CN106632342B - The 2- naphthalene sulfonate of benzodiazepine * derivative and the preparation method of crystal form and they - Google Patents
The 2- naphthalene sulfonate of benzodiazepine * derivative and the preparation method of crystal form and they Download PDFInfo
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Abstract
The invention discloses a kind of benzodiazepinesThe preparation method of the 2- naphthalene sulfonate and crystal form of derivative and they, by by the 2- naphthalene sulfonate of formula (I) compound crystal form or unformed formula (I) compound, or formula (I) compound and 2- naphthalene sulfonic acids are dissolved by heating in crystallization solvent, cooling, crystallization, it refilters crystallization and washs, dries, prepare the 2- naphthalene sulfonate or crystal form of formula (I) compound, the 2- naphthalene sulfonate or stability of crystal form of formula (I) compound prepared are good, with high purity, non-toxic, can be preferably applied to clinical treatment.
Description
Technical field
The invention belongs to chemicals preparation fields, and in particular to benzodiazepineThe 2- naphthalene sulfonate and crystalline substance of derivative
The preparation method of type and they.
Background technique
Entitled 3- [(4s) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles [l, 2-a] of chemistry of formula (I) compound
[l, 4] benzodiazepine- 4- base] methyl propionate,
The compound contains carboxylate and benzodiazepine *Structure, be short-acting central nervous system (CNS, Central
Nervous System) inhibitor, it is in particular in tranquilizing soporific, antianxiety, of flaccid muscles and anticonvulsant action.The compound
It can also be used in the intravenously administrable in clinical treatment, as the operation consent in during performing the operation is calm, antianxiety and forgets purposes；?
Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure；It is before applying other anesthetic and analgesic and/or same
When, the component as induction and maintenance for general anesthesia；ICU calmness etc..But the compound be it is unstable, according to China
Patent, application No. is 200780028964, patent name is " short-acting benzodiazepineSalt and its polymorphic " report, formula (I)
Free alkali be adapted only to 5 DEG C of low temperature preservations, under conditions of 40 DEG C/75% relative humidity (opening), the sample of storage deliquescence, face
Discoloration yellowly shows that content significantly reduces 7% or more to orange, and relative to initial content.
As researcher constantly studies, it is believed that salt can be prepared into increase its chemical stability.Now
Report tosilate, benzene sulfonate, the esilate of formula (I) compound, wherein chemistry, the light of tosilate
Purity is slightly good, and the chemistry of remaining two kinds of salt, optical purity are all undesirable, and recrystallization process fails to significantly improve its change
And optical purity.
Vilasette (nelfinavir mesilate) event that Europe in those early years occurs, let us are special for drug safety
Concern；After European Union occurs for the event, the risk warning file EMEA/44714/ of small-molecular-weight sulfonic acid esters is had issued
2008, wherein specifically mention, methanesulfonates, esilate, benzene sulfonate, p-methyl benzenesulfonic acid ester and isethionic acid esters
DNA alkylating will lead to mutagenic effect, carcinogenic effect and teratogenic effect.In view of vilasette (nelfinavir mesilate) thing
In part, Roche Holding Ag is in storage pharmaceutical procedures, since the ethyl alcohol of cleaning holding vessel largely remains, cause to react with methanesulfonic acid and
The methanesulfonates of severe overweight is produced, the security risk of the drug has been eventually led to, and is recalled by EMEA mandatory requirement.Simultaneously
Also require medicament research and development company that should avoid as far as possible in drug development to the sulfonic acid for the small-molecular-weight mentioned in above-mentioned file
It uses, and the acid group of no latent gene toxicity should be selected as far as possible.
In addition other than genotoxicity, p-methyl benzenesulfonic acid corresponding to three kinds of salt of existing formula (I) compound, benzene sulfonic acid,
The LD of ethanesulfonic acid itself50Toxicity is all bigger than normal, does toxicity test using rat, rat take orally respectively p-methyl benzenesulfonic acid, benzene sulfonic acid,
Ethanesulfonic acid, LD50Respectively 2480mg/kg, 0.89mg/kg, 48mg/kg, therefore, exploitation purity is high, stability are good, non-toxic
The salt of formula (I) compound be necessary.
