CN110511224A - The salt and its crystal form, preparation method and purposes of benzodiazepine * derivative - Google Patents
The salt and its crystal form, preparation method and purposes of benzodiazepine * derivative Download PDFInfo
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- CN110511224A CN110511224A CN201910687623.3A CN201910687623A CN110511224A CN 110511224 A CN110511224 A CN 110511224A CN 201910687623 A CN201910687623 A CN 201910687623A CN 110511224 A CN110511224 A CN 110511224A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to benzodiazepinesDerivative (formula (I), 3- [(4S) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazo [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
Description
The application be submit on April 6th, 2017, entitled " benzodiazepineThe salt and its crystal of derivative
The divisional application of the Chinese patent application 201710219936.7 of form, preparation method and purposes ".
Technical field
The present invention relates to benzodiazepinesDerivative (3- [(4S) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles
And [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine- 4- base] methyl propionate) salt and its crystal form, comprising its pharmaceutical composition,
Preparation method and purposes, especially in preparation for the use in calmness, hypnosis, antianxiety, of flaccid muscles or anticonvulsant drug
On the way.
Background technique
It is disclosed in European patent EP 1,183,243 a kind of with carboxylate and benzodiazepineThe chemical combination of structure feature
Object, and specifically disclose compound 3- [the bromo- 1- methyl -6- of (4S) -8- (2- pyridyl group)-of the structure with following formula (I)
4H- imidazo [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine- 4- base] methyl propionate:
The compound is short-acting central nervous system depressant, is had including calmness, hypnosis, antianxiety, of flaccid muscles
With anticonvulsant effect.The intravenously administrable that it can be used in following clinical treatment: operation consent calmness, antianxiety and forgetting are used
On the way；It is carried out during short-term diagnosis, operation or endoscope calm；Conduct before or while applying other anesthetic and analgesic
The component of induction and maintenance for general anesthesia；And ICU calmness etc..It is reported in Chinese patent CN101501019 B, the change
The free alkali of object is closed under conditions of 40 DEG C/75% relative humidity (opening), the sample of storage deliquesces, and color turns yellow orange
Color, and show that significant content reduces relative to initial content.Since the hygroscopicity and stability of compound directly influence
Can compound use as drug and the steadiness of drug, it is therefore necessary to which research and development have compared with agent of low hygroscopicity and have
The form of the compound of the formula (I) of higher stability (including physical stability and chemical stability), such as the compound of formula (I)
Salt, more particularly, with particular solid form (preferred crystal) formula (I) compound salt.
Chinese patent CN101501019 B and CN 103221414 B and 8642588 B2 of United States Patent (USP) US are reported respectively
Sour (toluenesulfonic acid) salt of the road benzene sulfonate of the compound of formula (I), Tosi and esilate, although these salt are than formula (I)
Compound itself makes moderate progress, and however, there remains certain properties of the compound to formula (I) to be further improved, such as mentions
High-purity improves Dissolution behaviours, improves bioavilability, improves stability to reduce drug toxicity, improve preparation preparation or
The feasibility and operability being synthetically prepared reduce adverse reaction or toxicity of the acid utilized at salt etc..
Unexpectedly, the inventors discovered that the salt of the compound of the formula (I) prepared in the application have the above advantages and
Better effect.
Summary of the invention
One aspect of the present invention provides the salt of the compound of formula (I),
It is inorganic acid salt or acylate, wherein
The inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and any combination thereof；
The organic acid be selected from formic acid, acetic acid, acetoacetate, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, enanthic acid,
Hendecanoic acid, lauric acid, stearic acid, palmitinic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid,
Lactic acid, citric acid, tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, flutters acid, niacin, orotic acid, methyl sulphur at malic acid
Acid, dodecyl sulphate, methanesulfonic acid, trifluoromethanesulfonic acid, ethionic acid, isethionic acid, 1,5- naphthalenedisulfonic acid, 2- naphthalene sulfonic acids,
Camphorsulfonic acid, sulfamic acid, glutamic acid, aspartic acid, gluconic acid, glucuronic acid and any combination thereof.
Another aspect of the present invention provides the method for the salt of the compound of preparation formula (I) comprising by any solid form
The compound of the formula (I) of (such as crystal form or amorphous) dissolves in organic solvent, and the inorganic acid is added or organic acid carries out
Reaction, is subsequently isolated and dries, the organic solvent includes alcohols, ethers, nitrile, ketone or esters solvent.
Another aspect of the present invention provides the hydrochloride of the compound of formula (I).Preferably, in the compound of the formula (I)
Hydrochloride in, the molar ratio of the compound of formula (I) and hydrochloric acid (HCl) are 1: 1.
Another aspect of the present invention provides the hydrochloric acid salt crystal of the compound of formula (I), and the crystal is by using Cu-K α spoke
X-ray powder diffraction (XRPD) map for penetrating acquisition is included in about 6.9 ± 0.2,9.0 ± 0.2,13.5 ± 0.2,13.8 ± 0.2,
At 17.6 ± 0.2,20.8 ± 0.2,21.3 ± 0.2,22.5 ± 0.2,27.8 ± 0.2 and 28.4 ± 0.2 angle of diffraction (2 θ)
Peak.
Another aspect of the present invention provides the method for preparing the hydrochloride and its crystal form of compound of above-mentioned formula (I),
It includes dissolving the compound of the formula (I) of any solid form (such as crystal form or amorphous) in organic solvent, and salt is added
Acid is reacted, and (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes the alcohol with 1-10 carbon atom
Class, ethers, nitrile, ketone or esters solvent.In a preferred embodiment, the present invention provides the change for preparing above-mentioned formula (I)
The method for closing the hydrochloric acid salt crystal of object comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous)
It is dissolved in the esters solvent ethyl acetate with 3-10 carbon atom, hydrochloric acid is added and is reacted, be subsequently isolated (such as
Centrifuge separation) and it is dry.
Another aspect of the present invention provides the sulfate of the compound of formula (I).Preferably, in the compound of the formula (I)
Sulfate in, the compound of formula (I) and sulfuric acid (H2SO4) molar ratio be 1: 1.
Another aspect of the present invention provides the vitriol of the compound of formula (I), and the crystal is by using Cu-K α spoke
The XRPD map for penetrating acquisition is included in about 10.1 ± 0.2,15.6 ± 0.2,16.5 ± 0.2,20.6 ± 0.2,21.0 ± 0.2,
Peak at 21.7 ± 0.2,22.3 ± 0.2,27.6 ± 0.2,28.6 ± 0.2 and 35.5 ± 0.2 angle of diffraction (2 θ).
Another aspect of the present invention provides the method for preparing the sulfate and its crystal of compound of above-mentioned formula (I), packet
Include and dissolve the compound of the formula (I) of any solid form (such as crystal form or amorphous) in organic solvent, be added sulfuric acid into
(such as centrifuge separation) and drying is subsequently isolated in row reaction, and the organic solvent includes the alcohols with 1-10 carbon atom, ether
Class, nitrile, ketone or esters solvent.In a preferred embodiment, the present invention provides the compound for preparing above-mentioned formula (I)
The method of vitriol comprising there is the compound of the formula (I) of any solid form (such as crystal form or amorphous)
It is dissolved in the preferred acetonitrile of the nitrile solvents of 2-6 carbon atom, sulfuric acid is added and is reacted, (such as centrifuge separation) is subsequently isolated simultaneously
It is dry.
Another aspect of the present invention provides 1, the 5- napadisilate of the compound of formula (I).Preferably, at the formula (I)
Compound 1,5- napadisilate in, the compound and 1 of formula (I), the molar ratio of 5- naphthalenedisulfonic acid is 1: 1.
Another aspect of the present invention provides 1, the 5- napadisilate solid form of the compound of formula (I), the solid shape
Formula is by using the peak that the XRPD map that Cu-K α radiation obtains includes at the angle of diffraction substantially the same with shown in Fig. 3 (2 θ).
