CN104800213A - Application of Daphmalenine A derivative in preparing medicaments for preventing or treating pancreatic fibrosis - Google Patents
Application of Daphmalenine A derivative in preparing medicaments for preventing or treating pancreatic fibrosis Download PDFInfo
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- daphmalenine
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- BNSQPPYRCUIFLZ-LSLDVNGTSA-N methyl (1R,5S,8S,11S,12R,15R,17R)-8-hydroxy-3-methyl-9-oxo-15-(3-oxopentyl)-13-oxa-3-azapentacyclo[9.4.2.01,12.05,15.08,12]heptadecane-17-carboxylate Chemical class C1C[C@@]2(O)C(=O)C[C@@H]3[C@]22OC[C@]4(CCC(=O)CC)[C@H]1CN(C)C[C@@]42C[C@H]3C(=O)OC BNSQPPYRCUIFLZ-LSLDVNGTSA-N 0.000 title claims abstract description 70
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 28
- 230000004761 fibrosis Effects 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 210000004907 gland Anatomy 0.000 claims description 20
- 241001597008 Nomeidae Species 0.000 claims description 19
- 210000000496 pancreas Anatomy 0.000 claims description 16
- 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 6
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 6
- 229960002591 hydroxyproline Drugs 0.000 claims description 6
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims description 6
- 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 12
- 238000002474 experimental method Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 229950002366 nafoxidine Drugs 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 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 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000002946 anti-pancreatic effect Effects 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 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
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- ONQBOTKLCMXPOF-UHFFFAOYSA-N 1-ethylpyrrolidine Chemical compound CCN1CCCC1 ONQBOTKLCMXPOF-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000012071 phase Substances 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
- 238000010828 elution Methods 0.000 description 4
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- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum 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
- 238000000746 purification Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 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
- 238000006243 chemical reaction Methods 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
- 238000002156 mixing Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- 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
- 241000208664 Daphniphyllum Species 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
- 229930013930 alkaloid Natural products 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
- 229930186810 daphmalenine Natural products 0.000 description 2
- 229940079593 drug Drugs 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
- 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
- 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
- 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
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
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- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
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- 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
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- 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
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- 238000002347 injection Methods 0.000 description 1
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- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a Daphmalenine A derivative, a preparation method thereof and an application of the Daphmalenine A derivative in preparing medicaments for preventing and treating pancreatic fibrosis. The novel Daphmalenine A derivative is synthesized, and the preparation method of the Daphmalenine A derivative is disclosed. Pharmacological experiments indicate that the Daphmalenine A derivative disclosed by the invention has an effect of preventing or treating the pancreatic fibrosis and has a value of developing the medicaments for preventing or treating the pancreatic fibrosis.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to Daphmalenine A derivant, preparation method and its usage.
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 D aphmalenine A that the present invention relates to is one and within 2011, delivers (Yu Zhang et al., 2011.Daphmalenines A and B:Two New Alkaloids with Unusual Skeletonsfrom Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) compound, we have carried out structural modification to Compound D aphmalenine A, obtain a new Daphmalenine A derivant, 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 a Daphmalenine A derivant, its structure is:
Daphmalenine A derivant (III) of the present invention is by method preparation below:
(1) Daphmalenine A (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Daphmalenine A;
(2) O-bromoethyl derivant (II) and the pyrrolidine generation substitution reaction of Daphmalenine A obtain O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
The preparation method of the O-(nafoxidine base) ethyl derivative (III) of further Daphmalenine A is:
(1) 419mg Compound D aphmalenine A (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.08g, the glycol dibromide of 7.520g and 50% sodium hydroxide solution of 6mL; Mixture stirs 12h at 35 degrees Celsius; After 12h, 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 4 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=100:1.5, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Daphmalenine A.
(2) the O-bromoethyl derivant (II) of the Daphmalenine A of 263mg is dissolved in the middle of 20mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the pyrrolidine of 2840mg, mixture reflux 12h; After reaction terminates, reactant liquor is poured in 20mL frozen water, with equivalent dichloromethane extraction four 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; Product crude product purification by silica gel column chromatography, mobile phase is: petroleum ether/acetone=100:1.5, v/v, collects the brown gummy solid 183.2mg that namely brown concentrated elution band obtains the O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, Daphmalenine A derivant (III) 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 D aphmalenine A
Document (the YuZhang et al. that the people such as the preparation method reference Yu Zhang of Compound D aphmalenine A (I) deliver, 2011.Daphmalenines A and B:Two New Alkaloids with UnusualSkeletons from Daphniphyllum himalense.Eur.J.Org.Chem.2011,4103 – 4107) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Daphmalenine A
By Compound I (419mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) and 6mL.Mixture stirs 12h at 35 degrees Celsius.After 12h, 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 4 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=100:1.5, v/v), collects the yellow yellow solid (320mg, 61%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ3.84(d,J＝1.6Hz,2H),3.76–3.50(m,5H),3.42(s,2H),3.09(s,1H),2.99(s,1H),2.88(s,1H),2.70(s,1H),2.64(d,J＝19.1Hz,3H),2.45(d,J＝5.6Hz,3H),2.33(s,1H),2.19–2.12(m,5H),2.07(s,1H),1.97(d,J＝9.2Hz,3H),1.84–1.76(m,3H),1.69(s,1H),1.15(s,1H),1.04(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.71(s),211.07(s),176.65(s),66.24(s),65.38(s),63.59(s),59.42(s),54.79(s),52.18(s),46.22(s),46.01(s),45.50(s),45.27(s),40.33(s),37.86(s),37.61(s),36.27(s),34.26(s),30.89(s),28.52(s),26.04(s),25.24(s),8.50(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
25H
37BrNO
6:526.1804；found 526.1801.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Daphmalenine A
Compound II per (263mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (2840mg, 40mmol), mixture reflux 12h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction four 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.(mobile phase is product crude product purification by silica gel column chromatography: petroleum ether/acetone=100:1.5, v/v), collect the brown gummy solid (183.2mg, 71%) that namely brown concentrated elution band obtains the O-(nafoxidine base) ethyl derivative (III) of Daphmalenine A.
