CN103221414B - Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof - Google Patents
Benzodiazepine derivatives tosylate salts, their polymorphic forms, preparation methods and uses thereof Download PDFInfo
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Abstract
Disclosed are tosylate salts of benzodiazepine derivatives, their polymorphic forms, preparation methods and uses thereof, in particular to a tosylate salt of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester of formula (I), which is a crystalline polymorph, its preparation method and use. The crystalline polymorph of tosylate salt of the compound of formula (I) has a low solvent residue and good stability, and can be used for the clinical treatment.
Description
Technical field
The present invention relates to 3-[(4s) the bromo-1-methyl-6-of-8-(2-pyridyl)-4H-imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
-4-yl] the tosilate polymorphic and its production and use of methyl propionate.
Background technology
The chemistry 3-[(4s by name of formula (I) compound) the bromo-1-methyl-6-of-8-(2-pyridyl)-4H-imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
-4-yl] methyl propionate,
Owing to containing carboxylicesters and benzodiazepine
structure, patent EP1, reports that this compounds is fugitive central nervous system (CNS, Central Nervous System) inhibitor, has the tranquilizing soporific of comprising, anxiety, of flaccid muscles and anticonvulsant action in 183,243.They can be used for the intravenously administrable in following clinical treatment: as calm before the operation in intra-operative, anxiety with forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other narcotic and pain killer and/or simultaneously, as the induction for general anesthesia and the component that maintains; ICU calmness etc., according to patent application CN101,501, report in 019, the free alkali of this compound is not very stable, is only suitable for 5 DEG C of preservations of low temperature, under the condition of 40 DEG C/75% relative humidity (opening), the sample deliquescence storing, color yellowing arrives orange, and shows that with respect to initial content content reduces significantly.Therefore the salt of people's synthesis type (I) compound, hope can increase its chemical stability, for use in the preparation of medicine.
Existing patent application CN101,501,019 and US20,100,075,955 have reported respectively benzene sulfonate, the esilate of formula (I) compound, but the chemistry of institute's salify and optical purity are not very desirable, and recrystallization process also fails to improve significantly its chemistry and optical purity, due to the chemistry of compound and the quality of optical purity, can directly have influence on compound and serve as the steadiness of drug use and medicine, therefore the salt of formula (I) compound of the higher chemistry of exploitation and optical purity just seems and is extremely necessary.Amazingly be, through research, the tosilate of our discoverable type (I) compound, although the same with benzene sulfonate and esilate, its crystallization exists polymorphic, but its toxicity is starkly lower than benzene sulfonate, the tosilate of same up-to-date style (I) compound also has how gratifying advantage, such as the I crystal formation of the tosilate of formula (I) compound of recrystallization in its water, have good chemistry and optical purity, thermostability and water-soluble, result of study shows that the stability of I type crystallization is significantly better than other crystal formation of salify gained.
Summary of the invention
The invention provides the tosilate (being the tosilate of formula (I) compound) of formula (I) compound.Preferably, the stoicheiometry of formula (I) compound and Tosi acid is 1: 1.Preferably, described tosilate is crystal salt.
The object of this invention is to provide a kind of stable formula (I) compound tosilate and polymorphic thereof and prepare the method for these crystal formations.
The tosilate of formula of the present invention (I) compound is easily to obtain, and only formula (I) compound and Tosi acid need be dissolved in respectively in solvent, and the two is reacted, and can obtain the tosilate of formula (I) compound.In the time that the two reacts in ethyl acetate/alcohol class system, as formula (I) compound is dissolved in to ethyl acetate, by acid-soluble Tosi in methyl alcohol, make afterwards the two reaction, operate without recrystallization, crystallization can easily directly obtain the crystallization of IV type, and the chemical purity of product and optical purity all very high.Aforementioned alcohols can be not limited to methyl alcohol, also can use other alcohol, as ethanol, propyl alcohol, Virahol.
