CN104257661A - Application of azaazulene alkaloids topreparing medicine for preventing or treating pulmonary fibrosis - Google Patents
Application of azaazulene alkaloids topreparing medicine for preventing or treating pulmonary fibrosis Download PDFInfo
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Abstract
The invention discloses application of alkaloids shown in the structural formula I to preparing medicines for preventing and/or treating pulmonary fibrosis. According to the alkaloids shown in the structural formula I, the inflammation degree of the lesion pulmonary tissue can be obviously reduced, the content of fibrosis prompting factors TGF-beta1 in the lesion pulmonary tissue can be reduced, excessive deposition of collagen in the lesion pulmonary tissue can be reduced, and obvious preventing and treating effects on the pulmonary fibrosis are achieved.
Description
Technical field
The present invention relates to an Azaazulene Alkaloid with pulmonary fibrosis resistant activity, the application of the alkaloid particularly as shown in structural formula I in preparation prevention or treatment pulmonary fibrosis medicine compositions.
Background technology
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) be a kind of agnogenic diseases causing diffuse lung, be characterized as quick progressive Pulmonary parenchyma lesion and fibrosis, finally fill the air to whole lungs, cause lung structure and function heavy damage.Clinical manifestation is gradual dyspnea, dry cough, and the Progressive symmetric erythrokeratodermia of pulmonary function reduces, hypoxemia, final respiratory failure and dead.Typical IPF pathological change is the one-tenth fiber focal lesion that fibroblast and myofibroblast are formed.In active fiber stove, myofibroblast in the highest flight, is the important effect cell of fiber forming process, can causes the abnormal deposition of extracellular matrix, is the important neuropathological hallmarks that IPF enters irreversibility progression of fibrosis.In recent years, due to the aggravation of environmental pollution, its sickness rate rises year by year.
Because etiology and pathogenesis is unclear, the treatment of pulmonary fibrosis is one of difficult problem of medical domain always, although constantly research and develop new drug, but still there is no effective therapeutic scheme and professional treatment medicine, poor prognosis, average survival time is only 3 years, and within 5 years, survival rate is less than 50%, and being called as is not cancer " cancer ".Inflammatory and immune response is had to participate in the formation of interstitial pulmonary fibrosis, therefore glucocorticoid (as prednisone) and immunosuppressant (as cyclophosphamide) are the medicines of traditional treatment pulmonary fibrosis, but its therapeutic effect is limited, life-time service also can increase the weight of, accelerate pulmonary fibrosis process, therefore finds the important topic that novel anti-fibrosis drug is study of pharmacy always.
In pulmonary fibrosis generating process, TGF-β 1 is generally acknowledged short fibrosis markers thing, is and the generation of pulmonary fibrosis and the closest mediated factor of formation relation, therefore becomes the main targeting target of fibrosis.Therefore, the content of collagen in tissue can be determined by measuring hydroxyproline content in lung tissue; By measuring the change of TGF-β 1 expression, possible the mechanism of action of pharmaceutical intervention pulmonary fibrosis can be described, namely medicine is not the level suppression TGF-β 1/Smad path by antiinflammatory but by reducing TGF-β 1, thus improves pulmonary fibrosis degree.As just at the pirfenidone (pirfenidone) of Japan, India and European Union's listing, fibrogenic factor such as TGF-β 1 grade can be suppressed, but clinically still there is more side effect as photosensitive.
Cough is the common sympton of respiratory system disease, and as a lot of respiratory system disease, pulmonary fibrosis also there will be cough symptom in early days.Although cough and pulmonary fibrosis have certain contact, they are completely different.Strictly speaking, cough is the form of expression of many respiratory system diseases, but is not a kind of real disease.Although also have cough phenomenon to occur in the early stage of pulmonary fibrosis and evolution, the symptom such as cough, asthma that pulmonary fibrosis causes in early days can be alleviated by antitussive, but antitussive is invalid when PD is serious, then can only use hormone, antibiosis usually relief of symptoms.These are all cured the symptoms, not the disease above, can not fundamentally treat or stop pulmonary fibrosis, and hormone, antibiotic life-time service even also can increase the weight of, accelerate pulmonary fibrosis process.
The Chinese medicine Radix Stemonae is the dried root of Stemonaceae (Stemonaceae) Stemona (Stemona) plant, has the effects such as nourishing the lung to keep the adverse QI downward, cough-relieving, parasite killing delousing, coughs for new chronic cough, pulmonary tuberculosis cough, pertussis.Pharmacology activity research shows, Stemona alkaloids is the main active of the Radix Stemonae, has effect of extraordinary insecticidal activity and expelling phlegm for arresting cough.Research about the Radix Stemonae mainly concentrates on the separation of chemical composition, and except parasite killing and antitussive activity, other activity researchs are less.Although one of symptom of pulmonary fibrosis is cough, so far, without any the research report that can improve or treat pulmonary fibrosis about antitussive.
