CN103720694A - Compound for treating cerebral palsy and use thereof - Google Patents
Compound for treating cerebral palsy and use thereof Download PDFInfo
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- CN103720694A CN103720694A CN201210385535.6A CN201210385535A CN103720694A CN 103720694 A CN103720694 A CN 103720694A CN 201210385535 A CN201210385535 A CN 201210385535A CN 103720694 A CN103720694 A CN 103720694A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound for treating cerebral palsy and its pharmaceutical composition and a novel use thereof. The novel use comprises that the compound is used for preparation of a drug for treating cerebral palsy. The compound has very obvious effects of treating cerebral palsy.
Description
Technical field
The present invention relates to compound and officinal salt and its analog of a class treatment cerebral palsy, the pharmaceutical composition of being prepared by above-claimed cpd and officinal salt thereof and its analog, and described compound or pharmaceutically acceptable salt thereof and the purposes of analog in the medicine of preparation treatment cerebral palsy thereof.
Background technology
Cerebral palsy also claims cerebral palsy clinically, is in utero to being born the hindbrain stage of development, and non-the carrying out property brain injury syndrome due to many reasons, is the principal disease that causes child limb deformity, and easily exists throughout one's life.Scientific circles are still underway to its pathogenetic research, and current carried arbitrary theory all cannot make an explanation for all patients with cerebral palsy causes of disease, and the further research of the science that needs discloses the pathogenesis of cerebral palsy.
About the treatment of cerebral palsy, there is no at present good method, bring huge spirit, financial burden to patient, family and society.Along with enclosing the development of obstetrics' medical science, neonatal mortality rate obviously declines, but due to inherited genetic factors or other external environment factors but make the sickness rate of cerebral palsy present ascendant trend, therefore, the treatment of cerebral palsy has become focus and the difficult point of countries in the world scientific research institution research.The method for the treatment of cerebral palsy has medicine, operation, rehabilitation and other treatment both at home and abroad at present.
Using in the treatment of medicine, a line medication of often using clinically at present has diazepam, baclofen, dantrolene, tizanidine etc., is mainly used in relieve muscle spasms, but that treatment is held time is limited, prolonged and repeated application has certain side reaction, also has larger research space.In addition, some somatomedin, Cerebrolysin Vial etc. are also as the medicine for the treatment of cerebral palsy, and it act as and promotes the growth of brain cell and strengthen the compensatory capacity of cerebral tissue, but curative effect is limited during clinical practice.In scientific research, meat poisoning rhzomorph etc. also can be used for treating cerebral palsy, but still has query for its Therapeutic Method and injected dose, needs further research.
Use at present surgery operating technology operational risk higher, treatment is very limited, and less people takes operation.Rehabilitation is to treat at present the most popular a kind for the treatment of means of infant cerebral palsy, because it can not cause excessive injury to infant, and can obtain suitable alleviation through the long-term treatment state of an illness.Rehabilitation mainly comprises: exercise therapy, conductive education, apparatus auxiliary treatment etc.The variation of its form of therapy has obtained infant and kinsfolk's consistent favorable comment with interest and appeal, but there is no obvious data and prove its definite curative effect, through practice for many years, rehabilitation does not reach the therapeutic effect of expection, and rehabilitation does not also form a set of complete theoretical system, many therapies also, in the middle of clinical experiment, need a large amount of objectively experimental results to do further confirmation.
Above treatment means only can be alleviated some symptoms of cerebral palsy of children, can not fundamentally treat.Be badly in need of at present the pathogenesis of research cerebral palsy, find out the total reason of various cerebral palsy, and find a kind of medicine root, cerebral palsy to be treated, reduce Their Incidence of Cerebral Palsy rate, alleviate the pressure bringing to family, society due to cerebral paralysis disease.
The inventor is surprised to find that one group of compound and similar compound or its officinal salt thereof have an unexpected effect on the medicine of preparation treatment cerebral palsy, there is no report for this compounds for treating cerebral palsy at present.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its officinal salt new purposes in the medicine of preparation treatment cerebral palsy.
Technical scheme of the present invention is as follows:
The invention provides the one group of compound or pharmaceutically acceptable salt thereof that can treat cerebral palsy diseases, and analog, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C).
