CN117720610A - 齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用 - Google Patents
齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用 Download PDFInfo
- Publication number
- CN117720610A CN117720610A CN202311727153.1A CN202311727153A CN117720610A CN 117720610 A CN117720610 A CN 117720610A CN 202311727153 A CN202311727153 A CN 202311727153A CN 117720610 A CN117720610 A CN 117720610A
- Authority
- CN
- China
- Prior art keywords
- compound
- cdcl
- oleanolic acid
- nmr
- mannoside
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 title claims abstract description 35
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229940100243 oleanolic acid Drugs 0.000 title claims abstract description 35
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 title claims abstract description 35
- -1 Oleanolic acid mannoside compound Chemical class 0.000 title claims abstract description 29
- 239000003472 antidiabetic agent Substances 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title description 8
- 229940127003 anti-diabetic drug Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 12
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims 1
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 abstract description 5
- 238000012360 testing method Methods 0.000 abstract description 5
- 230000003178 anti-diabetic effect Effects 0.000 abstract description 3
- 125000002899 fatty ester group Chemical group 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 125000003423 D-mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 abstract 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
- TVZNFYXAPXOARC-UHFFFAOYSA-N Dl-norleucine methyl ester Chemical compound CCCCC(N)C(=O)OC TVZNFYXAPXOARC-UHFFFAOYSA-N 0.000 abstract 1
- 102000002072 Non-Receptor Type 1 Protein Tyrosine Phosphatase Human genes 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 49
- 238000006243 chemical reaction Methods 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- 238000012512 characterization method Methods 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 11
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 6
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 229940125846 compound 25 Drugs 0.000 description 6
- 229940125851 compound 27 Drugs 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- 239000003729 cation exchange resin Substances 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- VCNKUCWWHVTTBY-UHFFFAOYSA-N 18alpha-Oleanane Natural products C1CCC(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C)(C)CC5C4CCC3C21C VCNKUCWWHVTTBY-UHFFFAOYSA-N 0.000 description 2
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 2
- 241000486679 Antitype Species 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- SIOMFBXUIJKTMF-UHFFFAOYSA-N hypoglauterpenic acid Natural products C1CC(O)C(C)(C)C2=CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C SIOMFBXUIJKTMF-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- BPAWXSVOAOLSRP-UHFFFAOYSA-N oleanane Natural products CCCCCCCCCCCCCCCC(=O)OC1CCC2(C)C(CCC3(C)C2CC=C4C5CC(C)(C)CCC5(C)C(O)CC34C)C1(C)C BPAWXSVOAOLSRP-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 2
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229930182474 N-glycoside Natural products 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- SHZGCJCMOBCMKK-SXUWKVJYSA-N alpha-L-fucose Chemical compound C[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-SXUWKVJYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KAKKHKRHCKCAGH-UHFFFAOYSA-L disodium;(4-nitrophenyl) phosphate;hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[O-][N+](=O)C1=CC=C(OP([O-])([O-])=O)C=C1 KAKKHKRHCKCAGH-UHFFFAOYSA-L 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- NUKZAGXMHTUAFE-UHFFFAOYSA-N hexanoic acid methyl ester Natural products CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000008146 mannosides Chemical class 0.000 description 1
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
本发明公开了一类齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用，该化合物的结构式为式中R代表脂肪酯基或杂原子取代基，R′代表氢原子或乙酰基，其是以齐墩果酸C28‑氨基正己酸甲酯为起始原料，在其3位羟基引入D‑甘露糖基，而后将D‑甘露糖基的C6‑OH转化为脂肪酯基或杂原子取代基、其它位羟基裸露或转化为乙酰基而成。药理活性测试显示该类化合物对蛋白质酪氨酸磷酸酯酶1B具有很好的抑制活性，说明此类齐墩果酸甘露糖苷化合物可以作为一种新型的抗糖尿病药物而加以研究利用。
Description
技术领域
本发明属于化学药物技术领域，具体涉及齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用。
背景技术
