CN106176720A - Meisoindigotin application in preparing anti-inflammatory drug - Google Patents
Meisoindigotin application in preparing anti-inflammatory drug Download PDFInfo
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- CN106176720A CN106176720A CN201610693002.2A CN201610693002A CN106176720A CN 106176720 A CN106176720 A CN 106176720A CN 201610693002 A CN201610693002 A CN 201610693002A CN 106176720 A CN106176720 A CN 106176720A
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- meisoindigotin
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- inflammatory drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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Abstract
The invention discloses Meisoindigotin application in preparing anti-inflammatory drug, belong to medical compounds and technical field of pharmaceuticals.The present invention utilize transgenic zebrafish model (Tg:zlyzEGFP) find that Meisoindigotin has good anti-inflammatory activity；And utilize Meisoindigotin to process human monocyte system THP 1 cell, find that Meisoindigotin can suppress mankind's inflammatory cell chemotactic migration；These results show that Meisoindigotin or the pharmaceutical composition containing Meisoindigotin can be used for preparing anti-inflammatory drug.Pharmaceutical composition containing Meisoindigotin comprises Meisoindigotin or Meisoindigotin pharmaceutically allows salt and the pharmaceutically acceptable carrier of Meisoindigotin.Present invention firstly discovers that Meisoindigotin demonstrates stronger anti-inflammatory activity in inflammatory model, can suppress mankind's inflammatory cell chemotactic migration, it can be used for preparing anti-inflammatory drug.The present invention is that new generation anti-inflammatory drug is laid a good foundation.
Description
Technical field
The invention belongs to medical compounds and technical field of pharmaceuticals, be specifically related to Meisoindigotin (Meisoindigo) in preparation
Application in anti-inflammatory drug.
Background technology
1976, Inst. of Hematology, Chinese Academy of Medical Sciences screened discovery from Chinese medicine compound " DANGGUI LUHUI WAN ", and one
It is treatment chronic myelocytic leukemia (Chronic myeloid that kind derives from the bis-indole compounds indirubin of Chinese medicine Indigo Naturalis
Leukemia, CML) effective ingredient (Qian Linsheng, Xue Yanping, Zhang little Mei, the Yang Tian principal columns of a hall, Yan Wenwei, Wang Zhi clear .1991. indirubin
Treat the observation of 57 example chronic myelocytic leukemia long-term efficacies. Chinese Journal of Hematology 12:125-127.), it can suppress many
The propagation of kind of tumor cell and promote its apoptotic process (Blazevic, T., E.H.Heiss, A.G.Atanasov,
J.M.Breuss,V.M.Dirsch,and P.Uhrin.2015.Indirubin and Indirubin Derivatives
for Counteracting Proliferative Diseases.Evid Based Complement Alternat Med
2015:654098.).Chemical constitution based on indirubin, China scientist is by-NH group (the 1st the atom N) first of indirubin
Base turns to-N-CH3(such as Fig. 1), and final synthesis of derivatives Meisoindigotin (Meisoindigo), and Meisoindigotin is carried out structure effect pass
System's research, it is determined that Meisoindigotin key pharmacophoric group and the potential probability of structure optimization(3).Further study showed that, Meisoindigotin
Biological activity and the water solublity of relatively indirubin are all greatly improved, and it also can promote apoptosis process (Liu Bing city, Xiao Zhi
Impact and the inducing cell Apoptosis mechanism of K562 cell bcr-abl signal path are studied by hard .2008. Meisoindigotin. China's blood
Liquid magazine 29:815-818.), become the safely and effectively medicine of clinical treatment chronic myelocytic leukemia.Clinical trial table
Bright, the remission effect at a specified future date of Meisoindigotin treatment CML is suitable with antitumor drug hydroxyurea, itself and the more single medicine of hydroxyurea therapeutic alliance
Application Meisoindigotin or hydroxyurea obtain more preferable therapeutic effect, and (Liu Bing city, Wang Yi, Hao Changlai, Liu Yinghui, Qian Linsheng .2001. is slow
The observation of property granulocyte leukemia late result. Chinese Journal of Hematology 22:61-63.).As can be seen here, Meisoindigotin is a kind of peace
The complete effective small-molecule drug treating chronic myelocytic leukemia, but currently to the other biological function of Meisoindigotin and answer
With knowing little about it, there is no the report in terms of Meisoindigotin antiinflammatory action and related mechanism.
