WO2022227743A1 - Memantine urea derivative, preparation method therefor, and application thereof - Google Patents
Memantine urea derivative, preparation method therefor, and application thereof Download PDFInfo
- Publication number
- WO2022227743A1 WO2022227743A1 PCT/CN2022/073961 CN2022073961W WO2022227743A1 WO 2022227743 A1 WO2022227743 A1 WO 2022227743A1 CN 2022073961 W CN2022073961 W CN 2022073961W WO 2022227743 A1 WO2022227743 A1 WO 2022227743A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- reaction
- dimethyladamantan
- ureido
- group
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 63
- -1 Memantine urea derivative Chemical class 0.000 title claims abstract description 36
- 229960004640 memantine Drugs 0.000 title claims abstract description 17
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 61
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical group C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 230000001404 mediated effect Effects 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 108010017796 epoxidase Proteins 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 552
- 238000006243 chemical reaction Methods 0.000 claims description 215
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 158
- 238000005917 acylation reaction Methods 0.000 claims description 151
- 239000007787 solid Substances 0.000 claims description 96
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 88
- 238000000034 method Methods 0.000 claims description 71
- 238000006722 reduction reaction Methods 0.000 claims description 45
- 238000007098 aminolysis reaction Methods 0.000 claims description 44
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 239000004202 carbamide Substances 0.000 claims description 38
- 125000005843 halogen group Chemical group 0.000 claims description 36
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 36
- 238000010992 reflux Methods 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 claims description 29
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 28
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 claims description 27
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 238000010511 deprotection reaction Methods 0.000 claims description 24
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 24
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 24
- 229940125904 compound 1 Drugs 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 17
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 claims description 17
- 238000005660 chlorination reaction Methods 0.000 claims description 17
- 208000002193 Pain Diseases 0.000 claims description 16
- 238000005886 esterification reaction Methods 0.000 claims description 16
- 230000002378 acidificating effect Effects 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- XJLSEXAGTJCILF-RXMQYKEDSA-N (R)-nipecotic acid zwitterion Chemical compound OC(=O)[C@@H]1CCCNC1 XJLSEXAGTJCILF-RXMQYKEDSA-N 0.000 claims description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 10
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 claims description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- 125000005262 alkoxyamine group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 8
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical compound NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 claims description 7
- 125000002958 pentadecyl 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])[H] 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims description 5
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 238000006477 desulfuration reaction Methods 0.000 claims description 5
- 230000023556 desulfurization Effects 0.000 claims description 5
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 claims description 5
- 208000004296 neuralgia Diseases 0.000 claims description 5
- 208000021722 neuropathic pain Diseases 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 claims description 4
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- JKXQTODLIZBUDE-UHFFFAOYSA-N tert-butyl n-carbamothioylcarbamate Chemical compound CC(C)(C)OC(=O)NC(N)=S JKXQTODLIZBUDE-UHFFFAOYSA-N 0.000 claims description 4
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010050685 Cytokine storm Diseases 0.000 claims description 3
- 208000002249 Diabetes Complications Diseases 0.000 claims description 3
- 206010012655 Diabetic complications Diseases 0.000 claims description 3
- 206010018367 Glomerulonephritis chronic Diseases 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 206010034010 Parkinsonism Diseases 0.000 claims description 3
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 3
- 206010040047 Sepsis Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 150000003973 alkyl amines Chemical class 0.000 claims description 3
- 150000001448 anilines Chemical group 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 206010052015 cytokine release syndrome Diseases 0.000 claims description 3
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000007344 nucleophilic reaction Methods 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 3
- 150000003672 ureas Chemical class 0.000 claims description 3
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical group C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 claims 1
- KSSJBGNOJJETTC-UHFFFAOYSA-N COC1=C(C=CC=C1)N(C1=CC=2C3(C4=CC(=CC=C4C=2C=C1)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC(=CC=C1C=1C=CC(=CC=13)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC=C(C=C1)OC Chemical compound COC1=C(C=CC=C1)N(C1=CC=2C3(C4=CC(=CC=C4C=2C=C1)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC(=CC=C1C=1C=CC(=CC=13)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC=C(C=C1)OC KSSJBGNOJJETTC-UHFFFAOYSA-N 0.000 claims 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000002209 hydrophobic effect Effects 0.000 abstract description 5
- 239000012634 fragment Substances 0.000 abstract description 3
- 238000003032 molecular docking Methods 0.000 abstract description 2
- 238000005411 Van der Waals force Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 244
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 162
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 152
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 134
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 126
- 230000002829 reductive effect Effects 0.000 description 121
- 239000000243 solution Substances 0.000 description 118
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 87
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 81
- 238000003786 synthesis reaction Methods 0.000 description 77
- 230000015572 biosynthetic process Effects 0.000 description 76
- 239000000706 filtrate Substances 0.000 description 74
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 63
- 238000000967 suction filtration Methods 0.000 description 57
- 239000012065 filter cake Substances 0.000 description 56
- 238000010009 beating Methods 0.000 description 55
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 53
- 239000002994 raw material Substances 0.000 description 53
- 239000011734 sodium Substances 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000001035 drying Methods 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 23
- 108020002908 Epoxide hydrolase Proteins 0.000 description 22
- 102100025357 Lipid-phosphate phosphatase Human genes 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000000284 extract Substances 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- 239000002002 slurry Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 239000012141 concentrate Substances 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 239000003480 eluent Substances 0.000 description 15
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 14
- 239000005457 ice water Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 10
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 8
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
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- 239000012043 crude product Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000002207 metabolite Substances 0.000 description 7
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 6
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- WUOQXNWMYLFAHT-QMMMGPOBSA-N tert-butyl n-[(3s)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCCNC1 WUOQXNWMYLFAHT-QMMMGPOBSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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- C—CHEMISTRY; METALLURGY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
Definitions
- the present invention relates to the technical field of medicine, in particular to memantamide derivatives and a preparation method and application thereof.
- Pain sensation is mediated through the action of a specialized subset of sensory afferent neurons (nociceptors), which are activated in response to thermal, mechanical, and chemical stimuli through a variety of mechanisms.
- nociceptors which are activated in response to thermal, mechanical, and chemical stimuli through a variety of mechanisms.
- ion channel modulation includes transient receptor potential (TRP) channels, G protein-coupled receptor (GPCR) activation, and changes in cell membranes, all of which demonstrate the mechanism of lipid mediator signaling in nociceptors (Nature, 2001, 413(6852):203-210).
- lipid mediators in pain signaling are demonstrated on the basis of studies showing that cyclooxygenase and lipoxygenase metabolites prostaglandins and leukotrienes can contribute to pain and inflammation.
- Specific long-chain polyunsaturated fatty acids PUFAs
- CYP450 cytochrome P450 enzymes
- EpFA epoxidized fatty acids
- Investigators have found that these metabolites mediate analgesic effects in several types of pain pathologies such as acute pain, chronic pain, cancer pain, or intractable pain.
- Arachidonic acid is a 20-carbon PUFA containing four unsaturated double bonds, which can be metabolized by CYP450 enzymes to epoxide metabolites (EETs) of any one or several of the four double bonds , including 5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET.
- EpFAs, including EETs limit pain and inflammation through multiple direct and indirect mechanisms, including nuclear receptor agonism, limiting endoplasmic reticulum stress, and blocking mitochondrial dysfunction.
- small-molecule inhibitors of soluble epoxide hydrolase have shown potent analgesic effects (Neurotherapeutics, 2020, 17, 900–916).
- EETs are easily inactivated by soluble epoxide hydrolase (sEH) metabolism in vivo, and EETs metabolite dihydroxy metabolite DHETs have pro-inflammatory effects, and small molecule inhibitors of soluble epoxide hydrolase can stabilize in vivo EpFA, therefore, increases the amount of EETs in the body by inhibiting the activity of sEH, becoming a new approach for the treatment of EETs-related diseases.
- sEH soluble epoxide hydrolase
- EpFA exerts analgesic effects through various mechanisms, such as reducing endoplasmic reticulum (ER) stress, preventing or reversing endothelial cell dysfunction (ECD), and stabilizing mitochondrial function (Cell Physiol Biochem, 2015, 36, 474-486).
- EpFA can modulate cellular stress induced by reactive oxygen species and divert the ER stress response to maintain homeostasis instead of activating inflammatory pathways leading to cellular senescence and cell death.
- EpFA can reduce ER stress response and limit reactive oxygen species (ROS), indirectly maintaining mitochondrial function stability.
- ROS reactive oxygen species
- EpFA can also directly block the effects of mitochondrial dysfunction. Inhibition of sEH activity can stabilize EpFA and also limit the production of some pro-inflammatory diol metabolites.
- EpFA mediates beneficial effects in all of these processes, shifting the ER stress response to homeostasis and reducing pain.
- EpFA EpFA in nociception
- sEH inhibitors and mimetics of EpFA have great potential for pain relief in humans.
- NSAIDs are divided into non-selective NSAIDs and selective cyclooxygenase-2 (COX- 2) Inhibitors, although they also have good analgesic effects, non-selective non-steroidal anti-inflammatory drugs have more severe gastrointestinal irritation, easily lead to gastric ulcers, and often have adverse reactions to coagulation and hematopoietic systems.
- COX-2 inhibitors have no adverse effects of gastrointestinal irritation, they are likely to cause an imbalance between prostacyclin and thromboxane, leading to cardiovascular disease.
- sEH inhibitors and EpFA In view of the importance of sEH inhibitors and EpFA in the occurrence and development of inflammation and pain, and their protective effects on the heart, kidney, brain and other organs, inhibition of sEH activity can increase and stabilize the content of EpFA in the body, such as EETs, thereby Play analgesic, anti-inflammatory and protective effects on various organs. Therefore, it is urgent and necessary to develop new and efficient sEH inhibitors for the treatment of pain.
- the purpose of the present invention is to provide a memantine derivative, a preparation method and application thereof.
- the memantamide derivative provided by the present invention has high inhibitory activity on human sEH (HsEH), and has few side effects, and can be used as sEH inhibitor
- the agent is used in the preparation of a medicament for the treatment of soluble cyclooxygenase-mediated diseases.
- the present invention provides a memantine derivative, which has the structure shown in formula A, formula B, formula C or formula D:
- R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;
- R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;
- R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;
- X is selected from -NH 2 ,
- Y is selected from -H
- R 5 is selected from alkyl or heterocyclyl
- Z and M are independently selected from -O-, -NH- or -S-;
- the halogen group selected from the R 1 and R 2 is independently -F, -Cl or -Br
- the alkyl group is independently methyl, ethyl, propyl, butyl, pentyl, isobutyl , isopropyl, isoamyl or tert-butyl
- alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy , phenoxy or benzyloxy.
- the R 1 and R 2 are methyl groups.
- the halogen group selected by the R 3 is -F, -Cl or -Br;
- the alkyl group is an unsubstituted or substituted C1-C6 alkyl group;
- the alkoxy group is an unsubstituted or substituted C1-C6 alkyl group oxy;
- the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
- the R 3 is -H, -F or -Cl.
- the alkoxy group selected by R 4 is an unsubstituted or substituted C1-C6 alkoxy group;
- the alkylamine group is an unsubstituted or substituted C1-C6 alkylamine group;
- the alkoxyamine group is Unsubstituted or substituted C1-C6 alkoxyamine group;
- aniline group is unsubstituted or substituted aniline group;
- naphthylamino group is unsubstituted or substituted naphthylamino group;
- heterocyclic group is unsubstituted or substituted 5-10 A membered heterocyclic group;
- the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
- the R 4 is -OH, -NH 2 , -OCH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHOCH 3 or -NHOH.
- the alkyl group selected from the R 5 is a chain alkyl group or a cycloalkyl group
- the alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, and the substituent in the substituted C1-C6 chain alkyl group is selected from -OH, -NH 2 or C1-C6 alkyl group ;
- the cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, and the substituents in the substituted C3-C6 cycloalkyl group are selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl;
- the heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the substituents in the substituted C3-C6 saturated or unsaturated heterocyclic group are independently selected from -F , -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
- the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , cyclopropyl or -CH(NH 2 )CH(CH 3 ) 2 .
- the memantine derivatives include 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzyl Acyl)piperidine-4-carboxylic acid, 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzoyl)piperidine Ethyl pyridine-4-carboxylate, 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzoyl)piperidine -4-Carboxamide, 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ benzoyl)-N-methyl ylpiperidine-4-carboxamide,
- the present invention provides the preparation method of the memantamide derivatives described in the above technical solution,
- the compound b is subjected to a first reduction reaction to obtain compound c;
- the compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;
- R 6 in compound e is a C 1 -C 6 alkyl group
- the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl
- the fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
- the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;
- the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound;
- the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound;
- the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;
- the compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;
- Described compound V is solid phosgene or thiophosgene
- R 6 is selected from -H or an alkyl group of C 1 -C 6 ;
- the seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;
- the compound f is subjected to a second reduction reaction to obtain compound g;
- the compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;
- the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;
- the preparation method comprises the following steps:
- the compound k is subjected to a third reduction reaction to obtain compound 1;
- the compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;
- n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;
- the compound o and compound VII are mixed, and the fourteenth step is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole Acylation reaction to obtain Y as The memantamide derivatives having the structure described in formula C;
- Compound 1 was prepared according to (3-1) method
- the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;
- the molar ratio of the compound I to the compound a is (1.8-2.2):1; the temperature of the first acylation reaction is -40-10° C., and the time is 10-50 min.
- the temperature of the first reduction reaction is 25-70° C., and the time is 10-15 h.
- the molar ratio of the compound c and the compound II is 1:(1-2); the second acylation reaction is performed under ice bath conditions, and the time of the second acylation reaction is 10-50 min.
- the molar ratio of the compound d and the compound III is 1:(0.8-1.3); the first aminolysis reaction is carried out under the reflux condition of the system, and the time of the first aminolysis reaction is 6-10 h.
- the dosage ratio of the compound e, thionyl chloride and ethanol is (0.5-0.8) mmol: (2-3) mmol: (15-25) mL; the esterification reaction is carried out under the system reflux condition , the time of the esterification reaction is 1.5-2.5h.
- the molar ratio of the compound e and the compound IV is 1:(1.8-2.2), and the compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- the molar ratio of the salt and 1-hydroxybenzotriazole is 1:(1.3-1.7):(1.3-1.7); the temperature of the third acylation reaction is 25-35°C, and the time is 6-10h.
- the chlorination reaction is carried out under the reflux condition of the system, and the time of the chlorination reaction is 1.5-2.5 h.
- the molar ratio of the acid chloride intermediate and the compound IV is 1:(1.0-1.5); the temperature of the fourth acylation reaction is -10-40°C, and the time is 1-6h.
- the temperature of the hydrolysis reaction is 25-70°C, and the time is 30min-6h.
- the temperature of the fifth acylation reaction is 0 ⁇ 40° C., and the time is 1 ⁇ 8 h.
- the temperature of the sixth acylation reaction is room temperature, and the time is 1.5-2.5 h.
- the first nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
- the temperature of the second aminolysis reaction is 0-25° C. and the time is 2-24 h.
- the temperature of the dethiocarbonylation reaction is 0-25° C. and the time is 2-24 h.
- the temperature of the first deprotection group reaction is 0-40°C, and the time is 30min-4h.
- the molar ratio of the compound VI to the compound a is 1:(0.8-1.2); the temperature of the seventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
- the temperature of the second reduction reaction is 25-70° C., and the time is 10-15 h.
- the molar ratio of the compound g and the compound II is 1:(1-2); the eighth acylation reaction is carried out at room temperature, and the time of the eighth acylation reaction is 5-8h.
- the molar ratio of the compound h and the compound III is 1:(0.8-1.3); the third aminolysis reaction is carried out under the reflux condition of the system, and the time of the third aminolysis reaction is 6-10 h.
- the temperature of the second deprotection group reaction is room temperature, and the time is 1.5-2.5 h.
- the molar ratio of the compound j to the compound VII is 1:(1.5-2.5); the temperature of the ninth acylation reaction is 20-40° C., and the time is 6-10 h.
- the molar ratio of the compound j and the compound VIII is 1:(1.5-2.5); the temperature of the tenth acylation reaction is room temperature, and the time is 1.5-2.5 h.
- the temperature of the eleventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
- the second nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
- the molar ratio of the compound IX to the compound a is 1:(0.8-1.2); the temperature of the dodecanoylation reaction is room temperature, and the time is 1.5-2.5 h.
- the temperature of the third reduction reaction is 70-90° C., and the time is 40-60 min.
- the molar ratio of the compound I and the compound II is 1:(1-2); the tridecylation reaction is carried out at room temperature, and the time of the tridecaylation reaction is 5-8h .
- the molar ratio of the compound m and the compound III is 1:(0.8-1.3); the fourth aminolysis reaction is carried out under the reflux condition of the system, and the time of the fourth aminolysis reaction is 6-10 h.
- the temperature of the third deprotecting group reaction is room temperature, and the time is 3.5-4.5 h.
- the molar ratio of the compound o to the compound VII is 1:(1.5 ⁇ 2.5); the temperature of the fourteenth acylation reaction is 20 ⁇ 40°C, and the time is 6 ⁇ 10h.
- the molar ratio of the compound o to the compound VIII is 1:(1.5-2.5); the temperature of the pentadecyl acylation reaction is room temperature, and the time is 1.5-2.5 h.
- the temperature of the sixteenthylation reaction is room temperature, and the time is 1.5-2.5 h.
- the third nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
- the present invention provides the application of the memantamide derivatives described in the above technical solutions in the preparation of medicines for treating diseases mediated by soluble epoxidase.
- the soluble cyclooxygenase-mediated disease includes inflammatory disease, pain, cardiovascular disease, neurodegenerative disease, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary artery Hypertension disease.
- the inflammatory disease comprises sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis.
- the pain comprises inflammatory pain or neuropathic pain.
- the cardiovascular disease comprises hypertension, stroke or atherosclerosis.
- the neurodegenerative disease comprises Parkinson's syndrome or Alzheimer's disease.
- the invention provides a memantine derivative.
- the memantine derivative provided by the invention has a typical urea structure as the primary pharmacophore of sEH, and the memantine part acts as a hydrophobic fragment to generate hydrophobicity with the receptor.
- the interaction force, molecular docking showed that the memantine moiety acts as a hydrophobic fragment to generate a hydrophobic interaction with the receptor, especially when both R 1 and R 2 are methyl (ie, 3,5-dimethyl substituted), which can enhance the van der Waals interaction force. Therefore, the memantine derivatives provided by the present invention have high inhibitory activity on human HsEH, and can be used as sEH inhibitors to prepare medicines for treating diseases mediated by soluble epoxidase.
- Fig. 1 is the reaction scheme of the memantamide derivatives having the structure shown in formula A when R3 is a group other than a halogen group in the present invention
- Fig. 2 is the reaction scheme diagram of the memantamide derivatives having the structure shown in formula A when R3 is a halogen group in the present invention
- Fig. 3 is in the present invention, when R3 is a group other than a halogen group, the reaction scheme of the memantamide derivatives having the structure shown in formula B;
- Fig. 4 is the reaction scheme diagram of the memantamide derivatives having the structure shown in formula B when R3 is a halogen group in the present invention
- Fig. 5 is the reaction scheme of the memantamide derivatives having the structure shown in formula C when R3 is a group other than a halogen group in the present invention
- Fig. 6 is the reaction scheme of the memantamide derivatives having the structure represented by formula C when R3 is a halogen group in the present invention.
- the present invention provides a memantine derivative, which has the structure shown in formula A, formula B, formula C or formula D:
- R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;
- R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;
- R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;
- X is selected from -NH 2 ,
- Y is selected from -H
- R 5 is selected from alkyl or heterocyclyl
- Z and M are independently selected from -O-, -NH- or -S-;
- the halogen group selected from R 1 and R 2 is independently -F, -Cl or -Br, and the alkyl group is independently methyl, ethyl, propyl, butyl, Amyl, isobutyl, isopropyl, isoamyl or tert-butyl, alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy , cyclohexyloxy, phenoxy or benzyloxy.
- the R 1 and R 2 are methyl groups.
- the halogen group selected from the R 3 is -F, -Cl or -Br; the alkyl group is an unsubstituted or substituted C1-C6 alkyl group; the alkoxy group is an unsubstituted or substituted alkyl group C1-C6 alkoxy group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkane
- the substituted substituent specifically refers to the substituent in the substituted C1-C6 alkyl group and the substituted C1-C6 alkoxy group.
- the R 3 is -H, -F or -Cl.
- the alkoxy group selected by R4 is an unsubstituted or substituted C1-C6 alkoxy group;
- the alkylamine group is an unsubstituted or substituted C1-C6 alkylamine group; an alkoxy group
- the amino group is an unsubstituted or substituted C1-C6 alkoxyamine group;
- the aniline group is an unsubstituted or substituted aniline group;
- the naphthylamino group is an unsubstituted or substituted naphthylamino group;
- the heterocyclic group is an unsubstituted or substituted 5-10-membered heterocyclic group;
- the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 Alkyl, the substituted substituent specifically refers to a substituted C1-C6 al
- the alkyl group selected by the R 5 is a chain alkyl group or a cycloalkyl group; the chain alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, so The substituents in the substituted C1-C6 chain alkyl group are selected from -OH, -NH 2 or C1-C6 alkyl group; the cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, The substituents in the substituted C3-C6 cycloalkyl are selected from -F, -Cl, -Br, -OH, -NH2 , -NHCH3, -N( CH3 )2 or C1-C6 alkyl; The heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the
- the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , cyclopropyl or -CH( NH2 )CH( CH3 ) 2 .
- the memantamide derivative when X is substituted at the 3-position of the piperidine ring in the memantamide derivative of the structure shown in formula B, the memantamide derivative is a chiral compound, and the specific structure is as shown in formula E or formula F shows:
- the memantine derivatives include 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl] Ureido ⁇ benzoyl)piperidine-4-carboxylic acid (GL-B404), 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- yl]ureido ⁇ benzoyl)piperidine-4-carboxylic acid ethyl ester (GL-B405), 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantine Alk-1-yl]ureido ⁇ benzoyl)piperidine-4-carboxamide (GL-B406), 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-di Methyladamantan-1-yl]ure
- the present invention provides a method for preparing the memantine derivatives described in the above technical solution, and the present invention selects the preparation method according to the specific structure of the memantamide derivatives, which will be described in detail below.
- a memantamide derivative having the structure shown in formula A is prepared, as shown in Figure 1. Specifically, (1-1) When R 3 is a group other than a halogen group, the preparation method include the following steps:
- the compound b is subjected to a first reduction reaction to obtain compound c;
- the compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;
- R 6 in compound e is a C 1 -C 6 alkyl group
- the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl
- the fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
- the compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;
- Described compound V is solid phosgene or thiophosgene
- R 6 is selected from -H or an alkyl group of C 1 -C 6 .
- compound I and compound a are subjected to the first acylation reaction to obtain compound b.
- the molar ratio of the compound I and the compound a is preferably (1.8-2.2):1, more preferably 2:1.
- the first acylation reaction when R 6 is -H, the first acylation reaction is preferably carried out in the presence of potassium carbonate, tetrahydrofuran and water; when R 6 is a C 1 -C 6 alkyl group, the first acylation reaction is performed
- the monoacylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
- the temperature of the first acylation reaction is preferably -40-10°C, more preferably -25°C, and the time is preferably 10-50 min, more preferably 30 min.
- the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, water is added, the pH value of the system is adjusted to 7 with hydrochloric acid under ice bath conditions, ethyl acetate is added, and hydrochloric acid is used to continue adjusting The pH value of the system was adjusted to 1, then suction filtration, the filter cake was rinsed with water and ethyl acetate successively, and dried to obtain compound b.
- the present invention performs the first reduction reaction on the compound b to obtain the compound c.
- the reducing agent used in the first reduction reaction is preferably hydrogen, and the catalyst used is preferably Pd-C; the first reduction reaction is preferably carried out in the presence of anhydrous ethanol.
- the temperature of the first reduction reaction is preferably 25-70°C, more preferably 60°C, and the time is preferably 10-15h, more preferably 12h.
- the present invention preferably waits for the reaction solution to be cooled to room temperature, then suction filtration, the filtrate is concentrated under reduced pressure, the obtained residue is mixed with ethyl acetate and then slurried, the system obtained after slurping is subjected to suction filtration, and the filter cake is used Rinse with ethyl acetate and dry to give compound c.
- the present invention performs the second acylation reaction on the compound c and the compound II to obtain the compound d.
- the molar ratio of the compound c and the compound II is preferably 1:(1-2), more preferably 1:(1.2-1.7).
- the second acylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran.
- the second acylation reaction is preferably carried out under ice bath conditions, and the time of the second acylation reaction is preferably 10-50 min, more preferably 30 min.
- the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, water is added, the pH value of the system is adjusted to 7 with hydrochloric acid under ice bath conditions, ethyl acetate is added, and the system is continuously adjusted with hydrochloric acid.
- the pH value was reduced to 1, then suction filtration, the obtained filter cake was washed with ethyl acetate and water in turn, dried to obtain a white solid, the white solid was slurried with ethyl acetate, the system obtained after the slurried beating was subjected to suction filtration, filtered The cake was rinsed with ethyl acetate and dried to give compound d.
- the present invention performs the first aminolysis reaction on the compound d and the compound III to obtain the compound e.
- the molar ratio of the compound d and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1.
- the first aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
- the first aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the first aminolysis reaction is preferably 6-10 hours, more preferably 8 hours.
- the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove the solvent, adds water, adjusts the pH of the system to 1 with hydrochloric acid under ice bath conditions, extracts with ethyl acetate, and then sequentially After washing with water, saturated brine and drying over anhydrous sodium sulfate, suction filtration, the obtained filtrate was concentrated under reduced pressure, acetonitrile was added to the obtained residue and boiled, white granular solid appeared in the system, cooled to room temperature, suction filtration, and the filter cake was used Rinse with acetonitrile and dry to give compound e.
- the compound e when R 6 in compound e is -H, the compound e is a memantamide derivative having the structure represented by formula A in which R 4 is -OH.
- compound a when compound a is p-nitrobenzoyl chloride, compound I is 4-piperidinecarboxylic acid, compound II is phenyl chloroformate, and compound III is memantine, the obtained compound is obtained through the first aminolysis reaction.
- Compound e is compound GL-B404; when compound a is p-nitrobenzoyl chloride, compound I is 3-piperidinecarboxylic acid, compound II is phenyl chloroformate, and compound III is memantine, after the first aminolysis reaction The obtained compound e is compound GL-B411.
- the present invention mixes compound e, thionyl chloride and ethanol, and carries out esterification reaction to obtain R 4 is -OEt and has the structure shown in formula A memantamide derivatives.
- the dosage ratio of the compound e, thionyl chloride and ethanol is preferably (0.5-0.8) mmol: (2-3) mmol: (15-25) mL, more preferably 0.66 mmol: 2.65 mmol : 20 mL; the esterification reaction is preferably carried out under the reflux condition of the system, and the time of the esterification reaction is preferably 1.5-2.5 h, more preferably 2 h.
- the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove ethanol, adds water, extracts with ethyl acetate, and then successively washes with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine and anhydrous. Dry over sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue to make a slurry, filter the obtained system with suction, rinse the filter cake with ether, and dry to obtain R 4 is -OEt and has the formula A. Memantamide derivatives showing the structure.
- compound GL-B405 is obtained by esterification according to the above method; when compound e is compound GL-B411, it is esterified according to the above method After the reaction, compound GL-B412 was obtained.
- the present invention mixes said compound e and compound IV, in 1-(3-dimethylaminopropyl)-3-ethylcarbon two
- the third acylation reaction is carried out in the presence of imine hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
- the molar ratio of the compound e and the compound IV is preferably 1:(1.8-2.2), more preferably 1:2.
- the molar ratio of compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1:( 1.3-1.7):(1.3-1.7), more preferably 1:1.5:1.5.
- the third acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the third acylation reaction is preferably 25-35° C., more preferably 30° C.; the time is preferably 6-10 h, more preferably 8 h.
- the present invention preferably pours the obtained reaction solution into water, extracts it with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then sequentially conducts 1 mol/L Washed with hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to make a slurry, and the system obtained after beating was made Perform suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
- a dichloromethane-methanol mixed solution the volume ratio of dichloromethane and methanol is preferably 10:1
- a memantamide derivative having the structure shown in formula A when compound e is compound GL-B404, after the third acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained, specifically compound GL-B407 , GL-B408, GL-B409 or GL-B410; when compound e is compound GL-B405, after the third acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained. is compound GL-B414, GL-B415, GL-B416 or GL-B417.
- the compound e is subjected to chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and Compound IV is subjected to the fourth acylation reaction to obtain a memantamide derivative having the structure shown in formula A.
- the chlorination reaction is preferably carried out in the presence of N,N-dimethylformamide and dichloromethane.
- the chlorination reaction is preferably carried out under the reflux condition of the system, and the time of the chlorination reaction is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably cooled to room temperature, concentrated under reduced pressure to remove the solvent, and used for later use.
- the molar ratio of the acid chloride intermediate and compound IV is preferably 1:(1.0-1.5), more preferably 1:1.1.
- the fourth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fourth acylation reaction is preferably -10 to 40°C, more preferably 0°C, and the time It is preferably 1 to 6 hours, and more preferably 1 hour.
- the present invention preferably concentrates the obtained system under reduced pressure to remove the solvent, adds water, extracts with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then Washed with 1mol/L hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue to make a slurry, The system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
- a dichloromethane-methanol mixed solution the volume ratio of dichloromethane and methanol is preferably 10:1
- Washed with 1mol/L hydrochloric acid washe
- a memantamide derivative having the structure shown in formula A is obtained after the fourth acylation reaction according to the above method, which can be specifically compound GL-B406 ;
- a memantamide derivative having the structure shown in formula A can be obtained, specifically compound GL-B413 (racemate).
- compounds S-GL-B413 and R-GL-B413 are preferably prepared with reference to the method of compound GL-B413 (racemate), and only the raw materials for preparing compound GL-B413 (racemate) are changed to The raw materials corresponding to a single configuration are sufficient, and the details are shown in the examples of the present invention.
- R 6 in compound e is a C 1 -C 6 alkyl group
- the compound e is subjected to hydrolysis reaction, and then mixed with compound IV to obtain a 1-(3-dimethylamino group)
- the fifth acylation reaction is carried out in the presence of propyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
- the hydrolysis reaction is preferably carried out in the presence of sodium hydroxide solution and ethanol, the temperature of the hydrolysis reaction is preferably 25-70°C, and the time is preferably 30min-6h.
- the fifth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fifth acylation reaction is preferably 0-40° C., and the time is preferably 1-8 h.
- the obtained system is preferably added to water, extracted with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then washed with 1 mol/L hydrochloric acid successively.
- a memantamide derivative having a structure shown in formula A is prepared, as shown in Figure 2, specifically, (1-2) when R 3 is a halogen group, the preparation method includes the following steps:
- the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;
- the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound;
- the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound;
- the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;
- the present invention prepares compound c according to step (1-1). Specifically, in the present invention, it is preferred to mix compound a, N,N-dimethylformamide, tetrahydrofuran and thionyl chloride, react at 60 to 70° C. for 50 to 70 min, and then concentrate the obtained reaction solution under reduced pressure. , the residue is dissolved in tetrahydrofuran to obtain a solution of acid chloride in tetrahydrofuran; then the tetrahydrofuran solution of acid chloride, compound I, triethylamine and tetrahydrofuran are mixed to carry out the first acylation reaction to obtain compound b.
- the temperature of the first acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, added with water, extracted with ethyl acetate, and then washed with 1 mol/L HCl, washed with saturated sodium carbonate solution, and washed with water. , washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was directly subjected to the next reaction.
- the present invention performs the first reduction reaction on the compound b to obtain the compound c.
- the reducing agent used in the first reduction reaction is preferably iron powder, and the first reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water.
- the temperature of the first reduction reaction is preferably 70-90°C, more preferably 80°C, and the time is preferably 40-60 min, more preferably 50 min.
- the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
- the present invention performs the sixth acylation reaction on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and Compound III undergoes a first nucleophilic substitution reaction to obtain compound e.
- the sixth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the sixth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain an intermediate compound solution, which is for later use.
- the first nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine.
- the first nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
- the present invention mixes the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride (TFAA) to carry out the second aminolysis reaction to obtain the second intermediate intermediate compound; mix the second intermediate compound, compound III and HgCl , carry out a dethiocarbonyl reaction to obtain the third intermediate compound; carry out the first deprotection group reaction of the third intermediate compound under acidic conditions , to obtain compound e.
- the second aminolysis reaction is preferably carried out in the presence of tetrahydrofuran; the temperature of the second aminolysis reaction is preferably 0-25° C., and the time is preferably 2-24 h.
- the desulfurization carbonylation reaction is preferably carried out in the presence of mercuric chloride, triethylamine and dichloromethane; the temperature of the desulfurization carbonylation reaction is preferably 0-25°C, and the time is preferably 2-24 h.
- the obtained system is preferably filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, the organic phase is washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtration, and the obtained filtrate is filtered.
- the reagent for providing the acidic conditions required for the first deprotection reaction is preferably trifluoroacetic acid (TFA); the first deprotection reaction is preferably carried out in the presence of dichloromethane.
- the temperature of the first deprotection reaction is preferably 0 to 40° C., and the time is preferably 30 min to 4 h.
- the present invention based on the compound e, prepares a memantamide derivative having the structure represented by the formula A according to the step (1-1), as follows:
- the present invention mixes compound e, thionyl chloride and ethanol, and carries out esterification reaction to obtain R 4 is -OEt and has the structure shown in formula A memantamide derivatives.
- the dosage ratio of the compound e, thionyl chloride and ethanol is preferably (0.5-0.8) mmol: (2-3) mmol: (15-25) mL, more preferably 0.66 mmol: 2.65 mmol : 20 mL; the esterification reaction is preferably carried out under the reflux condition of the system, and the time of the esterification reaction is preferably 1.5-2.5 h, more preferably 2 h.
- the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove ethanol, adds water, extracts with ethyl acetate, and then successively washes with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine and anhydrous. Dry over sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue to make a slurry, filter the obtained system with suction, rinse the filter cake with ether, and dry to obtain R 4 is -OEt and has the formula A. Memantamide derivatives showing the structure.
- the present invention mixes said compound e and compound IV, in 1-(3-dimethylaminopropyl)-3-ethylcarbon two
- the third acylation reaction is carried out in the presence of imine hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
- the molar ratio of the compound e and the compound IV is preferably 1:(1.8-2.2), more preferably 1:2.
- the molar ratio of compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1:( 1.3-1.7):(1.3-1.7), more preferably 1:1.5:1.5.
- the third acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the third acylation reaction is preferably 25-35° C., more preferably 30° C.; the time is preferably 6-10 h, more preferably 8 h.
- the present invention preferably pours the obtained reaction solution into water, extracts it with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then sequentially conducts 1 mol/L Washed with hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to make a slurry, and the system obtained after beating was made Perform suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
- a dichloromethane-methanol mixed solution the volume ratio of dichloromethane and methanol is preferably 10:1
- the compound e is subjected to chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and Compound IV is subjected to the fourth acylation reaction to obtain a memantamide derivative having the structure shown in formula A.
- the chlorination reaction is preferably carried out in the presence of N,N-dimethylformamide and dichloromethane.
- the chlorination reaction is preferably carried out at room temperature, and the time of the chlorination reaction is preferably 20-40 min, more preferably 30 min.
- the obtained reaction solution is cooled and concentrated under reduced pressure to remove the solvent, and is for later use.
- the molar ratio of the acid chloride intermediate and compound IV is preferably 1:(1.0-1.5), more preferably 1:1.1.
- the fourth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fourth acylation reaction is preferably -10 to 40°C, more preferably 0°C, and the time It is preferably 1 to 6 hours, and more preferably 2 hours.
- R 6 in compound e is a C 1 -C 6 alkyl group
- the compound e is subjected to hydrolysis reaction, and then mixed with compound IV to obtain a 1-(3-dimethylamino group)
- the fifth acylation reaction is carried out in the presence of propyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A.
- the hydrolysis reaction is preferably carried out in the presence of sodium hydroxide solution and ethanol, the temperature of the hydrolysis reaction is preferably 25-70°C, and the time is preferably 30min-6h.
- the fifth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fifth acylation reaction is preferably 0-40° C., and the time is preferably 1-8 h.
- the obtained system is preferably added to water, extracted with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then washed with 1 mol/L hydrochloric acid successively.
- compound a when compound a is 3-chloro-4-nitrobenzoic acid, compound I is ethyl piperidine-3-carboxylate, compound V is solid phosgene, compound III is memantine, and compound IV
- the memantamide derivative having the structure shown in formula A obtained by the above reaction is specifically compound GL-B435.
- a memantamide derivative having the structure shown in formula B is prepared, as shown in Figure 3, specifically, (2-1)
- R 3 is a group other than a halogen group
- the preparation method include the following steps:
- the seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;
- the compound f is subjected to a second reduction reaction to obtain compound g;
- the compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;
- compound VI and compound a are subjected to the seventh acylation reaction to obtain compound f.
- the molar ratio of the compound VI and the compound a is preferably 1:(0.8-1.2), more preferably 1:1.
- the seventh acylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
- the temperature of the seventh acylation reaction is preferably room temperature, and the time of the seventh acylation reaction is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added to the obtained residue, extracted with ethyl acetate, and the organic layer is washed with water, saturated brine and dried over anhydrous magnesium sulfate, suction filtered, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was directly subjected to the next reaction.
- the present invention performs the second reduction reaction on the compound f to obtain the compound g.
- the reducing agent used in the second reduction reaction, the type of the second catalyst, the conditions of the second reduction reaction and the post-treatment method are preferably the same as the reducing agent used in the first reduction reaction in step (1-1).
- the type of catalyst, the first reduction reaction and the post-treatment method are the same, and will not be repeated here.
- the present invention performs the eighth acylation reaction between the compound g and the compound II to obtain the compound h.
- the molar ratio of the compound g to the compound II is preferably 1:(1-2), more preferably 1:(0.2-1.7).
- the eighth acylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran.
- the eighth acylation reaction is preferably carried out at room temperature, and the time of the eighth acylation reaction is preferably 5-8h, more preferably 6h.
- the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added, and ethyl acetate is used for extraction, and the organic layer is washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate. , suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and dried to obtain compound h.
- the present invention performs the third aminolysis reaction on the compound h and the compound III to obtain the compound i.
- the molar ratio of the compound h and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1.
- the third aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
- the third aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the third aminolysis reaction is preferably 6-10 hours, more preferably 8 hours.
- the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove the solvent, adds water, extracts with ethyl acetate, and then sequentially washes with saturated sodium carbonate, water, and saturated brine. Dry over anhydrous sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain compound i.
- the present invention performs the second deprotection group reaction on the compound i under acidic conditions to obtain a memantamide derivative having the structure represented by formula B, where X is -NH 2 , which is denoted as compound j.
- the reagent for providing acidic conditions is preferably trifluoroacetic acid, and the second deprotection reaction is preferably carried out under the condition of dichloromethane.
- the temperature of the second deprotection group reaction is preferably room temperature, and the time is preferably 1.5-2.5 h.
- the obtained reaction solution is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions. , the organic layer was separated and removed, the aqueous layer was extracted with dichloromethane (100 mL ⁇ 2), washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure.
- the present invention mixes the compound j and compound VII, in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzene
- the ninth acylation reaction is carried out in the presence of triazole (HOBt) to obtain X as The memantamide derivatives having the structure described in formula B.
- the molar ratio of the compound j and the compound VII is preferably 1:(1.5-2.5); more preferably, 1:2.
- the ninth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the ninth acylation reaction is preferably 20 ⁇ 40° C., more preferably 30° C., and the time is preferably 6 ⁇ 10 h, more preferably 8 h.
- the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the organic layer is washed with 1mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine and anhydrous.
- the present invention performs tenth acylation reaction on the compound j and compound VIII to obtain X as The memantamide derivatives having the structure described in formula B.
- the molar ratio of the compound j and the compound VIII is preferably 1:(1.5-2.5); more preferably, it is 1:2.
- the tenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the tenth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
- the present invention preferably pours the obtained reaction solution into water, and extracts it with dichloromethane. Dry over sodium sulfate, suction filtration, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and obtain X after drying.
- the memantamide derivatives having the structure described in formula B.
- a memantamide derivative having the structure shown in formula B is prepared, as shown in Figure 4, specifically, (2-2) when R 3 is a halogen group, the preparation method includes the following steps:
- the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;
- the present invention prepares compound g according to step (2-1). Specifically, the present invention performs the seventh acylation reaction of compound VI and compound a to obtain compound f.
- the ratio of the compound VI and the compound a, the conditions of the seventh acylation reaction and the post-treatment method are preferably the same as those in step (2-1), and will not be repeated here.
- the present invention performs the second reduction reaction on the compound f to obtain the compound h.
- the reducing agent used in the second reduction reaction is preferably iron powder, and the second reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water.
- the temperature of the second reduction reaction is preferably 70-90° C., more preferably 80° C., and the time is preferably 40-60 min, more preferably 50 min.
- the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
- the present invention performs eleventh acylation reaction with compound g and compound V to obtain a fourth intermediate compound; the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h .
- the eleventh acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the eleventh acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain a fourth intermediate compound solution, which is for later use.
- the second nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine.
- the second nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
- the present invention prepares the memantamide derivative having the structure represented by the formula B based on the compound h according to step (2-1), which will not be repeated here.
- a memantamide derivative having the structure shown in formula C is prepared, as shown in Figure 5, specifically, (3-1)
- R 3 is a group other than a halogen group
- the preparation method include the following steps:
- the compound k is subjected to a third reduction reaction to obtain compound 1;
- the compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;
- n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;
- compound IX and compound a are subjected to dodecanoylation reaction to obtain compound k.
- the molar ratio of the compound IX to the compound a is preferably 1:(0.8-1.2), more preferably 1:1.
- the dodecanoylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
- the temperature of the dodecanoylation reaction is preferably room temperature, and the time of the dodecanoylation reaction is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added to the obtained residue, extracted with ethyl acetate, and the organic layer is washed with water and saturated brine successively. Drying with anhydrous magnesium sulfate, suction filtration, the obtained filtrate was concentrated under reduced pressure, ether was added to the obtained residue for beating, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with ether, and dried to obtain compound k.
- the present invention performs the third reduction reaction on the compound 1 to obtain the compound 1.
- the reducing agent used in the third reduction reaction is preferably hydrogen, and the catalyst used is preferably Pd-C; the third reduction reaction is preferably carried out in the presence of anhydrous ethanol.
- the temperature of the third reduction reaction is preferably 25-70°C, more preferably 60°C, and the time is preferably 10-15h, more preferably 12h.
- the present invention performs the tridecacylation reaction of the compound 1 and the compound II to obtain the compound m.
- the molar ratio of the compound I and the compound II is preferably 1:(1-2), more preferably 1:(0.2-1.7).
- the tridecylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran.
- the tridecylation reaction is preferably carried out at room temperature, and the time for the tridecaylation reaction is preferably 5 to 8 hours, more preferably 6 hours.
- the present invention preferably concentrates the obtained reaction solution under reduced pressure to remove most of the solvent, adds water, extracts with ethyl acetate, and the organic layer is washed with water, saturated brine and anhydrous magnesium sulfate in turn. Drying, suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and compound m is obtained after drying.
- the present invention performs the fourth aminolysis reaction on the compound m and the compound III to obtain the compound n.
- the molar ratio of the compound m and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1.
- the fourth aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran.
- the fourth aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the fourth aminolysis reaction is preferably 6-10 hours, more preferably 8 hours.
- the obtained reaction solution is preferably cooled to room temperature, filtered with suction, the filter cake is rinsed with tetrahydrofuran, and dried to obtain compound n.
- the present invention performs the third deprotection group reaction on the compound n under acidic conditions to obtain a memantamide derivative with the structure represented by formula C in which Y is -H, which is denoted as compound o.
- the reagent for providing acidic conditions is preferably trifluoroacetic acid, and the third deprotecting group reaction is preferably carried out under the condition of dichloromethane.
- the temperature of the third deprotecting group reaction is preferably room temperature, and the time is preferably 3.5-4.5 h, more preferably 4 h.
- the obtained reaction solution is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions. , the organic layer was separated and removed, the aqueous layer was extracted with dichloromethane, washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure.
- the present invention mixes the compound o with the compound VII, in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzene
- EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- the fourteen acylation reaction is carried out in the presence of triazole (HOBt) to obtain Y as The memantamide derivatives having the structure described in formula C.
- the molar ratio of the compound o to the compound VII is preferably 1:(1.5-2.5); more preferably, it is 1:2.
- the fourteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the fourteenth acylation reaction is preferably 20-40° C., more preferably 30° C., and the time is preferably 6-10 h, more preferably 8 h.
- the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the organic layer is washed with 1 mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine, and washed with water.
- the present invention carries out the pentadecyl acylation reaction of the compound o and the compound VIII to obtain Y as The memantamide derivatives having the structure described in formula C.
- the molar ratio of the compound o to the compound VIII is preferably 1:(1.5-2.5); more preferably, it is 1:2.
- the fifteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the pentadecyl acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
- the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the obtained organic layer is washed with 6mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine and washed with water. Dry over anhydrous sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain Y as The memantamide derivatives having the structure described in formula C.
- the memantamide derivatives having the structure shown in formula C are prepared, as shown in Figure 6, specifically, (3-2) when R 3 is a halogen group, the preparation method comprises the following steps:
- Compound 1 was prepared according to step (3-1);
- the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;
- step (3-1) Based on the compound n, according to step (3-1), a memantamide derivative having the structure represented by formula C is prepared.
- the present invention prepares compound 1 according to step (3-1). Specifically, in the present invention, compound IX and compound a are subjected to dodecanoylation reaction to obtain compound k.
- the ratio of the compound IX to the compound a, the conditions of the dodecanoylation reaction and the post-treatment method are preferably the same as those in step (3-1), and will not be repeated here.
- the present invention performs the third reduction reaction on the compound k to obtain the compound l.
- the reducing agent used in the third reduction reaction is preferably iron powder, and the third reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water.
- the temperature of the third reduction reaction is preferably 70-90° C., more preferably 80° C., and the time is preferably 40-60 min, more preferably 50 min.
- the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
- the present invention After obtaining compound 1, the present invention performs sixteen acylation reaction with compound 1 and compound V to obtain the fifth intermediate compound; the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound 1 .
- the sixteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane.
- the temperature of the sixteen acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h.
- the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain a fifth intermediate compound solution, which is for later use.
- the third nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine.
- the third nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
- the present invention based on the compound n, prepares a memantamide derivative having the structure represented by the formula C according to the step (3-1), which will not be repeated here.
- the memantamide derivatives having the structure shown in formula D are prepared. Specifically, the present invention is based on compounds The memantamide derivative having the structure shown in formula D is prepared according to the method of the third case, and will not be repeated here.
- the present invention provides the application of the memantamide derivatives described in the above technical solutions in the preparation of medicines for treating diseases mediated by soluble epoxidase.
- the diseases mediated by soluble cyclooxygenase specifically include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease disease or pulmonary hypertension disease;
- the inflammatory disease preferably includes sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis;
- the pain preferably includes inflammatory pain or neuropathic pain;
- the vascular disease preferably includes hypertension, stroke or atherosclerosis;
- the neurodegenerative disease preferably includes Parkinson's syndrome or Alzheimer's disease.
- reaction solution was concentrated under reduced pressure to remove THF, Add water (100 mL), adjust the pH of the system to 7 with 2 mol/L hydrochloric acid under ice bath (0°C) conditions, add ethyl acetate (100 mL), continue to adjust the pH of the system to 1 with 2 mol/L hydrochloric acid, and then pump Filtration, the filter cake was rinsed with water and ethyl acetate successively, and a white solid was obtained after drying, namely 1-(4-nitrobenzoyl)piperidine-4-carboxylic acid, the yield was 25.4 g, and the yield was 84%.
- the obtained system after beating is subjected to suction filtration, the filter cake is rinsed with ethyl acetate, and a white solid is obtained after drying, which is 1-(4-aminobenzoyl)piperidine-4-carboxylic acid, and the output is 15.5 g, the yield is 87%.
- the white solid was slurried with ethyl acetate.
- the system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with ethyl acetate and dried. After that, a white solid was obtained, which was 1- ⁇ 4-[(phenoxycarbonyl)amino]benzoyl ⁇ piperidine-4-carboxylic acid, and the yield was 5.28 g and the yield was 30%.
- Embodiment 6 Carboxylic acid is the first general operation of acylating agent
- Example 6 Operate according to the method of Example 6, take methylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B407, and the output is 0.27g , the yield is 66%, mp237-240 °C.
- methylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B407, and the output is 0.27g , the yield is 66%, mp237-240 °C.
- Example 6 Operate according to the method of Example 6, take methoxymethylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methoxymethylamine hydrochloride) to obtain a white solid, which is GL- B410, yield 0.12 g, 28% yield, mp 237-239°C.
- Example 18 Operate according to the method of Example 18, using methylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B414, and the output is 0.19g , the yield is 46%, mp210-212 °C.
- methylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B414, and the output is 0.19g , the yield is 46%, mp210-212 °C.
- Example 18 Operate according to the method of Example 18, take dimethylamine hydrochloride as a raw material (that is, the hydrochloride of amine in Example 18 is specifically dimethylamine hydrochloride) to obtain a white solid, which is GL-B415, and the output is 0.19g, 45% yield, mp 137-139°C.
- Example 18 Operate according to the method of Example 18, using methoxymethylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methoxymethylamine hydrochloride) to obtain a white solid, which is GL- B417, yield 0.28 g, 65% yield, mp 130-132°C.