Azaazulene type alkaloid as shown in structural formula I, as protostemonine etc., be from Radix Stemonae, be separated the compound obtained at first, to the cough model Cavia porcellus of citric acid induction, there is significant antitussive effect, in addition, there is not yet other active reporter.Patent about Stemona alkaloids is few, and mostly is total alkali preparation method or cough-relieving, insecticidal activity.Up to now, not yet retrieve the alkaloidal patent of Azaazulene type as shown in structural formula I, also not yet have this Alkaloid of bibliographical information to have prevention or treatment effect of pulmonary fibrosis disease or its application in treatment lung fiber disease medicine.
Summary of the invention
For the deficiency lacking effective prevention or treatment pulmonary fibrosis medicine, the invention discloses the purposes as shown in structural formula I alkaloid, this alkaloid can effectively prevent or treat pulmonary fibrosis disease.
Technical scheme of the present invention is: a kind of compound is preparing the application prevented and/or treated in pulmonary fibrosis medicine compositions, and described compound has structural formula I
Wherein:
R
1be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
R
2be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
Or R
1, R
2as shown in the formula:
Wherein: X is selected from oxygen, sulfur;
R
3be selected from hydrogen, α or β alkyl, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl;
R
4be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
R
5be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
Or R
4, R
5for as shown in the formula:
Wherein: Y is selected from oxygen, sulfur, or as shown in the formula:
Wherein: R
9be selected from methoxyl group, hydrogen;
R
6be selected from α or β hydrogen, α or β hydroxyl;
R
7be selected from α or β hydrogen, α or β hydroxyl;
R
8be selected from α or β hydrogen, α or β hydroxyl.
Compound, preparing the application prevented and/or treated in pulmonary fibrosis medicine compositions, is characterized in that described compound has structural formula Ia.
Wherein:
R
1be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
R
2be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
Or R
1, R
2for as shown in the formula:
Wherein: X is selected from oxygen, sulfur;
R
3be selected from hydrogen, α or β alkyl, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl;
R
4be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
R
5be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
Or R
4, R
5as shown in the formula:
Wherein: Y is selected from oxygen, sulfur, or as shown in the formula:
Wherein: R
6be selected from methoxyl group, hydrogen.
Described application, is characterized in that, described compound is the alkaloid shown in structural formula I or its medicinal derivative.
Described application, is characterized in that, described compound medicinal derivative is alkaloidal salt or ester shown in structural formula I.
Described application, is characterized in that, described pharmaceutical composition at least comprises the alkaloid of a kind of active component as shown in structural formula I and a kind of pharmaceutical carrier.
Described application, is characterized in that, described pharmaceutical composition comprises the alkaloid as shown in structural formula I that mass percent is 0.01% ~ 99% and mass percent is the pharmaceutical carrier of 0.01% ~ 99%.
The pulmonary fibrosis of the human or animal that it is feature that " pulmonary fibrosis " described in the present invention refers to idiopathic pulmonary fibrosis pathological change, caused by a variety of causes.
Described " prevention " refers to and deposits in case in the possible factor of pulmonary fibrosis that causes, and prevents or reduce the generation of pulmonary fibrosis after using; Described " treatment " refers to the degree alleviating pulmonary fibrosis, or healing pulmonary fibrosis makes it normal, or slows down the process of pulmonary fibrosis.
Alkaloidal salt or ester refer to the forms such as the acceptable salt of materia medica, ester.
Described pharmaceutical composition at least comprises one alkaloidal active component and a kind of pharmaceutical carrier as shown in structural formula I.So-called " active component " refers to the function with prevention or treatment pulmonary fibrosis.In the composition, this alkaloid can as active component separately or together with other compounds.Described pharmaceutical carrier comprises pharmaceutically acceptable excipient, filler, diluent etc.In this pharmaceutical composition, structure alkaloidal content is as shown in Equation 1 0.01% ~ 99%, and the content of pharmaceutical carrier is 0.01% ~ 99%, and percentage ratio is mass percent.
The dosage form of described drug regimen is not particularly limited, can be solid, semisolid or liquid form, can be aqueous solution, non-aqueous solution or suspension, can oral administration administration, through vein, muscle, Intradermal or subcutaneous administration, or through Sublingual, rectum, Transdermal absorption and respiratory tract aerosol administration.Every daily dose of this pharmaceutical composition is about 0.01 ~ 1000mg, preferably 1 ~ 500mg.
Prevent or treatment pulmonary fibrosis time, the described alkaloidal pharmaceutical composition as structural formula I can be used alone or with other drug conbined usage.
The alkaloid as structural formula I described in the present invention prepares to get (purity is greater than 98%) from Stemonaceae plant, and all the other raw materials or reagent are all commercially.
Beneficial effect
1. the invention provides the Azaazulene type alkaloid of compound as shown in structural formula I of a kind of new prevention or treatment pulmonary fibrosis, prove that this Alkaloid has significant preventive and therapeutic action for the mouse pulmonary fibrosis of bleomycin induced by experiment in vitro, obviously alleviate the pulmonary fibrosis degree of laboratory animal, can be used for the medicine preparing treatment lung fiber disease.Also illustrate that common cough suppressing medicine does not act on pulmonary fibrosis simultaneously.The present invention finds that the multiple Azaazulene type alkaloid (I ~ IV) as shown in structural formula I has pulmonary fibrosis resistant effect first time, does not have bibliographical information before.
