CN112851642B

CN112851642B - Salt of phenylpyrimidine piperazine compound and use thereof

Info

Publication number: CN112851642B
Application number: CN202011351471.9A
Authority: CN
Inventors: 许腾飞; 薛亚萍; 劳锦花
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2019-11-28
Filing date: 2020-11-26
Publication date: 2022-07-08
Anticipated expiration: 2040-11-26
Also published as: CN112851642A

Abstract

The present invention relates to salts of phenylpyrimidine piperazine compounds and their use. The invention also relates to a pharmaceutical composition containing the salt and application of the salt or the pharmaceutical composition in preparing a medicament for preventing, treating or relieving central nervous system dysfunction, in particular depression.

Description

Salt of phenylpyrimidine piperazine compound and use thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a salt of a phenylpyrimidine piperazine compound and application thereof, in particular to a salt of 3- (2- (4- (3- (5-cyano-1H-indole-3-yl) propyl) piperazine-1-yl) pyrimidine-5-yl) benzamide, a crystal form of the salt and application thereof, and further relates to a pharmaceutical composition containing the salt or the crystal form.

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 in 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. 5-HT_1AThe receptor, a G protein-coupled receptor, is widely distributed in the region capable of receiving 5-hydroxytryptamine from the nucleus of the central fissure, and comprises: frontal cortex, lateral septum, amygdala, hippocampus, and hypothalamus. In these cortical marginal regions, 5-HT_1ALocated in the postsynaptic membrane. At the same time, 5-HT_1AReceptors are also presynaptic membrane autoreceptors on the nucleus of the raphe, which reduce the firing rate of neurons (i.e., the amount of 5-hydroxytryptamine released per action potential), as well as the synthesis of neurotransmitters, which in turn reduce the activity of 5-hydroxytryptamine in the projection zone. 5-HT activating presynaptic Membrane_1AThe receptor can inhibit the synthesis of tyrosine hydroxylase and the activity of glutamate channel (generated in medial prefrontal cortex and pointing to the raphe nucleus), thereby indirectly reducing the transport of 5-hydroxytryptamine (Jonathan Savitz, Irwin Lucki, Wayne C.Drevets.5-HT)_1A receptor function in major depressive disorder.Prog Neurobiol.2009,88(1):17-31)。

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 the disability-adjusted life span for depression will jump to the second place for all diseases by 2020. (Bromet E, Andlade LH, Hwang I, et al, Cross-national epidemic of DSM-IV major de-pressing epimode. BMC Med.2011,9: 90).

Conventional selective 5-hydroxytryptamine reuptake inhibitor (SSRIs) treatments increase the level of 5-hydroxytryptamine by inhibiting reuptake and modulating transport of 5-hydroxytryptamine. However, after SSRIs, 5-HT of presynaptic membrane is also activated_1AThe autoreceptor causes the release amount of 5-hydroxytryptamine to be reduced, and the concentration of 5-hydroxytryptamine among synapses is reduced. However, SSRIs cause 5-HT with prolonged dosing time_1AThe autoreceptor is desensitized, and the activation effect is restrained, so that the normal regulation effect is exerted. From this, it is concluded that_1AThe activation of autoreceptors is a major reason for The delay in The onset of action of SSRIs (Celada P, Pu M, Amargos-Bosch M, et al, The therapeutic role of 5-HT_1A and 5-HT_2Areceptors in the expression. J Psychiatry Neurosci,2004,29(4): 252-65). Thus, overcoming 5-HT_1AThe negative feedback effect of the autoreceptor agonist has the prospect of enhancing and accelerating clinical antidepressant.

5-HT in contrast to SSRis_1AReceptor agonists or partial agonists act directly on the postsynaptic 5-hydroxytryptamine receptor to increase 5-hydroxytryptamine neurotransmission during the incubation period of SSRI. Feiger and Wilcox demonstrated that buspirone and gepirone are clinically effective 5-HT_1APartial agonists (Feiger, A. Psychopharmacol. Bull.1996,32: 659-65). Addition of buspirone to standard SSRIs treatment resulted in significant improvement in patients who previously failed to respond to standard treatment for depression (Dimitriou, E.J. Clin. Psychopharmacol.,1998,18: 465-9).

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.

International application WO 2016192657A 1 discloses the compound 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide, which has selective 5-hydroxytryptamine reuptake inhibitory activity and/or 5-HT_1AReceptor agonistic activity. However, no research report related to the salt or crystal form of the compound exists in the prior art.

The inventor discovers that the compound has poor water solubility and drug forming property when researching the compound, so that in order to find a solid form with better drug forming property, through a large amount of experimental researches, the preparation purity of a product is obviously improved after the compound shown in the formula (I) is salified, and the physical properties and various properties are more beneficial to the development of preparations.

Disclosure of Invention

The invention provides a salt of a compound shown in a formula (I), and researches on the preparation of the salt, the solid form of the salt, the physicochemical property and the pharmacological property of the salt are carried out, so that the salt formed by the compound and different acids has large difference of the physicochemical property; various physicochemical properties of the hydrochloride are better than those of other salts, for example, the hydrochloride crystal form I obtained after the compound shown in the formula (I) and hydrochloric acid are salified has good stability, and the pharmacokinetic property of the hydrochloride is better than that of other salts such as phosphate. Therefore, the hydrochloride crystal form I has better properties and better pharmacokinetic properties, thereby having better medicament forming property.

