CN103804351A - Compound with neuroprotective effect and use thereof - Google Patents
Compound with neuroprotective effect and use thereof Download PDFInfo
- Publication number
- CN103804351A CN103804351A CN201210462057.4A CN201210462057A CN103804351A CN 103804351 A CN103804351 A CN 103804351A CN 201210462057 A CN201210462057 A CN 201210462057A CN 103804351 A CN103804351 A CN 103804351A
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- CN
- China
- Prior art keywords
- compound
- administration
- neuroprotective
- acceptable salt
- analogue
- Prior art date
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Classifications
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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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- 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
-
- 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
- C07D401/14—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 three or more hetero rings
Abstract
The invention discloses a compound, a pharmaceutical composition thereof and new use thereof, wherein the new use means use in neuroprotection. The neuroprotective effect of the compound is very remarkable.
Description
Technical field
The present invention relates to compound and pharmacologically acceptable salt and its analogue that a class has neuroprotective; 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 analogue thereof have the purposes in the medicine of neuroprotective in preparation.
Background technology
Scientific circles, actively finding nerve protection medicine, use it for the nerve injury causing due to a variety of causes at present, exploitation nerve protection medicine, and the molecular mechanism of research neuroprotective is to be extensively subject to the hot issue that Chinese scholars is paid close attention at present.The importance of neuroprotective is well imagined; nearly hundred kinds of the medicines that has neuroprotective of reporting at present; conventional neuroprotective comprises calcium-channel antagonists, free-radical scavengers, glutamate antagonist, cell membrane stability agent etc.; but at present because pathogenesis is unintelligible; therefore very good neuroprotective so far does not produce effect; because patient colony is large and harm is large, need to develop a kind of medicine effectively with extraordinary neuroprotective.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof have in preparation on the medicine of neuroprotective and has an unexpected effect, has neuroprotective at present there is no report for this compounds.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt and there is the new purposes in the medicine of neuroprotective in preparation.
Technical scheme of the present invention is as follows:
The invention provides one group of compound or pharmaceutically acceptable salt thereof with neuroprotective, and analogue, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E).
Above formula compound and analogue thereof or its pharmacologically acceptable 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 administration in administration in head administration, canalis spinalis, spinal fluid administration, local skin administration, dosing eyes, ear or the powder injection of four limbs administration, aqueous injection, microball preparation, nanometer formulation, Liposomal formulation, dendrimer preparation, polyethyleneglycol modified preparation, aqueogel etc.Described parenteral administration preparation is the formulation of suitable intravenous injection, intramuscular injection, subcutaneous injection, bone marrow injection, transdermal administration, mucosa delivery and inhalation.
The inventor studies and finds that this compounds has extraordinary neuroprotective, and from the result of pharmacodynamic experiment, the effect of this compounds exceeds the medicine of current clinical application.The exploitation of this new compound will be significant for the misery of removing sufferer and its family.
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 150mg formula (A) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) 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 freeze-drying therapeutical agent and auxiliary materials;
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 injection:
1. altogether 50mg and 90mg formula (B) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) 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 freeze-drying therapeutical agent and auxiliary materials;
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 injection:
1. altogether 50mg and 1500mg formula (C) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) 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 freeze-drying therapeutical agent and auxiliary materials;
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 injection:
1. altogether 50mg and 1mg formula (D) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) 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 freeze-drying therapeutical agent and auxiliary materials;
4. carry out procedural freeze-drying;
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 8mg formula (E) compound mix and make it dissolving in water for injection to get N.F,USP MANNITOL, phosphatide, glycerine, cyclodextrin derivative, dimethyl sulfoxide (DMSO) 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 freeze-drying therapeutical agent and auxiliary materials;
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.
Effect embodiment
Medicine A-E is to neural provide protection
1 Animal Model and administration
Healthy adult new zealand rabbit, body weight 2kg, male and female half and half.Method according to Luo Wenlong, Zhou Cuiying report is carried out modeling (Initial Experiment of the pHGF opposite repairing of neural injury effect of Chongqing Medical the 32nd the 3rd phase of volume of March in 2003).Preoperative normal raising, postoperative routine gives penicillin 1 abdominal injection every day.Give new zealand rabbit Chloral Hydrate intraperitoneal injection of anesthesia by 500mg/kg body weight, expose and the about 1.5cm of the neural upper buccal branches of surface of separation, cross-section and cut 0.2cm.Two broken ends of fractured bone embed the each 0.2cm of the long silicone tube of 1cm (external diameter 3mm, internal diameter 2mm), merge fixing silicone tube in epineurium along 120 degree clearance gaps with 9-0 silk thread, form the gap of about 6mm between two broken ends of fractured bone, wherein the injection solution (5mg injection) of micro sample adding appliance injection of medicine A-E is used respectively on rabbit right side, every kind of medicine carries out 10 rabbit experiments, every rabbit right nervus lateralis is as medicine group, the physiological saline that equal volume amounts is all injected in left side is as model control group, stroke-physiological saline solution flush operation chamber, 4-0 silk thread layer-by-layer suture otch.
