CN115677718B - Methyl methylamine derivative preparation, pharmaceutical composition and application thereof - Google Patents
Methyl methylamine derivative preparation, pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN115677718B CN115677718B CN202110874949.4A CN202110874949A CN115677718B CN 115677718 B CN115677718 B CN 115677718B CN 202110874949 A CN202110874949 A CN 202110874949A CN 115677718 B CN115677718 B CN 115677718B
- Authority
- CN
- China
- Prior art keywords
- methyl
- pyran
- dihydro
- thiophene
- 500mhz
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 122
- 239000003814 drug Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 20
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 142
- -1 hydroxy, carboxy Chemical group 0.000 claims description 112
- 229910052739 hydrogen Inorganic materials 0.000 claims description 100
- 239000001257 hydrogen Substances 0.000 claims description 100
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 90
- 150000001412 amines Chemical class 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- XIRNKXNNONJFQO-UHFFFAOYSA-N ethyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC XIRNKXNNONJFQO-UHFFFAOYSA-N 0.000 claims description 8
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002723 alicyclic group Chemical group 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 229940067592 ethyl palmitate Drugs 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 3
- 208000026139 Memory disease Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000004060 metabolic process Effects 0.000 abstract description 10
- 210000001589 microsome Anatomy 0.000 abstract description 9
- 239000008280 blood Substances 0.000 abstract description 8
- 210000004369 blood Anatomy 0.000 abstract description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
- 239000000651 prodrug Substances 0.000 abstract description 5
- 229940002612 prodrug Drugs 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 174
- 238000005160 1H NMR spectroscopy Methods 0.000 description 87
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 39
- 239000007858 starting material Substances 0.000 description 35
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 239000003208 petroleum Substances 0.000 description 20
- WWQYTEPUEUNBOM-SANMLTNESA-N (2,5-dioxopyrrolidin-1-yl) (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(1h-indol-3-yl)propanoate Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)ON1C(=O)CCC1=O WWQYTEPUEUNBOM-SANMLTNESA-N 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- SMJYMSAPPGLBAR-UHFFFAOYSA-N chloromethyl acetate Chemical compound CC(=O)OCCl SMJYMSAPPGLBAR-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000012544 monitoring process Methods 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 8
- 239000012346 acetyl chloride Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 230000002503 metabolic effect Effects 0.000 description 8
- YRHYCMZPEVDGFQ-UHFFFAOYSA-N methyl decanoate Chemical compound CCCCCCCCCC(=O)OC YRHYCMZPEVDGFQ-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- QIAFMBKCNZACKA-UHFFFAOYSA-N Hippuric acid Natural products OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 7
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000010791 quenching Methods 0.000 description 7
- 230000000171 quenching effect Effects 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 7
- 229960000604 valproic acid Drugs 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 5
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- OQAGVSWESNCJJT-UHFFFAOYSA-N Methyl 3-methylbutanoate Chemical compound COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 4
- FLIACVVOZYBSBS-UHFFFAOYSA-N Methyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC FLIACVVOZYBSBS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 4
- 208000010877 cognitive disease Diseases 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- RGXWDWUGBIJHDO-UHFFFAOYSA-N ethyl decanoate Chemical compound CCCCCCCCCC(=O)OCC RGXWDWUGBIJHDO-UHFFFAOYSA-N 0.000 description 4
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- UQDUPQYQJKYHQI-UHFFFAOYSA-N methyl laurate Chemical compound CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 description 4
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 4
- JGHZJRVDZXSNKQ-UHFFFAOYSA-N methyl octanoate Chemical compound CCCCCCCC(=O)OC JGHZJRVDZXSNKQ-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- BEKZXQKGTDVSKX-UHFFFAOYSA-N propyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCCC BEKZXQKGTDVSKX-UHFFFAOYSA-N 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZELIFUTVXXSJMW-UHFFFAOYSA-N 2-[dodecanoyl(ethyl)amino]acetic acid Chemical compound CCCCCCCCCCCC(=O)N(CC)CC(O)=O ZELIFUTVXXSJMW-UHFFFAOYSA-N 0.000 description 3
- MADGNOWTNCFHDA-UHFFFAOYSA-N 2-[ethyl-(2-phenylacetyl)amino]acetic acid Chemical compound OC(=O)CN(CC)C(=O)CC1=CC=CC=C1 MADGNOWTNCFHDA-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 3
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 3
- KTHDTJVBEPMMGL-VKHMYHEASA-N N-acetyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(C)=O KTHDTJVBEPMMGL-VKHMYHEASA-N 0.000 description 3
- KTHDTJVBEPMMGL-UHFFFAOYSA-N N-acetyl-L-alanine Natural products OC(=O)C(C)NC(C)=O KTHDTJVBEPMMGL-UHFFFAOYSA-N 0.000 description 3
- DIJHWYJHANOOOH-UHFFFAOYSA-N OC(=O)C(F)(F)F.COC(=O)CCCN Chemical compound OC(=O)C(F)(F)F.COC(=O)CCCN DIJHWYJHANOOOH-UHFFFAOYSA-N 0.000 description 3
- 235000021314 Palmitic acid Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- CLDAJCQRVCXYIR-UHFFFAOYSA-N ethyl 2-[acetyl(methyl)amino]acetate Chemical compound CCOC(=O)CN(C)C(C)=O CLDAJCQRVCXYIR-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- UNEAEGWIVFZPFI-UHFFFAOYSA-N methyl 2-ethylbutanoate Chemical compound CCC(CC)C(=O)OC UNEAEGWIVFZPFI-UHFFFAOYSA-N 0.000 description 3
- CMYWRSONJASJJE-UHFFFAOYSA-N methyl 2-ethyldecanoate Chemical compound CCCCCCCCC(CC)C(=O)OC CMYWRSONJASJJE-UHFFFAOYSA-N 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- OVFMRFMJVFDSAA-UHFFFAOYSA-N propyl decanoate Chemical compound CCCCCCCCCC(=O)OCCC OVFMRFMJVFDSAA-UHFFFAOYSA-N 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- YVOFTMXWTWHRBH-UHFFFAOYSA-N pentanedioyl dichloride Chemical compound ClC(=O)CCCC(Cl)=O YVOFTMXWTWHRBH-UHFFFAOYSA-N 0.000 description 1
- XHRRYUDVWPPWIP-UHFFFAOYSA-N pentyl carbonochloridate Chemical compound CCCCCOC(Cl)=O XHRRYUDVWPPWIP-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- HCRMTRJXSDDOIK-ZETCQYMHSA-N phenyl (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC1=CC=CC=C1 HCRMTRJXSDDOIK-ZETCQYMHSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- QDQVXVRZVCTVHE-YFKPBYRVSA-N propan-2-yl (2s)-2-aminopropanoate Chemical compound CC(C)OC(=O)[C@H](C)N QDQVXVRZVCTVHE-YFKPBYRVSA-N 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- TZHVYFBSLOMRCU-YFKPBYRVSA-N tert-butyl (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC(C)(C)C TZHVYFBSLOMRCU-YFKPBYRVSA-N 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a methyl methylamine derivative preparation, a pharmaceutical composition and application thereof. The methyl methylamine derivative preparation is a derivative of (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine, or pharmaceutically acceptable salt or prodrug thereof, and can be used for preparing medicines for preventing or treating neurological diseases, wherein the neurological diseases are selected from schizophrenia, depression, dysmnesia and dysfunctional diseases related to intelligence and study. The compound has longer half-life period in the microsome metabolism process, relatively lower clearance rate and good microsome metabolism stability, and can maintain the effective blood concentration in the body for a longer time. The compound can maintain a certain concentration in the human plasma metabolism process, has good plasma metabolism stability, and can maintain the effective blood concentration in the human body for a long time.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a methyl methylamine derivative preparation, a pharmaceutical composition and application thereof, and more particularly relates to a prodrug derivative of (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine, a pharmaceutical composition and application thereof.
Background
Schizophrenia is a recurrent chronic persistent disease. Based on incomplete statistics, about 1% of the population worldwide suffers from such diseases, with domestic patients or up to 1000 tens of thousands. Schizophrenia is mainly manifested by positive symptoms (mania, hallucinations, delusions, thought disorder, etc.), negative symptoms (anorgasmia, aphasia, mental confusion, etc.), and cognitive disorders (memory impairment, attention deficit, execution deficit, etc.). The treatment of the schizophrenia is mainly drug treatment, and the research of the drugs for treating the schizophrenia has greatly progressed in the aspect of controlling positive symptoms in the last fifty years, but the drugs for treating the schizophrenia have no obvious improvement on negative symptoms and cognitive dysfunction at present, and have the problems of drug side effects and the like, so that the schizophrenia is still one of the most difficult diseases to control and cure.
In clinical treatment, patient non-compliance with oral antipsychotics is quite common. Relapse of the condition caused by discontinuation of treatment or self-administration of drugs to the patient has become a major difficulty in the overall treatment of schizophrenia. Therefore, the development of the long-acting preparation of the antipsychotic is not only beneficial to improving the treatment compliance, preventing relapse, relieving the care burden of patients, families and society, but also has great market value.
