CN106491592B - The application of alantolactone derivative and its salt in preparation treatment thyroiditis drug - Google Patents
The application of alantolactone derivative and its salt in preparation treatment thyroiditis drug Download PDFInfo
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- CN106491592B CN106491592B CN201610878771.XA CN201610878771A CN106491592B CN 106491592 B CN106491592 B CN 106491592B CN 201610878771 A CN201610878771 A CN 201610878771A CN 106491592 B CN106491592 B CN 106491592B
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- 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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- 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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- 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
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Abstract
The application of alantolactone derivative and its salt in preparation treatment thyroiditis drug, provides the application such as formula (I-II) or formula (I-III) the alantolactone derivative and its salt in preparation treatment thyroiditis drug；Acid at salt is inorganic acid or organic acid, the inorganic acid is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, phosphomolybdic acid, phosphorous acid, sulfurous acid, the organic acid is selected from citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, oxalic acid, methanesulfonic acid, valeric acid, oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, phthalandione, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, niacin, picolinic acid, isonicotinic acid, benzoic acid.
Description
Technical field:
The invention belongs to alantolactone derivative and its salt and its applications.
Background technique:
Elecampane (Inula helenium) is composite family (Compositae) Inulaplants, perennial herb, root confession
It is medicinal.There are strengthening the spleen and stomach, promoting the flow of qi and relieving stagnancy, analgesic tocolysis function, be used for chest side of body, abdominal distention, vomiting dysentery, chest side of body is dampened, trouble
Gas is had a pain, the diseases such as threatened abortion.Contain the ingredients such as alantolactone, isoalantolactone, chemistry knot in elecampane volatile oil
Structure is similar with santonin, has anthelmintic action to pig, dog, cat, curative effect is excellent compared with santonin, and toxicity is lower.
Alantolactone (CAS:546-43-0) belongs to sesquiterpenoids, is also that content is higher in elecampane medicinal material
Principle active component.Its structure is as followsRecent study finds sequiterpene-building in elecampane
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 may be the household function group of such compound antitumor cell proliferation and Ad tuberculosis.But due to
The water solubility of alantolactone is poor, it is difficult to act on human body with conventional administration route, and find building by further experiment
Fragrant lactone is more toxic.
Autoimmune thyroiditis (AIT) is also known as bridge sheet (Hashimoto) thyroiditis, or chronic lymphocytic
Thyroiditis is the most common thyroid gland inflammatory disease.Clinical manifestation is that thyroid gland is in diffusivity lymphocytic infiltration, fiber
Change, the acidophilus of interstitial atrophy and acinar cells sexually revises.The many factors collective effects such as heredity, gestation, gender and environment, make to suffer from
Person's immune function gets muddled and a variety of lymphocytic infiltrations of parathyroid tissue, to generate a series of for parathyroid tissue
Autoantibody-thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) etc. are more than just to often result in certainly
The generation and development of body autoimmune thyroiditis.Existing treatment method takes thyroid hormone (levothyroxine sodium tablet more
Deng), alternative medicine, immunosuppressor (Tripterygium wilfordii Polyglycosidium Tablets etc.), operative treatment etc., though have certain clinical efficacy,
There are still no small problems, such as Drug hyperthyroidism side effect still to perplex clinical treatment in safety, and is once discontinued and holds very much
It is easy to recur.So the drug that thyroiditis is safely and effectively treated in exploitation becomes urgent problem to be solved in the prior art
Summary of the invention
To solve foregoing problems, the present invention provides the following technical solution:
A kind of alantolactone derivative as shown in formula (I) is provided,
In formula (I), wherein Y is oxygen or singly-bound；
R1And R2Can be identical or different, respectively hydrogen, alkyl, naphthenic base, hydroxyl substituted alkyl group, alkenyl, alkynyl, aryl,
Alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl, heterocycle, trifluoromethyl, polyfluoro replace alkyl, itrile group, itrile group first
Base, acyl group, carbamoyl, sulfonyl, sulfoamido or aryloxyalkyl group；R1、R2Cyclic structure is formed with N atom, ring is preferably
3-9 member ring can be substituted by one or more substituents in cyclic structure, including hydrogen, alkyl, naphthenic base, alkenyl, alkynyl, virtue
Base, alkylaryl, aryl alkyl, aryl alkenyl, aromatic yl polysulfide yl or heterocycle.Wherein R1And R2Preferably hydrogen or C1-C6Alkyl
Or naphthenic base.More preferable R1And R2It is methyl, i.e., the described alantolactone derivative is formula (I-II) or formula (I-III) chemical combination
Object.
