CN102579462B - Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs - Google Patents
Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs Download PDFInfo
- Publication number
- CN102579462B CN102579462B CN 201210015822 CN201210015822A CN102579462B CN 102579462 B CN102579462 B CN 102579462B CN 201210015822 CN201210015822 CN 201210015822 CN 201210015822 A CN201210015822 A CN 201210015822A CN 102579462 B CN102579462 B CN 102579462B
- Authority
- CN
- China
- Prior art keywords
- glycyrrhetinic acid
- acid derivatives
- compound
- enoxolone
- structural formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 CC(C)([C@](CC[C@]1(C)[C@]([C@@](C)(CC2)[C@](C)(CC[C@@](C)(CC[C@](C)(*)C3)[C@@]33I=C)C3=C3)(C3=O)I=C)O)[C@@]12I=C Chemical compound CC(C)([C@](CC[C@]1(C)[C@]([C@@](C)(CC2)[C@](C)(CC[C@@](C)(CC[C@](C)(*)C3)[C@@]33I=C)C3=C3)(C3=O)I=C)O)[C@@]12I=C 0.000 description 2
- YEGPYGGAFHSXEB-WXYQZPBCSA-N C/C(/C(/C)=C/C(N)=O)=C\C=C(/C)\N Chemical compound C/C(/C(/C)=C/C(N)=O)=C\C=C(/C)\N YEGPYGGAFHSXEB-WXYQZPBCSA-N 0.000 description 1
- PMHVSMGLOCEQHG-UHFFFAOYSA-N N=C1NNC(c(cc2)ccc2O)=C1 Chemical compound N=C1NNC(c(cc2)ccc2O)=C1 PMHVSMGLOCEQHG-UHFFFAOYSA-N 0.000 description 1
- YWRDVUFISVOFHY-UHFFFAOYSA-N Nc(cc1)ccc1C(NN1)=CC1=N Chemical compound Nc(cc1)ccc1C(NN1)=CC1=N YWRDVUFISVOFHY-UHFFFAOYSA-N 0.000 description 1
Images
Abstract
The invention discloses the application of glycyrrhetinic acid derivatives in the preparation process of anti-inflammatory drugs, in particular to the glycyrrhetinic acid derivatives as well as pharmaceutically acceptable salt thereof, drug compositions containing the derivatives and anti-inflammatory action of the drug compositions, wherein, the glycyrrhetinic acid derivatives can release gaseous signal molecule hydrogen sulfide. The invention discloses and provides the glycyrrhetinic acid derivatives that can release gaseous signal molecule H2S, wherein, glycyrrhetinic acid and gaseous signal molecule hydrogen sulfide release groups are coupled through ester bonds or amido bonds so as to obtain the glycyrrhetinic acid derivatives. Pharmacology experimental results show that the glycyrrhetinic acid derivatives achieve remarkable anti-inflammatory action and have no significant gastrointestinal tract injury, and show that the glycyrrhetinic acid derivatives can be used for preparing the drugs for treating various inflammations and related diseases thereof.
Description
Technical field
The present invention relates to drug world, be specifically related to a class can discharge gaseous signal molecule hydrogen sulfide Enoxolone derivative and pharmaceutically acceptable salt thereof, contain the Pharmaceutical composition of these derivants, at antiinflammatory action, particularly in the application of the medicine of preparation anti-inflammatory disease.
Background technology
Glycyrrhizic legume is a kind of important Chinese medicine.The main effective ingredient of Radix Glycyrrhizae pharmacological action is glycyrrhizic acid and salt (being the glycyrrhizin rope) thereof, is hydrolyzed to enoxolone (glycyrrhetinic acid is called for short GA) through gastric acid in body.Modern study shows, GA has the multiple pharmacologically actives such as antiinflammatory, antioxidation, antiulcer, antiviral, arrhythmia, blood fat reducing, antitumor and anti-allergy action.GA is having obvious curative effects aspect inflammatory intestines disease, rheumatic arthritis, gingivitis, periodontitis, oral ulcer.But use clinically often with false aldosteronism, the hypokalemia phenomenon occurs after showing as patient's long-term taking.
Long-term or a large amount of medication meetings of classical NSAID (non-steroidal anti-inflammatory drug) have side effects to gastrointestinal tract, cause secondary damage to patient, bring Secondary cases financial burden for individual and society.Although a new generation NSAID (non-steroidal anti-inflammatory drug) such as former times dry goods medicine gastrointestinal side effect greatly alleviate, can cause cardiovascular event such as hypertension, apoplexy, myocardial infarction etc., still be difficult to satisfy clinical requirement.
