CN106727465A - The derivative composition of Atropurpuran is used to prevent and treat pancreatic fibrosis - Google Patents
The derivative composition of Atropurpuran is used to prevent and treat pancreatic fibrosis Download PDFInfo
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- CN106727465A CN106727465A CN201611204987.4A CN201611204987A CN106727465A CN 106727465 A CN106727465 A CN 106727465A CN 201611204987 A CN201611204987 A CN 201611204987A CN 106727465 A CN106727465 A CN 106727465A
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/13—Amines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/12—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
Derivative composition the invention discloses Atropurpuran is used to prevent and treat pancreatic fibrosis, application of the composition of the i.e. a kind of O of Atropurpuran (lignocaine) ethyls and O (two (2 methylmercaptoethyl) amidos) ethyl derivative in treating or preventing pancreatic fibrosis medicine, the present invention relates to organic synthesis and medicinal chemistry art, and in particular to the composition of Atropurpuran derivatives, preparation method and its purposes on prevention or treatment pancreatic fibrosis medicine is prepared.The invention discloses a kind of composition of Atropurpuran derivatives and preparation method thereof.Pharmacological experiment shows that the composition of Atropurpuran derivatives of the invention has the effect for preventing or treating pancreatic fibrosis, the value with exploitation prevention or treatment pancreatic fibrosis medicine.
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
Pancreatic fibrosis are the common trait of chronic pancreatitis caused by a variety of causes, while being also the tissue disease adjoint with it
Feature of science, shows as a large amount of fibroblast proliferations and the extracellular matrix rich in connection tissue.It is that many reasons cause pancreas
The result of gland injury repair, finds that pancreatic stellate cells and cytokine profiles are relevant with pancreatic fibrosis, pancreas fiber in the recent period
Change that the current incidence of disease is more and more high, be badly in need of the anti-pancreatic fibrosis medicine of research and development high-efficiency low-toxicity.
Existing medicine has that toxicity is big, security is low at present for the treatment of pancreatic fibrosis, from natural products
Find compound or lead compound and carry out structural modification and obtain its derivative, so as to obtain high-efficiency low-toxicity potential drug most
There is important value.
Compound I of 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, obtain two new derivatives i.e. chemical combination
Thing III and compound IV, and be prepared for composition with compound III and compound IV and the anti-pancreatic fibrosis of said composition are lived
Property evaluated, it has anti-pancreatic fibrosis activity.
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 80% and 20%.
Composition disclosed by the invention can be made pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows that composition of the invention has preferably anti-pancreatic fibrosis effect.Pharmacy of the 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 specific real
Any limitation of example is applied, but is defined in the claims.
Specific embodiment
The preparation of the compound Atropurpuran of embodiment 1
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- bromoethyls derivative (II) of the Atropurpuran of embodiment 2
Compound I (312mg, 1.00mmol) is dissolved in 10mL benzene, to addition TBAB (TBAB) in solution
50% sodium hydroxide solution of (0.08g), 1,2- Bromofume (3.760g, 20.00mmol) and 6mL.Mixture is Celsius 35
Degree stirring 6h.Reaction solution is poured into frozen water after 6h, 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=100:1.0, v/v), receive
Collection brown concentrates elution band and flings 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 O- (diethylin) ethyl derivative (III) of the Atropurpuran of embodiment 3
Compound II (209mg, 0.5mmol) is dissolved in the middle of 10mL acetonitriles, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and diethylamine (2920mg, 40mmol), mixture is heated to reflux 2h.Reaction knot
Reaction solution is poured into frozen water after beam, is extracted 2 times with equivalent dichloromethane, merge organic phase.Water and saturated aqueous common salt are used successively
Washing merge after organic phase, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.Product crude product
Purify that (mobile phase is with silica gel column chromatography：Petroleum ether/acetone=100:0.4, v/v), collect brown and concentrate elution band, concentration is
Obtain the brown solid (152mg, 74%) of compound III.
1H NMR(500MHz,DMSO-d6)δ10.34(s,1H),5.12(s,1H),4.77(s,1H),4.72(s,1H),
4.43(s,1H),3.74(s,1H),3.47(s,2H),2.91(s,1H),2.82(s,4H),2.57(s,2H),2.16(s,1H),
2.04(s,1H),1.98–1.84(m,5H),1.74–1.68(m,4H),1.24(s,2H),1.07(s,6H),0.88(s,3H).
13C NMR(125MHz,DMSO-d6)δ208.41(s),203.13(s),150.80(s),125.13(s),111.52
(s),78.60(s),66.92(s),57.74(s),52.16(s),47.59(s),47.36(s),40.76(s),34.44(s),
32.55(s),29.22(s),28.98(s),26.38(s),24.20(s),22.16(s),20.61(s),11.96(s).
HRMS(ESI):m/z[M+H]+calcd for C26H38N1O3:412.2852；found:412.2849.
