CN106420719A - Applications of composition of Atropurpuran derivatives in preparing medicines for preventing or treating pancreatic fibrosis - Google Patents
Applications of composition of Atropurpuran derivatives in preparing medicines for preventing or treating pancreatic fibrosis Download PDFInfo
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- CN106420719A CN106420719A CN201610614481.4A CN201610614481A CN106420719A CN 106420719 A CN106420719 A CN 106420719A CN 201610614481 A CN201610614481 A CN 201610614481A CN 106420719 A CN106420719 A CN 106420719A
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The invention relates to the fields of organic synthesis and medicinal chemistry, and in particular relates to a composition, a preparation method, and applications of the composition in preparing medicines for preventing or treating pancreatic fibrosis. The invention discloses a composition of Atropurpuran derivatives and a preparation method of the composition. The pharmacological experiment proves that the composition has the effect of preventing or treating pancreatic fibrosis, and has the value of being developed into the medicines for preventing or treating pancreatic fibrosis.
Description
Technical field
The present invention relates to organic synthesiss and medicinal chemistry art are and in particular to compositionss, preparation method and its usage.
Background technology
Pancreatic gland fibrosis are the common traits of chronic pancreatitiss caused by a variety of causes, are also the tissue disease adjoint with it simultaneously
Feature of science, shows as a large amount of fibroblast proliferations and rich in the extracellular matrix connecting tissue.It is that many reasons lead to pancreas
The result of gland injury repairing, finds that pancreatic stellate cells and cytokine profiles are relevant with pancreatic gland fibrosis, pancreas fiber in the recent period
Change that current sickness rate is more and more high, be badly in need of the anti-pancreatic gland fibrosis medicine of research and development high-efficiency low-toxicity.
Existing medicine has that toxicity is big, safety is low, from natural product at present for the treatment 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.
Compound I according to the present invention be one deliver within 2009 (Pei Tang et al.,
2009.Atropurpuran,a novel diterpene with an unprecedented pentacyclic cage
skeleton,from Aconitum hemsleyanum var.atropurpureum.Tetrahedron Letters 50
(2009) 460 462) compound, we have carried out structural modification to compound I, and obtaining two new derivants is chemical combination
Thing III and compound IV, and it is prepared for compositionss the anti-pancreatic gland fibrosis work to said composition with compound III and compound IV
Property evaluated, it has anti-pancreatic gland fibrosis activity.
Content of the invention
The invention discloses new compositionss, 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 65% and 35%.
Compositionss disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, the compositionss of the present invention have preferably 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 subject to concrete reality
Apply any restriction of example, but be defined in the claims.
Specific embodiment
The preparation of embodiment 1 compound Atropurpuran
Document (the Pei Tang et that the preparation method of compound Atropurpuran (I) is delivered with reference to Pei Tang et al.
al.,2009.Atropurpuran,a novel diterpene with an unprecedented pentacyclic
cage skeleton,from Aconitum hemsleyanum var.atropurpureum.Tetrahedron Letters
50 (2009) 460 462) method.
The synthesis of O- bromoethyl derivant (II) of embodiment 2Atropurpuran
Compound I (312mg, 1.00mmol) is dissolved in 10mL benzene, adds tetrabutyl ammonium bromide (TBAB) in solution
(0.08g), 50% sodium hydroxide solution of glycol dibromide (3.760g, 20.00mmol) and 6mL.Mixture is Celsius 35
Degree stirring 6h.After 6h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.Then
Successively water and saturated common salt water washing 3 times are used to organic phase solution, then uses anhydrous sodium sulfate drying, last concentrating under reduced pressure removal is molten
Agent obtains product crude product.(mobile phase is product crude product silica gel column chromatography purification：Petroleum ether/acetone=100:1.0, v/v), receive
Collection brown is concentrated elution band and is flung to the yellow powder (309mg, 74%) that solvent obtains compound II.
1H NMR(500MHz,DMSO-d6)δ9.86(s,1H),5.23(s,1H),4.87(s,1H),4.83(s,1H),
4.39 (s, 1H), 4.00 (s, 2H), 3.91 (s, 1H), 3.58 (s, 2H), 3.01 (s, 1H), 2.27 (s, 1H), 2.15 (d, J=
6.3Hz, 2H), 2.09 2.00 (m, 5H), 1.78 (dd, J=35.2,19.2Hz, 2H), 1.71 1.65 (m, 1H), 1.41 (s,
2H),0.99(s,3H).
