CN103221414A - 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
The present invention relates to benzodiazepines
The tosilate and its polymorphic of derivative, their preparation method and purposes, especially 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
- 4- base] methyl propionate (I) tosilate polymorphic and its preparation method and application. The crystallization of obtained formula (I) the compound tosilate of the present invention, dissolvent residual is low, has good stability, and can be preferably applied to clinical treatment.
Description
The tosilate and its polymorphic of benzodiazepines derivative, their preparation method and purposes technical field
The present invention relates to 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridine radicals) -4H- imidazoles [l, 2-a] [l, 4] benzodiazepine Bi
- 4- bases] methyl propionate tosilate polymorphic and its production and use.Background technology
Formula（I) chemical entitled 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridine radicals) -4H- imidazoles [l, 2-a] [l, the 4] benzodiazepine Bi -4- bases] methyl propionate of compound,
Due to the structure containing carboxylate and benzodiazepine * Bi, patent EP1 reports that such compound is short-acting central nervous system in 183,243（CNS, Central Nervous System) inhibitor, with including tranquilizing soporific, antianxiety, of flaccid muscles and anticonvulsant action.The intravenously administrable that they can be used in following clinical treatment：Operation consent calmness, antianxiety and forgetting purposes in during such as performing the operation；Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure；Before other anesthetic and anodyne is applied and/or simultaneously, the induction for general anesthesia and the component of maintenance are used as；ICU calmness etc., according to patent application CN101, is reported, the free alkali of the compound is not very stable in 501,019, is adapted only to 5 °C of preservations of low temperature, in 40 °C/75% relative humidity（It is open）Under conditions of, the sample deliquescence of storage, color yellowing shows that content is significantly reduced to orange, and relative to initial content.Therefore people's synthesis type（I) the salt of compound, it would be desirable to increase its chemical stability, for use in the preparation of medicine.
Existing patent application CN101,501,019 and US20,100,075,955 report formula respectively（I) benzene sulfonate of compound, esilate, but into salt chemistry and optical purity it is less desirable, and recrystallization process fails to significantly improve its chemistry and optical purity, due to the chemistry and the quality of optical purity of compound, directly influence compound can be used as medicine and medicine steadiness, therefore exploitation it is higher chemistry and optical purity formula（I) salt of compound, which just seems, is extremely necessary.It is amazing to be, by research, it has been found that formula（I) the tosilate of compound, although as benzene sulfonate and esilate, it, which is crystallized, has polymorphic, but its toxicity is significantly lower than benzene sulfonate, same to up-to-date style（I) tosilate of compound also has the formula recrystallized in more gratifying advantages, such as its water（I) the I crystal of the tosilate of compound, tool
There are chemistry and optical purity, heat endurance and water solubility well, result of study shows that the stability of I types crystallization is considerably better than into other crystal formations obtained by salt.The content of the invention
The invention provides formula（I) the tosilate of compound（That is formula（I) the tosilate of compound）.Preferably, formula（I) stoicheiometry of compound and Tosi acid is 1: 1.Preferably, described tosilate is crystal salt.
It is an object of the invention to provide a kind of formula of stabilization（I) compound tosilate and its polymorphic and the method for preparing these crystal formations.
The formula of the present invention（I) tosilate of compound is readily available, only need to be by formula（I) compound and Tosi acid are dissolved in solvent respectively, are reacted the two, you can to obtain formula（I) the tosilate of compound.When the two reacts in ethyl acetate/alcohol class system, such as by formula（I) compound is dissolved in ethyl acetate, and Tosi acid is dissolved in into methanol, the two is reacted afterwards, without recrystallization operation, and crystallization can easily directly obtain the crystallization of IV types, and the chemical purity and optical purity of product are all very high.Foregoing alcohols can be not limited to methanol, it is also possible to use other alcohol, such as ethanol, propyl alcohol, isopropanol.
We have investigated formula（I) the series of crystallization product that the tosilate of compound is obtained under different crystallization conditions, X-ray powder diffraction and DSC detections, discoverable type have been carried out to gained crystallized product（I) there is polymorphic in the tosilate of compound under conventional crystallization condition, into salt system（Ethyl acetate/alcohol class）Or recrystallize on this condition, what is obtained is a kind of crystal formation, we term it IV crystal formations, the DSC collection of illustrative plates of IV types crystallization in the application, which is shown near 196 ° 0 and 205 V, characteristic absorption peak, X-ray powder diffraction collection is as shown in Figure 7, radiated using Cu-Ka, with 2 Θ angles and interplanar distance（D values）The X-ray powder diffraction collection of expression, wherein in about 6.29 (14.05), 6.97 (12.67), 11.66 (7.59), 12.03 (7.35), 17.75 (4.99), 18.90 (4.69), there is characteristic peak 19.71 (4.50), 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56).
