Novel crystal form of quinazoline -2,4-dione compound and method for preparing same

Abstract

The present invention relates to: a novel crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-(4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl)acetamide hydrochloride of chemical formula 1; and a method for preparing same. [Chemical formula 1]

Description

Novel crystalline form of quinazoline-2,4-dione compound and method for preparing the same

[0001] The present invention relates to a novel crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the following chemical formula 1 and a method for preparing the same:

[0002] [Chemical Formula 1]

[0003]

[0004] When preparing a medicate, it is important that the drug substance be in a form that can be conveniently handled and processed. This is important not only from the perspective of obtaining a commercially viable manufacturing process but also from the perspective of the subsequent production of pharmaceutical formulations containing the active ingredient. The chemical stability, solid-state stability, and shelf life of the active ingredient are also very important factors. The drug substance and the composition containing it must be able to be effectively stored for a considerable period without exhibiting significant changes in the physicochemical properties of the active ingredient (e.g., chemical composition, density, hygroscopicity, and solubility). Furthermore, it is important whether the drug can be provided in the purest possible form. Amorphous materials can present significant problems in this regard. For example, amorphous materials are typically known to be more difficult to handle and prepare than crystalline materials, offer uncertain solubility, have lower stability, and are not chemically pure. Therefore, when manufacturing commercially viable and pharmaceutically acceptable drug compositions, it may be desirable to provide the drug in a substantially crystalline and stable form whenever possible. However, it should be noted that this goal is not always achievable. In fact, typically, the crystallization behavior of a compound can never be predicted from its molecular structure, and this can generally only be confirmed experimentally.

[0005] Neurological diseases involve the death of specific nerve cells, either temporarily or over a long period, leading to fatal loss of brain function. Stroke is one of the most frequently occurring cerebrovascular diseases; recently, with a significant increase in patients in their 40s and 50s—a highly active age group—it has become a national issue as well as a personal one. Stroke is broadly classified into cerebral infarction and cerebral hemorrhage. Cerebral infarction occurs when the blood supply to brain tissue is blocked by causes such as blood clots, leading to necrosis of the brain tissue. In contrast, cerebral hemorrhage occurs when blood leaks out of the blood vessels due to the rupture of cerebral blood vessels. Although the mechanisms of occurrence for cerebral infarction and cerebral hemorrhage differ, their symptoms are generally often similar. Currently, the widely recognized method for the acute treatment of cerebral infarction is "thrombolysis," which dissolves blood clots. In the treatment of cerebral infarction, the time between onset and the initiation of treatment is critical; it is known that administering thrombolytic agents within three hours of the onset of the infarction can improve the patient's functional status measured three months later. Many researchers are currently identifying the causes of brain cell necrosis due to ischemia, and major pathways proposed include excitotoxicity caused by excessive neurotransmitters, oxidative toxicity caused by oxidative stress, zinc toxicity, and apoptosis. Among excitotoxic substances, glutamate, an excitotoxic neurotransmitter of the central nervous system, acts on NMDA (N-methyl-D-aspartate) receptors; when excessively released due to ischemia or other factors, it induces neuronal death. It has been reported that such excitotoxicity may be the primary mechanism of neuronal death caused by conditions other than epilepsy, such as stroke. When the supply of oxygen and glucose to nerve tissue decreases after ischemia, the excitatory neurotransmitter glutamate accumulates at the synaptic site, leading to the death of nerve cells primarily due to the excessive activation of NMDA glutamate receptors.Therefore, the use of NMDA glutamate receptor antagonists can inhibit neuronal death caused by ischemic stroke. Free radicals are also one of the main mechanisms of neuronal death; an increase in free radicals within brain cells due to ischemia leads to fatal damage to factors essential for cell survival through lipid degradation of cell membranes caused by lipid oxidation, nucleic acid damage, and protein denaturation caused by oxygen radicals. Many researchers have shown that when ischemia occurs, reactive oxygen species in the brain increase, and furthermore, in Parkinson's disease, Huntington's disease, and Alzheimer's disease, there is an increase in reactive oxygen species, increased activity of radical scavenging enzymes such as catalase and Cu / Zn superoxide dismutase (SOD), and Fe. 2+ It has been reported that an increase is observed.

