CN113730419B - 20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物与其药物组合物 - Google Patents
20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物与其药物组合物 Download PDFInfo
- Publication number
- CN113730419B CN113730419B CN202111173432.9A CN202111173432A CN113730419B CN 113730419 B CN113730419 B CN 113730419B CN 202111173432 A CN202111173432 A CN 202111173432A CN 113730419 B CN113730419 B CN 113730419B
- Authority
- CN
- China
- Prior art keywords
- beta
- epoxy
- dammarane
- triol
- preparation
- 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.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 11
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims abstract description 7
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 claims abstract description 6
- 150000004072 triols Chemical class 0.000 claims abstract description 5
- 230000009467 reduction Effects 0.000 claims abstract description 3
- 102100024295 Maltase-glucoamylase Human genes 0.000 claims description 21
- 108010028144 alpha-Glucosidases Proteins 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- 239000003472 antidiabetic agent Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 3
- 229940126904 hypoglycaemic agent Drugs 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 230000000397 acetylating effect Effects 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 230000006196 deacetylation Effects 0.000 claims description 2
- 238000003381 deacetylation reaction Methods 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 abstract description 13
- 239000008280 blood Substances 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000008103 glucose Substances 0.000 abstract description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 15
- 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 14
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 241000233779 Cyclocarya paliurus Species 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 102000004877 Insulin Human genes 0.000 description 7
- 108090001061 Insulin Proteins 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 229940125396 insulin Drugs 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 230000000291 postprandial effect Effects 0.000 description 5
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 5
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010022489 Insulin Resistance Diseases 0.000 description 3
- 241000322338 Loeseliastrum Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960002632 acarbose Drugs 0.000 description 3
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IFBHRQDFSNCLOZ-ZIQFBCGOSA-N 4-nitrophenyl alpha-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-ZIQFBCGOSA-N 0.000 description 2
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 102000003746 Insulin Receptor Human genes 0.000 description 2
- 108010001127 Insulin Receptor Proteins 0.000 description 2