The present invention also provides the inorganic acid salt or acylate of one kind such as formula (I) alantolactone derivative, institutes
The inorganic acid stated is selected from hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, phosphorus molybdenum
Acid, phosphorous acid, sulfurous acid, the organic acid are selected from citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, L- cream
Acid, D-ALPHA-Hydroxypropionic acid, oxalic acid, methanesulfonic acid, valeric acid, oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, phthalandione, wine
It is stone acid, malonic acid, succinic acid, fumaric acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, niacin, picolinic acid, different
Niacin, benzoic acid.The preferably fumarate of formula (I) the alantolactone derivative.More preferably formula (II) or formula (III)
Compound
The present invention also provides such as formula (I) the alantolactone derivatives and its inorganic acid salt or acylate to prepare
Application in anti-inflammatory drug；The inorganic acid salt or acylate of formula (I) the alantolactone derivative are formula (II)
Compound or formula (III) compound.
The present invention also provides such as formula (I) the alantolactone derivatives and its salt to treat thyroiditis drug in preparation
In application；The alantolactone derivative salt is that formula (II) compound or formula (III) compound, the alantolactone spread out
Biology is formula (I-II) compound or formula (I-III) compound.
The present invention also provides a kind of composition for oral liquid, it is characterized in that including the compound (I- as active constituent
II), compound (I-III), compound (II) or compound (III) and at least one pharmaceutic adjuvant for being suitable for taking orally.
The dosage form of the Orally administered composition is selected from tablet, capsule, solution, granule, powder or syrup.Preferably
Tablet, the formula of the tablet are 50~200 parts by weight of active constituent, 10~20 parts by weight of adhesive, filler 400~600
Parts by weight, 1~5 parts by weight of lubricant, 50~100 parts by weight of disintegrating agent, help and collapse agent 30-50 parts by weight.
The filler is selected from and lactose, mannitol or sorbierite, described adhesive, is selected from Macrogol 6000, poly- second
At least one of glycol 4000, lubricant are selected from one of magnesium stearate, talcum powder, superfine silica gel powder, leucine etc. or several
Kind, it helps and collapses agent for microcrystalline cellulose, disintegrating agent is crosslinked polyvinylpyrrolidone.
The present invention carries out structure of modification by alantolactone, provides novel alantolactone derivative and its inorganic acid
Salt.Especially currently preferred compound (I-II), compound (I-III) and as its pro-drug compound (II),
Compound (III) can generate generate apparent therapeutic effect to thyroiditis animal pattern in animal experiments, especially will
Compound (II), the compound (III) that fumarate obtains is respectively prepared in compound (I-II), compound (I-III), treatment
Effect becomes apparent.
Specific embodiment
In order to understand the present invention, the present invention is further illustrated with embodiment below, but is not used in and limits protection of the invention
Range.
Embodiment 1:
The preparation of compound (II)
1) preparation of compound (I-II)
Alantolactone (300.0mg, 1.29mmol) is dissolved in methylene chloride (50mL), states mixed system upwards in turn
Middle addition dimethylamine hydrochloride (1.6g, 19.4mmol) and potassium carbonate (5.2g, 37.4mmol), system heating reflux reaction 3 are small
When, it is filtered to remove solid, filtrate water is washed, and dry concentration, column chromatographic purifying (petroleum ether: ethyl acetate=1:1) obtains chemical combination
Object (I-II) (white solid, 236.0g, yield: 50%).