The synthesis of O- (two (2-methylmercaptoethyl)) ethyl derivative of the Atropurpuran of embodiment 4
1st, the synthesis of O- (two hydroxyethylamines) ethyl derivative of Atropurpuran
Compound II (209mg, 0.5mmol) is dissolved in the middle of 15mL acetonitriles, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and diethanol amine (1051mg, 10mmol), mixture is heated to reflux 1h.Reaction
Reaction solution is poured into 15mL frozen water after end, is extracted 2 times with equivalent dichloromethane, merge organic phase.Water and saturation are used successively
Brine It merge after organic phase, then with anhydrous sodium sulfate drying, removal solvent concentrated under reduced pressure obtains product crude product.Produce
(mobile phase is the purifying of thing crude product silica gel column chromatography：Petroleum ether/acetone=100:0.5, v/v), collect light brown and concentrate wash-out
Band, concentration i.e. obtain compound Atropurpuran O- (two hydroxyethylamines) ethyl derivative yellow solid (159.5mg,
72%).
1H NMR (500MHz, DMSO-d6) δ 9.74 (s, 1H), 5.13 (s, 1H), 4.61 (d, J=10.5Hz, 2H),
4.25(s,1H),3.75(s,1H),3.54(s,2H),3.36(s,4H),2.89(s,1H),2.62(s,2H),2.51(s,4H),
2.32 (s, 2H), 2.17 (s, 1H), 2.05 (s, 1H), 1.95 (dd, J=13.4,11.6Hz, 4H), 1.78 (s, 1H), 1.76-
1.69(m,4H),1.44(s,2H),0.89(s,3H).
13C NMR(125MHz,DMSO-d6)δ208.46(s),203.18(s),150.85(s),125.18(s),111.57
(s),78.65(s),67.01(s),58.86(s),57.79(s),56.41(s),53.21(s),47.64(s),40.81(s),
34.49(s),32.60(s),29.27(s),29.03(s),26.43(s),24.25(s),22.21(s),20.66(s).
HRMS(ESI):m/z[M+H]+calcd for C26H38N1O5:444.2750；found:444.2744.
O- (two hydroxyethylamines) ethyl derivative of Atropurpuran
2nd, the synthesis of O- (bischloroethylamines base) ethyl derivative of Atropurpuran
O- (two hydroxyethylamines) ethyl derivative of the enough Atropurpuran of synthesis, by the O- of Atropurpuran
(two hydroxyethylamines) ethyl derivative (0.222g, 0.5mmol) is dissolved in 6mL chloroforms, be added dropwise over thionyl chloride (2.38g,
20mmol), reactant is heated to reflux 3h.Reactant is cooled to room temperature, the excessive thionyl chloride of Methanol Decomposition is added dropwise, depressurized dense
Contracting removes solvent.Product purifies (petroleum ether/acetone 100 through silica gel column chromatography:0.5, v/v) compound, is obtained
The faint yellow solid (143.7mg, 60%) of O- (bischloroethylamines base) ethyl derivative of Atropurpuran.
1H NMR(500MHz,DMSO-d6)δ9.69(s,1H),5.11(s,1H),4.76(s,1H),4.71(s,1H),
4.59(s,1H),3.84(s,1H),3.66(s,4H),3.53(s,2H),2.93(s,1H),2.76(s,2H),2.68(s,2H),
2.61 (s, 2H), 2.16 (s, 1H), 2.04 (s, 1H), 1.95 (dd, J=21.9,12.0Hz, 4H), 1.77 (s, 1H), 1.71
(d, J=5.4Hz, 2H), 1.46 (d, J=17.9Hz, 4H), 0.89 (s, 3H)
13C NMR(125MHz,DMSO-d6)δ208.41(s),203.13(s),150.80(s),125.13(s),111.52
(s),78.60(s),66.96(s),57.74(s),55.76(s),53.16(s),47.59(s),40.76(s),39.18(s),
34.44(s),32.55(s),29.22(s),28.98(s),26.38(s),24.20(s),22.16(s),20.61(s).
HRMS(ESI):m/z[M+H]+calcd for C26H36Cl2N1O3:480.2072；found:480.2069.
The synthesis of O- (bischloroethylamines base) ethyl derivative of Atropurpuran
3rd, the synthesis of O- (two (2-methylmercaptoethyl)) ethyl derivative of Atropurpuran
O- (bischloroethylamines base) ethyl derivative of enough compound Atropurpuran is prepared, by compound
The O- (bischloroethylamines base) ethyl derivative (0.240g, 0.5mmol) of Atropurpuran is dissolved in 12mL ethanol, adds at room temperature
Sodium methyl mercaptide (2.1g, 30mmol), reactant is heated to reflux 2h.It is concentrated under reduced pressure to remove solvent, products therefrom silica gel column chromatography
Purified (petroleum ether/acetone 100:0.5, v/v) yellow solid, i.e. compound IV (0.153g, 61%), are obtained.
1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),5.13(s,1H),4.68–4.58(m,3H),3.84(s,
1H), 3.54 (s, 2H), 2.94 (s, 1H), 2.64 (s, 2H), 2.58 (d, J=9.4Hz, 8H), 2.18 (s, 1H), 2.08-1.91
(m, 11H), 1.89-1.62 (m, 3H), 1.48 (d, J=18.3Hz, 4H), 0.91 (s, 3H)
13C NMR(125MHz,DMSO-d6)δ208.56(s),203.28(s),150.85(s),125.28(s),111.67
(s),78.75(s),67.11(s),57.89(s),53.31(s),52.25(s),47.74(s),40.91(s),34.59(s),
32.70(s),31.98(s),29.37(s),29.13(s),26.53(s),24.35(s),22.31(s),20.76(s),14.60
(s).