In particular, the invention relates to a salt of a compound shown in formula (I), and application of the salt of the compound or a pharmaceutical composition containing the salt in preparing a medicament for preventing, treating or relieving central nervous system dysfunction, particularly depression. The salt is hydrochloride of the compound shown in the formula (I). Further, the salt provided by the invention is a hydrochloride crystal form I of the compound shown in the formula (I). The crystalline forms of the present invention may also be in the form of solvates, for example hydrates.

In one aspect, the invention provides a salt of a compound of formula (I),

in some embodiments, the salts described herein are salts of organic or inorganic acids.

In other embodiments, the inorganic acid salts described herein include, but are not limited to, hydrochloride, hydrobromide, phosphate or sulfate salts and the like; the organic acid salt includes, but is not limited to, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzoate, benzenesulfonate, methanesulfonate, or p-toluenesulfonate, and the like.

In some embodiments, the salt of the compound of formula (I) of the present invention is a hydrochloride salt.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form I having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 10.36 ° ± 0.2 °,15.15 ° ± 0.2 °,18.40 ° ± 0.2 °,18.40 ° ± 0.2 °,18.99 ° ± 0.2 °,19.67 ° ± 0.2 °,21.66 ° ± 0.2 °,23.12 ° ± 0.2 °,24.74 ° ± 0.2 °,28.13 ° ± 0.2 °,30.15 ° ± 0.2 °.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form I having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.81 plus or minus 0.2 degrees, 8.53 plus or minus 0.2 degrees, 10.36 plus or minus 0.2 degrees, 10.71 plus or minus 0.2 degrees, 12.38 plus or minus 0.2 degrees, 12.66 plus or minus 0.2 degrees, 14.71 plus or minus 0.2 degrees, 15.15 plus or minus 0.2 degrees, 15.62 plus or minus 0.2 degrees, 16.20 plus or minus 0.2 degrees, 17.13 plus or minus 0.2 degrees, 18.13 plus or minus 0.2 degrees, 18.40 plus or minus 0.2 degrees, 18.99 plus or minus 0.2 degrees, 19.27 plus or minus 0.2 degrees, 19.67 plus or minus 0.2 degrees, 19.99 plus or minus 0.2 degrees, 20.82 plus or minus 0.2 degrees, 21.14 plus or minus 0.2 degrees, 21.66 plus or minus 0.2 degrees, 22.60 plus or minus 0.2 degrees, 22.92 plus or minus 0.2 degrees, 23.12 plus or minus 0.2 degrees, 24.00 plus or minus 0.2 degrees, 24.41 plus or minus 0.2 degrees, 24.2 degrees, 24.9 plus or minus 0.2 degrees, 21.9 plus or minus 0.2 degrees, 21.2 degrees, 2 plus or minus 0.2 degrees, 2 plus or minus 0.25 plus or minus 0.2 degrees, 28 plus or minus 0.2 degrees, 28.2 degrees, 9 plus or minus 0.2 degrees, 19.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2 degrees, 9 plus or minus 0.2.2.2.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2.2 degrees, 9 plus or minus 0.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0.2 degrees, 9 plus or minus 0..