- 239000007993 MOPS buffer Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- ZRNADTAFDQEXHG-UHFFFAOYSA-L disodium;(4-nitrophenyl)-dioxido-oxo-$l^{5}-phosphane Chemical compound [Na+].[Na+].[O-][N+](=O)C1=CC=C(P([O-])([O-])=O)C=C1 ZRNADTAFDQEXHG-UHFFFAOYSA-L 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000012089 stop solution Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- RPWPRIVEZXDLST-ZIQFBCGOSA-N (2s,3r,4s,5s,6r)-6-(hydroxymethyl)-2-(4-nitrophenyl)oxane-2,3,4,5-tetrol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]1(O)C1=CC=C([N+]([O-])=O)C=C1 RPWPRIVEZXDLST-ZIQFBCGOSA-N 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 235000009024 Ceanothus sanguineus Nutrition 0.000 description 1
- 240000000491 Corchorus aestuans Species 0.000 description 1
- 235000011777 Corchorus aestuans Nutrition 0.000 description 1
- 235000010862 Corchorus capsularis Nutrition 0.000 description 1
- 241000233778 Cyclocarya Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000758791 Juglandaceae Species 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 102100031775 Leptin receptor Human genes 0.000 description 1
- 240000003553 Leptospermum scoparium Species 0.000 description 1
- 235000015459 Lycium barbarum Nutrition 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 241000124015 Salix viminalis Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 108010019813 leptin receptors Proteins 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229960000621 suramin sodium Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供结构式(I)所示的20S,24R‑环氧‑达玛烷‑3β,12β,25‑三醇衍生物(1和2)，其药物组合物和其制备方法，以及衍生物1和2及其药物组合物在制备α‑葡萄糖苷酶和PTP1B抑制剂中和在制备治疗II型糖尿病和降血糖药物中的应用。属于药物技术领域。本发明的三醇衍生物对α‑葡萄糖苷酶和对PTP1B具有较好的抑制活性。
Description
技术领域
本发明属于药物技术领域，具体涉及20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2，以其为有效成分的药物组合物，制备方法，以及衍生物1和2及其药物组合物在制备α-葡萄糖苷酶和PTP1B抑制药物中和在制备治疗II型糖尿病、降血糖的药物中的应用。
背景技术
糖尿病(diabetes mellitus)是一组由遗传与环境因素相互作用而引起的常见的内分泌代谢性疾病，主要是由于胰岛素分泌的绝对或相对不足以及靶细胞对胰岛素敏感性降低而引起的糖、脂肪和蛋白质代谢紊乱。根据世界卫生组织(WHO)的报导，全球糖尿病人数呈持续上升趋势，预测2030年糖尿病将成为第七位主要死因。由于血糖水平较高，糖尿病人常会出现多尿，口渴，持续饥饿和体重减轻等症状，同时会出现失明、肾衰竭、心脏病发作、中风和下肢截肢等并发症。临床上以空腹时血糖浓度大于7.0mmol/L，一天中任意时间血糖值大于11.1mmol/L以及餐后2h，血糖浓度大于7.0mmol/L这三种症状作为糖尿病的判定依据。
糖尿病根据其病因和发病机理可以分为I型和II型糖尿病。I型糖尿病主要与遗传、环境因素有关，此外嗜胰腺病毒感染、化学物质损害、胰岛β细胞产生自身免疫炎性反应等都会导致胰岛β细胞的破坏，胰岛素分泌呈现绝对缺乏[8]。I型糖尿病起病较急，血浆的胰岛素水平低于正常限度，容易发生酮症酸中毒，需要依赖外源性的胰岛素才能够维持生命。II型糖尿病是机体能够产生胰岛素，但是由于胰岛素敏感性受损，内源性胰岛素分泌不足或作用效果差等导致胰岛素相对缺乏。
糖尿病患者需要终身服用降血糖药物来维持血糖处于正常水平。α-葡萄糖苷酶抑制剂可以在小肠上段竞争性地抑制α-糖苷酶，减少碳水化合物转化为葡萄糖，并能延迟小肠中葡萄糖的吸收，从而使饭后血糖升高幅度下降。蛋白酪氨酸磷酸酶1B(PTP1B)通过去磷酸化作用对瘦素和胰岛素受体进行负调节，使胰岛素受体无法和胰岛素结合，引起胰岛素抵抗。α-葡萄糖苷酶抑制剂是餐后降血糖的首选药物，PTP1B抑制剂能够提高胰岛素的敏感性。因此，α-葡萄糖苷酶和PTP1B的双重抑制剂可能会具有更少的副作用，发挥更好的功效。
青钱柳[Cyclocarya paliurus(Batal.)Ijinakaja]是胡桃科青钱柳属乔木植物，又名青钱李(江西)、山麻柳(四川)、甜茶树(贵州)、一串钱(湖北)等，广泛分布于江西、广西、四川、贵州、湖北等13个省区，是我国特有的单种属植物。青钱柳叶中含有多种化学成分，主要包括三萜、黄酮、有机酸、多糖、甾体等。青钱柳叶具有降压、降血糖、清热解暑等功效，民间常用其叶制成保健茶饮用，一些以青钱柳叶为主要原料的保健产品已经上市。
为了寻找青钱柳中降血糖活性成分，对青钱柳叶进行了化学成分和体内外降血糖活性研究。其活性部位分离酸解得到的20S,24R-环氧-达玛烷-3β,12β,25-三醇对α-葡萄糖苷酶具有抑制活性，在浓度为200μM时抑制率为32.2％。之后进行动物实验，单次给药浓度为60mg/kg时，2h内II型糖尿病模型BKS-db小鼠和正常小鼠(C57BL/6J)可以显著降低餐后血糖。这些结果表明20S,24R-环氧-达玛烷-3β,12β,25-三醇对正常小鼠和BKS-db小鼠的餐后血糖具有较好的调节作用。此外，20S,24R-环氧-达玛烷-3β,12β,25-三醇对蛋白酪氨酸磷酸酶1B(PTP1B)也具有抑制活性，在浓度为400μM时抑制率为16.4％。因此，本发明对20S,24R-环氧-达玛烷-3β,12β,25-三醇的结构进行修饰，以期获得活性更好的降血糖药物。