Since the fifties of the last century, the discovery of chlorpromazine has truly opened the pharmacotherapy of schizophrenia. Typical schizophrenia drugs represented by haloperidol are potent inhibitors of dopamine, have better efficacy on positive symptoms of schizophrenia, but serious side effects of EPS and intense mental inhibition have gradually exited the market; in the eighties, atypical anti-schizophrenia drugs represented by risperidone have appeared, and not only have good therapeutic effects on positive symptoms, but also EPS side effects have been improved [ neuroblastodermacol, 1999,21:106-115], but adverse effects of weight gain, blood glucose elevation, lactation elevation and QT gap prolongation are increasingly highlighted [ curr.opin.invest.drugs,2007,8:531-538]. Although the multi-target anti-schizophrenia drug based on D 2/5-HT2A has a good effect of improving the effectiveness and the dependency of the drug in recent years, a new choice is provided for the psychotic, but the side effects caused by the inhibition of D 2/5-HT2A cannot be fundamentally eliminated, and the efficacy on negative symptoms and cognitive impairment is limited.
Recent researches show that the TAAR1 agonist has good effects on positive symptoms, negative symptoms and cognitive dysfunction in an animal model of the schizophrenia, has no adverse reactions of the prior medicaments such as EPS, weight gain, prolactin increase and the like caused by a D 2/5-HT2A mechanism, shows good medicament formation of the antipsychotics, and indicates a new direction for the research of novel non-dopamine anti-schizophrenia medicaments although the exact mechanism is not clear.
SEP-363856[ (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methylmethylamine ] was developed from Sunovion and PsychoGenics. SEP-363856 activates the trace amine associated receptor (TAAR 1) [ J Pharmacol Exp Ther.2019,371 (1): 1-14,CNS Spectr.2019,24 (S1): 38-69], which is recognized by the U.S. FDA for breakthrough therapy granted for the treatment of schizophrenia. The FDA grant of breakthrough therapy to SEP-363856 was based on the results of a critical phase 2 clinical study (SEP 361-201) and an open label extension study (SEP 361-202) that explored safety and tolerability for 6 months. In clinical experimental results, SEP-363856 was significantly better than placebo for positive and negative symptoms; in terms of side effects, SEP-363856 does not raise the risk of extrapyramidal reactions (EPS), akathisia, hypercholesteremia, which are also consistent with its mechanism of action independent of the D 2 receptor [ N Engl J Med.2020,382 (16): 1497-1506]. It is expected to be a first new antipsychotic for treating schizophrenia without binding to the dopamine D 2 receptor.
In view of the above, there is a need to design an improved methyl methylamine derivative preparation, pharmaceutical composition and application thereof, so as to solve the above problems.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine derivatives, which are used for improving the absorbability of the medicaments and prolonging the release or reducing the side effects of the medicaments.
In order to achieve the above object, the present invention provides a methyl methylamine derivative preparation, which is one of the compounds represented by formulas (i) - (v), or a pharmaceutically acceptable salt thereof, or a prodrug thereof:
wherein R in formulas (I) and (II) and R 1、R2、R3 in formulas (III) - (V) are each independently a substituent formed by one or more of hydrogen, deuterium, hydroxy, carboxy, C 1-15 alkoxy, substituted or unsubstituted C 1-16 alkyl, heteroalkyl, cycloalkyl or alicyclic ring, aromatic ring or aromatic heterocyclic ring.
The compounds of the present invention may be stereoisomers, tautomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof of the compounds of the above formulas (I) - (V).
The term "pharmaceutically acceptable salt" as used herein refers to relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M. Bere et al, "Pharmaceutical Salts," J.Pharm.Sci.1977,66,1-19.
In another aspect, the invention relates to acceptable optical isomers of the compounds of formulas I-V.
As a further improvement of the present invention, R in the formulas (i) and (ii) are each independently a substituent formed by one or more of hydrogen, hydroxy, C 1-5 alkoxy, substituted or unsubstituted C 5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic ring, aromatic ring or aromatic heterocyclic ring;
R 1 and R 2 in the formulas (III) and (V) are each independently hydrogen, deuterium, hydroxy, C 1-5 alkoxy, substituted or unsubstituted C 1-5 alkyl, heteroalkyl;
r 1 and R 2 in formula (IV) and R 3 in formulas (III) - (V) are each independently a substituent formed by one or more of hydrogen, hydroxy, C 1-5 alkoxy, substituted or unsubstituted C 5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic ring, aromatic ring or aromatic heterocyclic ring.
As a further development of the invention, R 1 and R 2 in formulae (iii) and (v) are each independently hydrogen, deuterium or methyl.
As a further development of the invention, at least one of R 1 and R 2 in the formulae (III) and (V) is hydrogen.
As a further improvement of the present invention, the compound represented by the formula (i) is selected from the group consisting of compounds having the following structures:
the compound shown in the formula (II) is selected from compounds with the following structures:
the formula (III) or pharmaceutically acceptable salt thereof includes, but is not limited to, compounds of the structure:
The compound shown in the formula (IV) is selected from compounds with the following structures:
the formula (IV) or pharmaceutically acceptable salt thereof includes, but is not limited to, compounds of the structure:
As a further improvement of the present invention, the compound is selected from the group consisting of:
1- ((((S) -4, 7-dihydro-5H-thiophen [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl acetoacetate;
Isopropyl (((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (methoxymethyl) phosphono) -L-aminopropionate;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetoacetate;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl palmitate;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl-L-alanine ester;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-methylpropylacetoglycinate.
As a further improvement of the present invention, the pharmaceutically acceptable salt of the compound is a salt of the compound with an acid: is pamoate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.
The invention also provides a pharmaceutical composition, which comprises an effective component and pharmaceutically acceptable auxiliary materials; the active ingredient is one or more of the compounds described in any one of the above or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable excipients optionally further comprise pharmaceutically acceptable excipients, carriers, adjuvants, vehicles, or combinations thereof.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating the neurological diseases.
As a further improvement of the present invention, the neurological disorder is selected from the group consisting of schizophrenia, treatment of depression, memory impairment and dysfunction related to intelligence and learning.
In another aspect, the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the prevention or treatment of a neurological disease, optionally a neuralgia. The pharmaceutical composition of the invention is also used for preparing other medicines for treating central nervous system diseases, such as schizophrenia, depression, dysmnesia and dysfunction diseases related to intelligence and learning.
An effective dose of a compound of the invention may be administered orally, e.g., with an inert diluent or with some carrier. It may be enclosed in gelatin capsules or compressed into tablets. Or preparing the effective dose of the compound of the invention and liquid pharmaceutical auxiliary agents such as sodium chloride into injection liquid medicine, and taking the injection liquid medicine in an injection mode.
The compound and the pharmaceutically acceptable salts, solvates and hydrates thereof provided by the invention can be combined with pharmaceutically acceptable carriers or diluents to form a pharmaceutical preparation. Pharmaceutically acceptable suitable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
The amount of the compound of the present invention will depend on the type and severity of the disease or condition and also on the characteristics of the subject, such as general health, age, sex, weight and drug tolerance. The skilled artisan can determine the appropriate dosage based on these or other factors. Effective dosages of the central nervous system drugs commonly used are well known to the skilled artisan. The total daily dose is typically between about 0.05mg and 2000 mg.
The present invention relates to pharmaceutical compositions which are capable of providing about 0.01 to 1000mg of active ingredient per unit dose. The composition may be administered orally by any suitable route, for example, in the form of a capsule, parenterally in the form of an injection, topically in the form of a paste or lotion, rectally in the form of a suppository, transdermally in the form of a delivery system for a patch.
The beneficial effects of the invention are as follows:
The methyl methylamine derivative preparation provided by the invention is a derivative of (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine, or pharmaceutically acceptable salt or prodrug thereof, and can be used for preparing a medicament for preventing or treating neurological diseases; in addition, the plasma ion-exchange membrane has longer half-life period in the microsome metabolism process, relatively lower clearance rate, can maintain the effective blood concentration for a longer time in vivo, can also maintain a certain concentration in the human plasma metabolism process, the preparation provided by the invention has good microsome metabolic stability and good plasma metabolic stability, and can maintain the effective blood concentration for a long time in vivo.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in detail with reference to specific embodiments.
It should be further noted that, in order to avoid obscuring the present invention due to unnecessary details, only structures and/or processing steps closely related to aspects of the present invention are shown in the specific embodiments, and other details not greatly related to the present invention are omitted.
