CN113861184A - Phosphate of 2- (substituted pyrimidinyl) thiazole carboxamide compounds and uses thereof - Google Patents

Abstract

The present invention relates to phosphates of 2- (substituted pyrimidinyl) thiazole carboxamide compounds and their use. The invention also relates to a pharmaceutical composition containing the phosphate and application of the phosphate or the pharmaceutical composition in preparing a medicament for preventing, treating or relieving diseases related to central nervous system dysfunction, in particular depression.

Description

Phosphate of 2- (substituted pyrimidinyl) thiazole carboxamide compounds and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a phosphate of a 2- (substituted pyrimidinyl) thiazole carboxamide compound and application thereof, in particular to a phosphate of 2- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) -4-methylthiazole-5-carboxamide, a crystal form of the phosphate and application thereof, and further relates to a pharmaceutical composition containing the salt or the crystal form 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. 5-HT_1AThe receptor, a G protein-coupled receptor, is widely distributed in the region where 5-hydroxytryptamine derived from the nucleus of the midrift is accepted, and includes: 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 glutamate pathway (generated inside)Prefrontal cortex, pointing to the raphe nucleus), thereby indirectly reducing transport of 5-hydroxytryptamine (Jonathan Savitz, Irwin Lucki, Wayne c.dresets.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 the most harmful to human health. According to the report of Depression and Other Common Mental Disorders issued by the World Health Organization (WHO) in 2017, more than 3 hundred million people are expected to suffer from Depression worldwide, and the global average incidence rate is about 4.4%.

The traditional selective 5-hydroxytryptamine reuptake inhibitor SSRIs treats depression by increasing the level of 5-hydroxytryptamine by inhibiting reuptake of 5-hydroxytryptamine and regulating its transport. 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 for 5-HT_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 antagonist 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 SSRI 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 or different solid forms of the pharmaceutically active ingredient may have different properties. Different salts and/or solid forms may differ significantly in appearance, solubility, melting point, dissolution rate, bioavailability, etc., and may also have different effects on the stability, bioavailability, therapeutic efficacy, 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 2019062662A 1 discloses the compound 2- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) -4-methylthiazole-5-carboxamide (a compound of formula (I)) having selective 5-hydroxytryptamine reuptake inhibitory activity and/or 5-HT_1AThe receptor has the activity of stimulating and has potential antidepressant effect. However, none of the salts of the compound or its crystalline forms are disclosed in the prior art.

Disclosure of Invention

Through a large amount of experimental researches, the inventor finds that after the compound shown in the formula (I) and a proper acid form a salt, the preparation purity of the product is obviously improved, the physical properties and various properties are more suitable for industrial production, and the preparation development is more facilitated. The inventors have studied the salt formation process of the compound of formula (I) with different acids, the solid form of the obtained salt, its physicochemical properties and its pharmacological properties, and found that the compound does not necessarily form a stable salt when reacting with different acids, for example, the compound of formula (I) does not form a salt when reacting with acids commonly used in the art, such as maleic acid, citric acid, benzoic acid, etc., but the compound of formula (I) can combine with phosphoric acid to form a salt. Further research shows that the phosphate obtained by combining the compound and phosphoric acid has stable property, and the properties of all aspects can be greatly improved, particularly the phosphate crystal form K and/or the phosphate crystal form M have better properties such as stability and the like. Therefore, the phosphate crystal form K and/or the phosphate crystal form M of the compound shown in the formula (I) are better in property, have better pharmacokinetic property and further have better drugability.

In particular, the invention relates to a phosphate of a compound shown in formula (I), and application of the salt or a pharmaceutical composition containing the salt in preparing a medicament for preventing, treating or relieving central nervous system dysfunction, particularly depression. The phosphate is phosphate crystal form K or phosphate crystal form M. The crystalline forms of the present invention may also be in the form of a solvate, such as a hydrate, or a DMF solvate.

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

in some embodiments, the salt of the invention is a phosphate salt.

In some embodiments, the phosphate of the compound of formula (I) according to the present invention is phosphate form a1, phosphate form D, phosphate form F, phosphate form I, phosphate form J, phosphate form K, phosphate form L, phosphate form M, phosphate form N, or phosphate form O.

In other embodiments, the crystalline form D of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.54 ° ± 0.2 °,11.17 ° ± 0.2 °,15.61 ° ± 0.2 °,16.06 ° ± 0.2 °,16.73 ° ± 0.2 °,20.96 ° ± 0.2 °,22.67 ° ± 0.2 °,25.13 ° ± 0.2 °,26.84 ° ± 0.2 °.

In other embodiments, the crystalline form D of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.54 ° ± 0.2 °,11.17 ° ± 0.2 °,15.61 ° ± 0.2 °,16.06 ° ± 0.2 °,16.73 ° ± 0.2 °,18.96 ° ± 0.2 °,20.14 ° ± 0.2 °,20.96 ° ± 0.2 °,22.39 ° ± 0.2 °,22.67 ° ± 0.2 °,24.13 ° ± 0.2 °,25.13 ° ± 0.2 °,26.09 ° ± 0.2 °,26.84 ° ± 0.2 °,28.20 ° ± 0.2 °.

In other embodiments, the crystalline form D of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.54 ° ± 0.2 °,11.17 ° ± 0.2 °,13.41 ° ± 0.2 °,15.61 ° ± 0.2 °,16.06 ° ± 0.2 °,16.73 ° ± 0.2 °,18.28 ° ± 0.2 °,18.96 ° ± 0.2 °,19.80 ° ± 0.2 °,20.14 ° ± 0.2 °,20.96 ° ± 0.2 °,22.05 ° ± 0.2 °,22.39 ° ± 0.2 °,22.67 ° ± 0.2 °,24.13 ° ± 0.2 °,25.13 ° ± 0.2 °,26.09 ° ± 0.2 °,26.84 ° ± 0.2 °,27.34 ° ± 0.2 °,28.20 ° ± 0.2 °,28.57 ° ± 0.2 °,30.49 ° ± 0.2 °,31.73 ° ± 0.2.2 ° ± 0.2 °.

In still other embodiments, the crystalline form D of phosphate of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 1.

In other embodiments, a differential scanning calorimetry trace of form D phosphate according to the invention comprises endothermic peaks at 112.37 ℃ ± 3 ℃, 180.50 ℃ ± 3 ℃, 187.60 ℃ ± 3 ℃ and 243.85 ℃ ± 3 ℃.

In still other embodiments, the phosphate form D of the present invention has a differential scanning calorimetry trace substantially as shown in figure 2.

In other embodiments, the crystalline form F phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.55 degrees +/-0.2 degrees, 10.26 degrees +/-0.2 degrees, 11.21 degrees +/-0.2 degrees, 13.56 degrees +/-0.2 degrees, 16.09 degrees +/-0.2 degrees, 16.80 degrees +/-0.2 degrees, 18.39 degrees +/-0.2 degrees, 19.15 degrees +/-0.2 degrees, 21.26 degrees +/-0.2 degrees and 25.52 degrees +/-0.2 degrees.

In other embodiments, the crystalline form F phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.55 degrees +/-0.2 degrees, 10.26 degrees +/-0.2 degrees, 11.21 degrees +/-0.2 degrees, 12.39 degrees +/-0.2 degrees, 13.56 degrees +/-0.2 degrees, 14.21 degrees +/-0.2 degrees, 16.09 degrees +/-0.2 degrees, 16.80 degrees +/-0.2 degrees, 18.39 degrees +/-0.2 degrees, 19.15 degrees +/-0.2 degrees, 20.09 degrees +/-0.2 degrees, 20.35 degrees +/-0.2 degrees, 21.26 degrees +/-0.2 degrees, 22.71 degrees +/-0.2 degrees, 23.01 degrees +/-0.2 degrees, 25.52 degrees +/-0.2 degrees and 28.27 degrees +/-0.2 degrees.