13C NMR(125MHz,DMSO-d6)δ208.55(s),203.16(s),150.94(s),125.16(s),111.66
(s),78.63(s),71.39(s),57.77(s),47.73(s),40.79(s),34.58(s),33.01(s),32.69(s),
29.25(s),29.34(s),26.52(s),24.23(s),22.30(s),20.64(s).
HRMS(ESI)m/z[M+H]+calcd for C22H28BrO3:419.1222；found 419.1226.
The synthesis of the O- (nafoxidine base) ethyl derivative (III) of embodiment 3Atropurpuran
Compound II (209mg, 0.5mmol) is dissolved in the middle of 18mL acetonitrile, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg, 20mmol), mixture is heated to reflux 2h.Reaction knot
After bundle, reactant liquor is poured in frozen water, extracted 2 times with equivalent dichloromethane, merge organic faciess.Use water and saturated aqueous common salt successively
Washing merge after organic faciess, then use anhydrous sodium sulfate drying, concentrating under reduced pressure removal solvent obtain product crude product.Product crude product
Purify that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:1.0, v/v), collect brown and concentrate elution band, concentration is
Obtain the brown solid (125mg, 61%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 9.78 (s, 1H), 5.15 (s, 1H), 4.61 (d, J=10.5Hz, 2H),
4.45(s,1H),3.83(s,1H),3.53(s,2H),2.94(s,1H),2.62(s,2H),2.46(s,4H),2.20(s,1H),
2.08 (d, J=6.0Hz, 2H), 2.00 1.91 (m, 3H), 1.75 (d, J=2.1Hz, 2H), 1.69 (s, 2H), 1.62 (d, J=
5.5Hz,5H),1.30(s,2H),0.91(s,3H).
13C NMR(125MHz,DMSO-d6)δ208.65(s),203.36(s),151.04(s),125.36(s),111.76
(s), 78.83 (s), 67.20 (s), 57.97 (s), 54.33 (d, J=17.1Hz), 47.82 (s), 41.00 (s), 34.67 (s),
32.79(s),29.45(s),29.22(s),26.61(s),25.14(s),24.43(s),22.40(s),20.84(s).
HRMS(ESI):m/z[M+H]+calcd for C26H36NO3:410.2695；found:410.2699.
The synthesis of O- (the 1H- tetrazole base) ethyl derivative of embodiment 4Atropurpuran
Compound II (209mg, 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 4h.Reaction
After end, reactant liquor is poured in 20mL frozen water, extracted 3 times with equivalent dichloromethane, merge organic faciess.Use water and saturation successively
Brine It merge after organic faciess, then use anhydrous sodium sulfate drying, concentrating under reduced pressure removal solvent obtain 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
(mobile phase is product silica gel column chromatography purification：Petroleum ether/acetone=100:0.8, v/v), collect yellow and concentrate elution band, then will
Elution band concentrates, and purifies that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:0.4, v/v), collection two is light successively
The elution band of yellow, concentrates the yellow powder (83.6mg, 41%) that front 1 elution band obtains compound IV.
1H NMR(500MHz,DMSO-d6)δ10.51(s,1H),9.74(s,1H),5.05(s,1H),4.61–4.48(m,
3H),4.19(s,1H),4.12(s,1H),3.80(s,2H),3.75(s,1H),2.86(s,1H),2.08(s,1H),1.97(d,
J=2.9Hz, 2H), 1.90 1.81 (m, 3H), 1.69 1.57 (m, 4H), 1.54 (s, 1H), 1.25 (s, 2H), 0.80 (s,
3H).
13C NMR(125MHz,DMSO-d6)δ208.46(s),203.17(s),150.83(s),144.83(s),125.18
(s),111.56(s),78.65(s),66.57(s),57.79(s),47.63(s),46.37(s),40.80(s),34.49(s),
32.59(s),29.27(s),29.02(s),26.43(s),24.24(s),22.21(s),20.67(s).
HRMS(ESI):m/z[M+H]+calcd for C23H29N4O3:409.2240；found:409.2244.
Embodiment 5 compositionss 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 compositionss：Cross the powder of the 65mg compound III of 200 mesh nets after grinding and cross 200 after grinding
The powder of the 35mg compound IV of mesh net loads in tubule with cover and obtains 100mg compositionss with the mixing of turbine stirring instrument,
Obtain the solution of compositionss with the compositionss of this 100mg of water dissolution during use.
2 experimental techniques
2.1 modeling method：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 packets and medication
Rat model is randomly divided into model group, compositionss 0.9mg/kg group, compound III 0.9mg/kg group and compound
IV 0.9mg/kg group, separately sets blank control group.Administration group is administered after modeling starts, and is administered orally continuous 30 days；Dissect dynamic when 60 days
Thing.