1H NMR(500MHz,DMSO-d6)δ3.80(s,1H),3.71(s,3H),3.50(s,2H),3.14(s,1H),3.06(s,1H),2.86(s,1H),2.73(d,J＝2.7Hz,2H),2.67(d,J＝5.3Hz,4H),2.55(s,4H),2.53–2.36(m,4H),2.21–2.15(m,5H),2.16–1.86(m,4H),1.85(d,J＝7.5Hz,2H),1.78(s,1H),1.72(d,J＝10.7Hz,5H),1.14(s,1H),1.08(s,3H)。
13C NMR(125MHz,DMSO-d6)δ219.76(s),211.10(s),176.66(s),66.23(s),63.55(s),61.51(s),59.41(s),54.83(s),54.50(s),53.87(s),52.18(s),46.20(s),46.04(s),45.53(s),45.24(s),40.32(s),37.87(s),37.64(s),36.26(s),30.85(s),28.50(s),25.95(s),25.18(d,J＝8.8Hz),8.42(s)。
HRMS(ESI):m/z[M+H]
+calcd for C
29H
45N
2O
6:517.3278；found:517.3271。
The anti-pancreatic gland fibrosis of O-(nafoxidine base) ethyl derivative (III) of embodiment 4 Daphmalenine A is active
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
O-(nafoxidine base) ethyl derivative dosage: the 0.9mg/kg of 1.2Daphmalenine A.
1-ethyl pyrrolidine (compound IV) is commercially available analytical pure.
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 compound III 0.9mg/kg group, Compound I 0.9mg/kg group and 1-ethyl pyrrolidine 0.9mg/kg group, separately establish blank group.Administration group starts 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) and Ehrlich
,15min is placed in the mixing of s reagent.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
The O-(nafoxidine base) ethyl derivative (compound III) of 3.1Daphmalenine A is on the impact of rat pancreas organ coefficient
At the end of experiment, rat put to death, dissect, to weigh in and pancreas weighs and calculates the ratio (pancreas organ coefficient) of itself and body weight, the results are shown in Table 1.Compound III, on the impact of pancreas organ coefficient, compares with model group and has significant difference.Compound I and 1-ethyl pyrrolidine, on the impact of pancreas organ coefficient, compare there was no significant difference with model group.
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.Compound III, on the impact of hydroxyproline content, compares with model group and has significant difference.Compound I and 1-ethyl pyrrolidine, on the impact of hydroxyproline content, compare there was no significant difference with model group.
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.
Compound III can reduce inflammatory reaction and fibrosis.Appraisal result is in table 3.Compound III, 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 passes through the O-(nafoxidine base) ethyl derivative (compound III) of Daphmalenine A to the Fibrotic impact of pancreas in rat, confirms that the O-(nafoxidine base) ethyl derivative (compound III) of Daphmalenine A has the effect of anti-pancreatic gland fibrosis.Therefore, the O-(nafoxidine base) ethyl derivative (compound III) of Daphmalenine A can be used as the medicine of active component for the preparation of anti-pancreatic gland fibrosis.And Compound I and 1-ethyl pyrrolidine are without this activity, can not for the preparation of the medicine of anti-pancreatic gland fibrosis.
The preparation of O-(nafoxidine base) the ethyl derivative tablet of embodiment 5 Daphmalenine A involved in the present invention
Get the one in the middle of O-(nafoxidine base) ethyl derivative of 20 grams of Daphmalenine A or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of O-(nafoxidine base) the derivatized composite capsule of embodiment 6 Daphmalenine A involved in the present invention
Get the one in the middle of O-(nafoxidine base) ethyl derivative of 20 grams of Daphmalenine A or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (4)
1. there is Daphmalenine A derivant and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof of structure shown in formula III,
2. Daphmalenine A derivant 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 described Daphmalenine A derivant and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis declines.
3. Daphmalenine A derivant 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 described Daphmalenine A derivant and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis raises.
4. Daphmalenine A derivant 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 described Daphmalenine A derivant and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis raises.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| YU ZHANG ET AL.: "Daphmalenines A and B: Two New Alkaloids with Unusual Skeletons from Daphniphyllum himalense.", 《EUR. J. ORG. CHEM》 * |
| 许婷等: "苦豆子生物碱对消化***炎性疾病的影响.", 《国际消化病杂志》 * |
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