We have investigated the series of crystallization product that the tosilate of formula (I) compound obtains under different crystallization conditions, gained crystallized product has been carried out to X-ray powder diffraction and DSC detection, the tosilate of discoverable type (I) compound is under conventional crystallization condition, there is polymorphic, becoming salt system (ethyl acetate/alcohol class) or recrystallization with this understanding, what all obtain is a kind of crystal formation, we are referred to as IV crystal formation, the DSC collection of illustrative plates of the IV type crystallization in the application has charateristic avsorption band near being presented at 196 DEG C and 205 DEG C, X-ray powder diffraction as shown in Figure 7, use Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles and spacing (d value), wherein approximately 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56) have characteristic peak.
The compound of this IV crystal formation, recrystallization in water or moisture organic solvent, can obtain a kind of crystal formation having good stability, and we are called the crystallization of I type.In the application, the DSC collection of illustrative plates of I type crystallization is presented at You Dun peak, approximately 76 DEG C of vicinity of peak value and exists, and this blunt peak just dewaters gradually since 32 DEG C, is unsettled planar water, drying process after this blunt peak can disappear, the DSC of I type crystallization is at approximately 152 DEG C, 195 DEG C and 204 DEG C have charateristic avsorption band, X-ray powder diffraction as shown in Figure 1, use Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles and spacing (d value), wherein approximately 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peak.
Also find the compound of IV crystal formation simultaneously, at methyl alcohol, ethanol, Virahol, recrystallization in the single organic solvent such as acetone, all can generate II crystal formation, recrystallization in above-mentioned system is found in research, although can well improve chemical purity, but do not improve its optical purity, in the application, the DSC collection of illustrative plates of II type crystallization is presented at approximately 196 DEG C and 205 DEG C charateristic avsorption band, X-ray powder diffraction as shown in Figure 3, use Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles and spacing (d value), wherein approximately 6.93 (12.75), 10.46 (8.45), 12.19 (7.25), 13.89 (6.37), 14.33 (6.18), 15.21 (5.82), 15.68 (5.65), 17.47 (5.07), 18.36 (4.83), 19.06 (4.65), 20.95 (4.24), 21.94 (4.05), 23.41 (3.80), 24.51 (3.63) and 24.96 (3.57) have characteristic peak.
The compound of IV crystal formation recrystallization in acetonitrile, obtains III crystal formation.The DSC collection of illustrative plates of the III type crystallization in the application has charateristic avsorption band near being presented at approximately 195 DEG C and 206 DEG C, X-ray powder diffraction as shown in Figure 5, use Cu-Ka radiation, the X-ray powder diffraction representing with 2 θ angles and spacing (d value), wherein 5.76 (15.34), 7.13 (12.39), 11.55 (7.66), 12.65 (6.99), 14.52 (6.10), 17.69 (5.01), 18.32 (4.84), 18.98 (4.67), 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08) have characteristic peak.
The present invention is prepared in the method for I, II, III, the crystallization of IV type, the crystal formation kind that can be used as formula (I) the compound tosilate of raw material use is not particularly limited, can use crystallization or the unformed solid of any crystal formation, the preparation method of formula of the present invention (I) compound tosilate I, II, III, the crystallization of IV type is:
Use some rudimentary organic solvent (alcohols that preferably carbon atom quantity is little, the while can volatilize, ketone, ester class isopolarity organic solvent), water or their the mixing solutions solvent as crystallization; The above-mentioned solvent that preferably carbon atom quantity is less than 6; Make water or moisture organic solvent, can be stable obtain I crystal formation, wherein said organic solvent refers to organic solvent that can be miscible with water, as seen as long as the existence that contains water in system all can obtain I crystal formation; By methyl alcohol, ethanol, Virahol, acetone and other organic solvent as recrystallisation solvent, can be stable obtain II crystal formation; Do recrystallisation solvent with acetonitrile, can be stable obtain III crystal formation; Salify or crystallization in ethyl acetate, alcohols system, all can be stable obtain IV crystal formation.
Concrete, the method for preparation formula provided by the invention (I) compound tosilate crystallization comprises the following steps:
1) by the tosilate of any crystal formation or unformed formula (I) compound, or by formula (I) compound and Tosi acid heating for dissolving in crystallization solvent, cooling, crystallization, wherein said crystallization solvent is rudimentary organic solvent, water or both mixed solvents, described rudimentary organic solvent is alcohols, ketone, the lipid solvent that carbonatoms is less than 6, is preferably methyl alcohol, ethanol, Virahol, acetone, acetonitrile, ethyl acetate or their mixed solvent;
2) filtering for crystallizing washing, dry.