In other embodiments, the crystalline form F phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.55 ° ± 0.2 °,10.26 ° ± 0.2 °,11.21 ° ± 0.2 °,12.39 ° ± 0.2 °,13.56 ° ± 0.2 °,14.21 ° ± 0.2 °,16.09 ° ± 0.2 °,16.80 ° ± 0.2 °,18.39 ° ± 0.2 °,19.02 ° ± 0.2 °,19.15 ° ± 0.2 °,20.09 ° ± 0.2 °,20.35 ° ± 0.2 °,21.26 ° ± 0.2 °,22.71 ° ± 0.2 °,23.01 ° ± 0.2 °,24.43 ° ± 0.2 °,25.52 ° ± 0.2 °,26.33 ° ± 0.2 °,26.93 ° ± 0.2 °,28.27 ° ± 0.2 °,30.67 ° ± 0.2 °.

In still other embodiments, the crystalline form F of phosphate of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 3.

In other embodiments, a differential scanning calorimetry trace of form F of the phosphate salt of the present invention comprises endothermic peaks at 183.85 ℃ ± 3 ℃ and 198.54 ℃ ± 3 ℃.

In other embodiments, a differential scanning calorimetry trace of form F of the phosphate salt of the present invention comprises endothermic peaks at 83.53 ℃ ± 3 ℃, 183.85 ℃ ± 3 ℃ and 198.54 ℃ ± 3 ℃.

In still other embodiments, the phosphate form F of the present invention has a differential scanning calorimetry trace substantially as shown in figure 4.

In other embodiments, the phosphate form I of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.61 ° ± 0.2 °,7.53 ° ± 0.2 °,11.27 ° ± 0.2 °,13.55 ° ± 0.2 °,15.14 ° ± 0.2 °,16.20 ° ± 0.2 °,16.68 ° ± 0.2 °,16.96 ° ± 0.2 °,18.43 ° ± 0.2 °,21.37 ° ± 0.2 °,25.45 ° ± 0.2 °.

In other embodiments, the phosphate form I of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.61 ° ± 0.2 °,7.53 ° ± 0.2 °,11.27 ° ± 0.2 °,13.55 ° ± 0.2 °,15.14 ° ± 0.2 °,16.20 ° ± 0.2 °,16.68 ° ± 0.2 °,16.96 ° ± 0.2 °,18.43 ° ± 0.2 °,18.93 ° ± 0.2 °,19.75 ° ± 0.2 °,21.37 ° ± 0.2 °,22.45 ° ± 0.2 °,22.68 ° ± 0.2 °,22.88 ° ± 0.2 °,25.45 ° ± 0.2 °,28.40 ° ± 0.2 °.

In other embodiments, the phosphate form I of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.61 ° ± 0.2 °,7.53 ° ± 0.2 °,11.27 ° ± 0.2 °,13.55 ° ± 0.2 °,15.14 ° ± 0.2 °,16.20 ° ± 0.2 °,16.68 ° ± 0.2 °,16.96 ° ± 0.2 °,18.43 ° ± 0.2 °,18.93 ° ± 0.2 °,19.23 ° ± 0.2 °,19.75 ° ± 0.2 °,20.38 ° ± 0.2 °,20.64 ° ± 0.2 °,21.37 ° ± 0.2 °,22.45 ° ± 0.2 °,22.68 ° ± 0.2 °,22.88 ° ± 0.2 °,24.61 ° ± 0.2 °,25.45 ° ± 0.2 °,25.94 ° ± 0.2 °,27.89 ° ± 0.2 °,28.40 ° ± 0.89 ° ± 0.2 °,30.62 ° ± 0.2 °.

In still other embodiments, the crystalline phosphate form I of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 5.

In other embodiments, a differential scanning calorimetry trace of form I of the phosphate salt of the present invention comprises endothermic peaks at 67.19 ℃ ± 3 ℃, 184.50 ℃ ± 3 ℃ and 195.90 ℃ ± 3 ℃.

In still other embodiments, the phosphate form I of the present invention has a differential scanning calorimetry trace substantially as shown in figure 6.

In other embodiments, the phosphate form J of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.78 ° ± 0.2 °,7.20 ° ± 0.2 °,11.00 ° ± 0.2 °,12.97 ° ± 0.2 °,16.88 ° ± 0.2 °,21.03 ° ± 0.2 °,21.49 ° ± 0.2 °,21.65 ° ± 0.2 °,28.74 ° ± 0.2 °.

In other embodiments, the phosphate form J of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.78 ° ± 0.2 °,7.20 ° ± 0.2 °,11.00 ° ± 0.2 °,12.97 ° ± 0.2 °,16.44 ° ± 0.2 °,16.88 ° ± 0.2 °,19.59 ° ± 0.2 °,21.03 ° ± 0.2 °,21.49 ° ± 0.2 °,21.65 ° ± 0.2 °,25.17 ° ± 0.2 °,25.36 ° ± 0.2 °,25.82 ° ± 0.2 °,26.09 ° ± 0.2 °,26.98 ° ± 0.2 °,28.74 ° ± 0.2 °.

In other embodiments, the phosphate form J of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.78 ° ± 0.2 °,7.20 ° ± 0.2 °,11.00 ° ± 0.2 °,12.97 ° ± 0.2 °,16.44 ° ± 0.2 °,16.88 ° ± 0.2 °,17.69 ° ± 0.2 °,19.59 ° ± 0.2 °,20.30 ° ± 0.2 °,21.03 ° ± 0.2 °,21.49 ° ± 0.2 °,21.65 ° ± 0.2 °,22.06 ° ± 0.2 °,22.71 ° ± 0.2 °,25.17 ° ± 0.2 °,25.36 ° ± 0.2 °,25.82 ° ± 0.2 °,26.09 ° ± 0.2 °,26.98 ° ± 0.2 °,28.74 ° ± 0.2 °,29.00 ° ± 0.2 °,38.90 ° ± 0.2 °.

In still other embodiments, the phosphate form J of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 7.

In other embodiments, a differential scanning calorimetry thermogram of form J of phosphate according to the present invention comprises endothermic peaks at 173.96 ℃ ± 3 ℃ and 246.36 ℃ ± 3 ℃.

In still other embodiments, the phosphate form J of the present invention has a differential scanning calorimetry trace substantially as shown in figure 8.

In other embodiments, the phosphate form K of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 8.55 degrees +/-0.2 degrees, 11.06 degrees +/-0.2 degrees, 12.92 degrees +/-0.2 degrees, 14.84 degrees +/-0.2 degrees, 15.08 degrees +/-0.2 degrees, 15.36 degrees +/-0.2 degrees, 16.81 degrees +/-0.2 degrees, 17.87 degrees +/-0.2 degrees, 19.02 degrees +/-0.2 degrees, 21.49 degrees +/-0.2 degrees, 23.19 degrees +/-0.2 degrees, 25.18 degrees +/-0.2 degrees and 25.35 degrees +/-0.2 degrees.

