CN106943401A - Application of the Haouamine classes compound in preventing and treating medicine for treating rheumatoid arthritis is prepared - Google Patents
Application of the Haouamine classes compound in preventing and treating medicine for treating rheumatoid arthritis is prepared Download PDFInfo
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- CN106943401A CN106943401A CN201710116156.XA CN201710116156A CN106943401A CN 106943401 A CN106943401 A CN 106943401A CN 201710116156 A CN201710116156 A CN 201710116156A CN 106943401 A CN106943401 A CN 106943401A
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- haouamine
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- rheumatoid arthritis
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
The invention discloses application of the Haouamine classes compound in preventing and treating medicine for treating rheumatoid arthritis is prepared.Haouamine classes compound for the scorching rat toes swelling of Freund's complete adjuvant cause there is obvious functions of detumescence, relieving inflammation to act on, there is obvious inhibitory action for collagen-induced rheumatoid arthritis, and effect is better than diclofenac sodium, therefore it can be used for preventing and treating rheumatoid arthritis.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to Haouamine classes compound is preparing preventing and treating rheumatoid arthrosis
Application in scorching medicine.
Background technology
Rheumatoid arthritis (Rheumatoid Arthritis, RA) be a kind of cause of disease it is unknown it is chronic, slided with inflammatory
Systemic disease based on film inflammation.It is characterized in that hand, the multi-joint of sufficient Minor articulus, symmetry, aggressive arthritis, frequent companion
There is organ outside joint to be involved the serum rheumatoid factor (SRF) positive, joint deformity and function can be caused to lose, belong to autoimmunity
Inflammatory disease.There are joint red and swollen heat pain and dysfunction performance ill early stage, and when reaching late period, joint may occur in which different degrees of
Stiff deformity, and with the atrophy of bone and skeletal muscle, easily disable.From the perspective of pathological change, rheumatoid arthritis
It is that one kind mainly involves synovium of joint (can feed through to articular cartilage, bone tissue, articular ligament and tendon forceps later), is secondly slurry
The popularity diseases associated with inflammation of the connective tissues such as film, the heart, lung and eye.The systemic manifestation of rheumatoid arthritis removes arthropathy
Outside, also heating, fatigue and weak, pericarditis, subcutaneous nodule, pleurisy, arteritis, peripheral neuropathy etc..
At present, the treatment method of rheumatoid arthritis mainly carries out anti-inflammatory and immune using hormone and antimetabolite
Treatment, but the adverse reaction of existing treatment method is larger and is difficult to effect a radical cure.Therefore, finding effectively has immunoregulation effect
And the medicine of Small side effects, the treatment for rheumatoid arthritis is significant.
Haouamine classes compound includes Haouamine A and Haouamine B, and it is Zub í a in 2002 etc. from western class
The secondary metabolite for the Aplidium haouarianum ascidians biology Haouarianum that the affiliated Ruo Er islands of tooth are collected is favorite
Outer discovery.Ascidian biology belongs to Chordata, and Urochordata is distributed widely in each Large Marine Ecosystem in the world, species
It is various.Contain many important physiological activators in ascidian, be the important sources of low toxicity, high potency drugs.
Compared to the ascidian natural products found in the past, Haouamine class compounds have entirely different chemical skeleton.
It contains a very rare 3- nitrogen -7- paracyclophane, an indeno tetrahydropyridine structure and three chiral centres, wherein indenes
And containing double bond regular an anti-Bredt, they collectively form 11 Yuans paracyclophane bones of great tension force in tetrahydro pyridine ring
Frame.Confirm that its high tension comes from an on-plane surface by analysis means such as molecular model, X- single crystal diffractions and calculating chemistry
And the B rings existed with boat conformation.
Haouamine A：R=H
Haouamine B：R=OH
According to the literature, Haouamine A and Haouamine B have good anti-tumor biological (Garrido
L,Zubía E,Ortega M J, et al.Haouamines A and B:A new class of alkaloids from
the ascidian Aplidium haouarianum.J Org Chem,2003,68(2):293-299), it is significant
The important sources of high-efficiency low-toxicity medicine.However, applicant is had found by studying, Haouamine A and Haouamine B also have
The effect of good preventing and treating rheumatoid arthritis, available for the medicine for preparing preventing and treating rheumatoid arthritis.
The content of the invention
It is an object of the invention to provide a kind of Haouamine classes compound answering in terms of rheumatoid arthritis is prevented and treated
With the Haouamine classes compound includes Haouamine A and Haouamine B, and its structure is as follows：
Haouamine A：R=H
Haouamine B：R=OH
Another object of the present invention is to provide the Haouamine classes compound to prepare the medicine of preventing and treating rheumatoid arthritis
Application in thing.