Further, preparation I crystal formation, described crystallization solvent is the aqueous solution of water or organic solvent; Be preferably water.
Preparation II crystal formation, described crystallization solvent is alcohols and ketone, is preferably one or more in methyl alcohol, ethanol, Virahol, acetone.
Preparation III crystal formation, described crystallization solvent is acetonitrile.
Preparation IV crystal formation, described crystallization solvent is ethyl acetate and alcohols mixed solvent, wherein said alcohol is not particularly limited, and can be methyl alcohol, ethanol, propyl alcohol or Virahol, particular methanol.Also be not particularly limited for the two ratio of mixing of ethyl acetate and alcohols, contriver has adopted the mixed solvent of various ratios to test, and can both obtain well IV crystal formation.
The method of recrystallization is not particularly limited, and can be undertaken by common recrystallization working method.For example, can be with raw material formula (I) compound tosilate in organic solvent, water or both mixed solvents, cooling standing crystallization slowly after heating for dissolving, also can take stirring and crystallizing, after crystallization completes, dry after filtration, can obtain needed crystallization.What need special instruction is, the I type crystallization of formula (I) compound tosilate, in water when recrystallization, its chemical purity and chiral purity all increase significantly, become the good stability of crystal formation, formula (I) the compound tosilate of II, III and IV crystal formation is stirred in water, can be converted to stable I type crystallization.The influence factor experimental result of I crystal formation shows, this stable crystal form is good, and dissolvent residual is low, can well use as active constituents of medicine.
Research is found, the I crystal formation of formula (I) compound tosilate, its moisture can be removed through super-dry, or be controlled at below 1%, in the lower situation of moisture controlled, the detection of DSC just no longer shows the existence of the blunt absorption peak of dehydration, but the characteristic absorbance of its X-RAY is consistent, and result shows that crystal formation does not become.
Measure by differential scanning calorimeter (DSC), X-ray powder diffraction, the formula obtaining (I) compound tosilate xln has been carried out to crystal formation research, the dissolvent residual of gained crystallization is detected simultaneously, and test the solubleness of tosilate in water and physiological saline, be about respectively 10mg/ml and 11mg/ml, similar to benzene sulfonate.
The tosilate crystallization of formula (I) compound of preparing according to method of the present invention does not contain or only contains the residual solvent of lower aq, meet the limitation requirement of the relevant pharmaceutical prod residual solvent of state-promulgated pharmacopoeia regulation, thereby I of the present invention, II, III, the crystallization of IV type can be used as medicinal activity composition preferably.
Brief description of the drawings
The X-ray powder diffraction of the tosilate I type crystallization (20110607) of Fig. 1 formula (I) compound.
The DSC spectrogram of the tosilate I type crystallization (20110607) of Fig. 2 formula (I) compound.
The X-ray powder diffraction of the tosilate II type crystallization (20110519) of Fig. 3 formula (I) compound.
The DSC spectrogram of the tosilate II type crystallization (20110519) of Fig. 4 formula (I) compound.
The X-ray powder diffraction of the tosilate III type crystallization (20110523-1) of Fig. 5 formula (I) compound.
The DSC spectrogram of the tosilate III type crystallization (20110523-1) of Fig. 6 formula (I) compound.
The X-ray powder diffraction of the tosilate IV type crystallization (20110530) of Fig. 7 formula (I) compound.
The DSC spectrogram of the tosilate IV type crystallization (20110530) of Fig. 8 formula (I) compound.
Embodiment
Explain in more detail the present invention below with reference to embodiment, embodiments of the invention are only for technical scheme of the present invention is described, and non-limiting the spirit and scope of the invention.
Test testing tool used
1, DSC spectrum
Instrument model: Mettler Toledo DSC l Stare
esystem
Sweep gas: nitrogen
Temperature rise rate: 10.0 DEG C/min
Temperature range: 40-250 DEG C
2, x-ray diffraction pattern
Instrument model: D/Max-Bruker D8Focus X-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha-ray
Scan mode: θ/2 θ, sweep limit: 2-40 °
Voltage: 40KV electric current: 40mA
Embodiment 1: salt synthetic:
Modus ponens (I) compound alkali is (according to patent US200,700,934,75A preparation) 1g is dissolved in 6ml ethyl acetate, then 0.39g Tosi acid (equimolar ratio) is dissolved in 1ml methyl alcohol, and be added drop-wise in the ethyl acetate solution of formula (I) compound alkali, stirring and crystallizing, suction filtration, drying under reduced pressure obtains the tosilate of formula (I) compound, white solid 0.94g, yield is 75.0%.HPLC:99.18%, optical purity: 99.87%.
