Maleate of benzothiophene compound, crystal form and application thereof
阅读说明：本技术 一种苯并噻吩化合物的马来酸盐、其结晶形式及其用途 (Maleate of benzothiophene compound, crystal form and application thereof ) 是由 沈敬山 何洋 王震 李剑峰 柳永建 索瑾 田广辉 陈伟铭 杨飞瀑 王瑜 蒋翔锐 于 2019-06-21 设计创作，主要内容包括：本发明涉及一种苯并噻吩化合物的马来酸盐、其结晶形式及其用途。具体地,本发明涉及式(I-A)的化合物,其晶型A,及其制备方法,包含它们的药物组合物,及其在制备用于预防或治疗中枢神经系统疾病的药物中的用途。本发明的式(I-A)的化合物及其晶型A理化性质好,口服生物利用度高,综合成药性最好,更适于制成药物制剂应用,也更适于保存。<Image he="341" wi="700" file="DDA0002102507590000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a maleate salt of a benzothiophene compound, a crystalline form thereof, and use thereof. In particular, the inventionRelates to a compound of formula (I-A), a crystal form A thereof, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in preparing medicines for preventing or treating central nervous system diseases. The compound of the formula (I-A) and the crystal form A thereof have the advantages of good physicochemical property, high oral bioavailability and best comprehensive pharmaceutical property, and are more suitable for being prepared into pharmaceutical preparations and also more suitable for storage.)
1. A compound of formula (I-A), a pharmaceutically acceptable solvate, hydrate, co-crystal, anhydrate or amorphous form thereof:
2. form A of a compound of formula (I-A), wherein form A has an X-ray powder diffraction pattern having diffraction peaks at least at diffraction angles, 2 θ, of about 17.1 ° ± 0.2 °, 19.1 ° ± 0.2 °, 24.6 ° ± 0.2 °; preferably, the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at least at diffraction angle 2 theta angles of about 14.1 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 19.5 degrees +/-0.2 degrees, 20.7 degrees +/-0.2 degrees, 24.6 degrees +/-0.2 degrees and 25.8 degrees +/-0.2 degrees,
3. form a according to claim 2, wherein the melting point of form a is from about 227.79 ℃ ± 5 ℃ as determined from a differential scanning calorimetry analysis map.
4. Form A according to claim 2, wherein the form A has an infrared absorption spectrum of at least about 2823.28cm as measured by potassium bromide tableting-1、2435.65cm-1、1656.55cm-1、1625.70～1560.13cm-1、1454.06cm-1、1357.64cm-1、1247.72cm-1、1083.80cm-1、958.45cm-1、873.60cm-1、754.03cm-1Has characteristic peaks.
5. A process for the preparation of crystalline form a of the compound of formula (I-a) according to any one of claims 2 to 4, which is one of the following:
adding 7- (2- (4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl) ethyl) quinoline-2 (1H) -ketone into an alcohol-water mixed solvent, adding maleic acid, heating, optionally adding activated carbon for decoloring, filtering, cooling, standing or stirring to separate out a solid, and separating to obtain a crystal form A of the compound shown in the formula (I-A);
and secondly, adding the compound of the formula (I-A) into an alcohol-water mixed solvent, heating for dissolving, optionally adding activated carbon for decoloring, filtering, cooling to separate out a solid, and separating to obtain the crystal form A of the compound of the formula (I-A).
6. The method according to claim 5, wherein the alcohol in the alcohol-water mixed solvent is one or more selected from methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol and propylene glycol.
7. The method of claim 6, wherein the alcohol is selected from one or more of methanol, ethanol, propanol, and isopropanol.
8. A pharmaceutical composition comprising a compound of formula (I-a) as described in claim 1, a pharmaceutically acceptable solvate, hydrate, co-crystal, anhydrate or amorphous form thereof, or crystalline form a of a compound of formula (I-a) as described in any one of claims 2-4, and a pharmaceutically acceptable excipient.
9. Use of a compound of formula (I-a) according to claim 1, a pharmaceutically acceptable solvate, hydrate, co-crystal, anhydrate or amorphous form thereof, or a crystalline form a of a compound of formula (I-a) according to any of claims 2-4, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the prevention or treatment of a central nervous system disease.