[0006] With respect to neurological diseases, International Publication No. WO 2009 / 096667 (International Publication Date: August 6, 2009) discloses a novel quinazoline-2,4-dione derivative of the following chemical formula (I) and a pharmaceutical composition for the prevention and treatment of neurological diseases containing the same:

[0007]

[0008]

[0009] The compound of the above chemical formula (I) inhibits the death of brain cells and possesses protective activity against nerve cells, as well as antioxidant, anticonvulsant, and vasodilating effects. Therefore, it is useful for improving memory, as well as for the prevention and / or treatment of stroke, degenerative neurological diseases such as Alzheimer's disease, and convulsive disorders such as epilepsy.

[0010] Pharmaceutical ingredients require appropriate stability not only in themselves but also during the manufacturing stages of the pharmaceutical composition, such as grinding, mixing, granulation, or pressing, as well as during storage after the manufacturing of the pharmaceutical composition. In addition, pharmaceutical ingredients must not absorb moisture during the multi-stage manufacturing process of the composition and must have good flowability without electrostatic phenomena.

[0011] The compound of the above chemical formula (I) does not sufficiently possess the aforementioned physicochemical properties required for a pharmaceutical component. Therefore, it is necessary to develop a new pharmaceutical component with improved properties compared to the compound of the above chemical formula (I). The discovery of a new pharmaceutical component with different physicochemical properties not only expands the scope of formulation to enable the development of new release systems or compositions with new characteristics, but also provides an opportunity to manufacture pharmaceutical compositions more easily. However, when preparing acid addition salts by reacting basic substances with conventional organic or inorganic acids, despite various literature and common technical knowledge regarding the formation of acid addition salts, it is common to encounter cases where the formation of acid addition salts is not easy for certain substances. In particular, it is even more difficult to manufacture acid addition salts or crystalline forms that possess the various properties required for pharmaceuticals.

[0012] The object of the present invention is to provide a crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the following formula 1, having improved physicochemical properties necessary for the preparation of a pharmaceutical composition:

[0013] [Chemical Formula 1]

[0014]

[0015] Another object of the present invention is to provide a method for preparing the crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1.

[0016] Accordingly, the inventors conducted a thorough study on a new acid addition salt or crystal form and confirmed surprising results that a crystal polymorph (crystallial type I and crystal polymorph II) prepared by combining with hydrochloric acid has excellent physicochemical properties required for pharmaceuticals, improved product stability, strong crystallinity, non-hygroscopicity, and good flowability without electrostatic phenomena, and thus can be easily used in the preparation of a pharmaceutical composition containing it as an active ingredient, thereby completing the present invention.

[0017] The present invention provides a novel crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the following formula 1:

[0018] [Chemical Formula 1]

[0019]

[0020] In addition, the present invention provides a method for preparing the crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 in water and / or an organic solvent.

[0021] The crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 according to the present invention has a relatively high melting point, low hygroscopicity, excellent storage stability, excellent mechanical stability and fluidity, and has uniform particles, making it very suitable as a raw material and satisfying all the physicochemical properties required for the preparation of a pharmaceutical composition. Accordingly, the crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 according to the present invention can be usefully applied to the preparation of pharmaceutical compositions for the prevention or treatment of neurological diseases.

[0022] Figure 1 shows the X-ray diffraction analysis of crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 1.

[0023] Figure 2 shows the differential scanning calorimetry of crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 1.

[0024] Figure 3 shows the thermogravimetric analysis of crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 1 and then subjected to the accelerated test of Experimental Example 3.

[0025] Figure 4 shows the X-ray diffraction analysis of crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 12.

[0026] Figure 5 shows the differential scanning calorimetry of crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 12.

[0027] Figure 6 shows the thermogravimetric analysis of crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 12 and then subjected to the accelerated test of Experimental Example 3.