Another object of the present invention is to provide a kind of pharmaceutical composition for being used to prevent and treat rheumatoid arthritis, and it is comprising described
Haouamine class compounds, and pharmaceutically acceptable assistant agent.
As above-mentioned assistant agent, including filler, disintegrant, adhesive, emulsifying agent, lubricant, glidant, flavouring, rectify
One of olfactory agent, colouring agent are planted or several.
The filler may be selected from the one or more of combination of following material：Starch, amylum pregelatinisatum, dextrin, sucrose, breast
Sugar, fructose, glucose, xylitol, mannitol, microcrystalline cellulose, calcium carbonate, magnesium carbonate, calcium phosphate, calcium monohydrogen phosphate, calcium sulfate,
Magnesia, aluminium hydroxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose.It is preferred that glycitols, amylum pregelatinisatum, calcium phosphate, phosphorus
Sour hydrogen calcium, calcium sulfate, microcrystalline cellulose.
The disintegrant may be selected from the one or more of combination of following material：Starch, sodium carboxymethyl starch, hydroxypropyl form sediment
Powder, Ac-Di-Sol, PVPP, low substituted hydroxy-propyl methylcellulose, and effervesce disintegration
Agent and surfactant.
Described adhesive may be selected from the one or more of combination of following material：Hydroxypropyl methyl cellulose, polyvinyl pyrrole
Alkanone, starch slurry, dextrin, glucose and its syrup, sucrose and its syrup, lactose and its syrup, fructose and its syrup, sorb
Alcohol, gelatin rubber cement, mucialga of arabic gummy, bassora gum slurry, microcrystalline cellulose, methylcellulose, sodium carboxymethylcellulose, ethyl cellulose
It is element, hydroxypropyl cellulose, hydroxyethyl cellulose, calcium carboxymethylcellulose, polymethacrylates, alginic acid, sodium alginate, poly-
Ethylene glycol, veegum.
The emulsifying agent may be selected from the one or more of combination of following material：Poloxamer, lauryl sodium sulfate, 16
Sodium alkyl sulfate, sodium stearyl sulfate, fatty acid sorbitan, poly yamanashi esters, Emulsifier EL-60 class, caprylic capric gather
Glycol glycerin ester, Gelucire 44/14, stearic acid LABRAFIL M 1944CS.
The lubricant may be selected from the one or more of combination of following material：It is stearic acid, calcium stearate, magnesium stearate, hard
Resin acid zinc, talcum powder, glycerin monostearate, glyceryl palmitostearate, Stepanol MG, polyethylene glycol, stearyl
Fumaric acid sodium.
The glidant may be selected from the one or more of combination of following material：Cataloid, powdered cellulose, three silicon
Sour magnesium, talcum powder.
Using conventional preparation technique, pharmaceutical composition of the present invention is regard as tablet, pill, capsule, particle
It is prepared by the oral or non-oral administration thing of agent, pulvis, liquor, emulsion, suspending agent, ointment, injection, skin patch etc..
In the pharmaceutical composition according to the present invention, the amount of Haouamine class compounds can account for composition total weight
0.01% to 50%, preferably 0.1% to 10%, more preferably 0.5% to 5%, most preferably 1% to 2%.
In yet other embodiments, described pharmaceutical composition is included based on composition total weight：
Haouamine classes compound 0.01% to 50%, filler 10% to 80%, disintegrant 10% to 50%, emulsifying agent 5% to
30%, lubricant and glidant 0.1% to 30%.
In yet other embodiments, described pharmaceutical composition is included：Haouamine classes compound, paste
Essence, Ac-Di-Sol, poloxamer, talcum powder.
In yet other embodiments, described pharmaceutical composition is included：Haouamine classes compound, breast
Sugar, sodium carboxymethyl starch, lauryl sodium sulfate, magnesium stearate, powdered cellulose.
For adult patient, Haouamine classes compound of the present invention be able to will be made in oral or parenteral mode
For the 0.001mg to 500mg of the administered dose of 1 day, 1 day 1 time or it is divided into for several times and gives.It should illustrate, the administered dose can basis
The species of the disease for the treatment of target, the age of patient, body weight, symptom etc. suitably increase and decrease.
According to presently disclosed, rat foots of Haouamine A and the Haouamine B for Freund's complete adjuvant cause inflammation
There is obvious functions of detumescence, relieving inflammation to act on for toe swelling, have obvious inhibitory action for collagen-induced rheumatoid arthritis,
And effect is better than diclofenac sodium, therefore it can be used for preventing and treating rheumatoid arthritis.
Embodiment
The present invention is described below in more detail to contribute to the understanding of the present invention.
It should be appreciated that the term or word that use in the specification and in the claims are not construed as having
The implication limited in dictionary, and be interpreted as on the basis of following principle having and its implication one in the context of the present invention
The implication of cause：The concept of term can be limited suitably by inventor for the best illustration to the present invention.