The compound of the IV crystal formations, recrystallizes in water or aqueous organic solvent, can obtain a kind of crystal formation having good stability, and we are called the crystallization of I types.In the application I types crystallize DSC collection of illustrative plates be shown in about 76 °C of vicinity of peak value You Dun peaks presence, the blunt peak since 32 °C just be gradually dehydrated, be unstable absorption water, the blunt peak can disappear after drying process；The DSC of I types crystallization has characteristic absorption peak, X-ray powder diffraction collection as shown in figure 1, being radiated using Cu-Ka in about 152 °C, 195 °C and 204 °C, with 2 Θ angles and interplanar distance（D values）The X-ray powder diffraction collection of expression, wherein in about 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), there is characteristic peak 24.23 (3.67), 25.22 (3.53) and 27.22 (3.27).
Simultaneously it has also been found that the compound of IV crystal formations, recrystallized in the single organic solvents such as methanol, ethanol, isopropanol, acetone, II crystal formations can be generated, research finds to recrystallize in above-mentioned system, although can be very good to improve chemical purity, but do not improve the DSC collection of illustrative plates that Π types are crystallized in its optical purity, the application and be shown in about
196 °C and 205 °C have characteristic absorption peak, X-ray powder diffraction collection as shown in figure 3, being radiated using Cu-Ka, with 2 Θ angles and interplanar distance（D values）The X-ray powder diffraction collection of expression, wherein in about 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) standing grain Jie 24.96 (3.57) have characteristic peak.
The compound of IV crystal formations is recrystallized in acetonitrile, then obtains III crystal formations.The DSC collection of illustrative plates of type III crystallization in the application, which is shown in about 195 °C and 206 °C, nearby has characteristic absorption peak, and X-ray powder diffraction collection is radiated as shown in Fig. 5 using Cu-Ka, with 2 Θ angles and interplanar distance（D values）The X-ray powder diffraction collection of expression, wherein in 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), there is characteristic peak 19.64 (4.52), 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08).
The present invention is prepared in the method for I, II, III, IV type crystallization, the formula that can be used as raw material（I) the crystal formation species of compound tosilate is not particularly limited, and can use the crystallization of any crystal formation or unformed solid, formula of the invention（I) preparation method of compound tosilate I, II, III, IV types crystallization is：
Use some rudimentary organic solvents（It is preferred that carbon atom quantity it is small, while the alcohols that can be volatilized, ketone, esters polar organic solvent）, water or their mixed solution as crystallization solvent；It is preferred that carbon atom quantity is less than 6 above-mentioned solvent；Using water or aqueous organic solvent, I crystal can be stably obtained, wherein described organic solvent refers to water-miscible organic solvent, it is seen that as long as the presence containing water in system, can obtain I crystal formations；With methanol, ethanol, isopropanol, acetone and other organic solvent as recrystallisation solvent, Π crystal formations can be stably obtained；Recrystallisation solvent is done with acetonitrile, III crystal formations can be stably obtained；Into salt or crystallization in ethyl acetate, alcohols system, IV crystal formations can be stably obtained.
Specifically, the formula that the present invention is provided（I) method of compound tosilate crystallization comprises the following steps:
1) by any crystal formation or unformed formula（I) the tosilate of compound, or by formula（I) compound is dissolved by heating in crystallization solvent with Tosi acid, cooling, crystallization, wherein described crystallization solvent is the mixed solvent of rudimentary organic solvent, water or both, described rudimentary organic solvent is the alcohols, ketone, preferably lipid solvent, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate or their mixed solvent that carbon number is less than 6；
2) filtering for crystallizing and wash, dry.
Further, I crystal is prepared, described crystallization solvent is water or the aqueous solution of organic solvent；Preferably water.Π crystal formations are prepared, described crystallization solvent is alcohols and ketone, the preferably one or more in methanol, ethanol, isopropanol, acetone.