Current research is found, Endogenous Hydrogen Sulfide (H
2S) wide participation the physiological function of the systems such as nerve, cardiovascular, digestion regulate, be considered to the 3rd kind of gaseous signal molecule after NO and CO.More and more studies have shown that H
2S has important pathophysiological role in the multisystems such as cardiovascular, nerve, inflammation or lysis.Hydrogen sulfide can the vasodilator smooth muscle; The reconstruction of lung blood vessel structure is regulated in the formation of pulmonary hypertension when suppressing hypoxia; Significantly reduce the blood pressure of Hypertensive Rats, and suppress smooth muscle cell proliferation; Obviously reduce myocardial ischemia reperfusion injury.H
2S can alleviate lipopolysaccharide-induced rat edema and vascular permeability and the inflammatory reaction such as increase; In the effect that inflammation occurs to have in early days antiinflammatory, non-oxidizability is damaged, the mucosal lesion that NSAID (non-steroidal anti-inflammatory drug) is caused alleviates 60%～70%.
Some anti-inflammatory agents such as 5-aminosalicylic acid, diflunisal, naproxen, ketone promise phenol etc. and ADT-OH (a kind of release H
2The compound that the S ability is stronger, 5-p-hydroxybenzene-3H-1,2-dithiole-3-thioketone, abbreviation ADT-OH) compound after coupling obtains, its anti-inflammatory activity is stronger than parent compound, and significantly alleviate its gastrointestinal side effect (referring to: publication number is the patent application prospectus of WO 2006125293, WO 2006111791, WO2006037623, US 20080004245).
But, have no in prior art about to H
2S donator type Enoxolone derivative and pharmaceutically-acceptable salts thereof the report aspect anti-inflammatory activity research.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of new purposes of Enoxolone derivative, i.e. the application of Enoxolone derivative in the preparation anti-inflammatory drug.
To achieve the above object of the invention, the technical solution used in the present invention is: the application of Enoxolone derivative in the preparation anti-inflammatory drug, and the structural formula of described Enoxolone derivative is selected from:
Structural formula one
Structural formula two
Structural formula three
Or structural formula four
In formula, R
1Be selected from: H, CH
3CO, C
2H
5CO, C
3H
7CO or COCH
2COOH; R
2Be selected from:
Or
X is selected from: NH or O; Y is (CH
2)
n, CH (CH
3) (CH
2)
2, (CH
2)
2O (CH
2)
2, CH
2CH=CHCH
2Or CH
2C ≡ CCH
2, wherein, n=2～6; Z is selected from: O or NH.
In preferred technical scheme, described Enoxolone derivative is selected from: structural formula one or the represented compound of structural formula three.
In further preferred technical scheme, described Enoxolone derivative is:
In formula, R
1Be selected from: H or CH
3CO; X is O; Y is (CH
2)
n, n=2～4; Z represents O.
In technique scheme, described Enoxolone derivative is made of by ester bond or amido link coupling enoxolone group and hydrogen sulfide donor; Putting down in writing in application number is 201110139249.7 Chinese invention patent application of described Enoxolone derivative and preparation method thereof, in technique scheme, the preparation method of structural formula one described Enoxolone derivative comprises the following steps: with a kind of in the esterification derivative of enoxolone or enoxolone and
Or
Be reactant, the carboxyl in the esterification derivative of enoxolone or enoxolone and
In amino generation condensation reaction or
Bromine generation substitution reaction, prepare the described Enoxolone derivative of structural formula one;
Wherein, the structural formula of the esterification derivative of enoxolone is:
In formula, R
1Be selected from: CH
3CO, C
2H
5CO, C
3H
7CO or COCH
2COOH; The esterification derivative of described enoxolone is to be prepared by esterification by enoxolone;
Described
Be by
With bromo alkylamine BrYNH
2The generation substitution reaction prepares; Described
Be by
Prepare with two bromoalkane generation substitution reactions.
In technique scheme, the preparation method of structural formula two described Enoxolone derivatives is similar to the method for preparing structural formula one described Enoxolone derivative, difference is, at first the enoxolone reduction is obtained compound 1, then prepare its esterification derivative compound 2, with a kind of in compound 1 or compound 2 and
The structural formula of described compound 1 is
The structural formula of described compound 2 is
In technique scheme, the preparation method of structural formula three described Enoxolone derivatives is: enoxolone and halo chloroacetic chloride generate compound 3, compound 3 and piperidines
Piperazine
Morpholine
The pyrroles
Dimethylamine (CH
3)
2NH or diethylamine Et
2A kind of reaction in NH prepares compound 4; With compound 4 Hes
Or
Be reactant, the carboxyl in compound 4 and
Amino condensation or
In bromine replace, prepare the described Enoxolone derivative of structural formula three;
The structural formula of described compound 3 is
A is Br, Cl; The structural formula of described compound 4 is
In technique scheme, the preparation method of structural formula four described Enoxolone derivatives is similar with the preparation method of structural formula three described Enoxolone derivatives, difference is, at first the enoxolone reduction is obtained compound 1, then according to the preparation method of preparation structural formula three described Enoxolone derivatives, prepare the described Enoxolone derivative of structural formula four take compound 1 replacement enoxolone as initial reactant.