In other embodiments, the phosphate form K of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 8.55 ° ± 0.2 °,11.06 ° ± 0.2 °,12.92 ° ± 0.2 °,14.84 ° ± 0.2 °,15.08 ° ± 0.2 °,15.36 ° ± 0.2 °,16.81 ° ± 0.2 °,17.05 ° ± 0.2 °,17.87 ° ± 0.2 °,19.02 ° ± 0.2 °,21.49 ° ± 0.2 °,23.19 ° ± 0.2 °,25.18 ° ± 0.2 °,25.35 ° ± 0.2 °,26.25 ° ± 0.2 °,26.74 ° ± 0.2 °,27.74 ° ± 0.2 °.

In other embodiments, the phosphate form K of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 8.55 ° ± 0.2 °,11.06 ° ± 0.2 °,12.92 ° ± 0.2 °,13.22 ° ± 0.2 °,13.73 ° ± 0.2 °,14.84 ° ± 0.2 °,15.08 ° ± 0.2 °,15.36 ° ± 0.2 °,16.81 ° ± 0.2 °,17.05 ° ± 0.2 °,17.87 ° ± 0.2 °,18.33 ° ± 0.2 °,19.02 ° ± 0.2 °,19.47 ° ± 0.2 °,20.38 ° ± 0.2 °,20.90 ° ± 0.2 °,21.49 ° ± 0.2 °,22.46 ° ± 0.2 °,22.74 ° ± 0.2 °,23.19 ° ± 0.2 °,24.21 ° ± 0.2 °,25.18 ° ± 0.2 °,25.35 ° ± 0.2.26.2 ° ± 0.26 ° ± 0.2 °,22.74 ° ± 0.2 °, 0.2 ° ± 0.2 °,3 ° ± 0.2.2 °,24 ° ± 0.2.2.2 °, 2.2.28 ° ± 0.28 ° ± 0.3 ° ± 0.2 °, 25.28 ° ± 0.3 ° ± 0.2 °.

In still other embodiments, the phosphate form K of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 9.

In other embodiments, the differential scanning calorimetry trace of form K phosphate according to the present invention comprises an endothermic peak at 253.44 ℃ ± 3 ℃.

In still other embodiments, the phosphate form K of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 10.

In other embodiments, the thermogravimetric analysis of the phosphate form K of the present invention shows a weight loss of 1.821 ± 0.1% at around 200 ℃.

In still other embodiments, the phosphate form K of the present invention has a thermogravimetric analysis plot substantially as shown in figure 20.

In other embodiments, the crystalline phosphate form L of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.31 ° ± 0.2 °,11.24 ° ± 0.2 °,13.77 ° ± 0.2 °,13.94 ° ± 0.2 °,15.83 ° ± 0.2 °,16.00 ° ± 0.2 °,17.19 ° ± 0.2 °,20.46 ° ± 0.2 °,21.82 ° ± 0.2 °,22.58 ° ± 0.2 °,24.96 ° ± 0.2 °.

In other embodiments, the crystalline phosphate form L of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.31 ° ± 0.2 °,11.24 ° ± 0.2 °,13.77 ° ± 0.2 °,13.94 ° ± 0.2 °,15.57 ° ± 0.2 °,15.83 ° ± 0.2 °,16.00 ° ± 0.2 °,16.62 ° ± 0.2 °,17.19 ° ± 0.2 °,18.44 ° ± 0.2 °,18.73 ° ± 0.2 °,19.09 ° ± 0.2 °,19.52 ° ± 0.2 °,20.46 ° ± 0.2 °,21.82 ° ± 0.2 °,22.58 ° ± 0.2 °,24.96 ° ± 0.2 °,26.00 ° ± 0.2 °,34.93 ° ± 0.2 °.

In other embodiments, the crystalline phosphate form L of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.31 ° ± 0.2 °,11.24 ° ± 0.2 °,13.77 ° ± 0.2 °,13.94 ° ± 0.2 °,14.28 ° ± 0.2 °,14.95 ° ± 0.2 °,15.57 ° ± 0.2 °,15.83 ° ± 0.2 °,16.00 ° ± 0.2 °,16.62 ° ± 0.2 °,17.19 ° ± 0.2 °,18.44 ° ± 0.2 °,18.73 ° ± 0.2 °,19.09 ° ± 0.2 °,19.52 ° ± 0.2 °,19.80 ° ± 0.2 °,20.46 ° ± 0.2 °,20.80 ° ± 0.21 ° ± 0.2 °,22.30 ° ± 0.2 °,22.58 ° ± 0.2 °,23.10 ° ± 0.23.40 ° ± 0.2.2 ° ± 0.2 °, 20.24 ° ± 0.2.2 ° ± 0.2 °, 2.2 ° ± 0.2 °, 22.2.2 ° ± 0.2 °,22 ° ± 0.2.2 °,23.10 ° ± 0.3 ° ± 0.2 °, 2.3 ° ± 0.3 ° ± 0.2 °, 2.2.3 ° ± 0.2.2.2.2 °,2 °, 2.3 ° ± 0.3 ° ± 0.2.2 °, 2.3 ° ± 0.2 °,2 °, 2.2.2 ° ± 0.3 ° ± 0.2 °,3 ° ± 0.2.2.2 °,3 ° ± 0.2 °, 2.2.2 °,12 ° ± 0.2 °, 2.2.2 °,3 ° ± 0.2.2.2 °,3 ° ± 0.3 ° ± 0.2 °, 2.2.2.2.2.2.2 °,12 ° ± 0.2 °, 2.2 °,12 ° ± 0.2 °,2 °,3 ° ± 0.2 °,12 ° ± 0.2 °,3 ° ± 0.2.3 ° ± 0.2.2.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2.2 °,3 ° ± 0.2 °,12 ° ± 0.2.2.2.2.2.2 °,3 ° ± 0.3 ° ± 0.2 °,3 ° ± 0.2.2 °,3 ° ± 0.2.2.2.2.2 °,3 ° ± 0.2.2.3 ° ± 0.2.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2 °,3 ° ± 0.2.

In still other embodiments, the crystalline phosphate form L of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 11.

In other embodiments, a differential scanning calorimetry thermogram of crystalline phosphate form L of the present invention comprises endothermic peaks at 131.69 ℃ ± 3 ℃ and 184.98 ℃ ± 3 ℃.

In still other embodiments, the phosphate crystalline form L of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 12.

In other embodiments, the crystalline form M of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,8.91 ° ± 0.2 °,10.35 ° ± 0.2 °,12.23 ° ± 0.2 °,16.08 ° ± 0.2 °,19.36 ° ± 0.2 °,21.34 ° ± 0.2 °,22.42 ° ± 0.2 °,24.90 ° ± 0.2 °,26.14 ° ± 0.2 °.

In other embodiments, the crystalline form M of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,8.91 ° ± 0.2 °,10.35 ° ± 0.2 °,12.23 ° ± 0.2 °,15.74 ° ± 0.2 °,16.08 ° ± 0.2 °,16.32 ° ± 0.2 °,19.36 ° ± 0.2 °,21.34 ° ± 0.2 °,22.42 ° ± 0.2 °,24.90 ° ± 0.2 °,26.14 ° ± 0.2 °,29.36 ° ± 0.2 °,29.88 ° ± 0.2 °.

In other embodiments, the crystalline form M of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,8.91 ° ± 0.2 °,10.35 ° ± 0.2 °,12.23 ° ± 0.2 °,15.74 ° ± 0.2 °,16.08 ° ± 0.2 °,16.32 ° ± 0.2 °,19.36 ° ± 0.2 °,21.34 ° ± 0.2 °,22.42 ° ± 0.2 °,23.56 ° ± 0.2 °,24.04 ° ± 0.2 °,24.90 ° ± 0.2 °,26.14 ° ± 0.2 °,26.86 ° ± 0.2 °,27.41 ° ± 0.2 °,28.06 ° ± 0.2 °,29.36 ° ± 0.2 °,29.88 ° ± 0.2 °,30.19 ° ± 0.2 °,31.80 ° ± 0.2 °.