[0028] Figure 7 shows the amorphous X-ray diffraction analysis of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Comparative Example 1.

[0029] Figure 8 shows the amorphous differential scanning calorimetry of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Comparative Example 1.

[0030] Figure 9 shows the amorphous thermogravimetric analysis of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in the preparation example and then subjected to the accelerated test of Experimental Example 3.

[0031] FIG. 10 shows crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 1, crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride obtained in Example 43, and the crystalline form obtained in Comparative Example 1 This is the result of a hygroscopic experiment on the amorphous form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride using a moisture adsorption analyzer (DVS).

[0032] The present invention is described in more detail below.

[0033]

[0034] According to one aspect of the present invention, a crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the following formula 1 is provided:

[0035] [Chemical Formula 1]

[0036]

[0037]

[0038] A method for preparing N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the above chemical formula 1 is described in detail in International Publication No. WO 2009 / 096667 (International Publication Date: August 6, 2009), and the said document is incorporated herein by reference. N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Chemical Formula 1 can be synthesized according to the method described in the above literature, but this is merely an exemplary method and the order of unit operations, etc., may be selectively changed as needed, and is not intended to limit the scope of the invention.

[0039]

[0040] The N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention is crystalline. Specifically, the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may exist as crystalline form I and crystalline form II, and the present invention provides said crystalline form I and crystalline form II. The term "crystalline" as used in this specification means a crystalline solid that does not contain a substantially fixed molar ratio of solvent molecules within a crystal lattice, i.e., a crystalline solid that is not a solvate.

[0041] The term “polymorph” as used in this document refers to a crystal having the same constituent unit and differing only in its arrangement state. The polymorph of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention includes crystal form I and crystal form II.

[0042] The crystal polymorphs (crystallial type I and crystallial type II) of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 according to the present invention are such that, when the amount of hydrochloric acid is measured by various methods such as ion chromatography (hereinafter IC), one molecule of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide and one molecule of hydrochloric acid are combined in a 1:1 molar equivalent ratio. It is sanguitis.

[0043]

[0044] Determinant Type I

[0045] The present invention provides crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the above formula 1.

[0046] Crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may include diffraction peaks with diffraction angles 2θ of 7.6±0.2°, 8.1±0.2°, 10.4±0.2°, 16.2±0.2°, and 22.4±0.2° in the X-ray powder diffraction pattern irradiated with Cu-Kα. The crystal form I of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the present invention may include diffraction peaks with diffraction angles 2θ of 7.6±0.2°, 8.1±0.2°, 10.4±0.2°, 13.9±0.2°, 16.2±0.2°, 20.0±0.2°, 22.4±0.2°, 24.2±0.2°, 26.6±0.2°, and 29.2±0.2° in the X-ray powder diffraction pattern irradiated with Cu-Kα.

[0047] Crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may have a peak position of an X-ray powder diffraction pattern that substantially coincides with the peak position of FIG. 1.

[0048] Crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may have an onset temperature of 220°C (±5°C) and an endothermic peak of 225°C (±5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min. The crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may have a differential scanning calorimetry (DSC) endothermic peak that substantially matches that shown in FIG. 2.

[0049] Crystalline form I of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention was confirmed to be a crystalline form with almost no hygroscopicity in the normal humidity range.

[0050]

[0051] Determinant Type II

[0052] The present invention provides crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the above formula 1.

[0053] Crystalline form II of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may include diffraction peaks with diffraction angles 2θ of 6.5±0.2°, 9.5±0.2°, 10.5±0.2°, 17.6±0.2°, 25.4±0.2°, and 25.7±0.2° in the X-ray powder diffraction pattern irradiated with Cu-Kα. Crystalline form II of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may include diffraction peaks with diffraction angles 2θ of 6.5±0.2°, 9.5±0.2°, 10.5±0.2°, 17.6±0.2°, 18.4±0.2°, 19.1±0.2°, 23.5±0.2°, 24.4±0.2°, 25.4±0.2°, and 25.7±0.2° in the X-ray powder diffraction pattern irradiated with Cu-Kα. The crystalline form II of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may have a peak position of the X-ray powder diffraction pattern that substantially coincides with the peak position of FIG. 4.