In addition, it should be further noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
EXAMPLE 1 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methylacetamide (1)
Dissolving (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine in dichloromethane, adding triethylamine, dropwise adding acetyl chloride under ice bath, reacting for 1H at room temperature after the dropwise adding, monitoring by TLC (petroleum ether: ethyl acetate=4:1), quenching by adding water after the reaction is finished, then layering, washing a dichloromethane layer by water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with an eluent (petroleum ether: ethyl acetate=10:1) to obtain colorless oily matters.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.19(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.03-4.98(m,1H),4.12-4.08(m,1H),3.83-3.78(m,1H),3.33-3.29(m,2H),3.07(s,3H),2.94(s,3H),2.83-2.81(m,1H),2.66-2.63(m,1H).MS(ESI)m/z 226.1([M+H]+).
EXAMPLE 2 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methyl-N-tetradecanamide (2)
The title compound was prepared as in example 1, starting from tetradecyl chloride instead of acetyl chloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.20(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.03-4.99(m,1H),4.11-4.08(m,1H),3.83-3.79(m,1H),3.32-3.29(m,2H),3.06(s,3H),2.92(t,J＝10.0HZ,2H),2.83-2.81(m,1H),2.65-2.63(m,1H),1.72-1.66(m,2H),1.21-1.28(m,20H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z 394.3([M+H]+).
EXAMPLE 3 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methylisopropylamide (3)
The title compound was prepared as in example 1, using isopropyl chloride instead of acetyl chloride as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.20(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.04-4.99(m,1H),4.12-4.09(m,1H),3.84-3.78(m,1H),3.33-3.29(m,2H),3.08(s,3H),2.83-2.81(m,1H),2.65-2.62(m,1H),1.85-1.79(m,1H),1.12(d,J＝5.0HZ,6H).MS(ESI)m/z 354.2([M+H]+).
EXAMPLE 4 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methylcyclopropylamide (4)
The title compound was prepared as in example 1, starting from cyclopropylchloride instead of acetylchloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.18(d,J＝5.0HZ,1H),6.83(d,J＝5.0HZ,1H),5.04-5.02(m,1H),4.17-4.12(m,1H),3.77-3.72(m,1H),3.27-3.23(m,2H),3.07(s,3H),2.84-2.80(m,1H),2.65-2.62(m,1H),1.83-1.78(m,1H),0.89-0.75(m,4H).MS(ESI)m/z 252.2([M+H]+).
EXAMPLE 5 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methylcyclohexylamide (5)
The title compound was prepared as in example 1, starting from cyclohexenyl chloride instead of acetyl chloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.19(d,J＝5.0HZ,1H),6.83(d,J＝5.0HZ,1H),5.04-4.99(m,1H),4.17-4.11(m,1H),3.77-3.68(m,1H),3.27-3.24(m,2H),3.04(s,3H),2.86-2.79(m,1H),2.65-2.58(m,1H),1.86-1.81(m,1H),1.27-1.18(m,10H).MS(ESI)m/z 294.2([M+H]+)
EXAMPLE 6 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methylbenzamide (6)
The title compound was prepared as in example 1, starting from benzoyl chloride instead of acetyl chloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.59-7.51(m,2H),7.42-7.35(m,3H),7.21(d,J＝5.0HZ,1H),6.84(d,J＝5.0HZ,1H),5.02-4.99(m,1H),4.16-4.11(m,1H),3.75-3.68(m,1H),3.27-3.24(m,2H),3.07(s,3H),2.86-2.77(m,1H),2.65-2.62(m,1H).MS(ESI)m/z 288.1([M+H]+).
EXAMPLE 7 (S) -N- ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N-methylfuran-2-amide (7)
The title compound was prepared as in example 1, starting from furan-2-yl chloride instead of acetyl chloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.56(d,J＝5.0HZ,1H),7.41(d,J＝5.0HZ,1H),7.21(d,J＝5.0HZ,1H),6.89-6.84(m,2H),5.03-4.99(m,1H),4.16-4.12(m,1H),3.75-3.69(m,1H),3.27-3.22(m,2H),3.06(s,3H),2.86-2.78(m,1H),2.65-2.61(m,1H).MS(ESI)m/z 278.1([M+H]+).
EXAMPLE 8N 1,N5 -bis (((S) 4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) -N 1,N5 -dimethylglutaramide (8)
The title compound was prepared as in example 1, starting from glutaryl chloride instead of acetyl chloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,2H),6.85(d,J＝5.0HZ,2H),5.03-4.99(m,2H),4.16-4.12(m,2H),3.75-3.69(m,2H),3.27-3.22(m,4H),3.07(s,6H),2.96-2.93(m,4H),2.86-2.79(m,2H),2.65-2.63(m,2H),2.34-2.29(m,2H).MS(ESI)m/z 463.2([M+H]+).
EXAMPLE 9 dodecyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (9)
Dissolving (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine in dichloromethane, adding triethylamine, dropwise adding dodecyl chloroformate under ice bath, reacting for 1H at room temperature after the dropwise adding, monitoring by TLC (petroleum ether: ethyl acetate=4:1), quenching by adding water after the reaction is finished, then separating the dichloromethane layer, washing the dichloromethane layer with water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with eluent (petroleum ether: ethyl acetate=10:1) to obtain oily matters.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.04-5.01(m,1H),4.15-4.11(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.29(m,2H),3.07(s,3H),2.83-2.80(m,1H),2.65-2.62(m,1H),1.72-1.67(m,2H),1.26-1.21(m,20H),0.87(t,J＝10.0HZ,3H).MS(ESI)m/z 396.2([M+H]+).
EXAMPLE 10 hexadecyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (10)
The title compound was prepared as in example 9, starting from cetyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.85(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.29(m,2H),3.07(s,3H),2.83-2.80(m,1H),2.66-2.63(m,1H),1.72-1.69(m,2H),1.26-1.22(m,28H),0.87(t,J＝10.0HZ,3H).MS(ESI)m/z 452.3([M+H]+).
EXAMPLE 11 heptyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (11)
The title compound was prepared as in example 9, starting from heptyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.20(d,J＝5.0HZ,1H),6.85(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.11(m,1H),4.04(t,J＝10.0HZ,2H),3.84-3.78(m,1H),3.32-3.29(m,2H),3.08(s,3H),2.84-2.81(m,1H),2.66-2.62(m,1H),1.71-1.69(m,2H),1.26-1.22(m,10H),0.86(t,J＝10.0HZ,3H).MS(ESI)m/z326.2([M+H]+).
EXAMPLE 12 decyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (12)
The title compound was prepared as in example 9, starting from decyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.07(s,3H),2.84-2.81(m,1H),2.66-2.64(m,1H),1.72-1.68(m,2H),1.26-1.22(m,16H),0.85(t,J＝10.0HZ,3H).MS(ESI)m/z368.2([M+H]+).
EXAMPLE 13 octyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (13)
The title compound was prepared as in example 9, starting from octyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.26-1.22(m,12H),0.86(t,J＝10.0HZ,3H).MS(ESI)m/z 340.2([M+H]+).
EXAMPLE 14 nonylalkyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (14)
The title compound was prepared as in example 9, starting from nonyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.26-1.22(m,14H),0.86(t,J＝10.0HZ,3H).MS(ESI)m/z 354.2([M+H]+).
EXAMPLE 15 cyclopentyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (15)
The title compound was prepared as in example 9, starting from cyclopentyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.10(m,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.29-1.25(m,8H),.MS(ESI)m/z 296.2([M+H]+).
EXAMPLE 16 hexyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (16)
The title compound was prepared as in example 9, starting from hexyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.26-1.22(m,8H),0.88(t,J＝10.0HZ,3H).MS(ESI)m/z312.2([M+H]+).
EXAMPLE 17 amyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (17)
The title compound was prepared as in example 9, starting from amyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.04(t,J＝10.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,2H),1.29-1.24(m,6H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z298.2([M+H]+).
EXAMPLE 18 methoxyethyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (18)
The title compound was prepared as in example 9, starting from methoxy chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,4H),4.06-4.03(m,4H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H).MS(ESI)m/z 286.2([M+H]+).
EXAMPLE 19 2- (benzyloxy) ethyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (19)
The title compound was prepared as in example 9, starting from 2- (benzyloxy) ethyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.38-7.34(m,5H),7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.08-4.04(m,6H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H).MS(ESI)m/z 362.2([M+H]+).
EXAMPLE 20 2- (methylsulfonyl) ethyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (20)
The title compound was prepared as in example 9, starting from 2- (methylsulfonyl) ethyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.87(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.08-4.04(m,4H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,4H),2.67-2.63(m,1H).MS(ESI)m/z 334.1([M+H]+).
EXAMPLE 21 2-ethylbutyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (21)
The title compound was prepared as in example 9, starting from 2-ethylbutyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.03(d,J＝5.0HZ,2H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.72-1.68(m,3H),1.26-1.01(m,10H).MS(ESI)m/z 312.2([M+H]+).
EXAMPLE 22 Hexane-2-yl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (22)
The title compound was prepared as in example 9, starting from hexane-2-yl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.05-4.03(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.25-1.22(m,6H),0.95-0.89(m,6H).MS(ESI)m/z 312.2([M+H]+).
