CN110452252B - 二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 - Google Patents
二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 Download PDFInfo
- Publication number
- CN110452252B CN110452252B CN201910803271.3A CN201910803271A CN110452252B CN 110452252 B CN110452252 B CN 110452252B CN 201910803271 A CN201910803271 A CN 201910803271A CN 110452252 B CN110452252 B CN 110452252B
- Authority
- CN
- China
- Prior art keywords
- dihydroartemisinin
- thiosemicarbazide
- semicarbazide
- dmso
- nmr
- 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
- 229960002521 artenimol Drugs 0.000 title claims abstract description 43
- 229930016266 dihydroartemisinin Natural products 0.000 title claims abstract description 43
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 title claims abstract description 40
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 title claims description 47
- -1 thiosemicarbazone phenol derivative Chemical class 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 15
- 150000007659 semicarbazones Chemical class 0.000 claims abstract description 15
- 102000013691 Interleukin-17 Human genes 0.000 claims abstract description 13
- 108050003558 Interleukin-17 Proteins 0.000 claims abstract description 13
- 230000002365 anti-tubercular Effects 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 11
- 239000003472 antidiabetic agent Substances 0.000 claims abstract description 9
- 230000003178 anti-diabetic effect Effects 0.000 claims abstract description 6
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 150000002989 phenols Chemical class 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- GKLSXUGPECNEMX-UHFFFAOYSA-N 3-hydroxy-2-methylpyran-4-thione Chemical compound CC=1OC=CC(=S)C=1O GKLSXUGPECNEMX-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 229940127003 anti-diabetic drug Drugs 0.000 claims description 3
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 abstract description 9
- 150000003839 salts Chemical class 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 237
- 238000005481 NMR spectroscopy Methods 0.000 description 76
- 230000000694 effects Effects 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000004896 high resolution mass spectrometry Methods 0.000 description 19
- 238000012360 testing method Methods 0.000 description 16
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 12
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 12
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 11
- 230000004071 biological effect Effects 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 5
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 229960004191 artemisinin Drugs 0.000 description 3
- 229930101531 artemisinin Natural products 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 150000000138 dihydroartemisinin derivatives Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 102000000743 Interleukin-5 Human genes 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 102000000853 LDL receptors Human genes 0.000 description 2
- 108010001831 LDL receptors Proteins 0.000 description 2
- 108010044159 Proprotein Convertases Proteins 0.000 description 2
- 102000006437 Proprotein Convertases Human genes 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000000055 hyoplipidemic effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 150000003349 semicarbazides Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 240000000011 Artemisia annua Species 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- BJDCWCLMFKKGEE-KDTBHNEXSA-N Dihydroartemisinin (DHA) Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](O)[C@@H]4C BJDCWCLMFKKGEE-KDTBHNEXSA-N 0.000 description 1
- 101710172072 Kexin Proteins 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001512 anti-cytomegaloviral effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- JMSRBKPMLUGHCR-UHFFFAOYSA-N bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960001907 nitrofurazone Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003128 rodenticide Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003583 thiosemicarbazides Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
Classifications
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，或其消旋体、立体异构体、互变异构体、氮氧化物以及其药学上可接受的盐具有以下通式：
Description
技术领域
本发明涉及化学医药技术领域，具体涉及一种二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用。
背景技术
青蒿素是从植物青蒿中发现的萜类化合物。二氢青蒿素(DHA)是青蒿素的第一代衍生物，不仅结构独特，而且显示了比青蒿素更为优良的药学性质，是重要的临床抗疟药物。基于DHA的特殊结构和优异活性，对DHA的研究持续不断，目前主要集中在DHA新型衍生物的设计合成、DHA的旧分子或新分子的新活性探索。至今，众多DHA新型衍生物被合成出来，部分青蒿素衍生物已用于抗乳腺癌、结直肠癌、非小细胞肺癌等的临床试验中。研究还发现，某些DHA衍生物在抗病毒、抗菌增敏、抗艾滋病毒、抗巨细胞病毒及抗结核等疾病时表现出非常好的活性，显示了多靶点分子的潜质，值得进一步研究开发。
N,N＇-二取代脲类衍生物是众多天然产物或合成化合物中的一种重要组成成分，目前已运用于染料、杀虫剂、药物合成、农业化学等领域。脲类化合物具有广泛的生物活性，主要作为活性片段出现在大量药物或活性分子中，如苯巴比妥、苯妥英、卡马西平等。硫脲衍生物是医药化学中一类重要化合物，具有抗艾滋病、抗结核病、抗心律不齐、抑菌等生物活性。硫脲衍生物也是一类重要的有机合成中间体，可以合成多种杂环类化合物。
氨基脲作为有机合成原料，主要用于制备热敏记录纸上的光色染料，也用于医药、农药等有机合成的中间体，用于生产呋喃西林、呋喃妥因、肾上腺色腙、氢化泼尼松、氢化可的松等药物。硫代氨基脲是重要的农药原料，用于生产非选择性除草剂、杀虫剂、灭鼠剂和植物生长时间调节剂等。在医药领域，硫代氨基脲主要用于合成抗结核药氨硫脲、磺胺药物以及2-取代肼基-4-取代基噻唑类抗菌素等。
虽有文献报道了DHA取代缩氨(硫)脲衍生物，但是均为复杂结构；本发明将氨基脲或硫代氨基脲以简单形式引入DHA中，合成分子量不大、结构不复杂的DHA缩氨脲/缩氨硫脲衍生物TM9。
人类致力于更多、更有效的治疗疾病的新药，本发明提供了一类基于二氢青蒿素的与含缩氨脲/缩氨硫脲酚类反应得到的衍生物及其合成、应用，为新药制备及推广、疾病治疗起到了推动作用，可以应用到更为广泛的领域。
发明内容
本发明提供一种二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用。
本发明提供了一种二氢青蒿素与含缩氨脲/缩氨硫脲酚类反应生成的衍生物，或其消旋体、立体异构体、互变异构体、氮氧化物以及其药学上可接受的盐，所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物用TM9表示，结构式如下所示：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
较佳地，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
本发明还提供了所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，TM9的合成按以下反应方程式进行，包括以下步骤：
加入原料TM4、EtOH、氨基脲或氨基硫脲B，搅拌，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，即TM9。
较佳地，原料TM4和氨基脲或硫代氨基脲的物质的量比为(0.6～1.6):(2～4)，反应温度为3～20℃。
