CN104739846A - Application of O-(1H-tetrazole) ethyl derivative of cleistanone to preparing drug for preventing or treating pancreatic fibrosis - Google Patents
Application of O-(1H-tetrazole) ethyl derivative of cleistanone to preparing drug for preventing or treating pancreatic fibrosis Download PDFInfo
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- CN104739846A CN104739846A CN201510179836.7A CN201510179836A CN104739846A CN 104739846 A CN104739846 A CN 104739846A CN 201510179836 A CN201510179836 A CN 201510179836A CN 104739846 A CN104739846 A CN 104739846A
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- ethyl derivative
- cleistanone
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- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 title claims abstract description 69
- XURLTFUKDPZAPN-QFIPXVFZSA-N Cleistanone Natural products O(C)[C@H]1OC(=O)c2c(-c3cc4OCOc4cc3)c3c(c(O)c12)cc(OC)c(OC)c3 XURLTFUKDPZAPN-QFIPXVFZSA-N 0.000 title claims abstract description 45
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 34
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 27
- 230000004761 fibrosis Effects 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title abstract description 5
- GEIFQLXIDUDMNZ-PCJVTFPHSA-N (4aR,4bR,6aR,8S,10aR,10bR,12R,12aR)-12-hydroxy-1,1,1',1',4a,10a,10b-heptamethyl-3'-methylidenespiro[3,4,4b,5,6,6a,7,9,10,11,12,12a-dodecahydrochrysene-8,2'-cyclopentane]-2-one Chemical compound CC1(C)CCC(=C)[C@@]11C[C@@H](CC[C@H]2[C@]3(C[C@@H](O)[C@H]4C(C)(C)C(=O)CC[C@@]42C)C)[C@@]3(C)CC1 GEIFQLXIDUDMNZ-PCJVTFPHSA-N 0.000 claims description 34
- 241000785597 Cleistanthus Species 0.000 claims description 29
- 150000002576 ketones Chemical class 0.000 claims description 28
- 239000002023 wood Substances 0.000 claims description 28
- 210000004907 gland Anatomy 0.000 claims description 19
- 210000000496 pancreas Anatomy 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 11
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 5
- 229960002591 hydroxyproline Drugs 0.000 claims description 5
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 5
- 230000008595 infiltration Effects 0.000 claims description 3
- 238000001764 infiltration Methods 0.000 claims description 3
- 210000004969 inflammatory cell Anatomy 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 11
- 238000002474 experimental method Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 238000010828 elution Methods 0.000 description 9
- 241001597008 Nomeidae Species 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000002946 anti-pancreatic effect Effects 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 208000035126 Facies Diseases 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000010562 histological examination Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- RSBNUWAVVQOBHL-UHFFFAOYSA-N C(CC)O.CC1=C(C(=O)O)C=CC=C1C(=O)O Chemical compound C(CC)O.CC1=C(C(=O)O)C=CC=C1C(=O)O RSBNUWAVVQOBHL-UHFFFAOYSA-N 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- GGLZPLKKBSSKCX-UHFFFAOYSA-N S-ethylhomocysteine Chemical compound CCSCCC(N)C(O)=O GGLZPLKKBSSKCX-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000011536 extraction buffer Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 208000014674 injury Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
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- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 238000002483 medication Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000002705 pancreatic stellate cell Anatomy 0.000 description 1
- 210000004923 pancreatic tissue Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the fields of organic synthesis and medicinal chemistry, and relates to O-(1H-tetrazole) ethyl derivative of cleistanone, a preparation method thereof and an application thereof to preparing a drug for preventing or treating pancreatic fibrosis. The invention synthesizes a novel O-(1H-tetrazole) ethyl derivative of cleistanone and discloses a preparation method of the novel O-(1H-tetrazole) ethyl derivative. According to the pharmacology experiments, the O-(1H-tetrazole) ethyl derivative of cleistanone has the effect of preventing or treating pancreatic fibrosis, and has a value of developing a drug for preventing or treating pancreatic fibrosis.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O-(1H-tetrazole base) ethyl derivative, the preparation method and its usage of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
Background technology
Pancreatic gland fibrosis is the common trait of chronic pancreatitis caused by a variety of causes, is also the Histopathological characteristics adjoint with it simultaneously, shows as a large amount of fibroblast proliferation and the extracellular matrix being rich in conjunctive tissue.Be the result that many reasons causes injury of pancreas to be repaired, find that pancreatic stellate cells is relevant with pancreatic gland fibrosis with cytokine profiles in the recent period, the current sickness rate of pancreatic gland fibrosis is more and more high, is badly in need of the anti-pancreatic gland fibrosis medicine of research and development high-efficiency low-toxicity.
