CN103664798A - Compounds for treating traumatic brain injury diseases and application thereof - Google Patents
Compounds for treating traumatic brain injury diseases and application thereof Download PDFInfo
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- CN103664798A CN103664798A CN201210349742.6A CN201210349742A CN103664798A CN 103664798 A CN103664798 A CN 103664798A CN 201210349742 A CN201210349742 A CN 201210349742A CN 103664798 A CN103664798 A CN 103664798A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses compounds, and a pharmaceutical composition and new application thereof in preparing medicines for treating traumatic brain injury diseases. The compounds for treating traumatic brain injury diseases can have very obvious effect.
Description
Technical field
The present invention relates to three kinds of compound and pharmacologically acceptable salt and its analogues for the treatment of traumatic brain injury disease, the pharmaceutical composition of being prepared by above-claimed cpd and pharmacologically acceptable salt thereof and its analogue, and described compound or pharmaceutically acceptable salt thereof and the purposes of analogue in the medicine of preparation treatment traumatic brain injury disease thereof.
Background technology
In recent years, development and the extensive application of modernization mechanicalness equipment in productive life due to communications and transportation, the incidence of traumatic brain injury is rising, disability rate therefore and mortality ratio are in continuous increase, according to nearest epidemiology survey data, show, the sickness rate of China's traumatic brain injury is in every 100,000 people, to surpass 100 people, and its lethal disability rate is first, and levels of thyroid hormone in craniocerebral trauma patients has accounted for 20%.Although the progress along with medical technology, the Level of first-aid treatment of traumatic brain injury improves a lot, but in traumatic brain injury, mortality ratio is still located a high position so far, also can produce very serious sequela, it is the important injury of serious harm human health, this sick feature is that generation reason is more, damage is serious, clinical application medicine is also more, but the result for the treatment of of most drug performance is fainter, desirable not to the utmost, need a kind of medicine of very effectively treating comparatively all sidedly traumatic brain injury badly.
Traumatic brain injury is mainly clashed and is caused by head, and serious traumatic brain injury can destroy bone, damage skin of head, tractive, distortion or tear blood vessel, nerve and the hetero-organization thereof in brain.Be subject to after more serious destruction, will cause bleeding, oedema.Intracranial hemorrhage and with cerebral edema, cranial cavity content is increased, intracranial tissue and blood vessel sustain damage, and cerebral tissue further destroys.The reason of traumatic brain injury is varied, and the harm bringing is all maximum.In the treatment of traumatic brain injury, owing to not having clinically a kind of medicine effectively to treat, so the effect after morbidity treatment can only be different because of state of an illness weight, what have can recover, and what have disables, some death.The factor that affects prognosis depends primarily on damage which cerebral tissue, injury severity score and treatment measure and medication.Many brain functions are by the different zones shared of cerebral tissue, and the function that the cerebral tissue not coming to harm can compensatoryly be partially damaged, can partly recover.Not having clinically in the situation of active drug at present, for the treatment of traumatic brain injury, is generally that multi-medicament drug combination is treated.Widely application has a morphine similar drug, for example Rutundine, l-stepholidine, Naproxen Base, acetylsalicylic acid, Ibuprofen BP/EP, these medicines act as master to calm, therapeutic action is very limited, also give diphenhydramine, promethazine, trichloro-butyl alcohol etc., it can cause cental system toxicity, drowsiness or serious anaphylaxis, and effect is also very general; Some neuroprotectives are very slow to the treatment onset of traumatic brain injury, act on also very limitedly, often cannot reduce the mortality ratio of traumatic brain injury, often as adjuvant therapy medicaments.Some Chinese patent medicines, such as sedative and heart-invigorating pill, gastrodini, cow-bezoar bolus for resurrection etc., acts on slow and limited.
Totally it seems, because the pathogenic factor of traumatic brain injury is many, in many clinical treatment medicines, both do not had very effectively, also there is no extensive therapeutic action.And along with social high speed development, the diversification of traumatic brain injury conditions of patients of today, the adaptability of medicine and result for the treatment of are all not so good as in the past.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof the purposes in the medicine of preparation treatment traumatic brain injury disease.For this group compounds for treating traumatic brain injury, there is no report at present.