III crystal formations are prepared, described crystallization solvent is acetonitrile.
IV crystal formations are prepared, described crystallization solvent is ethyl acetate and alcohols mixed solvent, wherein described alcohol is not particularly limited, can be methanol, ethanol, propyl alcohol or isopropanol, preferably methanol.The ratio that is mixed for both ethyl acetate and alcohols can obtain IV crystal formations well it is not also specifically limited, the mixed solvent that inventor employs various ratios is tested.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, starting materials of formulae can be used（I) compound tosilate slowly cooling and standings crystallization after organic solvent, water or both in the mixed solvent, heating for dissolving, can also take stirring and crystallizing, after the completion of crystallization, through filtration drying, you can obtain required crystallization.Specifically, formula（I) compound tosilate I types crystallization, when being recrystallized in water, its chemical purity and chiral purity all increase significantly, into crystal formation stability it is good, by the formula of π, m and IV crystal formation（I) compound tosilate is stirred in water, can be converted to stable I types crystallization.The influence factor of I crystal test result indicates that, the stability of crystal form is good, and dissolvent residual is low, can be very good to use as active constituents of medicine.
Research discovery, formula（I) the I crystal of compound tosilate, its moisture can be by drying removal, or control below 1%, in the case of moisture control is relatively low, DSC detection just no longer shows the presence for being dehydrated blunt absworption peak, but its X-RAY characteristic absorption is consistent, as a result shows that crystal formation is unchanged.
Pass through differential scanning calorimeter（DSC), X-ray powder diffraction is determined, to obtained formula（I) compound tosilate crystalline solid has carried out crystal formation research, the dissolvent residual that gained is crystallized is detected simultaneously, and solubility of the tosilate in water and physiological saline is tested, and 10mg/ml and llmg/ml are respectively may be about, it is similar to benzene sulfonate.
Formula prepared by the method according to the present invention（I) the tosilate crystallization of compound is not contained or the only residual solvent containing lower content, meet the limitation requirement about medical product residual solvent as defined in NF, thus I, II, III, IV type crystallization of the present invention can use preferably as medicating active ingredients.Brief description of the drawings
Fig. 1 formulas（I) the tosilate I types crystallization of compound（20110607) X-ray powder diffraction collection.Fig. 2 formulas（I) the tosilate I types crystallization of compound（20110607) DSC spectrograms.
Fig. 3 formulas（I) the tosilate II types crystallization of compound（20110519) X-ray powder diffraction collection.
Fig. 4 formulas（I) the tosilate II types crystallization of compound（20110519) DSC spectrograms.
Fig. 5 formulas（I) the tosilate type III crystallization of compound（X-ray powder diffraction collection 20110523-1).
Fig. 6 formulas（I) the tosilate type III crystallization of compound（DSC spectrograms 20110523-1).
Fig. 7 formulas（I) the tosilate IV types crystallization of compound（20110530) X-ray powder diffraction collection.
Fig. 8 formulas（I) the tosilate IV types crystallization of compound（20110530) DSC spectrograms.Embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate technical scheme, and non-limiting the spirit and scope of the invention.
