Isoalantolactone derivative and application of salt of isoalantolactone derivative in preparation of medicine for treating thyroiditis

A kind of technology of xenotyrolactone and thyroiditis, which is applied in the direction of drug combination, medical formula, endocrine system diseases, etc., can solve the problems of easy recurrence and trouble clinical treatment, and achieve the effect of obvious therapeutic effect

Active Publication Date: 2017-03-08

NANKAI UNIV

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AI-Extracted Technical Summary

Problems solved by technology

Existing treatment methods mostly adopt thyroid hormones (levothyroxine sodium tablets, etc.), replacement therapy, immunosuppressants (tripterygium glycosides tablets, etc.), surgical treatment, etc. Although there are certain cl...

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Abstract

The invention discloses an isoalantolactone derivative and application of salt of the isoalantolactone derivative in preparation of a medicine for treating thyroiditis, and provides an isoalantolactone derivative as shown in formula (I); salifying acid 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, seleninic acid, phosphomolybdic acid, phosphorous acid and sulphurous acid; the organic acid is selected from citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-acid, oxalic acid, methanesulfonic acid, valeric acid, oleic acid, lauric acid, p-toluene sulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalene sulfonic acid, phthalic acid, tartaric acid, malonic acid, succinic acid, fumaric acid, glycollic acid, mercaptan acid, glycine, sarcosine, sulfonic acid, nicotinic acid, methyl pyridine acid, isonicotinic acid, benzoic acid or substituted benzoic acid.

Application Domain

Organic active ingredientsOrganic chemistry +1

Technology Topic

Hydroiodic acidNicotinic Acids +33

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Examples

Experimental program(3)

Example Embodiment

[0025] Example 1:

[0026] Preparation of compound (II)

[0027]

[0028] 1) Preparation of Compound (1.1)

[0029]

[0030] 1) Isoaurinolide (1.0g, 4.3mmol) was dissolved in dichloromethane (16mL), and peroxybenzoic acid (1.1g, 5.2mmol) was slowly added to the system in batches, reacted at room temperature for 3 hours, saturated The reaction was quenched with sodium thiosulfate (16 mL), extracted with dichloromethane (16 mL×3), the organic phase was washed with saturated aqueous sodium bicarbonate (16 mL), dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=20: 1) Obtain compound 1.2 (white solid, 984 mg, yield 92.0%).

[0031] 2) preparation of compound (I-II),

[0032]

[0033] The compound 1.2 obtained in step 1) was dissolved in dichloromethane (98mL), potassium carbonate (16.4g, 118.9mmol) and dimethylamine hydrochloride (4.8g, 59.4mmol) were added to the system in turn, and the mixed system was stirred Reflux reaction for 3 hours, after the reaction, remove the solid in the reaction solution by suction filtration, wash the filtrate with water (80mL×3), dry the organic layer with anhydrous sodium sulfate, and concentrate to obtain compound (I-II),

[0034] 3) Preparation of compound (II)

[0035] Dissolve the compound (I-II) obtained in step 2) in methanol (50mL), stir evenly, add fumaric acid (250mg, 2.1mmol) to the system, stir and react at room temperature for 20 minutes, spin off methanol and add Ethyl acetate (200 mL) was added to the system, and compound (II) was obtained by suction filtration (white solid, 1.1 g, two-step yield 70.0%)

[0036] Molecular formula of compound (II) determined by elemental analysis: C21H31NO7

[0037] HMR data: 1HNMR (400MHz, DMSO): δ6.57(s,2H), 4.50(s,1H), 3.19(m,1H), 2.74–2.66(m,2H), 2.61–2.54(m,1H) ,2.50(s,1H),2.46(m,1H),2.32(s,6H),1.96(d,J=15.4Hz,1H),1.19–1.10(m,1H),1.76(m,1H), 1.60(d,J=10.9Hz,3H),1.47(d,J=15.6Hz,2H),1.42–1.34(m,1H),1.27–1.20(m,1H),0.84(s,3H),0.60 (q, J=12.8Hz, 1H); 13C NMR (100MHz, DMSO) δ176.9, 166.7, 134.3, 77.4, 58.2, 53.3, 49.6, 44.3, 44.0, 43.5, 41.1, 40.6, 38.2, 34.9, 34.3, 20.0, 18.3, 16.0. .

Example Embodiment

[0038] Example 2:

[0039] Preparation of compound (III)

[0040]

[0041] 1) Preparation of Compound 1.3

[0042]

[0043] At 0°C, dissolve selenium dioxide (87.5mg, 0.75mmol) in dichloromethane (5mL), add tert-butanol peroxide (0.37mL), and stir for 30 minutes. , 2.15mmol) of dichloromethane (5mL) solution was slowly added to the above system, stirred at room temperature for 24 hours, quenched with saturated aqueous sodium thiosulfate (8mL), extracted with dichloromethane (8mL×3), dried Concentrate and purify by column chromatography (petroleum ether: ethyl acetate = 9:1 to 3:1) to obtain compound 1.23 (white solid, 350 mg, yield: 82.8%).