10. Use according to claim 9, wherein the central nervous system disorder is selected from: schizophrenia (e.g., refractory, intractable or chronic schizophrenia), affective disorders, psychotic disorders, mood disorders, bipolar disorder type I, bipolar disorder type II, depression (e.g., endogenous depression, major depression, refractory depression), dysthymic disorder, cyclothymic disorder, panic attacks, panic disorder, social phobia, obsessive compulsive disorder, impulsive disorders, post-traumatic stress disorder, acute stress disorder, hysteria, anorexia nervosa, sleep disorders, adaptive disorders, cognitive disorders, autism, headache, mania, parkinson's disease, huntington's chorea, alzheimer's disease, dementia, memory disorders, hyperactivity disorder, attention deficit, hyperactivity disorder and tic disorders.
Technical Field
The present invention relates to a maleate salt of a benzothiophene compound and a crystalline form thereof, as well as a pharmaceutical composition comprising the same, and its use in the preparation of a medicament for the treatment of central nervous system diseases.
Background
International application WO2015/131856 discloses a series of compounds having D2/5-HT1A/5-HT2AThe series of compounds have the advantages of strong activity, effective oral administration, low drug effect dosage, small toxic and side effect and the like. The series of compounds include compound 7- (2- (4- (benzo [ b ]))]Thiophen-4-yl) piperazin-1-yl) ethyl) quinolin-2 (1H) -one (hereinafter also referred to as: compound Z) having the formula:
compound Z is currently undergoing a phase I clinical trial in china for schizophrenia. However, the compound has the problem of low water solubility, is not easy to dissolve, and has certain influence on preparation technology in application as a pharmaceutical preparation. The object of the present invention was therefore to find a pharmaceutical suitable form of compound Z which has the advantages of good stability, high purity, high water solubility, low hygroscopicity, good reproducibility and the like.
Physical properties of a compound and a salt thereof, and a crystalline or amorphous form thereof, which are used as a pharmaceutical product, greatly affect bioavailability of a drug, purity of a drug substance, a formulation of a preparation, and the like, and therefore, in drug development, it is necessary to investigate which salt, crystalline form, or amorphous form of the compound is preferable as a pharmaceutical product. That is, since the physical properties depend on the properties of various compounds, it is generally difficult to predict salts, crystal forms, and amorphous forms for prodrugs having good physical properties, and thus various experimental studies on the respective compounds have been required.
Disclosure of Invention
The present invention aims to provide a salt of compound Z and crystalline forms thereof which have high stability, low hygroscopicity, high purity, and are easier to process and formulate pharmaceutically.
In one aspect of the invention, there is provided a compound of formula (I) and pharmaceutically acceptable polymorphs, solvates, hydrates, co-crystals, anhydrates or amorphous forms thereof:
wherein, X includes but is not limited to organic acid or inorganic acid. For example, the organic acids include, but are not limited to, maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, benzoic acid, phthalic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, 1, 5-naphthalenedisulfonic acid, camphoric acid, camphorsulfonic acid, salicylic acid, acetylsalicylic acid, aspartic acid, glutamic acid, lactic acid, gluconic acid, retinoic acid, gallic acid, mandelic acid, malic acid, sorbic acid, trifluoroacetic acid, taurine, homotaurine, 2-hydroxyethanesulfonic acid, cinnamic acid, mucic acid; such inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid; and other similar protic acids, wherein, preferably, X is maleic acid, succinic acid, citric acid, tartaric acid, fumaric acid, mucic acid, acetic acid, methanesulfonic acid, hydrochloric acid, nitric acid, or sulfuric acid, and more preferably, X is maleic acid.
Optionally, the compounds of formula (I) of the present invention will absorb moisture to produce a hydrate in the form of adsorbed water when left in air or by recrystallization, and acid addition salts containing such moisture are also encompassed by the present invention.
