CN108003164A - Benzodiazepine * class compounds - Google Patents
Benzodiazepine * class compounds Download PDFInfo
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- CN108003164A CN108003164A CN201711347393.3A CN201711347393A CN108003164A CN 108003164 A CN108003164 A CN 108003164A CN 201711347393 A CN201711347393 A CN 201711347393A CN 108003164 A CN108003164 A CN 108003164A
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- 0 *CC[C@@](c1ncc(*)[n]1-c1c2cc(*)cc1)N=C2c1ncccc1 Chemical compound *CC[C@@](c1ncc(*)[n]1-c1c2cc(*)cc1)N=C2c1ncccc1 0.000 description 1
Classifications
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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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to compound and preparation method thereof shown in a kind of formula (I), and the application in antithrombotic reagent or cardiovascular medicament is prepared.
Description
Technical field
The present invention relates to a kind of short 3- benzodiazepinesClass compound and preparation method thereof, and compound shown in formula (I)
As application of the antithrombotic reagent in cardiovascular medicament composite preparation.
Background technology
Benzodiazepines class medicine is clinically widely used in antianxiety, calmness and hypnosis.As first water solubility
Benzodiazepines analog derivative, midazolam are widely used for clinical sedation, hypnosis, analgesia, anti-epileptic, antianxiety and complete
Body is anaesthetized.After midazolam inputs human body as arcotic, Alpha-hydroxy miaow can be oxidized to by Cytochrome P450 isodynamic enzyme and is reached
Azoles logical sequence.But the oxide still has pharmacological activity, thus anesthetic effect time length, revival are slow.Therefore the research and development anesthesia induction time
The Novel benzodiazepine grass class soluble derivative hurry up, held time short is paid attention to by Pharmaceutical Chemist always.
Chemical entitled 3- [(4S) -8- bromo- 1- methyl -6- (2- pyridine radicals) -4H- imidazoles [1,2-a] of formula (II) compound
[Isosorbide-5-Nitrae] benzodiazepine -4- bases] methyl propionate,
Wherein, R is hydrogen, methyl, ethyl, isopropyl.
It is short-acting central nervous system (CNS, Central Nervous that such compound is reported in patent EP1183243
System) inhibitor, having includes tranquilizing soporific, antianxiety, of flaccid muscles and anticonvulsant action.Available for following clinical treatment
Intravenously administrable in scheme:Operation consent calmness, antianxiety and forgetting purposes in during such as performing the operation；Short-term diagnosis, operation or
Associated with conscious sedation during endoscopic procedure；Before other anesthetic and anodyne is applied and/or at the same time, as whole body
The induction of anesthesia and the component of maintenance；ICU calmness etc..The compound metabolism is rapid, is metabolized, can lead to independent of cell P450 enzymes
A variety of organ metabolism are crossed, and its metabolite activity is very low, reduces the interaction between medicine, while be also metabolic organ
The use of function impaired subjects provides possibility.
But compound shown in formula (II) is extremely unstable, in the influence factor experiment of forced degradation, it is easy to produce drop
Impurity is solved, the content that these degradation impurities have is seldom, it is necessary to which prolonged separation and concentration carries out Structural Identification, up to now, still
Have not seen the relevant report of the separation in relation to these degradation impurities, structural confirmation and application thereof research.
The content of the invention
We have found that the compound is very unstable, can produce more degraded when carrying out stability study to formula (II)
Impurity.Therefore, by compound shown in formula (II) and benzene sulfonic acid or p-methyl benzenesulfonic acid into salt to increase its stability, find its benzene sulphur
Hydrochlorate or tosilate are greatly enhanced than the stability of its base, but can still be produced in the stability study of forced degradation
Degradation impurity, but these impurity find no document report mistake before this.We spend the time more than a year, pass through preparation
Type liquid phase is separated these impurity, and carries out finishing structure confirmation, and discovery wherein has the structural formula of a degradation impurity such as
Structure shown in formula (I)：
Wherein, R is hydrogen, methyl, ethyl, isopropyl.
Then, our structures to the impurity have carried out study on the synthesis.
Therefore, it is an object of the invention to provide the degradation impurity of compound shown in a kind of formula (II), have shown in formula (I)
Structure.Another object of the present invention is to provide the synthetic method of structure shown in a kind of formula (I), it is characterised in that shown in formula (II)
Compound is hydrolyzed under reaction with alkali and obtains；
Further, wherein the hydrolysising reacting temperature is -40~0 DEG C.
