CN114685440B

CN114685440B - Salts of pyridyleiperidine derivatives and uses thereof

Info

Publication number: CN114685440B
Application number: CN202111620551.4A
Authority: CN
Inventors: 金传飞; 钟文和; 张英俊
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2020-12-29
Filing date: 2021-12-28
Publication date: 2023-07-18
Anticipated expiration: 2041-12-28
Also published as: CN114685440A

Abstract

The present invention relates to salts of pyridylenimine derivatives and their use. The invention also relates to pharmaceutical compositions comprising said salts, and the use of said salts or of said pharmaceutical compositions of said salts for the preparation of a medicament for the prevention, treatment or alleviation of 5-HT _1F Use in medicine of receptor-related diseases, in particular migraine.

Description

Salts of pyridyleiperidine derivatives and uses thereof

Technical Field

The invention belongs to the technical field of medicines, relates to salts of pyridine alkenyl piperidine derivatives and application thereof, in particular to salts of 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidine-4-subunit) methyl) pyridine-2-yl) benzamide, crystal forms of the salts and application thereof, and further relates to a pharmaceutical composition containing the salts or the crystal forms of the salts.

Background

Migraine is a type of episodic and often unilateral pulsating headache, often accompanied by nausea and vomiting, is a common chronic neurovascular disorder, is frequently observed in children and adolescents, reaches the peak of onset in the middle-aged and young, is commonly observed in women, and has a proportion of about 1: 2-3, the prevalence rate of the crowd is 5-10 percent, and genetic background is common.

Migraine is not a fatal disease but can severely affect the social life of a patient. In the united states, migraine causes a socioeconomic burden of dollars 10 to 17 billion. In China, a large number of patients influence work, study and life due to migraine. With the acceleration of the pace of life, the incidence of migraine tends to increase gradually. Recent surveys have found that about 5.7% of men and 17.6% of women have on average more than 1 migraine attacks per year. In addition, there are many people who have a genetic predisposition to migraine.

Migraine is complicated and diverse in pathogenesis, and mainly comprises vascular theory, neurogenic theory, trigeminal vascular theory, biochemical factors and genetic factors. The current drugs for migraine treatment are mainly 5-HT _1B/D The receptor agonist triptan is forbidden for patients suffering from cardiovascular and cerebrovascular diseases and peripheral vascular diseases because the triptan can shrink blood vessels. In addition, 40 to 70 percent of migraine patients have poorer curative effects on triptans, and 1/3 of patients with initial effective treatment can often suffer from headache recurrence, so that the curative effects of the triptans on moderately severe headache patients are obviously reduced. To overcome these adverse effects of triptans, calcitonin Gene Related Peptide (CGRP) receptor antagonists and selective 5-HT _1F Anti-migraine agents of the receptor agonist class have been developed. However, there are a number of drawbacks to CGRP receptor antagonists, such as the fact that olcagepant is only used by intravenous injection and not orally, and long-term use of telcagepant causes elevated liver enzymes, and BI-44370 ceases clinical development due to interactions with cytochrome P450. Therefore, development of new acute phase therapeutic drugs is urgently required. Development of Selective 5-HT _1F Receptor agonist anti-migraine drugs have been considered as a new promising approach.

Since 1938, graham and Wolff work (Arch. Neurol. Psychiary, 39:737-63,1938) has been dominant in theory regarding migraine pathophysiology. They suggested that the cause of migraine is vasodilation of the extracranial blood vessels. This view is supported by the following evidence: ergot alkaloid and ShuMa Tan as a water-absorbing 5-HT incapable of crossing the blood-brain barrier ₁ Agonists, which can constrict vascular smooth muscle in the head, are effective in the treatment of migraine (Humphrey, et al, ann.NY Acad.Sci.,600:587-600,1990). However, work by the Moskowitz group showed that migraine occurred independent of changes in vessel diameter (Cephalalgia, 12:5-7,1992).

The Moskowitz group suggests that the currently unknown pain trigger stimulates the trigeminal ganglion (which innervates the vasculature in the head tissue), causing the axons on the vasculature to release vasoactive neuropeptides. These released neuropeptides then activate a series of events, resulting in pain. This neurogenic inflammation is blocked by ergot alkaloids and sumatriptan, the blocking mechanism of which involves the 5-HT receptor and is associated with 5-HT located on the vascular fibres of the trigeminal nerve _1D The subtypes are closely related (Neurology, 43 (suppl 1.3): S16-S20,1993). In fact, sumatriptan vs 5-HT _1B And 5-HT _1D The receptor has a high affinity, ki of 10.3nM and 5.1nM, respectively, and this activity shows vasoconstrictor activity.

The 5-hydroxytryptamine receptor, also known as serotonin receptor or 5-HT receptor, is a group of G protein-coupled receptors which occur centrally in the central nervous system and peripherally in the peripheral nervous system and can be divided into seven subfamilies 5-HT ₁ 、5-HT ₂ 、5-HT ₃ 、5-HT ₄ 、5-HT ₅ 、5-HT ₆ And 5-HT ₇ Respectively mediate different physiological activities. Wherein 5-HT ₁ The receptor is the most bulky family of 5-HT receptors, currently 5-HT _1A 、5-HT _1B 、5-HT _1D 、5-HT _1E And 5-HT _1F Five subtypes. Isolation of expression of these 5-HT from Kao group ₁ One of the receptor subtypes (called 5-HT _1F ) Is described (Proc. Natl. Acad. Sci. USA,90:408-412, 1993). The 5-HT _1F The receptors exhibit pharmacological activity that is significantly different from any of the serotonin receptors disclosed. They found that sumatriptan was not only against 5-HT _1B And 5-HT _ID In addition to the strong affinities described above, the receptor has affinities for this receptor subtype, with a Ki of about 23nM. This indicates 5-HT _1F The receptor may play a role in migraine.

5-HT _1F Receptors are mainly expressed in mesentery, uterus and brain, but also in parts of the trigeminal vasculature such as cerebral vessels, trigeminal ganglia and the caudal nucleus of the trigeminal nerve, as well as cerebellum, hippocampus and neocortex. As with other 5-HT receptors, 5-HT _1F Receptors are expressed not only in neurons but also in glial cells. Presynaptic 5-HT _1F Activation of the receptor inhibits the release of Calcitonin Gene Related Peptide (CGRP) and blocks neuronal signaling in the tail nucleus of the trigeminal nerve, thereby producing an anti-migraine effect, and this selective 5-HT _1F The receptor agonism greatly reduces the side effects related to vasoconstriction caused by the triptan drugs.

Subsequent development of the 5-HT _1F Various 5-HT of receptor subtypes with relative selectivity _1F Receptor agonists, and this selectivity typically reduces the vasoconstrictor activity specific for other compounds used as prodrugs for the treatment of migraine and related diseases. Thus, selective 5-HT _1F Receptor agonists are a hotspot in current anti-migraine drug research.

As a result of continued research, the inventors have obtained an unexpected new class of selective 5-HT _1F Receptor agonists, which have different chemical and receptor binding properties, inhibit peptide extravasation while avoiding significant vasoconstrictor activity and are therefore useful in the treatment of migraine and other conditions associated with 5-HT _1F Receptor-related diseases.

Among them, international application WO 2020038435 A1 discloses the compound 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidin-4-ylidene) methyl) pyridin-2-yl) benzamide (a compound of formula (I)) which can be used for activating 5-HT _1F Receptors and inhibit neuronal protein extravasation. However, no studies have been made in the prior art on salts of the compound or crystalline forms thereof.

Different salts and solid forms of the pharmaceutically active ingredient may have different properties. Different salts and solid forms may vary significantly in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on stability, bioavailability, efficacy, etc. of the drug. Thus, problems with the salt form and/or solid form of the drug should be fully considered in drug development.

The inventor finds that the compound has poor water solubility and poor patent drug property when researching the compound, so in order to find a solid form with better patent drug property, a large amount of experimental researches show that after the compound shown as the formula (I) forms a salt, the physicochemical properties of different salts are greatly changed, and the properties of some salts are not better than those of the compound in a free state; the inventor discovers that various properties of the L-tartrate of the compound shown as the formula (I) prepared by the method can be obviously improved, and the preparation development is facilitated.