Embodiment 1
Prescription：
Prepare：Above-mentioned auxiliary material was crushed into 60 mesh sieves respectively；After Haouamine A and PLURONICS F87 are sufficiently mixed,
Mixed with dextrin, Ac-Di-Sol sieving, particle be prepared as in the method for dry granulation, including be compressed to sheet,
Crushed again, cross 14 mesh sieve whole grains, added talcum powder compressing tablet, produce, be made 1000.
Embodiment 2
Prescription：
Prepare：Above-mentioned auxiliary material was crushed into 60 mesh sieves respectively；Haouamine B are sufficiently mixed with lauryl sodium sulfate
Afterwards, mixed with lactose, sodium carboxymethyl starch sieving, add magnesium stearate and powdered cellulose compressing tablet, produce, be made 1000.
Pharmacological activity test embodiment：
1st, the compounds of this invention causes the antiinflammatory action after inflammation to test to SD rats toes
Mixed after mycobacterium butyricum is ground with atoleine, be made into after 10mg/ml, autoclaving that Freund is made is complete
Adjuvant.Male 180g-220g SD rats 80 are taken, 8 groups, i.e. model group, positive controls, experimental group is randomly divided into
(Haouamine A and Haouamine B low dosages, middle dosage, high dose), every group 10, by 0.1ml Freund's complete adjuvant skins
In the interior left back toes of injection, from after adjuvant injection the 16th day, the left back foot swelling of rat is obvious.Experimental group gives low dosage respectively
(5.0mg/kg), middle dosage (10.0mg/kg), Haouamine A and Haouamine the B gavages of high dose (20.0mg/kg)
Administration, positive controls give diclofenac sodium 20mg/kg, and model group gives isometric distilled water, and one time a day, continuous 7 days,
The 16th after adjuvant injection, 22 days, the left back toes swelling of rat is measured.Swelling rate (%)=(the 7th day toes body after administration
Toes volume before product-cause is scorching)/cause scorching preceding toes volume × 100%.As a result in table 1 listed below.
Table 1：Haouamine classes compound causes scorching antiphlogistic effects (n=10) to rat adjuvant
Compared with model group, * P<0.05, * * P<0.01；Compared with positive controls,#P<0.05
The middle and high dosage groups of Haouamine A and Haouamine B are can be seen that from result of the test shown in table 1 to rat not
Toes swelling has significant inhibitory action caused by family name's Freund's complete adjuvant, and its effect has pole significant difference (P compared with blank group<
0.01)；High dose group is compared with the positive control diclofenac sodium group of same dose, and inhibitory action more preferably, and has significant difference
(P<0.05), show that Haouamine classes compound causes scorching rat toes swelling to have and significantly disappeared for Freund's complete adjuvant
Swollen antiinflammatory action, points out the compounds of this invention to have excellent antiinflammatory action, and effect is better than diclofenac sodium.
2nd, treatment results of the compounds of this invention to mouse rheumatoid arthritis
Male 180g-220g SD rats 90 are taken, 9 groups, i.e. normal group, model group, positive controls, reality is randomly divided into
Test group (HaouamineA and HaouamineB low dosages, middle dosage, high dose), every group 10.In addition to normal group, remaining each group
Rat prepares rheumatoid arthritis in rats model in accordance with the following methods：Chicken II Collagen Type VIs are dissolved in acetic acid, 2mg/ml is configured to
Solution, Cord blood is standby.Chicken collagen acetum is sufficiently mixed at low temperature with isometric Fo Shi Freund's complete adjuvants, formed
Emulsion.0.1ml emulsions are expelled to rat tailses subcutaneous.Fo Shi is replaced to help completely at the 21st day, then with Freund incomplete adjunvant
Antigalactic is matched somebody with somebody in agent, in subcutaneous another location injection second of the emulsion of 0.1ml of afterbody.Typical rheumatoid is obtained after 6-8 weeks
Rat model of arthritis.It is administered after rheumatoid arthritis in rats model is built up, then respectively.Experimental group gives low dosage respectively
(5.0mg/kg), middle dosage (10.0mg/kg), Haouamine A and Haouamine the B gavages of high dose (20.0mg/kg)
Administration, positive controls give diclofenac sodium 20mg/kg, and normal group and model group give isometric distilled water, from second
Immune the previous day (the 20th day), one time a day to the 34th day.After administration 2 weeks, its arthritic arthritic volume with kind of calliper.
It is curative effect index with rat administration posterior joint volume, obtains the inhibiting rate after rat medication.Inhibiting rate=(model group arthritic volume
Value added-administration group arthritic volume value added)/(model group arthritic volume value added-normal group arthritic volume value added) ×
100%.