Another object of the present invention also resides in the synthetic method for providing structure shown in a kind of formula (I), by formula (II) shownization
Reaction is first hydrolyzed with alkali and then carries out bromo-reaction again and obtains for compound；
Further, the temperature that with alkali hydrolysis occurs for compound shown in formula (II) is~100 DEG C；
Further, the brominated reagent of the bromo-reaction is hydrogen bromide, acetyl bromide, bromine, NBS；
Further, the temperature of the bromo-reaction is -10~110 DEG C；
Further, the bromo-reaction occurs in non-protonic solvent；
Further, the aprotic solvent of the bromo-reaction be selected from tetrahydrofuran, acetonitrile, DMF, acetone, dichloromethane,
Chloroform, dichloroethanes, toluene, dimethylbenzene are any or it is combined.
Further, in above two method, the hydrolysis occurs in protonic solvent；
Further, the protonic solvent of the hydrolysis is methanol, ethanol, isopropanol, butanol, water are any or it
Combination；
Further, the alkali for sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate,
Any or its combination of potassium carbonate.
Further, the separation of compound shown in formula (I) of the present invention, purification process are selected from column chromatography, recrystallization or preparative
Any of liquid phase separation purifying or its combination.
Further, recrystallization method of the present invention for compound shown in formula (I) acylate methanol, ethanol,
Carried out in acetone, 2- butanone any or its combination.
Further, the acylate of compound refers to hydrochloride, hydrobromate, sulfuric acid shown in formula (I) of the present invention
Salt, nitrate, oxalates, maleate, tosilate or toluene fulfonate.
Further, the condition that column chromatography for separation of the present invention refines is that eluant, eluent is ethyl acetate-light petrol, second
Any or its combination of acetoacetic ester-n-hexane, carries out isocratic or gradient elution, collects product fraction, concentration or lyophilization,
To obtain the final product.
Further, the refined condition of preparative liquid of the present invention phase separation be mobile phase is methanol-acetonitrile, methanol-
Any or its combination of acetonitrile-water, methanol-water, carries out isocratic or gradient elution, collects product fraction, concentration or lyophilized dry
It is dry, to obtain the final product.
Compound shown in the formula (I) of the present invention is used as the application of standard items or reference substance in Pharmaceutical Analysis.
Inventor has found that compound shown in formula of the invention (I) has preferable by the research to compound shown in formula (I)
Antithrombotic acitivity, and its toxicity is conducted a preliminary study.Therefore, another object of the present invention is to provide formula (I) institute
Application of the compound or its composition stated in antithrombotic reagent.Thrombotic diseases are myocardial infarction, ischemic cardiomyopathy, brain
Thrombus, cerebral embolism, cerebral infarction, transient ischemic attack or lacunar infarction.Another object of the present invention is to provide one
Kind new thrombosis resisting composition, the compound in composition shown in the formula (I) containing effective dose, or its is pharmaceutically acceptable
Salt, stereoisomer, dynamic isomer.
The pharmaceutically acceptable salt of formula (I) compound refers to hydrochloride, hydrobromate, sulfate, nitric acid in the present invention
Salt, oxalates, maleate, tosilate or toluene fulfonate.
Formula (I) compound is emerged from by pharmaceutical preparation, medical instrument, daily chemical product form in the present invention；The medicine
Thing preparation, medical instrument, the form of daily chemical products are hydrogel, frothy gel, plastics, cataplasm, freeze-dried powder, aqua, gas
Mist agent, suppository, externally-applied liniment, ointment.
The drug excipient of the pharmaceutical preparation of formula (I) compound in the present invention, including traditional antiplastering aid, adhesive, collapse
Solve agent, filler, diluent, glidant, lubricant and preservative.
Adhesive include but is not limited to gelatin, cellulose, modified cellulose (such as microcrystalline cellulose), methylcellulose,
Polyvinyl pyrrolidone, starch, sucrose and polyethylene glycol；Particularly preferred polyvinyl pyrrolidone and/or microcrystalline cellulose.One
In a preferred embodiment, the content of antiplastering aid is from 0.001 to 30 weight %, in the range of more preferably 0.1 to 25 weight %.
Filler and/or diluent, be preferably selected from but be not restricted to by cellulose, DI-CALCIUM PHOSPHATE, lactose, sucrose, glucose,
The group that mannitol, sorbierite and calcium carbonate are formed；Particularly preferred microcrystalline cellulose and lactose.In a preferred embodiment
In, the content of filler and/or diluent is from 0.001 to 90 weight %, more preferably 0.1 to 80 weight %, and most preferably 10 to 75
In the range of weight %.
