CN106074480A - The compositions of the derivant of Artalbic acid prevents and treats pancreatic gland fibrosis medicine for preparation - Google Patents

The compositions of the derivant of Artalbic acid prevents and treats pancreatic gland fibrosis medicine for preparation Download PDF

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Publication number
CN106074480A
CN106074480A CN201610473712.4A CN201610473712A CN106074480A CN 106074480 A CN106074480 A CN 106074480A CN 201610473712 A CN201610473712 A CN 201610473712A CN 106074480 A CN106074480 A CN 106074480A
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compositions
pancreatic gland
compound
gland fibrosis
preparation
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丁秋菊
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Nanjing Haiaosi Biological Pharmaceutical Co Ltd
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Nanjing Haiaosi Biological Pharmaceutical Co Ltd
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses O (bischloroethylamines base) ethyl of a kind of Artalbic acid and in prevention or treat the application in pancreatic gland fibrosis medicine with the compositions of O (two (2 methylmercaptoethyl) amido) ethyl derivative, the present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O (bischloroethylamines base) ethyl and O (two (2 methylmercaptoethyl) amido) compositions of ethyl derivative, preparation method and the purposes in preparation prevention or treatment pancreatic gland fibrosis medicine thereof of Artalbic acid.The invention discloses O (bischloroethylamines base) ethyl of a kind of Artalbic acid and compositions of O (two (2 methylmercaptoethyl) amido) ethyl derivative and preparation method thereof.Pharmacological experiment shows, O (bischloroethylamines base) ethyl of the Artalbic acid of the present invention has prevention or the effect for the treatment of pancreatic gland fibrosis with the compositions of O (two (2 methylmercaptoethyl) amido) ethyl derivative, has exploitation prevention or the value for the treatment of pancreatic gland fibrosis medicine.

