酸; | R1=HO-CO- R2=-(CH2 )2 -CH3 R3= CH3 R4=CH3-O- R5= 胺基(-NH2) X1=O; X2=O | |
45 : 2-胺基-4-甲氧基-5-丙氧基苯甲酸丙炔酸酸酐; | R1=HCC-CO-O-CO- R2=-(CH2 )2 -CH3 R3= CH3; R4=H R5= 胺基(-NH2) X1=O; X2=O | |
50a : 5-(2-(1,3-二側氧基異吲哚啉-2-基)乙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2)2-(1,3-二側氧基異吲哚啉-2-基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
50b : 5-(3-(1,3-二側氧基異吲哚啉-2-基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -(1,3-二側氧基異吲哚啉-2-基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
50c : 5-(4-(1,3-二側氧基異吲哚啉-2-基)丁氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )4 -(1,3-二側氧基異吲哚啉-2-基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
54 : 4-甲氧基-2-丙炔醯胺基-5-(2-(N -丙炔醯基苯甲醯胺基)乙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )2 -N-(CO-CCH)-苯甲醯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
55 : 5-(3-胺基丙氧基)-4-甲氧基-2-硝基苯甲酸甲酯; | R1=CH3-O-CO- R2=NH2-(CH2)3- R3= CH3- ; R4= -H R5= -NO2 X1=O; X2=O | |
58a : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -丙炔醯基苯甲醯胺基)丙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58b : 5-(3-(2-氟-N -丙炔醯基苯甲醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-(2-氟) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58c : 5-(3-(3-氟-N -丙炔醯基苯甲醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-3-氟 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58d : 5-(3-(4-氟-N-丙炔醯基苯甲醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-(4-氟) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58e : 5-(3-(2,6-二氟-N -丙炔醯基苯甲醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-(2,6-二氟) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58f : 5-(3-(2,6-二甲氧基-N -丙炔醯基苯甲醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-(2, 6-二甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58g : 4-甲氧基-5-(3-(3-甲氧基-N -丙炔醯基苯甲醯胺基)丙氧基)-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-(3-甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58h : 4-甲氧基-5-(3-(4-甲氧基-N -丙炔醯基苯甲醯胺基)丙氧基)-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-苯甲醯基-(4-甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58i : 4-甲氧基-5-(3-(N -(2-苯乙醯基)丙炔醯胺基)丙氧基)-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58j : 5-(3-(N -(2-(2-氟苯基)乙醯基)丙炔醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(2-氟) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58k : 5-(3-(N -(2-(3-氟苯基)乙醯基)丙炔醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(3-氟) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58l : 5-(3-(N -(2-(4-氟苯基)乙醯基)丙炔醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(4-氟) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58m : 4-甲氧基-5-(3-(N -(2-(2-甲氧苯基)乙醯基)丙炔醯胺基)丙氧基)-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(2-甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58n : 4-甲氧基-5-(3-(N -(2-(3-甲氧基苯基)乙醯基)丙炔醯胺基)丙氧基)-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(3-甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58o : 4-甲氧基-5-(3-(N -(2-(4-甲氧基苯基)乙醯基)丙炔醯胺基)丙氧基)-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(4-甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58p : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -(2-(3,4,5-三甲氧基苯基)乙醯基)丙炔醯胺基)丙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-3,4,5-三甲氧基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58q : 5-(3-(N -(2-(2-氯苯基)乙醯基)丙炔醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯;及 | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(2-氯) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58r : 5-(3-(N -(2-(3-氯苯基)乙醯基)丙炔醯胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(3-氯) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58s : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -(2-(2-(三氟甲基)苯基)乙醯基)丙炔醯胺基)丙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(2-三氟甲基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58t : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -(2-(3-(三氟甲基)苯基)乙醯基)丙炔醯胺基)丙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(3-三氟甲基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58u : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -(2-(4-(三氟甲基)苯基)乙醯基)丙炔醯胺基)丙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-CH2-苯基-(4-三氟甲基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
58v : 4-甲氧基-2-丙炔醯胺基-5-(3-(N -丙炔醯基㗁唑-5-甲醯胺基)丙氧基)苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -N-(CO-CCH)-CO-㗁唑) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
61 : 5-(3-((第三丁氧基羰基)胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸甲酯; | R1=CH3-O-CO- R2=-(CH2 )3 -NH-CO-O-C-三甲基) R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
66 : (Z )-N -(3-(2-甲氧基-5-(甲氧基羰基)-4-丙炔醯胺基苯氧基)丙基)苯甲醯亞胺酸; | R1=CH3-O-CO- R2=-(CH2 )3 -N=C-OH-苯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
70 : (Z )-N -(3-(2-甲氧基-4-丙炔醯胺基-5-((2-(三甲基矽烷基)乙氧基)羰基)苯氧基)丙基)苯甲醯亞胺酸; | R1=(CH3 )3 -Si-O-CO- R2=-(CH2 )3 -N=C-OH-苯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O | |
71 : (Z )-5-(3-((羥基(苯基)亞甲基)胺基)丙氧基)-4-甲氧基-2-丙炔醯胺基苯甲酸; | R1=HO-CO- R2=-(CH2 )3 -N=C-OH-苯基 R3= -CH3; R4=H R5= -NH-CO-CCH X1=O; X2=O |
本說明書中引用及論述之所有參考文獻均以全文引用之方式併入本文中,其引用程度如同各參考文獻個別地以引用之方式併入一般。
圖1為流程圖,其描述自苗頭化合物至先導化合物及候選藥物中篩選出PDIA4抑制劑。(A)流程,其描述使用分子對接、PDIA4生物分析及總體合成之組合,自苗頭化合物至先導化合物及候選藥物中篩選出PDIA4抑制劑的策略。(B)針對葡萄糖誘導之胰島素分泌(GSIS)及細胞存活率進行的基於Min6胰島細胞株之分析。(C)對於PDIA4抑制劑而言,使用糖尿病db/db小鼠。
圖2顯示了分子對接,表明所選PDIA4抑制劑與PDIA4活性模體(AM)之間存在相互作用。(A) AM 1、2及3表示第一、第二及第三CGHC域。硫、氮及氧原子分別以黃色、藍色及紅色顯示。分別顯示了CPDP1
與PDIA4模型之胺基酸殘基之間的氫鍵及疏水性相互作用。(B):類似於(A),分子對接表明所選CPD8
與PDIA4之活性模體(AM)之間存在相互作用。
圖3顯示候選藥物對釋放胰島素的影響及細胞毒性。(A)候選藥物對β細胞分泌胰島素的影響。Min6細胞在氧飽和無血清克雷布斯-林格氏碳酸氫鹽(Krebs-Ringer bicarbonate,KRB)緩衝液中培育30分鐘,該緩衝液含有高葡萄糖(16.7 mM)、CCF642及候選藥物。收集上清液用於胰島素ELISA分析。(B)將Min6細胞分別與PBS、CCF642及候選藥物一起培育24小時。PBS洗滌之後,將WST-1添加至各孔中再培育20分鐘。
圖4顯示CPD8
本身及與二甲雙胍的組合可治療及逆轉Leprdb/db
小鼠的糖尿病。(A-B)將新發糖尿病Leprdb/db
小鼠分組且用PBS媒劑(CTR)、西格列汀(sitagliptin)(STG,30 mg/kg)、CPD8
(2.5 mg/kg)及CPD8
(2.5 mg/kg)與二甲雙胍(960 mg/kg)組合(CPD8 +
Met)治療指定的時間。監測小鼠的空腹血糖(FBG (A))及餐後血糖(PBG (B))。值(n)為括弧中所示之小鼠數目。