EXAMPLE 23 p-tolyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (23)
The title compound was prepared as in example 9, starting from p-tolyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22-7.18(m,5H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),4.05-4.03(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),2.26(s,3H).MS(ESI)m/z 318.2([M+H]+).
EXAMPLE 24 naphthalen-2-yl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (24)
The title compound was prepared as in example 9, starting from naphthalen-2-yl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.82-7.77(m,5H)7.51-7.45(m,2H)7.22-7.18(m,3H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.11(m,1H),4.05-4.03(m,1H),3.84-3.79(m,1H),3.32-3.29(m,2H),3.08(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H).MS(ESI)m/z 354.2([M+H]+).
EXAMPLE 25 t-butyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (25)
The title compound was prepared as in example 9, starting from tert-butyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.16-4.11(m,1H),3.84-3.79(m,1H),3.32-3.29(m,2H),3.08(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.47(s,9H).MS(ESI)m/z 284.2([M+H]+).
EXAMPLE 26 ethane-1, 2-Diylbis (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (26)
The title compound was prepared as in example 9, starting from ethane-1, 2-diyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,2H),6.86(d,J＝5.0HZ,2H),5.04-5.01(m,2H),4.15-4.11(m,2H),4.03(t,J＝10.0HZ,4H),3.84-3.79(m,2H),3.32-3.29(m,4H),3.07(s,6H),2.83-2.80(m,2H),2.65-2.62(m,2H).MS(ESI)m/z 481.2([M+H]+).
EXAMPLE 27 butane-1, 4-diylbis (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate (27)
The title compound was prepared as in example 9, starting from butane-1, 4-diyl chloroformate instead of dodecyl chloroformate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,2H),6.86(d,J＝5.0HZ,2H),5.04-5.01(m,2H),4.15-4.11(m,2H),4.03(t,J＝10.0HZ,4H),3.84-3.79(m,2H),3.32-3.29(m,4H),3.07(s,6H),2.83-2.80(m,2H),2.65-2.62(m,2H),1.29-1.24(m,4H).MS(ESI)m/z 509.2([M+H]+).
EXAMPLE 28 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl acetate (28)
Dissolving (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine in DMF, adding potassium carbonate, dropwise adding chloromethyl acetate, reacting for 8 hours at 80 ℃ after the dropwise adding, monitoring by TLC (PE: EA=4:1), adding water for quenching after the completion of the reaction, then layering, extracting with dichloromethane for 3 times, merging the extracts, drying with anhydrous sodium sulfate, passing through a silica gel column, and eluting with eluent (PE: EA=10:1) to obtain oily matters.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.45(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.81(m,1H),2.67-2.64(m,1H),2.38(s,3H).MS(ESI)m/z 256.1([M+H]+).
EXAMPLE 29 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methylbutyrate (29)
The title compound was prepared as in example 28, starting from chloromethyl butyrate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.45(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.92(t,J＝5.0HZ,2H),2.84-2.81(m,1H),2.67-2.64(m,1H),1.65-1.61(m,2H),0.92(t,J＝10.0HZ,3H).MS(ESI)m/z 284.2([M+H]+).
EXAMPLE 30 (S) - (((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl decanoate (30)
The title compound was prepared as in example 28, using chloromethyl decanoate instead of chloromethyl acetate as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.48(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.96(t,J＝5.0HZ,2H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.67-1.64(m,2H),1.27-1.22(m,12H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z 368.2([M+H]+)
EXAMPLE 31 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl palmitate (31)
The title compound was prepared as in example 28, using chloromethyl palmitate instead of chloromethyl acetate as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.48(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.96(t,J＝5.0HZ,2H),2.86-2.81(m,1H),2.67-2.64(m,1H),1.67-1.64(m,2H),1.27-1.22(m,24H),0.89(t,J＝10.0HZ,3H).MS(ESI)m/z 452.2([M+H]+).
EXAMPLE 32 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyloctanoate (32)
The title compound was prepared as in example 28, starting from chloromethyl octanoate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.47(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.97(t,J＝5.0HZ,2H),2.85-2.81(m,1H),2.67-2.64(m,1H),1.67-1.63(m,2H),1.27-1.23(m,8H),0.90(t,J＝10.0HZ,3H).MS(ESI)m/z 340.2([M+H]+).
EXAMPLE 33 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl tert-butyrate (33)
The title compound was prepared as in example 28, starting from chloromethyl tert-butyrate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.47(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.85-2.81(m,1H),2.67-2.64(m,1H),1.26(s,9H).MS(ESI)m/z298.2([M+H]+).
EXAMPLE 34 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl-3-methylbutanoate (34)
The title compound was prepared as in example 28, starting from chloromethyl 3-methylbutyrate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.47(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.97(t,J＝5.0HZ,2H),2.85-2.81(m,1H),2.67-2.64(m,1H),1.69-1.65(m,1H),0.92(d,J＝5.0HZ,6H).MS(ESI)m/z298.2([M+H]+).
EXAMPLE 35 (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methylbenzoate (35)
The title compound was prepared as in example 28, starting from chloromethyl benzoate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.59-7.51(m,2H),7.42-7.35(m,3H),7.21(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.47(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.85-2.81(m,1H),2.67-2.64(m,1H).MS(ESI)m/z318.2([M+H]+).
EXAMPLE 36 (S) - (((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) -methylcyclopentyl ester (36)
The title compound was prepared as in example 28, starting from chloromethyl cyclopentanate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.01(m,1H),4.47(s,2H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.83(m,2H),2.67-2.64(m,1H),1.93-1.65(m,8H).MS(ESI)m/z310.2([M+H]+).
Example 37.1- ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) ethyl-decanoate methyl ester (37)
The nuclear magnetic hydrogen spectrogram of this example shows the following results: the title compound was prepared as in example 28, starting from 1-chloroethyl decanoate instead of chloromethyl acetate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.88(d,J＝5.0HZ,1H),5.06-5.02(m,1H),4.46-4.44(m,1H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.96(t,J＝5.0HZ,2H),2.86-2.81(m,1H),2.67-2.63(m,1H),1.67-1.62(m,2H),1.27-1.21(m,12H),0.92-0.89(m,6H).MS(ESI)m/z382.2([M+H]+).
EXAMPLE 38.1- ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methylacetylglycine ester (38)
Preparation of (S) - (((4, 7-dihydro-5H-thiophen [2,3-c ] pyran-7-yl) methyl) (meth) amine) methanol
(1) 0.8G of compound 18[ methoxyethyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate ] is taken and dissolved in 50ml of dry THF, and then cooled in an ice bath, 0.4g of sodium borohydride is added in portions, about 15 minutes is spent, the temperature is raised to room temperature after the addition is finished, the reaction is carried out for 2 hours, TLC monitoring (petroleum ether: ethyl acetate=6:1), quenching is carried out by ice water, then the solvent is dried by spin-drying, the dichloromethane layer is extracted for 3 times, the dichloromethane layer is washed by water, dried by anhydrous sodium sulfate, and the silica gel column and the eluent (petroleum ether: ethyl acetate=12:1) are adopted to obtain colorless oily matters.
Preparation of 1- ((((S) -4, 7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl acetoacetate (38)
(2) Dissolving (S) - (((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methanol in dichloromethane, adding DMAP, adding EDC in batches, then adding acetylglycine, reacting for 6 hours at room temperature after adding, monitoring by TLC (petroleum ether: ethyl acetate=4:1), washing a dichloromethane layer by water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with an eluent (petroleum ether: ethyl acetate=10:1) to obtain colorless oily matters.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.02(m,1H),4.46(s,2H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,1H),2.67-2.62(m,3H),2.38(s,3H).MS(ESI)m/z 313.1([M+H]+).
Example 39.1- ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl 4-aminobutyrate trifluoroacetate salt (39)
(1) Dissolving (S) - (((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methanol in dichloromethane, adding DMAP, adding EDC in batches, then adding BOC aminobutyric acid, reacting for 6 hours at room temperature after adding, monitoring by TLC (petroleum ether: ethyl acetate=4:1), washing a dichloromethane layer with water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with an eluent (petroleum ether: ethyl acetate=10:1) to obtain colorless oily matters.
(2) In a reaction flask, 200mg of the product of step 1, 3mL of trifluoroacetic acid and 1.5mL of dichloromethane were added, and the reaction was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 170mg of a colorless oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.02(m,1H),4.46(s,2H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,2H),2.67-2.61(m,3H),1.45-1.38(m,2H).MS(ESI)m/z 299.2([M+H]+).
EXAMPLE 40 (S) - (((4, 7-dihydro-5H-thiophen [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl (2- (1- (aminomethyl) cyclohexyl) ethyl ester trifluoroacetate salt (40)
(1) Dissolving (S) - (((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methanol in dichloromethane, adding DMAP, adding EDC in batches, then adding 2- (1- (((tert-butoxycarbonyl) amino) methyl) cyclohexyl) acetic acid, reacting for 8 hours at room temperature after the addition, monitoring (petroleum ether: ethyl acetate=4:1) by TLC, washing a dichloromethane layer with water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with a petroleum ether: ethyl acetate=10:1 to obtain colorless oily matters.
