Salt crystal form of piperazinyl heterocyclic compound and preparation method thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a salt crystal form of a piperazinyl heterocyclic compound and a preparation method thereof. The compound provided by the invention has certain affinity to D3 and 5-HT6 and has potential application in improvement of cognition clinically, and in addition, the invention provides a salt of 5-[2-[4-(1, 2-benzisothiazole-3-yl) piperazinyl-1-ethyl]-6-bromo-1, 3-dihydro-2H-indole-2-(2H)-ketone and / or a hydrate crystal form thereof and a preparation method thereof. The preparation method of the crystal form is simple and easy to operate and suitable for industrial production, and the crystal form is high in solubility and good in stability and can be developed as a solid medicine.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a salt crystal form of a piperazine-based heterocyclic compound and a preparation method thereof. Background Art

[0002] Schizophrenia is the most serious and devastating of all mental illnesses, with a global prevalence of approximately 1-2%. The lifetime prevalence of schizophrenia is 0.7-0.8%, and the mortality rate is two to three times higher than that of the general population. Recent research shows that the social burden of mental illness ranks first among diseases in China, surpassing cardiovascular and cerebrovascular diseases, respiratory diseases, and malignant tumors.

[0003] After decades of research, it was found that D1, D2, D3, 5-HT 2A , 5-HT6 and H1 receptors play a very important role in schizophrenia. D1 receptors are mainly located in the cortex, and antagonism of D1 receptors helps to improve positive symptoms. D2 receptors are mainly located in the striatum, limbic system and tuberoinfundibulum, and antagonism of D2 receptors helps to improve positive symptoms. D3 receptors are mainly located in the nucleus accumbens at the edge of the midbrain, and there are also a small number of D3 receptors in the caudate nucleus and putamen. Antagonism of D3 receptors has the effects of improving cognition, reducing extrapyramidal side effects and calming down. The serotonin system plays an important role in regulating the functions of the prefrontal cortex, including emotional control, cognitive behavior and working memory. The pyramidal neurons and GABA interneurons of the prefrontal cortex contain serotonin receptors 5-HT 1A and 5-HT 2A 5-HT 1A It is associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment. 2A Receptors are involved in various aspects of perception, mood regulation, and motor control, blocking 5-HT 2A The receptors can normalize the release of dopamine, thus exerting an antipsychotic effect.

[0004] There are two kinds of electrical activities in DA neurons in the brain. Low-frequency electrical activity is the basic electrical activity of the neurons themselves. High-frequency electrical activity is generated by nerve impulses and is called "burst firing", which is related to the occurrence and maintenance of animal reward behavior. The 5-HT neural pathway in the prefrontal cortex can regulate the burst firing function. In animals with low prefrontal function (lower prefrontal temperature), the burst firing of DA neurons in the limbic system is inhibited (but the basic electrical activity is not affected). 5-HT 2A Antagonists can restore the firing of DA neurons, 5-HT 2A This regulatory effect of antagonists on DA may be the mechanism for treating negative symptoms. 2AAntagonists can cause a slight increase in DA release in the nigrostriatal system. Risperidone blocks both D2 receptors and a slight increase in DA release (by blocking 5-HT 2A The two compete with each other, and the slight increase in DA offsets part of the antagonistic effect of DA, reducing EPS (extrapyramidal side effects).

[0005] The mixed action of 5-HT2A / D2 receptors has become a hallmark of atypical antipsychotics. Only drugs with a greater 5-HT2A antagonist effect than D2 are classified as atypical antipsychotics. For example, atypical antipsychotics that are balanced 5-HT2A / D2 antagonists, such as risperidone, are mixed 5-HT2A / D2 receptor antagonists. Their characteristics are that relatively weak D2 receptor antagonism can improve positive symptoms and cause limited EPS, while strong 5-HT2A receptor antagonism can improve negative and affective symptoms and partially offset the EPS caused by D2 antagonism.

[0006] 5-HT6 receptor antagonists have the potential to improve cognitive function in patients with schizophrenia. First, blocking 5-HT6 receptors can increase glutamatergic and cholinergic neurotransmission in multiple brain regions and promote the release of DA and norepinephrine in the prefrontal cortex. Furthermore, the 5-HT6 receptor antagonist SB-399885 has a synergistic effect with anti-schizophrenia drugs in promoting DA release. Furthermore, the therapeutic effects of 5-HT6 receptor antagonists are also related to their inhibition of the mammalian target of rapamycin (mTOR) pathway. Studies have shown that 5-HT6 receptor activation can enhance the mTOR signaling pathway in the rat prefrontal cortex, and in a chronic PCP (phencyclidine)-induced schizophrenia model, mTOR activity in the prefrontal cortex is significantly enhanced. The mTOR receptor antagonist rapamycin can also improve cognitive deficits in model animals.

[0007] Among the targets related to antipsychotic drugs, H1 receptor is a target related to side effects. Antagonism of H1 receptor can produce the risks of drowsiness, weight gain and hypotension.

[0008] As described in Chinese patent application CN202211189347.6, the inventors have previously discovered that a series of piperazinyl heterocyclic compounds including bromoziprasidone, namely 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, have the potential to be developed as atypical antipsychotic drugs. At the same time, they have a certain affinity for D3 and 5-HT6, and may have potential applications in improving cognition in clinical practice. Compared with ziprasidone, they have no side effects such as drowsiness, weight gain, and hypotension. However, in subsequent development, it was found that the free base form of the compound 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one is essentially insoluble in water.

[0009] A general requirement for developing pharmaceutical compositions is that the active agent present in the composition exhibits appropriate physical properties, physicochemical properties, and chemical properties. An important property of an active agent is its solubility, particularly its solubility in water. When an active agent has insufficient solubility in water, the active agent must generally be converted into a form with appropriate solubility properties, such as a salt and / or solvate of the active agent. However, in the case of salts and / or solvates, only pharmaceutically acceptable salts and / or solvates of the active agent can be used in the preparation of pharmaceutical compositions. Another important issue is the stability of the active agent form used. The shelf life of a pharmaceutical composition (including the stability of the active agent itself) is particularly important for quality management purposes. These properties of commonly known active agents can be improved by selecting their appropriate salts and crystalline forms. However, selecting appropriate salts and crystalline forms for a specific active agent is not always simple and easy, because the properties of the salts formed by different compounds and various salt-forming agents, as well as specific stable forms, may be very different. Summary of the Invention

[0010] The present invention aims to provide a salt and / or crystalline form of a 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one compound, wherein the solubility and stability thereof meet the requirements for drugability. The entire contents of the aforementioned Chinese patent application CN202211189347.6 are hereby incorporated by reference.

[0011] The present invention is directed to providing salts and / or crystalline forms of piperazinyl heterocyclic compounds, methods for their preparation, and uses. After conducting extensive screening experiments, the inventors surprisingly discovered that, among the numerous salts described in the art, the hydrochloride, methanesulfonate, hydrobromide, and benzenesulfonate salts of the aforementioned compounds, as well as related crystalline forms, exhibit excellent stability and solubility, making them suitable for further development as pharmaceuticals.

[0012] Therefore, the present invention relates to novel hydrochlorides, methanesulfonates, hydrobromides and benzenesulfonates and / or hydrates thereof of piperazinyl heterocyclic compounds, their crystal forms, preparation methods, pharmaceutical compositions containing them, and their use in drugs for treating and / or preventing neuropsychiatric diseases.

[0013] To achieve the above object, the present invention provides the following technical solutions:

[0014] An acid salt of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and / or a hydrate thereof.

[0015] Furthermore, the acid salt in the present invention is one of hydrochloride, methanesulfonate, hydrobromide or benzenesulfonate.

[0016] Furthermore, the hydrate in the present invention is one of a monohydrate and a dihydrate.

[0017] Further preferably, the acid salt of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and / or its hydrate is the hydrochloride monohydrate, methanesulfonate monohydrate, hydrobromide monohydrate or benzenesulfonate of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one.

[0018] The present invention also provides a hydrochloride monohydrate crystalline form A of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, which uses Cu-Kα radiation to obtain an X-ray powder diffraction pattern expressed in diffraction angles of 2θ, with characteristic peaks at 7.98, 10.81, 14.38, 17.99, 19.46, 21.80, and 24.57.

[0019] Preferably, the X-ray powder diffraction pattern of the crystalline form A, expressed in 2θ angles, has characteristic peaks at 6.39, 7.98, 10.81, 14.38, 14.66, 16.04, 17.99, 19.46, 21.80, 24.57, 25.58, 28.84, and 32.76;

[0020] More preferably, the X-ray powder diffraction pattern of the crystalline form A, expressed in 2θ angles, has characteristic peaks at 6.39, 7.98, 10.81, 14.38, 14.66, 16.04, 16.62, 17.99, 19.18, 19.46, 21.37, 21.80, 23.86, 24.57, 25.58, 26.33, 26.70, 28.84, 32.20, 32.76, and 33.72, and the error range of the 2θ angle is ±0.2;

[0021] More preferably, the hydrochloride monohydrate form A of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics:

[0022] (1) Basically Figure 1 The DSC spectrum shown;

[0023] (2) Basically Figure 2 IR spectrum shown;

[0024] (3) Basically Figure 3 The X-ray powder diffraction pattern is shown.

[0025] The present invention also provides a crystalline form B of a methanesulfonate monohydrate of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one: using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angles of 2θ is obtained, with characteristic peaks at 4.28, 9.20, 12.91, 14.93, 16.30, 23.74, and 26.17.

[0026] Preferably, the X-ray powder diffraction pattern of the crystalline form B, expressed in 2θ angles, has characteristic peaks at 4.28, 9.20, 12.33, 12.91, 14.93, 16.30, 17.35, 19.48, 20.32, 21.24, 23.74, 24.87, and 26.17;

[0027] More preferably, the X-ray powder diffraction pattern of the crystalline form B, expressed in 2θ angles, has characteristic peaks at 4.28, 9.20, 12.33, 12.91, 14.93, 16.30, 16.73, 17.35, 17.76, 19.48, 20.32, 21.24, 21.76, 22.12, 23.74, 24.87, 25.30, 26.17, 27.51, and 30.63, and the error range of the 2θ angle is ±0.2;

[0028] More preferably, the mesylate monohydrate form B of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics:

[0029] (1) Basically Figure 4 The DSC spectrum shown;

[0030] (2) Basically Figure 5 IR spectrum shown;

[0031] (3) Basically Figure 6 The X-ray powder diffraction pattern is shown.

[0032] The present invention also provides a hydrobromide monohydrate crystalline form C of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one: using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ is obtained, with characteristic peaks at 15.33, 17.53, 19.11, 20.28, 21.75, 22.83, and 24.84.

[0033] Preferably, the X-ray powder diffraction pattern of the crystalline form C, expressed in 2θ angles, has characteristic peaks at 10.79, 15.33, 17.53, 19.11, 20.28, 21.24, 21.75, 22.83, 23.56, 24.84, 25.43, 28.34, and 29.20;

[0034] More preferably, the X-ray powder diffraction pattern of the crystalline form C, expressed in 2θ angles, has characteristic peaks at 10.79, 15.33, 15.58, 17.53, 17.96, 19.11, 19.38, 20.28, 20.73, 21.24, 21.75, 22.83, 23.56, 24.84, 25.43, 26.66, 27.10, 28.34, 29.20, 31.62, and 33.94, and the error range of the 2θ angle is ±0.2;

[0035] More preferably, the hydrobromide monohydrate form C of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics:

[0036] (1) Basically Figure 7 The DSC spectrum shown;

[0037] (2) Basically Figure 8 IR spectrum shown;

[0038] (3) Basically Figure 9 The X-ray powder diffraction pattern is shown.

[0039] The present invention also provides a benzenesulfonate crystalline form D of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one: using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ is obtained, with characteristic peaks at 9.16, 15.21, 16.12, 18.40, 21.22, 22.81, and 25.38;

[0040] Preferably, the X-ray powder diffraction pattern of the crystalline form D, expressed in 2θ angles, has characteristic peaks at 9.16, 13.93, 15.21, 16.12, 17.55, 18.40, 19.49, 21.22, 22.81, 23.87, 25.38, 26.01, and 28.10.

[0041] More preferably, the X-ray powder diffraction pattern of the crystalline form D, expressed in 2θ angles, has characteristic peaks at 8.00, 9.16, 10.23, 13.93, 15.21, 16.12, 17.55, 18.40, 19.49, 20.79, 21.22, 21.78, 22.41, 22.81, 23.87, 24.18, 25.38, 26.01, 26.76, 28.10, and 28.41, and the error range of the 2θ angle is ±0.2;

[0042] More preferably, the benzenesulfonate salt form D of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics:

[0043] (1) Basically Figure 10 The DSC spectrum shown;

[0044] (2) Basically Figure 11 IR spectrum shown;

[0045] (3) Basically Figure 12 The X-ray powder diffraction pattern is shown.

[0046] The present invention also provides a method for preparing the hydrochloride monohydrate crystal form A or the hydrobromide monohydrate crystal form C of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one:

[0047] 1) adding 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one to an organic solvent and water, and heating;

[0048] 2) Add acid and cool down;

[0049] 3) Filter, wash and dry to obtain the target compound.

[0050] Furthermore, in the present invention, the organic solvent in step 1) is one or more of tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, isopropanol, formic acid, acetic acid, dimethyl sulfoxide, formamide, acetamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0051] Furthermore, in step 2) of the present invention, the acid is preferably hydrochloric acid or hydrobromic acid.

[0052] Furthermore, in step 2) of the present invention, the cooling temperature is 0 to 50°C, preferably 10 to 20°C.

[0053] Furthermore, in step 3) of the present invention, the drying temperature is 25 to 80°C, preferably 40 to 45°C.

[0054] The present invention also provides a method for preparing the methanesulfonate monohydrate crystal form B or the benzenesulfonic acid crystal form D of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one:

[0055] 1) adding 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one to an organic solvent and water, and heating;

[0056] 2) adding acid;

[0057] 3) Cooling;

[0058] 4) Filter, wash and dry to obtain the target compound.

[0059] Furthermore, in the present invention, the organic solvent in step 1) is one or more of tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, isopropanol, formic acid, acetic acid, dimethyl sulfoxide, formamide, acetamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0060] Furthermore, in the present invention, the heating temperature in step 1) is 50-65°C, preferably 50-55°C.

[0061] Furthermore, in step 2) of the present invention, the acid is preferably methanesulfonic acid or benzenesulfonic acid.

[0062] Furthermore, in step 3) of the present invention, the cooling temperature is 0 to 50°C, preferably 5 to 20°C.

[0063] Furthermore, in step 3) of the present invention, the drying temperature is 25 to 80°C, preferably 40 to 45°C.

[0064] The present invention also provides a pharmaceutical composition comprising one or more of the above-mentioned pharmaceutically acceptable salts and / or hydrates and / or crystalline forms of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one.

[0065] The chemical name of ziprasidone is 5-[2-[4-(1,2-benzisothiazol-3-yl)-piperazinyl-1-]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, which is usually used in the form of hydrochloride for oral preparations or in the form of methanesulfonate for injections. The present inventors have found that the above-mentioned 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-one or its pharmaceutically acceptable salt and / or its hydrate and / or crystalline form has the effect of inhibiting 5-HT. 2A The receptor affinity is significantly stronger than that for the D2 receptor, and it also has a high affinity for SERT, NET and DAT receptors, indicating that the above-mentioned compound or its pharmaceutically acceptable salt and / or its hydrate and / or crystal form has obvious advantages in treating schizophrenia, preferably patients with schizophrenia accompanied by depression.

[0066] Furthermore, it is expected that 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-one of the present invention or a pharmaceutically acceptable salt and / or hydrate and / or crystal form thereof can be administered in combination with ziprasidone for the treatment of schizophrenia, preferably schizophrenia accompanied by depression.

[0067] Furthermore, the present invention provides a pharmaceutical composition comprising 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one or an acid salt and / or a hydrate and / or a crystalline form thereof, and ziprasidone. Preferably, the pharmaceutical composition comprises the acid salt and / or a hydrate and / or a crystalline form of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one described above, and ziprasidone.

[0068] Further preferably, the pharmaceutical composition comprises one or more crystalline forms selected from the aforementioned 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate crystalline form A, methanesulfonate monohydrate crystalline form B, hydrobromide monohydrate crystalline form C or benzenesulfonate crystalline form D, and ziprasidone.

[0069] Further preferably, in the pharmaceutical composition, one or more of the hydrochloride monohydrate crystalline form A, methanesulfonate monohydrate crystalline form B, hydrobromide monohydrate crystalline form C or benzenesulfonate crystalline form D of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one accounts for 95% or more, preferably 99% or more, or less than 5%, preferably less than 2%, further preferably less than 0.5%, further preferably less than 0.2%, and further preferably less than 0.1% of the total weight of the pharmaceutical composition.

[0070] Furthermore, the present invention provides use of the pharmaceutical composition in preparing drugs for treating neuropsychiatric diseases.

[0071] Furthermore, the neuropsychiatric disease is selected from one or more of schizophrenia, depression, and schizophrenia accompanied by depression.

[0072] Beneficial effects

[0073] The technical solution of the present invention has the following advantages:

[0074] (1) 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-one (bromoziprasidone) for 5-HT 2AThe receptor affinity is significantly stronger than that for the D2 receptor, and it can be used as a potential atypical antipsychotic drug for schizophrenia. Bromoziprasidone has a higher affinity for SERT, NET, and DAT receptors, which is significantly higher than ziprasidone, indicating that bromoziprasidone has obvious advantages for patients with schizophrenia accompanied by depression. Bromoziprasidone has a higher affinity for 5-HT6 receptors and can improve cognition. The affinity for D3 receptors is significantly stronger than ziprasidone. Antagonizing D3 receptors has the effects of improving cognition, reducing extrapyramidal side effects, and providing stability. It has no effect on H1 and does not pose a risk of weight gain or hypotension.

[0075] (2) The present invention provides the above-mentioned pharmaceutically acceptable salt and / or hydrate form of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, which has the advantages of high solubility and good stability and is suitable for preparation into tablets, capsules and other administrable preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 This is the DSC spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate Form A.

[0077] Figure 2 This is the IR spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate crystalline form A.

[0078] Figure 3 This is the XPRD spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate Form A.

[0079] Figure 4 This is the DSC spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one methanesulfonate monohydrate Form B.

[0080] Figure 5 This is the IR spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one methanesulfonate monohydrate Form B.

[0081] Figure 6This is the XPRD spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one methanesulfonate monohydrate Form B.

[0082] Figure 7 This is the DSC spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrobromide monohydrate Form C.

[0083] Figure 8 This is the IR spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrobromide monohydrate Form C.

[0084] Figure 9 This is the XPRD spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrobromide monohydrate Form C.

[0085] Figure 10 This is the DSC spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one benzenesulfonate Form D.

[0086] Figure 11 This is the IR spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one benzenesulfonate Form D.

[0087] Figure 12 This is the XPRD spectrum of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one benzenesulfonate Form D. DETAILED DESCRIPTION

[0088] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the above content of the present invention are encompassed within the scope of protection intended by the present invention.

[0089] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0090] Example 1: Preparation method

[0091]

[0092] 1. Preparation of 5-(2-chloroacetyl)-6-bromo-1,3-dihydro-indol-2-(2H)-one

[0093] Anhydrous aluminum chloride (266.6 g, 2.0 mol) and chloroacetyl chloride (84.7 g, 0.75 mol) were added to 530 ml of dichloromethane and stirred for 0.5 hour. 6-bromoindol-2-one (106.0 g, 0.5 mol) was then added and refluxed for 48 hours. The reaction mixture was poured into ice water to quench the mixture and filtered to obtain a crude product. The product was recrystallized by adding 2100 ml of glacial acetic acid, filtered, washed with water, and dried to obtain 101.0 g of a pink solid with a yield of 70% and an HPLC purity of 99.2%.

[0094] MS:([MH] - ):285.85,287.80;

[0095] 1 HNMR (400MHz, DMSO-d6) δ: 10.82 (s, 1H, NH); 7.70 (s, 1H, ArH); 7.10 (s, 1H, ArH); 4.99 (s, 2H, CH2); 3.53 (s, 2H, CH2).

[0096] 2. Preparation of 5-(2-chloroethyl)-6-bromo-1,3-dihydro-indol-2-(2H)-one

[0097] Add 5-(2-chloroacetyl)-6-bromo-1,3-dihydro-indol-2-(2H)-one (101.0 g, 0.35 mol) to 500 ml of trifluoroacetic acid, cool to 0°C, add triethylsilane (122.1 g, 1.05 mol), raise the temperature to 45°C, and react for 3 hours. Cool to 0°C, stir for 1 hour, filter, and dry to obtain 84.5 g of a pink solid with a yield of 88.0% and a HPLC purity of 99.0%. MS: ([MH] - ):271.90,273.90;

[0098] 1 HNMR(500MHz,DMSO-d6)δ:10.42(s,1H,NH);7.25(s,1H,ArH);6.98(s,1H,ArH);

[0099] 3.75~3.78(t,2H,CH2); 3.44(s,2H,CH2); 3.07~3.10(t,2H,CH2).

[0100] 3. Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one

[0101] 5-(2-Chloroethyl)-6-bromo-1,3-dihydro-indol-2-(2H)-one (84.5 g, 0.3 mol), 3-(1-piperazinyl)-1,2-benzisothiazole (65.8 g, 0.3 mol), and anhydrous sodium carbonate (79.4 g, 0.75 mol) were added to 1700 ml of water and refluxed for 20 hours. The mixture was cooled to room temperature, filtered, and washed with water to obtain a crude product. 850 ml of tetrahydrofuran was added, the mixture was refluxed and stirred for 1 hour, cooled to room temperature, filtered, and dried to obtain 107.0 g of a light yellow solid, with a yield of 78.0% and a purity of 99.0% by HPLC.

[0102] MS:([M+H] + ):456.95,459.00;

[0103] 1 HNMR (400MHz, DMSO-d6) δ: 10.41 (s, 1H, NH); 8.05~8.07 (d, J = 7.48, 2H, ArH); 7.56 (s, 1H, ArH); 7.43 (s, 1H, ArH); 7.2 4(s,1H,ArH); 6.96(s,1H,ArH); 3.33~3.46(m,6H,CH2); 2.86(s,2H,CH2); 2.70(s,4H,CH2); 2.50~2.54(m,2H,CH2).

[0104] Example 2: Pharmacological Example

[0105] 1. In vitro receptor binding assay

[0106] 1.1 Buffer and compound preparation

[0107] A: (used to prepare α 2B , α 2C Receptor membrane: Weigh 146 mg of EDTA and add 50 mM Tris-HCl buffer to a total volume of 1000 mL, adjusting the pH to 7.7. The final concentration is 0.5 mM EDTA.

[0108] B: (for the preparation of 5-HT 1A , 5-HT 2A, 5-HT6 receptor membrane): Weigh 11.7 mg EDTA and 380.84 mg MgCl2, add 50 mM Tris-HCl buffer to a total volume of 400 mL, and adjust the pH to 7.4. The final concentrations are 0.1 mM EDTA and 10 mM MgCl2, respectively.

[0109] C: (for preparation of D1, D2, and D3 receptor membranes): Dopamine Binding Buffer: 50 mM NaCl, 50 mM HEPES-HCl, 5 mM MgCl2, 0.5 mM EDTA, pH 7.4.

[0110] D: (for preparation of SERT, NET, and DAT receptor membranes): 50 mM Tris HCl, 150 mM NaCl, 5 mM KCl, pH 7.4.

[0111] E: (for preparation of Sigma-1 and Sigma-2 receptor membranes):

[0112] 1) 10 mM Tris-HCl buffer, containing 320 mM sucrose solution, pH 7.4.

[0113] 2) 10 mM Tris-HCl buffer, pH 7.4.

[0114] F: (for preparation of H1 receptor membrane): 50 mM Tris HCl, 0.5 mM EDTA, pH 7.4.

[0115] G: (for preparation of M1 receptor membrane): 50 mM Tris-HCl Buffer: pH 7.4.

[0116] H: (for preparation of NMDA receptor membranes): 50 mM Tris HCl, 1 mM EDTA, pH 7.4.

[0117] 1.2 Preparation of receptor membrane

[0118] 1.2.1 Preparation of cell receptor membrane

[0119] CHO-α 2B ,CHO-α 2C 、CHO-5-HT 1A 、CHO-5-HT 2ARemove cells such as CHO-5-HT6, CHO-D1, CHO-D2, CHO-D3, 293-NET, 293-SERT, 293-DAT, CHO-M1, and 293-H1 from a -80°C freezer and thaw naturally. Centrifuge at 2000g at 4°C for 10 min, discard the supernatant, and collect the pellet. Add buffer to the pellet and homogenize for 20-30 seconds. Centrifuge at 48,000g at 4°C for 25 minutes, discard the supernatant, add buffer again, homogenize for 20-30 seconds, and centrifuge at 48,000g at 4°C for 25 minutes. Discard the supernatant, collect the pellet, and store at -80°C.

[0120] 1.3 Receptor competition binding assay

[0121] 1.3.1 Radioactive binding test conditions

[0122] Table 1 Radioactive binding test conditions

[0123]

[0124]

[0125] In the above table 3 H is 3H labeled, for example 3 H-Methylspiperone is 3H-labeled methylspiperone; Paroxetine refers to paroxetine, Pyrilamine refers to pyrilamine, Quinuclidiny benzilate, Nisoxetine refers to nisoxetine, Methylspiperone is methylspiperone, Ketanserin refers to sertraline, 3 H-WIN35428 (codenamed WIN35428 is a dopamine reuptake inhibitor), 3 H-SCH 23390 (codenamed SCH 23390 is a dopamine D1 receptor antagonist), 3 H-8-OH-DPAT (codenamed 8-OH-DPAT) is a selective 5-HT1A agonist.

[0126] 1.3.2 Receptor Binding Assay Procedure

[0127] 1.3.2.1 Cell receptor affinity assay

[0128] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding well (TB) and 50 μL of non-specific binding well (final concentration 1.0×10 -5 M), and 50 μL of the test compound was added to each test compound well (CB).

[0129] Step 2: Add 100 μL of buffer to each reaction well.

[0130] Step 3: First, use the prepared membrane to make a suspension of membrane with corresponding concentration using homogenate for later use.

[0131] Step 4: Add 50 μL of radioligand to each reaction well.

[0132] Step 5: Add 50 μL of membrane suspension to each reaction well.

[0133] Step 6: Incubate each reaction well at 25°C for 90 minutes. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. The UniFilter-96GF / C plate is soaked in 0.5% PEI for more than 1 hour in advance. After filtration, the filter membrane is dried in an oven at 60°C. After attaching the base film, 40μL scintillation fluid is added, the membrane is sealed, and it is allowed to stand.

[0134] Step 7: Place the filter plate into the liquid scintillation counter for counting.

[0135] 1.3.2.2 Tissue receptor affinity assay

[0136] Step 1: Add 50 μL of solvent (1% DMSO) to the total binding tube (TB) and 50 μL of DMSO to the nonspecific binding tube (NB).

[0137] μL non-standard (final concentration 1.0×10 -5 M), add 50 μL of test compound to each test compound tube (CB). Step 2: add 100 μL of buffer to each reaction tube.

[0138] Step 3: First, use the prepared membrane homogenate to make a membrane suspension of corresponding concentration for later use.

[0139] Step 4: Add 50 μL of the corresponding radioligand to each reaction tube.

[0140] Step 5: Add 50 μL of membrane solution to each reaction tube.

[0141] Step 6: Incubate each reaction tube according to the incubation conditions. After the reaction is complete, the bound ligand is rapidly filtered under reduced pressure. Whatman GF / C test paper is saturated with 0.5% PEI solution 1 hour in advance and thoroughly washed with ice-cold Tris-HCl buffer. Remove the filter and place it in a 4mL scintillation cup. Dry it at 60°C for 30 minutes. Add 1mL of toluene scintillation fluid and mix well.

[0142] Step 7: Place the scintillation cup into the liquid scintillation counter for counting.

[0143] 2. Data Analysis

[0144] According to the effect values ​​of the compound samples at different concentration test points, GraphPad Prism software was used to fit the compound sample-receptor action curve and calculate the Ki value.

[0145] 3. Test results

[0146] The results of in vitro receptor test are shown in the table below.

[0147] Table 2 In vitro receptor binding assay data for ziprasidone and 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-one (bromoziprasidone)

[0148]

[0149] Ziprasidone bromide for 5-HT 2A The receptor affinity is significantly stronger than that of D2 receptors, which is similar to that of ziprasidone. Both belong to atypical antipsychotic drugs. 2A Antagonism can improve negative symptoms and reduce EPS (extrapyramidal side effects) caused by D2 receptor antagonism. In addition, ziprasidone bromide and ziprasidone have a high affinity for dopamine D1 receptors, and their antagonism of D1 receptors can help improve positive symptoms.

[0150] Surprisingly, it was found that brominated ziprasidone has a higher affinity for SERT, NET and DAT, which is significantly higher than that of ziprasidone, indicating that brominated ziprasidone has obvious advantages for patients with schizophrenia accompanied by depression.

[0151] In addition, it was unexpectedly discovered that brominated ziprasidone has a high affinity for 5-HT6 receptors, which suggests that it has a certain effect on improving cognition, while ziprasidone has no obvious affinity for 5-HT6 receptors. Studies have shown that 5-HT6 receptor antagonists regulate the levels of neurotransmitters such as Ach, Glu, DA, and GABA, and antagonizing 5-HT6 receptors has the effect of improving cognition. In addition, brominated ziprasidone has a significantly stronger affinity for D3 receptors than ziprasidone. D3 receptors are mainly located in the nucleus accumbens at the edge of the midbrain, and there are also small amounts of D3 receptors in the caudate nucleus and putamen. Therefore, antagonizing D3 receptors has the effect of improving cognition, reducing extrapyramidal side effects, and providing stability.

[0152] It was also found that ziprasidone has moderate affinity for the H1 receptor, while brominated ziprasidone has almost no affinity for the receptor and does not carry the risk of drowsiness, weight gain, or hypotension.

[0153] Example 3: Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate (ie, Compound 1)

[0154]

[0155] 6.3 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, 390 ml of tetrahydrofuran, and 39 ml of deionized water were added to a 1 L reaction flask and the temperature was raised to reflux; 1.7 g of hydrochloric acid was added, and after the addition was complete, the temperature was lowered to 10-20° C. and stirred for 1 hour; the mixture was filtered, and the filter cake was washed with water and 95% ethanol; the filter cake was air-dried at 40-45° C. overnight to obtain 6.7 g of compound 1, with a yield of 95.0%, an HPLC content of 99.7%, and a KF of 4.4% (water content determined by the Karl Fisher method).

[0156] 1)MS:([M+H]+):457.15;

[0157] 2)1H NMR (400MHz, DMSO-d6) δ: 11.46 (s, 1H, HCl); 10.56 (s, 1H, NH); 8.15~8.17 (d, J = 8.2, 1H, ArH); 8.11~8.13 (d, J=8.2, 1H, ArH); 7.59~7.62 (t, J=7.4, 1H, ArH); 7.46~7.50 ( t,J=7.7,1H,ArH); 7.30(s,1H,ArH); 7.03(s,1H,ArH); 4.09~4.13(d,J=13.3,2H,CH 2); 3.69~3.72(d,J=11.4,2H,CH2); 3.29~3.60(m,8H,CH2); 3.20-3.22(m,2H,CH2).

[0158] 3)DSC analysis:

[0159] The DSC differential scanner was used for analysis and identification. The test conditions were: nitrogen atmosphere, heating rate 10℃ / min, heating range 30℃~350℃, and there were two melting endothermic peaks at 110~120℃ and 290~300℃ respectively. The test results were as follows: Figure 1 shown.

[0160] 4) IR detection:

[0161] Detection method: Take about 180 mg of dry potassium bromide in a mortar and grind it into powder. Add 1.0 to 1.5 mg of the test sample and grind it thoroughly. Place it in a tableting mold and press it into a tablet. Take out the prepared test piece and put it into an infrared spectrophotometer for sample detection. IR (cm-1): 3408, 3192, 2936, 2829, 1712, 1625, 1488, 775; the test results are as follows: Figure 2 shown.

[0162] 5) Compound 1 was identified as Form A by X-ray powder diffraction (XPRD) analysis using Cu-Kα radiation, and had the following characteristic peaks expressed in angles 2θ°: 6.39, 7.98, 10.81, 14.38, 14.66, 16.04, 16.62, 17.99, 19.18, 19.46, 21.37, 21.80, 23.86, 24.57, 25.58, 26.33, 26.70, 28.84, 32.20, 32.76, and 33.72, with an error tolerance of ±0.2°; the test results are as follows: Figure 3 shown.

[0163] Example 4: Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one methanesulfonate monohydrate (ie, Compound 2)

[0164]

[0165] 6.3 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, 48 ml of tetrahydrofuran, and 30 ml of deionized water were added to a 250 ml reaction flask and the temperature was raised to 50-55° C. 1.7 g of methanesulfonic acid was added and the mixture was stirred for 20 minutes after the addition was completed. The temperature was then lowered to 5-15° C. and stirred for 1 hour. The mixture was filtered and the filter cake was washed with 50% acetone aqueous solution and dried overnight at 40-45° C. to obtain 4.2 g of compound 2 with a yield of 53.2%, an HPLC content of 99.8%, and a KF of 4.2% (water content determined by the Karl Fisher method).

[0166] 1)MS:([M+H]+):457.20;

[0167] 2)1H NMR (400MHz, DMSO-d6) δ: 10.53 (s, 1H, NH); 10.00 (s, 1H, OH); 8.17~8.19 (d, J=8.2, 1H, ArH); 8.11~8.13 (d, J=8.2, 1H, ArH); 7.59~7.6 3(t,J=7.3,1H,ArH); 7.47~7.51(t,J=7.7,1H,ArH); 7.32(s,1H,ArH); 7.05(s,1H,ArH); 4.14~4.16(d,J=8.8,2H,CH2); 3.74(m,2H,CH

[0168] 2); 3.48 (s, 2H, CH2); 3.40 (m, 6H, CH2); 3.13~3.17 (m, 2H, CH2); 2.40 (s, 3H, CH3).

[0169] 3)DSC analysis:

[0170] The DSC differential scanner was used for analysis and identification. The test conditions were: nitrogen atmosphere, heating rate 10℃ / min, heating range 30℃~350℃, and there were two melting endothermic peaks at 103~113℃ and 292~302℃ respectively. The test results were as follows: Figure 4 shown.

[0171] 4) IR detection:

[0172] Detection method: Take about 180 mg of dry potassium bromide in a mortar and grind it into powder. Add 1.0 to 1.5 mg of the test sample and grind it thoroughly. Place it in a tableting mold and compress it into a tablet. Take out the prepared test piece and put it into an infrared spectrophotometer for sample detection. IR (cm-1): 3445, 3188, 3014, 1703, 1625, 1482, 1042, 774; the test results are as follows: Figure 5 shown.

[0173] 5) Compound 2 was identified as Form B by X-ray powder diffraction (XPRD) analysis using Cu-Kα radiation, and had the following characteristic peaks expressed in angles 2θ°: 4.28, 9.20, 12.33, 12.91, 14.93, 16.30, 16.73, 17.35, 17.76, 19.48, 20.32, 21.24, 21.76, 22.12, 23.74, 24.87, 25.30, 26.17, 27.51, and 30.63, with an error tolerance of ±0.2°; the test results are as follows: Figure 6 shown.

[0174] Example 5: Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrobromide monohydrate (ie, compound 3)

[0175]

[0176] 5.0 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, 150 ml of tetrahydrofuran, and 15 ml of deionized water were added to a 250 ml reaction flask and the temperature was raised to reflux. 3.2 g of 33% hydrobromic acid and acetic acid solution was added. After the addition was complete, the temperature was lowered to 10-20° C. and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with water and then with 95% ethanol. The filter cake was air-dried at 40-45° C. overnight to obtain 5.2 g of compound 3, with a yield of 85.2% and a purity of 99.1% by HPLC.

[0177] 1)MS: [M+H]+): 457.00;

[0178] 2)1H NMR (400MHz, DMSO-d6) δ: 10.53 (s, 1H, NH); 10.15 (s, 1H, HBr); 8.16~8.18 (d, J = 7.7, 1H, ArH); 8.11~8.13 (d, J=7.8, 1H, ArH); 7.59~7.63 (m, 1H, ArH); 7.49~7.50 (m, 1H, Ar H); 7.32 (s, 1H, ArH); 7.04 (s, 1H, ArH); 4.14 (m, 2H, CH2); 3.77 (m, 2H, CH2); 3.38~3.49 (m, 8H, CH2), 3.17 (s, 2H, CH2).

[0179] 3)DSC analysis:

[0180] The DSC differential scanner was used for analysis and identification. The test conditions were: nitrogen atmosphere, heating rate 10℃ / min, heating range 30℃~350℃, and there were two melting endothermic peaks at 93~103℃ and 297~307℃ respectively. The test results were as follows: Figure 7 shown.

[0181] 4) IR detection:

[0182] Detection method: Take about 180 mg of dry potassium bromide in a mortar, grind it into powder, add 1.0 to 1.5 mg of the test sample, grind it thoroughly and mix it evenly, put it into a tablet mold and compress it into a tablet. Take out the prepared test piece and put it into an infrared spectrophotometer for sample detection. IR (cm-1): 3419, 3189, 2941, 1712, 1625, 1489, 795. The test results are as follows: Figure 8 shown.

[0183] 5) Compound 3 was identified as Form C by X-ray powder diffraction (PXRD) analysis using Cu-Kα radiation, and had the following characteristic peaks expressed in angles 2θ°: 10.79, 15.33, 15.58, 17.53, 17.96, 19.11, 19.38, 20.28, 20.73, 21.24, 21.75, 22.83, 23.56, 24.84, 25.43, 26.66, 27.10, 28.34, 29.20, 31.62, and 33.94, with an error tolerance of ±0.2°. The test results are as follows: Figure 9 shown.

[0184] Example 6: Preparation of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one benzenesulfonate (i.e., Compound 4)

[0185]

[0186] 5.0 g of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one, 40 ml of tetrahydrofuran, and 40 ml of deionized water were added to a 250 ml reaction flask and the temperature was raised to 50-55°C. 2.1 g of benzenesulfonic acid and 5 ml of the deionized mixed solution were added. After the addition was complete, the temperature was lowered to 10-20°C and stirred for 1 hour. The mixture was filtered, washed with water, and then washed with 95% ethanol. The filter cake was air-dried at 40-45°C overnight to obtain 5.4 g of compound 4 with a yield of 80.6% and a purity of 99.7% by HPLC.

[0187] 1)MS:([M+H]+):457.00

[0188] 2)1H NMR (400MHz, DMSO-d6) δ: 10.52 (s, 1H, NH); 9.85 (s, 1H, OH); 8.16~8.18 (d, J=8.1, 1H, A rH); 8.11~8.13(d,J=8.1,1H,ArH); 7.59~7.64(m,3H,ArH); 7.46~7.50(t,J=7.5,1H,Ar H);7.27~7.32(m,4H,ArH);7.05(s,1H,ArH);4.14~4.17(d,J=10.3,2H,CH2); 3.75~3.77(d,J=8.0,2H,CH2); 3.38~3.47(m,8H,CH2); 3.11~3.13(m,2H,CH2).

[0189] 3)DSC analysis:

[0190] The DSC differential scanner was used for analysis and identification. The test conditions were: nitrogen atmosphere, heating rate 10℃ / min, heating range 30℃~350℃, and one melting endothermic peak at 272℃~282℃. The test results were as follows: Figure 10 shown.

[0191] 4) IR detection:

[0192] Detection method: Take about 180 mg of dry potassium bromide in a mortar and grind it into powder. Add 1.0 to 1.5 mg of the test sample and grind it thoroughly. Place it in a tableting mold and compress it into a tablet. Take out the prepared test piece and put it into an infrared spectrophotometer for sample detection. IR (cm-1): 3445, 3226, 3003, 1703, 1624, 1483, 1162, 772. The test results are as follows: Figure 11 shown.

[0193] 5) Compound 4 was identified as Form D by X-ray powder diffraction (XPRD) analysis using Cu-Kα radiation, and had the following characteristic peaks expressed in angles 2θ°: 8.00, 9.16, 10.23, 13.93, 15.21, 16.12, 17.55, 18.40, 19.49, 20.79, 21.22, 21.78, 22.41, 22.81, 23.87, 24.18, 25.38, 26.01, 26.76, 28.10, and 28.41, with an error tolerance of ±0.2°. The test results are as follows: Figure 12 shown.

[0194] Example 7:

[0195] 1. Moisture absorption test

[0196] (1) Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and place it in a constant temperature desiccator at 25°C ± 1°C (with ammonium chloride or ammonium sulfate saturated solution placed at the bottom) or an artificial climate box (set temperature 25°C ± 1°C, relative humidity 80% ± 2%) the day before the test, and accurately weigh the weight (m1).

[0197] (2) Take an appropriate amount of the sample and spread it flat in the above-mentioned weighing bottle. The thickness of the sample should be about 1 mm. Accurately weigh the weight (m2).

[0198] (3) Open the weighing bottle and place it with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

[0199] (4) Cover the weighing bottle and accurately weigh the weight (m3).

[0200] The test results are shown in Table 1:

[0201]

[0202] Table 1 Hygroscopicity test results of different salt forms of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one

[0203]

[0204] Conclusion: Form A, Form C and Form D have no or almost no hygroscopicity.

[0205] 2. Saturated solubility test

[0206] Experimental method: Take an appropriate amount of sample, add it to the Buchi reactor test tube, add different media to make an incompletely dissolved solution, place it in the Buchi reactor, shake at 37℃ for 24 hours, and ensure that the sample is not completely dissolved during the shaking process. Filter with a microporous filter membrane and inject the sample for detection.

[0207] Table 2 Saturated solubility of different salt forms of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one under different conditions (ug / ml)

[0208]

[0209] Note:

[0210] (1) Solubility is based on bases;

[0211] (2) ND means not detected;

[0212] (3) Preparation of pH 1.2 solution: Accurately measure 0.765 ml of hydrochloric acid into a 100 ml volumetric flask, dilute to volume with water, and shake well;

[0213] (4) Preparation of pH 4.5 solution: Accurately weigh 0.2994 g of sodium acetate and place it in a 100 ml volumetric flask. Dissolve it with water. Pipette 1.4 ml of 2 mol / L acetic acid solution into the volumetric flask, dilute to volume with water, and shake well.

[0214] (5) Preparation of pH 6.8 solution: Place 25 ml of 0.2 mol / L KH2PO4 solution and 11.2 ml of 0.2 mol / L NaOH solution in a 100 ml volumetric flask, dilute to volume with water, and shake well.

[0215] (6) Preparation of pH 7.4 solution: Take 25 ml of 0.2 mol / L KH2PO4 solution and 19.5 ml of 0.2 mol / L NaOH solution and place them in a 100 ml volumetric flask, dilute to volume with water, and shake well.

[0216] Conclusion: Crystal forms A, B, C, and D all have certain solubility and meet the solubility requirements for drug development.

[0217] 3. Crystal mechanical stress investigation

[0218] Appropriate amounts of Form A and Form B were placed in a ball mill at 250 r / min. Samples were taken at 0.5 hours, 1 hour, 2 hours, and 4 hours, respectively, to investigate the mechanical stress of the crystals. The results are as follows:

[0219] name 0.5 hours 1 hour 2 hours 4 hours Form A unchanged unchanged unchanged unchanged Form B unchanged unchanged unchanged unchanged

[0220] Conclusion: Under ball milling conditions, the crystal forms A and B remain stable and do not change.

[0221] 4. Investigation of crystal stability

[0222] Appropriate amounts of Form A and Form B were placed under high temperature (60°C), light, and high humidity (92.5%). Samples were taken on the 5th, 10th, and 30th days to investigate the stability of the crystal forms. The results are as follows:

[0223] (1) Investigation of factors affecting Form A:

[0224] condition 5 days 10 days 30 days high temperature unchanged unchanged unchanged High humidity unchanged unchanged unchanged illumination unchanged unchanged unchanged

[0225] (2) Investigation of factors affecting Form B:

[0226] condition 5 days 10 days 30 days high temperature unchanged unchanged unchanged High humidity unchanged unchanged unchanged illumination unchanged unchanged unchanged

[0227] Conclusion: Under high temperature, high humidity and light conditions, crystal form A and crystal form B remained unchanged on the 30th day without crystal transformation, indicating that crystal form A and crystal form B have good stability.

[0228] The above is a description of a specific embodiment of the present invention. It should be understood that the present invention is not limited to the above embodiment, and the above embodiment and description are only for illustrating the principle of the present invention.

[0229] Without departing from the concept of the present invention, those skilled in the art may also make various non-substantial changes and improvements to the present invention, which all fall within the scope of protection claimed by the present invention.

Claims

An acid salt of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and / or a hydrate thereof.

2. The acid salt of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and / or its hydrate according to claim 1, characterized in that The acid salt is one of hydrochloride, methanesulfonate, hydrobromide or benzenesulfonate.

3. The acid salt and / or hydrate of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one according to any one of claims 1 to 2, characterized in that: The hydrate is one of a monohydrate and a dihydrate; Further preferably, the acid salt of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and / or its hydrate is the hydrochloride monohydrate, methanesulfonate monohydrate, hydrobromide monohydrate or benzenesulfonate of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one.

4. A crystalline form A of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate, characterized in that: Using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ degrees was obtained, with characteristic peaks at 7.98, 10.81, 14.38, 17.99, 19.46, 21.80, and 24.57; Preferably, the X-ray powder diffraction pattern of the crystalline form A, expressed in 2θ angles, has characteristic peaks at 6.39, 7.98, 10.81, 14.38, 14.66, 16.04, 17.99, 19.46, 21.80, 24.57, 25.58, 28.84, and 32.76; More preferably, the X-ray powder diffraction pattern of the crystalline form A, expressed in 2θ angles, has characteristic peaks at 6.39, 7.98, 10.81, 14.38, 14.66, 16.04, 16.62, 17.99, 19.18, 19.46, 21.37, 21.80, 23.86, 24.57, 25.58, 26.33, 26.70, 28.84, 32.20, 32.76, and 33.72, and the error range of the 2θ angle is ±0.2; More preferably, the hydrochloride monohydrate form A of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics: (1) a DSC pattern substantially as shown in FIG1 ; (2) an IR spectrum substantially as shown in FIG2 ; (3) An X-ray powder diffraction pattern substantially as shown in FIG3 .

5. A crystalline form B of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one methanesulfonate monohydrate, characterized in that: Using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ degrees was obtained, with characteristic peaks at 4.28, 9.20, 12.91, 14.93, 16.30, 23.74, and 26.17; Preferably, the X-ray powder diffraction pattern of the crystalline form B, expressed in 2θ angles, has characteristic peaks at 4.28, 9.20, 12.33, 12.91, 14.93, 16.30, 17.35, 19.48, 20.32, 21.24, 23.74, 24.87, and 26.17; More preferably, the X-ray powder diffraction pattern of the crystalline form B, expressed in 2θ angles, has characteristic peaks at 4.28, 9.20, 12.33, 12.91, 14.93, 16.30, 16.73, 17.35, 17.76, 19.48, 20.32, 21.24, 21.76, 22.12, 23.74, 24.87, 25.30, 26.17, 27.51, and 30.63, and the error range of the 2θ angle is ±0.2; More preferably, the mesylate monohydrate form B of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics: (1) a DSC pattern substantially as shown in FIG4 ; (2) an IR spectrum substantially as shown in FIG5 ; (3) An X-ray powder diffraction pattern substantially as shown in FIG6 .

6. A crystalline form C of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrobromide monohydrate, characterized in that: Using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ degrees was obtained, with characteristic peaks at 15.33, 17.53, 19.11, 20.28, 21.75, 22.83, and 24.84; Preferably, the X-ray powder diffraction pattern of the crystalline form C, expressed in 2θ angles, has characteristic peaks at 10.79, 15.33, 17.53, 19.11, 20.28, 21.24, 21.75, 22.83, 23.56, 24.84, 25.43, 28.34, and 29.20; More preferably, the X-ray powder diffraction pattern of the crystalline form C, expressed in 2θ angles, has characteristic peaks at 10.79, 15.33, 15.58, 17.53, 17.96, 19.11, 19.38, 20.28, 20.73, 21.24, 21.75, 22.83, 23.56, 24.84, 25.43, 26.66, 27.10, 28.34, 29.20, 31.62, and 33.94, and the error range of the 2θ angle is ±0.2; More preferably, the hydrobromide monohydrate form C of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics: (1) a DSC pattern substantially as shown in FIG7 ; (2) an IR spectrum substantially as shown in FIG8 ; (3) An X-ray powder diffraction pattern substantially as shown in FIG9 .

7. A crystalline form D of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one benzenesulfonate, characterized in that: Using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ degrees was obtained, with characteristic peaks at 9.16, 15.21, 16.12, 18.40, 21.22, 22.81, and 25.38; Preferably, the X-ray powder diffraction pattern of the crystalline form D, expressed in 2θ angles, has characteristic peaks at 9.16, 13.93, 15.21, 16.12, 17.55, 18.40, 19.49, 21.22, 22.81, 23.87, 25.38, 26.01, and 28.10; More preferably, the X-ray powder diffraction pattern of the crystalline form D, expressed in 2θ angles, has characteristic peaks at 8.00, 9.16, 10.23, 13.93, 15.21, 16.12, 17.55, 18.40, 19.49, 20.79, 21.22, 21.78, 22.41, 22.81, 23.87, 24.18, 25.38, 26.01, 26.76, 28.10, and 28.41, and the error range of the 2θ angle is ±0.2; More preferably, the benzenesulfonate salt form D of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one has one or more of the following characteristics: (1) a DSC pattern substantially as shown in FIG10 ; (2) an IR spectrum substantially as shown in FIG11 ; (3) An X-ray powder diffraction pattern substantially as shown in FIG12.

8. A method for preparing 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one hydrochloride monohydrate crystalline form A or hydrobromide monohydrate crystalline form C as claimed in any one of the preceding claims, characterized in that: 1) adding 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one to an organic solvent and water, and heating; 2) Add acid and cool down; 3) Filter, wash, and dry to obtain the target compound; The organic solvent in step 1) is one or more of tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, isopropanol, formic acid, acetic acid, dimethyl sulfoxide, formamide, acetamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; Step 2) the acid is hydrochloric acid or hydrobromic acid; the cooling temperature is 0-50°C, preferably 10-20°C; Step 3) The drying temperature is 25-80°C, preferably 40-45°C.

9. A method for preparing 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one methanesulfonate monohydrate B or benzenesulfonic acid crystalline form D as claimed in any one of the preceding claims, characterized in that: 1) adding 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one to an organic solvent and water, and heating; 2) adding acid; 3) Cooling; 4) Filter, wash, and dry to obtain the target compound; In step 1), the organic solvent is one or more of tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, isopropanol, formic acid, acetic acid, dimethyl sulfoxide, formamide, acetamide, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the heating temperature is 50-65° C., preferably 50-55° C.; Step 2) the acid is preferably methanesulfonic acid or benzenesulfonic acid; Step 3) The cooling temperature is 0-50°C, preferably 5-20°C; the drying temperature is 25-80°C, preferably 40-45°C.

10. A pharmaceutical composition comprising one or more of the salts of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and / or hydrates thereof according to any one of claims 1 to 7.

11. A pharmaceutical composition comprising 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one and ziprasidone.

12. A pharmaceutical composition comprising an acid salt and / or a hydrate and / or a crystal form of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one according to any one of claims 1 to 7, and ziprasidone; preferably comprising one or more crystal forms of 5-[2-[4-(1,2-benzisothiazol-3-yl)piperazinyl-1-]ethyl]-6-bromo-1,3-dihydro-2H-indol-2-(2H)-one according to any one of claims 1 to 7, and ziprasidone.

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