Embodiment 2
The tosilate 1.0g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 50ml, add in 20ml water, reflux 10min, dissolves solid completely, stop heating, filtered while hot, cooling crystallization, products therefrom spends the night at 45 DEG C of drying under reduced pressure, obtain white solid 0.64g, yield 64%.The X-ray diffraction spectrogram of this crystallized sample is shown in Fig. 1.This crystallization is approximately 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peak, DSC spectrogram is shown in Fig. 2, at approximately 152.02 DEG C, 195.05 DEG C and 204.49 DEG C have charateristic avsorption band, defining this crystal formation is I crystal formation.
Embodiment 3
The tosilate 1.0g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 10ml, add in 50% isopropanol water solution 5.0ml, reflux is dissolved solid completely, stop heating, cooling crystallization, products therefrom spends the night at 45 DEG C of drying under reduced pressure, obtain white solid 0.72g, yield 72%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is I crystal formation.
Embodiment 4
The tosilate 1.0g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 50ml, add in 30ml Virahol, reflux 10min, dissolves solid completely, stop heating, leave standstill crystallization, filter, the crystallization obtaining is spent the night at 45 DEG C of drying under reduced pressure, obtain white solid 0.67g, yield 67%.The X-ray diffraction spectrogram of this crystallized sample is shown in Fig. 3.This crystallization is approximately 6.93 (12.75), 10.46 (8.45), 12.19 (7.25), 13.89 (6.37), 14.33 (6.18), 15.21 (5.82), 15.68 (5.65), 17.47 (5.07), 18.36 (4.83), 19.06 (4.65), 20.95 (4.24), 21.94 (4.05), 23.41 (3.80), 24.51 (3.63) and 24.96 (3.57) have characteristic peak.DSC spectrogram is shown in Fig. 4, has charateristic avsorption band at 195.71 DEG C and 205.44 DEG C, and defining this crystal formation is II crystal formation.
Embodiment 5
The tosilate 0.5g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 50ml, add the acetone of 15ml, reflux 10min, dissolves solid completely, stop heating, stirring and crystallizing, filters, and the crystallization obtaining is spent the night at 45 DEG C of drying under reduced pressure, obtain white solid 0.81g, yield 81%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is II crystal formation.
Embodiment 6
The tosilate 1.0g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 25ml, add in 5.0ml acetonitrile, reflux 10min, dissolves solid completely, stop heating, leave standstill crystallization, filter, the crystallization obtaining is spent the night at 45 DEG C of drying under reduced pressure, obtain white solid 0.63g, yield 63%.The X-ray diffraction spectrogram of this crystallized sample is shown in Fig. 5.This crystallization is approximately 5.76 (15.34), 7.13 (12.39), 11.55 (7.66), 12.65 (6.99), 14.52 (6.10), 17.69 (5.01), 18.32 (4.84), 18.98 (4.67), 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08) have characteristic peak.DSC spectrogram is shown in Fig. 6, has charateristic avsorption band at 195.51 DEG C and 205.96 DEG C, and defining this crystal formation is III crystal formation.
Embodiment 7
The x-ray diffraction pattern of the tosilate sample of test implementation example 1 formula that obtains (I) compound and DSC spectrum, X-ray diffraction spectrogram is shown in Fig. 7.This white solid is approximately 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56) have characteristic peak.DSC spectrogram is shown in Fig. 8, has charateristic avsorption band at 195.98 DEG C and 205.49 DEG C, and defining this crystal formation is IV crystal formation.
Embodiment 8
The tosilate 1.0g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 25ml, add mixing solutions (volume ratio=3: 1) of 5.0ml ethyl acetate and methyl alcohol, reflux is dissolved solid completely, stops heating, leaves standstill crystallization, filter, the crystallization obtaining is spent the night at 45 DEG C of drying under reduced pressure, obtains white solid 0.35g, yield 35%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is IV crystal formation.