Description

The compositions of the derivant of Artalbic acid prevents and treats pancreatic gland fibrosis for preparation Medicine
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 (Antonella Maggio et al., 2011.Artalbic acid,a sesquiterpene with an unusual skeleton from Artemisia Alba (Asteraceae) from Sicily.Tetrahedron Letters, 52 (2011) 4,543 4545) compound, I Compound I has been carried out structural modification, it is thus achieved that two new derivant i.e. compound III and compound IV, and use chemical combination Thing III and compound IV is prepared for compositions and pancreatic gland fibrosis activity anti-to said composition is evaluated, and it has anti-pancreas Fibroadenia 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 90% and 10%.
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 Artalbic acid
The document that the preparation method of compound Artalbic acid (I) is delivered with reference to Antonella Maggio et al. (Antonella Maggio et al.,2011.Artalbic acid,a sesquiterpene with an unusual skeleton from Artemisia alba(Asteraceae)from Sicily.Tetrahedron Letters,52 (2011) 4,543 4545) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Artalbic acid
Compound I (266mg, 1.00mmol) is dissolved in 10mL benzene, in solution, adds tetrabutyl ammonium bromide (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% sodium hydroxide solution of 6mL.Mixture is Celsius 40 Degree stirring 16h.After 16h, reactant liquor is poured in frozen water, be extracted twice with dichloromethane immediately, merge organic phase solution.So Washing organic phase solution 5 times with water and saturated aqueous common salt successively afterwards, then be dried with anhydrous sodium sulfate, last concentrating under reduced pressure is removed Solvent obtains product crude product.Product crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), Collect brown concentrate elution band and fling to solvent and i.e. obtain the brown ceramic powder (272mg, 73%) of compound II.
1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),6.06(s,1H),5.76(s,1H),4.99(s,1H), 4.71(s,1H),4.56(s,1H),3.86(s,2H),3.54(s,2H),2.65(s,1H),2.43(s,2H),2.33(s,2H), 2.10(s,1H),1.64(s,3H),1.54(s,1H),1.44(s,2H),0.95(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.95(s),175.93(s),149.13(s),148.15(s),117.05 (s),109.43(s),81.86(s),70.27(s),57.68(s),41.26(s),39.07(s),38.86(s),35.69(s), 33.36(s),30.72(s),20.44(s),18.42(s).
HRMS(ESI)m/z[M+H]+calcd for C17H26BrO4:373.1014；found 373.1017.
The synthesis of the O-(bischloroethylamines base) ethyl derivative (III) of embodiment 3 Artalbic acid
1, the synthesis of O-(two hydroxyethylamines) ethyl derivative of Artalbic acid
Compound II (187mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, be added thereto to Anhydrous potassium carbonate (690mg, 5.0mmol), potassium iodide (252mg, 1.5mmol) and diethanolamine (1051mg, 10mmol), mixture is heated to reflux 1h.Reaction Reactant liquor is poured in 20mL frozen water after end, extract 3 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.Produce Thing crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects yellow and concentrates elution band And fling to the faint yellow solid that solvent i.e. obtains O-(two hydroxyethylamines) ethyl derivative of compound Artalbic acid (146.9mg, 74%).
1H NMR(500MHz,DMSO-d6)δ18.72(s,1H),δ6.11(s,1H),5.80(s,1H),5.14(s,1H), 4.73 (s, 1H), 4.63 (s, 1H), 3.57 (s, 2H), 3.45 (s, 4H), 2.70 (d, J=15.6Hz, 3H), 2.60 (s, 4H), 2.50 (s, 2H), 2.46 (s, 2H), 2.33 (s, 1H), 1.88 (s, 2H), 1.68 (s, 3H), 1.62 (d, J=19.9Hz, 3H), 1.02(s,3H).
13C NMR(125MHz,DMSO-d6)δ202.01(s),176.11(s),149.21(s),148.55(s),117.15 (s),109.60(s),81.93(s),67.25(s),59.28(s),57.88(s),56.83(s),53.74(s),41.36(s), 39.24(s),38.93(s),35.88(s),30.82(s),20.61(s),18.49(s).
HRMS(ESI):m/z[M+H]+calcd for C21H36N1O6:398.2543；found:398.2547.
O-(two hydroxyethylamines) ethyl derivative of Artalbic acid
2, the synthesis of the O-(bischloroethylamines base) ethyl derivative (III) of Artalbic acid
Synthesize O-(two hydroxyethylamines) ethyl derivative of abundant Artalbic acid, by Artalbic acid's O-(two hydroxyethylamines) ethyl derivative (0.100g, 0.5mmol) is dissolved in 4mL chloroform, be added dropwise over thionyl chloride (0.238g, 2mmol), reactant is heated to reflux 2h.Reactant is cooled to room temperature, the thionyl chloride of dropping Methanol Decomposition excess, reduces pressure dense Contracting removes solvent.Product, through silica gel column chromatography purification (petroleum ether/acetone 100:0.2, v/v), obtains the faint yellow of compound III Solid (145.4mg, 67%).
1H NMR(500MHz,DMSO-d6)δ13.05(s,1H),δ6.05(s,1H),5.75(s,1H),4.67(s,2H), 4.58 (d, J=7.5Hz, 1H), 3.68 (s, 4H), 3.50 (s, 2H), 2.86 (s, 2H), 2.74 (s, 2H), 2.62 (d, J= 0.9Hz,3H),2.44(s,2H),2.38(s,2H),2.22(s,1H),1.61(s,3H),1.49(s,1H),1.42(s,2H), 0.95(s,3H).
13C NMR(125MHz,DMSO-d6)δ201.68(s),175.56(s),148.88(s),147.80(s),116.82 (s),109.05(s),81.60(s),66.70(s),57.44(s),55.79(s),53.30(s),41.03(s),39.21(s), 38.80(s),38.49(s),35.44(s),30.38(s),20.17(s),18.05(s).
HRMS(ESI):m/z[M+H]+calcd for C21H34Cl2NO4 +:434.1865；found:434.1861.
The synthesis of O-(two (2-methylmercaptoethyl) amido) ethyl derivative (III) of embodiment 4 Artalbic acid
Prepare abundant compound III, compound III (0.217g, 0.5mmol) is dissolved in 10mL ethanol, under room temperature Adding sodium methyl mercaptide (0.21g, 3mmol), reactant is heated to reflux 2h.Concentrating under reduced pressure removes solvent, products therefrom silicagel column Chromatography is purified (petroleum ether/acetone 100:0.3, v/v), obtains yellow solid, i.e. compound IV (0.158g, 69%).
1H NMR(500MHz,Chloroform-d1)δ18.86(s,1H),6.14(s,1H),5.82(s,1H),5.33 (s, 1H), 4.75 (s, 1H), 4.62 (s, 1H), 3.54 (s, 2H), 2.86 (s, 1H), 2.72 (dd, J=18.2,6.8Hz, 11H),2.50(s,2H),2.39(s,2H),2.12(s,6H),1.71(s,3H),1.56(s,2H),1.41(s,1H),1.06 (s,3H).
13C NMR(125MHz,DMSO-d6)δ201.96(s),175.97(s),149.17(s),148.22(s),117.11 (s),109.47(s),81.85(s),67.07(s),57.69(s),53.56(s),52.49(s),41.29(s),39.00(s), 38.79(s),35.63(s),32.15(s),30.74(s),20.43(s),18.43(s),14.87(s).
HRMS(ESI):m/z[M+H]+calcd for C23H40NO4S2 +:434.1865；found:434.1863.
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 90mg compound III of 200 mesh nets after grinding crosses 200 after grinding The powder of the 10mg 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 buffering Liquid (5 parts of toluene: 5 parts of 2-methyl isophthalic acid-propanol: 2 parts of 1-propanol), shakes 30min, centrifugal.Tissue phase (0.6ml) and Ehrlich, 15min is placed in the mixing of s reagent.Measure trap at 565nm, make standard curve with 4-hydroxyl-1-proline and calculate concentration, content Represent 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 90% and 10%,
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 90% and 10%.
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.
CN201610473712.4A 2016-06-24 2016-06-24 The compositions of the derivant of Artalbic acid prevents and treats pancreatic gland fibrosis medicine for preparation Pending CN106074480A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105193791A (en) * 2015-07-16 2015-12-30 南京海澳斯生物医药科技有限公司 Composition and application thereof in medicine for preventing or treating pancreatic fibrosis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105193791A (en) * 2015-07-16 2015-12-30 南京海澳斯生物医药科技有限公司 Composition and application thereof in medicine for preventing or treating pancreatic fibrosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANTONELLA MAGGIO,ET AL.: "Artalbic acid, a sesquiterpene with an unusual skeleton from Artemisia alba (Asteraceae) from Sicily", 《TETRAHEDRON LETTERS》 *

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Application publication date: 20161109