CN106491593A - The application of alantolactone derivant and its salt in treatment inflammatory bowel medicine is prepared - Google Patents
The application of alantolactone derivant and its salt in treatment inflammatory bowel medicine is prepared Download PDFInfo
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- CN106491593A CN106491593A CN201610880822.2A CN201610880822A CN106491593A CN 106491593 A CN106491593 A CN 106491593A CN 201610880822 A CN201610880822 A CN 201610880822A CN 106491593 A CN106491593 A CN 106491593A
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- 0 C[C@]1C(C(CN(C)C)C(*)=O)C=C([C@@](C)CCC2)[C@@]2(C)C1 Chemical compound C[C@]1C(C(CN(C)C)C(*)=O)C=C([C@@](C)CCC2)[C@@]2(C)C1 0.000 description 2
- VXURNQHLUYJOEB-JBSOSPDQSA-N C[C@@H](CCC[C@]1(C)C[C@H]([C@H](C2)C3CN(C)C)OC3=O)[C@@]12O Chemical compound C[C@@H](CCC[C@]1(C)C[C@H]([C@H](C2)C3CN(C)C)OC3=O)[C@@]12O VXURNQHLUYJOEB-JBSOSPDQSA-N 0.000 description 1
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The application of alantolactone derivant and its salt in treatment inflammatory bowel medicine is prepared, there is provided as formula (I II) or formula (I III) the alantolactone derivant and its salt are preparing the application in treatment inflammatory bowel medicine；Acid into salt is mineral acid or organic acid, described mineral acid is selected from Fluohydric acid., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, Monohydrated selenium dioxide, phosphomolybdic acid, phosphorous acid, sulfurous acid, the organic acid is selected from citric acid, maleic acid, D malic acids, L malic acids, DL malic acids, L lactic acid, D lactic acid, DL acid, oxalic acid, methanesulfonic acid, valeric acid, Oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1 LOMAR PWA EINECS 246-676-2, 2 LOMAR PWA EINECS 246-676-2, phthalandione, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid, .gamma.-pyridinecarboxylic acid, benzoic acid or substituted benzoic acid.
Description
Technical field：
The invention belongs to alantolactone derivant and its salt and its application and preparation.
Background technology：
Radix Inulae (Inula helenium) is Compositae (Compositae) Inulaplants, and perennial herb, root are supplied
Medicinal.There are invigorating the spleen and regulating the stomach, promoting the flow of QI for relieving the stagnancy, analgesic tocolysis function, for chest side of body, abdominal distention, vomiting dysentery, chest side of body are dampened, trouble
Gas is had a pain, the disease such as frequent fetal movement.Containing compositions such as alantolactone, isoalantolactone in Radix Inulae volatile oil, its chemistry knot
Structure is similar with Santonin, has anthelmintic action to pig, dog, cat, and its curative effect is excellent compared with Santonin, and toxicity is relatively low.
Alantolactone (CAS：546-43-0) belong to sesquiterpenoidss, also it is that content is higher in Radix Inulae medical material
Principle active component.Its structure is as followsRecent study finds the sesquiterpene-building in Radix Inulae
Fragrant lactone constituents have the new roles such as the value-added effect of antitumor cell and Ad tuberculosis.Respectively at 1999 and 2002
Year, Charles and Konishi et al. propose α-methylene after the pharmacological action to alantolactone class compound is studied
Base-gamma lactone is probably the household function group of such compound antitumor cell proliferation and Ad tuberculosis.But due to
The water solublity of alantolactone is poor, it is difficult to acts on human body with conventional administration route, and finds building through further experiment
The toxicity of fragrant lactone is larger.