Embodiment 9
The tosilate 1.0g of formula (I) compound will be obtained in embodiment 1, add in the round-bottomed flask of 25ml, add mixing solutions (volume ratio=6: 1) of 20ml ethyl acetate and methyl alcohol, reflux is dissolved solid completely, stops heating, leaves standstill crystallization, filter, the crystallization obtaining is spent the night at 45 DEG C of drying under reduced pressure, obtains 0.21 gram of white solid, yield 21%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is IV crystal formation.
Embodiment 10
Modus ponens (I) compound alkali 1g is (according to patent US200,700,934,75A preparation) be dissolved in 6ml ethyl acetate, then 0.39g Tosi acid (equimolar ratio) is dissolved in 1ml ethanol, and is added drop-wise in the ethyl acetate solution of formula (I) compound alkali, stirring and crystallizing, suction filtration, drying under reduced pressure obtains white solid 0.9g, and yield is 72.0%.The X-ray diffraction of this crystallized sample and DSC spectrogram are compared after deliberation, determine that product is IV crystal formation.
Embodiment 11
By the I type of above gained and IV crystal form samples, (this sample is without purification, synthetic crude product) uncoveredly respectively divide placement, investigate in low temperature, heating (40 DEG C, 60 DEG C), illumination (4500Lux) stability of sample under high humidity (RH75%, RH90%) condition.Investigating sample time is 5 days and 10 days, and HPLC detects purity in table 1.
Study on the stability result shows, formula (I) compound tosilate I type and IV type crystallized sample are under the condition of uncovered placement, through low temperature, heating (40 DEG C, 60 DEG C), illumination (4500Lux), stability under the conditions such as high humidity (RH75%, RH90%) is relatively found, illumination is very large on both impacts, sample need keep in Dark Place, and under the condition of low temperature, high temperature, high humidity, the stability of I type crystallization is significantly better than the sample of IV crystal formation.
The tosilate I of table 1, formula (I) compound and the stability comparison of IV crystal form samples
Embodiment 12: the comparative experiments of the benzene sulfonate (calling CNS7056 in the following text) of the tosilate (calling HR7056 in the following text) of formula (I) compound and formula (I) compound on spontaneous activity in mice impact:
Single tail vein injection HR7056, CNS7056 (2.5,5 and 7.5mg/kg, i.v) and Normal group spontaneous activity in mice detailed data are in table 2.
Table 2, HR7056 and the CNS7056 impact on ICR spontaneous activity in mice
Embodiment 13:HR7056 and the CNS7056 impact experiment on ICR mouse righting reflex loss:
The impact experiment detailed data of single tail vein injection HR7056, CNS7056 (15,30 and 60mg/kg, i.v.) and the righting reflex of Normal group mouse is in table 3.
Table 3, HR7056 and the CNS7056 impact on ICR mouse righting reflex loss
Embodiment 14
Under HR7056I crystal form samples long-term (25 DEG C), acceleration (40 DEG C, RH75%) condition, the study on the stability of sample, the results are shown in Table 4.
Table 4, HR7056I crystal form samples are accelerated the study on the stability of sample for a long time
Upper table data presentation, compared with stability data in 4 tables 10 of embodiment in CN101501019A, the present invention has clear superiority.
Embodiment 15: rat acute toxicity test research
Object: this test is carried out SD rat single intravenous injection administration acute toxicity test to HR7056, observe character, degree, dose-effect and time-effect relationship that this medicine may cause toxic reaction, reversibility and on the neural situation that affects, and compare with similar drugs CNS7056, for HR7056 toxicity assessment provides reference information.
Method: 9 groups are established in this test, be respectively CNS7056 low, in, inferior high, high dose group (dosage be respectively 37.5,75,150,300mg/kg), HR7056 is low, in, inferior high, high dose group (dosage be respectively 37.5,75,150,300mg/kg), and solvent control group (0.9% sodium chloride injection that contains 0.375% glycine and 0.0125% Calcium Disodium Edetate, pH value 3.5 ± 0.1).Every group of 10 rats, male and female half and half.Each group all gives trial-product and the reference substance of respective concentration by the volume single intravenous injection of 30mL/kg.Taking administration same day as test the 1st day.
