CN103804364A - Compound for treatment of ischemic brain damage and application thereof - Google Patents
Compound for treatment of ischemic brain damage and application thereof Download PDFInfo
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- CN103804364A CN103804364A CN201210447104.8A CN201210447104A CN103804364A CN 103804364 A CN103804364 A CN 103804364A CN 201210447104 A CN201210447104 A CN 201210447104A CN 103804364 A CN103804364 A CN 103804364A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 44
- 230000000302 ischemic effect Effects 0.000 title claims abstract description 21
- 208000029028 brain injury Diseases 0.000 title claims abstract description 19
- 230000006931 brain damage Effects 0.000 title abstract 3
- 231100000874 brain damage Toxicity 0.000 title abstract 3
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 11
- 238000007911 parenteral administration Methods 0.000 claims description 3
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- 230000000694 effects Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
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- 238000001914 filtration Methods 0.000 description 15
- 241000700159 Rattus Species 0.000 description 14
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
- 206010028851 Necrosis Diseases 0.000 description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 5
- 230000002490 cerebral effect Effects 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 238000007689 inspection Methods 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
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- 238000002156 mixing Methods 0.000 description 5
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- -1 phosphatide Chemical compound 0.000 description 5
- 229960000502 poloxamer Drugs 0.000 description 5
- 229920001983 poloxamer Polymers 0.000 description 5
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 5
- 229960005486 vaccine Drugs 0.000 description 5
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
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- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical group COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 2
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- 206010048962 Brain oedema Diseases 0.000 description 1
- 0 C*(C(C(*(*)CC1=CC=CCC1)=O)=O)c(cc1N)ccc1OC(C=C*)=C(C=C(C(OCC1CC[U]CC1)=C1)OC)C1=C Chemical compound C*(C(C(*(*)CC1=CC=CCC1)=O)=O)c(cc1N)ccc1OC(C=C*)=C(C=C(C(OCC1CC[U]CC1)=C1)OC)C1=C 0.000 description 1
- KWOLFJPFCHCOCG-UHFFFAOYSA-N CC(c1ccccc1)=O Chemical compound CC(c1ccccc1)=O KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
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- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- 229940127218 antiplatelet drug Drugs 0.000 description 1
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- 230000036541 health Effects 0.000 description 1
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- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
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- 230000002427 irreversible effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
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- 238000000034 method Methods 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
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- 230000001338 necrotic effect Effects 0.000 description 1
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- 230000035778 pathophysiological process Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound, a pharmaceutical composition and new application thereof. The new application refers to application in drugs treating ischemic brain damage. The compound has a very significant effect in treatment of ischemic brain damage.
Description
Technical field
The present invention relates to compound and pharmacologically acceptable salt and its analogue of a class treatment ischemic brain injury, 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 ischemic brain injury thereof.
Background technology
Ischemic brain injury is common disease clinically, and this sick feature is that generation reason is more, and the medicine of clinical application is also a lot, but the result for the treatment of of most drug performance is fainter, so need a kind of medicine of very effectively treating ischemic brain injury badly.
Ischemic brain injury is very high in sickness rate, disability rate and the mortality ratio of China, because of the brain tissue cell hypoxic-ischemic necrosis due to brain ischemic and anoxic, is one of principal disease of serious harm human health.Ischemic brain injury is one and complicated pathophysiological process.At present, the medicine of clinical conventional treatment ischemic brain injury, for example antiplatelet drug, anticoagulant, thrombolytic drug, fine medicine falls and some herbal treatment texts are not good enough, often onset in time, even onset, effect is also bad, causes the irreversible deformity of sufferer, goes into lifelong regret.
The inventor is surprised to find that one group of compound and similar compound or its pharmacologically acceptable salt thereof have an unexpected effect on the medicine of preparation treatment ischemic brain injury, there is no report for this compounds for treating ischemic brain injury at present.
Summary of the invention
The invention provides one group of compound and similar compound thereof or its pharmacologically acceptable salt new purposes in the medicine of preparation treatment ischemic brain injury.
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 ischemic brain injury disease, and analogue, the structure of described compound is as follows:
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E);
Formula (I) 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 the powder injection of head 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 discovery: this compounds can greatly be alleviated ischemic brain injury shape, and from the result of pharmacodynamic experiment, the result for the treatment of of this compounds exceeds the medicine of current clinical application.The exploitation of this new indication is by for to play very large effect to following ischemic brain injury patient's recovery.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.
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
Compound (A);
Compound (B);
Compound (C);
Compound (D);
Compound (E);
Preparation containing compd A lyophilized injectable powder:
1. altogether 100mg and 20mg 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 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:
6. altogether 100mg and 1000mg 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;
7. after mixing dissolving, after stable, first use 0.45um millipore filtration coarse filtration, then use 0.2um filtering with microporous membrane;
8. be distributed into little cillin bottle, add other lyophilized vaccines and auxiliary material;
9. carry out procedural freeze-drying;
10. 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 50mg 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 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 80mg 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 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 E lyophilized injectable powder:
1. altogether 100mg and 500mg 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 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.