糖尿病已经成为一种全球流行性疾病，患病率持续上升。尤以II型糖尿病(T2DM)居多，患者占到了糖尿病患者人群的90％～95％，发病原因是产生了胰岛素抵抗，糖代谢外周组织对胰岛素敏感性降低。多项研究已表明，蛋白酪氨酸磷酸酯酶1B(PTP1B)是抗II型糖尿病的有效药物靶点，通过抑制PTP1B的过表达可以有效改善胰岛素抵抗。但到目前为止，还没有上市的PTP1B抑制剂，现处于临床试验阶段的药物大多数来自于天然产物及其类似物。天然产物齐墩果酸(OA)自1931年Winterstein从油橄榄中分离出以来，已被发现具有较好的PTP1B抑制活性，但其水溶性差，导致生物利用度低，是其发展成为药物的重要阻碍，对齐墩果酸进行化学合成和改性研究是实现创新药物研究的关键环节和重要课题。研究表明齐墩果烷类化合物作为一类新型的PTP1B抑制剂具有显著的抗II型糖尿病活性，目前已成为抗II型糖尿病药物研究领域的热点之一。抑制PTP1B的活性是目前针对齐墩果酸抗糖尿病的结构修饰的主要策略，其结构修饰主要对C-3、A环、C环和C-28位的修饰。发明人在之前的专利(CN 108530508)中报道了齐墩果烷型氮糖苷化合物及其在制备治疗糖尿病药物中的应用，其中，活性最佳的化合物为L-岩藻糖基氮苷，其抑制PTP1B蛋白酶的活性仍有待提高。
现有技术对齐墩果酸进行修饰筛选PTP1B抑制剂的报道较多，而在齐墩果酸甘露糖糖基C-6′位点引入杂原子等基团开展PTP1B酶抑制活性的研究尚未见报道。
发明内容
本发明的目的是提供一类齐墩果酸甘露糖苷化合物，并为该化合物提供一种新用途。
针对上述目的，本发明所采用的齐墩果酸甘露糖苷化合物的结构式如下所示：
其中，R选自CH3COO、I、Br、F、CH3S、CH3COS、N3、HS、NH2、CH3(CH2)16COO、CH3(CH2)14COO、CH3(CH2)6COO、CH3(CH2)5COO中任意一种，R′选自H或CH3CO中任意一种。
进一步，R′代表CH3CO时，优选所述R选自I、Br、F、CH3COS、N3、HS、NH2、CH3(CH2)16COO、CH3(CH2)14COO中任意一种。
进一步，R′代表H时，优选所述R选自CH3COO、I、Br、F、CH3S、N3、HS、NH2、CH3(CH2)6COO中任意一种。
本发明齐墩果酸甘露糖苷化合物的合成路线和具体合成方法如下：
1、合成化合物25
以干燥二氯甲烷为溶剂，4A分子筛为除水剂，将化合物24与全苯甲酰基保护的甘露糖三氯乙酰亚胺酯按摩尔比为1:1～3.5混合，在0℃及氮气保护下加入三氟甲基磺酸三甲基硅酯(TMSOTf)，化合物24与TMSOTf的摩尔比为1:0.1～0.2，室温搅拌反应1h；反应完毕后，过滤，减压蒸除溶剂，浓缩物经硅胶柱层析，得到化合物25。
2、合成化合物26
以甲醇和二氯甲烷体积比1～2:1的混合液为溶剂，将化合物25与甲醇钠按摩尔比为1:0.05～0.5，室温搅拌反应1h；反应完毕后，加入阳离子交换树脂中和至中性，过滤，减压蒸除溶剂，浓缩物经硅胶柱层析，得到化合物26。
3、合成化合物27
以干燥的吡啶为溶剂，将化合物26与三苯甲基氯(TrCl)按摩尔比为1:1～3，在80℃下搅拌反应10h；反应完毕后分离纯化，所得产物与醋酸酐(Ac2O)按摩尔比为1:3～6.5，室温反应2h；反应完毕后，减压蒸除溶剂，浓缩物溶解于二氯甲烷中，依次用1M盐酸溶液、饱和碳酸氢钠溶液和饱和食盐水溶液洗涤，无水硫酸钠干燥，过滤，浓缩；将浓缩物溶解于二氯甲烷中，与三氯化铁按摩尔比为1:2～4.5室温反应2～3h；反应完毕后，减压蒸除溶剂，硅胶柱层析，所得产物溶解于干燥吡啶中，与对甲苯磺酰氯(TsCl)按摩尔比为1:1～5，在50℃下搅拌反应3h；反应完毕后，减压蒸除溶剂，浓缩物经硅胶柱层析，得到化合物27。
4、合成齐墩果酸甘露糖苷化合物
当R选自CH3COO、R′选自CH3CO时，所述齐墩果酸甘露糖苷化合物的合成方法为：以干燥的吡啶为溶剂，将化合物26与醋酸酐按摩尔比为1:4～7.5，室温反应10h；反应完毕后，减压蒸除溶剂，浓缩物溶解于二氯甲烷中，依次用1M盐酸溶液、饱和碳酸氢钠溶液和饱和食盐水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，得到化合物1。
当R选自I、Br、F、CH3S、CH3COS、N3、HS、NH2、CH3(CH2)16COO、CH3(CH2)14COO、CH3(CH2)6COO、CH3(CH2)5COO中任意一种，R′选自CH3CO时，所述齐墩果酸甘露糖苷化合物的合成方法为：以无水乙腈或N,N-二甲基甲酰胺或二氯甲烷为溶剂，将化合物27与四丁基碘化铵或四丁基溴化铵或四丁基氟化铵或甲硫醇钠或硫代乙酸钾或叠氮化钠或硫化氢钠或氨基钠或硬脂酸或软脂酸或正辛酸或正庚酸按摩尔比为1:2～5，在0～90℃搅拌反应5～10h；反应结束后，减压浓缩，硅胶柱层析，依次得到齐墩果酸甘露糖苷化合物2～13。
当R选自I、Br、F、CH3S、CH3COS、N3、HS、NH2、CH3(CH2)16COO、CH3(CH2)14COO、CH3(CH2)6COO、CH3(CH2)5COO中任意一种，R′选自H时，所述齐墩果酸甘露糖苷化合物的合成方法为：以无水甲醇或N,N-二甲基甲酰胺或二氯甲烷为溶剂，分别将化合物2～13与甲醇钠或二乙胺按摩尔比为1:0.5～6，室温下搅拌反应1～3h；反应结束后，减压浓缩，硅胶柱层析，依次得到齐墩果酸甘露糖苷化合物14～23。
本发明齐墩果酸甘露糖苷化合物在制备治疗抗糖尿病药物中的用途，其按常规药用制剂，与药学上可接受的载体按照各种制剂的常规制备工艺制成，可以是片剂、颗粒剂、胶囊剂。
本发明的有益效果如下：
本发明以齐墩果酸C28-氨基正己酸甲酯为母体，在其3位羟基引入甘露糖后，将甘露糖C6-OH转化为不同的杂原子或脂肪酯基制备齐墩果酸甘露糖苷化合物。经药理活性检测，此类化合物对蛋白质酪氨酸磷酸酯酶1B显示出很好的抑制活性，可以用于制备治疗糖尿病的药物。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围不仅限于这些实施例。
实施例1
制备齐墩果烷型氮糖苷化合物1～23
1、合成化合物25
在0℃、N2保护的条件下，将化合物24(920mg，1.57mmol)和全苯甲酰化甘露糖三氯乙酰亚胺酯(3.50g，4.73mmol)溶解于80mL无水CH2Cl2中，并加入活化后的分子筛，搅拌30min，分子筛充分吸收反应瓶中的水分后，加入TMSOTf(290μL，0.157mmol)，于室温下搅拌1h，TLC板(EtOAc/CH2Cl2＝1/10，V/V)检测反应进程至完全后，用Et3N淬灭反应；抽滤，真空浓缩后通过硅胶柱层析(洗脱剂：EtOAc/PE＝1/2.5，V/V)纯化，得到白色固体化合物25(1.75g，95.5％)，其结构表征数据为：1H NMR(400MHz,CDCl3)δ7.23-8.09(m,20H,Ph-H),6.11(t,J＝10.1Hz,1H,N-H),5.96(t,J＝5.5Hz,1H,H-12),5.91(dd,J＝10.5,2.7Hz,1H,H-3’),5.62(d,J＝3.0Hz,1H,H-2’),5.38(t,J＝4.5Hz,1H,),5.28(s,1H,H-1’),4.69(d,J＝12.0Hz,1H,H-6’-1),4.60–4.52(m,1H),4.47(dd,J＝12.1,4.7Hz,1H,H-6’-2),3.67(s,3H,H-37),3.38(dt,J＝12.9,7.1Hz,2H),3.01(dd,J＝13.3,6.4Hz,1H),2.51(dd,J＝13.2,4.1Hz,1H),2.32(t,J＝7.4Hz,2H),1.95(d,J＝13.3Hz,2H),1.92(s,1H),1.80(dd,J＝28.4,14.2Hz,3H),1.71(s,3H),1.66(d,J＝9.2Hz,3H),1.64–1.42(m,10H),1.35(q,J＝8.1Hz,4H),1.25(dt,J＝23.7,6.7Hz,2H),1.15(2s,6H),0.97(s,6H),0.91(s,3H),0.91(s,3H),0.78(s,3H)；13C NMR(101MHz,CDCl3)δ178.20(C-28),174.03(C-36),166.19,165.64,165.60,165.58,145.15(C-13),133.47,133.21,133.07,129.92,129.85,129.77,129.72,129.41,129.12,128.99,128.61,128.46,128.41,128.37,128.34,122.68(C-12),94.54(C-1’),84.49(C-3),71.62,70.25,69.51,66.97,63.07,55.48,51.54,47.55,46.83,46.28,42.34,42.12,39.43,39.24,38.52,38.06,36.91,34.17,33.92,33.01,32.53,32.38,30.75,29.08,28.93,27.32,26.61,25.81,24.55,23.79,23.61,22.15,18.30,16.96,16.69,15.41；HRMS(ESI)：m/z理论值C71H87NO13[M+Na]+:1084.6075,实测值1084.5854。
2、合成化合物26
将化合物25(1.75g，1.50mmol)溶于CH3OH-CH2Cl2混合溶剂(150mL，V/V＝1/1)中，加入NaOMe(8mg，0.15mmol)，室温搅拌反应1h，TLC板(MeOH/CH2Cl2＝1/10，V/V)检测反应进程至完全后，用阳离子交换树脂调节至中性。过滤，真空浓缩后硅胶柱层析(洗脱剂：MeOH/CH2Cl2＝1/10，V/V)纯化得到白色固体化合物26(0.98g，87.2％)，其结构表征数据为：1HNMR(400MHz,CDCl3)δ5.94(t,J＝5.9Hz,1H,H-12),5.37(s,J＝5Hz,1H),5.12(d,J＝4.9Hz,1H),4.99(s,2H),3.95(d,J＝10.7Hz,2H),3.83(d,J＝9.9Hz,2H),3.74(d,J＝11.5Hz,1H),3.67(s,J＝1.8Hz,3H,H-37),3.63(s,1H),3.37(dq,J＝13.8,7.0Hz,1H),3.22–3.14(m,1H),3.04–2.94(m,1H),2.61(s,1H),2.55–2.47(m,1H),2.32(td,J＝7.4,1.8Hz,2H),1.98(d,J＝12.7Hz,1H),1.91(d,J＝9.5Hz,2H),1.74(d,J＝14.1Hz,2H),1.65(d,J＝7.4Hz,3H),1.62(s,2H),1.59–1.29(m,13H),1.23(dd,J＝23.5,10.0Hz,6H),1.15(s,3H),0.92(s,J＝12.7Hz,12H),0.76(s,6H)；13C NMR(101MHz,CDCl3)δ178.18(C-28),174.05(C-36),145.16(C-13),122.59(C-12),96.39(C-1’),82.67(C-3),72.74,71.95,71.86,66.19,60.96,55.35,51.56,47.53,46.81,46.25,42.26,42.07,39.39,39.23,38.34,38.07,36.87,34.13,33.91,33.03,32.55,32.39,30.75,29.10,28.70,27.29,26.58,25.79,24.53,23.77,23.62,21.74,18.24,16.94,16.55,15.41；HRMS(ESI)m/z理论值C43H71NO9[M+H]+:746.5207,实测值746.5067。