Summary of the invention
The invention provides the one group of compound or pharmaceutically acceptable salt thereof that can treat traumatic brain injury disease, and analogue, the structure of described compound is as follows:
The present invention also provides a kind of pharmaceutical composition, and it comprises compound (A), (B), (C) or (D); Said composition can also comprise auxiliary material etc.Described pharmaceutical composition can be through topical, and the various preparations of gastrointestinal administration or parenteral administration, comprise ordinary preparation, controlled release preparation, targeting preparation etc.Described controlled release preparation comprises superpolymer or film material, described superpolymer is selected from: one or more in polylactic-co-glycolic acid, poly-acid anhydrides, polyoxyalkylene, polymeric amide, polyester, polyacrylic resin, polyethers, polyphosphonitrile or glycan, or be selected from the multipolymer between the different monomers of described superpolymer, preferably, described superpolymer is selected from: poly lactic coglycolic acid, lactic-co-glycolic acid-glycol copolymer, PGA, glycollide rac-Lactide-ethylene glycol-glycollide rac-Lactide triblock copolymer, polyoxyethylene glycol, sebacic anhydride-glycol copolymer, octadecane diacid acid anhydride-ethylene glycol segmented copolymer, poly butyric ester, polybutylcyanoacrylate, poly(lactic acid), polymaleic anhydride, poly sebacic polyanhydride, polyvinyl alcohol, NIPA-acrylic copolymer, chitosan, polyethersulfone, Mierocrystalline cellulose, dextran, alginates, dextran, hyaluronic acid, gelatin, poloxamer, Fibrinogen, one or more in albumin or collagen protein etc.Described film material comprises that Yelkin TTS, fabaceous lecithin, phosphatidylethanolamine, cholesterol, kephalin, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, Glycocholate sodium, Yolk lecithin, phosphatidyl silk amino acid, phosphatidylinositols, sphingomyelin, sphingomyelin, two Cetyl Phosphates, two Pork and beans acyl Yelkin TTS, stearylamide, phosphatidic acid, phosphatidylserine etc. comprise natural or synthetic phosphatide, lipoid or its combination.
The present invention also provides compound (A), (B), (C) or (D) or its pharmacologically acceptable salt and the purposes of analogue in the medicine of preparation treatment traumatic brain injury disease thereof.Described purposes comprise by compound (A), (B), (C) (D) or its pharmacologically acceptable salt and analogue thereof be prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration, comprise that ordinary preparation, controlled release preparation, targeting preparation etc. treat for traumatic brain injury animal model.Described local administration preparation is the powder injection through head administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, aqueogel etc.; Described gastrointestinal administration preparation is tablet, capsule, powder, pill, granule, emulsion etc.; Described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, intracardiac injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.The dosage of described medicine is 0.1mg-500mg.
The head serious disease that traumatic brain injury causes due to external world damage, it requires prosecution rapidly, causes, also or the traumatic brain injury that causes of the multiple position of head all can have better performance to have treatment meaning to this type of disease for many reasons.Traumatic brain injury is difficult to sort out; cannot say which kind disease it belongs to; it is a kind of traumatism; be again the disease of a kind of blood vessel, tissue, nerve, skin, the concurrent damage of bone, usually also with infection, a lot of medicines are all only for a part, to treat simultaneously; therefore effect is bad; because the single often overall onset for the treatment of approach is very slow, be often that medicine does not also have enough time to play a role, patient is with regard to dead.When carrying out comparatively serious traumatic brain injury experimentation on animals, during medication, animal is usually just dead after just modeling.The invention of this group, the medicine of mentioning owing to may for number of ways, traumatic brain injury being treated simultaneously, blood vessel, brain inner tissue, nerve, skin and skeletal injury are recovered to have very great therapeutic action, because blood vessel, tissue, nerve, skin and bone are subject to pharmacological agent jointly, collaborative recovery, therefore promptly onset.Contriver finds pleasantly surprisedly, and dead (comprising the animal model that traumatic brain injury is very serious) all do not occur all traumatic brain injury animals after medication, and the far super positive control drug of recovery.
Embodiment
The present invention's compound used can be purchased TG-101348, HKI-272, and PHA-680632 and CCT137690, also can be prepared according to relevant disclosed preparation method, and it does not limit the scope of the invention.Below in conjunction with embodiment, the present invention is further explained.
