CN112851640A - Sulfate of pyrimidine benzamide compound and use thereof - Google Patents
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Abstract
The present invention relates to sulfate salts of pyrimidine benzamide compounds and their use. The invention also relates to a pharmaceutical composition comprising said sulfate salt and to the use of said sulfate salt or said pharmaceutical composition for the preparation of a medicament for the treatment and prevention of central nervous system dysfunction.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to sulfate of a pyrimidine benzamide compound and application thereof, in particular to sulfate of 3- (2- (4- (3- (5-cyano-1H-indole-3-yl) propyl) piperazine-1-yl) pyrimidine-5-yl) benzamide, a crystal form of the sulfate and application thereof.
Background
5-hydroxytryptamine, a neurotransmitter that transmits signals in the brain and nervous system, plays an important role in Central Nervous System (CNS) dysfunction, especially anxiety, depression, aggression and impulsive mood. Antagonism or agonism of certain types of 5-hydroxytryptamine receptors can be effective in modulating central nervous system dysfunction.
Of all indications associated with 5-hydroxytryptamine dysfunction, depression is of prime importance, as it has been reported by the world health organization as the fourth most burdensome disease in humans. It is expected that disability from depression will jump to the second place in all diseases by the year 2020. (Bromet E, Andlade LH, Hwang I, et al, Cross-national epidemic of DSM-IV major de-pressing epimode. BMC Med.2011,9: 90).
Patent application CN106243088A discloses the compound 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (compound of formula (I)) having selective 5-hydroxytryptamine reuptake inhibiting activity and/or 5-HT1AReceptor agonistic activity, may be used to treat diseases associated with 5-hydroxytryptamine dysfunction, such as depression. However, no research on the salt or crystal form of the compound is available in the prior art.
Different salts and solid forms of a pharmaceutically active ingredient may have different properties. Different salts and solid forms may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, etc., and may also have different effects on the stability, bioavailability, therapeutic effect, etc. of the drug. Therefore, in drug development, the problem of salt form and/or solid form of the drug should be fully considered.
The inventor discovers that the compound has poor water solubility and is not beneficial to the manufacturing and production of preparations when researching the compound, so that after the compound shown in the formula (I) forms salts through a large amount of experimental researches, the physicochemical properties of different salts are greatly changed, and the properties of some salts are not better than those of the compound in a free state; the inventor finds that the physical properties and various properties of the compound sulfate shown in the formula (I) prepared by the method can be obviously improved, and the preparation development is more facilitated.
Disclosure of Invention
The inventors have conducted extensive studies on the compound represented by formula (I), and found that the compound and sulfuric acid can form the sulfate salt crystal form a of the present invention, and the sulfate salt crystal form a has good pharmaceutical properties (e.g., good water solubility, stability, pharmacokinetics, etc.), especially good pharmacokinetic properties. The salt formed by the compound and hydrobromic acid has low plasma concentration and small exposure in dogs and has poor pharmacokinetic property. Therefore, the sulfate crystal form A has good pharmaceutical properties, so that the sulfate crystal form A has better drugability.
In particular, the invention relates to a sulfate of a compound shown in formula (I), and application of a crystal form of the sulfate or a pharmaceutical composition containing the sulfate in preparing a medicament for preventing, treating or relieving central nervous system dysfunction, particularly depression. Further, the sulfate is in a crystal form A. The form a of the present invention may also be in the form of a solvate, for example, a hydrate.
In one aspect, the present invention provides a sulfate salt of a compound of formula (I),
the sulfate is a sulfate crystal form A, and an X-ray powder diffraction pattern of the sulfate has diffraction peaks at the following 2 theta angles: 6.81 ° ± 0.2 °,13.61 ° ± 0.2 °,18.30 ° ± 0.2 °,19.49 ° ± 0.2 °,19.72 ° ± 0.2 °,20.46 ° ± 0.2 °,22.16 ° ± 0.2 °,23.21 ° ± 0.2 °,26.26 ° ± 0.2 °,27.36 ° ± 0.2 °,28.03 ° ± 0.2 °.
