Pharmaceutically acceptable salts of polyamine derivatives, their crystal forms, and methods for preparing same

Abstract

The present invention discloses bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, its crystal form, and preparation method. Compared with the free alkoxy and other salts of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine, it has excellent stability and high dynamic solubility, and is more advantageous in terms of safety as a drug and industrial production.

Description

[Technical field]

[0001] The present invention relates to the technical field of chemical medicine, specifically to bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, its crystalline form, and preparation method. [Background technology]

[0002] Systemic inflammatory response syndrome (SIRS) and autoimmune disorder-related diseases, such as sepsis and autoimmune diseases, are two types of diseases caused by the body's own excessive immune response. There is no effective therapeutic drug yet, and targeted prevention and treatment have become a topic of clinical attention.

[0003] Sepsis refers to a systemic inflammatory response syndrome (SIRS) mediated by infectious agents, and 19 million patients worldwide develop the disease every year. Although antibiotics and emergency medical technology have made great advances, sepsis remains the leading cause of death in infected patients, and there is still no ideal treatment. According to research, the mechanism of sepsis is that pathogen-associated molecular patterns (PAMPs) released by pathogens such as bacteria, viruses, and fungi are recognized by the pattern recognition receptors (PRRs) of the host's innate immune system, mediating the activation of inflammatory response cells, causing an excessive inflammatory response systemically. According to epidemiological surveys, the PAMP molecules that cause sepsis mainly include bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), lipoteichoic acid (LTA), viral RNA, and zymosan.

[0004] Patent document CN105348137B discloses a pharma- ceutically acceptable salt of a polyamine derivative, its preparation method, and its use in the treatment of sepsis. The pharma- ceutically acceptable salt of the polyamine derivative is the hydrochloride salt of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine with an acid / base ratio of 3.

[0005] However, in actual production, in the case of the hydrochloride salt of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine having an acid / alkali ratio of 3 disclosed in the prior art, there are drawbacks in that it is difficult to discharge the product due to serious adhesion to the vessel wall during production and manufacturing, and operability is reduced, making it useless for actual production.

[0006] Therefore, it is important to develop a stable pharma- ceutically acceptable salt of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine that is suitable for industrial production. Summary of the Invention [Problem to be solved by the invention]

[0007] In order to solve the shortcomings of the prior art, the present invention provides bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, its crystalline form, and preparation method. [Means for solving the problem]

[0008] A first aspect of the present invention provides bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate.

[0009] Furthermore, the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate has the following structure: [ka]

[0010] x represents the number of moles of phosphoric acid bound to 1 mole of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine, and further, the x is 1 to 3 (e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0), preferably 1.5 to 2.5, more preferably 1.9 to 2.1, and most preferably 2.0.

[0011] Preferably, the phosphate is: [ka]

[0012] Further, the phosphate salt may be in crystalline, amorphous form, or a mixture of crystalline and amorphous forms.

[0013] A second aspect of the invention provides a method for preparing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to the first aspect, comprising the step of mixing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine with phosphoric acid.

[0014] Furthermore, the manufacturing method includes: bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine is mixed with phosphoric acid and reacted, Further, the reaction solvent is one or more selected from ethyl acetate, methylene chloride, methanol, water, chloroform, ethanol, acetone, acetonitrile, butanol, dimethylformamide, dimethylsulfoxide, methyl tert-butyl ether, isopropylamine, and isopropanol, preferably, the reaction solvent is one or more selected from methanol, ethanol, ethyl acetate, acetone, and methylene chloride, more preferably, the reaction solvent is methanol or ethanol.

[0015] Furthermore, the reaction temperature is 0 to 30°C (for example, 0°C, 5°C, 15°C, 20°C, 25°C, 30°C), preferably 0 to 15°C.

[0016] Furthermore, the reaction time is 2 to 6 hours (for example, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours), preferably 3 to 5 hours, and more preferably 4 hours.

[0017] Additionally, seed crystals are added during the reaction.

[0018] Furthermore, the equivalent ratio of the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine to phosphoric acid is 1:1 to 2.5 (for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5), preferably 1:1 to 2, more preferably 1:1.8 to 2, and the equivalent ratio is a molar ratio.

[0019] Furthermore, the method for producing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate further comprises a step of separating the product.

[0020] Furthermore, the separation may include a filtration or centrifugation step.

[0021] Furthermore, the filtering operation means filtering to react, obtaining a reaction system, obtaining a filter cake, and optionally washing the filter cake.

[0022] Furthermore, the solvent used for washing is one selected from methanol, ethyl acetate, ethanol, and isopropanol, and preferably, the washing solvent is methanol or ethyl acetate.

[0023] Furthermore, the method for preparing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate further comprises a drying step.

[0024] Furthermore, the drying step refers to drying the material obtained by separation under normal pressure or reduced pressure.

[0025] Furthermore, the drying temperature is 0 to 35°C (for example, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C), preferably 25 to 35°C.

[0026] wherein said bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine may be prepared in gram or kilogram scale by any of a number of different methods, such as the preparation methods described in patent document CN201510729318.8, which is incorporated herein by reference.

[0027] Furthermore, the method for producing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate further includes a step of purifying (purifying) bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate.