There is the problem that toxicity is large, safety is low in the current existing medicine for the treatment of of pancreatic gland fibrosis, finds compound or lead compound and carry out structural modification to obtain its derivant from natural product, thus the potential drug obtaining high-efficiency low-toxicity has important value most.
The compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume 2011, Issue 22,pages 4108 – 4111, August 2011) compound, we have carried out structural modification to compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, obtain O-(the 1H-tetrazole base) ethyl derivative of a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, and its anti-pancreatic gland fibrosis activity is evaluated, it is active that it has anti-pancreatic gland fibrosis.
Summary of the invention
The invention discloses O-(the 1H-tetrazole base) ethyl derivative of a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, its structure is:
O-(the 1H-tetrazole base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is by method preparation below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone;
(2) the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) with 1H-tetrazole generation substitution reaction.
The preparation method of O-(the 1H-tetrazole base) ethyl derivative (III) of further Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is:
(1) 440mg compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution; Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
(2) the O-bromoethyl derivant of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of 273mg wood ketone Cleistanone is dissolved in the middle of 15mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the 1H-tetrazole of 1401mg, mixture reflux 10h; After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three times, merge organic facies; Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product; Because tautomerization, 1H-tetrazole base and 2H-tetrazole base two kinds of substitution products can be generated at reaction conditions; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1, v/v, collects faint yellow concentrated elution band; Concentrated by elution band, with purification by silica gel column chromatography, mobile phase is again: petroleum ether/acetone=100:0.5, v/v, namely concentrated front 1 elution band obtains the faint yellow solid of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, O-(the 1H-tetrazole base) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention has good anti-pancreatic gland fibrosis effect.Pharmaceutically acceptable salt of the present invention has same drug effect with its compound.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Document (the Van Trinh Thi Thanh et al. that the people such as the preparation method reference Van Trinh Thi Thanh of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) deliver, 2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.04g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 3 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
32H
52BrO
2:547.3151；found 547.3159.
The synthesis of O-(the 1H-tetrazole base) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound II per (273mg, 0.5mmol) be dissolved in the middle of 15mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) with 1H-tetrazole (1401mg, 20mmol), mixture reflux 10h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Because tautomerization, 1H-tetrazole base and 2H-tetrazole base two kinds of substitution products can be generated at reaction conditions.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1, v/v), collect yellow concentrated elution band, again elution band is concentrated, with purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collect two flaxen elution bands successively, namely concentrated front 1 elution band obtains the faint yellow solid (56.5mg, 21%) of compound III.
1H NMR(500MHz,DMSO-d6)δ10.10(s,1H),4.63(s,1H),4.53(s,1H),4.33(d,J＝4.7Hz,2H),4.26(s,1H),3.88(s,2H),2.37(d,J＝3.0Hz,2H),2.26(d,J＝13.0Hz,2H),2.20(s,1H),1.89(s,2H),1.81(s,1H),1.65(d,J＝15.0Hz,3H),1.56(s,2H),1.54–1.47(m,3H),1.42(s,1H),1.30(dd,J＝26.0,22.6Hz,3H),1.22(s,1H),1.04(s,6H),0.96(s,12H),0.87(d,J＝5.4Hz,4H),0.63(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.58(s),154.48(s),145.25(s),105.20(s),74.64(s),65.63(s),59.74(s),52.54(s),51.19(s),47.89(s),47.02(s),44.11(s),42.27(s),41.76(s),40.63(s),40.14(s),38.85(s),38.66(s),37.23(s),36.26(s),33.33(s),32.94(s),29.88(s),27.19(s),26.05(s),24.26(s),23.95(s),20.75(s),18.45(s),17.99(s),16.95(s).HRMS(ESI):m/z[M+H]
+calcd for C
33H
53N
4O
2:537.4169；found:537.4161。
The anti-pancreatic gland fibrosis of O-(1H-tetrazole base) ethyl derivative of embodiment 4Cleistanone is active
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
O-(1H-tetrazole base) ethyl derivative dosage: the 0.9mg/kg of 1.2Cleistanone.
2 experimental techniques
2.1 modeling methods: Wistar rat, with lumbar injection dl-ethionine 250mg/ days, continuous 2 months, can occur that pancreas glandular cell reduces, adipocellular hypertrophy in interstitial.
2.2 grouping and medications
Rat model is divided into model group at random, and O-(1H-tetrazole base) the ethyl derivative 0.9mg/kg group of Cleistanone, separately establishes blank group, start rear administration in modeling, oral continuous 30 days; Animal is dissected when 60 days.
2.3 Testing index
2.3.1 get pancreas at the end of experiment to weigh.