Another aspect of the present invention provides 1, the 5- napadisilate and its solid form for preparing the compound of above-mentioned formula (I)
Method comprising the compound of the formula (I) of any solid form (such as crystal form or amorphous) is dissolved in organic solvent,
1,5- naphthalenedisulfonic acid is added to be reacted, (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes having 1-
Alcohols, ethers, nitrile, ketone or the esters solvent of 10 carbon atoms.In a preferred embodiment, the present invention provides preparation
The method of 1, the 5- napadisilate solid form of the compound of above-mentioned formula (I) comprising by any solid form (such as crystal form
Or it is amorphous) the compound of formula (I) dissolved in the preferred tetrahydrofuran of ether solvent with 2-6 carbon atom, be added 1,
5- naphthalenedisulfonic acid is reacted, and is subsequently isolated (such as centrifuge separation) and dry.
Another aspect of the present invention provides the 2- naphthalene sulfonate of the compound of formula (I).Preferably, in the change of the formula (I)
In the 2- naphthalene sulfonate for closing object, the compound of formula (I) and the molar ratio of 2- naphthalene sulfonic acids are 1: 1.
Another aspect of the present invention provides the 2- naphthalene sulfonate crystal of the compound of formula (I), and the crystal is by using Cu-
The XRPD map that K α radiation obtains is included in about 6.3 ± 0.2,9.1 ± 0.2,11.8 ± 0.2,14.6 ± 0.2,17.7 ± 0.2,
Peak at 19.0 ± 0.2,19.3 ± 0.2,20.1 ± 0.2,21.7 ± 0.2 and 23.8 ± 0.2 angle of diffraction (2 θ).
Another aspect of the present invention provides the method for preparing the 2- naphthalene sulfonate and its crystal of compound of above-mentioned formula (I),
It includes dissolving the compound of the formula (I) of any solid form (such as crystal form or amorphous) in organic solvent, and 2- is added
Naphthalene sulfonic acids is reacted, and (such as centrifuge separation) and drying is subsequently isolated, and the organic solvent includes having 1-10 carbon atom
Alcohols, ethers, nitrile, ketone or esters solvent.In a preferred embodiment, present invention offer prepares above-mentioned formula (I)
Compound 2- naphthalene sulfonate crystal method comprising by the formula (I) of any solid form (such as crystal form or amorphous)
Compound dissolved in the esters solvent ethyl acetate with 3-10 carbon atom, be added 2- naphthalene sulfonic acids reacted,
It is subsequently isolated (such as centrifuge separation) and dry.
Another aspect of the present invention provides the oxalates of the compound of formula (I).Preferably, in the compound of the formula (I)
Oxalates in, the molar ratio of the compound of formula (I) and oxalic acid is 1: 2.
Another aspect of the present invention provides the oxalic acid salt crystal of the compound of formula (I), and the crystal is by using Cu-K α spoke
The XRPD map for penetrating acquisition is included in about 11.3 ± 0.2,13.4 ± 0.2,20.4 ± 0.2,21.0 ± 0.2,22.2 ± 0.2 Hes
Peak at 25.9 ± 0.2 angle of diffraction (2 θ).
Another aspect of the present invention provides the oxalic acid salt crystal of the compound of formula (I), and the crystal is by using Cu-K α spoke
The XRPD map for penetrating acquisition is included in about 11.3 ± 0.2,13.4 ± 0.2,15.2 ± 0.2,17.0 ± 0.2,19.7 ± 0.2,
Peak at 20.4 ± 0.2,21.0 ± 0.2,21.7 ± 0.2,22.2 ± 0.2 and 25.9 ± 0.2 angle of diffraction (2 θ).
Another aspect of the present invention provides the method for preparing the oxalates and its crystal of compound of above-mentioned formula (I), packet
Include and dissolve the compound of the formula (I) of any solid form (such as crystal form or amorphous) in organic solvent, be added oxalic acid into
(such as centrifuge separation) and drying is subsequently isolated in row reaction, and the organic solvent includes the alcohols with 1-10 carbon atom, ether
Class, nitrile, ketone or esters solvent.In a preferred embodiment, the present invention provides the compound for preparing above-mentioned formula (I)
The method of oxalic acid salt crystal comprising there is the compound of the formula (I) of any solid form (such as crystal form or amorphous)
It is molten in the esters solvent ethyl acetate of 3-10 carbon atom or the preferred tetrahydrofuran of ether solvent with 2-6 carbon atom
Solution is added oxalic acid and is reacted, and is subsequently isolated (such as centrifuge separation) and dry.
Another aspect of the present invention provides the mesylate of the compound of formula (I).Preferably, in the chemical combination of the formula (I)
In the mesylate of object, the compound of formula (I) and the molar ratio of methanesulfonic acid are 1: 1.
Another aspect of the present invention provides the mesylate crystals of the compound of formula (I), and the crystal is by using Cu-K α
The XRPD map that radiation obtains is included in about 5.7 ± 0.2,8.6 ± 0.2,9.6 ± 0.2,16.4 ± 0.2,17.8 ± 0.2,19.9
Peak at ± 0.2,21.7 ± 0.2,24.4 ± 0.2 and 28.6 ± 0.2 angle of diffraction (2 θ).
Another aspect of the present invention provides the method for preparing the mesylate and its crystal of compound of above-mentioned formula (I),
Including dissolving the compound of the formula (I) of any solid form (such as crystal form or amorphous) in organic solvent, methylsulphur is added
Acid is reacted, and (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes the alcohol with 1-10 carbon atom
Class, ethers, nitrile, ketone or esters solvent.In a preferred embodiment, the present invention provides the change for preparing above-mentioned formula (I)
The method for closing the mesylate crystals of object comprising by the chemical combination of the formula (I) of any solid form (such as crystal form or amorphous)
Object dissolves in the preferred tetrahydrofuran of ether solvent with 2-6 carbon atom, and methanesulfonic acid is added and is reacted, is subsequently isolated
(such as centrifuge separation) is simultaneously dry.
Another aspect of the present invention provides pharmaceutical composition, and it includes the salt of the compound of above-mentioned formula (I) or its any groups
It closes, especially the hydrochloride of the compound of formula (I), sulfate, 1,5- napadisilate, 2- naphthalene sulfonic acids, oxalates or methanesulfonic acid
Solid form (preferred crystal form) of salt or the salt or any combination thereof and one or more pharmaceutically acceptable
Carrier.
Another aspect of the present invention provides the salt of the compound of above-mentioned formula (I), the especially hydrochloric acid of the compound of formula (I)
The solid form of salt, sulfate, 1,5- napadisilate, 2- naphthalene sulfonic acids, oxalates or mesylate or the salt is (preferably
Crystal form) in preparation for the purposes in calmness, hypnosis, antianxiety, of flaccid muscles or anticonvulsant drug.
Another aspect of the invention provides the calmness for individual, hypnosis, antianxiety, of flaccid muscles or anticonvulsant side
Method comprising to the salt of the compound for a effective amount of above-mentioned formula (I) of individual administration for needing it, the especially compound of formula (I)
Hydrochloride, sulfate, 1,5- napadisilate, 2- naphthalene sulfonic acids, oxalates or mesylate or the salt solid form
(preferred crystal form).
The salt of the compound of above-mentioned formula (I) provided by the invention can be used alone or be suitable for prevent or treatment maincenter mind
One or more other drugs through systemic disease are used in combination；Especially and for calmness, hypnosis, antianxiety, muscle pine
It relaxes or anticonvulsant one or more other drugs is used in combination.And the salt of the compound of above-mentioned formula (I) provided by the invention
It can combine with other Reagents Drugs that at least one of other drugs have certain effect with using.
The present invention also provides a kind of salt of the compound of above-mentioned formula (I) be used alone or with other central nervous systems
Property it is medication combined be used to prepare prevention or treat central nervous system disease method.And above-mentioned formula provided by the invention
(I) salt of compound is being used alone or is having other Reagents Drugs of certain effect to combine at least one of other drugs
Method for preventing or treating central nervous system disease.
So-called joint includes simultaneously, sequence, alternately uses, and further includes being prepared into be present in one or more medicines accordingly
The suitable pharmaceutical dosage form or drug products being used in combination in object unit.
The central nervous system disease includes insomnia, anxiety, of flaccid muscles or convulsions etc..