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form I having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.81 plus or minus 0.2 °,8.53 plus or minus 0.2 °,10.36 plus or minus 0.2 °,10.71 plus or minus 0.2 °,12.38 plus or minus 0.2 °,12.66 plus or minus 0.2 °,14.71 plus or minus 0.2 °,15.15 plus or minus 0.2 °,15.62 plus or minus 0.2 °,16.20 plus or minus 0.2 °,17.13 plus or minus 0.2 °,18.13 plus or minus 0.2 °,18.40 plus or minus 0.2 °,18.99 plus or minus 0.2 °,19.27 plus or minus 0.2 °,19.67 plus or minus 0.2 °,19.99 plus or minus 0.2 °,20.82 plus or minus 0.2 °,21.14 plus or minus 0.2 °,21.66 plus or minus 0.2 °,22.60 plus or minus 0.2 °,22.92 plus or minus 0.12 plus or minus 0.2 °,24.00 plus or minus 0.2 °,24.41 plus or minus 0.2 ± 0.2 °,24.9 ± 0.9 ± 0.2 °,24.9 ± 0.2 °,21.9 ± 0.2 °,21.9 ± 0.2 °,21.2 ± 0.2 °, 21.0.2 °,2 ± 0.0.9 ± 0.2 °,2 ± 0.2 °,2 ± 0.2 °,2 ± 0.0.2 ± 0.2 ± 0.0.2 °,2 ± 0.0.2 ± 0.2 ± 0.0.2 ± 0.2 °,2 ± 0.2 °,2 ± 0.0.0.2 ± 0.0.2 ± 0.2 °,2 ± 0.2 ± 0.0.0.0.9 ± 0.0.0.0.0.0.0.9 ± 0.2 °,2 ± 0.0.0.2 ± 0.2 °,2 ± 0.2 °,2 ± 0.0.2 °,2 ± 0.2 °,2 ± 0.2 °,2 ± 0.0.0.0.0.0.0.0.0.2 ± 0.0.2 °,2 ± 0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.0.2 ± 0.0.0.2 °,2 ± 0.0.0.0.0.0.2 °,13 ± 0.2 °,2 ± 0.0.2 ± 0.2 °,2 ± 0.0.0.0.2 °,2 ± 0.0.0.0.0.0.0.2 °,2 ± 0.0.2 °,2 ± 0.0.0.0.0.0.0.0.0.0.2 ± 0.2 °,2 ± 0.2 ± 0.0.0.0.0.2 ± 0.0.2 ± 0.0.0.2 ± 0.0.2.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form I having an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form I, the differential scanning calorimetry trace of which comprises an endothermic peak at 273.54 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form I having a differential scanning calorimetry pattern substantially as shown in figure 5.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form II having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 10.61 ° ± 0.2 °,12.65 ° ± 0.2 °,15.45 ° ± 0.2 °,15.88 ° ± 0.2 °,18.39 ° ± 0.2 °,19.03 ° ± 0.2 °,19.46 ° ± 0.2 °,19.89 ° ± 0.2 °,20.17 ° ± 0.2 °,22.16 ° ± 0.2 °,25.79 ° ± 0.2 °.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form II having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.94 ° ± 0.2 °,8.45 ° ± 0.2 °,10.61 ° ± 0.2 °,11.22 ° ± 0.2 °,12.65 ° ± 0.2 °,13.16 ° ± 0.2 °,14.53 ° ± 0.2 °,15.45 ° ± 0.2 °,15.88 ° ± 0.2 °,17.57 ° ± 0.2 °,18.39 ° ± 0.2 °,19.03 ° ± 0.2 °,19.46 ° ± 0.2 °,19.89 ° ± 0.2 °,20.17 ° ± 0.2 °,21.22 ° ± 0.2 °,21.96 ° ± 0.2 °,22.16 ° ± 0.2 ° ± 0. 22.51 °,23.13 ° ± 0.2 °,23.46 ° ± 0.2 °,24.31 ° ± 0.2 °,25.03 ° ± 0.2.42 ° ± 0.26 ° ± 0.2 °, 2.26 ° ± 0.2 °, 23.53 ° ± 0.2.2 °, 23.26 ° ± 0.26 ° ± 0.2.2 °,24.31 ° ± 0.2.2 °, 24.2 °, 2.3 ° ± 0.2 °, 2.2 ° ± 0.27.2.27 ° ± 0.2 °, 2.3 ° ± 0.26 ° ± 0.2.2.2.26 ° ± 0.26 ° ± 0.2 °.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form II having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.94 +/-0.2 degrees, 8.45 +/-0.2 degrees, 10.61 +/-0.2 degrees, 11.22 +/-0.2 degrees, 12.65 +/-0.2 degrees, 13.16 +/-0.2 degrees, 14.53 +/-0.2 degrees, 15.45 +/-0.2 degrees, 15.88 +/-0.2 degrees, 17.57 +/-0.2 degrees, 18.39 +/-0.2 degrees, 19.03 +/-0.2 degrees, 19.46 +/-0.2 degrees, 19.89 +/-0.2 degrees, 20.17 +/-0.2 degrees, 21.22 +/-0.2 degrees, 21.96 +/-0.2 degrees, 22.16 +/-0.2 22.51 +/-0.2 degrees, 23.13 +/-0.2 degrees, 23.46 +/-0.2 degrees, 24.31 +/-0.2 degrees, 25.03 +/-0.2.42 degrees, 0.2 +/-0.2.2 degrees, 0.27 +/-0.2.2 degrees, 0.2 degrees, 0.26 +/-0.2 degrees, 2.2 degrees, 0.2 degrees, 27 +/-0.2.2 degrees, 23 +/-0.2.2.2.2 degrees, 23 +/-2.2.2.2.2 degrees, 23 +/-2.2.2.2 degrees, 23 +/-2.2.2 degrees, 23.2 degrees, 23 +/-2.2.2.2.2 degrees, 2 degrees, 2.2.2 degrees, 2 degrees, 2.2 degrees, 2.2.2 degrees, 2 degrees, 2.2.2 degrees, 2 degrees, 2.3 +/-0.3 degrees, 2 degrees, 2.3.3, 2.2 degrees, 2 degrees, 2.2 degrees, 2.3 degrees, 2 degrees, 2.2 degrees, 0.2.2.2 degrees, 2.2.2.2.2.2 degrees, 2 degrees, 0.2 degrees, 2 degrees, 2.3 degrees, 0.3 +/-0.2 degrees, 0.3 degrees, 0.2.2 degrees, 0.2 degrees, 0.2.2 degrees, 0.2.3 degrees, 0.2 degrees, 2 degrees, 0.3 degrees, 0.2 degrees, 0.3 degrees, 0.2 degrees, 0.2.2 degrees, 0.3 degrees, 0.2 degrees, 0.3 degrees, 0.2 degrees, 0.3 degrees, 0.2 degrees, 0.2.2.2.2 degrees, 0.3 degrees, 0.2 degrees, 0.2.2.2 degrees, 0.2 degrees, 0.2.3 degrees, 0.2 degrees, 0.3 degrees, 0.2 degrees, 0.3 degrees, 0.2.2 degrees, 0.2 degrees, 0.2.2.2 degrees, 0.3 degrees, 0.2.2 degrees, 0.3 degrees, 0.2 degrees, 0.3 degrees, 0.2.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form II having an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form III having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.11 ° ± 0.2 °,14.88 ° ± 0.2 °,16.31 ° ± 0.2 °,18.47 ° ± 0.2 °,18.68 ° ± 0.2 °,18.87 ° ± 0.2 °,20.27 ° ± 0.2 °,21.02 ° ± 0.2 °,21.32 ° ± 0.2 °,24.12 ° ± 0.2 °,27.52 ° ± 0.2 °.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form III having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.11 ° ± 0.2 °,12.84 ° ± 0.2 °,14.88 ° ± 0.2 °,15.14 ° ± 0.2 °,15.56 ° ± 0.2 °,16.31 ° ± 0.2 °,16.66 ° ± 0.2 °,17.62 ° ± 0.2 °,18.47 ° ± 0.2 °,18.68 ° ± 0.2 °,18.87 ° ± 0.2 °,19.72 ° ± 0.2 °,20.27 ° ± 0.2 °,21.02 ° ± 0.2 °,21.32 ° ± 0.2 °,21.57 ° ± 0.2 °,21.93 ° ± 0.2 °,22.48 ° ± 0.22 ° ± 0.2 °,22.86 ° ± 0.2 °,23.38 ° ± 0.2 °,24.12 ° ± 0.24.80 ° ± 0.2 °,2 ° ± 0.25 ° ± 0.2 °, 2.25 ° ± 0.2 °,2 ° ± 0.2 °, 2.25 ° ± 0.2 °,23.38 ° ± 0.2 °, 24.12.12.12 ° ± 0.12 ° ± 0.2 °, 2.2 °,2 ° ± 0.2.25 ° ± 0.2 °,2 °.