Experiment tester used
1st, DSC is composed
INSTRUMENT MODEL： Mettler Toledo DSC 1 Stare6 System
Purge gass：Nitrogen
Heating rate： 10.0 °C/min
Temperature range： 40-250°C
2nd, x-ray diffraction pattern
INSTRUMENT MODEL：D/Max-Bruker D8 Focus X-ray powder diffraction instrument
Ray：Monochromatic Cu- Κ alpha rays（λ=1.5406 Α)
Scan mode：The Θ of Θ/2, scanning range： 2— 40ο
Voltage：40KV electric currents：40mA embodiments 1:The synthesis of salt：
Modus ponens（I) chemical combination alkaloids（Prepared according to patent 118200,700,934,75）Lg is dissolved in 6ml ethyl acetate, then by 0.39g Tosis acid（Equimolar ratio）It is dissolved in 1ml methanol, and is added drop-wise to formula（I) in the ethyl acetate solution of chemical combination alkaloids, stirring and crystallizing, suction filtration is dried under reduced pressure to obtain formula（I) the tosilate of compound, white solid 0.94g, yield is 75.0%. HPLC:99.18%, optical purity： 99.87%.Embodiment 2
Formula will be obtained in embodiment 1（I) the tosilate 1.0g of compound, in the round-bottomed flask for adding 50ml, add in 20ml water, be heated to reflux 10min, be completely dissolved solid, stop heating, filter while hot, cooling crystallization, products therefrom is dried under reduced pressure overnight at 45 °C, obtain white solid 0.64g, yield 64%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 1.The crystallization is in about 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), there is characteristic peak 25.22 (3.53) and 27.22 (3.27), DSC spectrograms are shown in Fig. 2, there is characteristic absorption peak in about 152.02 °C 195.05 °C and 204.49 °C, the crystal formation is defined for I crystal formations.Embodiment 3
Formula will be obtained in embodiment 1（I) the tosilate 1.0g of compound, in the round-bottomed flask for adding 10ml, in the isopropanol water solution 5.0ml for adding 50%, it is heated to reflux being completely dissolved solid, stop heating, cooling crystallization, products therefrom is dried under reduced pressure overnight at 45 °C, obtain white solid 0.72g, yield 72%.The X-ray diffraction and DSC spectrograms of the crystallized sample are compared through research, and it is I crystal to determine product.Embodiment 4
Formula will be obtained in embodiment 1（I in) the tosilate 1.0g of compound, the round-bottomed flask for adding 50ml, add in 30ml isopropanols, be heated to reflux lOmin, be completely dissolved solid, stop heating, stand crystallization,
Filtering, resulting crystallization is dried under reduced pressure overnight at 45 °C, obtains white solid 0.67g, yield 67%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 3.The crystallization is in about 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) standing grain B 24.96 (3.57) have characteristic peak.DSC spectrograms are shown in Fig. 4, have characteristic absorption peak at 195.71 °C and 205.44 °C, define the crystal formation for Π crystal formations.Embodiment 5
Formula will be obtained in embodiment 1（I) the tosilate 0.5g of compound, in the round-bottomed flask for adding to 50ml, 15ml acetone is added, lOmin is heated to reflux, is completely dissolved solid, stop heating, stirring and crystallizing, filtering, resulting crystallization is dried under reduced pressure overnight at 45 °C, obtain white solid 0.81g, yield 81%.The X-ray diffraction and DSC spectrograms of the crystallized sample are compared through research, and it is II crystal formations to determine product.Embodiment 6
Formula will be obtained in embodiment 1（I) the tosilate 1.0g of compound, in the round-bottomed flask for adding 25ml, add in 5.0ml acetonitriles, be heated to reflux lOmin, be completely dissolved solid, stop heating, crystallization is stood, filtering, resulting crystallization is dried under reduced pressure overnight at 45 °C, obtain white solid 0.63g, yield 63%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 5.The crystallization is in about 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), there is characteristic peak 20.63 (4.30), 22.78 (3.90) and 28.93 (3.08).DSC spectrograms are shown in Fig. 6, have characteristic absorption peak at 195.51 °C and 205.96 °C, define the crystal formation for III crystal formations.Embodiment 7
Formula obtained by testing example 1（I) x-ray diffraction pattern of the tosilate sample of compound and DSC spectrums, X-ray diffraction spectrogram are shown in Fig. 7.The white solid is in about 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), there is characteristic peak 21.39 (4.15), 24.22 (3.67) and 24.97 (3.56).DSC spectrograms are shown in Fig. 8, at 195.98 °C and 205.49
° 〇 has characteristic absorption peak, defines the crystal formation for IV crystal formations.Embodiment 8
Formula will be obtained in embodiment 1（I in) the tosilate 1.0g of compound, the round-bottomed flask for adding 25ml, the mixed solution of 5.0ml ethyl acetate and methanol is added（Volume ratio=3:1), it is heated to reflux being completely dissolved solid, stops heating, stand crystallization, filtering, resulting crystallization is dried under reduced pressure overnight at 45 °C, obtains white solid 0.35g, yield 35%.The X-ray diffraction and DSC spectrograms of the crystallized sample are compared through research, and it is IV crystal formations to determine product.