The salt of the compound of formula (I) provided by the present invention have well can preparative (convenient for preparation), preparation method
Easy to operate, environmentally friendly, without significant difference between the product of reproducible each batch preparation, having is suitable for the excellent of industrialized production
Gesture；
Product prepared by the present invention have high-purity and higher chemical stability, the compound of formula (I) it is various
Dissolvent residual in the solid form (such as crystal form and/or amorphous) of salt is lower, even if storing under long-term and/or acceleration environment
Still there is lower impurity or solvent content after depositing, reduce the toxicological effect as caused by impurity or dissolvent residual；
The acid safety with higher utilized in the present invention at salt, will not cause undesirable toxicity.
In addition, various salt of the invention and its crystal can show the thermodynamic stability of enhancing or can be easier with high-purity
The a large amount of preparations of degree also can express other advantageous physical properties and (such as draw moist to be particularly suited for preparing pharmaceutical preparation
(hygroscopicity), mobility, filtrability, the solubility of raising) and pharmacokinetics form (such as due to different lattices
The dissolution rate of the raising of energy and the bioavilability of raising).
Detailed description of the invention
Fig. 1 shows the XRPD map of the hydrochloric acid salt crystal of the compound of formula (I).
Fig. 2 shows the XRPD map of the vitriol of the compound of formula (I).
Fig. 3 shows the XRPD map of 1, the 5- napadisilate solid form of the compound of formula (I).
Fig. 4 shows the XRPD map of the 2- naphthalene sulfonate crystal of the compound of formula (I).
Fig. 5 shows the XRPD map of the oxalic acid salt crystal of the compound of formula (I).
Fig. 6 shows the XRPD map of the mesylate crystals of the compound of formula (I).
Specific embodiment
The salt and its solid form and preparation method of the compound of formula (I)
In one embodiment, the present invention provides the hydrochloride of the compound of formula (I).Preferably, in the formula (I)
In the hydrochloride of compound, the compound of formula (I) and the molar ratio of hydrochloric acid (HCl) are 1: 1.
In a preferred embodiment, the present invention provides the hydrochloric acid salt crystal of the compound of formula (I), and the crystal passes through
It is included in about 6.9 ± 0.2,9.0 ± 0.2,13.5 ± 0.2,13.8 ± 0.2,17.6 using the XRPD map that Cu-K α radiation obtains
Peak at ± 0.2,20.8 ± 0.2,21.3 ± 0.2,22.5 ± 0.2,27.8 ± 0.2 and 28.4 ± 0.2 angle of diffraction (2 θ).
In a further preferred embodiment, the present invention provides the hydrochloric acid salt crystal of the compound of formula (I), the crystal
Be included in about 6.9 ± 0.2 by using the XRPD map that Cu-K α radiation obtains, 9.0 ± 0.2,13.5 ± 0.2,13.8 ± 0.2,
17.6±0.2、17.8±0.2、18.8±0.2、19.9±0.2、20.8±0.2、21.3±0.2、21.9±0.2、22.5±
0.2、23.7±0.2、24.8±0.2、26.0±0.2、26.4±0.2、27.8±0.2、28.4±0.2、29.5±0.2、
Peak at 29.7 ± 0.2,31.8 ± 0.2,33.0 ± 0.2 and 35.7 ± 0.2 angle of diffraction (2 θ).
In a preferred embodiment, the hydrochloric acid salt crystal of the compound of the formula (I) by using Cu-K α radiate
The XRPD map of acquisition includes the peak at the angle of diffraction substantially the same with shown in Fig. 1 (2 θ).
In a preferred embodiment, the hydrochloric acid salt crystal of the compound of the formula (I) by using Cu-K α radiate
The XRPD peak position of acquisition is substantially the same with shown in Fig. 1.
In another embodiment, the present invention provides the hydrochloride and its crystal form for preparing the compound of above-mentioned formula (I)
Method comprising the compound of the formula (I) of any solid form (such as crystal form or amorphous) is dissolved in organic solvent,
Hydrochloric acid is added to be reacted, (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes having 1-10 carbon former
Alcohols, ethers, nitrile, ketone or the esters solvent of son.
In a preferred embodiment, the present invention provides the side for preparing the hydrochloric acid salt crystal of compound of above-mentioned formula (I)
Method comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) with 3-10 carbon atom
Dissolution in esters solvent (ethyl acetate) is added hydrochloric acid and is reacted, and is subsequently isolated (such as centrifuge separation) and dry.
In another embodiment, the present invention provides the sulfate of the compound of formula (I).Preferably, in the formula (I)
In the sulfate of compound, the compound and sulfuric acid (H of formula (I)2SO4) molar ratio be 1: 1.
In a preferred embodiment, the present invention provides the vitriol of the compound of formula (I), and the crystal passes through
Be included in about 10.1 ± 0.2 using the XRPD map that Cu-K α radiation obtains, 15.6 ± 0.2,16.5 ± 0.2,20.6 ± 0.2,
At 21.0 ± 0.2,21.7 ± 0.2,22.3 ± 0.2,27.6 ± 0.2,28.6 ± 0.2 and 35.5 ± 0.2 angle of diffraction (2 θ)
Peak.
In a further preferred embodiment, the present invention provides the vitriol of the compound of formula (I), the crystal
It is included in about 10.1 ± 0.2,13.7 ± 0.2,15.0 ± 0.2,15.6 by using the XRPD map that Cu-K α radiation obtains ±
0.2、16.5±0.2、19.1±0.2、20.6±0.2、21.0±0.2、21.7±0.2、22.0±0.2、22.3±0.2、
23.5±0.2、24.2±0.2、26.0±0.2、27.1±0.2、27.6±0.2、28.6±0.2、30.2±0.2、31.0±
0.2, the peak at 32.4 ± 0.2,33.4 ± 0.2,34.7 ± 0.2 and 35.5 ± 0.2 angle of diffraction (2 θ).
In a preferred embodiment, the vitriol of the compound of the formula (I) by using Cu-K α radiate
The XRPD map of acquisition includes the peak position at the angle of diffraction substantially the same with shown in Fig. 2 (2 θ).
In a preferred embodiment, the vitriol of the compound of the formula (I) by using Cu-K α radiate
The XRPD peak position of acquisition is substantially the same with shown in Fig. 2.
In another embodiment, the present invention provides the side of the sulfate and its crystal that prepare the compound of above-mentioned formula (I)
Method comprising the compound of the formula (I) of any solid form (such as crystal form or amorphous) is dissolved in organic solvent, is added
Sulfuric acid is reacted, and (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes having 1-10 carbon atom
Alcohols, ethers, nitrile, ketone or esters solvent.
In a preferred embodiment, the present invention provides the side for preparing the vitriol of compound of above-mentioned formula (I)
Method comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) in the nitrile with 2-6 carbon atom
Dissolution in class solvent (preferably acetonitrile) is added sulfuric acid and is reacted, and is subsequently isolated (such as centrifuge separation) and dry.
In another embodiment, the present invention provides 1, the 5- napadisilate of the compound of formula (I).Preferably, in institute
In 1, the 5- napadisilate for stating the compound of formula (I), the compound and 1 of formula (I), the molar ratio of 5- naphthalenedisulfonic acid is 1: 1.
In a preferred embodiment, the present invention provides 1, the 5- napadisilate solid form of the compound of formula (I),
The solid form includes the angle of diffraction (2 substantially the same with shown in Fig. 3 by using the XRPD map that Cu-K α radiation obtains
θ) the peak at place.
In a preferred embodiment, 1, the 5- napadisilate solid form of the compound of the formula (I) passes through
The XRPD peak position obtained using Cu-K α radiation is substantially the same with shown in Fig. 3.
In another embodiment, the present invention provide prepare above-mentioned formula (I) compound 1,5- napadisilate and its
The method of solid form comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) organic molten
It is dissolved in agent, 1,5- naphthalenedisulfonic acid is added and is reacted, (such as centrifuge separation) and dry, the organic solvent packet is subsequently isolated
Include alcohols, ethers, nitrile, ketone or esters solvent with 1-10 carbon atom.
In a preferred embodiment, the present invention provides 1, the 5- napadisilate for preparing the compound of above-mentioned formula (I)
The method of solid form comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) with 2-6
Dissolution in the ether solvent (preferably tetrahydrofuran) of a carbon atom is added 1,5- naphthalenedisulfonic acid and is reacted, be subsequently isolated (such as
Centrifuge separation) and it is dry.