In some embodiments, the sulfate salt of the present invention is characterized by the sulfate salt form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.81 ° ± 0.2 °,13.07 ° ± 0.2 °,13.31 ° ± 0.2 °,13.61 ° ± 0.2 °,14.02 ° ± 0.2 °,14.35 ° ± 0.2 °,14.82 ° ± 0.2 °,15.12 ° ± 0.2 °,15.55 ° ± 0.2 °,16.05 ° ± 0.2 °,16.35 ° ± 0.2 °,17.85 ° ± 0.2 °,18.30 ° ± 0.2 °,18.50 ° ± 0.2 °,19.49 ° ± 0.2 °,19.72 ° ± 0.2 °,20.46 ° ± 0.2 °,20.71 ° ± 0.21 ° ± 0.2 °,22.16 ° ± 0.2 °,23.62 ° ± 0.23.89 ° ± 0.24.40 ° ± 0.2.2 °, 0.26 ° ± 0.2 °,23.2 ° ± 0.26 °,23.2 °,23.62 ° ± 0.26 °,23.2 °, 23.2.2 °, 23.2.2.26 ° ± 0.26 ° ± 0.2 °, 2.26 ° ± 0.2 °,2 °, 2.26 ° ± 0.26 ° ± 0.2.2.2 °,2 °, 2.2.2.2.2.2 °, 20.9 ° ± 0.26 ° ± 0.2 °, 20.2 °, 20.9 ° ± 0.9.9 ° ± 0.9 ° ± 0.2.2 °, 20.9 ° ± 0.9.9 ° ± 0., 38.27 ° ± 0.2 °,38.95 ° ± 0.2 °,39.69 ° ± 0.2 °,45.20 ° ± 0.2 °.
In some embodiments, the sulfate salt of the present invention is characterized by the sulfate salt form a having an X-ray powder diffraction pattern substantially as shown in figure 1.
In some embodiments, the sulfate salt of the present invention is characterized as sulfate form a having a differential scanning calorimetry trace comprising an endothermic peak at 257.69 ℃ ± 3 ℃.
In some embodiments, the sulfate salt of the present invention is characterized by the sulfate salt form a having a differential scanning calorimetry pattern substantially as shown in figure 2.
In one aspect, the present invention also provides crystalline form B, C, D or E of the sulfate salt of the compound of formula (I).
In some embodiments, the crystalline form B of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.69 ° ± 0.2 °,8.53 ° ± 0.2 °,10.65 ° ± 0.2 °,11.37 ° ± 0.2 °,13.48 ° ± 0.2 ° 14.06 ° ± 0.2 °,14.23 ° ± 0.2 °,14.45 ° ± 0.2 °,14.84 ° ± 0.2 °,15.38 ° ± 0.2 °,16.13 ° ± 0.2 °,16.88 ° ± 0.2 °,17.53 ° ± 0.2 °,18.64 ° ± 0.2 °,19.62 ° ± 0.2 °,19.96 ° ± 0.2 °,20.47 ° ± 0.2 °,21.69 ° ± 0.2 ° ± 0.10 ° ± 0.2 °,22.60 ° ± 0.2 °,22.90 ° ± 0.2 °,23.55 ° ± 0.2 °,24.13 ° ± 0.24.2 ° ± 0.2 °, 0.2 ° ± 0.03 ° ± 0.2 °,19 ° ± 0.2.2 °,19 ° ± 0.26 °,19 ° ± 0.2.2 °,19 ° ± 0.2 °,19 ° ± 0.26 °,19 ° ± 0.2.2 °,19 ° ± 0.2 °,19 ° ± 0.2.2.2 °,19 ° ± 0.2 °,19 ° ± 0.2.2 °,19 ° ± 0.2 °,30.2 °, 30.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2.2.2.2 °,30 °,3 ° ± 0.2.2.2 °,3 ° ±,43.63 DEG + -0.2 deg.
In some embodiments, the crystalline form B of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern substantially as shown in figure 3.