(2) In a reaction flask, 200mg of the product of step 1, 3mL of trifluoroacetic acid and 1.5mL of dichloromethane were added, and the reaction was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 180mg of a colorless oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.02(m,1H),4.46(s,2H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,2H),2.67-2.61(m,3H),1.61-1.38(m,10H).MS(ESI)m/z 367.2([M+H]+).
EXAMPLE 41(((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl-3- (aminomethyl) -5-methylhexyl ester trifluoroacetate salt (41)
(1) Dissolving (S) - (((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methanol in dichloromethane, adding DMAP, adding EDC in batches, then adding 3- (((tert-butoxycarbonyl) amino) methyl) -5-methylhexanoic acid, reacting for 8 hours at room temperature after the addition, monitoring (petroleum ether: ethyl acetate=4:1) by TLC, washing a dichloromethane layer with water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with an eluent (petroleum ether: ethyl acetate=10:1) to obtain colorless oily matters.
(2) In a reaction flask, 200mg of the product of step 1, 3mL of trifluoroacetic acid and 1.5mL of dichloromethane were added, and the reaction was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 160mg of a colorless oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-5.02(m,1H),4.46(s,2H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,2H),2.67-2.61(m,3H),1.69-1.61(m,2H),1.24–1.04(m,3H),0.92–0.88(m,6H).MS(ESI)m/z 355.2([M+H]+).
EXAMPLE 42 methyl (((S) -4, 7-dihydro-5H-thiophen [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (methoxymethyl) phosphono) -L-aminopropionate (42)
Compound (methoxymethyl) phosphonodichloride (1.2 g) is dissolved in dry dichloromethane (10 mL), cooled to-30 ℃ under the protection of nitrogen, a mixture of dichloromethane solution (5 mL) of L-alanine methyl ester (1.0 g) and triethylamine (3.0 g) is slowly added dropwise, after the dropwise addition, the reaction is continued for 30min at-30 ℃, compound 114A (1.150 g,3.491 mmol) is added, and the mixture is naturally warmed to room temperature and then heated for reflux reaction for 1h. To the reaction solution were added saturated aqueous sodium dihydrogen phosphate (20 mL) and methylene chloride (20 mL), the mixture was separated, the organic layer was dried over anhydrous sodium sulfate, and the organic layer was filtered, and the filtrate was purified by silica gel column separation (petroleum ether: ethyl acetate=1:1 to 1:4) to give compound 41 as an oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-4.98(m,3H),4.48(s,6H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,1H),2.67-2.61(m,2H),1.52(d,J＝5.0HZ,3H).MS(ESI)m/z 378.2([M+H]+).
EXAMPLE 43 isopropyl ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (methoxymethyl) phosphono) -L-aminopropionate (43)
The title compound was prepared as in example 42, starting from isopropyl L-alaninate instead of methyl L-alaninate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-4.98(m,3H),4.48-4.42(m,4H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,1H),2.67-2.61(m,2H),1.52-1.39(m,9H).MS(ESI)m/z 405.2([M+H]+).
EXAMPLE 44 isopropyl ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (phenoxymethyl) phosphono) -L-aminopropionate (44)
The title compound was prepared as in example 43, starting from (phenoxymethyl) phosphonodichloride instead of (methoxymethyl) phosphonodichloride.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.36-7.31(m,2H),7.24-7.19(m,4H),6.86(d,J＝5.0HZ,1H),5.05-4.98(m,3H),4.48-4.42(m,1H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,1H),2.67-2.61(m,2H),1.52-1.39(m,9H).MS(ESI)m/z 467.2([M+H]+).
EXAMPLE 45 tert-butyl ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (methoxymethyl) phosphono) -L-aminopropionate (45)
The title compound was prepared as in example 42, starting from t-butyl L-alaninate instead of methyl L-alaninate.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.86(d,J＝5.0HZ,1H),5.05-4.98(m,3H),4.48-4.42(m,3H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,1H),2.67-2.61(m,2H),1.54-1.39(m,12H).MS(ESI)m/z 419.2([M+H]+).
EXAMPLE 46 phenyl ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (methoxymethyl) phosphono) -L-aminopropionate (46)
The title compound was prepared as in example 42, starting from L-alanine phenyl ester instead of L-alanine methyl ester.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.39-7.31(m,2H),7.25-7.19(m,4H),6.86(d,J＝5.0HZ,1H),5.05-4.98(m,3H),4.17-4.12(m,4H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,1H),2.67-2.61(m,2H),1.52-1.39(m,3H).MS(ESI)m/z 439.2([M+H]+).
EXAMPLE 47 (S) - ((((4, 7-dihydro-5H-thiophen [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) methyl-2-ethylbutyrate (47)
Dissolving (S) -1- (4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) -N-methyl methylamine in dichloromethane, adding triethylamine, dropwise adding chloromethyl chloroformate under ice bath, reacting for 1H at room temperature after the dropwise adding, monitoring by TLC (petroleum ether: ethyl acetate=4:1), quenching by adding water after the reaction is finished, then separating the dichloromethane layer, washing the dichloromethane layer with water, drying by anhydrous sodium sulfate, passing through a silica gel column, and eluting with eluent (petroleum ether: ethyl acetate=10:1) to obtain oily matter.
1.5G of the product of the first step, 0.44g of TBAI are dissolved in 8mL of DMF, 2g of valproic acid are added and heated at 60℃overnight under argon. The reaction was stopped, 30mL of saturated NaCl and 40mL of ethyl acetate were added and stirred, the organic phase was separated, washed sequentially with saturated NaC (30 m), water (30 mL of stirred), saturated NaHCO 3 (30 mL), saturated NaCl (30 mL), anhydrous Na 2SO4 dried, filtered, spin-dried, and column chromatographed on silica gel (petroleum ether/ethyl acetate=3:1) to give an oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.92-6.87(m,3H),5.12-5.01(m,1H),4.16-4.11(m,1H),3.84-3.79(m,1H),3.32-3.29(m,2H),3.08(s,3H),2.86-2.81(m,1H),2.67-2.59(m,2H),1.47-1.32(m,4H),0.90(t,J＝5.0Hz,6H).MS(ESI)m/z 356.2([M+H]+).
EXAMPLE 48 (S) - ((((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) methylnicotinate (48)
The title compound was prepared as in example 47, using nicotinic acid instead of valproic acid as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.59-7.45(m,2H),7.39-7.35(m,1H),7.21(d,J＝5.0HZ,1H),6.92-6.87(m,3H),5.05-5.01(m,3H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.85-2.81(m,1H),2.67-2.64(m,1H).MS(ESI)m/z363.2([M+H]+).
EXAMPLE 49 (S) - ((((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) methyl decanoate (49)
The title compound was prepared as in example 47, using decanoic acid instead of valproic acid as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.92-6.87(m,3H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),,2.86-2.81(m,1H),2.67-2.64(m,1H),2.45(t,J＝5.0HZ,2H),1.27-1.22(m,14H),0.92(t,J＝10.0HZ,3H).MS(ESI)m/z 412.2([M+H]+).
EXAMPLE 50 (S) - ((((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) methyl dodecanoate (50)
The title compound was prepared as in example 47, starting from dodecanoic acid instead of valproic acid.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.92-6.87(m,3H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.79(m,1H),3.32-3.28(m,2H),3.09(s,3H),,2.86-2.81(m,1H),2.67-2.64(m,1H),2.43(t,J＝5.0HZ,2H),1.27-1.21(m,18H),0.91(t,J＝10.0HZ,3H).MS(ESI)m/z 440.2([M+H]+).
EXAMPLE 51((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) methyl-3- (aminomethyl) -5-methylhexyl ester trifluoroacetate (51)
1.5G chloromethyl (S) - ((4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate, 0.44g TBAI was dissolved in 8mL DMF and 2g 3- (((tert-butoxycarbonyl) amino) methyl) -5-methylhexanoic acid was added and heated under argon at 60℃overnight. The reaction was stopped, 30mL of saturated NaCl and 40mL of ethyl acetate were added and stirred, the organic phase was separated, washed sequentially with saturated NaC (30 m), water (30 mL of stirred), saturated NaHCO 3 (30 mL), saturated NaCl (30 mL), anhydrous Na 2SO4, dried, filtered, spin-dried, and column chromatographed on silica gel (petroleum ether/ethyl acetate=5:1) to give an oil.
(2) 220Mg of the product from step 1, 3mL of trifluoroacetic acid and 1.5mL of dichloromethane were added to the reaction flask, and the reaction was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 160mg of a colorless oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.23(d,J＝5.0HZ,1H),6.92-6.87(m,3H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,2H),2.67-2.60(m,3H),1.69-1.61(m,2H),1.21–1.02(m,3H),0.93-0.88(m,6H).MS(ESI)m/z 399.2([M+H]+).
