CN105998003A - Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis - Google Patents
Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis Download PDFInfo
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- CN105998003A CN105998003A CN201610256648.4A CN201610256648A CN105998003A CN 105998003 A CN105998003 A CN 105998003A CN 201610256648 A CN201610256648 A CN 201610256648A CN 105998003 A CN105998003 A CN 105998003A
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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
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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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
- A61K31/13—Amines
- 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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- 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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- 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
The invention discloses an application of a composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis, relates to the fields of organic synthesis and medicinal chemistry, and particularly relates to the composition of the Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives, and a preparation method and the application thereof in preparation of the drugs for preventing or treating pancreas fibrosis. Provided are the composition of the Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives and the preparation method thereof. Pharmacological experiments indicate that the composition has an effect for preventing or treating pancreas fibrosis, and has the value for development of the drugs for preventing or treating pancreas fibrosis.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and use thereof
On the way.
Background technology
Pancreatic gland fibrosis is the common trait of chronic pancreatitis caused by a variety of causes, is also the group adjoint with it simultaneously
Knit Pathologic Characteristics, show as a large amount of fibroblast proliferation and rich in the extracellular matrix connecting tissue.It is many
Plant the result that reason causes injury of pancreas to be repaired, find pancreatic stellate cells and cytokine profiles and pancreas in the recent period
Fibrosis is relevant, and the current sickness rate of pancreatic gland fibrosis is the highest, is badly in need of the anti-pancreas fiber of research and development high-efficiency low-toxicity
Chemical medicine thing.
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
Thing found compound or lead compound and carries out structural modification and obtain its derivant, thus obtaining high-efficiency low-toxicity
Potential drug most have important value.
The compound I that the present invention relates to be one within 2011, deliver (Ayumi Ohsaki et al., 2011.
Salviskinone A,a diterpene with a new skeleton from Salvia przewalskii.Tetrahedron
Letters 52 (2011) 1,375 1377) compound, we have carried out structural modification to compound I, it is thus achieved that
Two new derivants i.e. compound III and compound IV, and be prepared for compound III and compound IV
Compositions pancreatic gland fibrosis activity anti-to said composition are evaluated, and 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, should
In compositions, the mass percent of compound III and compound IV is respectively 60% and 40%.
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 present invention's
Pharmaceutically 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 had
Any restriction of body embodiment, but be defined in the claims.
Detailed description of the invention
The preparation of embodiment 1 compound Salviskinone A
The document that the preparation method of compound Salviskinone A (I) is delivered with reference to Ayumi Ohsaki et al.
(Ayumi Ohsaki et al.,2011.Salviskinone A,a diterpene with a new skeleton from
Salvia przewalskii.Tetrahedron Letters 52 (2011) 1,375 1377) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Salviskinone A
Compound I (312mg, 1.00mmol) is dissolved in 15mL benzene, in solution, adds tetrabutyl phosphonium bromide
Ammonium (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 6mL
Sodium hydroxide solution.Mixture stirs 12h at 35 degrees Celsius.After 12h, reactant liquor is poured in frozen water, vertical
I.e. it is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated food
Saline washs 4 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Produce
Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collects brown collection
Middle elution band is also flung to solvent and is i.e. obtained the brown ceramic powder (327mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ6.63(s,1H),6.37(s,1H),5.81(s,1H),4.51(s,2H),
3.84(s,1H),3.79(s,2H),2.15(s,1H),2.04(s,1H),1.91(s,1H),1.65(s,1H),1.39(s,
3H),1.08(s,6H),0.99(s,6H).
13C NMR(125MHz,DMSO-d6)δ188.07(s),183.70(s),154.38(s),147.57(s),
140.21(s),136.40(s),134.71(s),131.25(s),128.40(s),118.83(s),72.12(s),45.49
(s),37.54(s),33.58(s),31.78(s),26.17(s),25.12(s),24.66(s),23.51(s),23.17(s),
22.65(s).
HRMS(ESI)m/z[M+H]+calcd for C22H28BrO3:419.1222；found 419.1220.
The synthesis of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3 Salviskinone A
Compound II (209mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg,
10mmol), mixture is heated to reflux 5h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro
Methane extracts three times, merges organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then
Being dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silica gel column chromatography is pure
Change (flowing is mutually: petroleum ether/acetone=100:1.5, v/v), collect brown and concentrate elution band, concentrate and i.e. obtain
The brown solid (215mg, 43%) of compound III.
1H NMR (500MHz, DMSO-d6) δ 8.15 (s, 1H), 7.54 (d, J=25.0Hz, 2H), 7.15 (s,
1H), 7.06 (s, 1H), 6.33 (d, J=84.1Hz, 1H), 6.26 (s, 1H), 5.66 (s, 1H), 4.38 (d, J=
15.8Hz,4H),3.57(s,1H),1.96(s,1H),1.90(s,1H),1.77(s,1H),1.51(s,1H),1.20
(s,3H),0.99(s,6H),0.81(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.90(s),183.51(s),154.17(s),147.37(s),
146.27(s),139.98(s),139.63(s),136.22(s),134.51(s),133.48(s),131.05(s),
128.18 (s), 123.93 (s), 123.35 (s), 118.56 (d, J=9.6Hz), 110.85 (s), and 68.55 (s), 45.29
(s),44.74(s),37.34(s),33.36(s),25.96(s),24.94(s),24.46(s),23.32(s),22.96(s),
22.42(s).