[0054] Crystalline form II of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may have an onset temperature of 240°C (±5°C) and an endothermic peak of 245°C (±5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min. The crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention may have a differential scanning calorimetry (DSC) endothermic peak that substantially matches that shown in FIG. 5.

[0055] Crystalline form II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 of the present invention was confirmed to be a crystalline form with almost no hygroscopicity in the normal humidity range.

[0056]

[0057] The crystalline form of a pharmaceutical ingredient can be characterized by one or more of various methods, including melting point, XRD, DSC, solid-state nuclear magnetic resonance spectroscopy, infrared spectroscopy, Raman spectroscopy, and the presence of hydrates. In particular, 2theta (2θ), which indicates the diffraction angle in XRD, or the d-value, which indicates the interplanar spacing, serve as decisive means for characterizing the crystalline form. According to guidelines and regulations on good manufacturing practices for drugs published by drug regulatory authorities in each country, the uniformity of pharmaceutical ingredients is one of the requirements for drug approval. According to drug manufacturing regulations, it is not only necessary for the uniformity of pharmaceutical ingredients to comply with specifications, but it is also crucial to ensure that this uniformity is maintained consistently across every batch of pharmaceutical ingredient production. These requirements are demanded of drug manufacturers by the regulations of drug regulatory authorities in each country. Accordingly, the crystal polymorphism of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 according to the present invention, as defined above by XRD, DSC, and melting point, will always be confirmed to be uniform regardless of the manufacturing batch, drying time, storage period, storage method, and measurement method.

[0058]

[0059] According to another aspect of the present invention, a method for preparing a crystalline form according to the present invention is provided, comprising crystallizing the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 in water and / or an organic solvent.

[0060] As an organic solvent usable in the manufacturing method according to the present invention, an organic solvent that does not react with the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 and does not have an adverse effect on crystallization may be used. Specific examples include ketones such as acetone and methyl isobutyl ketone; esters such as ethyl acetate; alcohols such as isopropyl alcohol, ethanol, methanol, and n-butanol; ethers such as tetrahydrofuran, isopropyl ether, diethyl ether, and dioxane; and hydrocarbons such as heptane, toluene, cyclohexane, benzene, and xylene. Examples include chloroform, dichloromethane, dichloroethylene, acetonitrile, etc., and one of these may be used alone or in combination of two or more, but is not limited thereto.

[0061] The novel crystal polymorphs of the present invention can be produced by any one or more of the methods described below, each of which represents an embodiment of the present invention.

[0062] In one embodiment of the present invention, the crystal polymorph of the present invention may be produced by a slurry method comprising the step of “slurrying” the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 in a slurry solvent, preferably using a mechanical stirring device. To form the crystal polymorph by the slurry method, the slurry is stirred for a time sufficient to achieve a predetermined conversion. Stirring may be provided by any method known in the art, for example, using a thrust stirrer or magnetic stirrer inserted into the solution. The degree of conversion during stirring can be monitored, for example, by removing the slurry fraction, separating the solid, and analyzing the crystal form of the solid by X-ray diffraction. The generated crystal polymorphs can be separated from the slurry by any means known in the art. For example, filtration (gravity or suction) or centrifugation may be used, but is not limited thereto. If necessary, the product separated from the slurry method may be dried under atmospheric pressure or under reduced pressure.

[0063] In another embodiment of the present invention, the crystal polymorph of the present invention may be produced by a precipitation method comprising the steps of: dissolving and crystallizing the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 in a solvent using mechanical stirring; and mixing a solution of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1 in a first solvent with a second solvent to form a suspension. It is preferable that the second solvent is substantially insoluble in the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1.

[0064] The crystal polymorph of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Chemical Formula 1, prepared by the above-described manufacturing method, can have a high chemical purity of 98.5% or higher, which is the level typically required for pharmaceutical ingredients.