Disclosure of Invention

The invention provides a salt of a compound shown in a formula (I), and researches on preparation of the salt, solid form of the salt, physicochemical properties and pharmacological properties of the salt show that the salt formed by the compound and different acids has a large difference in physicochemical properties: for example, a part of the salt has a solubility worse than that of the compound, a part of the salt has a solubility comparable to that of the compound, and a part of the salt has a solubility higher than that of the compound. Wherein, various physical and chemical properties of the L-tartrate salt of the compound shown in the formula (I) are better than those of the compound and other salts, for example, the solubility of the L-tartrate salt crystal form A obtained by salifying the compound shown in the formula (I) with L-tartaric acid is higher than those of the compound shown in the formula (I) and corresponding benzenesulfonate salt crystal forms A and fumarate salt crystal form A. Experiments prove that the L-tartrate crystal form A has better property, higher solubility and better pharmacokinetic property, thereby having better patentability.

In particular, the present invention relates to salts of the compounds of formula (I), and the use of crystalline forms of the salts or pharmaceutical compositions comprising the salts or crystalline forms of the salts for the preparation of a pharmaceutical composition for the prevention, treatment or alleviation of 5-HT _1F Use in medicine of receptor-related diseases, in particular migraine. The salt is L-tartrate. Further, the salt is L-tartrate form A. The crystalline forms of the invention may also be in the form of solvates, for example hydrates.

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

in some embodiments, the salts of the present invention are organic or inorganic acid salts.

In other embodiments, the inorganic acid salts described herein include, but are not limited to, hydrochloride, hydrobromide, phosphate, nitrate, sulfate, or the like; the organic acid salts include, but are not limited to, acetates, succinates, oxalates, fumarates, maleates, tartrates, citrates, succinates, camphorsulfonates, malonates, benzoates, salicylates, benzenesulfonates, methanesulfonates, p-toluenesulfonates, and the like.

In some embodiments, the salt of the compound of formula (I) of the present invention is L-tartrate.

In some embodiments, the salt of the present invention is L-tartrate, wherein the L-tartrate is L-tartrate form a, and wherein the X-ray powder diffraction pattern of L-tartrate form a has diffraction peaks at the following 2Θ angles: 11.57 ° ± 0.2 °, 12.15 ° ± 0.2 °, 13.54 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.45 ° ± 0.2 °, 16.10 ° ± 0.2 °, 16.75 ° ± 0.2 °, 17.33 ° ± 0.2 °, 19.44 ° ± 0.2 °, 21.19 ° ± 0.2 °, 21.92 ° ± 0.2 °, 22.40 ° ± 0.2 °, 26.98 ° ± 0.2 °.

In some embodiments, the salt of the present invention is L-tartrate, wherein the L-tartrate is L-tartrate form a, and wherein the X-ray powder diffraction pattern of L-tartrate form a has diffraction peaks at the following 2Θ angles: 4.48 ° ± 0.2 °, 9.06 ° ± 0.2 °, 11.57 ° ± 0.2 °, 12.15 ° ± 0.2 °, 13.54 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.45 ° ± 0.2 °, 16.10 ° ± 0.2 °, 16.75 ° ± 0.2 °, 17.33 ° ± 0.2 °, 18.23 ° ± 0.2 °, 19.44 ° ± 0.2 °, 20.90 ° ± 0.2 °, 21.19 ° ± 0.2 °, 21.92 ° ± 0.2 °, 22.40 ° ± 0.2 °, 23.35 ° ± 0.2 °, 23.60 ° ± 0.2 °, 24.66 ° ± 0.2 °; 25.32 ° ± 0.2 °, 25.52 ° ± 0.2 °, 26.27 ° ± 0.2 °, 26.98 ° ± 0.2 °, 27.32 ° ± 0.2 °, 28.13 ° ± 0.2 °, 28.46 ° ± 0.2 °, 29.39 ° ± 0.2 °, 29.71 ° ± 0.2 °, 29.88 ° ± 0.2 °, 31.15 ° ± 0.2 °, 31.56 ° ± 0.2 °, 32.73 ° ± 0.2 °, 33.98 ° ± 0.2 °, 35.28 ° ± 0.2 °, 36.35 ° ± 0.2 °, 37.83 ° ± 0.2 ° and 38.55 ° ± 0.2 °.

In some embodiments, the salt of the present invention is L-tartrate, wherein the L-tartrate is L-tartrate form a, and wherein the X-ray powder diffraction pattern of L-tartrate form a has diffraction peaks at the following 2Θ angles: 4.48 ° ± 0.2 °, 9.06 ° ± 0.2 °, 11.57 ° ± 0.2 °, 12.15 ° ± 0.2 °, 13.54 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.45 ° ± 0.2 °, 16.10 ° ± 0.2 °, 16.75 ° ± 0.2 °, 17.33 ° ± 0.2 °, 18.23 ° ± 0.2 °, 19.44 ° ± 0.2 °, 20.49 ° ± 0.2 °, 20.90 ° ± 0.2 °, 21.19 ° ± 0.2 °, 21.92 ° ± 0.2 °, 22.40 ° ± 0.2 °, 23.35 ° ± 0.2 °, 23.60 ° ± 0.2 °, 24.66 ° ± 0.2 °; 25.32 ° ± 0.2 °, 25.52 ° ± 0.2 °, 26.27 ° ± 0.2 °, 26.98 ° ± 0.2 °, 27.32 ° ± 0.2 °, 28.13 ° ± 0.2 °, 28.46 ° ± 0.2 °, 29.39 ° ± 0.2 °, 29.71 ° ± 0.2 °, 29.88 ° ± 0.2 °, 31.15 ° ± 0.2 °, 31.56 ° ± 0.2 °, 32.73 ° ± 0.2 °, 33.98 ° ± 0.2 °, 35.28 ° ± 0.2 °, 36.35 ° ± 0.2 °, 37.21 ° ± 0.2 °, 37.83 ° ± 0.2 °, 38.55 ° ± 0.2 °.

In some embodiments, the salt of the present invention is L-tartrate, wherein the L-tartrate is L-tartrate form a, and wherein the L-tartrate form a has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the salt of the invention is L-tartrate, wherein the L-tartrate is form a of L-tartrate, and wherein the differential scanning calorimetry trace of form a of L-tartrate comprises an endothermic peak at 195.09 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is L-tartrate, wherein the L-tartrate is L-tartrate form a, and wherein the L-tartrate form a has a differential scanning calorimetry trace substantially as shown in figure 6.

In some embodiments, the salt of the present invention is L-tartrate salt, wherein the L-tartrate salt is L-tartrate form a, wherein the L-tartrate salt form a loses 1.177% weight when heated to 150.71 ℃, and wherein the loss-in-weight ratio has an error margin of + -0.1%.

In some embodiments, the salt of the present invention is L-tartrate, wherein the L-tartrate is L-tartrate form a, and wherein the L-tartrate form a has a thermogram substantially as shown in figure 11.

In some embodiments, the salt of the present invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form a, and the benzenesulfonate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 14.92 ° ± 0.2 °, 17.17 ° ± 0.2 °, 19.11 ° ± 0.2 °, 25.53 ° ± 0.2 °, 26.67 ° ± 0.2 °, 27.25 ° ± 0.2 °, 27.65 ° ± 0.2 °, 29.70 ° ± 0.2 °.

In some embodiments, the salt of the present invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form a, and the benzenesulfonate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 6.17 ° ± 0.2 °, 8.01 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.92 ° ± 0.2 °, 16.26 ° ± 0.2 °, 17.17 ° ± 0.2 °, 17.96 ° ± 0.2 °, 19.11 ° ± 0.2 °, 20.78 ° ± 0.2 °, 21.75 ° ± 0.2 °, 22.32 ° ± 0.2 °, 23.13 ° ± 0.2 °, 24.18 ° ± 0.2 °, 24.85 ° ± 0.2 °, 25.53 ° ± 0.2 °, 26.10 ° ± 0.2 °, 26.67 ° ± 0.2 °, 27.25 ° ± 0.2 °, 27.65 ° ± 0.2 °, 28.40 ° ± 0.2 °, 29.22 ° ± 0.2 °, 29.70 ° ± 0.2 °, 31.09 ° ± 0.2 °, 32.58 ° ± 0.2 °, 33.16 ° ± 0.2 °, 34.14 ° ± 0.2 °, 3756 ° ± 0.34 ° ± 0.36 ° ± 0.2 °, and 562 ° ± 0.36 ° ± 0.2.85 ° ± 0.2 °.

