CN105853427A - Application of composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis - Google Patents
Application of composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 43
- 206010016654 Fibrosis Diseases 0.000 title claims abstract description 25
- 230000004761 fibrosis Effects 0.000 title claims abstract description 25
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title abstract description 8
- FSDTUOKRYYZAQY-AEAJCJRFSA-N (1S,6S,8R,9R,12S,15R)-8-hydroxy-5,10-dioxa-11-azapentacyclo[7.6.0.02,6.06,12.011,15]pentadec-2-en-4-one Chemical class O[C@@H]([C@@H]1ON23)C[C@@]45[C@@H]3CC[C@@H]2[C@@H]1C4=CC(=O)O5 FSDTUOKRYYZAQY-AEAJCJRFSA-N 0.000 title abstract description 5
- 229940079593 drug Drugs 0.000 title abstract description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title abstract description 3
- 125000004193 piperazinyl group Chemical group 0.000 title abstract description 3
- 210000004907 gland Anatomy 0.000 claims description 19
- 210000000496 pancreas Anatomy 0.000 claims description 17
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 8
- 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
- 239000000843 powder Substances 0.000 claims description 4
- 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
- 230000007423 decrease Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000002946 anti-pancreatic effect Effects 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 208000035126 Facies Diseases 0.000 description 4
- 239000012043 crude product 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
- 210000001519 tissue Anatomy 0.000 description 4
- 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 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 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
- 238000010828 elution Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 240000007003 Flueggea virosa 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
- 241001597008 Nomeidae Species 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
- 241000867909 Securinega Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000010562 histological examination Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 238000000034 method Methods 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
- 239000012074 organic phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 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
- 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
- 238000005481 NMR spectroscopy Methods 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
- 230000003139 buffering effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000002027 dichloromethane extract Substances 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
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 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
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 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
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the fields of organic synthesis and pharmaceutical chemistry, in particular to application of a composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis and discloses a composition and a preparation method thereof. Pharmacological experiments show that the composition has the effect of preventing or treating the pancreatic fibrosis and has the value of developing the drugs 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 compositions, 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 that the tissue adjoint with it is sick simultaneously
Feature of science, shows as a large amount of fibroblast proliferation and rich in the extracellular matrix connecting tissue.It is that many reasons causes pancreas
The result of gland injury repairing, finds that pancreatic stellate cells is relevant with pancreatic gland fibrosis with cytokine profiles, pancreas fiber in the recent period
Change current sickness rate the highest, be 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 big, safety is low, from natural product in the current existing medicine for the treatment of of pancreatic gland fibrosis
Find compound or lead compound and carry out structural modification and obtain its derivant, thus obtaining the potential drug of high-efficiency low-toxicity
There is important value.
The compound I that the present invention relates to be one within 2012, deliver (Bing-Xin Zhao et al.,
2012.Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an
Unprecedented Skeleton from Flueggea virosa.Organic Letters 14(2012)3096–
3099) compound, we have carried out structural modification to compound I, it is thus achieved that two new derivants i.e. compound III and changes
Compound IV, and it is prepared for compositions with compound III and compound IV and pancreatic gland fibrosis activity anti-to said composition is carried out
Evaluating, it has anti-pancreatic gland fibrosis activity.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, said composition
The mass percent of middle compound III and compound IV is respectively 80% and 20%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the compositions of the present invention has preferable anti-pancreatic gland fibrosis effect.The pharmacy of the present invention
Upper acceptable salt has same drug effect.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by concrete real
Execute any restriction of example, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Virosaine A
Document (the Bing-that the preparation method of compound Virosaine A (I) is delivered with reference to Bing-Xin Zhao et al.
Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-Shaped Securinega
Alkaloids with an Unprecedented Skeleton from Flueggea virosa.Organic Letters
14 (2012) 3,096 3099) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2Virosaine A
Compound I (235mg, 1.00mmol) is dissolved in 20mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB)
(0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% sodium hydroxide solution of 5mL.Mixture is Celsius 35
Degree stirring 8h.After 8h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.Then
Washing organic phase solution 3 times with water and saturated aqueous common salt successively, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed molten
Agent obtains product crude product.Product crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), receives
Collection brown is concentrated elution band and flings to solvent and i.e. obtain the brown ceramic powder (261mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ5.91(s,1H),4.07(s,1H),3.81(s,2H),3.59(s,1H),
3.43 (s, 2H), 3.33 (s, 1H), 2.26 (s, 1H), 1.58 (d, J=9.8Hz, 3H), 1.41 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.81(s),106.71(s),79.95(s),74.33(s),69.81
(s),66.68(s),44.21(s),35.56(s),33.28(s),25.85(s),21.88(s).