In still other embodiments, the crystalline phosphate form M of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 13.

In other embodiments, the differential scanning calorimetry trace of form M of the phosphate salt of the present invention comprises an endothermic peak at 132.05 ℃ ± 3 ℃.

In still other embodiments, the phosphate crystalline form M of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 14.

In some embodiments, the crystalline form M of phosphate salt of the present invention is a hydrate.

In other embodiments, the phosphate form M of the present invention loses 11.79% weight at about 100 ℃ with a margin of error of ± 0.1%.

In still other embodiments, the crystalline form M of phosphate salt of the present invention has a thermogravimetric analysis substantially as shown in figure 21.

In other embodiments, the crystalline form N of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.88 ° ± 0.2 °,13.25 ° ± 0.2 °,16.47 ° ± 0.2 °,16.76 ° ± 0.2 °,17.75 ° ± 0.2 °,19.16 ° ± 0.2 °,19.39 ° ± 0.2 °,20.93 ° ± 0.2 °,21.25 ° ± 0.2 °,23.47 ° ± 0.2 °,24.24 ° ± 0.2 °.

In other embodiments, the crystalline form N of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.88 ° ± 0.2 °,13.25 ° ± 0.2 °,13.92 ° ± 0.2 °,16.47 ° ± 0.2 °,16.76 ° ± 0.2 °,17.38 ° ± 0.2 °,17.75 ° ± 0.2 °,19.16 ° ± 0.2 °,19.39 ° ± 0.2 °,20.93 ° ± 0.2 °,21.25 ° ± 0.2 °,21.75 ° ± 0.2 °,22.52 ° ± 0.2 °,23.47 ° ± 0.2 °,24.24 ° ± 0.2 °,27.30 ° ± 0.2 °.

In other embodiments, the crystalline form N of phosphate according to the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 10.88 ° ± 0.2 °,13.25 ° ± 0.2 °,13.92 ° ± 0.2 °,16.47 ° ± 0.2 °,16.76 ° ± 0.2 °,17.38 ° ± 0.2 °,17.75 ° ± 0.2 °,19.16 ° ± 0.2 °,19.39 ° ± 0.2 °,19.76 ° ± 0.2 °,20.23 ° ± 0.2 °,20.93 ° ± 0.2 °,21.25 ° ± 0.2 °,21.75 ° ± 0.2 °,22.52 ° ± 0.2 °,23.47 ° ± 0.2 °,24.24 ° ± 0.2 °,24.71 ° ± 0.2 °,25.74 ° ± 0.2 °,26.20 ° ± 0.2 °,27.30 ° ± 0.2 °,27.75 ° ± 0.29.03 ° ± 0.2.2 ° ± 0.36 ° ± 0.2 °, 352.2 ° ± 0.2 °,2 ° ± 0.38 ° ± 0.2 °.

In still other embodiments, the crystalline phosphate form N of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 15.

In other embodiments, the differential scanning calorimetry trace of form N of the phosphate salt of the present invention comprises endothermic peaks at 176.43 ℃ ± 3 ℃ and 220.95 ℃ ± 3 ℃.

In still other embodiments, the phosphate form N of the present invention has a differential scanning calorimetry pattern substantially as shown in figure 16.

In other embodiments, the phosphate form O of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.75 ° ± 0.2 °,10.63 ° ± 0.2 °,10.94 ° ± 0.2 °,16.05 ° ± 0.2 °,16.77 ° ± 0.2 °,19.02 ° ± 0.2 °,19.47 ° ± 0.2 °,20.12 ° ± 0.2 °,20.74 ° ± 0.2 °,21.42 ° ± 0.2 °,23.22 ° ± 0.2 °,25.72 ° ± 0.2 °.

In other embodiments, the phosphate form O of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.75 ° ± 0.2 °,6.95 ° ± 0.2 °,10.63 ° ± 0.2 °,10.94 ° ± 0.2 °,12.46 ° ± 0.2 °,12.86 ° ± 0.2 °,13.94 ° ± 0.2 °,15.66 ° ± 0.2 °,16.05 ° ± 0.2 °,16.77 ° ± 0.2 °,19.02 ° ± 0.2 °,19.47 ° ± 0.2 °,20.12 ° ± 0.2 °,20.74 ° ± 0.2 °,21.42 ° ± 0.2 °,23.22 ° ± 0.2 °,25.72 ° ± 0.2 °,26.85 ° ± 0.2 °,27.22 ° ± 0.2 °.

In other embodiments, the phosphate form O of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.75 ° ± 0.2 °,6.95 ° ± 0.2 °,10.63 ° ± 0.2 °,10.94 ° ± 0.2 °,12.46 ° ± 0.2 °,12.86 ° ± 0.2 °,13.94 ° ± 0.2 °,15.66 ° ± 0.2 °,16.05 ° ± 0.2 °,16.77 ° ± 0.2 °,19.02 ° ± 0.2 °,19.47 ° ± 0.2 °,20.12 ° ± 0.2 °,20.74 ° ± 0.2 °,21.42 ° ± 0.2 °,22.60 ° ± 0.2 °,23.22 ° ± 0.2 °,23.88 ° ± 0.2 °,25.03 ° ± 0.2 °,25.72 ° ± 0.2 °,26.85 ° ± 0.2 °,27.22 ° ± 0.2 °,28.08 ° ± 0.2 ± 0.63 ° ± 0.2 °, 25.19 ° ± 0.2 °,2 ° ± 0.19 ° ± 0.2 °,26.2 °,27.22 ° ± 0.2 °,27.2 °, 28.2.2 °,28.2 ° ± 0.2 °, 30.2 ° ± 0.2 °.

In still other embodiments, the crystalline phosphate form O of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 17.

In other embodiments, the differential scanning calorimetry trace of the phosphate form O of the present invention comprises an endothermic peak at 183.10 ± 3 ℃.

In still other embodiments, the phosphate form O of the present invention has a differential scanning calorimetry trace substantially as shown in figure 18.

In other embodiments, the phosphate form a1 of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.67 ° ± 0.2 °,7.23 ° ± 0.2 °,11.22 ° ± 0.2 °,12.55 ° ± 0.2 °,16.12 ° ± 0.2 °,17.16 ° ± 0.2 °,21.35 ° ± 0.2 °,25.45 ° ± 0.2 °.

In other embodiments, the phosphate form a1 of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.67 ° ± 0.2 °,7.23 ° ± 0.2 °,11.22 ° ± 0.2 °,12.55 ° ± 0.2 °,16.12 ° ± 0.2 °,17.16 ° ± 0.2 °,21.35 ° ± 0.2 °,21.96 ° ± 0.2 °,24.56 ° ± 0.2 °,25.45 ° ± 0.2 °,27.69 ° ± 0.2 °,28.41 ° ± 0.2 °.

In other embodiments, the phosphate form a1 of the present invention has an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 5.67 ° ± 0.2 °,7.23 ° ± 0.2 °,11.22 ° ± 0.2 °,12.55 ° ± 0.2 °,13.64 ° ± 0.2 °,14.43 ° ± 0.2 °,16.12 ° ± 0.2 °,17.16 ° ± 0.2 °,19.71 ° ± 0.2 °,20.49 ° ± 0.2 °,21.35 ° ± 0.2 °,21.96 ° ± 0.2 °,22.94 ° ± 0.2 °,24.56 ° ± 0.2 °,25.45 ° ± 0.2 °,27.69 ° ± 0.2 °,28.41 ° ± 0.2 °.