Formula (I) compound and analog thereof or its officinal salt can be prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.Described preparation comprises ordinary preparation, controlled release preparation, targeting preparation etc.Described local administration preparation is through the injectable powder of head administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the dosage form of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
The inventor studies discovery: this compounds can greatly be alleviated cerebral palsy symptom, and from the result of pharmacodynamic experiment, the therapeutic effect of this compounds exceeds the medicine of current clinical practice.The exploitation of this new indication is by for to play very large effect to the recovery of following cerebral palsy patients.For removing sufferer misery, alleviate the symptom of this class disease, improve patient and its household's quality of life, promote social harmony of far-reaching significance.
The specific embodiment
The present invention's formula (I) compound used can be purchased, and also can be prepared according to disclosed preparation method, and it does not limit the scope of the invention.
Medicine Preparation Example
Described compd A structure is:
Compound (A);
Described compd B structure is:
Compound (B);
Described Compound C structure is:
Compound (C).
Contain the preparation of compd A lyophilized injectable powder:
1. altogether 100mg and 300-800mg formula (A) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze drying protectants and adjuvant;
4. carry out procedural lyophilizing;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Contain the preparation of compd B lyophilized injectable powder:
1. altogether 100mg and 300-800mg formula (B) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze drying protectants and adjuvant;
4. carry out procedural lyophilizing;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Contain the preparation of Compound C lyophilized injectable powder:
1. altogether 100mg and 300-800mg formula (C) compound mix and make it dissolving in water for injection to get mannitol, phospholipid, glycerol, cyclodextrin derivative, dimethyl sulfoxide and poloxamer;
2. after mixing dissolving, after stable, first use 0.45um microporous filter membrane coarse filtration, then use 0.2um filtering with microporous membrane;
3. be distributed into little cillin bottle, add other freeze drying protectants and adjuvant;
4. carry out procedural lyophilizing;
5. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Effect embodiment:
The protective effect of 1 compound (A-C) to newborn rabbits cerebral palsy
1.1 laboratory animals and grouping
90 of the interior young rabbits of 24h after raw, average weight 50g, is divided into 6 groups at random by young rabbit, i.e. Normal group, model group, positive drug baclofen group and medicine A, B, C group.
1.2 experimental technique
1.2.1 bilirubin solution compound method
The bilirubin of getting aequum is dissolved in NaOH solution, and to make PH be 7.4, then uses 0.9%NaCl solution dilution to volume required.During medicine preparation, need lucifuge operation and use in 1h.
1.2.2 each treated animal processing
Except Normal group, all the other groups all give lumbar injection bilirubin, each 100mg/kg body weight, and the next day, injects 1 time, and totally 3 times, total amount 300mg/kg body weight, matched group gives the normal saline of lumbar injection Isodose, and the next day, injects 1 time, totally 3 times.After modeling, each medicine group all gives relative medicine (1mg.kg-1) once every 3d intravenous injection, and matched group gives isopyknic normal saline, successive administration 5 times, altogether 15d.After the young rabbit administration of each group, send back to immediately in female rabbit hutch, in equal constant temperature, constant humidity, lucifuge environment, natural breast feeding is to 45d.
1.3 Behavioral assessment
The young rabbit nurture laggard row Behavior Examination of 45d and scoring, 20 points of full marks, minimum 0 point, without negative point.5 points of muscular tension full marks, all have any one performance that enhancing, attenuating, migration strengthen and lower to detain 5 points; 5 points of involuntary action full marks, all have tremble, dance movement, wave that action, athetosis, spasm are reversed and any one performance of spasmodic torticollis detains 5 points; 5 points of autonomic activities full marks, allly respond that blunt, autonomic activities reduces, movement velocity slowly, kinematic dexterity reduce and kinetic stability to reduce be 1 point, every each button; 5 points of posture full marks, all 2 points, each buttons of abnormal posture while having motor pattern abnormal and static, 1 point, the button of can not standing, after every young rabbit is scored respectively and is averaged by 5 people, average as behavioristics's score of this group together with other animal averagings of income on the same group divide, mark is accurate to 0.01 point again.
1.4 serum bilirubin levels are measured
After treating young rabbit scoring, be fixed on operating-table, cut open breast and expose heart, heart puncturing extracting blood 0.5ml.Adopt 1500rpm/min, after centrifugal 5min, separate upper serum, diazo reaction method is measured serum total bilirubin content.