In some embodiments, the crystalline form C of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.80 ° ± 0.2 °,10.83 ° ± 0.2 °,11.28 ° ± 0.2 °,11.75 ° ± 0.2 °,12.75 ° ± 0.2 °,13.68 ° ± 0.2 °,14.39 ° ± 0.2 °,15.57 ° ± 0.2 °,16.00 ° ± 0.2 °,16.55 ° ± 0.2 °,16.96 ° ± 0.2 °,17.50 ° ± 0.2 °,18.12 ° ± 0.2 °,18.42 ° ± 0.2 °,19.02 ° ± 0.2 °,19.32 ° ± 0.2 °,19.58 ° ± 0.2 °,20.87 ° ± 0.21 ° ± 0.2 °,21.80 ° ± 0.2 °,22 ° ± 0.2 °, 23.24.2 ° ± 0.2 ° ± 0.26 ° ± 0.12 ° ± 0.26 °,2 ° ± 0.12 ° ± 0.2 °,2 °, 2.12 ° ± 0.12 °,23.22 °, 23.2.23.24.2 °, 0.2.24 ° ± 0.2 °, 0.9 ° ± 0.0.0.0.0.9 ° ± 0.0.0.0.9 ° ± 0.2 °,20 ° ± 0.0.0.0.2 °,20 ° ± 0.2 °, 20.0.2 °,2 °, 2.9 ° ± 0.0.0.2.0.0.0.0.0.0.0.9 ° ± 0.0.0., 37.96 DEG + -0.2 DEG, 39.02 DEG + -0.2 deg.
In some embodiments, the crystalline form C of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern substantially as shown in figure 4.
In some embodiments, the crystalline form D of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.85 ° ± 0.2 °,6.66 ° ± 0.2 °,9.12 ° ± 0.2 °,10.30 ° ± 0.2 °,10.75 ° ± 0.2 °,13.28 ° ± 0.2 °,14.58 ° ± 0.2 °,16.08 ° ± 0.2 °,16.77 ° ± 0.2 °,18.29 ° ± 0.2 °,18.97 ° ± 0.2 °,19.52 ° ± 0.2 °,20.06 ° ± 0.2 °,24.21 ° ± 0.2 °,25.47 ° ± 0.2 °,28.13 ° ± 0.2 °,30.27 ° ± 0.2 °.
In some embodiments, the crystalline form D of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern substantially as shown in figure 5.
In some embodiments, the crystalline form E of the sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 7.62 ° ± 0.2 °,9.09 ° ± 0.2 °,10.68 ° ± 0.2 °,11.04 ° ± 0.2 °,12.05 ° ± 0.2 °,13.83 ° ± 0.2 °,14.23 ° ± 0.2 °,14.48 ° ± 0.2 °,15.68 ° ± 0.2 °,17.23 ° ± 0.2 °,18.19 ° ± 0.2 °,18.87 ° ± 0.2 °,19.29 ° ± 0.2 °,20.36 ° ± 0.2 °,20.59 ° ± 0.2 °,21.10 ° ± 0.2 °,21.45 ° ± 0.2 °,21.72 ° ± 0.2 ° ± 0.02 ° ± 0.2 °,22.54 ° ± 0.2 °,22.99 ° ± 0.2 °,23.20 ° ± 0.23.52 ° ± 0.2 ° ± 0.23.2 ± 0.2 °, 21.24 ° ± 0.2 °,22 ° ± 0.2.2 °,22 ° ± 0.2.2.19 ° ± 0.2 °, 22.2 °, 22.2.2 °, 22.9.9 ° ± 0.2 °, 2.2 °,3 ° ± 0.2.2.2.2.2 °,3 ° ±.
In some embodiments, the crystalline form E of sulfate salt of the present invention is characterized by an X-ray powder diffraction pattern substantially as shown in figure 6.
In another aspect, the present invention relates to a pharmaceutical composition comprising a sulfate salt according to the present invention.
In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In one aspect, the invention relates to the use of said sulfate salt or said pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating central nervous system dysfunction.
In some embodiments, the central nervous system dysfunction of the present invention includes, but is not limited to, depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, parkinson's disease, huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction or premenstrual tension syndrome.