Specifically:
Result of the present invention shows, has the compound of parent nucleus as shown in structural formula I, as 4 alkaloids such as Compound I ~ IV, has the effect (embodiment 3) preventing and/or treating pulmonary fibrosis significantly.The activity research structure further illustrated as shown in structural formula I of Compound I has obvious pulmonary fibrosis resistant effect.The results of animal of multi objective shows, the effect that this compounds improves pulmonary fibrosis is better than or is equivalent to recently at the positive control drug pirfenidone of Japan's listing, the pulmonary fibrosis mice that can reduce bleomycin induced is significantly dead, the paragonimus cyst of remarkable reduction model mice, improve the pulmonary fibrosis degree of model mice, the content of Hyp and short fibrosis factor TGF-β 1 in obvious reduction lung tissue, the mouse lung inflammation that the alkaloid with structure shown in structural formula I can alleviate bleomycin modeling and causes is described, reduces pulmonary's collagen deposition.Result of the present invention provides scientific basis preventing and/or treating the application in pulmonary fibrosis medicine compositions for the Azaazulene type alkaloid with structure as shown in structural formula I.
2. the experiment material that the present invention relates to, from multiple Radix Stemonae medical material, is mainly radix stemonae tuberosae, Radix Stemonae and Radix stemonae japonicae, and cheap, material is easy to get.
Accompanying drawing explanation
Fig. 1 tetra-alkaloids and carbetapentane citrate are on the impact of bleomycin induced pulmonary fibrosis mice.A: hydroxyproline content; B:HE dyes pathological section; C:Masson dyes pathological section.Wherein, 1-sham operated rats, 2-model group, 3-carbetapentane citrate, 4-pirfenidone, 5-Compound I, 6-Compound II per, 7-compound III, 8-compound IV.Compared with sham operated rats,
#p < 0.05,
##p < 0.01; Compared with model group,
*p < 0.05,
*p < 0.01.
Fig. 2 Compound I is on the impact of bleomycin induced pulmonary fibrosis mice paragonimus cyst.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.Compared with sham operated rats,
#p < 0.05,
##p < 0.01; Compared with model group,
*p < 0.05,
*p < 0.01.
The impact (HE dyeing) that Fig. 3 Compound I changes bleomycin induced pulmonary fibrosis mice lung tissue disease Neo-Confucianism.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.
The impact (HE dyeing) that Fig. 4 Compound I is marked on bleomycin induced pulmonary fibrosis mice lung tissue inflammatory.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.Compared with sham operated rats,
#p < 0.05,
##p < 0.01; Compared with model group,
*p < 0.05,
*p < 0.01.
The impact (Masson dyeing) that Fig. 5 Compound I changes bleomycin induced pulmonary fibrosis mice lung tissue disease Neo-Confucianism.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.
Fig. 6 Compound I is on the impact (average optical Data-Statistics) of bleomycin induced pulmonary fibrosis mice collagen contents of lung tissues.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.Compared with sham operated rats,
#p < 0.05,
##p < 0.01; Compared with model group,
*p < 0.05,
*p < 0.01.
Fig. 7 Compound I is on the impact of bleomycin induced pulmonary fibrosis mice lung tissue hydroxyproline content.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.Compared with sham operated rats,
#p < 0.05,
##p < 0.01; Compared with model group,
*p < 0.05,
*p < 0.01.
Fig. 8 Compound I is on the impact (ELISA) of bleomycin induced pulmonary fibrosis mice lung tissue TGF β 1 content.Wherein, A: prevention group, B: treatment group; 1-sham operated rats, 2-model group, 3-Compound I low dosage (30mg/kg) group, 4-Compound I high dose (60mg/kg) group, 5-pirfenidone (300mg/kg) group.Compared with sham operated rats,
#p < 0.05,
##p < 0.01; Compared with model group,
*p < 0.05,
*p < 0.01.
Detailed description of the invention
The alkaloidal preparation of embodiment 1 and Structural Identification
1. medical material and reagent
Medical material is the dry root of Radix Stemonae (Stemona sessilifolia (Miq.) Miq.), is purchased from medical material market, Hui nationality.The reagent such as ethanol, dichloromethane, methanol are analytical pure.
2. extraction and isolation
Radix Stemonae medical material 95% alcohol reflux 3 times, is evaporated to without alcohol taste, adds 5% dilute hydrochloric acid and is acidified to pH1-2, filters, and filtrate is with strong aqua ammonia alkalization to pH10, and chloroform extraction, reclaims chloroform and obtain total alkaloids position.Total alkaloids is through silica gel column chromatography, methylene chloride-methanol gradient (100: 0 ~ 100: 5) eluting, identical flow point is merged according to TLC result, again through silica gel column chromatography repeatedly, Sephadex LH-20 pillar layer separation, be separated from methylene chloride-methanol (100: 2) elution fraction and obtain Compound II per (Isoprotostemonine) and Compound I (Protostemonine, protostermonine); Be separated from methylene chloride-methanol (100: 3) elution fraction and obtain compound IV (Stemoamide); Be separated from methylene chloride-methanol (100: 4) elution fraction and obtain compound III (Neostemonine); Above four compounds are analyzed through HPLC, purity more than 98%.