EXAMPLE 52((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) methyl (2- (1- (aminomethyl) cyclohexyl) ethyl ester trifluoroacetate (52)
(1) 1.5G chloromethyl (S) - ((4, 7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) (methyl) carbonate, 0.44g TBAI was dissolved in 8mL DMF, 2g 2- (1- (((tert-butoxycarbonyl) amino) methyl) cyclohexyl) acetic acid was added and heated under argon at 60℃overnight. The reaction was stopped, 30mL of saturated NaCl and 40mL of ethyl acetate were added and stirred, the organic phase was separated, washed sequentially with saturated NaC (30 m), water (30 mL of stirred), saturated NaHCO 3 (30 mL), saturated NaCl (30 mL), anhydrous Na 2SO4, dried, filtered, spin-dried, and column chromatographed on silica gel (petroleum ether/ethyl acetate=5:1) to give an oil.
(2) 220Mg of the product from step 1, 3mL of trifluoroacetic acid and 1.5mL of dichloromethane were added to the reaction flask, and the reaction was stirred at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 180mg of a colorless oil.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.92-6.87(m,3H),5.05-5.01(m,1H),4.16-4.11(m,1H),3.84-3.80(m,1H),3.32-3.26(m,2H),3.09(s,3H),2.86-2.81(m,2H),2.67-2.60(m,3H),1.59-1.39(m,10H).MS(ESI)m/z 411.2([M+H]+).
Example 53.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetoacetate (53)
The title compound was prepared as in example 47, using acetylglycine instead of valproic acid and 1-chloroethyl chloroformate instead of chloromethyl chloroformate as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.20(d,J＝5.0HZ,1H),6.92-6.87(m,2H),5.05-4.96(m,1H),4.16-4.12(m,1H),3.84-3.79(m,2H),3.36-3.28(m,1H),3.09(s,3H),,2.86-2.82(m,1H),2.69-2.64(m,1H),2.07(s,3H),1.86-1.85(m,2H)1.67-1.61(m,3H).MS(ESI)m/z 371.2([M+H]+).
EXAMPLE 54.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl-L-proline ester (54)
The title compound was prepared by the method of example 53 using N-acetyl-L-proline instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.20(d,J＝5.0HZ,1H),6.86-6.82(m,2H),5.04-4.97(m,1H),4.48-4.36(m,1H),4.16-4.12(m,1H),3.79-3.62(m,4H),3.36-3.28(m,1H),3.06(s,3H),,2.84-2.82(m,1H),2.68-2.64(m,1H),2.07-1.95(m,6H),1.52-1.48(m,3H).MS(ESI)m/z 411.2([M+H]+).
Example 55.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl (3-methylbutanoyl) glycinate (55)
The title compound was prepared as in example 53, using N-isovalerylglycine as starting material instead of acetylglycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.86-6.81(m,2H),5.05-4.97(m,1H),4.48-4.36(m,2H),4.16-4.12(m,1H),3.79-3.62(m,4H),3.36-3.28(m,1H),3.06(s,3H),,2.84-2.82(m,1H),2.68-2.64(m,1H),2.07-1.95(m,1H),1.52-1.48(m,3H),0.99-0.92(m,6H).MS(ESI)m/z 413.2([M+H]+).
EXAMPLE 56.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl phenylacetylglycine (56)
The title compound was prepared as in example 53, using phenylacetylglycine as the starting material instead of acetylglycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.23-7.12(m,6H),6.87-6.81(m,2H),5.06-4.97(m,1H),4.48-4.36(m,2H),4.16-4.12(m,1H),3.79-3.62(m,4H),3.36-3.28(m,1H),3.06(s,3H),,2.84-2.82(m,1H),2.68-2.64(m,1H),2.27-2.21(m,2H),1.52-1.48(m,3H).MS(ESI)m/z 413.2([M+H]+).
Example 57.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl-aminopropionate (57)
The title compound was prepared as in example 53, using N-acetyl-D-alanine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.89-6.82(m,2H),5.06-4.97(m,1H),4.48-4.36(m,2H),4.16-4.12(m,1H),3.79-3.62(m,4H),3.36-3.28(m,1H),3.06(s,3H),2.84-2.82(m,1H),2.68-2.64(m,1H),2.27-2.18(m,1H),2.07(s,3H),1.52-1.48(m,3H).MS(ESI)m/z 385.2([M+H]+).
EXAMPLE 58.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl benzoyl glycine ester (58)
The title compound was prepared as in example 53, using benzoylglycine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.56-7.49(m,2H)7.21-7.12(m,4H),6.87-6.81(m,2H),5.06-4.99(m,1H),4.48-4.39(m,2H),4.16-4.12(m,1H),3.79-3.63(m,4H),3.36-3.29(m,1H),3.07(s,3H),2.84-2.81(m,1H),2.68-2.62(m,1H),1.52-1.49(m,3H).MS(ESI)m/z 435.2([M+H]+).
EXAMPLE 59.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl palmitate (59)
The title compound was prepared as in example 53, using palmitic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.79(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.82(m,3H),2.67-2.64(m,1H),1.67-1.62(m,2H),1.27-1.21(m,24H),0.93-0.89(m,6H).MS(ESI)m/z 510.3([M+H]+).
Example 60.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl dodecanoate (60)
The title compound was prepared as in example 53, using dodecanoic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.06-5.01(m,1H),4.16-4.12(m,1H),3.83-3.72(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.87-2.81(m,1H),2.67-2.64(m,1H),1.67-1.62(m,2H),1.27-1.21(m,14H),0.93-0.89(m,6H).MS(ESI)m/z 454.3([M+H]+).
Example 61.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl decanoate (61)
The title compound was prepared as in example 53, using decanoic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.69(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.81(m,1H),2.67-2.62(m,1H),1.67-1.61(m,2H),1.27-1.20(m,12H),0.94-0.88(m,6H).MS(ESI)m/z 426.2([M+H]+).
Example 62.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethylcarboxyglycine ester (62)
The title compound was prepared as in example 53, using formylglycine as starting material instead of acetylglycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.80(m,2H),5.07-5.01(m,1H),4.16-4.11(m,1H),3.84-3.72(m,3H),3.32-3.29(m,2H),3.08(s,3H),2.89-2.80(m,1H),2.67-2.62(m,1H),0.95-0.92(m,3H).MS(ESI)m/z 457.1([M+H]+).
Exact Mass:356.10。
EXAMPLE 63.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethylhexanoylglycine ester (63)
The title compound was prepared as in example 53, using caproyl glycine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.73(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.87-2.81(m,1H),2.67-2.58(m,3H),1.67-1.61(m,2H),1.29-1.22(m,4H),0.97-0.92(m,6H).MS(ESI)m/z 427.2([M+H]+).
Example 64.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl 2- ((N-phthalimido) acetate (64)
The title compound was prepared as in example 53, using phthaloyl glycine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.26-7.18(m,5H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.94-3.73(m,3H),3.32-3.26(m,2H),3.08(s,3H),2.87-2.81(m,1H),2.67-2.58(m,1H),0.96-0.91(m,3H).MS(ESI)m/z 459.2([M+H]+).
Example 65.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl ((E) -2-methylbutan-2-enoyl) glycinate (65)
The title compound was prepared as in example 53, using crotonylglycine as the starting material instead of acetylglycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),6.46-6.35(m,1H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.94-3.73(m,3H),3.32-3.26(m,2H),3.08(s,3H),2.87-2.81(m,1H),2.67-2.38(m,7H),0.96-0.91(m,3H).MS(ESI)m/z 411.1([M+H]+).
Example 66.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyldodecanoylglycine (66)
The title compound was prepared as in example 53, using lauroyl glycine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,3H),3.84-3.69(m,3H),3.32-3.28(m,1H),3.09(s,3H),2.89-2.81(m,1H),2.67-2.62(m,3H),1.67-1.62(m,2H),1.27-1.20(m,16H),0.94-0.88(m,6H).MS(ESI)m/z 511.3([M+H]+).
Example 67.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl-levulinic acid ester (67)
The title compound was prepared by the method of example 53 using N-acetyl- β -alanine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.94-3.73(m,3H),3.32-3.26(m,3H),3.08(s,3H),2.87-2.81(m,1H),2.67-2.38(m,3H),1.96-1.71(m,6H).MS(ESI)m/z 385.1([M+H]+).
Example 68.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl-L-alanine ester (68)
The title compound was prepared by the method of example 53 using N-acetyl-L-alanine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.34-4.12(m,2H),3.94-3.73(m,3H),3.32-3.26(m,1H),3.08(s,3H),2.87-2.81(m,1H),2.67-2.38(m,1H),1.96-1.51(m,9H).MS(ESI)m/z 385.1([M+H]+).
EXAMPLE 69.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethylisobutyryl-L-alanine ester (69)
The title compound was prepared by the method of example 53 using N-isobutyryl-L-alanine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.36-4.12(m,2H),3.94-3.76(m,3H),3.32-3.27(m,1H),3.08(s,3H),2.87-2.82(m,1H),2.67-2.39(m,2H),1.96-1.51(m,12H).MS(ESI)m/z 413.2([M+H]+).