In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), said process being selected from one of the following processes:
the method comprises the following steps:
1) dissolving a compound Z in a solvent A to prepare a solution A;
2) dissolving corresponding acid X in solvent B to prepare solution B;
3) adding the solution A into the solution B, or adding the solution B into the solution A to prepare a mixed solution, and separating the mixed solution to obtain a salt of the compound Z (namely the compound of the general formula (I));
the second method comprises the following steps:
1) dissolving a compound Z in a solvent A to prepare a solution A;
2) directly adding corresponding acid X into the solution A, and separating to obtain salt of the compound Z (namely the compound of the general formula (I)) from the solution;
the third method comprises the following steps:
1) dissolving corresponding acid X in a solvent B to prepare a solution B;
2) directly adding the compound Z into the solution B, and separating the compound Z from the solution to obtain a salt of the compound Z (namely the compound of the general formula (I));
in each of the above methods, the solvent a and the solvent b may be each independently selected from water and a nonaqueous solvent or a mixed solvent thereof, more specifically selected from one or more mixed solvents of water, alcohols, ethers, esters, hydrocarbons, ketones, acids, nitriles, and the like, and the esters are selected from ethyl acetate, methyl acetate, propyl acetate, butyl acetate, methyl formate, ethyl formate, propyl formate, butyl formate; the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and propylene glycol; the ethers are selected from diethyl ether, propyl ether, isopropyl ether, petroleum ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol dimethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; the ketones are selected from acetone, butanone, N-methylpyrrolidone, diethyl ketone; the hydrocarbon is selected from n-pentane, n-hexane, heptane, aromatic hydrocarbons (such as toluene, benzene, xylene, chlorobenzene, dichlorobenzene), halogenated alkanes (such as dichloromethane, chloroform, 1, 2-dichloroethane or carbon tetrachloride); the acid is selected from acetic acid and propionic acid; the nitrile is selected from acetonitrile, propionitrile; preferably, the non-aqueous solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, propylene glycol, tetrahydrofuran, dioxane, acetone and acetonitrile.
The corresponding acid X is as defined for X in formula (I).
In a preferred embodiment, when X is hydrochloric acid, hydrogen chloride may be present in gaseous form, or in the form of an aqueous or non-aqueous solvent, such as concentrated hydrochloric acid solution, diluted hydrochloric acid solution, hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride dioxane solution.
In the above-mentioned first method, the temperature at which the solution A is added to the solution B varies depending on the reagent, the solvent or the like, and is usually from-20 ℃ to 200 ℃, preferably from 0 ℃ to 100 ℃.
The molar ratio of the compound Z to the acid X is 1: 0.5-1: 3.2, and preferably the molar ratio of the compound Z to the acid X is 1: 1-1: 2.
The reaction time of the compound Z with the acid X is not limited, and is usually 10 minutes to 10 hours.
In another aspect of the present invention, there is provided a process for the preparation of polymorphs of the compound of formula (I) and solvates thereof. Seeds may be added as required in the process. Seed crystals here refer to the "seeds" of the compound of formula (I) or the self-made crystalline mass of the compound of formula (I) which are used to induce crystallization. The process for the preparation of the polymorphic forms of the salt of compound Z (i.e. the compound of formula (I)) and solvates thereof is selected from one of the following processes:
the method comprises the following steps:
1) dissolving a compound of a general formula (I) in a propane solvent to prepare a solution F;
2) standing to slowly precipitate a target substance, or stirring to precipitate the target substance, or adding corresponding seed crystals to precipitate the target substance;
preferably, pentane solvent is also added into the solution F prepared in the step 1);
the second method comprises the following steps:
1) suspending a compound of a general formula (I) in a solvent C to prepare a suspension G;
2) heating, stirring, cooling to precipitate the target substance, or adding corresponding seed crystal to precipitate;
preferably, pentane solvent is also added into the suspension G prepared in the step 1) of the second method;
in the above methods, the acetone and acetone may be independently selected from water, a non-aqueous solvent and a mixed solvent thereof, more specifically from one or more of water, alcohols, ethers, esters, hydrocarbons, ketones, acids, nitriles and the like, and the esters may be selected from ethyl acetate, methyl acetate, propyl acetate, butyl acetate, methyl formate, ethyl formate, propyl formate and butyl formate; the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and propylene glycol; the ethers are selected from diethyl ether, propyl ether, isopropyl ether, petroleum ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol dimethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; the ketones are selected from acetone, butanone, N-methylpyrrolidone, diethyl ketone; the hydrocarbon is selected from n-pentane, n-hexane, heptane, aromatic hydrocarbons (such as toluene, benzene, xylene, chlorobenzene, dichlorobenzene), halogenated alkanes (such as dichloromethane, chloroform, 1, 2-dichloroethane or carbon tetrachloride); the acid is selected from acetic acid and propionic acid; the nitrile is selected from acetonitrile, propionitrile; preferably, the non-aqueous solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, propylene glycol, tetrahydrofuran, dioxane, acetone and acetonitrile.
In the process for the preparation of the polymorphic forms of the salt of compound Z (i.e. the compound of formula (I)) and solvates thereof, the temperature of each step varies with the solvent, generally from-20 ℃ to 200 ℃, preferably from 0 ℃ to 100 ℃.