[0028] Furthermore, the purification step may include recrystallization and / or washing.

[0029] Further, the recrystallization solvent is one or a combination of two selected from methanol, ethanol, and water, particularly methanol-water, ethanol-water, water-methanol, and water-ethanol.

[0030] Furthermore, the washing solvent is one selected from methanol, ethanol, ethyl acetate, and isopropanol, and preferably, the solvent for washing the crystals is methanol or ethyl acetate.

[0031] Furthermore, the purification step includes adding seed crystals.

[0032] A third aspect of the present invention provides a method for preparing the amorphous form of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to the first aspect.

[0033] Further, the production method is one or a combination of a plurality of methods selected from a gas-liquid diffusion method, a polymer induction method, a slow evaporation method, and a slow cooling method, preferably one or a combination of a plurality of methods selected from a gas-liquid diffusion method, a polymer induction method, and a slow evaporation method.

[0034] Furthermore, the gas-liquid diffusion method involves placing the target product in an open container, dissolving it in a good solvent, then placing the open container in a closed container containing a poor solvent, leaving it to stand (room temperature), and finally collecting it to obtain a solid.

[0035] Further, the polymer derivatization method includes dissolving the desired product in a solvent, filtering through a pin film, adding a polymer to the filtrate, and evaporating at room temperature to obtain a solid.

[0036] Moreover, the slow evaporation method involves dissolving the desired product in a solvent and then drying to obtain a solid.

[0037] Furthermore, the slow cooling method includes dissolving the target product in a solvent, heating at 40°C to 60°C, stirring for 1 to 4 hours to equilibrate, filtering the solution when it becomes clear, slowly cooling the filtrate from 40°C to 60°C to 0°C to 10°C, keeping it at -10 to 30°C (e.g., 10°C, 15°C, 20°C, 25°C, 30°C) for 3 to 8 days while keeping it clear, and finally evaporating it at 40 to 60°C (e.g., 40°C, 45°C, 50°C, 55°C, 60°C).

[0038] In one embodiment of the present invention, the method for preparing the amorphous form of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate is a slow evaporation method, specifically, 10-20 mg of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate is weighed into a 4 mL glass bottle, and added to a mixed solution of DMSO and water with a volume ratio of 2:1 to dissolve. The mixture is filtered through a pin film (pore size 0.22 μm), and the filtrate is sealed with Parafilm™, and 5 pinholes are opened to allow slow evaporation at a predetermined temperature. The final solid is subjected to XRPD characterization. Experimental results show that amorphous bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate is obtained by slow evaporation method at room temperature.

[0039] A fourth aspect of the present invention provides crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to the first aspect.

[0040] Furthermore, in the XRPD pattern of crystalline form A, characteristic peaks (major characteristic diffraction peaks) are present at at least three (or all) of the following 2θ values: 6.4°±0.2°, 9.7°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 22.9°±0.2°, and 26.1°±0.2°.

[0041] Furthermore, in the XRPD pattern of crystalline form A, characteristic peaks (major characteristic diffraction peaks) are present at at least three (or all) of the following 2θ values: 6.4°±0.2°, 9.7°±0.2°, 11.80°±0.2°, 13.0°±0.2°, 14.8°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 22.9°±0.2°, and 26.1°±0.2°.

[0042] Furthermore, in the XRPD pattern of crystalline form A, characteristic peaks (minor characteristic diffraction peaks) are present at at least three (at least four or all) of the following 2θ values: 11.80°±0.2°, 13.0°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 18.7°±0.2°, 20.8°±0.2°, 22.6°±0.2°, and 23.7°±0.2°.

[0043] Furthermore, said crystalline form A has an XRPD pattern substantially as shown in FIG.

[0044] Furthermore, in the DSC pattern of the crystalline form A, endothermic peaks are present at 175 to 195° C. (for example, about 175° C., 180° C., 185° C., 190° C., and 195° C.).

[0045] Furthermore, said crystalline form A has a DSC pattern substantially as shown in FIG.

[0046] Further, the crystalline form A exhibits a weight loss of about 3% (eg, 1.5%, 2.0%, 2.5%, 3.0%) when heated from 22°C to 150°C.

[0047] Furthermore, the crystalline form A has a TGA pattern substantially as shown in FIG.

[0048] A fifth aspect of the present invention provides a process for preparing crystalline form A according to the fourth aspect.

[0049] Furthermore, the preparation method is a poor solvent crystallization method and a poor-poor solvent crystallization method.

[0050] Furthermore, the anti-solvent crystallization method involves dissolving the target product in a good solvent and then adding an anti-solvent to the system, in which the anti-solvent does not dissolve or only slightly dissolves the substance to be crystallized, thereby reducing the solubility of the crystallization substance and causing it to precipitate from the mixed solution.

[0051] Furthermore, the poor-poor solvent crystallization method is a method that includes adding a solution of the target product dissolved in a good solvent to one or more poor solvents, and since the product is slightly dissolved in the solution, the solution is made supersaturated, thereby precipitating crystals.

[0052] In one embodiment of the present invention, the anti-solvent crystallization method for the bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate crystal form A is specifically carried out by: (1) mixing the reaction product obtained in the second aspect of the present invention with a good solvent; Step (2) of dropping a poor solvent into the mixed solution obtained in step (1); Step (3) of cooling and separating the solution obtained in step (2) to obtain a wet product; and step (4) of drying the wet product obtained in step (3) to obtain a dry product of phosphate crystals A.