The present invention is the application of the acceptable salt of medical science in the preparation anti-inflammatory drug of claimed above-mentioned Enoxolone derivative simultaneously.
Enoxolone derivative of the present invention or its medically acceptable salt can be made the preparation administration separately or with more than one acceptable carrier combination agent.For example, solvent, diluent etc.Can the peroral dosage form administration, but as tablet, capsule dispersed powders, granule etc.The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the method for knowing in pharmaceutical field.Can contain for example 0.05%～90% weight active component with carrier combinations in these pharmaceutical formulations, the more common approximately active component between 15%～60%.The compounds of this invention dosage can make 0.005～5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or dosage form.
The pharmacological results shows, above-mentioned Enoxolone derivative causes the dimethylbenzene ear expanding inflammatory model to mice and has stronger inhibitory action, and the activity of preferred Enoxolone derivative obviously is better than enoxolone; And have no obvious injury of gastrointestinal tract, can be used for the treatment of and prevent various inflammation or inflammation related disease.described inflammation or inflammation related disease are selected from rheumatoid arthritis, osteoarthritis, rheumatic arthritis, gouty arthritis, the lupus erythematosus syndrome, bronchitis, bursitis, tenosynovitis, psoriasis, eczema, burn, dermatitis, inflammatory bowel, Ke Laoen is sick, gastritis, irritable bowel syndrome, ulcerative colitis, colorectal carcinoma, arteritis nodosa, thyroiditis, rheumatic fever, gingivitis, periodontitis, oral ulcer, nephritis, the swelling that occurs after damage, myocardial ischemia, various infectious pneumonia, physics and chemistry pneumonia and allergy pneumonia, chronic backup pneumonopathy, proctalgia fugax and rectal laceration, the liver and gall capsulitis, cholangitis, sclerosing cholangitis, primary biliary cirrhosis and cholecystitis.
Because technique scheme is used, the present invention compared with prior art has following advantages:
1. the present invention on the structure of enoxolone, introduces a kind of gaseous signal molecule H that discharges
2The group of S has synthesized a series of novel compounds, obtains having the compound than the higher anti-inflammatory activity of enoxolone, and does not find obvious injury of gastrointestinal tract.
2. the hydrogen sulfide appropriate because meeting discharges of the compound in the present invention, can reduce the generation of cardiovascular event.Therefore, the compound in the present invention can be avoided injury of gastrointestinal tract and/or Cardia cevent or other toxicity due to the clinical NSAID (non-steroidal anti-inflammatory drug) of using.
Description of drawings
Fig. 1 is the result of injury of gastrointestinal tract experiment in embodiment nine.
The specific embodiment
The invention will be further described below in conjunction with drawings and Examples:
Embodiment one:
5-[4-(2-bromine oxethyl) phenyl]-preparation of D3T (5a)
ADT-OH (0.325g, 1.4mmol), glycol dibromide (0.50mL, 5.8mmol), anhydrous K
2C0
3(0.396g, 2.8mmol) is dissolved in the DMF of 10mL drying, 120 ℃ of reaction 2h.Add the dilution of 20mL ethyl acetate after cooling, and washing (3 * 20mL), anhydrous Na
2SO