In still other embodiments, the phosphate form a1 of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 19.

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

In one aspect, the invention relates to the use of said phosphate 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 phosphate or a crystalline form thereof or said pharmaceutical composition for the preparation of a medicament, said medicamentThe compounds are useful as selective 5-hydroxytryptamine reuptake inhibitors and/or 5-HT_1AA receptor agonist.

In one 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 method for producing the salt and/or crystal 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 show that the phosphate crystal form K and the phosphate crystal form M have unexpected technical advantages: the phosphate crystal form K or the phosphate crystal form M has better pharmacokinetic property; meanwhile, the phosphate crystal form K and the phosphate crystal form M have particularly good stability, for example, the phosphate crystal form K and the phosphate crystal form M are stirred in water at room temperature or under a heating condition, the crystal form structures are not changed, and therefore, the crystal forms are suitable for process production and easy to store.

In addition, phosphate form K and phosphate form M have further advantages: compared with other forms of phosphate such as forms D, I, L and O, forms K and M are substantially free of solvent residues, and TGA detection shows that: phosphate form K has a weight loss of about 1.821% when heated to 200 ℃; and the phosphate form M had a weight loss of about 11.79% when heated to 100 ℃, which was substantially consistent with karl fischer moisture test 10.16%; that is, phosphate form K is anhydrous and phosphate form M is a hydrate.

Therefore, the phosphate crystal form K and/or the phosphate crystal form M have good biological activity and stability, and the crystal form K and the crystal form M have no solvent residue basically, so that the phosphate crystal form K and/or the phosphate crystal form M are 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.

"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, ethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"solvate" refers to a compound having a solvent on a surface, in a crystal lattice, or on a surface 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, N-butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, N-heptane, N-hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, ethylene 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 in rangeUnder the control of sequence, the sample and the inert reference substance (commonly used alpha-Al) are measured by continuously heating or cooling₂O₃) 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" 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 figure.

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 salts of the compounds of formula (I) 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 (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 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 is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used 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. Annu 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, the use of carriers in the art is contemplated.

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 present invention relates to a process for the preparation of a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof; the process includes mixing the various 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, e.g., 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 adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.

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 pharmaceutical compositions therewith.

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 of the active ingredient. The therapeutically effective amount of the compound, salt of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the disease (disorder) or illness (disease) 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, and the pharmaceutical composition thereof should provide a dose of the compound of from 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, or from about 10mg to about 1,000mg of the principal active ingredient or 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 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, but are in no way limited to, in preventing, treating or alleviating central nervous system dysfunctional disorders by administering to a patient an effective amount of a salt or composition of the compounds of the present invention. The dysfunctional central nervous system diseases responsive to 5-hydroxytryptamine receptor modulation further include, but are not limited to, depression, anxiety, mania, schizophrenia, sleep disorders, bipolar disorder, 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, premenstrual tension syndrome, and the like.

Salts and pharmaceutical compositions of the compounds of the invention are useful in veterinary therapy for pets, animals of the introductory variety and mammals in farm animals, in addition to human therapy. Examples of other animals include horses, dogs, and cats.

Drawings

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

FIG. 2 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form D of the compound of formula (I).

Figure 3 is an X-ray powder diffraction (XRPD) pattern of phosphate form F of the compound of formula (I).

FIG. 4 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form F of the compound of formula (I).

Figure 5 is an X-ray powder diffraction (XRPD) pattern of the phosphate form I of the compound of formula (I).

FIG. 6 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form I of the compound of formula (I).

Figure 7 is an X-ray powder diffraction (XRPD) pattern of phosphate form J of the compound of formula (I).

FIG. 8 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form J of the compound of formula (I).

Figure 9 is an X-ray powder diffraction (XRPD) pattern of phosphate form K of the compound of formula (I).

FIG. 10 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form K of the compound of formula (I).

Figure 11 is an X-ray powder diffraction (XRPD) pattern of the phosphate form L of the compound of formula (I).

FIG. 12 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form L of the compound of formula (I).

Figure 13 is an X-ray powder diffraction (XRPD) pattern of phosphate form M of the compound of formula (I).

FIG. 14 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form M of the compound of formula (I).

Figure 15 is an X-ray powder diffraction (XRPD) pattern of phosphate form N of the compound of formula (I).

FIG. 16 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form N of the compound of formula (I).

Figure 17 is an X-ray powder diffraction (XRPD) pattern of phosphate form O of the compound of formula (I).

FIG. 18 is a Differential Scanning Calorimetry (DSC) profile of the phosphate form O of the compound of formula (I).

Figure 19 is an X-ray powder diffraction (XRPD) pattern of phosphate form a1 of the compound of formula (I).

FIG. 20 is a thermogravimetric analysis (TGA) plot of the phosphate crystalline form K of the compound of formula (I).

FIG. 21 is a thermogravimetric analysis (TGA) plot of the phosphate crystalline form M of the compound of formula (I).

Fig. 22 is a comparison of the X-ray powder diffraction pattern of the phosphate form L of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

Fig. 23 is a comparison of the X-ray powder diffraction pattern of the phosphate form N of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

FIG. 24 is a comparison of the X-ray powder diffraction pattern of the phosphate form O of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

Figure 25 is a comparison of the X-ray powder diffraction pattern of the phosphate form D of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

FIG. 26 is a comparison of the X-ray powder diffraction pattern of the phosphate form I of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

Figure 27 is a comparison of the X-ray powder diffraction pattern of the phosphate form J of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

Fig. 28 is a comparison of the X-ray powder diffraction pattern of the phosphate form K of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

Fig. 29 is a comparison of the X-ray powder diffraction pattern of the phosphate form M of the compound of formula (I) after stirring in water for 24h at room temperature with the X-ray powder diffraction pattern before stirring.

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. Preparing a powdery sample into a thin layer on a monocrystalline silicon sample holder or a domestic silicon wafer, placing the thin layer on a rotary sample table, and analyzing in a step length of 0.0167 DEG within the range of 3-40 DEG or 3-60 deg. Data Collector software was used to collect Data, HighScore Plus software processed the Data, and Data Viewer software read the Data. It is noted that the XRPD pattern of the test sample, when tested using a silicon wafer made in China, exhibited a diffraction peak at 32.97 deg., which is the background peak.

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.

The Thermal Gravimetric Analysis (TGA) method used in the invention is as follows: the thermogravimetric loss was performed using a TA Q500 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10mg of sample was accurately weighed into a platinum sample pan and sample analysis was performed from room temperature to approximately 350 ℃ using a 10 ℃/minute linear heating device. During use, the TGA furnace chamber was purged with dry nitrogen.

Detailed description of the invention

A specific synthesis of 2- (2- (4- (3- (5-cyano-1H-indol-3-yl) propyl) piperazin-1-yl) pyrimidin-5-yl) -4-methylthiazole-5-carboxamide, the compound of formula (I) in free form, is described in example 8 of International application WO 2019062662A 1.

Examples

Example 1 phosphate form a1 of the present invention

1. Preparation of phosphate form A1

A250 mL round-bottom flask was charged with the compound represented by the formula (I) in free form (2.01g) and DMF (40mL), and the mixture was dissolved with stirring at room temperature, and 1mmol/mL aqueous phosphoric acid (4.8mL) and acetone (50mL) were added and the mixture was stirred at room temperature for 24 hours to precipitate a large amount of solid. And (4) carrying out suction filtration, and carrying out vacuum drying on the solid to obtain a light yellow solid with the yield of about 85 percent, namely the phosphate crystal form A1.