[0053] Further, the good solvent described in step (1) is selected from water, a mixture of methanol and water, or a mixture of ethanol and water, and preferably, the good solvent described in step (1) is a mixture of methanol and water.

[0054] Further, the anti-solvent described in step (1) is one or more selected from methanol, ethanol, tetrahydrofuran, ethyl acetate, or toluene.

[0055] Furthermore, the temperature-reducing treatment described in step (3) means reducing the temperature to 0 to 15°C (e.g., 0°C, 5°C, 10°C, 15°C), and preferably, the temperature-reducing treatment described in step (3) means reducing the temperature to 5°C.

[0056] Furthermore, the time for the temperature-lowering treatment described in step (3) is 3 to 16 h (e.g., 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h), preferably 8 to 14 h (e.g., 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h), and more preferably 12 h.

[0057] Furthermore, the separation method described in step (3) includes centrifugation, filtration and / or suction filtration. Preferably, the centrifugation means centrifuging the mixed solution after the reaction to obtain a solid.

[0058] Furthermore, in the drying treatment described in step (4), the drying temperature is 25 to 35°C (eg, 25°C, 30°C, 35°C), preferably 30°C.

[0059] A sixth aspect of the present invention provides the use of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its crystalline form A in the manufacture of an anti-PAMP drug.

[0060] Furthermore, the PAMP is one or more selected from bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), lipoteichoic acid (LTA), viral RNA, and zymosan.

[0061] A seventh aspect of the present invention provides the use of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its crystalline form A in the manufacture of a medicament for preventing and / or treating systemic inflammatory response syndrome (SIRS).

[0062] Further, the systemic inflammatory response syndrome is sepsis.

[0063] An eighth aspect of the present invention provides the use of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate and its crystalline form A in the manufacture of a medicament for preventing and / or treating an autoimmune disease.

[0064] Furthermore, the autoimmune disease is one or more selected from organ-specific autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.

[0065] The bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate described in the present application has excellent stability and high dynamic solubility compared to the free alkoxy and other salts of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine, and is advantageous for industrial production. Here, bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine diphosphate has higher stability and is more advantageous in terms of safety as a drug compared to bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine triphosphate. In the production of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, when the equivalent ratio of phosphoric acid described in the present application is used, the salt can be easily precipitated from the reaction system and can be separated from the system by a simple filtration operation, which is advantageous for industrial mass production. [Brief description of the drawings]

[0066] [Figure 1] 1 shows the XRPD pattern of phosphate crystalline form A. [Diagram 2] 1 shows the TGA / DSC pattern of phosphate crystalline form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] Some of the abbreviations used in the present invention are explained below.

[0068] XRPD: X-ray powder diffraction

[0069] DSC: Differential scanning calorimetry

[0070] TGA: Thermogravimetric analysis

[0071] In the present invention, the term "crystalline form" is confirmed by characterization of the powder X-ray diffraction pattern. Those skilled in the art will understand that the physical and chemical properties discussed herein can be characterized, and that the experimental error depends on the instrument conditions, sample preparation, sample purity, etc. In particular, it is well known to those skilled in the art that X-ray diffraction patterns usually often change depending on the instrument conditions. In particular, the relative intensities of the powder X-ray diffraction pattern can also change depending on the experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor. In fact, the relative intensities of the diffraction peaks of the XRPD pattern are related to the preferred orientation of the crystal. The peak intensities shown herein are illustrative and not used for absolute comparison. In addition, the experimental error of the peak angles is usually not more than 5%, and the errors of these angles must also be taken into account, and an error of ±0.2° is usually allowed. In addition, the influence of experimental factors such as the thickness of the sample will cause an overall deviation in the peak angles, but a certain degree of deviation is usually allowed. Therefore, those skilled in the art will understand that the powder X-ray diffraction pattern of the crystalline form in the present invention does not necessarily have to be completely identical to the powder X-ray diffraction pattern in the examples referred to in the present specification, and the "XRPD pattern is the same" described in the present specification does not mean that they are exactly the same, and the same peak positions are allowed to have an error of ±0.2°, and the peak intensities are allowed to have a certain variation. Any crystalline form having the same or similar pattern of characteristic peaks in these patterns is included within the scope of the present invention. Those skilled in the art can compare the patterns listed in the present invention with the patterns of unknown crystalline forms to confirm whether the two sets of patterns reflect the same crystalline form or different crystalline forms. In some embodiments, the crystalline form A of the present invention is pure and single, and is almost free of other crystalline forms mixed with it. In the present invention, "substantially free" when referring to a new crystalline form refers to the crystalline form containing less than 20% (by weight), particularly less than 10% (by weight), even less than 5% (by weight), and even less than 1% (by weight) of other crystalline forms.