Inflammatory bowel (IBD) is a kind of cause of disease chronic nonspecific bowl inflammatory diseases still not fully aware of, bag
Include ulcerative colitiss (ulcerative colitis, UC) and Crohn disease (Crohn ' s disease, CD).Clinic is often adopted
Treated with nonsteroidal antiinflammatory drug and glucocorticoid medicine.But nonsteroidal antiinflammatory drug gastrointestinal reaction is big, can lure
Send out the clinical recessiveness enteropathy such as intestinal perforation and inflammatory lesion；Glucocorticoid medicine prolonged application can produce immunity because of systemic Absorption
The series of side effects such as suppression, adrenal cortex suppression.Therefore it provides the new activity that can be applied to treat IBD medicines into
It is divided into problem demanding prompt solution in prior art.
Content of the invention
For solving foregoing problems, the present invention provides following technical scheme：
A kind of alantolactone derivant as shown in formula (I) is provided,
In formula (I), wherein Y is oxygen or singly-bound；
R1And R2Can with identical or different, respectively hydrogen, alkyl, cycloalkyl, hydroxyl substituted alkyl group, thiazolinyl, alkynyl, aryl,
Alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, heterocyclic radical, trifluoromethyl, polyfluoro replace alkyl, itrile group, itrile group first
Base, acyl group, carbamoyl, sulfonyl, sulfoamido or aryloxyalkyl group；R1、R2Circulus is formed with N atoms, ring is preferably
3-9 yuan of rings, can be substituted by one or more substituents in circulus, including hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, virtue
Base, alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl or heterocyclic radical.Wherein R1And R2Preferably hydrogen or C1-C6Alkyl
Or cycloalkyl.More preferably R1And R2Methyl is, i.e., described alantolactone derivant is formula (I-II) or formula (I-III) chemical combination
Thing.
Present invention also offers the inorganic acid salt or acylate of one kind such as formula (I) alantolactone derivant, institute
The mineral acid that states is selected from Fluohydric acid., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, Monohydrated selenium dioxide, phosphorus molybdenum
Acid, phosphorous acid, sulfurous acid, the organic acid is selected from citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, L- breasts
Acid, D-ALPHA-Hydroxypropionic acid, DL- acid, oxalic acid, methanesulfonic acid, valeric acid, Oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- LOMAR PWA EINECS 246-676-2,
Phthalandione, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, methyl pyrrole
Pyridine acid .gamma.-pyridinecarboxylic acid, benzoic acid or substituted benzoic acid.The fumarate of preferably formula (I) the alantolactone derivant.More excellent
Elect formula (II) or formula (III) compound as
Present invention also offers if formula (I) the alantolactone derivant and its inorganic acid salt or acylate are in preparation
Application in anti-inflammatory drug；The inorganic acid salt or acylate of formula (I) described alantolactone derivant is changed for formula (II)
Compound or formula (III) compound.
Present invention also offers if formula (I) the alantolactone derivant and its salt are in preparation treatment inflammatory bowel medicine
Application in thing；The alantolactone derivative salt is formula (II) compound or formula (III) compound, the alantolactone
Derivant is formula (I-II) compound or formula (I-III) compound.The inflammatory bowel is ulcerative colitiss or Crow grace
Disease.
The present invention also provides a kind of colon targeting preparation, it is characterized in that including the compound (II) as active component, changes
Compound (II), compound (I-II) or compound (I-III) and at least one pharmaceutic adjuvant suitable for colon targeting preparation,
The colon targeting preparation is colon-targeted pellets, and the colon-targeted pellets are by the blank core without active component
Core, the coating layer containing active component and enteric coat layer composition.Described coating layer is the 1%～5% of percentage by weight
Active component, the beta-schardinger dextrin-of percentage by weight 10%～20%, the solubilizing agent of percentage by weight 20%-30%, 1%～
The methyl acrylate copolymer composition of 2% antiplastering aid and surplus；Described enteric coat layer be by percentage by weight 0.5%～
The methyl acrylate copolymer of 2% antiplastering aid, the plasticizer of percentage by weight 0.1%～2% and surplus；The acrylic acid first
Ester copolymer is that the solubilizing agent is selected from the copolymer of methacrylic acid, acrylic acid methyl ester. and methyl methacrylate preparation
For at least one in polyethylene glycol 6000, Macrogol 4000, the antiplastering aid in Pulvis Talci, magnesium stearate at least
One kind, at least one of the plasticizer in triethyl citrate, ethyl sebacate or 1,2-PD.