Lubricant, such as magnesium stearate, stearic acid and hard ester.In a preferred embodiment, the content of lubricant from
In the range of 0.001 to 5.0 weight %.
Disintegrant, such as Ac-Di-Sol (cross-linked carboxymethyl cellulose sodium), crosslinked polyethylene Pyrrolizidine ketone and shallow lake
Powder sodium glycollate.In a preferred embodiment, the content of disintegrant is in the range of 0.001 to 5.0 weight %.
Antioxidant, such as VitAVitE, vitamin C, retinyl palmitate and selenium；Cysteine, first sulphur ammonia
Acid, citric acid, sodium citrate, methyl benzoate and propyl benzoate.
Brief description of the drawings
The HPLC figures of compound (R is methyl) shown in Fig. 1 formulas (I),
The 1H-NMR figures of compound (R is methyl) shown in Fig. 2 formulas (I)
The mass spectrogram ([M-H]+) of compound (R is methyl) shown in Fig. 3 formulas (I)
The mass spectrogram ([M+H]+) of compound (R is methyl) shown in Fig. 4 formulas (I)
The mass spectrogram ([M+H]+) of compound (R is hydrogen) shown in Fig. 5 formulas (I)
The mass spectrogram ([M-H]+) of compound (R is ethyl) shown in Fig. 6 formulas (I)
The mass spectrogram ([M+H]+) of compound (R is isopropyl) shown in Fig. 7 formulas (I)
Embodiment
The present invention is further described in detail with reference to embodiment, the embodiment provided is only for explaining
The bright present invention, the scope being not intended to be limiting of the invention.The particular technique that is not specified in embodiment or condition, according to ability
The described technology of document or condition in domain are carried out according to product description.
In an embodiment of the present invention,
HPLC：Analytical column：DiamonsilTM C18(250mm×4.6mm)；Mobile phase：0.01mol·L-1Potassium dihydrogen phosphate
(0.3mmol·L-1Dodecyl sodium sulfate)-acetonitrile (65：35)；Flow velocity：1ml·min-1；Ultraviolet detection wavelength：240nm；
Sample size：10μl.
1H-NMR：AVANCE III 500M total digitalization superconduction nuclear magnetic resonance spectrometers
Mass spectrum：Bruker APEX IV Fourier transform synchrometers.
Embodiment 1：The preparation of compound (R is methyl) shown in formula (I)
Compound (R is methyl) shown in 5g formulas (II) is dissolved in 50ml methanol, -40 DEG C is cooled to, 10% hydrogen is added dropwise
Aqueous solution of sodium oxide tune pH makes reaction solution keep the pH value all the time to 9~10, keeps reaction temperature -40~-30 DEG C stirring extremely
Reaction is completed, and pH to 6~7 is washed with diluted hydrochloric acid aqueous solution, is extracted with 200ml dichloromethane, dichloromethane layer anhydrous slufuric acid
Magnesium is dried overnight, concentration, and crossing column, (eluant, eluent is ethyl acetate：Petroleum ether=1：15), eluent is concentrated under reduced pressure, and residue is with less
Amount ethanol is heated to 60 DEG C, adds 1g oxalic acid, stirs 30min, is cooled to 0~5 DEG C of stirring and crystallizing, filters, filter cake bicarbonate
Sodium neutralizes, dry, obtains compound 0.96g, HPLC area normalization methods shown in formula (I), measures its content as 99.7%.
Mp：210.2 DEG C~211.9 DEG C
MS：425.0[M+H]+, 423.1 [M-H]+
1H-NMR (500MHz, DMSO-d6)
δ：0.91~1.08 (m, 1H), 2.30 (s, 3H), 2.50~2.60 (m, 3H), 3.56 (s, 1H), 4.04~4.06
(d, 1H), 6.81 (d, 1H), 7.47~7.49 (m, 1H), 7.61~7.65 (m, 2H), 7.85~7.87 (m, 1H), 7.91~
7.95 (m, 1H), 8.10~8.11 (m, 1H), 8.53~8.54 (m, 1H) 12.07 (s, 1H).