2) step 1) is obtained compound (I-II) (200.0mg, 0.72mmol) and is dissolved in first by the preparation of compound (II)
In alcohol (7mL), fumaric acid (86.7mg, 0.74mmol) is added in Xiang Shangshu mixed system, is stirred to react 0.5 hour, rotation is except molten
Agent adds ethyl acetate to dissolve, and filters 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 methylene chloride (10mL), is slowly added dropwise in Xiang Shangshu system
Methylene chloride (20mL) solution of oxybenzoic acid (2.1g, 10.3mmol) reacts 3 hours, saturated sodium thiosulfate water at room temperature
Solution quenching reaction, organic layer are washed (20mL × 3) with saturated sodium bicarbonate aqueous solution, dry concentration, column chromatographic purifying (petroleum
Ether: ethyl acetate=5:2) compound (white solid, 2.0g, yield 94%) is obtained,
The compound (300.0mg, 1.29mmol) that upper step obtains is dissolved in methylene chloride (50mL), is stated upwards in turn
Dimethylamine hydrochloride (1.6g, 19.4mmol) and potassium carbonate (5.2g, 37.4mmol) are added in mixed system, system is heated to reflux
Reaction 3 hours, is filtered to remove solid, and filtrate water is washed, dry concentration, obtained compound (I-III) crude product；
2) preparation of compound (III)
Compound (I-III) crude product is dissolved in methanol (7mL), and fumaric acid is added in Xiang Shangshu mixed system
(130.1mg, 1.11mmol) is stirred to react 0.5 hour, and rotation removes solvent, is added ethyl acetate to dissolve, is filtered to obtain compound (III)
(white solid, 369.6mg, yield: 87.3%)
Determination of elemental analysis compound (II) molecular formula: C21H34NO7
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 3: the treatment to the Hashimoto thyroiditis disease model animals of high iodine water induction
1. experimental method
SPF grades of Kunming kind female mices are selected, weight 28-32g, (0.64g sodium iodide is dissolved in 1L originally using high iodine water
Water).Pig thyroglobulin 100mg is dissolved in sterilizing distilled water 50mL (2mg/mL), take 10mL and it is isometric completely not
Family name's adjuvant is sufficiently mixed into Water-In-Oil shape.After skin degerming, 0.1mL (100 μ g) is taken to carry out subcutaneous multiple spot to model group group mouse
(toes are subcutaneous, dorsal sc, subcutaneous abdomen, neck are subcutaneous) injection is used as initial immunity.It tests the 12nd day, takes pig thyroid gland ball
After protein 10 mL (2mg/mL) and incomplete Freund's adjuvant 10mL is sufficiently mixed into Water-In-Oil shape, take 0.1mL (100 μ g) to model
Group mouse multiple spot subcutaneous injection carries out booster immunization, then is spaced 12 days and carries out modeling evaluation after progress primary immunization.It models successfully
High iodine water is removed afterwards, gives normal water and drinks.