The antiplastering aid is Pulvis Talci, and the plasticizer is triethyl citrate, and the solubilizing agent is polyethylene glycol 6000.
The present invention carries out structure of modification by alantolactone, there is provided new alantolactone derivant and its mineral acid
Salt.Especially currently preferred compound (I-II), compound (I-III) and the compound (II) as its prodrug,
Compound (III), can produce in zoopery and produce obvious therapeutic effect to IBD animal patterns, especially by chemical combination
Thing (I-II), compound (I-III) are respectively prepared compound (II), the compound (III) that fumarate is obtained, its therapeutic effect
Become apparent from.
Specific embodiment
In order to understand the present invention, the present invention is further illustrated with embodiment below, but the protection for being not meant to limit the present invention
Scope.
Embodiment 1：
The preparation of compound (II)
1) preparation of compound (I-II)
Alantolactone (300.0mg, 1.29mmol) is dissolved in dichloromethane (50mL), successively to above-mentioned mixed system
Middle addition dimethylamine hydrochloride (1.6g, 19.4mmol) and potassium carbonate (5.2g, 37.4mmol), system heating reflux reaction 3 are little
When, solids removed by filtration, filtrate water are washed, and dry concentration, column chromatography purification (petroleum ether：Ethyl acetate=1:1) chemical combination is obtained
Thing (I-II) (white solid, 236.0g, yield：50%).
2) preparation of compound (II), by step 1) obtain compound (I-II) (200.0mg, 0.72mmol) and be dissolved in first
In alcohol (7mL), fumaric acid (86.7mg, 0.74mmol) is added in above-mentioned mixed system, stirring reaction 0.5 hour, rotation are removed molten
Agent, plus ethyl acetate dissolving, filter to obtain compound (II) (white solid, 246.4mg, yield：87.3%)
Determination of elemental analysis compound (II) molecular formula：C21H31NO6
HMR data：1HNMR(400MHz,CDCl3):δ 6.69 (s, 2H), 5.25 (d, J=2.8Hz, 1H), 3.56 (dd, J
=14.7,6.9Hz, 1H), 3.41 (dd, J=13.4,6.4Hz, 1H), 3.33 3.27 (m, 3H), 2.91 (s, 6H), 2.60
2.50 (m, 1H), 2.12 (dd, J=15.0,3.3Hz, 1H), 1.90 1.77 (m, 1H), 1.66 1.55 (m, 4H), 1.44 (m,
1H), 1.22 (d, J=8.8Hz, 3H), 1.17 (t, J=6.0Hz, 4H)；13C NMR(100MHz,CDCl3)δ180.6,173.7,
156.2,138.7,117.8,82.0,58.0,46.8,46.0,45.9,45.7,42.6,41.8,36.7,36.5,31.7,
25.8,20.4.