- the obtained reaction solution was concentrated under reduced pressure to remove most of the THF, added water (60 mL), extracted with ethyl acetate (60 mL ⁇ 3), combined the organic layers, washed with water (60 mL ⁇ 2), washed with saturated brine ( 60mL) and anhydrous magnesium sulfate, dried, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain a yellow oily substance, which was added with ether (15mL) for beating, and the obtained system was subjected to suction filtration after beating.
- a white solid was obtained, namely phenyl(4- ⁇ 4-[(tert-butoxycarbonyl)amino]piperidine-1-carbonyl ⁇ phenyl)carbamate, the yield was 5.32 g, and the yield was 86%.
- Example 28 Operate according to the method of Example 28, using methanesulfonyl chloride as a raw material (that is, the acid chloride raw material in Example 28 is specifically methanesulfonyl chloride) to obtain a white solid, namely GL-B419, the yield is 0.19g, and the yield is 40% , mp157-159°C.
- methanesulfonyl chloride that is, the acid chloride raw material in Example 28 is specifically methanesulfonyl chloride
- Example 28 Operate according to the method of Example 28, take acetyl chloride as raw material (that is, the acid chloride raw material in Example 28 is specifically acetyl chloride) to obtain a white solid, namely GL-B420, the output is 0.17g, the yield is 39%, mp244 -246°C.
- Example 28 Operate according to the method of Example 28, take propionyl chloride as raw material (that is, the acid chloride raw material in Example 28 is specifically propionyl chloride) to obtain a white solid, namely GL-B421, the yield is 0.12g, the yield is 27%, mp230 -232°C.
- Example 29 Operate according to the method of Example 29, take n-butyric acid as a raw material (that is, the carboxylic acid raw material in Example 29 is specifically n-butyric acid) to obtain a white solid, namely GL-B422, the output is 0.12g, and the yield is 26 %, mp236-237°C.
- Example 29 Operate according to the method of Example 29, using 2-methylbutyric acid as a raw material (that is, the carboxylic acid raw material in Example 29 is specifically 2-methylbutyric acid) to obtain a white solid, namely GL-B423, and the output is 0.35 g, 73% yield, mp 250-252°C.
- 2-methylbutyric acid that is, the carboxylic acid raw material in Example 29 is specifically 2-methylbutyric acid
- Boc-valine was used as a raw material (that is, the carboxylic acid raw material in Example 29 was specifically Boc-valine), and 1 mol/L hydrochloric acid was not used for washing in the post-treatment process to obtain half 1 g of the solid crude product was used for the next reaction without purification.
- N-Boc-piperazine (10.1g, 54.1mmol), triethylamine (16.4g, 0.16mol) and THF (80mL) were added to the there-necked flask, the ice-salt bath was cooled to below 0°C, and p-nitro was added dropwise.
- the THF solution 50 mL of benzoyl chloride (10.0 g, 54.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 h. TLC monitored the completion of the reaction; the obtained reaction solution was concentrated under reduced pressure to remove most of the THF, and water was added.
- the resulting reaction solution was concentrated under reduced pressure to remove most of the THF, water (100 mL) was added, extracted with ethyl acetate (100 mL ⁇ 3), the organic layers were combined, and washed with water (100 mL ⁇ 2) and saturated brine (100 mL) successively. ) and anhydrous sodium sulfate, suction filtration, and the obtained filtrate was concentrated under reduced pressure to obtain 27.6 g of a yellow oil, which was added with ether (60 mL) to make a slurry, and the obtained system was subjected to suction filtration after beating, and the filter cake was rinsed with ether and dried.
- the obtained reaction solution was distilled under reduced pressure to remove most of the trifluoroacetic acid, water (80 mL) and DCM (100 mL) were added, and the pH value of the system was adjusted to 14 with sodium hydroxide solid under ice-water bath conditions, and the organic layer was separated and removed, The aqueous layer was extracted with DCM (100 mL ⁇ 2), then washed with water (100 mL), saturated brine (100 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 18.88 g of pale yellow semi-solid , add ether (30mL) to make pulp, filter the obtained system after beating, rinse the filter cake with ether, and dry to obtain a white solid, namely GL-B426, the output is 9.60g, the yield is 80%, mp190-193 °C.
- Example 43 Operate according to the method of Example 43, using methanesulfonyl chloride as the raw material (that is, the acid chloride raw material in Example 43 is specifically methanesulfonyl chloride), and purified by beating with ether to obtain a white solid, namely GL-B427, the yield is 0.42g, and the yield is 0.42 g. The rate is 88%, mp226-229°C.
- Example 43 Operate according to the method of Example 43, take acetyl chloride as the raw material (that is, the acid chloride raw material in Example 43 is specifically acetyl chloride), purified by ether beating and then purified by silica gel column chromatography to obtain a white solid, namely GL-B428, Yield 0.23 g, 52% yield, mp 127-129°C.
- Example 43 Operate according to the method of Example 43, use propionyl chloride as raw material (that is, the acid chloride raw material in Example 43 is specifically propionyl chloride), and purified by ether beating to obtain a white solid, namely GL-B429, the yield is 0.37g, and the yield is 82%, mp234-235°C.
- n-butyric acid as the raw material (that is, the carboxylic acid raw material in Example 44 is specifically n-butyric acid), purified by beating with ether, and then purified by silica gel column chromatography to obtain a white solid, which is GL -B430, yield 0.33g, 70% yield, mp 222-224°C.
- 2-methylbutyric acid was used as the raw material (that is, the carboxylic acid raw material in Example 44 was specifically 2-methylbutyric acid), purified by beating with ether, and then purified by silica gel column chromatography to obtain The white solid, GL-B431, yielded 0.33 g, 69% yield, mp 119-122°C.
- Example 44 Operate according to the method of Example 44, using cyclopropanecarboxylic acid as a raw material (that is, the carboxylic acid raw material in Example 44 is specifically cyclopropanecarboxylic acid), purified by ether beating and then purified by silica gel column chromatography to obtain a white solid, namely GL- B432, yield 0.33 g, 70% yield, mp 231-234°C.
- cyclopropanecarboxylic acid that is, the carboxylic acid raw material in Example 44 is specifically cyclopropanecarboxylic acid
- Example 44 using Boc-valine as a raw material (that is, the carboxylic acid raw material in Example 43 is specifically Boc-valine), 1.04 g of a semi-solid crude product was obtained, which was directly used in the next step without purification. one-step reaction.
- Example 54 The procedure of Example 54 was followed except that ethyl 1-(3-chloro-4-nitrobenzoyl)piperidine-3-carboxylate was replaced by 1-(3-fluoro-4-nitro Benzoyl)piperidine-3-carboxylic acid ethyl ester to finally obtain 1.3 g of pale yellow oil.
- Example 55 The procedure of Example 55 was followed, except that ethyl 1-(4-amino-3-chlorobenzoyl)piperidine-3-carboxylate was replaced with 1-(4-amino-3-fluorobenzyl) acyl)piperidine-3-carboxylic acid ethyl ester, and finally obtain a light yellow solid 0.8g.
- Example 56 The procedure of Example 56 was followed, except that 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ -3-Chlorobenzoyl)piperidine-3-carboxylic acid ethyl ester was replaced with 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ]ureido ⁇ -3-fluorobenzoyl)piperidine-3-carboxylic acid ethyl ester to finally obtain 0.5 g of a white solid.
- Example 57 The procedure of Example 57 was followed except that 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido ⁇ -3-Chlorobenzoyl)piperidine-3-carboxylic acid was replaced with 1-(4- ⁇ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea yl ⁇ -3-fluorobenzoyl)piperidine-3-carboxylic acid, the white solid finally obtained was GL-B434, the yield was 60 mg, and the yield was 11%.
- Example 60 According to the operation method of Example 60, using (S)-ethyl 1-(4-amino-3-fluorobenzoyl) piperidine-3-carboxylate and memantine as raw materials, the finally obtained white solid is (S) -1-(4- ⁇ 3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido ⁇ -3-fluorobenzoyl)piperidine-3- Ethyl formate, yield 0.64 g, 70% yield.
- Example 58 According to the operation method of Example 58, using 3-fluoro-4-nitrobenzoic acid and (S)-3-Boc-aminopiperidine as raw materials, 1.98 g of brownish yellow oil was finally obtained. Used directly in the next step without purification.
- tert-butyl (S)-[1-(3-fluoro-4-nitrobenzoyl)piperidin-3-yl]carbamate was used as raw material to prepare 1.78g
- Example 60 According to the operation method of Example 60, using tert-butyl (S)-[1-(3-fluoro-4-aminobenzoyl)piperidin-3-yl]carbamate as raw material, a white solid 0.90 was finally obtained. g, 90% yield.
- the difference is that 3-fluoro-4-nitrobenzenesulfonyl chloride is used as the raw material; the light yellow solid finally obtained is compound GL-B440, the yield is 90 mg, and the yield is 30%. mp147-149°C.
- Detection principle The specific substrate (3-phenyl-oxy)-acetic acid cyano-(6-methoxy-naphthalen-2-yl) methyl ester, that is, PHOME itself has no fluorescence, but is hydrolyzed under the action of sEH enzyme
- the generated product 6-methoxy-2-naphthaldehyde, 6-methoxy-2-naphthaldehyde can emit fluorescence with a wavelength of 465nm under the excitation of 330nm light wave, and the detected fluorescence signal intensity is related to the inhibition of sEH enzyme Strength is inversely proportional.
- the inhibition rates of samples with different concentrations were calculated. SPSS 20 software was used to calculate the IC 50 values of the compounds according to the inhibition rate and concentration.
- PHOME solution Dissolve 0.79 mg of PHOME in 106 ⁇ L of DMSO to obtain a PHOME solution with a concentration of 20 mM, and use Tris-HCl buffer to dilute to 1/3 mM.
- sEH solution sEH (5mg/mL) stock solution was stored at -80°C in a refrigerator, and diluted to 4 ⁇ g/mL with 25mM Tris-HCl buffer when used.
- the sample powder to be tested was dissolved in DMSO into a 20 mM solution, stored in a -20°C refrigerator for later use, and diluted to the corresponding concentration with Tris-HCl buffer during use.
- the fluorescence signal data was detected by a microplate reader, the excitation wavelength was 330 nm, and the emission wavelength was 465 nm.
- Table 1 shows the inhibitory activities of compounds GL-B404 to GL-B441 on human sEH (HsEH).
- the compounds GL-B404 to GL-B441 provided by the present invention have a good inhibitory effect on HsEH IC 50 values between 0.1 nM and 1 ⁇ M.
- the experimental results showed that 15 compounds had better inhibitory activity on sEH than the lead compound GL-B401, namely compounds GL-B412, GL-B413, GL-B415, GL-B416, GL-B417, GL-B434, GL-B435 , GL-B436, GL-B437, GL-B438, GL-B439, GL-B440, GL-B441, R-GL-B413, S-GL-B413, among which compounds GL-B437 and GL-B440 have strong inhibitory activity , with IC50s of 0.06nM and 0.08nM , respectively, showing a very promising development prospect.
Abstract
The present invention relates to the technical field of medicines, and provides a memantine urea derivative, a preparation method therefore, and an application thereof. The memantine urea derivative provided by the present invention has a typical urea structure as a primary pharmacophore of sEH, and molecular docking shows that a memantine moiety acts as a hydrophobic fragment to generate a hydrophobic force with a receptor, especially when both R1 and R2 are methyl (i.e., 3,5-dimethyl substituted), the van der Waals force can be enhanced. Therefore, the memantine urea derivative provided by the present invention has high inhibiting activity on human sEH (HsEH), and can be used as an sEH inhibitor to prepare a drug for treating soluble epoxidase-mediated diseases.
Description
本申请要求于2021年04月28日提交中国专利局、申请号为CN202110469170.4、发明名称为“一种美金刚脲类衍生物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese patent application filed on April 28, 2021 with the application number CN202110469170.4 and the invention titled "A Memantamide Derivative and its Preparation Method and Application". The entire contents of this application are incorporated by reference.
本发明涉及医药技术领域，具体涉及美金刚脲类衍生物及其制备方法和应用。The present invention relates to the technical field of medicine, in particular to memantamide derivatives and a preparation method and application thereof.
疼痛感是通过感觉传入神经元的专门子集(伤害感受器)的作用介导的，伤害感受器通过多种机制对热、机械和化学刺激响应而被激活。研究表明离子通道调节包括瞬态受体电位(Transient receptor potential,TRP)通道、G蛋白偶联受体(GPCR)活化和细胞膜的改变，这些都显示了脂质介质在伤害感受器中信号传导的机制(Nature，2001，413(6852)：203-210)。Pain sensation is mediated through the action of a specialized subset of sensory afferent neurons (nociceptors), which are activated in response to thermal, mechanical, and chemical stimuli through a variety of mechanisms. Studies have shown that ion channel modulation includes transient receptor potential (TRP) channels, G protein-coupled receptor (GPCR) activation, and changes in cell membranes, all of which demonstrate the mechanism of lipid mediator signaling in nociceptors (Nature, 2001, 413(6852):203-210).
研究显示环氧合酶和脂氧合酶代谢产物前列腺素和白三烯可以导致疼痛和炎症，在此基础上证明了脂质介质在疼痛信号传导中的作用。特定长链多不饱和脂肪酸(PUFA)经细胞色素P450酶(CYP450)代谢形成环氧化物代谢产物，即环氧脂肪酸(EpFA)。研究者们已经发现这些代谢物在几种类型的疼痛病理学(如急性疼痛、慢性疼痛、癌性疼痛或顽固性疼痛)中介导镇痛作用。The role of lipid mediators in pain signaling is demonstrated on the basis of studies showing that cyclooxygenase and lipoxygenase metabolites prostaglandins and leukotrienes can contribute to pain and inflammation. Specific long-chain polyunsaturated fatty acids (PUFAs) are metabolized by cytochrome P450 enzymes (CYP450) to form epoxide metabolites, epoxidized fatty acids (EpFA). Investigators have found that these metabolites mediate analgesic effects in several types of pain pathologies such as acute pain, chronic pain, cancer pain, or intractable pain.
花生四烯酸(ARA)是一种含20碳原子的PUFA，含有四个不饱和双键，可被CYP450酶代谢为四个双键中的任何一个或几个的环氧代谢物(EETs)，包括5,6-EET、8,9-EET、11,12-EET以及14,15-EET。包括EETs在内的EpFA通过多种直接和间接机制来限制疼痛和炎症，包括核受体激动、限制内质网应激和阻断线粒体功能障碍。在动物炎性疼痛和糖尿病神经性疼痛模型中，可溶性环氧化物水解酶的小分子抑制剂显示出强的镇痛作用(Neurotherapeutics,2020,17,900–916)。EETs在体内极易被可溶性环氧化物水解酶(sEH)代谢而导致失活，且EETs代谢物二羟基代谢物DHETs具有致炎作用，可溶性环氧化物水解酶的小分子抑制剂可以在体内稳定EpFA，因此，通过抑制sEH活性，增加体内EETs的量，成为治疗EETs相关疾病的新方法。Arachidonic acid (ARA) is a 20-carbon PUFA containing four unsaturated double bonds, which can be metabolized by CYP450 enzymes to epoxide metabolites (EETs) of any one or several of the four double bonds , including 5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET. EpFAs, including EETs, limit pain and inflammation through multiple direct and indirect mechanisms, including nuclear receptor agonism, limiting endoplasmic reticulum stress, and blocking mitochondrial dysfunction. In animal models of inflammatory pain and diabetic neuropathic pain, small-molecule inhibitors of soluble epoxide hydrolase have shown potent analgesic effects (Neurotherapeutics, 2020, 17, 900–916). EETs are easily inactivated by soluble epoxide hydrolase (sEH) metabolism in vivo, and EETs metabolite dihydroxy metabolite DHETs have pro-inflammatory effects, and small molecule inhibitors of soluble epoxide hydrolase can stabilize in vivo EpFA, therefore, increases the amount of EETs in the body by inhibiting the activity of sEH, becoming a new approach for the treatment of EETs-related diseases.
EpFA通过多种机制发挥镇痛作用，如减轻内质网(ER)应激、预防或逆转内皮细胞功能障碍(ECD)以及稳定线粒体功能(Cell Physiol Biochem,2015,36,474-486)。EpFA可以调节由活性氧引起的细胞应激，并将ER应激反应转移到维持体内稳态，而不是激活炎症途径，导致细胞衰老和细胞死亡。EpFA可以减少ER应激反应并限制活性氧(ROS)，间接维持线粒体功能稳定。EpFA还可以直接阻断线粒体功能障碍的作用。抑制sEH活性可以稳定EpFA，也可以限制一些促炎作用的二醇代谢物产生。因此，EpFA在所有这些过程中均介导有益作用，将ER应激反应转变为体内平衡并减轻疼痛。EpFA exerts analgesic effects through various mechanisms, such as reducing endoplasmic reticulum (ER) stress, preventing or reversing endothelial cell dysfunction (ECD), and stabilizing mitochondrial function (Cell Physiol Biochem, 2015, 36, 474-486). EpFA can modulate cellular stress induced by reactive oxygen species and divert the ER stress response to maintain homeostasis instead of activating inflammatory pathways leading to cellular senescence and cell death. EpFA can reduce ER stress response and limit reactive oxygen species (ROS), indirectly maintaining mitochondrial function stability. EpFA can also directly block the effects of mitochondrial dysfunction. Inhibition of sEH activity can stabilize EpFA and also limit the production of some pro-inflammatory diol metabolites. Thus, EpFA mediates beneficial effects in all of these processes, shifting the ER stress response to homeostasis and reducing pain.
有大量证据表明EpFA在伤害感受中的作用包括阻断炎症性疼痛和神经性疼痛，因此sEH抑制剂和EpFA的模拟物在缓解人类疼痛方面具有巨大潜力。There is substantial evidence for the role of EpFA in nociception including blocking inflammatory pain and neuropathic pain, so sEH inhibitors and mimetics of EpFA have great potential for pain relief in humans.
目前临床使用的镇痛药主要包括阿片类镇痛药、非甾体抗炎药等，这二者均有一定的副作用，如传统的阿片类镇痛药作用比较强，但同时也有很强的成瘾性和呼吸抑制、血压降低、恶心、呕吐、便秘和排尿困难等副作用；非甾体抗炎药分为非选择性非甾体抗炎药和选择性环氧合酶-2(COX-2)抑制剂，虽也具有较好的镇痛作用，但非选择性非甾体抗炎药存在较严重的胃肠道刺激，容易导致胃溃疡，对凝血和造血系统往往存在不良反应，选择性COX-2抑制剂虽然没有胃肠道刺激性的不良反应，但容易引起前列环素和血栓烷的失衡，从而导致心血管疾病。Currently clinical analgesics mainly include opioid analgesics, non-steroidal anti-inflammatory drugs, etc., both of which have certain side effects, such as traditional opioid analgesics are relatively strong, but also have strong effects Addiction and respiratory depression, decreased blood pressure, nausea, vomiting, constipation and dysuria; NSAIDs are divided into non-selective NSAIDs and selective cyclooxygenase-2 (COX- 2) Inhibitors, although they also have good analgesic effects, non-selective non-steroidal anti-inflammatory drugs have more severe gastrointestinal irritation, easily lead to gastric ulcers, and often have adverse reactions to coagulation and hematopoietic systems. Although sexual COX-2 inhibitors have no adverse effects of gastrointestinal irritation, they are likely to cause an imbalance between prostacyclin and thromboxane, leading to cardiovascular disease.
鉴于sEH抑制剂和EpFA在炎症和疼痛发生、发展过程中的重要性以及对心、肾、大脑等多种器官的保护作用，其中抑制sEH活性可以提高和稳定体内EpFA的含量，如EETs，从而发挥镇痛、抗炎以及对多种器官的保护作用。因此，研发新型高效的sEH抑制剂对疼痛的治疗十分迫切和必要。In view of the importance of sEH inhibitors and EpFA in the occurrence and development of inflammation and pain, and their protective effects on the heart, kidney, brain and other organs, inhibition of sEH activity can increase and stabilize the content of EpFA in the body, such as EETs, thereby Play analgesic, anti-inflammatory and protective effects on various organs. Therefore, it is urgent and necessary to develop new and efficient sEH inhibitors for the treatment of pain.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种美金刚脲类衍生物及其制备方法和应用，本发明提供的美金刚脲类衍生物对人源sEH(HsEH)的抑制活性高，副作用小，能够作为sEH抑制剂用于制备治疗可溶性环氧化物酶介导的疾病的药物。The purpose of the present invention is to provide a memantine derivative, a preparation method and application thereof. The memantamide derivative provided by the present invention has high inhibitory activity on human sEH (HsEH), and has few side effects, and can be used as sEH inhibitor The agent is used in the preparation of a medicament for the treatment of soluble cyclooxygenase-mediated diseases.
为了实现上述发明目的，本发明提供以下技术方案：In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:
本发明提供了一种美金刚脲类衍生物，具有式A、式B、式C或式D所示结构：The present invention provides a memantine derivative, which has the structure shown in formula A, formula B, formula C or formula D:
其中，R
1和R
2独立地选自-H、-OH、-NH
2、-SH、-CN、卤素基团、烷基、烷氧基或杂环基；
wherein, R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;
R
3选自-H、-OH、-NH
2、-SH、-CN、卤素基团、烷基或烷氧基；
R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;
R
4选自-OH、-NH
2、羟胺基、烷基、烷氧基、烷基胺基、烷氧基胺基、醇胺基、苯胺基、萘胺基或杂环基；
R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;
X选自-NH
2、
X is selected from -NH 2 ,
Y选自-H、
Y is selected from -H,
R
5选自烷基或杂环基；
R 5 is selected from alkyl or heterocyclyl;
Z和M独立地选自-O-、-NH-或-S-；Z and M are independently selected from -O-, -NH- or -S-;
Q选自
Q is selected from
优选地，所述R
1和R
2选自的卤素基团独立地为-F、-Cl或-Br，烷基独立地为甲基、乙基、丙基、丁基、戊基、 异丁基、异丙基、异戊基或叔丁基，烷氧基独立地为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环戊氧基、环己氧基、苯氧基或苄氧基。
Preferably, the halogen group selected from the R 1 and R 2 is independently -F, -Cl or -Br, and the alkyl group is independently methyl, ethyl, propyl, butyl, pentyl, isobutyl , isopropyl, isoamyl or tert-butyl, alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy , phenoxy or benzyloxy.
优选地，所述R
1和R
2为甲基。
Preferably, the R 1 and R 2 are methyl groups.
优选地，所述R
3选自的卤素基团为-F、-Cl或-Br；烷基为未取代或取代的C1～C6烷基；烷氧基为未取代或取代的C1～C6烷氧基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基。
Preferably, the halogen group selected by the R 3 is -F, -Cl or -Br; the alkyl group is an unsubstituted or substituted C1-C6 alkyl group; the alkoxy group is an unsubstituted or substituted C1-C6 alkyl group oxy; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
优选地，所述R
3为-H、-F或-Cl。
Preferably, the R 3 is -H, -F or -Cl.
优选地，所述R
4选自的烷氧基为未取代或取代的C1～C6烷氧基；烷基胺基为未取代或取代的C1～C6烷基胺基；烷氧基胺基为未取代或取代的C1～C6烷氧基胺基；苯胺基为未取代或取代的苯胺基；萘胺基为未取代或取代的萘胺基；杂环基为未取代或取代的5～10元杂环基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基。
Preferably, the alkoxy group selected by R 4 is an unsubstituted or substituted C1-C6 alkoxy group; the alkylamine group is an unsubstituted or substituted C1-C6 alkylamine group; the alkoxyamine group is Unsubstituted or substituted C1-C6 alkoxyamine group; aniline group is unsubstituted or substituted aniline group; naphthylamino group is unsubstituted or substituted naphthylamino group; heterocyclic group is unsubstituted or substituted 5-10 A membered heterocyclic group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
优选地，所述R
4为-OH、-NH
2、-OCH
2CH
3、-NHCH
3、-N(CH
3)
2、
-NHOCH
3或-NHOH。
Preferably, the R 4 is -OH, -NH 2 , -OCH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHOCH 3 or -NHOH.
优选地，所述R
5选自的烷基为链烷基或环烷基；
Preferably, the alkyl group selected from the R 5 is a chain alkyl group or a cycloalkyl group;
所述R
5选自的链烷基为未取代或取代的C1～C6链烷基，所述取代的C1～C6链烷基中取代基选自-OH、-NH
2或C1～C6烷基；
The alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, and the substituent in the substituted C1-C6 chain alkyl group is selected from -OH, -NH 2 or C1-C6 alkyl group ;
所述R
5选自的环烷基为未取代或取代的C3～C6环烷基，所述取代的C3～C6环烷基中取代基选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基；
The cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, and the substituents in the substituted C3-C6 cycloalkyl group are selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl;
所述R
5选自的杂环基为未取代或取代的C3～C6饱和或不饱和杂环基，所述取代的C3～C6饱和或不饱和杂环基中取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基。
The heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the substituents in the substituted C3-C6 saturated or unsaturated heterocyclic group are independently selected from -F , -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
优选地，所述R
5为-CH
3、-CH
2CH
3、-CH
2CH
2CH
3、-CH(CH
3)CH
2CH
3、环丙基或-CH(NH
2)CH(CH
3)
2。
Preferably, the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , cyclopropyl or -CH(NH 2 )CH(CH 3 ) 2 .
优选地，所述美金刚脲类衍生物包括1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸乙酯、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-4-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N,N-二甲基哌啶-4-甲酰胺、N-环丙基-1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-4-甲酰胺、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸乙酯、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N,N-二甲基哌啶-3-甲酰胺、N-环丙基-1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-3-甲酰胺、1-[4-(4-氨基哌啶-1-羰基)苯基]-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]甲磺酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]乙酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丙酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丁酰胺、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-2-甲基丁酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]环丙烷甲酰胺、2-氨基-N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-3-甲基丁酰胺、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-[4-(哌嗪-1-羰基)苯基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-{4-[4-(甲基磺酰基)哌嗪-1-羰基]苯基}脲、1-[4-(4-乙酰基哌嗪-1-羰基)苯基]-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-[4-(4-丙酰基哌嗪-1-羰基)苯基]脲、1-[4-(4-丁酰基哌嗪-1-羰基)苯基]-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-{4-[4-(2-甲基丁酰基)哌嗪-1-羰基]苯基}脲、1-{4-[4-(环丙烷羰基)哌嗪-1-羰基]苯基}-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-[4-(4-戊基哌嗪-1-羰基)苯基]脲、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-羟基哌啶-3-甲酰胺、(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺、N-[(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-基]甲磺酰胺、(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、(R)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯基)磺酰基]哌啶-3-甲酰胺、(S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]哌啶-3-甲酰胺或(S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]-N-羟基哌啶-3-甲酰胺。Preferably, the memantine derivatives include 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzyl Acyl)piperidine-4-carboxylic acid, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine Ethyl pyridine-4-carboxylate, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine -4-Carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methyl ylpiperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)- N,N-Dimethylpiperidine-4-carboxamide, N-cyclopropyl-1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane- 1-yl]ureido}benzoyl)piperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- yl]ureido}benzoyl)-N-methoxypiperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantide Alk-1-yl]ureido}benzoyl)piperidine-3-carboxylic acid, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1 -yl]ureido}benzoyl)piperidine-3-carboxylic acid ethyl ester, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- yl]ureido}benzoyl)piperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl] Ureido}benzoyl)-N-methylpiperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1 -yl]ureido}benzoyl)-N,N-dimethylpiperidine-3-carboxamide, N-cyclopropyl-1-(4-{3-[(1r,3R,5S,7r) -3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3 ,5-Dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxypiperidine-3-carboxamide, 1-[4-(4-aminopiperidine-1-carbonyl) Phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea, N-[1-(4-{3-[(1r,3R, 5S,7r)-3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]methanesulfonamide, N-[1-(4-{3-[( 1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl yl)piperidin-4-yl]acetamide, N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido }benzoyl)piperidin-4-yl]propionamide, N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ]ureido}benzoyl)piperidin-4-yl]butanamide, N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane- 1-yl]ureido}benzoyl)piperidin-4-yl]-2-methylbutanamide, N-[1-(4-{3-[(1r,3R,5S,7r)-3, 5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]cyclopropanecarboxamide, 2-amino-N-[1-(4-{3-[(1r, 3R,5S,7r)-3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]-3-methylbutanamide, 1-[(1r,3R ,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(piperazine-1-carbonyl)phenyl]urea, 1-[(1r,3R,5S,7r )-3,5-dimethyladamantan-1-yl]-3-{4-[4-(methylsulfonyl)piperazine-1-carbonyl]phenyl}urea, 1-[4-(4 -Acetylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea, 1-[(1r,3R ,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4-propionylpiperazine-1-carbonyl)phenyl]urea, 1-[4-(4 -Butyrylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea, 1-[(1r,3R ,5S,7r)-3,5-dimethyladamantan-1-yl]-3-{4-[4-(2-methylbutyryl)piperazine-1-carbonyl]phenyl}urea, 1 -{4-[4-(Cyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl] Urea, 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4-pentylpiperazine-1-carbonyl)phenyl] Urea, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine-3 - Formamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine -3-Carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-hydroxyl Piperidine-3-carboxamide, (S)-1-(4-{3-[(1r,3R,5S,7S)- 3,5-Dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine-3-carboxamide, N-[(S)-1-(4-{3-[( 1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidin-3-yl]methanesulfonamide, (S)-1 -(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide, (R) -1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide, 1 -[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}phenyl)sulfonyl]piperidine-3-carboxamide, (S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorophenyl)sulfonyl ]piperidine-3-carboxamide or (S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido} -3-Fluorophenyl)sulfonyl]-N-hydroxypiperidine-3-carboxamide.
本发明提供了上述技术方案所述美金刚脲类衍生物的制备方法，The present invention provides the preparation method of the memantamide derivatives described in the above technical solution,
(1)制备具有式A所示结构的美金刚脲类衍生物，(1) preparing a memantamide derivative having the structure shown in formula A,
(1-1)当R
3为除卤素基团以外的基团时，制备方法包括以下步骤：
(1-1) When R 3 is a group other than a halogen group, the preparation method includes the following steps:
将化合物I和化合物a进行第一酰化反应，得到化合物b；Compound I and compound a are subjected to the first acylation reaction to obtain compound b;
将所述化合物b进行第一还原反应，得到化合物c；The compound b is subjected to a first reduction reaction to obtain compound c;
将所述化合物c和化合物II进行第二酰化反应，得到化合物d；The compound c and compound II are subjected to a second acylation reaction to obtain compound d;
将所述化合物d和化合物III进行第一胺解反应，得到化合物e；当化合物e中R
6为-H时，所述化合物e为R
4为-OH的具有式A所示结构的美金刚脲类衍生物；
The compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;
当化合物e中R
6为-H时，将所述化合物e、氯化亚砜和乙醇混合，进行酯化反应，得到R
4为-OEt的具有式A所示结构的美金刚脲类衍生物；
When R 6 in compound e is -H, the compound e, thionyl chloride and ethanol are mixed to carry out an esterification reaction to obtain a memantamide derivative having the structure shown in formula A, where R 4 is -OEt ;
或者，当化合物e中R
6为-H时，将所述化合物e和化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第三酰化反应，得到具有式A所示结构的美金刚脲类衍生物；
Alternatively, when R 6 in compound e is -H, the compound e and compound IV are mixed in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 - carry out the third acylation reaction in the presence of hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
或者，当化合物e中R
6为-H时，将所述化合物e在氯化亚砜存在条件下进行氯代反应，得到酰氯中间体；将所述酰氯中间体和化合物IV进行第四酰化反应，得到具有式A所示结构的美金刚脲类衍生物；
Alternatively, when R 6 in compound e is -H, the compound e is subjected to a chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and compound IV are subjected to fourth acylation reaction to obtain the memantamide derivatives having the structure shown in formula A;
当化合物e中R
6为C
1～C
6的烷基时，将所述化合物e经水解反应后，再与化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第五酰化反应，得到具有式A所示结构的美金刚脲类衍生物；
When R 6 in compound e is a C 1 -C 6 alkyl group, the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl The fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
(1-2)当R
3为卤素基团时，制备方法包括以下步骤：
(1-2) When R 3 is a halogen group, the preparation method comprises the following steps:
按照(1-1)方法制备化合物c；Compound c was prepared according to the method (1-1);
当Z为-O-或-S-时，将所述化合物c和化合物V进行第六酰化反应，得到第一中间体化合物；将所述第一中间体化合物和化合物III进行第一亲核取代反应，得到化合物e；When Z is -O- or -S-, the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;
当Z为-NH-时，将所述化合物c、N-Boc-硫脲、NaH和三氟乙酸酐混合，进行第二胺解反应，得到第二中间体化合物；将所述第二中间体化合物、化合物III和HgCl
2混合，进行脱硫羰基反应，得到第三中间体化合物；将所述第三中间体化合物在酸性条件下进行第一脱保护基反应，得到化合物e；
When Z is -NH-, the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound; the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound; the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;
基于所述化合物e，按照(1-1)方法制备得到具有式A所示结构的美金刚脲类衍生物；Based on the compound e, according to the method (1-1), a memantamide derivative having the structure represented by formula A is prepared;
所述化合物I、化合物II和化合物III的结构式依次为
The structural formulas of the compound I, compound II and compound III are sequentially
所述化合物IV为：NH
3、R
7-NH
2、R
7-OH、R
7-O-NH
2或
其中，R
7为取代或未取代的C1～C6的烷基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6的烷基；
The compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;
所述化合物V为固体光气或硫光气；Described compound V is solid phosgene or thiophosgene;
所述化合物a、化合物b、化合物c、化合物d以及化合物e的结构式如下：The structural formulas of the compound a, compound b, compound c, compound d and compound e are as follows:
其中，化合物I、化合物b、化合物c、化合物d和化合物e的结构式中R
6选自-H或C
1～C
6的烷基；
Wherein, in the structural formula of compound I, compound b, compound c, compound d and compound e, R 6 is selected from -H or an alkyl group of C 1 -C 6 ;
(2)制备具有式B所示结构的美金刚脲类衍生物，(2) preparing a memantamide derivative having the structure shown in formula B,
(2-1)当R
3为除卤素基团以外的基团时，制备方法包括以下步骤：
(2-1) When R 3 is a group other than a halogen group, the preparation method comprises the following steps:
将化合物VI和化合物a进行第七酰化反应，得到化合物f；The seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;
将所述化合物f进行第二还原反应，得到化合物g；The compound f is subjected to a second reduction reaction to obtain compound g;
将所述化合物g和化合物II进行第八酰化反应，得到化合物h；The compound g and compound II are subjected to the eighth acylation reaction to obtain compound h;
将所述化合物h和化合物III进行第三胺解反应，得到化合物i；The compound h and compound III are subjected to a third aminolysis reaction to obtain compound i;
将所述化合物i在酸性条件下进行第二脱保护基反应，得到X为-NH
2的具有式B所示结构的美金刚脲类衍生物，记为化合物j；
The compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;
将所述化合物j和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第九酰化反应，得到X为
的具有式B所述结构的美金刚脲类衍生物；
The compound j and compound VII are mixed, and the ninth acylamide is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. chemical reaction to obtain X as The memantamide derivatives having the structure described in formula B;
将所述化合物j和化合物VIII进行第十酰化反应，得到X为
的具有式B所述结构的美金刚脲类衍生物；
The compound j and compound VIII are subjected to tenth acylation reaction to obtain X as The memantamide derivatives having the structure described in formula B;
(2-2)当R
3为卤素基团时，制备方法包括以下步骤：
(2-2) When R 3 is a halogen group, the preparation method comprises the following steps:
按照(2-1)方法制备化合物g；Compound g was prepared according to the method (2-1);
将所述化合物g和化合物V进行第十一酰化反应，得到第四中间体化合物；The eleventh acylation reaction of compound g and compound V is carried out to obtain the fourth intermediate compound;
将所述第四中间体化合物和化合物III进行第二亲核取代反应，得到化合物h；The fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;
基于所述化合物h，按照(2-1)方法制备得到具有式B所示结构的美金刚脲类衍生物；Based on the compound h, a memantamide derivative having the structure shown in formula B is prepared according to the method (2-1);
其中，所述化合物VI的结构式为：
Wherein, the structural formula of described compound VI is:
所述化合物VII的结构式为：
The structural formula of the compound VII is:
所述化合物VIII的结构式为：
The structural formula of the compound VIII is:
所述化合物f、化合物g、化合物h、化合物i以及化合物j的结构式如下：The structural formulas of the compound f, compound g, compound h, compound i and compound j are as follows:
(3)制备具有式C所示结构的美金刚脲类衍生物，(3) preparing the memantamide derivatives having the structure shown in formula C,
(3-1)当R
3为除卤素基团以外的基团时，制备方法包括以下步骤：
(3-1) When R 3 is a group other than a halogen group, the preparation method comprises the following steps:
将化合物IX和化合物a进行第十二酰化反应，得到化合物k；The dodecanoylation reaction of compound IX and compound a is carried out to obtain compound k;
将所述化合物k进行第三还原反应，得到化合物l；The compound k is subjected to a third reduction reaction to obtain compound 1;
将所述化合物l和化合物II进行第十三酰化反应，得到化合物m；The compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;
将所述化合物m和化合物III进行第四胺解反应，得到化合物n；The compound m and compound III are subjected to the fourth aminolysis reaction to obtain compound n;
将所述化合物n在酸性条件下进行第三脱保护基反应，得到Y为-H的具有式C所示结构的美金刚脲类衍生物，记为化合物o；The compound n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;
将所述化合物o和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第十四酰化反应，得到Y为
的具有式C所述结构的美金刚脲类衍生物；
The compound o and compound VII are mixed, and the fourteenth step is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole Acylation reaction to obtain Y as The memantamide derivatives having the structure described in formula C;
将所述化合物o和化合物VIII进行第十五酰化反应，得到Y为
的具有式C所述结构的美金刚脲类衍生物；
The compound o and compound VIII are subjected to pentadecyl acylation to obtain Y as The memantamide derivatives having the structure described in formula C;
(3-2)当R
3为卤素基团时，制备方法包括以下步骤：
(3-2) When R 3 is a halogen group, the preparation method comprises the following steps:
按照(3-1)方法制备化合物l；Compound 1 was prepared according to (3-1) method;
将化合物l和化合物V进行第十六酰化反应，得到第五中间体化合物；Compound 1 and compound V are subjected to sixteen acylation reaction to obtain the fifth intermediate compound;
将所述第五中间体化合物和化合物III进行第三亲核取代反应，得到化合物n；The fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;
基于所述化合物n，按照(3-1)方法制备得到具有式C所示结构的美金刚脲类衍生物；Based on the compound n, a memantamide derivative having the structure shown in formula C is prepared according to the method (3-1);
其中，所述化合物IX的结构式为：
Wherein, the structural formula of described compound IX is:
所述化合物k、化合物l、化合物m、化合物m以及化合物o的结构式如下：The structural formulas of the compound k, compound 1, compound m, compound m and compound o are as follows:
(4)制备具有式D所示结构的美金刚脲类衍生物，(4) preparing a memantamide derivative having the structure shown in formula D,
将化合物IX替换为化合物
按照(3)方法制备得到具有式D所示结构的美金刚脲类衍生物。
Replace Compound IX with Compound According to the method (3), the memantamide derivatives having the structure represented by the formula D are prepared.
优选地，所述化合物I和化合物a的摩尔比为(1.8～2.2)：1；所述第一酰化反应的温度为-40～10℃，时间为10～50min。Preferably, the molar ratio of the compound I to the compound a is (1.8-2.2):1; the temperature of the first acylation reaction is -40-10° C., and the time is 10-50 min.
优选地，所述第一还原反应的温度为25～70℃，时间为10～15h。Preferably, the temperature of the first reduction reaction is 25-70° C., and the time is 10-15 h.
优选地，所述化合物c和化合物II的摩尔比为1：(1～2)；所述第二酰化反应在冰浴条件下进行，所述第二酰化反应的时间为10～50min。Preferably, the molar ratio of the compound c and the compound II is 1:(1-2); the second acylation reaction is performed under ice bath conditions, and the time of the second acylation reaction is 10-50 min.
优选地，所述化合物d和化合物III的摩尔比为1：(0.8～1.3)；所述第一胺解反应在体系回流条件下进行，所述第一胺解反应的时间为6～10h。Preferably, the molar ratio of the compound d and the compound III is 1:(0.8-1.3); the first aminolysis reaction is carried out under the reflux condition of the system, and the time of the first aminolysis reaction is 6-10 h.
优选地，所述化合物e、氯化亚砜和乙醇的用量比为(0.5～0.8)mmol：(2～3)mmol：(15～25)mL；所述酯化反应在体系回流条件下进行，所述酯化反应的时间为1.5～2.5h。Preferably, the dosage ratio of the compound e, thionyl chloride and ethanol is (0.5-0.8) mmol: (2-3) mmol: (15-25) mL; the esterification reaction is carried out under the system reflux condition , the time of the esterification reaction is 1.5-2.5h.
优选地，所述化合物e和化合物IV的摩尔比为1：(1.8～2.2)，所述化合物e、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑的摩尔比为1：(1.3～1.7)：(1.3～1.7)；所述第三酰化反应的温度为25～35℃，时间为6～10h。Preferably, the molar ratio of the compound e and the compound IV is 1:(1.8-2.2), and the compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride The molar ratio of the salt and 1-hydroxybenzotriazole is 1:(1.3-1.7):(1.3-1.7); the temperature of the third acylation reaction is 25-35°C, and the time is 6-10h.
优选地，所述氯代反应在体系回流条件下进行，所述氯代反应的时间为1.5～2.5h。Preferably, the chlorination reaction is carried out under the reflux condition of the system, and the time of the chlorination reaction is 1.5-2.5 h.
优选地，所述酰氯中间体和化合物IV的摩尔比为1：(1.0～1.5)；所述第四酰化反应的温度为-10～40℃，时间为1～6h。Preferably, the molar ratio of the acid chloride intermediate and the compound IV is 1:(1.0-1.5); the temperature of the fourth acylation reaction is -10-40°C, and the time is 1-6h.
优选地，所述水解反应的温度为25～70℃，时间为30min～6h。Preferably, the temperature of the hydrolysis reaction is 25-70°C, and the time is 30min-6h.
优选地，所述第五酰化反应温度为0～40℃，时间为1～8h。Preferably, the temperature of the fifth acylation reaction is 0˜40° C., and the time is 1˜8 h.
优选地，所述第六酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the temperature of the sixth acylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第一亲核取代反应为先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。Preferably, the first nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
优选地，所述第二胺解反应的温度为0～25℃，时间2～24h。Preferably, the temperature of the second aminolysis reaction is 0-25° C. and the time is 2-24 h.
优选地，所述脱硫羰基反应的温度为0～25℃，时间2～24h。Preferably, the temperature of the dethiocarbonylation reaction is 0-25° C. and the time is 2-24 h.
优选地，所述第一脱保护基反应的温度为0～40℃，时间为30min～4h。Preferably, the temperature of the first deprotection group reaction is 0-40°C, and the time is 30min-4h.
优选地，所述化合物VI和化合物a的摩尔比为1∶(0.8～1.2)；所述第七酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the molar ratio of the compound VI to the compound a is 1:(0.8-1.2); the temperature of the seventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第二还原反应的温度为25～70℃，时间为10～15h。Preferably, the temperature of the second reduction reaction is 25-70° C., and the time is 10-15 h.
优选地，所述化合物g和化合物II的摩尔比为1∶(1～2)；所述第八酰化反应在室温条件下进行，所述第八酰化反应的时间为5～8h。Preferably, the molar ratio of the compound g and the compound II is 1:(1-2); the eighth acylation reaction is carried out at room temperature, and the time of the eighth acylation reaction is 5-8h.
优选地，所述化合物h和化合物III的摩尔比为1∶(0.8～1.3)；所述第三胺解反应在体系回流条件下进行，所述第三胺解反应的时间为6～10h。Preferably, the molar ratio of the compound h and the compound III is 1:(0.8-1.3); the third aminolysis reaction is carried out under the reflux condition of the system, and the time of the third aminolysis reaction is 6-10 h.
优选地，所述第二脱保护基反应的温度为室温，时间为1.5～2.5h。Preferably, the temperature of the second deprotection group reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述化合物j和化合物VII的摩尔比为1∶(1.5～2.5)；所述第九酰化反应的温度为20～40℃，时间为6～10h。Preferably, the molar ratio of the compound j to the compound VII is 1:(1.5-2.5); the temperature of the ninth acylation reaction is 20-40° C., and the time is 6-10 h.
优选地，所述化合物j和化合物VIII的摩尔比为1∶(1.5～2.5)；所述第十酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the molar ratio of the compound j and the compound VIII is 1:(1.5-2.5); the temperature of the tenth acylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第十一酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the temperature of the eleventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第二亲核取代反应为先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。Preferably, the second nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
优选地，所述化合物IX和化合物a的摩尔比为1∶(0.8～1.2)；所述第十二酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the molar ratio of the compound IX to the compound a is 1:(0.8-1.2); the temperature of the dodecanoylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第三还原反应的温度为70～90℃，时间为40～60min。Preferably, the temperature of the third reduction reaction is 70-90° C., and the time is 40-60 min.
优选地，所述化合物l和化合物II的摩尔比为1∶(1～2)；所述第十三酰化反应在室温条件下进行，所述第十三酰化反应的时间为5～8h。Preferably, the molar ratio of the compound I and the compound II is 1:(1-2); the tridecylation reaction is carried out at room temperature, and the time of the tridecaylation reaction is 5-8h .
优选地，所述化合物m和化合物III的摩尔比为1∶(0.8～1.3)；所述第四胺解反应在体系回流条件下进行，所述第四胺解反应的时间为6～10h。Preferably, the molar ratio of the compound m and the compound III is 1:(0.8-1.3); the fourth aminolysis reaction is carried out under the reflux condition of the system, and the time of the fourth aminolysis reaction is 6-10 h.
优选地，所述第三脱保护基反应的温度为室温，时间为3.5～4.5h。Preferably, the temperature of the third deprotecting group reaction is room temperature, and the time is 3.5-4.5 h.
优选地，所述化合物o和化合物VII的摩尔比为1∶(1.5～2.5)；所述第十四酰化反应的温度为20～40℃，时间为6～10h。Preferably, the molar ratio of the compound o to the compound VII is 1:(1.5～2.5); the temperature of the fourteenth acylation reaction is 20～40°C, and the time is 6～10h.
优选地，所述化合物o和化合物VIII的摩尔比为1∶(1.5～2.5)；所述第十五酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the molar ratio of the compound o to the compound VIII is 1:(1.5-2.5); the temperature of the pentadecyl acylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第十六酰化反应的温度为室温，时间为1.5～2.5h。Preferably, the temperature of the sixteenthylation reaction is room temperature, and the time is 1.5-2.5 h.
优选地，所述第三亲核取代反应为先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。Preferably, the third nucleophilic substitution reaction is carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h.
本发明提供了上述技术方案所述美金刚脲类衍生物在制备治疗可溶性环氧化物酶介导的疾病的药物中的应用。The present invention provides the application of the memantamide derivatives described in the above technical solutions in the preparation of medicines for treating diseases mediated by soluble epoxidase.
优选地，所述可溶性环氧化物酶介导的疾病包括炎症性疾病、疼痛、心血管疾病、神经退行性疾病、糖尿病、糖尿病并发症、慢性肾炎、肾功能衰竭、慢性阻塞性肺疾病或肺动脉高压疾病。Preferably, the soluble cyclooxygenase-mediated disease includes inflammatory disease, pain, cardiovascular disease, neurodegenerative disease, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary artery Hypertension disease.
优选地，所述炎症性疾病包括脓毒症、细胞因子风暴、炎症性肠病、慢性消化性溃疡或关节炎。Preferably, the inflammatory disease comprises sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis.
优选地，所述疼痛包括炎性疼痛或神经性疼痛。Preferably, the pain comprises inflammatory pain or neuropathic pain.
优选地，所述心血管疾病包括高血压、中风或动脉粥样硬化。Preferably, the cardiovascular disease comprises hypertension, stroke or atherosclerosis.
优选地，所述神经退行性疾病包括帕金森综合征或阿尔兹海默病。Preferably, the neurodegenerative disease comprises Parkinson's syndrome or Alzheimer's disease.
本发明提供了一种美金刚脲类衍生物，本发明提供的美金刚脲类衍生物，具有典型的脲结构作为sEH的一级药效团，美金刚部分作为疏水性片段与受体产生疏水作用力，分子对接显示美金刚部分作为疏水性片段与受体产生疏水作用力，特别是当R
1和R
2均为甲基(即3，5-二甲基取代)时，可以增强范德华作用力。因此，本发明提供的美金刚脲类衍生物对人源性HsEH的抑制活性高，能够作为sEH抑制剂用于制备治疗可溶性环氧化物酶介导的疾病的药物。
The invention provides a memantine derivative. The memantine derivative provided by the invention has a typical urea structure as the primary pharmacophore of sEH, and the memantine part acts as a hydrophobic fragment to generate hydrophobicity with the receptor. The interaction force, molecular docking showed that the memantine moiety acts as a hydrophobic fragment to generate a hydrophobic interaction with the receptor, especially when both R 1 and R 2 are methyl (ie, 3,5-dimethyl substituted), which can enhance the van der Waals interaction force. Therefore, the memantine derivatives provided by the present invention have high inhibitory activity on human HsEH, and can be used as sEH inhibitors to prepare medicines for treating diseases mediated by soluble epoxidase.
