CN103800328A - Compound for treating neurodegenerative diseases and application thereof - Google Patents
Compound for treating neurodegenerative diseases and application thereof Download PDFInfo
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- CN103800328A CN103800328A CN201210454634.5A CN201210454634A CN103800328A CN 103800328 A CN103800328 A CN 103800328A CN 201210454634 A CN201210454634 A CN 201210454634A CN 103800328 A CN103800328 A CN 103800328A
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Abstract
The invention discloses a compound as well as a drug composition and new application thereof. The compound is newly applied to drugs for treating neurodegenerative diseases. The compound has very obvious effect of treating neurodegenerative diseases.
Description
Technical field
The present invention relates to compound and officinal salt and its analog of a class treatment neurodegenerative diseases, 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 neurodegenerative diseases thereof.
Background technology
Neurodegenerative diseases is a class common nerve degeneration degenerative disease clinically, shows as clinically the disease that judgment, memory, perception, motor capacity in various degree decline, and belongs to chronic progressive external nervous system degeneration disease.The irreversible lesion that such disease is mainly caused by nerve degeneration and many reasons causes.Neurodegenerative diseases has become senior health and fitness's serious disease at present, and along with the process of aging, this sick seriousness highlights day by day.
About pathogenic factor, scientific circles do not come to a conclusion at present, be known as by many reasons and cause, agnogenio owing to producing, therefore the means for the treatment of are very limited, at present take Drug therapy as main, mainly contain levodopa and anticholinergic agent benzhexol etc. clinically at the medicine for the treatment of neurodegenerative diseases, but the effect of these medicines is unsatisfactory, and be attended by comparatively obvious bad side reaction.Neurodegenerative diseases has become social problem, needs a kind of effectively medicine badly and treats.
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 neurodegenerative diseases, there is no report for this compounds for treating neurodegenerative diseases 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 neurodegenerative diseases.
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 neurodegenerative diseases disease, and analog, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E).
Above formula 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 head administration or the injectable powder of nervous system 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 neurodegenerative diseases symptom, and from the result of pharmacodynamic experiment, the effect of this compounds exceeds the medicine of current clinical practice.Great role is played in the recovery of the colony to neurodegenerative diseases by the exploitation of this noval chemical compound, is significant for the misery of removing sufferer and its family.
The specific embodiment
The present invention's compound used can be purchased, and also can be prepared according to disclosed preparation method, and it does not limit therapeutic domain of the present invention.
Medicine Preparation Example
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E).
Preparation containing compd A injection:
1. altogether 50mg and 100mg 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 lyophilizing therapeutic agent and adjuvants;
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.
Preparation containing compd B injection:
1. altogether 50mg and 400mg 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 lyophilizing therapeutic agent and adjuvants;
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.
Preparation containing Compound C injection:
1. altogether 50mg and 20mg 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 lyophilizing therapeutic agent and adjuvants;
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.
Preparation containing Compound D injection:
1. altogether 50mg and 50mg formula (D) 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 lyophilizing therapeutic agent and adjuvants;
4. carry out procedural lyophilizing;
6. carry out the corresponding inspections such as pyrogen, aseptic, visible foreign matters, particulate matter, stand-by after all meeting the requirements.
Preparation containing compd E injection:
1. altogether 50mg and 1mg formula (E) 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 lyophilizing therapeutic agent and adjuvants;
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:
Experiment one
SD rat, male and female half and half, body weight 200g.Stay one group of rat as normal control, all the other rat modelings.After rat anesthesia, be fixed on stereotaxic instrument, wipe out art district hair, partly sterilised, the sagittal otch of 1.5cm is done in center, the crown, and blunt separation periosteum, with reference to rat brain stereotaxic atlas, in the each hole that bores a diameter 1mm of the each corresponding point of bilateral skull, be dissolved in the amino-(3-hydroxy-5-isoxazolyl)acetic acid. solution 1ul (containing amino-(3-hydroxy-5-isoxazolyl)acetic acid. 5ug) of the pH7.4 phosphate buffer of 0.1 mole with the vertical injection of microsyringe.5 minutes inject time of every pin, let the acupuncture needle remain at a certain point 5 minutes, and partly sterilised after rear suture operation otch returns that cage is conventional raises after clear-headed.After modeling success, by rat random packet, be divided into model control group, gavage gives normal saline; Positive drug treatment group, gavage gives galanthamine hydrobromide, and dosage is 10mg/kg; Medicine A group, intramuscular injection, dosage is 10mg/kg; Medicine B group, intramuscular injection, dosage is 5mg/kg; Medicine C group, intramuscular injection, dosage is 1mg/kg; Medicine D group, intramuscular injection, dosage is 2mg/kg; Medicine E group, intramuscular injection, dosage is 0.5mg/kg.After administration, use classical Morris water maze to carry out behavioristics's detection.Water maze is diameter 90cm, the round pool of high 40cm, and depth of water 30cm, indicates 4 place of entry on pool wall, be divided into 4 quadrants, places a circular platform at the 3rd quadrant center, platform is lower than water surface 2cm, 25 ℃ of water temperatures.Each group rat carries out respectively water maze laboratory for one week after administration.Test event is sea trial, water maze laboratory first three day, every day trained rat 3 times.After training, rat is put into pond from 4 place of entry respectively towards pool wall, survey in its 90 seconds and successfully find platform required time, i.e. escape latency, does not find platform if rat enters after water in 90 seconds, is placed on platform and stops 10 seconds.The results are shown in Table 1.