Embodiment 2：
The preparation of compound (III)
1) preparation of compound (I-III)
Alantolactone (2.0g, 8.6mmol) is dissolved in dichloromethane (10mL), is slowly added dropwise in above-mentioned system
Dichloromethane (20mL) solution of oxybenzoic acid (2.1g, 10.3mmol), reacts 3 hours under room temperature, saturated sodium thiosulfate water
Solution is quenched reaction, and organic layer saturated sodium bicarbonate aqueous solution is washed (20mL × 3), dries concentration, column chromatography purification (oil
Ether：Ethyl acetate=5：2) (yield is 94%) for white solid, 2.0g to obtain compound (I-III)
2) preparation of compound (III)
The compound (I-III) (300.0mg, 1.29mmol) that upper step is obtained is dissolved in dichloromethane (50mL), according to
Secondary addition dimethylamine hydrochloride (1.6g, 19.4mmol) and potassium carbonate (5.2g, 37.4mmol), system in above-mentioned mixed system
Heating reflux reaction 3 hours, solids removed by filtration, filtrate water are washed, and dry concentration, and the dissolving crude product for obtaining is at methanol (7mL)
In, in above-mentioned mixed system, add fumaric acid (130.1mg, 1.11mmol), stirring reaction 0.5 hour, rotation to remove solvent, plus second
Acetoacetic ester dissolves, and filters to obtain compound (III) (white solid, 369.6mg, yield：87.3%)
Determination of elemental analysis compound (II) molecular formula：C22H35NO7
H NMR spectroscopy diagram data：1HNMR(400MHz,CDCl3):δ6.26(s,2H),4.59–4.53(m,1H),3.06(dd,J
=14.7,6.9Hz, 1H), 2.64 (t, J=12.5Hz, 1H), 2.46 (d, J=4.3Hz, 1H), 2.28 (s, 6H), 2.60
2.50 (m, 1H), 2.12 (dd, J=15.0,3.3Hz, 1H), 1.90 1.77 (m, 1H), 1.66 1.55 (m, 4H), 1.09
1.01 (m, 4H), 0.89 (d, J=8.8Hz, 3H), 0.88 (s, 3H)；13C NMR(100MHz,DMSO)δ177.0,167.6,
135.0,75.4,67.6,57.1,56.3,45.0,38.9,38.0,37.9,35.7,34.5,32.0,29.8,24.1,17.8,
16.6.
Pharmacological Examples 2：Treatment to exedens inflammatory bowel acute stage animal model
1. experimental technique
This test is C57BL/6 mices from animal strains, female, 18～22g, SPF rank, 10 per group.Experiment is adopted
With 3%DSS (dextran sulfate sodium) induced ulcerative inflammatory bowel acute stage model.At the laundering period, give mice and freely enter
Food and drink water, experiment start will drinking water change into 3% DSS solution (except Normal group), freely drink to mice.Per
Mice daily drink amount presses 6mL calculating, and next day is supplemented with enough DSS solution, and DSS solution gives 8 days altogether.DSS is given for the first time
After 24h, will appear from the mice of soft stool, diarrhoea or hemafecia phenomenon as modeling success animal and immediately mice is carried out gavage to
Medicine, Normal group and model control group mice give 0.1mL distilled waters daily, and mice gives positive controls daily
0.1mL sulfasalazines (SASP, 300mg/kg), candidate drug group are administered 0.1mL (50mg/kg) daily.7 days collares of administration
Vertebra dislocation method puts to death mice.
During administration, the general animation of mice, fecal character and diarrhoea and hemafecia situation, take pictures note are observed daily
Record, weighs Mouse Weight daily.And DAI (disease activity index) scorings, standards of grading such as following table is carried out after the completion of administration
After putting to death mice, dissect and take Colon and rectum and measure length, Colon and rectum is longitudinally cut off along mesentery direction, raw
Reason saline cleaning feces, are fixed with 10% neutral formalin solution.Take, carry out successively
Dehydration, paraffin embedding, section, Hematoxylin-eosin dyeing, basis of microscopic observation lesion tissue situation are simultaneously scored.Tissue disease
Become scoring (HI) standard and see the table below (score of two indices is added as lesion tissue scoring)
The exedens inflammatory bowel acute stages treated effect situation that alantolactone derivant and its salt are induced to DSS sees below
Table 3 (means conditions see, n=10)
By table 3：The impact of the exedens inflammatory bowel acute stage that compound (II) is induced to DSS than more significant,
There is certain curative effect, with the significance difference opposite sex compared with model group.Compound (III), compound (I-II) and compound
(I-III) there is certain mitigation to exedens inflammatory bowel.
Example of formulations 1～6, preparing becomes colon-targeted pellets, by the blank core without active component, containing work
Property composition coating layer and enteric coat layer composition, the blank core be cane sugar type medicinal fine pellet core.The antiplastering aid
For Pulvis Talci, the plasticizer is triethyl citrate, and the solubilizing agent is polyethylene glycol 6000.The weight of coating layer is blank
The 10% of core, the weight of enteric coat layer are the 10% of blank core.