HRMS(ESI)m/z[M+H]+calcd for C14H17BrNO4:342.0341；found 342.0343.
The synthesis of O-(piperazinyl) ethyl derivative (III) of embodiment 3Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (168mg, 1.0mmol) and Piperazine anhydrous (3446mg, 40mmol), mixture is heated to reflux 3h.Reaction
After end, reactant liquor is poured in frozen water, extract 2 times with equivalent dichloromethane, merge organic facies.Successively with water and saturated common salt
Organic facies after water washing merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product is thick
Product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects brown and concentrates elution band and wave
Solvent is gone i.e. to obtain the Light brown solid (123.2mg, 71%) of compound III.
1H NMR(500MHz,DMSO-d6)δ5.90(s,1H),4.04(s,1H),3.59(s,1H),3.50(s,2H),
3.40 (d, J=65.9Hz, 1H), 2.64 (s, 4H), 2.54 (s, 2H), 2.31 (s, 4H), 2.22 (s, 1H), 1.62 (s, 2H),
1.56(s,1H),1.43(s,2H),0.97(s,1H).
13C NMR(125MHz,DMSO-d6)δ171.84(s),106.72(s),79.94(s),74.33(s),66.72(d,
J=9.2Hz), 54.45 (s), 54.16 (s), 45.25 (s), 44.20 (s), 35.56 (s), 25.86 (s), 21.87 (s).
HRMS(ESI):m/z[M+H]+calcd for C18H26N3O4:348.1923；found:348.1927.
The synthesis of O-(imidazole radicals) ethyl derivative (IV) of embodiment 4Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 25mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), potassium iodide (252mg, 1.5mmol) and imidazoles (870mg, 10mmol), mixture is heated to reflux 2h.Reaction terminates
After reactant liquor is poured in 25mL frozen water, with equivalent dichloromethane extract 3 times, merge organic facies.Successively with water and saturated common salt
Organic facies after water washing merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product is thick
Product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:0.3, v/v), collects brown and concentrates elution band and wave
Solvent is gone i.e. to obtain the Light brown solid (144.1mg, 71%) of compound IV.
1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.12(s,1H),6.71(s,1H),5.99(s,1H),
4.09 (s, 1H), 3.89 (d, J=16.4Hz, 2H), 3.80 (s, 2H), 3.58 (s, 1H), 3.35 (s, 1H), 2.31 (s, 1H),
1.68(s,1H),1.58(s,2H),1.44(s,2H).
13C NMR(125MHz,DMSO-d6)13C NMR(125MHz,Common NMR Solvents)δ171.82(s),
139.64(s),128.67(s),119.31(s),106.70(s),79.92(s),74.31(s),67.61(s),66.66(s),
44.20(s),43.75(s),35.52(s),25.85(s),21.86(s).
HRMS(ESI):m/z[M+H]+calcd for C17H20N3O4:330.1454；found:330.1458.
Embodiment 5 compositions anti-pancreatic gland fibrosis activity
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
1.2 composition dosage: 0.9mg/kg.
The preparation of compositions: the powder that will cross the 80mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 20mg compound IV of mesh net loads in tubule with cover and i.e. obtains 100mg compositions with the mixing of turbine stirring instrument,
Obtain the solution of compositions by the compositions of this 100mg of water dissolution during use.
2 experimental techniques
2.1 modeling methods: Wistar rat, with lumbar injection dl-ethionine 250mg/ days, continuous 2 months, may occur in which
Pancreas glandular cell reduces, the adipocellular hypertrophy of interstitial.
2.2 packet and medications
Rat model is randomly divided into model group, compositions 0.9mg/kg group, compound III 0.9mg/kg group and compound
IV 0.9mg/kg group, separately sets blank group.Administration group is administered after modeling starts, oral continuous 30 days；Dissect dynamic when 60 days
Thing.
2.3 Testing index
2.3.1 take pancreas at the end of experiment to weigh.
2.3.2 pancreas hydroxyproline content measures and takes 100mg sample and be homogenized in water, and in 110 DEG C of 10N HCl, hydrolysis 20 is little
Time.HCl nitrogen volatilizees, and hydrolyzate filters after dissolving with distilled water.Take 0.5ml liquid and 3ml citric acid phosphate buffer
(0.15M citric acid adds 0.6M disodium hydrogen phosphate) and 0.5ml are dissolved in the 1M periodic acid mixing of 9M phosphoric acid.Add 1.75ml and extract buffering
Liquid (5 parts of toluene: 5 parts of 2-methyl isophthalic acid-propanol: 2 parts of 1-propanol), shakes 30min, centrifugal.Tissue phase (0.6ml) and Ehrlich,
15min is placed in the mixing of s reagent.Measure trap at 565nm, make standard curve with 4-hydroxyl-1-proline and calculate concentration, content
Represent with ug/g tissue.