In another embodiment, the present invention provides the 2- naphthalene sulfonate of the compound of formula (I).Preferably, in the formula
(I) in the 2- naphthalene sulfonate of compound, the compound of formula (I) and the molar ratio of 2- naphthalene sulfonic acids are 1: 1.
In a preferred embodiment, the present invention provides the 2- naphthalene sulfonate crystal of the compound of formula (I), the crystal
Be included in about 6.3 ± 0.2 by using the XRPD map that Cu-K α radiation obtains, 9.1 ± 0.2,11.8 ± 0.2,14.6 ± 0.2,
At 17.7 ± 0.2,19.0 ± 0.2,19.3 ± 0.2,20.1 ± 0.2,21.7 ± 0.2 and 23.8 ± 0.2 angle of diffraction (2 θ)
Peak.
In a further preferred embodiment, the present invention provides the 2- naphthalene sulfonate crystal of the compound of formula (I), described
Crystal is included in about 6.3 ± 0.2,9.1 ± 0.2,11.8 ± 0.2,12.7 by using the XRPD map that Cu-K α radiation obtains ±
0.2、13.3±0.2、13.7±0.2、14.6±0.2、15.5±0.2、16.4±0.2、17.7±0.2、18.1±0.2、
18.7±0.2、19.0±0.2、19.3±0.2、20.1±0.2、20.5±0.2、21.7±0.2、22.2±0.2、22.8±
0.2,23.2 ± 0.2,23.8 ± 0.2,24.8 ± 0.2,25.2 ± 0.2,25.9 ± 0.2,26.8 ± 0.2 and 27.8 ± 0.2
Peak at the angle of diffraction (2 θ).
In a preferred embodiment, the 2- naphthalene sulfonate crystal of the compound of the formula (I) by using Cu-K α
The XRPD map that radiation obtains includes the peak at the angle of diffraction substantially the same with shown in Fig. 4 (2 θ).
In a preferred embodiment, the 2- naphthalene sulfonate crystal of the compound of the formula (I) by using Cu-K α
It is substantially the same with shown in Fig. 4 to radiate the XRPD peak position obtained.
In another embodiment, the present invention provides the 2- naphthalene sulfonate and its crystal for preparing the compound of above-mentioned formula (I)
Method comprising the compound of the formula (I) of any solid form (such as crystal form or amorphous) is dissolved in organic solvent,
2- naphthalene sulfonic acids is added to be reacted, is subsequently isolated and dries, the organic solvent includes the alcohols with 1-10 carbon atom, ether
Class, nitrile, ketone or esters solvent.
In a preferred embodiment, the present invention provides the 2- naphthalene sulfonate crystal for preparing the compound of above-mentioned formula (I)
Method comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) former with 3-10 carbon
Dissolution in the esters solvent (ethyl acetate) of son is added 2- naphthalene sulfonic acids and is reacted, is subsequently isolated and dries.
In another embodiment, the present invention provides the oxalates of the compound of formula (I).Preferably, in the formula (I)
In the oxalates of compound, the compound of formula (I) and the molar ratio of oxalic acid are 1: 2.
In a preferred embodiment, the present invention provides the oxalic acid salt crystal of the compound of formula (I), and the crystal passes through
Be included in about 11.3 ± 0.2 using the XRPD map that Cu-K α radiation obtains, 13.4 ± 0.2,20.4 ± 0.2,21.0 ± 0.2,
Peak at 22.2 ± 0.2 and 25.9 ± 0.2 angle of diffraction (2 θ).
In a preferred embodiment, the present invention provides the oxalic acid salt crystal of the compound of formula (I), and the crystal passes through
Be included in about 11.3 ± 0.2 using the XRPD map that Cu-K α radiation obtains, 13.4 ± 0.2,15.2 ± 0.2,17.0 ± 0.2,
At 19.7 ± 0.2,20.4 ± 0.2,21.0 ± 0.2,21.7 ± 0.2,22.2 ± 0.2 and 25.9 ± 0.2 angle of diffraction (2 θ)
Peak.
In a further preferred embodiment, the present invention provides the oxalic acid salt crystal of the compound of formula (I), the crystal
Be included in about 6.7 ± 0.2 by using the XRPD map that Cu-K α radiation obtains, 8.7 ± 0.2,11.3 ± 0.2,12.6 ± 0.2,
13.4±0.2、13.6±0.2、14.9±0.2、15.2±0.2、17.0±0.2、19.7±0.2、20.1±0.2、20.4±
0.2、21.0±0.2、21.3±0.2、21.7±0.2、22.2±0.2、22.5±0.2、23.1±0.2、23.5±0.2、
24.2±0.2、24.7±0.2、25.3±0.2、25.9±0.2、27.3±0.2、28.5±0.2、30.0±0.2、30.7±
0.2,31.6 ± 0.2,32.6 ± 0.2,34.3 ± 0.2,34.6 ± 0.2,35.9 ± 0.2,36.4 ± 0.2 and 37.0 ± 0.2
Peak at the angle of diffraction (2 θ).
In a preferred embodiment, the oxalic acid salt crystal of the compound of the formula (I) by using Cu-K α radiate
The XRPD map of acquisition includes the peak at the angle of diffraction substantially the same with shown in Fig. 5 (2 θ).
In a preferred embodiment, the oxalic acid salt crystal of the compound of the formula (I) by using Cu-K α radiate
The XRPD peak position of acquisition is substantially the same with shown in Fig. 5.
In another embodiment, the present invention provides the side of the oxalates and its crystal that prepare the compound of above-mentioned formula (I)
Method comprising the compound of the formula (I) of any solid form (such as crystal form or amorphous) is dissolved in organic solvent, is added
Oxalic acid is reacted, and (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes having 1-10 carbon atom
Alcohols, ethers, nitrile, ketone or esters solvent.
In a preferred embodiment, the present invention provides the side for preparing the oxalic acid salt crystal of compound of above-mentioned formula (I)
Method comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) with 3-10 carbon atom
Dissolution in esters solvent (ethyl acetate) or ether solvent (preferably tetrahydrofuran) with 2-6 carbon atom, is added grass
Acid is reacted, and is subsequently isolated (such as centrifuge separation) and dry.
In another embodiment, the present invention provides the mesylate of the compound of formula (I).Preferably, at the formula (I)
Compound mesylate in, the molar ratio of the compound of formula (I) and methanesulfonic acid is 1: 1.
In a preferred embodiment, the present invention provides the mesylate crystals of the compound of formula (I), and the crystal is logical
Cross be included in about 5.7 ± 0.2 using the XRPD map that Cu-K α radiation obtains, 8.6 ± 0.2,9.6 ± 0.2,16.4 ± 0.2,
Peak at 17.8 ± 0.2,19.9 ± 0.2,21.7 ± 0.2,24.4 ± 0.2 and 28.6 ± 0.2 angle of diffraction (2 θ).
In a preferred embodiment, the mesylate crystals of the compound of the formula (I) by using Cu-K α spoke
The XRPD map for penetrating acquisition includes peak at the angle of diffraction substantially the same with shown in Fig. 6 (2 θ).
In a preferred embodiment, the mesylate crystals of the compound of the formula (I) by using Cu-K α spoke
The XRPD peak position for penetrating acquisition is substantially the same with shown in Fig. 6.
In another embodiment, the present invention provides the mesylate and its crystal for preparing the compound of above-mentioned formula (I)
Method comprising the compound of the formula (I) of any solid form (such as crystal form or amorphous) is dissolved in organic solvent, is added
Enter methanesulfonic acid to be reacted, (such as centrifuge separation) and drying is subsequently isolated, the organic solvent includes having 1-10 carbon former
Alcohols, ethers, nitrile, ketone or the esters solvent of son.
In a preferred embodiment, the present invention provides the mesylate crystals for preparing the compound of above-mentioned formula (I)
Method comprising by the compound of the formula (I) of any solid form (such as crystal form or amorphous) with 2-6 carbon atom
Dissolution in ether solvent (preferably tetrahydrofuran) is added methanesulfonic acid and is reacted, and is subsequently isolated (such as centrifuge separation) and dry.