[0065]

[0066] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of the above chemical formula 1 is a substance with neuroprotective activity and is useful for the treatment and prevention of brain diseases. When the crystal polymorph according to the present invention is introduced into a living organism, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide is released from the crystal polymorph of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride.

[0067]

[0068] According to another aspect of the present invention, a pharmaceutical composition for the prevention or treatment of neurological diseases is provided, comprising, as an active ingredient, the crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Formula 1, together with a pharmaceutically acceptable carrier.

[0069] The pharmaceutical composition according to the present invention can prevent or treat neurological disorders, neurodegenerative diseases, or neurological dysfunction. More specifically, the pharmaceutical composition according to the present invention is for neurological dysfunction, memory loss, cerebrovascular insufficiency, focal brain injury, traumatic brain injury, diffuse brain injury, spinal cord injury, cerebral ischemia, ischemic stroke, hemorrhagic stroke, cerebral infarction, cerebral hemorrhage, dementia, embolic occlusion, thrombotic occlusion, reperfusion after acute ischemia, transient ischemic attack, prenatal hypoxic-ischemic injury, cardiac arrest, intracranial hemorrhage, subarachnoid hemorrhage, cerebral aneurysm, Willis's aneurysm, acute pediatric hemiplegia, whiplash-induced shaken baby syndrome, Alzheimer's disease, Pick's disease, Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multiple system degeneration (Shy-Drager syndrome), chronic epilepsy associated with neurodegeneration, motor neuron disease, amyotrophic lateral sclerosis, primary lateral sclerosis, degenerative ataxia, corticobasal degeneration, It may be effective in preventing or treating subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, primary progressive dysphagia, spinal muscular atrophy and spinomedullary muscular atrophy (Kennedy's disease), multiple sclerosis, Tay-Sachs disease, spastic paraplegia, prion disease, Creutzfeldt-Jakob disease, epilepsy, plexopathy, or neuropathy, and may have an effect on improving memory.

[0070] In the present invention, the pharmaceutically acceptable carrier comprises lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc. Additionally, it comprises diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Oral solid dosage forms include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms may include at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc., and may include lubricants such as magnesium stearate or talc. Oral liquid dosage forms include suspensions, oral liquids, emulsions, syrups, etc., and may include diluents such as water or liquid paraffin, humectants, sweeteners, flavorings, preservatives, etc. Parenteral dosage forms include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Witepsol, Macrogol, Tween 61, cocoa oil, glycerol-gelatin, etc. can be used as bases for suppositories.

[0071] As used in this specification, the term "prevention" refers to reducing or eliminating the possibility of contracting a disease.

[0072] As used herein, the term "treatment" refers to the removal of a disease and / or its accompanying symptoms, in whole or in part.

[0073]

[0074] The present invention will be explained in detail below by way of examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited to the following examples.

[0075]

[0076] The analysis values ​​described in the following examples were measured as follows.

[0077] - The chemical purity of the product was measured by liquid chromatography [column Kromasil C18, inner diameter 4.6 mm X length 250 mm, particle size 5 μm; detector and detection wavelength, UV absorption spectrophotometer 220 nm; eluent: 0.01 M potassium phosphate buffer / acetonitrile, elution rate: 1.0 ml / min], and the peak area of ​​the compound of Formula 1 was expressed as a percentage (%) relative to the total peak area (excluding solvent peaks) shown in the chromatogram.

[0078] - The melting point was measured using an MP50 capillary digital melting point meter (Mettler Toledo, USA).

[0079] - Moisture content was measured using a V20 volumetric KF titrator (Mettler Toledo, USA).

[0080] - The infrared absorption spectrum (IR) was measured using Spectrum BX (perkin elmer, USA).

[0081] - Thermogravimetric analysis (TGA) was performed using a Discovery TGA (TA Instruments, USA) by increasing the temperature by 5°C per minute.

[0082] - Differential scanning calorimetry (DSC) was measured using DSC1 (Mettler Toledo, USA) by increasing the temperature by 10°C per minute.