In some embodiments, the salt of the invention is a hydrochloride salt, wherein the hydrochloride salt is hydrochloride form III having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 11.11 ° ± 0.2 °,12.84 ° ± 0.2 °,14.88 ° ± 0.2 °,15.14 ° ± 0.2 °,15.56 ° ± 0.2 °,16.31 ° ± 0.2 °,16.66 ° ± 0.2 °,17.62 ° ± 0.2 °,18.47 ° ± 0.2 °,18.68 ° ± 0.2 °,18.87 ° ± 0.2 °,19.72 ° ± 0.2 °,20.27 ° ± 0.2 °,21.02 ° ± 0.2 °,21.32 ° ± 0.2 °,21.57 ° ± 0.2 °,21.93 ° ± 0.2 °,22.48 ° ± 0.22 ° ± 0.2 °,22.86 ° ± 0.2 °,23.38 ° ± 0.2 °,24.12 ° ± 0.30 ° ± 0.2 °,30 ° ± 0.2 ± 0.27 ° ± 0 ° ± 0.2 °,23.38 ° ± 0.2 °,13 ° ± 0.0.2 °,13 ° ± 0 ° ± 0.2 °,13 ° ± 0.2 °,24 ° ± 0.0.0.2 °,13 ° ± 0.2 °,13 ° ± 0.0.0.0.0 ° ± 0.2 °,13 ° ± 0 ° ± 0.2 °,13 ° ± 0.2 °, 24.2 °,24.0 ° ± 0 ° ± 0.0.2 °,24 ° ± 0.0 ° ± 0.2 °,24 ° ± 0 ° ± 0.30 ° ± 0.2 °,13 ° ± 0.30 ° ± 0 ° ± 0.2 °,13 ° ± 0.30 ° ± 0.2 °,13 ° ± 0.2 °,24.30 ° ± 0.30 ° ± 0.2 °,13 ° ± 0.30 ° ± 0.2 °, 24.0.2 °,13 ° ± 0.2 °,24 ° ± 0.0.30 ° ± 0.2 °,13 ° ± 0.0.0.30 ° ± 0.30 ° ± 0.0.30 ° ± 0.0 ° ± 0.2 °,13 ° ± 0.0 ° ± 0.30 ° ± 0.2 °,13 ° ± 0 ° ± 0.2 °,24 ° ± 0.30 ° ±.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form III having an X-ray powder diffraction pattern substantially as shown in figure 3.

In another aspect, the invention relates to a pharmaceutical composition comprising any one of the salts or any one of the crystal forms of the salt of the invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

In one aspect, the invention relates to the use of said salt or a crystalline form thereof or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.

In some such embodiments, the central nervous system disorder 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 relates to the use of said salt or a crystalline form thereof or said pharmaceutical composition for the manufacture of a medicament for use as a selective 5-hydroxytryptamine reuptake inhibitor and/or 5-HT inhibitor_1AA receptor agonist.