Formula will be obtained in embodiment 1（I in) the tosilate 1.0g of compound, the round-bottomed flask for adding 25ml, the mixed solution of 20ml ethyl acetate and methanol is added（Volume ratio=6:1), it is heated to reflux being completely dissolved solid, stops heating, stand crystallization, filtering, resulting crystallization is dried under reduced pressure overnight at 45 °C, obtains 0.21 gram of white solid, yield 21%.The X-ray diffraction and DSC spectrograms of the crystallized sample are compared through research, and it is IV crystal formations to determine product.Embodiment 10
Modus ponens（I) chemical combination alkaloids lg (is prepared according to patent 118200,700,934,75）It is dissolved in 6ml ethyl acetate, then by 0.39g Tosis acid（Equimolar ratio）It is dissolved in 1ml ethanol, and is added drop-wise to formula（I) in the ethyl acetate solution of chemical combination alkaloids, stirring and crystallizing, suction filtration is dried under reduced pressure to obtain white solid 0.9g, and yield is 72.0%.The X-ray diffraction and DSC spectrograms of the crystallized sample are compared through research, and it is IV crystal formations to determine product.Embodiment 11
By I types and IV crystal form samples obtained as above（The sample is not purified, synthesizes crude product）Opening divides placement respectively, investigates in low temperature, heating (40 °C, 60 °C), illumination（4500Lux), under the conditions of high humidity (RH75%, RH90%) sample stability.It is 5 days and 10 days to investigate sample time, and HPLC detections purity is shown in Table 1.
Study on the stability result shows, formula（I) compound tosilate I types and IV types crystallized sample are under conditions of opening is placed, through low temperature, heating (40 °C, 60 °C), illumination（4500Lux), stability under the conditions of high humidity (RH75%, RH90%) etc. it was found that, influence of the illumination to both is very big, and sample need to be kept in dark place, under conditions of low temperature, high temperature, high humidity, the stability of I types crystallization is considerably better than the sample of IV crystal formations.
Table 1, formula（I) stability of tosilate I and the IV crystal form samples of compound compares lot number information drawing clef purity 4.9min 6.9min 14.4mi
20110506 startings 11,061,604 99.18 0.05 0.37 0.14
Chiral purity： 99.87%
Influence factor 5d
4°C 11062219 99.17 0.04 0.42 0.14
40 °C 11062220 99.15 0.04 0.43 0.14
60 °C 11,062,221 98.99 0.03 0.48 0.18 of IV crystal formations
RH75% 11062222 99.00 0.03 0.56 0.15
RH90% 11062223 98.89 0.03 0.67 0.14
Influence factor 10d
4°C 11062715 99.11 0.03 0.44 0.14
40 °C 11062716 99.08 0.03 0.48 0.14
60 °C 11,062,717 98.96 0.03 0.55 0.14 of IV crystal formations
RH75% 11062718 98.84 0.03 0.66 0.15
RH90% 11062719 98.71 0.02 0.81 0.14
20110607-4 startings 11,061,605 99.32 0.01 0.52 0.07
Chiral purity： 99.84%
Influence factor 5d
4°C 11062709 99.32 0.01 0.41 0.08
40 °C 11062710 99.41 0.01 0.41 0.08
60 °C 11062711 99.33 0.01 0.49 0.09
I crystal
RH75% 11062714 99.38 0.01 0.44 0.08
RH90% 11062213 99.38 0.02 0.43 0.08
Illumination 11,062,214 98.33 0.76 0.46 0.08
Influence factor lOd
4°C 11062709 99.32 0.01 0.41 0.08
40 °C 11062710 99.41 0.01 0.41 0.08
60 °C 11,062,711 99.33 0.01 0.49 0.09 of I crystal
RH75% 11062714 99.38 0.01 0.44 0.08
RH90% 11062713 99.40 0.01 0.43 0.08
The embodiment 12 of illumination 11,062,712 97.12 1.62 0.56 0.08:Formula（I) the tosilate of compound（Call HR7056 in the following text) and formula（I) the benzene sulfonate of compound（Call CNS 7056 in the following text) on spontaneous activity in mice influence comparative experiments：
Single tail vein injection HR7056, CNS 7056 (2.5,5 and 7.5 mg/kg, i.v.,）And Normal group spontaneous activity in mice detailed data is shown in Table 2.