[0083] - X-ray diffraction analysis (XRD) was measured using a D8 Advance X-ray diffraction analyzer (Bruker, Germany) by irradiating Cu-Kα radiation (wavelength λ=1.54056Å) at an angle of 2θ over a range of 3° to 40° with a step size of 0.02°.

[0084] As used herein with respect to the measured content, the term “approximately” means a deviation from the measured quantity as expected by a person skilled in the art performing the measurement and taking into account the accuracy of the measuring instrument used and the level of caution appropriate for the purpose of the measurement. In this document, “room temperature” means a temperature of 15-25℃.

[0085]

[0086] Preparation Example

[0087] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride was prepared in the same manner as in Example 3 of International Publication No. WO 2009 / 096667.

[0088]

[0089] Comparative Example: Preparation of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride amorphous

[0090] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (200 g), 800 ml of purified water, and 200 ml of methanol were added and heated to dissolve, then the methanol was distilled off, the mixture was cooled and frozen, and freeze-dried under reduced pressure to obtain an amorphous compound.

[0091]

[0092] Examples 1 to 10: Preparation of crystalline polymorphisms by the slurry method

[0093] Example 1

[0094] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in acetone (80 ml) and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form I.

[0095]

[0096] Example 2

[0097] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in dichloromethane (40 ml) and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0098]

[0099] Example 3

[0100] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was stirred as a slurry in acetonitrile (40 ml) at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0101]

[0102] Example 4

[0103] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in chloroform (40 ml) and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0104]

[0105] Example 5

[0106] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in isopropyl alcohol (40 ml) and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0107]

[0108] Example 6

[0109] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was stirred as a slurry in ethyl acetate (40 ml) at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0110]

[0111] Example 7

[0112] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was stirred as a slurry in tetrahydrofuran (40 ml) at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0113]

[0114] Example 8

[0115] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in n-butanol (40 ml) under reflux and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0116]

[0117] Example 9

[0118] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in dioxane (40 ml) and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0119]

[0120] Example 10

[0121] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was refluxed in dichloroethylene (40 ml) and stirred as a slurry for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0122]

[0123] Examples 11 to 43: Preparation of crystalline polymorphisms by precipitation method

[0124] Example 11

[0125] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in methanol (40 ml) and stirred under reflux for 24 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0126]

[0127] Example 12

[0128] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in anhydrous ethanol (40 ml) and stirred under reflux for 24 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0129]

[0130] Example 13

[0131] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in methanol (6 ml) at room temperature, and benzene (40 ml) was added and stirred in a mixed solvent at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0132]

[0133] Example 14

[0134] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was dissolved in methanol (6 ml) at room temperature, and tetrahydrofuran (20 ml) was added and stirred in a mixed solvent at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0135]

[0136] Example 15

[0137] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was dissolved in methanol (6 ml) at room temperature, and isopropyl ether (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0138]

[0139] Example 16

[0140] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in methanol (6 ml) at room temperature, and xylene (20 ml) was added and stirred in a mixed solvent at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0141]

[0142] Example 17

[0143] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was dissolved in methanol (6 ml) at room temperature, and toluene (40 ml) was added and stirred in a mixed solvent at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0144]

[0145] Example 18

[0146] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in methanol (6 ml) at room temperature, and n-butanol (20 ml) was added and stirred under reflux in a mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0147]

[0148] Example 19

[0149] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was dissolved in methanol (6 ml) at room temperature, and dioxane (24 ml) was added and stirred in a mixed solvent at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0150]

[0151] Example 20

[0152] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in methanol (6 ml) at room temperature, and methyl isobutyl ketone (20 ml) was added and stirred in a mixed solvent at room temperature for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0153]

[0154] Example 21

[0155] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was dissolved in methanol (6 ml) at room temperature, and dichloroethylene (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0156]

[0157] Example 22

[0158] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was dissolved in methanol (6 ml) at room temperature, and ethanol (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0159]

[0160] Example 23

[0161] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was dissolved in methanol (6 ml) at room temperature, and diethyl ether (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0162]

[0163] Example 24

[0164] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and cyclohexane (50 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0165]

[0166] Example 25

[0167] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and heptane (20 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0168]