In another aspect of the present invention, there is provided a compound of formula (I-a) (i.e., the maleate salt of compound Z), a pharmaceutically acceptable solvate, hydrate, co-crystal, anhydrate or amorphous form thereof:
in another aspect of the invention, there is provided a process for the preparation of a compound of formula (I-A), which may be selected from one of the following processes:
the method comprises the following steps:
1) dissolving a compound Z in a solvent A to prepare a solution A;
2) dissolving maleic acid in a solvent B to prepare a solution B;
3) adding the solution A into the solution B, or adding the solution B into the solution A to prepare a mixed solution, and separating the mixed solution to obtain a maleate of a compound Z (namely the compound of the formula I-A);
the second method comprises the following steps:
1) dissolving a compound Z in a solvent A to prepare a solution A;
2) directly adding corresponding maleic acid into the solution A, and separating to obtain maleate of the compound Z (namely the compound of the formula I-A) from the solution;
the third method comprises the following steps:
1) dissolving maleic acid in a solvent B to prepare a solution B;
2) adding the compound Z directly into the solution B, and separating the maleate salt of the compound Z (namely the compound of the formula I-A) from the solution.
In each of the above processes, the definitions of the solvent A and the solvent B are the same as those of the solvent A and the solvent B.
In another aspect of the present invention, there is provided crystalline form a of the compound of formula (I-a) wherein form a has an X-ray powder diffraction pattern having diffraction peaks at diffraction angles, 2 Θ, of at least about 17.1 ° ± 0.2 °, 19.1 ° ± 0.2 °, 24.6 ° ± 0.2 °; preferably, the X-ray powder diffraction pattern of the crystal form A has diffraction peaks at least at diffraction angle 2 theta angles of about 14.1 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 19.5 degrees +/-0.2 degrees, 20.7 degrees +/-0.2 degrees, 24.6 degrees +/-0.2 degrees and 25.8 degrees +/-0.2 degrees,
preferably, the form a of the compound of formula (I-a) has an X-ray powder diffraction pattern having an XRPD pattern substantially as shown in figure 2.
In general, the diffraction angle (2 θ) in the powder X-ray diffraction may be in the range of ± 0.2 °, and therefore the values of the diffraction angle described below are understood to include values in the range of about ± 0.2 °. Therefore, the present invention includes not only crystals that completely match the peak (diffraction angle) in the powder X-ray diffraction, but also crystals that match the peak (diffraction angle) with an error of about ± 0.2 °.
In one embodiment, the compound of formula (I-a) has a melting point of about 227.79 ℃ ± 5 ℃ as determined by Differential Scanning Calorimetry (DSC) pattern of form a with a Peak (Peak) of 232.91 ± 5 ℃; form a of the compound of formula (I-a) has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3.
In one embodiment, the compound of formula (I-A) has form A having an infrared absorption spectrum of at least about 2823.28cm as measured by potassium bromide tableting-1、2435.65cm-1、1656.55cm-1、1625.70～1560.13cm-1、1454.06cm-1、1357.64cm-1、1247.72cm-1、1083.80cm-1、958.45cm-1、873.60cm-1、754.03cm-1Has characteristic peaks.
In a specific embodiment, the Thermogravimetric (TG) analysis shows a 22.73% loss in the TG curve of form A of the compound of formula (I-A) between 50 ℃ and 250 ℃.
In another aspect of the present invention, there is provided a process for the preparation of form a of the compound of formula (I-a) selected from one of the following processes:
the method comprises the following steps: adding the compound Z into an alcohol-water mixed solvent, adding maleic acid, heating, optionally adding activated carbon for decoloring, filtering, cooling, standing or stirring until solid is separated out, and separating to obtain the crystal form A of the compound shown in the formula (I-A);
the second method comprises the following steps: adding compound Z maleate into an alcohol-water mixed solvent, heating for dissolving, optionally adding activated carbon for decoloring and filtering, cooling to separate out a solid, and separating to obtain the crystal form A of the compound shown in the formula (I-A).
The maleic acid may be in solid form or in the form of a solution dissolved in water, alcohol or a combination of alcohol and water.
Further preferably, the preparation method of the crystal form A of the compound of the formula (I-A) is as follows:
adding the compound Z into an alcohol-water mixed solvent, adding maleic acid, heating, optionally adding activated carbon for decoloring, filtering, cooling, standing or stirring to precipitate a solid, and separating to obtain the crystal form A of the compound shown in the formula (I-A).