Influence group n lOmin distances (m) the 20min distance Cm of table 2, HR7056 and CNS7056 to ICR spontaneous activity in mice) 30min distances (m) Normal group 10 66.84 ± 10.85 117.89 ± 15.13 160.61 ± 25.11
The * of 88.86 ± 29.55 * of HR7056 7.5mg/kg 10 44.50 ± 19.28 * * of group 124.72 ± 33.60
The * of 93.15 ± 26.19 * of HR7056 5.0mg/kg 10 50.57 ± 17.43 * of group 125.34 ± 31.48
HR7056 2.5mg/kg groups 10 57.41 ± 19.20 103.76 ± 20.24 140.24 ± 22.38
The * * 83.15 ± 32.59 113.48 ± 34.82 of CNS7056 7.5mg/kg groups 10 39.32 ± 20.17
The * of 99.31 ± 20.60 * of CNS7056 5.0mg/kg 10 49.10 ± 16.96 * of group 137.95 ± 22.77
The data of CNS7056 2.5mg/kg groups 10 64.69 ± 21.84 114.33 ± 33.69 153.91 ± 46.70 are expressed as Mean ± S.D.*P<0.05, * * P<0.01, compared with Normal group.Embodiment 13:Influence experiments of the HR7056 and CNS7056 to ICR mouse righting reflex loss：
Single tail vein injection HR7056, CNS 7056 (15,30 and 60 mg/kg, i.v.,）And the influence experiment detailed data of Normal group mouse righting reflex is shown in Table 3.
The influence of table 3, HR7056 and CNS7056 to ICR mouse righting reflex loss
Group (min) duration in n incubation periods（Min) Normal group 15 0.00 ± 0.00 0.00 ± 0.00
HR7056 60mg/kg groups 15 0.16 ± 0.05 10.75 ± 4.84
HR7056 30mg/kg groups 15 0.26 ± 0.23 2.36 ± 2.82
HR7056 15mg/kg groups 14 0.00 ± 0.00 0.00 ± 0.00
The 60mg/kg groups 15 0.19 ± 0.12 8.94 ± 5.27 of CNS 7056
The 30mg/kg groups 15 0.32 ± 0.37 1.89 ± 1.94 of CNS 7056
The data of 7056 15mg/kg groups of CNS 15 0.00 ± 0.00 0.00 ± 0.00 are expressed as Mean ± S.D.*P<0.05, * * P<0.01, compared with Normal group.Embodiment 14
HR7056 I crystal samples are long-term（25 °C), accelerate（40 °C, RH75%) under the conditions of sample study on the stability, the results are shown in Table 4.
Table 4, HR7056 I crystals sample accelerate the study on the stability of sample for a long time
Upper table data display, compared with the stability data in the table 10 of embodiment in CN101501019A 4, the present invention has a clear superiority.Embodiment 15:Rat acute toxicity test is studied
Purpose：This experiment carries out SD rats single intravenous injections to HR7056 and acute toxicity test is administered, and property, degree, dose-effect and the time-effect relationship of toxic reaction, invertibity may be caused and to nervous system by observing the medicine
Influence situation, and be compared with similar drugs CNS7056, reference information provided for HR7056 toxicity assessments.
Method：This experiment sets 9 groups, respectively CNS7056 is low, in, secondary high, high dose group（Dosage is respectively 37.5,75,150,300 mg/kg), HR7056 is low, in, secondary high, high dose group（Dosage is respectively 37.5,75,150,300 mg/kg), and solvent control group（0.9% sodium chloride injection containing 0.375% glycine and 0.0125% mosatil, pH value 3.5 ± 0.1).Every group of 10 rats, male and female half and half.Each group is given the test sample and reference substance of respective concentration by 30mL/kg volume single intravenous injection.It is experiment the 1st day so that the same day is administered.
Each group rat righting reflex loss and the time recovered are recorded after drug administration by injection and behavioral activity recovers the normal time, and continuous 14 days daily observation rat general status；Test the 1st day administration before, administration terminate after about 3 minutes, the 2nd, 7,14 days, observed and recorded each group rat behavior state, the state of mind, muscle tone and nociceptive reflex；The 1st is tested (before administration）, 4,8,12,15 days determine body weight；Test the 2nd, determine food ration within 5,9,12 days；Test the 15th day, blood sampling carries out hematology, blood bio-chemistry checking after being anaesthetized to each group survival rats, and imposes progress gross anatomy observation after euthanasia, and histopathological examination is carried out to the abnormal internal organs of gross examination of skeletal muscle or tissue.
Experimental result
Dead animal：
The 300mg/kg groups of CNS 7056 have 3 rats（3/10 ratio, 2 female 1 is male）Substantially it is short of breath after administration, is subsequently converted into shallow breathing and dead.HR7056 each groups have no rats death.