Summary of the invention
It is an object of the invention to provide Meisoindigotin or the pharmaceutical composition containing Meisoindigotin in preparing anti-inflammatory drug
Application.
The purpose of the present invention is achieved through the following technical solutions:
The present invention utilizes transgenic zebrafish model (Tg:zlyz-EGFP) discovery Meisoindigotin to have good anti-inflammatory activity,
25-75 μM of concentration Meisoindigotin shows obvious anti-inflammatory activity.And utilize Meisoindigotin to process human monocyte system THP-1 cell
(mankind inflammatory cell system), find that Meisoindigotin can suppress mankind's inflammatory cell chemotactic migration.Based on this, Meisoindigotin is in inflammation disease
Sick treatment aspect has preferable application prospect, Meisoindigotin or the pharmaceutical composition containing Meisoindigotin and can be used for preparing anti-inflammatory agent
Thing.
The described pharmaceutical composition containing Meisoindigotin comprises Meisoindigotin or Meisoindigotin pharmaceutically allows salt and Meisoindigotin medicine
Acceptable carrier on.
The salt that described Meisoindigotin pharmaceutically allows, can enumerate such as Meisoindigotin and hydrochloric acid, nitric acid, sulphuric acid, phosphoric acid, hydrogen
The mineral acids such as bromic acid, or maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, oneself two
The organic acid such as acid, Palmic acid, tannic acid, or the alkali such as alkali metal, the alkaline-earth metal such as calcium, magnesium, or lysine such as lithium, sodium, potassium
The salt that acidic amino acid generates.
The pharmaceutically acceptable carrier of described Meisoindigotin is one or more solids, semisolid and liquid diluent, fills out
Material and pharmaceutical preparation adjuvant.
When Meisoindigotin is used as medicine, can directly use, or use with the form of the pharmaceutical composition containing Meisoindigotin.Should
Pharmaceutical composition contains 0.1-99%, the salt that the Meisoindigotin of preferably 0.5-90% or Meisoindigotin pharmaceutically allow, and remaining is medicine
Pharmaceutically suitable carrier acceptable, nontoxic and inert to humans and animals on.With Meisoindigotin or the pharmaceutical composition containing Meisoindigotin
Preparation the adoptable dosage form of anti-inflammatory drug be usual Galen form of administration, such as: ointment, tablet, pill, suppository Emulsion,
Input liquid and injection etc..These dosage forms, according to well-known method, use traditional additive and excipient to prepare.Thus
Prepare medicine as required can by local, non-bowel, be administered orally etc. administration.
The amount of application of Meisoindigotin or the pharmaceutical composition containing Meisoindigotin can be according to route of administration, the age of patient, body weight, institute
The change such as the type of the disease for the treatment of and the order of severity, Meisoindigotin daily dose can be 0.01-10mg/kg body weight, preferably 0.1-
5mg/kg body weight；Can use with one or many.
Advantages of the present invention and providing the benefit that: present invention firstly discovers that Meisoindigotin demonstrates in inflammatory model stronger
Anti-inflammatory activity, can suppress mankind's inflammatory cell chemotactic migration, and it is the potential antiinflammatory active compound of a novelty, can be used for
Prepare anti-inflammatory drug.The present invention is that new generation anti-inflammatory drug is laid a good foundation.
Accompanying drawing explanation
Fig. 1 is the chemical structural drawing of Meisoindigotin (Meisoindigo).