3、合成化合物27
将化合物26(0.98g，1.31mmol)和TrCl(1.07g，3.93mmol)溶解在10mL吡啶中，加热至80℃，反应10h，TLC板检测反应进程(MeOH/CH2Cl2＝1/20，V/V)，反应完成后加入甲苯蒸出吡啶，残渣溶于CH2Cl2中，用1M盐酸溶液萃取反应液除去吡啶，收集有机相，用饱和碳酸氢钠溶液和饱和食盐水溶液依次各洗涤3次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂：MeOH/CH2Cl2＝1/20，V/V)纯化后，将所得产物(1.00g，1.02mmol)在0℃、N2保护的条件下溶于10mL吡啶中，加入Ac2O(485μL，5mmol)，在室温下反应2h，TLC板(EtOAc/PE＝1/1.5，V/V)检测反应进程至完全后，蒸除吡啶，残渣溶于CH2Cl2中，用1M盐酸溶液萃取反应液除去吡啶，收集有机相，用饱和碳酸氢钠溶液和饱和食盐水溶液依次各洗涤3次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂：EtOAc/PE＝1/1.5，V/V)纯化后，所得产物(1.08g，0.97mmol)溶于50mLCH2Cl2中，加入FeCl3·6H2O(524mg，1.94mmol)，室温下反应2.5h，TLC(EtOAc/PE＝1/1，V/V)检测反应进程，反应完毕后减压浓缩，乙酸乙酯溶解，纯化水洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析(洗脱剂：EtOAc/PE＝1/1，V/V)纯化后将所得产物(768mg，0.88mmol)溶解在5mL吡啶中，加入对甲苯磺酰氯(505mg，2.65mmol)50℃下搅拌反应3h，TLC(EtOAc/PE＝1/1，V/V)检测反应完全后，加入甲苯真空浓缩，残渣溶于CH2Cl2中，用1M盐酸溶液萃取反应液除去吡啶，收集有机相，用饱和碳酸氢钠溶液和饱和食盐水溶液依次各洗涤3次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂：EtOAc/PE＝1/1，V/V)纯化，得到白色固体化合物27(761mg，62.7％)，其结构表征数据为：1H NMR(400MHz,CDCl3)δ7.82–7.75(m,2H),7.34(d,J＝7.9Hz,2H),5.94(t,J＝5.6Hz,1H),5.37(d,J＝3.8Hz,1H),5.29(dt,J＝10.3,2.2Hz,1H),5.17(t,J＝10.1Hz,1H),5.11(d,J＝3.1Hz,1H),4.91(s,1H),4.18–4.03(m,3H),3.67(s,3H),3.37(dq,J＝13.6,6.9Hz,1H),3.19(dd,J＝11.6,3.9Hz,1H),2.99(dq,J＝12.6,6.3Hz,1H),2.55–2.46(m,1H),2.45(s,3H),2.32(td,J＝7.5,1.7Hz,2H),2.13(d,J＝1.7Hz,3H),1.95–1.87(m,2H),1.83–1.70(m,6H),1.70–1.64(m,4H),1.62(d,J＝6.9Hz,2H),1.50(tq,J＝19.0,6.7,4.6Hz,9H),1.39–1.27(m,5H),1.24(d,J＝17.5Hz,1H),1.17(s,4H),1.04(d,J＝14.3Hz,1H),0.98(s,3H),0.91(d,J＝4.1Hz,11H),0.82–0.79(m,3H),0.76(s,4H)；13C NMR(101MHz,CDCl3)δ178.18,174.03,170.26,169.87,169.76,145.21,144.92,132.74,129.79,128.11,122.59,94.22,84.23,70.53,69.03,68.93,68.25,66.31,55.21,51.54,47.48,46.80,46.26,42.32,42.11,39.39,39.21,38.36,37.93,36.84,34.15,33.92,33.01,32.51,32.32,30.75,29.09,28.76,27.29,26.60,25.79,24.55,23.79,23.61,21.95,21.70,20.98,20.72,20.66,18.23,16.94,16.51,15.37；HRMS(ESI)m/z理论值C56H83NO14S[M+H]+:1026.5534,实测值1026.5534。
4、齐墩果酸甘露糖苷化合物
将化合物26(500mg，0.65mmol)溶于10mL吡啶中，加入Ac2O(485μL，5mmol)，在室温下反应10h，TLC板(EtOAc/PE＝1/2，V/V)检测反应进程至完全后，蒸除吡啶，残渣溶于CH2Cl2中，用1M盐酸溶液萃取反应液除去吡啶，收集有机相，用饱和碳酸氢钠溶液和饱和食盐水溶液依次各洗涤3次，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂，EtOAc/PE＝1/2，V/V)纯化，得到化合物1(712mg，99％)，其结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(d,J＝6.1Hz,1H),5.39–5.24(m,3H),5.15(d,J＝2.9Hz,1H),4.98(s,1H),4.25(dd,J＝12.9,5.6Hz,1H),4.16–4.08(m,2H),3.67(s,3H),3.36(dq,J＝13.9,7.0Hz,1H),3.27–3.18(m,1H),2.99(dt,J＝10.6,4.8Hz,1H),2.48(t,J＝12.8Hz,1H),2.32(t,J＝7.4Hz,2H),2.16(s,3H),2.10(s,3H),2.06(s,3H),2.00(d,J＝2.0Hz,3H),1.92(dd,J＝13.7,8.1Hz,4H),1.81–1.64(m,5H),1.63(d,J＝6.4Hz,2H),1.50(ddd,J＝32.0,17.4,9.5Hz,7H),1.34(td,J＝20.1,17.2,11.2Hz,5H),1.23(d,J＝17.2Hz,3H),1.18(s,1H),1.15(s,3H),1.01(s,3H),0.92(d,J＝10.8Hz,10H),0.86(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.15,174.01,170.66,170.28,169.90,169.83,145.17,122.62,94.69,84.67,70.71,69.21,69.09,66.22,62.60,55.48,51.52,47.55,46.80,46.26,42.32,42.09,39.40,39.21,38.39,38.07,36.86,34.14,33.91,33.00,32.52,32.37,30.74,29.70,29.08,28.75,27.29,26.60,25.71,24.54,23.77,23.60,22.17,20.98,20.77,20.75,20.73,18.26,16.94,16.51,15.36；HRMS(ESI)m/z理论值C51H79NO13[M+Na]+:936.5449,实测值936.5262。
以2mL无水乙腈为溶剂，将化合物27(200mg，0.20mmol)与四丁基碘化铵(330mg，0.98mmol)在90℃下回流反应10h。反应完全后，减压浓缩，硅胶柱层析，得到白色固体化合物2(198mg，98％)。
上述化合物2的合成过程中，用等摩尔四丁基溴化铵、四丁基氟化铵、甲硫醇钠、硫代乙酸钾、叠氮化钠、硫化氢钠、氨基钠、硬脂酸、软脂酸、正辛酸、正庚酸分别替换四丁基碘化铵，其他步骤相同，依次得到化合物3～13。
化合物2的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.5Hz,1H),5.38(d,J＝3.8Hz,1H),5.37–5.29(m,1H),5.14(s,2H),5.03(s,1H),3.90(t,J＝8.9Hz,1H),3.67(s,3H),3.42–3.27(m,3H),3.22–3.13(m,1H),2.99(dq,J＝12.4,6.3Hz,1H),2.54–2.45(m,1H),2.15(s,3H),2.08(s,3H),1.99(s,3H),1.96–1.88(m,3H),1.82–1.70(m,3H),1.65(q,J＝7.3,6.8Hz,6H),1.60–1.24(m,1H),1.16(s,3H),1.06(s,3H),0.93(s,3H),0.90(s,6H),0.84(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.15,174.01,170.25,169.91,169.87,145.17,122.63,93.85,83.36,70.68,70.27,70.08,68.83,64.38,55.39,51.53,47.50,46.82,46.26,42.33,42.11,39.40,39.21,38.50,37.96,36.86,34.15,33.92,33.00,32.51,32.33,30.74,30.65,29.71,29.09,27.31,26.60,25.78,24.55,23.80,23.60,23.57,21.58,21.04,20.98,20.86,20.73,19.13,18.24,16.95,16.54,15.39,13.72,4.46；HRMS(ESI)m/z理论值C49H76INO11[M+H]+:982.4463,实测值982.4466.