2 experiment calibratings
The detection of 2.1 nerve conduction velocity
Postoperative one month, all rabbit are anaesthetized, and enter along former otch, with the pin electrode dry proximal part that directly excites nerve, on its domination muscle, use concentric needle electrode record, calculate nerve conduction velocity and compound muscle action potential latent period.
The each group of table 1 drug treatment nerve conduction velocity comparative result (m/s, n=10) after month
With relatively * P < 0.05**P < 0.01 of model control group
The each group of table 2 drug treatment compound muscle action potential comparative result in latent period (s, n=10) after month
With relatively * P < 0.05**P < 0.01 of model control group
2.2 nervous tissue dyeing are observed
Get the nerve segment of the each 0.5cm of the nearly far-end of previous anastomotic, be fixed with 10% formalin, after dehydration, embedding, section, dyeing, examine under a microscope.According to the method for Luo Wenlong, Zhou Cuiying report, after taking pictures, with ias, Regenerating Axons quantity, diameter, area and myelin thickness etc. are measured.The results are shown in Table 3-5.
The each group of table 3 drug treatment regenerating nerve examine of diameter comparative result (um, n=10) after month
With relatively * P < 0.05**P < 0.01 of model control group
The each group of table 4 drug treatment after one month regenerating nerve have marrow aixs cylinder Area comparison result (um
2, n=10)
With relatively * P < 0.05**P < 0.01 of model control group
The each group of table 5 drug treatment after one month regenerating nerve have marrow aixs cylinder counting comparative result (n=10)
With relatively * P < 0.05**P < 0.01 of model control group
Comprehensive above-mentioned experimental result is reached a conclusion: compound (A), (B), (C), (D), the medicine of (E) preparing all plays extraordinary neuroprotective.
Claims (9)
1. a compounds or its pharmacologically acceptable salt, and analogue, 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 pharmacologically acceptable salt and its analogue;
3. pharmaceutical composition as claimed in claim 2, it can be ordinary preparation, controlled release preparation, targeting preparation etc.;
4. pharmaceutical composition as claimed in claim 2, described compound and pharmacologically acceptable salt thereof and its analogue are prepared into through topical, the various preparations of gastrointestinal administration or parenteral administration;
5. topical is as claimed in claim 4 administration in administration in head administration, canalis spinalis, spinal fluid administration, local skin administration, dosing eyes, ear or the various preparations of four limbs administration;
6. pharmaceutical composition as claimed in claim 2, described compound and pharmacologically acceptable salt thereof and the purposes of its analogue in neuroprotective;
7. application as claimed in claim 6, described neuroprotective refers to comprising the unify neuroprotective of peripheral nervous system of central nervous system;
8. application as claimed in claim 6, described neuroprotective refers to the protection neural to facial nerve, auditory nerve, optic nerve, cranial nerve, spinal nerves etc.;
As claimed in claim 6 application, described neuroprotective for be people, animal and cell etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210462057.4A CN103804351A (en) | 2012-11-14 | 2012-11-14 | Compound with neuroprotective effect and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210462057.4A CN103804351A (en) | 2012-11-14 | 2012-11-14 | Compound with neuroprotective effect and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103804351A true CN103804351A (en) | 2014-05-21 |
Family
ID=50701786
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210462057.4A Pending CN103804351A (en) | 2012-11-14 | 2012-11-14 | Compound with neuroprotective effect and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103804351A (en) |
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 (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484427A (en) * | 2006-06-30 | 2009-07-15 | 协和发酵麒麟株式会社 | Abl kinase inhibitor |
| US20090286789A1 (en) * | 2005-11-01 | 2009-11-19 | Targegen, Inc. | Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases |
| US20110306599A1 (en) * | 2009-11-25 | 2011-12-15 | Japan Tobacco Inc. | Indole compounds and pharmaceutical use thereof |
| WO2012121939A2 (en) * | 2011-03-04 | 2012-09-13 | Locus Pharmaceuticals, Inc. | Aminopyrazine compounds |
-
2012
- 2012-11-14 CN CN201210462057.4A patent/CN103804351A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090286789A1 (en) * | 2005-11-01 | 2009-11-19 | Targegen, Inc. | Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases |
| CN101484427A (en) * | 2006-06-30 | 2009-07-15 | 协和发酵麒麟株式会社 | Abl kinase inhibitor |
| US20110306599A1 (en) * | 2009-11-25 | 2011-12-15 | Japan Tobacco Inc. | Indole compounds and pharmaceutical use thereof |
| WO2012121939A2 (en) * | 2011-03-04 | 2012-09-13 | Locus Pharmaceuticals, Inc. | Aminopyrazine compounds |
Non-Patent Citations (1)
| Title |
|---|
| KEVIN J. MORIARTY等: "Itk kinase inhibitors: Initial efforts to improve the metabolical stability and the cell activity of the benzimidazole lead", 《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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| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140521 |
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| RJ01 | Rejection of invention patent application after publication |