CN106619620A - Application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis - Google Patents
Application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis Download PDFInfo
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- CN106619620A CN106619620A CN201611205669.XA CN201611205669A CN106619620A CN 106619620 A CN106619620 A CN 106619620A CN 201611205669 A CN201611205669 A CN 201611205669A CN 106619620 A CN106619620 A CN 106619620A
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- composition
- pancreatic fibrosis
- atropurpuran
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- DJRLXHBFATVHJX-UHFFFAOYSA-N OCC[n]1c2ccccc2nc1 Chemical compound OCC[n]1c2ccccc2nc1 DJRLXHBFATVHJX-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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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
- 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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- 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 invention discloses an application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis, namely, an application of the composition of an O-(benzimidazolyl)-ethyl derivative and O-(morpholino)-ethyl derivative of Atropurpuran in preparation of drugs for treating or preventing pancreatic fibrosis, relates to the fields of organic synthesis and medicinal chemistry, in particular to the composition of Atropurpuran derivatives, a preparation method and the application of the composition in preparation of the drugs for preventing or treating pancreatic fibrosis, and discloses the composition of the Atropurpuran derivatives and the preparation method of the composition. The composition of the Atropurpuran derivatives has the function of preventing or treating pancreatic fibrosis and has the value of development of the drugs for preventing or treating pancreatic fibrosis.
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 traits 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 in the recent period pancreatic stellate cells and cytokine profiles are relevant with pancreatic fibrosis, pancreas fiber
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.
At present existing medicine has that toxicity is big, security is low 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 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, obtain two new derivatives i.e. compound III and compound IV,
And composition is prepared for compound III and compound IV and the anti-pancreatic fibrosis activity of said composition is evaluated, its
With 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 70% and 30%.
Composition disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows that the composition of the present invention has preferably anti-pancreatic fibrosis effect.The pharmacy of the present invention
Upper acceptable salt has same drug effect.
By the following examples the present invention is further detailed explanation, but protection scope of the present invention is not by concrete real
Any restriction 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- bromoethyl derivatives (II) of the Atropurpuran of embodiment 2
Compound I (312mg, 1.00mmol) is dissolved in into 10mL benzene, TBAB (TBAB) is added in solution
(0.08g), 50% sodium hydroxide solution of 1,2- Bromofumes (3.760g, 20.00mmol) and 6mL.Mixture is Celsius 35
Degree stirring 6h.Reactant liquor is poured in 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, last reduced pressure concentration removes molten
Agent obtains product crude product.(mobile phase is product crude product silica gel column chromatography purifying：Petroleum ether/acetone=100:1.0, v/v), receive
Collection brown concentrate elution band and fling to solvent obtain compound II yellow powder (309mg, 74%).
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- (benzimidazolyl) ethyl derivative (III) of the Atropurpuran of embodiment 3
Compound II (209mg, 0.5mmol) is dissolved in the middle of 12mL acetonitriles, be added thereto to Anhydrous potassium carbonate (345mg,
2.5mmol), KI (84mg, 0.5mmol) and benzimidazole (4720mg, 40mmol), mixture is heated to reflux 4h.Reaction
Reactant liquor is poured in frozen water after end, is extracted 3 times with equivalent dichloromethane, merge organic phase.Successively with water and saturated common salt
Water washing merge after organic phase, then with anhydrous sodium sulfate drying, reduced pressure concentration removes solvent and obtains product crude product.Product is thick
(mobile phase is product silica gel column chromatography purifying：Petroleum ether/acetone=100:0.7, v/v), collect brown and concentrate elution band, concentration
Obtain compound III brown solid (162mg, 71%).
1H NMR (500MHz, DMSO-d6) δ 10.05 (s, 1H), 8.21 (s, 1H), 7.61 (d, J=25.0Hz, 2H),
7.23 (s, 1H), 7.15 (s, 1H), 5.14 (s, 1H), 4.65 (d, J=10.5Hz, 2H), 4.39 (s, 1H), 4.04 (d, J=
5.5Hz, 2H), 3.86 (s, 2H), 3.80 (s, 1H), 2.94 (s, 1H), 2.18 (s, 1H), 2.06 (s, 1H), 1.97 (dd, J=
21.9,12.5Hz,4H),1.78–1.69(m,4H),1.66(s,1H),1.32(s,2H),0.90(s,3H).
13C NMR(125MHz,DMSO-d6)δ208.60(s),203.32(s),150.99(s),146.33(s),139.68
(s),133.53(s),125.32(s),123.98(s),123.41(s),118.59(s),111.71(s),110.90(s),
78.79(s),67.99(s),57.93(s),47.78(s),44.99(s),40.95(s),34.63(s),32.74(s),29.41
(s),29.17(s),26.57(s),24.39(s),22.52(s),20.80(s).