In another aspect, the invention also relates to a preparation method of the sulfate of the compound shown in the formula (I) and a crystal form thereof.
The solvent used in the method for producing a sulfate salt according to the present invention is not particularly limited, and any solvent that can dissolve the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.
The experiments for the preparation of the sulphate salts according to the invention are described in detail in the examples section. Meanwhile, the invention provides a property test experiment, such as a pharmacokinetic experiment and the like, of the sulfate. Experiments prove that the sulfate, particularly the sulfate crystal form A, has greatly improved properties, such as higher blood concentration and exposure under the condition of oral capsule administration; in particular, compared with other salts of the compound shown in the formula (I), such as hydrobromide, the sulfate of the invention has higher blood concentration and exposure in rats, better pharmacokinetic property and more suitability for pharmaceutical use.
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
"solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.
By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
"solvate" refers to a compound having a solvent on a surface, in a crystal lattice, or on and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, and the like.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. Diffraction peaks were found to have a margin of error of + -0.2 deg. depending on the condition of the instrument used in the experiment.
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program2O3) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions that are substantially identicalAs shown in the DSC diagram provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peak has a tolerance of + -3 deg.C depending on the instrument used in the experiment.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC diagram are shown in the diagram.
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
The present invention relates to the sulfate salt of 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide and/or a crystalline form thereof, e.g., the sulfate salt form a, present in a substantially pure crystalline form.
By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in the X-ray powder diffraction pattern (XRPD).
In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and the like.
Compositions, formulations, administration and uses of the sulfate salts of the present invention
The pharmaceutical compositions of the present invention are characterized by comprising a sulfate salt of a compound of formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of sulfate salt of the compound in the pharmaceutical composition of the present invention is effective to detectably treat or reduce central nervous system dysfunction in the patient.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of The references herein, indicate that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the sulfate salt of the compound of the invention, e.g., any adverse biological effect produced or interaction with any other component of a pharmaceutically acceptable composition in a deleterious manner, its use is contemplated by the present invention.
Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.
The pharmaceutical composition of the invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; administration can be by the following route: oral administration, injection administration, spray inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable kit.
Oral administration may be in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs and the like; administration by external application may be in the form of: ointment, gel, medicated plaster, etc.
The sulfate salt of the present invention is preferably formulated in a unit dosage form to reduce the dosage amount and uniformity of dosage. The term "dosage unit form" as used herein refers to physically discrete units of a drug required for proper treatment of a patient. It will be appreciated, however, that the total daily usage of a compound of formula (I) or a sulphate salt thereof, or a pharmaceutical composition of the invention, will be determined by the attending physician, within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition, the activity of the sulfate salt of the specific compound, the specific composition employed, the age, body weight, health, sex, and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the sulfate salt of the specific compound employed, the duration of the treatment, the pharmaceutical application in combination or association with the specific compound or salt or crystal form thereof, and other factors well known in the pharmaceutical arts.
The effective dosage of the active ingredient employed may vary with the compound employed, the salt or crystalline form thereof, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the sulfate salt of the compound of the present invention is administered at a dose of about 0.25 to 1000mg/kg animal body weight per day, preferably 2 to 4 divided doses per day, or in a sustained release form. For the majority of large mammals, the total daily dose is from about 1 to about 100mg/kg, preferably from about 2 to about 80mg/kg, of the active compound, salt or crystalline form thereof. A dosage form suitable for oral administration comprising about 0.25 to 500mg of the active compound, salt or crystalline form thereof, in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the best therapeutic response. In addition, due to the differences in the treatment conditions, several divided doses may be given daily, or the doses may be proportionally reduced.
The sulfate salts of the compounds of the present invention, the pharmaceutical compositions of the present invention are useful for preventing, treating or alleviating central nervous system disorders including, but not limited to, depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorders, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorders, sexual dysfunction, musculoskeletal pain disorders, cognitive disorders, memory disorders, Parkinson's disease, Huntington's disease, phobias, substance abuse or addiction, withdrawal symptoms from drug addiction or premenstrual tension syndrome.