2.3.2 pancreas hydroxyproline content measures and gets the homogenate in water of 100mg sample, is hydrolyzed 20 hours in 110 DEG C of 10N HCl.HCl nitrogen volatilizees, and hydrolyzate filters after dissolving with distilled water.Get 0.5ml liquid to mix with the 1M periodic acid that 3ml citric acid phosphate buffer (0.15M citric acid adds 0.6M sodium hydrogen phosphate) and 0.5ml are dissolved in 9M phosphoric acid.Add 1.75ml Extraction buffer (5 parts of toluene: 5 parts of 2-methyl isophthalic acid-propanol: 2 parts of 1-propanol), concussion 30min, centrifugal.Organize phase (0.6ml) to mix with Ehrlich ' s reagent and place 15min.Measure trap at 565nm, with 4-hydroxyl-1-proline production standard curve calculating concentration, content represents with ug/g tissue.
2.3.3 histological examination pancreatic tissues 10% formalin is fixed, paraffin embedding, microscopy after dyeing.To fibrosis situation scoring (0-3 divides).
3 results
O-(the 1H-tetrazole base) ethyl derivative of 3.1Cleistanone is on the impact of rat pancreas
At the end of experiment, rat put to death, dissect, to weigh in and pancreas weight, and calculate the ratio (pancreas organ coefficient) of itself and body weight, the results are shown in Table 1.O-(the 1H-tetrazole base) ethyl derivative of Cleistanone, on the impact of pancreas organ coefficient, compares with model group and has significant difference.
Table 1
* represent p<0.05, compare with model group
3.2 pancreas hydroxyproline contents measure
At the end of experiment, carry out pulmonary's hydroxyproline content mensuration to each group of rat, result is as table 2.O-(the 1H-tetrazole base) ethyl derivative of Cleistanone, on the impact of hydroxyproline content, compares with model group and has significant difference.
Table 2
* represent p<0.05, compare with model group
3.3 histological examination
At the end of experiment, rat put to death, dissect; The embedding of specimen routine, fixing, HE dyeing, microscopy.
Result: model group visible pancreas surrounding catheter extensive inflammation reaction in the 60th day; Addicted to middle granulocyte karyolymph cellular infiltration, interstitial edema, hemorrhage and accidental pancreas cystencyte is downright bad; Fibrosis is there is between pancreas cystencyte disappearance position and pancreas bubble.
O-(the 1H-tetrazole base) ethyl derivative of Cleistanone can reduce inflammatory reaction and fibrosis.Appraisal result is in table 3.O-(the 1H-tetrazole base) ethyl derivative of Cleistanone, on the impact of scoring, compares with model group and has significant difference.
Table 3
* represent p<0.05, compare with model group; The inflammatory cell infiltration of blank group and Fibrosis score are all 0.
Conclusion: the present invention on the Fibrotic impact of pancreas in rat, confirms that O-(the 1H-tetrazole base) ethyl derivative of Cleistanone has the effect of anti-pancreatic gland fibrosis by O-(the 1H-tetrazole base) ethyl derivative of Cleistanone.Therefore, O-(the 1H-tetrazole base) ethyl derivative of Cleistanone can be used as the medicine of active component for the preparation of anti-pancreatic gland fibrosis.
The preparation of O-(1H-tetrazole base) the ethyl derivative tablet of embodiment 5 Cleistanone involved in the present invention
Get the one in the middle of O-(the 1H-tetrazole base) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of O-(1H-tetrazole base) the derivatized composite capsule of embodiment 6 Cleistanone involved in the present invention
Get the one in the middle of O-(the 1H-tetrazole base) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (4)
1. there is O-(1H-tetrazole base) ethyl derivative and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III,
2. O-(the 1H-tetrazole base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1 and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof, is characterized by: the pancreas organ coefficient that O-(the 1H-tetrazole base) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis declines.
3. O-(the 1H-tetrazole base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1 and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof, is characterized by: the hydroxyproline content that O-(the 1H-tetrazole base) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis raises.
4. O-(the 1H-tetrazole base) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1 and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof, is characterized by: the inflammatory cell infiltration that O-(the 1H-tetrazole base) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis raises.
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| CN106038553A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of pancreatic fibrosis control drugs |
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| CN104147019A (en) * | 2014-07-31 | 2014-11-19 | 南京大学 | Application of O-(tetrahydropyrrole) ethyl derivative of cleistanone in preparation of medicines for preventing or treating pancreatic fibrosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104147019A (en) * | 2014-07-31 | 2014-11-19 | 南京大学 | Application of O-(tetrahydropyrrole) ethyl derivative of cleistanone in preparation of medicines for preventing or treating pancreatic fibrosis |
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| VAN TRINH THI THANH, ET AL.: "Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton", 《EUR. J. ORG. CHEM.》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106038553A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of pancreatic fibrosis control drugs |
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