较佳地，所述反应温度为6～16℃。
较佳地，TM4的合成按以下反应方程式进行，包括以下步骤：
加入含羰基的取代苯酚、IM1、K2CO3和溶剂二甲基甲酰胺,加热、搅拌溶解，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素与含羰基酚的偶联物，即TM4。
较佳地，原料IM1和原料含羰基的取代苯酚的物质的量比为(1～2):(1～2.5)，反应温度为40～85℃。
本发明所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物或其消旋体、立体异构体、互变异构体、氮氧化物以及其药学上可接受的盐在抗结核、抗糖尿病、降脂和抑制白细胞介素-17药物中的应用。
较佳地，所述衍生物结构式中的n＝2、R1为H、R2为-CH3、X为S、m＝0(TM9-38)，n＝3、R1为-OCH3、R2为H、X为S、m＝0(TM9-25)，n＝2、R1为H、R2为-CH3、X为S、m＝2(TM9-40)，n＝2、R1为-OCH3、R2为H、X为S、m＝0(TM9-29)，n＝3、R1为H、R2为CH3、X为S、m＝0(TM9-32)时在抗结核药物中的应用。
较佳地，所述衍生物结构式中的n＝3、R1为H、R2为H、X为S、m＝0(TM9-23)，n＝2、R1为H、R2为H、X为S、m＝0(TM9-27,TM9-28)，n＝2、R1为-OCH3、R2为H、X为S、m＝0(TM9-29,TM9-30)，n＝3、R1为H、R2为-CH3、X为S、m＝2(TM9-35)，n＝2、R1为H、R2为-CH3、X为S、m＝2(TM9-40)时在抗糖尿病药物中的应用；
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0(TM9-2,TM9-3)，n＝3、R1为-OCH3、R2为H、X为O、m＝0(TM9-4)，n＝2、R1为H、R2为H、X为O、m＝0(TM9-7)，n＝2、R1为-OCH3、R2为H、X为O、m＝0(TM9-9)，n＝3、R1为H、R2为-CH3、X为O、m＝0(TM9-13)，n＝3、R1为H、R2为-CH3、X为O、m＝2(TM9-15)，n＝3、R1为H、R2为H、X为S、m＝0(TM9-23)，n＝3、R1为-OCH3、R2为H、X为S、m＝0(TM9-25)，n＝2、R1为H、R2为H、X为S、m＝0(TM9-28)，n＝2、R1为-OCH3、R2为H、X为S、m＝0(TM9-30)，n＝3、R1为H、R2为-CH3、X为S、m＝0(TM9-33)，n＝2、R1为H、R2为-CH3、X为S、m＝0(TM9-36)在降脂药物中的应用。
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0(TM9-2,TM9-3)，n＝2、R1为H、R2为H、X为O、m＝0(TM9-6)，n＝2、R1为H、R2为-CH2CH3、X为O、m＝0(TM9-19)，n＝2、R1为H、R2为-CH3、X为O、m＝2(TM9-20)时在抑制白细胞介素-17药物中的应用。
与现有技术相比，本发明的有益效果是：本发明提供了二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，该类衍生物通过合适的连接结构将二氢青蒿素与含羰基酚类连接、随后与氨基脲/氨基硫脲反应获得，合成方法简单，合成收率较高；经过生物活性实验测试，发现本发明的衍生物具有抗结核、抗糖尿病、降血脂及抑制白细胞介素-17等多种生物活性，具有很好的应用前景。
具体实施方式
下面对本发明的具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1、二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的制备
(1)中间体IM1的制备方法如下：
加入二氢青蒿素、乙醚以及溴代醇，在冰浴冷却下加入三氟化硼-乙醚(BF3.Et2O)，搅拌下反应5～20h，反应完成后，加入饱和NaHCO3终止反应，静置分层，水层用乙酸乙酯(EA)萃取，合并有机相，饱和食盐水洗涤，无水MgSO4干燥，抽滤，滤液减压旋蒸除去溶剂得粗品，粗品用石油醚-EA混合溶剂重结晶即得中间体IM1。
(2)TM4的制备方法如下：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
进一步地，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
在100mL圆底烧瓶中依次加入含羰基取代苯酚12mmol、DMF 15mL、K2CO3(25mmol)和IM1(10mmol)，40～85℃水浴搅拌反应，TLC监测反应进程。反应完全后，加入水20mL和EA15mL，分液，水层用EA 10mL萃取，合并有机相，5mL 2NNaOH洗两次，20mL水洗两次。无水MgSO4干燥，抽滤，减压旋蒸除去EA，多数得到浅黄色粘液，柱层析得纯品TM4。
(3)TM9的制备方法如下：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、烷基、烷氧基或烷胺基，R2为H、烷基或芳基，X为O或S，m＝0，1，2，3或4。
进一步地，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
在100mL圆底烧瓶中依次加入TM40.6～1.6mmol、EtOH 3mL、氨基脲或硫代氨基脲B2～4mmol，环境温度(6～16℃)搅拌反应，TLC监测反应进程。反应完全后，加入水20mL和EA15mL，分液，水层用EA 10mL萃取，合并有机相，水洗(20mL×2)。无水MgSO4干燥，抽滤，减压旋蒸除去EA，多数得到浅黄色粘液，干燥得纯品TM9，但少数反应需简单柱层析后才能得纯品TM9。
实施例2、二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物TM9-1～TM9-40的制备
依照实施例1所述的制备方法当n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2，制备出TM9-1～TM9-40一系列产物，各自的反应条件、产量、产物得率、产物熔点如表1所示：
表1 TM9系列化合物合成实验结果
实施例3、TM9-1～TM9-40的测试与表征
对实施例2制备的TM9-1～TM9-40系列产物进行了1H NMR(AV-300)、13C NMR(AV-75)和HR MS(Varian 7.0T)测试和表征，数据如下所示：
TM9-1(E)-2-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:10.21(1H,s),8.23(1H,s,NH),7.99(1H,d,J＝7.8Hz),7.29(1H,t,J＝7.2Hz),7.01(1H,d,J＝8.4Hz),6.92(1H,t,J＝7.2Hz),6.42(2H,s,NH2),5.11(1H,s),4.72(1H,d,J＝2.7Hz),4.12-4.00(3H,m),3.46-3.42(1H,m),2.39-2.35(1H,m),2.14-0.95(13H,m),1.25(3H,s),0.80(3H,d,J＝7.2Hz),0.72-0.65(3H,m).13C NMR(75MHz,DMSO)δ:156.80,156.42,134.73,130.18,125.42,123.09,120.56,112.09,103.25,100.49,86.85,80.38,64.38,62.82,51.94,43.77,36.21,36.04,34.00,30.57,28.48,25.56,24.06,20.30,12.81.HR MS calcd for C26H37N3O7[M+Na]+526.2529,found526.2532.
TM9-2(E)-2-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.26(1H,s),7.79(1H,s,NH),7.31-7.25(2H,m),7.19(1H,d,J＝7.5 Hz),6.90(1H,d,J＝7.5 Hz),6.51(2H,s,NH2),5.13(1H,s),4.75-4.65(1H,m),4.07-3.95(3H,m),3.42-3.37(1H,m),2.44-2.30(1H,m),2.16-2.08(1H,m),1.99-1.02(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.73-0.65(3H,m).13C NMR(75 MHz,DMSO)δ:158.95,156.78,139.10,136.34,129.60,119.70,115.47,111.07,103.27,100.43,86.78,80.41,64.19,62.90,51.91,43.77,36.24,36.03,33.98,30.52,28.46,25.65,24.09,20.21,12.80.HR MS calcd for C26H37N3O7[M+Na]+526.2529,found 526.2531.
TM9-3(E)-2-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepin o[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s),7.77(1H,s,NH),7.64(2H,d,J＝8.4 Hz),6.92(2H,d,J＝8.7Hz),6.43(2H,s,NH2),5.16(1H,s),4.70(1H,d,J＝3.0 Hz),4.08-3.90(3H,m),3.49-3.40(1H,m),2.40-2.35(1 H,m),2.17-2.08(1H,m),1.99-1.04(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.72-0.66(3H,m).13C NMR(75MHz,DMSO)δ:159.43,156.89,139.14,128.07,127.59,114.36,103.30,100.49,86.82,80.43,64.31,63.00,51.90,43.76,36.28,36.01,34.01,30.51,28.44,25.67,24.19,24.02,20.25,12.80.HR MScalcd for C26H37N3O7[M+Na]+526.2529,found 526.2532.
TM9-4(E)-2-(3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s),7.74(1H,s,NH),7.42(1H,s),7.04(1H,d,J＝7.2 Hz),6.91(1H,d,J＝8.1 Hz),6.51(2H,s,NH2),5.14(1H,s),4.69(1H,d,J＝3.3Hz),4.08-3.92(3H,m),3.82(3H,s),3.38-3.27(1H,m),2.39-2.34(1H,m),2.17-2.08(1H,m),1.99-1.01(12H,m),1.28(3H,s),0.82(3H,d,J＝7.5 Hz),0.73-0.66(3H,m).13C NMR(75MHz,DMSO)δ:156.92,149.25,139.44,127.79,120.71,112.00,108.15,103.21,100.43,86.84,80.44,64.84,62.95,55.61,51.90,43.79,36.29,36.07,34.01,30.50,28.55,25.69,24.20,24.00,20.27,12.80.HR MS calcd for C27H39N3O8[M+Na]+556.2635,found556.2632.
TM9-5(E)-2-(4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s),7.73(1H,s,NH),7.41(1H,s),7.05(1H,d,J＝8.4 Hz),6.93(1H,d,J＝8.1 Hz),6.50(2H,s,NH2),5.05(1H,s),4.69(1H,d,J＝3.0Hz),4.08-3.99(3H,m),3.78(3H,s),3.53-3.40(1H,m),2.39-2.34(1H,m),2.15-2.06(1H,m),1.99-1.02(12H,m),1.27(3H,s),0.81(3H,d,J＝7.5 Hz),0.67(3H,d,J＝4.8 Hz).13CNMR(75 MHz,DMSO)δ:156.91,150.09,148.50,139.45,127.64,120.89,111.16,108.82,103.12,100.32,86.79,80.41,64.71,62.71,55.55,51.89,43.77,36.13,36.06,33.93,30.50,28.51,25.67,24.13,24.09,20.24,12.79.HR MS calcd for C27H39N3O8[M+Na]+556.2635,found 556.2632.