发明内容
本发明的目的在于提供一类新的具有药用价值的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2，及具有抑制α-葡萄糖苷酶和PTP1B有效量的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2及药用载体或赋形剂所形成的药物组合物，其制备方法，该衍生物及其药物组合物在制备α-葡萄糖苷酶和PTP1B抑制药物，以及在制备治疗II型糖尿病的药物中的应用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
结构式(I)所示的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2，
制备20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2的方法：以化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇为反应原料，使用氧化剂将其氧化为20S,24R-环氧-12-羰基-达玛烷-3β,25-二醇，再与邻苯二甲酸酐缩合制备得到三醇衍生物1；以化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇为反应原料，经乙酰化试剂作用得到20S,24R-环氧-3β,12β-二乙酰氧基-达玛烷-25-醇，随后经氧化剂氧化得到20S-环氧-3β,12β-二乙酰氧基-达玛烷-24-酮,脱乙酰基后得到20S-环氧-3β,12β-二羟基-达玛烷-24-酮，最后经氢化铝锂还原制备得到三醇衍生物2。
20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2在制备α-葡萄糖苷酶和PTP1B抑制剂中的应用。
20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2在制备治疗或改善II型糖尿病的药物中的应用。
20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2在制备降血糖药物中的应用。
含有治疗有效量的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2中的一种或其组合和药学上可接受的载体或赋形剂所组成的药物组合物。
制备所述的药物组合物的方法，以化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇为反应原料，合成20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2，分别加入可药用载体或赋形剂。
所述的药物组合物在制备α-葡萄糖苷酶和PTP1B抑制剂中的应用。
所述的药物组合物在制备治疗或改善II型糖尿病的药物中的应用。
所述的药物组合物在在制备降血糖药物中的应用。
本发明化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1-99％，优选0.5-90％的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂。
所述的药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经注射(静注、肌注)和口服两种形式给药。
附图说明
图1为本发明的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2的结构示意图。
具体实施方式
为了更好的理解本发明的实质，下面结合附图，用本发明的实施例和试验例来说明本发明20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物的合成方法和药理作用结果，但并不以此来限定本发明。
核磁共振谱(1H and 13C)在400MHz核磁共振谱仪(Bruker,Bremerhaven,Germany)上测定，以TMS(四甲基硅烷)为内标。所有的化合物通过硅胶柱层析进行纯化(200-300目，青岛美高集团有限公司)。所有的反应试剂和溶剂均购自于正规厂商。
实施例1
1、20S,24R-环氧-3β-邻甲酸苯甲酰基-12-羰基-达玛烷-25-醇(1)【化合物1】的合成方法：
20S,24R-环氧-达玛烷-3β,12β,25-三醇(30mg,0.06mmol)溶解于DCM中，搅拌情况下加入PCC(25.8mg,0.12mmol)，室温反应，TLC检测反应。反应液经硅藻土抽滤，二氯甲烷洗涤，收集滤液，减压回收溶剂得粗品，硅胶柱层析(乙酸乙酯-石油醚,35:65,v/v)纯化得目标化合物20S,24R-环氧-12-羰基-达玛烷-3β,25-二醇(收率20％)。
20S,24R-环氧-12-羰基-达玛烷-3β,25-二醇(12.0mg,0.03mmol)溶于0.6mL吡啶，加入邻苯二甲酸酐(22.2mg,0.15mmol)之后于80℃下回流反应。72h后停止反应，冷却至室温后，加入乙酸乙酯稀释反应液，依次用5％ HCl和饱和食盐水洗涤，回收有机溶剂，无水硫酸钠干燥，抽滤，减压回收溶剂得粗品。硅胶柱层析(丙酮-石油醚-冰醋酸,20:80:0.1,25:75:0.1,v/v/v)纯化得20S,24R-环氧-3β-邻甲酸苯甲酰基-12-羰基-达玛烷-25-醇(1)即化合物1(收率为76％)。
其中，20S,24R-环氧-12-羰基-达玛烷-3β,25-二醇的结构数据为：
性状：白色固体
1H-NMR和13C-NMR数据：1H NMR(600MHz,CDCl3)δ3.37(1H,m,H-3),3.70(1H,t,J＝7.4Hz,H-24),1.23(3H,s),1.18(3H,s),1.13(3H,s),1.09(3H,s),0.95(3H,s),0.91(3H,s),0.83(3H,s)；13C NMR(150MHz,CDCl3)δ32.6(CH2,C-1),25.3(CH2,C-2),76.2(CH,C-3),36.8(C,C-4),49.5(CH,C-5),18.0(CH2,C-6),34.5(CH2,C-7),43.5(C,C-8),44.3(CH,C-9),37.6(C,C-10),46.9(CH2,C-11),212.2(CO,C-12),63.5(CH,C-13),50.0(C,C-14),30.5(CH2,C-15),26.0(CH2,C-16),48.9(CH,C-17),17.9(CH3,C-18),16.8(CH3,C-19),85.9(C,C-20),23.4(CH3,C-21),36.1(CH2,C-22),26.3(CH2,C-23),83.7(CH,C-24),71.6(C,C-25),27.6(CH3,C-26),24.8(CH3,C-27),28.6(CH3,C-28),22.4(CH3,C-29),16.6(CH3,C-30).