3. Structural Identification
Compound I (Protostemonine, protostermonine): white crystals (chloroform), bismuth potassium iodide reaction is positive, ESI-MS (m/z:418 [M+H]
+).
1H?NMR(CDCl
3，300MHz)δ：1.92，1.55(2H，m，H-1)，1.89，1.48(2H，m，H-2)，3.27(1H，m，H-3)，3.48，2.92(2H，dd，J＝4.0，15.5Hz；dd，J＝7.1，15.2Hz，H-5)，1.50，1.65(2H，m，H-6)，2.32，1.50(2H，m，H-7)，4.08(1H，ddd，J＝10.4，3.4，14.3Hz，H-8)，2.19(1H，ddd，J＝10.4，4.1，9.5Hz，H-9)，3.73(1H，m，H-9a)，2.89(1H，m，H-10)，2.04(3H，s，H-16)，1.41(3H，d，J＝6.6Hz，H-17)，4.15(1H，ddd，J＝11.1，5.5，5.4Hz，H-18)，2.35，1.52(2H，m，H-19)，2.60(1H，m，H-20)，1.23(3H，d，J＝7.0Hz，H-22)，4.12(3H，s，H-23)。
13C?NMR(CDCl
3，75MHz)δ：26.8(C-1)，27.6(C-2)，64.1(C-3)，46.4(C-5)，20.2(C-6)，34.2(C-7)，84.3(C-8)，56.0(C-9)，58.5(C-9α)，39.5(C-10)，149.2(C-11)，124.4(C-12)，163.2(C-13)，97.4(C-14)，170.1(C-15)，20.8(C-16)，9.2(C-17)，83.4(C-18)，33.8(C-19)，34.9(C-20)，179.4(C-21)，14.9(C-22)，58.8(C-23)。
Compound II per (Isoprotostemonine): pale yellow crystals (methanol), bismuth potassium iodide reaction is positive, EI-MS (m/z:418 [M+H]
+).
1H?NMR(CDCl
3，300MHz)δ：1.89，1.55(2H，m，H-1)，1.87，1.48(2H，m，H-2)，3.24(1H，ddd，J＝7.3，7.5，11.5Hz，H-3)，3.50，2.89(2H，dd，J＝14.8，4.8Hz；dd，J＝11.2，14.8Hz，H-5)，1.50，1.65(2H，m，H-6)，2.32，1.50(2H，m，H-7)，4.18(1H，m，H-8)，2.12(1H，ddd，J＝10.4，10.3，5.3Hz，H-9)，3.69(1H，ddd，J＝5.6，10.7，10.6Hz，H-9a)，3.01(1H，dq，J＝6.7，10.5，H-10)，2.01(3H，s，H-16)，1.32(3H，d，J＝6.7Hz，H-17)，4.14(1H，m，H-18)，2.36，1.52(2H，m，19)，2.58(1H，m，H-20)，1.24(3H，d，J＝6.9Hz，H-22)，4.10(3H，s，H-23)。
13C?NMR(CDCl
3，75MHz)δ：26.5(C-1)，27.2(C-2)，64.4(C-3)，46.6(C-5)，20.2(C-6)，34.3(C-7)，82.5(C-8)，54.2(C-9)，58.4(C-9α)，41.7(C-10)，150.8(C-11)，125.7(C-12)，163.8(C-13)，98.3(C-14)，168.5(C-15)，18.1(C-16)，8.5(C-17)，83.3(C-18)，34.3(C-19)，34.8(C-20)，179.2(C-21)，14.9(C-22)，59.5(C-23)。
Compound III (Neostemonine): colorless needles (methanol), the reaction of improvement bismuth potassium iodide is positive, FAB-MS (m/z:320 [M+H]
+).
1H?NMR(CDCl
3，300MHz)δ：2.24，1.85(2H，m，H-1)，2.25，2.05(2H，m，H-2)，3.67，3.10(2H，m；ddd，J＝15.8，3.0，6.4Hz，H-3)，3.35(2H，m，H-5)，2.14，1.85(2H，m，H-6)，1.62，2.57(2H，m，H-7)，4.18(1H，ddd，J＝10.8，10.7，3.7Hz，H-8)，2.22(1H，m，H-9)，4.27(1H，m，H-9a)，2.91(1H，s，H-10)，2.05(3H，s，H-16)，1.40(3H，d，J＝6.8Hz，H-17)，4.10(3H，s，H-18)。
13C?NMR(CDCl
3，75MHz)δ：23.4(C-1)，26.8(C-2)，52.4(C-3)，49.8(C-5)，17.5(C-6)，32.6(C-7)，81.6(C-8)，52.1(C-9)，60.5(C-9α)，40.1(C-10)，146.9(C-11)，125.1(C-12)，163.0(C-13)，97.4(C-14)，170.0(C-15)，19.8(C-16)，9.1(C-17)，60.5(C-18)。
Compound IV (Stemoamide): white powder (methanol), bismuth potassium iodide reaction is positive, EI-MS (m/z:224 [M+H]
+).