HRMS(ESI):m/z[M+H]+calcd for C29H33N2O3:457.2491；found:457.2493.
The synthesis of O-(two hydroxyethylamines) ethyl derivative of embodiment 4 Salviskinone A
Compound II (209mg, 0.5mmol) is dissolved in the middle of 30mL acetonitrile, is added thereto to anhydrous carbon
Acid potassium (690mg, 5.0mmol), potassium iodide (252mg, 1.5mmol) and diethanolamine (1051mg,
10mmol), mixture is heated to reflux 9h.Reactant liquor is poured in 25mL frozen water after terminating by reaction, with etc.
Amount dichloromethane extracts 2 times, merges organic facies.Successively with water and saturated aqueous common salt washing merge after organic
Phase, then be dried with anhydrous sodium sulfate, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product silicagel column
Chromatography purification (flowing is mutually: petroleum ether/acetone=100:0.5, v/v), collects yellow and concentrates elution band and fling to
Solvent i.e. obtain O-(two hydroxyethylamines) ethyl derivative of Salviskinone A faint yellow solid (159.5mg,
72%).
1H NMR(500MHz,DMSO-d6)δ6.52(s,1H),6.40(s,1H),5.71(s,1H),4.15(s,
2H),3.70(s,1H),3.37(s,4H),3.00(s,2H),2.50(s,4H),2.07(s,1H),1.96(s,1H),
1.83 (s, 1H), 1.57 (d, J=1.4Hz, 3H), 1.30 (s, 3H), 0.99 (s, 6H), 0.90 (s, 6H).
13C NMR(125MHz,DMSO-d6)δ188.01(s),183.52(s),154.08(s),147.15(s),
140.11(s),136.23(s),134.42(s),130.84(s),128.31(s),118.62(s),68.93(s),58.73
(s),56.61(s),53.94(s),45.20(s),37.13(s),33.49(s),25.96(s),24.84(s),24.26(s),
23.43(s),22.97(s),22.33(s).
HRMS(ESI):m/z[M+H]+calcd for C26H38NO5:444.2750；found:444.2746.
O-(two hydroxyethylamines) ethyl derivative of Salviskinone A
The synthesis of O-(bischloroethylamines base) ethyl derivative of embodiment 5 Salviskinone A
O-(two hydroxyethylamines) ethyl derivative of Salviskinone A prepared by embodiment 4 (0.222g,
0.5mmol) being dissolved in 6mL chloroform, be added dropwise over thionyl chloride (0.238g, 2mmol), reactant heats
Backflow 1h.Reactant is cooled to room temperature, and the thionyl chloride of dropping Methanol Decomposition excess, concentrating under reduced pressure removes
Solvent.Product, through silica gel column chromatography purification (petroleum ether/acetone 100:0.3, v/v), obtains Salviskinone A
The faint yellow solid (170.0mg, 71%) of O-(bischloroethylamines base) ethyl derivative.
1H NMR(500MHz,Chloroform-d1)δ6.51(s,1H),6.22(s,1H),5.72(s,1H),4.16
(s,1H),3.66(s,1H),3.44(s,4H),3.01(s,2H),2.80(s,2H),2.64(s,2H),2.04(s,1H),
1.98(s,1H),1.85(s,1H),1.59(s,1H),1.28(s,3H),0.97(s,6H),0.93(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.90(s),183.41(s),153.97(s),147.04(s),
140.00(s),136.12(s),134.31(s),130.73(s),128.20(s),118.51(s),68.82(s),55.57
(s),53.94(s),45.20(s),39.10(s),37.02(s),33.39(s),25.87(s),24.76(s),24.19(s),
23.33(s),22.88(s),22.25(s).
HRMS(ESI):m/z[M+H]+calcd for C26H36Cl2NO3:480.2072；found:480.2070.
O-(bischloroethylamines base) ethyl derivative of Salviskinone A
The synthesis of O-(two (2-methylmercaptoethyl) amido) ethyl derivative of embodiment 6 Salviskinone A
O-(bischloroethylamines base) ethyl derivative of Salviskinone A prepared by embodiment 5 (0.240g, 0.5
Mmol) being dissolved in 15mL ethanol, add sodium methyl mercaptide (0.21g, 3mmol) under room temperature, reactant heats
Backflow 1h.Concentrating under reduced pressure removes solvent, and products therefrom silica gel column chromatography is purified (petroleum ether/acetone
100:0.5, v/v), obtain yellow solid, i.e. compound IV (0.169g, 67%).