In one aspect, the present invention provides a phosphate salt of a compound of formula (I); in particular, the phosphate salts of the present invention are in amorphous form having an X-ray powder diffraction pattern substantially as shown in figure 4.

In another aspect, the invention also relates to a preparation method of the salt and/or crystal form of the compound shown in the formula (I).

The solvent used in the preparation method of the salt, crystal form and/or amorphous form of 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 salts or crystalline forms according to the invention are described in detail in the examples section. Meanwhile, the invention provides property test experiments of the salt or the crystal form, such as pharmacokinetic experiments, solubility experiments, stability experiments, hygroscopicity experiments and the like. Experiments prove that the hydrochloride crystal form I has unexpected technical advantages:

1. the hydrochloride form I has better stability relative to other hydrochloride forms, such as hydrochloride form II. In the aspect of stability, the hydrochloride crystal form II is unstable and is easy to generate crystal transformation and is transformed into a stable crystal form I. For example, the hydrochloride form II will crystallize to the hydrochloride form I when left at room temperature. The hydrochloride crystal form I is very stable, does not generate crystal transformation under common conditions, for example, the crystal form I cannot change when being placed at normal temperature, is also very stable under high-temperature and high-humidity conditions, and has basically no change in appearance and purity.

2. The hydrochloride salt form I has higher plasma levels and exposures in dogs and thus better pharmacokinetic properties than other salts, such as phosphate.

Therefore, the hydrochloride crystal form I has better biological activity and higher stability, and is more suitable 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.

"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, and is characterized by a diffuse, non-peaked, X-ray powder diffraction pattern. Amorphous is a particular physical form of solid material, with locally ordered structural features suggesting a myriad of connections to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, 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. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

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 substantially as shown in the DSC profiles 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.

Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.

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 in the figures" 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 pattern or raman spectrum or infrared spectrum are shown in the figures.

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 invention relates to salts of said 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide and/or crystalline forms thereof, which exist in 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.

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.

Pharmaceutical compositions, formulations, administration and uses of the salts or crystalline forms thereof of the invention

The pharmaceutical composition of the invention is characterized by comprising a salt of the compound shown in the formula (I) and/or a crystal form thereof and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the salt of the compound or crystalline form thereof in the pharmaceutical composition of the present invention is effective to detectably treat or reduce central nervous system dysfunction in a patient. The pharmaceutical compositions of the present invention may also optionally comprise other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; gennaro a.r.et al, Remington: the Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a large number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and use them to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed 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-Ash 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising a salt of a compound of the invention, or a crystalline form thereof, may be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

The compounds of the present invention or salts thereof are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention or a pharmaceutical composition comprising a salt of a compound of the present invention. Various embodiments of the present invention encompass the treatment of the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention or a pharmaceutical composition comprising a salt of a compound of the present invention.

In one embodiment, a salt of a compound of the present invention or a pharmaceutical composition comprising a salt of a compound of the present invention may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention may be administered orally. In another embodiment, a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention may be administered by inhalation. In yet another embodiment, a salt of a compound of the invention or a salt comprising a compound of the invention may be administered intranasally.

In one embodiment, a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a salt of a compound of the invention or a pharmaceutical composition comprising a salt of a compound of the invention depend on the pharmacokinetic properties of the salt of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen, including the duration of the regimen, of the salt of the compound of the invention or of the pharmaceutical composition comprising the salt of the compound of the invention depends on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

Salts of the compounds of the present invention may be administered concurrently with, before or after one or more other therapeutic agents. The salts of the compounds of the present invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or in the same pharmaceutical composition.

For an individual of about 50-70kg, the pharmaceutical compositions and combinations of the present invention may be in unit dosage form containing about 1-1000mg, or about 1-500mg, of the active ingredient. The therapeutically effective amount of the compound, salt of the compound, pharmaceutical composition or combination thereof will depend upon the species, weight, age and condition of the subject, the disease (disorder) or condition being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (disease).

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof.

In one embodiment, the amount of the compound in a therapeutically effective dose of a salt of a compound of the invention is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg of the principal active ingredient or a combination of principal ingredients per dosage unit form.

The salts and pharmaceutical compositions of the compounds provided by the invention can be used for preparing medicaments for preventing, treating or alleviating central nervous system dysfunction of mammals including human beings, and can also be used for preparing medicaments for inhibiting 5-hydroxytryptamine reuptake and/or exciting 5-HT_1AA pharmaceutical product of a recipient.

In particular, the amount of compound in the pharmaceutical compositions of the present invention is effective to detectably selectively inhibit the reuptake of 5-hydroxytryptamine and to 5-HT_1AThe receptor has an agonistic effect, and the salts of the compounds of the present invention are useful as agents for treating Central Nervous System (CNS) disorders such as depression, anxiety in humans.

Salts of the compounds of the present invention may be used in, but are in no way limited to, the prevention, treatment, or alleviation of central nervous system dysfunctional disorders by administering to a patient an effective amount of a salt of the compound of the present invention or a pharmaceutical composition. The central nervous system dysfunctional diseases responsive to 5-hydroxytryptamine receptor modulation further include, but are not limited to, depression, anxiety, mania, schizophrenia, sleep disorders, bipolar disorder, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, 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, premenstrual tension syndrome, and the like.