[0044] 2) Preparation of compound (I-III)

[0045]

[0046] The compound 1.3 obtained in the previous step was dissolved in dichloromethane (35mL), potassium carbonate (5.8g, 42.2mmol) and dimethylamine hydrochloride (1.7g, 21.1mmol) were added to the system successively, and the mixed system was stirred and refluxed Reacted for 3 hours. After the reaction, the solid in the reaction liquid was removed by suction filtration, the filtrate was washed with water (30 mL×3), the organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain compound (I-III).

[0047] 3) Dissolve the obtained compound (I-III) in methanol (20mL), stir evenly, add fumaric acid (88.7mg, 0.7mmol) to the system, stir and react at room temperature for 20 minutes, spin off methanol and Ethyl acetate (70 mL) was added to the system, and compound (III) was obtained by suction filtration (white solid, 450 mg, two-step yield 75.0%)

[0048] Molecular formula of compound (III) determined by elemental analysis: C22H35NO7NMR spectrum data: 1HNMR (400MHz, DMSO): δ6.56(s, 2H), 6.14(s, 1H), 5.60(s, 1H), 4.52(t, J= 4.1Hz, 1H), 4.33(s, 1H), 2.61–2.54(m, 1H), 2.50(s, 1H), 2.42(d, J=12.4Hz, 1H), 2.32(s, 6H), 2.20( d,J=15.6Hz,1H),1.82–1.65(m,4H),1.59(d,J=4.3Hz,1H),1.43(d,J=8.9Hz,1H),1.35(t,J=12.6 Hz,2H),0.82(s,3H);13C NMR(100MHz,DMSO)δ177.0,166.7,151.7,134.4,107.7,77.7,71.3,53.2,44.3,44.1,40.5,39.8,38.4,35.4,34.3,29.4 ,20.2,17.0..

Example Embodiment

[0049] Example 3

[0050] Preparation of Compound IV

[0051]

[0052] 1) Preparation of Compound 1.4

[0053]

[0054] Compound 1.3 (112mg, 0.45mmol) was dissolved in dichloromethane (1mL), and a solution of peroxybenzoic acid (100mg, 0.60mmol) in dichloromethane (1mL) was slowly added dropwise to the above system, and reacted at room temperature for 2 hours , quenched the reaction with saturated sodium thiosulfate (2 mL), extracted with dichloromethane (2 mL×3), dried and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) to obtain compound 1.4 ( White solid, 89 mg, yield: 74.5%).

[0055] 2) Preparation of compound (I-IV)

[0056]

[0057] The compound 1.4 obtained in the previous step was dissolved in dichloromethane (35mL), potassium carbonate (5.8g, 42.2mmol) and dimethylamine hydrochloride (1.7g, 21.1mmol) were added to the system successively, and the mixed system was stirred and refluxed Reacted for 3 hours. After the reaction, the solid in the reaction liquid was removed by suction filtration, the filtrate was washed with water (30 mL×3), the organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain compound (I-IV).

[0058] 3) preparation of compound (IV),

[0059] Dissolve the obtained compound (I-IV) in methanol (20mL), stir evenly, add fumaric acid (88.7mg, 0.7mmol) to the system, stir and react at room temperature for 20 minutes, spin off methanol and add to the system Ethyl acetate (70 mL) was added, and a white solid (103 mg, two-step yield 72.1%) was obtained by suction filtration.

[0060] Elemental analysis determines the molecular formula of compound (IV): C 22 h 35 NO 8

[0061] HMR data: 1 HNMR(400MHz,DMSO):δ6.56(s,2H),4.52(t,J=4.1Hz,1H),4.33(s,1H),2.61–2.54(m,1H),2.50(s,1H) ,2.42(d,J=12.4Hz,1H),2.32(s,6H),2.24(d,J=13.0Hz,1H),2.20(d,J=15.6Hz,1H),2.17(d,J= 15.7Hz, 1H), 1.82–1.65(m, 4H), 1.59(d, J=4.3Hz, 1H), 1.43(d, J=8.9Hz, 1H), 1.35(t, J=12.6Hz, 2H) ,0.82(s,3H); 13 C NMR (100MHz, DMSO) δ177.0, 166.6, 134.3, 77.5, 71.0, 60.8, 53.4, 48.0, 44.4, 44.0, 41.2, 38.4, 36.7, 34.6, 34.2, 27.6, 17.9, 15.5.