图1为本发明中当R3为除卤素基团以外的基团时，具有式A所示结构的美金刚脲类衍生物的反应路线图；Fig. 1 is the reaction scheme of the memantamide derivatives having the structure shown in formula A when R3 is a group other than a halogen group in the present invention;
图2为本发明中当R3为卤素基团时，具有式A所示结构的美金刚脲类衍生物的反应路线图；Fig. 2 is the reaction scheme diagram of the memantamide derivatives having the structure shown in formula A when R3 is a halogen group in the present invention;
图3为本发明中当R3为除卤素基团以外的基团时，具有式B所示结构的美金刚脲类衍生物的反应路线图；Fig. 3 is in the present invention, when R3 is a group other than a halogen group, the reaction scheme of the memantamide derivatives having the structure shown in formula B;
图4为本发明中当R3为卤素基团时，具有式B所示结构的美金刚脲类衍生物的反应路线图；Fig. 4 is the reaction scheme diagram of the memantamide derivatives having the structure shown in formula B when R3 is a halogen group in the present invention;
图5为本发明中当R3为除卤素基团以外的基团时，具有式C所示结构的美金刚脲类衍生物的反应路线图；Fig. 5 is the reaction scheme of the memantamide derivatives having the structure shown in formula C when R3 is a group other than a halogen group in the present invention;
图6为本发明中当R3为卤素基团时，具有式C所示结构的美金刚脲类衍生物的反应路线图。Fig. 6 is the reaction scheme of the memantamide derivatives having the structure represented by formula C when R3 is a halogen group in the present invention.
本发明提供了一种美金刚脲类衍生物，具有式A、式B、式C或式D所示结构：The present invention provides a memantine derivative, which has the structure shown in formula A, formula B, formula C or formula D:
其中，R
1和R
2独立地选自-H、-OH、-NH
2、-SH、-CN、卤素基团、烷基、烷氧基或杂环基；
wherein, R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;
R
3选自-H、-OH、-NH
2、-SH、-CN、卤素基团、烷基或烷氧基；
R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;
R
4选自-OH、-NH
2、羟胺基、烷基、烷氧基、烷基胺基、烷氧基胺基、醇胺基、苯胺基、萘胺基或杂环基；
R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;
X选自-NH
2、
X is selected from -NH 2 ,
Y选自-H、
Y is selected from -H,
R
5选自烷基或杂环基；
R 5 is selected from alkyl or heterocyclyl;
Z和M独立地选自-O-、-NH-或-S-；Z and M are independently selected from -O-, -NH- or -S-;
Q选自
Q is selected from
在本发明中，进一步地，所述R
1和R
2选自的卤素基团独立地为-F、-Cl或-Br，烷基独立地为甲基、乙基、丙基、丁基、戊基、异丁基、异丙基、异戊基或叔丁基，烷氧基独立地为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环戊氧基、环己氧基、苯氧基或苄氧基。在本发明中，更进一步地，所述R
1和R
2为甲基。
In the present invention, further, the halogen group selected from R 1 and R 2 is independently -F, -Cl or -Br, and the alkyl group is independently methyl, ethyl, propyl, butyl, Amyl, isobutyl, isopropyl, isoamyl or tert-butyl, alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy , cyclohexyloxy, phenoxy or benzyloxy. In the present invention, further, the R 1 and R 2 are methyl groups.
在本发明中，进一步地，所述R
3选自的卤素基团为-F、-Cl或-Br；烷基为未取代或取代的C1～C6烷基；烷氧基为未取代或取代的C1～C6烷氧基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基，所述取代的取代基具体是指取代的C1～C6烷基和取代的C1～C6烷氧基中取代基。在本发明中，更进一步地，所述R
3为-H、-F或-Cl。
In the present invention, further, the halogen group selected from the R 3 is -F, -Cl or -Br; the alkyl group is an unsubstituted or substituted C1-C6 alkyl group; the alkoxy group is an unsubstituted or substituted alkyl group C1-C6 alkoxy group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkane The substituted substituent specifically refers to the substituent in the substituted C1-C6 alkyl group and the substituted C1-C6 alkoxy group. In the present invention, further, the R 3 is -H, -F or -Cl.
在本发明中，进一步地，所述R4选自的烷氧基为未取代或取代的C1～C6烷氧基；烷基胺基为未取代或取代的C1～C6烷基胺基；烷氧基胺基为未取代或取代的C1～C6烷氧基胺基；苯胺基为未取代或取代的苯胺基；萘胺基为未取代或取代的萘胺基；杂环基为未取代或取代的5～10元杂环基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基，所述取代的取代基具体是指取代的C1～C6烷氧基、取代的C1～C6烷基胺基、取代的C1～C6烷氧基胺基、取代的苯胺基、取代的萘胺基和取代的5～10元杂环基中取代基。在本发明中，更进一步地，所述R
4为-OH、-NH
2、-OCH
2CH
3、-NHCH
3、-N(CH
3)
2、
-NHOCH
3或-NHOH。
In the present invention, further, the alkoxy group selected by R4 is an unsubstituted or substituted C1-C6 alkoxy group; the alkylamine group is an unsubstituted or substituted C1-C6 alkylamine group; an alkoxy group The amino group is an unsubstituted or substituted C1-C6 alkoxyamine group; the aniline group is an unsubstituted or substituted aniline group; the naphthylamino group is an unsubstituted or substituted naphthylamino group; the heterocyclic group is an unsubstituted or substituted 5-10-membered heterocyclic group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 Alkyl, the substituted substituent specifically refers to a substituted C1-C6 alkoxy group, a substituted C1-C6 alkylamino group, a substituted C1-C6 alkoxyamino group, a substituted anilino group, a substituted naphthalene group Substituents in amino groups and substituted 5-10-membered heterocyclic groups. In the present invention, further, the R 4 is -OH, -NH 2 , -OCH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHOCH 3 or -NHOH.
在本发明中，进一步地，所述R
5选自的烷基为链烷基或环烷基；所述R
5选自的链烷基为未取代或取代的C1～C6链烷基，所述取代的C1～C6链烷基中取代基选自-OH、-NH
2或C1～C6烷基；所述R
5选自的环烷基为未取代或取代的C3～C6环烷基，所述取代的C3～C6环烷基中取代基选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基；所述R
5选自的杂环基为未取代或取代的C3～C6饱和或不饱和杂环基，所述取代的C3～C6饱和或不饱和杂环基中取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6烷基。在本发明中，更进一步地，所述R
5为-CH
3、-CH
2CH
3、-CH
2CH
2CH
3、-CH(CH
3)CH
2CH
3、环丙基或-CH(NH
2)CH(CH
3)
2。
In the present invention, further, the alkyl group selected by the R 5 is a chain alkyl group or a cycloalkyl group; the chain alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, so The substituents in the substituted C1-C6 chain alkyl group are selected from -OH, -NH 2 or C1-C6 alkyl group; the cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, The substituents in the substituted C3-C6 cycloalkyl are selected from -F, -Cl, -Br, -OH, -NH2 , -NHCH3, -N( CH3 )2 or C1-C6 alkyl; The heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the substituents in the substituted C3-C6 saturated or unsaturated heterocyclic group are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl. In the present invention, further, the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , cyclopropyl or -CH( NH2 )CH( CH3 ) 2 .
在本发明中，当式B所示结构的美金刚脲类衍生物中X在哌啶环的3位取代时，所述美金刚脲类衍生物为手性化合物，具体结构如式E或式F所示：In the present invention, when X is substituted at the 3-position of the piperidine ring in the memantamide derivative of the structure shown in formula B, the memantamide derivative is a chiral compound, and the specific structure is as shown in formula E or formula F shows:
在本发明中，进一步地，所述美金刚脲类衍生物包括1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸(GL-B404)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸乙酯(GL-B405)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺(GL-B406)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-4-甲酰胺(GL-B407)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N，N-二甲基哌啶-4-甲酰胺(GL-B408)、N-环丙基-1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺(GL-B409)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-4-甲酰胺(GL-B410)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸(GL-B411)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸乙酯(GL-B412)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(GL-B413)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-3-甲酰胺(GL-B414)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N，N-二甲基哌啶-3-甲酰胺(GL-B415)、N-环丙基-1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(GL-B416)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-3-甲酰胺(GL-B417)、1-[4-(4-氨基哌啶-1-羰基)苯基]-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B418)、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]甲磺酰胺(GL-B419)、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]乙酰胺(GL-B420)、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丙酰胺(GL-B421)、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丁酰胺(GL-B422)、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-2-甲基丁酰胺(GL-B423)、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]环丙烷甲酰胺(GL-B424)、2-氨基-N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-3-甲基丁酰胺(GL-B425)、1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-[4-(哌嗪-1-羰基)苯基]脲(GL-B426)、1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-{4-[4-(甲基磺酰基)哌嗪-1-羰基]苯基}脲(GL-B427)、1-[4-(4-乙酰基哌嗪-1-羰基)苯基]-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B428)、1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-[4-(4-丙酰基哌嗪-1-羰基)苯基]脲(GL-B429)、1-[4-(4-丁酰基哌嗪-1-羰基)苯基]-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B430)、1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-{4-[4-(2-甲基丁酰基)哌嗪-1-羰基]苯基}脲(GL-B431)、1-{4-[4-(环丙烷羰基)哌嗪-1-羰基]苯基}-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B432)、1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-[4-(4-戊基哌嗪-1-羰基)苯基]脲(GL-B433)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺(GL-B434)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酰胺(GL-B435)、1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-羟基哌啶-3-甲酰胺(GL-B436)、(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺(GL-B437)、N-[(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-基]甲磺酰胺(GL-B438)、(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(S-GL-B413)、(R)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(R-GL-B413)、1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯基)磺酰基]哌啶-3-甲酰胺(GL-B439)(S)-1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]哌啶-3-甲酰胺(GL-B440)或 (S)-1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]-N-羟基哌啶-3-甲酰胺(GL-B441)，结构式具体如下所示：In the present invention, further, the memantine derivatives include 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl] Ureido}benzoyl)piperidine-4-carboxylic acid (GL-B404), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- yl]ureido}benzoyl)piperidine-4-carboxylic acid ethyl ester (GL-B405), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantine Alk-1-yl]ureido}benzoyl)piperidine-4-carboxamide (GL-B406), 1-(4-{3-[(1r,3R,5S,7r)-3,5-di Methyladamantan-1-yl]ureido}benzoyl)-N-methylpiperidine-4-carboxamide (GL-B407), 1-(4-{3-[(1r,3R,5S, 7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N,N-dimethylpiperidine-4-carboxamide (GL-B408), N-cyclopropyl -1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4-carboxamide (GL -B409), 1-(4-{3-[(1r, 3R, 5S, 7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxy Piperidine-4-carboxamide (GL-B410), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzene Formyl)piperidine-3-carboxylic acid (GL-B411), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido }Benzoyl)piperidine-3-carboxylic acid ethyl ester (GL-B412), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- yl]ureido}benzoyl)piperidine-3-carboxamide (GL-B413), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane -1-yl]ureido}benzoyl)-N-methylpiperidine-3-carboxamide (GL-B414), 1-(4-{3-[(1r,3R,5S,7r)-3 , 5-dimethyladamantan-1-yl]ureido}benzoyl)-N,N-dimethylpiperidine-3-carboxamide (GL-B415), N-cyclopropyl-1-( 4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide (GL-B416), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxypiperidine-3 -Formamide (GL-B417), 1-[4-(4-aminopiperidine-1-carbonyl)phenyl]-3-[(1r, 3R , 5S,7r)-3,5-dimethyladamantan-1-yl]urea (GL-B418), N-[1-(4-{3-[(1r,3R,5S,7r)-3 , 5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]methanesulfonamide (GL-B419), N-[1-(4-{3-[(1r , 3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]acetamide (GL-B420), N-[1-( 4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]propionamide (GL-B421 ), N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4- yl]butanamide (GL-B422), N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzene Formyl)piperidin-4-yl]-2-methylbutanamide (GL-B423), N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-di Methyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]cyclopropanecarboxamide (GL-B424), 2-amino-N-[1-(4-{3-[( 1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]-3-methylbutanamide (GL-B425), 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(piperazine-1-carbonyl)phenyl]urea (GL-B426) , 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-{4-[4-(methylsulfonyl)piperazine-1-carbonyl] Phenyl}urea (GL-B427), 1-[4-(4-acetylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyl Adamantan-1-yl]urea (GL-B428), 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4 -Propionylpiperazine-1-carbonyl)phenyl]urea (GL-B429), 1-[4-(4-butyrylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S , 7r)-3,5-dimethyladamantan-1-yl]urea (GL-B430), 1-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1- base]-3-{4-[4-(2-methylbutyryl)piperazine-1-carbonyl]phenyl}urea (GL-B431), 1-{4-[4-(cyclopropanecarbonyl)piperidine oxazine-1-carbonyl]phenyl}-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea (GL -B432), 1-[(1r, 3R, 5S, 7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4-pentylpiperazine-1-carbonyl)benzene Base]urea (GL-B433), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzene Formyl)piperidine-3-carboxamide (GL-B434), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea yl}-3-chlorobenzoyl)piperidine-3-carboxamide (GL-B435), 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantine Alk-1-yl]ureido}benzoyl)-N-hydroxypiperidine-3-carboxamide (GL-B436), (S)-1-(4-{3-[(1r,3R,5S, 7S)-3,5-Dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine-3-carboxamide (GL-B437), N-[(S)-1- (4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidin-3-yl]methane Sulfonamide (GL-B438), (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzyl Acyl)piperidine-3-carboxamide (S-GL-B413), (R)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantane- 1-yl]ureido}benzoyl)piperidine-3-carboxamide (R-GL-B413), 1-[(4-{3-[(1r,3R,5S,7S)-3,5- Dimethyladamantan-1-yl]ureido}phenyl)sulfonyl]piperidine-3-carboxamide (GL-B439)(S)-1-[(4-{3-[(1r,3R, 5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorophenyl)sulfonyl]piperidine-3-carboxamide (GL-B440) or (S)-1 -[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorophenyl)sulfonyl]-N-hydroxyl Piperidine-3-carboxamide (GL-B441), the structural formula is as follows:
本发明提供了上述技术方案所述美金刚脲类衍生物的制备方法，本发明根据美金刚脲类衍生物的具体结构针对性选择制备方法，下面分别进行具体说明。The present invention provides a method for preparing the memantine derivatives described in the above technical solution, and the present invention selects the preparation method according to the specific structure of the memantamide derivatives, which will be described in detail below.
第一种情况，制备具有式A所示结构的美金刚脲类衍生物，如图1所示，具体的，(1-1)当R
3为除卤素基团以外的基团时，制备方法包括以下步骤：
In the first case, a memantamide derivative having the structure shown in formula A is prepared, as shown in Figure 1. Specifically, (1-1) When R 3 is a group other than a halogen group, the preparation method Include the following steps:
将化合物I和化合物a进行第一酰化反应，得到化合物b；Compound I and compound a are subjected to the first acylation reaction to obtain compound b;
将所述化合物b进行第一还原反应，得到化合物c；The compound b is subjected to a first reduction reaction to obtain compound c;
将所述化合物c和化合物II进行第二酰化反应，得到化合物d；The compound c and compound II are subjected to a second acylation reaction to obtain compound d;
将所述化合物d和化合物III进行第一胺解反应，得到化合物e；当化合物e中R
6为-H时，所述化合物e为R
4为-OH的具有式A所示结构的美金刚脲类衍生物；
The compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;
当化合物e中R
6为-H时，将所述化合物e、氯化亚砜和乙醇混合，进行酯化反应，得到R
4为-OEt的具有式A所示结构的美金刚脲类衍生物；
When R 6 in compound e is -H, the compound e, thionyl chloride and ethanol are mixed to carry out an esterification reaction to obtain a memantamide derivative having the structure shown in formula A, where R 4 is -OEt ;
或者，当化合物e中R
6为-H时，将所述化合物e和化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第三酰化反应，得到具有式A所示结构的美金刚脲类衍生物；
Alternatively, when R 6 in compound e is -H, the compound e and compound IV are mixed in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 - carry out the third acylation reaction in the presence of hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
或者，当化合物e中R
6为-H时，将所述化合物e在氯化亚砜存在条件下进行氯代反应，得到酰氯中间体；将所述酰氯中间体和化合物IV进行第四酰化反应，得到具有式A所示结构的美金刚脲类衍生物；
Alternatively, when R 6 in compound e is -H, the compound e is subjected to a chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and compound IV are subjected to fourth acylation reaction to obtain the memantamide derivatives having the structure shown in formula A;
当化合物e中R
6为C
1～C
6的烷基时，将所述化合物e经水解反应后，再与化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第五酰化反应，得到具有式A所示结构的美金刚脲类衍生物；
When R 6 in compound e is a C 1 -C 6 alkyl group, the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl The fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;
所述化合物I、化合物II和化合物III的结构式依次为
The structural formulas of the compound I, compound II and compound III are sequentially
所述化合物IV为：NH
3、R
7-NH
2、R
7-OH、R
7-O-NH
2或
其中，R
7为取代或未取代的C1～C6的烷基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH
2、-NHCH
3、-N(CH
3)
2或C1～C6的烷基；
The compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;
所述化合物V为固体光气或硫光气；Described compound V is solid phosgene or thiophosgene;
所述化合物a、化合物b、化合物c、化合物d以及化合物e的结构式如下：The structural formulas of the compound a, compound b, compound c, compound d and compound e are as follows:
其中，化合物I、化合物b、化合物c、化合物d和化合物e的结构式中R
6选自-H或C
1～C
6的烷基。
Wherein, in the structural formula of compound I, compound b, compound c, compound d and compound e, R 6 is selected from -H or an alkyl group of C 1 -C 6 .
本发明将化合物I和化合物a进行第一酰化反应，得到化合物b。在本发明中，所述化合物I和化合物a的摩尔比优选为(1.8～2.2)∶1，更优选为2∶1。在本发明中，当R
6为-H时，所述第一酰化反应优选在碳酸钾、四氢呋喃和水存在条件下进行；当R
6为C
1～C
6的烷基时，所述第一酰化反应优选在三乙胺和四氢呋喃存在条件下进行。在本发明中，所述第一酰化反应的温度优选为-40～10℃，更优选为-25℃，时间优选为10～50min，更优选为30min。所述第一酰化反应后，本发明优选将所得反应液进行减压浓缩以除去溶剂，加入水，在冰浴条件下用盐酸调节体系pH值至7，加入乙酸乙酯，用盐酸继续调节体系pH值至1，之后抽滤，滤饼依次用水和乙酸乙酯淋洗，干燥后得到化合物b。
In the present invention, compound I and compound a are subjected to the first acylation reaction to obtain compound b. In the present invention, the molar ratio of the compound I and the compound a is preferably (1.8-2.2):1, more preferably 2:1. In the present invention, when R 6 is -H, the first acylation reaction is preferably carried out in the presence of potassium carbonate, tetrahydrofuran and water; when R 6 is a C 1 -C 6 alkyl group, the first acylation reaction is performed The monoacylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran. In the present invention, the temperature of the first acylation reaction is preferably -40-10°C, more preferably -25°C, and the time is preferably 10-50 min, more preferably 30 min. After the first acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, water is added, the pH value of the system is adjusted to 7 with hydrochloric acid under ice bath conditions, ethyl acetate is added, and hydrochloric acid is used to continue adjusting The pH value of the system was adjusted to 1, then suction filtration, the filter cake was rinsed with water and ethyl acetate successively, and dried to obtain compound b.
得到化合物b后，本发明将所述化合物b进行第一还原反应，得到化合物c。在本发明中，所述第一还原反应所用还原剂优选为氢气，所用催化剂优选为Pd-C；所述第一还原反应优选在无水乙醇存在条件下进行。在本发明中，所述第一还原反应的温度优选为25～70℃，更优选为60℃，时间优选为10～15h，更优选为12h。第一还原反应后，本发明优选待反应液冷却至室温后，抽滤，滤液经减压浓缩，将所得剩余物与乙酸乙酯混合后打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到化合物c。After the compound b is obtained, the present invention performs the first reduction reaction on the compound b to obtain the compound c. In the present invention, the reducing agent used in the first reduction reaction is preferably hydrogen, and the catalyst used is preferably Pd-C; the first reduction reaction is preferably carried out in the presence of anhydrous ethanol. In the present invention, the temperature of the first reduction reaction is preferably 25-70°C, more preferably 60°C, and the time is preferably 10-15h, more preferably 12h. After the first reduction reaction, the present invention preferably waits for the reaction solution to be cooled to room temperature, then suction filtration, the filtrate is concentrated under reduced pressure, the obtained residue is mixed with ethyl acetate and then slurried, the system obtained after slurping is subjected to suction filtration, and the filter cake is used Rinse with ethyl acetate and dry to give compound c.
得到化合物c后，本发明将所述化合物c和化合物II进行第二酰化反应，得到化合物d。在本发明中，所述化合物c和化合物II的摩尔比优选为1∶(1～2)，更优选为1∶(1.2～1.7)。在本发明中，所述第二酰化反应优选在碳酸钾和四氢呋喃存在条件下进行。在本发明中，所述第二酰化反应优选在冰浴条件下进行，所述第二酰化反应的时间优选为10～50min，更优选为30min。所述第二酰化反应后，本发明优选将所得反应液进行减压浓缩以除去溶剂，加入水，冰浴条件下用盐酸调节体系pH值至7，加入乙酸乙酯，用盐酸继续调节体系pH值至1，之后抽滤，将所得滤饼依次用乙酸乙酯和水淋洗，干燥后得白色固体，将所述白色固体用乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到化合物d。After the compound c is obtained, the present invention performs the second acylation reaction on the compound c and the compound II to obtain the compound d. In the present invention, the molar ratio of the compound c and the compound II is preferably 1:(1-2), more preferably 1:(1.2-1.7). In the present invention, the second acylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran. In the present invention, the second acylation reaction is preferably carried out under ice bath conditions, and the time of the second acylation reaction is preferably 10-50 min, more preferably 30 min. After the second acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, water is added, the pH value of the system is adjusted to 7 with hydrochloric acid under ice bath conditions, ethyl acetate is added, and the system is continuously adjusted with hydrochloric acid. The pH value was reduced to 1, then suction filtration, the obtained filter cake was washed with ethyl acetate and water in turn, dried to obtain a white solid, the white solid was slurried with ethyl acetate, the system obtained after the slurried beating was subjected to suction filtration, filtered The cake was rinsed with ethyl acetate and dried to give compound d.
得到化合物d后，本发明将所述化合物d和化合物III进行第一胺解反应，得到化合物e。在本发明中，所述化合物d和化合物III的摩尔比优选为1∶(0.8～1.3)，更优选为1∶1.1。在本发明中，所述第一胺解反应优选在三乙胺和四氢呋喃存在条件下进行。在本发明中，所述第一胺解反应优选在体系回流条件下进行，所述第一胺解反应的时间优选为6～10h，更优选为8h。所述第一胺解反应后，本发明优选将所得反应液冷却至室温，减压浓缩以除去溶剂，加入水，冰浴条件下用盐酸调节体系pH值至1，乙酸乙酯萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙腈煮沸，体系中出现白色颗粒固体，冷却至室温后抽滤，滤饼用乙腈淋洗，干燥后得到化合物e。在本发明中，当化合物e中R
6为-H时，所述化合物e为R4为-OH的具有式A所示结构的美金刚脲类衍生物。在本发明的实施例中，当化合物a为对硝基苯甲酰氯、化合物I为4-哌啶甲酸、化合物II为氯甲酸苯酯、化合物III为美金刚时，经第一胺解反应所得化合物e即为化合物GL-B404；当化合物a为对硝基苯甲酰氯、化合物I为3-哌啶甲酸、化合物II为氯甲酸苯酯、化合物III为美金刚时，经第一胺解反应所得化合物e即为化合物GL-B411。
After the compound d is obtained, the present invention performs the first aminolysis reaction on the compound d and the compound III to obtain the compound e. In the present invention, the molar ratio of the compound d and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1. In the present invention, the first aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran. In the present invention, the first aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the first aminolysis reaction is preferably 6-10 hours, more preferably 8 hours. After the first aminolysis reaction, the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove the solvent, adds water, adjusts the pH of the system to 1 with hydrochloric acid under ice bath conditions, extracts with ethyl acetate, and then sequentially After washing with water, saturated brine and drying over anhydrous sodium sulfate, suction filtration, the obtained filtrate was concentrated under reduced pressure, acetonitrile was added to the obtained residue and boiled, white granular solid appeared in the system, cooled to room temperature, suction filtration, and the filter cake was used Rinse with acetonitrile and dry to give compound e. In the present invention, when R 6 in compound e is -H, the compound e is a memantamide derivative having the structure represented by formula A in which R 4 is -OH. In the embodiment of the present invention, when compound a is p-nitrobenzoyl chloride, compound I is 4-piperidinecarboxylic acid, compound II is phenyl chloroformate, and compound III is memantine, the obtained compound is obtained through the first aminolysis reaction. Compound e is compound GL-B404; when compound a is p-nitrobenzoyl chloride, compound I is 3-piperidinecarboxylic acid, compound II is phenyl chloroformate, and compound III is memantine, after the first aminolysis reaction The obtained compound e is compound GL-B411.
当化合物e中R
6为-H时，得到化合物e后，本发明将所述化合物e、氯化亚砜和乙醇混合，进行酯化反应，得到R
4为-OEt的具有式A所示结构的美金刚脲类衍生物。在本发明中，所述化合物e、氯化亚砜和乙醇的用量比优选为(0.5～0.8)mmol∶(2～3)mmol∶(15～25)mL，更优选为0.66mmol∶2.65mmol∶20mL；所述酯化反应优选在体系回流条件下进行，所述酯化反应的时间优选为1.5～2.5h，更优选为2h。所述酯化反应后，本发明优选将所得反应液冷却至室温，减压浓缩除去乙醇，加入水，用乙酸乙酯萃取，之后依次经饱和碳酸钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将所得体系抽滤，滤饼用乙醚淋洗，干燥后得到R
4为-OEt的具有式A所示结构的美金刚脲类衍生物。在本发明的实施例中，当化合物e为化合物GL-B404时，按照上述方法经经酯化反应后得到化合物GL-B405；当化合物e为化合物GL-B411时，按照上述方法经经酯化反应后得到化合物GL-B412。
When R 6 in compound e is -H, after obtaining compound e, the present invention mixes compound e, thionyl chloride and ethanol, and carries out esterification reaction to obtain R 4 is -OEt and has the structure shown in formula A memantamide derivatives. In the present invention, the dosage ratio of the compound e, thionyl chloride and ethanol is preferably (0.5-0.8) mmol: (2-3) mmol: (15-25) mL, more preferably 0.66 mmol: 2.65 mmol : 20 mL; the esterification reaction is preferably carried out under the reflux condition of the system, and the time of the esterification reaction is preferably 1.5-2.5 h, more preferably 2 h. After the esterification reaction, the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove ethanol, adds water, extracts with ethyl acetate, and then successively washes with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine and anhydrous. Dry over sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue to make a slurry, filter the obtained system with suction, rinse the filter cake with ether, and dry to obtain R 4 is -OEt and has the formula A. Memantamide derivatives showing the structure. In the embodiment of the present invention, when compound e is compound GL-B404, compound GL-B405 is obtained by esterification according to the above method; when compound e is compound GL-B411, it is esterified according to the above method After the reaction, compound GL-B412 was obtained.
或者，当化合物e中R
6为-H时，得到化合物e后，本发明将所述化合物e和化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第三酰化反应，得到具有式A所示结构的美金刚脲类衍生物。在本发明中，所述化合物e和化合物IV的摩尔比优选为1∶(1.8～2.2)，更优选为1∶2。在本发明中，所述化合物e、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑的摩尔比优选为1∶(1.3～1.7)∶(1.3～1.7)，更优选为1∶1.5∶1.5。在本发明中，所述第三酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第三酰化反应的温度优选为25～35℃，更优选为30℃；时间优选为6～10h，更优选为8h。所述第三酰化反应后，本发明优选将所得反应液倒入水中，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比优选为10∶1)萃取，之后依次经1mol/L盐酸洗、5wt％氢氧化钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到具有式A所示结构的美金刚脲类衍生物。在本发明的实施例中，当化合物e为化合物GL-B404时，按照上述方法经第三酰化反应后得到具有式A所示结构的美金刚脲类衍生物，具体可以为化合物GL-B407、GL-B408、GL-B409或GL-B410；当化合物e为化合物GL-B405时，按照上述方法经第三酰化反应后得到具有式A所示结构的美金刚脲类衍生物，具体可以为化合物GL-B414、GL-B415、GL-B416或GL-B417。
Or, when R 6 in compound e is -H, after obtaining compound e, the present invention mixes said compound e and compound IV, in 1-(3-dimethylaminopropyl)-3-ethylcarbon two The third acylation reaction is carried out in the presence of imine hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A. In the present invention, the molar ratio of the compound e and the compound IV is preferably 1:(1.8-2.2), more preferably 1:2. In the present invention, the molar ratio of compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1:( 1.3-1.7):(1.3-1.7), more preferably 1:1.5:1.5. In the present invention, the third acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the third acylation reaction is preferably 25-35° C., more preferably 30° C.; the time is preferably 6-10 h, more preferably 8 h. After the third acylation reaction, the present invention preferably pours the obtained reaction solution into water, extracts it with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then sequentially conducts 1 mol/L Washed with hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to make a slurry, and the system obtained after beating was made Perform suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A. In the embodiment of the present invention, when compound e is compound GL-B404, after the third acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained, specifically compound GL-B407 , GL-B408, GL-B409 or GL-B410; when compound e is compound GL-B405, after the third acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained. is compound GL-B414, GL-B415, GL-B416 or GL-B417.
或者，当化合物e中R
6为-H时，得到化合物e后，本发明将所述化合物e在氯化亚砜存在条件下进行氯代反应，得到酰氯中间体；将所述酰氯中间体和化合物IV进行第四酰化反应，得到具有式A所示结构的美金刚脲类衍生物。在本发明中，所述氯代反应优选在N，N-二甲基甲酰胺和二氯甲烷存在条件下进行。在本发明中，所述氯代反应优选在体系回流条件下进行，所述氯代反应的时间优选为1.5～2.5h，更优选为2h。所述氯代反应后，本发明优选将所得反应液冷却至室温，减压浓缩除去溶剂，备用。在本发明中，所述酰氯中间体和化合物IV的摩尔比优选为1∶(1.0～1.5)，更优选为1∶1.1。在本发明中，所述第四酰化反应优选在三乙胺和二氯甲烷存在条件下进行； 所述第四酰化反应的温度优选为-10～40℃，更优选为0℃，时间优选为1～6h，更优选为1h。所述第四酰化反应后，本发明优选将所得体系减压浓缩以除去溶剂，加入水，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比优选为10∶1)萃取，之后依次经1mol/L盐酸洗、5wt％氢氧化钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到具有式A所示结构的美金刚脲类衍生物。在本发明的实施例中，当化合物e为化合物GL-B404时，按照上述方法经第四酰化反应后得到具有式A所示结构的美金刚脲类衍生物，具体可以为化合物GL-B406；当化合物e为化合物GL-B405时，按照上述方法经第四酰化反应后得到具有式A所示结构的美金刚脲类衍生物，具体可以为化合物GL-B413(外消旋体)。在本发明中，化合物S-GL-B413和R-GL-B413优选参照化合物GL-B413(外消旋体)的方法制备，仅将制备化合物GL-B413(外消旋体)的原料改为相应单一构型的原料即可，具体见本发明实施例。
Or, when R 6 in compound e is -H, after obtaining compound e, in the present invention, the compound e is subjected to chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and Compound IV is subjected to the fourth acylation reaction to obtain a memantamide derivative having the structure shown in formula A. In the present invention, the chlorination reaction is preferably carried out in the presence of N,N-dimethylformamide and dichloromethane. In the present invention, the chlorination reaction is preferably carried out under the reflux condition of the system, and the time of the chlorination reaction is preferably 1.5-2.5 h, more preferably 2 h. After the chlorination reaction, in the present invention, the obtained reaction solution is preferably cooled to room temperature, concentrated under reduced pressure to remove the solvent, and used for later use. In the present invention, the molar ratio of the acid chloride intermediate and compound IV is preferably 1:(1.0-1.5), more preferably 1:1.1. In the present invention, the fourth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fourth acylation reaction is preferably -10 to 40°C, more preferably 0°C, and the time It is preferably 1 to 6 hours, and more preferably 1 hour. After the fourth acylation reaction, the present invention preferably concentrates the obtained system under reduced pressure to remove the solvent, adds water, extracts with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then Washed with 1mol/L hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue to make a slurry, The system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A. In the embodiment of the present invention, when compound e is compound GL-B404, a memantamide derivative having the structure shown in formula A is obtained after the fourth acylation reaction according to the above method, which can be specifically compound GL-B406 ; When compound e is compound GL-B405, after the fourth acylation reaction according to the above method, a memantamide derivative having the structure shown in formula A can be obtained, specifically compound GL-B413 (racemate). In the present invention, compounds S-GL-B413 and R-GL-B413 are preferably prepared with reference to the method of compound GL-B413 (racemate), and only the raw materials for preparing compound GL-B413 (racemate) are changed to The raw materials corresponding to a single configuration are sufficient, and the details are shown in the examples of the present invention.
当化合物e中R
6为C
1～C
6的烷基时，得到化合物e后，本发明将所述化合物e经水解反应后，再与化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第五酰化反应，得到具有式A所示结构的美金刚脲类衍生物。在本发明中，所述水解反应优选在氢氧化钠溶液和乙醇存在条件下进行，所述水解反应的温度优选为25～70℃，时间优选为30min～6h。在本发明中，所述第五酰化反应优选在三乙胺和二氯甲烷存在条件下进行；所述第五酰化反应温度优选为0～40℃，时间优选为1～8h。所述第五酰化反应后，本发明优选将所得体系加入水，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比优选为10∶1)萃取，之后依次经1mol/L盐酸洗、5wt％氢氧化钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到具有式A所示结构的美金刚脲类衍生物。
When R 6 in compound e is a C 1 -C 6 alkyl group, after obtaining compound e, in the present invention, the compound e is subjected to hydrolysis reaction, and then mixed with compound IV to obtain a 1-(3-dimethylamino group) The fifth acylation reaction is carried out in the presence of propyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A. In the present invention, the hydrolysis reaction is preferably carried out in the presence of sodium hydroxide solution and ethanol, the temperature of the hydrolysis reaction is preferably 25-70°C, and the time is preferably 30min-6h. In the present invention, the fifth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fifth acylation reaction is preferably 0-40° C., and the time is preferably 1-8 h. After the fifth acylation reaction, in the present invention, the obtained system is preferably added to water, extracted with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then washed with 1 mol/L hydrochloric acid successively. , washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue for beating, and the obtained system after beating was pumped. filter, the filter cake is rinsed with ethyl acetate, and after drying, a memantamide derivative having the structure shown in formula A is obtained.
在本发明中，制备具有式A所示结构的美金刚脲类衍生物，如图2所示，具体的，(1-2)当R
3为卤素基团时，制备方法包括以下步骤：
In the present invention, a memantamide derivative having a structure shown in formula A is prepared, as shown in Figure 2, specifically, (1-2) when R 3 is a halogen group, the preparation method includes the following steps:
按照步骤(1-1)制备化合物c；Compound c was prepared according to step (1-1);
当Z为-O-或-S-时，将所述化合物c和化合物V进行第六酰化反应，得到第一中间体化合物；将所述第一中间体化合物和化合物III进行第一亲核取代反应，得到化合物e；When Z is -O- or -S-, the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;
当Z为-NH-时，将所述化合物c、N-Boc-硫脲、NaH和三氟乙酸酐混合，进行第二胺解反应，得到第二中间体化合物；将所述第二中间体化合物、化合物III和HgCl
2混合，进行脱硫羰基反应，得到第三中间体化合物；将所述第三中间体化合物在酸性条件下进行第一脱保护基反应，得到化合物e；
When Z is -NH-, the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound; the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound; the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;
基于所述化合物e，按照步骤(1-1)制备得到具有式A所示结构的美金刚脲类衍生物。Based on the compound e, according to step (1-1), a memantamide derivative having the structure represented by formula A is prepared.
本发明按照步骤(1-1)制备化合物c。具体的，本发明优选将化合物a、N，N-二甲基甲酰胺、四氢呋喃和氯化亚砜混合后，在60～70℃条件下反应50～70min后，将所得反应液进行减压浓缩，将剩余物溶解于四氢呋喃中，得到酰氯的四氢呋喃溶液；之后将所述酰氯的四氢呋喃溶液、化合物I、三乙胺和四氢呋喃混合后进行第一酰化反应，得到化合物b。在本发明中，所述第一酰化反应的温度优选为室温，时间优选为1.5～2.5h，更优选为2h。所述第一酰化反应后，本发明优选将所得反应液进行减压浓缩以除去溶剂，加入水，用乙酸乙酯萃取，之后依次经1mol/L的HCl洗涤、饱和碳酸钠溶液洗涤、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，所得剩余物直接进行下一步反应。The present invention prepares compound c according to step (1-1). Specifically, in the present invention, it is preferred to mix compound a, N,N-dimethylformamide, tetrahydrofuran and thionyl chloride, react at 60 to 70° C. for 50 to 70 min, and then concentrate the obtained reaction solution under reduced pressure. , the residue is dissolved in tetrahydrofuran to obtain a solution of acid chloride in tetrahydrofuran; then the tetrahydrofuran solution of acid chloride, compound I, triethylamine and tetrahydrofuran are mixed to carry out the first acylation reaction to obtain compound b. In the present invention, the temperature of the first acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h. After the first acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated under reduced pressure to remove the solvent, added with water, extracted with ethyl acetate, and then washed with 1 mol/L HCl, washed with saturated sodium carbonate solution, and washed with water. , washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was directly subjected to the next reaction.
得到化合物b后，本发明将所述化合物b进行第一还原反应，得到化合物c。在本发明中，所述第一还原反应所用还原剂优选为铁粉，所述第一还原反应优选在氯化铵、乙醇和水存在条件下进行。在本发明中，所述第一还原反应的温度优选为70～90℃，更优选为80℃，时间优选为40～60min，更优选为50min。所述第一还原反应后，本发明优选将所得反应液冷却至室温，硅藻土抽滤，滤饼用乙醇淋洗，滤液减压浓缩至干；向残余物中加入水，用乙酸乙酯萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，所得剩余物直接进行下一步反应。After the compound b is obtained, the present invention performs the first reduction reaction on the compound b to obtain the compound c. In the present invention, the reducing agent used in the first reduction reaction is preferably iron powder, and the first reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water. In the present invention, the temperature of the first reduction reaction is preferably 70-90°C, more preferably 80°C, and the time is preferably 40-60 min, more preferably 50 min. After the first reduction reaction, in the present invention, the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
当Z为-O-或-S-时，得到化合c后，本发明将所述化合物c和化合物V进行第六酰化反应，得到第一中间体化合物；将所述第一中间体化合物和化合物III进行第一亲核取代反应，得到化合物e。在本发明中，所述第六酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第六酰化反应的温度优选为室温，时间优选为1.5～2.5h，更优选为2h。所述第六酰化反应后，本发明优选将所得反应液减压浓缩至干，向残余物中加入二氯甲烷溶解，得到中间体化合物溶液，备用。在本发明中，所述第一亲核取代反应优选在四氢呋喃(或二氯甲烷)和三乙胺存在条件下进行。在本发明中，所述第一亲核取代反应优选先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。所述第一亲核取代反后，本发明优选将所得反应液倒入水中，用二氯甲烷萃取，之后依次经1mol/L的HCl洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物经硅胶柱层析纯化(洗脱剂为EA∶PE＝1∶5(v/v))，得到化合物e。When Z is -O- or -S-, after the compound c is obtained, the present invention performs the sixth acylation reaction on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and Compound III undergoes a first nucleophilic substitution reaction to obtain compound e. In the present invention, the sixth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the sixth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h. After the sixth acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain an intermediate compound solution, which is for later use. In the present invention, the first nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine. In the present invention, the first nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h. After the first nucleophilic substitution is reversed, the present invention preferably pours the obtained reaction solution into water, extracts it with dichloromethane, and then successively washes with 1 mol/L HCl, water, saturated brine and anhydrous sodium sulfate, and then extracts the solution. Filtration, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: EA:PE=1:5 (v/v)) to obtain compound e.
当Z为-NH-时，得到化合c后，本发明将所述化合物c、N-Boc-硫脲、NaH和三氟乙酸酐(TFAA)混合，进行第二胺解反应，得到第二中间体化合物；将所述第二中间体化合物、化合物III和HgCl
2混合，进行脱硫羰基反应，得到第三中间体化合物；将所述第三中间体化合物在酸性条件下进行第一脱保护基反应，得到化合物e。在本发明中，所述第二胺解反应优选在四氢呋喃存在条件下进行；所述第二胺解反应的温度优选为0～25℃，时间优选2～24h。所述第二胺解反应后，本发明优选将所得体系冷却至0℃，缓慢加水淬灭，用乙酸乙酯萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物经硅胶柱层析纯化(洗脱剂优选为EA∶PE＝1∶3(v/v))，得到第二中间体。在本发明中，所述脱硫羰基反应优选在氯化汞、三乙胺和二氯甲烷存在条件下进行；所述脱硫羰基反应的温度优选为0～25℃，时间优选2～24h。所述脱硫羰基反应后，本发明优选将所得体系经硅藻土过滤，滤饼用乙酸乙酯洗涤，有机相依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物经硅胶柱层析纯化(洗脱剂优选为EA∶PE＝1∶3(v/v))，得到第三中间体。在本发明中，提供第一脱保护基反应所需酸性条件的试剂优选为三氟乙酸(TFA)；所述第一脱保护基反应优选在二氯甲烷存在条件下进行。在本发明中，所述第一脱保护基反应的温度优选为0～40℃，时间优选为30min～4h。所述第一脱保护基反应后，本发明优选将所得体系进行减压蒸馏，向所得剩余物中加入水和二氯甲烷，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用二氯甲烷萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物经硅胶柱层析纯化(洗脱剂优选为EA∶PE＝1∶1(v/v))，得到化合物e。
When Z is -NH-, after the compound c is obtained, the present invention mixes the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride (TFAA) to carry out the second aminolysis reaction to obtain the second intermediate intermediate compound; mix the second intermediate compound, compound III and HgCl , carry out a dethiocarbonyl reaction to obtain the third intermediate compound; carry out the first deprotection group reaction of the third intermediate compound under acidic conditions , to obtain compound e. In the present invention, the second aminolysis reaction is preferably carried out in the presence of tetrahydrofuran; the temperature of the second aminolysis reaction is preferably 0-25° C., and the time is preferably 2-24 h. After the second aminolysis reaction, the present invention preferably cools the obtained system to 0° C., slowly adds water to quench, extracts with ethyl acetate, then washes with water, saturated brine and anhydrous sodium sulfate in sequence, and suction filtration, The obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (the eluent is preferably EA:PE=1:3 (v/v)) to obtain the second intermediate. In the present invention, the desulfurization carbonylation reaction is preferably carried out in the presence of mercuric chloride, triethylamine and dichloromethane; the temperature of the desulfurization carbonylation reaction is preferably 0-25°C, and the time is preferably 2-24 h. After the desulfocarbonylation reaction, in the present invention, the obtained system is preferably filtered through diatomaceous earth, the filter cake is washed with ethyl acetate, the organic phase is washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtration, and the obtained filtrate is filtered. It was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (the eluent is preferably EA:PE=1:3 (v/v)) to obtain the third intermediate. In the present invention, the reagent for providing the acidic conditions required for the first deprotection reaction is preferably trifluoroacetic acid (TFA); the first deprotection reaction is preferably carried out in the presence of dichloromethane. In the present invention, the temperature of the first deprotection reaction is preferably 0 to 40° C., and the time is preferably 30 min to 4 h. After the first deprotection group reaction, in the present invention, the obtained system is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions, The organic layer was separated and removed, the aqueous layer was extracted with dichloromethane, washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography ( The eluent is preferably EA:PE=1:1 (v/v)) to give compound e.
得到化合物e后，本发明基于所述化合物e，按照步骤(1-1)制备得到具有式A所示结构的美金刚脲类衍生物，具体如下：After the compound e is obtained, the present invention, based on the compound e, prepares a memantamide derivative having the structure represented by the formula A according to the step (1-1), as follows:
当化合物e中R
6为-H时，得到化合物e后，本发明将所述化合物e、氯化亚砜和乙醇混合，进行酯化反应，得到R
4为-OEt的具有式A所示结构的美金刚脲类衍生物。在本发明中，所述化合物e、氯化亚砜和乙醇的用量比优选为(0.5～0.8)mmol∶(2～3)mmol∶(15～25)mL，更优选为0.66mmol∶2.65mmol∶20mL；所述酯化反应优选在体系回流条件下进行，所述酯化反应的时间优选为1.5～2.5h，更优选为2h。所述酯化反应后，本发明优选将所得反应液冷却至室温，减压浓缩除去乙醇，加入水，用乙酸乙酯萃取，之后依次经饱和碳酸钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将所得体系抽滤，滤饼用乙醚淋洗，干燥后得到R
4为-OEt的具有式A所示结构的美金刚脲类衍生物。
When R 6 in compound e is -H, after obtaining compound e, the present invention mixes compound e, thionyl chloride and ethanol, and carries out esterification reaction to obtain R 4 is -OEt and has the structure shown in formula A memantamide derivatives. In the present invention, the dosage ratio of the compound e, thionyl chloride and ethanol is preferably (0.5-0.8) mmol: (2-3) mmol: (15-25) mL, more preferably 0.66 mmol: 2.65 mmol : 20 mL; the esterification reaction is preferably carried out under the reflux condition of the system, and the time of the esterification reaction is preferably 1.5-2.5 h, more preferably 2 h. After the esterification reaction, the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove ethanol, adds water, extracts with ethyl acetate, and then successively washes with saturated aqueous sodium carbonate solution, washed with water, washed with saturated brine and anhydrous. Dry over sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue to make a slurry, filter the obtained system with suction, rinse the filter cake with ether, and dry to obtain R 4 is -OEt and has the formula A. Memantamide derivatives showing the structure.
或者，当化合物e中R
6为-H时，得到化合物e后，本发明将所述化合物e和化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第三酰化反应，得到具有式A所示结构的美金刚脲类衍生物。在本发明中，所述化合物e和化合物IV的摩尔比优选为1∶(1.8～2.2)，更优选为1∶2。在本发明中，所述化合物e、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑的摩尔比优选为1∶(1.3～1.7)∶(1.3～1.7)，更优选为1∶1.5∶1.5。在本发明中，所述第三酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第三酰化反应的温度优选为25～35℃，更优选为30℃；时间优选为6～10h，更优选为8h。所述第三酰化反应后，本发明优选将所得反应液倒入水中，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比优选为10∶1)萃取，之后依次经1mol/L盐酸洗、5wt％氢氧化钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到具有式A所示结构的美金刚脲类衍生物。
Or, when R 6 in compound e is -H, after obtaining compound e, the present invention mixes said compound e and compound IV, in 1-(3-dimethylaminopropyl)-3-ethylcarbon two The third acylation reaction is carried out in the presence of imine hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A. In the present invention, the molar ratio of the compound e and the compound IV is preferably 1:(1.8-2.2), more preferably 1:2. In the present invention, the molar ratio of compound e, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably 1:( 1.3-1.7):(1.3-1.7), more preferably 1:1.5:1.5. In the present invention, the third acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the third acylation reaction is preferably 25-35° C., more preferably 30° C.; the time is preferably 6-10 h, more preferably 8 h. After the third acylation reaction, the present invention preferably pours the obtained reaction solution into water, extracts it with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then sequentially conducts 1 mol/L Washed with hydrochloric acid, washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue to make a slurry, and the system obtained after beating was made Perform suction filtration, the filter cake is rinsed with ethyl acetate, and dried to obtain a memantamide derivative having the structure shown in formula A.
或者，当化合物e中R
6为-H时，得到化合物e后，本发明将所述化合物e在氯化亚砜存在条件下进行氯代反应，得到酰氯中间体；将所述酰氯中间体和化合物IV进行第四酰化反应，得到具有式A所示结构的美金刚脲类衍生物。在本发明中，所述氯代反应优选在N，N-二甲基甲酰胺和二氯甲烷存在条件下进行。在本发明中，所述氯代反应优选在室温条件下进行，所述氯代反应的时间优选为20～40min，更优选为30min。所述氯代反应后，本发明优选将所得反应液冷减压浓缩除去溶剂，备用。在本发明中，所述酰氯中间体和化合物IV的摩尔比优选为1∶(1.0～1.5)，更优选为1∶1.1。在本发明中，所述第四酰化反应优选在三乙胺和二氯甲烷存在条件下进行；所述第四酰化反应的温度优选为-10～40℃，更优选为0℃，时间优选为1～6h，更优选为2h。所述第四酰化反应后，本发明优选向所得产物体系中加入水，用二氯甲烷萃取，之后依次经1mol/L的HCl洗涤、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，所得剩余物经硅胶柱层析纯化(洗脱剂优选为DCM∶MeOH＝50∶1(v/v))，洗脱液浓缩后，向所得残余物中加入乙醚打浆，抽滤，滤饼用乙醚淋洗，干燥后得到具有式A所示结构的美金刚脲类衍生物。
Or, when R 6 in compound e is -H, after obtaining compound e, in the present invention, the compound e is subjected to chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and Compound IV is subjected to the fourth acylation reaction to obtain a memantamide derivative having the structure shown in formula A. In the present invention, the chlorination reaction is preferably carried out in the presence of N,N-dimethylformamide and dichloromethane. In the present invention, the chlorination reaction is preferably carried out at room temperature, and the time of the chlorination reaction is preferably 20-40 min, more preferably 30 min. After the chlorination reaction, in the present invention, preferably, the obtained reaction solution is cooled and concentrated under reduced pressure to remove the solvent, and is for later use. In the present invention, the molar ratio of the acid chloride intermediate and compound IV is preferably 1:(1.0-1.5), more preferably 1:1.1. In the present invention, the fourth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fourth acylation reaction is preferably -10 to 40°C, more preferably 0°C, and the time It is preferably 1 to 6 hours, and more preferably 2 hours. After the fourth acylation reaction, the present invention preferably adds water to the obtained product system, extracts with dichloromethane, then successively washes with 1 mol/L HCl, water, saturated brine, and anhydrous sodium sulfate drying, suction filtration , the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (the eluent is preferably DCM:MeOH=50:1 (v/v)). After the eluent was concentrated, the obtained residue was added Diethyl ether is slurried, suction filtered, the filter cake is rinsed with diethyl ether, and dried to obtain a memantamide derivative having the structure shown in formula A.