Effect embodiment
Described compd A structure is:
Described compd B structure is:
Described Compound C structure is:
Described Compound D structure is:
Preparation containing compd A lyophilized injectable powder:
1. altogether 100mg and 900mg formula (A) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd B lyophilized injectable powder:
1. altogether 100mg and 900mg formula (B) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing Compound C lyophilized injectable powder:
1. altogether 100mg and 900mg formula (C) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.Preparation containing Compound D lyophilized injectable powder:
1. altogether 100mg and 900mg formula (D) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
4. carry out procedural freeze-drying;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
1 compound (A-D) and similar compound thereof or the provide protection of its pharmacologically acceptable salt to rabbit cerebral trauma brain injury
1.1 laboratory animal and grouping
Healthy adult rabbit is divided into 7 groups at random, 10 every group.Be Normal group, model group, compd A group injection liquid, compd B group injection liquid, Compound C group injection liquid, Compound D group injection liquid (described injection liquid is that the powder injection of getting the compd A-D of above-mentioned preparation is made with physiological saline solution), and positive drug Piracetam Injection.Normal group is not caused injury, and only in volume crown drill hole, right side, all causes injury for other several groups.
1.2 experimental technique
1.2.1 model preparation
Auricular vein is injected 3% vetanarcol 1ml.kg
-1.After anesthesia, through auricular vein, inject 2.5% Evans Blue (Evans blue, EB) 1ml.kg again
-1.The rabbit position of bowing is fixed on experimentation on animals operator's console, and hair is shaved at rabbit volume top, center sagittal otch, and otch is about 3cm.The boring of right volume top, stings out a diameter 0.8cm similar round bone window, keeps dura mater complete.Be used for placing cranium Doppler (TCD) probe.The seat cushion of causing injury is placed on the parietal bone of left side, and 1kg metal weight is placed in apart from skull 50cm eminence freely falling body and is discharged, and metal is hit on the pad of causing injury, and hitting power conducts to skull, causes local depressed fracture of skull and contusion and laceration of brain.Make rabbit produce bone, many-sided damage in skin, blood vessel, tissue and brain.
1.2.2 methods for the treatment of and index detect
Medicine group intravenous injection relative medicine immediately after modeling, compd A, B, C, D group are injected respectively A, B, C, D injection liquid, positive control drug treated animal injection Piracetam Injection (1.5mg.kg
-1), blank group gives isopyknic physiological saline.5min before cranium Doppler (TCD) is surveyed each treated animal wound and after wound, 30min, 1h, 2h,, 3h, the arteria cerebri media systolic blood Flow Velocity (Vs) of 4h, end diastolic velocity (Vd) and PI (PI), and survey Evans Blue (EB) content by methane amide infusion method, with atomic absorption spectrophotometry, survey Ca
2+.
1.3 statistical method
Each is organized data and represents by mean ± standard deviation, relatively adopts t check between group, and there is statistical significance P≤0.05 for difference.
1.4 result
1.4.1 the behavior of rabbit after causing injury changes
Model group animal hinders latter 5 and occurs breathlessness, needs can recover autonomous respiration after human assistance breathing, occurs that breathing shoals slack-off after Some Animals wound, and heartbeat is slow, improvement voluntarily after 2 minutes.After all animal wounds, all there is irritated, tic in various degree.
1.4.2 CBFV (CBV) and PI (PI) change
1.4.2.1Vs variation
Vs value no significant difference before each treated animal cerebral trauma.Model group animal craniocerebral injury Vs value starts to reduce, from 30min hindering, before wound, obviously reduce, each organizes injured animal at 30min, 1hVs hinders front obvious reduction, medicine A, B, C, D group after wound medication after 2 hours Vs value raise gradually, with there was no significant difference before wound, and after wound, 3h, 4h Vs value are compared with model group obviously rising (P < 0.01) (in Table 1) of Vs value in the same time, and successful is better than and contrasts positive drug group.Its Chinese traditional medicine A, B, C, D group rising speed are fast, illustrate that medicine may directly enter target organ, corresponding lesion location, and onset is very fast.