The sulfate salts of the compounds of the present invention, the pharmaceutical compositions of the present invention are also useful as selective 5-hydroxytryptamine reuptake inhibitors and/or 5-HT1AReceptor agonists, prophylaxis or treatment with 5-hydroxytryptamine and/or 5-HT1AA receptor associated disease.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form a of the compound of formula (I).
FIG. 2 is a Differential Scanning Calorimetry (DSC) chart of the sulfate salt form A of the compound of formula (I).
Figure 3 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form B of the compound of formula (I).
Figure 4 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form C of the compound of formula (I).
Figure 5 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form D of the compound of formula (I).
Figure 6 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form E of the compound of formula (I).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. The powdered sample was prepared as a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage and analyzed in 0.0167 ° steps over a range of 3 ° -60 °. Data Collector software was used to collect Data, HighScore Plus software processed the Data, and Data Viewer software read the Data.
The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.
Detailed description of the invention
A specific synthesis method of 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide compound of formula (I) is referred to example 2 in patent application CN 106243088A.
Examples
Example 1 sulfate form a
1. Preparation of sulfate form A
3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (150.1mg, 0.3224mmol) was added to tetrahydrofuran (10.0mL), stirred at 70 ℃ and added to a self-made aqueous solution of sulfuric acid (0.35mL) at a concentration of 1M, and the mixture was incubated for 3.5 hours and then cooled to room temperature. Filtering and vacuum drying to obtain the target crystal form 181.1mg with the yield of 99.67%.
2. Identification of sulfate form a
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.81 °,13.07 °,13.31 °,13.61 °,14.02 °,14.35 °,14.82 °,15.12 °,15.55 °,16.05 °,16.35 °,17.85 °,18.30 °,18.50 °,19.49 °,19.72 °,20.46 °,20.71 °,21.47 °,22.16 °,23.21 °,23.62 °,23.89 °,24.40 °,25.51 °,25.89 °,26.26 °,26.73 °,27.36 °,28.03 °,28.41 °,29.40 °,30.27 °,30.88 °,31.21 °,31.68 °,32.46 °,32.86 °,34.43 °,35.59 °,36.11 °,37.37 °,37.98 °,38.27 °,38.95 °,39.69 °,45.20 °, and an error tolerance of ± 0.2 ° exists.
(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 257.69 ℃, with a margin of error of ± 3 ℃.
Example 2 sulfate form B
1. Preparation of sulfate form B
After mixing 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (151mg, 0.3243mmol) and N' N-dimethylacetamide (1.0mL), stirring until complete dissolution, then adding a self-made aqueous solution of sulfuric acid (0.35mL) at a concentration of 1M to precipitate white crystals, stirring for 5 hours, filtering, and vacuum drying to obtain the target crystal form 154.4mg with a yield of 84.47%.
2. Identification of sulfate form B
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the sulfate form B has an X-ray powder diffraction pattern substantially as shown in figure 3 using Cu-ka radiation.
Example 3 sulfate form C
1. Preparation of sulfate form C
3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (150.6mg, 0.3235mmol) was added to N' N-dimethylformamide (1.5mL) and after complete dissolution, tetrahydrofuran (1.5mL) was added and after stirring well, a self-made aqueous solution of sulfuric acid (0.35mL) at a concentration of 1M was added and crystallized at room temperature overnight. And (3) evaporating a part of solvent under reduced pressure, filtering, washing a filter cake by using absolute ethyl alcohol (1.0mL), and drying in vacuum to obtain the target crystal form 152.9mg with the yield of 83.87%.
2. Identification of sulfate form C
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the sulfate form C has an X-ray powder diffraction pattern substantially as shown in figure 4 using Cu-ka radiation.
Example 4 sulfate form D
1. Preparation of sulfate form D
3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (151.1mg, 0.3245mmol) and isopropanol (3.0mL) were mixed, stirred well, then dimethylsulfoxide (2.0mL) was added, after clearing, a self-made aqueous solution of sulfuric acid (0.36mL) at a concentration of 1M was added, and stirred at room temperature overnight. Then cooling to-10 ℃ and stirring for 4 hours, naturally recovering the room temperature, then dropwise adding water (6.0mL), crystallizing for 5 hours, filtering, and drying in vacuum to obtain the target crystal form 156mg with the yield of 85.29%.