Escape latency test result after the administration of the each treatment group rat of table 1 (unit: second, n=20)
Experiment two
Wistar rat, male and female half and half, body weight 200g.Stay one group of rat as normal control, all the other rat modelings.After rat anesthesia, be fixed on stereotaxic instrument, wipe out art district hair, partly sterilised, with reference to rat brain stereotaxic atlas, right substantia nigra position coordinate is positioned, then at twice 6-hydroxy dopamine is injected to right substantia nigra portion with microsyringe and set up rat model.After modeling success, random packet, is respectively model group matched group, and gavage gives normal saline; Positive controls, gavage gives body of Pramipexole dihydrochloride, and dosage is 1.5mg/kg; Medicine A group, intramuscular injection, dosage is 10mg/kg; Medicine B group, intramuscular injection, dosage is 8mg/kg; Medicine C group, intramuscular injection, dosage is 0.5mg/kg; Medicine D group, intramuscular injection, dosage is 2mg/kg; Medicine E group, intramuscular injection, dosage is 0.1mg/kg.After administration completes, respectively organize the apomorphine of rats by intraperitoneal injection 0.01%, bring out rat circling behavior, record the number of revolutions in each group of rat 1 minute.The results are shown in Table 2.
Number of revolutions comparison (n=20) after the administration of the each treatment group rat of table 2
Experiment three
Wistar rat, male, body weight 200g.Stay one group of rat as Normal group, all the other rat modelings.After rat anesthesia, be fixed on stereotaxic instrument, with reference to rat brain stereotaxic atlas, divide and four times quinolinic acid is injected to right side surcingle shell core and set up rat model with microsyringe.After modeling success, random packet, is respectively model group matched group, and gavage gives normal saline; Positive drug control group, gavage gives tetrabenazine, and dosage is 8mg/kg; Medicine A group, intramuscular injection, dosage is 5mg/kg; Medicine B group, intramuscular injection, dosage is 10mg/kg; Medicine C group, intramuscular injection, dosage is 0.5mg/kg; Medicine D group, intramuscular injection, dosage is 1.5mg/kg; Medicine E group, intramuscular injection, dosage is 0.1mg/kg.After administration 12 hours, each group of rat carried out to behavioristics's experiment, experimental project is classical spacious experiment.Experimental period is the morning, and spacious experimental box is 100cm × 100cm × 50cm black inwall opaque plastics case, and bottom surface is divided into the large grids such as 25 20cm × 20cm.Before experiment, plastic box is cleaned and eliminates residual abnormal smells from the patient, experiment is carried out under quiet environment.Rat is placed in and records rat after plastic box and climbed lattice at 5 minutes and count summation, erect number of times.The number of times of standing more than two fore paw built on stilts 1cm is for erectting number of times.The results are shown in Table 3.
After the administration of the each treatment group rat of table 3, climb the statistics (n=20) that lattice are counted summation (A), erect number of times (B)
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), (C), (D), (E) medicine of preparing all can obviously improve the symptom of neurodegenerative diseases, plays the very well therapeutical effect to neurodegenerative diseases.
Claims (6)
1. a compounds or its officinal salt, and analog, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E).
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. topical described in claim 4, for head administration or for the various preparations of nervous system administration.
6. compound and officinal salt thereof and its analog purposes in the medicine of preparation treatment neurodegenerative diseases described in claim 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210454634.5A CN103800328A (en) | 2012-11-07 | 2012-11-07 | Compound for treating neurodegenerative diseases and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210454634.5A CN103800328A (en) | 2012-11-07 | 2012-11-07 | Compound for treating neurodegenerative diseases and application thereof |
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| Publication Number | Publication Date |
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| CN103800328A true CN103800328A (en) | 2014-05-21 |
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| CN201210454634.5A Pending CN103800328A (en) | 2012-11-07 | 2012-11-07 | Compound for treating neurodegenerative diseases and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11661419B2 (en) | 2019-12-20 | 2023-05-30 | Pfizer Inc. | Benzimidazole derivative compounds and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
| CN1684964A (en) * | 2002-08-14 | 2005-10-19 | 阿斯利康(瑞典)有限公司 | Use of and some novel imidazopyridines |
| CN102712624A (en) * | 2009-11-25 | 2012-10-03 | 日本烟草产业株式会社 | Indole compound and pharmaceutical use thereof |
-
2012
- 2012-11-07 CN CN201210454634.5A patent/CN103800328A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1684964A (en) * | 2002-08-14 | 2005-10-19 | 阿斯利康(瑞典)有限公司 | Use of and some novel imidazopyridines |
| WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
| CN102712624A (en) * | 2009-11-25 | 2012-10-03 | 日本烟草产业株式会社 | Indole compound and pharmaceutical use thereof |
Non-Patent Citations (2)
| Title |
|---|
| DORIS RIETHER等: "5-Aminomethylbenzimdazoles as potent ITK antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| JAGABANDHU DAS等: "Discovery and SAR of 2-amino-5-(thioaryl)thiazoles as potent and selective Itk inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11661419B2 (en) | 2019-12-20 | 2023-05-30 | Pfizer Inc. | Benzimidazole derivative compounds and uses thereof |
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