EXAMPLE 70.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetaminophenylalanine ester (70)
The title compound was prepared in the same manner as in example 53 using N-acetylphenylalanine instead of acetylglycine as a starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22-7.11(m,6H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.45-4.12(m,2H),3.94-3.76(m,2H),3.32-3.27(m,3H),3.08(s,3H),2.87-2.82(m,1H),2.67-2.39(m,2H),1.96-1.51(m,6H).MS(ESI)m/z 461.2([M+H]+).
Example 71.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl tryptophan ester (71)
The title compound was prepared as in example 53, using acetyltryptophan instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.65-7.45(m,2H),7.26-7.15(m,3H),6.87-6.81(m,2H),5.07-5.02(m,1H),4.45-4.15(m,1H),3.94-3.79(m,2H),3.32-3.28(m,3H),3.09(s,3H),2.89-2.82(m,1H),2.67-2.42(m,2H),1.96-1.59(m,6H).MS(ESI)m/z 500.2([M+H]+).
Example 72.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl valine (72)
The title compound was prepared as in example 53, using acetylvaline instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.23(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.07-5.02(m,1H),4.45-4.15(m,1H),3.94-3.79(m,2H),3.32-3.28(m,3H),3.09(s,3H),2.89-2.82(m,1H),2.67-2.42(m,1H),1.96-1.59(m,6H),0.99-0.92(m,6H).MS(ESI)m/z 413.2([M+H]+).
EXAMPLE 73.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl N-acetyl-N-methylglycinate (73)
The title compound was prepared by the method of example 53 using N-acetyl-N-methylglycine instead of acetylglycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.92-6.86(m,2H),5.05-4.99(m,1H),4.16-4.11(m,1H),3.84-3.79(m,2H),3.36-3.29(m,3H),3.09(s,3H),,2.86-2.82(m,1H),2.69-2.62(m,1H),2.07(s,3H),1.86-1.85(m,2H)1.67-1.61(m,3H).MS(ESI)m/z 385.1([M+H]+).
Example 74.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl (2, 2-trifluoroacetyl) glycinate (74)
The title compound was prepared as in example 53, substituting trifluoroacetyl glycine for acetyl glycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.23(d,J＝5.0HZ,1H),6.95-6.86(m,2H),5.06-4.99(m,1H),4.18-4.14(m,1H),3.84-3.79(m,2H),3.36-3.29(m,3H),3.09(s,3H),,2.86-2.82(m,1H),2.72-2.62(m,1H),1.96-1.89(m,3H).MS(ESI)m/z 425.1([M+H]+).
Example 75.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl dimethylglycine ester (75)
The title compound was prepared as in example 53, substituting dimethylglycine for acetylglycine.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.95-6.86(m,2H),5.06-5.01(m,1H),4.18-4.12(m,1H),3.84-3.65(m,8H),3.36-3.29(m,3H),3.09(s,3H),2.87-2.81(m,1H),2.72-2.62(m,1H),1.92-1.86(m,3H).MS(ESI)m/z 357.1([M+H]+).
Example 76.1- ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl-3- (aminomethyl) -5-methylhexyl ester trifluoroacetate (76)
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.92-6.86(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.81(m,1H),3.32-3.28(m,2H),3.09(s,3H),2.86-2.82(m,2H),2.67-2.60(m,3H),1.89-1.61(m,5H),1.21-1.02(m,3H),0.93-0.88(m,6H).MS(ESI)m/z 413.2([M+H]+).
Example 77.1- ((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl (2- (1- (aminomethyl) cyclohexyl) ethyl ester trifluoroacetate (77)
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.94-6.87(m,2H),5.06-5.01(m,1H),4.16-4.10(m,1H),3.84-3.81(m,1H),3.32-3.26(m,2H),3.08(s,3H),2.86-2.80(m,2H),2.67-2.60(m,3H),1.89-1.76(m,3H),1.59-1.39(m,10H).MS(ESI)m/z 425.2([M+H]+).
EXAMPLE 78.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) propyl acetyl glycine ester (78)
The title compound was prepared as in example 47, using acetylglycine instead of valproic acid and 1-chloropropylchloroformate instead of chloromethyl chloroformate as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.92-6.87(m,2H),5.05-4.96(m,1H),4.16-4.12(m,1H),3.84-3.79(m,2H),3.36-3.28(m,1H),3.09(s,3H),,2.86-2.82(m,1H),2.69-2.64(m,1H),2.07(s,3H),1.86-1.62(m,8H).MS(ESI)m/z 385.2([M+H]+).
Example 79.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) propyl acetyl-L-aminopropionate (79)
The title compound was prepared as in example 78 using N-acetyl-L-alanine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.89-6.82(m,2H),5.06-4.97(m,1H),4.48-4.36(m,2H),4.16-4.12(m,1H),3.79-3.62(m,2H),3.36-3.28(m,1H),3.06(s,3H),2.84-2.82(m,1H),2.68-2.64(m,1H),2.27-2.18(m,1H),2.07(s,3H),1.79-1.52(m,6H).MS(ESI)m/z 399.2([M+H]+).
Example 80.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) propyl benzoyl glycinate (80)
The title compound was prepared as in example 78, using benzoylglycine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.56-7.48(m,2H)7.21-7.11(m,4H),6.87-6.81(m,2H),5.06-5.01(m,1H),4.48-4.39(m,1H),4.16-4.12(m,1H),3.79-3.63(m,4H),3.36-3.29(m,1H),3.07(s,3H),2.84-2.81(m,1H),2.68-2.62(m,1H),1.79-1.52(m,6H).MS(ESI)m/z 447.2([M+H]+).
Example 81.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) propyl decanoate (81)
The title compound was prepared as in example 78, using decanoic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.69(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.81(m,1H),2.67-2.62(m,1H),1.88-1.61(m,4H),1.27-1.20(m,12H),0.99-0.88(m,6H).MS(ESI)m/z 440.2([M+H]+).
Example 82.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) propyl palmitate (82)
The title compound was prepared as in example 78, using palmitic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.79(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.82(m,3H),2.67-2.64(m,1H),1.89-1.62(m,4H),1.27-1.20(m,24H),0.93-0.88(m,6H).MS(ESI)m/z 510.3([M+H]+).
Example 83.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-methylpropylacetoglycinate (83)
The title compound was prepared as in example 47, using acetylglycine instead of valproic acid and 1-chloro-2-methylpropyl chloroformate instead of chloromethyl chloroformate as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.95-6.87(m,2H),5.06-4.96(m,1H),4.16-4.12(m,1H),3.84-3.79(m,2H),3.36-3.28(m,1H),3.09(s,3H),,2.86-2.82(m,1H),2.69-2.64(m,1H),2.07(s,3H),1.86-1.62(m,10H).MS(ESI)m/z 399.2([M+H]+).
Example 84.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-methylpropylacetyl-L-aminopropionate (84)
The title compound was prepared as in example 83, using N-acetyl-L-alanine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.89-6.82(m,2H),5.06-4.97(m,1H),4.48-4.36(m,2H),4.16-4.12(m,1H),3.79-3.62(m,2H),3.36-3.28(m,1H),3.06(s,3H),2.84-2.82(m,1H),2.68-2.64(m,1H),2.07(s,3H),1.89-1.57(m,6H).MS(ESI)m/z 413.2([M+H]+).
Example 85.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-propylbenzoylglycine ester (85)
The title compound was prepared as in example 83 using benzoylglycine instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.56-7.48(m,2H)7.21-7.11(m,4H),6.87-6.81(m,2H),5.06-5.01(m,1H),4.48-4.39(m,1H),4.16-4.12(m,1H),3.79-3.63(m,3H),3.36-3.29(m,1H),3.07(s,3H),2.84-2.81(m,1H),2.68-2.62(m,1H),1.79-1.52(m,6H).MS(ESI)m/z 461.2([M+H]+).
Example 86.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-propyldecanoate (86)
The title compound was prepared as in example 83, using decanoic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.22(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.69(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.81(m,1H),2.67-2.62(m,1H),1.88-1.61(m,3H),1.27-1.20(m,12H),0.99-0.90(m,9H).MS(ESI)m/z 454.2([M+H]+).
Example 87.1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-propyl palmitate (87)
The title compound was prepared as in example 83, using palmitic acid instead of acetylglycine as starting material.
The nuclear magnetic hydrogen spectrogram of the embodiment results in that ：1H NMR(500MHz,CDCl3)δ7.21(d,J＝5.0HZ,1H),6.87-6.81(m,2H),5.05-5.01(m,1H),4.16-4.12(m,1H),3.84-3.79(m,3H),3.32-3.28(m,2H),3.09(s,3H),2.89-2.82(m,3H),2.67-2.64(m,1H),1.89-1.62(m,3H),1.27-1.20(m,24H),0.96-0.88(m,9H).MS(ESI)m/z 524.3([M+H]+).