Unless hereinafter defined otherwise, the meaning of all technical terms and scientific terms used herein is intended to and this
Field technical staff is generally understood identical.It refers to that technology used herein is intended to refer to be generally understood in the art
Technology, the replacement of variation or equivalence techniques including those technologies that will be apparent to those skilled in the art.While it is believed that with
Lower term is for those skilled in the art it is well understood that but still illustrating defined below preferably to explain the present invention.
"include", "comprise", " having ", " containing " or " being related to " and its herein as used herein, the term
Other variant forms are the (inclusive) or open of inclusive, and are not excluded for other unlisted elements or method step
Suddenly.
Word " about " as used herein refers to that those skilled in the art think in the acceptable of described value
Standard error in, such as ± 0.05, ± 0.1, ± 0.2, ± 0.3, ± 0.5, ± 1, ± 2 or ± 3 etc..
" solid form " includes all solid-state forms of the salt of the compound of formula (I), example as used herein, the term
Such as crystal form or amorphous form.
" amorphous " refers to any solid matter in three-dimensional without sequence as used herein, the term.In some cases
In, amorphous solid can be characterized by known technology, and the technology includes XRPD crystallographic analysis, solid state nmr
(ssNMR) some combinations of Spectrum Analysis, differential scanning calorimetry (DSC) or these technologies.As explained below, amorphous solid
The XRPD map of generation is without apparent diffractive features peak.
" crystal form " or " crystal " refers to any solid matter that three-dimensional sequence is presented as used herein, the term, with nothing
White amorphous solid substance is on the contrary, it generates the characteristic XRPD map with the peak of clear border.
" X-ray powder diffraction pattern (XRPD map) " refers to the diffraction pattern of Germicidal efficacy as used herein, the term
Or parameter, data or value derived from it.XRPD map is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
" 2 θ " refers to based on being indicated with degree (°) of being arranged in x-ray diffraction experiment as used herein, the term
Peak position, and be usually the abscissa unit in diffracting spectrum.If reflection is spread out when incident beam and certain lattice plane shape into θ angle
It penetrates, then experimental setup needs to record reflecting bundle with 2 angles θ.It should be appreciated that specific 2 θ for the particular crystalline mentioned herein
Value is intended to indicate using 2 θ values (being indicated with degree) measured by x-ray diffraction experiment condition as described herein.For example, as herein
It is described, use Cu-K α (K α 11.540598 with K α 21.544426) it is used as radiation source.
As used herein, the term " substantially the same " at X-ray diffraction peak is meant representative peak position and
Strength Changes are taken into account.For example, it will be understood by those skilled in the art that peak position (2 θ) can show some variations, usually up to 0.1-
0.2 degree, and the instrument for measuring diffraction also results in some variations.In addition, it will be understood by those skilled in the art that opposite peak
Intensity can because between instrument difference and crystallinity degree, preferred orientation, the sample surfaces of preparation and those skilled in the art
Known other factors and change, and should be regarded as only observational measurement.
" alcohols solvent " preferably means the alcohol with 1-10 carbon atom as used herein, the term comprising but not
It is limited to methanol, ethyl alcohol, 1- propyl alcohol, 2- propyl alcohol (isopropanol), n-butyl alcohol, 2- butanol and the tert-butyl alcohol.
" ether solvent " preferably means the ether with 2-6 carbon atom as used herein, the term comprising but not
It is limited to ether, Di Iso Propyl Ether, tetrahydrofuran, dioxanes and dimethoxy-ethane.
" nitrile solvents " preferably mean the nitrile with 2-6 carbon atom as used herein, the term comprising but not
It is limited to acetonitrile and propionitrile.
" ketones solvent " preferably means the ketone with 2-6 carbon atom as used herein, the term comprising but not
It is limited to acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) and metacetone.
" esters solvent " preferably means the ester with 3-10 carbon atom as used herein, the term comprising but not
It is limited to ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate.
The salt of preparation or its solid form (preferred crystal form) can be passed through including decantation, centrifugation, evaporation, gravity mistake
Filter, filter or under elevated pressure or under reduced pressure it is any other for solid separation technology including method separate back
It receives.Isolated solid can be optionally dried." drying " in the present invention preferably under decompression (preferably vacuum), in appointing
It carries out being reduced to International Conference on until the content of residual solvent under meaning temperature (preferably room temperature)
Harmonisation of Technical Requirements for Registration of Pharmaceuticals
In the range of limit given by for Human Use (" ICH ") guide.Residual solvent levels depend on the type of solvent, but
No more than about 5000ppm or preferably from about 4000ppm or more preferably from about 3000ppm.The drying can be in pan dryer, true
Empty baking oven, air -oven, conical vacuum drier (cone vacuum dryer), rotary vacuum dryer, fluidized bed drying
It is carried out in device, spin flash dryer, flash dryer etc..The drying can be below about 100 DEG C, be below about 80 DEG C, low
In about 60 DEG C, below about at 50 DEG C, the temperature below about 30 DEG C or any other suitable temperature, it is (excellent in atmospheric pressure or decompression
Select vacuum) under within any desired time that can be realized desired result (such as from about 1,2,3,5,10,15,20,24 hour or
Person stays overnight) it carries out.The drying can carry out any desired number, the product qualities needed for realizing.Dry product
It can be optionally subjected to crushing operation, to generate desired granularity.It can be ground before the drying of product or after the completion of dry
Or micronization.The technology that can be used for reducing granularity includes but is not limited to ball milling, roller mill and sledge mill and jet grinding (jet
milling)。
Pharmaceutical composition and treatment method
In another embodiment, the present invention provide pharmaceutical composition, it includes the salt of the compound of above-mentioned formula (I) or its
The hydrochloride of the compound of any combination, especially formula (I), sulfate, 1,5- napadisilate, 2- naphthalene sulfonic acids, oxalates or
Solid form (preferred crystal form) of mesylate or the salt or any combination thereof and it is one or more pharmaceutically
Acceptable carrier.It is optionally present other therapeutic agents in the composition.
In another embodiment, the present invention provides the salt of the compound of above-mentioned formula (I), the especially compound of formula (I)
Hydrochloride, sulfate, 1,5- napadisilate, 2- naphthalene sulfonic acids, oxalates or mesylate or the salt solid form
(preferred crystal form) is in preparation for the purposes in calmness, hypnosis, antianxiety, of flaccid muscles or anticonvulsant drug.
In still another embodiment, the present invention is provided to the calmness of individual, hypnosis, antianxiety, of flaccid muscles or anti-frightened
The method fainted comprising to the salt of the compound for a effective amount of above-mentioned formula (I) of individual administration for needing it, especially formula (I)
The hydrochloride of compound, sulfate, 1,5- napadisilate, 2- naphthalene sulfonic acids, oxalates or mesylate or its salt solid
Form (preferred crystal form).
As used herein, the term " pharmaceutically acceptable carrier " refer to the diluent being administered together with therapeutic agent,
Adjuvant, excipient or medium, and it is adapted for contact with the mankind and/or other animals in the range of reasonable medical judgment
Tissue without excessive toxicity, stimulation, allergic reaction or with reasonable benefit/risk compared with corresponding other problems or concurrently
Disease.
Workable pharmaceutically acceptable carrier includes but is not limited to sterile liquid in pharmaceutical composition of the invention,
Such as water and oil, the oil including those petroleum, animal, plant or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame
Oil etc..When described pharmaceutical composition is administered intravenously (IV, water is exemplary carrier.Physiological saline and grape can also be used
Sugar and glycerine water solution are especially used for injection as liquid-carrier.Suitable drug excipient include starch, glucose,
Lactose, sucrose, gelatin, maltose, chalk, silica gel, odium stearate, glycerin monostearate, talcum, sodium chloride, skimmed milk power,
Glycerol, propylene glycol, water, ethyl alcohol etc..The composition can also optionally include a small amount of wetting agent, emulsifier or pH buffering
Agent.Oral preparation may include standard vector, such as the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, saccharin sodium, fiber
Element, magnesium carbonate etc..The example of suitable pharmaceutically acceptable carrier is such as in Remington ' s Pharmaceutical
Described in Sciences (1990).
Composition of the invention can be acted on systematically and/or locally be acted on.For this purpose, the way that they can be suitble to
Diameter administration, for example, by injection, intravenous, intra-arterial, subcutaneous, peritonaeum, intramuscular or percutaneous dosing；Or by it is oral, buccal,
Intranasal, it is transmucosal, local, in the form of eye-drops preparations or pass through inhalation.