In some embodiments, the salt of the present invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form a, and the benzenesulfonate salt form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 6.17 ° ± 0.2 °, 8.01 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.92 ° ± 0.2 °, 16.26 ° ± 0.2 °, 17.17 ° ± 0.2 °, 17.96 ° ± 0.2 °, 19.11 ° ± 0.2 °, 20.78 ° ± 0.2 °, 21.75 ° ± 0.2 °, 22.32 ° ± 0.2 °, 23.13 ° ± 0.2 °, 24.18 ° ± 0.2 °, 24.85 ° ± 0.2 °, 25.53 ° ± 0.2 °, 26.10 ° ± 0.2 °, 26.67 ° ± 0.2 °, 27.25 ° ± 0.2 °, 27.65 ° ± 0.2 °, 28.40 ° ± 0.2 °, 29.22 ° ± 0.2 °, 29.70 ° ± 0.2 °, 31.09 ° ± 0.2 °, 31.85 ° ± 0.2 °, 32.58 ° ± 0.2 °, 33.16 ° ± 0.2 °, 96 ° ± 0.35 ° ± 0.36 °, 35 ° ± 0.35 ° ± 0.67 °, and 35.35 ° ± 0.2 ° ± 0.36.67 ° ± 0.2.35 ° ± 0.2.67 ° ± 0.2.

In some embodiments, the salts of the present invention are benzenesulfonate salts, wherein the benzenesulfonate salt is benzenesulfonate salt form a having an X-ray powder diffraction pattern substantially as shown in fig. 2.

In some embodiments, the salts of the present invention are benzenesulfonate salts, wherein the benzenesulfonate salt is benzenesulfonate salt form a, and the differential scanning calorimetry pattern of benzenesulfonate salt form a comprises the endothermic peaks at 112.84 ℃ ± 3 ℃, 121.04 ℃ ± 3 ℃ and 198.05 ℃ ± 3 ℃.

In some embodiments, the salts of the present invention are benzenesulfonates, wherein the benzenesulfonate salt is benzenesulfonate salt form a having a differential scanning calorimetry pattern substantially as shown in figure 7.

In some embodiments, the salt of the present invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form B, and the benzenesulfonate salt form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 9.48 ° ± 0.2 °, 11.62 ° ± 0.2 °, 12.56 ° ± 0.2 °, 14.87 ° ± 0.2 °, 19.06 ° ± 0.2 °, 19.94 ° ± 0.2 °, 22.33 ° ± 0.2 °, 25.43 ° ± 0.2 °.

In some embodiments, the salt of the present invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form B, and the benzenesulfonate salt form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 5.88 ° ± 0.2 °, 9.48 ° ± 0.2 °, 11.62 ° ± 0.2 °, 11.81 ° ± 0.2 °, 12.56 ° ± 0.2 °, 14.24 ° ± 0.2 °, 14.87 ° ± 0.2 °, 16.23 ° ± 0.2 °, 17.14 ° ± 0.2 °, 17.40 ° ± 0.2 °, 17.75 ° ± 0.2 °, 18.11 ° ± 0.2 °, 19.06 ° ± 0.2 °, 19.94 ° ± 0.2 °, 20.20 ° ± 0.2 °, 20.76 ° ± 0.2 °, 20.88 ° ± 0.2 °, 21.38 ° ± 0.2 °, 21.68 ° ± 0.2 °, 22.33 ° ± 0.2 °, 22.65 ° ± 0.2 °, 23.12 ° ± 0.2 ° >, 19.06 ° ± 0.2 °; 23.67 ° ± 0.2 °, 24.09 ° ± 0.2 °, 24.33 ° ± 0.2 °, 24.80 ° ± 0.2 °, 25.43 ° ± 0.2 °, 25.83 ° ± 0.2 °, 26.66 ° ± 0.2 °, 27.08 ° ± 0.2 °, 27.69 ° ± 0.2 °, 27.95 ° ± 0.2 °, 28.74 ° ± 0.2 °, 29.21 ° ± 0.2 °, 29.45 ° ± 0.2 °, 29.81 ° ± 0.2 °, 30.04 ° ± 0.2 °, 30.67 ° ± 0.2 °, 30.94 ° ± 0.2 °, 31.22 ° ± 0.2 °, 31.60 ° ± 0.2 °, 34.79 ° ± 0.2 °, 35.15 ° ± 0.2 °.

In some embodiments, the salt of the present invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form B, and the benzenesulfonate salt form B has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ angles: 5.88 ° ± 0.2 °, 9.48 ° ± 0.2 °, 11.62 ° ± 0.2 °, 11.81 ° ± 0.2 °, 12.56 ° ± 0.2 °, 14.24 ° ± 0.2 °, 14.87 ° ± 0.2 °, 16.23 ° ± 0.2 °, 17.14 ° ± 0.2 °, 17.40 ° ± 0.2 °, 17.75 ° ± 0.2 °, 18.11 ° ± 0.2 °, 19.06 ° ± 0.2 °, 19.94 ° ± 0.2 °, 20.20 ° ± 0.2 °, 20.76 ° ± 0.2 °, 20.88 ° ± 0.2 °, 21.38 ° ± 0.2 °, 21.68 ° ± 0.2 °, 22.33 ° ± 0.2 °, 75 ° ± 0.2 °, 23.12 ° ± 0.2 °, 23.67 ° ± 0.2 °, 24.09 ° ± 0.2 °, 3524.33 ° ± 0.2.2 ° ± 0.2; 24.80 ° ± 0.2 °, 25.43 ° ± 0.2 °, 25.83 ° ± 0.2 °, 26.66 ° ± 0.2 °, 27.08 ° ± 0.2 °, 27.69 ° ± 0.2 °, 27.95 ° ± 0.2 °, 28.74 ° ± 0.2 °, 29.21 ° ± 0.2 °, 29.45 ° ± 0.2 °, 29.81 ° ± 0.2 °, 30.04 ° ± 0.2 °, 30.67 ° ± 0.2 °, 30.94 ° ± 0.2 °, 31.22 ° ± 0.2 °, 31.60 ° ± 0.2 °, 31.92 ° ± 0.2 °, 32.60 ° ± 0.2 °, 34.28 ° ± 0.2 °, 34.79 ° ± 0.2 °, 35.15 ° ± 0.2 °, 36.53 ° ± 0.2 °, 37.15 ° ± 0.2 °, 39.71 ° ± 0.2 °.

In some embodiments, the salts of the present invention are benzenesulfonate salts, wherein the benzenesulfonate salt is benzenesulfonate salt form B having an X-ray powder diffraction pattern substantially as shown in fig. 3.

In some embodiments, the salt of the invention is a benzenesulfonate salt, wherein the benzenesulfonate salt is benzenesulfonate salt form B, and the differential scanning calorimetry pattern of benzenesulfonate salt form B comprises an endothermic peak at 198.42 ℃ ± 3 ℃.