Comparison (n=10, the cm.s of Vs value before and after each treated animal cerebral trauma of table 1
-1)
With control group comparison
#p < 0.05
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
1.4.2.2Vd variation
Vd value no significant difference before each treated animal wound.Model group craniocerebral injury Vd value obviously reduces before wound from 5min hindering, reaches Schwellenwert to 4h, and with the obviously reduction (P < 0.01) of comparing also of Normal group Vd value in the same time; 30min after medicine A, B, C, D treatment group animal wound, 1h Vd value obviously reduces before hindering, and 3h after wound, 4h, Vd value compared with model group in the same time Vd value obviously raise (P < 0.05 or P < 0.01) (in Table 2), and all show than positive drug group have better result for the treatment of (P < 0.05) after medicine A, B, the medication of C, D group.
Comparison (n=10, the cm.s of Vd value before and after each treated animal cerebral trauma of table 2
-1)
With control group comparison
#p < 0.05
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
1.4.2.3PI variation
PI value no significant difference before each treated animal wound.Model group PI value from 5min hindering significantly raises before hindering, and reaches maximum to 4h, and with the obviously rising (P < 0.05 or P < 0.01) of comparing also of Normal group PI value in the same time; Medicine A, B, C, D treatment group animal 5min to 30min PI value from hindering significantly raises before hindering.3h, before 4h and wound, comparing difference is without significance, and model group PI value significantly reduces (P < 0.05 or P < 0.01) (in Table 3) more in the same time from 30min hindering, after medicine A, B, the medication of C, D group, effect is far better than positive drug control group.
The comparison (n=10) of PI value before and after each treated animal cerebral trauma of table 3
With control group comparison
#p < 0.05
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
1.4.3 cerebral tissue EB content
1.4.3.1EB typical curve
Utilize optical density(OD) (X) and the corresponding EB content (Y) of each standard pipe to carry out straight-line regression, obtain equation EB relation equation.
1.4.3.2 cerebral tissue EB content
Each treated animal causes craniocerebral injury 4h, and cerebral tissue EB content is all apparently higher than Normal group (P < 0.01).With model group comparison, each medication therapy groups EB content all obviously reduces (P < 0.05 or P < 0.01) (in Table 4).Result shows, through pharmacological agent, can make blood-brain barrier permeability reduce, and can alleviate the blood vessel source cerebral edema of craniocerebral injury.
1.4.4 cerebral tissue Ca
2+content
With Normal group comparison, the Ca of model group animal brain
2+content obviously raise (P < 0.01); With model group comparison, medicine A, B, C, D treatment group Ca
2+content obviously reduces (P < 0.01), the Ca after A, B, C, D treatment
2+content and Normal group be (in Table 4) quite.Illustrate that medicine A, B, C, D can better suppress the generation of the calcium overload that causes due to brain injury, thereby play the provide protection to cerebral tissue.
Table 4 each treated animal cerebral tissue EB and Ca
2+content (n=10)
With control group comparison
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
2 medicine A, B, C, the D therapeutic action after to experimental rat traumatic brain injury
2.1 laboratory animal and grouping
Healthy Wistar rat, male, heavy 300g left and right, experiment is divided into 7 groups, 30 every group, is divided into Normal group, model group, compd A group, compd B group, Compound C group, Compound D group and positive drug Naproxen Base group.
2.2 experimental technique
2.2.1 cerebral trauma animal model
Cerebral trauma animal model adopts the Feeney method of improvement, and each organizes rat 12h fasting in the preoperative, freely drinks water, and rat is with vetanarcol (30mg.kg
-1) anaesthetize, be fixed on stereotactic apparatus rat is prostrate, head cropping, routine disinfection drape, operation head hits exactly the sagittal of taking back and cuts skin, appear left top, peel off periosteum and expose skull, the surging force of causing injury is 800g/cm, and cone is maximum sink apart from 3mm, cause left parietal lobe contusion and laceration of brain, the area of causing injury is 3mm * 3mm.Rat all recovers diet in operation in latter 12 hours.