HRMS(ESI):m/z[M+H]+calcd for C28H42N1O3S2:504.2606；found:504.2600.
The anti-pancreatic fibrosis activity of the composition of embodiment 5
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
1.2 composition dosages：0.9mg/kg.
The preparation of composition：The powder of the 80mg compounds III of 200 mesh nets will be crossed after grinding and 200 will be crossed after grinding
The powder of the 20mg 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.
2 experimental techniques
2.1 modeling methods：Wistar rats continuous 2 months, may occur in which with intraperitoneal injection dl- ethionines 250mg/ days
Pancreas gland cell is reduced, the adipocellular hyperplasia of interstitial.
2.2 packets and medication
Rat model is randomly divided into model group, composition 0.9mg/kg groups, compound III 0.9mg/kg groups and compound
IV 0.9mg/kg groups, separately set blank control group.Administration group is administered after modeling starts, oral continuous 30 days；Dissected at 60 days dynamic
Thing.
2.3 Testing index
2.3.1 at the end of testing pancreas is taken to weigh.
2.3.2 pancreas hydroxyproline content measure takes 100mg samples and is homogenized in water, 20 is hydrolyzed in 110 DEG C of 10N HCl small
When.HCl nitrogen is volatilized, and hydrolysate is filtered after being dissolved with distilled water.Take 0.5ml liquid and 3ml citric acid phosphate buffers
(0.15M citric acids add 0.6M disodium hydrogen phosphates) and 0.5ml are dissolved in the 1M periodic acids mixing of 9M phosphoric acid.Plus 1.75ml extracts buffering
Liquid (5 parts of toluene：5 parts of 2- methyl isophthalic acids-propyl alcohol：2 parts of 1- propyl alcohol), shake 30min, centrifugation.Tissue phase (0.6ml) and Ehrlich,
15min is placed in the mixing of s reagents.Trap is determined in 565nm, making standard curve with 4- hydroxyl -1- proline calculates concentration, content
Represented with ug/g tissues.
2.3.3 10% formalin fix of histological examination pancreatic tissues, FFPE, microscopy after dyeing.To fiber
Change situation scoring (0-3 points).
3 results
Influence of 3.1 compositions to rat pancreas organ coefficient
At the end of experiment, rat is put to death, dissected, weighed in and its ratio (pancreas with body weight is weighed and calculated with pancreas
Organ coefficient), the results are shown in Table 1.Influence of the composition to pancreas organ coefficient, comparing with model group has significant difference.Chemical combination
The influence of thing III and compound IV to pancreas organ coefficient, compares that there was no significant difference with model group.
Table 1
* p is represented<0.05, compare with model group
3.2 pancreas hydroxyproline contents are determined
At the end of experiment, lung's hydroxyproline content measure is carried out to each group rat, as a result such as table 2.Composition is to hydroxyl dried meat
The influence of histidine content, comparing with model group has significant difference.Shadows of the compound III and compound IV to hydroxyproline content
Ring, compare that there was no significant difference with model group.
Table 2
* p is represented<0.05, compare with model group
3.3 histological examinations
At the end of experiment, rat is put to death, dissected；Sample routinely embedding, fixed, HE dyeing, microscopy.
As a 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；There is fibrosis between steeping in pancreas cystencyte disappearance position and pancreas.
Composition can reduce inflammatory reaction and fibrosis.Appraisal result is shown in Table 3.Influence of the composition to scoring, with model
Group compares significant difference.
Table 3
* p is represented<0.05, compare with model group；The inflammatory cell infiltration and Fibrosis score of blank control group are all 0.
Conclusion：The present invention passes through influence of the composition to pancreas in rat fibrosis, it was confirmed that composition has anti-pancreas fine
The effect of dimensionization.Therefore, composition can be used to prepare the medicine of anti-pancreatic fibrosis as active component.And compound III and
Compound IV is without this activity, it is impossible to the medicine for preparing anti-pancreatic fibrosis.
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 80% and 20%,
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 80% and 20% according to mass percent and be sufficiently mixed.
3. application of a kind of composition as claimed in claim 1 in pancreatic fibrosis medicine is treated.
4. application of the composition as claimed in claim 3 in pancreatic fibrosis medicine is treated, it is characterized by：The composition
The pancreas organ coefficient caused by pancreatic fibrosis is reversed to decline.
5. application of the composition as claimed in claim 3 in pancreatic fibrosis medicine is treated, it is characterized by：The composition
The hydroxyproline content caused by pancreatic fibrosis is reversed to raise.
6. application of the composition as claimed in claim 3 in pancreatic fibrosis medicine is treated, it is characterized by：The composition
The inflammatory cell infiltration caused by pancreatic fibrosis is reversed to raise.
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Application publication date: 20170531 |
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| WW01 | Invention patent application withdrawn after publication |