In addition to being beneficial for human therapy, salts and pharmaceutical compositions of the compounds of the invention may also find application in veterinary therapy of pets, animals of the introductory species and mammals in farms. Examples of other animals include horses, dogs, and cats.

Drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of the hydrochloride salt of the compound of formula (I).

Figure 2 is an X-ray powder diffraction (XRPD) pattern of the hydrochloride form II of the compound of formula (I).

Figure 3 is an X-ray powder diffraction (XRPD) pattern of crystalline form III of the hydrochloride salt of the compound of formula (I).

FIG. 4 is an X-ray powder diffraction (XRPD) pattern of the amorphous phosphate salt of the compound of formula (I).

FIG. 5 is a Differential Scanning Calorimetry (DSC) profile of the hydrochloride form I of the compound of formula (I).

Figure 6 shows a comparison of the X-ray powder diffraction (XRPD) pattern of the hydrochloride form II of the compound of formula (I) after standing at room temperature for 7 days, the X-ray powder diffraction (XRPD) pattern of the hydrochloride form II before standing, and the X-ray powder diffraction (XRPD) pattern of the hydrochloride form I 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 Data, and Data Viewer software read 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 sample was accurately weighed into a specially made aluminum crucible with a lid and analyzed from room temperature to about 300 c using a linear heating device of 10 c/min. During use, the DSC cell was purged with dry nitrogen.

The solubility of the invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the type of a chromatographic column is Agilent XDB-C18(4.6 multiplied by 50mm, 5 mu m). The detection wavelength is 266nm, the flow rate is 1.0mL/min, the column temperature is 35 ℃, and the ratio of mobile phase A: acetonitrile-0.01M ammonium acetate ═ 10: 90 (V: V) analysis method: acetonitrile-mobile phase a ═ 70: 30 (V: V), runtime: for 10 minutes.

The moisture absorption of the invention is measured by adopting a DVS INT-Std type dynamic moisture and gas adsorption analyzer of Surface Measurement Systems company in England, and the humidity test range is as follows: 0% to 95%, air flow: 200mL/min, temperature: 25 ℃, test point: one test point was taken per liter of 5% humidity.

Detailed description of the preferred embodiment

A specific synthesis of 3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide of formula (I) is described in example 2 of International application WO 2016192657A 1.

Examples

Example 1 crystalline form I of the hydrochloride salt of the invention

1. Preparation of hydrochloride form I

3- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) benzamide (51.08g,108.0mmol) was added to N, N-dimethylacetamide (100.0mL), warmed to 60 ℃ and the solid completely dissolved; carrying out suction filtration after heat preservation for 1-2 hours, removing insoluble impurities, carrying out heat preservation on the filtrate at 60 ℃, mechanically stirring, then adding acetone (200.0mL) into the filtrate, and separating out solids in the system; adding a self-made hydrochloric acid (110.0mL,110mmol,1.0mol/L) solution, dissolving the solid, clarifying the solution, and then beginning to separate out the solid; after reacting for 2-5 hours, stopping heating, naturally cooling the reaction to room temperature, and growing crystals for 6-12 hours; suction filtration, the filter cake washed with acetone (100 mL. times.2), then brine (100 mL. times.2), then water (100 mL. times.2), and finally acetone (50 mL. times.2), and the filter cake was dried under vacuum at 120 ℃ overnight to give a white solid powder with about 89% yield.

2. Identification of crystalline form I of the hydrochloride

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.81 °,8.53 °,10.36 °,10.71 °,12.38 °,12.66 °,14.71 °,15.15 °,15.62 °,16.20 °,17.13 °,18.13 °,18.40 °,18.99 °,19.27 °,19.67 °,19.99 °,20.82 °,21.14 °,21.66 °,22.60 °,22.92 °,23.12 °,24.00 °,24.41 °,24.74 °,24.89 °,25.48 °,25.99 °,26.71 °,27.57 °,27.88 °,28.13 °,28.58 °,29.21 °,30.15 °,32.02 °,36.38 °, with an error tolerance of ± 0.2 °. The XRPD pattern of form I of the hydrochloride salt prepared according to the method of example 1 of the present invention is substantially as shown in figure 1.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 273.54 ℃, with a margin of error of ± 3 ℃. A DSC diagram of crystalline form I hydrochloride prepared according to the method of example 1 of the present invention is substantially as shown in figure 5.

Example 2 crystalline form II of the hydrochloride salt of the invention

1. Preparation of hydrochloride form II

Putting the hydrochloride crystal form I (2.00g) into a vacuum drying oven, heating to 120 ℃, drying at constant temperature for 12 hours, and cooling to obtain a white-like powder solid with the yield of about 93 percent.

2. Identification of hydrochloride form II

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.94 °,8.45 °,10.61 °,11.22 °,12.65 °,13.16 °,14.53 °,15.45 °,15.88 °,17.57 °,18.39 °,19.03 °,19.46 °,19.89 °,20.17 °,21.22 °,21.96 °,22.16 °,22.51 °,23.13 °,23.46 °,24.31 °,25.03 °,25.42 °,26.08 °,26.53 °,27.09 °,27.67 °,28.31 °,29.68 °,30.94 °,34.29 °,36.73 °, with an error tolerance of ± 0.2 °.