[0072] It should be noted that the numerical values ​​and numerical ranges referred to in the present invention should not be understood in the narrow sense as numerical values ​​or numerical ranges themselves. Those skilled in the art will understand that specific values ​​may vary depending on the specific technical environment without departing from the spirit and principles of the present invention. In the present invention, such a variation range that can be predicted by a person skilled in the art is often expressed by the term "about". In the present invention, when the term "about" is used before a numerical value to refer to the numerical value, it means any value within the range of ±10% of the value, preferably within the range of ±5%, more preferably within the range of ±2%, and more preferably within the range of ±1%. For example, "about 10" should be interpreted as meaning 9 to 11, preferably 9.5 to 10.5, more preferably 9.8 to 10.2, and more preferably 9.9 to 10.1.

[0073] In addition, in the powder X-ray diffraction pattern of a sample, the diffraction pattern obtained from a crystalline compound is often characteristic of a particular crystal form, and the relative intensities of the bands (especially at low angles) may vary due to predominant orientation effects resulting from differences in crystallization conditions, particle size, relative contents of the mixture, and other test conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the target crystal, and when judging whether a known crystal form is the same, attention should be paid to the positions of the peaks rather than the relative intensities.

[0074] In the present invention, the term "substantially as shown in Figure . . . " means that at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in an XRPD pattern, DSC pattern, or TGA pattern are represented in that pattern.

[0075] In the present invention, the term "room temperature" means that the temperature of the item is close to or the same as the temperature of the space (e.g., the location of the ventilation hood where the item is placed). Typically, room temperature is about 20°C to about 30°C, about 22°C to 27°C, or about 25°C.

[0076] The anti-solvent crystallization method (also called anti-solvent addition, precipitation crystallization, salting out, or forced crystallization) is a method in which one or more anti-solvents are added to a solution in which the target product is dissolved in a good solvent, and the product is slightly dissolved in the solution, making the solution supersaturated and causing crystals to precipitate. The anti-poor-solvent crystallization method is a method in which one or more anti-solvents are added to a solution in which the target product is dissolved in a good solvent, and the product is slightly dissolved in the solution, making the solution supersaturated and causing crystals to precipitate.

[0077] The dissolving ability of the poor solvent for the target product is inferior to that of the good solvent, for example, the difference is more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%. Therefore, the poor solvent in the system is relative. The good solvent and the poor solvent may be polar or non-polar solvents, for example, one or more selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), water, alcohol-based solvents, ether-based solvents, ketone-based solvents, ester-based solvents, alkane-based solvents, aromatic hydrocarbon-based solvents, and nitrile-based solvents. Among them, the alcohol-based solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, 1,3-propanediol, 1,2-propanediol, chlorobutanol, or a combination thereof. The ether-based solvents include, but are not limited to, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, or a combination thereof. Ketone solvents include, but are not limited to, acetone, methyl ethyl ketone, or 4-methyl-2-pentanone, or combinations thereof. Ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate, n-butyl acetate, or tert-butyl acetate, or combinations thereof. Alkane solvents include, but are not limited to, methylene chloride, chloroform, n-hexane, cyclohexane, pentane, n-heptane, or combinations thereof. Aromatic hydrocarbon solvents include, but are not limited to, benzene, toluene, or combinations thereof. Nitrile solvents include, but are not limited to, acetonitrile and malononitrile.

[0078] Anti-solvent crystallization, poor-anti-solvent crystallization may be a batch, semi-batch or continuous crystallization operation. The anti-solvent may be added to the solution (anti-solvent crystallization) or the solution of the product may be added to the anti-solvent (poor-poor anti-solvent crystallization) at a constant rate or slowly at first and then gradually increase in rate.

[0079] The disclosures of various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entireties.

[0080] The technical solutions of the present invention are clearly and completely described below with reference to the embodiments of the present invention, but obviously, the described embodiments are only a part, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative efforts shall be included in the scope of protection of the present invention.

[0081] The information on the instruments and methods used in the experiments of the examples are as follows:

[0082] 1. X-ray Powder Diffraction (XRPD) TIFF2025516011000004.tif43170

[0083] 2. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) Thermogravimetric data for the phosphate salts were collected using a TA Discovery series thermogravimetric apparatus (TGA). A few milligrams of sample were placed in a Tzero aluminum pan and heated with N 2 Heat from room temperature to the target temperature under protection of N 2 The flow rate is 25 mL / min and the heating rate is 10 °C / min. Thermal data of the samples was collected using a TA Discovery series differential scanning calorimeter (DSC). For crystalline samples, a few milligrams of sample were weighed into a Tzero aluminum pan, sealed with a Tzero sealing lid, and argon-free. 2 Heat under protection of N 2Set the flow rate to 50 mL / min and the heating rate to 10 °C / min. For amorphous samples, set the modulation mode for testing. Weigh out approximately 10 mg into a Tzero aluminum pan, seal with a Tzero sealing lid, and infuse with N. 2 Heat under protection of N 2 The flow rate is 50 mL / min, the temperature amplitude is modulated to ±1 °C, the modulation period is 40 s, the heating rate is 1 °C / min, and the test temperature range is 25 °C to 200 °C.

[0084] 3. High Performance Liquid Chromatography (HPLC) The stability of the samples was confirmed using HPLC, specifically, an Agilent 1260 model high performance liquid chromatograph (equipped with a DAD detector) was used to collect the purity and solubility data of the samples, and the test method is shown in Table 1.