Claims (15)
- 一種式(I)化合物或其醫藥學上可接受之鹽,
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R6為H或(C1-C6)烷基、苯甲基、鹵基(C1-C6)烷基、-(CH2)n-Si(CH3)3,或羰基(C1-C6)炔烴。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R2為(C1-C6)烷基,或-L-R11,其中L為(C1-C6)伸烷基,且R11為二側氧基異吲哚啉、-NR7R8或-NR7-CO-R8,其中R7及R8各自獨立地為H、苯基、苯甲醯基、鹵基苯甲醯基、苯甲基或羰基(C1-C6)炔烴。
- 如請求項3之化合物或其醫藥學上可接受之鹽,其中該苯基、苯甲醯基及/或苯甲基各自獨立地經一或多個選自F、Cl、Br、I或鹵基(C1-C6)烷基的取代基取代。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R5為-NR7R8或-NR7-CO-R8,其中R7及R8各自獨立地為H或羰基(C1-C6)炔烴。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R5為硝基。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R6為羰基 (C1-C6)炔烴。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R2為-L-R11,其中L為(C1-C6)伸烷基,且R11為-NR7R8,其中R7及R8連同N原子一起形成苯甲醯亞胺酸。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R2為-L-R11,R11為-NR7R8或-NR7-CO-R8;R7為羰基(C1-C6)炔烴且R8為苯甲醯基。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R2為(C1-C6)烷基;R3為(C1-C6)烷基,R4為H;R5為-NR7-CO-R8,其中R7為H且R8為(C2)炔烴。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R5為-NR7R8或-NR7-CO-R8,其中R7及R8各自獨立地為H、羰基(C1-C6)炔烴,或(C1-C6)炔烴。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R2為-L-R11,其中L為(C1-C6)伸烷基,且R11為二側氧基異吲哚啉或-NR7R8,其中R7及R8各自獨立地為苯甲醯基或羰基(C1-C6)炔烴。
- 一種醫藥組合物,其包含: (a)如請求項1至13中任一項之化合物或其醫藥學上可接受之鹽;及(b)二甲雙胍。
- 一種如請求項1至13中任一項之化合物或其醫藥學上可接受之鹽或如請求項14之醫藥組合物的用途,其用於製造供在有需要之個體中增強胰臟β細胞所分泌的胰島素、治療糖尿病及/或逆轉及恢復血糖濃度至正常水準的藥劑。
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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 |
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- 2020-11-15 WO PCT/US2020/060639 patent/WO2021113062A1/en unknown
- 2020-11-15 MX MX2022006397A patent/MX2022006397A/es unknown
- 2020-11-15 EP EP20895256.4A patent/EP4069252A4/en active Pending
- 2020-11-15 AU AU2020397821A patent/AU2020397821A1/en active Pending
- 2020-11-15 BR BR112022010783A patent/BR112022010783A2/pt unknown
- 2020-11-15 IL IL292837A patent/IL292837A/en unknown
- 2020-11-15 KR KR1020227021729A patent/KR20220110235A/ko unknown
- 2020-11-15 JP JP2022532668A patent/JP2023504162A/ja active Pending
- 2020-11-15 CN CN202080082502.7A patent/CN114761025B/zh active Active
- 2020-11-15 US US17/780,482 patent/US20230046445A1/en active Pending
- 2020-11-30 TW TW109142118A patent/TWI769600B/zh active
Patent Citations (1)
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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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WO2021113062A1 (en) | 2021-06-10 |
IL292837A (en) | 2022-07-01 |
MX2022006397A (es) | 2022-06-24 |
EP4069252A4 (en) | 2024-01-10 |
BR112022010783A2 (pt) | 2022-11-22 |
CN114761025B (zh) | 2024-03-12 |
US20230046445A1 (en) | 2023-02-16 |
EP4069252A1 (en) | 2022-10-12 |
KR20220110235A (ko) | 2022-08-05 |
JP2023504162A (ja) | 2023-02-01 |
TW202136204A (zh) | 2021-10-01 |
CN114761025A (zh) | 2022-07-15 |
AU2020397821A1 (en) | 2022-06-23 |
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