化合物3的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.94(dd,J＝6.4,4.6Hz,1H),5.39(dd,J＝7.3,3.6Hz,1H),5.37–5.33(m,1H),5.32(s,1H),5.24(t,J＝9.9Hz,1H),5.17(dd,J＝3.3,1.8Hz,1H),5.05(d,J＝1.8Hz,1H),4.15(ddd,J＝10.0,7.1,2.7Hz,1H),3.69(s,3H),3.53–3.31(m,4H),3.01(dtd,J＝13.5,7.1,4.4Hz,1H),2.52(dd,J＝13.2,4.3Hz,1H),2.34(t,J＝7.4Hz,2H),2.17(s,3H),2.10(s,3H),2.02(s,3H),2.00–1.90(m,3H),1.77–1.70(m,3H),1.65–1.44(m,9H),1.44–1.29(m,6H),1.28(d,J＝2.4Hz,6H),1.18(s,3H),1.07(s,3H),0.95(s,3H),0.92(s,6H),0.86(s,3H),0.78(s,3H)；13C NMR(101MHz,CDCl3)δ178.15,174.00,170.25,169.88,145.16,122.62,93.99,83.71,70.61,70.33,69.02,68.76,55.33,51.52,47.49,46.81,46.26,42.33,42.11,39.40,39.21,38.45,37.96,36.86,34.15,33.91,32.99,32.52,32.33,31.71,30.74,29.08,29.04,27.30,26.60,25.77,24.54,23.79,23.60,23.57,21.73,20.95,20.82,20.72,18.24,16.94,16.52,15.39；HRMS(ESI)m/z理论值C49H76BrNO11[M+H]+:936.0550,实测值936.4506。
化合物4的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.6Hz,1H),5.40–5.34(m,2H),5.29(t,J＝10.1Hz,1H),5.16(d,J＝3.1Hz,1H),4.98(d,J＝12.1Hz,1H),4.54(d,J＝14.5Hz,1H),4.41(s,1H),4.11(dd,J＝12.7,4.9Hz,1H),3.67(s,3H),3.36(m,J＝13.8,7.0Hz,1H),3.25(dt,J＝11.4,5.6Hz,1H),2.99(td,J＝10.9,9.2,5.2Hz,1H),2.50(dd,J＝13.1,4.2Hz,1H),2.32(t,J＝7.4Hz,2H),2.15(s,3H),2.11(s,3H),2.07(s,3H),2.05–1.88(m,6H),1.78(d,J＝13.4Hz,1H),1.73(s,2H),1.69(s,2H),1.67–1.58(m,5H),1.53–1.37(m,6H),1.37–1.20(m,7H),1.18(s,2H),1.15(s,3H),1.02–0.85(m,12H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.15,174.00,170.29,169.92,169.81,145.16,122.61,94.24,84.07,70.55,69.91,69.72,69.15,65.78,65.71,55.29,51.52,47.50,46.80,46.26,42.32,42.10,39.40,39.21,38.41,38.13,37.98,36.86,36.80,34.15,33.91,33.00,32.52,32.35,30.74,29.08,28.78,28.00,27.29,26.60,25.74,24.54,23.78,23.60,21.94,21.05,20.96,20.75,20.73,18.25,16.93,16.52,16.38,15.38；HRMS(ESI)m/z理论值C49H76FNO11[M+H+:874.5402,实测值874.5310。
化合物5的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.8Hz,1H),5.37(t,J＝5.4Hz,1H),5.35–5.27(m,1H),5.21(td,J＝9.9,1.8Hz,1H),5.14(t,J＝2.6Hz,1H),4.97(s,1H),4.07(dd,J＝10.1,5.3Hz,1H),3.67(s,3H),3.37(dt,J＝13.5,6.9Hz,1H),3.34–3.26(m,1H),2.98(dt,J＝11.0,5.6Hz,1H),2.69–2.63(m,2H),2.54–2.45(m,1H),2.32(td,J＝7.4,1.8Hz,2H),2.15(2s,6H),2.06(s,3H),1.95(2s,6H),1.82–1.59(m,10H),1.57(d,J＝9.2Hz,3H),1.51–1.42(m,4H),1.42–1.19(m,8H),1.16(s,3H),1.07(s,3H),0.92(2s,9H),0.84(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.16,174.00,170.30,170.06,169.94,145.16,122.65,93.88,83.57,71.03,70.75,69.40,69.19,55.34,51.52,47.48,46.82,46.26,42.33,42.11,39.40,39.21,38.42,37.98,36.86,36.19,34.15,33.91,32.99,32.51,32.33,30.74,29.08,29.03,27.30,26.60,25.78,24.54,23.80,23.60,21.79,20.99,20.90,20.75,18.25,16.94,16.53,15.37；HRMS(ESI)m/z理论值C50H79NO11S[M+H]+:902.5455,实测值902.5286。
化合物6的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.92(t,J＝5.6Hz,1H),5.38(t,J＝5.2Hz,1H),5.29(dt,J＝10.1,2.3Hz,1H),5.24–5.15(m,1H),5.13(d,J＝2.9Hz,1H),4.92(s,1H),4.03(td,J＝10.0,7.6Hz,1H),3.67(s,3H),3.36(dq,J＝13.7,6.9Hz,1H),3.24(ddd,J＝16.0,6.9,3.2Hz,2H),3.00(dt,J＝14.6,6.9Hz,2H),2.50(dd,J＝13.1,4.3Hz,1H),2.32(dd,J＝7.4,1.6Hz,5H),2.13(2s,6H),1.99(s,3H),1.92(dt,J＝9.2,5.2Hz,3H),1.74(q,J＝12.8,12.1Hz,2H),1.65(dd,J＝14.9,6.4Hz,6H),1.59–1.49(m,5H),1.49(s,1H),1.49–1.41(m,7H),1.41–1.28(m,3H),1.27(d,J＝12.3Hz,1H),1.16(s,3H),0.98(s,3H),0.92(s,3H),0.91(s,6H),0.82(s,3H),0.76(s,3H)；13CNMR(101MHz,CDCl3)δ194.77,178.11,174.00,170.28,170.17,169.89,145.16,122.64,94.24,84.01,70.74,69.96,69.12,68.69,55.54,51.52,47.57,46.82,46.26,42.32,42.09,39.41,39.21,38.37,38.06,36.86,34.15,33.91,33.00,32.52,32.40,30.74,30.65,30.44,29.09,28.86,27.29,26.60,25.72,24.54,23.78,23.60,21.89,21.00,20.87,20.74,18.24,16.94,16.46,15.36；HRMS(ESI)m/z理论值C51H79NO12S[M+H]+:930.5323,实测值930.5329。
化合物7的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.6Hz,1H),5.37(t,J＝5.6Hz,1H),5.33(dt,J＝10.2,2.2Hz,1H),5.29–5.19(m,1H),5.15(d,J＝3.2Hz,1H),4.99(s,1H),4.13–4.05(m,1H),3.67(s,3H),3.36(dd,J＝13.6,6.7Hz,2H),3.26(td,J＝9.9,8.2,3.0Hz,2H),2.99(dq,J＝12.5,6.4Hz,1H),2.50(dd,J＝13.2,4.3Hz,1H),2.32(t,J＝7.4Hz,2H),2.16(d,J＝1.6Hz,3H),2.05(d,J＝1.6Hz,3H),2.00(d,J＝1.6Hz,3H),1.98–1.88(m,3H),1.82–1.71(m,3H),1.69–1.61(m,7H),1.60–1.27(m,14H),1.27–1.17(m,3H),1.16(s,3H),1.05(s,4H),0.93(s,3H),0.90(s,3H),0.85(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.15,174.00,170.27,169.93,169.90,145.17,122.62,94.11,84.21,70.74,70.58,68.98,67.25,55.32,51.52,51.18,47.49,46.81,46.27,42.33,42.11,39.40,39.21,38.39,37.98,36.86,34.15,33.91,32.99,32.52,32.33,30.74,29.08,28.74,27.30,26.60,25.76,24.54,23.79,23.60,21.94,20.96,20.77,20.73,18.26,16.94,16.52,15.37；HRMS(ESI)m/z理论值C49H76N4O11[M+H]+:897.5589,实测值897.5430。