[0169] Example 26

[0170] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and acetone (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0171]

[0172] Example 27

[0173] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and dichloromethane (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0174]

[0175] Example 28

[0176] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and isopropyl ether (20 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0177]

[0178] Example 29

[0179] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and ethyl acetate (30 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0180]

[0181] Example 30

[0182] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and isopropyl alcohol (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0183]

[0184] Example 31

[0185] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and n-butanol (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0186]

[0187] Example 32

[0188] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and toluene (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0189]

[0190] Example 33

[0191] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and tetrahydrofuran (40 ml) was added and stirred under reflux in a mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0192]

[0193] Example 34

[0194] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and benzene (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0195]

[0196] Example 35

[0197] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and xylene (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0198]

[0199] Example 36

[0200] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and acetonitrile (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0201]

[0202] Example 37

[0203] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and dioxane (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0204]

[0205] Example 38

[0206] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and methyl isobutyl ketone (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0207]

[0208] Example 39

[0209] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and dichloroethylene (60 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0210]

[0211] Example 40

[0212] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was heated and dissolved in ethanol (20 ml) at 60°C, and diethyl ether (40 ml) was added and stirred under reflux in the mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0213]

[0214] Example 41

[0215] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was heated and dissolved in purified water (10 ml) at 60°C, and dioxane (200 ml) was added and stirred under reflux in a mixed solvent for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0216]

[0217] Example 42

[0218] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazoline-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form (2 g) was heated and dissolved in isopropyl alcohol (60 ml) at 80°C and stirred under reflux for 48 hours. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0219]

[0220] Example 43

[0221] Amorphous N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride (2 g) was refluxed in ethanol (20 ml) and purified water (2 ml) for 2-4 hours and stirred at 68-72°C for at least 1 hour. The mixture was filtered, and the separated solid was dried at 40°C for 24 hours to obtain crystalline form II.

[0222]

[0223] Experimental Example 1: Hygroscopicity Experiment in Solid State

[0224] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form I prepared in Example 1, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form II prepared in Example 43, and Comparative Example 1 Hygroscopicity tests were conducted using DVS with N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form, and changes in weight and properties are shown in Fig. 10 and Table 1.

[0225]

[0226]

[0227] As shown in Table 1 and Figure 10 above, crystalline forms I and II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride exhibited low hygroscopicity and remained undissolved even after the hygroscopicity test was completed, indicating excellent storage stability and suitability for formulation. Additionally, the amorphous form showed high hygroscopicity in a short time as humidity increased and did not undergo dehumidification even under dehumidification conditions, consequently confirming that it was unsuitable for formulation.

[0228]

[0229] Experimental Example 2: Severe Stability Test in Solid State

[0230] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form I prepared in Example 1, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form II prepared in Example 43 and the one prepared in Comparative Example 1 N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form was subjected to a harsh test (harsh conditions: 60°C, RH 75%), and the results of the analysis of relative purity (%), moisture content (weight%), and properties are shown in Table 2.

[0231]

[0232]

[0233] As shown in Table 2 above, crystalline forms I and II of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride remained undissolved, indicating low hygroscopicity and excellent storage stability, which confirmed their suitability for formulation. Additionally, the amorphous form exhibited high hygroscopicity in a short period of time and was found to be unsuitable for formulation. From the above results, it was confirmed that crystalline form II is stable under harsh conditions.

[0234]

[0235] Experimental Example 3: Accelerated Stability Experiment in Solid State 1

[0236] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form I prepared in Example 1, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form II prepared in Example 43 and Comparative Example 1 N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride amorphous form was subjected to an accelerated test (accelerated conditions: 40℃ / RH 75%), and the results of the analysis of relative purity (%), moisture content (weight%), and properties are shown in Table 3.

[0237]

[0238]

[0239] As shown in Table 3 above, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline forms I and II remained undissolved under accelerated conditions, similar to the harsh test, indicating low hygroscopicity and excellent storage stability, which confirmed their suitability for formulation. Additionally, the amorphous form exhibited high hygroscopicity in a short period of time and was found to be unsuitable for formulation. From the above results, it was confirmed that crystalline forms I and II were stable under accelerated conditions.