Effect embodiment:
1, the provide protection of medicine A-E to rat cerebral ischemia
1.1 laboratory animal and grouping
Wistar male rat, body weight 250-300g, animal rearing is in there being circadian Animal House, and envrionment temperature is controlled at 20 ℃ of left and right, humidity 55% left and right, rat can ad lib and drinking-water.Adapt to after 3 days at Animal House, rat random packet, is divided into sham operated rats (but performing an operation not modeling), model group (modeling is not still treated), medicine (A-E) injection group and positive drug nimodipine group.The experiment administration cycle is one week, and wherein injection preparation group gives intravenously administrable 0.5mg lyophilized injection/kg, and control group gives the physiological saline of equivalent, in the administration of carrying out for the 1st, 4,7 days of experiment.
The foundation of 1.2 animal models
Animal after last administration 1 hour with 3% vetanarcol the dosage intraperitoneal injection of anesthesia with 30mg/kg, femoral arteriography recording blood pressure, femoral venous catheter is for filling with again, plastics tubing inserts right atrium for bloodletting from external jugular vein.Continuous recording electrocardiogram(ECG (EEG), with the method bloodletting of blood drawing, lose blood and while reaching 10.7pKa (80mmHg), separate bilateral common carotid arteries ligation, continue again blood drawing, in the time that blood pressure drops arrives 6.7pKa (50mmHg), the wave amplitude of EEG is very low, but does not disappear, now cause incomplete cerebral ischemic model, maintain 15 minutes.Sham operated rats is only performed an operation, not ligation bilateral common carotid arteries.
The mensuration of 1.3 experimentation on animals parameters
1.3.1 brain water content is measured
After 15 minutes, get 10 animals for every group, open cranium and get brain, after removal rhinencephalon, brain stem, cerebellum, claim brain weight in wet base, then put into baking box and bake to constant weight, claim dry weight, calculate brain water content.
Brain water content calculates according to following formula:
Brain water content=(brain weight in wet base-brain stem weight)/brain weight in wet base × 100%
1.3.2 study of behaviour scoring is observed
Animal is postoperative revive after, separately get 10 animals for every group, carry out study of behaviour condition grading, standards of grading are without 0 point of behavioral function disappearance symptom; Carry rat tail and see that paralysis side forelimb reclaims flexing and can not normally stretch to 1 point, ground; During to a thruster, feel resistance compared with 2 points of the obvious reductions of offside; When rat creeps to 3 points of sideway swivels; With 4 points of the disturbances of consciousness.
1.3.3 cerebral tissue Necrosis volume is measured
Get at random 10 rats in postoperative, after anesthesia, broken end is got brain, removes olfactory bulb, cerebellum and low brain stem, and remaining part is crown is immediately cut into 5, is placed in 2% TTC solution and dyes, and necrotic area is pale asphyxia, be normally redness.Measure the necrosis area of each layer with image analysis system, total area sum is multiplied by bed thickness and is volume (mm
3).
1.4 statistical analysis
Each group rat is observed the data obtained with mean ± standard deviation (x ± s) represent.Between group, carry out t check.
1.5 experimental result
1.5.1 the impact of medicine on rat brain water content
The results are shown in Table 1: sham operated rats brain water content is 75.1%, and model group brain water content is 83.8%.Two groups of comparing differences are remarkable, illustrate that model that this time experiment is done can cause the obvious oedema of cerebral tissue.Have and obviously alleviate cerebral edema effect (p < 0.01) with model group comparative drug A-E group; And the result for the treatment of of medicine group A-E is all better than nimodipine group (p < 0.05).
The impact (n=10) of table 1 different dosing group on rat brain water content
With control group comparison
###p < 0.05, with relatively * P < 0.05**P < 0.01 of model group
1.5.2 study of behaviour scoring observations
The results are shown in Table 2
The impact (n=10) that table 2 different dosing group is learned rat behavior
With relatively * P < 0.05**P < 0.01 of model group
1.5.3 cerebral tissue Necrosis volume measurement result
The results are shown in Table 3.
The impact (n=10) of table 3 different dosing group on cerebral tissue Necrosis volume
With relatively * P < 0.05**P < 0.01 of model group
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 ischemic brain injury, play extraordinary therapeutic action, its result for the treatment of is significantly better than clinical application.
Claims (6)
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. the pharmaceutical composition of 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.
4. the pharmaceutical composition of claim 3, the various preparations described in it can be ordinary preparation, controlled release preparation and targeting preparation etc.
5. topical described in claim 3 is the various preparations of head administration.
6. compound and pharmacologically acceptable salt thereof and its analogue purposes in the medicine of preparation treatment ischemic brain injury described in claim 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210447104.8A CN103804364A (en) | 2012-11-06 | 2012-11-06 | Compound for treatment of ischemic brain damage and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210447104.8A CN103804364A (en) | 2012-11-06 | 2012-11-06 | Compound for treatment of ischemic brain damage and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103804364A true CN103804364A (en) | 2014-05-21 |
Family
ID=50701797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210447104.8A Pending CN103804364A (en) | 2012-11-06 | 2012-11-06 | Compound for treatment of ischemic brain damage and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103804364A (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 |
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|---|---|---|---|---|
| WO2008076415A1 (en) * | 2006-12-14 | 2008-06-26 | Exelixis, Inc. | Methods of using mek inhibitors |
| WO2010106016A1 (en) * | 2009-03-17 | 2010-09-23 | Glaxo Group Limited | Pyrimidine derivatives used as itk inhibitors |
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