化合物8的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.94(t,J＝5.5Hz,1H),5.36(d,J＝3.9Hz,1H),5.32(dd,J＝9.9,3.3Hz,1H),5.22–5.11(m,2H),4.95(s,1H),4.11(dt,J＝10.8,5.8Hz,1H),3.67(s,3H),3.36(dq,J＝13.8,7.0Hz,1H),3.27(dd,J＝11.6,4.2Hz,1H),3.05–2.94(m,2H),2.91(d,J＝5.7Hz,2H),2.32(t,J＝7.4Hz,2H),2.15(s,3H),2.07(s,3H),1.99(s,3H),1.92(td,J＝17.6,17.0,8.8Hz,4H),1.81–1.58(m,9H),1.58–1.51(m,5H),1.49(s,2H),1.44(dd,J＝21.4,9.5Hz,3H),1.33(dt,J＝17.9,9.2Hz,6H),1.15(s,3H),1.05(s,3H),0.92(s,3H),0.91(s,6H),0.84(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.11,174.01,170.22,170.07,169.85,145.14,122.62,94.17,84.01,70.72,69.43,69.26,69.04,55.32,51.52,47.49,46.84,46.24,42.27,42.09,41.74,39.40,39.23,38.43,38.01,36.85,34.15,33.91,33.01,32.55,32.34,30.74,29.70,29.11,29.09,27.32,26.59,25.78,24.54,23.80,23.61,21.93,20.96,20.88,20.73,18.26,16.94,16.56,15.35；HRMS(ESI)m/z理论值C49H77NO11S[M+Na]+:910.5115,实测值909.9888。
化合物9的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.03(t,J＝6.4Hz,1H),5.93(t,J＝5.6Hz,1H),5.37(s,1H),5.23(dt,J＝10.2,2.4Hz,1H),5.15(d,J＝3.3Hz,1H),4.85(s,1H),4.14(d,J＝4.3Hz,1H),4.00(dd,J＝14.8,8.0Hz,1H),3.88–3.80(m,1H),3.67(s,3H),3.36(dq,J＝13.8,7.0Hz,1H),3.15(dd,J＝12.3,4.1Hz,2H),2.99(dq,J＝12.7,6.4Hz,1H),2.50(dd,J＝13.2,4.3Hz,1H),2.32(t,J＝7.4Hz,2H),2.14–2.03(m,9H),2.01–1.92(m,2H),1.90(d,J＝4.2Hz,2H),1.79(s,1H),1.71–1.58(m,10H),1.56–1.52(m,3H),1.52–1.47(m,3H),1.47–1.40(m,2H),1.33(ddd,J＝28.3,19.4,11.2Hz,6H),1.15(s,3H),0.98(s,3H),0.92(s,3H),0.90(s,6H),0.82(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.12,174.01,172.21,170.30,170.09,145.17,122.63,95.24,84.44,72.50,71.22,70.49,65.47,55.52,51.53,47.57,46.83,46.25,42.30,42.09,40.11,39.41,39.22,38.39,38.14,36.87,34.15,33.91,33.01,32.52,32.38,30.74,29.07,28.67,27.28,26.59,25.73,24.54,23.78,23.60,23.58,23.04,22.21,20.96,18.25,16.92,16.49,15.34；HRMS(ESI)m/z理论值C49H78N2O11[M+H]+:771.5684,实测值771.5525。
化合物10的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.6Hz,1H),5.40–5.23(m,3H),5.16(d,J＝3.1Hz,1H),4.98(s,1H),4.10(dd,J＝26.2,16.2Hz,3H),3.67(s,3H),3.36(dt,J＝14.0,7.0Hz,1H),3.23(dd,J＝11.8,4.1Hz,1H),3.00(dt,J＝13.4,6.5Hz,1H),2.49(d,J＝10.6Hz,1H),2.33(q,J＝8.6,7.9Hz,4H),2.16(s,3H),2.05(s,3H),2.00(s,3H),1.93(dd,J＝16.0,5.8Hz,4H),1.74(dd,J＝25.8,12.7Hz,4H),1.65(dd,J＝14.9,6.3Hz,9H),1.59–1.28(m,18H),1.25(s,20H),1.15(s,4H),1.13–1.03(m,2H),1.01(s,3H),0.95–0.86(m,12H),0.84(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.12,173.98,173.40,170.23,169.90,169.76,145.16,122.61,94.48,84.37,70.71,69.25,69.17,66.29,62.46,55.52,51.50,49.11,47.57,46.81,46.26,42.33,42.08,39.41,39.21,38.40,38.07,36.87,34.14,33.97,33.90,32.99,32.53,32.39,31.92,30.73,29.70,29.66,29.52,29.36,29.32,29.22,29.08,28.80,27.30,26.59,25.72,25.64,24.95,24.82,24.53,23.78,23.59,22.69,22.06,20.94,20.74,20.71,18.26,16.94,16.50,15.35,14.12；HRMS(ESI)m/z理论值C67H111NO13[M+H]+:1038.8134,实测值1038.7924。
化合物11的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.6Hz,1H),5.40–5.23(m,3H),5.16(d,J＝3.0Hz,1H),4.97(s,1H),4.23(dd,J＝12.5,5.6Hz,1H),4.12(dd,J＝14.1,8.4Hz,2H),3.67(s,3H),3.37(dq,J＝13.8,6.9Hz,1H),3.27–3.18(m,1H),3.00(dt,J＝13.4,6.3Hz,1H),2.54–2.45(m,1H),2.33(q,J＝8.0,7.1Hz,4H),2.16(s,3H),2.05(s,3H),2.00(s,3H),1.96–1.88(m,3H),1.74(dd,J＝25.3,12.6Hz,3H),1.68–1.61(m,13H),1.55(s,2H),1.49(dt,J＝14.7,7.1Hz,5H),1.30–1.27(m,6H),1.25(s,16H),1.21–0.99(m,10H),0.95–0.85(m,13H),0.84(s,3H),0.76(s,4H)；13C NMR(101MHz,CDCl3)δ178.11,173.99,173.40,170.24,169.90,169.77,145.17,122.61,94.49,84.37,70.71,69.25,69.17,66.30,62.46,55.52,51.50,47.58,46.82,46.26,42.33,42.08,39.42,39.21,38.40,38.07,36.87,34.14,33.96,33.91,32.99,32.53,32.39,31.93,30.73,29.71,29.69,29.66,29.64,29.52,29.36,29.32,29.22,29.08,28.80,27.30,26.59,25.72,24.95,24.82,24.54,23.78,23.59,22.69,22.06,20.95,20.74,20.72,18.27,16.94,16.51,15.36,14.12；HRMS(ESI)m/z理论值C65H107NO13[M+Na]+:1132.7640,实测值1132.7429。