Summary of the invention
The present invention provides a kind of benzodiazepinesThe preparation method of the 2- naphthalene sulfonate and crystal form of derivative and they,
Preparation method is simple, at low cost, the benzodiazepine prepared2- naphthalene sulfonate and the crystal form purity height of derivative, stability
It is good, it can be used as active pharmaceutical ingredient use, in addition, the LD of 2- naphthalene sulfonic acids50For 4440mg/kg, therefore the benzodiazepine * prepared
It is miscellaneousIt is avirulent within the scope of the 2- naphthalene sulfonate usage amount appropriate of derivative.
To achieve the above object, the technical solution adopted by the present invention to solve the technical problems is:
The 2- naphthalene sulfonate of formula (I) compound:
Further, formula (I) compound and 2- naphthalene sulfonic acids stoicheiometry are 1:1, and further, which is crystal salt.
Further, I crystal form of the 2- naphthalene sulfonate of the formula (I) compound, is radiated using Cu-Ka, is obtained with 2 θ
The X-ray powder diffraction spectrogram that angle indicates, 6.3,11.8,17.7,19.0,19.4,20.5,21.7,22.2,22.8,
23.3, there is characteristic peak at 23.9,25.9,27.9.
The preparation method of the 2- naphthalene sulfonic acids crystal salt of described formula (I) compound, comprising the following steps:
1) by crystal form or the 2- naphthalene sulfonate of unformed formula (I) compound, or by formula (I) compound and 2- naphthalene sulfonic acids
Dissolve by heating in crystallization solvent, cooling, crystallization, wherein the crystallization solvent be rudimentary organic solvent, water or they
Mixed solvent, the rudimentary organic solvent are alcohols of the carbon atom number less than 6, ketone, esters, ether solvent or acetonitrile, N,
Dinethylformamide.
2) it filtering for crystallizing and washs, dry.
Further, in the preparation method of the 2- naphthalene sulfonic acids crystal salt of the formula (I) compound, formula (I) compound with
2- naphthalene sulfonic acids reaction solvent used is the mixed solvent of ethyl acetate and alcohols；Further, alcohols is methanol, ethyl alcohol, third
Alcohol or isopropanol.
Further, in the preparation method of the 2- naphthalene sulfonic acids crystal salt of the formula (I) compound, the crystallization solvent
For methanol, ethyl alcohol, propyl alcohol, isopropanol, acetone, butanone, ethyl acetate, butyl acetate, methyl tertiary butyl ether(MTBE), isopropyl ether, acetonitrile,
One or more of N,N-dimethylformamide.
The preparation method of I crystal form of 2- naphthalene sulfonate of described formula (I) compound, including described formula (I) compound
The preparation step of 2- naphthalene sulfonic acids crystal salt, wherein the crystallization solvent is alcohols, ketone, ethyl acetate, acetonitrile, one in water
Kind is several.
Further, in the preparation method of I crystal form of 2- naphthalene sulfonate of the formula (I) compound, the crystallization solvent
For one or more of methanol, ethyl alcohol, isopropanol, acetone, butanone, ethyl acetate, acetonitrile, water.
Benzodiazepine provided by the inventionThe preparation method of the 2- naphthalene sulfonate and crystal form of derivative and they, has
Below the utility model has the advantages that preparation method is simple, at low cost, the 2- naphthalene sulfonate and its crystal form purity of formula (I) compound prepared
Height, stability are good, can be used as active pharmaceutical ingredient use.
Detailed description of the invention
Fig. 1 is the DSC spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 1；
Fig. 2 is the X-ray powder diffraction spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 1；
Fig. 3 is the DSC spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 2；
Fig. 4 is the X-ray powder diffraction spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 2.
Fig. 5 is the DSC spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 3；
Fig. 6 is the X-ray powder diffraction spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 3；
Fig. 7 is the DSC spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 4；
Fig. 8 is the X-ray powder diffraction spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 4；
Fig. 9 is the DSC spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 5；
Figure 10 is the X-ray powder diffraction spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 5；
Figure 11 is the DSC spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 6；
Figure 12 is the X-ray powder diffraction spectrogram of I crystal form of 2- naphthalene sulfonate of formula (I) compound in embodiment 6.