Start drug treatment (weighing before administration) after mouse modeling success, the successful experimental animal of modeling be grouped at random,
Every group 10,10 normal mouses is separately taken to make blank group, grouping see the table below with administrations:
2. experimental result
After administration, the weight of each group experimental animal is measured respectively, and monitors TPOAb (anti-first in experimental animal blood
Shape gland Peroxidase Antibody) and TGAb (thyroglobulin antibody) content variation
Monitoring result see the table below
| Experimental group | Weight (g) | TGAb(ng/L) | TGAb(IU/ml) |
| Blank group | 28.6±1.40 | 31.7±10.8 | 34.2±7.4 |
| Model group | 19.9±1.99 | 80.7±17.9 | 65.5±24.8 |
| Dexamethasone group | 27.4±1.67 | 39.7±11.0 | 42.4±8.5 |
| Compound (II) group | 25.1±2.11 | 54.2±8.7 | 59.6±10.6 |
| Compound (III) group | 27.3±1.57 | 41.3±8.2 | 48.1±7.6 |
| Compound (I-II) group | 23.5±1.98 | 46.6±7.2 | 60.6±9.4 |
| Compound (I-III) group | 24.7±1.68 | 45.1±6.2 | 53.9±8.0 |
After administration, compared to the blank group, model group mouse body weight is significantly reduced；And compound (II), compound
(III), the body weight increase situation of compound (I-II) and compound (I-III) group is better than model group, shows compound (II)
And compound (III) can be obviously improved mouse weight situation.Compared to the blank group, model group mouse TPOAb and TGAb significantly rises
Height, respectively 255%, the 192% of naive mice, and compound (II) group TPOAb and TGAb is respectively blank group
171%, 174%, the TPOAb and TGAb of compound (III) group are respectively the 130% of blank group, 141%, compared with model group
The TPOAb and TGAb of mouse are significantly reduced.The TPOAb and TGAb of the mouse of compound (I-II) and compound (I-III) group
It also decreases compared with model group.
The above result shows that compound (II), compound (III), compound (I-II) and compound (I-III) are to bridge
This thyroiditis has must therapeutic effect.
Example of formulations 1~6 provides the tablet as composition for oral liquid.Formula see the table below (unit is parts by weight)
In the formula, adhesive is selected from Macrogol 4000 (PEG4000) or Macrogol 6000 (PEG6000), collapses
Solution agent is crosslinked polyvinylpyrrolidone, helps and collapses agent for microcrystalline cellulose, lubricant is magnesium stearate.
The preparation method of the tablet is
After active constituent is dissolved in ethanol in proper amount, the adhesive of recipe quantity is added, filler, helps and collapses agent, disintegrating agent mixing, and
Wet granulation is carried out with dehydrated alcohol, obtains particle；With tabletting after mix lubricant after particle is dried, tablet is obtained.
Claims (3)
1. if formula (I-II) or formula (I-III) the alantolactone derivative and its salt are in preparation treatment thyroiditis drug
Application；
With the alantolactone derivative at salt acid be inorganic acid or organic acid, the inorganic acid be selected from hydrofluoric acid, salt
Acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, phosphomolybdic acid, phosphorous acid, sulfurous acid are described to have
Machine acid be selected from citric acid, maleic acid, D-malic acid, L MALIC ACID, DL-malic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, oxalic acid, methanesulfonic acid,
Valeric acid, oleic acid, lauric acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2- naphthalene sulfonic acids, phthalandione, tartaric acid, malonic acid, succinic acid, richness
Horse acid, glycolic, thiolic acid, glycine, sarcosine, sulfonic acid, niacin, picolinic acid, isonicotinic acid, benzoic acid.
2. application as described in claim 1, it 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, it is characterized in that the thyroiditis is Hashimoto thyroiditis.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004066912A2 (en) * | 2003-01-31 | 2004-08-12 | Technion Research & Development Foundation Ltd. | Anti-inflammatory compositions and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004066912A2 (en) * | 2003-01-31 | 2004-08-12 | Technion Research & Development Foundation Ltd. | Anti-inflammatory compositions and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| Cytotoxic Michael-Type Amine Adducts of α-Methylene Lactones Alantolactone and Isoalantolactone;Nicholas J. Lawrence et al.;《Bioorganic & Medicinal Chemistry Letters》;20011231;第11卷;429-431 * |
| Structural Investigation and Biological Activity of Sesquiterpene Lactones from the Traditional Chinese Herb Inula racemosa;Yan-Yan Ma et al.;《Journal of Natural Products》;20130301;第76卷;564-570 * |
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