1.5 serum myelin basic proteins (MBP) assay
12h and 45d after modeling, get blood centrifugalize serum.Serum MBP adopts enzyme-linked immunoassay method, after freezing serum is moved to 4 ℃ of refrigerators and slowly thaws, strictly presses the operation of test kit operation instruction, parallel two-tube mensuration.
1.6 statistical method
Each group data represent with mean ± standard deviation, relatively adopt t to check between group, and there is statistical significance P≤0.05 for difference.
1.7 result
1.7.1 behavioristics's appraisal result
Compared with Normal group, the scoring of model group Zai Tu behavioristics obviously reduces (P < 0.01), with model group comparison, each medication therapy groups behavioristics scoring obviously increases (P < 0.01), and its Chinese medicine A-C group therapeutic effect is more obvious.Can obviously improve the behavior disorder producing because of young Medulla Leporis seu Oryctolagi paralysis due to bilirubin.Refer to table 1.
The impact (n=15) of table 1 medicine on the scoring of cerebral palsy behavioristics and serum bilirubin level due to bilirubin
With relatively ##P < 0.01 of Normal group, with model group comparison
*p < 0.01
1.7.2 serum bilirubin level result
The content of the young rabbit anteserum mesobilirubin of Normal group is starkly lower than model group (P < 0.01); Through the treatment of medicine, each treatment group all can make the content of young rabbit anteserum mesobilirubin reduce, and relatively have significant difference (P < 0.01), and medicine A-C group effect is better than positive drug group with model group.Refer to table 1.
1.7.3 serum MBP content results
After model group modeling, in 12h serum, MBP content is than the obvious rising of matched group (P < 0.01), and after 45d, two groups relatively still have statistical significance (P < 0.05); With model group comparison, each medicine A-C treatment group all can reduce MBP content in serum (P < 0.05 or P < 0.01), can obviously improve the young Medulla Leporis seu Oryctolagi damage status of cerebral palsy.Refer to table 2.
The impact (μ g/L, n=15) of table 2 medicine on cerebral palsy serum MBP content due to bilirubin
With relatively #P < 0.05##P < 0.01 of matched group, with model group comparison
*p < 0.05
*p < 0.01
The protective effect of 2 medicines (A-C) to Mus cerebral palsy
2.1 laboratory animals and grouping
120 of healthy 7 day-old Wistar neonatal rats, clean level, male and female are not limit, body weight 14 ± 0.5g, raising condition is 21 ± 2 ℃ of room temperatures, illumination control 12 hours, free diet water.Neonatal rat is divided into 6 groups at random, i.e. matched group, model group, positive drug dantrolene group and medicine A-C group.
2.2 experimental technique
2.2.1 Mus cerebral palsy model preparation
The 7th day Wisrar neonatal rat isoflurane inhalation anesthesia after being born, 75% ethanol disinfection skin of neck, the descending neck of operating microscope center longitudinal incision, is about 0.5cm, carefully separates subcutaneous and superficial fascia, dual ligation common carotid artery from breaking, skin suture otch.Postoperative anesthesia recovery is positioned over after 2 hours and mixes in 8% oxygen+92% nitrogen anoxia case 2 hours.Matched group will be given birth to latter 7 days Wisrar children Mus isoflurane inhalation anesthesias equally, 75% ethanol disinfection skin of neck, the descending neck median incision of operating microscope, sews up the incision after exposure right carotid, puts back to female Mus free diet water at one's side after its holonarcosis recovery 2h.
2.2.2 each treated animal processing
After modeling, each medicine group all gives relative medicine (2mg.kg-1) once every 3d intravenous injection, and matched group gives isopyknic normal saline, successive administration 5 times, altogether 15d.After the administration of each group neonatal rat, sending immediately female Mus back to raises at one's side.
2.3 Beam balance test
Rat to postoperative 3 weeks, 7 weeks carries out Beam balance test detection.Training stage, moves into laboratory by animal from receptacle, adapts to 60 minutes, trains with diameter 28mm square column.Animal is placed in to the initiating terminal of spreader, stopwatch is counted it and is passed through the middle 80cm of spreader apart from the time that enters magazine, i.e. incubation period.Setting long latency is 60 seconds.Every animal is trained 10 times every day, for three days on end.Test phase, adapt to after 60 minutes, test respectively rat incubation period, left and right metapedes slippage number of times on diameter cross bar, every Mus is measured 10 times and averages, after every Mus walks to average for 10 times, with the landing number of times at this time point as this group of averaging together with the landing number of times meansigma methods of every Mus on the same group, after being completed, send receptacle back to, with 70% ethanol washing test device again.All tests must keep laboratory temperatures, humidity, intensity of illumination consistent.