化合物12的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.5Hz,1H),5.37(t,J＝5.2Hz,1H),5.35-5.25(m,2H),5.16(s,1H),4.98(s,1H),4.20(d,J＝5.1Hz,1H),4.12(dd,J＝14.1,8.5Hz,2H),3.67(s,3H),3.54–3.42(m,1H),3.37(dq,J＝13.7,6.9Hz,1H),3.23(dd,J＝11.7,4.1Hz,1H),2.99(dq,J＝12.6,6.4Hz,1H),2.50(dd,J＝13.5,4.3Hz,1H),2.39–2.28(m,4H),2.16(s,3H),2.05(s,3H),2.00(s,3H),1.97–1.89(m,5H),1.81–1.60(m,10H),1.58(d,J＝4.6Hz,1H),1.55(s,3H),1.52(d,J＝6.9Hz,1H),1.51–1.38(m,2H),1.42–1.20(m,18H),1.15(s,3H),1.01(s,3H),0.93(s,3H),0.9(s,6H),0.84(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.15,174.02,173.44,170.28,169.94,169.80,156.85,145.16,122.61,94.45,84.32,70.68,69.23,69.13,66.25,62.44,55.49,51.55,49.13,47.56,46.80,46.25,42.31,42.07,39.39,39.22,38.39,38.05,36.85,34.14,33.96,33.91,33.00,32.51,32.36,31.69,30.74,29.16,29.08,28.96,28.80,27.29,26.60,25.72,25.63,24.96,24.81,24.54,23.76,23.60,23.57,22.62,22.03,20.99,20.78,20.75,18.25,16.93,16.51,15.37,14.11；HRMS(ESI)m/z理论值C57H91NO13[M+H]+:998.6490,实测值998.6542。
化合物13的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.93(t,J＝5.6Hz,1H),5.41–5.23(m,3H),5.16(d,J＝3.1Hz,1H),4.98(s,1H),4.28–4.08(m,4H),3.67(s,3H),3.54–3.43(m,1H),3.37(dq,J＝13.7,6.9Hz,1H),3.23(dd,J＝11.7,4.0Hz,1H),2.99(dq,J＝12.5,6.6Hz,1H),2.50(dd,J＝12.3,4.6Hz,1H),2.39–2.28(m,4H),2.16(s,3H),2.05(s,3H),2.00(s,3H),1.97–1.88(m,5H),1.81–1.60(m,13H),1.53–1.39(m,6H),1.39–1.20(m,10H),1.15(s,3H),1.01(s,3H),0.95–0.88(m,12H),0.84(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.14,174.02,173.43,170.27,169.93,169.79,156.78,145.16,122.61,94.45,84.32,70.68,69.23,69.13,66.24,62.43,55.49,51.54,49.10,47.56,46.79,46.25,42.31,42.07,39.39,39.21,38.39,38.05,36.85,34.14,33.98,33.91,33.00,32.51,32.36,31.47,30.74,29.71,29.08,28.86,28.79,27.29,26.60,25.72,25.64,24.97,24.76,24.54,23.77,23.60,22.51,22.03,20.98,20.77,20.75,18.25,16.93,16.51,15.37,14.06；HRMS(ESI)m/z理论值C56H89NO13[M+H]+:984.6412,实测值984.6227。
将化合物2(100mg，0.12mmol)溶于5mL无水甲醇中，并加入(5mg，0.01mmol)甲醇钠，室温下搅拌反应1.5h；反应结束后，用阳离子交换树脂中和至中性，过滤，减压浓缩，硅胶柱层析，得到齐墩果酸甘露糖苷化合物14。
上述化合物14的合成过程中，将化合物2依次用等摩尔的化合物3～7替换，相应得到齐墩果酸甘露糖苷化合物15～19。
上述化合物14的合成过程中，将化合物2依次用等摩尔的化合物10～13替换，甲醇钠用等摩尔二乙胺替换，相应得到齐墩果酸甘露糖苷化合物20～23。
化合物14的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.02(t,J＝5.7Hz,1H),5.38(s,1H),5.05(s,1H),3.88(s,1H),3.84(d,J＝9.1Hz,1H),3.67(s,3H),3.64–3.61(m,1H),3.56(dd,J＝16.1,8.6Hz,3H),3.43(s,1H),3.35(dq,J＝14.4,7.4,6.9Hz,3H),2.99(dt,J＝13.4,6.2Hz,1H),2.92–2.87(m,1H),2.48(dd,J＝12.9,4.3Hz,1H),2.32(td,J＝7.4,1.8Hz,2H),1.98(d,J＝14.1Hz,1H),1.93–1.88(m,2H),1.81(d,J＝9.8Hz,2H),1.72(d,J＝6.1Hz,1H),1.68–1.61(m,4H),1.59(d,J＝15.8Hz,5H),1.50(dd,J＝17.3,10.7Hz,5H),1.43(s,1H),1.38–1.30(m,4H),1.30–1.21(m,3H),1.16(s,3H),1.01(s,3H),0.92(s,3H),0.90(s,6H),0.77(s,3H),0.75(s,3H)；13C NMR(101MHz,CDCl3)δ178.67,174.10,145.04,122.80,95.78,82.04,72.04,71.85,71.71,71.09,55.35,51.60,47.47,46.76,46.29,42.32,42.10,39.39,39.33,38.42,37.99,36.86,34.12,33.90,32.98,32.46,32.31,30.73,28.98,28.93,27.26,26.56,25.78,24.50,23.81,23.58,21.40,18.21,16.95,16.55,15.43,7.87；HRMS(ESI)m/z理论值C43H70INO8[M+H]+:855.4146,实测值855.4155。
化合物15的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.98(t,J＝5.6Hz,1H),5.40(s,1H),5.09(d,J＝1.6Hz,1H),3.91(m,2H),3.85(dd,J＝9.2,3.1Hz,1H),3.81–3.71(m,2H),3.69(s,4H),3.45–3.36(m,1H),3.36–3.30(m,1H),3.07–2.95(m,1H),2.55–2.47(m,3H),2.35(d,J＝7.4Hz,2H),2.05–1.90(m,3H),1.84–1.20(m,25H),1.18(s,3H),1.08(s,1H),1.03(s,3H),0.94(2s,9H),0.79(2s,6H)；13C NMR(101MHz,CDCl3)δ178.64,174.08,145.05,122.78,95.95,82.38,77.35,77.04,76.72,72.02,71.65,71.33,70.13,55.32,51.57,47.47,46.76,46.30,42.32,42.11,39.40,39.33,38.38,38.00,36.87,34.12,33.89,33.74,32.97,32.47,32.32,30.72,28.98,28.92,27.26,26.56,25.77,24.50,23.80,23.58,21.53,18.22,16.94,16.51,15.42；HRMS(ESI)m/z理论值C43H70BrNO8[M+H]+:810.4343,实测值810.9194。
化合物16的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.99(t,J＝5.6Hz,1H),5.37(s,1H),5.03(s,1H),3.88(s,2H),3.82(s,2H),3.67(s,3H),3.35(dq,J＝14.0,7.1Hz,1H),3.24(dd,J＝11.5,4.1Hz,1H),2.99(dd,J＝13.4,6.3Hz,1H),2.49(dd,J＝13.1,4.4Hz,1H),2.32(t,J＝7.4Hz,2H),2.08–1.96(m,2H),1.92(d,J＝8.2Hz,2H),1.76(t,J＝12.9Hz,3H),1.64(p,J＝6.9Hz,6H),1.56(t,J＝8.3Hz,3H),1.49(dt,J＝15.2,7.3Hz,5H),1.40–1.24(m,7H),1.20(d,J＝10.7Hz,3H),1.15(s,3H),0.97(s,3H),0.91(d,J＝4.6Hz,9H),0.78(s,3H),0.75(s,3H).；13C NMR(101MHz,CDCl3)δ178.52,174.08,145.08,122.72,96.22,82.70,72.16,71.63,55.27,51.56,47.49,46.76,46.28,42.30,42.09,39.40,39.29,38.34,38.02,36.87,34.12,33.89,32.98,32.49,32.35,30.72,29.00,28.73,27.25,26.55,25.74,24.50,23.77,23.58,21.67,18.22,16.93,16.48,15.40；HRMS(ESI)m/z理论值C43H70FNO8[M+H]+:748.5085,实测值748.5033。