Fig. 2 is the fluorescence microscopy after transgenic zebrafish Tg:zlyz-EGFP embryo's afterbody inflammatory otch and drug incubation
Figure, M is Meisoindigotin abbreviation.
Fig. 3 is boxed area inflammatory cell number cartogram in Fig. 2, and M is Meisoindigotin abbreviation.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this,
The change made under other any spirit without departing from the present invention and principle, modify, substitute, combine, simplify, all should be
The substitute mode of equivalence, within being included in protection scope of the present invention.
Anti-inflammatory activity test example:
Study display before this, transgenic zebrafish system Tg:zlyz-EGFP period of embryo's inflammatory cell (neutrophilic granulocyte and huge
Phagocyte etc.) can specific expressed GFP albumen, utilize the fluorescence microscope can be with viviperception embryo's inflammatory cell biological behaviour
(ZhangY,Bai XT,Zhu KY,Jin Y,Deng M,Le HY,Fu YF,Chen Y,Zhu J,Look AT,Kanki J,
Chen Z,Chen SJ,Liu TX(2008)In vivo interstitial migration of primitive
macrophages mediated by JNK-matrix metalloproteinase 13signaling in response
to acute injury.J Immunol 181:2155-2164).One is manufactured in this zebrafish embryo afterbody sterile razor blade
Inflammatory otch, by the inflammatory reaction of induction zebrafish embryo incision, inflammatory cell will migrate to incision, by statistics zebra
Fish Inflammatory cell emigration is to the number of incision, quantitative assessment inflammatory reaction degree.
Concrete experimental technique is: collects transgenic zebrafish Tg:zlyz-EGFP and grows the embryo that phase is 3 days, by nothing
Bacterium blade manufactures an inflammatory otch in embryo's afterbody, then by the zebrafish embryo after back-end crop and 25,50,75 μMs of Meisoindigotins or
(Vehicle, for zebrafish embryo culture medium (the 60 μ g/mL " Instant containing 0.5%DMSO for blank" sea
Salt)) hatch 6h, finally to take pictures and the inflammatory cell number in height inflammatory area is added up, result is shown in Fig. 2 and Fig. 3.Figure
2 display drug treating after 6 hours, the state of Inflammatory cell emigration to incision；Fig. 3 is each group of embryo's tail height inflammatory district
Territory (i.e. Fig. 2 boxed area) inflammatory cell number cartogram.Fig. 2 result shows, 25,50,75 μMs of Meisoindigotin concentration process zebra
Fish embryo, the number of the inflammatory cell migrating to height inflammatory area gradually decreases along with increasing of drug level；Fig. 3 shows
Meisoindigotin has dose dependent to the inhibitory action of inflammatory cell migration, and has significant difference.As can be seen here, Meisoindigotin energy
The effective inflammatory reaction suppressing Brachydanio rerio, has anti-inflammatory activity, possesses the Potential feasibility preparing anti-inflammatory drug.
Utilize Meisoindigotin to process human monocyte system THP-1 cell (mankind inflammatory cell system), find that Meisoindigotin is to becoming
The THP1 cell chemotaxis changing the induction of factor M CP-1 migrates the inhibitory action with significance, shows that Meisoindigotin can suppress the mankind
Inflammatory cell chemotactic migration, consistent with the result in zebrafish embryo, prompting Meisoindigotin has potential antiinflammatory action, available
In preparing anti-inflammatory drug.
Example of formulations 1:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, inject with water routinely, fine straining, injection is made in embedding sterilizing.
Example of formulations 2:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, it is dissolved in sterile water for injection, stirring makes molten, with the filtration of aseptic suction funnel, more aseptic fine straining,
Being sub-packed in 2 ampoules, after frozen drying, aseptic sealing by fusing obtains injectable powder.
Example of formulations 3:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, add excipient with excipient weight than the ratio for 9:1 in it, make powder.
Example of formulations 4:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, add excipient, pelletizing press sheet with excipient weight than the ratio for 1:5-1:10 in it.