4Dry.Filter, evaporated under reduced pressure, the acetone-water recrystallization gets pitchy product 0.388g, productive rate 81.5%, mp:126.0～127.0 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.59(d，2H，J＝8.9Hz，ArH)，7.36(s，1H，＝CH)，6.96(d，2H，J＝8.9Hz，ArH)，4.33(t，2H，J＝6.1Hz，CH
2)，3.65(t，2H，J＝6.1Hz，CH
2)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：212.554，170.180，158.775，132.260，126.120，122.226，113.014，65.455，26.026。
Above-mentioned appraising datum proof gained compound is 5-[4-(2-bromine oxethyl) phenyl]-D3T (5a), its structural formula is:
Compound I
1Preparation
With GA (0.47g, 1.0mmol is available from Sichuan superman's plant company limited, content＞98%), 5a (0.33g, 1.0mmol), anhydrous K
2CO
3(0.138g, 1.0mmol) and catalytic amount KI add in the 15mL dry DMF room temperature reaction 16h.The dilution of 50mL water, and ethyl acetate extraction (3 * 30ml), merge organic layer, anhydrous Na
2SO
4Dry.Filter, evaporate to dryness, column chromatography [petroleum ether (60-90): ethyl acetate=3: 1 (v/v)] gets red solid 0.62g, yield 86.2%, mp:220.5～221.5 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.62(d，2H，J＝8.8Hz，ArH)，7.39(s，1H，＝CH)，7.01(d，2H，J＝8.8Hz，ArH)，5.60(s，1H，C
12-H)，4.50(m，2H，OCH
2)，4.27(t，2H，OCH
2)，3.23(m，1H，C
3-H)，2.78(brs，1H，OH)，2.32(s，1H，C
9-H)，1.35(s，3H，CH
3)，1.16(s，3H，CH
3)，1.12(s，3H，CH
3)，1.09(s，3H，CH
3)，1.00(s，3H，CH
3)，0.81(s，3H，CH
3)，0.74(s，3H，CH
3)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：215.533，200.554，176.753，173.349，169.535，169.518，162.089，135.186，129.113，128.886，124.996，115.961，79.140，66.660，62.727，62.232，55.308，48.714，45.785，44.558，43.551，41.437，39.538，39.514，38.079，37.471，33.101，32.188，31.551，28.983，28.687，28.497，27.708，26.832，26.794，23.842，19.030，17.863，16.796，16.002；IR(KBr，cm
-1)：3442.0(OH)，1725.9(C＝O)，1653.1(C＝O)，1635.0，1602.8，1575.8，1489.6(C＝C)，1172.0(C＝S)；HR-MS：Calcd.For C
41H
54O
5S
3[M+H]
+：723.3206，Found：723.3191。
Above-mentioned appraising datum proof gained compound is Compound I
1, its structural formula is:
Embodiment two:
5-[4-(3-bromine propoxyl group) phenyl]-preparation of D3T (5b)
Be raw material with 1,3-dibromopropane, with reference to the preparation of the method for 5a, productive rate 83.2%, mp:79.0～80.0 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.62(d，2H，J＝8.8Hz，ArH)，7.40(s，1H，＝CH)，7.00(d，2H，J＝8.7Hz，ArH)，4.19(t，2H，J＝5.8Hz，CH
2)，3.62(t，2H，J＝6.3Hz，CH
2)，2.36(p，2H，J＝6.0Hz，CH
2)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：212.460，170.437，159.454，132.073，126.065，121.751，112.886，63.118，29.453，27.178。
Above-mentioned appraising datum proof gained compound is 5-[4-(3-bromine propoxyl group) phenyl]-3H-1,2-two sulfur-3-thioketone (5b), its structural formula is:
Compound I
2Preparation
Take GA and 5b as raw material, with reference to I
1Synthetic method preparation, red solid, yield 86.6%, mp:79.1～80.7 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.54(d，2H，J＝8.8Hz，ArH)，7.31(s，1H，＝CH)，6.91(d，2H，J＝8.8Hz，ArH)，5.54(s，1H，C
12-H)，4.24(t，2H，OCH
2)，4.06(t，2H，OCH
2)，3.16(dd，1H，C
3-H)，2.72(brs，1H，OH)，2.26(s，1H，C
9-H)，2.10(p，2H，CH
2)，1.29(s，3H，CH
3)，1.08(s，3H，CH
3)，1.07(s，3H，CH
3)，1.03(s，3H，CH
3)，0.93(s，3H，CH
3)，0.74(s，3H，CH
3)，0.69(s，3H，CH
3)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：215.213，200.442，176.583，173.337，169.515，162.304，134.798，128.899，128.658，124.447，115.692，78.889，72.011，65.004，62.039，61.222，55.101，48.673，45.620，44.286，43.420，41.251，39.342，37.923，37.288，32.918，32.038，31.292，28.757，28.717，28.642，28.320，27.919，27.467，26.632，26.566，23.641，21.307，19.397，18.850，16.618，15.853；IR(KBr，cm
-1)：3567.4(OH)，1732.1(C＝O)，1652.4(C＝O)，1599.4，1522.6，1492.6(C＝C)，1179.7(C＝S)；HR-MS：Calcd.For C
42H
56O
5S
3[M+H]
+：737.3383，Found：737.3387.