2. Identification of sulfate form D
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the sulfate form D has an X-ray powder diffraction pattern substantially as shown in figure 5 using Cu-ka radiation.
Example 5 crystalline form E of sulfate salt
1. Preparation of sulfate form E
3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (152mg, 0.3265mmol) was added to acetonitrile (3.0mL), and after stirring, dimethylsulfoxide (3.0mL) was added, and after clearing, an aqueous sulfuric acid solution (0.36mL) having a concentration of 1M was added thereto, and the mixture was stirred at room temperature overnight. Dropwise adding water (9.0mL), crystallizing for 2 hours, filtering, and drying in vacuum to obtain the target crystal form 90.7mg with a yield of 49.3%.
2. Identification of sulfate form E
Identified by Empyrean X-ray powder diffraction (XRPD) analysis: the sulfate form E has an X-ray powder diffraction pattern substantially as shown in figure 6 using Cu-ka radiation.
Example 6 hydrobromide salt
3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (0.8g) was added to a 250mL one-necked flask, added to isopropanol (70mL), heated to 100 ℃ until the solids were all dissolved, and a mixed solution of aqueous hydrobromic acid (1.2g, 40% mass) and isopropanol (10mL) was slowly added to precipitate a solid. After the addition, the heating and stirring are continued for 20 minutes; cooling and evaporation of the solvent under reduced pressure gave an orange solid (0.931g, 99.1%).
Example 7 pharmacokinetic experiments
The sulfate crystal form A and the hydrobromide of the compound shown in the formula (I) are respectively filled into capsules for oral administration.
8-12kg of male Beagle dogs were divided into 3 groups of 3 dogs, and capsules containing test samples were orally administered at a dose of 5mg/kg by collecting blood at time points of 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours. A standard curve of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the WinNonLin 6.3 software non-compartmental model method. The results of the experiment are shown in table 1.
TABLE 1 pharmacokinetic experimental data for the salts of the invention
| Test sample | Tmax(h) | Cmax(ng/mL) | AUClast(h*ng/mL) |
| Sulfate form A | 1.33 | 104 | 438 |
| |
4 | 3.94 | 40.3 |
And (4) experimental conclusion:
as can be seen from table 1, the sulfate form a of the present invention has higher blood concentration and greater exposure in beagle dogs, and has better pharmacokinetic properties than the hydrobromide salt of the compound represented by formula (I).
Example 8 stability test
(1)High temperature experiment: taking a proper amount of a sample to be tested, putting the sample into a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, placing the sample at the temperature of 40 +/-2 ℃ and 60 +/-2 ℃ for 30 days, sampling the sample at the 5 th, 10 th and 30 th days, and detecting according to the stability key examination items: the color change of the sample is observed, and the purity of the sample is detected by HPLC.
(2)High humidity experiment: taking a proper amount of a batch of test samples, putting the test samples into a flat weighing bottle, spreading the test samples into a thin layer with the thickness of less than or equal to 5mm, placing the test samples for 30 days at 25 ℃ under the condition of RH 90% +/-5%, sampling the test samples for 5 days, 10 days and 30 days according to the key stability study items, observing the color change of the samples, and detecting the purity of the samples by HPLC.
(3)Light test: taking a proper amount of a batch of samples, placing into a flat weighing bottle, spreading into a thin layer with thickness of less than or equal to 5mm, placing in a light box (with an ultraviolet lamp) with an opening, and irradiating at an illuminance of 4500 + -500 lx and an ultraviolet light of more than or equal to 0.7w/m2Was left under the conditions of (1) for 30 days, samples were taken on days 5, 13 and 30, and the purity of the samples was checked by HPLC.