20S,24R-环氧-3β-邻甲酸苯甲酰基-12-羰基-达玛烷-25-醇(化合物1)的结构数据为：
性状：白色固体
1H-NMR和13C-NMR数据：1H NMR(400MHz,CDCl3)δ4.92(1H,m,H-3),3.70(1H,t,J＝7.4Hz,H-24),1.23(3H,s),1.20(3H,s),1.19(3H,s),1.13(3H,s),1.10(3H,s),1.08(3H,s),0.94(3H,s),0.89(3H,s),7.90(1H,m,H-4'),7.59(3H,m,H-5'-H-7')；13C NMR(100MHz,CDCl3)δ33.3(CH2,C-1),22.2(CH2,C-2),80.1(CH,C-3),36.5(C,C-4),50.0(CH,C-5),17.7(CH2,C-6),34.2(CH2,C-7),43.3(C,C-8),44.1(CH,C-9),36.9(C,C-10),46.6(CH2,C-11),212.1(C,C-12),63.1(CH,C-13),49.8(C,C-14),30.3(CH2,C-15),25.8(CH2,C-16),49.3(CH,C-17),17.7(CH3,C-18),16.7(CH3,C-19),85.7(C,C-20),23.2(CH3,C-21),35.9(CH2,C-22),26.1(CH2,C-23),83.4(CH,C-24),71.6(C,C-25),27.3(CH3,C-26),24.5(CH3,C-27),28.0(CH3,C-28),21.9(CH3,C-29),16.4(CH3,C-30),167.9(C,C-1',C-8'),134.1(C,C-2',C-3'),130.0(C,C-4'),130.6(C,C-5'),131.9(C,C-6'),128.5(C,C-7').
2、20S-原人参二醇-24-醇(2)【化合物2】的合成方法：
20S,24R-环氧-达玛烷-3β,12β,25-三醇(56.0mg,0.12mmol)溶于1.2mL无水吡啶，搅拌情况下加入1.2mL醋酸酐，室温下反应过夜。反应结束后，乙酸乙酯(15.0mL)稀释反应液后依次用5％盐酸(10.0mL×3)，饱和碳酸氢钠(10.0mL×3)和饱和食盐水(10.0mL×3)洗涤，合并有机溶剂，无水硫酸钠干燥，抽滤，减压回收溶剂得粗品，硅胶柱层析(乙酸乙酯-石油醚,10:90,v/v)纯化得目标化合物20S,24R-环氧-3β,12β-乙酰氧基-达玛烷-25-醇(收率为32％)。
20S,24R-环氧-3β,12β-乙酰氧基-达玛烷-25-醇(30.0mg,0.05mmol)溶于1.0mL甲醇，加入PCC(46.6mg,0.22mmol)，40℃反应。反应过夜后，经硅藻土抽滤反应液，回收滤液，硅胶柱层析(丙酮-石油醚,5:95,10:90,v/v)纯化得目标化合物20S-环氧-3β,12β-二乙酰氧基-达玛烷-24-酮(收率为54％)。该化合物(24.0mg,0.05mmol)溶于3.0mL甲醇，加入1.0mL 10％ NaOH溶液，回流反应过夜。冷却至室温后加入乙酸乙酯稀释反应液，依次用5％HCl和饱和食盐水洗涤，合并有机溶剂，无水硫酸钠干燥，抽滤，回收溶剂，硅胶柱层析(丙酮-石油醚,25:75,10:90,v/v)纯化得目标化合物20S-环氧-3β,12β-二羟基-达玛烷-24-酮(收率为91％)。