General status：
Hypoactivity, walking step state are unstable until righting reflex loss, four limbs and abdominal wall muscle relax after the administration of the mg/kg groups partial rats of HR7056 37.5, but nociceptive reflex is normal.The visible hypoactivity of remaining rat of the group, minister of bowing is foretold, but righting reflex does not disappear, and muscle tone and nociceptive reflex are normal.It is visible righting reflex loss after the administration of the mg/kg groups rats of HR7056 75,150,300, four limbs and abdominal wall muscle relaxation, have that hypoactivity in short-term, walking step state are unstable after revival, indivedual rats are visible to be short of breath, and 300 mg/kg rats still see that nociceptive reflex weakens.Most rats are visible the unconscious movement such as to lick, chews.HR7056 each group rats sleeping duration about 3 13 minutes, the symptom duration occurred after administration about 6 21 minutes, sleeping duration and symptom duration are respectively provided with dosage correlation, increase with dosage and extend.CNS7056 each groups and the general status and neurobehavioral symptom of same dose HR7056 group rats are basically identical.
Until observation in 14 days terminates after administration same day above-mentioned symptom recovers, the non-goodbye abnormal symptom of each group rat and reaction occur.
Body weight and food ration：
After administration during observation in 14 days, HR7056 and CNS7056 each groups are 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：
After administration at the end of observation in 14 days, HR7056 and CNS7056 each group rat blood index leucocyte meters
Number（WBC) and classification, red blood cell count(RBC)（RBC), hemoglobin（HGB), red cell volume（HCT), granulophilocyte（RET), platelet count（) and the clotting time PLT（PT and APTT) etc., it is showed no the related abnormal change of medicine.
After administration at the end of observation in 14 days, HR7056 and CNS7056 each group blood biochemistry of rats index alkaline phosphatases（ALP), ALT（ALT), aspartate amino transferase（AST), total protein (TP), albumin（ALB), blood glucose（GLU), total bilirubin（TBIL), bilirubin direct（DBIL), T-CHOL（CHOL), triglycerides（TG), cretinephosphokinase（CK), urea（Urea), creatinine (Crea), amylopsin（AMY-P), lipase（) and electrolyte LIP（K+, Na-, C1-) level etc., be showed no the related abnormal change of medicine.
Gross anatomy is observed：
After administration at the end of observation in 14 days, HR7056 and CNS7056 each groups rat implements substantially to analyse, color, form, quality and size of the internal organs such as heart, liver, spleen, lung, kidney, intestines and stomach, reproductive system etc., are showed no the abnormal change related to medicine.
Experiment conclusion：
Under this experimental condition, SD rat single intravenous injections give 37.5,75,150,300mg/kg HR7056.Each dosage can cause rat the symptom such as dose-dependent hypoactivity, instability of gait, righting reflex loss, of flaccid muscles occur after administration, related to HR7056 pharmacotoxicological effect.After administration in 14 day observation period, have no that rats death and other toxic reactions 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 300 mg/kg;SD rat single intravenous injection CNS7056, maximum tolerated dose is 150 mg/kg.
Claims (10)
- Claims：1st, formula（I) the support of compound:(I)2nd, formula according to claim 1（I) tosilate of compound, wherein formula（I) stoicheiometry of compound and Tosi acid is 1:1.3rd, formula according to claim 2（I) the tosilate of compound, wherein described salt is crystal salt.4th, formula according to claim 3（I) the I types crystallization of the tosilate of compound, it is characterized in that being radiated using Cu-Ka, obtain the X-ray powder diffraction collection represented with 2 Θ angles and interplanar distance, the crystallization has X-ray powder diffraction collection as shown in Figure 1, wherein in about 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) standing grain B 27.22 (3.27) have characteristic peak.5th, formula according to claim 3（I) the II types crystallization of the tosilate of compound, it is characterized in that being radiated using Cu-Ka, obtain the X-ray powder diffraction collection represented with 2 Θ angles and interplanar distance, the crystallization has X-ray powder diffraction collection as shown in Figure 3, wherein in about 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), there is characteristic peak 24.51 (3.63) and 24.96 (3.57).6th, formula according to claim 3（I) the type III crystallization of the tosilate of compound, it is characterized in that being radiated using Cu-Ka, obtain the X-ray powder diffraction collection represented with 2 Θ angles and interplanar distance, the crystallization has X-ray powder diffraction collection as shown in Figure 5, wherein in about 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), there is characteristic peak 22.78 (3.90) and 28.93 (3.08). 