TM9-6(E)-2-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.17(1H,s),8.21(1H,s,NH),7.99(1H,d,J＝7.5 Hz),7.30(1H,t,J＝7.2Hz),7.06(1H,d,J＝8.4 Hz),6.94(1H,t,J＝7.5 Hz),6.45(2H,s,NH2),5.27(1H,s),4.80(1H,d,J＝3.0 Hz),4.22-3.99(3H,m),3.72-3.68(1H,m),2.42-2.37(1H,m),2.21-2.11(1H,m),1.99-1.03(10H,m),1.29(3H,s),0.83(3H,d,J＝6.0 Hz),0.80(3H,d,J＝7.5 Hz).13C NMR(75 MHz,DMSO)δ:156.81,156.43,134.84,130.27,125.59,123.09,120.61,112.71,103.39,101.36,87.02,80.54,67.75,66.19,52.05,43.90,36.59,36.04,34.07,30.51,25.66,24.26,23.96,20.12,12.73.
TM9-7(E)-2-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.28(1H,s),7.78(1H,s,NH),7.34-7.25(2H,m),7.20(1H,d,J＝7.2 Hz),6.90(1H,d,J＝7.5 Hz),6.54(2H,s,NH2),5.35(1H,s),4.82-4.70(1H,m),4.21-3.97(3H,m),3.70-3.67(1H,m),2,43-2.33(1H,m),2.21-2.13(1H,m),1.99-1.09(10H,m),1.29(3H,s),0.86-0.80(6H,m).13C NMR(75 MHz,DMSO)δ:158.87,156.81,139.02,136.31,129.66,119.74,115.80,111.25,103.35,100.70,86.96,80.53,67.13,65.81,52.05,43.88,36.71,36.04,34.12,30.52,25.68,24.35,23.96,20.15,12.78.
TM9-8(E)-2-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.12,7.77(1H,s,NH),7.65(2H,d,J＝8.4 Hz),6.94(2H,d,J＝8.4 Hz),6.44(2H,s,NH2),5.36(1H,s),4.78(1H,d,J＝2.7Hz),4.18-3.97,3.71-3.67(1H,m),2.43-2.38(1H,m),2.23-2.13(1H,m),2.02-1.07(10,m),1.29(3H,s),0.87-0.82(6H,m).13C NMR(75 MHz,DMSO)δ:159.35,156.89,139.10,128.06,127.58,114.63,103.35,100.73,86.95,80.51,67.19,65.76,52.03,43.85,36.73,36.03,34.12,30.50,25.66,24.36,23.94,20.16,12.76.
TM9-9(E)-2-(3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.13(1H,s),7.75(1H,s,NH),7.44(1H,s),7.05(1H,d,J＝8.4 Hz),6.96(1H,d,J＝8.1 Hz),6.53(2H,s,NH2),5.39(1H,s),4.77(1H,d,J＝3.0Hz,),4.15-3.98(3H,m),3.81(3H,s),3.70-3.66(1H,m),2.42-2.37(1H,m),2.23-2.13(1H,m),2.02-1.07(10H,m),1.29(3H,s),0.87(3H,d,J＝6.0 Hz),0.83(3H,d,J＝7.2 Hz).13CNMR(75 MHz,DMSO)δ:156.91,149.38,149.15,139.38,127.87,120.77,112.67,108.53,103.27,100.66,86.98,80.56,67.72,65.57,55.75,52.08,43.95,36.47,36.06,34.22,30.50,25.66,24.34,23.90,20.17,12.72.
TM9-10(E)-2-(4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:10.13(1H,s),7.73(1H,s,NH),7.44(1H,s),7.07(1H,d,J＝8.4 Hz),6.94(1H,d,J＝8.4 Hz),6.53(2H,s,NH2),5.40(1H,s),4.78(1H,d,J＝3.0Hz),4.21-3.99(3H,m),3.77(3H,s),3.71-3.67(1H,m),2.42-2.37(1H,m),2.22-2.13(1H,m),2.02-1.07(10H,m),1.29(3H,s),0.87(3H,d,J＝6.0 Hz),0.81(3H,d,J＝7.2 Hz).13CNMR(75 MHz,DMSO)δ:156.97,150.11,148.38,139.37,127.68,120.96,111.49,109.35,103.31,100.61,87.00,80.60,67.67,65.70,55.69,52.11,43.99,36.52,36.09,34.25,30.54,25.69,24.35,23.95,20.17,12.74.
TM9-11(E)-2-(1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.21(1H,s,NH),7.39(1H,dd,J＝1.2 Hz and 7.5 Hz),7.30(1H,t,J＝7.5Hz),7.01(1H,d,J＝8.1 Hz),6.92(1H,t,J＝7.5 Hz),6.31(2H,s,NH2),5.15(1H,s),4.69(1H,d,J＝3.0 Hz),4.10-3.86(3H,m),3.45-3.36(1H,m),2.40-2.35(1H,m),2.15-1.15(13H,m),2.14(3H,s),1.26(3H,s),0.82(3H,d,J＝7.2 Hz),0.74(3H,d,J＝5.1 Hz).13C NMR(151 MHz,DMSO)δ:157.28,156.39,145.85,129.62,129.37,129.03,120.25,111.85,103.25,100.53,86.83,80.37,64.40,63.21,51.96,43.77,36.38,35.96,34.03,30.51,28.68,25.57,24.11,24.04,21.05,20.17,12.75.HR MS calcd forC27H39N3O7[M+Na]+540.2684,found540.2684.
TM9-12(E)-2-(1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.36(1H,s,NH),7.46(1H,d,J＝7.8 Hz),7.30-7.24(2H,m),6.91(1H,d,J＝7.8 Hz),6.49(2H,s,NH2),5.13(1H,s),4.70(1H,d,J＝3.3 Hz),4.13-3.95(3H,m),3.41-3.37(1H,m),2.40-2.35(1H,m),2.17(3H,s),2.12-2.06(1H,m),1.99-1.00(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.69-0.58(3H,m).13C NMR(151MHz,DMSO)δ:158.66,157.31,143.87,139.79,129.17,118.49,114.10,111.97,103.24,100.43,86.78,80.38,64.17,62.88,51.89,43.77,36.20,36.03,33.98,30.50,28.44,25.64,24.04,24.01,20.16,13.44,12.75.HR MS calcd for C27H39N3O7[M+Na]+540.2684,found 540.2687.
TM9-13(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.21(1H,s,NH),7.77(2H,d,J＝8.4 Hz),6.89(2H,d,J＝8.7 Hz),6.44(2H,s,NH2),5.16(1H,s),4.70(1H,d,J＝2.4 Hz),4.06-3.90(3H,m),3.42-3.37(1H,m),2.46-2.37(1H,m),2.14-1.04(13H,m),2.14(3H,s),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.72-0.63(3H,m).13C NMR(151 MHz,DMSO)δ:158.99,157.38,143.82,130.87,127.32,113.82,103.25,100.48,86.79,80.39,64.23,63.03,51.91,43.75,36.23,36.00,33.99,30.47,28.45,25.62,24.12,23.97,20.09,13.16,12.74.HR MS calcd forC27H39N3O7[M+Na]+540.2684,found 540.2688.
TM9-14(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.36(1H,s,NH),7.77(2H,d,J＝8.1 Hz),6.90(2H,d,J＝8.1 Hz),6.44(2H,s,NH2),5.17(1H,s),4.76-4.64(1H,m),4.06-3.93(3H,m),3.42-3.39(1H,m),2.76-2.62(2H,m),2.44-2.30(1H,m),2.17-2.09(1H,m),1.99-1.07(12H,m),1.28(3H,s),1.76(3H,t,J＝6.9 Hz)0.83(3H,d,J＝7.2 Hz),0.72-0.62(3H,m).13C NMR(151MHz,DMSO)δ:158.92,157.33,147.89,129.61,127.33,113.94,103.25,100.47,86.79,80.39,64.21,63.02,51.91,43.75,36.26,36.00,34.00,30.48,28.45,25.62,24.13,23.97,20.75,20.12,12.74,10.56.