[0085] [Table 1]

[0086] 4. Phosphate ion content For bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, the data of the phosphate ion content of the sample was collected using a DIONEX ICS-6000+DP ion chromatography system, and the test method is shown in Table 2.

[0087] [Table 2]

[0088] 5. Biosolvent Preparation The specific procedure for producing the biosolvent is shown in Table 3.

[0089] [Table 3]

[0090] 6. Hygroscopicity Measurement

[0091] The measurement of hygroscopicity shall refer to the Guiding Principles for Drug Hygroscopicity Testing in the 2015 Edition of the Chinese Pharmacopoeia, and the specific test methods are as follows:

[0092] 1. Prepare a dry stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm) and on the day before the test, place it in an appropriate thermostatic dryer at 25°C ± 1°C (put a saturated solution of ammonium chloride or ammonium sulfate in the bottom) or in an artificial climate box (set to a temperature of 25°C ± 1°C and a relative humidity of 80% ± 2%) and accurately weigh its weight (m1).

[0093] 2. Take an appropriate amount of the test item and place it flat in the weighing bottle. The thickness of the test item is usually about 1 mm, and the weight (m2) is accurately measured.

[0094] 3. Open the weighing bottle and leave it with the lid on under the above constant temperature and humidity conditions for 24 hours.

[0095] 4. Close the lid of the weighing bottle and accurately measure the weight (m3). Weight increase rate = (m3-m2) / (m2-m1)×100%

[0096] 5. Explain the characteristics of hygroscopicity and define weight gain due to hygroscopicity Deliquescence: Absorbing enough water to form a liquid. Very hygroscopic: Weight increase due to moisture absorption is 15% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15% and more than 2%. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2% and more than 0.2%. No or little moisture absorption: Weight increase due to moisture absorption is less than 0.2%.

[0097] Example 1 Salt type selection An ethanol solution of the free alkalyl of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine (hereafter referred to as free alkalyl) was prepared at room temperature. An acid solution with an acid / alkalyl molar ratio of 1:1 was placed in an HPLC vial, to which the ethanol solution of the free alkalyl was added and magnetically stirred at room temperature. After magnetic stirring at room temperature for 2-4 days, a small amount of the system gave a cloudy solid, and some of the systems showed wall adhesion and colloidal formation, but the remaining systems remained clear. In the later processing steps, 1) the cloudy systems were centrifuged to separate the solids. 2) For systems where wall adhesion / colloidal formation occurred, a circulating heating / cooling treatment from 25°C to 50°C (see Table 5 for heating / cooling procedure) was performed to improve the apparent state / obtain solids. 3) For clear or slightly cloudy systems, magnetic stirring was performed at 5°C for about 5 hours, followed by standing at -20°C overnight in an attempt to collect a sufficient amount of solids for later characterization. If the amount of solids was small, it was slowly evaporated at room temperature, and if the system remained clear, anti-solvent (n-heptane) was added or slowly evaporated at room temperature. The solids obtained above were separated by centrifugation. The test results are shown in Table 4.

[0098] [Table 4] α The acid / alkali molar input ratio is 1:1. β The acid / alkali molar input ratio is 3:1. *: Because the amount of solids is small or the system is clear, process at a low temperature of 5°C / -20°C, then evaporate slowly at room temperature (18~22°C). # : Since the amount of solids is small or the system is clear, treat at low temperature 5°C / -20°C and then add anti-solvent. † The system is colloidal. Improvement in the state was observed during the circulating temperature increase / decrease treatment at 25-50℃. & : A small amount of solid was obtained from the reaction, but when dried in vacuum at 30℃ for 17 hours, it became a colloid. ※:The solid obtained by the reaction becomes a colloid when left sealed at room temperature for a week.

[0099] [Table 5]

[0100] Stability Testing To evaluate the solid-state stability of the various salts, approximately 15 mg of sample was weighed into an HPLC vial and left open at 25°C / 60%RH. Chemical purity tests (HPLC) and hygroscopicity tests were performed on the initial sample and the samples stored for 5 days and 2 weeks. The stability data are shown in Table 6. The results clearly show that the phosphate salts prepared with an acid / alkali input ratio of 1 showed no obvious changes in properties and purity after being left under the specified conditions for 5 days and 2 weeks, while the hydrochloride, sulfate, and oxalate salts prepared with an acid / alkali input ratio of 1 and the phosphate salt prepared with an acid / alkali input ratio of 3 turned from powdery solid to liquid on the 4th day and also showed some decrease in purity. The phosphate salt prepared with an acid / alkali input ratio of 1 is slightly hygroscopic with a hygroscopicity of 1.29%. The other samples are all very hygroscopic with a hygroscopicity of over 15%. From the above experimental data, it can be seen that among the five salt forms, only the phosphate prepared with an acid / alkali input ratio of 1 was relatively stable. Samples were taken from the phosphate solids prepared with an acid / alkali input ratio of 1 or 3 to measure the acid / alkali ratio, and the test method for the content of phosphate ions is shown in Table 2. The test results clearly show that the phosphate prepared with an acid / alkali input ratio of 1 has an acid / alkali ratio of 1.9, and the phosphate prepared with an acid / alkali input ratio of 3 has an acid / alkali ratio of 3.0.