当化合物e中R
6为C
1～C
6的烷基时，得到化合物e后，本发明将所述化合物e经水解反应后，再与化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第五酰化反应，得到具有式A所示结构的美金刚脲类衍生物。在本发明中，所述水解反应优选在氢氧化钠溶液和乙醇存在条件下进行，所述水解反应的温度优选为25～70℃，时间优选为30min～6h。在本发明中，所述第五酰化反应优选在三乙胺和二氯甲烷存在条件下进行；所述第五酰化反应温度优选为0～40℃，时间优选为1～8h。所述第五酰化反应后，本发明优选将所得体系加入水，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比优选为10∶1)萃取，之后依次经1mol/L盐酸洗、5wt％氢氧化钠水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到具有式A所示结构的美金刚脲类衍生物。
When R 6 in compound e is a C 1 -C 6 alkyl group, after obtaining compound e, in the present invention, the compound e is subjected to hydrolysis reaction, and then mixed with compound IV to obtain a 1-(3-dimethylamino group) The fifth acylation reaction is carried out in the presence of propyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a memantamide derivative having the structure shown in formula A. In the present invention, the hydrolysis reaction is preferably carried out in the presence of sodium hydroxide solution and ethanol, the temperature of the hydrolysis reaction is preferably 25-70°C, and the time is preferably 30min-6h. In the present invention, the fifth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane; the temperature of the fifth acylation reaction is preferably 0-40° C., and the time is preferably 1-8 h. After the fifth acylation reaction, in the present invention, the obtained system is preferably added to water, extracted with a dichloromethane-methanol mixed solution (the volume ratio of dichloromethane and methanol is preferably 10:1), and then washed with 1 mol/L hydrochloric acid successively. , washed with 5wt% sodium hydroxide aqueous solution, washed with water, washed with saturated brine and dried with anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure, ethyl acetate was added to the obtained residue for beating, and the obtained system after beating was pumped. filter, the filter cake is rinsed with ethyl acetate, and after drying, a memantamide derivative having the structure shown in formula A is obtained.
在本发明的实施例中，当化合物a为3-氯-4-硝基苯甲酸、化合物I为哌啶-3-甲酸乙酯、化合物V为固体光气、化合物III为美金刚、化合物IV为氨气时，经上述反应所得具有式A所示结构的美金刚脲类衍生物具体为化合物GL-B435。In the embodiment of the present invention, when compound a is 3-chloro-4-nitrobenzoic acid, compound I is ethyl piperidine-3-carboxylate, compound V is solid phosgene, compound III is memantine, and compound IV In the case of ammonia gas, the memantamide derivative having the structure shown in formula A obtained by the above reaction is specifically compound GL-B435.
第二种情况，制备具有式B所示结构的美金刚脲类衍生物，如图3所示，具体的，(2-1)当R
3为除卤素基团以外的基团时，制备方法包括以下步骤：
In the second case, a memantamide derivative having the structure shown in formula B is prepared, as shown in Figure 3, specifically, (2-1) When R 3 is a group other than a halogen group, the preparation method Include the following steps:
将化合物VI和化合物a进行第七酰化反应，得到化合物f；The seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;
将所述化合物f进行第二还原反应，得到化合物g；The compound f is subjected to a second reduction reaction to obtain compound g;
将所述化合物g和化合物II进行第八酰化反应，得到化合物h；The compound g and compound II are subjected to the eighth acylation reaction to obtain compound h;
将所述化合物h和化合物III进行第三胺解反应，得到化合物i；The compound h and compound III are subjected to a third aminolysis reaction to obtain compound i;
将所述化合物i在酸性条件下进行第二脱保护基反应，得到X为-NH
2的具有式B所示结构的美金刚脲类衍生物，记为化合物j；
The compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;
将所述化合物j和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第九酰化反应，得到X为
的具有式B所述结构的美金刚脲类衍生物；
The compound j and compound VII are mixed, and the ninth acylamide is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. chemical reaction to obtain X as The memantamide derivatives having the structure described in formula B;
将所述化合物j和化合物VIII进行第十酰化反应，得到X为
的具有式B所述结构的美金刚脲类衍生物；
The compound j and compound VIII are subjected to tenth acylation reaction to obtain X as The memantamide derivatives having the structure described in formula B;
其中，所述化合物VI和化合物VII的结构式依次为：
Wherein, the structural formulas of described compound VI and compound VII are successively:
所述化合物VIII的结构式为：
The structural formula of the compound VIII is:
所述化合物f、化合物g、化合物h、化合物i以及化合物j的结构式如下：The structural formulas of the compound f, compound g, compound h, compound i and compound j are as follows:
本发明将化合物VI和化合物a进行第七酰化反应，得到化合物f。在本发明中，所述化合物VI和化合物a的摩尔比优选为1∶(0.8～1.2)，更优选为1∶1。在本发明中，所述第七酰化反应优选在三乙胺和四氢呋喃存在条件下进行。在本发明中，所述第七酰化反应的温度优选为室温，所述第七酰化反应的时间优选为1.5～2.5h，更优选为2h。所述第七酰化反应后，本发明优选将所得反应液进行减压浓缩以除去大部分溶剂，向所得剩余物中加入水，采用乙酸乙酯萃取，有机层依次经水洗、饱和食盐水洗和无水硫酸镁干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物直接进行下一步反应。In the present invention, compound VI and compound a are subjected to the seventh acylation reaction to obtain compound f. In the present invention, the molar ratio of the compound VI and the compound a is preferably 1:(0.8-1.2), more preferably 1:1. In the present invention, the seventh acylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran. In the present invention, the temperature of the seventh acylation reaction is preferably room temperature, and the time of the seventh acylation reaction is preferably 1.5-2.5 h, more preferably 2 h. After the seventh acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added to the obtained residue, extracted with ethyl acetate, and the organic layer is washed with water, saturated brine and dried over anhydrous magnesium sulfate, suction filtered, the filtrate obtained was concentrated under reduced pressure, and the obtained residue was directly subjected to the next reaction.
得到化合物f后，本发明将所述化合物f进行第二还原反应，得到化合物g。在本发明中，所述第二还原反应所用还原剂、第二催化剂的种类、第二还原反应的条件以及后处理方法优选与步骤(1-1)中第一还原反应所用还原剂、第一催化剂的种类、第一还原反应以及后处理方法一致，在此不再赘述。After the compound f is obtained, the present invention performs the second reduction reaction on the compound f to obtain the compound g. In the present invention, the reducing agent used in the second reduction reaction, the type of the second catalyst, the conditions of the second reduction reaction and the post-treatment method are preferably the same as the reducing agent used in the first reduction reaction in step (1-1). The type of catalyst, the first reduction reaction and the post-treatment method are the same, and will not be repeated here.
得到化合物g后，本发明将所述化合物g和化合物II进行第八酰化反应，得到化合物h。在本发明中，所述化合物g和化合物II的摩尔比优选为1∶(1～2)，更优选为1∶(0.2～1.7)。在本发明中，所述第八酰化反应优选在碳酸钾和四氢呋喃存在条件下进行。在本发明中，所述第八酰化反应优选在室温条件下进行，所述第八酰化反应的时间优选为5～8h，更优选为6h。所述第八酰化反应后，本发明优选将所得反应液进行减压浓缩以除去大部分溶剂，加入水，采用乙酸乙酯萃取，有机层依次经水洗、饱和食盐水洗和无水硫酸镁干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到化合物h。After the compound g is obtained, the present invention performs the eighth acylation reaction between the compound g and the compound II to obtain the compound h. In the present invention, the molar ratio of the compound g to the compound II is preferably 1:(1-2), more preferably 1:(0.2-1.7). In the present invention, the eighth acylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran. In the present invention, the eighth acylation reaction is preferably carried out at room temperature, and the time of the eighth acylation reaction is preferably 5-8h, more preferably 6h. After the eighth acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added, and ethyl acetate is used for extraction, and the organic layer is washed with water, washed with saturated brine and dried over anhydrous magnesium sulfate. , suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and dried to obtain compound h.
得到化合物h后，本发明将所述化合物h和化合物III进行第三胺解反应，得到化合物i。在本发明中，所述化合物h和化合物III的摩尔比优选为1∶(0.8～1.3)，更优选为1∶1.1。在本发明中，所述第三胺解反应优选在三乙胺和四氢呋喃存在条件下进行。在本发明中，所述第三胺解反应优选在体系回流条件下进行，所述第三胺解反应的时间优选为6～10h，更优选为8h。所述第三胺解反应后，本发明优选将所得反应液冷却至室温，减压浓缩以除去溶剂，加入水，采用乙酸乙酯萃取，之后依次经饱和碳酸钠洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到化合物i。After the compound h is obtained, the present invention performs the third aminolysis reaction on the compound h and the compound III to obtain the compound i. In the present invention, the molar ratio of the compound h and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1. In the present invention, the third aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran. In the present invention, the third aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the third aminolysis reaction is preferably 6-10 hours, more preferably 8 hours. After the third aminolysis reaction, the present invention preferably cools the obtained reaction solution to room temperature, concentrates under reduced pressure to remove the solvent, adds water, extracts with ethyl acetate, and then sequentially washes with saturated sodium carbonate, water, and saturated brine. Dry over anhydrous sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain compound i.
得到化合物i后，本发明将所述化合物i在酸性条件下进行第二脱保护基反应，得到X为-NH
2的具有式B所示结构的美金刚脲类衍生物，记为化合物j。在本发明中，提供酸性条件的试剂优选为三氟乙酸，所述第二脱保护基反应优选在二氯甲烷条件下进行。在本发明中，所述第二脱保护基反应的温度优选为室温，时间优选为1.5～2.5h。所述第二脱保护基反应后，本发明优选将所得反应液进行减压蒸馏，向所得剩余物中加入水和二氯甲烷，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用二氯甲烷萃取(100mL×2)，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到X为-NH
2的具有式B所示结构的美金刚脲类衍生物，记为化合物j。
After the compound i is obtained, the present invention performs the second deprotection group reaction on the compound i under acidic conditions to obtain a memantamide derivative having the structure represented by formula B, where X is -NH 2 , which is denoted as compound j. In the present invention, the reagent for providing acidic conditions is preferably trifluoroacetic acid, and the second deprotection reaction is preferably carried out under the condition of dichloromethane. In the present invention, the temperature of the second deprotection group reaction is preferably room temperature, and the time is preferably 1.5-2.5 h. After the second deprotection group reaction, in the present invention, the obtained reaction solution is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions. , the organic layer was separated and removed, the aqueous layer was extracted with dichloromethane (100 mL×2), washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure. Diethyl ether was added for beating, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with diethyl ether, and dried to obtain a memantamide derivative with the structure represented by formula B in which X was -NH 2 , denoted as compound j.
得到化合物j后，本发明将所述化合物j和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBt)存在条件下进行第九酰化反应，得到X为
的具有式B所述结构的美金刚脲类衍生物。在本发明中，所述化合物j和化合物VII的摩尔比优选为1∶(1.5～2.5)；更优选为1∶2。在本发明中，所述第九酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第九酰化反应的温度优选为20～40℃，更优选为30℃，时间优选为6～10h，更优选为8h。所述第九酰化反应后，本发明优选将所得反应液倒入水中，采用二氯甲烷萃取，有机层依次经1mol/L盐酸洗、5wt％NaOH水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到X为
的具有式B所述结构的美金刚脲类衍生物。
After obtaining compound j, the present invention mixes the compound j and compound VII, in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzene The ninth acylation reaction is carried out in the presence of triazole (HOBt) to obtain X as The memantamide derivatives having the structure described in formula B. In the present invention, the molar ratio of the compound j and the compound VII is preferably 1:(1.5-2.5); more preferably, 1:2. In the present invention, the ninth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the ninth acylation reaction is preferably 20˜40° C., more preferably 30° C., and the time is preferably 6˜10 h, more preferably 8 h. After the ninth acylation reaction, the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the organic layer is washed with 1mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine and anhydrous. Drying with sodium sulfate, suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and X is obtained after drying. The memantamide derivatives having the structure described in formula B.
得到化合物j后，本发明将所述化合物j和化合物VIII进行第十酰化反应，得到X为
的具有式B所述结构的美金刚脲类衍生物。在本发明中，所述化合物j和化合物VIII的摩尔比优选为1∶(1.5～2.5)；更优选为1∶2。在本发明中，所述第十酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第十酰化反应的温度优选为室温，时间优选为1.5～2.5h，更优选为2h。所述第十酰化反应后，本发明优选将所得反应液倒入水中，采用二氯甲烷萃取，所得有机层依次经6mol/L盐酸洗、5wt％NaOH水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到X为
的具有式B所述结构的美金刚脲类衍生物。
After obtaining compound j, the present invention performs tenth acylation reaction on the compound j and compound VIII to obtain X as The memantamide derivatives having the structure described in formula B. In the present invention, the molar ratio of the compound j and the compound VIII is preferably 1:(1.5-2.5); more preferably, it is 1:2. In the present invention, the tenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the tenth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h. After the tenth acylation reaction, the present invention preferably pours the obtained reaction solution into water, and extracts it with dichloromethane. Dry over sodium sulfate, suction filtration, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and obtain X after drying. The memantamide derivatives having the structure described in formula B.
在本发明中，制备具有式B所示结构的美金刚脲类衍生物，如图4所示，具体的，(2-2)当R
3为卤素基团时，制备方法包括以下步骤：
In the present invention, a memantamide derivative having the structure shown in formula B is prepared, as shown in Figure 4, specifically, (2-2) when R 3 is a halogen group, the preparation method includes the following steps:
按照步骤(2-1)制备化合物g；Compound g was prepared according to step (2-1);
将所述化合物g和化合物V进行第十一酰化反应，得到第四中间体化合物；The eleventh acylation reaction of compound g and compound V is carried out to obtain the fourth intermediate compound;
将所述第四中间体化合物和化合物III进行第二亲核取代反应，得到化合物h；The fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;
基于所述化合物h，按照步骤(2-1)制备得到具有式B所示结构的美金刚脲类衍生物。Based on the compound h, according to step (2-1), a memantamide derivative having the structure represented by formula B was prepared.
本发明按照步骤(2-1)制备化合物g，具体的，本发明将化合物VI和化合物a进行第七酰化反应，得到化合物f。在本发明中，所述化合物VI和化合物a的配比、第七酰化反应的条件以及后处理方法优选与步骤(2-1)一致，在此不再赘述。The present invention prepares compound g according to step (2-1). Specifically, the present invention performs the seventh acylation reaction of compound VI and compound a to obtain compound f. In the present invention, the ratio of the compound VI and the compound a, the conditions of the seventh acylation reaction and the post-treatment method are preferably the same as those in step (2-1), and will not be repeated here.
得到化合物f后，本发明将所述化合物f进行第二还原反应，得到化合物h。在本发明中，所述第二还原反应所用还原剂优选为铁粉，所述第二还原反应优选在氯化铵、乙醇和水存在条件下进行。在本发明中，所述第二还原反应的温度优选为70～90℃，更优选为80℃，时间优选为40～60min，更优选为50min。所述第二还原反应后，本发明优选将所得反应液冷却至室温，硅藻土抽滤，滤饼用乙醇淋洗，滤液减压浓缩至干；向残余物中加入水，用乙酸乙酯萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，所得剩余物直接进行下一步反应。After the compound f is obtained, the present invention performs the second reduction reaction on the compound f to obtain the compound h. In the present invention, the reducing agent used in the second reduction reaction is preferably iron powder, and the second reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water. In the present invention, the temperature of the second reduction reaction is preferably 70-90° C., more preferably 80° C., and the time is preferably 40-60 min, more preferably 50 min. After the second reduction reaction, in the present invention, the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
得到化合物g后，本发明将化合物g和化合物V进行第十一酰化反应，得到第四中间体化合物；将所述第四中间体化合物和化合物III进行第二亲核取代反应，得到化合物h。在本发明中，所述第十一酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第十一酰化反应的温度优选为室温，时间优选为1.5～2.5h，更优选为2h。所述第十一酰化反应后，本发明优选将所得反应液减压浓缩至干，向残余物中加入二氯甲烷溶解，得到第四中间体化合物溶液，备用。在本发明中，所述第二亲核取代反应优选在四氢呋喃(或二氯甲烷)和三乙胺存在条件下进行。在本发明中，所述第二亲核取代反应优选先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。所述第二亲核取代反后，本发明优选将所得反应液倒入水中，用二氯甲烷萃取，之后依次经1mol/L的HCl洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物经硅胶柱层析纯化(洗脱剂为EA∶PE＝1∶5(v/v))，得到化合物h。After obtaining compound g, the present invention performs eleventh acylation reaction with compound g and compound V to obtain a fourth intermediate compound; the fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h . In the present invention, the eleventh acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the eleventh acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h. After the eleventh acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain a fourth intermediate compound solution, which is for later use. In the present invention, the second nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine. In the present invention, the second nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h. After the second nucleophilic substitution is reversed, the present invention preferably pours the obtained reaction solution into water, extracts it with dichloromethane, and then successively washes with 1 mol/L HCl, water, saturated brine, and anhydrous sodium sulfate, and then dry with suction. Filtration, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: EA:PE=1:5 (v/v)) to obtain compound h.
得到化合物h后，本发明基于所述化合物h，按照步骤(2-1)制备得到具有式B所示结构的美金刚脲类衍生物，在此不再赘述。After the compound h is obtained, the present invention prepares the memantamide derivative having the structure represented by the formula B based on the compound h according to step (2-1), which will not be repeated here.
第三种情况，制备具有式C所示结构的美金刚脲类衍生物，如图5所示，具体的，(3-1)当R
3为除卤素基团以外的基团时，制备方法包括以下步骤：
In the third case, a memantamide derivative having the structure shown in formula C is prepared, as shown in Figure 5, specifically, (3-1) When R 3 is a group other than a halogen group, the preparation method Include the following steps:
将化合物IX和化合物a进行第十二酰化反应，得到化合物k；The dodecanoylation reaction of compound IX and compound a is carried out to obtain compound k;
将所述化合物k进行第三还原反应，得到化合物l；The compound k is subjected to a third reduction reaction to obtain compound 1;
将所述化合物l和化合物II进行第十三酰化反应，得到化合物m；The compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;
将所述化合物m和化合物III进行第四胺解反应，得到化合物n；The compound m and compound III are subjected to the fourth aminolysis reaction to obtain compound n;
将所述化合物n在酸性条件下进行第三脱保护基反应，得到Y为-H的具有式C所示结构的美金刚脲类衍生物，记为化合物o；The compound n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;
将所述化合物0和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第十四酰化反应，得到Y为
的具有式C所述结构的美金刚脲类衍生物；
Mixing the compound 0 and compound VII, carrying out the fourteenth step in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole Acylation reaction to obtain Y as The memantamide derivatives having the structure described in formula C;
将所述化合物o和化合物VIII进行第十五酰化反应，得到Y为
的具有式C所述结构的美金刚脲类衍生物；
The compound o and compound VIII are subjected to pentadecyl acylation to obtain Y as The memantamide derivatives having the structure described in formula C;
其中，所述化合物IX的结构式为：
Wherein, the structural formula of described compound IX is:
所述化合物k、化合物l、化合物m、化合物n以及化合物o的结构式如下：The structural formulas of the compound k, compound 1, compound m, compound n and compound o are as follows:
本发明将化合物IX和化合物a进行第十二酰化反应，得到化合物k。在本发明中，所述化合物IX和化合物a的摩尔比优选为1∶(0.8～1.2)，更优选为1∶1。在本发明中，所述第十二酰化反应优选在三乙胺和四氢呋喃存在的条件下进行。在本发明中，所述第十二酰化反应的温度优选为室温，所述第十二酰化反应的时间优选为1.5～2.5h，更优选为2h。所述第十二酰化反应后，本发明优选将所得反应液进行减压浓缩以除去大部分溶剂，向所得剩余物中加入水，采用乙酸乙酯萃取，有机层依次采用水洗、饱和食盐水洗和无水硫酸镁干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到化合物k。In the present invention, compound IX and compound a are subjected to dodecanoylation reaction to obtain compound k. In the present invention, the molar ratio of the compound IX to the compound a is preferably 1:(0.8-1.2), more preferably 1:1. In the present invention, the dodecanoylation reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran. In the present invention, the temperature of the dodecanoylation reaction is preferably room temperature, and the time of the dodecanoylation reaction is preferably 1.5-2.5 h, more preferably 2 h. After the dodecanoylation reaction, in the present invention, the obtained reaction solution is preferably concentrated under reduced pressure to remove most of the solvent, water is added to the obtained residue, extracted with ethyl acetate, and the organic layer is washed with water and saturated brine successively. Drying with anhydrous magnesium sulfate, suction filtration, the obtained filtrate was concentrated under reduced pressure, ether was added to the obtained residue for beating, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with ether, and dried to obtain compound k.
得到化合物k后，本发明将所述化合物l进行第三还原反应，得到化合物l。在本发明中，所述第三还原反应所用还原剂优选为氢气，所用催化剂优选为Pd-C；所述第三还原反应优选在无水乙醇存在条件下进行。在本发明中，所述第三还原反应的温度优选为25～70℃，更优选为60℃，时间优选为10～15h，更优选为12h。第三还原反应后，本发明优选待反应液冷却至室温后，抽滤，滤液经减压浓缩，得到化合物l。After the compound k is obtained, the present invention performs the third reduction reaction on the compound 1 to obtain the compound 1. In the present invention, the reducing agent used in the third reduction reaction is preferably hydrogen, and the catalyst used is preferably Pd-C; the third reduction reaction is preferably carried out in the presence of anhydrous ethanol. In the present invention, the temperature of the third reduction reaction is preferably 25-70°C, more preferably 60°C, and the time is preferably 10-15h, more preferably 12h. After the third reduction reaction, in the present invention, preferably, after the reaction solution is cooled to room temperature, suction filtration, and the filtrate is concentrated under reduced pressure to obtain compound 1.
得到化合物l后，本发明将所述化合物l和化合物II进行第十三酰化反应，得到化合物m。在本发明中，所述化合物l和化合物II的摩尔比优选为1∶(1～2)，更优选为1∶(0.2～1.7)。在本发明中，所述第十三酰化反应优选在碳酸钾和四氢呋喃存在条件下进行。在本发明中，所述第十三酰化反应优选在室温条件下进行，所述第十三酰化反应的时间优选为5～8h，更优选为6h。所述第十三酰化反应后，本发明优选将所得反应液进行减压浓缩以除去大部分溶剂，加入水，采用乙酸乙酯萃取，有机层依次经水洗、饱和食盐水洗和无水硫酸镁干燥，抽滤，将所得滤 液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到化合物m。After the compound 1 is obtained, the present invention performs the tridecacylation reaction of the compound 1 and the compound II to obtain the compound m. In the present invention, the molar ratio of the compound I and the compound II is preferably 1:(1-2), more preferably 1:(0.2-1.7). In the present invention, the tridecylation reaction is preferably carried out in the presence of potassium carbonate and tetrahydrofuran. In the present invention, the tridecylation reaction is preferably carried out at room temperature, and the time for the tridecaylation reaction is preferably 5 to 8 hours, more preferably 6 hours. After the thirteen acylation reaction, the present invention preferably concentrates the obtained reaction solution under reduced pressure to remove most of the solvent, adds water, extracts with ethyl acetate, and the organic layer is washed with water, saturated brine and anhydrous magnesium sulfate in turn. Drying, suction filtration, the obtained filtrate is concentrated under reduced pressure, ether is added to the obtained residue for beating, the system obtained after beating is subjected to suction filtration, the filter cake is rinsed with ether, and compound m is obtained after drying.
得到化合物m后，本发明将所述化合物m和化合物III进行第四胺解反应，得到化合物n。在本发明中，所述化合物m和化合物III的摩尔比优选为1∶(0.8～1.3)，更优选为1∶1.1。在本发明中，所述第四胺解反应优选在三乙胺和四氢呋喃存在条件下进行。在本发明中，所述第四胺解反应优选在体系回流条件下进行，所述第四胺解反应的时间优选为6～10h，更优选为8h。所述第四胺解反应后，本发明优选将所得反应液冷却至室温，抽滤，滤饼用四氢呋喃淋洗，干燥后得到化合物n。After the compound m is obtained, the present invention performs the fourth aminolysis reaction on the compound m and the compound III to obtain the compound n. In the present invention, the molar ratio of the compound m and the compound III is preferably 1:(0.8-1.3), more preferably 1:1.1. In the present invention, the fourth aminolysis reaction is preferably carried out in the presence of triethylamine and tetrahydrofuran. In the present invention, the fourth aminolysis reaction is preferably carried out under the reflux condition of the system, and the time of the fourth aminolysis reaction is preferably 6-10 hours, more preferably 8 hours. After the fourth aminolysis reaction, in the present invention, the obtained reaction solution is preferably cooled to room temperature, filtered with suction, the filter cake is rinsed with tetrahydrofuran, and dried to obtain compound n.
得到化合物n后，本发明将所述化合物n在酸性条件下进行第三脱保护基反应，得到Y为-H的具有式C所示结构的美金刚脲类衍生物，记为化合物o。在本发明中，提供酸性条件的试剂优选为三氟乙酸，所述第三脱保护基反应优选在二氯甲烷条件下进行。在本发明中，所述第三脱保护基反应的温度优选为室温，时间优选为3.5～4.5h，更优选为4h。所述第三脱保护基反应后，本发明优选将所得反应液进行减压蒸馏，向所得剩余物中加入水和二氯甲烷，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用二氯甲烷萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到Y为-H的具有式C所示结构的美金刚脲类衍生物，记为化合物o。After the compound n is obtained, the present invention performs the third deprotection group reaction on the compound n under acidic conditions to obtain a memantamide derivative with the structure represented by formula C in which Y is -H, which is denoted as compound o. In the present invention, the reagent for providing acidic conditions is preferably trifluoroacetic acid, and the third deprotecting group reaction is preferably carried out under the condition of dichloromethane. In the present invention, the temperature of the third deprotecting group reaction is preferably room temperature, and the time is preferably 3.5-4.5 h, more preferably 4 h. After the third deprotection group reaction, in the present invention, the obtained reaction solution is preferably subjected to vacuum distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 14 with sodium hydroxide solid under ice-water bath conditions. , the organic layer was separated and removed, the aqueous layer was extracted with dichloromethane, washed with water, washed with saturated brine and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure. After beating, the obtained system is subjected to suction filtration, the filter cake is rinsed with diethyl ether, and dried to obtain a memantamide derivative having the structure represented by formula C in which Y is -H, denoted as compound o.
得到化合物o后，本发明将所述化合物o和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并三唑(HOBt)存在条件下进行第十四酰化反应，得到Y为
的具有式C所述结构的美金刚脲类衍生物。在本发明中，所述化合物o和化合物VII的摩尔比优选为1∶(1.5～2.5)；更优选为1∶2。在本发明中，所述第十四酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第十四酰化反应的温度优选为20～40℃，更优选为30℃，时间优选为6～10h，更优选为8h。所述第十四酰化反应后，本发明优选将所得反应液倒入水中，采用二氯甲烷萃取，有机层依次经1mol/L盐酸洗、5wt％NaOH水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到Y为
的具有式C所述结构的美金刚脲类衍生物。
After the compound o is obtained, the present invention mixes the compound o with the compound VII, in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzene The fourteen acylation reaction is carried out in the presence of triazole (HOBt) to obtain Y as The memantamide derivatives having the structure described in formula C. In the present invention, the molar ratio of the compound o to the compound VII is preferably 1:(1.5-2.5); more preferably, it is 1:2. In the present invention, the fourteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the fourteenth acylation reaction is preferably 20-40° C., more preferably 30° C., and the time is preferably 6-10 h, more preferably 8 h. After the fourteenth acylation reaction, the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the organic layer is washed with 1 mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine, and washed with water. Dry over sodium sulfate, suction filtration, concentrate the obtained filtrate under reduced pressure, add ether to the obtained residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and obtain Y after drying. The memantamide derivatives having the structure described in formula C.
得到化合物o后，本发明将所述化合物o和化合物VIII进行第十五酰化反应，得到Y为
的具有式C所述结构的美金刚脲类衍生物。在本发明中，所述化合物o和化合物VIII的摩尔比优选为1∶(1.5～2.5)；更优选为1∶2。在本发明中，所述第十五酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第十五酰化反应的温度优选为室温，时间优选为1.5～2.5h，更优选为2h。所述第十五酰化反应后，本发明优选将所得反应液倒入水中，采用二氯甲烷萃取，所得有机层依次经6mol/L盐酸洗、5wt％NaOH水溶液洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，向所得剩余物中加入乙醚打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到Y为
的具有式C所述结构的美金刚脲类衍生物。
After the compound o is obtained, the present invention carries out the pentadecyl acylation reaction of the compound o and the compound VIII to obtain Y as The memantamide derivatives having the structure described in formula C. In the present invention, the molar ratio of the compound o to the compound VIII is preferably 1:(1.5-2.5); more preferably, it is 1:2. In the present invention, the fifteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the pentadecyl acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h. After the fifteenth acylation reaction, the present invention preferably pours the obtained reaction solution into water, extracts with dichloromethane, and the obtained organic layer is washed with 6mol/L hydrochloric acid, washed with 5wt% NaOH aqueous solution, washed with water, washed with saturated brine and washed with water. Dry over anhydrous sodium sulfate, filter with suction, concentrate the obtained filtrate under reduced pressure, add ether to the residue for beating, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain Y as The memantamide derivatives having the structure described in formula C.
在本发明中，制备具有式C所示结构的美金刚脲类衍生物，如图6所示，具体的，(3-2)当R
3为卤素基团时，制备方法包括以下步骤：
In the present invention, the memantamide derivatives having the structure shown in formula C are prepared, as shown in Figure 6, specifically, (3-2) when R 3 is a halogen group, the preparation method comprises the following steps:
按照步骤(3-1)制备化合物l； Compound 1 was prepared according to step (3-1);
将化合物l和化合物V进行第十六酰化反应，得到第五中间体化合物； Compound 1 and compound V are subjected to sixteen acylation reaction to obtain the fifth intermediate compound;
将所述第五中间体化合物和化合物III进行第三亲核取代反应，得到化合物n；The fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;
基于所述化合物n，按照步骤(3-1)制备得到具有式C所示结构的美金刚脲类衍生物。Based on the compound n, according to step (3-1), a memantamide derivative having the structure represented by formula C is prepared.
本发明按照步骤(3-1)制备化合物l，具体的，本发明将化合物IX和化合物a进行第十二酰化反应，得到化合物k。在本发明中，所述合物IX和化合物a的配比、第十二酰化反应的条件以及后处理方法优选与步骤(3-1)一致，在此不再赘述。The present invention prepares compound 1 according to step (3-1). Specifically, in the present invention, compound IX and compound a are subjected to dodecanoylation reaction to obtain compound k. In the present invention, the ratio of the compound IX to the compound a, the conditions of the dodecanoylation reaction and the post-treatment method are preferably the same as those in step (3-1), and will not be repeated here.
得到化合物k后，本发明将所述化合物k进行第三还原反应，得到化合物l。在本发明中，所述第三还原反应所用还原剂优选为铁粉，所述第三还原反应优选在氯化铵、乙醇和水存在条件下进行。在本发明中，所述第三还原反应的温度优选为70～90℃，更优选为80℃，时间优选为40～60min，更优选为50min。所述第三还原反应后，本发明优选将所得反应液冷却至室温，硅藻土抽滤，滤饼用乙醇淋洗，滤液减压浓缩至干；向残余物中加入水，用乙酸乙酯萃取，之后依次经水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，所得剩余物直接进行下一步反应。After the compound k is obtained, the present invention performs the third reduction reaction on the compound k to obtain the compound l. In the present invention, the reducing agent used in the third reduction reaction is preferably iron powder, and the third reduction reaction is preferably carried out in the presence of ammonium chloride, ethanol and water. In the present invention, the temperature of the third reduction reaction is preferably 70-90° C., more preferably 80° C., and the time is preferably 40-60 min, more preferably 50 min. After the third reduction reaction, in the present invention, the obtained reaction solution is preferably cooled to room temperature, filtered through diatomaceous earth, the filter cake is rinsed with ethanol, and the filtrate is concentrated to dryness under reduced pressure; water is added to the residue, and ethyl acetate is used. After extraction, washing with water, saturated brine, and drying over anhydrous sodium sulfate in sequence, suction filtration, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is directly subjected to the next reaction.
得到化合物l后，本发明将化合物l和化合物V进行第十六酰化反应，得到第五中间体化合物；将所述第五中间体化合物和化合物III进行第三亲核取代反应，得到化合物l。在本发明中，所述第十六酰化反应优选在三乙胺和二氯甲烷存在条件下进行。在本发明中，所述第十六酰化反应的温度优选为室温，时间优选为1.5～2.5h，更优选为2h。所述第十六酰化反应后，本发明优选将所得反应液减压浓缩至干，向残余物中加入二氯甲烷溶解，得到第五中间体化合物溶液，备用。在本发明中，所述第三亲核取代反应优选在四氢呋喃(或二氯甲烷)和三乙胺存在条件下进行。在本发明中，所述第三亲核取代反应优选先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。所述第三亲核取代反后，本发明优选将所得反应液倒入水中，用二氯甲烷萃取，之后依次经1mol/L的HCl洗、水洗、饱和食盐水洗和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，将所得剩余物经硅胶柱层析纯化(洗脱剂为EA∶PE＝1∶5(v/v))，得到化合物n。After obtaining compound 1, the present invention performs sixteen acylation reaction with compound 1 and compound V to obtain the fifth intermediate compound; the fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound 1 . In the present invention, the sixteenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present invention, the temperature of the sixteen acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 h, more preferably 2 h. After the sixteenth acylation reaction, in the present invention, the obtained reaction solution is preferably concentrated to dryness under reduced pressure, and dichloromethane is added to the residue for dissolution to obtain a fifth intermediate compound solution, which is for later use. In the present invention, the third nucleophilic substitution reaction is preferably carried out in the presence of tetrahydrofuran (or dichloromethane) and triethylamine. In the present invention, the third nucleophilic substitution reaction is preferably carried out at room temperature for 1.5-2.5 h, and then under the reflux condition of the system for 1.5-2.5 h. After the third nucleophilic substitution is reversed, the present invention preferably pours the obtained reaction solution into water, extracts it with dichloromethane, and then successively washes with 1 mol/L HCl, water, saturated brine, and anhydrous sodium sulfate, and then extracts. Filtration, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: EA:PE=1:5 (v/v)) to obtain compound n.
得到化合物n后，本发明基于所述化合物n，按照步骤(3-1)制备得到具有式C所示结构的美金刚脲类衍生物，在此不再赘述。After the compound n is obtained, the present invention, based on the compound n, prepares a memantamide derivative having the structure represented by the formula C according to the step (3-1), which will not be repeated here.
第四种情况，制备具有式D所示结构的美金刚脲类衍生物，具体的，本发明基于化合物
按照上述第 三种情况的方法制备得到具有式D所示结构的美金刚脲类衍生物，在此不再赘述。
In the fourth case, the memantamide derivatives having the structure shown in formula D are prepared. Specifically, the present invention is based on compounds The memantamide derivative having the structure shown in formula D is prepared according to the method of the third case, and will not be repeated here.
本发明提供了上述技术方案所述美金刚脲类衍生物在制备治疗可溶性环氧化物酶介导的疾病的药物中的应用。在本发明中，所述可溶性环氧化物酶介导的疾病具体包括炎症性疾病、疼痛、心血管疾病、神经退行性疾病、糖尿病、糖尿病并发症、慢性肾炎、肾功能衰竭、慢性阻塞性肺疾病或肺动脉高压疾病；所述炎症性疾病优选包括脓毒症、细胞因子风暴、炎症性肠病、慢性消化性溃疡或关节炎；所述疼痛优选包括炎性疼痛或神经性疼痛；所述心血管疾病优选包括高血压、中风或动脉粥样硬化；所述神经退行性疾病优选包括帕金森综合征或阿尔兹海默病。The present invention provides the application of the memantamide derivatives described in the above technical solutions in the preparation of medicines for treating diseases mediated by soluble epoxidase. In the present invention, the diseases mediated by soluble cyclooxygenase specifically include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease disease or pulmonary hypertension disease; the inflammatory disease preferably includes sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis; the pain preferably includes inflammatory pain or neuropathic pain; the cardiac The vascular disease preferably includes hypertension, stroke or atherosclerosis; the neurodegenerative disease preferably includes Parkinson's syndrome or Alzheimer's disease.
下面将结合本发明中的实施例，对本发明中的技术方案进行清楚、完整地描述。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
实施例1 1-(4-硝基苯甲酰基)哌啶-4-甲酸的合成Example 1 Synthesis of 1-(4-nitrobenzoyl)piperidine-4-carboxylic acid
向三口瓶中加入4-哌啶甲酸(27.8g,0.22mol)、碳酸钾粉末(59.5g,0.43mol)、水(100mL)和四氢呋喃(THF,200mL)，冷肼降温至-25℃，逐滴加入对硝基苯甲酰氯(20.0g，0.11mol)的THF溶液(120mL)，滴加完毕后，-25℃反应30min，TLC监测反应完全；将所得反应液进行减压浓缩以除去THF，加入水(100mL)，在冰浴(0℃)条件下用2mol/L盐酸调节体系pH值至7，加入乙酸乙酯(100mL)，用2mol/L盐酸继续调节体系pH值至1，之后抽滤，滤饼依次用水和乙酸乙酯淋洗，干燥后得到白色固体，即为1-(4-硝基苯甲酰基)哌啶-4-甲酸，产量为25.4g，收率为84％。Add 4-piperidinecarboxylic acid (27.8g, 0.22mol), potassium carbonate powder (59.5g, 0.43mol), water (100mL) and tetrahydrofuran (THF, 200mL) to the there-necked flask, cool hydrazine to -25°C, and gradually A THF solution (120 mL) of p-nitrobenzoyl chloride (20.0 g, 0.11 mol) was added dropwise, and after the addition was completed, the reaction was performed at -25° C. for 30 min, and the reaction was completed by TLC monitoring; the obtained reaction solution was concentrated under reduced pressure to remove THF, Add water (100 mL), adjust the pH of the system to 7 with 2 mol/L hydrochloric acid under ice bath (0°C) conditions, add ethyl acetate (100 mL), continue to adjust the pH of the system to 1 with 2 mol/L hydrochloric acid, and then pump Filtration, the filter cake was rinsed with water and ethyl acetate successively, and a white solid was obtained after drying, namely 1-(4-nitrobenzoyl)piperidine-4-carboxylic acid, the yield was 25.4 g, and the yield was 84%.
实施例2 1-(4-氨基苯甲酰基)哌啶-4-甲酸的合成Example 2 Synthesis of 1-(4-aminobenzoyl)piperidine-4-carboxylic acid
向单口瓶中加入1-(4-硝基苯甲酰基)哌啶-4-甲酸(20.0g,80.6mmol)、5％Pd-C(2.0g)和无水乙醇(250mL)，氩气置换三次，氢气置换三次，升温至60℃搅拌反应12h，TLC监测反应完全；待反应液冷却至室温(25℃)后，抽滤，滤液经减压浓缩得浅黄色固体，加入乙酸乙酯(30mL)后打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到白色固体，即为1-(4-氨基苯甲酰基)哌啶-4-甲酸，产量为15.5g，收率为87％。Add 1-(4-nitrobenzoyl)piperidine-4-carboxylic acid (20.0g, 80.6mmol), 5% Pd-C (2.0g) and absolute ethanol (250mL) to a single-necked flask, and replace with argon Three times, hydrogen was replaced three times, the temperature was raised to 60 °C and the reaction was stirred for 12 h. TLC monitored the reaction to complete the reaction; after the reaction solution was cooled to room temperature (25 °C), suction filtration, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid, which was added with ethyl acetate (30 mL). ) after beating, the obtained system after beating is subjected to suction filtration, the filter cake is rinsed with ethyl acetate, and a white solid is obtained after drying, which is 1-(4-aminobenzoyl)piperidine-4-carboxylic acid, and the output is 15.5 g, the yield is 87%.
实施例3 1-{4-[(苯氧羰基)氨基]苯甲酰基}哌啶-4-甲酸的合成Example 3 Synthesis of 1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-4-carboxylic acid
向三口瓶中加入1-(4-氨基苯甲酰基)哌啶-4-甲酸(12.0g,48.4mmol)、碳酸钾粉末(20.0g,0.15mol)和干燥的THF(160mL)，冰浴条件下逐滴加入氯甲酸苯酯(9.05g,58.0mmol)的THF溶液(40mL)，滴加完毕后，冰浴条件下反应30min，TLC监测反应完全；将所得反应液进行减压浓缩以除去THF，加入水(100mL)，冰浴条件下用2mol/L盐酸调节体系pH值至7，加入乙酸乙酯(40mL)，用2mol/L盐酸继续调节体系pH值至1，之后抽滤，将所得滤饼依次用乙酸乙酯和水淋洗，干燥后得白色固体6.55g，将所述白色固体用乙酸乙酯打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到白色固体，即为1-{4-[(苯氧羰基)氨基]苯甲酰基}哌啶-4-甲酸，产量为5.28g，收率为30％。Add 1-(4-aminobenzoyl)piperidine-4-carboxylic acid (12.0g, 48.4mmol), potassium carbonate powder (20.0g, 0.15mol) and dry THF (160mL) to the there-necked flask, ice bath condition A THF solution (40 mL) of phenyl chloroformate (9.05 g, 58.0 mmol) was added dropwise, and after the addition was completed, the reaction was performed under ice bath conditions for 30 min, and TLC monitored the reaction to complete the reaction; the obtained reaction solution was concentrated under reduced pressure to remove THF , add water (100mL), adjust the pH value of the system to 7 with 2mol/L hydrochloric acid under ice bath conditions, add ethyl acetate (40mL), continue to adjust the pH value of the system to 1 with 2mol/L hydrochloric acid, then suction filtration, the obtained The filter cake was successively rinsed with ethyl acetate and water, and dried to obtain 6.55 g of white solid. The white solid was slurried with ethyl acetate. The system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with ethyl acetate and dried. After that, a white solid was obtained, which was 1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-4-carboxylic acid, and the yield was 5.28 g and the yield was 30%.
实施例4 1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸(GL-B404)的合成Example 4 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4-carboxylic acid ( GL-B404) synthesis
向单口瓶中加入1-{4-[(苯氧羰基)氨基]苯甲酰基}哌啶-4-甲酸(5.28g,14.3mmol)、美金刚(2.83g,15.8mmol)、三乙胺(2.90g,28.7mmol)和干燥的THF(50mL)，升温至回流反应8h，TLC检测反应完全；将所得反应液冷却至室温，减压浓缩以除去THF，加入水(50mL)，冰浴条件下用6mol/L盐酸调节体系pH值至1，乙酸乙酯萃取(60mL×3)，之后依次经水洗(60mL×3)、饱和食盐水洗(60mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到7.13g淡黄色油状物；加入乙腈(20mL)煮沸，体系中出现白色颗粒固体，冷却至室温后抽滤，滤饼用乙腈淋洗，干燥后得到白色固体，即为GL-B404，产量为3.89g，收率为60％，m.p.241-443℃。
1H NMR(400MHz,DMSO-d
6,GL-B404)δ12.20(br,1H),8.43(s,1H),7.37(d,J＝8.5Hz,2H),7.23(d,J＝8.5Hz,2H),5.96(s,1H),3.95(br,2H),3.00(br,2H),2.54(br,1H),2.09(s,1H),1.84-1.82(m,2H),1.76-1.75(m,2H),1.61-1.54(m,4H),1.53-1.44(m,2H),1.34-1.24(m,4H),1.12(s,2H),0.83(s,6H).
13C NMR(100MHz,DMSO-d
6,GL-B404)δ176.2,169.7,154.3,142.4,128.5,128.4,117.1,52.0,50.8,48.1,42.8,40.7,40.6,32.4,30.5,30.1,28.5.HRMS(ESI)calcd for C
26H
35N
3O
4Na[M+Na]
+:476.2520,found:476.2506。
1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-4-carboxylic acid (5.28g, 14.3mmol), memantine (2.83g, 15.8mmol), triethylamine ( 2.90g, 28.7mmol) and dry THF (50mL), heated to reflux for 8h, TLC detected that the reaction was complete; the obtained reaction solution was cooled to room temperature, concentrated under reduced pressure to remove THF, added water (50mL), under ice bath conditions The pH value of the system was adjusted to 1 with 6 mol/L hydrochloric acid, extracted with ethyl acetate (60 mL×3), washed with water (60 mL×3), washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained The filtrate was concentrated under reduced pressure to obtain 7.13 g of light yellow oil; acetonitrile (20 mL) was added and boiled, white granular solid appeared in the system, cooled to room temperature, filtered with suction, the filter cake was rinsed with acetonitrile, and dried to obtain a white solid, which is GL-B404, yield 3.89 g, 60% yield, mp 241-443°C. 1 H NMR (400MHz, DMSO-d 6 , GL-B404) δ 12.20 (br, 1H), 8.43 (s, 1H), 7.37 (d, J=8.5Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 5.96(s, 1H), 3.95(br, 2H), 3.00(br, 2H), 2.54(br, 1H), 2.09(s, 1H), 1.84-1.82(m, 2H), 1.76 -1.75(m,2H),1.61-1.54(m,4H),1.53-1.44(m,2H),1.34-1.24(m,4H),1.12(s,2H),0.83(s,6H) .13 C NMR (100MHz, DMSO-d 6 , GL-B404) δ176.2, 169.7, 154.3, 142.4, 128.5, 128.4, 117.1, 52.0, 50.8, 48.1, 42.8, 40.7, 40.6, 32.4, 30.5, 30.1, 28.5.HRMS ( ESI) calcd for C26H35N3O4Na [ M + Na] + : 476.2520 , found: 476.2506.
实施例5 1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸乙酯(GL-B405)的合成Example 5 Ethyl 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4-carboxylic acid Synthesis of Esters (GL-B405)
向三口瓶中加入GL-B404(0.3g,0.66mmol)和无水乙醇(20mL)，冰浴降温至0℃，逐滴滴加氯化亚砜(0.32g,2.65mmol)，滴毕后升温至回流反应2h，TLC监测反应完全；将所得反应液冷却至室温，减压浓缩除去乙醇，加入水(30mL)，用乙酸乙酯萃取(30mL×3)，之后依次经饱和碳酸钠水溶液洗(30mL×2)、水洗(30mL×2)、饱和食盐水洗(30mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到无色透明油状物，加入乙醚(10mL)打浆，体系中出现白色固体，抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为GL-B405，产量为0.26g，收率为82％，m.p.227-229℃。
1H NMR(400MHz,CDCl
3,GL-B405)δ7.73(s,1H),7.18-7.12(m,4H),5.51(br,1H),4.42(br,1H),4.15(q,J＝7.1Hz,2H),3.81(br,1H),3.09-3.03(m,2H),2.60-2.53(m,1H),2.14-2.13(m,1H),1.93(br,2H),1.71-1.60(m,6H),1.39-1.36(m,2H)，1.32-1.28(m，2H)，1.26(t，J＝7.1Hz，3H)，1.19-1.11(m，4H)，0.84(s，6H).
13C NMR(100MHz，CDCl
3，GL-B405)δ174.1,171.1,154.6,142.0,127.9,127.8,118.4,60.7,52.6,50.7,48.2,42.8,41.0,40.7,32.4,30.2,30.1,28.3,14.2.HRMS(ESI)calcd for C
28H
39N
3O
4Na[M+Na]
+:5042833,found:504.2833。
Add GL-B404 (0.3g, 0.66mmol) and absolute ethanol (20mL) to the there-necked flask, cool down to 0°C in an ice bath, dropwise add thionyl chloride (0.32g, 2.65mmol), and heat up after dropping After refluxing for 2 h, the reaction was completed by TLC monitoring; the obtained reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol, added water (30 mL), extracted with ethyl acetate (30 mL×3), and washed with saturated aqueous sodium carbonate solution ( 30mL×2), washed with water (30mL×2), washed with saturated brine (30mL) and dried over anhydrous sodium sulfate, filtered with suction, and the obtained filtrate was concentrated under reduced pressure to obtain a colorless transparent oil, which was added with ether (10mL) to make a slurry, A white solid appeared in the system, suction filtered, the filter cake was rinsed with ether, and dried to obtain a white solid, namely GL-B405, the yield was 0.26 g, the yield was 82%, and the mp was 227-229°C. 1 H NMR(400MHz, CDCl 3 , GL-B405)δ7.73(s,1H),7.18-7.12(m,4H),5.51(br,1H),4.42(br,1H),4.15(q,J =7.1Hz,2H),3.81(br,1H),3.09-3.03(m,2H),2.60-2.53(m,1H),2.14-2.13(m,1H),1.93(br,2H),1.71- 1.60(m, 6H), 1.39-1.36(m, 2H), 1.32-1.28(m, 2H), 1.26(t, J=7.1Hz, 3H), 1.19-1.11(m, 4H), 0.84(s, 6H). 13 C NMR (100MHz, CDCl 3 , GL-B405) δ174.1, 171.1, 154.6, 142.0, 127.9, 127.8, 118.4, 60.7, 52.6, 50.7, 48.2, 42.8, 41.0, 40.7, 32.4, 30.2, 30.1, 28.3, 14.2. HRMS(ESI) calcd for C28H39N3O4Na [ M + Na] + : 5042833 , found: 504.2833.