7th, formula according to claim 3（I) the IV types crystallization of the tosilate of compound, it is characterized in that being radiated using Cu-Ka, obtain the X-ray powder diffraction collection represented with 2 Θ angles and interplanar distance, the crystallization has X-ray powder diffraction collection as shown in Figure 7, wherein in about 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.8th, a kind of method for preparing crystal salt according to claim 3, it comprises the steps：1) by any crystal formation or unformed formula（I) the tosilate of compound, or by formula（I) compound is dissolved by heating in crystallization solvent with Tosi acid, cooling, crystallization, wherein described crystallization solvent is the mixed solvent of rudimentary organic solvent, water or both, described rudimentary organic solvent is the alcohols, ketone, preferably lipid solvent, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate or their mixed solvent that carbon number is less than 6；2) filtering for crystallizing and wash, dry.9th, a kind of method for preparing I types crystallization as claimed in claim 4, it includes the step described in claim 8, wherein described crystallization solvent is the aqueous solution of water or organic solvent；Preferably water.10th, a kind of method for preparing II types crystallization according to claim 5, it includes the step described in claim 8, wherein described crystallization solvent is alcohols and ketone, the preferably one or more in methanol, ethanol, isopropanol, acetone.11st, a kind of method for preparing type III crystallization according to claim 6, it includes the step described in claim 8, wherein described crystallization solvent is acetonitrile.12nd, a kind of method for preparing IV types crystallization according to claim 7, it includes the step described in claim 8, wherein described crystallization solvent is the mixed solvent of ethyl acetate and alcohols, wherein described alcohols is preferably methanol, ethanol, propyl alcohol or isopropanol.13rd, a kind of formula prepared described in claims 1 to 3 any one（I) the method for the tosilate of compound, it includes making formula（I) compound and Tosi acid reaction.14th, method according to claim 13, wherein the reaction is carried out in a solvent, the solvent is the mixed solvent of ethyl acetate and alcohols, and described alcohols is preferably methanol, ethanol, propyl alcohol or isopropanol.15th, a kind of pharmaceutical composition, it is containing the formula described in good grounds claims 1 to 3 any one（I) tosilate of compound or the formula according to claim 4 to 7 any one（I) the tosilate of compound Crystallization and pharmaceutically acceptable carrier.16th, the formula according to claims 1 to 3 any one（I) tosilate of compound, the formula according to claim 4 to 7 any one（I) the purposes of the crystallization of the tosilate of compound or pharmaceutical composition according to claim 15 in calm, sleeping, antianxiety, of flaccid muscles or anticonvulsant drug is prepared.
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| WO2018103119A1 (en) | 2016-12-09 | 2018-06-14 | 成都倍特药业有限公司 | Hydrobromate of benzodiazepine derivative, preparation method and use thereof |
| CN109422798A (en) * | 2017-08-22 | 2019-03-05 | 江苏恒瑞医药股份有限公司 | A kind of free alkali crystal form of phenylpropionyl amine derivant and preparation method thereof |
| WO2019158075A1 (en) | 2018-02-13 | 2019-08-22 | 江苏恩华络康药物研发有限公司 | Benzodiazepine derivative hydrochloride and crystal form, preparation method, and application thereof |
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| ES2651389T3 (en) | 2012-05-22 | 2018-01-26 | Paion Uk Limited | Compositions comprising short-acting benzodiazepines |
| AR094963A1 (en) | 2013-03-04 | 2015-09-09 | Ono Pharmaceutical Co | EXCELLENT OXIDATION REACTION IN THE CONVERSION INDEX |
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| ES2803099B2 (en) * | 2019-07-22 | 2021-11-08 | Moehs Iberica Sl | Procedure for obtaining amorphous remimazolam besilate |
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Effective date of registration: 20160822 Address after: 222047 Kunlun Road, Lianyungang economic and Technological Development Zone, Jiangsu, No. 7 Patentee after: Hengrui Medicine Co., Ltd., Jiangsu Prov. Patentee after: Hengrui Pharmaceutical Co., Ltd., Shanghai Address before: No. 7, Kunlun mountain road, Lianyungang economic and Technological Development Zone, Jiangsu, China Patentee before: Hengrui Medicine Co., Ltd., Jiangsu Prov. |