2. Characterization of phosphate form a1

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.67 °,7.23 °,11.22 °,12.55 °,13.64 °,14.43 °,16.12 °,17.16 °,19.71 °,20.49 °,21.35 °,21.96 °,22.94 °,24.56 °,25.45 °,27.69 °,28.41 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of phosphate form a1 prepared according to the method of example 1 of the present invention is substantially as shown in figure 19.

Example 2 phosphate form D of the invention

1. Preparation of phosphate form D

Phosphate form A1(502.50mg) of the compound of formula (I) and N, N-dimethylacetamide (5mL) were added in this order to a 25mL round-bottomed flask, and the mixture was suspended and stirred at 50 ℃ for 24 hours. After suction filtration, vacuum drying is carried out at 50 ℃ to obtain a light yellow solid, the yield is about 88 percent, and the light yellow solid is phosphate crystal form D.

2. Characterization of phosphate form D

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.54 °,11.17 °,13.41 °,15.61 °,16.06 °,16.73 °,18.28 °,18.96 °,19.80 °,20.14 °,20.96 °,22.05 °,22.39 °,22.67 °,24.13 °,25.13 °,26.09 °,26.84 °,27.34 °,28.20 °,28.57 °,30.49 °,31.73 °,32.65 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of the phosphate form D prepared according to the method of example 2 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 endothermic peaks at 112.37 ℃, 180.50 ℃, 187.60 ℃ and 243.85 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate form D prepared according to the method of example 2 of the present invention is substantially as shown in fig. 2.

Example 3 phosphate form F of the invention

1. Preparation of phosphate form F

Phosphate form a1(100.50mg) of the compound of formula (I) and DMF (3mL) were added to a round bottom flask, stirred and dissolved at room temperature, and rotary evaporated at 60 ℃ under reduced pressure to give a pale yellow solid with about 88% yield as phosphate form F.

2. Characterization of phosphate form F

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.55 degrees, 10.26 degrees, 11.21 degrees, 12.39 degrees, 13.56 degrees, 14.21 degrees, 16.09 degrees, 16.80 degrees, 18.39 degrees, 19.02 degrees, 19.15 degrees, 20.09 degrees, 20.35 degrees, 21.26 degrees, 22.71 degrees, 23.01 degrees, 24.43 degrees, 25.52 degrees, 26.33 degrees, 26.93 degrees, 28.27 degrees, 30.67 degrees, and error tolerance of +/-0.2 degrees exists. Specifically, the XRPD pattern of the phosphate form F prepared according to the invention as in example 3 is substantially as shown in figure 3.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 83.53 ℃, 183.85 ℃ and 198.54 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate form F prepared according to the method of example 3 of the present invention is substantially as shown in fig. 4.

Example 4 phosphate form I of the invention

1. Preparation of phosphate form I

The phosphate form A1 of the compound of formula (I) (501.50mg) and tetrahydrofuran (15mL) were added sequentially in a 50mL round bottom flask and suspended and stirred at 65 ℃ for 24 h. And (4) carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain a light yellow solid with the yield of about 80 percent, wherein the light yellow solid is the phosphate crystal form I.

2. Characterization of phosphate form I

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.61 °,7.09 °,7.53 °,11.27 °,13.55 °,15.14 °,16.20 °,16.68 °,16.96 °,18.43 °,18.93 °,19.23 °,19.75 °,20.38 °,20.64 °,21.37 °,22.45 °,22.68 °,22.88 °,24.61 °,25.45 °,25.94 °,27.89 °,28.40 °,29.89 °,30.62 °, with an error tolerance of ± 0.2 °. Specifically, the XRPD pattern of the phosphate form I prepared according to the invention as in example 4 is substantially as shown in figure 5.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 67.19 ℃, 184.50 ℃ and 195.90 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate form I prepared according to the method of example 4 of the present invention is substantially as shown in fig. 6.

Example 5 phosphate form J of the invention

1. Preparation of phosphate form J

The phosphate form A1 of the compound of formula (I) (50.50mg) and sec-butanol (1mL) were added sequentially to a round bottom flask and suspended and stirred at 80 ℃ for 24 h. And (4) carrying out suction filtration and vacuum drying at 50 ℃ to obtain a light yellow solid which is a phosphate crystal form J.

2. Characterization of phosphate form J

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.78 °,7.20 °,11.00 °,12.97 °,16.44 °,16.88 °,17.69 °,19.59 °,20.30 °,21.03 °,21.49 °,21.65 °,22.06 °,22.71 °,25.17 °,25.36 °,25.82 °,26.09 °,26.98 °,28.74 °,29.00 °,38.90 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of phosphate form J prepared according to the method of example 5 of the present invention is substantially as shown in figure 7.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 173.96 ℃ and 246.36 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of form J of phosphate prepared according to the method of example 5 of the present invention is substantially as shown in figure 8.

Example 6 phosphate form K of the invention

1. Preparation of phosphate form K

The phosphate form A1 of the compound of formula (I) (500.50mg) and butyl formate (10mL) were added sequentially to a 25mL round bottom flask and suspended and stirred at 80 ℃ for 48 h. Filtering, and vacuum drying at 50 ℃ to obtain a light yellow solid which is phosphate crystal form K with the yield of about 86%.

2. Characterization of phosphate form K

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 8.55 °,11.06 °,12.92 °,13.22 °,13.73 °,14.84 °,15.08 °,15.36 °,16.81 °,17.05 °,17.87 °,18.33 °,19.02 °,19.47 °,20.38 °,20.90 °,21.49 °,22.46 °,22.74 °,23.19 °,24.21 °,25.18 °,25.35 °,26.25 °,26.74 °,27.46 °,27.74 °,28.24 °,28.86 °,31.48 °,32.53 °,33.80 °,36.20 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of phosphate form K prepared according to the method of example 6 of the present invention is substantially as shown in figure 9.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 253.44 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate form K prepared according to the method of example 6 of the present invention is substantially as shown in fig. 10.

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/min, the weight loss is 1.821 percent at about 200 ℃, and the error tolerance of +/-0.1 percent exists. Specifically, the TGA profile of phosphate form K prepared according to the method of example 6 of the present invention is substantially as shown in figure 20.

Example 7 crystalline phosphate form L of the invention

1. Preparation of phosphate form L

The phosphate form A1 of the compound of formula (I) (500.50mg) and N-methylpyrrolidone (NMP,7mL) were added sequentially to a 50mL round bottom flask, dissolved with stirring at 60 deg.C, water (10mL) as an anti-solvent was added, and stirring continued at room temperature for 24 h. And (4) carrying out suction filtration, and carrying out vacuum drying at 50 ℃ to obtain a light yellow solid which is a phosphate crystal form L, wherein the yield is about 89%.

2. Characterization of phosphate form L

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.31 °,11.24 °,13.77 °,13.94 °,14.28 °,14.95 °,15.57 °,15.83 °,16.00 °,16.62 °,17.19 °,18.44 °,18.73 °,19.09 °,19.52 °,19.80 °,20.46 °,20.80 °,21.82 °,22.30 °,22.58 °,23.10 °,23.40 °,24.15 °,24.96 °,25.35 °,25.69 °,26.00 °,26.75 °,27.63 °,28.48 °,28.77 °,29.73 °,30.61 °,31.75 °,33.71 °,34.21 °,34.93 °,39.80 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of the crystalline form L of phosphate prepared according to the method of example 7 of the present invention is substantially as shown in figure 11.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 131.69 ℃ and 184.98 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate crystalline form L prepared according to the method of example 7 of the present invention is substantially as shown in fig. 12.