In some embodiments, the salts of the present invention are benzenesulfonates, wherein the benzenesulfonate salt is benzenesulfonate salt form B having a differential scanning calorimetry pattern substantially as shown in figure 8.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form a, and the X-ray powder diffraction pattern of fumarate salt form a has diffraction peaks at the following 2θ angles: 13.51 ° ± 0.2 °, 16.00 ° ± 0.2 °, 19.47 ° ± 0.2 °, 19.88 ° ± 0.2 °, 21.14 ° ± 0.2 °, 22.74 ° ± 0.2 °, 24.89 ° ± 0.2 °, 25.02 ° ± 0.2 °, 27.27 ° ± 0.2 °, 28.71 ° ± 0.2 ° 29.33 ° ± 0.2 °.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form a, and the X-ray powder diffraction pattern of fumarate salt form a has diffraction peaks at the following 2θ angles: 6.71 ° ± 0.2 °, 7.94 ° ± 0.2 °, 11.66 ° ± 0.2 °, 13.23 ° ± 0.2 °, 13.51 ° ± 0.2 °, 14.52 ° ± 0.2 °, 15.07 ° ± 0.2 °, 16.00 ° ± 0.2 °, 17.05 ° ± 0.2 °, 18.45 ° ± 0.2 °, 19.08 ° ± 0.2 °, 19.47 ° ± 0.2 °, 19.88 ° ± 0.2 °, 21.14 ° ± 0.2 °, 22.74 ° ± 0.2 °, 23.25 ° ± 0.2 °, 24.89 ° ± 0.2 °, 25.02 ° ± 0.2 °, 25.19 ° ± 0.2 °, 25.69 ° ± 0.2 °, 25.91 ° ± 0.2 °, 26.47 ° ± 0.2 °, 27.27 ° ± 0.76 ° ± 0.2 °, 28.71 ° ± 0.2 °, 3.47 ° ± 0.2 °, 35 ° ± 0.35 ° ± 0.2 °, 35 ° ± 0.35 ° ± 0.2 °, 35 ° ± 0.35.35 ° ± 0.37 ° ± 0.2 °, and 35.37 ° ± 0.2.2.2 ° ± 0.2.2.1 ° ± 0.2.2.2.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form a, and the X-ray powder diffraction pattern of fumarate salt form a has diffraction peaks at the following 2θ angles: 6.71 ° ± 0.2 °, 7.94 ° ± 0.2 °, 11.66 ° ± 0.2 °, 13.23 ° ± 0.2 °, 13.51 ° ± 0.2 °, 14.52 ° ± 0.2 °, 15.07 ° ± 0.2 °, 16.00 ° ± 0.2 °, 17.05 ° ± 0.2 °, 18.45 ° ± 0.2 °, 19.08 ° ± 0.2 °, 19.47 ° ± 0.2 °, 19.88 ° ± 0.2 °, 20.35 ° ± 0.2 °, 21.14 ° ± 0.2 °, 22.74 ° ± 0.2 °, 23.25 ° ± 0.2 °, 24.30 ° ± 0.2 °, 24.89 ° ± 0.2 °, 25.02 ° ± 0.2 °, 25.19 ° ± 0.2 °, 25.69 ° ± 0.2 °, 25.91 ° ± 0.2 °, 26.47 ° ± 0.2 °, 27.27.27.27.27 ° ± 0.76 ° ± 0.28.31.32 °, 35 ° ± 0.31.32 °, 35.32 °, 35 ° ± 0.32 °, 35.32 ° ± 0.31.32 °, 35.32 ° ± 0.32 °, 35.32 ° ± 0.31.31.31.31.32 °, 35 ° ± 0.32 °, 35.32 ° ± 0.32.32.32 °, and 35.32 ° ± 0.2.32.2 °, 35 ° ± 0.2.2.2 °, 35.2 ° and 35.32.2 ° and 35.2.2.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form a, and wherein the fumarate salt form a has an X-ray powder diffraction pattern substantially as shown in fig. 4.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form a, and the differential scanning calorimetry trace of fumarate salt form a comprises an endothermic peak at 202.39 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form a, and wherein the fumarate salt form a has a differential scanning calorimeter substantially as shown in fig. 9.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form B, and the X-ray powder diffraction pattern of the fumarate salt form B has diffraction peaks at the following 2θ angles: 8.53 ° ± 0.2 °, 8.90 ° ± 0.2 °, 14.45 ° ± 0.2 °, 15.32 ° ± 0.2 °, 15.51 ° ± 0.2 °, 16.70 ° ± 0.2 °, 17.07 ° ± 0.2 °, 19.22 ° ± 0.2 °, 19.66 ° ± 0.2 °, 22.41 ° ± 0.2 °, 23.18 ° ± 0.2 ° and 26.51 ° ± 0.2 °.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form B, and the X-ray powder diffraction pattern of the fumarate salt form B has diffraction peaks at the following 2θ angles: 8.53 ° ± 0.2 °, 8.90 ° ± 0.2 °, 11.35 ° ± 0.2 °, 11.87 ° ± 0.2 °, 14.45 ° ± 0.2 °, 15.32 ° ± 0.2 °, 15.51 ° ± 0.2 °, 16.15 ° ± 0.2 °, 16.70 ° ± 0.2 °, 17.07 ° ± 0.2 °, 17.76 ° ± 0.2 °, 18.11 ° ± 0.2 °, 18.36 ° ± 0.2 °, 19.22 ° ± 0.2 °, 19.66 ° ± 0.2 °, 19.98 ° ± 0.2 °, 20.20 ° ± 0.2 °, 20.50 ° ± 0.2 °, 21.22 ° ± 0.2 °, 22.41 ° ± 0.2 °, 23.18 ° ± 0.2 °, 23.40 ° ± 0.2 °, 23.99 ° ± 0.2 °, 25.10 ° ± 0.2 °, 26.05 ° ± 0.2 °, 26.51 ° ± 0.2 °, 26.32 ° ± 0.62 °, 28.34 ° ± 0.27 ° ± 0.2 °, 28.56 ° ± 0.33 ° ± 0.24.56 ° ± 0.26.33 ° ± 0.2 °, and/24 ° ± 0.2.33 ° ± 0.2.56 ° ± 0.2.2 °, 28.35 ° ± 0.2.2 ° ± 0.2.2.2 °.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form B, and the X-ray powder diffraction pattern of the fumarate salt form B has diffraction peaks at the following 2θ angles: 8.53 ° ± 0.2 °, 8.90 ° ± 0.2 °, 11.35 ° ± 0.2 °, 11.87 ° ± 0.2 °, 14.45 ° ± 0.2 °, 15.32 ° ± 0.2 °, 15.51 ° ± 0.2 °, 16.15 ° ± 0.2 °, 16.70 ° ± 0.2 °, 17.07 ° ± 0.2 °, 17.76 ° ± 0.2 °, 18.11 ° ± 0.2 °, 18.36 ° ± 0.2 °, 19.22 ° ± 0.2 °, 19.66 ° ± 0.2 °, 19.98 ° ± 0.2 °, 20.20 ° ± 0.2 °, 20.50 ° ± 0.2 °, 21.22 ° ± 0.2 °; 22.41 ° ± 0.2 °, 23.18 ° ± 0.2 °, 23.40 ° ± 0.2 °, 23.99 ° ± 0.2 °, 25.10 ° ± 0.2 °, 26.05 ° ± 0.2 °, 26.51 ° ± 0.2 °, 26.79 ° ± 0.2 °, 27.62 ° ± 0.2 °, 27.83 ° ± 0.2 °, 28.87 ° ± 0.2 °, 29.85 ° ± 0.2 °, 30.63 ° ± 0.2 °, 31.33 ° ± 0.2 °, 31.85 ° ± 0.2 °, 32.49 ° ± 0.2 °, 34.63 ° ± 0.2 °, 36.71 ° ± 0.2 °.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form B, and wherein the fumarate salt form B has an X-ray powder diffraction pattern substantially as shown in fig. 5.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form B, and the differential scanning calorimetry trace of fumarate salt form B comprises an endothermic peak at 219.88 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a fumarate salt, wherein the fumarate salt is fumarate salt form B, and wherein the fumarate salt form B has a differential scanning calorimeter substantially as shown in fig. 10.

In another aspect, the present invention relates to a pharmaceutical composition comprising any of the salts described herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

In one aspect, the invention relates to the use of said salt or said pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating 5-HT in a patient _1F Receptor-related diseases.

In some of these embodiments, the invention is described herein as being 5-HT _1F The receptor-related disorder is migraine, general pain, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive-compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorders, impulse control disorders, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, trichotillomania, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

In a further aspect, the present invention relates to the use of said salt or said pharmaceutical composition for the preparation of a medicament for activating 5-HT _1F A receptor.

In another aspect, the present invention also relates to a process for the preparation of a salt of a compound of formula (I) or a crystalline form thereof.

The solvent used in the process for producing a salt or a crystal form thereof of the present invention is not particularly limited, and any solvent which can dissolve the starting material to a degree and does not affect the properties thereof is included in the present invention. In addition, many similar modifications, equivalent substitutions, or equivalent solvents, combinations of solvents, and different proportions of solvent combinations described herein are considered to be encompassed by the present invention. The present invention gives the preferred solvents to be used in each reaction step.

The experiments for preparing the salts or crystal forms thereof according to the present invention will be described in detail in the examples section. Meanwhile, the invention provides pharmacological property test experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments, hygroscopicity experiments and the like of the salt or the crystal form thereof. Experiments prove that the L-tartrate crystal form A has unexpected technical advantages:

1. the L-tartrate crystal form A has good stability, for example, no or almost no hygroscopicity, does not change when being placed at normal temperature, is stable under high temperature, high humidity and illumination experimental conditions, and has basically no change in appearance, purity and crystal form.