TM9-15(E)-2-(4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-ylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:8.91(1H,s,NH),7.13(2H,d,J＝8.1 Hz),6.81(2H,d,J＝8.1 Hz),6.17(2H,s,NH2),5.20(1H,s),4.70(1H,d,J＝2.1 Hz),4.06-3.90(3H,m),3.42-3.38(1H,m),2.75-2.63(2H,m),2.45-2.40(3H,m),2.18-2.09(1H,m),1.99-1.04(12H,m),1.79(3H,s),1.28(3H,s),0.82(3H,d,J＝6.9 Hz),0.78-0.70(3H,m).13C NMR(151MHz,DMSO)δ:157.38,156.74,148.59,133.47,129.13,114.03,103.25,100.49,86.81,80.41,64.08,63.22,51.95,43.78,40.01,36.29,36.02,34.03,31.00,30.49,28.62,25.63,24.15,23.97,20.16,14.08,12.75.HR MS calcd for C29H43N3O7[M+Na]+568.2999,found 568.2996.
TM9-16(E)-2-(1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300 MHz,DMSO)δ:9.24(1H,s,NH),7.37-7.29(2H,m),7.05(1H,d,J＝8.1Hz),6.93(1H,t,J＝7.5 Hz),6.30(2H,s,NH2),5.33(1H,s),4.76(1H,d,J＝3.0 Hz),4.19-3.98(3H,m),3.71-3.66(1H,m),2.43-2.38(1H,m),2.21-2.09(1H,m),2.14(3H,s),2.02-1.06(10H,m),1.30(3H,s),0.87(3H,d,J＝6.0 Hz),0.82(3H,d,J＝7.2 Hz).13C NMR(151MHz,DMSO)δ:157.23,156.38,146.04,129.65,129.55,129.20,120.30,112.17,103.34,101.09,86.97,80.48,67.39,66.39,52.07,43.85,36.61,36.03,34.04,30.45,25.63,24.22,23.91,20.17,17.35,12.69.
TM9-17(E)-2-(1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:9.34(1H,s,NH),7.38(1H,d,J＝7.8Hz),7.33(1H,s),7.27(1H,t,J＝8.1Hz),6.92(1H,dd,J＝1.5Hz and 7.8Hz),6.50(2H,s,NH2),5.35(1H,s),4.77(1H,d,J＝3.3Hz),4.21-3.97(3H,m),3.70-3.67(1H,m),2.42-2.37(1H,m),2.21-2.13(1H,m),2.16(3H,s),1.99-1.11(10H,m),1.30(3H,s),0.83-0.81(6H,m).13C NMR(151MHz,DMSO)δ:158.56,157.52,143.78,139.81,129.19,118.56,114.63,112.01,103.30,100.67,86.92,80.48,67.13,65.77,52.03,43.86,36.68,36.01,34.10,30.48,25.63,24.28,23.91,20.09,13.46,12.72.
TM9-18(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:9.22(1H,s,NH),7.78(2H,d,J＝8.7Hz),6.91(2H,d,J＝8.7H),6.46(2H,s,NH2),5.36(1H,s),4.78(1H,d,J＝3.0Hz),4.17-3.97(3H,m),3.72-3.68(1H,m),2.41-2.38(1H,m),2.23-2.14(1H,m),2.14(3H,s),2.02-1.07(10H,m),1.29(3H,s),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:158.91,157.40,143.83,130.90,127.34,114.09,103.30,100.73,86.93,80.47,67.13,65.75,52.02,43.83,36.68,36.01,34.09,30.47,25.63,24.32,23.89,20.11,13.20,12.71.
TM9-19(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:9.36(1H,s,NH),7.77(2H,d,J＝8.7Hz),6.91(2H,d,J＝8.4Hz,),6.44(2H,s,NH2),5.35(1H,s),4.78(1H,d,J＝3.0Hz),4.18-3.97(3H,m),3.71-3.68(1H,m),2.70(2H,q,J＝7.2Hz),2.41-2.39(1H,m),2.22-2.13(1H,m),2.01-1.07(10H,m),1.29(3H,s),0.98(3H,t,J＝7.2Hz),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:158.86,157.36,148.00,130.08,127.38,114.23,103.30,100.72,86.93,80.48,67.12,65.73,52.03,43.84,36.69,36.02,32.47,30.48,25.63,24.32,23.90,21.05,20.12,12.72,10.55.25个C
TM9-20(E)-2-(4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-ylidene)hydrazinecarboxamide
1H NMR(300MHz,DMSO)δ:8.90(1H,s,NH),7.13(2H,d,J＝8.4Hz),6.83(2H,d,J＝8.4Hz),6.17(2H,s,NH2),5.36(1H,s),4.77(1H,d,J＝3.0Hz),4.09-3.94(3H,m),3.69-3.62(1H,m),2.75-2.70(2H,m),2.45-2.39(3H,m),2.23-2.13(1H,m),2.09-1.07(10H,m),1.79(3H,s),1.29(3H,s),0.87(3H,d,J＝6.0Hz),0.83(3H,d,J＝7.2 Hz).13C NMR(75 MHz,DMSO)δ:157.47,156.73,148.60,133.65,129.22,114.34,103.35,100.71,86.96,80.53,67.05,65.75,52.07,43.90,40.13,36.73,36.06,34.16,31.04,30.53,25.67,24.37,23.96,20.19,14.13,12.78.
TM9-21(E)-2-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.48(1H,s),8.50(1H,s,NH2),8.11-8.09(2H,m),7.85(1H,s,NH2),7.33(1H,t,J＝7.2 Hz),7.02(1H,d,J＝8.1 Hz),6.93(1H,t,J＝7.5 Hz),5.06(1H,s),4.72(1H,d,J＝3.0 Hz),4.12-4.02(3H,m),3.46-3.43(1H,m),2.37-2.35(1H,m),2.07-1.08(13H,m),1.27(3H,s),0.80(3H,d,J＝7.2 Hz),0.65(3H,d,J＝6.0 Hz).13CNMR(75 MHz,DMSO)δ:177.52,157.13,138.02,131.09,125.88,122.45,120.56,112.08,103.22,100.40,86.77,80.33,64.24,62.43,51.92,43.73,36.09,36.07,33.97,30.57,28.32,25.64,24.04,20.33,12.81.HR MS calcd for C26H37N3O6S[M+Na]+542.2301,found542.2304.
TM9-22(E)-2-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.44(1H,s),8.25(1H,s,NH2),8.05(1H,s,NH2),8.00(1H,s,NH),7.43(1H,s),7.33-7.24(2H,m),6.94(1H,d,J＝7.8 Hz),5.12(1H,s),4.70(1H,d,J＝2.7 Hz),4.69-3.93(3H,m),3.42-3.36(1H,m),2.37-2.36(1H,m),2.16-2.06(1H,m),1.99-1.01(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.71-0.62(3H,m).13C NMR(75MHz,CDCl3)δ:177.93,159.00,142.16,135.72,129.69,120.67,116.49,111.41,103.26,100.43,86.77,80.41,64.26,62.85,51.90,43.75,36.25,36.03,33.96,30.52,28.46,25.66,24.10,20.23,12.81.HR MS calcd for C26H37N3O6S[M+Na]+542.2301,found542.2399.
TM9-23(E)-2-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.31(1H,s),8.12(1H,s,NH2),7.99(1H,s,NH),7.92(1H,s,NH2),7.73(2H,d,J＝8.7 Hz),6.94(2H,d,J＝8.7 Hz),5.16(1H,s),4.70(1H,d,J＝3.0 Hz),4.07-3.90(3H,m),3.42-3.37(1H,m),2.39-2.37(1H,m),2.17-2.09(1H,m),1.99-1.04(12H,m),1.28(3H,s),0.82(3H,d,J＝7.2 Hz),0.73-0.64(3H,m).13C NMR(75 MHz,DMSO)δ:177.57,160.09,142.18,128.95,126.89,114.44,103.30,100.48,86.81,80.41,64.38,62.96,51.88,43.75,36.28,36.02,33.99,30.50,28.40,25.66,24.19,24.01,20.26,12.79.HR MS calcd for C26H37N3O6S[M+Na]+542.2301,found 542.2302.