The time and the behavioral activity that after drug administration by injection, record each group of rat righting reflex loss and recovery recover the normal time, and observe rat general status continuous 14 day every day; Test before administration in the 1st day, administration finishes latter approximately 3 minutes, the 2nd, 7,14 days, observed and recorded is respectively organized rat behavior state, the mental status, muscle tone and nociceptive reflex; Test the 1st (before administration), within 4,8,12,15 days, measure body weight; Test and within the 2nd, 5,9,12 days, measure food ration; Test the 15th day, blood sampling after each group of survival rats anesthesia is carried out to hematology, blood biochemical analysis, and carry out gross anatomy observation after imposing euthanasia, the abnormal internal organs of gross examination of skeletal muscle or tissue are carried out to histopathological examination.
Experimental result
Dead animal:
CNS7056300mg/kg group is obviously short of breath after having 3 rats (3/10 ratio, 2 female 1 heros) administration, changes subsequently shallow breathing dead into.Each group of HR7056 has no rats death.
General status:
Hypoactivity after the administration of HR705637.5mg/kg group part rat, walking step state shakiness are until righting reflex loss, and four limbs and abdominal wall muscle are lax, but nociceptive reflex is normal.The visible hypoactivity of all the other rats of this group, prostrate, but righting reflex do not disappear, and muscle tone and nociceptive reflex are all normal.After the administration of HR705675,150,300mg/kg group rat, it is visible righting reflex loss, four limbs and abdominal wall muscle are lax, after reviving, have hypoactivity, walking step state shakiness in short-term, indivedual rats are short of breath as seen, and 300mg/kg rat still visible nociceptive reflex weakens.Most rats such as lick, chew as seen at the unconscious movement.HR7056 respectively organizes rat sleeping duration approximately 3～13 minutes, the duration of symptoms occurring after administration approximately 6～21 minutes, and sleeping duration and duration of symptoms all have dosage correlation, increase and extend with dosage.The each group of CNS7056 is basically identical with general status and the neurobehavioral symptom of same dose HR7056 group rat.
After the recovery of administration above-mentioned symptom on the same day, until observation in 14 days finishes, respectively organize not goodbye abnormal symptom and reaction appearance of rat.
Body weight and food ration:
14 days viewing durations after administration, the each group of HR7056 and CNS7056 is female, male rat Normal-weight increases, and each time point body weight is showed no difference compared with control group, and food ration also shows no obvious abnormalities change.
Hematology and blood biochemistry:
Within after administration 14 days, observe while end, HR7056 and CNS7056 respectively organize rat blood and learn index white blood cell count(WBC) (WBC) and classification, red blood cell count(RBC) (RBC), oxyphorase (HGB), red cell volume (HCT), reticulocyte (RET), platelet count (PLT) and clotting time (PT and APTT) etc., are showed no the abnormal change that medicine is relevant.
Within after administration 14 days, observe while end, HR7056 and CNS7056 respectively organize blood biochemistry of rats index alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate amino transferase (AST), total protein (TP), albumin (ALB), blood sugar (GLU), total bilirubin (TBIL), bilirubin direct (DBIL), total cholesterol (CHOL), triglyceride level (TG), creatine phosphokinase (CK), urea (Urea), creatinine (Crea), pancreatic amylase (AMY-P), lipase (LIP) and ionogen (K+, Na-, Cl-) level etc., be showed no the abnormal change that medicine is relevant.
Gross anatomy is observed:
Within after administration 14 days, observe while end, HR7056 and CNS7056 respectively organize rat and implement substantially to analyse, color, form, quality and the size etc. of the internal organs such as heart, liver, spleen, lung, kidney, gi tract, reproductive system, be showed no the abnormal change relevant to medicine.
Experiment conclusion:
Under this test conditions, SD rat single intravenous injection gives 37.5,75,150, the HR7056 of 300mg/kg.After administration, each dosage can cause hypoactivity that rat occurs that dosage is relevant, instability of gait, righting reflex loss, the symptom such as of flaccid muscles, relevant to the pharmacotoxicological effect of HR7056.After administration, in 14 day observation period, have no rats death and other toxic reaction and occur, the indices such as body weight, food ration, hematology and blood biochemistry are showed no abnormal change.