2. The L-tartrate salt form A has higher solubility than the compound shown in the formula (I) and other salts, such as benzenesulfonate salt form A and fumarate salt form A.

3. Compared with the compound shown in the formula (I), the L-tartrate crystal form A has higher blood concentration and exposure in beagle bodies, so that the L-tartrate crystal form A has better pharmacokinetic properties.

Therefore, the L-tartrate crystal form A disclosed by the invention 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 the compounds. The crystalline form of a substance may 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, crystallization on a surface or template, e.g., on a polymer, crystallization in the presence of additives such as co-crystallizing anti-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, solvent drop milling, and the like.

"amorphous" or "amorphous form" refers to a substance that forms when particles (molecules, atoms, ions) of the substance are non-periodically arranged in three dimensions, characterized by a diffuse, non-spiking X-ray powder diffraction pattern. Amorphous is a special physical form of solid material whose locally ordered structural features suggest a myriad of interactions with crystalline material. 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, antisolvent 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, dimethyl carbonate, 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.

"antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent 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" means a compound having a solvent on, in, or on and in the crystal lattice of water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, dimethyl carbonate, 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 both is water. The hydrate may or may not have other solvents than water on the surface of the substance, in the crystal lattice, or both.

The crystalline forms may be identified by a variety of techniques such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point, differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

The X-ray powder diffraction (XRPD) can detect the information of crystal form change, crystallinity, crystal structure state and the like, and is a common means for identifying the crystal form. The peak positions of the XRPD patterns are largely dependent on the structure of the crystalline form, relatively insensitive to experimental details, and their relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystalline forms of the invention are characterized by XRPD patterns having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the invention. Meanwhile, the measure of 2θ of the XRPD pattern may have experimental errors, and the measure of 2θ of the XRPD pattern may slightly differ from instrument to instrument and sample to sample, so the value of 2θ cannot be regarded as absolute. Depending on the instrument conditions used in this test, diffraction peaks have a margin of error of + -0.2 deg..

Differential scanning volumeThermal (DSC) is a method of measuring the temperature of a sample and an inert reference (commonly used alpha-Al) by continuously heating or cooling under program control ₂ O ₃ ) A technique in which the energy difference between them varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms of the invention are characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profile provided in the accompanying figures of the invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ from instrument to instrument and from sample to sample, so that the peak position or the value of the DSC endothermic peak cannot be regarded as absolute. Depending on the instrument conditions used in this test, there is an error margin of + -3deg.C for the endothermic peak.

Thermogravimetric analysis (TGA) is a technique for measuring the mass of a substance as a function of temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition processes of a sample, and can be used to infer the presence of water of crystallization or a crystallization solvent in the crystal. The quality change exhibited by the TGA profile depends on many factors such as sample preparation and instrumentation; the quality of TGA detection varies slightly from instrument to instrument and from sample to sample. Depending on the instrument conditions used in this test, there was a margin of error of + -0.1% for the mass change.

In the context of the present invention, the 2 theta 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 the graph, a "peak" refers to a feature that one skilled in the art can recognize that is not attributable to background noise.

The present invention relates to salts of said 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidin-4-ylidene) methyl) pyridin-2-yl) benzamide and/or crystalline forms thereof, which are present in a substantially pure crystalline form.

By "substantially pure" is meant that one form is substantially free of the other form or forms, i.e., the purity of the 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%, or the form contains 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% of the total volume or total weight of the forms.

By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or weight of the crystalline forms 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 intensity peak to the intensity of the first intensity peak of all diffraction peaks of the X-ray powder diffraction pattern, taken as 100%.

In the context of the present invention, when used or whether or not the word "about" or "about" is used, means within 10%, suitably within 5%, particularly within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the average value to one of ordinary skill in the art. Whenever a number is disclosed having 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% will be explicitly disclosed, where "+/-" means plus or minus.

"room temperature" in the present invention means a temperature from about 10℃to about 40 ℃. In some embodiments, "room temperature" refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃,22.5 ℃,25 ℃,27.5 ℃, and so forth.

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 salts of the compound shown in the formula (I) and/or crystal forms thereof and pharmaceutically acceptable carriers, auxiliary agents or excipients. The amount of a salt of a compound or crystalline form thereof in a pharmaceutical composition of the invention is effective to detectably treat or reduce the risk of 5-HT in a patient _1F Receptor-related diseases, particularly migraine. The pharmaceutical compositions of the present invention may optionally further 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 in, for example, ansel h.c. et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, williams & Wilkins, philiadelphia; 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 artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. 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,1988-1999,Marcel Dekker,New York, the contents of each of which are incorporated herein by reference. It is within the scope of the present invention to contemplate its use in addition to any common carrier that is incompatible with the compounds of the present invention, such as by producing any undesirable biological effect, or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.

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

In another aspect, the present 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 mixing the various ingredients. Pharmaceutical compositions comprising salts of the compounds of the invention or crystalline forms thereof may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

Salts of the compounds of the invention, or crystalline forms thereof, are typically formulated into dosage forms suitable for administration to a patient by the 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 patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, 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 invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as Dry Filled Capsules (DFCs), consist of two segments, one being filled 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 described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared 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 methods of treatment 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 crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof. Embodiments of the present invention include treating the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the salt of the compound of the present invention or a crystalline form thereof.

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

In one embodiment, a salt of a compound of the invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof may be administered at one time or, depending on the dosing regimen, several times at different time intervals over a specified period of time. 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 performed until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for salts of the compounds of the invention or crystalline forms thereof or pharmaceutical compositions comprising the salts of the compounds of the invention or crystalline forms thereof depend on the pharmacokinetic properties of the salts of the compounds, such as absorption, distribution and half-life, which can be determined by the skilled person. Furthermore, suitable dosing regimens for salts of the compounds of the invention, or crystalline forms thereof, or pharmaceutical compositions comprising the salts of the compounds of the invention, or crystalline forms thereof, include factors within the knowledge and experience of the skilled artisan, including the duration of time for which the regimen is performed, the disease to be treated, the severity of the disease to be treated, the age and physical condition of the patient to be treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and the like. Such a skilled artisan will also appreciate that adjustments to the appropriate dosing regimen may be required for the individual patient's response to the dosing regimen, or as the individual patient needs to change over time.

The salts of the compounds of the invention or crystalline forms thereof may be administered simultaneously with, or before or after, one or more other therapeutic agents. The salts of the compounds of the present invention or crystalline forms thereof may be administered separately from other therapeutic agents by the same or different routes of administration, or in the same pharmaceutical composition as they are.

The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a beneficial therapeutic effect. For example, an amount sufficient to treat, cure, or alleviate symptoms of the disease is administered or equilibrated in vivo. The effective amount required for a particular therapeutic regimen will depend upon a variety of factors including the disease being treated, the severity of the disease, the activity of the particular agent being used, the mode of administration, the rate of clearance of the particular agent, the duration of the treatment, the combination, the age, body weight, sex, diet and health of the patient, etc. Other factors that need to be considered in the art for "therapeutically effective amounts" can be described in Gilman et al, eds., goodman And Gilman's: the Pharmacological Bases of Therapeutics,8th ed., pergamon Press,1990; remington's Pharmaceutical Sciences,17th ed., mack Publishing Company, easton, pa.,1990.

The compounds of formula (I) are preferably formulated in unit dosage form containing from about 0.001 to 100mg of active ingredient per dose, more often from about 1.0 to 30mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable excipient as described above.

The active compounds are generally effective over a wide dosage range. For example, the daily dose is typically about 0.0001-30mg/kg body weight. For adult treatment, a particularly preferred dose (single or divided) is about 0.1-15 mg/kg/day. However, it will be understood that the actual amount of compound administered will be determined by the attending physician according to the circumstances, including the condition being treated, the route of administration selected, the compound or compounds actually to be administered, the age, weight and response of the particular patient, and the severity of the patient's symptoms, and therefore, the above dosage ranges should not be limiting in any way. In some cases, dosage levels below the lower limit of the above dosage range may be more suitable, while in other cases higher doses may be employed which do not produce any side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

The optimal therapeutically effective amount to be administered can be readily determined by one skilled in the art and will vary substantially depending on the strength of the formulation, the mode of administration, and the advancement of the disease or condition being treated. In addition, factors related to the particular subject being treated include the subject's age, weight, diet, and time of administration, resulting in the need to adjust the dosage to an appropriate therapeutically effective level.

The term "administering" refers to providing a therapeutically effective amount of a drug to an individual by means including oral, sublingual, intravenous, subcutaneous, transdermal, intramuscular, intradermal, intrathecal, epidural, intraocular, intracranial, inhalation, rectal, vaginal, and the like. The administration form includes paste, lotion, tablet, capsule, pill, powder, granule, suppository, pellet, lozenge, injection, sterile solution or nonaqueous solution, suspension, emulsion, patch, etc. The active ingredient is compounded with a non-toxic pharmaceutically acceptable carrier (e.g., dextrose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, silica gel, potato starch, urea, dextran, etc.).

The preferred route of administration will vary with clinical characteristics, and the dosage will vary depending on the condition of the patient being treated, and the physician will determine the appropriate dosage for the individual patient. The therapeutically effective amount per unit dose depends on the body weight, physiology and the chosen vaccination regimen. The weight of the compound per unit dose is the weight of the compound per administration and does not include the weight of the carrier (the carrier is contained in the drug).

The salts of the compounds or crystalline forms and pharmaceutical compositions provided herein are useful in the preparation of compositions useful for preventing, treating or alleviating 5-HT in patients _1F Medicaments for receptor-related diseases, in particular for the preparation of medicaments for the prophylaxis, treatment or alleviation of migraine, and for the preparation of medicaments for the activation of 5-HT _1F A drug of the recipient.

In particular, the amount of compound in the pharmaceutical compositions of the present invention is effective to detectably selectively activate 5-HT _1F The receptor, a salt of a compound of the invention or a crystalline form thereof may be useful as a therapeutic agent for 5-HT _1F A medicament for the treatment of a subject-related disorder such as migraine.

The salts of the compounds of the invention or crystalline forms thereof may be used, but are in no way limited to, administration to a patient of an effective amount of a salt of the compound of the invention or crystalline form or pharmaceutical composition thereof to prevent, treat or ameliorate 5-HT _1F Receptor-related diseases. Said and 5-HT _1F Receptor-related disorders, further including but not limited to migraine, general pain, trigeminal nervePain, toothache or temporomandibular joint dysfunction pain, autism, obsessive compulsive disorder, panic disorder, depression, social phobia, anxiety, generalized anxiety disorder, sleep disorders, post traumatic syndrome, chronic fatigue syndrome, premenstrual syndrome or post luteal phase syndrome, borderline personality disorder, destructive behavioral disorders, impulse control disorders, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-pulling addiction, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss and dementia.

An "effective amount" or "effective dose" of a salt of a compound of the invention or a crystalline form or pharmaceutically acceptable composition thereof refers to an amount effective to treat or reduce the severity of one or more of the conditions referred to herein. According to the methods of the invention, the salts of the compounds of the invention, or crystalline forms or pharmaceutically acceptable compositions thereof, may be in any amount and by any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient's condition, depending on the race, age, general condition of the patient, severity of the infection, particular factors, mode of administration, and the like. Salts of the compounds of the invention, or crystalline forms or pharmaceutically acceptable compositions thereof, may be administered in combination with one or more other therapeutic agents, as discussed herein.

The salts of the compounds of the invention or their crystalline forms and pharmaceutical compositions are useful in veterinary therapy for mammals, in addition to human therapy, in companion animals, animals of introduced species and farm animals. Examples of other animals include horses, dogs, and cats.

Drawings

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of form A of the L-tartrate salt of the compound of formula (I).

FIG. 2 is an X-ray powder diffraction (XRPD) pattern of benzenesulfonate salt form A of the compound of formula (I).

FIG. 3 is an X-ray powder diffraction (XRPD) pattern of benzenesulfonate salt form B of the compound of formula (I).

Fig. 4 is an X-ray powder diffraction (XRPD) pattern of fumarate salt form a of the compound of formula (I).

Fig. 5 is an X-ray powder diffraction (XRPD) pattern of fumarate salt form B of the compound of formula (I).

FIG. 6 is a Differential Scanning Calorimeter (DSC) of crystalline form A of L-tartrate of the compound of formula (I).

FIG. 7 is a Differential Scanning Calorimeter (DSC) of benzenesulfonate form A of a compound of formula (I).

FIG. 8 is a Differential Scanning Calorimeter (DSC) of besylate form B of a compound of formula (I).

Fig. 9 is a Differential Scanning Calorimeter (DSC) diagram of fumarate salt form a of the compound of formula (I).

Fig. 10 is a Differential Scanning Calorimeter (DSC) diagram of fumarate salt form B of the compound of formula (I).

FIG. 11 is a thermogravimetric analysis (TGA) of crystalline form A of L-tartrate of the compound of formula (I).

Detailed Description

The invention is further illustrated by way of examples which are not intended to limit the scope of the invention.

The X-ray powder diffraction analysis method used in the invention comprises the following steps: an Empyrean diffractometer was used to obtain X-ray powder diffraction patterns using Cu-K alpha radiation (45 KV,40 mA). The powdered sample was prepared as a thin layer on a monocrystalline silicon sample holder, placed on a rotating sample stage and analyzed in steps of 0.0167 ° in the range of 3 ° -40 °. Data was collected using Data Collector software, highScore Plus software processed the Data, and Data Viewer software read the Data.

The Differential Scanning Calorimeter (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimeter was performed using a TA Q2000 module with a thermal analysis 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 sample analysis was performed from room temperature to about 300 ℃ using a linear heating device of 10 ℃/min. During use, the DSC cell was purged with dry nitrogen.

The thermal weight loss (TGA) analysis method used in the invention comprises the following steps: thermogravimetric analysis was performed using a TA Q500 module with a thermogravimetric analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10-30mg of the sample was placed in a platinum crucible and the sample analysis was performed from room temperature to about 300 c using a linear heating device at 10 c/min. During use, the TGA 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 model of the chromatographic column is Agilent XDB-C18 (4.6X10 mm,5 μm). The detection wavelength is 266nm, the flow rate is 1.0mL/min, the column temperature is 35 ℃, and the mobile phase A: acetonitrile/0.01M ammonium acetate = 10/90 (V/V) analytical method: acetonitrile/mobile phase a=70/30 (V/V), run time: 10 minutes.

Detailed description of the preferred embodiments

A compound of formula (I): 2,4, 6-trifluoro-N- (6- (fluoro (1-methylpiperidin-4-ylidene) methyl) pyridin-2-yl) benzamide was synthesized by the method described in International application WO 2020038435 A1, example 12.

Examples

Example 1: the L-tartrate form A of the invention

Preparation of L-tartrate form A

Weighing a compound (388 mg) shown in a formula (I), adding ethyl acetate (8 mL), heating to 50 ℃ and stirring to dissolve, then adding L-tartaric acid (308 mg, molar ratio 1:2), stirring, continuously stirring at 50 ℃ for 2 hours, increasing turbidity, obviously crystallizing, continuously stirring overnight, filtering, and performing vacuum drying at 50 ℃ to obtain white solid powder, wherein the yield is about 85 percent, and the L-tartrate crystal form A is obtained.

Identification of L-tartrate form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ: an error margin of ±0.2° exists for 4.48 °, 9.06 °, 11.57 °, 12.15 °, 13.54 °, 13.90 °, 14.45 °, 16.10 °, 16.75 °, 17.33 °, 18.23 °, 19.44 °, 20.49 °, 20.90 °, 21.19 °, 21.92 °, 22.40 °, 23.35 °, 23.60 °, 24.66 °, 25.32 °, 25.52 °, 26.27 °, 26.98 °, 27.32 °, 28.13 °, 28.46 °, 29.39 °, 29.71 °, 29.88 °, 31.15 °, 31.56 °, 32.73 °, 33.98 °, 35.28 °, 36.35 °, 37.21 °, 37.83 °, 38.55 °.

(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 c/min, including an endothermic peak at 195.09 c, with an error margin of ± 3 c.

(3) Identification by TA Q500 for Thermogravimetric (TGA) analysis: the temperature rise rate was 10 ℃/min, and when heated to 150.71 ℃, the weight loss was 1.177%, with a margin of error of + -0.1%.

Example 2: the benzene sulfonate crystal form A of the invention

1. Preparation of benzenesulfonate salt form A

The compound (388 mg) represented by the formula (I) was weighed, isopropyl alcohol (4 mL) and an aqueous benzenesulfonic acid solution (425 mg,75mass% in a molar ratio of 1:2) were added, and the mixture was stirred at room temperature, the turbidity increased, crystallization was apparent, and stirring was continued overnight. The solid was filtered, rinsed with n-heptane (2 mL), and dried under vacuum at 50deg.C to give a white solid powder as benzenesulfonate form A in about 83% yield.

2. Identification of benzenesulfonate form a

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ: an error margin of ±0.2° exists at 6.17 °, 8.01 °, 13.92 °, 14.92 °, 16.26 °, 17.17 °, 17.96 °, 19.11 °, 20.78 °, 21.75 °, 22.32 °, 23.13 °, 24.18 °, 24.85 °, 25.53 °, 26.10 °, 26.67 °, 27.25 °, 27.65 °, 28.40 °, 29.22 °, 29.70 °, 31.09 °, 31.85 °, 32.58 °, 33.16 °, 34.14 °, 35.13 °, 35.75 °, 36.32 °, 36.85 °, 37.30 °, 39.36 °.

(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 c/min, including endothermic peaks at 112.84 ℃, 121.04 ℃ and 198.05 ℃, with a margin of error of ±3 ℃.

Example 3: the benzene sulfonate crystal form B of the invention

1. Preparation of benzenesulfonate salt form B

The compound (1.14 g) shown in the formula (I) is weighed, ethyl acetate (12 mL) is added, the mixture is heated to 60 ℃ for dissolution, benzenesulfonic acid aqueous solution (0.76 g,75mass percent, molar ratio 1:1.2) is added dropwise, stirring is continued, turbidity is increased, crystallization is obvious, and stirring is continued overnight after cooling to room temperature. The solid was filtered, rinsed with n-heptane (10 mL), and dried under vacuum at 50deg.C to give a white solid powder, as benzenesulfonate form B, in about 93% yield.

2. Identification of benzenesulfonate form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:5.88 °, 9.48 °, 11.62 °, 11.81 °, 12.56 °, 14.24 °, 14.87 °, 16.23 °, 17.14 °, 17.40 °, 17.75 °, 18.11 °, 19.06 °, 19.94 °, 20.20 °, 20.76 °, 20.88 °, 21.38 °, 21.68 °, 22.33 °, 22.65 °, 23.12 °, 23.67 °, 24.09 °, 24.33 °, 24.80 °, 25.43 °, 25.83 °, 26.66 °, 27.08 °, 27.69 °, 27.95 °, 28.74 °, 29.21 °, 29.45 °, 29.81 °, 30.04 °, 30.67 °, 30.94 °, 31.22 °, 31.60 °, 31.92 °, 32.60 °, 34.28 °, 34.79 °, 35.15 °, 36.53 °, 37.15 °, 39.71 °; there is a margin of error of + -0.2 deg..

(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 c/min, including an endothermic peak at 198.42 c, with an error margin of ± 3 c.

Example 4: fumarate salt crystal form A of the invention

1. Preparation of fumarate salt form A

The compound (388 mg) shown in the formula (I) is weighed, ethyl acetate (8 mL) is added, the mixture is heated to 50 ℃ and stirred for dissolving, fumaric acid (245 mg, molar ratio 1:2.07) is added for stirring, stirring is continued after the temperature is reduced to room temperature, turbidity is increased, crystallization is obvious, and stirring is continued overnight. Filtering, and vacuum drying at 50 ℃ to obtain white solid powder, wherein the white solid powder is fumarate salt crystal form A, and the yield is about 85%.

2. Identification of fumarate salt form A

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ: an error margin of ±0.2° exists in 6.71 °, 7.94 °, 11.66 °, 13.23 °, 13.51 °, 14.52 °, 15.07 °, 16.00 °, 17.05 °, 18.45 °, 19.08 °, 19.47 °, 19.88 °, 20.35 °, 21.14 °, 22.74 °, 23.25 °, 24.30 °, 24.89 °, 25.02 °, 25.19 °, 25.69 °, 25.91 °, 26.47 °, 27.27 °, 27.76 °, 28.71 °, 29.33 °, 31.10 °, 31.68 °, 32.52 °, 34.24 °, 35.24 °, 35.84 °, 36.29 °, 37.70 °, 38.64 °.

(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 c/min, including an endothermic peak at 202.39 c, with an error margin of ± 3 c.

Example 5: fumarate salt form B of the invention

1. Preparation of fumarate salt form B

The compound (380 mg) shown in the formula (I) is weighed, added with ethyl acetate (8 mL), heated to 60 ℃ and stirred for dissolving, then added with fumaric acid (69.6 mg, molar ratio 1:0.6) for stirring, the turbidity is increased, crystallization is obvious, and stirring is continued overnight after cooling to room temperature. Filtering, and vacuum drying at 50 ℃ to obtain white solid powder, wherein the white solid powder is fumarate salt crystal form B, and the yield is about 88%.

2. Identification of fumarate salt form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, there are the following characteristic peaks expressed in degrees 2θ:8.53 °, 8.90 °, 11.35 °, 11.87 °, 14.45 °, 15.32 °, 15.51 °, 16.15 °, 16.70 °, 17.07 °, 17.76 °, 18.11 °, 18.36 °, 19.22 °, 19.66 °, 19.98 °, 20.20 °, 20.50 °, 21.22 °, 22.41 °, 23.18 °, 23.40 °, 23.99 °, 25.10 °, 26.05 °, 26.51 °, 26.79 °, 27.62 °, 27.83 °, 28.87 °, 29.85 °, 30.63 °, 31.33 °, 31.85 °, 32.49 °, 34.63 °, 36.71 °, and there is an error margin of ±0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimeter (DSC) analysis: the scan rate was 10 c/min, including an endothermic peak at 219.88 c, with an error margin of ± 3 c.

Example 6: pharmacokinetic experiments of the salts or crystalline forms of the invention

The inventors performed pharmacokinetic evaluations of the salts of the invention or crystalline forms thereof in Beagle dogs. Wherein, the animal information is shown in Table 1.

Table 1: subject animal information table of the invention

Germ line	Grade	Sex (sex)	Weight of body	Age of	Source
						Beagle dog	Common grade	Male male	8～12kg	For 6-12 months	BEIJING MARSHALL BIOTECHNOLOGY Co.,Ltd.

Experimental method

The sample for administration (i.e., the salt of the present invention or a crystalline form thereof, or the compound of formula (I) of the present invention) is filled into capsules for oral administration. Animals were fasted for 12h before dosing and were free to drink water. The capsule containing the sample to be tested was orally administered at a dose of 5mg/kg and was subjected to intravenous blood sampling (blood sampling amount of about 0.15 mL) at the following time points after administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours, EDTA-K is added in advance into the blood collection tube ₂ As an anticoagulant, the blood samples were centrifuged at 12,000rpm for 2 minutes, and the plasma was collected and stored at-20℃or-70 ℃.

The collected plasma samples were treated (frozen plasma was thawed at room temperature, vortexed for 5min, 20. Mu.L of plasma was taken, 120. Mu.L of acetonitrile solution containing an internal standard was added, vortexed for 5min, centrifuged at 4,000rpm for 5min, 100. Mu.L of supernatant was taken, 130. Mu.L of methanol-water (V/V=1/1) was added, and mixed, and then a standard curve was established in a suitable range according to the sample concentration, and the concentration of the sample to be tested in the plasma sample was measured in MRM mode using AB SCIEX API model 5500 LC-MS/MS, and quantitative analysis was performed. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated using the WinNonLin 6.3 software non-compartmental model method. The experimental results are shown in table 2.

Table 2: pharmacokinetic experimental data of the salts or crystalline forms of the invention

Sample for sample	T _max (h)	C _max (ng/ml)	AUC _last (h*ng/ml)
				Example 1 (L-tartrate crystal form A)	1.17	91.2	348
Compounds of formula (I)	3.67	32.8	117

Conclusion of experiment:

as shown in Table 2, compared with the compound shown in the formula (I), the L-tartrate crystal form A has higher blood concentration and larger exposure in Beagle dogs and has better pharmacokinetic property.

Example 7: stability test of the salt or the crystal form of the invention

(1)High temperature experiments: a batch of samples for sample supply is taken and put into a flat weighing bottle with a proper amount, and spread into a thin layer with the thickness less than or equal to 5mm, the weighing bottle is put into a constant temperature box with the temperature of 40+/-2 ℃/75+/-5% RH and/or 60+/-2 ℃/75+/-5% RH for 30 days, sampling is carried out on the 5 th, 10 th and 30 th days, and detection is carried out according to the important investigation item of stability: the color change of the sample was observed, the purity of the sample was checked by HPLC, and the structure was analyzed by X-ray powder diffraction.

(2)High humidity experiment: a batch of samples for sample preparation is taken and put into a flat weighing bottle, spread into a thin layer with the thickness less than or equal to 5mm, placed for 30 days under the conditions of 25 ℃ and RH 75% +/-5% or RH 90% +/-5%, sampled on the 5 th, 10 th and 30 th days, detected according to stability key investigation projects, sample color change is observed, sample purity is detected by HPLC, and an X-ray powder diffraction analysis structure is obtained.

(3)Illumination experiment: taking a batch of samples, placing into a flat weighing bottle, spreading into a thin layer with thickness less than or equal to 5mm, placing into an illumination box (with ultraviolet lamp), and placing the sample into a light box with illuminance of 4500+ -500 lx and ultraviolet light of more than or equal to 0.7w.h/m ² Is placed for 30 days, is sampled on days 5, 10 and 30, and is tested according to the stability important investigation project: the color change of the sample was observed, the purity of the sample was checked by HPLC, and the structure was analyzed by X-ray powder diffraction.

Experiments prove that under the experimental conditions of high temperature, high humidity and illumination, the appearance, purity and crystal form of the L-tartrate crystal form A are not obviously changed. Namely, the L-tartrate crystal form A has good stability under various lofting conditions and is suitable for pharmaceutical use.

Example 8: hygroscopicity test of the salt or the crystal form of the invention

The experimental method comprises the following steps:

1) Dry glass weighing bottle with stopper (outer diameter 50mm, height)15 mm) was placed in a constant temperature dryer (with saturated ammonium chloride solution placed in the lower part) at 25.+ -. 1 ℃ the previous day, and precisely weighed (m ₁ )。

2) Taking a proper amount of sample, spreading in the weighing bottle, and precisely weighing (m ₂ )。

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

4) The lid of the weighing bottle is covered, and the bottle is precisely weighed (m ₃ ) And (3) calculating: percent weight gain = (m ₃ -m ₂ )/(m ₂ -m ₁ )×100％

5) The wet permeability results are shown in Table 3.

Table 3: moisture absorption performance result judgment

Conclusion of experiment:

the L-tartrate crystal form A disclosed by the invention has no or almost no hygroscopicity, and is not easy to be affected by high humidity to deliquesce.

Example 9: solubility test of the salt or its crystal form of the present invention

And (3) placing the sample in organic ultrapure water at 37 ℃ to prepare supersaturated solution, oscillating for 24 hours, filtering with a water-based filter membrane to obtain filtrate, and detecting the solubility of the target sample in water by using an HPLC method. The experimental results are shown in table 4.

Table 4: solubility experimental data of the salt or the crystal form of the invention

Sample for sample	Concentration (mg/mL) of the compound represented by formula (I) in saturated aqueous solution
		Implementation of the embodimentsExample 1 (L-tartrate crystal form A)	42.91
Example 2 (benzenesulfonate Crystal form A)	1.89
		Example 4 (fumarate Crystal form A)	3.39
Compounds of formula (I)	2.59

Conclusion of experiment:

experimental results show that compared with the compound shown in the formula (I), the benzenesulfonate crystal form A and the fumarate crystal form A of the compound shown in the formula (I), the L-tartrate crystal form A has higher solubility in water, so that the L-tartrate crystal form A has better drug property and is more suitable for formulation development.

The above description is merely a basic description of the inventive concept, and any equivalent transformation according to the technical solution of the present invention shall fall within the protection scope of the present invention.

In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means 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 present invention. In this specification, schematic representations of the above terms are not necessarily directed 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, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.

While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims

1. Salts of the compounds of formula (I),

the salt is L-tartrate, the L-tartrate is L-tartrate crystal form A, and the X-ray powder diffraction pattern of the L-tartrate crystal form A has diffraction peaks at the following 2 theta angles: 11.57 ° ± 0.2 °, 12.15 ° ± 0.2 °, 13.54 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.45 ° ± 0.2 °, 16.10 ° ± 0.2 °, 16.75 ° ± 0.2 °, 17.33 ° ± 0.2 °, 19.44 ° ± 0.2 °, 21.19 ° ± 0.2 °, 21.92 ° ± 0.2 °, 22.40 ° ± 0.2 °, 26.98 ° ± 0.2 °.

2. The salt according to claim 1, wherein the L-tartrate salt is L-tartrate form a, and wherein the X-ray powder diffraction pattern of the L-tartrate form a has diffraction peaks at the following 2Θ angles: 4.48 ° ± 0.2 °, 9.06 ° ± 0.2 °, 11.57 ° ± 0.2 °, 12.15 ° ± 0.2 °, 13.54 ° ± 0.2 °, 13.90 ° ± 0.2 °, 14.45 ° ± 0.2 °, 16.10 ° ± 0.2 °, 16.75 ° ± 0.2 °, 17.33 ° ± 0.2 °, 18.23 ° ± 0.2 °, 19.44 ° ± 0.2 °, 20.90 ° ± 0.2 °, 21.19 ° ± 0.2 °, 21.92 ° ± 0.2 °, 22.40 ° ± 0.2 °, 23.35 ° ± 0.2 °, 23.60 ° ± 0.2 °, 24.66 ° ± 0.2 °; 25.32 ° ± 0.2 °, 25.52 ° ± 0.2 °, 26.27 ° ± 0.2 °, 26.98 ° ± 0.2 °, 27.32 ° ± 0.2 °, 28.13 ° ± 0.2 °, 28.46 ° ± 0.2 °, 29.39 ° ± 0.2 °, 29.71 ° ± 0.2 °, 29.88 ° ± 0.2 °, 31.15 ° ± 0.2 °, 31.56 ° ± 0.2 °, 32.73 ° ± 0.2 °, 33.98 ° ± 0.2 °, 35.28 ° ± 0.2 °, 36.35 ° ± 0.2 °, 37.83 ° ± 0.2 ° and 38.55 ° ± 0.2 °.

3. The salt of claim 1, wherein the L-tartrate salt is L-tartrate form a, said L-tartrate form a having the X-ray powder diffraction pattern substantially as shown in figure 1.

4. The salt of claim 1, wherein the L-tartrate salt is form a of L-tartrate salt, and wherein the differential scanning calorimetry trace of form a of L-tartrate salt comprises an endothermic peak at 195.09 ℃ ± 3 ℃.

5. The salt of claim 1, wherein the L-tartrate salt is L-tartrate form a, the L-tartrate salt form a having a differential scanning calorimeter substantially as shown in figure 6.

6. A pharmaceutical composition comprising the salt of any one of claims 1-5, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

7. Use of a salt according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for preventing, treating or alleviating 5-HT in a patient _1F Receptor-related diseases.

8. The use according to claim 7, wherein said peptide is associated with 5-HT _1F The receptor-related disorder is migraine, trigeminal neuralgia, toothache or temporomandibular joint dysfunction pain, autism, obsessive compulsive disorder, panic disorder, depression, social phobia, generalized anxiety disorder, sleep disorders, post-traumatic syndrome, chronic fatigue syndrome, premenstrual or post-luteal phase syndrome, borderline personality disorder, destructive behavior disorder, impulse control disorder, attention deficit hyperactivity disorder, alcoholism, tobacco abuse, mutism, hair-plucking nodules, bulimia, anorexia nervosa, premature ejaculation, erectile dysfunction, memory loss or dementia.

9. The use according to claim 7, wherein said peptide is associated with 5-HT _1F The receptor-related disorder is general pain or anxiety.

10. Use of a salt according to any one of claims 1-5 or a pharmaceutical composition according to claim 6 for the manufacture of a medicament for activating 5-HT _1F A receptor.