氮气氛围下，氢化铝锂(5.3mg,0.14mmol)悬浮于1.5mL干燥的四氢呋喃，冰浴条件下加入1.0mL化合物20S-环氧-3β,12β-二羟基-达玛烷-24-酮(20.0mg,0.05mmol)的四氢呋喃溶液。加料完毕后，撤除冰浴升温至50℃反应。反应过夜后，缓慢加入水和0.1M的氢氧化钠溶液淬灭反应，抽滤，收集滤液，回收溶剂，硅胶柱层析(丙酮-石油醚,20:80,35:65,v/v)纯化得化合物20S-原人参二醇-24-醇(化合物2)(收率为35％)。
其中，20S,24R-环氧-12β-乙酰氧基基-达玛烷-3β,25-二醇的结构数据为：
性状：白色固体
1H-NMR和13C-NMR数据：1H NMR(500MHz,CDCl3)δ3.36(1H,m,H-3),5.11(1H,td,J＝10.7,5.5Hz,H-12),3.70(1H,t,J＝7.4Hz,H-24),1.20(3H,s),1.11(3H,s),1.10(3H,s),0.99(3H,s),0.96(3H,s),0.94(3H,s),0.94(3H,s),0.84(3H,s),1.96(3H,s,H-2')；13C NMR(125MHz,CDCl3)δ34.9(CH2,C-1),25.5(CH2,C-2),75.8(CH,C-3),37.9(C,C-4),49.1(CH,C-5),18.0(CH2,C-6),35.0(CH2,C-7),41.2(C,C-8),52.5(CH,C-9),38.9(C,C-10),34.5(CH2,C-11),73.2(CH,C-12),40.6(CH,C-13),49.8(C,C-14),31.1(CH2,C-15),26.0(CH2,C-16),48.9(CH,C-17),16.8(CH3,C-18),16.7(CH3,C-19),86.1(C,C-20),23.9(CH3,C-21),35.7(CH2,C-22),25.9(CH2,C-23),83.5(CH,C-24),71.2(C,C-25),27.4(CH3,C-26),24.9(CH3,C-27),28.8(CH3,C-28),22.2(CH3,C-29),16.3(CH3,C-30),170.4(CO,C-1'),22.1(CH3,C-2').
20S-环氧-3β,12β-二羟基-达玛烷-24-酮的结构数据为：
性状：白色固体
1H-NMR和13C-NMR数据：1H NMR(400MHz,CD3OD)δH:3.30(1H,m,H-3),3.90(1H,td,J＝10.5,5.5Hz,H-12),1.37(3H,s),1.06(3H,s),1.00(6H,s),0.98(3H,s),0.92(3H,s),0.86(3H,s)；13C NMR(100MHz,CD3OD)δC:36.3(CH2,C-1),26.2(CH,C-2),76.8(CH,C-3),38.9(C,C-4),50.5(CH,C-5),19.1(CH2,C-6),37.1(CH2,C-7),42.1(C,C-8),56.1(CH,C-9),40.3(C,C-10),39.6(CH2,C-11),71.4(CH,C-12),42.9(CH,C-13),51.2(C,C-14),31.8(CH2,C-15),26.5(CH2,C-16),50.6(CH,C-17),17.2(CH3,C-18),17.1(CH3,C-19),91.9(C,C-20),25.5(CH3,C-21),31.8(CH2,C-22),30.0(CH2,C-23),179.6(CO,C-24),29.6(CH3,C-28),23.0(CH3,C-29),16.5(CH3,C-30).