TM9-24(E)-2-(3-Methoxy-4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:8.17(1H,s,NH2),8.01(1H,s,NH2),7.96(1H,s,NH),7.52(1H,s),7.10(1H,d,J＝7.8 Hz),6.93(1H,d,J＝8.1 Hz),5.13(1H,s),4.75-4.62(1H,m),4.06-3.97(3H,m),3.83(3H,s),3.61-3.42(1H,m),2.43-2.29(m,1H),2.18-2.09(m,1H),1.99-1.02(12H,m),1.28(3H,s),0.82(3H,d,J＝6.6 Hz),0.73-0.65(3H,m).13C NMR(75MHz,DMSO)δ:177.48,149.98,149.31,142.57,127.04,122.06,111.89,108.39,103.20,100.42,86.83,80.42,64.85,62.89,55.70,51.88,43.77,36.28,36.07,34.00,30.50,28.48,25.70,24.20,23.98,20.28,12.80.HR MS calcd for C27H39N3O7S[M+Na]+572.2406,found 572.2409.
TM9-25(E)-2-(4-Methoxy-3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.30(1H,s),8.16(1H,s,NH2),8.01(1H,s,NH2),7.95(1H,s,NH),7.52(1H,s,),7.20-7.04(1H,m),7.02-6.89(1H,m),5.03(1H,s),4.75-4.60(1H,m),4.24-3.95(3H,m),3.79(3H,s),3.56-3.48(1H,m),2.44-2.28(m,1H),2.10-0.99(13H,m),1.27(3H,s),0.90-0.75(3H,m),0.74-0.56(3H,m).13C NMR(75 MHz,DMSO)δ:177.46,150.82,148.60,142.58,126.92,122.30,111.09,108.99,103.13,100.29,86.78,80.42,64.74,62.58,55.61,51.88,43.76,36.10,36.08,33.93,30.52,28.46,25.70,24.13,20.31,12.83.HR MS calcd for C27H39N3O7S[M+Na]+572.2406,found 572.2408.
TM9-26(E)-2-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.42(1H,s),8.45(1H,s,NH),8.14-8.08(2H,m),7.92(1H,s,NH2),7.34(1H,t,J＝7.2 Hz),7.07(1H,d,J＝8.1 Hz),6.94(1H,t,J＝7.5 Hz),5.29(1H,s),4.86-4.78(1H,m),4.22-4.01(3H,m),3.79-3.67(1H,m),2.45-2.33(1H,m),2.20-2.11(1H,m),2.02-1.12(10,m),1.30(3H,s),0.83(3H,d,J＝4.5 Hz),0.77(3H,d,J＝6.9 Hz).13C NMR(75 MHz,DMSO)δ:177.76,157.25,138.05,131.18,126.08,122.49,120.62,112.81,103.38,101.46,87.02,80.54,68.05,66.31,52.06,43.88,36.56,36.05,34.07,30.50,25.69,24.25,23.90,20.13,12.72.
TM9-27(E)-2-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.46(1H,s),8.26(1H,s,NH2),8.07(1H,s,NH2),8.00(1H,s,NH),7.45(1H,s),7.33-7.24(2H,m),6.95(1H,d,J＝7.8 Hz),5.34(1H,s),4.77(1H,d,J＝3.0 Hz),4.33-4.13(2H,m),4.06-3.97(1H,m),3.71-3.67(1H,m),2.42-2.37(1H,m),2.22-2.10(1H,m),2.01-1.02(10,m),1.29(3H,s),0.85(3H,d,J＝6.0 Hz),0.81(3H,d,J＝7.5 Hz).13C NMR(75 MHz,DMSO)δ:177.95,158.91,142.05,135.66,129.72,120.66,116.75,111.62,103.33,100.71,86.94,80.51,67.17,65.84,52.04,43.86,36.70,36.03,34.12,30.49,25.67,24.33,23.95,20.14,12.75.
TM9-28(E)-2-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.33(1H,s),8.13(1H,s,NH2),7.99(1H,s,NH),7.93(1H,s,NH2),7.73(2H,d,J＝8.4 Hz),6.96(2H,d,J＝8.4 Hz),5.35(1H,s),4.78(1H,d,J＝2.7Hz),4.28-4.10(2H,m),4.06-3.97(1H,m),3.71-3.68(1H,m),2.41-2.39(1H,m),2.22-2.13(1H,m),2.02-1.10(10,m),1.29(3H,s),0.87-0.81(6H,m).13C NMR(75 MHz,DMSO)δ:177.59,160.02,142.15,128.96,126.88,114.7123,103.36,100.72,86.95,80.51,67.24,65.73,52.02,43.84,36.74,36.04,34.12,30.50,25.67,24.37,23.94,20.18,12.77.
TM9-29(E)-2-(3-Methoxy-4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.33(1H,s),8.18(1H,s,NH2),8.03(1H,s,NH2),7.96(1H,s,NH),7.53(1H,s),7.12(1H,d,J＝8.1 Hz),6.98(1H,d,J＝8.1 Hz),5.38(1H,s),4.85-4.69(1H,m),4.17-3.99(3H,m),3.82(3H,s),3.70-3.67(1H,m),2.46-2.33(m,1H),2.22-2.14(m,1H),1.99-1.10(10H,m),1.29(3H,s),0.87(3H,d,J＝5.7 Hz),0.83(3H,d,J＝7.2 Hz).13C NMR(75 MHz,DMSO)δ:177.52,149.86,149.38,142.47,127.08,122.11,112.44,108.67,103.29,100.61,86.98,80.57,67.17,65.52,55.84,52.07,43.94,36.47,36.06,34.22,30.51,25.67,24.35,23.91,20.18,12.74.
TM9-30(E)-2-(4-Methoxy-3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethoxy)benzylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:11.33(1H,s),8.18(1H,s,NH2),8.02(1H,s,NH2),7.95(1H,s,NH),7.54(1H,s),7.13(1H,d,J＝7.5 Hz),6.96(1H,d,J＝8.4 Hz),5.39(1H,s),4.77(1H,d,J＝3.0 Hz),4.23-3.99(3H,m),3.78(3H,s),3.71-3.67(1H,m),2.42-2.37(m,1H),2.22-2.09(m,1H),2.02-1.06(10H,m),1.29(3H,s),0.87(3H,d,J＝6.0 Hz),0.81(3H,d,J＝7.2 Hz).13C NMR(75 MHz,DMSO)δ:177.56,150.80,148.43,142.41,126.92,122.19,111.45,109.65,103.24,100.60,86.96,80.54,67.67,65.70,55.70,52.07,43.94,36.48,36.05,34.21,30.48,25.64,24.30,23.90,20.11,12.67.
TM9-31(E)-2-(1-(2-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:10.12(1H,s,NH),8.26(1H,s,NH2),7.60(1H,s,NH2),7.49(1H,d,J＝7.2Hz),7.31(1H,t,J＝7.5 Hz),7.03(1H,d,J＝8.1 Hz),6.93(1H,t,J＝7.2 Hz),5.12(1H,),4.69(1H,d,J＝2.4 Hz),4.08-3.90(3H,m),3.65-3.52(1H,m),2.43-2.35(1H,m),2.27(3H,s),2.23-1.031.99-1.03(13H,m),1.28(3H,s),0.82(3H,d,J＝6.9Hz),0.76-0.68(3H,m).13C NMR(75 MHz,DMSO)δ:178.83,156.64,149.81,130.24,129.64,128.29,120.30,111.87,103.30,100.44,86.81,80.36,64.35,62.98,51.94,43.76,36.32,35.95,34.04,30.52,28.55,25.64,24.13,24.06,20.26,18.11,12.81.HR MS calcd forC27H39N3O6S[M+Na]+556.2457,found556.2409.
TM9-32(E)-2-(1-(3-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:10.23(1H,s,NH),8.32(1H,s,NH2),7.88(1H,s,NH2),7.48(1H,d,J＝7.5Hz),7.40(1H,s),7.29(1H,t,J＝7.8Hz),6.95(1H,d,J＝7.8Hz),5.13(1H,s),4.72-4.65(1H,m),4.10-3.94(3H,m),3.41-3.38(1H,m),2.43-2.32(1H,m),2.28(3H,s),2.15-0.99(13H,m),1.28(3H,s),0.82(3H,d,J＝7.2Hz),0.71-0.66(3H,m).13C NMR(151MHz,DMSO)δ:178.91,158.66,147.68,139.13,129.24,119.12,114.95,112.50,103.24,100.41,86.75,80.37,67.02,64.24,51.87,43.74,36.21,36.00,33.97,30.48,28.42,25.63,24.03,24.01,20.18,14.14,12.75.HR MS calcd for C27H39N3O6S[M+Na]+556.2457,found 556.2410.27个C
TM9-33(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:10.14(1H,s,NH),8.23(1H,s,NH2),7.89(3H,d,J＝8.7Hz),6.90(2H,d,J＝8.7Hz),5.15(1H,s),4.70(1H,d,J＝3.0Hz),4.07-3.91(3H,m),3.41-3.35(1H,m),2.40-2.35(1H,m),2.25(3H,s),2.17-2.09(1H,m),1.99-1.03(12H,m),1.22(3H,s),0.82(3H,d,J＝7.2Hz),0.69-0.63(3H,m).13C NMR(151MHz,DMSO)δ:178.62,159.61,147.68,130.10,128.11,113.86,103.25,100.47,86.78,80.37,64.28,63.00,51.88,43.74,36.23,35.99,33.98,30.46,28.40,25.63,24.12,23.96,20.10,13.78,12.74.HR MS calcd for C27H39N3O6S[M+Na]+556.2457,found 556.2410.