EXAMPLE 88 Metabolic stability in microsomes
Experimental system
(1) Stock solutions of the compounds to be tested and the positive control were prepared at a concentration of 10mM using DMSO as diluent, and then all stock solutions were diluted with 70% acetonitrile to a working concentration of 0.25 mM;
(2) The cofactor used in the test was NADPH regeneration system consisting of 6.5mM NADP,16.5mM G-6-P,3U/mL G-6-P D;
(3) The quencher consists of acetonitrile containing tosyl butyramide and propanol (used as internal standard);
(4) The buffer used in the test was 100mM phosphate buffer containing 3.3mM MgCl 2;
(5) The mixture contained 0.2mg/mL liver microsomal protein and 1 μm test compound/positive control and incubated in 100mM potassium phosphate buffer.
Experimental method
(1) A 0 minute sample was prepared by adding 80 μl aliquots of each incubation mixture to 300 μl of quenching reagent to precipitate the protein. The sample was vortexed and then an aliquot of 20. Mu.L of NADPH regeneration system was added.
(2) The reaction was started by adding 130. Mu.L of NADPH regeneration system to 520. Mu.L of each incubation mixture. The final incubation conditions reached in 650 μl were: 0.2mg/mL microsomal protein, 1. Mu.M test substance/positive control, 1.3mM NADP,3.3mM 6-phosphoglucose, 0.6U/mL 6-phosphoglucose dehydrogenase.
(3) The mixture was incubated with gentle shaking in a 37℃water bath. 100. Mu.L aliquots of each mixture were transferred to clean 96-well plates at 5, 10, 30, 60 minutes, which contained 300. Mu.L of quencher to precipitate the protein, followed by centrifugation (5000 Xg, 10 minutes).
(4) 100. Mu.L of the supernatant was placed in a 96-well assay plate into which 300. Mu.L of ultrapure water was previously added, and then analyzed by LC-MS/MS.
Metabolic conditions of the Compounds of Table 1 in microsomes
Enzymatic kinetic parameters of the compounds of Table 2
The results show that the compound of the invention has longer half-life period in the microsome metabolism process and relatively lower clearance rate, which indicates that the compound of the invention has good microsome metabolism stability and can maintain effective blood concentration in vivo for a longer time.
Example 89
Human plasma metabolic stability test
Experimental system
(1) Stock solutions of test compounds and positive controls were prepared at a concentration of 10mM using DMSO as diluent. The stock solution of the positive control was then diluted with 50% acetonitrile to a working concentration of 0.2mM, and the stock solution of the test compound was then diluted with 50% acetonitrile to a working concentration of 1 mM.
(2) The quencher consisted of acetonitrile containing tosyl butyramide and propranolol (used as internal standard).
Experimental method
(1) Positive control and test article working solutions (in duplicate) were added to human plasma and concentrated to 1. Mu.M and 5. Mu.M, respectively.
(2) A 0 minute sample was prepared by adding 80 μl aliquots of each incubation mixture to 320 μl of quenching reagent to precipitate the protein.
(3) The mixture was incubated in a 37 ℃ water bath with gentle shaking. 80. Mu.L aliquots of each mixture were transferred to clean 96-well plates at 0, 1h, 2h, 3h, 4h, 5h, 6h, 7h and 8h, which contained 320. Mu.L quencher to precipitate the protein, followed by centrifugation (4000 Xg, 15 min).
(4) 80. Mu.L of the supernatant was placed in a 96-well assay plate with 160. Mu.L of ultrapure water added in advance, and then analyzed by LC-MS/MS.
Table 3 results of test for human plasma Metabolic stability of Compounds
The results show that the compound can keep a certain concentration in the human plasma metabolism process, which shows that the compound has good plasma metabolism stability and can maintain the effective blood concentration for a long time in vivo.
Example 90
Tablet preparation
TABLE 6 tablet formulations
Sieving the raw materials with 80 mesh sieve for use, weighing the active ingredients, microcrystalline cellulose, lactose and povidone K30 according to the proportion in table 6, adding into a high-speed mixing preparation machine, stirring at low speed, mixing well, adding a proper amount of purified water, stirring at low speed, cutting at high speed, granulating, drying at 60 ℃ for 3h, and sieving with 24 mesh sieve to obtain granules; and adding the sodium carboxymethyl starch, the silicon dioxide and the magnesium stearate in the prescribed amount, mixing, and tabletting by a rotary tablet press.
Example 91
Preparation of capsules (230 mg)
TABLE 7 Capsule ingredients
Sieving the raw materials with 80 mesh sieve for use, weighing the active ingredients, lactose, starch and povidone K30 according to the proportion in table 7, adding into a high-speed mixing preparation machine, stirring at low speed, mixing uniformly, adding a proper amount of purified water, stirring at low speed, cutting at high speed, granulating, drying at 60 ℃ for 3h, and sieving with 24 mesh sieve to obtain granules; then adding the prescribed amount of silicon dioxide and magnesium stearate, mixing, and filling the capsule by a capsule filling machine.
Example 92
Preparation of injection (5 mL)
TABLE 7 injection compositions
Weighing active ingredients, lactose and sodium chloride according to the amount, dissolving the active ingredients, lactose and sodium chloride by using water for injection, preparing 0.1mol/L solution of sodium citrate by using water for injection, dripping the solution into the solution, monitoring the pH value to 6.8-7.0, and stopping dripping to obtain a medicine aqueous solution; filtering the above aqueous solution with a filter membrane, drying, aseptically pulverizing, and packaging to obtain injection.
In conclusion, the methyl formamide derivative preparation provided by the invention has good microsome metabolic stability and good plasma metabolic stability, and can maintain the effective blood concentration in the body for a long time, so that the medicine effect is durable, and the side effect is small.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention.
Claims (9)
1. The methyl methylamine derivative preparation is characterized in that the methyl methylamine derivative preparation is one of compounds shown in formulas (I) - (V), or pharmaceutically acceptable salts thereof:
、、、、；
Wherein R in formulas (I) and (II) and R 1、R2、R3 in formulas (III) - (V) are each independently a substituent formed by one or more of hydrogen, deuterium, hydroxy, carboxy, C 1-15 alkoxy, substituted or unsubstituted C 1-16 alkyl, heteroalkyl, cycloalkyl or alicyclic ring, aromatic ring or aromatic heterocyclic ring;
R in the formulas (I) and (II) are each independently a substituent formed by one or more of hydrogen, hydroxyl, C 1-5 alkoxy, substituted or unsubstituted C 5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic ring, aromatic ring or aromatic heterocyclic ring;
R 1 and R 2 in the formulas (III) and (V) are each independently hydrogen, deuterium, hydroxy, C 1-5 alkoxy, substituted or unsubstituted C 1-5 alkyl, heteroalkyl;
R 1 and R 2 in formula (IV) and R 3 in formulas (III) - (V) are each independently a substituent formed by one or more of hydrogen, hydroxy, C 1-5 alkoxy, substituted or unsubstituted C 5-16 alkyl, heteroalkyl, cycloalkyl or alicyclic ring, aromatic ring or aromatic heterocyclic ring.
2. The formulation of methylmethylamine derivatives as claimed in claim 1, wherein R 1 and R 2 in formulae (iii) and (v) are each independently hydrogen, deuterium or methyl.
3. The preparation of methyl methylamine derivatives as claimed in claim 2, wherein at least one of R 1 and R 2 in the formulae (III) and (V) is hydrogen.
4. The preparation of methylmethylamine derivatives as claimed in claim 1, wherein the formula (i) is selected from the group consisting of compounds of the following structure:
the formula (II) is selected from compounds of the following structure:
the formula (III) or pharmaceutically acceptable salt thereof is a compound of the following structure:
the formula (IV) is selected from the group consisting of compounds of the following structures:
the formula (IV) or a pharmaceutically acceptable salt thereof is a compound of the structure:
。
5. the formulation of methyl methylamine derivatives as claimed in claim 4, wherein the compound is selected from the group consisting of:
1- ((((S) -4, 7-dihydro-5H-thiophen [2,3-c ] pyran-7-yl) methyl) (methyl) amine) methyl acetoacetate;
Isopropyl (((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) amine) (methoxymethyl) phosphono) -L-aminopropionate;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetoacetate;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl palmitate;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) ethyl acetyl-L-alanine ester;
1- (((((S) -4, 7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methyl) (methyl) carbamoyl) oxy) -2-methylpropylacetoglycinate.
6. The formulation of methyl methylamine derivatives as claimed in claim 1, wherein the pharmaceutically acceptable salt of the compound is a salt of the compound with an acid: is pamoate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.
7. A pharmaceutical composition, which is characterized by comprising an effective component and pharmaceutically acceptable auxiliary materials; the active ingredient is one or more of the compounds of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
8. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for the prevention or treatment of neurological disorders.
9. The use according to claim 8, wherein said neurological disorder is selected from the group consisting of schizophrenia, treatment of depression, memory disorders and dysfunctional disorders related to intelligence, learning.
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