Example of formulations 5:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, oral liquid preparation method makes oral liquid routinely.
Example of formulations 6:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, add excipient with excipient weight than the ratio for 5:1 in it, make capsule or granule or electuary.
Example of formulations 7:
Meisoindigotin is utilized organic acid (tartaric acid, citric acid, formic acid, ethanedioic acid etc.) or mineral acid (hydrochloric acid, sulphuric acid, phosphorus
Acid etc.) salt made, add excipient with excipient weight than the ratio for 3:1 in it, make capsule or granule or electuary.
Claims (5)
1. Meisoindigotin application in preparing anti-inflammatory drug.
2. the application in preparing anti-inflammatory drug of the pharmaceutical composition containing Meisoindigotin.
Application the most according to claim 2, it is characterised in that: described compositions comprises Meisoindigotin and Meisoindigotin pharmaceutically
Acceptable carrier.
Application the most according to claim 2, it is characterised in that: described compositions comprises the salt that Meisoindigotin pharmaceutically allows
Carrier pharmaceutically acceptable with Meisoindigotin.
Application the most according to claim 4, it is characterised in that: the salt that described Meisoindigotin pharmaceutically allows comprises Meisoindigotin
The salt generated with mineral acid, Organic Acid and Base metal, alkaline-earth metal or basic amino acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610693002.2A CN106176720A (en) | 2016-08-17 | 2016-08-17 | Meisoindigotin application in preparing anti-inflammatory drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610693002.2A CN106176720A (en) | 2016-08-17 | 2016-08-17 | Meisoindigotin application in preparing anti-inflammatory drug |
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| Publication Number | Publication Date |
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| CN106176720A true CN106176720A (en) | 2016-12-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610693002.2A Pending CN106176720A (en) | 2016-08-17 | 2016-08-17 | Meisoindigotin application in preparing anti-inflammatory drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113069448A (en) * | 2021-05-18 | 2021-07-06 | 南京大学 | Application of methylisoindigo in preparation of medicine for treating acute lung injury |
| CN113365990A (en) * | 2018-12-07 | 2021-09-07 | 纳特罗根治疗国际有限公司 | Polymorphs of methylisoindin and improved formulations of methylisoindin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120058121A1 (en) * | 2004-01-12 | 2012-03-08 | Natrogen Therapeutics International, Inc. | Methods and compositions for treating lupus |
| US8563525B2 (en) * | 2004-01-12 | 2013-10-22 | Natrogen Therapeutics International, Inc. | Methods of treating an inflammatory-related disease |
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2016
- 2016-08-17 CN CN201610693002.2A patent/CN106176720A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120058121A1 (en) * | 2004-01-12 | 2012-03-08 | Natrogen Therapeutics International, Inc. | Methods and compositions for treating lupus |
| US8563525B2 (en) * | 2004-01-12 | 2013-10-22 | Natrogen Therapeutics International, Inc. | Methods of treating an inflammatory-related disease |
Non-Patent Citations (3)
| Title |
|---|
| J.W. CHIAO,ET AL.: "Interaction of a small molecule Natura-a and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis", 《BIOCHEMICAL PHARMACOLOGY》 * |
| SIMON GLATIGNY,ET AL.: "Treatment of collagen-induced arthritis by Natura-α via regulation of Th-1/Th-17 responses", 《EUR. J. IMMUNOL.》 * |
| 张海婧等: "甲异靛通过TLR4-TAK-NF-κB途径治疗银屑病的机制研究", 《药学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113365990A (en) * | 2018-12-07 | 2021-09-07 | 纳特罗根治疗国际有限公司 | Polymorphs of methylisoindin and improved formulations of methylisoindin |
| CN113069448A (en) * | 2021-05-18 | 2021-07-06 | 南京大学 | Application of methylisoindigo in preparation of medicine for treating acute lung injury |
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Application publication date: 20161207 |