CN116425678A

CN116425678A - Hydrochloride of aminocyclobutane derivative and crystal form and preparation thereof

Info

Publication number: CN116425678A
Application number: CN202310003140.3A
Authority: CN
Inventors: 路苹; 张玲; 孙占莉; 董达文
Original assignee: Suzhou Enhua Biomedical Technology Co ltd
Current assignee: Suzhou Enhua Biomedical Technology Co ltd
Priority date: 2022-01-11
Filing date: 2023-01-03
Publication date: 2023-07-14

Abstract

The invention provides hydrochloride of an aminocyclobutane derivative, a crystal form and a preparation method thereof, and in particular relates to hydrochloric acid of a compound IThe hydrochloride and the crystal form thereof have the beneficial effects of better in-vivo bioavailability and quick effect, and particularly the crystal form I and the crystal form IV also have the advantages of good stability and no hygroscopicity. The invention also provides a pharmaceutical composition containing the crystal form and application thereof.

Description

Hydrochloride of aminocyclobutane derivative and crystal form and preparation thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to hydrochloride of an aminocyclobutane derivative, a crystal form and a preparation method thereof, in particular to hydrochloride of trans-3-amino-6 ' -chloro-2 ' -methyl-1 ',2' -dihydro-3 ' H-spiro [ cyclobutane-1, 4' -isoquinoline ] -3' -ketone, a crystal form and a preparation method thereof, a pharmaceutical composition containing the compound hydrochloride and application of the pharmaceutical composition in the field of medicines.

Background

NMDAR (N-methyl-D-aspartate receptor) is an ionic glutamate receptor, mainly against Ca ²⁺ The ions are permeable and can be activated after binding to glycine and glutamic acid, playing an important role in excitatory synaptic plasticity. Physiologically, they activate and trigger the opening of ion channels and produce input currents that deactivate only slowly. Can lead to the excessive activation of NMDAR in pathological conditions, and is an important pathogenesis of receptor excitotoxicity.

The physiological activity of NMDAR is essential for normal neurological function, excessive activation of NMDAR is involved in acute neurological diseases such as stroke or craniocerebral injury, and in chronic stress conditions such as neurodegenerative diseases, many pathologies are thought to be associated with NMDAR hyperactivity and are therefore potentially sensitive to NMDA antagonists ([ J ]. Journal of neurochemistry,2006,97 (6): 1611-1626.).

There is growing evidence that NMDAR is important in inducing and maintaining central sensitization in painful conditions. Furthermore NMDAR may also mediate peripheral sensitization andvisceral pain ([ J)]Nature,2005,438 (7071):1162.). A large amount of preclinical data supports the potential for NMDA antagonists to treat opioid-induced incurable pain, postoperative pain, cancer pain. Additional studies have shown that typical antidepressants alter the affinity of the glycine site of the NMDA receptor, that reduced NMDAR function contributes to the antidepressant response, that administration of a single intoxicated dose of ketamine by intravenous route to patients with refractory depression significantly improves their condition, and that the antidepressant effect obtained lasts for one week ([ J]Archives of general psychiatry,2006,63 (8): 856-864.) current nasal spray of S-ketamine

Batches have been marketed in the united states at 3 months 2019 for adjuvant therapy to treat resistant depression.

Depending on the site of action of NMDAR, they can be broadly classified into three classes, including non-competitive (or allosteric) antagonists (ATD sites), such as ifenprodil, RGH-896, evt101; competitive antagonists (LBD sites), such as GLYX-13, NRX-1074; non-competitive antagonists, channel pore blockers (TMD sites), such as ketamine, dextromethorphan, memantine, and the like. However, there are a number of side effects that remain widespread in the currently marketed NMDAR antagonists that limit their use, such as hallucinations, confusion, personality disorders, nightmares, agitation, attention deficit, mood changes, tics, sedation, and the like ([ J ]. Biochemical pharmacology,2003,66 (6): 877-886.). The higher the affinity of the NMDAR channel Kong Jie antibody, the slower its dissociation from the NMDAR, and the permanent blockade of NMDAR may lead to nerve hyperexcitability, producing a range of side effects and adverse reactions, such as MK-801, which dissociate at a slower rate from the NMDAR, leading to larger psychotropic side effects.

There have been studies to date that demonstrate that high affinity non-competitive NMDA receptor antagonists such as MK-801, while preventing NMDAR activation, prevent Ca ²⁺ Internal flow, but its use is limited by significant psychomimetic adverse effects. In contrast, low affinity, non-competitive NMDAR antagonists (such as memantine) can reduce toxicity due to the faster rate of blocking and leaving NMDAR by memantine ([ J)].European journal of pharmacolog, 1996,317 (2-3): 377-381). Additional studies have shown that the clinically good tolerability and symptomatic effect of memantine in the treatment of alzheimer's disease is due to its moderate affinity for the NMDA receptor channel and rapid dissociation from NMDAR ([ J]Neuropharmacology,2009,56 (5): 866-875); it has also been studied that memantine (diazocilpine) has better kinetics of inhibition recovery and is considered to be the main determinant of better clinical tolerability of memantine ([ J)]ACS chemical neuroscience,2018,9 (11): 2722-2730.). The ability to rapidly dissociate from NMDAR is therefore one of the keys to the development of NMDAR antagonists.

At present, although NMDAR inhibitors with a channel hole blocker (TMD site) are marketed, the effect of rapidly dissociating from NMDAR and reducing the mental side effects cannot be achieved, so that the NMDAR inhibitor is still a research hot spot in the field of mental nerves.

A series of 1',2' -dihydro-3 'H-spiro [ cyclobutane 1,4' -isoquinolines ] are disclosed in patent application PCT/CN2020/129826 ]-3' -ketone derivatives wherein 3-amino-6 ' -chloro-2 ' -methyl-1 ',2' -dihydro-3 ' h-spiro [ cyclobutane-1, 4' -isoquinoline]The 3' -ketone and the isomer thereof are novel reversible NMDAR antagonists, belong to channel hole blockers (TMD sites) and can inhibit channel opening caused by NMDAR overactivation under pathological conditions to avoid Ca ²⁺ Without affecting the normal function of NMDAR. Compared with the marketed NMDAR antagonist, the anti-depression drug has remarkable analgesic and anti-depression activities, has more outstanding therapeutic advantages of reducing the psychic-like adverse reaction, and has greater clinical use value.

3-amino-6 '-chloro-2' -methyl-1 ',2' -dihydro-3 'h-spiro [ cyclobutane-1, 4' -isoquinoline ] -3 '-one and trans-3-amino-6' -chloro-2 '-methyl-1', 2 '-dihydro-3' h-spiro [ cyclobutane-1, 4 '-isoquinoline ] -3' -one having structures represented by the following formula M and formula I, respectively:

there is no study reported in the prior art on the solid form of compound M, compound I.

Disclosure of Invention

The inventor finds that 3-amino-6 '-chloro-2' -methyl-1 ',2' -dihydro-3 'H-spiro [ cyclobutane-1, 4' -isoquinoline ] -3 '-ketone and trans-3-amino-6' -chloro-2 '-methyl-1', 2 '-dihydro-3' H-spiro [ cyclobutane-1, 4 '-isoquinoline ] -3' -ketone are poor in stability and easy to oxidize, and contact with oxygen in the production process can cause more oxidation impurities, which is unfavorable for the controllability of medicine quality.