[0240]

[0241] Experimental Example 4: Accelerated Stability Experiment in Solid State 2

[0242] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form I and N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form II were used to conduct an accelerated test (accelerated conditions: 40℃ / RH 75%), and the analysis results are shown in Table 4.

[0243]

[0244]

[0245] As shown in Table 4 above, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline forms I and II maintained their initial characteristics for up to 6 months under accelerated conditions, and other test items also showed results that met the standards. However, unlike crystalline form II, it was confirmed that in the case of crystalline form I, the amount of impurities increased as the stability test progressed compared to the initial state. Therefore, based on the results of the accelerated stability test above, it can be determined that crystalline form II has superior storage stability compared to crystalline form I and is suitable for formulation.

[0246]

[0247] Experimental Example 5: Long-term storage stability test in the solid state

[0248] N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form I and N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline form II were used to conduct a long-term storage test (long-term storage conditions: 25℃ / RH 60%), and the analysis results are shown in Table 5.

[0249]

[0250]

[0251] As shown in Table 5 above, N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride crystalline forms I and II maintained their initial characteristics for up to 36 months under long-term storage conditions, and other test items also showed results that met the standards. However, as seen in the accelerated stability test of Experimental Example 4, it was confirmed that the amount of impurities in crystalline form I increased as the stability test progressed compared to the initial state. Therefore, based on the results of the long-term storage stability test, it can be determined that crystalline form II has superior storage stability compared to crystalline form I and is suitable for formulation.

Claims

1. Crystalline form of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride of Chemical Formula 1 below: [Chemical Formula 1] 2. A crystalline form according to claim 1, characterized in that the characteristic peak values ​​(2θ) in X-ray powder diffraction (XRPD) analysis are 7.6±0.2°, 8.1±0.2°, 10.4±0.2°, 16.2±0.2°, and 22.4±0.2°.

3. A crystalline form according to claim 2, characterized in that the characteristic peak values ​​(2θ) in X-ray powder diffraction (XRPD) analysis are 7.6±0.2°, 8.1±0.2°, 10.4±0.2°, 13.9±0.2°, 16.2±0.2°, 20.0±0.2°, 22.4±0.2°, 24.2±0.2°, 26.6±0.2°, and 29.2±0.2°.

4. A crystalline form according to claim 1, characterized in that the characteristic peak values ​​(2θ) in X-ray powder diffraction (XRPD) analysis are 6.5±0.2°, 9.5±0.2°, 10.5±0.2°, 17.6±0.2°, 25.4±0.2°, and 25.7±0.2°.

5. A crystalline form according to claim 4, characterized in that the characteristic peak values ​​(2θ) in X-ray powder diffraction (XRPD) analysis are 6.5±0.2°, 9.5±0.2°, 10.5±0.2°, 17.6±0.2°, 18.4±0.2°, 19.1±0.2°, 23.5±0.2°, 24.4±0.2°, 25.4±0.2°, and 25.7±0.2°.

6. A method for preparing the crystalline form according to claim 1, comprising crystallizing N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride in water and / or an organic solvent.

7. The method according to claim 6, wherein the organic solvent is selected from the group consisting of acetone, methyl isobutyl ketone, ethyl acetate, isopropyl alcohol, ethanol, methanol, n-butanol, tetrahydrofuran, isopropyl ether, diethyl ether, dioxane, heptane, toluene, cyclohexane, benzene, xylene, chloroform, dichloromethane, dichloroethylene, acetonitrile, and mixtures thereof.

8. A method according to claim 6, characterized in that the crystallization of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride is performed by a slurry method.

9. A method according to claim 6, characterized in that the crystallization of the N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide hydrochloride is performed by a precipitation method.

10. A pharmaceutical composition for the prevention or treatment of neurological diseases comprising, as an active ingredient, a crystalline form according to any one of claims 1 to 5 together with a pharmaceutically acceptable carrier.

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