Example 8 phosphate form M of the invention

1. Preparation of phosphate form M

The phosphate form A1 of the compound of formula (I) (500.50mg) and N-methylpyrrolidone (NMP,7mL) were added sequentially to a 50mL round bottom flask, dissolved with stirring at 60 deg.C, water (10mL) as an anti-solvent was added, and stirring continued at room temperature for 24 h. Suction filtration and vacuum drying were carried out, and water (10mL) was added to the dried solid, followed by stirring at room temperature for 24 hours. And (4) carrying out suction filtration and drying to obtain a light yellow solid which is a phosphate crystal form M with the yield of about 91%.

2. Characterization of phosphate form M

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 6.12 °,8.91 °,10.35 °,12.23 °,15.74 °,16.08 °,16.32 °,19.36 °,21.34 °,22.42 °,23.56 °,24.04 °,24.90 °,26.14 °,26.86 °,27.41 °,28.06 °,29.36 °,29.88 °,30.19 °,31.80 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of the phosphate form M prepared according to the invention as in example 8 is substantially as shown in figure 13.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 132.05 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate form M prepared according to the method of example 8 of the present invention is substantially as shown in figure 14.

(3) Thermogravimetric analysis (TGA) identification by TA Q500: the heating rate is 10 ℃/minute, the weight loss is 11.79 percent at about 100 ℃, and the error tolerance of +/-0.1 percent exists. Specifically, the TGA profile of the crystalline form M of phosphate salt prepared according to the method of example 8 of the present invention is substantially as shown in figure 21.

Example 9 phosphate form N of the invention

1. Preparation of phosphate crystal form N

To a 10mL round bottom flask was added phosphate form A1 of compound of formula (I) (500.50mg) followed by trifluoroethanol (10mL) and suspended and stirred at 50 ℃ for 24 h. And (4) carrying out suction filtration, and drying at 50 ℃ to obtain a light yellow solid which is phosphate crystal form N with the yield of about 85%.

2. Characterization of phosphate form N

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 10.88 °,13.25 °,13.92 °,16.47 °,16.76 °,17.38 °,17.75 °,19.16 °,19.39 °,19.76 °,20.23 °,20.93 °,21.25 °,21.75 °,22.52 °,23.47 °,24.24 °,24.71 °,25.74 °,26.20 °,27.30 °,27.75 °,29.03 °,31.36 °,32.38 °,36.17 °,38.92 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of phosphate form N prepared according to the method of example 9 of the present invention is substantially as shown in figure 15.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 176.43 ℃ and 220.95 ℃, with a margin of error of ± 3 ℃. Specifically, the DSC diagram of the phosphate crystal form N prepared according to the method of example 9 of the present invention is substantially as shown in fig. 16.

Example 10 phosphate form O of the invention

1. Preparation of phosphate form O

The phosphate form A1 of compound of formula (I) (500.50mg) and isopropanol (10mL) were added sequentially in a 25mL round bottom flask and suspended with stirring at 50 ℃. And (4) carrying out suction filtration, and drying at 50 ℃ to obtain a light yellow solid which is phosphate crystal form O, wherein the yield is about 82%.

2. Characterization of phosphate form O

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, comprising the following diffraction peaks expressed in angle 2 θ: 5.75 °,6.95 °,10.63 °,10.94 °,12.46 °,12.86 °,13.94 °,15.66 °,16.05 °,16.77 °,19.02 °,19.47 °,20.12 °,20.74 °,21.42 °,22.60 °,23.22 °,23.88 °,25.03 °,25.72 °,26.85 °,27.22 °,28.08 °,28.63 °,29.19 °,30.47 °,32.05 °,33.10 °,34.30 °,37.30 °,38.15 °, with a tolerance of ± 0.2 °. Specifically, the XRPD pattern of phosphate form O prepared according to the method of example 10 of the present invention is substantially as shown in figure 17.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 183.10 ℃, with a margin of error of ± 3 ℃. Specifically, a DSC diagram of the phosphate form O prepared according to the method of example 10 of the present invention is substantially as shown in figure 18.

EXAMPLE 11 pharmacokinetic experiments on the salts of the invention

The test samples were encapsulated for oral administration.

3 male Beagle dogs (8-12 kg) were orally administered to 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 experimental results are as follows: the crystal forms of the phosphate, particularly the crystal form F, the crystal form K and/or the crystal form M, have good pharmacokinetic properties.

Example 12 stability test of salts according to the invention

1. Stability test experiment A

At room temperature, weighing samples to be detected (50mg) in an EP tube respectively, adding water (1mL), suspending and stirring at room temperature for 24h, filtering, drying, and then carrying out X-ray powder diffraction (XRPD) analysis and identification respectively. Wherein the experimental results of the phosphate crystal form D, I, J, K, L, M, N and O of the present invention are shown in FIGS. 22-29.

As can be seen from fig. 22-29, the phosphate crystal form K and the phosphate crystal form M of the present invention are not changed when stirred in water at room temperature, while the other crystal forms, such as the phosphate crystal form D, I, J, L, N and O, are also changed when stirred in water. Namely, the phosphate crystal form K and the phosphate crystal form M have stable crystal structures and are suitable for industrial production and preparation development.

2. Stability test experiment B

(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: and observing the color change of the sample, detecting the purity of the sample by HPLC, and detecting the crystal structure of the sample by XRPD.

(2)High humidity experiment: taking a proper amount of a test sample, placing 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 at 25 ℃ under the condition of RH 90% +/-5%, sampling for 5 days, 10 days and 30 days, detecting according to a stability key examination item, observing the color change of the sample, detecting the purity of the sample by HPLC, and detecting the crystal structure of the sample by XRPD.

(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, observing color change of the sample, detecting purity of the sample by HPLC, and detecting crystal structure of the sample by XRPD.

The experimental results are as follows: after being respectively placed under the conditions of high temperature (40 ℃ or 60 ℃), high humidity (25 ℃, RH 90% +/-5%) and illumination for 30 days, the appearance and the purity of the phosphate crystal form K and the phosphate crystal form M of the invention have no obvious change; at the same time, the XRPD patterns of the phosphate form K and the phosphate form M are also substantially unchanged. Namely, the phosphate crystal form K and/or the phosphate crystal form M have good stability under various lofting conditions, and are suitable for pharmaceutical use.

EXAMPLE 13 hygroscopicity test of the salts according to the invention

The experimental method comprises the following steps:

1) the dried glass weighing bottle with stopper was placed in a suitable thermostatic desiccator at 25 ℃. + -. 1 ℃ the day before, and precision weighed (m 1).

2) And taking a proper amount of the test sample, flatly paving the test sample in the weighing bottle, wherein the thickness of the test sample is about 1mm, and precisely weighing (m 2).

3) The weighing bottle is opened and is placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.

4) The weighing bottle cap is closed, precision weighing (m3) is performed, and the following calculation is performed: percent weight gain ═ m3-m2)/(m2-m1) × 100%.