1H?NMR(CDCl
3，300MHz)δ：1.93，1.61(2H，m，H-1)，2.32(2H，m，H-2)，2.55(1H，ddd，J＝14.2，12.5，1.5Hz，H-5α)，4.01(1H，ddd，J＝14.2，4.7，2.1Hz，H-5β)，1.75，1.41(2H，m，H-6)，1.62(2H，m，H-7)，4.09(1H，ddd，J＝2.9，10.2，11.1Hz，H-8)，2.29(1H，ddd，J＝11.1，12.4，6.4Hz，H-9)，3.88(1H，ddd，J＝6.4，11.1，6.3Hz，H-9a)，2.48(1H，dq，J＝12.4，6.7Hz，H-10)，1.18(3H，d，J＝6.7Hz，H-12)。
13C?NMR(CDCl
3，75MHz)δ：30.4(C-1)，34.8(C-2)，173.8(C-3)，40.0(C-5)，22.3(C-6)，25.5(C-7)，77.5(C-8)，52.5(C-9)，55.8(C-9α)，37.1(C-10)，177.2(C-11)，13.9(C-12)。
The preparation of embodiment 2 pulmonary fibrosis animal model
1. main agents and laboratory animal
Test bleomycin used purchased from Nippon Kayaku K. K, lot number 730342.
Test SPF level C57BL/6 mice (female, 8 week age) used, purchased from Yangzhou University's comparative medicine center.
2. model preparation
The mouse pulmonary fibrosis of bleomycin induced is the animal model of internationally recognized screening anti-fibrosis drug.Cause acute lung injury after bleomycin modeling, initial stage main manifestations is inflammation, within about 10 days, starts to occur fibrosis, and a large amount of collagen is concentrated and appeared at pulmonary, and these pathological changes are very similar to the pathological change of clinical middle idiopathic pulmonary fibrosis.Although the pathogenic factor of idiopathic pulmonary fibrosis and mechanism and unclear, but the pulmonary fibrosis of bleomycin induction and idiopathic pulmonary fibrosis are damaged lung tissue wound causes immunity and inflammatory reaction, then cause fibrosis pathological change, the pulmonary fibrosis model of therefore bleomycin induction can represent idiopathic pulmonary fibrosis and the similar pulmonary fibrosis disease of a series of pathological change caused by different paathogenic factor.
Pulmonary fibrosis model preparation method: female C57BL/6 mice (8 week age), starts modeling after conforming 7 days.Mice fasting overnight, 3% chloral hydrate (10ml/kg, i.p.) anaesthetize, fixing mice, sterilization mice cervical region, longitudinally skin of neck is cut with as far as possible little wound, longitudinally fascia and muscle is separated with tweezers, expose trachea, thrust trachea with microsyringe and inject about 35 μ l (3.5mg/kg) bleomycin, then rapidly upright and rotate mice 3 ~ 5 minutes, to make bleomycin enter the left and right lobe of the lung equably, observe mouse breathing situation, with 75% alcohol swab sterilization cervical region wound, sew up, drip 1-2 at suture and drip penicillin injection liquid, the mouse cage putting back to dried and clean is had a rest, normally raise after reviving.Operation technique carries out at the operating-table of about about 60 DEG C.The injection normal saline of sham operated rats intratracheal injection equivalent.
The qualification of embodiment 3 four alkaloids and carbetapentane citrate anti-mouse pulmonary fibrosis activity
The present embodiment is intended to the research alkaloid got in embodiment 1 being carried out to anti-mouse pulmonary fibrosis activity, to identify whether it has the effect of pulmonary fibrosis resistant.Due to the cough-relieving effective ingredient that these alkaloids are all the Chinese medicine Radixs Stemonae, whether can pulmonary fibrosis resistant in order to understand antitussive, the present embodiment selects clinical conventional antitussive---carbetapentane citrate (pentoxyverine, pentoxyverine citrate sheet, positive control drug conventional in cough-relieving pharmacological evaluation) synchronously carry out pulmonary fibrosis resistant screening active ingredients.
1. main agents and laboratory animal
Compound I ~ IV according to embodiment 1 point, purity > 98%.Carbetapentane citrate purchased from Sinopharm Group Rongsheng Pharmaceutical Co., Ltd., lot number 13110221.Test bleomycin used purchased from Nippon Kayaku K. K, lot number 730342.It is biological that pirfenidone (prifenidone, positive drug) is purchased from the U.S. logical sequence in Dalian, purity > 99%.Pirfenidone is the treatment pulmonary fibrosis new drug of Marnac company of U.S. exploitation, and gives Japanese Yan Yeyi company by the development rights mandate of Japan, Taiwan, Korea S, and on October 17th, 2008, the said firm took the lead in going on the market in Japan.
Experiment SPF level C57BL/6 mice (female, 8 week age), purchased from Yangzhou University's comparative medicine center.