Embodiment 2：The preparation of compound (R is hydrogen) shown in formula (I)
Compound (R is hydrogen) shown in 5g formulas (II) is dissolved in 35ml ethanol, is cooled to -30~-20 DEG C, 5% hydrogen is added dropwise
Aqueous solutions of potassium tune pH to 10~12 is aoxidized, keeps the pH value, -20~-10 DEG C of insulation reactions during the reaction, reaction, which finishes, to be added
Enter 200ml dichloromethane, pH to 6~7 is washed with acetic acid aqueous solution, anhydrous magnesium sulfate is dried overnight, and concentration, crosses column (eluant, eluent
For ethyl acetate：N-hexane=1：20), eluent is concentrated under reduced pressure, and residue is heated to 45 DEG C with a small amount of acetone, adds 1.6g horses
It is next sour, 30min is stirred, is cooled to 0~5 DEG C of stirring and crystallizing, is filtered, filter cake is neutralized with sodium acid carbonate, dry, is obtained shown in formula (I)
Compound 1.57g.
Mp：203.4 DEG C~205.1 DEG C
MS：411.2[M+H]+
Embodiment 3：The preparation of compound (R is ethyl) shown in formula (I)
Compound (R is ethyl) shown in 5g formulas (II) is dissolved in 60ml isopropanols, is cooled to -10~-5 DEG C, is added in batches
Enter a hydronium(ion) lithia 0.5g, be stirred at room temperature to reaction and complete, add 200ml dichloromethane, pH is washed with dilute hydrochloric acid solution
To 6~7, anhydrous magnesium sulfate is dried overnight, concentration, and crossing column, (eluant, eluent is ethyl acetate：Petroleum ether=1：10), eluent depressurizes
Concentration, residue are separated with preparative liquid phase, and mobile phase is methanol：Acetonitrile：Water：Triethylamine=45：25：30：0.01, connect
Receive cut and concentrate, obtain compound 1.15g shown in formula (I).
Mp：213.4 DEG C~215.1 DEG C
MS：437.1[M-H]+
Embodiment 4：The preparation of compound (R is isopropyl) shown in formula (I)
Compound (R is isopropyl) shown in 5g formulas (II) is dissolved in 30ml n-butanols and 10ml water and is down to 0 DEG C, is added in batches
Enter potassium carbonate 1.58g, be stirred at room temperature to reaction and complete, add 200ml dichloromethane, pH to 6~7 is washed with aqueous hydrochloric acid solution,
Anhydrous magnesium sulfate is dried overnight, concentration, and crossing column, (eluant, eluent is ethyl acetate：Hexamethylene=1：15), eluent is concentrated under reduced pressure, residual
Stay thing to be heated to 50 DEG C with a small amount of methanol, add 1.6g fumaric acid, stir 30min, be cooled to 0~5 DEG C of stirring and crystallizing, filter,
Filter cake is neutralized with sodium acid carbonate, obtains compound 1.48g shown in formula (I).
Mp：214.6 DEG C~216.4 DEG C
MS：453.4[M+H]+
Embodiment 5：The preparation of compound (R is isopropyl) shown in formula (I)
Compound (R is isopropyl) shown in 5g formulas (II) is dissolved in 15ml methanol and 10ml water, room temperature adds hydroxide
Sodium 0.45g, 45 DEG C of stirrings to reaction are completed, add 300ml dichloromethane, pH to 6~7, anhydrous sulphur are washed with aqueous hydrochloric acid solution
Sour magnesium is dried overnight, concentration, and residue 50ml toluene dissolves, and is heated to 110 DEG C, 40% hydrogen bromide acetic acid solution is added dropwise
8ml, in 110~120 DEG C of reactions to finishing, 60 DEG C of solvents that are concentrated under reduced pressure out, residue 100ml dichloromethane dissolves, with full
Neutrality is neutralized to sodium bicarbonate solution, the drying of dichloromethane layer anhydrous sodium sulfate, is filtered, concentration, residue crosses column (eluant, eluent
For ethyl acetate：Petroleum ether=1：30), eluent is concentrated under reduced pressure, and residue is heated to 45 DEG C with a small amount of 2- butanone, adds 2g wine
Stone acid, stirs 30min, is cooled to 0~5 DEG C of stirring and crystallizing, filters, and filter cake is neutralized with sodium acid carbonate, dry, obtains shown in formula (I)
Compound 0.36g.