化合物17的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.99(t,J＝5.5Hz,1H),5.38(d,J＝3.8Hz,1H),5.00(s,1H),3.87(d,J＝6.9Hz,2H),3.80(d,J＝9.3Hz,1H),3.75–3.62(m,6H),3.34(m,3H),3.26(s,1H),2.98(ddd,J＝17.0,12.8,4.7Hz,2H),2.76(dd,J＝13.8,7.2Hz,1H),2.49(dd,J＝12.8,4.2Hz,1H),2.32(t,J＝7.4Hz,2H),2.19(s,3H,H-SMe),2.01(s,3H),1.95–1.88(m,2H),1.82–1.63(m,6H),1.63–1.41(m,10H),1.40–1.25(m,6H),1.16(s,3H),1.02(s,3H),0.92(s,3H),0.90(s,6H),0.78(s,3H),0.75(s,3H)；13C NMR(101MHz,CDCl3)δ178.52,174.07,145.08,122.75,95.81,82.21,72.20,72.07,71.64,70.87,55.33,51.55,47.47,46.79,46.29,42.32,42.11,39.40,39.29,38.35,38.02,36.87,36.28,34.13,33.89,32.98,32.48,32.33,30.72,29.00,28.91,27.27,26.56,25.78,24.51,23.80,23.58,21.57,18.22,16.96,16.94,16.53,15.40；HRMS(ESI)m/z理论值C44H73NO8S[M+H]+:776.5135,实测值776.4998。
化合物18的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.00(t,J＝5.6Hz,1H),5.43–5.36(m,1H),5.06(d,J＝1.5Hz,1H),3.91(p,J＝4.6Hz,2H),3.82(s,1H),3.74(d,J＝9.5Hz,1H),3.69(s,3H),3.54(d,J＝4.5Hz,2H),3.44–3.26(m,2H),3.01(m,2H),2.58–2.48(m,2H),2.34(t,J＝7.4Hz,2H),2.05–1.90(m,3H),1.84–1.28(m,26H),1.19(s,3H),1.04(s,3H),0.95(s,3H),0.93(s,6H),0.81(s,3H),0,78(s,3H)；13CNMR(101MHz,CDCl3)δ178.64,174.08,145.05,122.78,95.96,82.66,72.08,71.99,71.62,68.84,55.28,51.64,51.57,47.45,46.75,46.30,42.32,42.11,39.40,39.32,38.33,38.01,36.87,34.12,33.89,32.97,32.48,32.32,30.72,28.98,28.68,27.26,26.55,25.77,24.50,23.80,23.57,21.62,18.23,16.94,16.50,15.40；HRMS(ESI)m/z理论值C43H70N4O8[M+H]+:771.5272,实测值771.5127。
化合物19的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.20(t,J＝6.1Hz,1H,C-6’N-H),5.94(t,J＝5.6Hz,1H,C-12),5.42–5.36(m,1H),5.32(s,3H),4.98(s,1H),4.05(dd,J＝14.7,8.7Hz,1H),3.92(d,J＝9.7Hz,2H),3.73(d,J＝9.7Hz,1H),3.69(s,3H),3.57–3.48(m,1H),3.38(dq,J＝13.7,7.0Hz,1H),3.18(dd,J＝11.6,4.2Hz,2H),3.03(s,3H),2.52(dd,J＝13.2,4.3Hz,1H),2.33(t,J＝7.4Hz,2H),2.07(d,J＝8.4Hz,3H),2.05–1.90(m,4H),1.80–1.42(m,16H),1.42–1.31(m,6H),1.17(s,3H),0.98(s,3H),0.94(s,3H),0.92(s,6H),0.79(s,3H),0.78(s,3H)；13C NMR(101MHz,CDCl3)δ178.18,174.04,145.17,122.62,96.52,83.09,71.70,71.26,70.83,67.24,55.49,51.54,47.57,46.81,46.26,42.29,42.09,40.04,39.41,39.23,38.34,38.14,36.89,34.14,33.91,33.01,32.53,32.39,30.74,29.07,28.64,27.28,26.58,25.74,24.53,23.77,23.60,23.05,21.88,18.24,16.94,16.47,15.37；HRMS(ESI)m/z理论值C45H74N2O9[M+H]+:787.5473,实测值787.5321。
化合物20的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.96(t,J＝5.6Hz,1H),5.37(s,1H),5.02(s,1H),4.55(dd,J＝11.9,4.5Hz,1H),4.22(d,J＝12.1Hz,1H),3.92–3.81(m,3H),3.67(s,3H),3.60(t,J＝9.7Hz,1H),3.36(dq,J＝14.2,7.2Hz,2H),3.23(dd,J＝11.7,4.0Hz,1H),2.99(dq,J＝13.1,6.7Hz,2H),2.50(dd,J＝12.9,3.9Hz,1H),2.38(t,J＝7.6Hz,2H),2.31(t,J＝7.4Hz,2H),1.72(t,J＝16.0Hz,6H),1.64(t,J＝7.7Hz,6H),1.60–1.50(m,3H),1.50–1.41(m,3H),1.41–1.27(m,15H),1.26(s,24H),1.15(s,4H),0.98(s,3H),0.92(s,3H),0.90(s,7H),0.87(d,J＝7.0Hz,3H),0.77(d,J＝9.0Hz,6H)；13C NMR(101MHz,CDCl3)δ178.34,175.12,174.03,145.13,122.69,96.23,82.89,77.23,71.61,71.34,71.03,67.70,63.41,55.50,51.52,47.57,46.79,46.28,42.34,42.09,39.42,39.26,38.34,38.10,36.88,34.24,34.14,33.90,32.98,32.51,32.39,31.93,30.73,29.71,29.68,29.66,29.64,29.50,29.37,29.30,29.19,29.04,28.74,27.28,26.58,25.72,24.97,24.52,23.79,23.58,22.69,21.76,18.24,16.94,16.46,15.38,14.12；HRMS(ESI)m/z理论值C61H105NO10[M+H]+:1012.7818,实测值1012.7632。
化合物21的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.99(d,J＝5.8Hz,1H),5.38(s,1H),5.03(s,1H),4.54(dd,J＝12.6,4.4Hz,1H),4.23(d,J＝12.1Hz,1H),3.90(s,1H),3.85(d,J＝9.1Hz,2H),3.67(s,3H),3.62(t,J＝9.7Hz,1H),3.47(s,1H),3.36(dq,J＝13.8,6.9Hz,1H),3.22(dt,J＝13.6,6.7Hz,2H),2.99(dq,J＝12.7,6.3Hz,1H),2.72(s,1H),2.53–2.45(m,1H),2.35(dt,J＝24.2,7.5Hz,5H),2.06–1.94(m,2H),1.92(d,J＝8.8Hz,3H),1.83–1.74(m,4H),1.70(d,J＝18.5Hz,4H),1.66–1.60(m,6H),1.48(ddd,J＝40.3,22.3,10.2Hz,12H),1.37–1.27(m,12H),1.25(s,10H),0.98(s,3H),0.89(q,J＝6.7Hz,15H),0.76(2s,6H)；13C NMR(101MHz,CDCl3)δ178.42,175.09,174.08,145.11,122.71,96.19,82.79,71.63,71.33,71.00,67.67,63.46,55.47,51.58,47.54,46.77,46.26,42.30,42.07,39.39,39.27,38.33,38.07,36.86,34.24,34.12,33.90,33.00,32.47,32.35,31.95,30.74,29.73,29.69,29.66,29.53,29.39,29.33,29.21,29.03,28.75,27.25,26.58,25.72,24.98,24.52,23.78,23.58,22.72,21.72,18.23,16.93,16.47,15.40,14.17；HRMS(ESI)m/z理论值C59H101NO10[M+H]+:984.7425,实测值984.7479。