2. experimental technique
Experiment mice is divided into 8 groups at random, and model group and each 10 of carbetapentane citrate group, all the other respectively organize equal 5.1st group is sham operated rats, and the 2nd group is model group, and the 3rd group is carbetapentane citrate group, and the 4th group is positive drug pirfenidone group, and 5th ~ 8 groups are respectively Compound I ~ IV administration group.2nd ~ 8 groups with bleomycin modeling, method is with embodiment 2.The 1st day after modeling starts, 3rd group every day gavage give the carbetapentane citrate of 30mg/kg, the 4th group every day gavage give the pirfenidone of 300mg/kg, 5th ~ 8 groups of every days, gavage gave the Compound I ~ IV of 30mg/kg respectively, sham operated rats and model group give same dose solvent, terminate to the 21st day.Put to death mice after last administration, take out lung tissue, right lobule is for measuring the content of hydroxyproline, and left lobule is for making pathological section.
3. experimental result
From Fig. 1-A, with sham operated rats ratio, the hydroxyproline content significance in model group mouse lung tissue increases, and collagen protein showed increased in model group mouse lung tissue is described, fibrosis lesion is serious; All significantly can reduce the hydroxyproline content that mice modeling causes after the administration of 4 Azaazulene type alkaloid monomers to increase, wherein the effect of Compound I, II is better than positive control pirfenidone, and effect and the pirfenidone of compound III, IV are suitable; But after carbetapentane citrate administration, Hyp content and model group are without significant difference, but significantly raise compared with sham operated rats.From Fig. 1-B, 1-C, modeling is after 21 days, and sham operated rats mouse lung leaflet structure is normal, and alveolar wall is complete, has no inflammation and fibrosis pathological change; There is obvious inflammation damnification and organize agglomerate in model group mice lungs, normal lung tissue disappears, and alveolar is inaccessible, has obvious collagen deposition; The mouse lung inflammation that bleomycin causes all significantly can be alleviated after the administration of 4 Azaazulene type alkaloids, obviously improve injury of lung degree, Compound I, II, III can Restoration model mouse lung normal configuration substantially, and wherein the effect of Compound I is especially obvious, several and suitable with blank group; And carbetapentane citrate can not improve lung injury and the fibrosis of model mice, its tissue slice is similar to model group, and inflammation damnification is serious, and alveolar is inaccessible, and collagen deposition is obvious.This experimental result describes the alkaloid with structural formula I parent nucleus and has the effect significantly suppressing and improve the pulmonary fibrosis of bleomycin model mice, and antitussive can not improve the pulmonary fibrosis of model mice.
The effect of embodiment 4 Compound I prevention and therapy pulmonary fibrosis
1. experiment material and method
(1) main agents and laboratory animal
Compound I according to embodiment 1 point, purity > 98%.It is biological that pirfenidone (prifenidone, positive drug) is purchased from the U.S. logical sequence in Dalian, purity > 99%.Pirfenidone is the treatment pulmonary fibrosis new drug of Marnac company of U.S. exploitation, and gives Japanese Yan Yeyi company by the development rights mandate of Japan, Taiwan, Korea S, and on October 17th, 2008, the said firm took the lead in going on the market in Japan.
Laboratory animal is the model mice prepared by embodiment 2, and modeling same day is 0 day.
(2) experimental technique
By animal pattern according to preventing, treating administration of dividing into groups respectively.According to the international medication of this model, prevention administration, terminated by the 14th day, continuous gastric infusion the 2nd day from modeling; Therapeutic administratp, from after modeling the 8th day, terminated by the 21st day, continuous gastric infusion.Grouping and administrations as shown in table 1.
Grouping and dosage regimen after the modeling of table 1. pulmonary fibrosis mice
2. the mensuration of mouse death rate
Prevention administration from modeling same day that is the 0th day by the 14th day, therapeutic administratp from modeling the 8th day by the 21st day, each treated animal death condition of statistics prevention administration every day, and calculate the survival rate of each treated animal, the results are shown in Table 2.
From table 2, compared with sham operated rats, the bleomycin modeling mice mortality rate of 14 days is the mortality rate of 20%, 21 days is 33%.Compared with model group; Compound I has significant protective effect to model mice; low dose group (30mg/kg) prevention and therapy administration mouse death rate is respectively 0% and 17%, and high dose group (60mg/kg) prevention and therapy administration mouse death rate is respectively 20% and 17%.This experimental result also shows, and no matter prevents administration or therapeutic administratp, and the protective effect of low dose group to model mice is slightly better than low dose group.In general, the effect of Compound I reduction mouse death rate is obviously better than positive control pirfenidone.
Dead mouse situation is respectively organized in the administration of table 2. prevention and therapy
3. the detection of mouse lung coefficient
Put to death mice after last administration, peel off mice lungs and take weight in wet base, lung heavy (mg) is obtained paragonimus cyst (Fig. 2) divided by Mouse Weight (g).
As seen from Figure 2, compared with sham operated rats, the paragonimus cyst of model group all significantly raises.No matter prevent administration or therapeutic administratp, 2 dosage groups of Compound I (30,60mg/kg) all significantly can reduce the paragonimus cyst of model mice, and wherein the effect of low dose group is better than high dose group.All in all, the effect of Compound I reduction model mice paragonimus cyst is slightly better than positive control pirfenidone.