2.3.3 histological examination pancreatic tissues is fixed with 10% formalin, paraffin embedding, microscopy after dyeing.To fiber
Change situation scoring (0-3 divides).
3 results
The impact on rat pancreas organ coefficient of 3.1 compositionss
At the end of experiment, rat put to death, dissect, weigh in and pancreas weighs and calculate the ratio (pancreas of itself and body weight
Organ coefficient), the results are shown in Table 1.The compositions impact on pancreas organ coefficient, compares with model group and has significant difference.Chemical combination
Thing III and the compound IV impact on pancreas organ coefficient, compare with model group and there was no significant difference.
Table 1
* represent p < 0.05, compare with model group
3.2 pancreas hydroxyproline content measures
At the end of experiment, each group of rat is carried out pulmonary's hydroxyproline content mensuration, result such as table 2.Compositions is to hydroxyl dried meat
The impact of histidine content, compares with model group and has significant difference.Compound III and the compound IV shadow to hydroxyproline content
Ring, compare with model group and there was no 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: pancreas surrounding catheter extensive inflammation reaction seen from model group the 60th day；Addicted to middle granulocyte karyolymph cellular infiltration,
Interstitial edema, hemorrhage and accidental pancreas cystencyte necrosis；Between pancreas cystencyte disappearance position and pancreas bubble, fibrosis occurs.
Compositions can reduce inflammatory reaction and fibrosis.Appraisal result is shown in Table 3.The compositions impact on scoring, with model
Group compares 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 by compositions impact Fibrotic on pancreas in rat it was confirmed compositions to have anti-pancreas fine
The effect of dimensionization.Therefore, compositions can be as active component for preparing the medicine of anti-pancreatic gland fibrosis.And compound III and
Compound IV is without this activity, it is impossible to for preparing the medicine of anti-pancreatic gland fibrosis.
The preparation of embodiment 6 composition tablet involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant 18 grams of tablet is prepared in addition, and mixing, conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Taking 2 grams of compositionss, the customary adjuvant such as starch 18 grams of capsule is prepared in addition, mixing, encapsulated makes 100.
Claims (6)
1. a compositions, is characterized by that said composition is made up of compound III and compound IV, compound in said composition
The mass percent of III and compound IV is respectively 80% and 20%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the compound IV of compound III
Powder be sufficiently mixed according to mass percent respectively 80% and 20%.
3. a compositions as claimed in claim 1 application in treatment pancreatic gland fibrosis medicine.
4. the compositions as claimed in claim 3 application in treatment pancreatic gland fibrosis medicine, is characterized by: described compositions
Reverse the pancreas organ coefficient caused by pancreatic gland fibrosis to decline.
5. the compositions as claimed in claim 3 application in treatment pancreatic gland fibrosis medicine, is characterized by: described compositions
Reverse the hydroxyproline content caused by pancreatic gland fibrosis to raise.
6. the compositions as claimed in claim 3 application in treatment pancreatic gland fibrosis medicine, is characterized by: described compositions
Reverse the inflammatory cell infiltration caused by pancreatic gland fibrosis to raise.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278424.3A CN105853427A (en) | 2016-04-28 | 2016-04-28 | Application of composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610278424.3A CN105853427A (en) | 2016-04-28 | 2016-04-28 | Application of composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis |
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| Publication Number | Publication Date |
|---|---|
| CN105853427A true CN105853427A (en) | 2016-08-17 |
Family
ID=56629748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610278424.3A Withdrawn CN105853427A (en) | 2016-04-28 | 2016-04-28 | Application of composition of piperazine and imidazole based derivatives of Virosaine A in preparation of drugs for preventing or treating pancreatic fibrosis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105853427A (en) |
-
2016
- 2016-04-28 CN CN201610278424.3A patent/CN105853427A/en not_active Withdrawn
Non-Patent Citations (3)
| Title |
|---|
| BING-XIN ZHAO等: "Virosaines A and B, Two New Birdcage-Shaped Securinega Alkaloids with an unprecedented Skeleton from Flueggea virosa", 《ORGANIC LETTERS》 * |
| 刘毅等: "一叶萩碱的研究进展", 《中国药事》 * |
| 王营等: "胰腺癌组织中GABA和GAD的表达", 《第九届国际治疗内镜和消化疾病学术会议论文汇编》 * |
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