TM9-34(E)-2-(1-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)propylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:10.25(1H,s,NH),8.24(1H,s,NH2),7.88(3H,d,J＝8.4Hz),6.91(2H,d,J＝8.7Hz),5.16(1H,s),4.70(1H,d,J＝3.0Hz),4.06-3.91(3H,m),3.42-3.36(1H,m),2.84(2H,q,J＝6.9Hz),2.40-2.37(1H,m),2.17-2.09(1H,m),1.99-1.07(12H,m),1.28(3H,s),1.01(3H,t,J＝7.5Hz),0.82(3H,d,J＝7.2Hz),0.71-0.64(3H,m).13CNMR(151MHz,DMSO)δ:178.64,159.56,151.56,128.81,128.18,114.00,103.26,100.47,86.80,80.39,64.27,62.99,51.90,43.75,36.27,36.00,33.99,30.48,28.41,25.63,24.13,23.98,20.14,19.08,12.75,11.08.HR MS calcd for C28H41N3O6S[M+Na]+570.2614,found 570.2615.
TM9-35(E)-2-(4-(4-(3-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)propoxy)phenyl)butan-2-ylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:9.96(1H,s,NH),8.06(1H,s,NH2),7.45(1H,s,NH2),7.132H,d,J＝7.2Hz),6.812H,d,J＝6.9 Hz),5.20(1H,s),4.75-4.65(1H,m),3.98-3.90(3H,m),3.46-3,38(1H,m),2.75-2.65(2H,m),2.50-2.38(3H,m),2.18-1.07(13H,m),1.91(3H,s),1.28(3H,s),0.82(3H,d,J＝6.0 Hz),0.78-0.71(3H,m).13C NMR(75 MHz,DMSO)δ:178.49,156.78,153.64,133.33,129.19,114.03,103.29,100.48,86.83,80.44,64.06,63.19,51.95,43.79,40.07,36.30,36.04,34.05,30.75,30.52,28.61,25.67,24.19,24.01,20.23,16.75,12.81.HR MS calcd for C29H43N3O6S[M+Na]+584.2770,found584.2773.
TM9-36(E)-2-(1-(2-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:10.11(1H,s,NH),8.21(1H,s,NH2),7.64(1H,s,NH2),7.44(1H,d,J＝7.5Hz),7.35(1H,t,J＝7.5 Hz),7.07(1H,d,J＝8.1 Hz),6.94(1H,d,J＝7.5 Hz),5.33(1H,s),4.76(1H,d,J＝2.7Hz),4.21-3.98(3H,m),3.69-3.58(1H,m),2.44-2.34(1H,m),2.26(3H,s),2.20-1.09(11H,m),1.31(3H,s),0.87-0.81(6H,m).13C NMR(151MHz,DMSO)δ:178.91,156.63,150.15,130.24,129.80,128.51,120.33,112.30,103.37,101.03,86.97,80.47,67.49,66.30,52.06,43.84,36.64,36.02,34.06,30.45,25.64,24.26,23.91,20.18,17.90,12.71.
TM9-37(E)-2-(1-(3-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarbothioamide
1H NMR(300 MHz,DMSO)δ:10.23(1H,s,NH),8.33(1H,s,NH2),7.94(1H,s,NH2),7.48-7.43(2H,m),7.29(1H,t,J＝8.1 Hz),6.96(1H,dd,J＝1.5 Hz and 8.1 Hz),5.35(1H,s),4.78(1H,d,J＝3.3 Hz),4.23-3.97(3H,m),3.71(1H,m),2.42-2.34(1H,m),2.28(3H,s),2.22-2.09(1H,m),2.01-1.09(10H,m),1.29(3H,s),0.85-0.81(6H,m).13C NMR(151MHz,DMSO)δ:178.92,158.58,147.66,139.16,129.25,119.21,115.53,112.47,103.30,100.68,86.91,80.47,67.18,65.78,52.03,43.85,36.69,36.01,34.10,30.47,25.63,24.28,23.91,20.10,14.18,12.71.
TM9-38(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)ethylidene)hydrazinecarbothioamide
1HNMR(300MHz,DMSO)δ:10.14(1H,s,NH),8.23(1H,s,NH2),7.89(3H,d,J＝8.1Hz),6.92(2H,d,J＝8.4Hz),5.35(1H,s),4.84-4.73(1H,m),4.19-3.97(3H,m),3.72-3.68(1H,m),2.46-2.34(1H,m),2.26(3H,s),2.18-2.09(1H,m),2.02-1.15(10H,m),1.29(3H,s),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:178.64,159.54,147.71,130.13,128.13,114.12,103.30,100.72,86.93,80.46,67.17,65.72,52.01,43.82,36.69,36.01,34.09,30.46,25.62,24.32,23.89,20.11,13.82,12.70.
TM9-39(E)-2-(1-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)propylidene)hydrazinecarbothioamide
1HNMR(300MHz,DMSO)δ:10.25(1H,s,NH),8.23(1H,s,NH2),7.87(3H,d,J＝8.4Hz),6.92(2H,d,J＝8.7Hz),5.35(1H,s),4.78(1H,d,J＝3.0Hz),4.19-3.97(3H,m),3.72-3.68(1H,m),2.91-2.76(2H,m),2.42-2.39(1H,m),2.22-2.13(1H,m),2.09-1.15(10H,m),1.29(3H,s),1.00(3H,t,J＝7.2Hz),0.86-0.82(6H,m).13C NMR(151MHz,DMSO)δ:178.66,159.48,151.63,128.82,128.22,114.27,103.30,100.72,86.92,80.47,67.15,65.69,52.02,43.83,36.69,36.01,34.09,30.47,25.63,24.32,23.90,20.76,20.12,12.71,11.05.
TM9-40(E)-2-(4-(4-(2-(((3R,6R,8aS,9R,10S,12R,12aR)-3,6,9-Trimethyldecahydro-3H-3,12-epoxy[1,2]dioxepi no[4,3-i]isochromen-10-yl)oxy)ethoxy)phenyl)butan-2-ylidene)hydrazinecarbothioamide
1H NMR(300MHz,DMSO)δ:9.96(1H,s,NH),8.06(1H,s,NH2),7.45(1H,s,NH2),7.13(2H,d,J＝8.1Hz),6.83(2H,d,J＝8.1Hz),5.37(1H,s),4.80-4.71(1H,m),4.09-3.94(3H,m),3.69-3.60(1H,m),2.79-2.66(2H,m),2.48-2.39(3H,m),2.22-2.13(1H,m),2.02-1.03(10H,m),1.91(3H,s),1.31(3H,s),0.87(3H,d,J＝6.0Hz),0.83(3H,d,J＝7.5Hz).13C NMR(75MHz,DMSO)δ:178.50,156.73,153.62,133.46,129.21,114.34,103.33,100.70,86.94,80.52,67.05,65.74,52.05,43.88,40.08,36.72,36.05,34.14,30.74,30.51,25.66,24.36,23.95,20.18,16.75,12.77.