Specific embodiment
Embodiment 1: the preparation of the 2- naphthalene sulfonate of formula (I) compound
Formula (I) compound 100mg (0.228mmol) is accurately weighed into 10mL single port bottle, and 0.5mL ethyl acetate is added
Stirring dissolves it all, then 47mg 2- naphthalene sulfonic acids (0.228mmol) is dissolved in 0.25mL ethyl alcohol, and be added drop-wise to formula
(I) in the ethyl acetate solution of compound, stirring and crystallizing is filtered, and ethyl acetate elution, 40 DEG C are dried under reduced pressure to obtain formula (I) chemical combination
The 2- naphthalene sulfonate of object, white solid 138mg, yield 94%.
The X-ray diffraction spectrogram of the crystallization is shown in attached drawing 2,6.3,11.8,17.7,19.0,19.4,20.5,21.7,
22.2, there is characteristic peak at 22.8,23.3,23.9,25.9,27.9, DSC map is shown in attached drawing 1, at 120 DEG C, 200 DEG C and 214 DEG C
Nearby there is characteristic absorption peak, defines I crystal form of 2- naphthalene sulfonate that the crystal form is formula (I) compound.
1H NMR (400MHz, MeOD) δ 8.54 (d, J=4.3Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=7.9Hz,
1H), 8.03-7.98 (m, 2H), 7.93-7.84 (m, 4H), 7.78 (d, J=8.7Hz, 1H), 7.68 (d, J=2.2Hz, 1H),
7.58-7.51 (m, 3H), 7.43 (d, J=1.0Hz, 1H), 4.43 (dd, J=9.9,4.2Hz, 1H), 3.68 (s, 3H),
2.86-2.54 (m, 5H), 2.47 (d, J=0.8Hz, 3H)
Embodiment 2: the preparation of I crystal form of 2- naphthalene sulfonate of formula (I) compound
The 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1 is added in the round-bottomed flask of 25mL, is added
8mL acetonitrile, is heated to reflux 10min, is completely dissolved solid, stops heating, filters while hot, is cooled to room temperature crystallization and stays overnight, institute
It obtains product to be dried under reduced pressure at 40 DEG C overnight, obtains white solid 74mg, yield 74%.
The DSC spectrogram of the crystallized sample is shown in that attached drawing 3, X-ray diffraction spectrogram are shown in attached drawing 4.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrogram are compared through research, determine that product is I crystal form of 2- naphthalene sulfonate of formula (I) compound.
Embodiment 3: the preparation of I crystal form of 2- naphthalene sulfonate of formula (I) compound
The 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1 is added in the round-bottomed flask of 25mL, is added
The mixed solution (volume ratio=5:1) of 6.0mL isopropyl alcohol and water, is heated to reflux 10min, is completely dissolved solid, stops heating,
It filters while hot, is cooled to room temperature crystallization and stays overnight, products therefrom is dried under reduced pressure overnight at 40 DEG C, obtains white solid 90mg, yield
90%.
The DSC spectrogram of the crystallized sample is shown in that attached drawing 5, X-ray diffraction spectrogram are shown in attached drawing 6.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrogram are compared through research, determine that product is I crystal form of 2- naphthalene sulfonate of formula (I) compound.
Embodiment 4: the preparation of I crystal form of 2- naphthalene sulfonate of formula (I) compound
The 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1 is added in the round-bottomed flask of 25mL, is added
The mixed solution (volume ratio=1:6) of 15ml methanol and butanone, is heated to reflux 10min, is completely dissolved solid, stops heating,
It filters while hot, is cooled to room temperature crystallization and stays overnight, products therefrom is dried under reduced pressure overnight at 40 DEG C, obtains white solid 87mg, yield
87%.
The DSC spectrogram of the crystallized sample is shown in that attached drawing 7, X-ray diffraction spectrogram are shown in attached drawing 8.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrogram are compared through research, determine that product is I crystal form of 2- naphthalene sulfonate of formula (I) compound.