实施例6羧酸为酰化剂的第一通用操作Embodiment 6 Carboxylic acid is the first general operation of acylating agent
向单口瓶中加入GL-B404(0.40g,0.88mol)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI,0.25g,1.32mmol)、1-羟基苯并三氮唑(HOBt，0.18g，1.32mmol)、三乙胺(0.45g，44.1mmol)和干燥的二氯甲烷(10mL)，30℃条件下搅拌30min后加入胺或者胺的盐酸盐(1.76mmol)，30℃条件下反应8h，TLC监测反应完全；将所得反应液倒入水(30mL)中，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比为10:1)萃取(50mL×3)，之后依次经1mol/L盐酸洗(30mL×2)、5wt％氢氧化钠水溶液洗(30mL×2)、水洗(30mL)、饱和食盐水洗(30mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，至剩余约2mL残余物，加入乙酸乙酯(10mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到相应的目标产物。Add GL-B404 (0.40g, 0.88mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 0.25g, 1.32mmol), 1-hydroxyl to the single-necked bottle Benzotriazole (HOBt, 0.18g, 1.32mmol), triethylamine (0.45g, 44.1mmol) and dry dichloromethane (10mL), stir at 30°C for 30min, add amine or amine hydrochloride (1.76mmol), reacted at 30°C for 8h, and TLC monitored the completion of the reaction; pour the obtained reaction solution into water (30mL), and use a dichloromethane-methanol mixture (dichloromethane to methanol volume ratio of 10:1) Extraction (50mL×3), then washed with 1mol/L hydrochloric acid (30mL×2), 5wt% sodium hydroxide aqueous solution (30mL×2), washed with water (30mL), washed with saturated brine (30mL) and anhydrous sodium sulfate Drying, suction filtration, the obtained filtrate was concentrated under reduced pressure until about 2 mL of residue remained, ethyl acetate (10 mL) was added to make a slurry, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with ethyl acetate, and dried to obtain the corresponding target product.
实施例7 1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-4-甲酰胺(GL-B407)的合成Example 7 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methylpiperidine Synthesis of -4-carboxamide (GL-B407)
按照实施例6的方法操作，以甲胺盐酸盐为原料(即实施例6中胺的盐酸盐具体为甲胺盐酸盐)，得到白色固体，即为GL-B407，产量为0.27g，收率为66％，m.p.237-240℃。
1H NMR(400MHz,DMSO-d
6,GL-B407)δ8.42(s,1H),7.73-7.72(m,1H),7.37(d,J＝8.6Hz,2H),7.24(d,J＝8.6Hz,2H),5.95(s,1H),4.06(br,2H),2.90(br,2H),2.56(d,J＝4.5Hz，3H)，2.38-2.33(m，1H)，2.10-2.08(m，1H)，1.76(br，2H)，1.70-1.67(m，2H)，1.61-1.55(m，4H)，1.53-1.43(m，2H)，1.34-1.25(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B407)δ174.6，169.6，154.3，142.3，128.5,128.4,117.1,52.1,50.8,48.1,42.8,42.3,40.6,32.4,30.5,30.1,29.1,26.0.HRMS(ESI)calcd for C
27H
38N
4O
3Na[M+Na]
+:489.2836,found:489.2828。
Operate according to the method of Example 6, take methylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B407, and the output is 0.27g , the yield is 66%, mp237-240 ℃. 1 H NMR (400MHz, DMSO-d 6 , GL-B407) δ 8.42(s, 1H), 7.73-7.72(m, 1H), 7.37(d, J=8.6Hz, 2H), 7.24(d, J ＝8.6Hz, 2H), 5.95(s, 1H), 4.06(br, 2H), 2.90(br, 2H), 2.56(d, J＝4.5Hz, 3H), 2.38-2.33(m, 1H), 2.10 -2.08(m, 1H), 1.76(br, 2H), 1.70-1.67(m, 2H), 1.61-1.55(m, 4H), 1.53-1.43(m, 2H), 1.34-1.25(m, 4H) , 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100MHz, DMSO-d 6 , GL-B407) δ174.6, 169.6, 154.3, 142.3, 128.5, 128.4, 117.1, 52.1, 50.8, 48.1, 42.8, 42.3, 40.6, 32.4, 30.5, 30.1, 29.1, 26.0. HRMS(ESI) calcd for C27H38N4O3Na [ M + Na] + : 489.2836 ,found:489.2828.
实施例8 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N，N-二甲基哌啶-4-甲酰胺(GL-B408)的合成Example 8 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N,N-dimethyl Synthesis of ylpiperidine-4-carboxamide (GL-B408)
按照实施例6的方法操作，以二甲胺盐酸盐为原料(即实施例6中胺的盐酸盐具体为二甲胺盐酸盐)，得到白色固体，即为GL-B408，产量为0.27g，收率为64％，m.p.128-130℃。
1H NMR(400MHz，DMSO-d
6，GL-B408)δ8.42(s，1H)，7.38(d，J＝8.4Hz，2H)，7.24(d，J＝8.4Hz，2H)，5.95(s，1H)，4.04(br，2H)，3.03(s，3H)，2.94-2.88(m，2H)，2.81(s，3H)，2.09(br，1H)，1.76(s，2H)，1.63-1.61(m，2H)，1.58-1.55(m，4H)，1.51-1.41(m，2H)，1.35-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B408)δ173.9，169.6，154.3，142.3，128.5，128.4，117.1，52.1，50.8，48.1，42.8，40.6，37.8，37.1，35.5，32.4，30.6，30.1，28.8.HRMS(ESI)calcd for C
28H
40N
4O
3Na[M+Na]
+：503.2993，found：503.2996。
Operate according to the method of embodiment 6, take dimethylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically dimethylamine hydrochloride), obtain a white solid, namely GL-B408, and the output is 0.27g, 64% yield, mp 128-130°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B408) δ 8.42 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.95 ( s, 1H), 4.04 (br, 2H), 3.03 (s, 3H), 2.94-2.88 (m, 2H), 2.81 (s, 3H), 2.09 (br, 1H), 1.76 (s, 2H), 1.63 13 C NMR (100MHz, DMSO-d 6 , GL-B408) δ 173.9, 169.6, 154.3, 142.3, 128.5, 128.4, 117.1, 52.1, 50.8, 48.1, 42.8, 40.6, 37.8, 37.1, 35.5, 32.4, 30.6, 30.1, 28.8. HRMS(ESI) calcd for C28H40N4O3Na [ M + Na] + : 503.2993 , found: 503.2996.
实施例9 N-环丙基-1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺(GL-B409)的合成Example 9 N-cyclopropyl-1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine Synthesis of pyridine-4-carboxamide (GL-B409)
按照实施例6的方法操作，以环丙胺为原料(即实施例6中胺具体为环丙胺)，得到白色固体，即为GL-B409，产量为0.30g，收率为70％，m.p.200-203℃。
1H NMR(400MHz，DMSO-d
6，GL-B409)δ8.44(s，1H)，7.83(d，J＝4.1Hz，1H)，7.37(d，J＝8.5Hz，2H)，7.23(d，J＝8.5Hz，2H)，5.96(s，1H)，4.04(br，2H)，2.88(br，2H)，2.64-2.57(m，1H)，2.32-2.27(m，1H)，2.09-2.08(m，1H)，1.76(s，2H)，1.67-1.64(m，2H)，1.61-1.55(m，4H)，1.52-1.42(m，4H)，1.34-1.24(m，4H)，1.12(s，2H)，0.83(s，6H)，0.61-0.56(m，2H)，0.38-0.35(m，2H).
13C NMR(100MHz，DMSO-d
6，GL-B409)δ175.3，169.6，154.3，142.4，128.5，128.4，117.1，52.0，50.8，48.1，42.8，42.2，40.6，32.4，30.5，30.1，29.0，22.7，6.1.HRMS(ESI)calcd for C
29H
40N
4O
3Na[M+Na]
+：515.2993，found：515.2987。
Operate according to the method of embodiment 6, take cyclopropylamine as raw material (that is, amine is specifically cyclopropylamine in embodiment 6), obtain white solid, be GL-B409, output is 0.30g, yield is 70%, mp200-203 °C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B409) δ 8.44 (s, 1H), 7.83 (d, J=4.1 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.23 ( d, J=8.5Hz, 2H), 5.96(s, 1H), 4.04(br, 2H), 2.88(br, 2H), 2.64-2.57(m, 1H), 2.32-2.27(m, 1H), 2.09 -2.08(m, 1H), 1.76(s, 2H), 1.67-1.64(m, 2H), 1.61-1.55(m, 4H), 1.52-1.42(m, 4H), 1.34-1.24(m, 4H) , 1.12(s, 2H), 0.83(s, 6H), 0.61-0.56(m, 2H), 0.38-0.35(m, 2H). 13 C NMR (100MHz, DMSO-d 6 , GL-B409)δ175. 3, 169.6, 154.3, 142.4, 128.5, 128.4, 117.1, 52.0, 50.8, 48.1, 42.8, 42.2, 40.6, 32.4, 30.5, 30.1, 29.0, 22.7, 6.1.HRMS(ESI)calcd for C 29 H 40 N 4 O3Na[ M +Na] + : 515.2993, found: 515.2987.
实施例10 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-4-甲酰胺(GL-B410)的合成Example 10 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxypiperidine Synthesis of pyridine-4-carboxamide (GL-B410)
按照实施例6的方法操作，以甲氧基甲胺盐酸盐为原料(即实施例6中胺的盐酸盐具体为甲氧基甲胺盐酸盐)，得到白色固体，即为GL-B410，产量为0.12g，收率为28％，m.p.237-239℃。
1H NMR(400MHz，DMSO-d
6，GL-B410)δ11.04(s，1H)，8.45(s，1H)，7.38(d，J＝8.6Hz，2H)，7.24(d，J＝8.6Hz，2H)，5.97(s，1H)，4.05(br，2H)，3.57(s，3H)，2.90(br，2H)，2.27-2.21(m，1H)，2.10-2.08(m，1H)，1.76(d，J＝2.1Hz，2H)，1.67-1.64(m，2H)，1.61-1.55(m，4H)，1.54-1.45(m，2H)，1.34-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B410)δ171.2，169.7，154.3，142.4，128.4，128.3，117.1，63.6，52.1，50.8，48.1，42.8，40.6，32.4，30.5，30.1，28.7.HRMS(ESI)calcd for C
27H
38N
4O
4Na[M+Na]
+：505.2785，found：505.2778。
Operate according to the method of Example 6, take methoxymethylamine hydrochloride as raw material (that is, the hydrochloride of amine in Example 6 is specifically methoxymethylamine hydrochloride) to obtain a white solid, which is GL- B410, yield 0.12 g, 28% yield, mp 237-239°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B410) δ 11.04 (s, 1H), 8.45 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 5.97(s, 1H), 4.05(br, 2H), 3.57(s, 3H), 2.90(br, 2H), 2.27-2.21(m, 1H), 2.10-2.08(m, 1H) , 1.76(d, J=2.1Hz, 2H), 1.67-1.64(m, 2H), 1.61-1.55(m, 4H), 1.54-1.45(m, 2H), 1.34-1.24(m, 4H), 1.12 (s, 2H), 0.83 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B410) δ 171.2, 169.7, 154.3, 142.4, 128.4, 128.3, 117.1, 63.6, 52.1, 50.8, 48.1 , 42.8, 40.6, 32.4, 30.5, 30.1, 28.7. HRMS(ESI) calcd for C27H38N4O4Na[M+Na]+ : 505.2785 , found : 505.2778.
实施例11 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺(GL-B406)的合成Example 11 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4-carboxamide Synthesis of (GL-B406)
向三口瓶中加入GL-B404(0.50g，1.10mmol)、DMF(4滴)和干燥的THF(20mL)，冰盐浴降温至0℃以下，逐滴加入SOCl
2(0.40g，3.36mmol)的THF溶液(5mL)，滴毕后自然升温至室温反应2h，TLC监测反应完全；将所得反应液进行减压蒸馏以除去SOCl
2，向残余物中加入干燥的THF(20mL)，冰盐浴降温至0℃以下，通入氨气，自然升温至室温反应4h，TLC监测反应完全；将所得反应液进行减压蒸馏以除去THF，向残余物中加入水(30mL)，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比为10∶1)萃取(50mL×3)，之后依次经1mol/L盐酸洗(30mL×2)、5wt％氢氧化钠水溶液洗(30mL×2)、水洗(30mL)、饱和食盐水洗(30mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，至剩余约2mL残余物，加入乙酸乙酯(10mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到白色固体，即为GL-B406，产量为0.15g，收率为30％，m.p.227-229℃。
1H NMR(400MHz，DMSO-d
6，GL-B406)δ8.42(s，1H)，7.37(d，J＝8.4Hz，2H)，7.26(s，1H)，7.23(d，J＝8.4Hz，2H)，6.78(s，1H)，5.95(s，1H)，4.04(br，2H)，2.90(br，2H)，2.38-2.33(m，1H)，2.09(brs，1H)，1.76-1.70(m，4H)，1.61-1.55(m，4H)，1.52-1.42(m，2H)，1.35-1.27(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B406)δ176.3，169.6，154.3，142.3，128.6，128.4，117.1，52.1，50.8，48.1，42.8，42.0，40.6，32.4，30.5，30.1，29.0.HRMS(ESI)calcd for C
26H
36N
4O
3Na[M+Na]
+：475.2680，found：475.2682。
GL-B404 (0.50g, 1.10mmol), DMF (4 drops) and dry THF (20mL) were added to the there-necked flask, the ice-salt bath was cooled to below 0°C, SOCl 2 (0.40g, 3.36mmol) was added dropwise The THF solution (5 mL) of 100 mL was heated to room temperature for 2 h after dripping, and the reaction was completed by TLC monitoring; the obtained reaction solution was distilled under reduced pressure to remove SOCl 2 , and dry THF (20 mL) was added to the residue, followed by an ice-salt bath. The temperature was lowered to below 0°C, ammonia gas was introduced, the temperature was naturally raised to room temperature and the reaction was completed for 4 h. TLC monitored the completion of the reaction; the obtained reaction solution was subjected to vacuum distillation to remove THF, water (30 mL) was added to the residue, and dichloromethane- Methanol mixture (dichloromethane to methanol volume ratio of 10:1) was extracted (50mL×3), then washed with 1mol/L hydrochloric acid (30mL×2), 5wt% aqueous sodium hydroxide solution (30mL×2), Washed with water (30 mL), saturated brine (30 mL) and dried over anhydrous sodium sulfate, suction filtered, the obtained filtrate was concentrated under reduced pressure until about 2 mL of residue remained, ethyl acetate (10 mL) was added for beating, and the system obtained after beating was slurried. Carry out suction filtration, rinse the filter cake with ethyl acetate, and obtain a white solid after drying, namely GL-B406, the yield is 0.15g, the yield is 30%, mp227-229°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B406) δ 8.42 (s, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.26 (s, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.78(s, 1H), 5.95(s, 1H), 4.04(br, 2H), 2.90(br, 2H), 2.38-2.33(m, 1H), 2.09(brs, 1H), 1.76 13 C NMR (100MHz, DMSO-d 6 , GL-B406) δ 176.3, 169.6, 154.3, 142.3, 128.6, 128.4, 117.1, 52.1, 50.8, 48.1, 42.8, 42.0, 40.6, 32.4, 30.5, 30.1, 29.0. HRMS (ESI) calcd for C26H36N4O3Na [ M + Na] + : 475.2680 , found: 475.2682.
实施例12 1-(4-硝基苯甲酰基)哌啶-3-甲酸的合成Example 12 Synthesis of 1-(4-nitrobenzoyl)piperidine-3-carboxylic acid
按照实施例1的方法操作，不同之处仅在于将4-哌啶甲酸替换为3-哌啶甲酸，最终得到的白色固体为1-(4-硝基苯甲酰基)哌啶-3-甲酸，产量为21.7g，收率为72％。Operate according to the method of Example 1, except that 4-piperidinecarboxylic acid is replaced with 3-piperidinecarboxylic acid, and the white solid finally obtained is 1-(4-nitrobenzoyl)piperidine-3-carboxylic acid , the yield was 21.7 g, and the yield was 72%.
实施例13 1-(4-氨基苯甲酰基)哌啶-3-甲酸的合成Example 13 Synthesis of 1-(4-aminobenzoyl)piperidine-3-carboxylic acid
按照实施例2的方法操作，不同之处仅在于将1-(4-硝基苯甲酰基)哌啶-4-甲酸替换为1-(4-硝基苯甲酰基)哌啶-3-甲酸，最终得到的白色固体为1-(4-氨基苯甲酰基)哌啶-3-甲酸，产量为12.5g，收率为65％。Follow the method of Example 2, except that 1-(4-nitrobenzoyl)piperidine-4-carboxylic acid is replaced with 1-(4-nitrobenzoyl)piperidine-3-carboxylic acid , the finally obtained white solid was 1-(4-aminobenzoyl)piperidine-3-carboxylic acid, the yield was 12.5 g, and the yield was 65%.
实施例14 1-{4-[(苯氧羰基)氨基]苯甲酰基}哌啶-3-甲酸的合成Example 14 Synthesis of 1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-3-carboxylic acid
按照实施例3的方法操作，不同之处仅在于将1-(4-氨基苯甲酰基)哌啶-4-甲酸替换为1-(4-氨基苯甲酰基)哌啶-3-甲酸，最终得到的白色固体为1-{4-[(苯氧羰基)氨基]苯甲酰基}哌啶-3-甲酸，产量为6.10g，收率为33％。Operate according to the method of Example 3, except that 1-(4-aminobenzoyl)piperidine-4-carboxylic acid is replaced with 1-(4-aminobenzoyl)piperidine-3-carboxylic acid, and finally The obtained white solid was 1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-3-carboxylic acid, the yield was 6.10 g, and the yield was 33%.
实施例15 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸(GL-B411)的合成Example 15 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxylic acid ( Synthesis of GL-B411)
向单口瓶中加入1-{4-[(苯氧羰基)氨基]苯甲酰基}哌啶-3-甲酸(6.10g，16.6mmol)、美金刚(3.27g，18.2mmol)、三乙胺(3.35g，33.1mmol)和干燥的THF(50mL)，升温至回流反应8h，TLC检测反应完全；将所得反应液冷却至室温，减压浓缩以除去THF，加入水(50mL)，冰浴条件下用6mol/L盐酸调节体系pH值至1，乙酸乙酯萃取(60mL×3)，之后依次经水洗(60mL×3)、饱和食盐水洗(60mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到7.13g淡黄色油状物；加入乙腈(20mL)煮沸，体系中出现白色颗粒固体，冷却至室温后抽滤，滤饼用乙腈淋洗，干燥后得到白色固体，即为GL-B411，产量为4.66g，收率为62％，m.p.180-182℃。
1H NMR(400MHz，DMSO-d
6，GL-B411)δ8.42(s，1H)，7.38(d，J＝8.6Hz，2H)，7.24(d，J＝8.6Hz，2H)，5.96(s，1H)，3.88(br，2H)，3.06(br，2H)，2.46-2.39(m，1H)，2.10-2.08(m，1H)，2.00-1.96(m，1H)，1.76(d，J＝2.2Hz，2H)，1.68-1.56(m，6H)，1.47-1.42(m，1H)，1.35-1.26(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B411)δ174.7，169.8，154.3，142.4，128.5，128.4，117.0，52.0，50.8，48.1，42.8，41.3，40.6，32.4，30.5，30.1，27.4.HRMS(ESI)calcd for C
26H
35N
3O
4Na[M+Na]
+：476.2520，found：476.2512。
1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-3-carboxylic acid (6.10g, 16.6mmol), memantine (3.27g, 18.2mmol), triethylamine ( 3.35 g, 33.1 mmol) and dry THF (50 mL) were heated to reflux for 8 h, and the reaction was complete after TLC detection; the obtained reaction solution was cooled to room temperature, concentrated under reduced pressure to remove THF, added water (50 mL), under ice bath conditions The pH value of the system was adjusted to 1 with 6 mol/L hydrochloric acid, extracted with ethyl acetate (60 mL×3), washed with water (60 mL×3), washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained The filtrate was concentrated under reduced pressure to obtain 7.13 g of light yellow oil; acetonitrile (20 mL) was added and boiled, white granular solid appeared in the system, cooled to room temperature, filtered with suction, the filter cake was rinsed with acetonitrile, and dried to obtain a white solid, which is GL-B411, yield 4.66 g, 62% yield, mp 180-182°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B411) δ 8.42 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 5.96 ( s, 1H), 3.88(br, 2H), 3.06(br, 2H), 2.46-2.39(m, 1H), 2.10-2.08(m, 1H), 2.00-1.96(m, 1H), 1.76(d, 13 C NMR (100MHz, DMSO-d 6 , GL-B411) δ 174.7, 169.8, 154.3, 142.4, 128.5, 128.4, 117.0, 52.0, 50.8, 48.1, 42.8, 41.3, 40.6, 32.4, 30.5, 30.1, 27.4. HRMS (ESI) calcd for C26H35N3O4Na [ M + Na] + : 476.2520 , found: 476.2512.
实施例16 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸乙酯(GL-B412)的合成Example 16 Ethyl 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxylic acid Synthesis of Esters (GL-B412)
向三口瓶中加入GL-B411(0.3g，0.66mmol)和无水乙醇(20mL)，冰浴降温至0℃，逐滴滴加氯化亚砜(0.32g，2.65mmol)，滴毕后升温至回流反应2h，TLC监测反应完全；将所得反应液冷却至室温，减压浓缩除去乙醇，加入水(30mL)，用乙酸乙酯萃取(30mL×3)，之后依次经1wt％的NaOH水溶液洗(30mL×2)、水洗(30mL×2)、饱和食盐水洗(30mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到无色透明油状物，加入乙醚(10mL)打浆，体系中出现白色固体，抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为GL-B412，产量为0.23g，收率为72％，m.p. 180-183℃。
1H NMR(400MHz，DMSO-d
6，GL-B412)δ8.42(s，1H)，7.37(d，J＝8.6Hz，2H)，7.24(d，J＝8.6Hz，2H)，5.95(s，1H)，4.05(q，J＝7.0Hz，2H)，3.75(br，2H)，3.16(br，1H)，3.11-3.04(m，1H)，2.57-2.53(m，1H)，2.10-2.08(m，1H)，1.98-1.96(m，1H)，1.76(d，J＝2.4Hz，2H)，1.67-1.64(m，2H)，1.61-1.55(m，4H)，1.49-1.40(m，1H)，1.35-1.25(m，4H)，1.15(t，J＝7.0Hz，3H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B412)δ173.0，169.8，154.3，142.4，128.4，128.4，117.0，60.5，52.1，50.8，48.1，41.1，40.6，32.4，30.5，30.1，27.2，14.5.HRMS(ESI)calcd for C
28H
39N
3O
4Na[M+Na]
+：504.2833，found：504.2833.
GL-B411 (0.3g, 0.66mmol) and absolute ethanol (20mL) were added to the there-necked flask, the ice bath was cooled to 0°C, thionyl chloride (0.32g, 2.65mmol) was added dropwise, and the temperature was raised after dropping. The reaction was refluxed for 2 h, and the reaction was completed by TLC; the obtained reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol, added water (30 mL), extracted with ethyl acetate (30 mL×3), and washed with 1 wt% NaOH aqueous solution in turn. (30mL×2), washed with water (30mL×2), washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered with suction, and the obtained filtrate was concentrated under reduced pressure to obtain a colorless transparent oil, which was added with ether (10mL) to make a slurry , a white solid appeared in the system, suction filtered, the filter cake was rinsed with ether, dried to obtain a white solid, namely GL-B412, the yield was 0.23g, the yield was 72%, mp 180-183°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B412) δ 8.42 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 5.95 ( s, 1H), 4.05 (q, J=7.0Hz, 2H), 3.75 (br, 2H), 3.16 (br, 1H), 3.11-3.04 (m, 1H), 2.57-2.53 (m, 1H), 2.10 -2.08(m, 1H), 1.98-1.96(m, 1H), 1.76(d, J=2.4Hz, 2H), 1.67-1.64(m, 2H), 1.61-1.55(m, 4H), 1.49-1.40 (m, 1H), 1.35-1.25 (m, 4H), 1.15 (t, J=7.0Hz, 3H), 1.12 (s, 2H), 0.83 (s, 6H). 13 C NMR (100 MHz, DMSO-d) 6 , GL-B412) δ173.0, 169.8, 154.3, 142.4, 128.4, 128.4, 117.0, 60.5, 52.1, 50.8, 48.1, 41.1, 40.6, 32.4, 30.5, 30.1, 27.2, 14.5.HRMS(ESI)calcd for C 28 H 39 N 3 O 4 Na[M+Na] + : 504.2833, found: 504.2833.
实施例17 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(GL-B413)的合成Example 17 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide Synthesis of (GL-B413)
按照实施例11的方法操作，不同之处仅在于将GL-B404替换为GL-B411，最终所得白色固体为GL-B413，产量为0.21g，收率为42％，m.p.196-198℃。
1H NMR(400MHz，DMSO-d
6，GL-B413)δ8.42(s，1H)，7.38(d，J＝8.4Hz，2H)，7.33(br，1H)，7.24(d，J＝8.6Hz，2H)，6.83(s，1H)，5.95(s，1H)，4.15(br，2H)，2.89(br，2H)，2.31-2.26(m，1H)，2.09(br，1H)，1.92-1.89(m，1H)，1.76(s，2H)，1.66-1.63(m，1H)，1.58-1.55(m，5H)，1.42-1.39(m，1H)，1.35-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B413)δ175.1，169.7，154.3，142.4，128.5，128.4，117.1，52.1，50.8，48.1，42.8，40.6，32.4，30.5，30.1，28.2.HRMS(ESI)calcd for C
26H
36N
4O
3Na[M+Na]
+：475.2680，found：475.2682。
According to the method of Example 11, the only difference is that GL-B404 is replaced by GL-B411, and finally the obtained white solid is GL-B413, the yield is 0.21 g, the yield is 42%, mp196-198°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B413) δ 8.42 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.33 (br, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.83(s, 1H), 5.95(s, 1H), 4.15(br, 2H), 2.89(br, 2H), 2.31-2.26(m, 1H), 2.09(br, 1H), 1.92 -1.89(m, 1H), 1.76(s, 2H), 1.66-1.63(m, 1H), 1.58-1.55(m, 5H), 1.42-1.39(m, 1H), 1.35-1.24(m, 4H) , 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100MHz, DMSO-d 6 , GL-B413) δ 175.1, 169.7, 154.3, 142.4, 128.5, 128.4, 117.1, 52.1, 50.8, 48.1, 42.8, 40.6, 32.4, 30.5, 30.1, 28.2. HRMS(ESI) calcd for C26H36N4O3Na [ M + Na] + : 475.2680 , found: 475.2682.
实施例18羧酸为酰化剂的第二通用操作Example 18 Second general operation with carboxylic acid as acylating agent
按照实施例6的方法操作，不同之处仅在于将GL-B404替换为GL-B411，具体如下：Operate according to the method of Example 6, except that GL-B404 is replaced with GL-B411, as follows:
向单口瓶中加入GL-B411(0.40g，0.88mol)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI，0.25g，1.32mmol)、1-羟基苯并三氮唑(HOBt，0.18g，1.32mmol)、三乙胺(0.45g，44.1mmol)和干燥的二氯甲烷(10mL)，30℃条件下搅拌30min后加入胺或胺的盐酸盐(1.76mmol)，30℃条件下反应8h，TLC监测反应完全；将所得反应液倒入水(30mL)中，用二氯甲烷-甲醇混合液(二氯甲烷与甲醇体积比为10∶1)萃取(50mL×3)，之后依次经1mol/L盐酸洗(30mL×2)、5wt％氢氧化钠水溶液洗(30mL×2)、水洗(30mL)、饱和食盐水洗(30mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，至剩余约2mL残余物，加入乙酸乙酯(10mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙酸乙酯淋洗，干燥后得到相应的目标产物。Add GL-B411 (0.40g, 0.88mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, 0.25g, 1.32mmol), 1-hydroxyl to the single-necked bottle Benzotriazole (HOBt, 0.18g, 1.32mmol), triethylamine (0.45g, 44.1mmol) and dry dichloromethane (10mL), stir at 30°C for 30min and add amine or amine hydrochloride (1.76mmol), reacted at 30°C for 8h, and the reaction was completed by TLC monitoring; the obtained reaction solution was poured into water (30mL), and a dichloromethane-methanol mixed solution was used (dichloromethane to methanol volume ratio was 10:1) Extraction (50mL×3), then washed with 1mol/L hydrochloric acid (30mL×2), 5wt% sodium hydroxide aqueous solution (30mL×2), washed with water (30mL), washed with saturated brine (30mL) and anhydrous sodium sulfate Drying, suction filtration, the obtained filtrate was concentrated under reduced pressure until about 2 mL of residue remained, ethyl acetate (10 mL) was added to make a slurry, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with ethyl acetate, and dried to obtain the corresponding target product.
实施例19 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-3-甲酰胺(GL-B414)的合成Example 19 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methylpiperidine Synthesis of -3-carboxamide (GL-B414)
按照实施例18的方法操作，以甲胺盐酸盐为原料(即实施例18中胺的盐酸盐具体为甲胺盐酸盐)，得到白色固体，即为GL-B414，产量为0.19g，收率为46％，m.p.210-212℃。
1H NMR(400MHz，DMSO-d
6，GL-B414)δ8.42(s，1H)，7.80(br，1H)，7.37(d，J＝8.6Hz，2H)，7.23(d，J＝8.6Hz，2H)，5.95(s，1H)，4.17(br，1H)，3.78(br，1H)，2.89(br，2H)，2.55-2.54(m，3H)，2.30-2.25(m，1H)，2.09-2.08(m，1H)，1.87-1.84(m，1H)，1.76(d，J＝1.6Hz，2H)，1.65-1.55(m，6H)，1.42-1.39(m，1H)，1.35-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B414)δ173.3，169.7，154.3，142.4，128.4，117.1，52.1，50.8，48.1，42.8，40.6，32.4，30.5，30.1，28.1，25.9.HRMS(ESI)calcd for C
27H
38N
4O
3Na[M+Na]
+：489.2836，found：489.2831。
Operate according to the method of Example 18, using methylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methylamine hydrochloride) to obtain a white solid, which is GL-B414, and the output is 0.19g , the yield is 46%, mp210-212 ℃. 1 H NMR (400 MHz, DMSO-d 6 , GL-B414) δ 8.42 (s, 1H), 7.80 (br, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 5.95(s, 1H), 4.17(br, 1H), 3.78(br, 1H), 2.89(br, 2H), 2.55-2.54(m, 3H), 2.30-2.25(m, 1H) , 2.09-2.08(m, 1H), 1.87-1.84(m, 1H), 1.76(d, J=1.6Hz, 2H), 1.65-1.55(m, 6H), 1.42-1.39(m, 1H), 1.35 -1.24(m, 4H), 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B414) δ 173.3, 169.7, 154.3, 142.4, 128.4, 117.1 , 52.1, 50.8, 48.1, 42.8, 40.6, 32.4, 30.5, 30.1, 28.1, 25.9.HRMS(ESI) calcd for C27H38N4O3Na [ M + Na] + : 489.2836 , found: 489.2831.
实施例20 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N，N-二甲基哌啶-3-甲酰胺(GL-B415)的合成Example 20 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N,N-dimethyl Synthesis of pyridine-3-carboxamide (GL-B415)
按照实施例18的方法操作，以二甲胺盐酸盐为原料(即实施例18中胺的盐酸盐具体为二甲胺盐酸盐)，得到白色固体，即为GL-B415，产量为0.19g，收率为45％，m.p.137-139℃。
1H NMR(400MHz，DMSO-d
6，GL-B415)δ8.42(s，1H)，7.37(d，J＝8.1Hz，2H)，7.26(d，J＝8.1Hz，2H)，5.96(s，1H)，4.30(br，1H)，3.71(br，1H)，2.97-2.78(m，8H)，2.09(s，1H)，1.86-1.83(m，1H)，1.76(s，2H)，1.86-1.83(m，1H)，1.76(s，2H)，1.64-1.47(m，6H)，1.40(s，2H)，1.34-1.25(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B415)δ171.5，168.7，153.2，141.2，127.3，116.0，50.9，49.6，47.0，41.7，39.5，35.9，34.2，31.3，29.5，29.0，26.7，25.7.HRMS(ESI)calcd for C
28H
40N
4O
3Na[M+Na]
+：503.2993，found：503.3005。
Operate according to the method of Example 18, take dimethylamine hydrochloride as a raw material (that is, the hydrochloride of amine in Example 18 is specifically dimethylamine hydrochloride) to obtain a white solid, which is GL-B415, and the output is 0.19g, 45% yield, mp 137-139°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B415) δ 8.42 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 5.96 ( s, 1H), 4.30 (br, 1H), 3.71 (br, 1H), 2.97-2.78 (m, 8H), 2.09 (s, 1H), 1.86-1.83 (m, 1H), 1.76 (s, 2H) , 1.86-1.83(m, 1H), 1.76(s, 2H), 1.64-1.47(m, 6H), 1.40(s, 2H), 1.34-1.25(m, 4H), 1.12(s, 2H), 0.83 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B415) δ 171.5, 168.7, 153.2, 141.2, 127.3, 116.0, 50.9, 49.6, 47.0, 41.7, 39.5, 35.9, 34.2, 31.3 , 29.5, 29.0, 26.7, 25.7. HRMS(ESI) calcd for C28H40N4O3Na [ M + Na] + : 503.2993 , found: 503.3005.
实施例21 N-环丙基-1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(GL-B416)的合成Example 21 N-Cyclopropyl-1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine Synthesis of pyridine-3-carboxamide (GL-B416)
按照实施例18的方法操作，以环丙胺为原料(即实施例18中胺具体为环丙胺)，得到白色固体，即为GL-B416，产量为0.10g，收率为23％，m.p.200-202℃。
1H NMR(400MHz，DMSO-d
6，GL-B416)δ8.42(s，1H)，7.92(br，1H)，7.37(d，J＝8.5Hz，2H)，7.23(d，J＝8.5Hz，2H)，5.95(s，1H)，4.09(br，2H)，2.90(br，2H)，2.58(br，1H)，2.22-2.19(m，1H)，2.09(br，1H)，1.84-1.81(m，1H)，1.76(s，2H)，1.64-1.55(m，6H)，1.40-1.34(m，1H)，1.34-1.25(m，4H)，1.12(s，2H)，0.83(s，6H)，0.58(d，J＝5.1Hz，2H)，0.36(br，2H).
13C NMR(100MHz，DMSO-d
6，GL-B416)δ174.1，169.7，154.3，142.4，128.4，117.1，52.1，50.8，48.1，42.8，40.6，32.4，30.5，30.1，28.1，22.6.HRMS(ESI)calcd for C
29H
40N
4O
3Na[M+Na]
+：515.2993，found：515.2992。
Operate according to the method of embodiment 18, take cyclopropylamine as raw material (that is, amine is specifically cyclopropylamine in embodiment 18), obtain white solid, namely GL-B416, output is 0.10g, yield is 23%, mp200-202 °C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B416) δ 8.42 (s, 1H), 7.92 (br, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 5.95(s, 1H), 4.09(br, 2H), 2.90(br, 2H), 2.58(br, 1H), 2.22-2.19(m, 1H), 2.09(br, 1H), 1.84 -1.81(m, 1H), 1.76(s, 2H), 1.64-1.55(m, 6H), 1.40-1.34(m, 1H), 1.34-1.25(m, 4H), 1.12(s, 2H), 0.83 (s, 6H), 0.58 (d, J=5.1 Hz, 2H), 0.36 (br, 2H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B416) δ 174.1, 169.7, 154.3, 142.4, 128.4, 117.1, 52.1, 50.8, 48.1, 42.8, 40.6, 32.4, 30.5, 30.1, 28.1, 22.6. HRMS(ESI) calcd for C 29 H 40 N 4 O 3 Na[M+Na] + : 515.2993, found: 515.2992.
实施例22 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-3-甲酰胺(GL-B417)的合成Example 22 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxypiperidine Synthesis of pyridine-3-carboxamide (GL-B417)
按照实施例18的方法操作，以甲氧基甲胺盐酸盐为原料(即实施例18中胺的盐酸盐具体为甲氧基甲胺盐酸盐)，得到白色固体，即为GL-B417，产量为0.28g，收率为65％，m.p.130-132℃。
1H NMR(400MHz，DMSO-d
6，GL-B417)δ8.43(s，1H)，7.38(d，J＝8.6Hz，2H)，7.24(d，J＝8.6Hz，2H)，5.96(s 1H)，4.13(br，2H)，2.92(br，2H)，2.17-2.09(m，2H)，1.83-1.81(m，1H)，1.76(d，J＝2.0Hz，2H)，1.68-1.61(m，2H)，1.61-1.55(m，4H)，1.40-1.37(m，1H)，1.35-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B417)δ169.9，169.7，154.3，142.4，128.5，128.3，117.1，63.7，52.1，50.8，48.1，42.8，40.6，32.4，30.5，30.1，27.8.HRMS(ESI)calcd for C
27H
38N
4O
4Na[M+Na]
+：505.2785，found：505.2791。
Operate according to the method of Example 18, using methoxymethylamine hydrochloride as a raw material (that is, the hydrochloride of the amine in Example 18 is specifically methoxymethylamine hydrochloride) to obtain a white solid, which is GL- B417, yield 0.28 g, 65% yield, mp 130-132°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B417) δ 8.43 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 5.96 ( s 1H), 4.13 (br, 2H), 2.92 (br, 2H), 2.17-2.09 (m, 2H), 1.83-1.81 (m, 1H), 1.76 (d, J=2.0Hz, 2H), 1.68- 1.61(m, 2H), 1.61-1.55(m, 4H), 1.40-1.37(m, 1H), 1.35-1.24(m, 4H), 1.12(s, 2H), 0.83(s, 6H). 13 C HRMS (ESI) calcd for C27H38N4O4Na [M + Na] + : 505.2785 , found: 505.2791 .
实施例23[1-(4-硝基苯甲酰基)哌啶-4-基]氨基甲酸叔丁酯的合成Example 23 Synthesis of [1-(4-nitrobenzoyl)piperidin-4-yl]carbamic acid tert-butyl ester
向三口瓶中加入4-叔丁氧羰基氨基哌啶(5.4g，27.0mmol)、三乙胺(8.2g，80.9mmol)和THF(50mL)，冰盐浴降温至0℃以下，逐滴加入对硝基苯甲酰氯(5.0g，27.0mmol)的THF溶液(50mL)，滴加完毕后，在室温条件下反应2h，TLC监测反应完全；将所得反应液进行减压浓缩以除去大部分THF，加入水(60mL)，采用乙酸乙酯萃取(60mL×3)，合并有机层，之后依次经水洗(60mL×2)、饱和食盐水洗(60mL)和无水硫酸镁干燥，抽滤，将所得滤液进行减压浓缩，得到黄色粘稠油状物9.4g，未经纯化，直接进行下一步反应(收率按照100％计算)。To the there-necked flask, add 4-tert-butoxycarbonylaminopiperidine (5.4g, 27.0mmol), triethylamine (8.2g, 80.9mmol) and THF (50mL), cool down to below 0°C in an ice-salt bath, add dropwise The THF solution (50 mL) of p-nitrobenzoyl chloride (5.0 g, 27.0 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 h. TLC monitored the reaction to complete; the obtained reaction solution was concentrated under reduced pressure to remove most of the THF. , water (60 mL) was added, extracted with ethyl acetate (60 mL×3), the organic layers were combined, washed with water (60 mL×2), washed with saturated brine (60 mL) and dried over anhydrous magnesium sulfate, suction filtered, and the obtained The filtrate was concentrated under reduced pressure to obtain 9.4 g of yellow viscous oil, which was directly subjected to the next reaction without purification (the yield was calculated as 100%).
实施例24[1-(4-氨基苯甲酰基)哌啶-4-基]氨基甲酸叔丁酯的合成Example 24 Synthesis of [1-(4-aminobenzoyl)piperidin-4-yl]carbamic acid tert-butyl ester
向250mL单口瓶中加入[1-(4-硝基苯甲酰基)哌啶-4-基]氨基甲酸叔丁酯(9.4g，27.0mmol)、5％Pd-C(0.94g)和无水乙醇(100mL)，氩气置换三次，氢气置换三次，升温至60℃搅拌反应12h，TLC监测反应完全；待反应液冷却至室温后，抽滤，滤液经减压浓缩得浅黄色固体，加入乙醚(30mL)后打浆，将打浆后所得体系进行抽滤，滤饼用乙 醚淋洗，干燥后得到白色固体，即为[1-(4-硝基苯甲酰基)哌啶-4-基]氨基甲酸叔丁酯，产量为4.87g，两步收率(即实施例23和实施例24中两个反应步骤的总收率)为56％。To a 250mL single-necked flask was added [1-(4-nitrobenzoyl)piperidin-4-yl]carbamic acid tert-butyl ester (9.4g, 27.0mmol), 5% Pd-C (0.94g) and anhydrous Ethanol (100 mL) was replaced by argon three times, and hydrogen replaced three times. The temperature was raised to 60 °C and stirred for 12 h. TLC monitored the reaction to complete. After the reaction solution was cooled to room temperature, suction filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid, which was added with ether. (30mL) after beating, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with diethyl ether, and a white solid was obtained after drying, which was [1-(4-nitrobenzoyl)piperidin-4-yl]amino tert-Butyl formate, the yield was 4.87 g, and the two-step yield (ie, the total yield of the two reaction steps in Example 23 and Example 24) was 56%.
实施例25苯基(4-{4-[(叔丁氧基羰基)氨基]哌啶-1-羰基}苯基)氨基甲酸酯的合成Example 25 Synthesis of phenyl(4-{4-[(tert-butoxycarbonyl)amino]piperidine-1-carbonyl}phenyl)carbamate
向三口瓶中加入[1-(4-氨基苯甲酰基)哌啶-4-基]氨基甲酸叔丁酯(4.5g，14.1mmol)、碳酸钾粉末(5.84g，42.3mmol)和干燥的THF(30mL)，冰盐浴降温至0℃以下，逐滴加入氯甲酸苯酯(3.74g，24.0mmol)的THF溶液(10mL)，滴加完毕后，在室温条件下反应6h，TLC监测反应完全；将所得反应液进行减压浓缩以除去大部分THF，加入水(60mL)，采用乙酸乙酯萃取(60mL×3)，合并有机层，之后依次经水洗(60mL×2)、饱和食盐水洗(60mL)和无水硫酸镁干燥，抽滤，将所得滤液进行减压浓缩，得到黄色油状物，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为苯基(4-{4-[(叔丁氧基羰基)氨基]哌啶-1-羰基}苯基)氨基甲酸酯，产量为5.32g，收率为86％。To the there-necked flask was added tert-butyl [1-(4-aminobenzoyl)piperidin-4-yl]carbamate (4.5g, 14.1mmol), potassium carbonate powder (5.84g, 42.3mmol) and dry THF (30 mL), the ice-salt bath was cooled to below 0 °C, and a THF solution (10 mL) of phenyl chloroformate (3.74 g, 24.0 mmol) was added dropwise. After the dropwise addition, the reaction was carried out at room temperature for 6 h, and TLC monitored the completion of the reaction. The obtained reaction solution was concentrated under reduced pressure to remove most of the THF, added water (60 mL), extracted with ethyl acetate (60 mL×3), combined the organic layers, washed with water (60 mL×2), washed with saturated brine ( 60mL) and anhydrous magnesium sulfate, dried, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain a yellow oily substance, which was added with ether (15mL) for beating, and the obtained system was subjected to suction filtration after beating. A white solid was obtained, namely phenyl(4-{4-[(tert-butoxycarbonyl)amino]piperidine-1-carbonyl}phenyl)carbamate, the yield was 5.32 g, and the yield was 86%.
实施例26叔丁基[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]氨基甲酸酯的合成Example 26 tert-Butyl[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine- Synthesis of 4-yl]carbamate
向单口瓶中加入苯基(4-{4-[(叔丁氧基羰基)氨基]哌啶-1-羰基}苯基)氨基甲酸酯(5.32g，12.1mmol)、美金刚(2.39g，13.3mmol)、三乙胺(2.45g，24.2mmol)和干燥的THF(50mL)，升温至回流反应8h，TLC检测反应完全；将所得反应液冷却至室温，减压浓缩以除去THF，加入水(50mL)，采用乙酸乙酯萃取(80mL×3)，之后依次经饱和碳酸钠洗(60mL×2)、水洗(60mL)、饱和食盐水洗(60mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到白色固体7.23g，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为叔丁基[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]氨基甲酸酯，产量为5.77g，收率为91％。Phenyl (4-{4-[(tert-butoxycarbonyl)amino]piperidine-1-carbonyl}phenyl)carbamate (5.32g, 12.1mmol), memantine (2.39g) were added to the one-necked flask , 13.3mmol), triethylamine (2.45g, 24.2mmol) and dry THF (50mL), heated to reflux for 8h, TLC detected the reaction was complete; the obtained reaction solution was cooled to room temperature, concentrated under reduced pressure to remove THF, added Water (50 mL), extracted with ethyl acetate (80 mL×3), washed with saturated sodium carbonate (60 mL×2), washed with water (60 mL), washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate, filtered with suction, The obtained filtrate was concentrated under reduced pressure to obtain 7.23 g of a white solid. Diethyl ether (15 mL) was added to make a slurry, and the system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with diethyl ether. -(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]carbamate , the yield was 5.77g, and the yield was 91%.
实施例27 1-[4-(4-氨基哌啶-1-羰基)苯基]-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B418)的合成Example 27 1-[4-(4-Aminopiperidine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl] Synthesis of Urea (GL-B418)
向三口瓶中加入叔丁基[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]氨基甲酸酯(5.77g，11.0mmol)和二氯甲烷(40mL)，冰水浴条件下逐滴加入三氟乙酸(15mL)，滴加完毕后室温搅拌反应2h，TLC检测反应完全；将所得反应液进行减压蒸馏以除去大部分三氟乙酸，加入水(50mL)和DCM(100mL)，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用DCM萃取(100mL×2)，之后依次经水洗(100mL)、饱和食盐水洗(100mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到白色固体4.70g，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为GL-B418，产量为3.60g，收率为77％，m.p.148-150℃。
1H NMR(400MHz，DMSO-d
6，GL-B418)δ8.61(s，1H)，7.39(d，J＝8.3Hz，2H)，7.22(d，J＝8.4Hz，2H)，6.10(s，1H)，3.74(br，4H)，2.92(br，2H)，2.09(s，1H)，1.84(s，1H)，1.76(s，4H)，1.61-1.55(m，4H)，1.34-1.27(m，4H)，1.24-1.11(m，2H)，1.11(s，2H)，0.82(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B418)δ169.6，154.4，142.5，128.5，128.3，117.1，52.0，50.8，48.4，48.1，42.8，40.6，34.5，32.4，30.5，30.1.HRMS(ESI)calcd for C
25H
37N
4O
2[M+H]
+：425.2911，found：425.2909。
Add tert-butyl[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine to the there-necked flask Pyridin-4-yl]carbamate (5.77g, 11.0mmol) and dichloromethane (40mL), trifluoroacetic acid (15mL) was added dropwise under ice-water bath conditions, after the dropwise addition was completed, the reaction was stirred at room temperature for 2h, TLC detection The reaction was completed; the obtained reaction solution was subjected to vacuum distillation to remove most of the trifluoroacetic acid, water (50 mL) and DCM (100 mL) were added, and the pH value of the system was adjusted to 14 with sodium hydroxide solid under ice-water bath conditions, and the organic layer, the aqueous layer was extracted with DCM (100 mL×2), then washed with water (100 mL), saturated brine (100 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 4.70 g of white solid , add ether (15mL) to make slurry, filter the obtained system after beating with suction, rinse the filter cake with ether, and obtain a white solid after drying, which is GL-B418, the output is 3.60g, the yield is 77%, mp148-150 °C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B418) δ 8.61 (s, 1H), 7.39 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.10 ( s, 1H), 3.74(br, 4H), 2.92(br, 2H), 2.09(s, 1H), 1.84(s, 1H), 1.76(s, 4H), 1.61-1.55(m, 4H), 1.34 -1.27(m, 4H), 1.24-1.11(m, 2H), 1.11(s, 2H), 0.82(s, 6H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B418) δ 169.6, 154.4, 142.5, 128.5, 128.3, 117.1, 52.0, 50.8, 48.4, 48.1, 42.8, 40.6, 34.5, 32.4, 30.5, 30.1.HRMS(ESI)calcd for C 25 H 37 N 4 O 2 [M+H] + : 425.2911, found: 425.2909.
实施例28酰氯为酰化剂的第一通用操作The first general operation of embodiment 28 acid chloride as acylating agent
向三口瓶中加入GL-B418(0.40g，0.94mmol)、三乙胺(0.29g，2.84mmol)和干燥的DCM(8mL)，冰盐浴降温至0℃，逐滴加入酰氯原料(1.89mmol)的DCM溶液(2mL)，滴加完毕后室温搅拌反应2h，TLC检测反应完全；将所得反应液倒入水中(30mL)，采用DCM萃取(40mL×3)，合并有机层，之后依次经6mol/L盐酸洗(40mL)、5wt％NaOH水溶液洗(40mL)、水洗(40mL)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到粗品，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到相应的目标产物。GL-B418 (0.40g, 0.94mmol), triethylamine (0.29g, 2.84mmol) and dry DCM (8mL) were added to the there-necked flask, the ice-salt bath was cooled to 0°C, and the acid chloride raw material (1.89mmol) was added dropwise. ) in DCM solution (2 mL), the reaction was stirred at room temperature for 2 h after the dropwise addition, and the reaction was complete after TLC detection; the obtained reaction solution was poured into water (30 mL), extracted with DCM (40 mL×3), the organic layers were combined, and then 6 mol /L hydrochloric acid wash (40mL), 5wt% NaOH aqueous solution (40mL), water wash (40mL), saturated brine (40mL) and anhydrous sodium sulfate drying, suction filtration, the obtained filtrate was concentrated under reduced pressure to obtain a crude product, which was added Diethyl ether (15 mL) was used for beating, and the system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with diethyl ether, and the corresponding target product was obtained after drying.
