CN106943401B - Haouamine classes compound is preparing the application in preventing medicine for treating rheumatoid arthritis - Google Patents
Haouamine classes compound is preparing the application in preventing medicine for treating rheumatoid arthritis Download PDFInfo
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- CN106943401B CN106943401B CN201710116156.XA CN201710116156A CN106943401B CN 106943401 B CN106943401 B CN 106943401B CN 201710116156 A CN201710116156 A CN 201710116156A CN 106943401 B CN106943401 B CN 106943401B
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- haouamine
- 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 Haouamine classes compound to prepare the application in preventing medicine for treating rheumatoid arthritis.Haouamine classes compound causes scorching rat toes swelling to be acted on obvious functions of detumescence, relieving inflammation for Freund's complete adjuvant, there is obvious inhibitory action for collagen-induced rheumatoid arthritis, and effect is better than diclofenac sodium, therefore can be used for preventing rheumatoid arthritis.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to Haouamine classes compound is preparing prevention 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 in diseased 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 fever, fatigue and weak, pericarditis, subcutaneous nodule, pleurisy, arteritis, peripheral neuropathy etc..
At present, the treatment method of rheumatoid arthritis mainly carries out anti-inflammatory using hormone and antimetabolite and is immunized
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 are of great significance.
Haouamine classes compound includes Haouamine A and Haouamine B, it is Zub í a in 2002 etc. from western class
The secondary metabolite for the Aplidium haouarianum ascidian biologies 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 low toxicity, the important sources of high potency drugs.
Compared to the ascidian natural products found in the past, Haouamine classes compound has entirely different chemical skeleton.
It contains a very rare 3- nitrogen -7- paracyclophane, an indeno tetrahydropyridine structure and three chiral centres, wherein indenes
And the double bond containing an anti-Bredt rule in tetrahydro pyridine ring they collectively form 11 Yuans paracyclophane bones of great tension force
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 with B rings existing for 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 prevention rheumatoid arthritis, available for the medicine for preparing prevention 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
With the Haouamine classes compound includes Haouamine A and Haouamine B, its structure is as follows：
Haouamine A：R=H
Haouamine B：R=OH
Another object of the present invention is that providing the Haouamine classes compound is preparing the medicine of prevention rheumatoid arthritis
Application in thing.
Another object of the present invention is to provide a kind of pharmaceutical composition for being used to prevent rheumatoid arthritis, and it includes 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 kind or several.
The filler may be selected from the combination of following material one or more：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 combination of following material one or more：Starch, sodium carboxymethyl starch, hydroxypropyl form sediment
Powder, Ac-Di-Sol, crosslinked polyvinylpyrrolidone, low substituted hydroxy-propyl methylcellulose, and effervesce disintegration
Agent and surfactant.
Described adhesive may be selected from the combination of following material one or more：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 combination of following material one or more：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 combination of following material one or more：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 combination of following material one or more：Cataloid, powdered cellulose, three silicon
Sour magnesium, talcum powder.
Using common preparation technique, using pharmaceutical composition of the present invention 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 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 includes 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 includes：Haouamine classes compound, paste
Essence, Ac-Di-Sol, poloxamer, talcum powder.
In yet other embodiments, described pharmaceutical composition includes：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 a manner of oral or parenteral
0.001mg to 500mg for the administered dose of 1 day, 1 day 1 time or be divided into for several times to give.It should illustrate that the administered dose can basis
The species of the disease for the treatment of target, the age of patient, weight, symptom etc. suitably increase and decrease.
Disclosed according to the present invention, Haouamine A and Haouamine B cause scorching rat foot for Freund's complete adjuvant
Toe swelling is acted on obvious functions of detumescence, relieving inflammation, has obvious inhibitory action for collagen-induced rheumatoid arthritis,
And effect is better than diclofenac sodium, therefore can be used for preventing 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 be 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 tabletting, to obtain the final product, be made 1000.
Embodiment 2
Prescription：
Prepare：Above-mentioned auxiliary material be 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 tabletting, to obtain the final product, be made 1000.