The XRPD pattern of crystalline form II hydrochloride prepared according to the method of example 2 of the present invention is substantially as shown in figure 2. The hydrochloride salt form II was analyzed and characterized by Empyrean X-ray powder diffraction (XRPD) at room temperature for 7 days, the XRPD pattern of which is shown in figure 6. As can be seen from a comparison of the three XRPD patterns in fig. 6, the hydrochloride form II converts to hydrochloride form I after 7 days at room temperature.

Example 3 crystalline form III of the hydrochloride salt of the present invention

1. Preparation of hydrochloride form III

Adding hydrochloride form I (2.00g) into DMSO (10mL), heating to 75 ℃ to completely dissolve, then adding into ethanol (50mL), stirring for 1h at room temperature, filtering, vacuum drying at room temperature, then heating to 50 ℃ and vacuum drying overnight, and cooling to obtain white powder solid with the yield of about 85%.

2. Identification of crystalline form III of the hydrochloride

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks, expressed in degrees 2 θ: 11.11 °,12.84 °,14.88 °,15.14 °,15.56 °,16.31 °,16.66 °,17.62 °,18.47 °,18.68 °,18.87 °,19.72 °,20.27 °,21.02 °,21.32 °,21.57 °,21.93 °,22.48 °,22.74 °,22.86 °,23.38 °,24.12 °,24.80 °,24.97 °,25.33 °,25.68 °,26.12 °,26.61 °,27.37 °,27.52 °,28.48 °,29.13 °,30.45 °,31.19 °, and an error tolerance of ± 0.2 ° exists. An XRPD pattern of form III hydrochloride salt prepared according to the method of example 3 of the invention is substantially as shown in figure 3.

Example 4 phosphate salt of the invention

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 single-necked flask, added to isopropanol (70mL), heated to 100 ℃ until all the solid dissolved, and a solution of phosphoric acid (0.231g, 85% mass) in 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 off-white solid (0.931g, 99.6%). The phosphate salt was amorphous as identified by Empyrean X-ray powder diffraction (XRPD) analysis, having an XRPD pattern substantially as depicted in figure 4.

EXAMPLE 5 pharmacokinetic experiments on the salts of the invention

The test samples were encapsulated for oral administration.

8-12kg of male Beagle dogs, 3 dogs in one group, were orally administered with capsules containing test samples at a dose of 5mg/kg, and blood was collected 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	T_max(h)	C_max(ng/ml)	AUC_last(h*ng/ml)
				Example 1	1.67	122	532
Example 4	2	6	20.6

And (4) experimental conclusion:

as can be seen from table 1, the hydrochloride form I of the present invention has greater exposure in beagle dogs and better pharmacokinetic properties than the phosphate salt of the compound of formula (I).

Example 6 stability test of salts according to the invention

(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 a stability key examination item: 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 test sample, putting the test sample into a flat weighing bottle, spreading the test sample into a thin layer with the thickness of less than or equal to 5mm, placing the test sample for 30 days under the conditions of 25 ℃, 75 +/-5% RH or 25 ℃ and 90 +/-5% RH, sampling the test sample on the 5 th, 10 th and 30 th days, detecting according to key stability investigation items, observing the color change of the sample, and detecting the purity of the sample 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/m²Standing for 30 days, sampling at 5, 10 and 30 days, detecting according to stability key items, observing color change of the sample, and detecting the purity of the sample by HPLC.

The experimental conclusion is that: the experimental result shows that the appearance and the purity of the hydrochloride crystal form I of the invention have no obvious change when the hydrochloride crystal form I is placed under the conditions of high temperature (40 ℃ or 60 ℃), high humidity (25 ℃, RH 75% +/-5% or RH 90% +/-5%) and illumination. Therefore, the crystal form I of the hydrochloride has better stability under various lofting conditions and is suitable for pharmaceutical application.

EXAMPLE 7 hygroscopicity test of the salts according to the invention

A proper amount of a test sample (namely, the salt or the crystal form thereof) is taken, and the hygroscopicity of the test sample is tested by adopting a dynamic moisture adsorption instrument. According to experimental results, the hydrochloride crystal form is not easy to deliquesce under the influence of high humidity.

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. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.

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

1. A salt of a compound represented by the formula (I),

characterized in that the salt is hydrochloride; wherein the hydrochloride is hydrochloride form I, and the X-ray powder diffraction pattern of the hydrochloride form I has diffraction peaks at the following 2 theta angles: 10.36 ° ± 0.2 °,15.15 ° ± 0.2 °,18.40 ° ± 0.2 °,18.99 ° ± 0.2 °,19.67 ° ± 0.2 °,21.66 ° ± 0.2 °,23.12 ° ± 0.2 °,24.74 ° ± 0.2 °,28.13 ° ± 0.2 °,30.15 ° ± 0.2 °.