2.2.2 each treated animal is processed
After modeling, medicine group gives relative medicine (3mg.kg immediately
-1), control group gives isopyknic physiological saline.After experiment the 5th day, with 4% paraformaldehyde (4 ℃, pH7.4) through aorta ascendens perfusion, fixedly after the about 30min of brain, take out rapidly hemicerebrum, immerse in above-mentioned stationary liquid.
2.2.3 hemicerebrum moisture determination
Get 10 samples for every group, after taking-up hemicerebrum, with electronic analytical balance, claim hemicerebrum weight in wet base, then put into 100 ℃ of baking boxs baking 24h, then claim dry weight with electronic analytical balance.By dry wet method, calculate brain water content, i.e. brain water content=(weight in wet base-dry weight)/weight in wet base * 100%.
2.2.4 serological index detects
Utilize xanthine oxidase to detect serum superoxide dismutases (SOD) activity; Utilize thiobarbituricacidα-method to measure Serum MDA (MDA) concentration; Utilize ELISA method to measure serum il-1 β (IL-1 β), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) concentration.
2.3 statistical method
Each is organized data and represents by mean ± standard deviation, relatively adopts t check between group, and P < 0.05 has statistical significance for difference.
2.4 result
2.4.1 the impact of medicine on Rats with Cerebral Injury brain hemisphere water content
Result shows (in Table 5), and Normal group brain water content is 75.34%, and model group brain water content is 80.98%.Two groups of comparing differences remarkable (p < 0.001) illustrate that this model can cause the obvious oedema of cerebral tissue.With model group comparison, medicine A, B, C, D group have and obviously alleviate cerebral edema effect (p < 0.01).
The impact (n=10) of table 5 medicine on traumatic brain injury in rats brain hemisphere water content
With control group comparison
###p < 0.001, with model group comparison
*p < 0.05
*p < 0.01
2.4.2 the impact of medicine on Rats with Cerebral Injury SOD in serum, MDA
The results are shown in Table 6, with Normal group comparison, model group SOD is active obviously to be reduced, and MDA obviously increases (P < 0.01).With model group comparison, medicine A, B, C, the D group SOD that can obviously raise in serum is active, reduces MDA (P < 0.01 or P < 0.05).Though and the Naproxen Base group SOD that also can raise in serum is active and reduce MDA, but effect differs more (P < 0.05) compared with medicine A, B, C, D group.
Table 6 different dosing group is on the impact of Rats with Cerebral Injury SOD in serum, MDA (n=10)
With control group comparison
##p < 0.01, with model group comparison
*p < 0.05
*p < 0.01
In sum, visible medicine A, B, C and D have very large therapeutic action on treatment traumatic brain injury, can to brain injury, carry out strong treatment from many aspects.
Claims (10)
1. a class can be treated the compound or pharmaceutically acceptable salt thereof of traumatic brain injury disease, and analogue, and the structure of described compound is as follows:
2. a pharmaceutical composition, it comprises compound claimed in claim 1 and pharmacologically acceptable salt and its analogue.
3. the pharmaceutical composition of claim 2, it can be ordinary preparation, controlled release preparation, targeting preparation etc., the packaging material of described controlled release preparation is selected from: the natural or synthetic superpolymer of one or more in polylactic-co-glycolic acid, polyoxyethylene glycol, poly-acid anhydrides, polymeric amide, polyester, polyene, polyethers, polyphosphonitrile or glycan, or natural or synthetic phosphatide, lipoid or its combination.
4. compound and pharmacologically acceptable salt thereof and its analogue purposes in the medicine of preparation treatment traumatic brain injury disease described in claim 1.
5. the purposes of claim 4, the treatment of described traumatic brain injury disease comprises treatment traumatic brain injury, alleviates the related symptoms of traumatic brain injury.
6. the purposes of claim 5, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
7. the purposes of claim 6, described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.
8. the purposes of claim 6, described local administration preparation is the powder injection through head administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.
9. the purposes of claim 6, described gastrointestinal administration preparation is tablet, capsule, powder, pill, granule, emulsion etc.
10. the purposes of claim 6, described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
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| CN103724351A (en) * | 2012-10-11 | 2014-04-16 | 韩冰 | Compound for treating cerebral palsy and use thereof |
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| CN103724351A (en) * | 2012-10-11 | 2014-04-16 | 韩冰 | Compound for treating cerebral palsy and use thereof |
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