Formula see the table below
The preparation method of the colon-targeted pellets, comprises the following steps：
1), under room temperature, by the component that recipe quantity weighs coating layer, and active component is dissolved in ethanol in proper amount it is prepared into coating
Liquid；
2), the material of enteric coat layer is weighed by recipe quantity：Methyl acrylate copolymer and appropriate water, by acrylic acid first
Ester copolymer is dispersed in water to form enteric coating liquid.
3), using pan coating mode, blank core is put into coating pan, sprays in the case of rolling and apply medicinal liquid, while blowing
Hot blast is dried.Air compressor pressure is 4 9MPa, and coating pan rotating speed is 55r/min.The pastille micropill that will be obtained is finished in spray
Put 50 DEG C of oven drying 6h of people.
4), using and step 3) identical condition, by step 2) enteric coating liquid for preparing is sprayed on step 3) prepare
Pastille micropill on, 60 DEG C of oven ageing 10h obtain colon-targeted pellets.
Claims (8)
1. as formula (I-II) or formula (I-III) the alantolactone derivant and its salt are preparing treatment inflammatory bowel medicine
In application；
It is mineral acid or organic acid with the alantolactone derivant into the acid of salt, described mineral acid is selected from Fluohydric acid., salt
Acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, Monohydrated selenium dioxide, phosphomolybdic acid, phosphorous acid, sulfurous acid, described have
Machine acid is selected from citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, DL- acid, oxalic acid, first
Sulfonic acid, valeric acid, Oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- LOMAR PWA EINECS 246-676-2, phthalandione, tartaric acid, malonic acid, fourth two
Acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, nicotinic acid, picolinic acid .gamma.-pyridinecarboxylic acid, benzoic acid take
For benzoic acid.
2. application as claimed in claim 1, is characterized in that the alantolactone derivative salt is formula (II) compound or formula
(III) compound.
3. application as claimed in claim 1 or 2, is characterized in that the inflammatory bowel is ulcerative colitiss or Crow grace
Disease.
4. a kind of colon targeting preparation, it is characterized in that including compound (I-II) as active component, compound (I-III),
Compound (II) or compound (II) and at least one pharmaceutic adjuvant suitable for colon targeting preparation,
5. colon targeting preparation as claimed in claim 4, is characterized in that the colon targeting preparation for colon-targeted pellets, institute
Colon-targeted pellets are stated by the blank core without active component, the coating layer containing active component and enteric coat layer group
Into.
6. colon targeting preparation as claimed in claim 5, it is characterized in that described coating layer be percentage by weight 1%～
5% active component, the beta-schardinger dextrin-of percentage by weight 10%～20%, the solubilizing agent of percentage by weight 20%-30%, 1%
The methyl acrylate copolymer composition of～2% antiplastering aid and surplus；Described enteric coat layer is by percentage by weight 0.5%
The methyl acrylate copolymer of～2% antiplastering aid, the plasticizer of percentage by weight 0.1%～2% and surplus；The acrylic acid
Methyl terpolymer is the copolymer prepared with methacrylic acid, acrylic acid methyl ester. and methyl methacrylate, the solubilizing agent choosing
At least one from for polyethylene glycol 6000, Macrogol 4000, the antiplastering aid are selected from Pulvis Talci, magnesium stearate extremely
Few one kind, at least one of the plasticizer in triethyl citrate, ethyl sebacate or 1,2-PD.
7. colon targeting preparation as claimed in claim 4, it is characterised in that the antiplastering aid is Pulvis Talci, the plasticizer is
Triethyl citrate, the solubilizing agent are polyethylene glycol 6000, and the blank core is cane sugar type medicinal fine pellet core.
8. the colon targeting preparation as described in claim 5～7 is arbitrary, it is characterised in that the coating layer weight is for should be
The 7%～15% of blank core, the weight of enteric coat layer are the 7%～15% of blank core.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112920146A (en) * | 2021-01-29 | 2021-06-08 | 武汉大学 | Sesquiterpenoids, preparation method thereof and application thereof in preparing anti-inflammatory drugs |
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