Pharmacological activity test embodiment：
1st, the compounds of this invention causes SD rats toes the anti-inflammatory effect after inflammation to test
Mixed after mycobacterium butyricum is ground with atoleine, be made into 10mg/ml, it is complete that Freund is made after autoclaving
Adjuvant.The SD rats 80 of male 180g-220g are taken, are randomly divided into 8 groups, i.e. model group, positive controls, experimental group
(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, one time a day, continuous 7 days,
The the 16th, 22 day after adjuvant injection, the left back toes swelling of rat is measured.Swelling rate (%)=(the 7th day toes body after administration
Toes volume before product-cause inflammation)/cause toes volume × 100% before inflammation.The results are shown in table 1 below.
Table 1：Haouamine classes compound causes rat adjuvant scorching antiphlogistic effects (n=10)
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 caused by family name's Freund's complete adjuvant has significant inhibitory action, its effect has pole significant difference (P compared with blank group<
0.01)；For high dose group compared with the positive control diclofenac sodium group of same dose, 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 disappears for Freund's complete adjuvant
Swollen anti-inflammatory effect, prompts the compounds of this invention to have excellent anti-inflammatory effect, and effect is better than diclofenac sodium.
2nd, treatment results of the compounds of this invention to mouse rheumatoid arthritis
Take the SD rats 90 of male 180g-220g, be randomly divided into 9 groups, i.e., normal group, model group, positive controls, reality
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, are configured to 2mg/ml
Solution, Cord blood are spare.Chicken collagen acetum and isometric Fo Shi Freund's complete adjuvants are sufficiently mixed at low temperature, formed
Emulsion.It is subcutaneous that 0.1ml emulsions are expelled to rat tails.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.After rheumatoid arthritis in rats model is built up, then it is administered 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
The previous day (the 20th day) is immunized to the 34th day, one time a 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
It can be seen that the joint body of the middle and high dosage groups of Haouamine A and Haouamine B from result of the test shown in table 2
Product is obviously reduced than model group, 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 has significant difference (P<0.05), show
Haouamine classes compound has obvious inhibitory action for collagen-induced rheumatoid arthritis, prompts the present inventionization
Compound has the function that the excellent rheumatoid arthritis that suppresses becomes, 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
Toe swelling is acted on obvious functions of detumescence, relieving inflammation, has obvious inhibitory action for collagen-induced rheumatoid arthritis,
And effect is better than diclofenac sodium, therefore can be used for preventing 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 (6)
- Application of the 1.Haouamine classes compound in the medicine for preparing prevention rheumatoid arthritis, the Haouamine classes Compound is selected from Haouamine A and Haouamine B：
- 2. application according to claim 1, it is characterised in that the medicine is to be made by the Haouamine classes compound For pharmaceutical composition made of active ingredient 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 granula, pulvis, emulsion, suspending agent, ointment, injection, the oral or non-oral administration thing of skin patch.
- 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 kind or several.
- 5. application according to claim 2, it is characterised in that described pharmaceutical composition includes：Haouamine classes compound, Dextrin, Ac-Di-Sol, poloxamer, talcum powder.
- 6. application according to claim 2, it is characterised in that described pharmaceutical composition includes：Haouamine classes compound, Lactose, sodium carboxymethyl starch, lauryl sodium sulfate, magnesium stearate, powdered cellulose.
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 CN106943401A (en) | 2017-07-14 |
| CN106943401B true CN106943401B (en) | 2018-05-08 |
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ID=59466604
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 |
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| Country | Link |
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| CN (1) | CN106943401B (en) |
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2017
- 2017-03-01 CN CN201710116156.XA patent/CN106943401B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum;Leda Garrido等;《J. Org. Chem.》;20031231(第68期);293-299 * |
| Synthesis of the 3-aza-[7]-paracyclophane core of haouamine A and B;Peter Wipf and Markus Furegati;《Org. Lett.》;20060404;第8卷(第9期);1901-1904 * |
| 天然产物Haouamine A的全合成研究进展;刘升长等;《广州化学》;20140630;第39卷(第2期);66-78 * |
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| CN106943401A (en) | 2017-07-14 |
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Granted publication date: 20180508 Termination date: 20210301 |