20S-原人参二醇-24-醇(化合物2)的结构数据为：
性状：白色固体
1H-NMR和13C-NMR数据：1H NMR(400MHz,CD3OD)δ3.53(1H,m,H-3),3.91(1H,td,J＝11.0,5.5Hz,H-12),3.73(1H,t,J＝7.3Hz,H-24),1.13(3H,s),1.06(3H,s),0.99(6H,s),0.96(3H,s),0.92(3H,s),0.86(3H,s)；13C NMR(100MHz,CD3OD)δ35.0(CH2,C-1),24.5(CH,C-2),74.5(CH,C-3),37.5(C,C-4),49.2(CH,C-5),17.8(CH2,C-6),35.8(CH2,C-7),40.5(C,C-8),54.8(CH,C-9),38.9(C,C-10),39.1(CH2,C-11),70.3(CH,C-12),40.7(CH,C-13),50.0(C,C-14),30.4(CH2,C-15),25.6(CH2,C-16),49.4(CH,C-17),15.8(CH3,C-18),15.7(CH3,C-19),74.2(C,C-20),23.9(CH3,C-21),37.1(CH2,C-22),26.4(CH2,C-23),62.3(CH2,C-24),28.2(CH3,C-28),23.9(CH3,C-29),15.4(CH3,C-30).
实施例2：
20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2(化合物1和2)对α-葡萄糖苷酶和PTP1B的抑制活性。
1材料和方法
1.1材料
α-葡萄糖苷酶(Sigma Aldrich,美国)；对硝基苯基-α-D-吡喃葡萄糖(源叶生物,上海)；阿卡波糖(拜耳医药,北京)；磷酸盐缓冲液(PB,Na2HPO4和NaH2PO4·2H2O,大连美仑生物有限公司)，碳酸钠(大连美仑生物有限公司)，3-(N-吗啉代)丙磺酸(MOPS,北京索莱宝科技有限公司)，二硫苏糖醇(DTT,大连美仑生物技术有限公司)，乙二胺四乙酸钠(EDTA,北京索莱宝科技有限公司)；牛血清蛋白(BSA,amresco)，对硝基苯膦酸二钠盐(p-NPP,北京索莱宝科技有限公司)，苏拉明钠(Acros organics)，PTP1B酶(SINO,10304-H07E)。
1.2仪器
Flex Station 3台式多功能酶标仪(Bio-RAD 680,美国)；分析天平(AG135,Metler Toledo,中国)；恒温箱(DHP-9082,上海)。
1.3实验步骤
α-葡萄糖苷酶抑制活性根据文献报道的方法进行测试。阳性对照阿卡波糖和底物对硝基苯基-α-D-吡喃葡萄糖苷(p-NPG，2.5mM)用磷酸盐缓冲溶液(PB,0.1mM,pH＝6.8)溶解。待测样品用甲醇-PB(1:1，v/v)溶解，α-葡萄糖苷酶用PB溶解(0.2U/mL)，分别取30μL和20μL加入到96孔板中于37℃孵育5min。然后加入20μLα-葡萄糖苷酶，孵育15min，最后加入40μL碳酸钠终止反应。孵育5min后，用酶标仪测试405nm处的吸光值。空白组用PB代替样品，背景用PB代替α-葡萄糖苷酶。α-葡萄糖苷酶抑制率＝[(ΔOD空白-ΔOD空白背景)-(ΔOD样品-ΔOD样品背景)]/(ΔOD空白-ΔOD空白背景)。使用Graphpad prism 5软件处理数据，做出样品和酶之间的浓度依数关系曲线，计算IC50值。
PTP1B酶活性筛选方法根据实验室的方法进行。首先配置所需要的试剂，3-(N-吗啉代)丙磺酸(MOPS,361.0mg)、二硫苏糖醇(DTT,15.0mg)、乙二胺四乙酸钠(EDTA,12.8mg)、牛血清蛋白(BSA,100.0mg)和氯化钠(6.05g)溶于50.0mL纯水，配置成工作缓冲液，于4℃冰箱内保存；对硝基苯膦酸二钠盐(p-NPP,37.0mg)溶于1.0mL纯水，配置成浓度为0.1M的底物，避光保存；苏拉明钠(3.43mg)溶于200μL DMSO依次2倍稀释得到7个浓度梯度的阳性；样品用DMSO溶解；无水碳酸钠(1.06g)溶于100.0mL蒸馏水，得到浓度为0.1M的终止液；PTP1B酶(1.92mg/mL,5μL)用1935μL的工作缓冲液稀释成浓度为4.9mg/L的溶液。PTP1B酶活性筛选方法，96微孔板中加入70μL工作缓冲液，10μL待测样品和10μL酶，于37℃恒温箱中孵育15min；然后加入10μL底物，再孵育30min；之后加入100μL碳酸钠终止液，于酶标仪中震动30s后于405nm下测试吸光度值，每组3个副孔，取平均值计算抑制率。空白组用10μL DMSO代替样品，背景用10μL DMSO代替酶。用Graphad Prism 5软件计算IC50。
2实验结果
本发明化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1、2对α-葡萄糖苷酶和PTP1B的抑制抑制活性如表1所示。
表1 20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1、2(化合物1、2)对α-葡萄糖苷酶和PTP1B的抑制活性
α-葡萄糖苷酶抑制活性测试中阳性为阿卡波糖，样品浓度为200μM；PTP1B酶抑制活性测试中阳性为苏拉明钠,样品浓度为400μM；“-”表示无抑制活性。
3结论