It is therefore an object of the present invention to provide a solid form of a compound having better medicinal prospects, satisfying drug development and maximum therapeutic effects of the above-mentioned active substances in clinical use, for example, providing 3-amino-6 ' -chloro-2 ' -methyl-1 ',2' -dihydro-3 ' -methyl-1 ',2' -dihydro-3 ' h-spiro [ cyclobutane-1, 4' -isoquinoline ] -3' -one in a solid form having advantages in one or more of facilitating product handling during pharmaceutical development, enhancing thermodynamic stability, improving purity or improving bioavailability (e.g., better absorption, solubility, etc.), through extensive systematic studies on salts and crystalline forms of 3-amino-6 ' -chloro-2 ' -methyl-1 ',2' -dihydro-3 ' h-spiro [ cyclobutane-1, 4' -isoquinoline ] -3' -one.

The inventors unexpectedly found and demonstrated during the development process that the hydrochloride of the compound shown in formula I, in particular the hydrochloride hydrate of the compound shown in formula I and its crystalline form, have better physicochemical properties and improved pharmaceutical properties.

First, the present invention provides a hydrochloride salt of a compound of formula I: the hydrochloride is a hydrate of the hydrochloride of the compound shown in the formula I:

in one embodiment of the present invention, the water content of the hydrate of the hydrochloride of the compound of formula I is 5% to 12% (w/w), preferably 5.5% to 6.5% (w/w).

In one embodiment of the present invention, there is provided the hydrochloride monohydrate of the compound of formula I. Wherein, the mol ratio of the compound shown in the formula I to the hydrochloric acid is 1:1 to 1.5.

In one embodiment of the present invention, the hydrochloride of the compound represented by formula I is a monohydrochloride of compound I;

in one embodiment of the present invention, the hydrochloride of the compound of formula I is polymorphic, form I, form III or form IV; preferably, the crystal form I, the crystal form III or the crystal form IV is a hydrate or a solvate; when the crystalline form is a hydrate, the moisture content is generally 5% to 12% (w/w), preferably 5.5% to 6.5% (w/w). Wherein the moisture is preferably crystal water.

More preferably, the form I comprises water of crystallization, optionally also comprising adsorbed water, further preferably, the water of crystallization in the form I is 1 molar equivalent; preferably, form IV does not contain water of crystallization.

In a preferred embodiment of the present invention, there is provided a hydrochloride monohydrate of a compound of formula I, wherein the molar ratio of the compound of formula I to hydrochloric acid is 1:1, having a structure represented by the following formula IC:

crystal form I

In one embodiment of the present invention, there is provided a crystalline form I of the hydrochloride salt of a compound of formula I,

Powder X-ray diffraction pattern expressed in terms of 2θ using Cu-kα radiation: the powder X-ray diffraction pattern of form I includes peaks at diffraction angles (2θ) of 8.85 ° ± 0.2 °,9.38 ° ± 0.2 °,15.81 ° ± 0.2 °,18.84 ° ± 0.2 °,20.67 ° ± 0.2 °,23.24 ° ± 0.2 °,24.24 ° ± 0.2 °,26.40 ° ± 0.2 °,28.09 ° ± 0.2 °, and 31.98 ° ± 0.2 °.

Preferably, the powder X-ray diffraction pattern of form I includes peaks at diffraction angles (2θ) of 8.85 ° ± 0.2 °,9.38 ° ± 0.2 °,12.00 ° ± 0.2 °,15.81 ° ± 0.2 °,17.80 ° ± 0.2 °,18.84 ° ± 0.2 °,20.67 ° ± 0.2 °,23.24 ° ± 0.2 °,24.24 ° ± 0.2 °,26.40 ° ± 0.2 °,26.85 ° ± 0.2 °,28.09 ° ± 0.2 ° and 31.98 ° ± 0.2 °.

More preferably, the powder X-ray diffraction data for form I of the hydrochloride salt of the compound of formula I are shown in table 1:

table 1:

the crystal form I can also be characterized by DSC, and is analyzed and identified by a differential scanner, the temperature rising rate is 20 ℃/min, the DSC graph of the crystal form I shows an endothermic Peak in the range of 144.03 ℃ to 150.22 ℃, the initial value (Oset) temperature is 144.03 ℃, and the Peak value (Peak) temperature is 146.64 ℃; there is an endothermic Peak in the range of 264.98 ℃to 273.73 ℃with a start value (Oset) temperature of 264.98 ℃and a Peak (Peak) temperature of 269.38 ℃.

Form I of the present invention may also be characterized by thermal weight loss (TGA), analyzed by TGA: the rate of heating was 20 ℃/min and the weight loss was about 6.02% over a temperature range of 30 ℃ to about 160 ℃.

Thus, in a more preferred embodiment of the invention, the crystalline form I has one or more of the following features:

(1) A powder X-ray diffraction pattern substantially as shown in figure 1;

(2) By DSC analysis, the temperature rise rate is 20 ℃, and the temperature rise rate has endothermic peaks at the peak temperatures of 146.64 +/-3 ℃ and 269.38 +/-3 ℃;

(3) The temperature rise rate was 20 ℃/min by thermal weight loss (TGA) analysis, with a weight loss peak at a temperature range of 30 ℃ to 160 ℃ and a weight loss of about 6.02%.

In a preferred embodiment of the invention, form I of the hydrochloride salt of the compound of formula I, the water of crystallization is present in an amount of about 5.9% (w/w) to about 6.0% (w/w) as determined by DSC and TGA combinations, i.e. one molecule of water of crystallization is present per molecule of compound I hydrochloride form I.

In another aspect of the present invention, there is also provided a method for preparing the hydrochloride crystal form I of the compound of formula I, comprising the steps of:

dissolving a compound I in a first organic solvent, then adding the first organic solvent into a second organic solvent, then dropwise adding hydrochloric acid, stirring at room temperature, separating solid after the reaction is finished, and drying to obtain the compound I;

Preferably, the volume ratio of the first organic solvent to the second organic solvent is 1:10 to 20, the mol ratio of the compound I to the hydrochloric acid is 1:1 to 1.5;

further preferably, the first organic solvent is ethanol and the second organic solvent is tetrahydrofuran.

Form III

In another embodiment of the present invention, there is provided crystalline form III of the hydrochloride salt of the compound of formula I using Cu-ka radiation in a powder X-ray diffraction pattern expressed in terms of 2θ: the powder X-ray diffraction pattern of form III includes peaks at diffraction angles (2θ) of 10.82 ° ± 0.2 °,14.42 ° ± 0.2 °,16.83 ° ± 0.2 °,18.71 ° ± 0.2 °,19.02 ° ± 0.2 °,21.19 ° ± 0.2 °,21.58 ° ± 0.2 °,22.58 ° ± 0.2 ° and 25.27 ° ± 0.2 ° and 28.82 ° ± 0.2 °.

Further preferred, the powder X-ray diffraction pattern of form III of the hydrochloride salt of the compound of formula I comprises peaks at diffraction angles (2θ) of 10.82 ° ± 0.2 °,14.42 ° ± 0.2 °,15.99 ° ± 0.2 °,16.83 ° ± 0.2 °,18.71 ° ± 0.2 °,19.02 ° ± 0.2 °,21.19 ° ± 0.2 °,21.58 ° ± 0.2 °,22.58 ° ± 0.2 °,25.27 ° ± 0.2 °,25.96 ° ± 0.2 °,26.95 ° ± 0.2 °,28.82 ° ± 0.2 ° and 32.03 ° ± 0.2 °.

More preferably, the powder X-ray diffraction data for form III of the hydrochloride salt of the compound of formula I are shown in table 2:

Table 2:

most preferably, form III of the hydrochloride salt of the compound of formula I has a powder X-ray diffraction pattern substantially as shown in figure 2.

Form III can also be characterized by thermal loss on weight (TGA) using a simultaneous thermal analyzer, identified by TGA analysis: the heating rate was 10 c/min and there was about 10.56% (w/w) weight loss at a temperature ranging from room temperature to about 157 c.

In a preferred embodiment of the present invention, the form III is a solvate and the solvent is ethanol. Further, the inventors have found that form III is metastable relative to form I, and that form III can be converted to form I after desolvation of form III by vacuum drying.

In another aspect of the present invention, there is also provided a method for preparing form III, comprising the steps of:

dissolving a compound I in a first organic solvent, then adding the first organic solvent into a second organic solvent, then dropwise adding hydrochloric acid, stirring at room temperature, and separating solids after the reaction is finished to obtain the compound I;

preferably, the volume ratio of the first organic solvent to the second organic solvent is 1:3 to 5; the molar ratio of the compound I to the hydrochloric acid is 1:1 to 2.2, preferably 1:1.5 to 1.6;

further preferably, the first organic solvent is ethanol, and the second organic solvent is 1, 4-dioxane.

Crystal form IV

In another embodiment of the present invention, there is provided crystalline form IV of the hydrochloride salt of the compound of formula I, in powder X-ray diffraction pattern as expressed in terms of 2Θ: the powder X-ray diffraction pattern of form IV includes peaks at diffraction angles (2θ) of 5.16 ° ± 0.2 °,6.07 ° ± 0.2 °,10.03 ° ± 0.2 °,15.32 ° ± 0.2 °,15.78 ° ± 0.2 °,17.03 ° ± 0.2 °,19.87 ° ± 0.2 °,20.62 ° ± 0.2 °,21.88 ° ± 0.2 °,23.45 ° ± 0.2 °,24.56 ° ± 0.2 °,26.37 ° ± 0.2 °,28.05 ° ± 0.2 °, and 30.25 ° ± 0.2 °.

Further preferably, the powder X-ray diffraction pattern of form IV includes peaks at diffraction angles (2θ) of 5.16 ° ± 0.2 °,6.07 ° ± 0.2 °,10.03 ° ± 0.2 °,15.32 ° ± 0.2 °,15.78 ° ± 0.2 °,17.03 ° ± 0.2 °,18.80 ° ± 0.2 °,19.87 ° ± 0.2 °,20.62 ° ± 0.2 °,21.56 ° ± 0.2 °,21.88 ° ± 0.2 °,23.45 ° ± 0.2 °,24.56 ° ± 0.2 °,26.37 ° ± 0.2 °,27.36 ° ± 0.2 °,28.05 ° ± 0.2 °,28.68 ° ± 0.2 ° and 30.25 ° ± 0.2 °.

In a preferred embodiment of the present invention, the powder X-ray diffraction data for form IV are shown in table 3:

table 3:

form IV can also be characterized by DSC, with a scan rate of 10 ℃/min as determined by simultaneous thermal analysis, the DSC profile of form IV containing an endothermic peak (peak temperature) at 137.09 ℃ ± 3 ℃.

Thus, in a more preferred embodiment of the invention, the form IV has one or more of the following features:

(1) An X-ray powder diffraction pattern substantially as shown in figure 3;

(2) DSC characterization was performed by a simultaneous thermal analyzer, scanning at a rate of 10 ℃/min, with an endothermic peak (peak temperature) containing 137.09 ℃ + -3 ℃,

preferably, form IV of the present invention is free of water of crystallization.

In another aspect of the present invention, a method for preparing the crystal form IV is provided, comprising the steps of:

and (3) dissolving the compound I in a first organic solvent, then adding the first organic solvent into a second organic solvent, then dropwise adding a hydrogen chloride solution, stirring at room temperature, separating the solid after the reaction is finished, and drying to obtain the compound. Wherein the hydrogen chloride solution is dissolved in the second organic solvent from hydrogen chloride;

preferably, the volume ratio of the first solvent to the second organic solvent is 1:5 to 15, the mol ratio of the compound I to the hydrochloric acid is 1:1 to 1.5;

further preferably, the first organic solvent is ethanol, and the second organic solvent is ethyl acetate; the drying is vacuum drying at 40-60 ℃.

Hydrate of the salt：

The hydrate of the hydrochloride of the compound represented by formula I according to the present invention is a crystalline hydrate of the hydrochloride of the compound represented by formula I, and the hydrate contains about 5 to 12% (w/w) of water, preferably 5.5 to 6.5% (w/w) of water, and particularly 5.9 to 6.0% (w/w). The term "monohydrate" in this application means that crystalline hydrate containing 0.8 to 1.2 molecules of water per hydrochloride of the compound of formula I is referred to as "monohydrate", and preferably crystalline hydrate containing 1 molecule of water per molecule is referred to as "monohydrate".

In a preferred embodiment of the present invention, the water content in the hydrate is 5% to 12% (w/w), preferably 5.5% to 6.5% (w/w). Although the hydrate typically contains about 5% to 12% (w/w) water, it may also occur at lower water contents, for example, 5.5% to 6.5% (w/w), especially 5.9 to 6.0% (w/w). The crystal structure of the hydrate remains even if the hydrate is dried and the residual moisture content is as low as about 6.0% (w/w). If the humidity in the environment rises again, the water absorption (uptake) is reversible. The water content of the isolated product depends on the drying conditions during post-treatment of the hydrate after crystallization.

Therefore, the hydrochloride of the compound shown in the formula I or the crystal form thereof can absorb moisture due to the change of relative humidity, namely, water molecules in the air can easily enter and exit the crystal solid in the crystal lattice in the form of crystal water due to the change of external humidity; the above-mentioned crystalline solid may be interpreted as a crystalline solid which is substantially the same as the powder X-ray diffraction pattern having characteristic peaks described in the present specification even when the powder X-ray diffraction pattern varies slightly with the variation of the moisture content.

The water content of the hydrochloride hydrate of the compound shown in the formula I can be one or more of residual solvents such as crystal water, adhesion water and the like. For example, the hydrochloride salt of the compound of formula I, form I, contains 5% to 12% (w/w) moisture, preferably 5.5% to 6.5% (w/w), and form III is an ethanol solvate. In addition, the crystallization water may be introduced from moisture in the solvent during the crystallization.

The term "w/w" refers to the ratio of the weight of water in the sample to the weight of the sample, which is 100%.

In a preferred embodiment of the present invention, there is provided a hydrochloride monohydrate of a compound having the formula I, the structure being shown in formula IC below:

in a preferred embodiment of the invention, the hydrate of formula IC has a crystalline water content of about 5.9%.

In a preferred embodiment of the present invention, there is provided a hydrochloride monohydrate of the compound of formula I in crystalline form as described for form I above.

The water of crystallization in the hydrochloride hydrate can also be characterized from DSC and TGA profiles. In one embodiment of the invention, form I is analyzed by TGA as shown in TGA profile in fig. 6 and DSC profile in fig. 7: the weight loss is about 6.02% over a temperature range of 30 ℃ to about 160 ℃. The DSC graph shows an endothermic Peak in the range of 144.03-150.22 ℃, the initial value (Oset) temperature is 144.03 ℃, the Peak (Peak) temperature is 146.64 ℃, and the DSC graph is combined with TGA analysis, and the DSC graph is the endothermic Peak when the sample loses crystal water; there is an endothermic Peak in the range 264.98 ℃to 273.73 ℃with a start value (Oset) temperature of 264.98 ℃and a Peak (Peak) temperature of 269.38 ℃which is the melting point of the sample.

The water content of the hydrate may also be determined by other methods known in the art, such as Karl-Fischer titration.

Crystalline composition

The term "crystalline composition" refers to a solid form comprising one or more crystalline forms of the invention (e.g., forms I, III and/or IV). The amount of the crystalline form included in the crystalline composition may each independently be 50% or more, 80% or more, 90% or more, or 95% or more. In addition to the crystalline forms of the invention, the crystalline composition may optionally contain other crystalline forms or other amorphous forms of the compound of formula I or a salt thereof (e.g. hydrochloride salt) or impurities other than these. It will be appreciated by those skilled in the art that the sum of the contents of the individual components in the crystalline composition should be 100%.

In one embodiment of the present invention, there is provided a crystalline composition wherein the crystalline form I of the hydrochloride salt of the compound of formula I according to the present invention comprises 50% or more, or 80% or more, or 90% or more, or 95% or more by weight of the crystalline composition;

in another embodiment of the present invention, there is provided a crystalline composition wherein form III of the hydrochloride salt of the compound of formula I of the present invention comprises 50% or more, or 80% or more, or 90% or more, or 95% or more by weight of the crystalline composition;

In another embodiment of the present invention, there is provided a crystalline composition wherein form IV of the hydrochloride salt of the compound of formula I of the present invention comprises 50% or more, or 80% or more, or 90% or more, or 95% or more by weight of the crystalline composition.

In another embodiment of the present invention, there is provided a crystalline composition wherein the crystalline form I of the present invention comprises not less than 90% by weight of the crystalline composition and the sum of the amounts of crystalline form III and crystalline form IV comprises not more than 10% by weight of the crystalline composition.

Pharmaceutical composition and indications

In another embodiment of the present invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of the hydrochloride salt of the compound of formula I, and/or the hydrochloride hydrate of the compound of formula I, and/or the hydrochloride form I of the compound of formula I, and/or the hydrochloride form III of the compound of formula I, and/or the hydrochloride form IV of the compound of formula I.

In addition, the pharmaceutical composition may or may not further comprise pharmaceutically acceptable carriers, excipients and/or vehicles.

The pharmaceutical compositions of the invention may be prepared by combining a compound of the invention or a salt thereof with a suitable pharmaceutically acceptable carrier, e.g., in solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.

Typical routes of administration of the hydrochloride salt of compound I of the present invention or a crystalline form thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

In a preferred embodiment, the pharmaceutical composition is in oral form.

In another embodiment of the invention, the use of the hydrochloride of the compound of formula I, and/or the hydrochloride hydrate of the compound of formula I, and/or the hydrochloride crystal form I of the compound of formula I, and/or the hydrochloride crystal form III of the compound of formula I, and/or the hydrochloride crystal form IV of the compound of formula I in the preparation of a medicament for treating neuropsychiatric diseases is also provided.

Preferably, the neuropsychiatric disorder is one or more of pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative disorders, bipolar disorders, post-traumatic stress syndrome, addictive disorders, withdrawal syndrome or attention deficit disorder; more preferably, the neuropsychiatric disease is any one or more of pain, depression, anxiety, schizophrenia, sleep disorders, neurodegenerative diseases or bipolar disorders, and even more preferably, the neuropsychiatric disease is depression, neurodegenerative diseases or pain.

The beneficial effects of the invention are as follows:

firstly, the hydrochloride of the compound shown in the formula I and the crystal form thereof have the advantage of good solubility compared with the compound in a free base form, and the hydrochloride of the compound shown in the formula I, particularly the crystal form I, also has the advantage of improved pharmacokinetic performance, better in vivo bioavailability and quick effect; in addition, form I and form IV also have good stability, and solubility.

And secondly, compared with free alkali, the hydrochloride of the compound shown in the formula I has better chemical stability, effectively solves the problem that amino groups in the free alkali structure are easy to be oxidized and degraded, has obvious significance for preparation production, storage, use, safety, effectiveness, quality controllability and the like of medicines, and can meet the performance requirements of preparing preparations for oral administration.

Thirdly, the hydrochloride hydrate of the compound shown in the formula I, particularly the crystal form I, has the advantages of enhanced thermodynamic stability, improved solubility, hygroscopicity and improved pharmacokinetic performance, is beneficial to simplifying product treatment and storage procedures in the later drug development and maximally plays a role in treating active substances.

Drawings

The technical scheme of the application is further described below with reference to the accompanying drawings and examples.

FIG. 1 is an XRPD pattern for form I of the hydrochloride salt of the compound of formula I;

FIG. 2 is an XRPD pattern for form III of the hydrochloride salt of the compound of formula I;

FIG. 3 is an XRPD pattern for form IV of the hydrochloride salt of the compound of formula I;

FIG. 4 is a graph comparing XRPD patterns of the hydrochloride salt of the compound of formula I for 10 days at 25 ℃ + -3 ℃, 60% + -5% RH and 40 ℃ + -3 ℃, 75% + -5% RH, respectively, with those of the hydrochloride salt of the compound of formula I for 0 day;

FIG. 5 is a comparison of XRPD patterns of form I of the hydrochloride salt of the compound of formula I after 5 days of standing at 80% + -4% RH humidity with XRPD patterns at day 0 of standing;

FIG. 6 is a TGA spectrum of form I of the hydrochloride salt of the compound of formula I;

FIG. 7 is a DSC of form I of the hydrochloride of the compound of formula I;

fig. 8 is a graph of the solubility curves of the hydrochloride form I of the compound of formula I in different media species.

Detailed Description

All parts and percentages in this application are by weight unless otherwise indicated, implied from the context or routine in the art. If the definition of a particular term disclosed in the prior art does not conform to any definition provided in this application, the definition of that term provided in this application controls.

The words "preferably," "preferred," "more preferred," and the like in the present disclosure refer to embodiments of the present disclosure that may provide certain benefits in some instances. However, other embodiments may be preferred under the same or other circumstances.

The term "polymorphism" as used herein means a crystal having a certain crystal form and comprising atoms, ions, molecules, and the like constituting a solid in a regular arrangement. Unless otherwise indicated, the term "crystalline" in this specification is synonymous with "polymorphic form" and "crystalline form". The crystallinity of the crystalline form can be measured by a variety of techniques including, for example, powder X-ray diffraction measurement, differential scanning calorimetry (TGA) analysis, dissolution characteristics, and the like.

The invention discloses a compound I and a compound shown in a formula I, wherein the compound I and the compound shown in the formula I can be mutually replaced by trans-3-amino-6 ' -chloro-2 ' -methyl-1 ',2' -dihydro-3 ' H-spiro [ cyclobutane-1, 4' -isoquinoline ] -3' -ketone, and all refer to a compound with a structure shown in the formula I:

the crystalline forms of the hydrochloride salts of compound I according to the invention are characterized by their powder X-ray diffraction patterns. That is, using cu—kα radiation, a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ angle was obtained. The term "2θ" or "2θ angle" refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree.

In powder X-ray diffraction spectra, diffraction patterns derived from crystalline compounds are often characteristic for specific crystals, where the absolute and relative intensities of the peaks displayed may vary due to various factors, such as the effect of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the substance analyzed, or the degree of crystallization of the sample. Thus, the relative intensities of the diffraction peaks are not characteristic for the crystals aimed at. It is determined whether or not the relative positions of peaks, rather than their relative intensities, are concurrent with the known crystalline phases.

Furthermore, there may be slight errors in the position of the peaks for any given crystal, as is also well known in the crystallographic arts. For example, the position of the peak may be shifted due to a change in temperature at the time of analyzing the sample, a shift in the sample, or calibration of the instrument, etc., and the measurement error range of the 2θ value may be ±0.3, ±0.2, ±0.1, preferably ±0.2. Therefore, this error should be taken into account when determining each crystalline structure. For isomorphous crystals of the same compound, the peak positions of the XRPD spectra have similarities overall, and the relative intensity errors may be large.

In addition to the aforementioned determination of the polymorphic form of the hydrochloride salt of compound I or a hydrate thereof by powder X-ray diffraction spectroscopy, the determination may also be performed by thermal analysis methods, including, for example, but not limited to DSC, TG/DTA, raman.

The "differential scanning calorimetric analysis or DSC" described in the present invention measures the transition temperature when the crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal. For the isoforms of the same compound, the thermal transition temperature and melting point errors may be within about 5 ℃, typically within about 3 ℃ in successive assays. When a compound is described as having a given DSC peak or melting point, it is referred to that DSC peak or melting point ± 5 ℃. "substantially" also takes such temperature variations into account.

As used herein, "thermogravimetric analysis (TGA)" is a common method of determining the thermal stability of a compound. In the present invention, TGA can also be used to determine the hydration state of a compound, and the rate of temperature rise during the test will have some effect on the profile. The error in TGA may be within about ±0.5 mass%.

In the present invention, the powder X-ray diffraction pattern is collected on an alis X-ray powder diffractometer of the family panaceae, and the test temperature is a conventional temperature, for example 25 ℃. The X-ray powder diffraction method has the following parameters:

X-ray reflection parameters: cu, K alpha

Wavelength:

tube pressure: 40KV

Tube flow: 15mA

Step size: 0.0110 DEG

Scanning each step of time: 18.87s

Scanning range: from 3.0 to 40.0 degrees.

The conventional chemicals used in the examples below are all commercially available. The test method is carried out according to conventional conditions or conditions recommended by manufacturers.

Preparation of Compound I:

step 1:2- (3-chlorophenyl) -N-methylacetamide (M01)

In a 100mL single-necked flask, 5g of 3-chloroacetic acid (29.31 mmol) was dissolved in 50mL of methylene chloride, and 4.53g of thionyl chloride (38.10 mmol) and 1.07g of N, N-dimethylformamide (14.66 mmol) were added at 0℃and stirred at room temperature under nitrogen for 1 hour. The solvent was pumped dry by a concentrated oil pump, dissolved in 25mL of dichloromethane, 29.3mL of methylamine (2M THF) (58.62 mmol) was added at 0deg.C, and the reaction was stirred at room temperature for 12 hours. After the reaction, 50mL of water and 40mL of dichloromethane were added to extract an organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (dichloromethane: methanol=30:1, v/v) to obtain the title compound M01.

Step 2: 6-chloro-2-methyl-1, 4-dihydroisoquinolin-3 (2H) -one (M02)

In a 50mL single-necked flask, 1.95g of Compound M01 (11.43 mmol), 412mg of paraformaldehyde (13.72 mmol) and 15mL of Eaton's reagent were added, and the mixture was stirred at 80℃for 2 hours under nitrogen atmosphere. After the reaction, 70mL of water and 25mL of dichloromethane were added to extract an organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate=5:1, v/v) to obtain the title compound M02.

Step 3: tert-butyl ((1, 3-dibromoprop-2-yl) oxy) dimethylsilane (M03)

In a 250mL single-necked flask, 10g of 1, 3-dibromo-2-propanol (45.89 mmol), 6.25g of imidazole (91.78 mmol) and methylene chloride (100 mL) were added, and 8.3g of t-butyldimethylchlorosilane (TBSCl, 55.07 mmol) was added at 0℃and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, 200mL of water and 100mL of methylene chloride were added, an organic phase was extracted, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate=30:1, v/v) to obtain 14.96g of the title compound as a colorless liquid, with a yield of 99.7%.

Step 4:3- ((tert-Butyldimethylsilanyloxy) -6' -chloro-2 ' -methyl-1 ',2' -dihydro-3 ' H-spiro [ cyclobutane-1, 4' -isoquinolin-3 ' -one (M04)

In a 100mL single-necked flask, 0.93g of Compound M02 (4.77 mmol) was dissolved in 20mL of Tetrahydrofuran (THF), 2mL of hexamethylphosphoric triamide (HMPA) was added thereto, and 4.2mL of n-butyllithium (10.49 mmol) was added dropwise thereto at-40℃under nitrogen protection, and the mixture was stirred at that temperature for 1 hour. A further 1.9g of Compound M03 (5.72 mmol) in THF (5 mL) was added and the reaction stirred at room temperature for 12 hours. After the reaction, 40mL of water and 25mL of ethyl acetate are added for extraction to obtain an organic phase, the organic phase is decompressed and concentrated to obtain a crude product, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate=5:1, v/v) to obtain the target compound M04.

Step 5:6' -chloro-2 ' -ethyl-3-hydroxy-1 ',2' -dihydro-3 ' H-spiro [ cyclobutane-1, 4' -isoquinoline ] -3' -one (M05)

In a 50mL single-necked flask, 731.9mg of Compound M04 (2.0 mmol) was dissolved in 10mL of Tetrahydrofuran (THF), 3mL of tetrabutylammonium fluoride (TBAF, 3.0 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, 40mL of water and 25mL of ethyl acetate were added to extract an organic phase, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate=1:1, v/v) to obtain the title compound M05.

Step 6:2- (6 ' -chloro-2 ' -ethyl-3 ' -oxo-2 ',3' -dihydro-1 ' H-spiro [ cyclobutane-1, 4' -isoquinoline ] -3-yl) isoindoline-1, 3-dione (M06)

In a 50mL single-necked flask, 435.4mg of Compound M05 (1.73 mmol), 305mg of phthalimide (2.08 mmol) and 545mg of triphenylphosphine (PPh) were added ₃ 2.08 mmol) was dissolved in 5mL Tetrahydrofuran (THF), 362mg diethyl azodicarboxylate (DEAD, 2.08 mmol) was added at 0deg.C, and the reaction was stirred under nitrogen for 12 hours from 0deg.C to room temperature. After the reaction, adding 40mL of water and 25mL of ethyl acetate for extraction to obtain an organic phase, concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by a pre-prepared plate (petroleum ether: ethyl acetate=1:1, v/v) to obtain a crude product of the target compound M06.

Step 7: 3-amino-6 ' -chloro-2 ' -ethyl-1 ',2' -dihydro-3 ' hydro-spiro [ cyclobutane-1, 4' -isoquinoline ] -3' -one (M)

In a 50mL single-necked flask, 315mg of the product of the previous step (0.86 mmol) and 5mL of ethanolamine were added, and the mixture was stirred at 70℃for 1 hour. After the reaction, 20mL of water and 15mL of dichloromethane are added for extraction to obtain an organic phase, the organic phase is decompressed and concentrated to obtain a crude product, and the crude product is separated by a pre-prepared plate (dichloromethane: methanol=10:1, v/v) to obtain the target compound M with the purity of 99.40%.

Subjecting the compound of formula M to preparative HPLC (mobile phase A: H ₂ O (0.1% TFA), mobile phase B acetonitrile, column chromatography C18,5um,4.6X250mm, flow rate 15mL min ^-1 ) The separation can obtain the compound I and the compound II respectively.

A compound of formula I: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.58(d,J＝4.0Hz,1H),7.26-7.20(m,2H),4.47(s,2H),3.75-3.67(m,1H),3.10(s,3H),2.98-2.92(m,2H),2.20-2.13(m,2H)；[M+H] ⁺ 251.1

a compound of formula II: ¹ H NMR(400MHz,Methanol-d ₄ )δ7.67(d,J＝4.0Hz,1H),7.32-7.24(m,2H),4.53(s,2H),4.12-4.03(m,1H),3.12(s,3H),3.05-3.02(m,2H),2.53-2.27(m,2H).；[M+H] ⁺ 251.1

EXAMPLE 1 preparation of Compound I hydrochloride form I

Compound I (0.3982 g,1.59 mmol) was dissolved in ethanol (0.53 mL), 34. Mu.L of solution was taken and 480. Mu.L of tetrahydrofuran was added, 10.2. Mu.L of 37% by mass hydrochloric acid was added dropwise, the reaction was stirred at room temperature for 8 hours, centrifuged, and the resulting solid was dried in vacuo for 4 hours.

1) Cl was measured by ion chromatography ^- The actual content is 11.62%, and the molar ratio of the compound I to the hydrochloric acid is 1:1 when salifying, cl ^- The theoretical content is 11.64%.

2) ¹ H NMR(400MHz,DMSO-d6)：δ8.41(s,3H),7.83(s,1H),7.34(d,J＝8.2Hz,1H),7.26(d,J＝8.2Hz,1H),4.49(s,2H),3.94-3.88(m,1H),3.01(s,3H),2.84-2.79(m,2H),2.58-2.52(m,2H)。

3) Identified by the aeies X-ray powder diffraction (XRPD) analysis, using Cu-ka radiation, had the following characteristic peaks expressed in degrees 2θ:8.85 °,9.38 °,15.81 °,18.84 °,20.67 °,23.24 °,24.24 °,26.40 °,28.09 °, and 31.98 °, there is a margin of error of ±0.2 °. The XRPD data are shown in table 1, supra, and the XRPD pattern is shown in fig. 1.

4) Thermogravimetric analysis (TGA)

TGA detection was performed using a TGA thermal analyzer model PerkinElmer Pyris,

test conditions:

sweep gas: nitrogen gas;

rate of temperature rise: 20 ℃/min

Temperature range: 30-300 ℃;

detection result: as shown in the TGA profile of fig. 6, form I loses weight 6.02% from 30 ℃ to 160 ℃ and, in combination with the moisture detection results of the sample, the sample contains water of crystallization.

(5) DSC analysis:

analysis and identification by METLER TOLEDO DSC differential scanner, determination conditions: the nitrogen atmosphere and the heating rate are 20 ℃/min, the heating range is 30 ℃ to 300 ℃, and the detection results are shown in the following table 4 and fig. 7:

table 4: DSC detection result

As can be seen from the DSC analysis chart (fig. 7), there is an endothermic Peak in the range of 144.03-150.22 ℃, the Onset value is 144.03 ℃, the Peak value is 146.64 ℃, and the endothermic Peak is shown by combining with the TGA chart when the sample loses crystal water; there is an endothermic Peak in the range of 264.98-273.73 ℃, the Oset value is 264.98 ℃, the Peak value is 269.38 ℃, and the melting point of the sample is obtained.

The resulting crystalline form of compound I hydrochloride (1:1) is the monohydrate crystalline form, combining DSC and TGA profile analysis.

Instrument model: METLER TOLEDO DSC differential scanner

Example 2: preparation of Compound I hydrochloride form III

Compound I (1.237 g,4.95 mmol) was dissolved in ethanol (2 mL), 100. Mu.L of the solution was taken and added to 800. Mu.L of 1, 4-dioxane, 24. Mu.L of 37% by mass hydrochloric acid was added dropwise, the reaction was stirred at room temperature for 12 hours, the solid hydrochloride of compound I was obtained by centrifugation, and the residual solid containing the solvent was directly tested for XRPD.

1) Identified by the aeies X-ray powder diffraction (XRPD) analysis, using Cu-ka radiation, had the following characteristic peaks expressed in degrees 2θ:10.82 °,14.42 °,16.83 °,18.71 °,19.02 °,21.19 °,21.58 °,22.58 °,25.27 °,26.95 °,28.82 °, and 32.03 ° have an error margin of ±0.2°, XRPD data are shown in table 2 above, XRPD patterns are shown in fig. 2, and compound I hydrochloride form III is shown.

2) Thermogravimetric analysis (TGA) plots were collected on a mertrer-tolidol TGA/DSC 3+ simultaneous thermal analyzer, scan rate: 10 ℃/min, shielding gas: nitrogen gas; TGA profile shows a ramp rate of 10 ℃/min and a weight loss of 10.56% over a temperature range from room temperature to about 157 ℃.

3) The hydrochloride was dried in vacuo to remove the solvent and form III was converted to form I, with the XRPD pattern shown in figure 1.

EXAMPLE 3 preparation of Compound I hydrochloride form IV

Compound I (9.38 g,37.52 mmol) was dissolved in ethanol (12 mL), 150mL of ethyl acetate was added, and an ethyl acetate solution of about 19.7mL of 2.0mol/L hydrogen chloride was added dropwise, the reaction was stirred at room temperature for 20 hours, centrifuged, and the resulting solid was dried under vacuum at 40℃for 6 hours.

1) Identified by the aeies X-ray powder diffraction (XRPD) analysis, using Cu-ka radiation, had the following characteristic peaks expressed in degrees 2θ: there are error margins of + -0.2 deg. for 5.16 deg., 6.07 deg., 10.03 deg., 15.32 deg., 15.78 deg., 17.03 deg., 19.87 deg., 20.62 deg., 21.56 deg., 21.88 deg., 23.45 deg., 26.37 deg., 28.05 deg., and 30.25 deg.. XRPD data are shown in table 3 above, XRPD patterns are shown in fig. 3, compound I hydrochloride form IV.

2) Differential Scanning Calorimetric (DSC) plots were collected on TA DSC25 and mertrel-tolidol TGA/DSC 3+ simultaneous thermal analyzers, respectively, with ramp rates: 10 ℃/min, shielding gas: nitrogen gas.

DSC showed a scan rate of 10 ℃/min, containing an endothermic peak (peak temperature) of 137.09 ℃, with a margin of error of + -3 ℃.

Test example 1: accelerated stability study

Samples of a suitable amount of compound I hydrochloride form I were taken, tiled in glass vials to a thickness of about 1.5mm, and the vials were placed in an open environment at 25 ℃ ± 3 ℃ and 60% ± 5% relative humidity (i.e., room temperature, room humidity) and 40 ℃ ± 3 ℃ and 75% ± 5% relative humidity, respectively, sampled at 5 days and 10 days, subjected to XRPD assay while HPLC purity (%) assay, and compared to the 0 day results, as shown in table 5 and fig. 4.

Table 5: accelerated stability test results

Annotation: HPLC purity was normalized.

The test result shows that the physical and chemical purity of the hydrochloride crystal form I of the compound I is not changed under the conditions of 25+/-3 ℃, 60+/-5% RH and 75% RH of 40+/-3 ℃ respectively, which indicates that the stability is good and the compound I is not easy to oxidize after salification.

As can be seen from fig. 4, the compound I hydrochloride form I has better stability, and no seeding occurs when it is left for 10 days under the conditions of 25 ℃ ± 3 ℃, 60% rh±5% and 40 ℃ ± 3 ℃, 75% rh±5%.

Test example 2: hygroscopicity test

Taking a proper amount of hydrochloride crystal form I sample of the compound I, spreading the sample in a glass bottle with the thickness of about 1mm, placing the glass bottle in a sealed environment with the temperature of 25+/-1 ℃ and the relative humidity of 80+/-4%, and checking the hygroscopicity of the crystal form I after constant humidity for 5 days. The results of hygroscopicity of the hydrochloride form I are shown in table 6 and fig. 5 below.

Table 6: results of hygroscopicity detection of hydrochloride form I of Compound I

The test results show that: the hydrochloride crystal form I has moisture absorption weight gain of 0.11 percent and less than 0.2 percent after being placed for 5 days under the RH condition of 80% +/-4 percent, and the crystal form I has no moisture absorption property according to the guiding principle of a drug moisture absorption property test, and the XRPD result shows that the crystal form is not changed.

The hydrochloride form IV of the compound I is tested by the same method, and the result shows that the form IV has basically no hygroscopicity.

Test example 3: solubility test

The solubility of the drug substance in 4 conventional pH media (1.0, 4.5, 6.8 and water) was examined

Test article: compound I, compound I hydrochloride form I as free base (prepared in example 1).

(1) 4 media (pH 1.0, 4.5, 6.8 and water) were formulated according to the 2020 chinese pharmacopoeia 4 part convention:

pH1.0 hydrochloric acid solution: hydrochloric acid 9.00ml, diluted with water to 1000ml, to give a hydrochloric acid solution of pH 1.22;

acetate buffer at pH 4.5: sodium acetate (18.02 g) acetic acid (9.80+3ml) was diluted to 1000ml with water to give acetate buffer at pH 4.55;

phosphate buffer at pH 6.8:

0.2mol/L NaOH solution: 8.00g NaOH is taken, and water is added for dissolution and dilution to 1000ml;

0.2mol/L KH ₂ PO ₄ solution: 27.22g KH was taken ₂ PO ₄ Adding water to dissolve and dilute to 1000ml;

taking 0.2mol/L KH ₂ PO ₄ 250ml of solution and 118ml of 0.2mol/L NaOH solution, and adding water to dilute to 1000ml to obtain phosphate buffer solution with pH of 6.85;

Water: the pH was 7.23;

(2) Lofting and sampling detection-constant temperature steam bath oscillation box (37.0 ℃,250 rpm): triplicate samples were prepared in parallel for each medium, 1g/3ml, measured for pH at 0, 0.5h, 2h, 4h, 12h, 24h, and sampled for 200ul filtration, diluted 400-fold for liquid phase detection.

The detection result of the compound I hydrochloride crystal form I is shown in fig. 8, and the compound I hydrochloride crystal form I can be seen to have better solubility in 4 media.

Wherein the solubility of the hydrochloride crystal form I of the compound I in a phosphate buffer solution medium with the pH value of 6.8 is 242.8mg/mL (the solubility is reduced to 211.97mg/mL of free base), and the solubility of the compound I in the free base form in the phosphate buffer solution medium with the pH value of 6.8 is 39.4mg/mL which is obviously lower than that of the hydrochloride crystal form I by the same method.

The results of testing the crystal form IV by the same method show that the hydrochloride crystal form IV of the compound I has remarkable advantages in the aspect of improving the solubility compared with the free alkali.

Test example 4: pharmacokinetic testing

The above-mentioned compound I in the form of a free base (abbreviated as "free base") and the hydrochloride form I (abbreviated as "form I") of the compound I prepared in example 1 were each dissolved in physiological saline (injectable grade) to prepare test samples.

This study examined the pharmacokinetic profile of the free base as well as of oral administration of form I in rats (PO: oral administration) using LC-MS method.

Experiment design:

animal administration

Each group of 4 SD rats were fasted for 12 hours before the experiment, were freely drunk, were given with the above-mentioned free base and the crystal form I liquid medicine according to the set dose and the administration mode (PO: 10mg/kg; calculated as free base), 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h after administration, respectively orbital blood sampling of 0.3mL, placed in a centrifuge tube, centrifuged to separate plasma, and frozen and stored in a refrigerator at-20 ℃ for testing. The pharmacokinetic parameters of the free base, form I, in rats are shown in table 7.

TABLE 7 rat pharmacokinetic parameters of free base and Crystal form I

In vivo pharmacokinetic study is carried out on the hydrochloride crystal form IV of the compound I by adopting the same method, and the result shows that the hydrochloride crystal form IV of the compound I has better pharmacokinetic performance compared with free alkali.

Claims

1. A hydrochloride salt of a compound of formula I, wherein the hydrochloride salt is an hydrate of the compound of formula I:

preferably, the water content of the hydrochloride hydrate is 5% to 12% (w/w), more preferably 5.5% to 6.5% (w/w).

2. The hydrochloride of the compound of formula I according to claim 1, wherein the hydrochloride is a hydrochloride monohydrate of the compound of formula I having the structure of formula IC:

3. A crystalline form I of the hydrochloride salt of the compound of formula I, characterized by a powder X-ray diffraction pattern expressed in terms of 2Θ angles using Cu-ka radiation: the powder X-ray diffraction pattern of form I includes peaks at diffraction angles (2θ) of 8.85 ° ± 0.2 °,9.38 ° ± 0.2 °,15.81 ° ± 0.2 °,18.84 ° ± 0.2 °,20.67 ° ± 0.2 °,23.24 ° ± 0.2 °,24.24 ° ± 0.2 °,26.40 ° ± 0.2 °,28.09 ° ± 0.2 °, and 31.98 ° ± 0.2 °

4. Form I according to claim 3, characterized in that it has one or more of the following features:

(1) A powder X-ray diffraction pattern substantially as shown in figure 1;

(2) By DSC analysis, the temperature rise rate is 20 ℃/min, and the peak temperature is 146.64 ℃ +/-3 ℃ and 269.38 ℃ +/-3 ℃ and has an endothermic peak;

(3) By TGA analysis, the temperature rise rate was 20 ℃/min, and the weight loss peak was found to be about 6.02% at a temperature range of 30 ℃ to 160 ℃.

5. The crystalline form I according to any one of claims 3 to 4, wherein the hydrochloride salt of the compound of formula I is the hydrochloride monohydrate of the compound of formula I.

6. A process for the preparation of the hydrochloride crystalline form I of a compound of formula I according to any one of claims 3 to 5, comprising the steps of:

7. A crystalline form III of the hydrochloride salt of the compound of formula I, characterized by a powder X-ray diffraction pattern expressed in terms of 2Θ angles using Cu-ka radiation: the powder X-ray diffraction pattern of form III comprises peaks at diffraction angles (2θ) of 10.82 ° ± 0.2 °,14.42 ° ± 0.2 °,16.83 ° ± 0.2 °,18.71 ° ± 0.2 °,19.02 ° ± 0.2 °,21.19 ° ± 0.2 °,21.58 ° ± 0.2 °,22.58 ° ± 0.2 ° and 25.27 ° ± 0.2 ° and 28.82 ° ± 0.2 °;

Preferably, the powder X-ray diffraction pattern of form III comprises peaks at diffraction angles (2θ) of 10.82 ° ± 0.2 °,14.42 ° ± 0.2 °,15.99 ° ± 0.2 °,16.83 ° ± 0.2 °,18.71 ° ± 0.2 °,19.02 ° ± 0.2 °,21.19 ° ± 0.2 °,21.58 ° ± 0.2 °,22.58 ° ± 0.2 °,25.27 ° ± 0.2 °,25.96 ° ± 0.2 °,26.95 ° ± 0.2 °,28.82 ° ± 0.2 ° and 32.03 ° ± 0.2 °;

more preferably, the form III has a powder X-ray diffraction pattern substantially as shown in figure 2;

further preferably, the hydrochloride of the compound shown in formula I in the crystal form III of the hydrochloride of the compound shown in formula I is a solvate, and the solvent is ethanol.

8. A process for the preparation of form III according to claim 7, comprising the steps of:

9. Form IV of the hydrochloride salt of the compound of formula I, characterized by a powder X-ray diffraction pattern expressed in terms of 2Θ angles using Cu-ka radiation: the powder X-ray diffraction pattern of form IV includes peaks at diffraction angles (2θ) of 5.16 ° ± 0.2 °,6.07 ° ± 0.2 °,10.03 ° ± 0.2 °,15.32 ° ± 0.2 °,15.78 ° ± 0.2 °,17.03 ° ± 0.2 °,19.87 ° ± 0.2 °,20.62 ° ± 0.2 °,21.88 ° ± 0.2 °,23.45 ° ± 0.2 °,24.56 ° ± 0.2 °,26.37 ° ± 0.2 °,28.05 ° ± 0.2 °, and 30.25 ° ± 0.2 °;

preferably, the powder X-ray diffraction pattern of form IV comprises peaks at diffraction angles (2θ) of 5.16 ° ± 0.2 °,6.07 ° ± 0.2 °,10.03 ° ± 0.2 °,15.32 ° ± 0.2 °,15.78 ° ± 0.2 °,17.03 ° ± 0.2 °,18.80 ° ± 0.2 °,19.87 ° ± 0.2 °,20.62 ° ± 0.2 °,21.56 ° ± 0.2 °,21.88 ° ± 0.2 °,23.45 ° ± 0.2 °,24.56 ° ± 0.2 °,26.37 ° ± 0.2 °,27.36 ° ± 0.2 °,28.05 ° ± 0.2 °,28.68 ° ± 0.2 ° and 30.25 ° ± 0.2 °;

more preferably, the form IV has an X-ray powder diffraction pattern substantially as shown in figure 3;

further preferably, the form IV does not contain water of crystallization.

10. A process for the preparation of form IV of the hydrochloride salt of the compound of formula I according to claim 9, comprising the steps of:

Dissolving a compound I in a first organic solvent, then adding the first organic solvent into a second organic solvent, then dropwise adding a hydrogen chloride solution, stirring at room temperature, separating solids after the reaction is finished, and drying to obtain the compound I, wherein the hydrogen chloride solution is formed by dissolving hydrogen chloride in the second organic solvent;

11. A crystalline composition comprising 80% by weight or more of the crystalline composition of form I of any one of claims 3-5; or alternatively, the process may be performed,

comprising more than 80% by weight of the crystalline composition of form III of claim 7; or alternatively, the process may be performed,

comprising more than 80% by weight of the crystalline composition of form IV of claim 9;

preferably, the crystalline composition, wherein form I of any one of claims 3 to 5 comprises not less than 90% by weight of the crystalline composition, and the sum of the contents of form III of claim 7 and form IV of claim 9 comprises not more than 10% by weight of the crystalline composition.

12. A pharmaceutical composition comprising a hydrochloride salt of a compound of formula I according to any one of claims 1 to 2, and/or form I according to any one of claims 3 to 5, and/or form III according to claim 7, and/or form IV according to claim 9.

13. Use of a hydrochloride of a compound of formula I according to any one of claims 1 to 2, and/or of a crystalline form I according to any one of claims 3 to 5, and/or of a crystalline form III according to claim 7, and/or of a crystalline form IV according to claim 9 for the preparation of a medicament for the treatment of neuropsychiatric disorders;

preferably, the neuropsychiatric disorder is one or more of pain, schizophrenia, depression, anxiety, sleep disorders, neurodegenerative disorders, bipolar disorders, post-traumatic stress syndrome, addictive disorders, withdrawal syndrome or attention deficit disorder;

more preferably, the neuropsychiatric disorder is any one or more of pain, depression, anxiety, schizophrenia, sleep disorders, neurodegenerative disorders or bipolar disorder;

further preferably, the neuropsychiatric disease is depression, a neurodegenerative disease or pain.