实施例29羧酸为酰化剂的第三通用操作Example 29 Third general operation with carboxylic acid as acylating agent
向单口瓶中加入羧酸原料(1.89mmol)、EDCI(0.54g，2.83mmol)、HOBt(0.38g，2.83mmol)、三乙胺(0.48g，4.75mmol)和干燥的二氯甲烷(10mL)，30℃条件下搅拌30min后加入GL-B418(0.40g，0.94mmol)，30℃条件下反应8h，TLC监测反应完全；将所得反应液倒入水中(30mL)，采用二氯甲烷萃取(40mL×3)，之后依次经1mol/L盐酸洗(40mL)、5％氢氧化钠水溶液洗(40mL)、水洗(40mL)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到粗品，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到相应的目标产物。To a single-necked flask was added carboxylic acid raw material (1.89 mmol), EDCI (0.54 g, 2.83 mmol), HOBt (0.38 g, 2.83 mmol), triethylamine (0.48 g, 4.75 mmol) and dry dichloromethane (10 mL) , stirred at 30°C for 30min, added GL-B418 (0.40g, 0.94mmol), reacted at 30°C for 8h, TLC monitored the completion of the reaction; poured the obtained reaction solution into water (30mL), extracted with dichloromethane (40mL) ×3), then washed with 1 mol/L hydrochloric acid (40 mL), 5% aqueous sodium hydroxide solution (40 mL), washed with water (40 mL), washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained The filtrate was concentrated under reduced pressure to obtain a crude product, and ether (15 mL) was added to make a slurry. The system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with ether and dried to obtain the corresponding target product.
实施例30 N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]甲磺酰胺(GL-B419)的合成Example 30 N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4 Synthesis of -yl]methanesulfonamide (GL-B419)
按照实施例28的方法操作，以甲磺酰氯为原料(即实施例28中的酰氯原料具体为甲磺酰氯)，得到白色固体，即为GL-B419，产量为0.19g，收率为40％，m.p.157-159℃。
1H NMR(400MHz，CDCl
3，GL-B419)δ7.92(s，1H)，7.17-7.10(m，4H)，5.65(br，1H)，5.47(d，J＝6.4Hz，1H)，4.40(br，1H)，3.70(br，1H)，3.50(br，1H)，3.02-3.01(m，2H)，2.98(s，3H)，2.14(s，1H)，1.97(br，2H)，1.84(s，2H)，1.68-1.60(m，4H)，1.39-1.27(m，6H)，1.19-1.12(m，2H)，0.85(s，6H).
13C NMR(100MHz，CDCl
3，GL-B419)δ170.9，154.8，142.1，127.9，127.6，118.3，52.8，50.7，50.6，48.2，42.7，42.1，40.7，32.4，30.2.HRMS(ESI)calcd for C
26H
38N
4O
4SNa[M+Na]
+：525.2506，found：525.2500。
Operate according to the method of Example 28, using methanesulfonyl chloride as a raw material (that is, the acid chloride raw material in Example 28 is specifically methanesulfonyl chloride) to obtain a white solid, namely GL-B419, the yield is 0.19g, and the yield is 40% , mp157-159°C. 1 H NMR (400MHz, CDCl 3 , GL-B419) δ 7.92 (s, 1H), 7.17-7.10 (m, 4H), 5.65 (br, 1H), 5.47 (d, J=6.4Hz, 1H), 4.40(br, 1H), 3.70(br, 1H), 3.50(br, 1H), 3.02-3.01(m, 2H), 2.98(s, 3H), 2.14(s, 1H), 1.97(br, 2H) , 1.84(s, 2H), 1.68-1.60(m, 4H), 1.39-1.27(m, 6H), 1.19-1.12(m, 2H), 0.85(s, 6H). 13 C NMR (100MHz, CDCl 3 , GL-B419) δ170.9, 154.8, 142.1, 127.9, 127.6, 118.3, 52.8, 50.7, 50.6, 48.2, 42.7, 42.1, 40.7, 32.4, 30.2.HRMS(ESI)calcd for C 26 H 38 N 4 O 4 SNa[M+Na] + : 525.2506, found: 525.2500.
实施例31 N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]乙酰胺(GL-B420)的合成Example 31 N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4 Synthesis of -yl]acetamide (GL-B420)
按照实施例28的方法操作，以乙酰氯为原料(即实施例28中的酰氯原料具体为乙酰氯)，得到白色固体，即为GL-B420，产量为0.17g，收率为39％，m.p.244-246℃。
1H NMR(400MHz，DMSO-d
6，GL-B420)δ8.57(s，1H)，7.82(d，J＝7.5Hz，2H)，7.38(d，J＝8.5Hz，2H)，7.23(d，J＝8.5Hz，2H)，6.05(s，1H)，3.97(br，1H)，3.83-3.76(m，2H)，3.03(br，4H)，2.09(s，1H)，1.79(s，3H)，1.76(br，4H)，1.61-1.55(m，4H)，1.34-1.24(m，6H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B420)δ169.7，168.8，154.3，142.5，128.4，128.3，117.1，52.0，50.8，48.1，46.1，42.8，40.6，32.4，30.5，30.1，23.2.HRMS(ESI)calcd for C
27H
38N
4O
4Na[M+Na]
+：489.2836，found：489.2834。
Operate according to the method of Example 28, take acetyl chloride as raw material (that is, the acid chloride raw material in Example 28 is specifically acetyl chloride) to obtain a white solid, namely GL-B420, the output is 0.17g, the yield is 39%, mp244 -246°C. 1 H NMR (400MHz, DMSO-d 6 , GL-B420) δ 8.57 (s, 1H), 7.82 (d, J=7.5Hz, 2H), 7.38 (d, J=8.5Hz, 2H), 7.23 ( d, J=8.5Hz, 2H), 6.05(s, 1H), 3.97(br, 1H), 3.83-3.76(m, 2H), 3.03(br, 4H), 2.09(s, 1H), 1.79(s , 3H), 1.76(br, 4H), 1.61-1.55(m, 4H), 1.34-1.24(m, 6H), 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100MHz, DMSO) calcd for C27H38N4O4Na [M + Na] + : 489.2836 , found: 489.2834 .
实施例32 N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丙酰胺(GL-B421)的合成Example 32 N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4 Synthesis of -yl]propionamide (GL-B421)
按照实施例28的方法操作，以丙酰氯为原料(即实施例28中的酰氯原料具体为丙酰氯)，得到白色固体，即为GL-B421，产量为0.12g，收率为27％，m.p.230-232℃。
1H NMR(400MHz，CDCl
3，GL-B421)δ7.96(s，1H)，7.13(s，4H)，6.16(d，J＝5.9Hz，1H)，5.66(s，1H)，4.50(br，1H)，4.01-4.00(m，1H)，3.74-3.73(m，1H)，2.99(br，2H)，2.20(q，J＝7.5Hz，2H)，2.14(br，1H)，1.97-1.92(m，4H)，1.67-1.59(m，6H)，1.39-1.28(m，6H)，1.15(d，J＝7.4Hz，3H)，1.12(s，2H)，0.84(s，6H).
13C NMR(100MHz，CDCl
3，GL-B421)δ173.6，170.9，154.8，142.0，127.9，127.8，118.2，52.7，50.7，48.3，46.4，42.7，40.7，32.4，30.2，30.1，29.7，9.9.HRMS(ESI)calcd for C
28H
40N
4O
3Na[M+Na]
+：503.2993，found：503.2996。
Operate according to the method of Example 28, take propionyl chloride as raw material (that is, the acid chloride raw material in Example 28 is specifically propionyl chloride) to obtain a white solid, namely GL-B421, the yield is 0.12g, the yield is 27%, mp230 -232°C. 1 H NMR (400 MHz, CDCl 3 , GL-B421) δ 7.96 (s, 1H), 7.13 (s, 4H), 6.16 (d, J=5.9 Hz, 1H), 5.66 (s, 1H), 4.50 ( br, 1H), 4.01-4.00 (m, 1H), 3.74-3.73 (m, 1H), 2.99 (br, 2H), 2.20 (q, J=7.5Hz, 2H), 2.14 (br, 1H), 1.97 -1.92(m, 4H), 1.67-1.59(m, 6H), 1.39-1.28(m, 6H), 1.15(d, J=7.4Hz, 3H), 1.12(s, 2H), 0.84(s, 6H) ). 13 C NMR (100MHz, CDCl 3 , GL-B421) δ 173.6, 170.9, 154.8, 142.0, 127.9, 127.8, 118.2, 52.7, 50.7, 48.3, 46.4, 42.7, 40.7, 32.4, 30.2, 30.1, 29.7 , 9.9. HRMS(ESI) calcd for C 28 H 40 N 4 O 3 Na[M+Na] + : 503.2993, found: 503.2996.
实施例33 N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丁酰胺(GL-B422)的合 成Example 33 N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4 Synthesis of -yl]butanamide (GL-B422)
按照实施例29的方法操作，以正丁酸为原料(即实施例29中的羧酸原料具体为正丁酸)，得到白色固体，即为GL-B422，产量为0.12g，收率为26％，m.p.236-237℃。
1H NMR(400MHz，CDCl
3，GL-B422)δ8.01(s，1H)，7.17-7.10(m，4H)，6.16(d，J＝6.3Hz，1H)，5.69(br，1H)，4.50(br，1H)，4.03-4.01(m，1H)，3.73(br，1H)，3.00(br，2H)，2.17-2.13(m，3H)，1.99-1.84(m，4H)，1.70-1.60(m，6H)，1.39-1.28(m，4H)，1.19-1.12(m，2H)，0.93(t，J＝7.3Hz，3H)，0.85(s，6H).
13C NMR(100MHz，CDCl
3，GL-B422)δ172.8，170.9，154.8，142.1，127.8，127.7，118.2，52.7，50.7，48.3，46.4，42.8，40.7，38.7，32.4，30.2，30.1，19.2，13.7.HRMS(ESI)calcd for C
29H
42N
4O
3Na[M+Na]
+：517.3149，found：517.3150。
Operate according to the method of Example 29, take n-butyric acid as a raw material (that is, the carboxylic acid raw material in Example 29 is specifically n-butyric acid) to obtain a white solid, namely GL-B422, the output is 0.12g, and the yield is 26 %, mp236-237°C. 1 H NMR (400 MHz, CDCl 3 , GL-B422) δ 8.01 (s, 1H), 7.17-7.10 (m, 4H), 6.16 (d, J=6.3 Hz, 1H), 5.69 (br, 1H), 4.50(br, 1H), 4.03-4.01(m, 1H), 3.73(br, 1H), 3.00(br, 2H), 2.17-2.13(m, 3H), 1.99-1.84(m, 4H), 1.70- 1.60 (m, 6H), 1.39-1.28 (m, 4H), 1.19-1.12 (m, 2H), 0.93 (t, J=7.3Hz, 3H), 0.85 (s, 6H). 13 C NMR (100MHz, CDCl 3 , GL-B422) δ172.8, 170.9, 154.8, 142.1, 127.8, 127.7, 118.2, 52.7, 50.7, 48.3, 46.4, 42.8, 40.7, 38.7, 32.4, 30.2, 30.1, 19.2, 13.7.HRMS (ESI )calcd for C29H42N4O3Na [ M + Na] + : 517.3149 , found: 517.3150.
实施例34 N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-2-甲基丁酰胺(GL-B423)的合成Example 34 N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4 Synthesis of -yl]-2-methylbutanamide (GL-B423)
按照实施例29的方法操作，以2-甲基丁酸为原料(即实施例29中的羧酸原料具体为2-甲基丁酸)，得到白色固体，即为GL-B423，产量为0.35g，收率为73％，m.p.250-252℃。
1H NMR(400MHz，DMSO-d
6，GL-B423)δ8.45(s，1H)，7.69(d，J＝7.6Hz，1H)，7.38(d，J＝8.6Hz，2H)，7.22(d，J＝8.6Hz，2H)，5.97(s，1H)，3.94(br，1H)，3.85-3.78(m，2H)，3.02(br，2H)，2.16-2.09(m，2H)，1.76-1.75(m，4H)，1.61-1.55(m，4H)，1.51-1.42(m，1H)，1.34-1.25(m，7H)，1.12(s，2H)，0.96(d，J＝6.8Hz，3H)，0.83(s，6H)，0.79(t，J＝7.4Hz，3H).
13C NMR(100MHz，DMSO-d
6，GL-B423)δ175.2，169.7，154.3，142.4，128.5，128.3，117.1，52.1，50.8，48.1，46.0，42.8，41.7，40.6，32.4，30.5，30.1，27.3，18.0，12.2.HRMS(ESI)calcd for C
30H
44N
4O
3Na[M+Na]
+：531.3306，found：531.3309。
Operate according to the method of Example 29, using 2-methylbutyric acid as a raw material (that is, the carboxylic acid raw material in Example 29 is specifically 2-methylbutyric acid) to obtain a white solid, namely GL-B423, and the output is 0.35 g, 73% yield, mp 250-252°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B423) δ 8.45 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.22 ( d, J=8.6Hz, 2H), 5.97(s, 1H), 3.94(br, 1H), 3.85-3.78(m, 2H), 3.02(br, 2H), 2.16-2.09(m, 2H), 1.76 -1.75(m, 4H), 1.61-1.55(m, 4H), 1.51-1.42(m, 1H), 1.34-1.25(m, 7H), 1.12(s, 2H), 0.96(d, J=6.8Hz , 3H), 0.83 (s, 6H), 0.79 (t, J=7.4Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B423) δ 175.2, 169.7, 154.3, 142.4, 128.5, 128.3, 117.1, 52.1, 50.8, 48.1, 46.0, 42.8, 41.7, 40.6, 32.4, 30.5, 30.1, 27.3, 18.0, 12.2.HRMS(ESI)calcd for C 30 H 44 N 4 O 3 Na[M+Na] + : 531.3306, found: 531.3309.
实施例35 N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]环丙烷甲酰胺(GL-B424)的合成Example 35 N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4 Synthesis of -yl]cyclopropanecarboxamide (GL-B424)
按照实施例29的方法操作，以环丙甲酸为原料(即实施例29中的羧酸原料具体为环丙甲酸)，得到白色固体，即为GL-B424，产量为0.34g，收率为74％，m.p.239-242℃。
1H NMR(400MHz，DMSO-d
6，GL-B424)δ4.85(s，1H)，0.86(d，J＝7.6Hz，1H)，7.28(d，J＝8.5Hz，2H)，7.23(d，J＝8.4Hz，2H)，5.97(s，1H)，4.48-3.68(m，3H)，3.02(br，2H)，2.09(br，1H)，1.76(br，4H)，1.64-1.55(m，4H)，1.53-1.48(m，1H)，1.34-1.24(m，6H)，1.12(s，2H)，0.83(s，6H)，0.66-0.62(m，4H).
13C NMR(100MHz，DMSO-d
6，GL-B424)δ172.2，169.6，154.3，142.4，128.4，128.4，117.1，52.1，50.8，48.1，46.3，42.8，40.6，32.4，30.5，30.1，14.1，6.6.HRMS(ESI)calcd for C
29H
40N
4O
3Na[M+Na]
+：515.2993，found：515.2996。
Operate according to the method of embodiment 29, take cyclopropanecarboxylic acid as raw material (that is, the carboxylic acid raw material in embodiment 29 is specifically cyclopropanecarboxylic acid), obtain a white solid, namely GL-B424, the output is 0.34g, and the yield is 74 %, mp239-242°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B424) δ 4.85 (s, 1H), 0.86 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.23 ( d, J=8.4Hz, 2H), 5.97(s, 1H), 4.48-3.68(m, 3H), 3.02(br, 2H), 2.09(br, 1H), 1.76(br, 4H), 1.64-1.55 (m, 4H), 1.53-1.48 (m, 1H), 1.34-1.24 (m, 6H), 1.12 (s, 2H), 0.83 (s, 6H), 0.66-0.62 (m, 4H). 13 C NMR (100MHz, DMSO-d 6 , GL-B424) δ172.2, 169.6, 154.3, 142.4, 128.4, 128.4, 117.1, 52.1, 50.8, 48.1, 46.3, 42.8, 40.6, 32.4, 30.5, 30.1, 14.1, 6.6. HRMS (ESI) calcd for C29H40N4O3Na [ M + Na] + : 515.2993 , found: 515.2996.
实施例36叔丁基{1-{[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]氨基}-3-甲基-1-氧代丁烷-2-基}氨基甲酸酯的合成Example 36 tert-butyl{1-{[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl ) synthesis of piperidin-4-yl]amino}-3-methyl-1-oxobutan-2-yl}carbamate
按照实施例29的方法操作，以Boc-缬氨酸为原料(即实施例29中的羧酸原料具体为Boc-缬氨酸)，且后处理过程中未使用1mol/L盐酸洗涤，得到半固体粗品1g，未进行纯化，直接用于下一步反应。According to the method of Example 29, Boc-valine was used as a raw material (that is, the carboxylic acid raw material in Example 29 was specifically Boc-valine), and 1 mol/L hydrochloric acid was not used for washing in the post-treatment process to obtain half 1 g of the solid crude product was used for the next reaction without purification.
实施例37 2-氨基-N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-3-甲基丁酰胺(GL-B425)的合成Example 37 2-Amino-N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl) Synthesis of Piperidin-4-yl]-3-methylbutanamide (GL-B425)
向三口瓶中加入叔丁基(1-((1-(4-(3-(((1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基)脲基)苯甲酰基)哌啶-4-基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸酯(1.0g)和二氯甲烷(10mL)，冰水浴条件下逐滴加入三氟乙酸(4mL)，滴加完毕后，在室温条件下搅拌反应2h，TLC检测反应完全；将所得反应液进行减压蒸馏以除去大部分三氟乙酸，加入水(50mL)和DCM(100mL)，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用DCM萃取(100mL×2)，之后依次经水洗(100mL)、饱和食盐水洗(100mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色半固体0.4g，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体0.14g，两步收率(即实施例36和实施例37中两个反应步骤的总收率)为29％，m.p.219-222℃。
1H NMR(400MHz，DMSO-d
6，GL-B425)δ8.66(s，1H)，7.85(d，J＝7.7Hz，1H)，7.38(d，J＝8.5Hz，2H)，7.23(d，J＝8.4Hz，2H)，6.07(s，1H)，4.09-3.86(m，2H)，3.85-3.84(m，1H)，3.04-2.97(m，4H)，2.09(br，1H)，1.87-1.83(m，1H)，1.76(br，4H)，1.61-1.54(m，4H)，1.34-1.22(m，7H)，1.12(s，2H)，0.86(d，J＝6.8Hz，3H)，0.83(s，6H)，0.80(d，J＝6.9Hz，3H).
13C NMR(100MHz，DMSO-d
6，GL-B425)δ173.4，169.7，154.4，142.5，128.3，117.1，60.1，52.0，50.8，48.1，46.1，42.8，40.6，32.4，32.0，30.5，30.1，19.8，17.8.HRMS(ESI)calcd for C
30H
45N
5O
3Na[M+Na]
+：546.3415，found：546.3416。
Add tert-butyl (1-((1-(4-(3-(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido) to the there-necked flask Benzoyl)piperidin-4-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (1.0 g) and dichloromethane (10 mL) under ice-water bath conditions Trifluoroacetic acid (4 mL) was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 2 h. TLC detected the reaction was complete; the obtained reaction solution was distilled under reduced pressure to remove most of the trifluoroacetic acid, and water (50 mL) and DCM (100 mL), the pH value of the system was adjusted to 14 with sodium hydroxide solid under ice-water bath conditions, the organic layer was separated and removed, the aqueous layer was extracted with DCM (100 mL×2), and then washed with water (100 mL) and saturated brine ( 100mL) and anhydrous sodium sulfate, dried with suction, filtered with suction, and the filtrate obtained was concentrated under reduced pressure to obtain 0.4 g of a light yellow semi-solid. Diethyl ether (15 mL) was added to make a slurry, the system obtained after the beating was subjected to suction filtration, and the filter cake was rinsed with ether. , 0.14 g of white solid was obtained after drying, the two-step yield (ie, the total yield of the two reaction steps in Example 36 and Example 37) was 29%, mp 219-222° C. 1 H NMR (400MHz, DMSO-d 6 , GL-B425)δ8.66(s, 1H), 7.85(d, J=7.7Hz, 1H), 7.38(d, J=8.5Hz, 2H), 7.23(d, J=8.4Hz, 2H) , 6.07(s, 1H), 4.09-3.86(m, 2H), 3.85-3.84(m, 1H), 3.04-2.97(m, 4H), 2.09(br, 1H), 1.87-1.83(m, 1H) , 1.76(br, 4H), 1.61-1.54(m, 4H), 1.34-1.22(m, 7H), 1.12(s, 2H), 0.86(d, J=6.8Hz, 3H), 0.83(s, 6H) The _ , 46.1, 42.8, 40.6, 32.4, 32.0, 30.5, 30.1, 19.8, 17.8. HRMS(ESI) calcd for C30H45N5O3Na [ M +Na] + : 546.3415 , found: 546.3416 .
实施例38 4-(4-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯的合成Example 38 Synthesis of 4-(4-nitrobenzoyl)piperazine-1-carboxylate tert-butyl ester
向三口瓶中加入N-Boc-哌嗪(10.1g，54.1mmol)、三乙胺(16.4g，0.16mol)和THF(80mL)，冰盐浴降温至0℃以下，逐滴加入对硝基苯甲酰氯(10.0g，54.1mmol)的THF溶液(50mL)，滴加完毕后，在室温条件下反应2h，TLC监测反应完全；将所得反应液进行减压浓缩以除去大部分THF，加入水(100mL)，采用乙酸乙酯萃取(100mL×3)，合并有机层，之后依次采用水洗(60mL×2)、饱和食盐水洗(60mL)和无水硫酸镁干燥，抽滤，将所得滤液进行减压浓缩，得到黄色粘稠油状物，加入乙醚(30mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为4-(4-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯，产量为15.1g，收率为83％。N-Boc-piperazine (10.1g, 54.1mmol), triethylamine (16.4g, 0.16mol) and THF (80mL) were added to the there-necked flask, the ice-salt bath was cooled to below 0°C, and p-nitro was added dropwise. The THF solution (50 mL) of benzoyl chloride (10.0 g, 54.1 mmol) was added dropwise, and the reaction was carried out at room temperature for 2 h. TLC monitored the completion of the reaction; the obtained reaction solution was concentrated under reduced pressure to remove most of the THF, and water was added. (100 mL), extracted with ethyl acetate (100 mL×3), combined the organic layers, washed with water (60 mL×2), washed with saturated brine (60 mL) and dried over anhydrous magnesium sulfate, suction filtered, and the obtained filtrate was reduced Concentrate under pressure to obtain a yellow viscous oil, add ether (30 mL) to make a slurry, filter the obtained system after beating with suction, rinse the filter cake with ether, and dry to obtain a white solid, which is 4-(4-nitrobenzyl) Acyl)piperazine-1-carboxylate tert-butyl ester, yield 15.1 g, 83% yield.
实施例39 4-(4-氨基苯甲酰基)哌嗪-1-羧酸叔丁酯的合成Example 39 Synthesis of 4-(4-aminobenzoyl)piperazine-1-carboxylate tert-butyl ester
向单口瓶中加入4-(4-硝基苯甲酰基)哌嗪-1-羧酸叔丁酯(15.1g，45.1mmol)、5％Pd-C(1.5g)和无水乙醇(100mL)，氩气置换三次，氢气置换三次，升温至60℃搅拌反应12h，TLC监测反应完全；待反应液冷却至室温后，抽滤，滤液经减压浓缩，得到白色固体，即为4-(4-氨基苯甲酰基)哌嗪-1-羧酸叔丁酯，产量为13.7g，收率为99％。To a single-necked flask was added tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (15.1 g, 45.1 mmol), 5% Pd-C (1.5 g) and absolute ethanol (100 mL) , replaced by argon three times, replaced by hydrogen three times, heated to 60°C and stirred for 12h, and TLC monitored the completion of the reaction; after the reaction solution was cooled to room temperature, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid, which was 4-(4 -Aminobenzoyl)piperazine-1-carboxylate tert-butyl ester, yield 13.7 g, yield 99%.
实施例40 4-{4-[(苯氧基羰基)氨基]苯甲酰基}哌嗪-1-甲酸叔丁酯的合成Example 40 Synthesis of tert-butyl 4-{4-[(phenoxycarbonyl)amino]benzoyl}piperazine-1-carboxylate
向三口瓶中加入4-(4-氨基苯甲酰基)哌嗪-1-羧酸叔丁酯(13.7g，44.9mmol)、碳酸钾粉末(18.6g，0.13mol)和干燥的THF(150mL)，冰盐浴条件下降温至0℃以下，逐滴加入氯甲酸苯酯(11.9g，76.3mmol)的THF溶液(40mL)，滴加完毕后，在室温条件下反应6h，TLC监测反应完全；将所得反应液进行减压浓缩以除去大部分THF，加入水(100mL)，采用乙酸乙酯萃取(100mL×3)，合并有机层，之后依次经水洗(100mL×2)、饱和食盐水洗(100mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到黄色油状物27.6g，加入乙醚(60mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为4-{4-[(苯氧基羰基)氨基]苯甲酰基}哌嗪-1-甲酸叔丁酯，产量为16.95g，收率为89％。To the there-necked flask was added tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (13.7g, 44.9mmol), potassium carbonate powder (18.6g, 0.13mol) and dry THF (150mL) , the temperature in an ice-salt bath was lowered to below 0 °C, and a THF solution (40 mL) of phenyl chloroformate (11.9 g, 76.3 mmol) was added dropwise. The resulting reaction solution was concentrated under reduced pressure to remove most of the THF, water (100 mL) was added, extracted with ethyl acetate (100 mL×3), the organic layers were combined, and washed with water (100 mL×2) and saturated brine (100 mL) successively. ) and anhydrous sodium sulfate, suction filtration, and the obtained filtrate was concentrated under reduced pressure to obtain 27.6 g of a yellow oil, which was added with ether (60 mL) to make a slurry, and the obtained system was subjected to suction filtration after beating, and the filter cake was rinsed with ether and dried. After that, a white solid was obtained, which was tert-butyl 4-{4-[(phenoxycarbonyl)amino]benzoyl}piperazine-1-carboxylate, and the yield was 16.95 g and the yield was 89%.
实施例41 4-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌嗪-1-甲酸叔丁酯的合成Example 41 Tertiary 4-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperazine-1-carboxylic acid Synthesis of Butyl Ester
向单口瓶中加入4-{4-[(苯氧基羰基)氨基]苯甲酰基}哌嗪-1-甲酸叔丁酯(16.95g，39.9mmol)、美金刚(7.86g，43.8mmol)、三乙胺(8.05g，79.7mmol)和干燥的THF(100mL)，升温至回流反应8h，TLC检测反应完全；将所得反应液冷却至室温，抽滤，滤饼用THF淋洗，干燥后得到白色固体，即为4-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌嗪-1-甲酸叔丁酯，产量为17.68g，收率为87％。To a single-necked flask was added tert-butyl 4-{4-[(phenoxycarbonyl)amino]benzoyl}piperazine-1-carboxylate (16.95g, 39.9mmol), memantine (7.86g, 43.8mmol), Triethylamine (8.05g, 79.7mmol) and dry THF (100mL) were heated to reflux for 8h, and TLC detected the reaction was complete; the obtained reaction solution was cooled to room temperature, filtered with suction, the filter cake was rinsed with THF, and dried to obtain White solid, namely 4-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperazine-1- Tert-butyl formate, yield 17.68 g, yield 87%.
实施例42 1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-[4-(哌嗪-1-羰基)苯基]脲(GL-B426)的合成Example 42 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(piperazine-1-carbonyl)phenyl]urea (GL -B426) synthesis
向三口瓶中加入4-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌嗪-1-甲酸叔丁酯(15.0g，29.4 mmol)和二氯甲烷(50mL)，冰水浴条件下逐滴加入三氟乙酸(20mL)，滴加完毕后，在室温条件下搅拌反应4h，TLC检测反应完全；将所得反应液进行减压蒸馏以除去大部分三氟乙酸，加入水(80mL)和DCM(100mL)，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用DCM萃取(100mL×2)，之后依次经水洗(100mL)、饱和食盐水洗(100mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色半固体18.88g，加入乙醚(30mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为GL-B426，产量为9.60g，收率为80％，m.p.190-193℃。
1H NMR(400MHz，DMSO-d
6，GL-B426)δ8.46(s，1H)，7.37(d，J＝8.6Hz，2H)，7.23(d，J＝8.6Hz，2H)，5.98(s，1H)，3.41-3.36(m，3H)，3.25(br，2H)，2.69(br，4H)，2.10-2.08(m，1H)，1.76(d，J＝2.2Hz，2H)，1.61-1.55(m，4H)，1.35-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B426)δ169.6，154.3，142.4，128.6，128.4，117.1，52.0，50.8，48.1，46.1，42.8，40.4，32.4，30.5，30.1.HRMS(ESI)calcd for C
24H
34N
4O
2Na[M+Na]
+：433.2574，found：433.2569。
Add 4-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperazine-1-to the there-necked flask tert-Butyl formate (15.0 g, 29.4 mmol) and dichloromethane (50 mL) were added dropwise with trifluoroacetic acid (20 mL) in an ice-water bath. After the addition was completed, the reaction was stirred at room temperature for 4 h. TLC detected that the reaction was complete. The obtained reaction solution was distilled under reduced pressure to remove most of the trifluoroacetic acid, water (80 mL) and DCM (100 mL) were added, and the pH value of the system was adjusted to 14 with sodium hydroxide solid under ice-water bath conditions, and the organic layer was separated and removed, The aqueous layer was extracted with DCM (100 mL×2), then washed with water (100 mL), saturated brine (100 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 18.88 g of pale yellow semi-solid , add ether (30mL) to make pulp, filter the obtained system after beating, rinse the filter cake with ether, and dry to obtain a white solid, namely GL-B426, the output is 9.60g, the yield is 80%, mp190-193 °C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B426) δ 8.46 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 5.98 ( s, 1H), 3.41-3.36 (m, 3H), 3.25 (br, 2H), 2.69 (br, 4H), 2.10-2.08 (m, 1H), 1.76 (d, J=2.2Hz, 2H), 1.61 -1.55(m, 4H), 1.35-1.24(m, 4H), 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B426) δ 169.6, 154.3, 142.4, 128.6, 128.4, 117.1, 52.0, 50.8, 48.1, 46.1, 42.8, 40.4, 32.4, 30.5, 30.1. HRMS(ESI) calcd for C 24 H 34 N 4 O 2 Na[M+Na] + : 433.2574, found: 433.2569.
实施例43酰氯为酰化剂的第二通用操作The second general operation of embodiment 43 acid chloride as acylating agent
向三口瓶中加入GL-B426(0.40g，0.97mmol)、三乙胺(0.30g，2.92mmol)和干燥的DCM(8mL)，冰盐浴降温至0℃，缓慢滴加酰氯原料(1.95mmol)的DCM溶液(2mL)，滴加完毕后室温搅拌反应2h，TLC检测反应完全；将所得反应液倒入水中(30mL)，采用DCM萃取(40mL×3)，合并有机层，之后依次经6mol/L盐酸洗(40mL)、5wt％NaOH水溶液洗(40mL)、水洗(40mL)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到粗品，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到相应的目标产物；打浆不纯(纯度低于90％)的化合物经硅胶柱层析纯化得到目标产物。GL-B426 (0.40g, 0.97mmol), triethylamine (0.30g, 2.92mmol) and dry DCM (8mL) were added to the there-necked flask, the ice-salt bath was cooled to 0°C, and the acid chloride raw material (1.95mmol) was slowly added dropwise. ) in DCM solution (2 mL), the reaction was stirred at room temperature for 2 h after the dropwise addition, and the reaction was complete after TLC detection; the obtained reaction solution was poured into water (30 mL), extracted with DCM (40 mL×3), the organic layers were combined, and then 6 mol /L hydrochloric acid wash (40mL), 5wt% NaOH aqueous solution (40mL), water wash (40mL), saturated brine (40mL) and anhydrous sodium sulfate drying, suction filtration, the obtained filtrate was concentrated under reduced pressure to obtain a crude product, which was added Diethyl ether (15 mL) was slurried, the system obtained after beating was subjected to suction filtration, the filter cake was rinsed with diethyl ether, and the corresponding target product was obtained after drying; the impure (purity less than 90%) compound was purified by silica gel column chromatography to obtain the target product product.
实施例44羧酸为酰化剂的第四通用操作Example 44 Fourth general operation with carboxylic acid as acylating agent
向单口瓶中加入羧酸原料(1.95mmol)、EDCI(0.56g，2.92mmol)、HOBt(0.40g，2.92mmol)、三乙胺(0.49g，4.87mmol)和干燥的二氯甲烷(10mL)，30℃条件下搅拌30min后加入GL-B426(0.40g，0.97mmol)，30℃条件下反应8h，TLC监测反应完全；将所得反应液倒入水中(30mL)，采用二氯甲烷萃取(40mL×3)，之后依次经1mol/L盐酸洗(40mL)、5％氢氧化钠水溶液洗(40mL)、水洗(40mL)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到粗品，加入乙醚(15mL)打浆，将打浆后所得体系进行抽滤，滤饼用乙醚淋洗，干燥后得到相应的目标产物；打浆不纯(纯度低于90％)的化合物经硅胶柱层析纯化得到目标产物。To a single-necked flask was added carboxylic acid starting material (1.95 mmol), EDCI (0.56 g, 2.92 mmol), HOBt (0.40 g, 2.92 mmol), triethylamine (0.49 g, 4.87 mmol) and dry dichloromethane (10 mL) , stirred for 30 min at 30 °C, then added GL-B426 (0.40 g, 0.97 mmol), reacted at 30 °C for 8 h, and TLC monitored the reaction to complete; the resulting reaction solution was poured into water (30 mL) and extracted with dichloromethane (40 mL). ×3), then washed with 1 mol/L hydrochloric acid (40 mL), 5% aqueous sodium hydroxide solution (40 mL), washed with water (40 mL), washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained The filtrate was concentrated under reduced pressure to obtain the crude product, and ether (15 mL) was added to make a slurry, and the system obtained after beating was subjected to suction filtration, and the filter cake was rinsed with ether, and the corresponding target product was obtained after drying; the pulping was impure (purity lower than 90%) The compound was purified by silica gel column chromatography to obtain the target product.
实施例45 1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-{4-[4-(甲基磺酰基)哌嗪-1-羰基]苯基}脲(GL-B427)的合成Example 45 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-{4-[4-(methylsulfonyl)piperazine-1- Synthesis of Carbonyl]phenyl}urea (GL-B427)
按照实施例43的方法操作，以甲磺酰氯为原料(即实施例43中的酰氯原料具体为甲磺酰氯)，经乙醚打浆纯化得到白色固体，即为GL-B427，产量为0.42g，收率为88％，m.p.226-229℃。
1H NMR(400MHz，DMSO-d
6，GL-B427)δ9.01(br，1H)，7.42(d，J＝8.5Hz，2H)，7.28(d，J＝8.5Hz，2H)，6.32(br，1H)，3.58(br，4H)，3.16-3.15(m，4H)，2.90(s，3H)，2.09(br，1H)，1.77(br，2H)，1.62-1.53(m，4H)，1.34-1.24(m，4H)，1.11(s，1H)，0.82(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B427)δ169.8，154.5，143.3，128.8，127.3，116.9，52.0，50.8，48.2，45.9，42.8，40.6，34.6，32.4，30.6，30.1.HRMS(ESI)calcd for C
25H
36N
4O
4SNa[M+Na]
+：511.2349，found：511.2355。
Operate according to the method of Example 43, using methanesulfonyl chloride as the raw material (that is, the acid chloride raw material in Example 43 is specifically methanesulfonyl chloride), and purified by beating with ether to obtain a white solid, namely GL-B427, the yield is 0.42g, and the yield is 0.42 g. The rate is 88%, mp226-229℃. 1 H NMR (400 MHz, DMSO-d 6 , GL-B427) δ 9.01 (br, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 6.32 ( br, 1H), 3.58 (br, 4H), 3.16-3.15 (m, 4H), 2.90 (s, 3H), 2.09 (br, 1H), 1.77 (br, 2H), 1.62-1.53 (m, 4H) , 1.34-1.24(m, 4H), 1.11(s, 1H), 0.82(s, 6H). 13 C NMR (100MHz, DMSO-d 6 , GL-B427) δ 169.8, 154.5, 143.3, 128.8, 127.3 , 116.9 , 52.0, 50.8, 48.2, 45.9, 42.8, 40.6, 34.6, 32.4, 30.6, 30.1.HRMS(ESI)calcd for C25H36N4O4SNa[M+Na]+ : 511.2349 , found : 511.2355 .
实施例46 1-[4-(4-乙酰基哌嗪-1-羰基)苯基]-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B428)的合成Example 46 1-[4-(4-Acetylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ] Urea (GL-B428) Synthesis
按照实施例43的方法操作，以乙酰氯为原料(即实施例43中的酰氯原料具体为乙酰氯)，经乙醚打浆纯化后再经硅胶柱层析纯化得白色固体，即为GL-B428，产量为0.23g，收率为52％，m.p.127-129℃。
1H NMR(400MHz，DMSO-d
6，GL-B428)δ8.44(s，1H)，7.39(d，J＝8.6Hz，2H)，7.28(d，J＝8.6Hz，2H)，5.96(s，1H)，3.47-3.46(m，8H)，2.10-2.09(m，1H)，2.02(s，3H)，1.76(d，J＝2.1Hz，2H)，1.61-1.55(m，4H)，1.35-1.25(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B428)δ169.8，168.9，154.3，142.6，128.8，127.9，117.1，52.1，50.8，48.1，46.1，42.8，41.3，40.6，32.4，30.5，30.1，21.7.HRMS(ESI)calcd for C
26H
36N
4O
3Na[M+Na]
+：475.2680，found：475.2686。
Operate according to the method of Example 43, take acetyl chloride as the raw material (that is, the acid chloride raw material in Example 43 is specifically acetyl chloride), purified by ether beating and then purified by silica gel column chromatography to obtain a white solid, namely GL-B428, Yield 0.23 g, 52% yield, mp 127-129°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B428) δ 8.44 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 5.96 ( s, 1H), 3.47-3.46 (m, 8H), 2.10-2.09 (m, 1H), 2.02 (s, 3H), 1.76 (d, J=2.1Hz, 2H), 1.61-1.55 (m, 4H) , 1.35-1.25(m, 4H), 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100MHz, DMSO-d 6 , GL-B428) δ 169.8, 168.9, 154.3, 142.6, 128.8 , 127.9, 117.1, 52.1, 50.8, 48.1, 46.1, 42.8, 41.3, 40.6, 32.4, 30.5, 30.1, 21.7.HRMS(ESI)calcd for C 26 H 36 N 4 O 3 Na[M+Na] + : 475.2680 , found: 475.2686.
实施例47 1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-[4-(4-丙酰基哌嗪-1-羰基)苯基]脲(GL-B429)的合成Example 47 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4-propionylpiperazine-1-carbonyl)phenyl ] Urea (GL-B429) Synthesis
按照实施例43的方法操作，以丙酰氯为原料(即实施例43中的酰氯原料具体为丙酰氯)，经乙醚打浆纯化得到白色固体，即为GL-B429，产量为0.37g，收率为82％，m.p.234-235℃。
1H NMR(400MHz，DMSO-d
6，GL-B429)δ8.48(s，1H)，7.39(d，J＝8.4Hz，2H)，7.28(d，J＝8.4Hz，2H)，5.98(s，1H)，3.48(br，8H)，2.33(q，J＝7.3Hz，2H)，2.09(br，1H)，1.76(s，2H)，1.61-1.55(m，4H)，1.35-1.25(m，4H)，1.12(s，2H)，0.99(t，J＝7.4Hz，3H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，GL-B429)δ172.0，169.8，154.3，142.6，128.8，127.8，117.1，52.1，50.8，48.1，45.1，42.8，41.5，40.6，32.4，30.5，30.1，26.0，9.8.HRMS(ESI)calcd for C
27H
38N
4O
3Na[M+Na]
+：489.2836，found：489.2842。
Operate according to the method of Example 43, use propionyl chloride as raw material (that is, the acid chloride raw material in Example 43 is specifically propionyl chloride), and purified by ether beating to obtain a white solid, namely GL-B429, the yield is 0.37g, and the yield is 82%, mp234-235°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B429) δ 8.48 (s, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 5.98 ( s, 1H), 3.48 (br, 8H), 2.33 (q, J=7.3Hz, 2H), 2.09 (br, 1H), 1.76 (s, 2H), 1.61-1.55 (m, 4H), 1.35-1.25 (m, 4H), 1.12 (s, 2H), 0.99 (t, J=7.4Hz, 3H), 0.83 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B429) δ 172.0 , 169.8, 154.3, 142.6, 128.8, 127.8, 117.1, 52.1, 50.8, 48.1, 45.1, 42.8, 41.5, 40.6, 32.4, 30.5, 30.1, 26.0, 9.8.HRMS(ESI)calcd for C 27 H 38 N 4 O 3 Na[M+Na] + : 489.2836, found: 489.2842.
实施例48 1-[4-(4-丁酰基哌嗪-1-羰基)苯基]-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B430)的合成Example 48 1-[4-(4-Butyrylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ] Urea (GL-B430) Synthesis
按照实施例44的方法操作，以正丁酸为原料(即实施例44中的羧酸原料具体为正丁酸)，经乙醚打浆纯化后再经硅胶柱层析纯化得白色固体，即为GL-B430，产量为0.33g，收率为70％，m.p.222-224℃。
1H NMR(400MHz，DMSO-d
6，GL-B430)δ8.44(s，1H)，7.39(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，2H)，5.96(s，1H)，3.49(br，8H)，2.30(t，J＝7.3Hz，2H)，2.10-2.08(m，1H)，1.76(d，J＝2.2Hz，2H)，1.61-1.56(m，4H)，1.54-1.47(m，2H)，1.35-1.25(m，4H)，1.12(s，2H)，0.89(t，J＝7.4Hz，3H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6，B430)δ171.2，169.8，154.3，142.6，128.8，127.9，117.1，52.1，50.8，48.1，45.3，42.8，41.4，40.6，34.7，32.4，30.5，30.1，18.6，14.3.HRMS(ESI)calcd for C
28H
40N
4O
3Na[M+Na]
+：503.2993，found：503.3006。
Operate according to the method of Example 44, use n-butyric acid as the raw material (that is, the carboxylic acid raw material in Example 44 is specifically n-butyric acid), purified by beating with ether, and then purified by silica gel column chromatography to obtain a white solid, which is GL -B430, yield 0.33g, 70% yield, mp 222-224°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B430) δ 8.44 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 5.96 ( s, 1H), 3.49 (br, 8H), 2.30 (t, J=7.3Hz, 2H), 2.10-2.08 (m, 1H), 1.76 (d, J=2.2Hz, 2H), 1.61-1.56 (m , 4H), 1.54-1.47(m, 2H), 1.35-1.25(m, 4H), 1.12(s, 2H), 0.89(t, J=7.4Hz, 3H), 0.83(s, 6H). 13 C NMR (100MHz, DMSO-d 6 , B430) δ 171.2, 169.8, 154.3, 142.6, 128.8, 127.9, 117.1, 52.1, 50.8, 48.1, 45.3, 42.8, 41.4, 40.6, 34.7, 32.4, 30.5, 30.1, 18.6 , 14.3. HRMS(ESI) calcd for C 28 H 40 N 4 O 3 Na[M+Na] + : 503.2993, found: 503.3006.
实施例49 1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-{4-[4-(2-甲基丁酰基)哌嗪-1-羰基]苯基}脲(GL-B431)的合成Example 49 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-{4-[4-(2-methylbutyryl)piperazine- Synthesis of 1-Carbonyl]phenyl}urea (GL-B431)
按照实施例44的方法操作，以2-甲基丁酸为原料(即实施例44中的羧酸原料具体为2-甲基丁酸)，经乙醚打浆纯化后再经硅胶柱层析纯化得白色固体，即GL-B431，产量为0.33g，收率为69％，m.p.119-122℃。
1H NMR(400MHz，DMSO-d
6，GL-B431)δ8.45(s，1H)，7.39(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，2H)，5.96(s，1H)，3.54-3.46(m，8H)，2.73-2.68(m，1H)，2.09(br，1H)，1.76(d，J＝1.6Hz，2H)，1.62-1.58(m，4H)，1.34-1.25(m，6H)，1.12(s，2H)，0.98(d，J＝6.7Hz，3H)，0.83(s，6H)，0.80(t，J＝7.4Hz，3H).
13C NMR(100MHz，DMSO-d
6，GL-B431)δ174.5，169.8，154.3，142.6，128.8，127.8，117.1，52.1，50.8，48.1，45.3，42.8，40.7，38.2，32.4，30.5，30.1，27.1，17.6，12.1.HRMS(ESI)calcd for C
29H
42N
4O
3Na[M+Na]
+：517.3149，found：517.3167。
According to the method of Example 44, 2-methylbutyric acid was used as the raw material (that is, the carboxylic acid raw material in Example 44 was specifically 2-methylbutyric acid), purified by beating with ether, and then purified by silica gel column chromatography to obtain The white solid, GL-B431, yielded 0.33 g, 69% yield, mp 119-122°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B431) δ 8.45 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 5.96 ( s, 1H), 3.54-3.46 (m, 8H), 2.73-2.68 (m, 1H), 2.09 (br, 1H), 1.76 (d, J=1.6Hz, 2H), 1.62-1.58 (m, 4H) , 1.34-1.25(m, 6H), 1.12(s, 2H), 0.98(d, J=6.7Hz, 3H), 0.83(s, 6H), 0.80(t, J=7.4Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 , GL-B431) δ 174.5, 169.8, 154.3, 142.6, 128.8, 127.8, 117.1, 52.1, 50.8, 48.1, 45.3, 42.8, 40.7, 38.2, 32.4, 30.5, 30.1, 27.1 , 17.6, 12.1. HRMS(ESI) calcd for C29H42N4O3Na [ M + Na] + : 517.3149 , found: 517.3167.
实施例50 1-{4-[4-(环丙烷羰基)哌嗪-1-羰基]苯基}-3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲(GL-B432)的合成Example 50 1-{4-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-3-[(1r,3R,5S,7r)-3,5-dimethyladamantane- Synthesis of 1-yl]urea (GL-B432)
按照实施例44的方法操作，以环丙甲酸为原料(即实施例44中的羧酸原料具体为环丙甲酸)，经乙醚打浆纯化后再经硅胶柱层析纯化得白色固体，即GL-B432，产量为0.33g，收率为70％，m.p.231-234℃。
1H NMR(400MHz，DMSO-d
6，GL-B432)δ8.45(s，1H)，7.39(d，J＝8.7Hz，2H)，7.30(d，J＝8.6Hz，2H)，5.96(s，1H)，3.72(br，2H)，3.50(br， 6H)，2.10-2.09(m，1H)，1.99-1.95(m，1H)，1.76(d，J＝2.3Hz，2H)，1.62-1.55(m，4H)，1.12(s，2H)，0.83(s，6H)，0.76-0.70(m，4H).
13C NMR(100MHz，DMSO-d
6，GL-B432)δ171.7，169.8，154.3，142.6，128.8，127.9，117.1，52.1，50.8，48.1，45.3，42.8，40.6，32.4，30.5，30.1，10.8，7.6.HRMS(ESI)calcd for C
28H
38N
4O
3Na[M+Na]
+：501.2836，found：501.2851。
Operate according to the method of Example 44, using cyclopropanecarboxylic acid as a raw material (that is, the carboxylic acid raw material in Example 44 is specifically cyclopropanecarboxylic acid), purified by ether beating and then purified by silica gel column chromatography to obtain a white solid, namely GL- B432, yield 0.33 g, 70% yield, mp 231-234°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B432) δ 8.45 (s, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 5.96 ( s, 1H), 3.72 (br, 2H), 3.50 (br, 6H), 2.10-2.09 (m, 1H), 1.99-1.95 (m, 1H), 1.76 (d, J=2.3Hz, 2H), 1.62 -1.55(m, 4H), 1.12(s, 2H), 0.83(s, 6H), 0.76-0.70(m, 4H). 13 C NMR (100 MHz, DMSO-d 6 , GL-B432) δ 171.7, 169.8, 154.3, 142.6, 128.8, 127.9, 117.1, 52.1, 50.8, 48.1, 45.3, 42.8, 40.6, 32.4, 30.5, 30.1, 10.8, 7.6.HRMS(ESI)calcd for C 28 H 38 N 4 O 3 Na[ M+Na] + : 501.2836, found: 501.2851.
实施例51叔丁基{1-[4-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌嗪-1-基]-3-甲基-1-氧丁烷-2-基}氨基甲酸酯的合成Example 51 tert-butyl{1-[4-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl) Synthesis of Piperazin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate
按照实施例44的方法操作，以Boc-缬氨酸为原料(即实施例43中的羧酸原料具体为Boc-缬氨酸)，得半固体粗品1.04g，未进行纯化，直接用于下一步反应。According to the method of Example 44, using Boc-valine as a raw material (that is, the carboxylic acid raw material in Example 43 is specifically Boc-valine), 1.04 g of a semi-solid crude product was obtained, which was directly used in the next step without purification. one-step reaction.