4.HE dyeing pathological evaluation and inflammatory are marked
After last administration, mice is put to death in anesthesia, takes out mouse lung tissue, and left lobule lung immerses the fixing rear paraffin embedding of 10% formalin, and section, its pathological change is observed in HE dyeing.As seen from Figure 3, sham operated rats mouse lung leaflet structure is normal, and alveolar wall is complete, has no obvious inflammation and fibrosis pathological change.There is obvious inflammation damnification and organize agglomerate in model group mice lungs, normal lung tissue disappears, and alveolar is inaccessible.No matter be prevention administration or therapeutic administratp, Compound I all significantly can alleviate the pneumonia that bleomycin causes, and improves injury of lung, recover pulmonary's normal configuration, wherein the effect of low dose group (30mg/kg) is slightly better than high dose, and pneumonia disappears substantially, and alveolar structure is clear.
To the classification of HE coloration result inflammatory, carry out sxemiquantitative statistical analysis.0 grade: normal structure or minimum inflammation change; 1 grade (+): slight to the change of medium inflammation, does not have obvious lung tissue to destroy; 2 grades (++): in the inflammation damnification of by the time severe, alveolar membranes thickens, formative tissue agglomerate, or pneumonitis district causes lung tissue structure to destroy; 3 grades (+++): serious inflammation damnification, the heavy damage of regional area lung tissue structure causes obliteration etc.The inflammatory appraisal result that prevention administration and therapeutic administratp are respectively organized is shown in Fig. 4.Compared with sham operated rats, there is remarkable inflammation in bleomycin modeling mouse lung; 2 dosage groups of Compound I (30,60mg/kg) all can reduce the pneumonia that bleomycin causes significantly, and the effect of low dosage is slightly better than high dose; Generally speaking, positive control pirfenidone is slightly better than.
5.Masson dyeing pathological evaluation and imaging Analysis
Masson dyeing is the method for carrying out specific stain for fibrillar collagen.After last administration, mice is put to death in anesthesia, take out mouse lung tissue, left lobule lung immerses the fixing rear paraffin embedding of 10% formalin, section, Collagen fiber deposition situation is observed in Masson dyeing, and the Masson coloration result that prevention administration and therapeutic administratp are respectively organized is shown in Fig. 5 respectively.Image-Pro Plus6.0 is used to carry out semi-quantitative analysis, measure the integral optical density value (IOD) of the rear collagen of each visual field Masson dyeing, every group analysis 5 specimen, each specimen gets 5 visuals field at random, gets average and carries out statistical analysis as the relative amount often organizing collagen.The analysis result that prevention and therapy administration is respectively organized is shown in Fig. 6 respectively.
From Fig. 5 and Fig. 6, sham operated rats mouse lung has no obvious Masson collagen deposition; Give bleomycin after 14 days and 21 days mice lungs there is obvious collagen deposition, a large amount of fibrosed tissue is formed, even more serious compared with 14 days of 21 days.2 dosage groups of Compound I (30,60mg/kg) all significantly can alleviate the collagen deposition that bleomycin causes, and it is extremely obvious that pulmonary fibrosis improves effect.Wherein, prevention administration low dose group effect is better than high dose group, and therapeutic administratp high dose group effect is slightly better than low dose group.In general, the effect that Compound I improves model mice collagen deposition is all better than positive control pirfenidone.
6. hydroxyproline content measures
Hydroxyproline is mainly present in collagen protein, and in elastin laminin, content is few, does not exist in other albumen, and the content therefore by measuring hydroxyproline can show the height of collagen content, thus evaluates the degree of pulmonary fibrosis.The mensuration of hydroxyproline adopts test kit (biotech company is built up in Nanjing) method, carries out, the results are shown in Figure 7 according to test kit description.
As seen from Figure 7, compared with sham operated rats, the hydroxyproline content significance in model group mouse lung tissue increases, and illustrates that model group mouse lung tissue fibrosis lesion is serious.No matter be prevention administration or therapeutic administratp, the high and low dose group of Compound I (30,60mg/kg) all can reduce the content of model mice hydroxyproline effectively, illustrates that Compound I significantly can improve the mouse pulmonary fibrosis of bleomycin modeling induction.
The Elisa assay of 7.TGF-β 1
TGF-β 1 is generally acknowledged powerful fibrogenic factor, can synthesize and extracellular matrix secretion component by irritation cell, also can change the activity of substrate degradation enzyme component, directly aggravate the deposition of ECM.Reduce TGF-β 1 content in lung tissue and can slow down pulmonary fibrosis process.Adopt Elisa test kit (Shanghai Excell Biology Product Co., Ltd.) to measure the content of TGF-β 1 in mouse lung tissue, carry out according to test kit description, the results are shown in Figure 8.
As seen from Figure 8, with sham operated rats ratio, TGF-β 1 content of bleomycin administration mouse lung tissue significantly increases.Compared with model group, no matter be prevention administration or therapeutic administratp, the high and low dose of Compound I (30,60mg/kg) all obviously can reduce the level of TGF-β 1, and significantly improve pulmonary fibrosis degree, wherein the effect of low dosage (30mg/kg) is more remarkable.