And (4) experimental conclusion: the experimental results show that the appearance and the purity of the sulfate have no obvious change under the conditions of high temperature (60 ℃), high humidity (25 ℃, RH 90% +/-5%) and illumination. Namely, the sulfate of the invention has good stability under various lofting conditions and is suitable for pharmaceutical use.
The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (9)
1. A sulfate salt of a compound of formula (I),
the sulfate is a sulfate crystal form A, and an X-ray powder diffraction pattern of the sulfate has diffraction peaks at the following 2 theta angles: 6.81 ° ± 0.2 °,13.61 ° ± 0.2 °,18.30 ° ± 0.2 °,19.49 ° ± 0.2 °,19.72 ° ± 0.2 °,20.46 ° ± 0.2 °,22.16 ° ± 0.2 °,23.21 ° ± 0.2 °,26.26 ° ± 0.2 °,27.36 ° ± 0.2 °,28.03 ° ± 0.2 °.
2. The sulfate salt of claim 1, wherein the form a of the sulfate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.81 ° ± 0.2 °,13.07 ° ± 0.2 °,13.31 ° ± 0.2 °,13.61 ° ± 0.2 °,14.02 ° ± 0.2 °,14.35 ° ± 0.2 °,14.82 ° ± 0.2 °,15.12 ° ± 0.2 °,15.55 ° ± 0.2 °,16.05 ° ± 0.2 °,16.35 ° ± 0.2 °,17.85 ° ± 0.2 °,18.30 ° ± 0.2 °,18.50 ° ± 0.2 °,19.49 ° ± 0.2 °,19.72 ° ± 0.2 °,20.46 ° ± 0.2 °,20.71 ° ± 0.21 ° ± 0.2 °,22.16 ° ± 0.2 °,23.62 ° ± 0.23.89 ° ± 0.24.40 ° ± 0.2.2 °, 0.26 ° ± 0.2 °,23.2 ° ± 0.26 °,23.2 °,23.62 ° ± 0.26 °,23.2 °, 23.2.2 °, 23.2.2.26 ° ± 0.26 ° ± 0.2 °, 2.26 ° ± 0.2 °,2 °, 2.26 ° ± 0.26 ° ± 0.2.2.2 °,2 °, 2.2.2.2.2.2 °, 20.9 ° ± 0.26 ° ± 0.2 °, 20.2 °, 20.9 ° ± 0.9.9 ° ± 0.9 ° ± 0.2.2 °, 20.9 ° ± 0.9.9 ° ± 0., 38.27 ° ± 0.2 °,38.95 ° ± 0.2 °,39.69 ° ± 0.2 °,45.20 ° ± 0.2 °.
3. The sulfate salt of any one of claims 1-2, wherein the sulfate salt form a has an X-ray powder diffraction pattern substantially as shown in figure 1.
4. A sulfate salt of a compound of formula (I), wherein the sulfate salt is form A of the sulfate salt, and the differential scanning calorimetry trace thereof comprises an endothermic peak at 257.69 ℃ ± 3 ℃.
5. The sulfate salt of claim 4, wherein the sulfate form A has a differential scanning calorimetry trace substantially as shown in figure 2.
6. A pharmaceutical composition comprising the sulfate salt of any one of claims 1 to 5.
7. The pharmaceutical composition of claim 6, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
8. Use of a sulfate salt according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 6 to 7 for the preparation of a medicament for the prevention, treatment or alleviation of a central nervous system dysfunction disease.
9. The use according to claim 8, wherein the central nervous system dysfunctional disorder is depression, anxiety, mania, schizophrenia, bipolar disorder, sleep disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, movement disorder, sexual dysfunction, musculoskeletal pain disorder, cognitive disorder, memory disorder, Parkinson's disease, Huntington's disease, phobias, substance abuse or addiction, withdrawal from drug addiction or premenstrual tension syndrome.
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| CN101243066A (en) * | 2005-08-26 | 2008-08-13 | 诺瓦提斯公司 | Delta and epsilon crystal forms of imatinib mesylate |
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| CN106243088A (en) * | 2015-06-03 | 2016-12-21 | 广东东阳光药业有限公司 | Substituted diethylenediamine compound and using method thereof and purposes |
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