The molar ratio of the compound Z to the maleic acid is 1: 1-1: 1.2; preferably 1:1 to 1: 1.05.
In the alcohol-water mixed solvent, the volume ratio of alcohol to water is 1: 10-10: 1; preferably 1:1 to 10: 1.
The mass-volume ratio of the compound Z to the alcohol-water mixed solvent is 1g/1 mL-1 g/100mL, and preferably, the mass-volume ratio of the compound Z to the alcohol-water mixed solvent is 1g/10 mL-1 g/50 mL.
Particularly preferably, the preparation method of the crystal form A of the compound of the formula (I-A) is as follows:
adding the compound of the formula (I-A) into an alcohol-water mixed solvent, heating for dissolving, cooling to separate out a solid, and separating to obtain the crystal form A of the compound of the formula (I-A).
The heating temperature range is 30-100 ℃; the cooling temperature range is-20 ℃ to room temperature.
In the alcohol-water mixed solvent, the volume ratio of alcohol to water is 1: 10-10: 1; preferably 1:1 to 10: 1.
The mass-to-volume ratio of the compound of formula (I-A) to the mixed solvent of alcohol and water is 1g/1 mL-1 g/100mL, preferably, the mass-to-volume ratio of the compound of formula (I-A) to the mixed solvent of alcohol and water is 1g/10 mL-1 g/50 mL.
The alcohol is preferably C1-C4Linear or branched alkanols, such as methanol, ethanol, isopropanol; the alcohol is more preferably ethanol.
The crystal form A of the compound shown in the formula (I-A) obtained by adopting an alcohol-water mixed solvent system has high yield, less impurities and good liquid phase purity.
In another aspect of the invention, there is provided form B of compound Z citrate.
An X-ray powder diffraction pattern of form B of the compound Z citrate salt having an XRPD pattern substantially as shown in figure 9.
The melting point of the compound Z citrate in the crystal form B is about 216.69 +/-3 ℃ as measured by a Differential Scanning Calorimetry (DSC) chart, and the Peak value (Peak) is 222.85 +/-3 ℃; form B of the compound Z citrate salt has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 8.
Form B of the compound Z citrate salt has an infrared absorption spectrum of at least about 1722.90cm as measured by potassium bromide tableting-1、1640.04cm-1、1604.77cm-1、1550.52cm-1、1450.01cm-1、1347.95cm-1、1246.62cm-1、1208.30cm-1Has characteristic peaks.
In another aspect of the invention, there is provided crystalline form C of compound Z fumarate.
An X-ray powder diffraction pattern of form C of compound Z fumarate having an XRPD pattern substantially as shown in figure 10.
Form C of the fumarate salt of Compound Z has an infrared absorption spectrum of at least about 1718.81cm as measured by potassium bromide tableting-1、1656.39cm-1、1605.71cm-1、1557.89cm-1、1451.67cm-1、1416.77cm-1、1291.50cm-1、1242.60cm-1、1173.51cm-1、756.32cm-1Has characteristic peaks.
In another aspect of the invention, there is provided crystalline form D of compound Z phosphate.
An X-ray powder diffraction pattern of form D of the compound Z phosphate salt having an XRPD pattern substantially as shown in figure 12.
The melting point of the compound Z phosphate in the crystal form D is about 232.87 +/-3 ℃ and the Peak value (Peak) is 234.67 +/-3 ℃ as measured by a Differential Scanning Calorimetry (DSC) chart; form D of the compound Z phosphate has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 11.
The compound Z phosphate has a crystal form D of at least about 1639.35cm in the infrared absorption spectrum measured by potassium bromide tableting-1、1594.99cm-1、1562.59cm-1、1450.53cm-1、1123.64cm-1、959.54cm-1、942.99cm-1、514.76cm-1Has characteristic peaks.
In another aspect of the invention, there is provided a pharmaceutical composition comprising one or more compounds of formula (I), a pharmaceutically acceptable solvate, hydrate, co-crystal, anhydrate or amorphous form thereof together with a pharmaceutically acceptable excipient.
Preferably, said compound of formula (I) may be compound Z maleate, compound Z succinate, compound Z mesylate, compound Z citrate, compound Z hydrochloride, compound Z hydrobromide, compound Z tartrate, compound Z fumarate, compound Z mucate, compound Z acetate, compound Z sulphate, compound Z phosphate, more preferably said compound of formula (I) may be compound Z maleate.