Discuss
Result of the present invention shows, has the compound of parent nucleus as shown in structural formula I, as 4 Azaazulene type alkaloids such as Compound I ~ IV, has the effect (embodiment 3) preventing and/or treating pulmonary fibrosis significantly.The activity research structure further illustrated as shown in structural formula I of Compound I has obvious pulmonary fibrosis resistant effect.The results of animal of multi objective shows, the effect that such Azaazulene type alkaloid improves pulmonary fibrosis is better than or is equivalent to recently at the positive control drug pirfenidone of Japan's listing, the pulmonary fibrosis mice that can reduce bleomycin induced is significantly dead, the paragonimus cyst of remarkable reduction model mice, improve the pulmonary fibrosis degree of model mice, the content of Hyp and short fibrosis factor TGF-β 1 in obvious reduction lung tissue, the mouse lung inflammation that the compound with structure shown in structural formula I can alleviate bleomycin modeling and causes is described, reduces pulmonary's collagen deposition.
Result of the present invention provides scientific basis preventing and/or treating the application in pulmonary fibrosis medicine compositions for the Azaazulene Alkaloid with structure as shown in structural formula I.
Claims (6)
1. compound is preparing the application prevented and/or treated in pulmonary fibrosis medicine compositions, and described compound has structural formula I
Wherein:
R
1be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
R
2be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
Or R
1, R
2as shown in the formula:
Wherein: X is selected from oxygen, sulfur;
R
3be selected from hydrogen, α or β alkyl, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl;
R
4be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
R
5be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
Or R
4, R
5as shown in the formula:
Wherein: Y is selected from oxygen, sulfur, or as shown in the formula:
Wherein: R
9be selected from methoxyl group, hydrogen;
R
6be selected from α or β hydrogen, α or β hydroxyl;
R
7be selected from α or β hydrogen, α or β hydroxyl;
R
8be selected from α or β hydrogen, α or β hydroxyl.
2., if compound a kind of in claim 1 is preparing the application prevented and/or treated in pulmonary fibrosis medicine compositions, it is characterized in that described compound has structural formula Ia.
Wherein:
R
1be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
R
2be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, the Alpha-Methyl-gamma-butyrolacton base of α or β;
Or R
1, R
2as shown in the formula:
Wherein: X is selected from oxygen, sulfur;
R
3be selected from hydrogen, α or β alkyl, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl;
R
4be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
R
5be selected from α or β hydrogen, α or β hydroxyl, α or β carboxyl, α or β halogeno-group, α or β alkoxyl, α or β alkyl, Alpha-Methyl-gamma-butyrolacton thiazolinyl;
Or R
4, R
5for as shown in the formula:
Wherein: Y is selected from oxygen, sulfur, or as shown in the formula:
Wherein: R
6be selected from methoxyl group, hydrogen.
3. apply as described in claim 1, it is characterized in that, described compound is the alkaloid shown in structural formula I or its medicinal derivative.
4. apply as described in claim 3, it is characterized in that, described compound medicinal derivative is alkaloidal salt or ester shown in structural formula I.
5. apply as described in claim 1, it is characterized in that, described pharmaceutical composition at least comprises the alkaloid of a kind of active component as shown in structural formula I and a kind of pharmaceutical carrier.
6. apply as described in claim 5, it is characterized in that, described pharmaceutical composition comprises the alkaloid as shown in structural formula I that mass percent is 0.01% ~ 99% and mass percent is the pharmaceutical carrier of 0.01% ~ 99%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030229071A1 (en) * | 2002-04-24 | 2003-12-11 | The Chinese University Of Hong Kong | Plant extracts and alkaloids having antitussive activity |
| CN1931171A (en) * | 2005-09-12 | 2007-03-21 | 香港赛马会中药研究院有限公司 | Method of making antitussive medicine and relieving cough |
| CN101088553A (en) * | 2006-06-13 | 2007-12-19 | 上海中医药大学 | Effective part of seesile stemona alkaloid and its application |
| CN102961656A (en) * | 2012-09-04 | 2013-03-13 | 浙江大学 | Chinese medicinal composition for treating pulmonary fibrosis and its application |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030229071A1 (en) * | 2002-04-24 | 2003-12-11 | The Chinese University Of Hong Kong | Plant extracts and alkaloids having antitussive activity |
| CN1931171A (en) * | 2005-09-12 | 2007-03-21 | 香港赛马会中药研究院有限公司 | Method of making antitussive medicine and relieving cough |
| CN101088553A (en) * | 2006-06-13 | 2007-12-19 | 上海中医药大学 | Effective part of seesile stemona alkaloid and its application |
| CN102961656A (en) * | 2012-09-04 | 2013-03-13 | 浙江大学 | Chinese medicinal composition for treating pulmonary fibrosis and its application |
Non-Patent Citations (1)
| Title |
|---|
| 张亚中等: "百部生物碱的研究现状和思考", 《中成药》 * |
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