CN106727571A - The piperazinyl and 1H tetrazole radical derivatives composition of Psiguadial A are used for anti-hepatic fibrosis - Google Patents
The piperazinyl and 1H tetrazole radical derivatives composition of Psiguadial A are used for anti-hepatic fibrosis Download PDFInfo
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- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 206010019668 Hepatic fibrosis Diseases 0.000 title claims abstract description 17
- AXYPZJGNRHOELX-UHFFFAOYSA-N psiguadial A Natural products CC1CCC(C2(C)C)C2C2C3(C)CCC12OC1=C(C=O)C(O)=C(C=O)C(O)=C1C3C1=CC=CC=C1 AXYPZJGNRHOELX-UHFFFAOYSA-N 0.000 title abstract description 9
- 125000004193 piperazinyl group Chemical class 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 15
- 230000035755 proliferation Effects 0.000 claims abstract description 8
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims abstract description 4
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims abstract description 4
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims abstract description 4
- 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 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 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
- 239000003102 growth factor Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 5
- 210000000630 fibrocyte Anatomy 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical class C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 230000006698 induction Effects 0.000 abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- -1 (piperazinyl) ethyl Chemical class 0.000 abstract 2
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000003328 fibroblastic effect Effects 0.000 description 7
- 208000019425 cirrhosis of liver Diseases 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000835 fiber Substances 0.000 description 5
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 210000002744 extracellular matrix Anatomy 0.000 description 4
- 210000004024 hepatic stellate cell Anatomy 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
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 240000001679 Psidium guajava Species 0.000 description 2
- 235000013929 Psidium pyriferum Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229930188068 psiguadial Natural products 0.000 description 2
- 229930184353 psiguadials Natural products 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 210000004500 stellate cell Anatomy 0.000 description 2
- 230000000638 stimulation Effects 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
- 238000005406 washing Methods 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 230000002300 anti-fibrosis Effects 0.000 description 1
- 230000002942 anti-growth Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000003995 blood forming stem cell Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 231100000012 chronic liver injury Toxicity 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 229910000437 dibromine pentoxide Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid 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
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001131 transforming effect 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (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 present invention relates to organic synthesis and medicinal chemistry art.The present invention discloses and is 10 according to mass ratio there is provided O (piperazinyl) ethyl derivative (III) by Psiguadial A and O (1H tetrazoles base) ethyl derivatives (IV)：90 composition compositions and by above-claimed cpd according to 10：90 mass ratio is mixed the method so as to prepare the present composition.Pharmacological experiment shows that the composition that the present invention is provided can significantly inhibit NIH/3T3 propagation and transforming growth factor β in 20ug/ml1The fibroblast proliferation of induction, effect with anti-hepatic fibrosis, thus present invention also offers Psiguadial A O (piperazinyl) ethyl derivative (III) and O (1H tetrazoles base) ethyl derivative (IV) according to mass ratio be 10：Purposes of the composition of 90 compositions in anti-hepatic fibrosis medicines are prepared.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, and in particular to composition, preparation method and its usage.
Background technology
Liver fibrosis is dynamic process of the chronic liver injury to cirrhosis progress, shows as extracellular matrix (ECM) a large amount of
Synthesis, secretion, and absolute or relative deficiency of degrading, make ECM that deposition is diffused in liver.It originates in liver cell (HC) necrosis,
It is therewith inflammatory reaction, fiber generation medium release, HSCs (FSC) activation, finally with liver connective tissue elements
Synthesis and the obvious disequilibrium of degraded.Liver fibrosis is the common pathologic process of various chronic liver diseases, is the important of influence prognosis
Factor.
Between past 20 years, the research of liver fibrosis makes significant progress, it was demonstrated that liver fibrosis and a certain degree of liver
Hardening is all reversible.Occur in that some Strategies of Anti-fibrosis Therapy methods successively in recent years, including chemical drugs, biological agent, in
Medicine and gene therapy etc., but preferably clinical treatment means still lack that (Liu Ping strengthen grinding for effect of anti hepatic fibrosis mechanism
Study carefully China hepatopathy magazine, 2005,8 (13)：561).The key of preventing and treating liver fiber is directed to and hepatic stellate cell activator phase at present
The link of pass, mainly：Mitigate hepatic injury；Suppress stellate cell activator, reduce extracellular matrix and produce；Regulation cell factor is disorderly
Disorderly, activated hepatic stellate cells apoptosis is promoted；Suppress the fibroblastic propagation of liver and stellate cell activator is largely secreted and lured
Lead the fibroblastic propagation of liver.
Compound or lead compound are found from natural products and structural modification is carried out and obtains its derivative, so as to obtain
The potential drug of high-efficiency low-toxicity most has important value.
Compound I of the present invention is one and delivers within 2011 (Meng Shao et al., 2010.Psiguadials
A and B,Two Novel Meroterpenoids with Unusual Skeletons from the Leaves of
Psidium guajava.Organic Letters 12 (2010) 5040-5043) compound, we are carried out to compound I
Structural modification, obtains two new derivatives i.e. compound III and compound IV, and with compound III and compound IV
It is prepared for composition and said composition anti-hepatic fibrosis activity is evaluated, it has anti-hepatic fibrosis activity.
Due to the activation of hepatic stellate cell, so as to cause a large amount of secretions of various growth factors, these growth factors
The meeting fibroblastic fast breeding of induced liver, so that one of accelerating fibers, most important of which growth factor are exactly
TGF.Therefore, one of screening anti-hepatic fibrosis medicines important thinking screening can suppress liver fibroblast proliferation
Medicine or screening can suppress fibroblastic propagation of the growth factor-induceds such as TGF, screen usually in fibroblast
On carry out, NIH/3T3 cells are the most frequently used cell lines.
The content of the invention
The invention discloses a new composition, 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 10% and 90%.
Composition disclosed by the invention can be made pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows that composition of the invention has preferable effect of anti hepatic fibrosis.It is of the invention pharmaceutically
Acceptable salt has same drug effect.
Further, the experiment in vitro of composition shows that composition has the activity of very strong anti-fibroblast proliferation,
Therefore composition of the invention is expected to be used to prepare new anti-hepatic fibrosis medicines.
Further, the experiment in vitro of composition shows, composition have very strong anti-growth factor-induced into fiber
The activity of cell propagation, composition is a compound for great exploitation potential, it can be directly used for the treatment of corresponding disease with
And the preparation of related drugs.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by specific real
Any limitation of example is applied, but is defined in the claims.
Specific embodiment
The preparation of the compound Psiguadial A of embodiment 1
Document (the Meng Shao that the preparation method of compound Psiguadial A (I) is delivered with reference to Meng Shao et al.
et al.,2010.Psiguadials A and B,Two Novel Meroterpenoids with Unusual
Skeletons from the Leaves of Psidium guajava.Organic Letters 12(2010)5040–
5043) method.
The synthesis of O- bromoethyls derivative (II) of the Psiguadial A of embodiment 2
Compound I (474mg, 1.00mmol) is dissolved in 20mL benzene, to addition TBAB (TBAB) in solution
50% sodium hydroxide solution of (0.16g), 1,2- Bromofume (7.520g, 40.00mmol) and 12mL.Mixture is Celsius 35
Degree stirring 8h.Reaction solution is poured into frozen water after 8h, is extracted twice with dichloromethane immediately, merge organic phase solution.Then
To organic phase solution successively with water and saturated common salt water washing 3 times, then with anhydrous sodium sulfate drying, the removal that is finally concentrated under reduced pressure is molten
Agent obtains product crude product.(mobile phase is the purifying of product crude product silica gel column chromatography：Petroleum ether/acetone=100:0.5, v/v), receive
Collection brown concentrates elution band and flings to the brown ceramic powder (502mg, 73%) that solvent obtains compound II.
1H NMR(500MHz,DMSO-d6) δ 10.44 (s, 2H), 7.24 (s, 2H), 7.20 (d, J=10.0Hz, 3H),
4.31(s,4H),3.89(s,1H),3.74(s,4H),2.30(s,1H),2.12(s,1H),2.02(s,1H),1.92(s,1H),
1.79 (s, 1H), 1.73 (s, 1H), 1.51 (d, J=19.8Hz, 3H), 0.99 (s, 3H), 0.95 (d, J=4.7Hz, 7H),
0.85(s,3H),0.53(s,1H),0.43(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.69(s),170.54(s),165.42(s),163.38(s),142.72
(s),129.71(s),127.96(s),127.08(s),118.00(s),116.82(s),114.82(s),72.73(s),
40.19(s),34.75(s),34.32(s),31.75(s),30.93(s),28.09(s),26.43(s),24.48(s),23.74
(s),21.18(s),20.77(s),19.99(s),14.39(s).
HRMS(ESI)m/z[M+H]+calcd for C34H41Br2O5:689.1300；found 689.1303.
The synthesis of O- (piperazinyl) ethyl derivative (III) of the Psiguadial A of embodiment 3
Compound II (344mg, 0.5mmol) is dissolved in the middle of 25mL acetonitriles, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), KI (168mg, 1.0mmol) and Piperazine anhydrous (3446mg, 40mmol), mixture is heated to reflux 4h.Reaction
Reaction solution is poured into frozen water after end, is extracted 3 times with equivalent dichloromethane, merge organic phase.Water and saturated common salt are used successively
Water washing merge after organic phase, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.Product is thick
(mobile phase is the purifying of product silica gel column chromatography：Petroleum ether/acetone=100:1.0, v/v) yellow, is collected to concentrate elution band and wave
Solvent is gone to obtain the yellow powder (254.8mg, 73%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 10.46 (s, 2H), 7.23 (s, 2H), 7.20 (d, J=10.0Hz, 3H),
4.02 (s, 4H), 3.96 (s, 1H), 2.62 (d, J=8.0Hz, 12H), 2.31 (s, 8H), 2.10 (s, 1H), 2.01-1.85 (m,
3H),1.79(s,1H),1.66(s,1H),1.44(s,2H),1.38(s,1H),1.27(s,1H),1.05(s,2H),1.03(d,
J=45.8Hz, 3H), 0.93-0.70 (m, 9H), 0.52 (s, 1H), 0.23 (s, 1H)13C NMR(125MHz,DMSO-d6)δ
188.62(s),170.44(s),165.27(s),163.22(s),142.59(s),129.52(s),127.80(s),126.91
(s),117.86(s),116.67(s),114.65(s),69.34(s),54.61(s),54.05(s),45.17(s),40.02
(s),34.61(s),34.17(s),30.77(s),27.92(s),26.29(s),24.33(s),23.57(s),21.00(s),
20.62(s),19.84(s),14.21(s).
HRMS(ESI):m/z[M+H]+calcd for C42H59N4O5:699.4485；found:699.4480.
The synthesis of O- (1H- tetrazoles base) ethyl derivative (IV) of the Psiguadial A of embodiment 4
Compound II (344mg, 0.5mmol) is dissolved in the middle of 20mL acetonitriles, be added thereto to Anhydrous potassium carbonate (690mg,
5.0mmol), KI (168mg, 1.0mmol) and 1H- tetrazoles (1401mg, 20mmol), mixture is heated to reflux 2h.Instead
Reaction solution is poured into 20mL frozen water after should terminating, is extracted 2 times with equivalent dichloromethane, merge organic phase.Water is used successively and is satisfied
Organic phase after merging with brine It, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.
Because tautomerization, two kinds of substitution products of 1H- tetrazoles base and 2H- tetrazoles base can be generated at reaction conditions.Product
(mobile phase is the purifying of crude product silica gel column chromatography：Petroleum ether/acetone=100:1, v/v), collect yellow and concentrate elution band, then will
Elution band is concentrated, and purifies that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:0.5, v/v), collection two is light successively
The elution band of yellow, it is the faint yellow solid (89.9mg, 27%) for obtaining compound IV to concentrate preceding 1 elution band.
1H NMR(500MHz,DMSO-d6)δ10.47(s,2H),10.40(s,1H),10.26(s,1H),7.24(s,
2H), 7.21 (d, J=10.0Hz, 3H), 4.65 (s, 1H), 4.60 (s, 1H), 4.45 (d, J=2.6Hz, 5H), 4.42 (s,
1H),4.07(s,1H),2.20(s,1H),1.93–1.84(m,4H),1.72(s,1H),1.60–1.21(m,4H),0.99(s,
3H),0.92–0.71(m,9H),0.55(s,1H),0.25(s,1H).
13C NMR(125MHz,DMSO-d6)δ188.53(s),170.35(s),165.18(s),163.13(s),144.94
(s),142.48(s),129.45(s),127.69(s),126.84(s),117.75(s),116.60(s),114.54(s),
67.03(s),47.04(s),39.95(s),34.52(s),34.10(s),30.66(s),27.85(s),26.18(s),24.26
(s),23.46(s),20.93(s),20.51(s),19.77(s),14.10(s).
HRMS(ESI):m/z[M+H]+calcd for C36H43N8O5:667.3356；found:667.3352.
The composition anti-hepatic fibrosis activity of embodiment 5
Due to the activation of hepatic stellate cell, so as to cause a large amount of secretions of various growth factors, these growth factors
The meeting fibroblastic fast breeding of induced liver, so that one of accelerating fibers, most important of which growth factor are exactly
TGF.Therefore, one of screening anti-hepatic fibrosis medicines important thinking screening can suppress liver fibroblast proliferation
Medicine or screening can suppress fibroblastic propagation of the growth factor-induceds such as TGF, screen usually in fibroblast
On carry out, NIH/3T3 cells are the most frequently used cell lines.
The preparation of composition：The powder of the 10mg compounds III of 200 mesh nets will be crossed after grinding and 200 will be crossed after grinding
The powder of the 90mg compounds IV of mesh net is fitted into tubule with cover and obtains 100mg compositions with the mixing of turbine stirring instrument,
The solution of composition is obtained when using with the composition of water dissolves this 100mg.
Experimental example 1：The inhibitory action that composition is bred to fibroblast NIH/3T3
First, experimental technique：
NIH/3T3 cell lines are purchased from quoted from the Chinese Academy of Sciences of ATCC (American Type Culture Collection)
Extra large cell institute cell bank.
The NIH/3T3 cells of the sub- fusion of exponential phase are digested with 0.25% pancreatin, is washed, after centrifugation, use DMEM
Nutrient solution (containing 10%FCS) is made 1 × 104The cell suspension of cell/ml, Trypan Blue identification survival rate is more than 95%, presses
Per hole 100ul in 96 orifice plates of addition, in 37 DEG C, 5%CO2After culture 24h synchronization process, supernatant is abandoned, addition contains medicine
DMEM nutrient solutions (containing 10%FCS) 200ul, cultivates 48h, adds MTT solution to be incubated 4h per hole.Nutrient solution is discarded, is added
150ulDMSO, vibrates 10 minutes, dissolves crystallization, OD values is read at ELIASA 490nm, as a result with OD490Represent.
2nd, experimental result：
1st, morphological observation
NIH/3T3 stretches well before medication, and refractivity is weaker, directional, radial, the speed of cell propagation
Hurry up；And after adding composition 24h, fibroblast number is reduced, shape becomes irregular, and projection shortens, and cell arrangement is chaotic, carefully
Intracellular metabolite concentration increases.Compound III and compound IV is acted on without this.
The inhibitory action that mtt assay detection composition is bred to NIH/3T3 cells.
Table 1：The inhibitory action that mtt assay detection composition is bred to NIH/3T3
Note：*, with cell negative control P<0.05
As a result：Composition has significant inhibitory action in 20ug/ml to the cell propagation of fibroblast NIH/3T3.Table
Bright composition is external to significantly inhibit effect to fibroblastic propagation.Compound III and compound IV is acted on without this.
Experimental example 2：Composition is to transforming growth factor-β1(TGF-β1) induction fibroblast proliferation inhibitory action
TGF-β1It is to promote cell propagation and the collagenogenic strongly active factor, TGF-β is added in cell110ng/ml is pierced
Swash cell propagation, then detect the inhibitory action that the cell that medicine is induced TGF-β 1 is bred, the effect of composition is judged to analyze
Mechanism.
Table 2：Inhibitory action of the mtt assay detection composition to TGF induction NIH/3T3 propagation
Note：*, P is compareed with cell+TGF<0.05
As a result：Composition is in 20ug/ml to fibroblast NIH/3T3 in TGF-β1Induction under cell propagation have aobvious
The inhibitory action of work, compound III and compound IV are acted on without this.Show that the external suppression to fibrocyte proliferation of composition is made
With may be by intervening what TGF signal paths were realized.
Conclusion：Cell propagation of the composition to fibroblast NIH/3T3 under the stimulation of 10% calf serum has significantly
Inhibitory action；Composition is to fibroblast NIH/3T3 in TGF-β1Induction under cell propagation have and significant suppress to make
With.Composition can be used to prepare anti-hepatic fibrosis medicines.Compound III and compound IV exist to fibroblast NIH/3T3
Cell under the stimulation of 10% calf serum is bred without significant inhibitory action, to fibroblast NIH/3T3 in TGF-β1's
Cell under induction is bred without significant inhibitory action, it is not possible to for preparing anti-hepatic fibrosis medicines.
The preparation of the composition tablet involved in the present invention of embodiment 6
2 grams of compositions are taken, addition prepares 18 grams of the customary adjuvant of tablet, mixed, conventional tablet presses are made 100.
The preparation of the composition capsule involved in the present invention of embodiment 7
2 grams of compositions are taken, addition prepares customary adjuvant such as 18 grams of the starch of capsule, mixed, it is encapsulated to be made 100.
Claims (6)
1. a kind of composition, it is characterized by 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 10% and 90%,
2. the preparation method of composition as claimed in claim 1, it is characterized by：By the powder of compound III and compound IV
Powder be respectively 10% and 90% according to mass percent and be sufficiently mixed.
3. application of a kind of composition as claimed in claim 1 in hepatic fibrosis medicines are treated.
4. application of the composition as claimed in claim 3 in hepatic fibrosis medicines are treated, it is characterized by the composition presses down
It is made fibrocyte proliferation.
5. application of the composition as claimed in claim 3 in hepatic fibrosis medicines are treated, it is characterized by the composition presses down
The fibroblast proliferation of growth factor-induced processed.
6. application of the composition as claimed in claim 5 in hepatic fibrosis medicines are treated, it is characterized by the growth factor
It is TGF-β 1.
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| CN107540672A (en) * | 2017-10-10 | 2018-01-05 | 牡丹江医学院 | A kind of medicine and its synthetic method for treating hepatic sclerosis |
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