2.4 Motion Evoked Potentials detect
In going out each group of rat to be carried out respectively to the compound muscular movement of quadriceps femoris in postoperative 3 weeks, 7 weeks to bring out current potential (CMAP) detection.Rats by intraperitoneal injection 10% chloral hydrate 0.4ml/100g body weight, top skin unhairing, iodine tincture, ethanol disinfection, center, top sagittal is cut scalp, pushes periosteum open, exposes coronal suture and sagittal suture, with 3mm after coronal suture, the other 2mm that opens of center line, for stimulating central point, keeps local skull moistening.Surface, bipolar stimulation electrode stimulating zona rolandica skull, stimulus intensity 2mA-10mA, the wide 0.1ms of ripple, single stimulates.Needle-like recording electrode is placed in quadriceps femoris.Reference electrode is placed in homonymy tibialis anterior, filtering 30Hz-300Hz, and sensitivity 5 μ V, repeat 1-5 time.Ground electrode is placed in root of the tail portion.Record current potential, find maximum amplitude stimulus intensity, analyze wave amplitude and peak incubation period of first negative wave upwards of Motion Evoked Potential (MEP).Thorn electric current increases to twice and closes electric current still cannot to draw waveform negative.
2.5 statistical method
Each group data represent with mean ± standard deviation, relatively adopt t to check between group, and there is statistical significance P≤0.05 for difference.
2.6 result
2.6.1 Beam balance test result
Experimental result is in Table 3, and freely, harmony is good for matched group experimental mouse bilateral hind leg joint motion.It is indefinite that model group experimental mouse expression before by balance beam cross bar is hesitated, exploratory behaviour is more, during by cross bar, bilateral hind leg joint motion is stiff, the coordination ability is poor, according to postoperative 3 weeks, 7 weeks average latencies and metapedes landing number of times result show, with matched group ratio, have statistical significance (P < 0.05 or P < 0.01); With model group comparison, postoperative 3 weeks of each medication therapy groups, 7 weeks average latencies and metapedes landing number of times all reduce (P < 0.05 or P < 0.01), and its Chinese medicine A-C group therapeutic effect is more obvious.
The impact (n=20) of table 3 medicine on postoperative 3 weeks, 7 week incubation period of cerebral palsy neonatal rat and metapedes landing number of times
With relatively #P < 0.05##P < 0.01 of matched group, with model group comparison
*p < 0.05
*p < 0.01
2.6.2 potentiometric detection result
With matched group comparison, within postoperative 3 weeks, 7 weeks, model group experimental mouse hind leg CMAP wave amplitude obviously reduces (P < 0.01), reaches the required stimulus intensity of maximum amplitude and increases; With model group comparison, each treatment group all can make experimental mouse hind leg CMAP wave amplitude obviously raise (P < 0.01), and medicine A-C group effect is more obvious.Refer to table 4.
The impact (n=20) of table 4 medicine on postoperative 3 weeks, 7 weeks rat CMAP of cerebral palsy neonatal rat
With relatively ##P < 0.01 of matched group, with model group comparison
*p < 0.01.
Claims (6)
1. a class can be treated the compound or pharmaceutically acceptable salt thereof of brain diseases, and analog, and the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C).
2. a pharmaceutical composition, it comprises compound claimed in claim 1 and officinal salt and its analog.
3. the pharmaceutical composition of claim 2, it can be ordinary preparation, controlled release preparation, targeting preparation etc.
4. the pharmaceutical composition of claim 2, described compound and officinal salt thereof and its analog are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration.
5. compound and officinal salt thereof and its analog purposes in the medicine of preparation treatment brain diseases described in claim 2.
6. the purposes of claim 5, the brain diseases described in it refers to cerebral palsy.
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| RAJINDER SINGH等: "Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| WANG, XIAO-JIAN等: "The Pharmacophore Hypothesis of Novel Inhibitors for Aurora A Kinase", 《CHINESE JOURNAL OF CHEMISTRY》 * |
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