For these administration routes, composition of the invention is administered in the dosage form that can be suitble to.
The dosage form includes but is not limited to tablet, capsule, pastille, hard candy agent, powder, spray, cream, ointment
Agent, suppository, gelling agent, paste, lotion, ointment, aqueous suspension, injection, elixir, syrup.
" therapeutically effective amount " refers to as used herein, the term be administered after can alleviate to a certain extent and treat disease
The amount of the compound of one or more symptoms of disease.
Dosage regimen be can adjust to provide optimal required response.For example, single bolus can be administered, can be administered at any time several
Divided dose, or dosage can be proportionally reduced or increased as indicated in the urgent need for the treatment of condition.It should be noted that dose value can be with will subtract
The type and seriousness of the light patient's condition and change, and may include single or multiple dosage.It further understands, for any specific
Individual, specific dosage regimen should be sentenced according to the profession of individual need and administration composition or the personnel for the administration for supervising composition
Break to adjust at any time.
The amount of the compound of the present invention being administered can depend on individual treated, the seriousness of illness or the patient's condition, to
The rate of medicine, the disposition of compound and the judgement of prescriber.In general, effective dose per kg body weight per day about
0.0001mg to about 50mg, for example, about 0.01mg/kg/ to about 10mg/kg/ (single or divided doses).To the people of 70kg
For, this can be added up to about 0.007mg/ to about 3500mg/, for example, about 0.7mg/ to about 700mg/.In some feelings
It under condition, can be not higher than the dosage level of the lower limit of aforementioned range enough, and in other cases, still can not cause to appoint
Use larger dose in the case where what harmful side effect, condition be first by the larger dose be divided into several smaller doses with
It is administered throughout the day.
Content or dosage of the compound of the present invention in pharmaceutical composition can be about 0.01mg to about 1000mg, be suitble to
Ground is 0.1mg-500mg, preferably 0.5mg-300mg, more preferable 1mg-150mg, particularly preferred 1mg-50mg, such as 1.5mg,
2mg, 4mg, 10mg and 25mg etc..
Unless otherwise stated, otherwise as used herein, term " treatment (treating) " means to reverse, mitigate, suppression
Make the progress of one or more symptoms of illness or the patient's condition applied by such term or such illness or the patient's condition, or prevention
One or more symptoms of such illness or the patient's condition or such illness or the patient's condition.
" individual " includes people or non-human animal as used herein.Exemplary individual human include with disease (such as this
Disease described in text) individual human (referred to as patient) or normal individual." non-human animal " includes all vertebrates in the present invention,
Such as nonmammalian (such as birds, amphibian, reptile) and mammal, such as non-human primates, domestic animal and/or
Domesticated animal (such as sheep, dog, cat, milk cow, pig etc.).
Embodiment
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention
Art scheme, is not intended to limit the scope of the present invention.
Experiment test equipment information and method used
Method 1, XRPD
XRPD map acquires on PANalyticalEmpyrean X-ray powder diffraction analyzer, and the X of XRPD test is penetrated
Line is Cu-k α (K α 11.540598；Kα21 intensity of 1.544426K α 2/K α: 0.50).
Method 2, thermogravimetric analysis (TGA) and dsc analysis
TGA and DSC is adopted on TA Q500/5000 thermogravimetric analyzer and TAQ200/2000 differential scanning calorimeter respectively
Collection.
Method 3, ion chromatography (IC)
Gegenion content is measured using ion chromatography (IC), and it is combined with HPLC with the resulting salt Chinese style of determination
(I) molar ratio of compound and salt-forming ion.
Method 4, petrographic microscope (PLM) test
PLM test is acquired at room temperature by Axio Lab.A1 positively fixed type microscope.
Method 5, dynamic water absorption (DVS)
DVS numerical value acquires on the DVS Intrinsic of SMS (Surface Measurement Systems).DVS is surveyed
Try relative humidity LiCl, Mg (NO at 25 DEG C3)2It is corrected with the deliquescence point of KCl.
Method 6, solubility
It is fed in simulation fasting intestinal juice (simulated intestinal fluid i.e. under the fasting state of pH 6.5, abbreviation FaSSIF) and/or simulation
Solubility test is carried out in food intestinal juice (i.e. simulated intestinal fluid under the fed conditions of pH 5.0, abbreviation FeSSIF) solvent.It will about 20 millis
Gram each test article, reference substance are mixed with 2.0 milliliters of solvents respectively, at room temperature rotation mixing, and each time point (such as
1 hour, 2 hours, 4 hours or 24 hours) sampling, muddy sample is centrifugated, filtered supernatant is measured by HPLC
The concentration of test article is in liquid to get to each time point of the test article in solvent, (such as 1 hour, 2 hours, 4 hours or 24 are small
When) solubility.Clear sample was become for 1 hour solution, according to the range of sample-adding amount and solvent amount estimated concentration.It is small 24
If when observation be still the clear state of solution, do not continuously add sample and test.
Method 7, the stability under the acceleration environment of high temperature or high humidity
By test article and reference substance respectively hot conditions (40 DEG C) and super-humid conditions (25 DEG C, relative humidity (RH)
92.5%) scheduled time (such as 10 days) are stored under.Then test article and reference substance are subjected to HPLC analysis respectively, with detection
The generation of impurity.
Initialism:
Mg milligrams
ML milliliters
μ L microlitre
Embodiment 1: the preparation and representation of the hydrochloric acid salt crystal of formula (I) compound
The hydrochloric acid salt crystal of the compound of formula (I) is prepared by following steps:
1. weighing the compound of the formula (I) of 196.3mg；
2. 8.0mL ethyl acetate and 40 μ L concentrated hydrochloric acids are added；
3. reactant is stirred at room temperature 24 hours；
4. centrifuge separation, obtains lower layer's solid；
5. resulting solid is dried overnight in vacuum at room temperature, crystal is obtained.
Ion chromatography (IC) detection is carried out to crystal obtained according to method 3, in the hydrochloric acid of the compound of the formula (I)
In salt, the compound of formula (I) and the molar ratio of HCl are 1: 1.
XRPD analysis is carried out to crystal obtained according to method 1, gained XRPD map is as shown in fig. 1, related data
As shown in table 1.
Table 1: the XRPD spectrum data of the hydrochloric acid salt crystal of the compound of formula (I)
PLM test is carried out to crystal obtained according to method 4, gained crystal is in needle-shaped.
According to method 5, DVS test is carried out to obtained crystal.The result shows that resulting crystal is in 25 DEG C/80%RH condition
Lower moisture adsorbance is 0.29%, and DVS test front and back sample crystal form does not change.This shows the hygroscopicity of resulting crystal
It is lower, and preferable physical stability is shown under test conditions.
According to method 6, the benzenesulfonate crystalline to be prepared according to Chinese patent CN102753525B compares as reference substance
The hydrochloric acid salt crystal and reference substance that the present embodiment obtains 1 hour, 2 hours and 4 hours solubility in FaSSIF solvent, as a result
As shown in table 2
Solubility of 2: the two kinds of crystal of table in FaSSIF
Table 2 the results show that in FaSSIF solvent, the hydrochloric acid salt crystal of the present embodiment time point be respectively 1 hour,
2 hours, 4 hours solubility be respectively 5.5mg/mL, 5.3mg/mL, 5.5mg/mL, noticeably greater than reference substance benzene sulfonate is brilliant
Solubility of the body in FaSSIF solvent.Show that the hydrochloric acid salt crystal of the present embodiment is significantly excellent in the solubility of various time points
In reference substance benzenesulfonate crystalline.
Embodiment 2: the preparation and representation of the vitriol of the compound of formula (I)
The vitriol of the compound of formula (I) is prepared by following steps:
1. weighing the compound of the formula (I) of 301.0mg；
2. 8.0mL acetonitrile and the 34 μ L concentrated sulfuric acids are added；
3. reactant is stirred at room temperature 24 hours；
4. centrifuge separation, obtains lower layer's solid；
5. resulting solid is dried overnight in vacuum at room temperature, crystal is obtained.