Table 2：Treatment results (n=10) of the Haouamine classes compound to rat rheumatoid arthritis
Compared with model group, * P<0.05, * * P<0.01；Compared with positive controls,#P<0.05
The joint body of the middle and high dosage groups of Haouamine A and Haouamine B is can be seen that from result of the test shown in table 2
Product is obviously reduced than model group, and its effect has pole significant difference (P compared with blank group<0.01)；High dose group with it is identical
The positive control diclofenac sodium group of dosage is compared, and diminution degree is more, and with significant difference (P<0.05), show
Haouamine classes compound has obvious inhibitory action for collagen-induced rheumatoid arthritis, points out the present inventionization
Compound has the excellent effect that rheumatoid arthritis becomes that suppresses, and effect is better than diclofenac sodium.
Above-mentioned pharmacological testing shows that Haouamine A and Haouamine B cause scorching rat foot for Freund's complete adjuvant
There is obvious functions of detumescence, relieving inflammation to act on for toe swelling, have obvious inhibitory action for collagen-induced rheumatoid arthritis,
And effect is better than diclofenac sodium, therefore it can be used for preventing and treating rheumatoid arthritis.
The preferred embodiment for the present invention is the foregoing described, so it is not limited to the present invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the change without departing from scope and spirit.
Claims (9)
1.Haouamine classes compound is preparing the application in preventing and treating the medicine of rheumatoid arthritis, the Haouamine classes
Compound includes Haouamine A and Haouamine B:
Haouamine A：R=H
Haouamine B：R=OH.
2. application according to claim 1, it is characterised in that preferred, the medicine is by the Haouamine classes
The pharmaceutical composition that compound is made as active component and pharmaceutically acceptable assistant agent.
3. application according to claim 2, it is characterised in that described pharmaceutical composition as tablet, pill, capsule,
It is prepared by the oral or non-oral administration thing of granula, pulvis, liquor, emulsion, suspending agent, ointment, injection, skin patch etc..
4. application according to claim 2, it is characterised in that the assistant agent includes filler, disintegrant, adhesive, emulsification
One of agent, lubricant, glidant, flavouring, strong olfactory agent, colouring agent are planted or several.
5. application according to claim 2, it is characterised in that described pharmaceutical composition is included：Haouamine classes compound,
Dextrin, Ac-Di-Sol, poloxamer, talcum powder.
6. application according to claim 2, it is characterised in that described pharmaceutical composition is included：Haouamine classes compound,
Lactose, sodium carboxymethyl starch, lauryl sodium sulfate, magnesium stearate, powdered cellulose.
7. a kind of pharmaceutical composition for being used to prevent and treat rheumatoid arthritis, it includes Haouamine class compounds, and pharmaceutically
Acceptable assistant agent, the Haouamine classes compound includes Haouamine A and Haouamine B:
Haouamine A：R=H
Haouamine B：R=OH.
8. pharmaceutical composition according to claim 7, it is characterised in that described pharmaceutical composition is used as tablet, pill, glue
The oral or non-oral administration of wafer, granule, pulvis, liquor, emulsion, suspending agent, ointment, injection, skin patch etc.
It is prepared by thing.
9. pharmaceutical composition according to claim 7, it is characterised in that the assistant agent includes filler, disintegrant, bonding
One of agent, emulsifying agent, lubricant, glidant, flavouring, strong olfactory agent, colouring agent are planted or several.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710116156.XA CN106943401B (en) | 2017-03-01 | 2017-03-01 | Haouamine classes compound is preparing the application in preventing medicine for treating rheumatoid arthritis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710116156.XA CN106943401B (en) | 2017-03-01 | 2017-03-01 | Haouamine classes compound is preparing the application in preventing medicine for treating rheumatoid arthritis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106943401A true CN106943401A (en) | 2017-07-14 |
| CN106943401B CN106943401B (en) | 2018-05-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710116156.XA Expired - Fee Related CN106943401B (en) | 2017-03-01 | 2017-03-01 | Haouamine classes compound is preparing the application in preventing medicine for treating rheumatoid arthritis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106943401B (en) |
-
2017
- 2017-03-01 CN CN201710116156.XA patent/CN106943401B/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| LEDA GARRIDO等: "Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum", 《J. ORG. CHEM.》 * |
| PETER WIPF AND MARKUS FUREGATI: "Synthesis of the 3-aza-[7]-paracyclophane core of haouamine A and B", 《ORG. LETT.》 * |
| 刘升长等: "天然产物Haouamine A的全合成研究进展", 《广州化学》 * |
| 张振秋、马宁主编: "《全国普通高等医学院校药学类专业十三五规划教材 药物分析》", 31 January 2016 * |
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| Publication number | Publication date |
|---|---|
| CN106943401B (en) | 2018-05-08 |
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