实施例52 1-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]-3-[4-(4-戊基哌嗪-1-羰基)苯基]脲(GL-B433)的合成Example 52 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4-pentylpiperazine-1-carbonyl)phenyl ] Urea (GL-B433) Synthesis
向三口瓶中加入叔丁基{1-[4-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌嗪-1-基]-3-甲基-1-氧丁烷-2-基}氨基甲酸酯(1.04g)和二氯甲烷(8mL)，冰水浴条件下逐滴加入三氟乙酸(3mL)，滴加完毕后，在室温条件下搅拌反应2h，TLC检测反应完全；将所得反应液进行减压蒸馏以除去大部分三氟乙酸，加入水(50mL)和DCM(100mL)，冰水浴条件下用氢氧化钠固体调节体系的pH值至14，分离去除有机层，水层用DCM萃取(100mL×2)，之后依次经水洗(100mL)、饱和食盐水洗(100mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色半固体0.53g，经硅胶柱层析纯化得到白色固体0.29g，两步收率(即实施例51和实施例52中两个反应步骤的总收率)为58％，m.p.151-154℃。
1H NMR(400MHz，DMSO-d
6，GL-B433)δ8.54(s，1H)，7.39(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，2H)，6.02(s，1H)，3.57-3.37(m，9H)，2.68-2.67(m，2H)，2.10-2.08(m，1H)，1.76(d，J＝2.3Hz，2H)，1.74-1.69(m，1H)，1.62-1.55(m，4H)，1.35-1.25(m，4H)，1.12(s，2H)，0.88(d，J＝6.7Hz，3H)，0.83(s，6H)，0.82(d，J＝6.8Hz，3H).
13C NMR(100MHz，DMSO-d
6，GL-B433)δ169.6，154.3，142.4，128.6，128.4，117.1，52.0，50.8，48.1，46.1，42.8，40.4，32.4，30.5，30.1.HRMS(ESI)calcd for C
29H
43N
5O
3Na[M+Na]
+：532.3258，found：532.3278。
Add tert-butyl{1-[4-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzyl to the there-necked flask Acyl)piperazin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (1.04g) and dichloromethane (8mL), trifluorotrifluorocarbon was added dropwise under ice-water bath conditions Acetic acid (3 mL) was added dropwise, and the reaction was stirred at room temperature for 2 h. TLC detected that the reaction was complete; the obtained reaction solution was distilled under reduced pressure to remove most of the trifluoroacetic acid, water (50 mL) and DCM (100 mL) were added, The pH value of the system was adjusted to 14 with solid sodium hydroxide under ice-water bath conditions, the organic layer was separated and removed, the aqueous layer was extracted with DCM (100 mL×2), and then washed with water (100 mL), saturated brine (100 mL) and anhydrous. Dry over sodium sulfate, filter with suction, and concentrate the obtained filtrate under reduced pressure to obtain 0.53 g of a pale yellow semi-solid, which was purified by silica gel column chromatography to obtain 0.29 g of a white solid. The overall yield for each reaction step) was 58%, mp 151-154°C. 1 H NMR (400 MHz, DMSO-d 6 , GL-B433) δ 8.54 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 6.02 ( s, 1H), 3.57-3.37 (m, 9H), 2.68-2.67 (m, 2H), 2.10-2.08 (m, 1H), 1.76 (d, J=2.3Hz, 2H), 1.74-1.69 (m, 1H), 1.62-1.55(m, 4H), 1.35-1.25(m, 4H), 1.12(s, 2H), 0.88(d, J=6.7Hz, 3H), 0.83(s, 6H), 0.82(d , J=6.8Hz, 3H). 13 C NMR (100MHz, DMSO-d 6 , GL-B433) δ169.6, 154.3, 142.4, 128.6, 128.4, 117.1, 52.0, 50.8, 48.1, 46.1, 42.8, 40.4, 32.4, 30.5, 30.1. HRMS(ESI) calcd for C29H43N5O3Na [ M +Na] + : 532.3258 , found: 532.3278 .
实施例53 1-(3-氯-4-硝基苯甲酰基)哌啶-3-甲酸乙酯的合成Example 53 Synthesis of 1-(3-chloro-4-nitrobenzoyl)piperidine-3-carboxylic acid ethyl ester
向三口瓶中加入3-氯-4-硝基苯甲酸(1.0g，4.96mmol)、DMF(4d)和干燥的THF(15mL)，冰盐浴降温至0℃以下，滴加SOCl
2(1.77g，14.88mmol)的THF溶液(5mL)，滴毕后升温至65℃反应60min，TLC显示反应完全；将所得反应液进行减压浓缩除去残余SOCl
2，加入THF(1mL)溶解，得到酰氯的THF溶液，备用。
3-chloro-4-nitrobenzoic acid (1.0g, 4.96mmol), DMF (4d) and dry THF (15mL) were added to the there-necked flask, the ice-salt bath was cooled to below 0°C, and SOCl 2 (1.77 g) was added dropwise. g, 14.88 mmol) in THF solution (5 mL), heated to 65° C. for 60 min after dropping, TLC showed that the reaction was complete; the obtained reaction solution was concentrated under reduced pressure to remove residual SOCl 2 , and THF (1 mL) was added to dissolve to obtain acid chloride THF solution, ready for use.
向三口瓶中加入哌啶-3-甲酸乙酯(0.86g，5.46mmol)、三乙胺(1.50g，14.88mmol)和干燥的THF(5mL)，冰盐浴降温至0℃以下，滴加上述酰氯的THF溶液，滴毕后移至室温反应2h，TLC显示反应完全；将所得反应液进行减压浓缩除去THF，加入水(40mL)，用乙酸乙酯萃取(40mL×3)，之后依次经1mol/L的HCl洗涤(40mL×2)、饱和碳酸钠溶液洗涤(40mL×2)、水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色液体2.0g，未经纯化直接用于下一步。Add piperidine-3-ethyl carboxylate (0.86g, 5.46mmol), triethylamine (1.50g, 14.88mmol) and dry THF (5mL) to the there-necked flask, cool down to below 0°C in an ice-salt bath, add dropwise The THF solution of the above acid chloride was moved to room temperature for reaction for 2 h after dropping, and TLC showed that the reaction was complete; the obtained reaction solution was concentrated under reduced pressure to remove THF, added water (40 mL), extracted with ethyl acetate (40 mL×3), and then successively Washed with 1 mol/L HCl (40 mL×2), saturated sodium carbonate solution (40 mL×2), water (40 mL×2), saturated brine (40 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was Concentration under reduced pressure gave 2.0 g of a pale yellow liquid, which was used in the next step without purification.
实施例54 1-(4-氨基-3-氯苯甲酰基)哌啶-3-甲酸乙酯的合成Example 54 Synthesis of 1-(4-amino-3-chlorobenzoyl)piperidine-3-carboxylic acid ethyl ester
向单口瓶中加入1-(3-氯-4-硝基苯甲酰基)哌啶-3-甲酸乙酯(1.46g，4.29mmol)、铁粉(0.79g，14.2mmol)、氯化铵(2.30g，42.9mmol)、乙醇(15mL)和水(15mL)，升温至80℃反应50min，TLC显示反应完全；将所得反应液冷却至室温，硅藻土抽滤，滤饼用乙醇淋洗，滤液减压浓缩至干；向残余物中加入水(40mL)，用乙酸乙酯萃取(40mL×3)，之后依次经水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色油状物1.2g，未经纯化直接用于下一步。Add 1-(3-chloro-4-nitrobenzoyl) piperidine-3-carboxylic acid ethyl ester (1.46g, 4.29mmol), iron powder (0.79g, 14.2mmol), ammonium chloride ( 2.30g, 42.9mmol), ethanol (15mL) and water (15mL), warmed up to 80 ℃ and reacted for 50min, TLC showed that the reaction was complete; the obtained reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was rinsed with ethanol, The filtrate was concentrated to dryness under reduced pressure; water (40 mL) was added to the residue, extracted with ethyl acetate (40 mL×3), washed with water (40 mL×2), washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. , suction filtration, and the obtained filtrate was concentrated under reduced pressure to obtain 1.2 g of light yellow oil, which was used directly in the next step without purification.
实施例55 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸乙酯的合成Example 55 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine- Synthesis of Ethyl 3-formate
向三口瓶中加入1-(4-氨基-3-氯苯甲酰基)哌啶-3-甲酸乙酯(0.80g，2.58mmol)和干燥的DCM(10mL)，冰盐浴降温至0℃以下，滴加固体光气(0.38g，1.29mmol)的DCM溶液(5mL)，然后滴加三乙胺(0.52g，5.16mmol)的DCM溶液(5mL)，控温在0℃以下，滴毕后移至室温搅拌反应2h，之后停止反应；将所得反应液减压浓缩至干，向残余物中加入干燥的DCM(10mL)溶解，得到异氰酸酯溶液，备用。Add 1-(4-amino-3-chlorobenzoyl) piperidine-3-carboxylic acid ethyl ester (0.80g, 2.58mmol) and dry DCM (10mL) to the there-necked flask, cool to below 0°C in ice-salt bath , dropwise add solid phosgene (0.38g, 1.29mmol) in DCM solution (5mL), then dropwise add triethylamine (0.52g, 5.16mmol) in DCM solution (5mL), control the temperature below 0 ℃, after dropping The reaction was moved to room temperature and stirred for 2 h, and then the reaction was stopped; the obtained reaction solution was concentrated to dryness under reduced pressure, and dry DCM (10 mL) was added to the residue for dissolution to obtain an isocyanate solution for use.
向三口瓶中加入美金刚(0.46g，2.58mmol)、三乙胺(0.52g，5.16mmol)和干燥的DCM(10mL)，冰盐浴降温至0℃以下，滴加上述异氰酸酯溶液，滴毕后移至室温反应2h，升温至回流状态反应2h，TLC显示反应完全；将反应液倒入水中(40mL)，用DCM萃取(40mL×3)，之后依次经1mol/L的HCl洗(40mL×2)、水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色油状物1.48g；之后经硅胶柱层析纯化，洗脱剂为EA∶PE＝1∶5(v/v)，得到淡黄色固体，即为1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸乙酯，产量为0.93g。HRMS(ESI)calcd for C
28H
38ClN
3O
4Na[M+Na]
+：538.2443，found：538.2467，540.2445。
Add memantine (0.46g, 2.58mmol), triethylamine (0.52g, 5.16mmol) and dry DCM (10mL) to the there-necked flask, cool down to below 0°C in an ice-salt bath, add the above-mentioned isocyanate solution dropwise, and finish dropping The reaction was then moved to room temperature for 2 hours, heated to reflux for 2 hours, and TLC showed that the reaction was complete; the reaction solution was poured into water (40 mL), extracted with DCM (40 mL×3), and washed with 1 mol/L HCl (40 mL×3) in turn. 2), washed with water (40 mL×2), washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 1.48 g of light yellow oil; then purified by silica gel column chromatography, The eluent is EA:PE=1:5 (v/v), and a pale yellow solid is obtained, which is 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyl Adamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine-3-carboxylic acid ethyl ester, yield 0.93 g. HRMS (ESI) calcd for C28H38ClN3O4Na [ M + Na] + : 538.2443 , found: 538.2467, 540.2445.
实施例56 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸的合成Example 56 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine- Synthesis of 3-carboxylic acid
向单口瓶中加入1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸乙酯(0.93g，1.80mmol)、乙醇(10mL)、水(1.2mL)和氢氧化钠(0.36g，9.00mmol)，升温至70℃反应30min，TLC显示反应完全；将反应液冷却至室温，减压浓缩除去乙醇，向残余物中加入水(40mL)，冰浴下用浓盐酸调pH值至1，用乙酸乙酯萃取(40mL×3)，之后依次经水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到淡黄色油状物0.90g(直接用于下一步)。Add 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine to the single-necked flask Ethyl pyridine-3-carboxylate (0.93g, 1.80mmol), ethanol (10mL), water (1.2mL) and sodium hydroxide (0.36g, 9.00mmol) were heated to 70°C and reacted for 30min, TLC showed that the reaction was complete; The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove ethanol, water (40 mL) was added to the residue, the pH value was adjusted to 1 with concentrated hydrochloric acid under ice bath, extracted with ethyl acetate (40 mL×3), and then washed with water ( 40 mL×2), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 0.90 g of pale yellow oil (used directly in the next step).
实施例57 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酰胺(GL-B435)的合成Example 57 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine- Synthesis of 3-Carboxamide (GL-B435)
向三口瓶中加入1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸(0.90g，1.85mmol)、DMF(5d)和干燥的DCM(10mL)，冰盐浴降温至0℃以下，滴加SOCl
2(0.66g，5.54mmol)的DCM溶液(5mL)，滴毕后移至室温反应30min，TLC显示反应完全；将反应液进行减压浓缩除去残余SOCl
2，加入干燥的DCM(20mL)，冰盐浴降温至0℃以下，缓慢通入氨气进行反应2h，TLC显示反应完全；向所得产物体系中加入水(40mL)，用DCM萃取(40mL×3)，之后依次经1mol/L的HCl洗涤(40mL×2)、水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到白色固体0.8g，之后经硅胶柱层析纯化，洗脱剂为DCM∶MeOH＝50∶1(v/v)，洗脱液浓缩后，向所得残余物中加入乙醚(10mL)打浆，抽滤，滤饼用乙醚淋洗，干燥得到白色固体，即为GL-B435，产量为0.14g，收率为16％。
1H NMR(DMSO-d
6，400MHz)δ8.22(d，J＝8.6Hz，1H)，8.02(s，1H)，7.40(d，J＝1.1Hz，1H)，7.33(br，1H)，7.23(dd，J＝8.5，1.2Hz，1H)，6.96(s，1H)，6.84(s，1H)，4.26(br，1H)，3.63(br，1H)，2.92(br，2H)，2.32-2.26(m，1H)，2.10(br，1H)，1.92-1.89(m，1H)，1.77(s，2H)，1.66-1.55(m，6H)，1.43-1.40(m，1H)，1.35-1.25(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(DMSO-d
6，100MHz)δ175.0，168.2，153.7，138.5，129.8，128.4，126.7，120.6，119.8，52.3，50.7，48.0，42.8，42.4，32.4，30.5，30.1，28.1，24.8.HRMS(ESI)calcd for C
26H
35ClN
4O
3Na[M+Na]
+：509.2290，found：509.2325，511.2300。
Add 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-chlorobenzoyl)piperidine to the there-necked flask pyridine-3-carboxylic acid (0.90 g, 1.85 mmol), DMF (5d) and dry DCM (10 mL), cooled to below 0 °C in an ice-salt bath, and a solution of SOCl 2 (0.66 g, 5.54 mmol) in DCM (5 mL) was added dropwise ), moved to room temperature and reacted for 30 min after dripping, TLC showed that the reaction was complete; the reaction solution was concentrated under reduced pressure to remove residual SOCl 2 , dry DCM (20 mL) was added, the ice-salt bath was cooled to below 0° C., and ammonia gas was slowly introduced into it. The reaction was carried out for 2 h, and TLC showed that the reaction was complete; water (40 mL) was added to the obtained product system, extracted with DCM (40 mL×3), and then washed with 1 mol/L HCl (40 mL×2) and water (40 mL×2) successively. , washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, suction filtered, and the obtained filtrate was concentrated under reduced pressure to obtain 0.8 g of a white solid, which was then purified by silica gel column chromatography, eluent: DCM:MeOH=50:1 (v/v), after the eluent was concentrated, diethyl ether (10 mL) was added to the obtained residue for slurrying, suction filtration, the filter cake was rinsed with diethyl ether, and dried to obtain a white solid, which was GL-B435, and the yield was 0.14 g, The yield was 16%. 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.22 (d, J=8.6 Hz, 1H), 8.02 (s, 1H), 7.40 (d, J=1.1 Hz, 1H), 7.33 (br, 1H) , 7.23(dd, J=8.5, 1.2Hz, 1H), 6.96(s, 1H), 6.84(s, 1H), 4.26(br, 1H), 3.63(br, 1H), 2.92(br, 2H), 2.32-2.26(m, 1H), 2.10(br, 1H), 1.92-1.89(m, 1H), 1.77(s, 2H), 1.66-1.55(m, 6H), 1.43-1.40(m, 1H), 1.35-1.25 (m, 4H), 1.12 (s, 2H), 0.83 (s, 6H). 13 C NMR (DMSO-d 6 , 100MHz) δ 175.0, 168.2, 153.7, 138.5, 129.8, 128.4, 126.7, 120.6, 119.8, 52.3, 50.7, 48.0, 42.8, 42.4, 32.4, 30.5, 30.1, 28.1, 24.8. HRMS(ESI) calcd for C 26 H 35 ClN 4 O 3 Na[M+Na] + : 509.2290, found: 509.2325, 511.2300.
实施例58 1-(3-氟-4-硝基苯甲酰基)哌啶-3-甲酸乙酯的合成Example 58 Synthesis of 1-(3-fluoro-4-nitrobenzoyl)piperidine-3-carboxylic acid ethyl ester
按照实施例53的方法操作，不同之处仅在于将3-氯-4-硝基苯甲酸替换为3-氟-4-硝基苯甲酸，最终得到1.76g 淡黄色液体。The operation was carried out according to the method of Example 53, except that 3-chloro-4-nitrobenzoic acid was replaced with 3-fluoro-4-nitrobenzoic acid, and finally 1.76 g of pale yellow liquid was obtained.
实施例59 1-(4-氨基-3-氟苯甲酰基)哌啶-3-甲酸乙酯的合成Example 59 Synthesis of 1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylic acid ethyl ester
按照实施例54的方法操作，不同之处仅在于将1-(3-氯-4-硝基苯甲酰基)哌啶-3-甲酸乙酯替换为1-(3-氟-4-硝基苯甲酰基)哌啶-3-甲酸乙酯，最终得到淡黄色油状物1.3g。The procedure of Example 54 was followed except that ethyl 1-(3-chloro-4-nitrobenzoyl)piperidine-3-carboxylate was replaced by 1-(3-fluoro-4-nitro Benzoyl)piperidine-3-carboxylic acid ethyl ester to finally obtain 1.3 g of pale yellow oil.
实施例60 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸乙酯的合成Example 60 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine- Synthesis of Ethyl 3-formate
按照实施例55的方法操作，不同之处仅在于将1-(4-氨基-3-氯苯甲酰基)哌啶-3-甲酸乙酯替换为1-(4-氨基-3-氟苯甲酰基)哌啶-3-甲酸乙酯，最终得到淡黄色得淡黄色固体0.8g。The procedure of Example 55 was followed, except that ethyl 1-(4-amino-3-chlorobenzoyl)piperidine-3-carboxylate was replaced with 1-(4-amino-3-fluorobenzyl) acyl)piperidine-3-carboxylic acid ethyl ester, and finally obtain a light yellow solid 0.8g.
实施例61 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸的合成Example 61 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine- Synthesis of 3-carboxylic acid
按照实施例56的方法操作，不同之处仅在于将1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸乙酯替换为1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸乙酯，最终得到0.5g白色固体。The procedure of Example 56 was followed, except that 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido} -3-Chlorobenzoyl)piperidine-3-carboxylic acid ethyl ester was replaced with 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ]ureido}-3-fluorobenzoyl)piperidine-3-carboxylic acid ethyl ester to finally obtain 0.5 g of a white solid.
实施例62 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺(GL-B434)的合成Example 62 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine- Synthesis of 3-Carboxamide (GL-B434)
按照实施例57的方法操作，不同之处仅在于将1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酸替换为1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸，最终得到的白色固体即为GL-B434，产量为60mg，收率为11％。
1H NMR(DMSO-d
6，400MHz)δ8.23(s，1H)，8.20(t，J＝8.3Hz，1H)，7.33(br，1H)，7.20(d，J＝11.7Hz，1H)，7.09(d，J＝8.6Hz，1H)，6.84(s，1H)，6.56(s，1H)，4.23(br，1H)，3.65(br，1H)，2.90(br，2H)，2.32-2.26(m，1H)，2.09(br，1H)，1.92-1.89(m，1H)，1.76(s，2H)，1.63-1.58(m，6H)，1.40-1.35(m，1H)，1.34-1.25(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(DMSO-d
6，100MHz)δ175.0，168.4，153.8，151.0(d，J＝240.3Hz)，130.3(d，J＝10.2Hz)，128.8(d，J＝6.3Hz)，123.8，119.3，114.3(d，J＝20.3)，52.2，50.7，48.0，42.8，42.4，32.4，30.5，30.1，28.1，24.9.HRMS(ESI)calcd for C
26H
35FN
4O
3Na[M+Na]
+：493.2585，found：493.2593。
The procedure of Example 57 was followed except that 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido} -3-Chlorobenzoyl)piperidine-3-carboxylic acid was replaced with 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea yl}-3-fluorobenzoyl)piperidine-3-carboxylic acid, the white solid finally obtained was GL-B434, the yield was 60 mg, and the yield was 11%. 1 H NMR (DMSO-d 6 , 400 MHz) δ 8.23 (s, 1H), 8.20 (t, J=8.3 Hz, 1H), 7.33 (br, 1H), 7.20 (d, J=11.7 Hz, 1H) , 7.09(d, J=8.6Hz, 1H), 6.84(s, 1H), 6.56(s, 1H), 4.23(br, 1H), 3.65(br, 1H), 2.90(br, 2H), 2.32- 2.26(m, 1H), 2.09(br, 1H), 1.92-1.89(m, 1H), 1.76(s, 2H), 1.63-1.58(m, 6H), 1.40-1.35(m, 1H), 1.34- 1.25 (m, 4H), 1.12 (s, 2H), 0.83 (s, 6H). 13 C NMR (DMSO-d 6 , 100 MHz) δ 175.0, 168.4, 153.8, 151.0 (d, J=240.3 Hz), 130.3 (d, J=10.2Hz), 128.8 (d, J=6.3Hz), 123.8, 119.3, 114.3 (d, J=20.3), 52.2, 50.7, 48.0, 42.8, 42.4, 32.4, 30.5, 30.1, 28.1 , 24.9. HRMS(ESI) calcd for C 26 H 35 FN 4 O 3 Na[M+Na] + : 493.2585, found: 493.2593.
实施例63 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸甲酯的合成Example 63 Methyl 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxylate Synthesis of Esters
向三口瓶中加入GL-B411(1.0g，2.21mmol)和无水甲醇(20mL)，冰盐浴降温至0℃以下，滴加氯化亚砜(0.79g，6.63mmol)，滴毕后升温至回流状态反应1h，TLC显示反应完全；将所得产物体系进行减压浓缩除去甲醇，向残余物中加入水(20mL)，用乙酸乙酯萃取(20mL×3)，合并有机层，之后依次经水洗(20mL×2)、饱和食盐水洗(20mL)和无水硫酸钠干燥，抽滤，将所得滤液进行减压浓缩，得到白色固体，即为1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸甲酯，产量为0.99g，产率为96％。GL-B411 (1.0g, 2.21mmol) and anhydrous methanol (20mL) were added to the there-necked flask, the ice-salt bath was cooled to below 0°C, thionyl chloride (0.79g, 6.63mmol) was added dropwise, and the temperature was raised after dropping The reaction was carried out under reflux for 1 h, and TLC showed that the reaction was complete; the obtained product system was concentrated under reduced pressure to remove methanol, water (20 mL) was added to the residue, extracted with ethyl acetate (20 mL×3), the organic layers were combined, and the Wash with water (20 mL×2), saturated brine (20 mL) and dry with anhydrous sodium sulfate, suction filtration, and concentrate the obtained filtrate under reduced pressure to obtain a white solid, which is 1-(4-{3-[(1r, 3R , 5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxylic acid methyl ester, the yield was 0.99 g, and the yield was 96%.
实施例64 1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-羟基哌啶-3-甲酰胺(GL-B436)的合成Example 64 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-hydroxypiperidine- Synthesis of 3-Carboxamide (GL-B436)
向三口瓶中加入1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸甲酯(0.3g，0.64mmol)、甲醇(30mL)和1mol/L的NaOH水溶液(6mL)，冰浴降温至0℃以下，滴加浓度为50wt％的羟胺水溶液(6mL)，滴毕后移至室温反应1h，TLC显示反应完全；将所得产物体系进行减压浓缩除去甲醇，向残余物中加入水(20mL)，用乙酸乙酯萃取(20mL×3)，合并有机层，之后依次经水洗(20mL×2)、饱和食盐水洗(20mL)和无水硫酸钠干燥，抽滤，将所得滤液减压浓缩至剩余溶剂约2mL，加入乙醚(10mL)打浆，抽滤，滤饼用乙醚淋洗，得到白色固体，即为GL-B436，产量为0.20g，产率为67％。
1H NMR(DMSO-d
6，400MHz)δ10.52(s，1H)，8.75(s，1H)，8.44(s，1H)，7.38(d，J＝8.4Hz，2H)，7.24(d，J＝8.4Hz，2H)，5.97(s，1H)，4.27(br，1H)，2.90(br，2H)，2.71-2.15(m，1H)，2.09(s，1H)，1.81-1.76(m，3H)，1.70-1.61(m，2H)，1.60-1.55(m，4H)，1.42-1.38(m，1H)，1.34-1.24(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(DMSO-d
6，100MHz)δ169.6，154.3，142.4，128.4，128.3，117.1，52.0，50.7，48.1，42.8，40.6，32.4，30.5，30.1，27.9.HRMS(ESI)calcd for C
26H
36N
4O
4Na[M+Na]
+：491.2629，found：491.2664。
Add 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-to the there-necked flask Methyl formate (0.3 g, 0.64 mmol), methanol (30 mL) and 1 mol/L NaOH aqueous solution (6 mL), cooled to below 0 °C in an ice bath, and a 50 wt% hydroxylamine aqueous solution (6 mL) was added dropwise. Move to room temperature and react for 1 h, TLC showed that the reaction was complete; the obtained product system was concentrated under reduced pressure to remove methanol, water (20 mL) was added to the residue, extracted with ethyl acetate (20 mL×3), the organic layers were combined, and then Washed with water (20mL×2), washed with saturated brine (20mL) and dried over anhydrous sodium sulfate, filtered with suction, the obtained filtrate was concentrated under reduced pressure to about 2mL of residual solvent, ether (10mL) was added to make slurry, suction filtered, and the filter cake was rinsed with ether Washed to obtain a white solid, namely GL-B436, with a yield of 0.20 g and a yield of 67%. 1 H NMR (DMSO-d 6 , 400MHz) δ 10.52(s, 1H), 8.75(s, 1H), 8.44(s, 1H), 7.38(d, J=8.4Hz, 2H), 7.24(d, J=8.4Hz, 2H), 5.97(s, 1H), 4.27(br, 1H), 2.90(br, 2H), 2.71-2.15(m, 1H), 2.09(s, 1H), 1.81-1.76(m , 3H), 1.70-1.61(m, 2H), 1.60-1.55(m, 4H), 1.42-1.38(m, 1H), 1.34-1.24(m, 4H), 1.12(s, 2H), 0.83(s , 6H). 13 C NMR (DMSO-d 6 , 100MHz) δ 169.6, 154.3, 142.4, 128.4, 128.3, 117.1, 52.0, 50.7, 48.1, 42.8, 40.6, 32.4, 30.5, 30.1, 27.9.HRMS (ESI )calcd for C26H36N4O4Na [M + Na] + : 491.2629 , found: 491.2664 .
实施例65(S)-1-(4-硝基苯甲酰基)哌啶-3-甲酸乙酯的合成Example 65 Synthesis of (S)-1-(4-nitrobenzoyl) piperidine-3-carboxylic acid ethyl ester
向三口瓶中加入(S)-3-甲酸乙酯(1.87g，11.9mmol)、三乙胺(3.28g，32.4mmol)和干燥的THF(20mL)，冰盐浴降温至0℃以下，滴加对硝基苯甲酰氯(2.0g，10.8mmol)的THF溶液(10mL)，滴毕后移至室温反应1h，TLC显示反应完全；将所得产物体系进行减压浓缩除去THF，加入水(50mL)，采用乙酸乙酯萃取(50mL×3)，有机相依次经1mol/L盐酸洗(40mL×2)、饱和碳酸钠水溶液洗(40mL×2)、水洗(40mL)、饱和食盐水洗(40mL)和无水硫酸镁干燥，抽滤，滤液经减压浓缩，得到淡黄色油状物，即为(S)-1-(4-硝基苯甲酰基)哌啶-3-甲酸乙酯，产量为2.95g，产率为89％。Add (S)-ethyl 3-carboxylate (1.87g, 11.9mmol), triethylamine (3.28g, 32.4mmol) and dry THF (20mL) to the there-necked flask, cool down to below 0°C in an ice-salt bath, dropwise Add the THF solution (10 mL) of p-nitrobenzoyl chloride (2.0 g, 10.8 mmol), move it to room temperature for 1 h after dropping, TLC showed that the reaction was complete; the obtained product system was concentrated under reduced pressure to remove THF, and water (50 mL) was added. ), extracted with ethyl acetate (50mL×3), the organic phase was washed with 1mol/L hydrochloric acid (40mL×2), saturated aqueous sodium carbonate solution (40mL×2), water (40mL), and saturated brine (40mL) successively It was dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oil, which was (S)-1-(4-nitrobenzoyl)piperidine-3-carboxylic acid ethyl ester, and the output was 2.95 g, 89% yield.
实施例66(S)-1-(4-氨基苯甲酰基)哌啶-3-甲酸乙酯的合成Example 66 Synthesis of (S)-1-(4-aminobenzoyl) piperidine-3-carboxylic acid ethyl ester
向单口瓶中加入(S)-1-(4-氨基苯甲酰基)哌啶-3-甲酸乙酯(2.95g，9.64mmol)、无水乙醇(20mL)和5％Pd-C(0.3g)，氩气置换三次，氢气置换三次，升温至60℃反应8h，TLC显示反应完全；将所得产物体系抽滤，滤饼用少量无水乙醇淋洗，滤液减压浓缩，得到淡黄色油状物，即为(S)-1-(4-氨基苯甲酰基)哌啶-3-甲酸乙酯，产量为2.66g，产率为100％。Add (S)-ethyl (S)-1-(4-aminobenzoyl)piperidine-3-carboxylate (2.95g, 9.64mmol), absolute ethanol (20mL) and 5% Pd-C (0.3g) to a single-necked flask ), replaced by argon three times, replaced by hydrogen three times, heated to 60 °C for 8 h, TLC showed that the reaction was complete; the obtained product system was suction filtered, the filter cake was rinsed with a small amount of anhydrous ethanol, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oil , namely (S)-1-(4-aminobenzoyl)piperidine-3-carboxylic acid ethyl ester, the yield is 2.66g, and the yield is 100%.
实施例67(S)-1-{4-[(苯氧基羰基)氨基]苯甲酰基}哌啶-3-甲酸乙酯的合成Example 67 Synthesis of (S)-1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-3-carboxylic acid ethyl ester
向三口瓶中加入(S)-1-(4-氨基苯甲酰基)哌啶-3-甲酸乙酯(2.66g，9.63mmol)、碳酸钾粉末(4.15g，28.9mmol)和干燥的DCM(15mL)，冰浴下滴加氯甲酸苯酯(2.25g，14.4mmol)的DCM溶液(5mL)，滴毕后移至室温搅拌反应6h，TLC显示反应完全；将所得产物体系倒入水中(30mL)，采用DCM萃取(40mL×3)，有机相依次经饱和碳酸钠水溶液洗(40mL×2)、水洗(40mL)、饱和食盐水洗(40mL)和无水硫酸镁干燥，抽滤，滤液经减压浓缩，得到黄棕色油状物4.69g。未经纯化直接用于下一步。To a three-necked flask was added (S)-ethyl 1-(4-aminobenzoyl)piperidine-3-carboxylate (2.66g, 9.63mmol), potassium carbonate powder (4.15g, 28.9mmol) and dry DCM ( 15mL), dropwise add the DCM solution (5mL) of phenyl chloroformate (2.25g, 14.4mmol) under ice bath, move to room temperature and stir the reaction for 6h after dropping, TLC shows that the reaction is complete; Pour the obtained product system into water (30mL) ), extracted with DCM (40 mL × 3), the organic phase was washed with saturated aqueous sodium carbonate solution (40 mL × 2), washed with water (40 mL), washed with saturated brine (40 mL) and dried over anhydrous magnesium sulfate, suction filtered, and the filtrate was reduced It was concentrated under pressure to obtain 4.69 g of a yellow-brown oil. Used directly in the next step without purification.
实施例68(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸乙酯的合成Example 68 (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine- Synthesis of Ethyl 3-formate
向单口瓶中加入(S)-1-{4-[(苯氧基羰基)氨基]苯甲酰基}哌啶-3-甲酸乙酯(4.69g，9.63mmol，以上步100％收率计算)、美金刚(1.90g，10.6mmol)、三乙胺(1.95g，19.3mmol)和THF(30mL)，升温至体系回流反应6h，TLC显示反应完全；将所得产物体系冷却至室温，减压浓缩除去THF，加入水(40mL)，采用乙酸乙酯萃取(40mL×3)，有机相依次经1mol/L盐酸洗(40mL×2)、水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸镁干燥，抽滤，滤液经减压浓缩，得到棕黄色油状物6.3g，未经纯化直接下一步。Add (S)-1-{4-[(phenoxycarbonyl)amino]benzoyl}piperidine-3-carboxylic acid ethyl ester (4.69g, 9.63mmol, above step 100% yield calculation) to single-necked flask , memantine (1.90g, 10.6mmol), triethylamine (1.95g, 19.3mmol) and THF (30mL), warmed up to the system reflux reaction for 6h, TLC showed that the reaction was complete; the obtained product system was cooled to room temperature, concentrated under reduced pressure THF was removed, water (40 mL) was added, extracted with ethyl acetate (40 mL×3), and the organic phase was washed with 1 mol/L hydrochloric acid (40 mL×2), water (40 mL×2), saturated brine (40 mL) and no Dry over magnesium sulfate, suction filtration, and concentrate the filtrate under reduced pressure to obtain 6.3 g of a brownish-yellow oil, which is directly next step without purification.
实施例69(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸的合成Example 69 (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine- Synthesis of 3-carboxylic acid
向单口瓶中加入(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸乙酯(6.30g，15.1mmol，以上步100％收率计算)、乙醇(20mL)、水(10mL)和氢氧化钠(3.0g，75.3mmol)，升温至70℃反应1h，TLC显示反应完全；将所得产物体系冷却至室温，减压浓缩除去乙醇，加入水(40mL)，冰浴下用浓盐酸调pH至1，采用乙酸乙酯萃取(40mL×3)，有机相依次经水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸镁干燥，抽滤， 滤液经减压浓缩，得到棕黄色油状物5.92g，加入乙醚打浆(20mL)，抽滤，滤饼用少量乙醚淋洗，干燥后得到淡黄色固体2.5g，粗品经硅胶柱层析纯化，洗脱剂DCM∶MeOH∶AcOH＝20∶1∶0.05(v/v/v)，得到的白色固体即为(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸，产量为1.37g。Add (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine to the single-necked flask Ethyl pyridine-3-carboxylate (6.30 g, 15.1 mmol, calculated as 100% yield in the above step), ethanol (20 mL), water (10 mL) and sodium hydroxide (3.0 g, 75.3 mmol), heated to 70 °C and reacted for 1 h , TLC showed that the reaction was complete; the obtained product system was cooled to room temperature, concentrated under reduced pressure to remove ethanol, water (40 mL) was added, the pH was adjusted to 1 with concentrated hydrochloric acid under an ice bath, and extracted with ethyl acetate (40 mL×3). Washed with water (40 mL×2), washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 5.92 g of a brown oily substance, which was added with ether to make a slurry (20 mL), filtered with suction, and filtered. The cake was rinsed with a small amount of ether, dried to obtain 2.5 g of a pale yellow solid, the crude product was purified by silica gel column chromatography, eluent DCM:MeOH:AcOH=20:1:0.05 (v/v/v), the obtained white solid That is (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3 - Formic acid, yield 1.37 g.
实施例70(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(S-GL-B413)的合成Example 70 (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine- Synthesis of 3-Carboxamide (S-GL-B413)
向三口瓶中加入(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸(1.37g，3.02mmol)、DMF(5滴)和干燥的THF(15mL)，冰盐浴降温至0℃以下，滴加SOCl
2(1.10g，9.06mmol)的THF溶液(5mL)，滴毕后移至室温反应30min，TLC显示反应完全；将所得产物体系进行减压浓缩除去残余SOCl
2，加入干燥的THF(20mL)，冰盐浴降温至0℃以下，缓慢通入氨气反应2h，TLC显示反应完全；将所得产物体系进行减压浓缩除去THF，加入水(40mL)，采用乙酸乙酯萃取(40mL×3)，有机相依次经1mol/L盐酸洗(40mL×2)、水洗(40mL×2)、饱和食盐水洗(40mL)和无水硫酸钠干燥，抽滤，滤液经减压浓缩得到白色固体，加入乙醚(15mL)打浆，抽滤，滤饼用乙醚淋洗，干燥后得到白色固体，即为化合物S-GL-B413，产量为0.77g，产率为56％。
Add (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine to the there-necked flask pyridine-3-carboxylic acid (1.37 g, 3.02 mmol), DMF (5 drops) and dry THF (15 mL), cooled to below 0 °C in an ice-salt bath, and added dropwise a solution of SOCl 2 (1.10 g, 9.06 mmol) in THF ( 5mL), moved to room temperature to react for 30min after dripping, TLC showed that the reaction was complete; the obtained product system was concentrated under reduced pressure to remove residual SOCl 2 , added dry THF (20mL), cooled to below 0°C in an ice-salt bath, and slowly poured in Ammonia was reacted for 2 h, and TLC showed that the reaction was complete; the obtained product system was concentrated under reduced pressure to remove THF, water (40 mL) was added, and ethyl acetate was used for extraction (40 mL×3), and the organic phase was washed with 1mol/L hydrochloric acid (40 mL×3) successively. 2), washed with water (40mL×2), washed with saturated brine (40mL) and dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure to obtain a white solid, added ether (15mL) to make a slurry, suction filtered, and the filter cake was rinsed with ether After washing and drying, a white solid was obtained, which was compound S-GL-B413, and the yield was 0.77 g, and the yield was 56%.
实施例71(R)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺(R-GL-B413)的合成Example 71 (R)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine- Synthesis of 3-Carboxamide (R-GL-B413)
参照化合物S-GL-B413的合成方法操作，不同之处在于采用对硝基苯甲酰氯(2.0g，10.8mmol)和(R)-3-甲酸乙酯(1.87g，11.9mmol)为原料，最终制备得到的白色固体为化合物R-GL-B413，产量为0.40g，产率为29％。With reference to the synthetic method of compound S-GL-B413, the difference is that p-nitrobenzoyl chloride (2.0g, 10.8mmol) and (R)-ethyl 3-carboxylate (1.87g, 11.9mmol) are used as raw materials, The white solid finally prepared was compound R-GL-B413, the yield was 0.40 g, and the yield was 29%.
实施例72(S)-1-(3-氟-4-硝基苯甲酰基)哌啶-3-甲酸乙酯的合成Example 72 Synthesis of (S)-1-(3-fluoro-4-nitrobenzoyl)piperidine-3-carboxylic acid ethyl ester
按照实施例58的操作方法，以3-氟-4-硝基苯甲酸和(S)-哌啶-3-甲酸乙酯为原料，最终得到棕黄色油状物2.25g。未经纯化直接用于下一步。According to the operation method of Example 58, 3-fluoro-4-nitrobenzoic acid and (S)-piperidine-3-carboxylic acid ethyl ester were used as raw materials to finally obtain 2.25 g of a brownish yellow oil. Used directly in the next step without purification.
实施例73(S)-1-(4-氨基-3-氟苯甲酰基)哌啶-3-甲酸乙酯的合成Example 73 Synthesis of (S)-1-(4-amino-3-fluorobenzoyl) piperidine-3-carboxylic acid ethyl ester
按照实施例59的操作方法，以(S)-1-(3-氟-4-硝基苯甲酰基)哌啶-3-甲酸乙酯为原料，最终得棕黄色油状物1.28g，两步收率81％。According to the operation method of Example 59, using (S)-1-(3-fluoro-4-nitrobenzoyl) piperidine-3-carboxylic acid ethyl ester as a raw material, 1.28g of brownish yellow oil was finally obtained, two steps Yield 81%.
实施例74(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸乙酯的合成Example 74 (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl ) Synthesis of ethyl piperidine-3-carboxylate
按照实施例60的操作方法，以(S)-1-(4-氨基-3-氟苯甲酰基)哌啶-3-甲酸乙酯和美金刚为原料，最终得到的白色固体即为(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸乙酯，产量为0.64g，产率为70％。According to the operation method of Example 60, using (S)-ethyl 1-(4-amino-3-fluorobenzoyl) piperidine-3-carboxylate and memantine as raw materials, the finally obtained white solid is (S) -1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine-3- Ethyl formate, yield 0.64 g, 70% yield.
实施例75(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸的合成Example 75 (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl ) synthesis of piperidine-3-carboxylic acid
按照实施例61的操作方法，以(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸乙酯为原料，最终得到的淡黄色固体即为(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸，产量为0.60g，产率为100％。According to the procedure of Example 61, (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}- 3-Fluorobenzoyl)piperidine-3-ethyl carboxylate is used as the raw material, and the finally obtained pale yellow solid is (S)-1-(4-{3-[(1r, 3R, 5S, 7S)-3 , 5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine-3-carboxylic acid, the yield was 0.60 g, and the yield was 100%.
实施例76(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺(GL-B437)的合成Example 76 (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl ) Synthesis of piperidine-3-carboxamide (GL-B437)
按照实施例62的操作方法，以(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酸为原料，最终得到的白色固体即为GL-B437，产量为0.30g，收率为48％；m.p.165-166℃。HRMS(ESI)calcd for C
26H
35FN
4O
3Na[M+Na]
+：493.2585，found：493.2611。
According to the procedure of Example 62, with (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}- 3-Fluorobenzoyl)piperidine-3-carboxylic acid was used as the raw material, and the finally obtained white solid was GL-B437, the yield was 0.30 g, and the yield was 48%; mp165-166°C. HRMS (ESI) calcd for C26H35FN4O3Na [ M + Na] + : 493.2585 , found: 493.2611.
实施例77叔丁基(S)-[1-(3-氟-4-硝基苯甲酰基)哌啶-3-基]氨基甲酸酯的合成Example 77 Synthesis of tert-butyl (S)-[1-(3-fluoro-4-nitrobenzoyl)piperidin-3-yl]carbamate
按照实施例58的操作方法，以3-氟-4-硝基苯甲酸和(S)-3-Boc-氨基哌啶为原料，最终得到1.98g棕黄色油状物。未经纯化直接用于下一步。According to the operation method of Example 58, using 3-fluoro-4-nitrobenzoic acid and (S)-3-Boc-aminopiperidine as raw materials, 1.98 g of brownish yellow oil was finally obtained. Used directly in the next step without purification.
实施例78叔丁基(S)-[1-(3-氟-4-氨基苯甲酰基)哌啶-3-基]氨基甲酸酯的合成Example 78 Synthesis of tert-butyl (S)-[1-(3-fluoro-4-aminobenzoyl)piperidin-3-yl]carbamate
按照实施例59的操作方法，以叔丁基(S)-[1-(3-氟-4-硝基苯甲酰基)哌啶-3-基]氨基甲酸酯为原料，制备得到1.78g棕黄色油状物，经硅胶柱层析纯化，洗脱剂为EA∶PE＝1∶5(v/v)，得倒无色油状物1.64g，两步收率为90％。According to the operation method of Example 59, tert-butyl (S)-[1-(3-fluoro-4-nitrobenzoyl)piperidin-3-yl]carbamate was used as raw material to prepare 1.78g The brown-yellow oil was purified by silica gel column chromatography with EA:PE=1:5 (v/v) as the eluent to obtain 1.64 g of a colorless oil with a two-step yield of 90%.
实施例79叔丁基[(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-基]氨基甲酸酯的合成Example 79 tert-butyl[(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3- Synthesis of Fluorobenzoyl)piperidin-3-yl]carbamate
按照实施例60的操作方法，以叔丁基(S)-[1-(3-氟-4-氨基苯甲酰基)哌啶-3-基]氨基甲酸酯为原料，最终得到白色固体0.90g，产率为90％。According to the operation method of Example 60, using tert-butyl (S)-[1-(3-fluoro-4-aminobenzoyl)piperidin-3-yl]carbamate as raw material, a white solid 0.90 was finally obtained. g, 90% yield.
实施例80 1-{4-[(S)-3-氨基哌啶-1-羰基]-2-氟苯基}-3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲的合成Example 80 1-{4-[(S)-3-aminopiperidine-1-carbonyl]-2-fluorophenyl}-3-[(1r,3R,5S,7S)-3,5-dimethyl Synthesis of Fundamantane-1-yl]urea
向三口瓶中加入叔丁基[(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-基]氨基甲酸酯(5.77g，11.0mmol)和二氯甲烷(8mL)，冰水浴条件下滴加三氟乙酸(2mL)，滴毕后室温搅拌反应2h，TLC显示反应完全；将所得产物体系进行减压蒸馏，除去大部分三氟乙酸，加入水(30mL)和DCM(30mL)，冰水浴条件下用氢氧化钠固体调pH至14，分出有机层，水层用DCM萃取(30mL×2)，合并有机层，依次经水洗(30mL)、饱和食盐水洗(30mL)和无水硫酸钠干燥，抽滤，滤液经减压浓缩，得到淡黄色固体，即为1-{4-[(S)-3-氨基哌啶-1-羰基]-2-氟苯基}-3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲，产量为0.56g，产率为77％。Add tert-butyl [(S)-1-(4-{3-[(1r, 3R, 5S, 7S)-3,5-dimethyladamantan-1-yl]ureido}- 3-Fluorobenzoyl)piperidin-3-yl]carbamate (5.77g, 11.0mmol) and dichloromethane (8mL), trifluoroacetic acid (2mL) was added dropwise under ice-water bath conditions, after the drop was completed, room temperature The reaction was stirred for 2 h, and TLC showed that the reaction was complete; the obtained product system was distilled under reduced pressure to remove most of the trifluoroacetic acid, water (30 mL) and DCM (30 mL) were added, and the pH was adjusted to 14 with solid sodium hydroxide under ice-water bath conditions. The organic layer was separated, the aqueous layer was extracted with DCM (30 mL×2), the organic layers were combined, washed with water (30 mL), saturated brine (30 mL) and dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain Light yellow solid, which is 1-{4-[(S)-3-aminopiperidine-1-carbonyl]-2-fluorophenyl}-3-[(1r,3R,5S,7S)-3,5 - Dimethyladamantan-1-yl]urea, yield 0.56 g, 77% yield.
实施例81 N-[(S)-1-(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-基]甲磺酰胺(GL-B438)的合成Example 81 N-[(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluoro Synthesis of Benzoyl)piperidin-3-yl]methanesulfonamide (GL-B438)
向三口瓶中加入1-{4-[(S)-3-氨基哌啶-1-羰基]-2-氟苯基}-3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲(0.56g，1.27mmol)、三乙胺(0.38g，3.80mmol)和干燥的DCM(8mL)，冰盐浴降温至0℃，缓慢滴加甲磺酰氯(0.22g，1.90mmol)的DCM溶液(2mL)，滴毕后移至室温反应1h；将所得产物体系倒入水中(20mL)，DCM萃取(20mL×3)，合并有机层，依次经6mol/L HCl洗(40mL)、饱和碳酸钠水溶液洗(20mL)、水洗(20mL)、饱和食盐水洗(20mL)和无水硫酸钠干燥，抽滤，滤液经减压浓缩得黄色固体0.7g，经硅胶柱层析纯化，洗脱剂EA∶PE＝1∶(1～3)(v/v)，梯度洗脱，洗脱液浓缩至5mL后加入乙醚(15mL)打浆，抽滤，滤饼用少量乙醚淋洗，干燥后得到白色固体(0.20g，30％)，m.p.150-151℃。
1H NMR(400MHz，DMSO-d
6)δ(ppm)8.29(s，1H)，8.19(t，J＝8.3Hz，1H)，7.25(d，J＝11.0Hz，2H)，7.13(d，J＝8.2Hz，1H)，6.57(s，1H)，4.04(brs，2H)，3.32(brs，1H)，2.91(brs，5H)，2.09(brs，1H)，1.95(brs，1H)，1.76(s，2H)，1.71-1.58(m，4H)，1.47(t，J＝9.4Hz，2H)，1.35-1.25(m，4H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6)δ(ppm)168.5，153.8，150.9(J＝240.2Hz)，130.3(J＝10.1Hz)，128.6，124.0，119.1，114.4(J＝20.4Hz)，52.1，50.7，49.6，48.0，42.8，41.1，32.4，31.5，30.5，30.0，23.7.HRMS(ESI)calcd for C
26H
37FN
4O
4SNa[M+Na]
+：543.2412，found：543.2441。
Add 1-{4-[(S)-3-aminopiperidine-1-carbonyl]-2-fluorophenyl}-3-[(1r,3R,5S,7S)-3,5- Dimethyladamantan-1-yl]urea (0.56 g, 1.27 mmol), triethylamine (0.38 g, 3.80 mmol) and dry DCM (8 mL), cooled to 0 °C in an ice-salt bath, and slowly added dropwise methanesulfonic acid Acyl chloride (0.22 g, 1.90 mmol) in DCM (2 mL) was added to room temperature and reacted for 1 h; the obtained product system was poured into water (20 mL), extracted with DCM (20 mL×3), the organic layers were combined, and 6 mol /L HCl washing (40 mL), saturated aqueous sodium carbonate solution (20 mL), water washing (20 mL), saturated brine (20 mL) and drying over anhydrous sodium sulfate, suction filtration, and the filtrate was concentrated under reduced pressure to obtain 0.7 g of a yellow solid, which was subjected to Purified by silica gel column chromatography, eluent EA:PE=1:(1～3)(v/v), gradient elution, the eluent was concentrated to 5mL, then diethyl ether (15mL) was added for slurrying, suction filtration, and the filter cake was used Rinse with a small amount of ether and dry to give a white solid (0.20 g, 30%), mp 150-151°C. 1 H NMR (400 MHz, DMSO-d 6 ) δ (ppm) 8.29 (s, 1H), 8.19 (t, J=8.3 Hz, 1H), 7.25 (d, J=11.0 Hz, 2H), 7.13 (d, J=8.2Hz, 1H), 6.57(s, 1H), 4.04(brs, 2H), 3.32(brs, 1H), 2.91(brs, 5H), 2.09(brs, 1H), 1.95(brs, 1H), 1.76(s, 2H), 1.71-1.58(m, 4H), 1.47(t, J=9.4Hz, 2H), 1.35-1.25(m, 4H), 1.12(s, 2H), 0.83(s, 6H) . 13 C NMR (100 MHz, DMSO-d 6 ) δ (ppm) 168.5, 153.8, 150.9 (J=240.2 Hz), 130.3 (J=10.1 Hz), 128.6, 124.0, 119.1, 114.4 (J=20.4 Hz), 52.1 , 50.7, 49.6, 48.0, 42.8, 41.1, 32.4, 31.5, 30.5, 30.0, 23.7. HRMS(ESI) calcd for C26H37FN4O4SNa[M+Na]+ : 543.2412 , found : 543.2441.