以20S,24R-环氧-达玛烷-3β,12β,25-三醇为活性化合物进行修饰，合成2个衍生物。与原化合物相比，化合物2对α-葡萄糖苷酶的活性保持，化合物1对α-葡萄糖苷酶具有较好的抑制活性，IC50为467.7μM，提高了2倍；浓度为400μM时，化合物2对PTP1B的抑制率和20S,24R-环氧-达玛烷-3β,12β,25-三醇相当(16.6％vs 16.4％)，而化合物1对PTP1B的抑制活性和阳性苏拉明钠相当(IC50339.0μM)，IC50为269.1μM。
制剂实施例：
1.取化合物1和2，用少量的DMSO溶解后，按常规加注射用水，精滤，灌封灭菌制成注射液。
2.取化合物1和2，用少量的DMSO溶解后，将其溶于无菌注射用水中，搅拌使溶解，用无菌抽滤漏斗过滤，再无菌精滤，分装于安中，低温冷冻干燥后无菌熔封得粉针剂。
3.取化合物1和2，按其与赋形剂重量比为9:1的比例加入赋形剂，制成粉剂。
4.取化合物1和2，按其与赋形剂重量比为5:1的比例加入赋形剂，制成压片。
5.取化合物1和2，按常规口服液制法制成口服液。
6.取化合物1和2，按其与赋形剂重量比为5:1的比例加入赋形剂，制成胶囊。
7.取化合物1和2，按其与赋形剂重量比为3:1的比例加入赋形剂，制成胶囊。
8.取化合物1和2，按其与赋形剂重量比为5:1的比例加入赋形剂，制成颗粒剂。
Claims (10)
1.结构式(I)所示的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2，
2.制备权利要求1所示的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2的方法，其特征在于：以化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇为反应原料，使用氧化剂将其氧化为20S,24R-环氧-12-羰基-达玛烷-3β,25-二醇，再与邻苯二甲酸酐缩合制备得到三醇衍生物1；以化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇为反应原料，经乙酰化试剂作用得到20S,24R-环氧-3β,12β-二乙酰氧基-达玛烷-25-醇，随后经氧化剂氧化得到20S-环氧-3β,12β-二乙酰氧基-达玛烷-24-酮,脱乙酰基后得到20S-环氧-3β,12β-二羟基-达玛烷-24-酮，最后经氢化铝锂还原制备得到三醇衍生物2。
3.权利要求1所述的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2在制备α-葡萄糖苷酶和PTP1B抑制剂中的应用。
4.权利要求1所述的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2在制备治疗或改善II型糖尿病的药物中的应用。
5.权利要求1所述的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2在制备降血糖药物中的应用。
6.含有治疗有效量的权利要求1所述的20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2中的一种或其组合和药学上可接受的载体或赋形剂所组成的药物组合物。
7.制备权利要求6所述的药物组合物的方法，以化合物20S,24R-环氧-达玛烷-3β,12β,25-三醇为反应原料，合成20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物1和2，分别加入可药用载体或赋形剂。
8.权利要求6所述的药物组合物在制备α-葡萄糖苷酶和PTP1B抑制剂中的应用。
9.权利要求6所述的药物组合物在制备治疗或改善II型糖尿病的药物中的应用。
10.权利要求6所述的药物组合物在制备降血糖药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111173432.9A CN113730419B (zh) | 2021-10-08 | 2021-10-08 | 20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物与其药物组合物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111173432.9A CN113730419B (zh) | 2021-10-08 | 2021-10-08 | 20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物与其药物组合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113730419A CN113730419A (zh) | 2021-12-03 |
| CN113730419B true CN113730419B (zh) | 2023-10-27 |
Family
ID=78726158
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111173432.9A Active CN113730419B (zh) | 2021-10-08 | 2021-10-08 | 20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物与其药物组合物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113730419B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018701A (zh) * | 2010-10-27 | 2011-04-20 | 大理学院 | 角型黄酮醇木脂素用于制备糖苷酶抑制剂的药物用途 |