Embodiment 6：The preparation of compound (R is ethyl) shown in formula (II)
Compound (R is ethyl) shown in 5g formulas (II) is dissolved in 25ml ethanol and 5ml water, room temperature adds sodium carbonate
1.5g, 65 DEG C of stirrings to reaction are completed, add 300ml dichloromethane, pH to 6~7, anhydrous magnesium sulfate are washed with aqueous hydrochloric acid solution
It is dried overnight, concentrates, residue 50ml xylene solubles, be heated to 110 DEG C, acetyl bromide 10ml is added dropwise, at 110~120 DEG C
Reaction is to finishing, and 80 DEG C of solvents that are concentrated under reduced pressure out, residue 100ml dichloromethane dissolves, with saturated sodium bicarbonate solution
With to neutrality, the drying of dichloromethane layer anhydrous sodium sulfate, is filtered, concentration, residue is separated with preparative liquid phase, mobile phase
For methanol：Acetonitrile：Water：Triethylamine=45：25：30：0.01, receive cut and concentrate, obtain compound 0.47g shown in formula (I).
Embodiment 7：Pharmacological experimental method and result of the compound (R is methyl) shown in formula (I) to platelet aggregation activity
Experimental method：Rabbit 2 is taken, with lidocaine local anaesthesia, operation separation arteria carotis communis takes blood, takes 3.8%
Sodium citrate 1:9 anti-freezings, centrifuge 10min with 500r/min, prepare platelet rich plasma (PRP), remainder is again with 3000r/
Min is centrifuged, and prepares platelet poor plasma (PPP), and platelet aggregation test is carried out by turbidimetry.Measure and 240 μ of PRP are added in pipe
L, 30 μ L of various concentrations test medicine, 37 DEG C of temperature incubate 5min, respectively with 30 μ L adenosine diphosphate (ADP)s sodium salts (ADP) (final concentration of 10 μ
Mol/L it is) derivant, observes and records maximum aggregation rate in 5min.Blank control aspirin is made with DMSO and makees positive control, is counted
Calculate the L-Arginine (AIR) of target compound.
Test result：Formula (I) compound of the present invention is listed in table 1 Platelet Aggregation in Rabbits activity data is induced to ADP,
Positive control drug is aspirin
Inhibitory activity of 1 part of compounds of the present invention of table to the ADP Platelet Aggregation in Rabbits induced
Above pharmacology data shows that formula (I) compound of the present invention can suppress platelet aggregation, and with than Ah Si
The stronger inhibition on platelet aggregation of woods.
R also obtains similar results when being hydrogen, ethyl, isopropyl.
Claims (16)
- A kind of 1. 3- benzodiazepinesClass compound, or its pharmaceutically acceptable salt, stereoisomer, dynamic isomer, The compound has structure shown in formula (I)：Wherein, R is hydrogen, methyl, ethyl, isopropyl.
- 2. compound according to claim 1, it is characterised in that the pharmaceutically acceptable salt of formula (I) compound is Refer to hydrochloride, hydrobromate, sulfate, nitrate, oxalates, maleate, tosilate or toluene fulfonate.
- 3. the method that one kind prepares compound shown in formula described in claim 1 (I), it is characterised in that by chemical combination shown in formula (II) Thing is hydrolyzed reaction with alkali and obtainsWherein, R is hydrogen, methyl, ethyl, isopropyl.
- 4. according to the method described in claim 3, it is characterized in that, the temperature of reaction is hydrolyzed with alkali for compound shown in formula (II) Spend for -40~0 DEG C.
- 5. the method that one kind prepares compound shown in formula described in claim 1 (I), it is characterised in that by chemical combination shown in formula (II) Thing is hydrolyzed reaction and then carries out bromo-reaction and obtains with alkali.
- 6. according to the synthetic method described in claim 5, it is characterised in that the brominated reagent of the bromo-reaction for hydrogen bromide, Acetyl bromide, bromine, NBS.
- 7. the synthetic method according to claim 3 or 5, it is characterised in that the alkali for sodium hydroxide, potassium hydroxide, Any or its combination of lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate.
- 8. according to the synthetic method described in claim 5, it is characterised in that compound shown in formula (II) is hydrolyzed instead with alkali The temperature answered is room temperature -40~100 DEG C.
- 9. any synthetic method according to claim 5,6, it is characterised in that the temperature of the bromo-reaction for- 10~110 DEG C.
- A kind of 10. 3- benzodiazepinesClass compound, or its pharmaceutically acceptable salt, stereoisomer, dynamic isomer, Application in antithrombotic reagent is prepared, the compound have structure shown in formula (I)：Wherein, R is hydrogen, methyl, ethyl, isopropyl.
- 11. the application described in claim 10, it is characterised in that the pharmaceutically acceptable salt of formula (I) compound refers to salt Hydrochlorate, hydrobromate, sulfate, nitrate, oxalates, maleate, tosilate or toluene fulfonate.