Above-mentioned appraising datum proof gained compound is Compound I
2, its structural formula is:
Embodiment three:
5-[4-(4-bromine butoxy) phenyl]-preparation of D3T (5c)
Take Isosorbide-5-Nitrae-dibromobutane as raw material, with reference to the preparation of the method for 5a, productive rate 79.4%, mp:70.0～71.0 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.60(d，2H，J＝8.7Hz，ArH)，7.38(s，1H，＝CH)，6.96(d，2H，J＝8.7Hz，ArH)，4.07(t，2H，J＝5.9Hz，CH
2)，3.50(t，2H，J＝6.4Hz，CH
2)，2.08(m，2H，CH
2)，1.99(m，2H，CH
2)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：212.439，170.554，159.670，132.006，126.057，121.553，112.834，64.759，30.795，26.729，25.133。
Above-mentioned appraising datum proof gained compound is 5-[4-(4-bromine butoxy) phenyl]-D3T (5c), its structural formula is:
Compound I
3Preparation
Take GA and 5c as raw material, with reference to I
1Synthetic method preparation, red solid, yield 89.2%, mp:138.2～139.2 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.60(d，2H，J＝8.8Hz，)，7.39(s，1H，＝CH)，6.98(d，2H，J＝8.8Hz，ArH)，5.64(s，1H，C
12-H)，4.20(t，2H，CH
2)，4.08(t，2H，CH
2)，3.23(m，1H，C
3-H)，2.78(brs，1H，OH)，2.34(s，1H，C
9-H)，1.37(s，3H，CH
3)，1.16(s，3H，CH
3)，1.13(s，3H，CH
3)，1.12(s，3H，CH
3)，1.01(s，3H，CH
3)，0.81(s，6H，CH
3)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：215.234，200.481，176.668，173.396，169.582，162.512，134.737，128.810，128.690，124.261，115.706，78.893，67.907，64.179，62.053，55.122，48.687，45.619，44.250，43.434，41.266，39.349，37.950，37.299，32.951，32.068，31.309，28.794，28.668，28.328，27.492，26.671，26.602，26.027，25.743，23.630，18.884，17.691，16.604，15.844；IR(KBr，cm
-1)：3446.9(OH)，1722.7(C＝O)，1653.4(C＝O)，1647.7，1602.3，1489.6(C＝C)，1177.1(C＝S)；HR-MS：Calcd.For C
43H
58O
5S
3[M+H]
+751.3519，Found：751.3477.
Above-mentioned appraising datum proof gained compound is Compound I
3, its structural formula is:
Embodiment four:
The preparation of 3-O-acetyl group enoxolone (6a):
GA (1.88g, 4.0mmol) is dissolved in the 10mL pyridine, drips acetic anhydride (3.78mL, 40.0mmol) under stirring at room.Then reaction 12h pours in frozen water, filters, and the acetone-water recrystallization gets white solid 1.90g, productive rate 92.7%, mp:312.0～313.0 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：5.72(s，1H，C
12-H)，4.52(dd，1H，J＝11.13，4.51Hz，C
3-H)，2.37(s，1H，C
9-H)，2.06(s，3H，CH
3)，1.37(s，3H，CH
3)，1.23(s，3H，CH
3)，1.17(s，3H，CH
3)，1.13(s，3H，CH
3)，0.88(s，6H，CH
3)，0.84(s，3H，CH
3)。
Above-mentioned appraising datum proof gained compound is 3-O-acetyl group enoxolone (6a), and its structural formula is:
Compound I
4Preparation
Take 6a and 5a as raw material, with reference to I
1Synthetic method preparation, red solid, productive rate 86.0%.96.0～97.0 ℃ of fusing points.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.63(d，2H，J＝8.8Hz，ArH)，7.40(s，1H，＝CH)，7.01(d，2H，J＝8.8Hz，ArH)，5.60(s，1H，C
12-H)，4.50(m，2H，OCH
2)，4.27(t，2H，OCH
2)，3.23(m，1H，C
3-H)，2.78(brs，1H，OH)，2.32(s，1H，C
9-H)，2.05(s，3H，CH
3)，1.35(s，3H，CH
3)，1.16(s，3H，CH
3)，1.12(s，3H，CH
3)，1.09(s，3H，CH
3)，1.00(m，4H，CH
3 & CH
2)，0.80(s，3H，CH
3)，0.72(s，3H，CH
3)；IR(KBr，cm
-1)：1732.1(C＝O)，1692.4(C＝O)，1602.6，1575.6，1491.4，1464.5(C＝C)，1178.9(C＝S)；HR-MS：Calcd.For C
43H
57O
6S
3[M+H]
+：765.3312，Found：765.3314.