实施例82 1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}苯基)磺酰基]哌啶-3-甲酰胺(GL-B439)的合成Example 82 1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}phenyl)sulfonyl]piperidine-3 -Synthesis of formamide (GL-B439)
按照化合物S-GL-B413的合成方法操作，不同之处具体是以对硝基苯磺酰氯为原料，最终得到的白色固体即为化合物GL-B439，产量为0.52g，产率为42％。m.p.147-148℃。
1H NMR(400MHz，DMSO-d
6)δ8.77(s，1H)，7.58-7.53(m，4H)，7.40(s，1H)，6.90(s，1H)，6.09(s，1H)，3.59-3.51(m，2H)，2.38-2.33(m，1H)，2.16-2.05(m，3H)，1.77-1.70(m，4H)，1.62-1.56(m，4H)，1.49-1.40(m，1H)，1.35-1.25(m，4H)，1.23-1.19(m，1H)，1.12(s，2H)，0.83(s，6H).
13C NMR(100MHz，DMSO-d
6)δ174.6，153.9，145.5，129.2，126.5，117.3，52.2，50.7，48.8，48.0，46.5，42.8，41.8，32.4，30.5，30.0，27.0，24.2。
According to the synthesis method of compound S-GL-B413, the difference is that p-nitrobenzenesulfonyl chloride is used as the raw material, and the finally obtained white solid is compound GL-B439, and the yield is 0.52 g and the yield is 42%. mp147-148°C. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.77(s, 1H), 7.58-7.53(m, 4H), 7.40(s, 1H), 6.90(s, 1H), 6.09(s, 1H), 3.59-3.51(m, 2H), 2.38-2.33(m, 1H), 2.16-2.05(m, 3H), 1.77-1.70(m, 4H), 1.62-1.56(m, 4H), 1.49-1.40(m , 1H), 1.35-1.25(m, 4H), 1.23-1.19(m, 1H), 1.12(s, 2H), 0.83(s, 6H). 13 C NMR (100MHz, DMSO-d 6 )δ174.6 , 153.9, 145.5, 129.2, 126.5, 117.3, 52.2, 50.7, 48.8, 48.0, 46.5, 42.8, 41.8, 32.4, 30.5, 30.0, 27.0, 24.2.
实施例83(S)-1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]哌啶-3-甲酰胺(GL-B440)的合成Example 83 (S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorophenyl )sulfonyl]piperidine-3-carboxamide (GL-B440)
按照化合物GL-B437的合成方法操作，不同之处具体是以3-氟-4-硝基苯磺酰氯为原料；最终得到的淡黄色固即为化合物GL-B440，产量为90mg，产率为30％。m.p.147-149℃。
1H NMR(400MHz，CDCl
3)：δ8.44(t，J＝8.16Hz，1H)，7.56(s，1H)，7.44-7.37(dd，J＝10.7，4.0Hz，2H)，6.25(s，1H)，5.81(s，1H)，5.72(s，1H)，3.65(d，J＝8.16Hz，1H)，3.51(d，J＝11.2Hz，1H)，2.59-2.58(m，2H)，2.45(t，J＝10.0Hz，1H)，2.15(s，1H)，2.06(d，J＝11.0Hz，1H)，1.82(s，4H)，1.65(s，4H)，1.39-1.28(dd，J＝12.4，12.0Hz，4H)，1.26-1.24(m，1H)，1.15(s，2H)，0.84(s，6H).ESI-MS(m/z)：529.2[M+Na]
+。
According to the synthesis method of compound GL-B437, the difference is that 3-fluoro-4-nitrobenzenesulfonyl chloride is used as the raw material; the light yellow solid finally obtained is compound GL-B440, the yield is 90 mg, and the yield is 30%. mp147-149°C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.44 (t, J=8.16 Hz, 1H), 7.56 (s, 1H), 7.44-7.37 (dd, J=10.7, 4.0 Hz, 2H), 6.25 (s , 1H), 5.81(s, 1H), 5.72(s, 1H), 3.65(d, J=8.16Hz, 1H), 3.51(d, J=11.2Hz, 1H), 2.59-2.58(m, 2H) , 2.45(t, J=10.0Hz, 1H), 2.15(s, 1H), 2.06(d, J=11.0Hz, 1H), 1.82(s, 4H), 1.65(s, 4H), 1.39-1.28( dd, J=12.4, 12.0 Hz, 4H), 1.26-1.24 (m, 1H), 1.15 (s, 2H), 0.84 (s, 6H). ESI-MS (m/z): 529.2 [M+Na] + .
实施例84(S)-1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]-N-羟基哌啶-3-甲酰胺(GL-B441)的合成Example 84 (S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorophenyl )Sulfonyl]-N-Hydroxypiperidine-3-carboxamide (GL-B441) Synthesis
按照化合物GL-B436的合成方法操作，不同之处具体是以3-氟-4-硝基苯磺酰氯和(S)-3-哌啶甲酸乙酯为原料；最终得到的白色固体即为化合物GL-B441，产量为185mg，产率为65％。
1H NMR(400MHz，DMSO-d
6)：δ10.56(s，1H)，8.78(s，1H)，8.44(t，J＝8.48Hz，1H)，7.53-7.50(dd，J＝2.0，2.0Hz，1H)，7.45-7.42(dd，J＝1.7，1.7Hz，1H)，6.71(s，1H)，3.58-3.55(m，2H)，2.27-2.09(m，4H)，1.76(d，J＝2.1Hz，1H)，1.72-1.70(m，2H)，1.59(s，4H)，1.35-1.18(m，6H)，1.12(s，2H)，0.84(s，6H).ESI-MS(m/z)：520.9[M-H]
-。
According to the synthesis method of compound GL-B436, the difference is that 3-fluoro-4-nitrobenzenesulfonyl chloride and (S)-ethyl 3-piperidinecarboxylate are used as raw materials; the white solid finally obtained is the compound GL-B441, yield 185 mg, 65% yield. 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.56 (s, 1H), 8.78 (s, 1H), 8.44 (t, J=8.48Hz, 1H), 7.53-7.50 (dd, J=2.0, 2.0Hz, 1H), 7.45-7.42(dd, J=1.7, 1.7Hz, 1H), 6.71(s, 1H), 3.58-3.55(m, 2H), 2.27-2.09(m, 4H), 1.76(d , J=2.1Hz, 1H), 1.72-1.70(m, 2H), 1.59(s, 4H), 1.35-1.18(m, 6H), 1.12(s, 2H), 0.84(s, 6H). ESI- MS (m/z): 520.9 [MH] − .
测试例1Test Example 1
1、抑制活性测试1. Inhibitory activity test
检测原理：特异性底物(3-苯基-氧基)-乙酸氰基-(6-甲氧基-萘-2-基)甲酯即PHOME本身无荧光，但在sEH酶的作用下水解生成产物6-甲氧基-2-萘醛，6-甲氧基-2-萘醛能在330nm光波激发下发出波长为465nm的荧光，检测到的荧光信号强弱与对sEH酶的抑制作用强弱成反比。基于以上原理，与阳性对照组相比，计算出不同浓度样品的抑制率。根据抑制率与浓度利用SPSS 20软件计算化合物的IC
50值。
Detection principle: The specific substrate (3-phenyl-oxy)-acetic acid cyano-(6-methoxy-naphthalen-2-yl) methyl ester, that is, PHOME itself has no fluorescence, but is hydrolyzed under the action of sEH enzyme The generated product 6-methoxy-2-naphthaldehyde, 6-methoxy-2-naphthaldehyde can emit fluorescence with a wavelength of 465nm under the excitation of 330nm light wave, and the detected fluorescence signal intensity is related to the inhibition of sEH enzyme Strength is inversely proportional. Based on the above principles, compared with the positive control group, the inhibition rates of samples with different concentrations were calculated. SPSS 20 software was used to calculate the IC 50 values of the compounds according to the inhibition rate and concentration.
2、试剂与药物的配制2. Preparation of reagents and drugs
25mM Tris-HCl缓冲液(pH＝7.4，含0.1mg/mL BSA)：取12.5mL的1M Tris-HCl缓冲液，加入5mg BAS，用纯净水稀释并用盐酸调节pH值为7.4，定容至500mL。25mM Tris-HCl buffer (pH=7.4, containing 0.1mg/mL BSA): Take 12.5mL of 1M Tris-HCl buffer, add 5mg BAS, dilute with purified water and adjust the pH to 7.4 with hydrochloric acid, and make up to 500mL .
PHOME溶液：取0.79mg PHOME溶于106μL DMSO中，得到浓度为20mM的PHOME溶液，使用时用Tris-HCl缓冲液稀释至1/3mM。PHOME solution: Dissolve 0.79 mg of PHOME in 106 μL of DMSO to obtain a PHOME solution with a concentration of 20 mM, and use Tris-HCl buffer to dilute to 1/3 mM.
sEH溶液：sEH(5mg/mL)母液于-80℃冰箱保存，使用时用25mM Tris-HCl缓冲液稀释至4μg/mL。sEH solution: sEH (5mg/mL) stock solution was stored at -80°C in a refrigerator, and diluted to 4μg/mL with 25mM Tris-HCl buffer when used.
待测样品粉末用DMSO溶解为20mM的溶液，-20℃冰箱保存备用，使用时用Tris-HCl缓冲液稀释至对应浓度。The sample powder to be tested was dissolved in DMSO into a 20 mM solution, stored in a -20°C refrigerator for later use, and diluted to the corresponding concentration with Tris-HCl buffer during use.
3、实验分组3. Experimental grouping
实验设计：溶剂组，100％活力组(A)，抑制剂组(B)，阳性对照组(C)，具体如表1所示。Experimental design: solvent group, 100% activity group (A), inhibitor group (B), positive control group (C), as shown in Table 1.
表1实验分组情况Table 1 Experimental grouping
| 孔hole | 缓冲液buffer | DMSODMSO | 抑制剂inhibitor | sEHsEH | 底物substrate |
| 溶剂组Solvent group | 168μL168μL | 2μL2μL | -- | -- | 30μL30μL |
| 100％活力组(A)100% Vitality Group (A) | 148μL148μL | 2μL2μL | -- | 20μL20μL | 30μL30μL |
| 抑制剂组(B)Inhibitor group (B) | 148μL148μL | -- | 2μL2μL | 20μL20μL | 30μL30μL |
| 阳性对照组(C)Positive control group (C) | 148μL148μL | -- | 2μL2μL | 20μL20μL | 30μL30μL |
4、实验步骤4. Experimental steps
(a)向96黑底微孔板中加入148μL/孔Tris-HCl缓冲液；(a) Add 148 μL/well Tris-HCl buffer to 96 black bottom microplate;
(b)加入待测样品溶液2μL，溶剂组和100％活力组用等体积DMSO代替，阳性对照组加入先导化合物GL-B401，结构式为
(b) Add 2 μL of the sample solution to be tested, the solvent group and the 100% activity group were replaced with an equal volume of DMSO, and the positive control group was added with the lead compound GL-B401, the structural formula is
(c)抑制剂组共5个浓度，终浓度分别为10nM、5nM、2.5nM、1.25nM、0.625nM；(c) There are 5 concentrations of inhibitor group, the final concentrations are 10nM, 5nM, 2.5nM, 1.25nM, 0.625nM;
(d)加入s-EH溶液20μL(终浓度为400ng/mL)，溶剂组用等体积Tris-HCl缓冲液代替；(d) 20 μL of s-EH solution was added (final concentration was 400 ng/mL), and the solvent group was replaced with an equal volume of Tris-HCl buffer;
(e)加入PHOME底物30μL起始反应(终浓度为50μM)，于37℃恒温箱孵育10min；(e) Add 30 μL of PHOME substrate to start the reaction (final concentration is 50 μM), and incubate at 37°C for 10 min;
(f)酶标仪检测荧光信号数据，激发波长330nm，发射波长465nm。(f) The fluorescence signal data was detected by a microplate reader, the excitation wavelength was 330 nm, and the emission wavelength was 465 nm.
5、数据分析5. Data analysis
每个样品设置三个复孔，三个复孔的均值为待测化合物的荧光值(F)，抑制率％＝[(AF-BF)/AF]×100，其中，AF为100％活力组荧光值，BF为抑制剂组荧光值。根据抑制率与浓度利用SPSS 20软件计算化合物的IC
50值。
Three replicate wells were set for each sample, and the average of the three replicate wells was the fluorescence value (F) of the tested compound, and the inhibition rate %=[(AF-BF)/AF]×100, where AF was the 100% activity group Fluorescence value, BF is the fluorescence value of inhibitor group. SPSS 20 software was used to calculate the IC 50 values of the compounds according to the inhibition rate and concentration.
化合物GL-B404～GL-B441对人源sEH(HsEH)抑制活性如表1所示。Table 1 shows the inhibitory activities of compounds GL-B404 to GL-B441 on human sEH (HsEH).
表1化合物GL-B404～GL-B441对人源sEH(HsEH)的抑制活性Table 1 Inhibitory activity of compounds GL-B404～GL-B441 on human sEH (HsEH)
由表1可知，本发明提供的化合物GL-B404～GL-B441对HsEH IC
50值在0.1nM～1μM之间，具有较好的抑制作用。实验结果显示有15个化合物对sEH的抑制活性优于先导化合物GL-B401，分别为化合物GL-B412、GL-B413、GL-B415、GL-B416、GL-B417、GL-B434、GL-B435、GL-B436，GL-B437、GL-B438、GL-B439、GL-B440、GL-B441、R-GL-B413、S-GL-B413，其中化合物GL-B437和GL-B440抑制活性很强，IC
50分别为0.06nM和0.08nM，显示出非常好的开发前景。
It can be seen from Table 1 that the compounds GL-B404 to GL-B441 provided by the present invention have a good inhibitory effect on HsEH IC 50 values between 0.1 nM and 1 μM. The experimental results showed that 15 compounds had better inhibitory activity on sEH than the lead compound GL-B401, namely compounds GL-B412, GL-B413, GL-B415, GL-B416, GL-B417, GL-B434, GL-B435 , GL-B436, GL-B437, GL-B438, GL-B439, GL-B440, GL-B441, R-GL-B413, S-GL-B413, among which compounds GL-B437 and GL-B440 have strong inhibitory activity , with IC50s of 0.06nM and 0.08nM , respectively, showing a very promising development prospect.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made. It should be regarded as the protection scope of the present invention.
Claims (50)
- 一种美金刚脲类衍生物，其特征在于，具有式A、式B、式C或式D所示结构：A memantine derivative, characterized in that it has the structure shown in formula A, formula B, formula C or formula D:
其中，R 1和R 2独立地选自-H、-OH、-NH 2、-SH、-CN、卤素基团、烷基、烷氧基或杂环基； wherein, R 1 and R 2 are independently selected from -H, -OH, -NH 2 , -SH, -CN, a halogen group, an alkyl group, an alkoxy group or a heterocyclic group;R 3选自-H、-OH、-NH 2、-SH、-CN、卤素基团、烷基或烷氧基； R3 is selected from -H, -OH, -NH2 , -SH, -CN, halogen group, alkyl or alkoxy;R 4选自-OH、-NH 2、羟胺基、烷基、烷氧基、烷基胺基、烷氧基胺基、醇胺基、苯胺基、萘胺基或杂环基； R 4 is selected from -OH, -NH 2 , hydroxylamine, alkyl, alkoxy, alkylamine, alkoxyamine, alcoholamine, anilino, naphthylamino or heterocyclic;X选自-NH 2、X is selected from -NH 2 ,
Y选自-H、Y is selected from -H,
R 5选自烷基或杂环基； R 5 is selected from alkyl or heterocyclyl;Z和M独立地选自-O-、-NH-或-S-；Z and M are independently selected from -O-, -NH- or -S-;Q选自Q is selected from
- 根据权利要求1所述的美金刚脲类衍生物，其特征在于，所述R 1和R 2选自的卤素基团独立地为-F、-Cl或-Br，烷基独立地为甲基、乙基、丙基、丁基、戊基、异丁基、异丙基、异戊基或叔丁基，烷氧基独立地为甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、环戊氧基、环己氧基、苯氧基或苄氧基。 The memantamide derivative according to claim 1, wherein the halogen group selected from the R 1 and R 2 is independently -F, -Cl or -Br, and the alkyl group is independently a methyl group , ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isoamyl or tert-butyl, alkoxy is independently methoxy, ethoxy, propoxy, isopropoxy group, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy or benzyloxy.
- 根据权利要求2所述的美金刚脲类衍生物，其特征在于，所述R 1和R 2为甲基。 The memantamide derivative according to claim 2, wherein the R 1 and R 2 are methyl groups.
- 根据权利要求1所述的美金刚脲类衍生物，其特征在于，所述R 3选自的卤素基团为-F、-Cl或-Br；烷基为未取代或取代的C1～C6烷基；烷氧基为未取代或取代的C1～C6烷氧基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C1～C6烷基。 The memantamide derivative according to claim 1, wherein the halogen group selected from the R 3 is -F, -Cl or -Br; the alkyl group is an unsubstituted or substituted C1-C6 alkane Alkoxy is unsubstituted or substituted C1-C6 alkoxy; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 or C1-C6 alkyl.
- 根据权利要求4所述的美金刚脲类衍生物，其特征在于，所述R 3为-H、-F或-Cl。 The memantamide derivative according to claim 4, wherein the R 3 is -H, -F or -Cl.
- 根据权利要求1所述的美金刚脲类衍生物，其特征在于，所述R 4选自的烷氧基为未取代或取代的C1～C6烷氧基；烷基胺基为未取代或取代的C1～C6烷基胺基；烷氧基胺基为未取代或取代的C1～C6烷氧基胺基；苯胺基为未取代或取代的苯胺基；萘胺基为未取代或取代的萘胺基；杂环基为未取代或取代的5～10元杂环基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C1～C6烷基。 The memantamide derivative according to claim 1, wherein the alkoxy group selected by R 4 is an unsubstituted or substituted C1-C6 alkoxy group; the alkylamino group is an unsubstituted or substituted group C1-C6 alkylamine group; alkoxyamine group is unsubstituted or substituted C1-C6 alkoxyamine group; aniline group is unsubstituted or substituted aniline group; naphthylamino group is unsubstituted or substituted naphthalene Amine group; heterocyclic group is an unsubstituted or substituted 5-10 membered heterocyclic group; the substituted substituent is independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
- 根据权利要求6所述的美金刚脲类衍生物，其特征在于，所述R 4为-OH、-NH 2、-OCH 2CH 3、-NHCH 3、-N(CH 3) 2、-NHOCH 3或-NHOH。 The memantine derivative according to claim 6, wherein the R 4 is -OH, -NH 2 , -OCH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 ,
-NHOCH 3 or -NHOH. - 根据权利要求1所述的美金刚脲类衍生物，其特征在于，所述R 5选自的烷基为链烷基或环烷基； The memantamide derivative according to claim 1, wherein the alkyl group selected from the R 5 is a chain alkyl group or a cycloalkyl group;所述R 5选自的链烷基为未取代或取代的C1～C6链烷基，所述取代的C1～C6链烷基中取代基选自-OH、-NH 2或C1～C6烷基； The alkyl group selected by the R 5 is an unsubstituted or substituted C1-C6 chain alkyl group, and the substituent in the substituted C1-C6 chain alkyl group is selected from -OH, -NH 2 or C1-C6 alkyl group ;所述R 5选自的环烷基为未取代或取代的C3～C6环烷基，所述取代的C3～C6环烷基中取代基选自-F、-Cl、-Br、-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C1～C6烷基； The cycloalkyl group selected from the R 5 is an unsubstituted or substituted C3-C6 cycloalkyl group, and the substituents in the substituted C3-C6 cycloalkyl group are selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl;所述R 5选自的杂环基为未取代或取代的C3～C6饱和或不饱和杂环基，所述取代的C3～C6饱和或不饱和杂环基中取代基独立地选自-F、-Cl、-Br、-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C1～C6烷基。 The heterocyclic group selected from the R 5 is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the substituents in the substituted C3-C6 saturated or unsaturated heterocyclic group are independently selected from -F , -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 or C1-C6 alkyl.
- 根据权利要求8所述的美金刚脲类衍生物，其特征在于，所述R 5为-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3)CH 2CH 3、环丙基或-CH(NH 2)CH(CH 3) 2。 The memantine derivative according to claim 8, wherein the R 5 is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3. Cyclopropyl or -CH( NH2 )CH( CH3 ) 2 .
- 根据权利要求1～9任一项所述的美金刚脲类衍生物，其特征在于，包括1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酸乙酯、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-4-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N,N-二甲基哌啶-4-甲酰胺、N-环丙基-1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-4-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酸乙酯、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲基哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N,N-二甲基哌啶-3-甲酰胺、N-环丙基-1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-甲氧基哌啶-3-甲酰胺、1-[4-(4-氨基哌啶-1-羰基)苯基]-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]甲磺酰胺、N-[1-(4-{3-[(1r，3R，5S，7r)-3，5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]乙酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丙酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]丁酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-2-甲基丁酰胺、N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]环丙烷甲酰胺、2-氨基-N-[1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-4-基]-3-甲基丁酰胺、 1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-[4-(哌嗪-1-羰基)苯基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-{4-[4-(甲基磺酰基)哌嗪-1-羰基]苯基}脲、1-[4-(4-乙酰基哌嗪-1-羰基)苯基]-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-[4-(4-丙酰基哌嗪-1-羰基)苯基]脲、1-[4-(4-丁酰基哌嗪-1-羰基)苯基]-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-{4-[4-(2-甲基丁酰基)哌嗪-1-羰基]苯基}脲、1-{4-[4-(环丙烷羰基)哌嗪-1-羰基]苯基}-3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲、1-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]-3-[4-(4-戊基哌嗪-1-羰基)苯基]脲、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}-3-氯苯甲酰基)哌啶-3-甲酰胺、1-(4-{3-[(1r,3R,5S,7r)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)-N-羟基哌啶-3-甲酰胺、(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-甲酰胺、N-[(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯甲酰基)哌啶-3-基]甲磺酰胺、(S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、(R)-1-(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}苯甲酰基)哌啶-3-甲酰胺、1-[(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}苯基)磺酰基]哌啶-3-甲酰胺、(S)-1-[(4-{3-[(1r，3R，5S，7S)-3，5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]哌啶-3-甲酰胺或(S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-二甲基金刚烷-1-基]脲基}-3-氟苯基)磺酰基]-N-羟基哌啶-3-甲酰胺。The memantine derivative according to any one of claims 1 to 9, characterized in that it comprises 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyl Adamantan-1-yl]ureido}benzoyl)piperidine-4-carboxylic acid, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane- 1-yl]ureido}benzoyl)piperidine-4-carboxylic acid ethyl ester, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1 -yl]ureido}benzoyl)piperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ]ureido}benzoyl)-N-methylpiperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane- 1-yl]ureido}benzoyl)-N,N-dimethylpiperidine-4-carboxamide, N-cyclopropyl-1-(4-{3-[(1r,3R,5S,7r )-3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)- 3,5-Dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxypiperidine-4-carboxamide, 1-(4-{3-[(1r,3R,5S ,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxylic acid, 1-(4-{3-[(1r,3R,5S,7r) -3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxylic acid ethyl ester, 1-(4-{3-[(1r,3R,5S,7r)- 3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3, 5-Dimethyladamantan-1-yl]ureido}benzoyl)-N-methylpiperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r) -3,5-Dimethyladamantan-1-yl]ureido}benzoyl)-N,N-dimethylpiperidine-3-carboxamide, N-cyclopropyl-1-(4-{ 3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidine-3-carboxamide, 1-(4-{3- [(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)-N-methoxypiperidine-3-carboxamide, 1-[4 -(4-Aminopiperidine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea, N-[1- (4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]methanesulfonamide, N -[1-(4-{3-[(1r, 3R, 5S, 7r)-3, 5-2 Methyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]acetamide, N-[1-(4-{3-[(1r,3R,5S,7r)-3, 5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]propionamide, N-[1-(4-{3-[(1r,3R,5S,7r) -3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]butanamide, N-[1-(4-{3-[(1r,3R,5S ,7r)-3,5-Dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]-2-methylbutanamide, N-[1-(4-{3 -[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]cyclopropanecarboxamide, 2-amino-N -[1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]ureido}benzoyl)piperidin-4-yl]- 3-Methylbutanamide, 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(piperazine-1-carbonyl)phenyl ]urea, 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-{4-[4-(methylsulfonyl)piperazine-1- Carbonyl]phenyl}urea, 1-[4-(4-acetylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantane -1-yl]urea, 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-(4-propionylpiperazine-1- Carbonyl)phenyl]urea, 1-[4-(4-butyrylpiperazine-1-carbonyl)phenyl]-3-[(1r,3R,5S,7r)-3,5-dimethyladamantane -1-yl]urea, 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-{4-[4-(2-methylbutyryl] ) piperazine-1-carbonyl]phenyl}urea, 1-{4-[4-(cyclopropanecarbonyl)piperazine-1-carbonyl]phenyl}-3-[(1r,3R,5S,7r)- 3,5-Dimethyladamantan-1-yl]urea, 1-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-3-[4-( 4-Pentylpiperazine-1-carbonyl)phenyl]urea, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]urea yl}-3-fluorobenzoyl)piperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl ]ureido}-3-chlorobenzoyl)piperidine-3-carboxamide, 1-(4-{3-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1 -yl]ureido}benzoyl)-N-hydroxypiperidine-3-carboxamide, (S)-1-(4-{ 3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine-3-carboxamide, N-[( S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}-3-fluorobenzoyl)piperidine- 3-yl]methanesulfonamide, (S)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzyl Acyl)piperidine-3-carboxamide, (R)-1-(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido} Benzoyl)piperidine-3-carboxamide, 1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl]ureido}benzene yl)sulfonyl]piperidine-3-carboxamide, (S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl ]ureido}-3-fluorophenyl)sulfonyl]piperidine-3-carboxamide or (S)-1-[(4-{3-[(1r,3R,5S,7S)-3,5- Dimethyladamantan-1-yl]ureido}-3-fluorophenyl)sulfonyl]-N-hydroxypiperidine-3-carboxamide.
- 权利要求1～10任一项所述美金刚脲类衍生物的制备方法，其特征在于，The method for preparing a memantine derivative according to any one of claims 1 to 10, characterized in that:(1)制备具有式A所示结构的美金刚脲类衍生物，(1) preparing a memantamide derivative having the structure shown in formula A,(1-1)当R 3为除卤素基团以外的基团时，制备方法包括以下步骤： (1-1) When R 3 is a group other than a halogen group, the preparation method includes the following steps:将化合物I和化合物a进行第一酰化反应，得到化合物b；Compound I and compound a are subjected to the first acylation reaction to obtain compound b;将所述化合物b进行第一还原反应，得到化合物c；The compound b is subjected to a first reduction reaction to obtain compound c;将所述化合物c和化合物II进行第二酰化反应，得到化合物d；The compound c and compound II are subjected to a second acylation reaction to obtain compound d;将所述化合物d和化合物III进行第一胺解反应，得到化合物e；当化合物e中R 6为-H时，所述化合物e为R 4为-OH的具有式A所示结构的美金刚脲类衍生物； The compound d and the compound III are subjected to the first aminolysis reaction to obtain the compound e; when the R 6 in the compound e is -H, the compound e is the memantine having the structure shown in formula A in which R 4 is -OH Urea derivatives;当化合物e中R 6为-H时，将所述化合物e、氯化亚砜和乙醇混合，进行酯化反应，得到R 4为-OEt的具有式A所示结构的美金刚脲类衍生物； When R 6 in compound e is -H, the compound e, thionyl chloride and ethanol are mixed to carry out an esterification reaction to obtain a memantamide derivative having the structure shown in formula A, where R 4 is -OEt ;或者，当化合物e中R 6为-H时，将所述化合物e和化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第三酰化反应，得到具有式A所示结构的美金刚脲类衍生物； Alternatively, when R 6 in compound e is -H, the compound e and compound IV are mixed in 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1 - carry out the third acylation reaction in the presence of hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;或者，当化合物e中R 6为-H时，将所述化合物e在氯化亚砜存在条件下进行氯代反应，得到酰氯中间体；将所述酰氯中间体和化合物IV进行第四酰化反应，得到具有式A所示结构的美金刚脲类衍生物； Alternatively, when R 6 in compound e is -H, the compound e is subjected to a chlorination reaction in the presence of thionyl chloride to obtain an acid chloride intermediate; the acid chloride intermediate and compound IV are subjected to fourth acylation reaction to obtain the memantamide derivatives having the structure shown in formula A;当化合物e中R 6为C 1～C 6的烷基时，将所述化合物e经水解反应后，再与化合物IV混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第五酰化反应，得到具有式A所示结构的美金刚脲类衍生物； When R 6 in compound e is a C 1 -C 6 alkyl group, the compound e is subjected to hydrolysis reaction, and then mixed with compound IV, in 1-(3-dimethylaminopropyl)-3-ethyl The fifth acylation reaction is carried out in the presence of carbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain the memantamide derivatives having the structure shown in formula A;(1-2)当R 3为卤素基团时，制备方法包括以下步骤： (1-2) When R 3 is a halogen group, the preparation method comprises the following steps:按照(1-1)方法制备化合物c；Compound c was prepared according to the method (1-1);当Z为-O-或-S-时，将所述化合物c和化合物V进行第六酰化反应，得到第一中间体化合物；将所述第一中间体化合物和化合物III进行第一亲核取代反应，得到化合物e；When Z is -O- or -S-, the sixth acylation reaction is performed on the compound c and the compound V to obtain the first intermediate compound; the first intermediate compound and the compound III are subjected to the first nucleophilic reaction Substitution reaction to obtain compound e;当Z为-NH-时，将所述化合物c、N-Boc-硫脲、NaH和三氟乙酸酐混合，进行第二胺解反应，得到第二中间体化合物；将所述第二中间体化合物、化合物III和HgCl 2混合，进行脱硫羰基反应，得到第三中间体化合物；将所述第三中间体化合物在酸性条件下进行第一脱保护基反应，得到化合物e； When Z is -NH-, the compound c, N-Boc-thiourea, NaH and trifluoroacetic anhydride are mixed to carry out a second aminolysis reaction to obtain a second intermediate compound; the second intermediate Compound, compound III and HgCl 2 are mixed, and a desulfurization carbonyl reaction is carried out to obtain a third intermediate compound; the third intermediate compound is subjected to a first deprotection group reaction under acidic conditions to obtain compound e;基于所述化合物e，按照(1-1)方法制备得到具有式A所示结构的美金刚脲类衍生物；Based on the compound e, according to the method (1-1), a memantamide derivative having the structure represented by formula A is prepared;所述化合物I、化合物II和化合物III的结构式依次为The structural formulas of the compound I, compound II and compound III are sequentially
所述化合物IV为：NH 3、R 7-NH 2、R 7-OH、R 7-O-NH 2或其中，R 7为取代或未取代的C1～C6的烷基；所述取代的取代基独立地选自-F、-Cl、-Br、-OH、-NH 2、-NHCH 3、-N(CH 3) 2或C1～C6的烷基； The compound IV is: NH 3 , R 7 -NH 2 , R 7 -OH, R 7 -O-NH 2 or
wherein, R 7 is a substituted or unsubstituted C1-C6 alkyl group; the substituted substituents are independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NHCH 3 , -N( CH 3 ) 2 or an alkyl group of C1-C6;所述化合物V为固体光气或硫光气；Described compound V is solid phosgene or thiophosgene;所述化合物a、化合物b、化合物c、化合物d以及化合物e的结构式如下：The structural formulas of the compound a, compound b, compound c, compound d and compound e are as follows:
其中，化合物I、化合物b、化合物c、化合物d和化合物e的结构式中R 6选自-H或C 1～C 6的烷基； Wherein, in the structural formula of compound I, compound b, compound c, compound d and compound e, R 6 is selected from -H or an alkyl group of C 1 -C 6 ;(2)制备具有式B所示结构的美金刚脲类衍生物，(2) preparing a memantamide derivative having the structure shown in formula B,(2-1)当R 3为除卤素基团以外的基团时，制备方法包括以下步骤： (2-1) When R 3 is a group other than a halogen group, the preparation method comprises the following steps:将化合物VI和化合物a进行第七酰化反应，得到化合物f；The seventh acylation reaction is carried out with compound VI and compound a to obtain compound f;将所述化合物f进行第二还原反应，得到化合物g；The compound f is subjected to a second reduction reaction to obtain compound g;将所述化合物g和化合物II进行第八酰化反应，得到化合物h；The compound g and compound II are subjected to the eighth acylation reaction to obtain compound h;将所述化合物h和化合物III进行第三胺解反应，得到化合物i；The compound h and compound III are subjected to a third aminolysis reaction to obtain compound i;将所述化合物i在酸性条件下进行第二脱保护基反应，得到X为-NH 2的具有式B所示结构的美金刚脲类衍生物，记为化合物j； The compound i is subjected to the second deprotection group reaction under acidic conditions to obtain a memantamide derivative having a structure represented by formula B, where X is -NH 2 , which is denoted as compound j;将所述化合物j和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第九酰化反应，得到X为的具有式B所述结构的美金刚脲类衍生物； The compound j and compound VII are mixed, and the ninth acylamide is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. chemical reaction to obtain X as
The memantamide derivatives having the structure described in formula B;将所述化合物j和化合物VIII进行第十酰化反应，得到X为的具有式B所述结构的美金刚脲类衍生物； The compound j and compound VIII are subjected to tenth acylation reaction to obtain X as
The memantamide derivatives having the structure described in formula B;(2-2)当R 3为卤素基团时，制备方法包括以下步骤： (2-2) When R 3 is a halogen group, the preparation method comprises the following steps:按照(2-1)方法制备化合物g；Compound g was prepared according to the method (2-1);将所述化合物g和化合物V进行第十一酰化反应，得到第四中间体化合物；The eleventh acylation reaction of compound g and compound V is carried out to obtain the fourth intermediate compound;将所述第四中间体化合物和化合物III进行第二亲核取代反应，得到化合物h；The fourth intermediate compound and compound III are subjected to a second nucleophilic substitution reaction to obtain compound h;基于所述化合物h，按照(2-1)方法制备得到具有式B所示结构的美金刚脲类衍生物；Based on the compound h, a memantamide derivative having the structure shown in formula B is prepared according to the method (2-1);其中，所述化合物VI的结构式为：Wherein, the structural formula of described compound VI is:
所述化合物VII的结构式为：The structural formula of the compound VII is:
所述化合物VIII的结构式为：The structural formula of the compound VIII is:
所述化合物f、化合物g、化合物h、化合物i以及化合物j的结构式如下：The structural formulas of the compound f, compound g, compound h, compound i and compound j are as follows:
(3)制备具有式C所示结构的美金刚脲类衍生物，(3) preparing the memantamide derivatives having the structure shown in formula C,(3-1)当R 3为除卤素基团以外的基团时，制备方法包括以下步骤： (3-1) When R 3 is a group other than a halogen group, the preparation method comprises the following steps:将化合物IX和化合物a进行第十二酰化反应，得到化合物k；The dodecanoylation reaction of compound IX and compound a is carried out to obtain compound k;将所述化合物k进行第三还原反应，得到化合物l；The compound k is subjected to a third reduction reaction to obtain compound 1;将所述化合物l和化合物II进行第十三酰化反应，得到化合物m；The compound 1 and compound II are subjected to a tridecacylation reaction to obtain compound m;将所述化合物m和化合物III进行第四胺解反应，得到化合物n；The compound m and compound III are subjected to the fourth aminolysis reaction to obtain compound n;将所述化合物n在酸性条件下进行第三脱保护基反应，得到Y为-H的具有式C所示结构的美金刚脲类衍生物，记为化合物o；The compound n is subjected to the third deprotection group reaction under acidic conditions to obtain a memantamide derivative with the structure represented by formula C, wherein Y is -H, which is denoted as compound o;将所述化合物o和化合物VII混合，在1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在条件下进行第十四酰化反应，得到Y为的具有式C所述结构的美金刚脲类衍生物； The compound o and compound VII are mixed, and the fourteenth step is carried out in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole Acylation reaction to obtain Y as
The memantamide derivatives having the structure described in formula C;将所述化合物o和化合物VIII进行第十五酰化反应，得到Y为的具有式C所述结构的美金刚脲类衍生物； The compound o and compound VIII are subjected to pentadecyl acylation to obtain Y as
The memantamide derivatives having the structure described in formula C;(3-2)当R 3为卤素基团时，制备方法包括以下步骤： (3-2) When R 3 is a halogen group, the preparation method comprises the following steps:按照(3-1)方法制备化合物l；Compound 1 was prepared according to (3-1) method;将化合物l和化合物V进行第十六酰化反应，得到第五中间体化合物；Compound 1 and compound V are subjected to sixteen acylation reaction to obtain the fifth intermediate compound;将所述第五中间体化合物和化合物III进行第三亲核取代反应，得到化合物n；The fifth intermediate compound and compound III are subjected to a third nucleophilic substitution reaction to obtain compound n;基于所述化合物n，按照(3-1)方法制备得到具有式C所示结构的美金刚脲类衍生物；Based on the compound n, a memantamide derivative having the structure shown in formula C is prepared according to the method (3-1);其中，所述化合物IX的结构式为：Wherein, the structural formula of described compound IX is:
所述化合物k、化合物l、化合物m、化合物m以及化合物o的结构式如下：The structural formulas of the compound k, compound 1, compound m, compound m and compound o are as follows:
(4)制备具有式D所示结构的美金刚脲类衍生物，(4) preparing a memantamide derivative having the structure shown in formula D,将化合物IX替换为化合物按照(3)方法制备得到具有式D所示结构的美金刚脲类衍生物。 Replace Compound IX with Compound
According to the method (3), the memantamide derivatives having the structure represented by the formula D are prepared. - 根据权利要求11所述的制备方法，其特征在于，所述化合物I和化合物a的摩尔比为(1.8～2.2)：1；所述第一酰化反应的温度为-40～10℃，时间为10～50min。The preparation method according to claim 11, wherein the molar ratio of the compound I and the compound a is (1.8-2.2): 1; the temperature of the first acylation reaction is -40-10°C, and the time 10 to 50 minutes.
- 根据权利要求11所述的制备方法，其特征在于，所述第一还原反应的温度为25～70℃，时间为10～15h。The preparation method according to claim 11, wherein the temperature of the first reduction reaction is 25-70°C, and the time is 10-15h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物c和化合物II的摩尔比为1：(1～2)；所述第二酰化反应在冰浴条件下进行，所述第二酰化反应的时间为10～50min。The preparation method according to claim 11, wherein the molar ratio of the compound c and the compound II is 1:(1-2); the second acylation reaction is carried out under ice bath conditions, and the second The time of diacylation reaction is 10～50min.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物d和化合物III的摩尔比为1：(0.8～1.3)；所述第一胺解反应在体系回流条件下进行，所述第一胺解反应的时间为6～10h。The preparation method according to claim 11, wherein the molar ratio of the compound d and the compound III is 1:(0.8-1.3); the first aminolysis reaction is carried out under reflux conditions of the system, and the second The time of the monoamine hydrolysis reaction is 6-10h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物e、氯化亚砜和乙醇的用量比为(0.5～0.8)mmol：(2～3)mmol：(15～25)mL；所述酯化反应在体系回流条件下进行，所述酯化反应的时间为1.5～2.5h。The preparation method according to claim 11, wherein the dosage ratio of the compound e, thionyl chloride and ethanol is (0.5-0.8) mmol: (2-3) mmol: (15-25) mL; The esterification reaction is carried out under the condition of system reflux, and the time of the esterification reaction is 1.5-2.5h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物e和化合物IV的摩尔比为1：(1.8～2.2)，所述化合物e、1-(3-二甲胺基丙基)-3-乙基碳二亚胺盐酸盐和1-羟基苯并三唑的摩尔比为1：(1.3～1.7)：(1.3～1.7)；所述第三酰化反应的温度为25～35℃，时间为6～10h。The preparation method according to claim 11, wherein the molar ratio of the compound e and the compound IV is 1:(1.8-2.2), and the compound e, 1-(3-dimethylaminopropyl) -The molar ratio of 3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole is 1:(1.3～1.7):(1.3～1.7); the temperature of the third acylation reaction is 25～ 35℃, the time is 6～10h.
- 根据权利要求11所述的制备方法，其特征在于，所述氯代反应在体系回流条件下进行，所述氯代反应的时间为1.5～2.5h。The preparation method according to claim 11, wherein the chlorination reaction is carried out under the reflux condition of the system, and the time of the chlorination reaction is 1.5-2.5h.
- 根据权利要求11所述的制备方法，其特征在于，所述酰氯中间体和化合物IV的摩尔比为1：(1.0～1.5)；所述第四酰化反应的温度为-10～40℃，时间为1～6h。The preparation method according to claim 11, wherein the molar ratio of the acid chloride intermediate and the compound IV is 1:(1.0～1.5); the temperature of the fourth acylation reaction is -10～40°C, The time is 1～6h.
- 根据权利要求11所述的制备方法，其特征在于，所述水解反应的温度为25～70℃，时间为30min～6h。The preparation method according to claim 11, wherein the temperature of the hydrolysis reaction is 25-70°C, and the time is 30min-6h.
- 根据权利要求11所述的制备方法，其特征在于，所述第五酰化反应温度为0～40℃，时间为1～8h。The preparation method according to claim 11, wherein the temperature of the fifth acylation reaction is 0-40°C, and the time is 1-8h.
- 根据权利要求11所述的制备方法，其特征在于，所述第六酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the temperature of the sixth acylation reaction is room temperature, and the time is 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述第一亲核取代反应为先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。The preparation method according to claim 11, characterized in that, the first nucleophilic substitution reaction is firstly reacted at room temperature for 1.5-2.5 h, and then reacted under the system reflux condition for 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述第二胺解反应的温度为0～25℃，时间2～24h。The preparation method according to claim 11, wherein the temperature of the second aminolysis reaction is 0-25°C, and the time is 2-24h.
- 根据权利要求11所述的制备方法，其特征在于，所述脱硫羰基反应的温度为0～25℃，时间2～24h。The preparation method according to claim 11, wherein the temperature of the dethiocarbonylation reaction is 0-25°C and the time is 2-24h.
- 根据权利要求11所述的制备方法，其特征在于，所述第一脱保护基反应的温度为0～40℃，时间为30min～4h。The preparation method according to claim 11, wherein the temperature of the first deprotection group reaction is 0-40°C, and the time is 30min-4h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物VI和化合物a的摩尔比为1：(0.8～1.2)；所述第七酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the molar ratio of the compound VI and the compound a is 1:(0.8-1.2); the temperature of the seventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述第二还原反应的温度为25～70℃，时间为10～15h。The preparation method according to claim 11, wherein the temperature of the second reduction reaction is 25-70°C, and the time is 10-15 h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物g和化合物II的摩尔比为1：(1～2)；所述第八酰化反应在室温条件下进行，所述第八酰化反应的时间为5～8h。The preparation method according to claim 11, wherein the molar ratio of the compound g to the compound II is 1:(1-2); the eighth acylation reaction is carried out at room temperature, and the eighth The time of acylation reaction is 5～8h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物h和化合物III的摩尔比为1：(0.8～1.3)；所述第三胺解反应在体系回流条件下进行，所述第三胺解反应的时间为6～10h。The preparation method according to claim 11, wherein the molar ratio of the compound h and the compound III is 1:(0.8-1.3); the third aminolysis reaction is carried out under the reflux condition of the system, the third The time of triamine hydrolysis reaction is 6～10h.
- 根据权利要求11所述的制备方法，其特征在于，所述第二脱保护基反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the temperature of the second deprotection group reaction is room temperature, and the time is 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物j和化合物VII的摩尔比为1：(1.5～2.5)；所述第九酰化反应的温度为20～40℃，时间为6～10h。The preparation method according to claim 11, wherein the molar ratio of the compound j to the compound VII is 1:(1.5～2.5); the temperature of the ninth acylation reaction is 20～40°C, and the time is 6 ~ 10h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物j和化合物VIII的摩尔比为1：(1.5～2.5)；所述第十酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the molar ratio of the compound j to the compound VIII is 1:(1.5～2.5); the temperature of the tenth acylation reaction is room temperature, and the time is 1.5～2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述第十一酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the temperature of the eleventh acylation reaction is room temperature, and the time is 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述第二亲核取代反应为先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。The preparation method according to claim 11, wherein the second nucleophilic substitution reaction is firstly reacted at room temperature for 1.5-2.5 h, and then reacted under the system reflux condition for 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物IX和化合物a的摩尔比为1：(0.8～1.2)；所述第十二酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the molar ratio of the compound IX to the compound a is 1:(0.8～1.2); the temperature of the dodecanoylation reaction is room temperature, and the time is 1.5～1.2 2.5h.
- 根据权利要求11所述的制备方法，其特征在于，所述第三还原反应的温度为70～90℃，时间为40～60min。The preparation method according to claim 11, wherein the temperature of the third reduction reaction is 70-90°C, and the time is 40-60 min.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物l和化合物II的摩尔比为1：(1～2)；所述第十三酰化反应在室温条件下进行，所述第十三酰化反应的时间为5～8h。The preparation method according to claim 11, wherein the molar ratio of the compound l and the compound II is 1:(1-2); the tridecylation reaction is carried out at room temperature, and the third The time of tridecacylation reaction is 5-8h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物m和化合物III的摩尔比为1：(0.8～1.3)；所述第四胺解反应在体系回流条件下进行，所述第四胺解反应的时间为6～10h。The preparation method according to claim 11, wherein the molar ratio of the compound m and the compound III is 1:(0.8-1.3); the fourth aminolysis reaction is carried out under the reflux condition of the system, and the first The time of tetraamine hydrolysis reaction is 6～10h.
- 根据权利要求11所述的制备方法，其特征在于，所述第三脱保护基反应的温度为室温，时间为3.5～4.5h。The preparation method according to claim 11, wherein the temperature of the third deprotecting group reaction is room temperature, and the time is 3.5-4.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物o和化合物VII的摩尔比为1：(1.5～2.5)；所述第十四酰化反应的温度为20～40℃，时间为6～10h。The preparation method according to claim 11, wherein the molar ratio of the compound o to the compound VII is 1:(1.5～2.5); the temperature of the fourteen acylation reaction is 20～40°C, and the time For 6 ~ 10h.
- 根据权利要求11所述的制备方法，其特征在于，所述化合物o和化合物VIII的摩尔比为1：(1.5～2.5)；所述第十五酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the molar ratio of the compound o to the compound VIII is 1:(1.5～2.5); the temperature of the pentadecyl acylation reaction is room temperature, and the time is 1.5～2.5 2.5h.
- 根据权利要求11所述的制备方法，其特征在于，所述第十六酰化反应的温度为室温，时间为1.5～2.5h。The preparation method according to claim 11, wherein the temperature of the sixteen acylation reaction is room temperature, and the time is 1.5-2.5 h.
- 根据权利要求11所述的制备方法，其特征在于，所述第三亲核取代反应为先在室温条件下反应1.5～2.5h，之后在体系回流条件下反应1.5～2.5h。The preparation method according to claim 11, wherein the third nucleophilic substitution reaction is firstly reacted at room temperature for 1.5-2.5 h, and then reacted under the system reflux condition for 1.5-2.5 h.
- 权利要求1～10任一项所述美金刚脲类衍生物在制备治疗可溶性环氧化物酶介导的疾病的药物中的应用。The use of the memantamide derivative according to any one of claims 1 to 10 in the preparation of a medicament for treating diseases mediated by soluble epoxidase.
- 根据权利要求45所述的应用，其特征在于，所述可溶性环氧化物酶介导的疾病包括炎症性疾病、疼痛、心血管疾病、神经退行性疾病、糖尿病、糖尿病并发症、慢性肾炎、肾功能衰竭、慢性阻塞性肺疾病或肺动脉高压疾病。The use according to claim 45, wherein the soluble cyclooxygenase-mediated diseases include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, chronic nephritis, renal functional failure, chronic obstructive pulmonary disease, or pulmonary hypertension.
- 根据权利要求46所述的应用，其特征在于，所述炎症性疾病包括脓毒症、细胞因子风暴、炎症性肠病、慢性消化性溃疡或关节炎。The use according to claim 46, wherein the inflammatory disease comprises sepsis, cytokine storm, inflammatory bowel disease, chronic peptic ulcer or arthritis.
- 根据权利要求46所述的应用，其特征在于，所述疼痛包括炎性疼痛或神经性疼痛。The use of claim 46, wherein the pain comprises inflammatory pain or neuropathic pain.
- 根据权利要求46所述的应用，其特征在于，所述心血管疾病包括高血压、中风或动脉粥样硬化。The use of claim 46, wherein the cardiovascular disease comprises hypertension, stroke or atherosclerosis.
- 根据权利要求46所述的应用，其特征在于，所述神经退行性疾病包括帕金森综合征或阿尔兹海默病。The use of claim 46, wherein the neurodegenerative disease comprises Parkinson's syndrome or Alzheimer's disease.
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