More preferably, said compound of general formula (I) may be compound Z maleate in crystalline form a.
The pharmaceutically acceptable excipients may be excipients, binders, lubricants, disintegrants, colorants, taste and odor modifiers, emulsifiers, surfactants, cosolvents, suspending agents, isotonizing agents, buffers, preservatives, antioxidants, stabilizers, absorption enhancers, etc. which are generally used in the field of medicine, and may also be used in combination with the above additives as needed.
In a preferred embodiment, the salt of compound Z of the present invention is formulated in a pharmaceutical composition in admixture with at least one pharmaceutical excipient.
In a preferred embodiment, when preparing a solid composition in the form of a tablet, the main active ingredient component, which is a compound of general formula (I) according to the invention, preferably a compound of formula (I-a) or its crystalline form a, is mixed with a pharmaceutical carrier, such as starch, lactose, magnesium stearate, etc., and the tablets may be sugar coated or otherwise suitably treated to provide a prolonged or retarded release and to provide a continuous release of a predetermined amount of the active ingredient.
In a preferred embodiment, the active ingredient is mixed with a diluent and the resulting mixture is encapsulated to obtain a capsule.
When the compound of the general formula (I) of the present invention is used as a therapeutic agent or a prophylactic agent for central nervous system diseases, it may be mixed with a suitable pharmacologically acceptable excipient, diluent, or the like, and administered orally in the form of tablets, capsules, granules, powders, syrups, or the like, or non-orally in the form of injections, powder injections, sprays, suppositories, or the like. These formulations can be prepared by conventional methods.
The amount of the drug to be used varies depending on the severity of symptoms, age, sex, etc., and the amount of the active ingredient is usually about 0.01 to 10mg/kg body weight/day, and it is preferable that the pharmaceutical preparation in a unit administration form contains the active ingredient in an amount of about 0.1 to 100mg, and the administration manner is not limited.
In a further aspect of the present invention there is provided the use of a compound of formula (I) or a polymorph thereof, in particular a compound of formula (I-a) or a crystalline form a thereof, or a pharmaceutically acceptable solvate, hydrate, co-crystal, anhydrate or amorphous form of a compound of formula (I), in particular a compound of formula (I-a), or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention or treatment of a central nervous system disease.
The central nervous system disorder is selected from: schizophrenia (e.g., refractory, intractable or chronic schizophrenia), affective disorders, psychotic disorders, mood disorders, bipolar disorder type I, bipolar disorder type II, depression (e.g., endogenous depression, major depression, refractory depression), dysthymic disorder, cyclothymic disorder, panic attacks, panic disorder, social phobia, obsessive compulsive disorder, impulsive disorders, post-traumatic stress disorder, acute stress disorder, hysteria, anorexia nervosa, sleep disorders, adaptive disorders, cognitive disorders, autism, headache, mania, parkinson's disease, huntington's chorea, alzheimer's disease, dementia, memory disorders, hyperactivity disorder, attention deficit/hyperactivity disorder and tic disorders.
Advantageous effects
The compound of the general formula (I), all crystal forms and mixed crystals or amorphous substances and solvates thereof have the advantages of high solubility, good stability, good pharmacokinetics and existence form of the compound suitable for patent medicine.
The compound of formula (I-A) of the invention has the advantages of high stability, high purity, improved water solubility, no electrostatic phenomenon and the like.
The crystal form A of the compound shown in the formula (I-A) has the advantages of small hygroscopicity, good chemical stability, high purity, constant composition, simple and easily repeated preparation method, easy storage of samples and the like, can meet the requirement of large-scale industrial production, and has the advantages of good physicochemical property, high oral bioavailability, small toxicity, good comprehensive pharmacy, suitability for preparing pharmaceutical preparations and the like.