Ion chromatography (IC) detection is carried out to crystal obtained according to method 3, in the sulfuric acid of the compound of the formula (I)
In salt, the compound and sulfuric acid (H of formula (I)2SO4) molar ratio be 1: 1.
XRPD analysis is carried out to crystal obtained according to method 1, gained XRPD map is as shown in Figure 2, related data
As shown in table 3.
Table 3: the XRPD spectrum data of the vitriol of the compound of formula (I)
PLM test is carried out to crystal obtained according to method 4, the particle of gained crystal is smaller.
According to method 5, DVS test is carried out to obtained crystal.The result shows that resulting crystal is in 25 DEG C/80%RH condition
Lower moisture adsorbance is 0.74%, and DVS test front and back sample crystal form does not change.This shows the hygroscopicity of resulting crystal
It is lower, and preferable physical stability is shown under test conditions.
According to method 6, the benzenesulfonate crystalline to be prepared according to Chinese patent CN102753525B compares as reference substance
Vitriol and the reference substance dissolution in 1 hour, 2 hours, 4 hours and 24 hours in FaSSIF solvent that the present embodiment obtains
Degree, as a result as shown in table 4.
Solubility of 4: the two kinds of crystal of table in FaSSIF
Table 4 the results show that in FaSSIF solvent, the vitriol of the present embodiment is equal in the solubility of each time
Greater than 7.4 mg/mls, it is significantly better than the solubility of reference substance benzenesulfonate crystalline.
Embodiment 3: the preparation and representation of 1, the 5- napadisilate solid form of formula (I) compound
1, the 5- napadisilate solid form of the compound of formula (I) is prepared by following steps:
1. weighing the compound of the formula (I) of 301.5mg；
2. 8.0mL tetrahydrofuran and 210.0mg1,5- naphthalenedisulfonic acid is added；
3. reactant is stirred at room temperature 24 hours；
4. centrifuge separation, obtains lower layer's solid；
5. resulting solid is dried overnight in vacuum at room temperature, the solid form is obtained.
It is measured according to method 3, in 1, the 5- napadisilate of the compound of the formula (I), the compound and 1 of formula (I),
The molar ratio of 5- naphthalenedisulfonic acid is 1: 1.
XRPD analysis is carried out to solid form obtained according to method 1, gained XRPD map is as shown in Figure 3.
TGA is carried out to solid form obtained according to method 2, by analyzing it is found that sample weightlessness before 150.0 DEG C is about
5.1%.
PLM test is carried out to solid form obtained according to method 4, obtained solid form particle is smaller, and with group
It is poly-.
Embodiment 4: the preparation and representation of the 2- naphthalene sulfonate crystal of the compound of formula (I)
The 2- naphthalene sulfonate crystal of the compound of formula (I) is prepared by following steps:
1. weighing the compound of the formula (I) of 301.8mg；
2. 8.0mL ethyl acetate and 152.1mg2- naphthalene sulfonic acids is added；
3. reactant is stirred at room temperature 24 hours；
4. centrifuge separation, obtains lower layer's solid；
5. resulting solid is dried overnight in vacuum at room temperature, crystal is obtained.
It is measured according to method 3, in the 2- naphthalene sulfonate of the compound of the formula (I), the compound and 2- naphthalene sulphur of formula (I)
The molar ratio of acid is 1: 1.
XRPD analysis is carried out to crystal obtained according to method 1, gained XRPD map is as shown in Figure 4, related data
As shown in table 5.
Table 5: the XRPD spectrum data of the 2- naphthalene sulfonate crystal of the compound of formula (I)
PLM test is carried out to crystal obtained according to method 4, gained crystal grain is smaller.
According to method 5, DVS test is carried out to obtained crystal.The result shows that resulting crystal is in 25 DEG C/80%RH condition
Lower moisture adsorbance is 1.23%, and DVS test front and back sample crystal form does not change.This shows the hygroscopicity of resulting crystal
It is lower, and preferable physical stability is shown under test conditions.
According to method 6, the benzenesulfonate crystalline to be prepared according to Chinese patent CN102753525B compares as reference substance
The 2- naphthalene sulfonic acids crystal and reference substance that the present embodiment obtains 1 hour, 2 hours, 4 hours and 24 hours molten in FeSSIF solvent
Xie Du, the results are shown in Table 6.
Solubility of 6: the two kinds of crystal of table in FeSSIF
Table 6 the result shows that, the 2- naphthalene sulfonate crystal of the present embodiment is in FeSSIF solvent in the dissolution of each time
Degree is significantly better than benzenesulfonate crystalline.
Embodiment 5: the preparation and representation of the oxalic acid salt crystal of the compound of formula (I)
The oxalic acid salt crystal of the compound of formula (I) is prepared by following steps:
1. weighing the compound of the formula (I) of 300.6mg；
2. 8.0mL tetrahydrofuran and 60.2mg oxalic acid is added；
3. reactant is stirred at room temperature 24 hours；
4. centrifuge separation, obtains lower layer's solid and supernatant liquid；
5. resulting solid is dried overnight in vacuum at room temperature, crystal is obtained；
6. recycling remaining formula (I) compound and its related substances from resulting supernatant liquid.
Ion chromatography (IC) detection is carried out to crystal obtained according to method 3, in the oxalic acid of the compound of the formula (I)
In salt, the compound of formula (I) and the molar ratio of oxalic acid are 1: 2.
XRPD analysis is carried out according to the crystal of 1 pair of obtained oxalates of method, gained XRPD map is as shown in Figure 5, phase
It is as shown in table 7 to close data.
Table 7: the XRPD spectrum data of the oxalic acid salt crystal of the compound of formula (I)
PLM test is carried out to crystal obtained according to method 4, gained crystal grain is smaller.
According to method 5, DVS test is carried out to obtained crystal.The result shows that resulting crystal is in 25 DEG C/80%RH condition
Lower moisture adsorbance is 0.2%, and DVS test front and back sample crystal form does not change.This shows the hygroscopicity of resulting crystal
It is lower, and preferable physical stability is shown under test conditions.
The resulting crystal of the present embodiment and reference substance are tested (according to Chinese patent CN using HPLC according to method 7
102753525B preparation formula (I) compound benzenesulfonate crystalline) purity and its at acceleration environment (high temperature or high humidity)
The generation of purity and impurity after lower storage.Test result is as shown in table 8 and table 9.
Table 8: the purity of sample
Table 9-1: the impurity situation after being stored under the hot conditions described in method 7
Table 9-2: the impurity situation after being stored under the super-humid conditions described in method 7
Note: in table 9-1 and 9-2, the HPLC dwarf shown in * stays the peak area percentage of the impurity afforded under the time
Than.
By the data of table 8 it is found that the purity of oxalic acid salt crystal prepared in the present embodiment is higher than reference substance benzene sulfonic acid
The purity of salt crystal, and under the acceleration environment of high temperature and high humidity, the decline of the purity of oxalic acid salt crystal is significantly less than control
Product, this shows that oxalic acid salt crystal of the invention has better chemical stability.
Data in table 9-1 and table 9-2 show that oxalic acid salt crystal or reference substance benzenesulfonate crystalline are stored in acceleration environment
Exemplary impurity (the content including impurity peaks a, impurity peaks b and impurity peaks c) for causing purity to reduce generated afterwards.
By the data of table 9-1 it is found that sample is stored 10 days under the high temperature conditions after: in reference substance benzenesulfonate crystalline
Impurity a increases to 0.09% from 0.08%, and prepared oxalic acid salt crystal does not detect impurity a in the present embodiment；Reference substance benzene
The content of impurity b is 0.17% in sulfonic acid salt crystal, and impurity b is 0.10% in prepared oxalic acid salt crystal in the present embodiment；
The content of impurity c increases to 0.46% from 0.00% in reference substance benzenesulfonate crystalline, prepared oxalates in the present embodiment
Crystal does not detect impurity c.This shows that the impurity content of oxalic acid salt crystal prepared in the present embodiment is low, oxalic acid salt crystal
Purity influenced by hot conditions it is smaller.Under the high temperature conditions, made in the present embodiment compared with reference substance benzenesulfonate crystalline
Standby oxalic acid salt crystal has better stability, especially chemical stability.