1H NMR(500MHz,Chloroform-d1)δ6.48(s,1H),6.41(s,1H),5.65(s,1H),4.12
(s, 2H), 3.99 (s, 1H), 2.94 (s, 2H), 2.53 (d, J=15.4Hz, 8H), 1.99 (s, 1H), 1.94 (s, 6H),
1.90(s,1H),1.77(s,1H),1.51(s,1H),1.23(s,3H),0.92(s,6H),0.83(s,6H).
13C NMR(125MHz,DMSO-d6)δ187.81(s),183.42(s),154.08(s),147.28(s),
139.90(s),136.12(s),134.44(s),130.96(s),128.09(s),118.53(s),68.94(s),53.83
(s),52.15(s),45.21(s),37.24(s),33.29(s),31.87(s),25.85(s),24.86(s),24.38(s),
23.21(s),22.88(s),22.34(s),14.38(s).
HRMS(ESI):m/z[M+H]+calcd for C28H42NO3S2:504.2606；found:504.2603.
Embodiment 7 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: powder and the grinding of the 60mg compound III of 200 mesh nets will be crossed after grinding
The powder of the 40mg compound IV of rear mistake 200 mesh net loads in tubule with cover and mixes with turbine stirring instrument
I.e. obtain 100mg compositions, during use, obtain the solution of compositions by the compositions of this 100mg of water dissolution.
2 experimental techniques
2.1 modeling methods: Wistar rat with lumbar injection dl-ethionine 250mg/ days, continuous 2 months,
May occur in which that 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；Animal is dissected when 60 days.
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, 110 DEG C of 10 N HCl
Middle hydrolysis 20 hours.HCl nitrogen volatilizees, and hydrolyzate filters after dissolving with distilled water.Take 0.5ml liquid
Body is dissolved in 3ml citric acid phosphate buffer (0.15M citric acid adds 0.6M disodium hydrogen phosphate) and 0.5ml
The 1M periodic acid mixing of 9M phosphoric acid.Add 1.75ml Extraction buffer (5 parts of toluene: 5 parts of 2-methyl isophthalic acids-
Propanol: 2 parts of 1-propanol), shake 30min, centrifugal.Tissue phase (0.6ml) and the mixing of Ehrlich, s reagent
Place 15min.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.
Fibrosis situation is marked (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 of itself and body weight
(pancreas organ coefficient), the results are shown in Table 1.The compositions impact on pancreas organ coefficient, compares with model group
There is significant difference.Compound III and the compound IV impact on pancreas organ coefficient, compare nothing with model group
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
Impact on hydroxyproline content, compares with model group and has significant difference.Compound III and compound IV pair
The impact of hydroxyproline content, compares 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；Thin addicted to middle granulocyte karyolymph
Born of the same parents infiltrate, interstitial edema, hemorrhage and accidental pancreas cystencyte necrosis；Go out between pancreas cystencyte disappearance position and pancreas bubble
Existing fibrosis.
Compositions can reduce inflammatory reaction and fibrosis.Appraisal result is shown in Table 3.The compositions impact on scoring,
Compare with model group and have 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 has anti-pancreas
The effect of fibroadenia.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 8 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
Sheet.
The preparation of embodiment 9 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 system
Become 100.
Claims (6)
1. a compositions, is characterized by that said composition is made up of, in said composition compound III and compound IV
The mass percent of compound III and compound IV is respectively 60% and 40%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: by powder and the change of compound III
The powder of compound IV is sufficiently mixed according to mass percent respectively 60% and 40%.
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: institute
State compositions and reverse the pancreas organ coefficient decline caused by pancreatic gland fibrosis.
5. the compositions as claimed in claim 3 application in treatment pancreatic gland fibrosis medicine, is characterized by: institute
State compositions and reverse the hydroxyproline content rising caused by pancreatic gland fibrosis.
6. the compositions as claimed in claim 3 application in treatment pancreatic gland fibrosis medicine, is characterized by: institute
State compositions and reverse the inflammatory cell infiltration rising caused by pancreatic gland fibrosis.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610256648.4A CN105998003A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610256648.4A CN105998003A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis |
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| CN201610256648.4A Pending CN105998003A (en) | 2016-04-22 | 2016-04-22 | Application of composition of Salviskinone A benzimidazolyl and di(2-methylmercapto ethyl)amido derivatives in drugs for preventing or treating pancreas fibrosis |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032492A (en) * | 2006-03-06 | 2007-09-12 | 上海医药工业研究院 | Application of Asiatic Acid in the preparing of medicine for preventing and curing pancreatic fibrosis |
-
2016
- 2016-04-22 CN CN201610256648.4A patent/CN105998003A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101032492A (en) * | 2006-03-06 | 2007-09-12 | 上海医药工业研究院 | Application of Asiatic Acid in the preparing of medicine for preventing and curing pancreatic fibrosis |
Non-Patent Citations (1)
| Title |
|---|
| AYUMI OHSAKI等: "Salviskinone A, a diterpene with a new skeleton from Salvia przewalskii.", 《TETRAHEDRON LETTERS》 * |
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Application publication date: 20161012 |