Embodiment 5: the preparation of I crystal form of 2- naphthalene sulfonate of formula (I) compound
The 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1 is added in the round-bottomed flask of 25mL, is added
The mixed solution (volume ratio=1:2) of 12mL ethyl alcohol and ethyl acetate, is heated to reflux 10min, is completely dissolved solid, stops adding
Heat filters while hot, is cooled to room temperature crystallization and stays overnight, and products therefrom is dried under reduced pressure overnight at 40 DEG C, obtains white solid 93mg, receives
Rate 93%.
The DSC spectrogram of the crystallized sample is shown in that attached drawing 9, X-ray diffraction spectrogram are shown in attached drawing 10.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrogram are compared through research, determine that product is I crystal form of 2- naphthalene sulfonate of formula (I) compound.
Embodiment 6: the preparation of I crystal form of 2- naphthalene sulfonate of formula (I) compound
The 2- naphthalene sulfonate 100mg of formula (I) compound in embodiment 1 is added in the round-bottomed flask of 25mL, is added
The mixed solution (volume ratio=3:1) of 4mL acetone and water, is heated to reflux 10min, is completely dissolved solid, stops heating, while hot
Filtering is cooled to 4 DEG C of crystallizations and stays overnight, and products therefrom is dried under reduced pressure overnight at 40 DEG C, obtains white solid 76mg, yield 76%.
The DSC spectrogram of the crystallized sample is shown in that attached drawing 11, X-ray diffraction spectrogram are shown in attached drawing 12.The X-ray of the crystallized sample
Diffraction spectrogram and DSC spectrogram are compared through research, determine that product is I crystal form of 2- naphthalene sulfonate of formula (I) compound.
Embodiment 7: the 2- naphthalene sulfonate aqueous solution stability test of formula (I) compound
Experiment condition:
Mobile phase:
(3.5) 0.025mol/L potassium dihydrogen phosphate aqueous solution is with phosphorus acid for adjusting pH value to A- phosphate buffer
B- acetonitrile
Chromatographic column: Féraud door luna C18 (2) 4.6*250mm, 5 μm
Elution program:
| Time/min | A phase/% | B phase/% |
| 0 | 80 | 20 |
| 20 | 30 | 70 |
| 40 | 30 | 70 |
Column temperature: 45 DEG C
Detection wavelength: 230nm
Sample introduction concentration: 0.5mg/mL
Sample volume: 10 μ l
The stability of the different salt of formula (I) compound compares, and is shown in Table 1:
The stability of the different salt of 1 formula of table (I) compound compares
Note: normalization method calculates content (%) according to area
As it can be seen from table 1 the 2- naphthalene sulfonate of formula (I) compound provided by the invention in aqueous solution steady at room temperature
It is qualitative very good, hence it is evident that the benzene sulfonate and tosilate for being better than reported formula (I) compound are at room temperature in aqueous solution
In stability.
The stability of the 2- naphthalene sulfonate of formula (I) compound provided by the invention is mainly manifested in two aspects:
1. in the growth rate of relative retention time (RRT) the principal degradation impurity for being 0.69 or so, formula (I) chemical combination
The benzene sulfonate and tosilate of object increase by 0.08% and 0.10% respectively within the time of 15h, and provided by the invention
The 2- naphthalene sulfonate of formula (I) compound is up to increasing by 0.04% in time for 24 hours；
2. the benzene sulfonate and tosilate of formula (I) compound are in addition to above-mentioned principal degradation impurity increases, there are also other
Impurity is adjoint to be increased together, and the other impurity performances of the 2- naphthalene sulfonate of formula provided by the invention (I) compound are extremely stablized
There is no significant change trend.
Embodiment 8: the purity and stability of the 2- naphthalene sulfonate of detection formula (I) compound
Sample (sample is crude product, not purified) opening of I crystal form of 2- naphthalene sulfonate of formula (I) compound is divided
Place, detect heating (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) condition stability.When sampling
Between be 5 days and 10 days, HPLC detect purity be shown in Table 2.
I crystal form purity of the 2- naphthalene sulfonate detection of formula (I) compound under 2 different condition of table
Comparison 1: application No. is 200780028964, patent name is " short-acting benzodiazepineSalt and its polymorphic ",
Crystallized sample surrounding and the every seven days absorption samples in total that benzene sulfonate is stored at 40 DEG C/75%RH of 4 table 10 of embodiment report
Product are used for HPLC, and purity is shown in Table 3:
The conclusion table of the crystallized sample of 3 benzene sulfonate of table purity salt after the research of 4 peripheral stabilities
| Sample ID | Salt | T0 | T1 | T2 | T3 | T4 |
| LJC-039-037-1 | Benzene sulfonate | 97.1 | 97.3 | 97.4 | 96.7 | 96.7 |
Comparison 2: application No. is 201280003321.6, apply for entitled " benzodiazepineThe tosilate of derivative
And its polymorphic, their preparation method and purposes " in 11 table 1 of embodiment describe the tosilate I and IV of formula (I) compound
Opening divides placement to crystal form samples respectively, investigate heating (40 DEG C, 60 DEG C), illumination (4500lux), high humidity (RH75%,
RH92.5% the temperature stability of sample under the conditions of), investigating sample time is 5 days and 10 days, and HPLC detection purity is shown in Table 4:
The stability of the crystal form samples of tosilate I and IV of 4 formula of table (I) compound compares
As can be seen from Table 2, (60 DEG C), illumination (4500lux), high humidity (RH75%, RH92.5%) each factor are heated to formula
(I) I crystal form of 2- naphthalene sulfonate (present invention) of compound is nearly free from influence, illustrates formula provided by the present application (I) compound
I crystal form of 2- naphthalene sulfonate under conditions of high temperature, high humidity, illumination purity it is almost the same, show fabulous stability.
From table 3 it can be seen that storing the crystallized sample of benzene sulfonate at 40 DEG C/75%RH, purity keeps one in two weeks
It causes, about 97.1%, but temperature, humidity are respectively higher than the condition of storage of the crystallized sample for the benzene sulfonate reported in the application,
Under the conditions of 60 DEG C, RH92.5%, purity is also consistent sample in the present invention, and stability is substantially better than comparison 1.From table
4 can be seen that I crystal form of tosilate of formula (I) compound in 60 DEG C, high humidity (RH75%, RH90%) and illumination
Under the conditions of (4500lux), stability is not very well that IV crystal form is in 60 DEG C, high humidity (RH75%, RH90%) and illumination
Stability under the conditions of (4500lux) is better than I crystal form, the especially stability under illumination condition and obviously provides than the present invention
Formula (I) compound I poor crystal form of 2- naphthalene sulfonate.
Embodiment 9: the purity and stability of the 2- naphthalene sulfonate of detection formula (I) compound
I crystal form samples of 2- naphthalene sulfonate of formula (I) compound are respectively in long-term (25 DEG C), acceleration (40 DEG C, RH75%) item
Study on the stability under part, the results are shown in Table 5:
I crystal form purity of the 2- naphthalene sulfonate measurement of formula (I) compound under 5 acceleration environment of table
Comparison: application No. is 201280003321.6, apply for entitled " benzodiazepineThe tosilate of derivative and
Its polymorphic, their preparation method and purposes " in I crystal form samples of HR7056 long-term (25 DEG C) introduced of 14 table 4 of embodiment plus
Study on the stability under the conditions of fast (40 DEG C, RH75%), the results are shown in Table 6:
6 HR7056 of table, I crystal form samples accelerate the study on the stability of sample for a long time
Can be obtained by table 3, table 5, table 6, I crystal form of 2- naphthalene sulfonate of formula (I) compound provided by the invention with application No. is
200780028964, patent name is " short-acting benzodiazepineSalt and its polymorphic ", the benzene sulfonic acid of 4 table 10 of embodiment report
The crystallized sample stability data of salt is compared, and I crystal form of 2- naphthalene sulfonate of formula (I) compound provided by the invention has obvious excellent
Gesture；With application No. is 201280003321.6, apply for entitled " benzodiazepineThe tosilate and its polycrystalline of derivative
Type, their preparation method and purposes " in stability data in 14 table 4 of embodiment compare, the present invention also has advantage.