化合物22的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.98(t,J＝5.6Hz,1H),5.38(s,1H),5.01(s,1H),4.48(dd,J＝12.2,4.9Hz,1H),4.27(d,J＝12.0Hz,1H),3.91–3.80(m,3H),3.67(s,3H),3.61(d,J＝9.2Hz,2H),3.36(dq,J＝13.8,7.0Hz,2H),3.23(dd,J＝11.9,4.0Hz,1H),2.99(dq,J＝13.2,7.1,6.7Hz,2H),2.50(dd,J＝13.1,4.3Hz,1H),2.34(dt,J＝20.7,7.5Hz,4H),1.76(t,J＝13.4Hz,3H),1.64(p,J＝7.1,6.1Hz,9H),1.55–1.44(m,15H),1.40(d,J＝13.8Hz,3H),1.34(d,J＝9.8Hz,4H),1.30(d,J＝7.3Hz,7H),1.26(s,3H),1.15(s,3H),0.98(s,3H),0.92(s,3H),0.9(s,3H),0.78-0.76(2s,6H)；13C NMR(101MHz,CDCl3)δ178.42,174.87,174.04,145.09,122.72,96.25,82.84,71.72,71.40,71.00,67.77,63.59,55.52,51.53,47.57,46.78,46.28,42.32,42.08,39.41,39.28,38.33,38.11,36.88,34.24,34.13,33.89,32.97,32.49,32.39,31.67,30.71,29.69,29.14,29.01,28.94,28.76,27.27,26.56,25.71,24.95,24.51,23.78,23.57,22.60,21.75,18.23,16.93,16.46,15.38,14.09；HRMS(ESI)m/z理论值C51H85NO10[M+H]+:872.6173,实测值872.6099。
化合物23的结构表征数据为：1H NMR(400MHz,CDCl3)δ5.97(t,J＝5.7Hz,1H),5.38(t,J＝5.3Hz,1H),5.02(s,1H),4.50(dd,J＝12.1,4.7Hz,1H),4.26(d,J＝12.0Hz,1H),3.89(s,1H),3.84(d,J＝7.4Hz,2H),3.67(s,3H),3.54(s,1H),3.35(dt,J＝13.8,6.8Hz,2H),2.98(dt,J＝12.6,6.2Hz,1H),2.50(dd,J＝13.1,4.3Hz,1H),2.34(dt,J＝22.6,7.5Hz,4H),2.02–1.85(m,5H),1.78(d,J＝12.9Hz,2H),1.73(s,1H),1.64(dt,J＝12.2,6.6Hz,10H),1.53–1.36(m,8H),1.36–1.31(m,3H),1.27(d,J＝12.9Hz,8H),1.15(s,3H),0.98(s,3H),0.92(s,3H),0.89(d,J＝8.8Hz,12H),0.78(s,3H),0.76(s,3H)；13C NMR(101MHz,CDCl3)δ178.41,174.91,174.04,145.10,122.71,96.24,82.84,77.24,71.70,71.39,71.01,67.76,63.55,55.51,51.53,47.57,46.78,46.28,42.33,42.08,39.41,39.27,38.33,38.11,36.88,34.24,34.13,33.89,32.97,32.49,32.38,31.45,30.72,29.70,29.01,28.84,28.75,27.27,26.57,25.71,24.91,24.51,23.79,23.58,22.49,21.75,18.24,16.94,16.46,15.38,14.04；HRMS(ESI)m/z理论值C50H84NO10[M+H]+:858.6094,实测值859.5943。
表1化合物1～23的取代基和产率
/>
实施例2
本发明齐墩果酸甘露糖苷化合物在制备治疗抗糖尿病药物中的应用
分别将上述合成的化合物1～23作为受试化合物，测试其对蛋白质酪氨酸磷酸酯酶1B(PTP1B)的抑制活性，具体试验情况如下：
200μL反应体系中含PTP1B(重组表达)、缓冲液(25mM HEPES，50mM氯化钠，2.5mMEDTA，0.1％ BSA，pH 7.2)和上述的齐墩果烷型氮糖苷化合物，同时设立空白对照(不含酶和受试化合物)和阴性对照(不含受试化合物)，37℃反应10min，加入蛋白质酪氨酸磷酸酶底物PNPP，37℃再反应30min，加入2MNa2CO3水溶液终止反应，405nm测定OD值。根据OD值计算抑制率，抑制率＝[1-(OD样品-OD空白)/(OD阴性-OD空白)]×100％。试验结果见表2。
表2化合物1～23体外PTP1B的抑制活性
由表2的活性结果可见，本发明的齐墩果酸甘露糖苷化合物对蛋白质酪氨酸磷酸酯酶1B表现出了很好的抑制活性，除了化合物5、12、13、20和21，其它化合物效果明显优于阳性对照正钒酸钠和之前专利(CN 108530508)报道的活性最佳的化合物齐墩果烷α-L-岩藻糖氮苷(化合物18)，说明齐墩果酸甘露糖苷化合物可用于制备治疗糖尿病的药物。
Claims (4)
1.齐墩果酸甘露糖苷化合物，其特征在于该化合物的结构式如下所示：
其中，R选自CH3COO、I、Br、F、CH3S、CH3COS、N3、HS、NH2、CH3(CH2)16COO、CH3(CH2)14COO、CH3(CH2)6COO、CH3(CH2)5COO中任意一种，R′选自H或CH3CO中任意一种。
2.根据权利要求1所述的齐墩果酸甘露糖苷化合物，其特征在于：所述的R选自I、Br、F、CH3COS、N3、HS、NH2、CH3(CH2)16COO、CH3(CH2)14COO中任意一种，R′代表CH3CO。
3.根据权利要求1所述的齐墩果酸甘露糖苷化合物，其特征在于：所述的R选自CH3COO、I、Br、F、CH3S、N3、HS、NH2、CH3(CH2)6COO中任意一种，R′代表H。
4.权利要求1所述的齐墩果酸甘露糖苷化合物在制备治疗抗糖尿病药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311727153.1A CN117720610A (zh) | 2023-12-15 | 2023-12-15 | 齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311727153.1A CN117720610A (zh) | 2023-12-15 | 2023-12-15 | 齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117720610A true CN117720610A (zh) | 2024-03-19 |
Family
ID=90204714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311727153.1A Pending CN117720610A (zh) | 2023-12-15 | 2023-12-15 | 齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117720610A (zh) |
-
2023
- 2023-12-15 CN CN202311727153.1A patent/CN117720610A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108864024B (zh) | 一类灯盏乙素苷元氮芥类衍生物及其制备方法和用途 | |
| CN112979733B (zh) | 抗乙肝病毒的化合物及其制备方法和应用 | |
| JP2016145212A (ja) | Ｃｄｄｏエチルエステルの多形体及びその用途 | |
| CN111808117B (zh) | 青蒿素-苯胺基喹唑啉类d类衍生物及其药物组合物和应用 | |
| CN112538099B (zh) | 一种全酰基保护的1-硫代葡萄糖、葡萄糖1-硫醇的制备方法及其应用 | |
| CN108530508B (zh) | 齐墩果烷型氮糖苷化合物及其在制备治疗抗糖尿病药物中的应用 | |
| AU618536B2 (en) | Novel 3',4'-dinitrogen substituted epipodophyllotoxin glucoside derivatives | |
| CN117720610A (zh) | 齐墩果酸甘露糖苷化合物及其在制备治疗抗糖尿病药物中的应用 | |
| CN115073406B (zh) | 一种桉烷型倍半萜内酯类tba衍生物及其用途 | |
| CN109503697B (zh) | 3-(l-苯丙氨酸)-五环三萜衍生物及其合成方法和应用 | |
| CN113717138A (zh) | 一类氮芥类色原酮衍生物与应用 | |
| CN115057839A (zh) | 一种桉烷型倍半萜烯内酯化合物及其制备和用途 | |
| CN108586564B (zh) | 一种c5位取代薯蓣皂苷元衍生物及其制备和应用 | |
| US5034380A (en) | Alkoxymethylidene epipodophyllotoxin glucosides | |
| JPH0560474B2 (zh) | ||
| JPS61243096A (ja) | シアル酸誘導体及びその製造方法 | |
| CN113402578B (zh) | 薯蓣皂苷元衍生物及其制备方法和医药用途 | |
| CN109517025B (zh) | 28-(l-苯丙氨酸)-五环三萜衍生物及其合成方法和应用 | |
| CN110759961A (zh) | 一类熊果酸吲哚醌酰胺衍生物及其制备方法和应用 | |
| CN112110966B (zh) | 白藜芦醇糖苷类衍生物、制备和用途 | |
| JP2640980B2 (ja) | Ｎ▲上６▼，ｎ▲上６▼―ジ置換―アデノシン―３’，５’―環状リン酸及びその製法 | |
| CN113788809B (zh) | 一类色原酮的3位拼合氮芥衍生物与应用 | |
| CN114105807B (zh) | 一种羟基环己二酰胺类化合物及其制备方法与应用 | |
| CN112745310B (zh) | 色原酮2-位哌嗪连接呋咱衍生物及其制备方法和用途 | |
| JPS6152839B2 (zh) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |