CN106038553A - Application of composition of Schiglautone A derivatives in preparation of pancreatic fibrosis control drugs - Google Patents
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- CN106038553A CN106038553A CN201610417036.9A CN201610417036A CN106038553A CN 106038553 A CN106038553 A CN 106038553A CN 201610417036 A CN201610417036 A CN 201610417036A CN 106038553 A CN106038553 A CN 106038553A
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- 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
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a composition, a preparation method of the composition and application of the composition in pancreatic fibrosis control drugs. The invention discloses a composition and a preparation method thereof. Pharmacological experiments show that the composition of the invention can prevent or treat pancreatic fibrosis and is worthy of the development of liver injury preventive or treatment drugs.
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 2011, deliver (Fan-Yu Meng et al.,
2011.Schiglautone A,a New Tricyclic Triterpenoid with a Unique 6/7/9-Fused
Skeleton from the Stems of Schisandra glaucescens.Organic Letters 13(2011)
1502 1505) compound, we have carried out structural modification to compound I, it is thus achieved that two i.e. compounds of new derivant
III and compound IV, and it is prepared for compositions pancreatic gland fibrosis anti-to said composition activity with compound III and compound IV
Being evaluated, 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 70% and 30%.
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 Schiglautone A
Document (the Fan-Yu that the preparation method of compound Schiglautone A (I) is delivered with reference to Fan-Yu Meng et al.
Meng et al.,2011.Schiglautone A,a New Tricyclic Triterpenoid with a Unique 6/
7/9-Fused Skeleton from the Stems of Schisandra glaucescens.Organic Letters
13 (2011) 1,502 1505) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2Schiglautone A
Compound I (502mg, 1.00mmol) is dissolved in 15mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB)
(0.08g), glycol dibromide (7.520g, 40.00mmol) and 50% sodium hydroxide solution of 6mL.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 (508mg, 71%) of compound II.
1H NMR(500MHz,DMSO-d6)δ13.40(s,1H),6.10(s,1H),5.63(s,1H),5.53(s,1H),
3.85 (d, J=11.2Hz, 4H), 3.52 (d, J=10.8Hz, 4H), 2.96 (s, 1H), 2.20 (s, 1H), 2.16 (s, 2H),
2.00 (s, 1H), 1.84 (d, J=13.9Hz, 4H), 1.69 (s, 1H), 1.58 (dd, J=22.2,8.5Hz, 4H), 1.51 (s,
1H), 1.47 (s, 1H), 1.26 (dd, J=9.1,4.4Hz, 4H), 1.21 (s, 1H), 1.08 0.98 (m, 4H), 0.96-0.94
(m,9H),0.94-0.85(m,6H).
13C NMR(125MHz,DMSO-d6)δ211.46(s),209.14(s),170.06(s),161.12(s),143.51
(s),132.01(s),127.77(s),85.96(s),82.40(s),70.19(s),69.10(s),57.14(s),52.73
(s),51.90(s),45.77(s),40.67(s),38.57(s),38.32(s),35.04(s),33.55(s),33.27(s),
29.85(s),28.98(s),26.71(s),25.50(s),24.05(s),22.31(s),21.06(s),20.56(s),20.00
(s),18.69(s),18.11(s),15.07(s).
HRMS(ESI)m/z[M-H]-calcd for C34H51Br2O6:715.2032；found 715.2027.
The synthesis of O-(the 1H-tetrazole base) ethyl derivative (III) of embodiment 3Schiglautone A
Compound II (358mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and 1H-tetrazole (1401mg, 20mmol), mixture is heated to reflux 5h.Reaction
Reactant liquor is poured in 20mL frozen water after end, extract three times with equivalent dichloromethane, merge organic facies.Successively with water and saturated
Organic facies after brine It merging, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Cause
For tautomerization, 1H-tetrazole base and two kinds of substitution products of 2H-tetrazole base can be generated at reaction conditions.Product is thick
Product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1, v/v), collects faint yellow concentration elution band, then will
Faint yellow elution band concentrates, and purifies (flowing is mutually: petroleum ether/acetone=100:0.5, v/v) with silica gel column chromatography, collects successively
Two flaxen elution bands, concentrate front 1 elution band and i.e. obtain the faint yellow solid (79.8mg, 23%) of compound III.
1H NMR(500MHz,DMSO-d6)δ16.29(s,1H),9.99(s,1H),9.93(s,1H),6.25(s,1H),
5.76 (s, 1H), 5.40 (s, 1H), 4.57 (s, 1H), 4.38 (s, 1H), 4.32 (s, 1H), 4.21 (s, 1H), 3.96 (d, J=
11.9Hz,4H),3.33(s,1H),2.55(s,1H),2.51(s,2H),2.39(s,1H),1.98(s,3H),1.82–1.76
(m, 3H), 1.73 (s, 1H), 1.65 (d, J=6.5Hz, 2H), 1.60 (s, 1H), 1.53 (s, 1H), 1.47 1.37 (m, 4H),
1.30 (s, 1H), 1.19 (s, 1H), 1.10 (t, J=12.5Hz, 3H), 1.08 (t, J=12.5Hz, 9H), 1.03 (s, 3H),
0.86(s,3H).
13C NMR(125MHz,DMSO-d6)δ211.72(s),209.42(s),170.36(s),161.38(s),145.37
(s),143.80(s),132.29(s),128.04(s),86.25(s),82.68(s),66.14(s),65.60(s),57.33
(s),52.91(s),52.08(s),46.81(s),45.95(s),40.84(s),38.76(s),38.50(s),35.21(s),
33.74(s),30.01(s),29.16(s),26.91(s),25.66(s),24.23(s),22.51(s),21.22(s),20.74
(s),20.20(s),18.85(s),18.29(s),15.27(s).
HRMS(ESI):m/z[M+H]+calcd for C36H55N8O6:695.4245；found:695.4248.
The synthesis of O-(benzimidazolyl) ethyl derivative of embodiment 4Schiglautone A
Compound II (358mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg, 10mmol), mixture is heated to reflux 6h.Reaction
After end, reactant liquor is poured in frozen water, extract three 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=100:1.5, v/v), collects brown and concentrates elution band, concentrate
I.e. obtain the brown solid (169.9mg, 43%) of compound IV.
1H NMR (500MHz, DMSO-d6) δ 13.32 (s, 1H), 8.38 (s, 2H), 7.66 (d, J=25.0Hz, 4H),
7.39 (s, 2H), 7.32 (s, 2H), 6.25 (s, 1H), 5.64 (d, J=18.7Hz, 2H), 4.34 (s, 1H), 4.28 (s, 1H),
4.18 (d, J=13.7Hz, 2H), 4.04 (s, 2H), 3.99 (s, 2H), 3.13 (s, 1H), 2.65 (s, 2H), 2.26 (s, 1H),
2.17 (s, 1H), 2.06 (s, 1H), 1.98 (s, 3H), 1.87 (d, J=16.4Hz, 2H), 1.66 (dd, J=8.0,6.6Hz,
4H), 1.62 (s, 1H), 1.49 (s, 1H), 1.41 (dd, J=19.6,10.4Hz, 2H), 1.37 (d, 2H), 1.20 1.11 (m,
4H), 1.07 (d, J=20.0Hz, 6H), 103 (d, J=20.0Hz, 3H), 1.01 (d, J=20.0Hz, 3H), 0.95 (d, J=
20.0Hz,3H).
13C NMR(125MHz,DMSO-d6)δ211.30(s),208.98(s),169.90(s),160.96(s),146.28
(s),143.34(s),139.64(s),133.48(s),131.85(s),127.61(s),123.92(s),123.35(s),
118.55(s),110.85(s),85.79(s),82.26(s),67.74(s),67.20(s),57.00(s),52.56(s),
51.73(s),45.63(s),44.94(s),40.49(s),38.42(s),38.17(s),34.86(s),33.40(s),29.68
(s),28.81(s),26.57(s),25.33(s),23.88(s),22.17(s),20.89(s),20.39(s),19.86(s),
18.52(s),17.87(s),14.93(s).
HRMS(ESI):m/z[M+H]+calcd for C48H63N4O6:791.4748；found:791.4744.
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 70mg compound III of 200 mesh nets after grinding crosses 200 after grinding
The powder of the 30mg 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 slow
Rush liquid (5 parts of toluene: 5 parts of 2-methyl isophthalic acid-propanol: 2 parts of 1-propanol), shake 30min, centrifugal.Tissue phase (0.6ml) with
15min is placed in the mixing of Ehrlich, s reagent.Measure trap at 565nm, make standard curve with 4-hydroxyl-1-proline and calculate
Concentration, content represents 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 contents measure
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 70% and 30%,
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 70% and 30%.
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.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104739846A (en) * | 2015-04-15 | 2015-07-01 | 南京大学 | Application of O-(1H-tetrazole) ethyl derivative of cleistanone to preparing drug for preventing or treating pancreatic fibrosis |
| CN104825466A (en) * | 2015-04-29 | 2015-08-12 | 南京广康协生物医药技术有限公司 | Applications of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for preventing or treating pancreatic fibrosis |
| CN105232508A (en) * | 2015-11-09 | 2016-01-13 | 南京大学 | Composition and application thereof to drugs for preventing or treating pancreas fibrosis |
-
2016
- 2016-06-13 CN CN201610417036.9A patent/CN106038553A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104739846A (en) * | 2015-04-15 | 2015-07-01 | 南京大学 | Application of O-(1H-tetrazole) ethyl derivative of cleistanone to preparing drug for preventing or treating pancreatic fibrosis |
| CN104825466A (en) * | 2015-04-29 | 2015-08-12 | 南京广康协生物医药技术有限公司 | Applications of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for preventing or treating pancreatic fibrosis |
| CN105232508A (en) * | 2015-11-09 | 2016-01-13 | 南京大学 | Composition and application thereof to drugs for preventing or treating pancreas fibrosis |
Non-Patent Citations (1)
| Title |
|---|
| FAN-YU MENG ET AL.: "Schiglautone A, a New Tricyclic Triterpenoid with a Unique 6/7/9-Fused Skeleton from the Stems of Schisandra glaucescens", 《OGRANIC LETTERS》 * |
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Application publication date: 20161026 |