实施例4、TM9目标分子抗结核活性测试
美国礼来制药(Eli Lilly and Company)公司对实施例2制备出的TM9-1～TM9-40样品的抗结核活性进行了测试，首先测试单浓度样品对结核分枝杆菌的百分抑制率；其次筛选出高活性分子进行多浓度测试；最后对多种细胞进行测试。测试结果如表2所示。
表2 TM9系列目标分子对结核分枝杆菌H37Rv的抑制率(抗结核)
表3 部分TM9目标分子对HELA Cytotox的抑制率
抗结核活性筛选结果显示(见表2、表3)，在20μM样品测试浓度下，40个化合物中有18个目标分子活性超过60％，其中有16个超过80％，对结核分支杆菌表现出较强的抑制作用；发现X为硫原子(缩氨硫脲)的活性普遍高于X为氧原子(缩氨脲)，同一类型结构中对位间位者的活性强于邻位者；更重要的是，二氢青蒿素和缩氨脲/缩氨硫脲酚类两者本身均无抗结核活性，但二氢青蒿素与某些缩氨脲/缩氨硫脲酚类的偶联物(目标化合物)却具有中等或很强的生物活性。这是首次发现DHA的某些缩氨脲/缩氨硫脲酚类衍生物具有抗结核活性。值得注意的是，TM9-38,TM9-25,TM9-40,TM9-29,TM9-32毒性很低，值得进一步开发。
实施例5、TM9目标分子的胰高血糖素样肽-1(GLP-1)活性测试
目标分子的GLP-1活性是由美国礼来制药公司进行测试的。本研究测试的是目标分子的GLP-1分泌结果。实验操作如下：
实验之前,先把人源NCI-H716细胞的培养基换成分化培养基。实验当天,首先用含有BSA和DPP-IV抑制剂(终浓度分别为0.1％和1％)的HBSS缓冲液洗细胞2遍,然后用该缓冲液(含有终浓度分别为0.1％和1％的BSA和DPP-IV抑制剂的HBSS缓冲液)重悬细胞。接下来,把细胞按照10000个细胞/50μL/孔的密度接种到包被了多聚D-赖氨酸的透明底黑色384孔板中。
待测化合物配制：待测化合物起始浓度为40μM,按照3倍梯度往下稀释。
化合物量效曲线确定：将上面配制好的化合物加到之前已经接种好细胞的384孔板孔中,然后在37℃培养2小时。在化合物刺激下,细胞分泌GLP-1到培养基中。细胞分泌的GLP-1用384孔板格式的Alpha LISA assay试剂盒来定量。信号采集用的是Perkin Elmer公司的全功能酶标仪Envision。采集到的信号再通过GLP-1标准曲线拟合计算出细胞合成的GLP-1多肽的量。
相对激动百分比的计算：以能激起细胞分泌最多GLP-1的化合物为标准,其余待测化合物的每个数据点得到的信号和标准化合物的最高信号(Maximum response)相除得出相对激动百分比。激动率(stimulation(％))和抑制率(inhibition(％))的计算公式如下所示：
其中，Max和Min的定义根据每个实验的最高信号和最低信号来定。IC50或EC50的计算是通过把计算出来的激动率或抑制率用standard 4parameter logistic andnon-linear regression拟合方程拟合算出。实验结果如表4、表5所示：
表4 TM9目标化合物的GLP-1百分激动活性
表5 部分TM9目标化合物GLP-1激动活性的EC50值
由目标分子的胰高血糖素样肽-1活性测试结果显示(见表4、表5)，在20μM样品测试浓度下，40个化合物中有11个目标分子活性超过30％，其中有7个超过60％，活性最好为TM9-25，达到了70.5％，生物活性较佳；其中，X为硫原子(缩氨硫脲)的活性普遍高于X为氧原子(缩氨脲)；TM9-35和TM9-40的EC50值均低于1μM。更重要的是，二氢青蒿素和缩氨脲/缩氨硫脲酚类两者本身均无GLP-1这方面的活性，但二氢青蒿素与某些缩氨脲/缩氨硫脲酚类的偶联物(目标化合物)却具有中等或很强的生物活性。这是首次发现DHA的某些缩氨脲/缩氨硫脲酚类衍生物具有GLP-1的生物活性，可以开发为抗糖尿病药物。
实施例6、TM9降血脂活性研究
蛋白转化酶枯草溶菌素9(Proprotein convertase subtilisin/kexin type 9，PCSK9)是2003年发现的一个脂质代谢调节蛋白，属于前蛋白转化酶(proproteinconvertase，PC)家族,由信号肽、前结构域、催化结构域和羧基末端结构域组成，在肝脏、小肠和肾脏中表达量较多，皮肤、神经系统中少量表达。大量研究发现，PCSK9能介导低密度脂蛋白受体(low density lipoprotein receptor,LDLR)降解，调节血浆低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平。因此，抑制或降低PCSK9水平的治疗方法可有效治疗高胆固醇血症，目前PCSK9作为一个新的治疗靶点已成为高胆固醇血症研究的热点。
美国礼来制药公司公司对部分TM9进行PCSK9抑制活性测试，在5μM的样品浓度下，测定了目标分子的PCSK9抑制活性，活性结果见表6、表7。
表6 部分TM9目标化合物的PCSK9(Eff-1)的抑制活性结果
表7 部分TM9目标化合物PCSK抑制活性的IC50值
由表6发现，当样品浓度为5μM时，40个分子中，31个分子的Basal_PCSK9 HepG2抑制活性超过70％，24个分子的抑制活性高于80％，且这些分子中38个分子的细胞毒性低于15％。从表7发现，对Basal_PCSK9 HepG2细胞，40个分子中有20个分子的IC50值低于4.8μM，13个分子的IC50值低于3.0μM，其中TM9-2和TM9-31的IC50值低至0.730μM和0.867μM；结构分析发现，含硫脲结构单元的分子的活性强于含脲结构单元的分子；此外，这些分子的细胞毒性很低，毒性最低者其IC50>50μM，具有优秀的应用潜力。本发明首次发现DHA与氨基脲/氨基硫脲酚类反应生成的衍生物具有降血脂活性。
实施例7、TM9目标分子的白细胞介素-17(IL-17)活性测试
TM9的化合物的白细胞介素-17(IL-17)活性委托美国礼来公司Open InnovationDrug Discovery(OIDD)program进行测试。结果见表8
表8 TM9目标化合物的IL-17活性结果
表8活性结果显示：TM9系列的目标分子在10μM的样品浓度下对IL-17有中等偏上的抑制作用，所有分子的IL-17分泌抑制活性超过50％，细胞毒性很低(<25％)，而且X为氧原子的毒性低于X为硫原子，且和IL-5分泌抑制活性存在差别，显示一定的选择性；测试过的分子，其IL-17和IL-5分泌抑制活性有高有低，低者IC50<0.5μM；测试过的分子，对antiCD3/antiCD28/IL23_PBMC的细胞毒性很低(EC50>30μM)。对HEK-293细胞的第二轮测试中，两种测试结果都有差别，且IC50有高有低，最低者达到0.04034μM。有5个目标化合物经过两轮活性，说明有进一步研究的价值和应用的潜力。本发明首次发现DHA与含羧基酚/酯基酚/酰胺基酚偶联物具有免疫病方面的生物活性。
本发明中涉及的未说明部分与现有技术相同或采用现有技术加以实施。
以上公开的仅为本发明的几个具体实施例，但是，本发明实施例并非局限于此，任何本领域的技术人员能思之的变化都应落入本发明的保护范围。
Claims (10)
1.二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，其特征在于，所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物用TM9表示，结构式如下所示：
其中，n＝1，2，3或4，R1为H、卤素、羟基、氨基、氰基、硝基、甲基、乙基或甲氧基，R2为H、甲基或乙基，X为O或S，m＝0，1，2，3或4。
2.如权利要求1所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，其特征在于，n＝2或3，R1为H或-OCH3，R2为H、-CH3或-CH2CH3，X为O或S，m＝0或2。
3.如权利要求1或2所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，TM9的合成按以下反应方程式进行，包括以下步骤：
加入原料TM4、EtOH、氨基脲或氨基硫脲B，搅拌，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物，即TM9。
4.如权利要求3所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，原料TM4和氨基脲或硫代氨基脲的物质的量比为0.6～1.6:2～4，反应温度为3～20℃。
5.如权利要求4所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，所述反应温度为6～16℃。
6.如权利要求3所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物的合成方法，其特征在于，TM4的合成按以下反应方程式进行，包括以下步骤：
加入含羰基的取代苯酚、IM1、K2CO3和溶剂二甲基甲酰胺，加热、搅拌溶解，反应1～12h，反应结束后，进行后处理，得到所述二氢青蒿素与含羰基酚的偶联物，即TM4。
7.如权利要求6所述的合成方法，其特征在于，原料IM1和原料含羰基的取代苯酚的物质的量比为1～2:1～2.5，反应温度为40～85℃。
8.二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物在制备药物中的应用，其特征在于，权利要求1或2所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物在制备抗结核、抗糖尿病、降脂和抑制白细胞介素-17药物中的应用。
9.如权利要求8所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物在制备药物中的应用，其特征在于，所述衍生物结构式中的n＝2、R1为H、R2为-CH3、X为S、m＝0，n＝3、R1为-OCH3、R2为H、X为S、m＝0，n＝2、R1为H、R2为-CH3、X为S、m＝2，n＝2、R1为-OCH3、R2为H、X为S、m＝0，n＝3、R1为H、R2为CH3、X为S、m＝0时的化合物在制备抗结核药物中的应用。
10.如权利要求8所述的二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物在制备药物中的应用，其特征在于，所述衍生物结构式中的n＝3、R1为H、R2为H、X为S、m＝0，n＝2、R1为H、R2为H、X为S、m＝0，n＝2、R1为-OCH3、R2为H、X为S、m＝0，n＝3、R1为H、R2为-CH3、X为S、m＝2，n＝2、R1为H、R2为-CH3、X为S、m＝0时的化合物在制备抗糖尿病药物中的应用；
