CN105878252A - Application of pyrrolidyl and morpholino derivative composition of virosaine A in drugs for preventing or treating pancreatic fibrosis - Google Patents

Application of pyrrolidyl and morpholino derivative composition of virosaine A in drugs for preventing or treating pancreatic fibrosis Download PDF

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Publication number
CN105878252A
CN105878252A CN201610278597.5A CN201610278597A CN105878252A CN 105878252 A CN105878252 A CN 105878252A CN 201610278597 A CN201610278597 A CN 201610278597A CN 105878252 A CN105878252 A CN 105878252A
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compositions
compound
application
pancreatic gland
gland fibrosis
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蒋登旭
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Zhenjiang Makerao Biomedical Technology Co Ltd
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Zhenjiang Makerao Biomedical Technology 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
    • A61K31/33—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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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 relates to the field of organic synthesis and pharmaceutical chemistry, in particular to a composition, a preparation method, and use of the composition in the preparation of drugs for preventing and treating pancreatic fibrosis. The invention discloses a composition and a preparation method thereof. Pharmacological experiments show that the composition can prevent or treat pancreatic fibrosis and is worthy of the development of drugs for preventing or treating pancreatic fibrosis.

Description

The nafoxidine base of Virosaine A and the compositions of morpholinyl-derivatives are at prevention or treatment pancreatic gland fibrosis medicine Application in thing
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 2012, deliver (Bing-Xin Zhao et al., 2012. Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa.Organic Letters 14(2012)3096–3099) Compound, we have carried out structural modification to compound I, it is thus achieved that two i.e. compound III of new derivant With compound IV, and it is fine to be prepared for compositions pancreas anti-to said composition with compound III and compound IV Dimensionization activity is 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 75% and 25%.
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 Virosaine A
The document that the preparation method of compound Virosaine A (I) is delivered with reference to Bing-Xin Zhao et al. (Bing-Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa.Organic Letters 14 (2012) 3,096 3099) method.
The synthesis of O-bromoethyl derivant (II) of embodiment 2 Virosaine A
Compound I (235mg, 1.00mmol) is dissolved in 20mL benzene, in solution, adds tetrabutyl phosphonium bromide Ammonium (TBAB) (0.08g), glycol dibromide (3.760g, 20.00mmol) and 50% hydrogen of 5mL Sodium hydroxide solution.Mixture stirs 8h at 35 degrees Celsius.After 8h, reactant liquor is poured in frozen water, immediately It is extracted twice with dichloromethane, merges organic phase solution.Then to organic phase solution successively with water and saturated common salt Water washs 3 times, then is dried with anhydrous sodium sulfate, and last concentrating under reduced pressure is removed solvent and obtained product crude product.Product Crude product silica gel column chromatography purification (flowing is mutually: petroleum ether/acetone=100:1.0, v/v), collects brown and concentrates Elution band is also flung to solvent and is i.e. obtained the brown ceramic powder (261mg, 78%) of compound II.
1H NMR(500MHz,DMSO-d6)δ5.91(s,1H),4.07(s,1H),3.81(s,2H),3.59(s,1H), 3.43 (s, 2H), 3.33 (s, 1H), 2.26 (s, 1H), 1.58 (d, J=9.8Hz, 3H), 1.41 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.81(s),106.71(s),79.95(s),74.33(s),69.81 (s),66.68(s),44.21(s),35.56(s),33.28(s),25.85(s),21.88(s).
HRMS(ESI)m/z[M+H]+calcd for C14H17BrNO4:342.0341；found 342.0343.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3 Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and pyrrolidine (1420mg, 20mmol), mixture is heated to reflux 1h.Reactant liquor is poured in frozen water after terminating by reaction, uses equivalent dichloro Methane extracts 2 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 faint yellow concentration elution band and i.e. obtain Virosaine The faint yellow colloidal solid (111.6mg, 67%) of the O-(nafoxidine base) ethyl derivative (III) of A.
1H NMR(500MHz,DMSO-d6)δ5.92(s,1H),4.11(s,1H),3.66(s,1H),3.53(s, 2H), 3.45 (d, J=66.9Hz, 1H), 2.64 (s, 2H), 2.52 (s, 4H), 2.29 (s, 1H), 1.71 (s, 4H), 1.64(s,2H),1.61(s,1H),1.50(s,2H).
13C NMR(125MHz,DMSO-d6)δ171.83(s),106.73(s),79.97(s),74.35(s),66.72 (d, J=9.2Hz), 54.42 (d, J=17.1Hz), 44.23 (s), 35.58 (s), 25.86 (s), and 25.23 (s), 21.90 (s).
HRMS(ESI):m/z[M+H]+calcd for C18H25N2O4:333.1814；found:333.1811.
The synthesis of O-(morpholinyl) ethyl derivative of embodiment 4 Virosaine A
Compound II (171mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, is added thereto to anhydrous carbon Acid potassium (345mg, 2.5mmol), potassium iodide (84mg, 0.5mmol) and morpholine (1742mg, 20mmol), Mixture is heated to reflux 1h.Reactant liquor is poured in 20mL frozen water after terminating by reaction, uses equivalent dichloromethane Extract three times, merge organic facies.Organic facies after merging with water and saturated aqueous common salt washing successively, then use nothing Aqueous sodium persulfate is dried, and concentrating under reduced pressure is removed solvent and obtained product crude product.Product crude product silica gel column chromatography purify (stream Move and be mutually: petroleum ether/acetone=100:1.0, v/v), collect yellow and concentrate elution band i.e. to obtain Virosaine A's The yellow solid (IV) (125.3mg, 72%) of O-(morpholinyl) ethyl derivative.
1H NMR(500MHz,DMSO-d6)δ5.95(s,1H),4.12(s,1H),3.68(s,1H),3.63(d,J =8.4Hz, 1H), 3.61 (s, 4H), 3.57 3.26 (m, 3H), 2.61 (s, 2H), 2.56 (s, 2H), 2.51 2.03 (m, 5H), 1.70 (d, J=3.1Hz, 1H), 1.65 (d, J=25.6Hz, 1H), 1.52 (s, 2H).
13C NMR(125MHz,DMSO-d6)δ171.85(s),106.73(s),79.95(s),74.34(s),66.75 (t, J=4.6Hz), 54.46 (s), 52.93 (s), 44.22 (s), 35.55 (s), 25.88 (s), 21.89 (s).
HRMS(ESI):m/z[M+H]+calcd for C18H25N2O5:349.1763；found:349.1761.
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: powder and the grinding of the 75mg compound III of 200 mesh nets will be crossed after grinding The powder of the 25mg 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 10N 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 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 Sheet.
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 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 75% and 25%,
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 75% and 25%.
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.
CN201610278597.5A 2016-04-28 2016-04-28 Application of pyrrolidyl and morpholino derivative composition of virosaine A in drugs for preventing or treating pancreatic fibrosis Withdrawn CN105878252A (en)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BING-XIN ZHAO等: "Virosaines A and B, Two New Birdcage-Shaped Securinega Alkaloids with an unprecedented Skeleton from Flueggea virosa", 《ORGANIC LETTERS》 *
刘毅等: "一叶萩碱的研究进展", 《中国药事》 *
王营等: "胰腺癌组织中GABA和GAD的表达", 《第九届国际治疗内镜和消化疾病学术会议论文汇编》 *

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