[0062] Pharmacological Example 3: Treatment of Hashimoto's Thyroiditis Model Animals Induced by High Iodine Water

[0063] 1. Experimental method

[0064] SPF grade Kunming female mice were selected, weighing 28-32 g, and high iodine water (0.64 g of sodium iodide dissolved in 1 L of tap water) was used. Dissolve 100 mg of porcine thyroglobulin in 50 mL of sterilized double distilled water (2 mg/mL), take 10 mL and fully mix with an equal volume of complete Freund's adjuvant to form a water-in-oil state. After the skin was disinfected, 0.1 mL (100 μg) was given to the mice in the model group for multiple subcutaneous injections (subcutaneous on the toes, subcutaneous on the back, subcutaneous on the abdomen, subcutaneous on the neck) as the initial immunization. On the 12th day of the experiment, take 10mL (2mg/mL) of porcine thyroglobulin and 10mL of incomplete Freund's adjuvant and fully mix it into a water-in-oil state. After immunization, the modeling evaluation was carried out after immunization was carried out at intervals of 12 days. After successful modeling, the high iodine water was removed and normal water was given for drinking.

[0065] After the mice were successfully modeled, drug therapy was started (weighing before drug administration). The experimental animals that were successfully modeled were randomly divided into groups of 10, and another 10 normal mice were taken as the blank group. For grouping and drug administration, see The following table:

[0066]

[0067]

[0068] 2. Experimental results

[0069] After the administration, the body weight of the experimental animals in each group was measured respectively, and the changes of TPOAb (anti-thyroid peroxidase antibody) and TGAb (thyroglobulin antibody) contents in the blood of the experimental animals were monitored.

[0070] The monitoring results are shown in the table below

[0071] Experimental group weight(g) TGAb (ng/L) TGAb (IU/ml) blank group 29.4±1.58 32.6±6.6 35.2±6.1 model group 18.7±1.89 79.4±16.5 69.4±20.1 Dexamethasone group 26.2±1.98 44.5±6.2 42.2±4.3 Compound (II) group 27.1±1.34 45.7±9.3 46.3±8.9 Compound (III) group 26.9±1.71 41.8±7.7 40.6±6.9 Compound (IV) group 27.2±1.71 43.5±8.4 42.4±7.8 Compound (I-II) group 24.5±1.67 50.6±6.7 45.9±8.1 Compound (I-III) group 24.1±1.72 48.5±7.0 47.4±8.5 Compound (I-IV) group 23.9±1.66 49.1±6.9 46.8±7.9

[0072] After the administration, compared with the blank group, the body weight of the mice in the model group decreased significantly; while compound (II), compound (III), compound (I-V), compound (I-II), compound (I-III) and compound The weight gain of the (I-IV) groups was better than that of the model group, indicating that the above compounds could improve the body weight of the mice. Compared with the blank group, the TPOAb and TGAb of the mice in the model group were significantly increased, which were 244% and 197% of the blank group mice respectively, and the TPOAb and TGAb of the compound (II) group were 140% and 132% of the blank group respectively. The TPOAb and TGAB of the (III) group were respectively 128% and 115% of the blank group, and the TPOAb and TGAb of the compound (IV) group were respectively 133% and 120% of the blank group. Compared with the model group, the TPOAb and TGAb of the mice were significantly reduced. The TPOAb and TGAb of the mice in the compound (I-II)-(I-IV) groups were also lower than those in the model group.

[0073] The above results show that compound (II), compound (III), compound (I-V), compound (I-II), compound (I-III) and compound (I-IV) all have a certain therapeutic effect on Hashimoto's thyroiditis.

[0074] Formulation Examples 1-6 provide tablets as oral pharmaceutical compositions. Formula sees the following table (unit is weight part)

[0075] In the formula, the binder is selected from polyethylene glycol 4000 (PEG4000) or polyethylene glycol 6000 (PEG6000), the disintegrant is cross-linked polyvinylpyrrolidone, the disintegrating aid is microcrystalline cellulose, and the lubricant is Magnesium stearate.

[0076]

[0077] The compound method of described tablet is

[0078] After the active ingredient is dissolved in an appropriate amount of ethanol, add the prescribed amount of binder, filler, disintegrating agent, and disintegrating agent to mix, and perform wet granulation with absolute ethanol to obtain granules; dry the granules and mix with lubricant After compression, tablets are obtained.

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Good treatment effect

Isoalantolactone derivative and application of salt of isoalantolactone derivative in preparation of medicine for treating thyroiditis

A kind of technology of xenotyrolactone and thyroiditis, which is applied in the direction of drug combination, medical formula, endocrine system diseases, etc., can solve the problems of easy recurrence and trouble clinical treatment, and achieve the effect of obvious therapeutic effect

AI-Extracted Technical Summary

Problems solved by technology

Abstract

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Examples

Example Embodiment

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Example Embodiment

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Description & Claims & Application Information

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