- 12. a kind of thrombosis resisting composition is preparing the application in being used to prevent and treat cardiovascular and cerebrovascular diseases medicament, the combination It is different containing the compound described in the formula (I) described in a effective amount of claim 1 or its pharmaceutically acceptable salt, solid in thing Structure body, dynamic isomer.
- 13. application according to claim 12, it is characterized in that the cardiovascular and cerebrovascular disease refers to thrombotic diseases.
- 14. application according to claim 13, wherein thrombotic diseases are myocardial infarction, ischemic cardiomyopathy, cerebral thrombus, brain bolt Plug, cerebral infarction, transient ischemic attack or lacunar infarction.
- 15. application according to claim 12, it is characterized in that：The application is by pharmaceutical preparation, medical instrument, daily chemical product Form emerges from；The pharmaceutical preparation, medical instrument, the form of daily chemical products be hydrogel, frothy gel, plastics, bar Cloth agent, freeze-dried powder, aqua, aerosol, suppository, externally-applied liniment, ointment.
- 16. one kind is used to prevent and treat cardiovascular and cerebrovascular diseases medicament composition, it is characterized in that：The pharmaceutical composition contains treatment A effective amount of (I) compound of formula according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomerism Body, pharmaceutic adjuvant, pharmaceutical carrier or auxiliary material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201711347393.3A CN108003164A (en) | 2017-12-15 | 2017-12-15 | Benzodiazepine * class compounds |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711347393.3A CN108003164A (en) | 2017-12-15 | 2017-12-15 | Benzodiazepine * class compounds |
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| CN108003164A true CN108003164A (en) | 2018-05-08 |
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ID=62059310
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| CN201711347393.3A Pending CN108003164A (en) | 2017-12-15 | 2017-12-15 | Benzodiazepine * class compounds |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209932A (en) * | 2019-07-12 | 2021-01-12 | 成都倍特药业股份有限公司 | New solid form of compound hydrobromide, preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1183243B1 (en) * | 1999-05-14 | 2006-02-08 | CeNeS Limited | Short-acting benzodiazepines |
| EP3162804A1 (en) * | 2014-07-23 | 2017-05-03 | Li, Qingeng | New benzodiazepine derivative and use thereof |
| WO2017081483A1 (en) * | 2015-11-13 | 2017-05-18 | Mavalon Therapeutics Limited | Substituted tricyclic 1,4-benzodiazepinone derivatives as allosteric modulators of group ii metabotropic glutamate receptors |
-
2017
- 2017-12-15 CN CN201711347393.3A patent/CN108003164A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1183243B1 (en) * | 1999-05-14 | 2006-02-08 | CeNeS Limited | Short-acting benzodiazepines |
| EP3162804A1 (en) * | 2014-07-23 | 2017-05-03 | Li, Qingeng | New benzodiazepine derivative and use thereof |
| WO2017081483A1 (en) * | 2015-11-13 | 2017-05-18 | Mavalon Therapeutics Limited | Substituted tricyclic 1,4-benzodiazepinone derivatives as allosteric modulators of group ii metabotropic glutamate receptors |
Non-Patent Citations (4)
| Title |
|---|
| JU-YE RO: "Anti-platelet Effects of Dimethyl Sulfoxide via Down-regulation of COX-1 and TXA2 Synthase Activiy in Rat Plateles", 《BIOMEDICAL SCIENCE LETTERS》 * |
| YAN LIU: "Design, Synthesis, and Biological Evaluation of Novel CNS 7056 Derivatives as Sedatives in Rats and Rabbits", 《CHEMICAL BIOLOGY & DRUG DESIGN》 * |
| YAN LIU: "Design, Synthesis, and Biological Evaluation of Novel CNS 7056 Derivatives", 《CHEMICAL BIOLOGY & DRUG DESIGN》 * |
| 赖东生: "二甲基亚砜（DMSO）对血小板体外聚集功能的影响", 《中国输血杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209932A (en) * | 2019-07-12 | 2021-01-12 | 成都倍特药业股份有限公司 | New solid form of compound hydrobromide, preparation method and application thereof |
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Address after: 443005 No. 19 Dalian Road, Yichang Development Zone, Hubei Applicant after: Yichang Humanwell Pharmaceutical Co., Ltd. Address before: 443005 Technology Department, Dalian Road, Yichang Development Zone, Hubei, 19 Applicant before: Yichang Humanwell Pharmaceutical Co., Ltd. |
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