5) And (4) judging the moisture absorption result:

the experimental results are as follows: the phosphate crystal form K and the phosphate crystal form M are 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. 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 (10)

1. A phosphate salt of a compound of formula (I),

2. the phosphate according to claim 1, characterized in that the phosphate is phosphate form F, phosphate form K or phosphate form M, wherein,

the X-ray powder diffraction pattern of the crystalline form F of the halophosphate has diffraction peaks at the following 2 Θ angles: 5.55 ° ± 0.2 °,10.26 ° ± 0.2 °,11.21 ° ± 0.2 °,13.56 ° ± 0.2 °,16.09 ° ± 0.2 °,16.80 ° ± 0.2 °,18.39 ° ± 0.2 °,19.15 ° ± 0.2 °,21.26 ° ± 0.2 °,25.52 ° ± 0.2 °;

the X-ray powder diffraction pattern of the crystalline form K of the halophosphate has diffraction peaks at the following 2 Θ angles: 8.55 ° ± 0.2 °,11.06 ° ± 0.2 °,12.92 ° ± 0.2 °,14.84 ° ± 0.2 °,15.08 ° ± 0.2 °,15.36 ° ± 0.2 °,16.81 ° ± 0.2 °,17.87 ° ± 0.2 °,19.02 ° ± 0.2 °,21.49 ° ± 0.2 °,23.19 ° ± 0.2 °,25.18 ° ± 0.2 °,25.35 ° ± 0.2 °;

the X-ray powder diffraction pattern of the crystalline form M of the halophosphate salt has diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,8.91 ° ± 0.2 °,10.35 ° ± 0.2 °,12.23 ° ± 0.2 °,16.08 ° ± 0.2 °,19.36 ° ± 0.2 °,21.34 ° ± 0.2 °,22.42 ° ± 0.2 °,24.90 ° ± 0.2 °,26.14 ° ± 0.2 °.

3. The phosphate salt of claim 2, wherein the salt phosphate form F has an X-ray powder diffraction pattern having diffraction peaks at the following 2 θ angles: 5.55 ° ± 0.2 °,10.26 ° ± 0.2 °,11.21 ° ± 0.2 °,12.39 ° ± 0.2 °,13.56 ° ± 0.2 °,14.21 ° ± 0.2 °,16.09 ° ± 0.2 °,16.80 ° ± 0.2 °,18.39 ° ± 0.2 °,19.15 ° ± 0.2 °,20.09 ° ± 0.2 °,20.35 ° ± 0.2 °,21.26 ° ± 0.2 °,22.71 ° ± 0.2 °,23.01 ° ± 0.2 °,25.52 ° ± 0.2 °,28.27 ° ± 0.2 °;

the phosphate form K has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.55 ° ± 0.2 °,11.06 ° ± 0.2 °,12.92 ° ± 0.2 °,14.84 ° ± 0.2 °,15.08 ° ± 0.2 °,15.36 ° ± 0.2 °,16.81 ° ± 0.2 °,17.05 ° ± 0.2 °,17.87 ° ± 0.2 °,19.02 ° ± 0.2 °,21.49 ° ± 0.2 °,23.19 ° ± 0.2 °,25.18 ° ± 0.2 °,25.35 ° ± 0.2 °,26.25 ° ± 0.2 °,26.74 ° ± 0.2 °,27.74 ° ± 0.2 °;

the X-ray powder diffraction pattern of the crystalline form M of the halophosphate salt has diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,8.91 ° ± 0.2 °,10.35 ° ± 0.2 °,12.23 ° ± 0.2 °,15.74 ° ± 0.2 °,16.08 ° ± 0.2 °,16.32 ° ± 0.2 °,19.36 ° ± 0.2 °,21.34 ° ± 0.2 °,22.42 ° ± 0.2 °,24.90 ° ± 0.2 °,26.14 ° ± 0.2 °,29.36 ° ± 0.2 °,29.88 ° ± 0.2 °.

4. The phosphate salt of claim 2 or 3, wherein the salt phosphate form F has an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 5.55 ° ± 0.2 °,10.26 ° ± 0.2 °,11.21 ° ± 0.2 °,12.39 ° ± 0.2 °,13.56 ° ± 0.2 °,14.21 ° ± 0.2 °,16.09 ° ± 0.2 °,16.80 ° ± 0.2 °,18.39 ° ± 0.2 °,19.02 ° ± 0.2 °,19.15 ° ± 0.2 °,20.09 ° ± 0.2 °,20.35 ° ± 0.2 °,21.26 ° ± 0.2 °,22.71 ° ± 0.2 °,23.01 ° ± 0.2 °,24.43 ° ± 0.2 °,25.52 ° ± 0.2 °,26.33 ° ± 0.2 °,26.93 ° ± 0.2 °,28.27 ° ± 0.2 °,30.67 ° ± 0.2 ° ±;

the phosphate form K has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.55 ° ± 0.2 °,11.06 ° ± 0.2 °,12.92 ° ± 0.2 °,13.22 ° ± 0.2 °,13.73 ° ± 0.2 °,14.84 ° ± 0.2 °,15.08 ° ± 0.2 °,15.36 ° ± 0.2 °,16.81 ° ± 0.2 °,17.05 ° ± 0.2 °,17.87 ° ± 0.2 °,18.33 ° ± 0.2 °,19.02 ° ± 0.2 °,19.47 ° ± 0.2 °,20.38 ° ± 0.2 °,20.90 ° ± 0.2 °,21.49 ° ± 0.2 °,22.46 ° ± 0.2 °,22.74 ° ± 0.2 °,23.19 ° ± 0.2 °,24.21 ° ± 0.2 °,25.18 ° ± 0.2 °,25.35 ° ± 0.26.2.25 ° ± 0.26 ° ± 0.2.26 ° ± 0.2.2 °,22.74 ° ± 0.2.2 °, 36.28 ° ± 0.28 ° ± 0.2.3 ° ± 0.2.2 ° ± 0.2 ° ± 0.28 ° ± 0.3 ° ± 0.2.2.2.2 ° 0.2 ° ± 0.2 ° 20.2 ° 0.2 ° ± 0.2 ° ± 0.2 °;

the X-ray powder diffraction pattern of the crystalline form M of the halophosphate salt has diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,8.91 ° ± 0.2 °,10.35 ° ± 0.2 °,12.23 ° ± 0.2 °,15.74 ° ± 0.2 °,16.08 ° ± 0.2 °,16.32 ° ± 0.2 °,19.36 ° ± 0.2 °,21.34 ° ± 0.2 °,22.42 ° ± 0.2 °,23.56 ° ± 0.2 °,24.04 ° ± 0.2 °,24.90 ° ± 0.2 °,26.14 ° ± 0.2 °,26.86 ° ± 0.2 °,27.41 ° ± 0.2 °,28.06 ° ± 0.2 °,29.36 ° ± 0.2 °,29.88 ° ± 0.2 °,30.19 ° ± 0.2 °,31.80 ° ± 0.2 °.

5. The phosphate salt of claim 2, wherein the phosphate form F has an X-ray powder diffraction pattern substantially as shown in figure 3;

the phosphate form K has an X-ray powder diffraction pattern substantially as shown in figure 9;

the phosphate crystalline form M has an X-ray powder diffraction pattern substantially as shown in figure 13.

6. The phosphate salt of claim 2, wherein the differential scanning calorimetry trace of phosphate form F comprises endothermic peaks at 83.53 ℃ ± 3 ℃, 183.85 ℃ ± 3 ℃ and 198.54 ℃ ± 3 ℃;

a differential scanning calorimetry trace of said phosphate form K comprising an endothermic peak at 253.44 ℃ ± 3 ℃;

the differential scanning calorimetry trace of the phosphate form M comprises an endothermic peak at 132.05 ℃ ± 3 ℃.

7. The phosphate salt of claim 2, wherein the phosphate form F has a differential scanning calorimetry trace substantially as shown in figure 4;

said phosphate form K having a differential scanning calorimetry trace substantially as shown in figure 10;

the phosphate crystalline form M has a differential scanning calorimetry trace substantially as shown in figure 14.

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

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

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

Images