SD rat single intravenous injection HR7056, maximum tolerated dose is more than or equal to 300mg/kg; SD rat single intravenous injection CNS7056, maximum tolerated dose is 150mg/kg.
Claims (21)
1. the tosilate of formula (I) compound:
2. the tosilate of formula according to claim 1 (I) compound, the stoicheiometry of its Chinese style (I) compound and Tosi acid is 1: 1.
3. the tosilate of formula according to claim 2 (I) compound, wherein said salt is crystal salt.
4. the I type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using Cu-Ka radiation, obtain the X-ray powder diffraction representing with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 1, wherein approximately 6.05 (14.61), 7.18 (12.30), 8.02 (11.02), 12.25 (7.22), 14.00 (6.32), 14.50 (6.10), 15.71 (5.64), 16.68 (5.31), 17.62 (5.03), 18.60 (4.77), 19.69 (4.50), 21.25 (4.18), 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27) have characteristic peak.
5. the II type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using Cu-Ka radiation, obtain the X-ray powder diffraction representing with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 3, wherein approximately 6.93 (12.75), 10.46 (8.45), 12.19 (7.25), 13.89 (6.37), 14.33 (6.18), 15.21 (5.82), 15.68 (5.65), 17.47 (5.07), 18.36 (4.83), 19.06 (4.65), 20.95 (4.24), 21.94 (4.05), 23.41 (3.80), 24.51 (3.63) and 24.96 (3.57) have characteristic peak.
6. the III type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using Cu-Ka radiation, obtain the X-ray powder diffraction representing with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 5, wherein approximately 5.76 (15.34), 7.13 (12.39), 11.55 (7.66), 12.65 (6.99), 14.52 (6.10), 17.69 (5.01), 18.32 (4.84), 18.98 (4.67), 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08) have characteristic peak.
7. the IV type crystallization of the tosilate of formula according to claim 3 (I) compound, it is characterized in that using Cu-Ka radiation, obtain the X-ray powder diffraction representing with 2 θ angles and spacing, described crystallization has X-ray powder diffraction as shown in Figure 7, wherein approximately 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56), there is characteristic peak.
8. prepare a method for crystal salt according to claim 3, it comprises the steps:
1) by the tosilate of any crystal formation or unformed formula (I) compound, or by formula (I) compound and Tosi acid heating for dissolving in crystallization solvent, cooling, crystallization, wherein said crystallization solvent is rudimentary organic solvent, water or both mixed solvents, and described rudimentary organic solvent is alcohols, ketone, lipid solvent or the acetonitrile that carbonatoms is less than 6;
2) filtering for crystallizing washing, dry.
9. method according to claim 8, is characterized in that described crystallization solvent is methyl alcohol, ethanol, Virahol, acetone, acetonitrile, ethyl acetate or their mixed solvent.
10. prepare a method for I type as claimed in claim 4 crystallization, it comprises the step described in claim 8 or 9, and wherein said crystallization solvent is the aqueous solution of water or organic solvent.
11. methods of preparing the crystallization of I type according to claim 10, is characterized in that described crystallization solvent is water.
Prepare the method for II type according to claim 5 crystallization for 12. 1 kinds, it comprises the step described in claim 8 or 9, and wherein said crystallization solvent is alcohols and ketone.
13. methods of preparing the crystallization of II type according to claim 12, is characterized in that described crystallization solvent is one or more in methyl alcohol, ethanol, Virahol, acetone.
Prepare the method for III type according to claim 6 crystallization for 14. 1 kinds, it comprises the step described in claim 8 or 9, and wherein said crystallization solvent is acetonitrile.
Prepare the method for IV type according to claim 7 crystallization for 15. 1 kinds, it comprises the step described in claim 8 or 9, and wherein said crystallization solvent is the mixed solvent of ethyl acetate and alcohols.
16. methods of preparing the crystallization of IV type according to claim 15, wherein said alcohols is methyl alcohol, ethanol, propyl alcohol or Virahol.
Prepare the method for the tosilate of formula (I) compound described in claims 1 to 3 any one for 17. 1 kinds, it comprises makes formula (I) compound and Tosi acid-respons.