Above-mentioned appraising datum proof gained compound is Compound I
4, its structural formula is:
Embodiment five:
Compound I
5Preparation
Take 6a and 5b as raw material, with reference to I
1Synthetic method make, red solid, yield 89.5%, mp:253.2～254.2 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.62(d，2H，J＝8.8Hz，ArH)，7.40(s，1H，CH＝CH)，6.98(d，2H，J＝8.8Hz，ArH)，5.61(s，1H，C
12-H)，4.52(m，1H，C
3-H)，4.31(t，2H，J＝6.2Hz，OCH
2)，4.12(t，2H，J＝6.1Hz，OCH
2)，2.35(s，1H，C
9-H)，2.18(m，2H，CH
2)，2.06(s，3H，CH
3)，1.35(s，3H，CH
3)，1.16(s，3H，CH
3)，1.15(s，3H，CH
3)，1.10(s，3H，CH
3)，0.88(s，6H，CH
3)，0.75(s，3H，CH
3)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：215.341，200.253，176.574，173.274，171.275，169.441，162.292，134.889，128.901，128.681，124.528，115.698，80.797，64.973，61.972，61.199，55.220，48.704，45.631，44.299，43.431，41.246，39.024，38.261，37.930，37.161，32.884，32.048，31.314，28.750，28.650，28.258，26.595，23.787，23.582，21.567，18.865，17.580，16.908，16.659；IR(KBr，cm
-1)：1732.1(C＝O)，1651.9(C＝O)，1596.7 1577.3，1520.7，1489.9(C＝C)，1180.4(C＝S)；HR-MS：Calcd.ForC
44H
59O
6S
3[M+H]
+ 779.3468，Found：779.3468。
Above-mentioned appraising datum proof gained compound is Compound I
5, its structural formula is:
Embodiment six:
Compound I
6Preparation
Take 6a and 5c as raw material, with reference to I
1Synthetic method make, red solid, yield 89.6%, mp:253.8～254.8 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.61(d，2H，J＝8.7Hz，ArH)，7.40(s，1H，CH＝CH)，6.98(d，2H，J＝8.7Hz，ArH)，5.64(s，1H，C
12-H)，4.23-4.16(m，2H，OCH
2)，4.08(t，2H，OCH
2)，2.36(s，1H，C
9-H)，2.06(s，3H，CH
3)，1.36(s，3H，CH
3)，1.16(s，6H，CH
3)，1.12(s，3H，CH
3)，0.88(s，6H，CH
3)，0.80(s，3H，CH
3)；IR(KBr，cm
-1)：1729.1(C＝O)，1705.8(C＝O)，1654.0(C＝O)，1601.0，1576.6，1491.2(CH＝CH)，1178.8(C＝S)；HR-MS：Calcd.For C
45H
61O
6S
3[M+H]
+793.3625，Found：793.3635。
Above-mentioned appraising datum proof gained compound is Compound I
6, its structural formula is:
Embodiment seven:
The preparation of 11-deoxidation enoxolone (1)
In the 20mL dioxane, add the 20g zinc powder (to use HgCl
2The activation), GA (2.0g, 4.26mmol), room temperature reaction drips the 1.20mL concentrated hydrochloric acid simultaneously, filter after 2h, concentrated, column chromatography [petroleum ether (60-90): ethyl acetate=7: 1 (v/v)], obtain white solid 1.48g, productive rate 74.0%, mp:330.1～331.0 ℃.IR(KBr，cm
-1)：3437.7(-COOH)，1707.4(-COOH)；HR-MS：Calcd.For C
30H
47O
3[M-H]
-455.3531，Found：455.3524。
Above-mentioned appraising datum proof gained compound is 11-deoxidation enoxolone (1), and its structural formula is:
Compound I
7Preparation
Take compound 1 and 5b as raw material, with reference to Compound I in embodiment one
1Synthetic method make, red solid, yield 92.2%, mp:141.0～142.0 ℃.
1HNMR(400MHz，CDCl
3)，δ(ppm)：7.62(d，2H，J＝8.6Hz，ArH)，7.40(s，1H，＝CH)，6.98(d，2H，J＝8.6Hz，ArH)，5.13(m，1H，C
12-H)，4.30(t，2H，J＝6.5Hz，CH
2)，4.14(t，2H，J＝6.1Hz，CH
2)，3.22(m，1H，C
3-H)，2.18(p，2H，J＝6.1Hz，CH
2)，1.14(s，3H，CH
3)，1.12(s，3H，CH
3)，0.99(s，3H，CH
3)，0.92(s，3H，CH
3)，0.91(s，3H，CH
3)，0.78(s，3H，CH
3)，0.74(s，3H，CH
3)；
13CNMR(400MHz，CDCl
3)，δ(ppm)：177.314，173.157，162.385，144.711，134.857，131.169，129.067，128.816，122.712，115.689，79.213，65.822，65.072，60.765，55.362，48.610，47.787，44.539，43.068，41.728，39.963，38.984，38.535，37.120，32.801，32.179，31.472，28.861，28.781，28.444，28.307，27.431，27.102，26.328，26.197，23.685，18.549，16.956，15.825，15.715；IR(KBr，cm
-1)：1725.0(C＝O)，1669.6，1653.4，1635.9，1601.7(CH＝CH)，1178.9(C＝S)；HR-MS：Calcd.For C
42H
59O
4S
3[M+H]
+ 723.3570，Found：723.3570。
Above-mentioned appraising datum proof gained compound is Compound I
7, its structural formula is:
Embodiment eight:
The test of mice caused by dimethylbenzene xylene ear swelling, and the experimental technique reference literature ([1] Xu Shuyun, Bian Rulian, Chen Xiu chief editor. pharmacological experimental methodology [M]. the third edition, Beijing: People's Health Publisher, 2002,911; [2] bureau of drug administration of Ministry of Health of the People's Republic of China compiles. new drug (Western medicine) preclinical study guideline compilation [B] (pharmacy pharmacology's toxicology), and 1993,121-124).