2.3 Testing index
2.3.1 pancreas is taken to weigh at the end of testing.
2.3.2 pancreas hydroxyproline content measures and takes 100mg sample to be homogenized in water, hydrolyzes 20 in 110 DEG C of 10N HCl
Hour.HCl nitrogen volatilizees, and hydrolyzate is filtered with after distilled water dissolving.Take 0.5ml liquid and 3ml citric acid phosphoric acid buffer
Liquid (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.Plus 1.75ml extracts and delays
Rush liquid (5 parts of toluene：5 parts of 2- methyl isophthalic acid-propanol：2 parts of 1- propanol), shake 30min, centrifugation.Tissue phase (0.6ml) with
15min is placed in the mixing of Ehrlich, s reagent.Measure trap in 565nm, make standard curve with 4- hydroxyl -1- proline and calculate
Concentration, content is represented with ug/g tissue.
2.3.3 histological examination pancreatic tissues 10% formalin fix, paraffin embedding, microscopy after dyeing.To fiber
Change situation scores (0-3 divides).
3 results
The impact to rat pancreas organ coefficient for 3.1 compositionss
At the end of experiment, rat put to death, dissect, weigh in and pancreas weighs and calculates the ratio (pancreas of itself and body weight
Organ coefficient), the results are shown in Table 1.The impact to pancreas organ coefficient for the compositionss, comparing with model group has significant difference.Chemical combination
The thing III and compound IV impact to pancreas organ coefficient, compares with model group that 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 rat is carried out with pulmonary's hydroxyproline content mensure, result such as table 2.Compositionss are to hydroxyl dried meat
The impact of histidine content, comparing with model group has significant difference.The compound III and compound IV shadow to hydroxyproline content
Ring, compare with model group that 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 conventional embedding of specimen, fixing, HE dyeing, microscopy.
Result：Model group visible pancreas surrounding catheter extensive inflammation reaction in the 60th day；Thermophilic middle granulocyte karyolymph cellular infiltration,
Interstitial edema, bleeding and the necrosis of accidental pancreas cystencyte；Between pancreas cystencyte disappearance position and pancreas bubble, fibrosiss occur.
Compositionss can reduce inflammatory reaction and fibrosiss.Appraisal result is shown in Table 3.The impact to scoring for the compositionss, with model
Group compares significant difference.
Table 3
* represent p<0.05, compare with model group；The inflammatory cell infiltration of blank control group and Fibrosis score are all 0.
Conclusion：The present invention is by compositionss impact Fibrotic on pancreas in rat it was confirmed compositionss have anti-pancreas fibre
The effect of dimensionization.Therefore, compositionss can be used for preparing the medicine of anti-pancreatic gland fibrosis as active component.And compound III and
Compound IV no this activity is it is impossible to be used for preparing the medicine of anti-pancreatic gland fibrosis.
The preparation of embodiment 6 composition tablet involved in the present invention
Take 2 grams of compositionss, 18 grams of the customary adjuvant of tablet is prepared in addition, mix, conventional tablet presses make 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Take 2 grams of compositionss, customary adjuvant such as 18 grams of the starch of capsule is prepared in addition, mix, encapsulated make 100.
Claims (6)
1. a kind of compositionss, 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 65% and 35%,
2. the preparation method of compositionss as claimed in claim 1, it is characterized by：By the powder of compound III and compound IV
Powder be respectively according to mass percent and 65% and 35% be sufficiently mixed.
3. application in treatment pancreatic gland fibrosis medicine for a kind of compositionss as claimed in claim 1.
4. application in treatment pancreatic gland fibrosis medicine for the compositionss as claimed in claim 3, it is characterized by：Described compositionss
The pancreas organ coefficient caused by pancreatic gland fibrosis is reversed to decline.
5. application in treatment pancreatic gland fibrosis medicine for the compositionss as claimed in claim 3, it is characterized by：Described compositionss
The hydroxyproline content caused by pancreatic gland fibrosis is reversed to raise.
6. application in treatment pancreatic gland fibrosis medicine for the compositionss as claimed in claim 3, it is characterized by：Described compositionss
The inflammatory cell infiltration caused by pancreatic gland fibrosis is reversed to raise.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610614481.4A CN106420719A (en) | 2016-07-29 | 2016-07-29 | Applications of composition of Atropurpuran derivatives in preparing medicines for preventing or treating pancreatic fibrosis |
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| CN201610614481.4A CN106420719A (en) | 2016-07-29 | 2016-07-29 | Applications of composition of Atropurpuran derivatives in preparing medicines for preventing or treating pancreatic fibrosis |
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