| CN103059088A (zh) * | 2013-01-16 | 2013-04-24 | 烟台大学 | 一类结构新颖的达玛烷型皂苷衍生物、其制备方法及抗菌用途 |
| CN112336719A (zh) * | 2020-10-19 | 2021-02-09 | 济南大学 | 一种噻唑衍生物作为α-葡萄糖苷酶抑制剂及其应用 |
-
2021
- 2021-10-08 CN CN202111173432.9A patent/CN113730419B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018701A (zh) * | 2010-10-27 | 2011-04-20 | 大理学院 | 角型黄酮醇木脂素用于制备糖苷酶抑制剂的药物用途 |
| CN103059088A (zh) * | 2013-01-16 | 2013-04-24 | 烟台大学 | 一类结构新颖的达玛烷型皂苷衍生物、其制备方法及抗菌用途 |
| CN112336719A (zh) * | 2020-10-19 | 2021-02-09 | 济南大学 | 一种噻唑衍生物作为α-葡萄糖苷酶抑制剂及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| 罗勒化学成分的研究;尹锋等;《中国天然药物》;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113730419A (zh) | 2021-12-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5539224B2 (ja) | アジアティック酸（ａｓｉａｔｉｃａｃｉｄ）及びその選択される塩に基づく治療用製剤 | |
| EP0684254A1 (en) | Propiophenone derivative and a process for preparing the same | |
| JP3006513B2 (ja) | 医薬組成物 | |
| EP1559703B1 (en) | A natural compound useful for treating diabetes, its preparation and use | |
| CN113730419B (zh) | 20S,24R-环氧-达玛烷-3β,12β,25-三醇衍生物与其药物组合物 | |
| CN107531745A (zh) | 一种新的18α‑甘草次酸衍生物及其医药用途 | |
| CN114315855B (zh) | 莪术醇类衍生物、制备方法及其在制备抗炎药物中的应用 | |
| CN106967143A (zh) | 结构新颖的pyxinol衍生物及其制备方法和用途 | |
| 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 | |
| CN111647036B (zh) | 一类Ocotillol型酯化衍生物及其制备方法和制作抗炎药物的用途 | |
| CN105037480A (zh) | 呋甾皂苷及其作为α-糖苷酶抑制剂在抗糖尿病药物中的应用 | |
| CN113493374B (zh) | Sirt1受体激动剂及包含其的药物 | |
| CN101735286A (zh) | 氨基酸修饰的氨基葡萄糖及其制备方法和应用 | |
| WO2021204192A1 (zh) | 化合物作为Sirt1受体激动剂的应用 | |
| CN102250197A (zh) | 一种麦冬总甾体皂苷提取物的制备方法及应用 | |
| TWI518094B (zh) | One kind of derivatives of sterols, their preparation and use | |
| CN113307731A (zh) | 一种隐丹参酮衍生物及其制备方法与在抗心肌纤维化中的应用 | |
| JP2002529409A (ja) | グルコース及び脂質低下化合物類 | |
| CN110467624B (zh) | 一类黄烷与二苯乙烯类化合物骈合而成的加合物 | |
| CN112176018B (zh) | 基于炙甘草制备甘草次酸及其衍生物的方法和用途 | |
| CN109206470A (zh) | 刺囊酸衍生物制备方法及医药新用途 | |
| CN109970540B (zh) | 一种基于对羟基苯醌骨架α-葡萄糖苷酶抑制剂及其制备方法与应用 | |
| CN111233702A (zh) | 先花铃子香素a衍生物与其药物组合物及其制备方法和应用 | |
| CN115368428B (zh) | 马铃薯三糖桦木酸皂苷酯类衍生物及其制备方法和应用 | |
| JPS6312448B2 (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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |