An acid salt of a condensed heterocyclic derivative and a crystal form thereof, a preparation method therefor, and an application thereof

Abstract

The present application relates to an acid salt of a condensed heterocyclic derivative and a crystal form thereof, a preparation method and application thereof. In particular, the present application relates to an acid salt of a compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one and a crystal form thereof, a preparation method and application thereof and a pharmaceutical composition containing a therapeutically effective amount of the acid salt of the compound or the crystal form thereof, and a use thereof in preparing a drug for preventing and / or treating neuropsychiatric diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to an acid salt of a fused heterocyclic derivative, its crystal form, preparation method, and application. Background Technology

[0002] Schizophrenia is a disorder characterized by a deep split between cognitive and emotional states, manifesting as impaired basic human behaviors such as language, thought, perception, and self-perception. The symptoms of this disorder are broad, with the most common being mental disturbances such as hallucinations, delusions, and illusions.

[0003] Approximately 1% of the global population suffers from schizophrenia, and only 5% of all treated patients ultimately achieve a full recovery. Furthermore, schizophrenia often leads to complications such as anxiety disorders, depression, or substance abuse.

[0004] Traditionally, antipsychotics that exert their pharmacological effects by blocking dopamine D2 receptors are referred to as first-generation antipsychotics, or "typical" antipsychotics (such as haloperidol). These drugs have been groundbreaking in treating the positive symptoms of schizophrenia, but have failed to treat the negative symptoms and cognitive impairment. Typical antipsychotics generally have severe EPS (extracorporeal membrane oxygenation) side effects and are ineffective in one-third of schizophrenia patients.

[0005] Since the 1960s, a series of new-generation antipsychotics have been developed, including ziprasidone and risperidone, known as second-generation antipsychotics, or novel antipsychotics. Although their individual pharmacological effects are not entirely consistent, they share common pharmacological characteristics: their affinity for serotonin (5-HT) receptors (5-HT1A, 2A, 2c) and norepinephrine (NA) receptors (α1, α2) is much higher than that for D2 receptors, resulting in a higher D2 / 5-HT2A ratio. Their clinical efficacy is superior to that of first-generation antipsychotics, being effective for both positive and negative symptoms (including cognitive impairment) as well as traditional antipsychotics, offering a broader spectrum of action. However, these drugs have adverse reactions such as QT interval prolongation, hyperprolactinemia, and weight gain. Therefore, finding drugs that are effective for both positive and negative symptoms and cognitive impairment in schizophrenia, with fewer side effects, is currently a hot research topic.

[0006] The serotonin system plays a crucial role in regulating the function of the prefrontal cortex (PFC), including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high densities. Recent studies have demonstrated that the PFC and NMDA receptor channels are targets of 5-HT1AR, which modulates excitatory neurons in the cerebral cortex, thereby affecting cognitive function. Indeed, various preclinical data suggest that 5-HT1AR may be a novel target for antipsychotic drug development. The high affinity of atypical antipsychotics (such as olanzapine and aripiprazole) for 5-HT1AR and their low EPS side effects underscore the important role of the serotonin system in regulating PFC function, including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5-HT1A and 5-HT2A, with particularly high densities. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment, improving negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT2A has been found to play a crucial role, involved in various aspects of perception, mood regulation, and motor control. Blocking 5-HT2A receptors normalizes dopamine release, thus exerting an antipsychotic effect. Furthermore, 5-HT2C receptors are closely related to weight gain.

[0007] D3 receptors are selectively distributed in the limbic system. There are two main dopamine (DA) pathways in the brain: one is the substantia nigra-striatal pathway, which regulates motor function; the other is the DA pathway in the ventral tegmental area of ​​the midbrain, specifically the nucleus accumbens and prefrontal cortex, which is closely related to learning, cognition, and emotional activities. Abnormalities in this pathway can lead to schizophrenia. This DA pathway is also a major pathway for reward effects in the brain. D3 receptors are distributed in both DA pathways and exhibit complex interactions with other DA receptor subtypes. They may be a target for antipsychotic drug treatment. Selective antagonism of D3 receptors can reduce negative and cognitive symptoms of schizophrenia and prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease. Therefore, finding an antipsychotic drug with multiple receptor binding pathways and fewer side effects is of great clinical significance.

[0008] WO201771576A1 discloses a fused heterocyclic compound with potential therapeutic effects for schizophrenia, the structure of which is shown below:

[0009]

[0010] Where Z represents unsubstituted or substituted with one or more hydroxyl groups, carbonyl groups, and C. 1-5 The alkyl substituent of -(CH2) m -

[0011] Despite the availability of numerous medications for treating schizophrenia, a variety of adverse reactions persist in clinical use. For instance, over 10% of patients using aripiprazole, a widely used atypical antipsychotic, experience adverse reactions including weight gain, headache, akathisia, insomnia, and gastrointestinal discomfort, leading to discontinuation and relapse. Furthermore, while medications for negative symptoms (referring to deficits in normal emotional responses and other thought processes) have been used clinically and improved the symptoms in some patients, overall effectiveness is limited. Many patients remain unable to fully recover and restore normal social functioning due to negative symptoms, hindering their return to normal social work. Additionally, cognitive impairment is a key focus of schizophrenia treatment, affecting verbal memory, semantic processing, and attention in most patients. Currently available or under-market antipsychotic drugs offer very limited improvement in cognitive function.

[0012] In addition to the aforementioned problems, the treatment of treatment-resistant schizophrenia remains fraught with difficulties. Treatment-resistant schizophrenia refers to patients who do not achieve ideal therapeutic effects with conventional treatments. These patients have undergone treatment with three different antipsychotic drugs with varying active ingredients, receiving adequate dosages and durations, but with poor treatment response or intolerance to the adverse reactions of antipsychotic drugs. Even with sufficient maintenance or preventative treatment, their condition may relapse or worsen. Therefore, antipsychotic drugs for treating treatment-resistant schizophrenia remain a challenging problem in current clinical drug research and a direction that urgently needs to be addressed.

[0013] In summary, antipsychotic drugs that have good and sustained efficacy in treating negative symptoms, improve patients' cognitive function, and effectively treat treatment-resistant schizophrenia should also have low adverse drug reactions (such as extrapyramidal reactions, weight gain, nausea, vomiting, etc.). Furthermore, antipsychotic drugs that act on multiple targets remain a hot research area in the field of central nervous system.

[0014] Patent PCT / CN2020 / 129850 discloses the structures of a series of fused and heterocyclic derivatives. In subsequent research and development, in order to improve the solubility and solid stability of the compounds, facilitate separation and purification, reduce storage costs, extend product cycle, and / or improve the bioavailability of the compounds, this invention has conducted a comprehensive study on the acid salts and crystal forms of the above compounds. Summary of the Invention

[0015] All contents relating to patent PCT / CN2020 / 129850 are incorporated herein by reference.

[0016] The technical problem to be solved by the present invention is to provide an acid salt of a fused heterocyclic derivative, its crystal form, its preparation method and application.

[0017] The purpose of this invention is to provide an acid salt of the compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one.

[0018] In a preferred embodiment of the present invention, the acid is selected from hydrobromic acid, phosphoric acid, fumaric acid, oxalic acid, maleic acid, malonic acid, 1,2-ethanedisulfonic acid, para-aminosalicylic acid, methanesulfonic acid, citric acid, acetic acid, para-hydroxybenzoic acid, para-toluenesulfonic acid, benzenesulfonic acid, nicotinic acid, benzoic acid, lactic acid, and succinic acid; more preferably, fumaric acid, oxalic acid, phosphoric acid, or hydrobromic acid.

[0019] In a preferred embodiment of the present invention, the acid is nitric acid, L-malic acid, gentianic acid, or salicylic acid.

[0020] In a further preferred embodiment of the present invention, the acid is fumaric acid, oxalic acid, phosphoric acid, methanesulfonic acid, succinic acid, or hydrobromic acid.

[0021] In a further preferred embodiment of the present invention, the number of acids in the acid salt of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one is 0.2-3; preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3; and even more preferably 1.

[0022] In a further preferred embodiment of the invention, the acid salt of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one is a solvate or a non-solvent, wherein the solvent is selected from water, anhydrous methanol, anhydrous ethanol, 95% ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butyl... One or more of the following: alcohol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene.

[0023] In a further preferred embodiment of the present invention, the number of solvents is 0-3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0, 0.5, 1, 2 or 3.

[0024] In a further preferred embodiment of the present invention, the acid salt of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one is either crystalline or amorphous.

[0025] The present invention further provides polymorphs of the acid salt of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one.

[0026] In a preferred embodiment of the present invention, the polymorph of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-keto acid salt is selected from fumarate, oxalate, phosphate, or hydrobromide forms, preferably fumarate form I, oxalate form I, phosphate form I, or hydrobromide form I, wherein:

[0027] Fumarate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 24.68±0.2°, 14.15±0.2°, and 19.34±0.2°, preferably also containing diffraction peaks at 2θ of 13.63±0.2°, 24.07±0.2°, 26.57±0.2°, 22.00±0.2°, and 22.53±0.2°, more preferably also containing diffraction peaks at 2θ of 1... The diffraction peaks are located at 9.74±0.2°, 20.90±0.2°, 18.77±0.2°, 18.20±0.2°, 8.27±0.2°, 28.49±0.2°, and 21.27±0.2°. Further preferred diffraction peaks are also found at 2θ values ​​of 17.11±0.2°, 27.76±0.2°, 34.54±0.2°, 31.02±0.2°, and 11.93±0.2°.

[0028] More preferably, Cu-Kα radiation was used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 1.

[0029] Table 1. XRPD diffraction data of fumarate crystal form I of the compound.

[0030] Serial Number 2θ (±0.2°) d value Peak height Proportion(I%) 1 8.27 10.679 1026 22.7 2 11.93 7.412 560 12.4 3 13.63 6.493 2943 65.2 4 14.15 6.256 3603 79.8 5 17.11 5.180 740 16.4 6 18.20 4.872 1098 24.3 7 18.77 4.723 1154 25.6 8 19.34 4.586 3199 70.9 9 19.74 4.493 1327 29.4 10 20.90 4.246 1222 27.1 11 21.27 4.173 868 19.2 12 22.00 4.036 1409 31.2 13 22.53 3.944 1370 30.4 14 24.07 3.695 2277 50.4 15 24.68 3.605 4514 100 16 26.57 3.352 1905 42.2 17 27.76 3.211 611 13.5 18 28.49 3.130 887 19.6 19 31.02 2.880 572 12.7 20 34.54 2.595 599 13.3

[0031] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one fumarate crystal form I is essentially as follows: Figure 1 As shown; its DSC spectrum is basically as follows. Figure 2 As shown; its TGA spectrum is basically as follows. Figure 3 As shown.

[0032] Oxalate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 14.32±0.2°, 23.55±0.2°, and 26.90±0.2°, preferably also containing diffraction peaks at 2θ of 21.81±0.2°, 22.57±0.2°, 10.33±0.2°, 18.00±0.2°, and 21.43±0.2°, more preferably also containing diffraction peaks at 2θ of 14.32±0.2°, 23.55±0.2°, 26.90±0.2°, and ... The diffraction peaks are located at 5.09±0.2°, 24.51±0.2°, 18.46±0.2°, 11.53±0.2°, 20.70±0.2°, 4.89±0.2°, and 17.61±0.2°. Further preferred diffraction peaks are also present at 2θ values ​​of 28.75±0.2°, 30.80±0.2°, 33.43±0.2°, 34.80±0.2°, and 37.67±0.2°.

[0033] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 2.

[0034] Table 2. XRPD diffraction data of oxalate crystal form I of the compound.

[0035] Serial Number 2θ (±0.2°) d value Peak height Proportion(I%) 1 4.89 18.074 888 7.7 2 10.33 8.555 1522 13.2 3 11.53 7.670 961 8.3 4 14.32 6.182 11522 100 5 15.09 5.868 1203 10.4 6 17.61 5.032 677 5.9 7 18.00 4.924 1248 10.8 8 18.46 4.802 983 8.5 9 20.70 4.288 917 8 10 21.43 4.144 1211 10.5 11 21.81 4.072 1693 14.7 12 22.57 3.937 1589 13.8 13 23.55 3.775 4835 42 14 24.51 3.629 1175 10.2 15 26.90 3.312 2046 17.8 16 28.75 3.103 597 5.2 17 30.80 2.901 565 4.9 18 33.43 2.678 546 4.7 19 34.80 2.576 517 4.5 20 37.67 2.386 512 4.4

[0036] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one oxalate crystal form I is essentially as follows: Figure 4 As shown; its DSC spectrum is basically as follows. Figure 5 As shown; its TGA spectrum is basically as follows. Figure 6 As shown.

[0037] Phosphate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 13.18±0.2°, 25.67±0.2°, and 18.51±0.2°, preferably also containing diffraction peaks at 2θ of 17.46±0.2°, 19.71±0.2°, 13.96±0.2°, 17.18±0.2°, and 23.49±0.2°, more preferably containing diffraction peaks at 2θ of 16°. The diffraction peaks are located at 0.94±0.2°, 22.49±0.2°, 21.59±0.2°, 11.97±0.2°, 26.32±0.2°, 28.24±0.2°, and 27.27±0.2°. Further preferred diffraction peaks are also found at 2θ values ​​of 12.70±0.2°, 15.30±0.2°, 11.54±0.2°, 15.01±0.2°, and 11.13±0.2°.

[0038] More preferably, Cu-Kα radiation was used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 3.

[0039] Table 3. XRPD diffraction data of phosphate crystal form I of the compound.

[0040] Serial Number 2θ (±0.2°) d value Peak height Proportion(I%) 1 11.13 7.947 407 13.2 2 11.54 7.661 494 16 3 11.97 7.387 891 28.9 4 12.70 6.963 686 22.3 5 13.18 6.711 3079 100 6 13.96 6.340 1306 42.4 7 15.01 5.898 461 15 8 15.30 5.788 648 21 9 16.94 5.231 960 31.2 10 17.18 5.157 1105 35.9 11 17.46 5.075 1440 46.8 12 18.51 4.789 1789 58.1 13 19.71 4.501 1315 42.7 14 21.59 4.114 900 29.2 15 22.49 3.950 904 29.4 16 23.49 3.784 1064 34.6 17 25.67 3.468 1924 62.5 18 26.32 3.383 839 27.2 19 27.27 3.267 745 24.2 20 28.24 3.157 826 26.8

[0041] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form I is essentially as follows: Figure 7 As shown; its DSC spectrum is basically as follows. Figure 8 As shown; its TGA spectrum is basically as follows. Figure 9 As shown.

[0042] Hydrobromide crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 13.53±0.2°, 25.18±0.2°, and 24.45±0.2°, preferably also containing diffraction peaks at 2θ of 21.64±0.2°, 10.84±0.2°, 12.57±0.2°, 26.67±0.2°, and 22.96±0.2°, more preferably also containing diffraction peaks at 2θ of 2... The diffraction peaks are located at 1.21±0.2°, 23.62±0.2°, 18.09±0.2°, 27.96±0.2°, 27.38±0.2°, 34.71±0.2°, and 16.55±0.2°. Further preferred configurations include diffraction peaks at 2θ values ​​of 31.35±0.2°, 20.55±0.2°, 32.57±0.2°, 19.01±0.2°, and 28.48±0.2°.

[0043] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 4.

[0044] Table 4. XRPD diffraction data of hydrobromide crystal form I of the compound.

[0045] Serial Number 2θ (±0.2°) d value Peak height Proportion(I%) 1 10.84 8.152 1642 62.3 2 12.57 7.037 1591 60.4 3 13.53 6.541 2635 100 4 16.55 5.354 616 23.4 5 18.09 4.900 909 34.5 6 19.01 4.666 494 18.7 7 20.55 4.319 522 19.8 8 21.21 4.185 1032 39.2 9 21.64 4.104 1753 66.5 10 22.96 3.871 1189 45.1 11 23.62 3.763 1021 38.7 12 24.45 3.638 2172 82.4 13 25.18 3.534 2184 82.9 14 26.67 3.340 1474 55.9 15 27.38 3.255 771 29.3 16 27.96 3.189 791 30 17 28.48 3.131 490 18.6 18 31.35 2.851 567 21.5 19 32.57 2.747 512 19.4 20 34.71 2.582 620 23.5

[0046] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrobromide crystal form I is essentially as follows: Figure 10 As shown; its DSC spectrum is basically as follows. Figure 11 As shown; its TGA spectrum is basically as follows. Figure 12 As shown.

[0047] In a preferred embodiment of the present invention, the polymorph of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-keto acid salt is selected from methanesulfonate, phosphate, or succinate forms, preferably methanesulfonate form I, phosphate form II, phosphate form III, or succinate form I, wherein:

[0048] Methanesulfonate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 15.74±0.2°, 17.09±0.2°, and 23.66±0.2°, preferably also containing diffraction peaks at 2θ of 20.32±0.2°, 21.57±0.2°, 24.78±0.2°, 27.21±0.2°, and 27.58±0.2°, more preferably containing diffraction peaks at 2θ of 15.74±0.2°, 17.09±0.2°, 23.66±0.2°, and ... 23.66±0.2°. The diffraction peaks are located at 1.63±0.2°, 12.68±0.2°, 14.24±0.2°, 16.67±0.2°, 21.23±0.2°, 22.44±0.2°, and 24.31±0.2°, and more preferably, they also include diffraction peaks located at 2θ of 11.02±0.2°, 13.73±0.2°, 15.30±0.2°, 18.86±0.2°, and 22.19±0.2°.

[0049] More preferably, Cu-Kα radiation was used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 5.

[0050] Table 5. XRPD diffraction data of methanesulfonate crystal form I of the compound.

[0051] Serial Number 2θ (±0.2°) d value 1 11.02 8.023 2 11.63 7.605 3 12.68 6.974 4 13.73 6.444 5 14.24 6.217 6 15.30 5.787 7 15.74 5.627 8 16.67 5.315 9 17.09 5.185 10 18.86 4.702 11 20.32 4.366 12 21.23 4.181 13 21.57 4.118 14 22.19 4.002 15 22.44 3.959 16 23.66 3.758 17 24.31 3.659 18 24.78 3.590 19 27.21 3.275 20 27.58 3.231

[0052] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one methanesulfonate crystal form I is essentially as follows: Figure 13 As shown; its DSC spectrum is basically as follows. Figure 14 As shown; its TGA spectrum is basically as follows. Figure 15 As shown.

[0053] Phosphate crystal form II, its X-ray powder diffraction pattern includes diffraction peaks at 2θ of 17.87±0.2°, 19.72±0.2°, and 24.00±0.2°, preferably also including diffraction peaks at 2θ of 10.72±0.2°, 14.21±0.2°, 17.17±0.2°, 18.11±0.2°, and 21.84±0.2°, more preferably also including diffraction peaks at 2θ of 11.78°. The diffraction peaks are located at ±0.2°, 21.37±0.2°, 22.64±0.2°, 25.17±0.2°, 26.85±0.2°, 29.54±0.2°, and 30.02±0.2°, and more preferably, they also include diffraction peaks located at 2θ of 15.70±0.2°, 24.48±0.2°, 25.85±0.2°, 26.46±0.2°, and 28.11±0.2°.

[0054] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 6.

[0055] Table 6. XRPD diffraction data of phosphate crystal form II of the compound.

[0056] Serial Number 2θ (±0.2°) d value 1 10.72 8.248 2 11.78 7.504 3 14.21 6.226 4 15.70 5.639 5 17.17 5.159 6 17.87 4.959 7 18.11 4.896 8 19.72 4.499 9 21.37 4.155 10 21.84 4.067 11 22.64 3.925 12 24.00 3.704 13 24.48 3.634 14 25.17 3.536 15 25.85 3.444 16 26.46 3.366 17 26.85 3.318 18 28.11 3.172 19 29.54 3.022 20 30.02 2.975

[0057] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form II is essentially as follows: Figure 16 As shown; its DSC spectrum is basically as follows. Figure 17 As shown; its TGA spectrum is basically as follows. Figure 18 As shown.

[0058] Phosphate crystal form III, its X-ray powder diffraction pattern includes diffraction peaks at 2θ of 8.99±0.2°, 12.99±0.2°, and 17.22±0.2°, preferably also including diffraction peaks at 2θ of 14.22±0.2°, 16.88±0.2°, 17.83±0.2°, 23.12±0.2°, and 25.45±0.2°, more preferably including diffraction peaks at 2θ of 7.67°. The diffraction peaks are located at ±0.2°, 13.39±0.2°, 15.37±0.2°, 19.90±0.2°, 21.06±0.2°, 24.04±0.2°, and 25.20±0.2°, and more preferably, they also include diffraction peaks located at 2θ of 11.56±0.2°, 18.72±0.2°, 22.78±0.2°, 23.72±0.2°, and 25.95±0.2°.

[0059] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 7.

[0060] Table 7. XRPD diffraction data of phosphate crystal form III of the compounds.

[0061] Serial Number 2θ (±0.2°) d value 1 7.67 11.517 2 8.99 9.830 3 11.56 7.647 4 12.99 6.812 5 13.39 6.608 6 14.22 6.224 7 15.37 5.759 8 16.88 5.250 9 17.22 5.147 10 17.83 4.972 11 18.72 4.736 12 19.90 4.459 13 21.06 4.216 14 22.78 3.901 15 23.12 3.844 16 23.72 3.748 17 24.04 3.699 18 25.20 3.532 19 25.45 3.498 20 25.95 3.430

[0062] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form III is essentially as follows: Figure 19 As shown; its DSC spectrum is basically as follows. Figure 20As shown; its TGA spectrum is basically as follows. Figure 21 As shown.

[0063] Succinate crystal form I, with an acid number of 1, has an X-ray powder diffraction pattern containing diffraction peaks at 2θ of 14.00±0.2°, 18.78±0.2°, and 19.53±0.2°, preferably also containing diffraction peaks at 2θ of 17.82±0.2°, 22.05±0.2°, 24.31±0.2°, 24.52±0.2°, and 26.19±0.2°, more preferably also containing diffraction peaks at 2θ of 14.00±0.2°, 18.78±0.2°, 19.53±0.2°, preferably also containing diffraction peaks at 2θ of 17.82±0.2°, 22.05±0.2°, 24.31±0.2°, 24.52±0.2°, and 26.19±0.2°, preferably also containing diffraction peaks at 2θ of 14.00±0.2°, 18.78±0.2°, 19.53 ...9.53±0.2°, 19.53±0.2°, 19.53±0.2°, 19.53±0.2°, 1 The diffraction peaks are located at 7.06±0.2°, 8.20±0.2°, 17.28±0.2°, 20.09±0.2°, 20.95±0.2°, 25.11±0.2°, and 27.72±0.2°, and more preferably, diffraction peaks are also located at 2θ of 15.51±0.2°, 26.89±0.2°, 31.75±0.2°, 33.88±0.2°, and 42.68±0.2°.

[0064] More preferably, Cu-Kα radiation is used, and the X-ray diffraction peaks expressed in terms of 2θ angle and interplanar spacing d are shown in Table 8.

[0065] Table 8. XRPD diffraction data of succinate crystal form I of the compound.

[0066] Serial Number 2θ (±0.2°) d value 1 7.06 12.504 2 8.20 10.775 3 14.00 6.319 4 15.51 5.708 5 17.28 5.127 6 17.82 4.973 7 18.78 4.721 8 19.53 4.541 9 20.09 4.417 10 20.95 4.236 11 22.05 4.028 12 24.31 3.659 13 24.52 3.627 14 25.11 3.544 15 26.19 3.400 16 26.89 3.313 17 27.72 3.216 18 31.75 2.816 19 33.88 2.644 20 42.68 2.117

[0067] More preferably, the X-ray powder diffraction pattern of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one succinate crystal form I is essentially as follows: Figure 22 As shown; its DSC spectrum is basically as follows. Figure 23 As shown; its TGA spectrum is basically as follows. Figure 24 As shown.

[0068] In a further preferred embodiment of the present invention, the above-mentioned crystal form is a solvate or a non-solvent, wherein the solvent is selected from one or more of water, anhydrous methanol, anhydrous ethanol, 95% ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene.

[0069] In a further preferred embodiment of the present invention, the number of solvents is 0-3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0, 0.5, 1, 2 or 3.

[0070] On the other hand, the present invention also relates to a method for preparing the compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-keto acid salt, specifically comprising the following steps:

[0071] (1) Weigh an appropriate amount of free base and dissolve it in solvent 1;

[0072] (2) Weigh an appropriate amount of acid and, optionally, dissolve it in solvent 2; the amount of acid is preferably 0.5-8.0 equivalents;

[0073] (3) Mix the two above, stir to precipitate or heat to reflux and then cool and filter;

[0074] (4) The target product is obtained by rapid centrifugation or static drying;

[0075] in:

[0076] Solvent 1 and Solvent 2 are each independently selected from water, anhydrous methanol, anhydrous ethanol, 95% ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene; Solvent 1 and Solvent 2 must be miscible when used.

[0077] The acid is selected from hydrobromic acid, phosphoric acid, fumaric acid, oxalic acid, maleic acid, malonic acid, 1,2-ethanedisulfonic acid, p-aminosalicylic acid, methanesulfonic acid, citric acid, acetic acid, p-hydroxybenzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, nicotinic acid, benzoic acid, lactic acid, and succinic acid; preferably fumaric acid, oxalic acid, phosphoric acid, or hydrobromic acid.

[0078] On the other hand, the present invention also provides a method for preparing the acid salt crystal form of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one, specifically comprising the following steps:

[0079] (1) Weigh an appropriate amount of free base and dissolve it in solvent 1;

[0080] (2) Weigh an appropriate amount of acid and, optionally, dissolve it in solvent 2; the amount of acid is preferably 0.5-8.0 equivalents;

[0081] (3) Mix the two above, stir and react at room temperature for a period of time, filter, reflux the filter cake in solvent 3 for a period of time, cool to room temperature, filter, and dry with a forced air to obtain the target product;

[0082] or,

[0083] (1) Weigh an appropriate amount of free base and dissolve it in solvent 1;

[0084] (2) Weigh an appropriate amount of acid and, optionally, dissolve it in solvent 2; the amount of acid is preferably 0.5-8.0 equivalents;

[0085] (3) Mix the two above, heat under reflux for a period of time, cool to room temperature, filter, and dry the filter cake by blowing air to obtain the target product;

[0086] in:

[0087] Solvent 1, solvent 2, or solvent 3 are each independently selected from water, anhydrous methanol, anhydrous ethanol, 95% ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene; wherein solvent 1 and solvent 2 must be miscible when used.

[0088] The acid is selected from hydrobromic acid, phosphoric acid, fumaric acid, oxalic acid, maleic acid, malonic acid, 1,2-ethanedisulfonic acid, p-aminosalicylic acid, methanesulfonic acid, citric acid, acetic acid, p-hydroxybenzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, nicotinic acid, benzoic acid, lactic acid, and succinic acid; preferably fumaric acid, oxalic acid, phosphoric acid, or hydrobromic acid.

[0089] On the other hand, the present invention also provides a method for preparing the acid salt crystal form of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one, specifically comprising the following steps:

[0090] (1) Weigh an appropriate amount of free alkali, mix it with solvent 1, and beat it at a certain temperature for a certain time.

[0091] (2) Weigh an appropriate amount of acid and dissolve it in solvent 2; the amount of acid is preferably 0.5-2.0 equivalents;

[0092] (3) Mix the two above, stir and react at a certain temperature for a certain time, filter and dry to obtain the target product;

[0093] or,

[0094] (1) Weigh an appropriate amount of free alkali, mix it with solvent 1, and beat it at a certain temperature for a certain time.

[0095] (2) Weigh an appropriate amount of acid and dissolve it in solvent 2; the amount of acid is preferably 0.5-2.0 equivalents;

[0096] (3) Mix the two above, stir and react at a certain temperature for a certain time, add solvent 3 and continue stirring and reacting for a certain time, filter and dry to obtain the target product;

[0097] in:

[0098] Solvent 1, Solvent 2, and Solvent 3 are each independently selected from water, anhydrous methanol, anhydrous ethanol, 95% ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene, or toluene; wherein Solvent 1 and Solvent 2 must be miscible when used.

[0099] The acid is hydrobromic acid, phosphoric acid, fumaric acid, oxalic acid, maleic acid, malonic acid, 1,2-ethanedisulfonic acid, p-aminosalicylic acid, methanesulfonic acid, citric acid, acetic acid, p-hydroxybenzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, nicotinic acid, benzoic acid, lactic acid, succinic acid, nitric acid, L-malic acid, gentian acid, or salicylic acid; preferably fumaric acid, oxalic acid, phosphoric acid, methanesulfonic acid, succinic acid, or hydrobromic acid.

[0100] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the shown acid salts of the compound or its polymorphs, and one or more pharmaceutically acceptable carriers or excipients.

[0101] The present invention further relates to the use of any of the shown acid salts or polymorphs of the compounds, or pharmaceutical compositions thereof, in the preparation of medicaments for treating neuropsychiatric diseases.

[0102] In a further preferred embodiment of the present invention, the neuropsychiatric disease is selected from one or more of schizophrenia, depression, anxiety disorder, sleep disorder, neurodegenerative disease, bipolar disorder, post-traumatic stress disorder, addictive disease, withdrawal syndrome or attention deficit, preferably any one or more of depression, anxiety disorder, schizophrenia, sleep disorder, neurodegenerative disease or bipolar disorder, more preferably schizophrenia.

[0103] Detailed description of the invention

[0104] The different terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0105] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0106] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted cycloalkyl" means that alkyl may but does not have to be present, and the description includes cases where cycloalkyl is substituted with alkyl and cases where cycloalkyl is not substituted with alkyl.

[0107] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in this invention or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0108] "Medicinal salts" refers to salts of the compounds of this invention that are safe and effective when used in mammals and have the appropriate biological activity.

[0109] The term "polymorph" or "polymorphic compound" as used in this article refers to a crystal form with the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions constituting the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement, and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. The relative stability between the two solid phases is interchanged based on their temperature-stability relationship. This phenomenon of compounds existing in different lattice structures is called pharmaceutical polymorphism.

[0110] Crystal structures disclosed or claimed in this invention may exhibit similar but not identical analytical properties within a reasonable margin of error, depending on experimental conditions, purity, equipment, and other commonly used variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made within the scope and spirit of this invention without departing from its scope. Other embodiments of the invention will be apparent to those skilled in the art based on consideration of the specification and practice of the invention disclosed herein. The applicant expects this specification and examples to be considered exemplary and not limiting of its scope.

[0111] It is well known to those skilled in the art that XRPD may exhibit certain displacement and intensity deviations due to differences in detection methods, conditions, and instruments. Samples of the same crystal form typically possess the same major XRPD characteristic peaks, but operational errors may exist. When samples of the same crystal form obtained by those skilled in the art using appropriate methods are detected using the same instruments and methods, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally encounter a few characteristic peaks with errors exceeding this range. Errors within ±0.5° or ±0.3° should be considered as XRPD characteristic peaks of the same crystal form. Therefore, as a specific example of the crystal form of this invention, its XRPD is shown in spectrum X. However, those skilled in the art understand that when the 2θ shift of the key characteristic peak is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be considered as the same crystal form and can be interpreted as within the scope of protection of this invention.

[0112] Beneficial effects

[0113] The polymorphic forms of the acid salts of the compounds of this invention not only have good solubility, solid stability or hygroscopicity, but also show certain advantages in biological research. Attached Figure Description

[0114] Figure 1 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one fumarate.

[0115] Figure 2 DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one fumarate.

[0116] Figure 3TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one fumarate.

[0117] Figure 4 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one oxalate.

[0118] Figure 5 DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one oxalate.

[0119] Figure 6 TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one oxalate.

[0120] Figure 7 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0121] Figure 8 DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0122] Figure 9 TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0123] Figure 10 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrobromide.

[0124] Figure 11DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrobromide.

[0125] Figure 12 TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrobromide.

[0126] Figure 13 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one methanesulfonate.

[0127] Figure 14 DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one methanesulfonate.

[0128] Figure 15 TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one methanesulfonate.

[0129] Figure 16 XRPD illustration of crystal form II of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0130] Figure 17 DSC illustration of crystal form II of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0131] Figure 18 TGA illustration of crystal form II of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0132] Figure 19XRPD illustration of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form III.

[0133] Figure 20 DSC illustration of crystal form III of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate.

[0134] Figure 21 TGA illustration of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form III.

[0135] Figure 22 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one succinate.

[0136] Figure 23 DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one succinate.

[0137] Figure 24 TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one succinate.

[0138] Figure 25 DVS diagram of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form II.

[0139] Figure 26 DVS diagram of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one phosphate crystal form III.

[0140] Figure 27DVS diagram of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one succinate.

[0141] Figure 28 XRPD illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrochloride.

[0142] Figure 29 DSC illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrochloride.

[0143] Figure 30 TGA illustration of crystal form I of 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one hydrochloride. Detailed Implementation

[0144] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0145] The compound of the present invention, 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one, hereinafter referred to as compound A, is prepared by reference to patent PCT / CN2020 / 129850.

[0146] Experimental apparatus:

[0147]

[0148]

[0149] I. Salt Form Study of Compound A

[0150] 100 mg of compound A (free base) was weighed and dissolved in dichloromethane, N,N-dimethylformamide, and isopropanol, respectively. Then, different acids or solutions of these acids were added (base:acid = 1:1.5), and the solutions were stirred for 2 hours at different temperatures (reflux temperature for dichloromethane and isopropanol, and reaction temperature for N,N-dimethylformamide was 110℃). The results are as follows:

[0151]

[0152] As described above, those skilled in the art can obtain more pharmaceutically usable salts using conventional methods based on the invention, and are not limited to the solvent types listed in this invention.

[0153] II. Study on the crystal form of salt A of compound

[0154] 1. Preparation of the crystal form of salt A of compound A

[0155] 1.1 Preparation of Compound A Fumarate Crystal Form I

[0156] 2.0 g of free base A and 0.57 g of fumaric acid were added to isopropanol (30 mL), refluxed for 1 h, then the heating was turned off and the mixture was gradually cooled to room temperature. The mixture was then filtered, and the filter cake was dried at 40 °C to constant weight to obtain fumarate crystal form I of compound A.

[0157] 1 H NMR(600MHz,DMSO-d6)δ:8.02(dd,J=8.4,5.4Hz,1H),7.69(dd,J=9.0,1.8Hz,1H),7.30- 7.26(m,1H),6.72(s,1H),6.64(s,1H),6.59(d,J=0.4Hz,2H),3.97(t,J=6.6Hz,2H),3.9 0(t,J=8.4Hz,2H),3.21(s,1H),3.09(t,J=8.4Hz,4H),2.86(t,J=7.8Hz,2H),2.63-2.61 (m,2H),2.51-2.48(m,2H),2.33-2.31(m,2H),2.07(d,J=13.2Hz,2H),1.94-1.89(m,4H).

[0158] After testing and analysis, it has the following properties: Figure 1 The XRPD diagram shown is as follows: Figure 2 The DSC diagram shown and as follows Figure 3 The TGA graph shown is an example of a solvate. Analysis of the DSC and TGA results confirms that it is not a solvate.

[0159] 1.2 Preparation of Compound A Oxalate Crystal Form I

[0160] 2.0 g of free base A and 0.44 g of oxalic acid were added to isopropanol (30 mL), refluxed for 1 h, then the heating was turned off and the mixture was gradually cooled to room temperature. The mixture was then filtered, and the filter cake was dried at 40 °C to constant weight to obtain oxalate crystal form I of compound A.

[0161] 1 H NMR(600MHz, DMSO-d6)δ:8.09(dd,J=8.4,4.8Hz,1H),7.74(d,J=9.0Hz,1H),7.33(t,J=8.4Hz,1H),6.75(s,1H),6.66(s,1H),4.01(t,J=6 .0Hz,2H),3.92(t,J=8.4Hz,2H),3.55-3.48(m,3H),3.06-3.18(m,6H),2.88(t,J=7.8Hz,2H),2.25(d,J=12.6Hz,2H),2.18-2.10(m,4H).

[0162] After testing and analysis, it has the following properties: Figure 4 The XRPD diagram shown is as follows: Figure 5 The DSC diagram shown and as follows Figure 6 The TGA graph shown is an example of a solvate. Analysis of the DSC and TGA results confirms that it is not a solvate.

[0163] 1.3 Preparation of phosphate crystal form I of compound A

[0164] 2.0 g of free base A was added to 30 mL of isopropanol, and 1 mL of 85% phosphoric acid aqueous solution was added dropwise under reflux. After the addition was completed, the mixture was refluxed for 1 h, the heating was turned off, and the mixture was gradually cooled to room temperature and then filtered. The filter cake was dried at 40 °C to constant weight to obtain phosphate crystal form I of compound A.

[0165] 1 H NMR(600MHz, DMSO-d6)δ:8.10(brs,1H),7.70(dd,J=9.0,1.8Hz,1H),7.30(td,J=9.0,2.4Hz,1H),6.74(s,1H),6.65(s,1H),3.99(t,J=6.0Hz,2H) ,3.91(t,J=8.4Hz,2H),3.35(brs,3H),3.09(t,J=8.4Hz,2H),2.93(brs, 2H),2.87(t,J=7.8Hz,2H),2.75(s,1H),2.48(s,1H),2.17-2.04(m,6H).

[0166] After testing and analysis, it has the following properties: Figure 7The XRPD diagram shown is as follows: Figure 8 The DSC diagram shown and as follows Figure 9 The TGA graph shown is an example of a solvate. Analysis of the DSC and TGA results confirms that it is not a solvate.

[0167] 1.4 Preparation of Compound A Hydrobromide Crystal Form I

[0168] Add 2.0 g of free base A to 20 mL of dichloromethane, and add 6 mL of 33% hydrobromic acid-glacial acetic acid solution dropwise. After the addition is complete, stir at room temperature for 3 h, filter, and reflux the filter cake in 20 mL of isopropanol for 1 h. Then turn off the heating and gradually cool to room temperature, filter again, and dry the filter cake at 40 °C to constant weight to obtain hydrobromide crystal form I of compound A.

[0169] 1 H NMR(600MHz,DMSO-d6)δ:9.61(s,1H),8.13(dd,J=8.4,4.8Hz,1H),7.74(dd,J=9.0,1.8Hz, 1H),7.36(td,J=9.0,2.4Hz,1H),6.76(s,1H),6.67(s,1H),4.03(t,J=6.0Hz,2H),3.92(t, J=8.4Hz,2H),3.71(d,J=12.0Hz,2H),3.54-3.49(m,1H),3.32-3.29(m,2H),3.23-3.17(m, 2H),3.10(t,J=8.4Hz,2H),2.88(t,J=7.8Hz,2H),2.30(d,J=12.6Hz,2H)2.24-2.16(m,4H).

[0170] After testing and analysis, it has the following properties: Figure 10 The XRPD diagram shown is as follows: Figure 11 The DSC diagram shown and as follows Figure 12 The TGA graph shown is an example of a solvate. Analysis of the DSC and TGA results confirms that it is not a solvate.

[0171] 1.5 Preparation of Compound A Methanesulfonate Crystal Form I

[0172] In a 25 mL round-bottom flask, compound A free base (53.4 mg, 0.12 mmol) and isopropanol (2.0 mL) were added and stirred at room temperature. Then, 1 M isopropanol methanesulfonate solution (0.13 mL, 0.13 mmol) was added, the mixture was stirred, filtered, and dried under vacuum at 50 °C for 7 hours to obtain a white solid compound A methanesulfonate crystal form I (42 mg).

[0173] After testing and analysis, it has the following properties: Figure 13 The XRPD diagram shown is as follows: Figure 14 The DSC diagram shown and as follows Figure 15 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0174] 1.6 Preparation of phosphate form II of compound A

[0175] In a 25 mL round-bottom flask, compound A free base (104 mg, 0.23 mmol) and dimethyl sulfoxide (2.0 mL) were added and stirred at room temperature for half an hour. A self-prepared 1 M phosphoric acid aqueous solution (0.28 mL, 0.28 mmol) was added to the above solution, and the mixture was stirred for 1 hour. Then, ethyl acetate (4.0 mL) was added, and the mixture was stirred overnight. The mixture was filtered, dried under vacuum at 60 °C for 5 hours, and yielded a white solid, compound A phosphate crystal form II (69 mg).

[0176] After testing and analysis, it has the following properties: Figure 16 The XRPD diagram shown is as follows: Figure 17 The DSC diagram shown and as follows Figure 18 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0177] 1.7 Preparation of phosphate form III of compound A

[0178] In a 25 mL round-bottom flask, compound A free base (408 mg, 0.91 mmol) and isopropanol (6.0 mL) were added, and the mixture was stirred at 60 °C for 1 hour. Then, a self-made 1 M phosphoric acid aqueous solution (1.0 mL, 1.0 mmol) was added, and the mixture was kept warm and stirred for 3 hours. After cooling naturally to room temperature, the mixture was stirred and reacted overnight. The mixture was then filtered and dried under vacuum at 60 °C for 7 hours to obtain a white solid compound A phosphate crystal form III (422 mg).

[0179] After testing and analysis, it has the following properties: Figure 19 The XRPD diagram shown is as follows: Figure 20 The DSC diagram shown and as follows Figure 21 The TGA diagram shown.

[0180] 1.8 Preparation of Compound A Succinate Crystal Form I

[0181] In a 25 mL round-bottom flask, compound A free base (53 mg, 0.12 mmol) and acetone (2.0 mL) were added, and the mixture was stirred at room temperature for 40 minutes. Then, a solution of succinic acid (17 mg, 0.14 mmol) in acetone (1.0 mL) was added, and the mixture was stirred overnight. The mixture was then filtered and dried under vacuum at 50 °C for 7 hours to obtain a white solid compound A succinate crystal form I (62.2 mg).

[0182] After testing and analysis, it has the following properties: Figure 22The XRPD diagram shown is as follows: Figure 23 The DSC diagram shown and as follows Figure 24 The TGA image shown is an example of a non-solvent compound, as determined by analysis of its DSC and TGA results.

[0183] 1.9 Preparation of Compound A Hydrochloride Crystal Form I

[0184] The free base of compound A (1.0 g) was dissolved in dichloromethane (10 mL), and 4N isopropanol hydrochloride (2 mL / g) was slowly added dropwise to the filtrate until the pH reached 1. After the addition was complete, the mixture was stirred at room temperature for 2 h and then filtered. The filter cake was refluxed with methanol (10 mL) for 20 min and then gradually cooled to room temperature before being filtered. The filter cake was dried at 40 °C to constant weight to obtain the hydrochloride crystal form I of compound A.

[0185] 1 H NMR(600MHz, DMSO-d6)δ:10.80(s,1H),8.22(dd,J=9.0,5.4Hz,1H),7.73(dd,J=9.0,2.4H z,1H),7.35(td,J=9.0,2.4Hz,1H),6.76(s,1H),6.67(s,1H),4.03(t,J=6.0Hz,2H),3.92( t,J=7.8Hz,2H),3.67(d,J=12.0Hz,2H),3.51-3.45(m,1H),3.27-3.23(m,2H),3.18-3.14( m,2H),3.10(t,J=8.4Hz,2H),2.88(t,J=7.8Hz,2H),2.40-2.33(m,2H),2.24-2.19(m,4H).

[0186] After testing and analysis, it has the following properties: Figure 28 The XRPD diagram shown is as follows: Figure 29 The DSC diagram shown and as follows Figure 30 The TGA diagram shown.

[0187] 2. Solubility Experiment

[0188] 2.1 Experimental Objective:

[0189] The solubility of different salt crystal forms of compound A in water was investigated.

[0190] 2.2 Experimental Scheme:

[0191] Excessive amounts of compound A free base, hydrochloride crystal form I, fumarate crystal form I, oxalate crystal form I, phosphate crystal form I, and hydrobromide crystal form I were added to degassed water, stirred until supersaturated, filtered through a filter membrane, and then the solubility of the compound was determined by HPLC using the external standard method.

[0192] Excess amounts of compound A phosphate crystal form II, phosphate crystal form III, methanesulfonate crystal form I, and succinate crystal form I were weighed and placed in different 10 mL centrifuge tubes. 1 mL of deionized water was added, the tubes were sealed with a sealing film, and the samples were shaken at 37 °C and 150 rpm for 24 h on a constant temperature shaker. After passing the samples through a 0.45 μm organic filter, the samples were diluted and injected for HPLC analysis.

[0193] 2.3 Experimental Results:

[0194] sample Solubility (mg / mL) free base ＜0.20 Hydrochloride crystal form I 4.40 Fumarate crystal form I 2.01 Oxalate crystal form I 0.88 Phosphate crystal form I 3.94 Hydrobromide crystal form I 0.61 Phosphate crystal form II 8.11 Phosphate crystal form III 6.85 Methanesulfonate crystal form I 12.35 Succinate Crystal Form I 2.16

[0195] 2.4 Experimental Conclusions:

[0196] Comparing the above data, it can be seen that compound A has good solubility after salt formation.

[0197] 3. Solid stability test

[0198] 3.1 Experimental Objective:

[0199] The physicochemical stability of compound A under different salt crystal forms was investigated under light, high temperature, and high humidity conditions.

[0200] 3.2 Experimental Procedure:

[0201] Approximately 1 g each of compound A in fumarate (crystal form I), oxalate (crystal form I), phosphate (crystal form I), hydrobromide (crystal form I), and hydrochloride (crystal form I) were weighed and investigated for 5 and 10 days under conditions of 5000 lx light, 60°C high temperature, and 40°C high temperature and high humidity at 75% RH. The contents were determined by HPLC using the external standard method, and the changes in related substances were calculated using the chromatographic peak area normalization method.

[0202] Appropriate amounts of phosphate crystal form II, phosphate crystal form III, methanesulfonate crystal form I, and succinate crystal form I were weighed and placed separately in weighing dishes. Three samples of each salt were prepared and placed openly in a 60℃ oven and a stability test chamber under 5000 lx light conditions for 10 days. All samples were mixed thoroughly at 0, 5, and 10 days, and then samples were taken. After dissolving the samples in acetonitrile and water, the content and changes in impurities were detected by HPLC related substances method.

[0203] In addition, the XRPD spectra of the samples were analyzed separately for comparison. HPLC analysis conditions:

[0204] (1) Mobile phase:

[0205]

[0206] (2) Chromatographic conditions:

[0207] chromatographic column InertSustain C18(4.6*250mm, 5μm) Flow rate 1.0 mL / min Column temperature 35℃ Injection volume 16μL Detection wavelength 210nm

[0208] (3) Gradient elution:

[0209] Time / min Mobile phase A (%) Mobile phase B (%) 0 92 8 10 78 22 30 64 36 34 55 45 45 40 60 60 20 80 61 92 8 70 92 8

[0210] 3.3 Experimental Results: The stability results are shown in the table below:

[0211]

[0212]

[0213] 3.4 Experimental Conclusions:

[0214] The above data show that the compounds A of the present invention, namely fumarate crystal form I, oxalate crystal form I, phosphate crystal form I, hydrobromide crystal form I, phosphate crystal form II, phosphate crystal form III, methanesulfonate crystal form I and succinate crystal form I, have certain stability under light, high temperature or high humidity conditions, and the XRPD spectra do not change. In particular, under high temperature conditions, the stability of all salt crystal forms is better than that of hydrochloride crystal form I.

[0215] 4. Hygroscopicity test

[0216] 4.1 Experimental Objective:

[0217] The hygroscopic and deliquescent properties of compound A in phosphate form II, phosphate form III, and succinate form I were investigated.

[0218] 4.2 Experimental Procedure:

[0219] At room temperature (25°C), 45.28 mg of phosphate crystal form II, 52.06 mg of phosphate crystal form III, and 43.38 mg of succinate crystal form I of compound A were weighed and placed in a DVS sample pan for testing.

[0220] 4.3 Experimental Results:

[0221] The DVS diagram of phosphate form II of compound A is shown below. Figure 25 As shown in the figure, the two curves represent the adsorption curve and the desorption curve, respectively. Due to the possible hysteresis phenomenon during desorption, the two curves do not overlap. Figure 25 The results show that when the relative humidity (RH) is between 0% and 80%, the mass change ΔW% is less than 2% as the humidity increases, indicating that the sample is slightly hygroscopic.

[0222] The DVS diagram of phosphate form III of compound A is shown below. Figure 26 As shown in the figure, the two curves represent the adsorption curve and the desorption curve, respectively. Due to the possible hysteresis phenomenon during desorption, the two curves do not overlap. Figure 26The results show that when the relative humidity (RH) is between 0% and 80%, the mass change ΔW% of the sample approaches 2% as the humidity increases, indicating that the sample is hygroscopic.

[0223] The DVS diagram of succinate I of compound A is shown below. Figure 27 As shown in the figure, the two curves represent the adsorption curve and the desorption curve, respectively. Due to the possible hysteresis phenomenon during desorption, the two curves do not overlap. Figure 27 The results show that when the relative humidity (RH) is between 0% and 80%, the mass change ΔW% is less than 2% as the humidity increases, indicating that the sample is slightly hygroscopic.

[0224] 4.4 Experimental Conclusions:

[0225] Compound A, phosphate crystal form III, exhibits a hygroscopic weight gain of nearly 2% under conditions of 80% RH and 25°C, indicating hygroscopicity. Compound A, phosphate crystal form II, and compound A, succinate crystal form I, both exhibit a hygroscopic weight gain of 0.2%-2% under conditions of 80% RH and 25°C, indicating slight hygroscopicity.

Claims

1. The phosphate crystal form II of compound 8-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one, characterized in that, The X-ray powder diffraction pattern of the phosphate crystal form II includes diffraction peaks at 2θ of 10.72±0.2°, 14.21±0.2°, 17.17±0.2°, 17.87±0.2°, 18.11±0.2°, 19.72±0.2°, 21.84±0.2°, and 24.00±0.2°.

2. The phosphate crystal form II according to claim 1, characterized in that, The X-ray powder diffraction pattern of the phosphate crystal form II also includes diffraction peaks located at 2θ of 11.78±0.2°, 21.37±0.2°, 22.64±0.2°, 25.17±0.2°, 26.85±0.2°, 29.54±0.2°, and 30.02±0.2°.

3. The phosphate crystal form II according to claim 2, characterized in that, The X-ray powder diffraction pattern of the phosphate crystal form II also includes diffraction peaks located at 2θ of 15.70±0.2°, 24.48±0.2°, 25.85±0.2°, 26.46±0.2°, and 28.11±0.2°.

4. The phosphate crystal form II according to claim 3, characterized in that, The X-ray powder diffraction pattern of the phosphate crystal form II is shown in Figure 16.

5. The method for preparing the phosphate crystal form II as described in claim 1, characterized in that, Specifically, the steps include the following: (1) Weigh an appropriate amount of free base and dissolve it in solvent 1; Alternatively, take an appropriate amount of free alkali, mix it with solvent 1, and beat it at a certain temperature for a certain time. (2) Weigh 0.5-2.0 equivalents of acid and, optionally, dissolve it in solvent 2; (3) Mix the two above, stir and react at a certain temperature for a certain time, add solvent 3 and continue stirring and reacting for a certain time, filter and dry to obtain the target product; in: Solvent 1, solvent 2, and solvent 3 are each independently selected from water, dimethyl sulfoxide, and ethyl acetate; wherein solvent 1 and solvent 2 must be miscible when used. The acid mentioned is phosphoric acid.

6. A pharmaceutical composition comprising a therapeutically effective dose of phosphate crystal form II as shown in any one of claims 1-4, and one or more pharmaceutically acceptable carriers or excipients.

7. Use of the phosphate crystal form II according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating neuropsychiatric diseases.

8. The use according to claim 7, characterized in that, The neuropsychiatric disorders mentioned are selected from one or more of the following: schizophrenia, depression, anxiety disorder, sleep disorder, neurodegenerative disease, bipolar disorder, post-traumatic stress disorder, addictive disorders, withdrawal syndrome, or attention deficit.

9. The use according to claim 8, characterized in that, The neuropsychiatric disorders mentioned are selected from any one or more of the following: depression, anxiety disorder, schizophrenia, sleep disorders, neurodegenerative diseases, or bipolar disorder.

10. The use according to claim 9, characterized in that, The neuropsychiatric diseases mentioned are selected from schizophrenia.

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