18. methods according to claim 17, wherein said reaction is carried out in solvent, and described solvent is the mixed solvent of ethyl acetate and alcohols.
19. methods according to claim 18, wherein said alcohols is methyl alcohol, ethanol, propyl alcohol or Virahol.
20. 1 kinds of pharmaceutical compositions, it is containing the tosilate of formula (I) compound described in good grounds claims 1 to 3 any one or according to crystallization and the pharmaceutically acceptable carrier of the tosilate of the formula of claim 4 to 7 any one (I) compound.
21. according to the tosilate of formula (I) compound described in claims 1 to 3 any one, according to crystallization or the pharmaceutical composition according to claim 20 of the tosilate of formula (I) compound described in claim 4 to 7 any one calm in preparation, sleep peacefully, purposes in anxiety, of flaccid muscles or anticonvulsant drug.
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| EP2450039A1 (en) | 2010-11-08 | 2012-05-09 | PAION UK Ltd. | Dosing regimen for sedation with CNS 7056 (Remimazolam) |
| MA37581B1 (en) | 2012-05-22 | 2016-07-29 | Paion Uk Ltd | Compositions comprising fast-acting benzodiazepines |
| AR094963A1 (en) | 2013-03-04 | 2015-09-09 | Ono Pharmaceutical Co | EXCELLENT OXIDATION REACTION IN THE CONVERSION INDEX |
| CN103232454A (en) * | 2013-05-05 | 2013-08-07 | 王元青 | Medicine for treating mental disease |
| CN104146970A (en) * | 2013-05-05 | 2014-11-19 | 王元青 | Freeze-dried powder injection for treating mental disease |
| CN106804107B (en) * | 2014-07-23 | 2019-03-12 | 江苏恩华络康药物研发有限公司 | New benzodiazepine * analog derivative and application thereof |
| CN106632342B (en) * | 2015-08-07 | 2019-01-25 | 成都倍特药业有限公司 | The 2- naphthalene sulfonate of benzodiazepine * derivative and the preparation method of crystal form and they |
| CN106854197B (en) * | 2015-12-08 | 2020-09-01 | 浙江亚太药业股份有限公司 | Polycrystal of pyridine derivative and preparation method and application thereof |
| CN107266452A (en) * | 2016-04-08 | 2017-10-20 | 四川科伦药物研究院有限公司 | The salt and its crystal form, preparation method and purposes of benzodiazepine * derivatives |
| CN109641000A (en) | 2016-04-14 | 2019-04-16 | Paion英国有限公司 | The benzodiazepine * class of oral sucking and intranasal |
| CN108503644B (en) * | 2016-12-09 | 2019-06-14 | 成都倍特药业有限公司 | A kind of hydrobromate and its preparation method and application of benzodiazepine * derivative |
| CN109422798B (en) * | 2017-08-22 | 2021-07-02 | 江苏恒瑞医药股份有限公司 | Free alkali crystal form of phenylpropionamide derivative and preparation method thereof |
| CN108047229A (en) * | 2017-12-15 | 2018-05-18 | 宜昌人福药业有限责任公司 | Benzodiazepine * class compounds |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
| AU2019222052B2 (en) | 2018-02-13 | 2022-05-12 | Jiangsu Nhwaluokang Pharmaceutical Research And Development Co., Ltd. | Benzodiazepine derivative hydrochloride and crystal form, preparation method, and application thereof |
| ES2803099B2 (en) * | 2019-07-22 | 2021-11-08 | Moehs Iberica Sl | Procedure for obtaining amorphous remimazolam besilate |
| CN114478535B (en) * | 2020-10-23 | 2024-02-09 | 成都苑东生物制药股份有限公司 | Preparation method of crystal form Malun II of benzenesulfonic acid |
| CN113717176B (en) * | 2021-10-09 | 2022-07-05 | 上海再启生物技术有限公司 | Method for preparing remazolam |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
| WO2008007081A1 (en) * | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
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| EP2305647A1 (en) * | 2009-09-18 | 2011-04-06 | PAION UK Limited | Process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4 H-imidazo[1,2-a][1,4]benzodiazepine-4-yl] propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
| WO2008007081A1 (en) * | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
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