Test-compound becomes 2.00mmolL with the 0.5%CMC-Na solution preparation
-1Suspension.Positive control drug aspirin dosage is set as 200mgkg
-1Fasting 12h before every group of 10 mices, administration freely drinks water.To the mouse stomach administration, the administration capacity is 0.2mL10g
-1After administration 1h, mouse right ear wide both sides evenly are coated with dimethylbenzene 20 μ L with microsyringe and cause inflammation, left auricle is done contrast.After causing scorching 1h, mice is taken off cervical vertebra execution, take off two ears along the auricle baseline, respectively take off an auricle scales/electronic balance weighing in same position with card punch (diameter mm).Causing scorching auricle weight deducts control sides auricle weight and is swelling.
Suppression ratio=(negative control-test-compound)/negative control * 100%
With the model evaluation of mice caused by dimethylbenzene xylene ear swelling the anti-inflammatory activity of 7 Enoxolone derivatives, the results are shown in Table 1.
As can be seen from Table 1, all I compounds all show stronger ear swelling inhibitory action, and the suppression ratio of some compounds surpasses 60%, and the suppression ratio of the most of noval chemical compound all parent compound than original is high, and what have reaches nearly 20 percentage points.
Table 1 I compounds xylol causes the antiinflammatory action of mice ear model
| Compound | Dosage (mg.kg -1) | Suppression ratio (%) |
| CMC-Na | _ | _ |
| Aspirin | 200 | 41.5 |
| GA | 18.8 | 37.8 |
| I 1 | 28.9 | 26.5 |
| I 2 | 29.4 | 33.9 |
| I 3 | 30.0 | 55.6 |
| I 4 | 30.6 | 60.7 |
| I 5 | 31.1 | 47.0 |
| I 6 | 31.7 | 56.1 |
| I 7 | 28.9 | 39.4 |
Embodiment nine: the injury of gastrointestinal tract experiment
Get healthy male SD rat, be purchased from the Nicole Haislett Experimental Animal Center, body weight (average 100g), random packet, fasting 24h before experiment can't help water.Standard feed is fed, and in time changes bedding and padding and Mus grain every day, keeps the mouse cage cleaning.During experiment, establish respectively the solvent matched group, diclofenac group, tested medicine group.Every animal solvent gastric infusion of solvent matched group; The diclofenac matched group, every animal is pressed the dosage gavage diclofenac sodium solution of 20mg/kg; Tested medicine group, every treated animal are put to death after every treated animal administration 6h by 62.8 μ mol/kg gastric infusions, observe by the following method, comparative drug is on the impact of rat gastrointestinal tract, and calculate the index of correlation.Along the greater gastric curvature side, stomach is cut off flattening, by Guth criterion calculation ulcer index (UI): the length of ulcer surface is 1 minute less than 1mm, and 1～2mm is 2 minutes, and 2～3mm is 3 minutes, and 3～4mm is 4 minutes, greater than 4mm, it is divided into some sections, and every section is calculated by upper method.Ulcer width＞1mm is score value * 2, and petechial hemorrhage is pressed calculating in each 0.5 minute, and the cumulative addition score of every rat is total ulcer index of this rat.Between each group of employing t check analysis, ulcer index has there was no significant difference.Experimental result is seen Fig. 1.
The result of Fig. 1 shows, compares with the diclofenac group, and the ulcer index of each tested material group is very little, and utmost point significant difference (P＜0.01) is arranged.Simultaneously, find after dissecting, diclofenac group rat stomach has color change in various degree, mainly is HUANGBAI(sic) or pale asphyxia; And tested material is respectively organized rat, and the stomach naked eyes are not observed above-mentioned variation, and other difference changes obviously not to be discovered yet.
Claims (2)
1. Enoxolone derivative or the acceptable salt of its medical science application in the preparation anti-inflammatory drug, the structural formula of described Enoxolone derivative is selected from:
Structural formula one
,
Structural formula two
In formula, R
1Be H or CH
3CO; X is O; Y is (CH
2)
n, wherein, n=2 ~ 6; Z is O.