Drawings
FIG. 1: differential Scanning Calorimetry (DSC) profile of the basic compound Z prepared in example 1;
FIG. 2: an X-ray powder diffraction (XRPD) pattern of form a of the compound of formula (I-a) prepared in example 14;
FIG. 3: a Differential Scanning Calorimetry (DSC) profile of crystalline form A of the compound of formula (I-A) prepared in example 14;
FIG. 4: the infrared spectrum of crystalline form A of the compound of formula (I-A) prepared in example 14;
FIG. 5: a photomicrograph of the crystalline form A of the compound of formula (I-A) prepared in example 14;
FIG. 6: a thermogravimetric analysis (TG) profile of crystalline form a of the compound of formula (I-a) prepared in example 14;
FIG. 7: a blood concentration-time curve chart of the compound Z and different salts thereof after administration to rats;
FIG. 8: a Differential Scanning Calorimetry (DSC) profile of form B of compound Z citrate prepared in example 15;
FIG. 9: an X-ray powder diffraction (XRPD) pattern of form B of compound Z citrate prepared as in example 15;
FIG. 10: an X-ray powder diffraction (XRPD) pattern of form C of compound Z fumarate prepared as in example 16;
FIG. 11: a Differential Scanning Calorimetry (DSC) profile of form D of compound Z phosphate prepared in example 17;
FIG. 12: an X-ray powder diffraction (XRPD) pattern of form D of compound Z phosphate prepared as in example 17;
FIG. 13: a Raman spectrum (Raman) of form a of the compound of formula (I-a) prepared in example 14.
Detailed Description
Term(s) for
As used herein, "salt" includes pharmaceutically acceptable salts, as well as pharmaceutically unacceptable salts. It is not preferred to use pharmaceutically unacceptable salts for patients, but the salts can be used to provide pharmaceutical intermediates and bulk pharmaceutical forms.
As used herein, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable acid addition salt" refers to salts prepared using different pharmaceutically acceptable acids. Including but not limited to organic and inorganic acid salts, preferably maleate, succinate, citrate, tartrate, fumarate, mucate, acetate, mesylate, hydrochloride, hydrobromide, phosphate, nitrate or sulfate, most preferably maleate.
The solvent contained in the "solvate" is not particularly limited as long as it is a solvent used for producing a salt or a crystal, and specifically, the solvate may be, for example, an alcohol, an acetonate, a toluate, or the like, and preferably an alcohol.
The present invention is further illustrated by the following examples, which are intended to be merely more specific illustrations of preferred embodiments of the present invention and are not intended to limit the scope of the invention. The temperatures and reagents used in the following examples may be replaced by the corresponding temperatures and reagents described above to achieve the objects of the invention.
In the following examples, reagents such as acetonitrile involved in the preparation experiments were all analytical reagents and were provided by national pharmaceutical group chemical reagents ltd, and the reagents and solvents used were not specifically treated unless otherwise specified. 1- (benzothiophen-4-yl) piperazine dihydrochloride is provided by Shanghai specialized pharmaceutical technology, Inc., with a purity of greater than 98%; 2- (2-oxo-1, 2-dihydroquinolin-7-yl) ethyl methanesulfonate was provided by Shanghai speciality pharmaceutical science, Inc. at a purity of greater than 98%. Triethylamine and phosphoric acid involved in the high performance liquid chromatography experiment are in chromatographic purity and are provided by the chemical reagent company Limited of the national drug group. Room temperature herein means 20 ℃ to 25 ℃.
DSC test instrument: METTLER TOLEDO differential scanning calorimeter, temperature range: 50-260 ℃, scan rate: 20 ℃/min, nitrogen flow rate: 50 mL/min.
X-ray powder diffraction pattern tester: bruker D8advance X target rotation polycrystallme diffractometer, target: cu ka (40kV, 40mA), sample-to-detector distance: 30cm, continuous type: locked couppled, step width 0.02 °, scan range: 3 to 40 ° (2 θ value), scanning step diameter: 0.1 s.
Infrared absorption spectrum test instrument: thermo Nicolet FTIR 6700 infrared spectrometer. The wave number (cm)-1) Errors of-0.5 to + 0.5% may be included, but such levels of error are within acceptable ranges in the present invention.
Thermogravimetric (TG) analysis test instrument: netzsch TG 209F3 thermogravimetric analyzer. Temperature range: 30-400 ℃, scan rate: 10 ℃/min, purge gas: 25mL/min, protective gas: 15 mL/min.
Elemental analysis was measured using an elementar vario EL instrument; mass spectra were determined on a MAT-95 type mass spectrometer (Finnigan Co.); NMR spectra were measured on Mercury-300 and Mercury-400 NMR spectrometers (Varian Corp.).
Raman spectroscopy apparatus: thermo Scientific DXR raman microscope. Exposure time: 2.0s, number of exposures: 32, laser: 780nm, laser energy: 100.0mW, spectrometer aperture: 50 μm slit (slit).