Claims (9)
- The 2- naphthalene sulfonate of formula 1. (I) compound；Formula (I) compound and 2- naphthalene sulfonic acids stoicheiometry are 1:1；
- 2. the 2- naphthalene sulfonate of formula (I) compound according to claim 1, which is characterized in that the salt is crystal salt.
- 3. I crystal form of the 2- naphthalene sulfonate of formula (I) compound according to claim 2, which is characterized in that use Cu-Ka Radiation, obtains the X-ray powder diffraction collection indicated with 2 θ angles, 6.3,11.8,17.7,19.0,19.4,20.5, 21.7, there is characteristic peak at 22.2,22.8,23.3,23.9,25.9,27.9.
- 4. a kind of preparation method of the 2- naphthalene sulfonic acids crystal salt of formula as claimed in claim 2 (I) compound, including following step It is rapid:1) by crystal form or the 2- naphthalene sulfonate of unformed formula (I) compound, or formula (I) compound and the heating of 2- naphthalene sulfonic acids is molten Solution is in crystallization solvent, cooling, crystallization, wherein the crystallization solvent is that rudimentary organic solvent, water or their mixing are molten Agent, the rudimentary organic solvent are alcohols of the carbon atom number less than 6, ketone, esters, ether solvent or acetonitrile, N, N- diformazan Base formamide,2) it filtering for crystallizing and washs, dry.
- 5. the preparation method of the 2- naphthalene sulfonic acids crystal salt of formula (I) compound according to claim 4, which is characterized in that formula (I) compound reacts the mixed solvent that solvent used is ethyl acetate and alcohols with 2- naphthalene sulfonic acids.
- 6. according to the preparation method of the 2- naphthalene sulfonic acids crystal salt of formula described in right 5 (I) compound, formula (I) compound and 2- naphthalene Sulfonic acid reaction solvent used is the mixed solvent of ethyl acetate and alcohols, which is characterized in that alcohols is methanol, ethyl alcohol, propyl alcohol Or isopropanol.
- 7. the preparation method of the 2- naphthalene sulfonic acids crystal salt of formula (I) compound according to claim 4, which is characterized in that institute The crystallization solvent stated be methanol, ethyl alcohol, propyl alcohol, isopropanol, acetone, butanone, ethyl acetate, butyl acetate, methyl tertiary butyl ether(MTBE), One or more of isopropyl ether, acetonitrile, N,N-dimethylformamide.
- 8. a kind of preparation method of I crystal form of 2- naphthalene sulfonate of formula as claimed in claim 3 (I) compound, including right are wanted Step described in asking 4, which is characterized in that the crystallization solvent be one of alcohols, ketone, ethyl acetate, acetonitrile, water or It is several.
- 9. the preparation method of I crystal form of 2- naphthalene sulfonate of preparation formula (I) compound according to claim 8, feature exist In the crystallization solvent is one or more of methanol, ethyl alcohol, isopropanol, acetone, butanone, ethyl acetate, acetonitrile, water.
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| 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 |
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| 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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| WO1995001964A1 (en) * | 1993-07-06 | 1995-01-19 | Yamanouchi Pharmaceutical Co., Ltd. | Novel crystal of benzodiazepine derivative |
| GB0613693D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts (3) |
| CN101274290B (en) * | 2007-03-30 | 2011-04-20 | 中国石油天然气股份有限公司 | Late transition metal catalyst and preparation method and application thereof |
| CN102964349A (en) * | 2011-08-31 | 2013-03-13 | 江苏恒瑞医药股份有限公司 | Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application |
| CN103230595B (en) * | 2013-05-05 | 2014-10-08 | 李友香 | Composition for treating mental diseases |
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2015
- 2015-09-18 CN CN201510604777.3A patent/CN106632342B/en active Active
- 2015-09-18 CN CN201510600942.8A patent/CN105130996B/en active Active
- 2015-11-16 CN CN201510786075.1A patent/CN106380470B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
| CN104768557A (en) * | 2012-08-31 | 2015-07-08 | Paion英国有限公司 | Method for administering hypnotic/sedative agent |
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| CN106380470A (en) | 2017-02-08 |
| CN106380470B (en) | 2019-03-19 |
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