2. Enoxolone derivative or the acceptable salt of its medical science application in the preparation anti-inflammatory drug according to claim 1, is characterized in that, described Enoxolone derivative is selected from: the compound that structural formula one is represented.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210015822 CN102579462B (en) | 2012-01-18 | 2012-01-18 | Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210015822 CN102579462B (en) | 2012-01-18 | 2012-01-18 | Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102579462A CN102579462A (en) | 2012-07-18 |
| CN102579462B true CN102579462B (en) | 2013-05-22 |
Family
ID=46469068
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210015822 Expired - Fee Related CN102579462B (en) | 2012-01-18 | 2012-01-18 | Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102579462B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106243183B (en) * | 2016-07-29 | 2018-11-23 | 广西师范大学 | Ursolic acid-hydrogen sulfide donor reagent derivatives and its synthetic method |
| CN106243182B (en) * | 2016-07-29 | 2018-11-23 | 广西师范大学 | Enoxolone-hydrogen sulfide donor reagent derivatives and its synthetic method and application |
| CN107312057A (en) * | 2017-06-13 | 2017-11-03 | 佛山科学技术学院 | A kind of conjugate containing cancer cell targeted molecular and its production and use |
| CN107325149B (en) * | 2017-06-27 | 2018-04-03 | 亿利耐雀生物科技有限公司 | A kind of radix glycyrrhizae gadoleic acid derivative and preparation method thereof and purposes |
| CN111233966A (en) * | 2020-03-31 | 2020-06-05 | 江苏崇佩生物科技有限公司 | Glycyrrhetinic acid derivative ASBT (ascorbyl transferase) as well as preparation method and application thereof |
| CN112574172B (en) * | 2020-12-14 | 2022-03-29 | 杭州海醍思医疗科技有限公司 | Gallic acid hydrogen sulfide derivative, preparation method and medical application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101240007B (en) * | 2004-12-29 | 2011-01-12 | 浙江大学 | Oleanane triterpene compound with containing multiple unsaturated double bonds and use thereof |
| CN100488979C (en) * | 2005-10-14 | 2009-05-20 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN102241726B (en) * | 2011-05-27 | 2013-06-12 | 苏州大学 | Glycyrrhetinic acid derivative and application thereof as antitumor medicament |
| CN102552280A (en) * | 2011-09-09 | 2012-07-11 | 中国科学院生物物理研究所 | Pharmaceutical applications of glycyrrhizic acid or salt and derivative thereof |
-
2012
- 2012-01-18 CN CN 201210015822 patent/CN102579462B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102579462A (en) | 2012-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102579462B (en) | Application of glycyrrhetinic acid derivatives in preparation process of anti-inflammatory drugs | |
| CN105037355B (en) | The indazole inhibitors and its therapeutical uses of Wnt signal transduction paths | |
| ES2528302T3 (en) | Heterocycles with 6 phenyl nitrogen rings substituted as inhibitors of microtubule polymerization | |
| CN101854804B (en) | Hdac inhibitors | |
| Gurupadaswamy et al. | Synthesis and evaluation of 2, 5-di (4-aryloylaryloxymethyl)-1, 3, 4-oxadiazoles as anti-cancer agents | |
| CN102127142B (en) | Ilicis routundae cortex derivants and application thereof in preparing medicament capable of resisting tumors | |
| CN103304564A (en) | Beta-carboline derivative containing hydroximic acid as well as preparation method and medical application thereof | |
| CN107445896B (en) | Phenyl hydroxamic acid compound with anti-tumor activity and application thereof | |
| CN102471273B (en) | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof | |
| CN100497337C (en) | Folacin dimethylbiguanide and process for production thereof | |
| CN102241726B (en) | Glycyrrhetinic acid derivative and application thereof as antitumor medicament | |
| JP7018514B2 (en) | Compounds and their pharmaceutical applications | |
| EP1586557A1 (en) | 4-nitro-2- (4 -methoxy)-phenoxy -methanesulfonanilide derivates and their pharmaceutical use | |
| CN104119330B (en) | The synthesis of berberinc derivate and preparing the application in antitumor drug and collaborative Zorubicin antineoplastic pharmaceutical compositions | |
| CN106255691A (en) | 4,5 dihydro 1H pyrrolo-[2,3 F] quinoline 2,7,9 tricarboxylic acids and the polymorphic forms of disodium salt, Preparation Method And The Uses | |
| EP2813495A1 (en) | 2-arylbenzofuran-7-formamide compounds, preparation method and use thereof | |
| WO2018209972A1 (en) | Antianxiety deuterated compounds and medical use thereof | |
| CN103919778A (en) | Application of curcumin analog S1 containing piperidone structure in preparation of anti-inflammation drugs | |
| CN109721579B (en) | 7, 8-dehydrograpevine derivatives, preparation method, pharmaceutical composition and use thereof | |
| JPS6252A (en) | Isoprenoidamine derivative and antiulcer agent | |
| CN104710499A (en) | Crystal form of Abiraterone propionate and preparation method thereof | |
| WO2013086980A1 (en) | Sulfonylurea guanidine, preparation method and use thereof | |
| JPWO2008029912A1 (en) | Compound having benzamide as skeleton having cyclooxygenase 1 (COX-1) selective inhibitory activity | |
| CN102504005B (en) | Compound with novel structure and preparation method and applications thereof | |
| ES2222988T3 (en) | SPECIFIC SALT FORMS OF TRIFENYLETHYLENE DERIVATIVES AS SELECTIVE MODULATORS OF STROGEN RECEIVERS. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP02 | Change in the address of a patent holder |
Address after: Suzhou City, Jiangsu province 215137 Xiangcheng District Ji Road No. 8 Patentee after: Soochow University Address before: 215123 Suzhou City, Suzhou Province Industrial Park, No. love road, No. 199 Patentee before: Soochow University |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130522 Termination date: 20160118 |
|
| EXPY | Termination of patent right or utility model |