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0，n＝3、R1为-OCH3、R2为H、X为O、m＝0，n＝2、R1为H、R2为H、X为O、m＝0，n＝2、R1为-OCH3、R2为H、X为O、m＝0，n＝3、R1为H、R2为-CH3、X为O、m＝0，n＝3、R1为H、R2为-CH3、X为O、m＝2，n＝3、R1为H、R2为H、X为S、m＝0，n＝3、R1为-OCH3、R2为H、X为S、m＝0，n＝2、R1为H、R2为H、X为S、m＝0，n＝2、R1为-OCH3、R2为H、X为S、m＝0，n＝3、R1为H、R2为-CH3、X为S、m＝0，n＝2、R1为H、R2为-CH3、X为S、m＝0时的化合物在制备降脂药物中的应用；
所述衍生物结构式中的n＝3、R1为H、R2为H、X为O、m＝0，n＝2、R1为H、R2为H、X为O、m＝0，n＝2、R1为H、R2为-CH2CH3、X为O、m＝0，n＝2、R1为H、R2为-CH3、X为O、m＝2时的化合物在制备抑制白细胞介素-17药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910803271.3A CN110452252B (zh) | 2019-08-28 | 2019-08-28 | 二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910803271.3A CN110452252B (zh) | 2019-08-28 | 2019-08-28 | 二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110452252A CN110452252A (zh) | 2019-11-15 |
| CN110452252B true CN110452252B (zh) | 2022-06-24 |
Family
ID=68489659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910803271.3A Active CN110452252B (zh) | 2019-08-28 | 2019-08-28 | 二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110452252B (zh) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879158A (zh) * | 2010-07-01 | 2010-11-10 | 中国科学院广州生物医药与健康研究院 | 青蒿素衍生物的新应用 |
| CN102010420A (zh) * | 2010-10-12 | 2011-04-13 | 沈阳药科大学 | [(10s)-9,10-二氢青蒿素-10-氧基]苯甲醛缩氨基(硫)脲系列物及其制备方法和用途 |
| CN103113386A (zh) * | 2013-02-20 | 2013-05-22 | 沈阳药科大学 | 氮杂环取代二氢青蒿素衍生物及其应用 |
| CN104418864A (zh) * | 2013-08-30 | 2015-03-18 | 西南大学 | 双氢青蒿素与喹诺酮类化合物的偶联物及其制备方法和应用 |
| CN104892626A (zh) * | 2015-05-29 | 2015-09-09 | 石家庄学院 | 氨基脲二氢青蒿素衍生物及其制备方法与应用 |
| CN104892633A (zh) * | 2015-05-29 | 2015-09-09 | 石家庄学院 | 氨基二硫代甲酸二氢青蒿素酯及其制备方法与应用 |
| CN104892627A (zh) * | 2015-05-29 | 2015-09-09 | 石家庄学院 | 氨基酸二氢青蒿素衍生物及其制备方法与应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070231300A1 (en) * | 2006-03-28 | 2007-10-04 | Washington, University Of | Covalent conjugates between endoperoxides and transferrin and lactoferrin receptor-binding agents |
-
2019
- 2019-08-28 CN CN201910803271.3A patent/CN110452252B/zh active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879158A (zh) * | 2010-07-01 | 2010-11-10 | 中国科学院广州生物医药与健康研究院 | 青蒿素衍生物的新应用 |
| CN102010420A (zh) * | 2010-10-12 | 2011-04-13 | 沈阳药科大学 | [(10s)-9,10-二氢青蒿素-10-氧基]苯甲醛缩氨基(硫)脲系列物及其制备方法和用途 |
| CN103113386A (zh) * | 2013-02-20 | 2013-05-22 | 沈阳药科大学 | 氮杂环取代二氢青蒿素衍生物及其应用 |
| CN104418864A (zh) * | 2013-08-30 | 2015-03-18 | 西南大学 | 双氢青蒿素与喹诺酮类化合物的偶联物及其制备方法和应用 |
| CN104892626A (zh) * | 2015-05-29 | 2015-09-09 | 石家庄学院 | 氨基脲二氢青蒿素衍生物及其制备方法与应用 |
| CN104892633A (zh) * | 2015-05-29 | 2015-09-09 | 石家庄学院 | 氨基二硫代甲酸二氢青蒿素酯及其制备方法与应用 |
| CN104892627A (zh) * | 2015-05-29 | 2015-09-09 | 石家庄学院 | 氨基酸二氢青蒿素衍生物及其制备方法与应用 |
Non-Patent Citations (2)
| Title |
|---|
| In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents;Kalani Komal et al.;《Current Topics in Medicinal Chemistry》;20190603;第633-644页 * |
| 双氢青蒿素类多靶点创新药物的发现;杨大成;《中国化学会.全国第十五届有机合成化学学术研讨会》;20180802;I-12 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110452252A (zh) | 2019-11-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2020260400B2 (en) | Human plasma kallikrein inhibitors | |
| US7338950B2 (en) | Amide compounds as ion channel ligands and uses thereof | |
| JP7511557B2 (ja) | ブロモドメインタンパク質阻害薬としてのイミノスルホン化合物、医薬組成物及びその医薬用途 | |
| JP6918378B2 (ja) | ＣａＭＫＩＩ阻害剤及びその使用 | |
| MXPA05004206A (es) | Derivados de metilenurea. | |
| US20120095024A1 (en) | Toluidine sulfonamides and their use | |
| WO2010085968A1 (en) | Toluidine sulfonamides and their use as hif-inhibitors | |
| EP3154944B1 (en) | Substituted pyridinones as mgat2 inhibitors | |
| CN109053841B (zh) | 6-双硫取代-2’-脱氧鸟苷类化合物及其制备方法和应用 | |
| CN110452252B (zh) | 二氢青蒿素含缩氨脲/缩氨硫脲酚类衍生物、合成方法及应用 | |
| CN110483547B (zh) | 二氢青蒿素的简单酚类偶联物、合成方法及应用 | |
| CN110483545B (zh) | 二氢青蒿素含肟酚类衍生物、合成方法及应用 | |
| WO2020258971A1 (zh) | 腙酰胺类衍生物及其在制备抗骨质疏松药物中的应用 | |
| Lund et al. | Synthesis and anticancer activity of prodigiosenes bearing C-ring esters and amides | |
| CN116210706B (zh) | 生物碱polyaurine B衍生物在抗植物病毒和病菌中的应用 | |
| CN103910688B (zh) | 2-丙基-4-氯喹唑啉衍生物及其制备方法和应用 | |
| WO2015080665A1 (en) | Chalcone-urea derivatives as insulin sensors | |
| JP2016537306A (ja) | 駆虫薬として使用するための有機金属化合物 | |
| GB2413129A (en) | Aromatic amide compounds as ion channel ligands and uses thereof | |
| CN105566267A (zh) | 一类新型肟醚衍生物、其制备方法及其作为药物的用途 | |
| EP2382190A1 (en) | Toluidine sulfonamides and their use as-inhibitors | |
| JP2016533336A (ja) | 駆虫薬として使用するためのビス−有機金属２−アミノ−３−ヒドロキシ−２−メチルプロパンニトリル誘導体 |
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 |