2. The salt of claim 1, wherein the hydrochloride salt form I has an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 7.81 plus or minus 0.2 degrees, 8.53 plus or minus 0.2 degrees, 10.36 plus or minus 0.2 degrees, 10.71 plus or minus 0.2 degrees, 12.38 plus or minus 0.2 degrees, 12.66 plus or minus 0.2 degrees, 14.71 plus or minus 0.2 degrees, 15.15 plus or minus 0.2 degrees, 15.62 plus or minus 0.2 degrees, 16.20 plus or minus 0.2 degrees, 17.13 plus or minus 0.2 degrees, 18.13 plus or minus 0.2 degrees, 18.40 plus or minus 0.2 degrees, 18.99 plus or minus 0.2 degrees, 19.27 plus or minus 0.2 degrees, 19.67 plus or minus 0.2 degrees, 19.99 plus or minus 0.2 degrees, 20.82 plus or minus 0.2 degrees, 21.14 plus or minus 0.2 degrees, 21.66 plus or minus 0.2 degrees, 22.60 plus or minus 0.2 degrees, 22.92 plus or minus 0.2 degrees, 23.12 plus or minus 0.2 degrees, 24.00 plus or minus 0.2 degrees, 24.41 plus or minus 0.2 degrees, 24.2 degrees, 21.2 degrees, 21.9 plus or minus 0.2 degrees, 21.2 degrees, 28 plus or minus 0.2 degrees, 28 plus or minus 0.2 degrees, 28.2 degrees, 0.2 degrees, 28 plus or minus 0.2 degrees, 28.2 degrees, 0.2 degrees, 9.2 degrees, 0.2 degrees, 28 plus or minus 0.2 degrees, 28.2 degrees, 28 plus or minus 0.2 degrees, 28 + -0.2 degrees, 9.2 degrees, 9 + -0.2 degrees, 28 + -0.2 degrees, 9 + -0.2 degrees, 0..

3. The salt of claim 1, wherein the hydrochloride salt form I has an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 7.81 plus or minus 0.2 degrees, 8.53 plus or minus 0.2 degrees, 10.36 plus or minus 0.2 degrees, 10.71 plus or minus 0.2 degrees, 12.38 plus or minus 0.2 degrees, 12.66 plus or minus 0.2 degrees, 14.71 plus or minus 0.2 degrees, 15.15 plus or minus 0.2 degrees, 15.62 plus or minus 0.2 degrees, 16.20 plus or minus 0.2 degrees, 17.13 plus or minus 0.2 degrees, 18.13 plus or minus 0.2 degrees, 18.40 plus or minus 0.2 degrees, 18.99 plus or minus 0.2 degrees, 19.27 plus or minus 0.2 degrees, 19.67 plus or minus 0.2 degrees, 19.99 plus or minus 0.2 degrees, 20.82 plus or minus 0.2 degrees, 21.14 plus or minus 0.2 degrees, 21.66 plus or minus 0.2 degrees, 22.60 plus or minus 0.2 degrees, 22.92 plus or minus 0.2 degrees, 23.12 plus or minus 0.2 plus or minus 2 degrees, 24.00 plus or minus 0.41 plus or minus 0.2 degrees, 28 plus or minus 0.2 degrees, 19.2 degrees, 21.2 plus or minus 0.2 degrees, 30 plus or minus 0.2 degrees, 19.2 degrees, 30 plus or minus 0.2 degrees, 9 plus or minus 0.2 degrees, 19.2 plus or minus 0.2 plus or minus 0.2.2 plus or minus 0.2, 9 plus or minus 0.2 plus or minus 0.2 degrees, 19.2 plus or minus 0.9 + -0.2 degrees, 19 + -0.9 + -0.2 degrees, 9 + -0.2 + -0.2.2 + -0.2 degrees, 19 + -0.2 degrees, 21.2 + -0.2 degrees, 21.2.2 + -0.2.2 degrees, 21.2 + -0.2.2.2 + -0.2 + -0.2.2 + -0.2 degrees, 9 + -0.2 degrees, 9 + -0.2 + -0.2.2 degrees, 9 + -0.2 degrees, 9 + -0.2.2.2 + -0.2.2 degrees, 9 + -0.2 degrees, 9 + -0.2 degrees, 9 + -0.2.2 + -0.2 degrees, 21.2 + -0.2.2 degrees, 9 + -0.2 degrees, 21.2.2 + -0.2.9 + -0.2 degrees, 9 + -.

4. The salt of any of claims 1-3, wherein the hydrochloride salt form I has an X-ray powder diffraction pattern substantially as shown in figure 1.

5. The salt of claim 1, wherein the hydrochloride salt is form I hydrochloride salt and wherein the differential scanning calorimetry trace of form I hydrochloride salt comprises an endothermic peak at 273.54 ℃ ± 3 ℃.

6. The salt of claim 5, wherein the hydrochloride salt form I has a differential scanning calorimetry trace substantially as shown in figure 5.

7. A pharmaceutical composition comprising a salt of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

8. Use of a salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the prevention, treatment or alleviation of central nervous system dysfunction.

9. The use according to claim 8, wherein the central nervous system dysfunction 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 symptoms from drug addiction or premenstrual tension syndrome.