[0101] [Table 6]

[0102] The stability of the samples was measured by HPLC, specifically, the purity and solubility data of the samples were collected by Agilent 1260 model high performance liquid chromatograph (equipped with a DAD detector), and the test method is shown in Table 1. The hygroscopicity of the samples was measured according to the method described in the Chinese Pharmacopoeia, and the specific measurement method is referred to "6. Measurement of hygroscopicity" in the specification.

[0103] dynamic solubility The dynamic solubility of phosphate in water and three kinds of biosolvents (simulated gastric fluid SGF, fasted simulated intestinal fluid FaSSIF, fed simulated intestinal fluid FeSSIF) was tested under the condition of 37 ° C. The specific method of testing the solubility is as follows. Four portions of 30 mg of sample were weighed, and 3 mL of water and three kinds of biosolvents were added, respectively, and the suspension was kept at 37 ° C and shaken (100 rpm). At 1 / 4 / 24 hours, 1.0 mL of suspension (or clear solution) was taken respectively, the suspension was centrifuged for 3 min, and the supernatant / clear solution was filtered and then used for solubility test (HPLC) and pH measurement (pH meter). The specific operation of producing the biosolvent is shown in Table 3.

[0104] Phosphate has a solubility of more than 9mg / mL in water / SGF / FaSSIF / FeSSIF. The solubility of the samples was measured by HPLC, specifically, Agilent 1260 model high performance liquid chromatograph (equipped with DAD detector) was used to collect the purity and solubility data of the samples, and the test method is shown in Table 1 above. The pH value did not change within 24 hours. Phosphate has high solubility in both water and simulated organism environment.

[0105] Conclusion: Compared with bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, the free alkalyl of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine is less stable, and the purity drops from 97.56% to 73.73% after 7 days at room temperature, and therefore it is necessary to store it at -20°C. Bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine hydrochloride is extremely hygroscopic and becomes colloidal at room temperature, and non-vacuum drying gave a sample with good solid properties. The sulfate prepared with an acid / alkali input ratio of 1 becomes solid at room temperature, but the salt formed is very hygroscopic and stability occurs at room temperature. The L-tartrate salt can be a solid at room temperature, but the resulting solid becomes a colloid when left sealed at room temperature for a week. The oxalate salt and the phosphate salt produced with an acid / alkali input ratio of 3 are very hygroscopic and have poor stability. Because they are very hygroscopic, adhesion to the walls of containers occurs during production, although to different degrees, which is disadvantageous for industrial production.

[0106] The phosphate produced with an acid / alkali input ratio of 1 is well suspended during formation and easily precipitates and separates from the system. Moreover, the stability of the produced phosphate is excellent, and even after being left for two weeks, no obvious changes are observed in its properties and purity. It also has low hygroscopicity, which is particularly advantageous for industrial mass production.

[0107] Salt production Example 2 In a 100 ml three-neck flask, 2 g of free allylic bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine was added at room temperature. Next, 20 g of methylene chloride was added, stirred, dissolved and clarified to obtain a methylene chloride solution of free allylic, which was then cooled to 0-5°C.

[0108] Phosphoric acid (695 mg, 85%) was added to the centrifuge tube, and then 10 g of ethyl acetate was added to obtain a solution of phosphoric acid in ethyl acetate, which was shaken uniformly and prepared for use.

[0109] A solution of phosphoric acid in ethyl acetate was slowly added dropwise to a solution of free ally in methylene chloride. The mixture was stirred at 0-5°C for 4 hours to react, during which a white solid gradually precipitated, the system became turbid, and began to form spheres. During stirring, a white suspension was formed. The mixture was filtered, and the filter cake was washed with ethyl acetate to obtain a wet product. The solid was placed in an oven at 30°C and baked for 16 hours to obtain 2.1 g of a white solid. A solid sample was taken to measure the purity, content, and acid / alkali ratio, and the test results are shown in Table 7.

[0110] Example 3 In a 100 ml three-neck flask, 1 g of the free alkoxy of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine was added at room temperature. Next, methanol (10 g) was added, stirred, dissolved, and clarified to obtain a methanol solution of the free alkoxy, which was then cooled to 0-5°C.

[0111] Phosphoric acid (347.8 mg, 85%) was added to the centrifuge tube, and then 5 g of methanol was added to obtain a solution of phosphoric acid in methanol, which was shaken uniformly and prepared for use.

[0112] A methanol solution of phosphoric acid was slowly added dropwise to a methanol solution of free ally. The mixture was stirred at 0-5°C for 4 hours to react. Initially, the system was clear, but after 0.5 hours, it gradually became cloudy, and then a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with ethyl acetate to obtain a wet product. The solid was placed in an oven at 30°C and baked for 16 hours to obtain 1.1 g of a white solid. A solid sample was taken to measure the purity, content, and acid / alkali ratio. The test results are shown in Table 7.

[0113] Example 4 5 g of the free alkali of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine was added to a 100 ml three-necked flask at room temperature. Next, 50 g of methanol was added, and the mixture was stirred and dissolved to clarify, obtaining a methanol solution of the free alkali, which was then cooled to 0 - 5 °C.

[0114] 1.65 g (85%) of phosphoric acid was added to a 50 ml beaker, and then 25 g of methanol was added to obtain a methanol solution of phosphoric acid, which was shaken uniformly and prepared for use.

[0115] The methanol solution of phosphoric acid was slowly added dropwise to the methanol solution of the free alkali. When stirred at 0 - 5 °C for 4 h for reaction, initially the system was in a clear state, but from 0.5 h, it gradually became turbid, and subsequently, a large amount of solid was precipitated. It was filtered, and the filter cake was washed with methanol to obtain a white wet product. The solid was placed in an oven at 30 °C and baked for 16 h to obtain 5.5 g of a white solid. Solid samples were taken to measure the purity, content, and acid / alkali ratio. The test results are shown in Table 7.

[0116] Example 5 3.4 g of the free alkali of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine was added to a 100 ml three-necked flask at room temperature. Next, 34 g of methanol was added, and the mixture was stirred and dissolved to clarify, obtaining a methanol solution of the free alkali, which was then cooled to 0 - 5 °C.

[0117] 1.12 g of phosphoric acid (85%) was added to a 50 ml beaker, and then 17 g of methanol was added to obtain a methanol solution of phosphoric acid, which was shaken uniformly and prepared for use.

[0118] A solution of phosphoric acid in methanol was slowly added dropwise to a solution of free ally in methanol. The mixture was stirred at 0-5°C for 4 hours to react. Initially, the system was clear, but after 0.5 hours, it gradually became cloudy, and then a large amount of solid precipitated. The mixture was filtered and the filter cake was washed with methanol to obtain a white wet product. The solid was placed in a 30°C oven and baked for 16 hours to obtain 5.5g of a white solid. A solid sample was taken to measure the purity, content, and acid / alkali ratio. The test results are shown in Table 7.

[0119] Example 6 In a 100 ml three-neck flask, 1.0 g of the free alkoxy of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine was added at room temperature. Next, 10 g of methanol was added, stirred, dissolved, and clarified to obtain a methanol solution of the free alkoxy, which was then cooled to 0-5°C.

[0120] Phosphoric acid (183 mg, 85%) was added to the centrifuge tube, and then 5 g of methanol was added to obtain a methanol solution of phosphoric acid, which was then shaken uniformly and prepared for use.

[0121] The methanol solution of phosphoric acid was slowly added dropwise to the methanol solution of free ally. The mixture was stirred at 0-5°C for 4 hours to react, filtered, and the filter cake was washed with methanol to obtain a white wet product. The solid was placed in a 30°C oven and baked for 16 hours to obtain 0.8g of a white solid. A solid sample was taken to measure the purity, content, and acid / alkali ratio. The test results are shown in Table 7.

[0122] The researchers found that when the produced phosphate salts with an acid / alkali ratio of about 2 were recrystallized in a methanol-water or water-methanol recrystallization system, the acid / alkali ratio remained almost unchanged, making the salts stable to the recrystallization process.

[0123] Comparative Example 1 In a 100 ml three-neck flask, 1.0 g of the free alkoxy of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine was added at room temperature. Next, 10 g of methanol was added, stirred, dissolved, and clarified to obtain a methanol solution of the free alkoxy, which was then cooled to 0-5°C.

[0124] Phosphoric acid (558.3 ​​mg, 85%) was added to the centrifuge tube, and then 5 g of methanol was added to obtain a solution of phosphoric acid in methanol, which was shaken uniformly and prepared for use.

[0125] A methanol solution of phosphoric acid was slowly dropped into a methanol solution of free ally. After stirring and reacting for 4 hours at 0-5°C, adhesion to the vessel wall became serious. Methanol was concentrated to dryness, the solids attached to the vessel wall were scraped off with a spatula, and the mixture was slurried with ethyl acetate and filtered. The solids absorbed a lot of moisture and quickly became oily. The oily product was placed in an oven at 30°C and baked for 16 hours to obtain a solid. Samples were taken to measure the purity, content, and acid / alkali ratio. The acid / alkali ratio is the molar amount of phosphoric acid / the molar amount of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine, that is, the acid / alkali molar ratio. The test method for the content of phosphate ions is shown in Table 2, and the test results are shown in Table 7.

[0126] The researchers found that when the phosphate with an acid / alkali ratio of 3 was recrystallized in a methanol-water or water-methanol recrystallization system, the acid / alkali ratio decreased by 10%, which means that the phosphate with an acid / alkali ratio of 3 produced with a phosphoric acid equivalent of 3.05 eq was not stable.

[0127] [Table 7]

[0128] From the above table, it is clear that the process for forming free alkanes and phosphates produced products with high purity, which was not lower than the raw material purity but was improved by 1%, that is, the process for forming free alkanes and phosphates confirmed a significant impurity removal effect.

[0129] When the equivalent of phosphoric acid is 1.0eq, 1.8eq or 1.9eq, the acid / alkali ratio of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate produced by the reaction is 1.9-2.1. In addition, since the salt is easily precipitated from the reaction system in the production process, it can be separated from the system by a simple filtration operation, which is more advantageous for industrial mass production. On the other hand, when the equivalent of phosphoric acid is 3.05eq, the acid / alkali ratio of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate produced by the reaction is 3.0, and the reaction process has serious adhesion to the vessel wall. When the equivalent of phosphoric acid is 1.9eq, the reaction system is good and solids are uniformly produced. When the equivalent of phosphoric acid is 3.05eq, the mixture in the reaction system is obviously not uniform, the mixture system is white at the bottom, and there is a small amount of buttery material attached to the inner wall of the flask in the center. The phosphate salt cannot be separated by direct filtration in the whole reaction system, and needs to be slurried with a solvent and then filtered. In addition, the solid obtained by filtration is very hygroscopic at room temperature and quickly becomes oily, which is unfavorable for industrial mass production of the product.