HRMS(ESI):m/z[M+H]+calcd for C29H33N2O3:457.2491；found:457.2484.
The synthesis of O- (morpholinyl) ethyl derivative of the Atropurpuran of embodiment 4
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 morpholine (3484mg, 40mmol), mixture is heated to reflux 1h.Reaction terminates
Reactant liquor is poured in 15mL frozen water afterwards, is extracted 2 times with equivalent dichloromethane, merge organic phase.Successively with water and saturated common salt
Water washing merge after organic phase, then with anhydrous sodium sulfate drying, reduced pressure concentration removes solvent and obtains product crude product.Product is thick
(mobile phase is product silica gel column chromatography purifying：Petroleum ether/acetone=100:0.5, v/v), collect light brown and concentrate elution band, it is dense
Contracting obtain compound III yellow solid (157.3mg, 74%).
1H NMR (500MHz, DMSO-d6) δ 9.76 (s, 1H), 5.13 (s, 1H), 4.59 (d, J=10.5Hz, 2H),
4.30 (s, 1H), 4.02 (s, 1H), 3.52 (d, J=14.0Hz, 6H), 2.92 (s, 1H), 2.51 (s, 2H), 2.44 (s, 4H),
2.10 (t, J=29.7Hz, 3H), 1.99-1.90 (m, 3H), 1.72 (d, J=4.2Hz, 2H), 1.67 (s, 2H), 1.62 (s,
1H),1.29(s,2H),0.89(s,3H).
13C NMR(125MHz,DMSO-d6)δ208.61(s),203.33(s),151.00(s),125.33(s),111.72
(s),78.80(s),67.16(s),66.64(s),57.94(s),54.34(s),52.79(s),47.79(s),40.96(s),
34.64(s),32.75(s),29.42(s),29.18(s),26.58(s),24.40(s),22.36(s),20.81(s).
HRMS(ESI):m/z[M+H]+calcd for C26H36N1O4:426.2644；found:426.2641.
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 dosage：0.9mg/kg.
The preparation of composition：The powder of the 70mg compound III of 200 mesh nets will be crossed after grinding and 200 is crossed after grinding
The powder of the 30mg compound IV of mesh net is fitted in 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 method：Wistar rats continuous 2 months, may occur in which with lumbar 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；Dissect when 60 days dynamic
Thing.
2.3 Testing index
2.3.1 take pancreas at the end of testing to weigh.
2.3.2 pancreas hydroxyproline content measure takes 100mg samples and is homogenized in water, and hydrolysis 20 is little in 110 DEG C of 10N HCl
When.HCl nitrogen volatilizees, hydrolysate filtration after distilled water dissolving.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, calibration curve is made with 4- hydroxyl -1- proline and is calculated 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 point).
3 results
Impact of 3.1 compositions to rat pancreas organ coefficient
At the end of experiment, rat 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.Impact of the composition to pancreas organ coefficient, comparing with model group has significant difference.Chemical combination
The impact 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 impact of histidine content, comparing with model group has significant difference.The shadow of 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 examination
At the end of experiment, rat 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 fibrillatable between steeping in pancreas cystencyte disappearance position and pancreas.
Composition can reduce inflammatory reaction and fibrillatable.Appraisal result is shown in Table 3.Impact 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 is all 0.
Conclusion：The present invention is by composition on the Fibrotic impact of pancreas in rat, 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 for preparing the medicine of 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 make 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 make 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 70% and 30%,
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 70% and 30% according to mass percent and be sufficiently mixed.
3. application of a kind of composition as claimed in claim 1 in treatment pancreatic fibrosis medicine.
4. application of the composition as claimed in claim 3 in treatment pancreatic fibrosis medicine, 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 treatment pancreatic fibrosis medicine, 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 treatment pancreatic fibrosis medicine, it is characterized by：The composition
The inflammatory cell infiltration caused by pancreatic fibrosis is reversed to raise.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611205669.XA CN106619620A (en) | 2016-12-23 | 2016-12-23 | Application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611205669.XA CN106619620A (en) | 2016-12-23 | 2016-12-23 | Application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis |
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| Publication Number | Publication Date |
|---|---|
| CN106619620A true CN106619620A (en) | 2017-05-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201611205669.XA Withdrawn CN106619620A (en) | 2016-12-23 | 2016-12-23 | Application of benzimidazolyl derivative and morpholino derivative composition of Atropurpuran in prevention and treatment of pancreatic fibrosis |
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| Country | Link |
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| CN (1) | CN106619620A (en) |
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2016
- 2016-12-23 CN CN201611205669.XA patent/CN106619620A/en not_active Withdrawn
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