By the data of table 9-2 it is found that sample is stored 10 days under conditions of high humidity after: in reference substance benzenesulfonate crystalline
Impurity a is 0.08%, and the content of impurity b is 0.43% in reference substance benzenesulfonate crystalline；Prepared oxalic acid in the present embodiment
Impurity a and c are not detected in salt crystal, the content of impurity b is 0.30%.This shows oxalates prepared in the present embodiment
The impurity content of crystal is low, and the purity of oxalic acid salt crystal is influenced small by super-humid conditions.Prepared oxalates is brilliant in the present embodiment
Body is with good stability under conditions of high humidity, especially chemical stability.
According to method 6, the benzenesulfonate crystalline to be prepared according to Chinese patent CN102753525B compares as reference substance
The oxalic acid salt crystal and reference substance that the present embodiment obtains are 1 hour, 2 hours, 4 hours and 24 hours in FaSSIF, FeSSIF
Solubility, as a result as shown in Table 10 and Table 11.
Solubility of 10: the two kinds of crystal of table in FaSSIF
Solubility of 11: the two kinds of crystal of table in FeSSIF
Table 10 and table 11 the result shows that, the oxalic acid salt crystal of the present embodiment in two kinds of solvents of FaSSIF and FeSSIF
The solubility of each time is better than reference substance benzenesulfonate crystalline.
Embodiment 6: the preparation and representation of the mesylate crystals of the compound of formula (I)
The mesylate crystals of the compound of formula (I) are prepared by following steps:
1. weighing the compound of the formula (I) of 300.6mg；
2. 8.0mL tetrahydrofuran and 60 μ L methanesulfonic acids are added；
3. reactant is stirred at room temperature 24 hours；
4. centrifuge separation, obtains lower layer's solid；
5. resulting solid is dried overnight in vacuum at room temperature, crystal is obtained.
Ion chromatography (IC) detection is carried out to crystal obtained according to method 3, in the methylsulphur of the compound of the formula (I)
In hydrochlorate, the compound of formula (I) and the molar ratio of methanesulfonic acid are 1: 1.
XRPD analysis is carried out to crystal obtained according to method 1, gained XRPD map is as shown in Figure 6, related data
As shown in Table 12.
Table 12: the XRPD spectrum data of the mesylate crystals of the compound of formula (I)
PLM test is carried out to crystal obtained according to method 4, gained crystal grain is smaller.
According to method 6, the benzenesulfonate crystalline to be prepared according to Chinese patent CN102753525B compares as reference substance
The mesylate crystals and reference substance that the present embodiment obtains 1 hour, 2 hours and 4 hours solubility in FaSSIF, as a result such as
Shown in table 13.
Solubility of 13: the two kinds of crystal of table in FaSSIF
Table 13 the result shows that, the mesylate crystals of the present embodiment are in FaSSIF solvent in the solubility of each time
It is significantly better than reference substance benzenesulfonate crystalline.
In conclusion hydrochloride, sulfate, 1, the 5- napadisilate, 2- of the compound of formula (I) provided by the present invention
Naphthalene sulfonate, oxalates, mesylate crystals hygroscopicity are lower, have excellent physical stability；In high temperature and super-humid conditions
Under, compared with reference substance benzenesulfonate crystalline, hydrochloride, sulfate, 1, the 5- naphthalene of the compound of formula (I) provided by the present invention
Disulfonate, 2- naphthalene sulfonate, oxalates, mesylate crystals have better stability, especially chemical stability；In
In FaSSIF or FeSSIF solvent, hydrochloride, sulfate, 1, the 5- naphthalenedisulfonic acid of the compound of formula (I) provided by the present invention
Salt, 2- naphthalene sulfonate, oxalates, mesylate crystals solubility be significantly better than the dissolution of reference substance benzenesulfonate crystalline
Degree, the bioavilability for being conducive to the Dissolution behaviours for improving product and improving drug.
Other salt crystals of the compound of formula (I) provided by the present invention have property similar to the above.
The present invention is described in further detail for above-mentioned specific embodiment.But it is above-mentioned that this should not be interpreted as to the present invention
The range of theme is only limitted to embodiment below, and all technical solutions implemented based on the content of present invention are each fallen in of the invention
Range.
Claims (9)
1. the salt of the compound of formula (I),
It is acylate, wherein the organic acid is oxalic acid；Wherein the molar ratio of the compound and oxalic acid of formula (I) is 1: 2；Its
Described in formula (I) compound oxalates be crystal.
2. the salt of the compound of the formula (I) of claim 1, wherein the oxalic acid salt crystal is obtained by using Cu-K α radiation
XRPD map is included in about 11.3 ± 0.2,13.4 ± 0.2,20.4 ± 0.2,21.0 ± 0.2,22.2 ± 0.2 and 25.9 ± 0.2
The angle of diffraction (2 θ) at peak.
3. the salt of the compound of the formula (I) of claim 2, wherein what the oxalates crystal was obtained by using Cu-K α radiation
XRPD map is included in about 11.3 ± 0.2,13.4 ± 0.2,15.2 ± 0.2,17.0 ± 0.2,19.7 ± 0.2,20.4 ± 0.2,
Peak at 21.0 ± 0.2,21.7 ± 0.2,22.2 ± 0.2 and 25.9 ± 0.2 angle of diffraction (2 θ).
4. the salt of the compound of the formula (I) of claim 3, wherein the XRPD that the oxalates crystal is obtained using Cu-K α radiation
Map includes the peak at the angle of diffraction substantially the same with shown in Fig. 5 (2 θ).
5. the method for preparing the salt of the compound of the formula (I) of any one of claim 1-4 comprising by any solid form
The compound of formula (I) dissolves in organic solvent, and oxalic acid is added and is reacted, is subsequently isolated and dries, the organic solvent packet
Include alcohols, ethers, nitrile, ketone or esters solvent with 1-10 carbon atom.
6. pharmaceutical composition, it includes the salt of the compound of the formula of any one of claim 1-4 (I) and one or more medicines
Acceptable carrier on.
7. the pharmaceutical composition of claim 6, wherein described pharmaceutical composition is injection.
8. the salt of the compound of the formula (I) of any one of claim 1-4 is in preparation for calmness, hypnosis, antianxiety, muscle pine
Purposes in relaxation or anticonvulsant drug.
9. the purposes of claim 8, wherein the drug is injection.
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| CN109970678B (en) * | 2017-12-28 | 2024-03-08 | 四川科伦药物研究院有限公司 | Amorphous 4-phenylthiazole derivative, and preparation method and application thereof |
| MX2020008465A (en) * | 2018-02-13 | 2020-12-07 | Jiangsu Nhwaluokang Pharmaceutical Res And Development Co Ltd | Benzodiazepine derivative hydrochloride and crystal form, preparation method, and application thereof. |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
| CN102753525A (en) * | 2009-09-18 | 2012-10-24 | Paion英国有限公司 | Process for preparing 3-[(4s)-8-bromo-1-methyl-6-(2-pyridinyl)-4h-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
| 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 |
| CN103288834A (en) * | 2006-07-10 | 2013-09-11 | 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 |
| CN105130996A (en) * | 2015-08-07 | 2015-12-09 | 成都倍特药业有限公司 | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form |
-
2017
- 2017-04-06 CN CN201710219936.7A patent/CN107266452A/en active Pending
- 2017-04-06 CN CN201910687623.3A patent/CN110511224A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000069836A1 (en) * | 1999-05-14 | 2000-11-23 | Glaxo Group Limited | Short-acting benzodiazepines |
| CN103288834A (en) * | 2006-07-10 | 2013-09-11 | Paion英国有限公司 | Short-acting benzodiazepine salts and their polymorphic forms |
| CN102753525A (en) * | 2009-09-18 | 2012-10-24 | Paion英国有限公司 | Process for preparing 3-[(4s)-8-bromo-1-methyl-6-(2-pyridinyl)-4h-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
| 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 |
| CN104768557A (en) * | 2012-08-31 | 2015-07-08 | Paion英国有限公司 | Method for administering hypnotic/sedative agent |
| CN105130996A (en) * | 2015-08-07 | 2015-12-09 | 成都倍特药业有限公司 | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form |
Non-Patent Citations (2)
| Title |
|---|
| 刘绍雄: "《药物化学》", 30 June 1991 * |
| 林丽美: "《药物分析学》", 30 April 2015 * |
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