[0130] Preparation of crystalline forms Example 7 By referring to the method of Example 4, bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate was prepared. 3.27 g of the prepared bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate was added to 11.4 g of purified water, 13.3 g of methanol was added to the reaction vessel, the temperature in the reaction vessel was adjusted to 0-10°C, and then 193.0 g of methanol was slowly added to the reaction vessel. After the addition, the temperature in the reaction vessel was controlled to 0-10°C, and the mixture was stirred for 3-16 hours to obtain a white solid, which was separated by centrifugation to obtain a wet product, which was vacuum dried at 25°C and then characterized by XRPD. The XRPD pattern of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, crystalline form A of the phosphate salt, is shown in FIG. 1 and the corresponding powder X-ray diffraction pattern data is shown in Table 8, listing the diffraction angle 2θ and relative intensity (expressed as a percentage of the most intense peak).

[0131] [Table 8]

[0132] The phosphate crystal form A was subjected to TGA and DSC characterization, and the results are shown in Figure 2. The TGA result shows that when the sample is heated from 22°C to 150°C, 2.714% weight loss occurs, and this weight loss is due to the desorption of adsorbed water. The DSC result shows that the sample has an endothermic peak at 71.28°C, which is due to the desorption of adsorbed water, and the sample has an endothermic peak at 185.64°C, which is the peak corresponding to the crystal form transformation of the sample. It is estimated that the DSC heating start signal is the instrumental signal.

[0133] As a result of the detection, the produced phosphate crystal form A had an acid / alkali ratio of 2.0, was slightly hygroscopic, and had good stability. After being left for 2 weeks under conditions of 25°C / 60% RH, light exposure, 60°C, and 80°C, the crystal form did not change.

Claims

1. 1. Bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, characterized by having the following structure: 【Chemistry 1】 (wherein x is 1 to 3, preferably, said x is 1.5 to 2.5, more preferably, said x is 1.9 to 2.1, and most preferably, said x is 2.0.)

2. The method comprises mixing and reacting bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine with phosphoric acid to obtain a solid, The method for producing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to claim 1, characterized in that the reaction solvent is preferably one or more selected from ethyl acetate, methylene chloride, methanol, water, chloroform, ethanol, acetone, acetonitrile, butanol, dimethylformamide, dimethylsulfoxide, methyl tert-butyl ether, isopropylamine, and isopropanol, more preferably one or more selected from methanol, ethanol, ethyl acetate, acetone, and methylene chloride, more preferably methanol and / or ethanol, and the reaction temperature is preferably 0 to 35° C.

3. Crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate is characterized in that the crystal form A has characteristic peaks at at least three of the following positions of 2θ values ​​in an XRPD pattern: 6.4°±0.2°, 9.7°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 22.9°±0.2°, and 26.1°±0.2°.

4. 4. Crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl))) aminopropylamine phosphate according to claim 3, characterized in that the XRPD pattern has characteristic peaks at at least three of the following positions of 2θ values: 11.80°±0.2°, 13.0°±0.2°, 14.8°±0.2°, 15.3°±0.2°, 18.7°±0.2°, 20.8°±0.2°, 22.6°±0.2°, and 23.7°±0.2°.

5. Crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to claim 3 or 4, characterized in that it has an XRPD pattern substantially as shown in FIG. 1, preferably a DSC pattern substantially as shown in FIG. 2, preferably a TGA pattern substantially as shown in FIG.

2.

6. A method for producing crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate, comprising mixing bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate with a good solvent, then mixing with a poor solvent, and crystallizing the mixture to obtain phosphate crystal A.

7. The method for preparing crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to claim 6, characterized in that the reaction temperature is 0-30°C, preferably 0-10°C, and more preferably 0-5°C.

8. The method for producing crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to claim 6, wherein the good solvent is water, a mixture of methanol and water, or a mixture of ethanol and water, and the poor solvent is one or more selected from the group consisting of methanol, ethanol, tetrahydrofuran, ethyl acetate, and toluene.

9. Use of crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to claim 1 or bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to any one of claims 3 to 5 in the manufacture of an anti-PAMP drug, Preferably, the PAMP is one or more selected from bacterial lipopolysaccharide, bacterial genome, peptidoglycan, teichoic acid, viral RNA, and zymosan.

10. Use of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to claim 1 or crystalline form A of bis((N-3-aminopropyl)-(N-(3,4-dimethoxyphenylpropionyl)))aminopropylamine phosphate according to any one of claims 3 to 5 in the manufacture of a medicament for preventing and / or treating systemic inflammatory response syndrome or an autoimmune disease, Preferably, the systemic inflammatory response syndrome is sepsis; Preferably, the autoimmune disease is one or more selected from organ-specific autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, and ulcerative colitis.

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