WO2024230805A1 - 一种脂蛋白化合物晶型及其制备方法 - Google Patents

一种脂蛋白化合物晶型及其制备方法 Download PDF

Info

Publication number
WO2024230805A1
WO2024230805A1 PCT/CN2024/092233 CN2024092233W WO2024230805A1 WO 2024230805 A1 WO2024230805 A1 WO 2024230805A1 CN 2024092233 W CN2024092233 W CN 2024092233W WO 2024230805 A1 WO2024230805 A1 WO 2024230805A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethyl
pyrrolidin
phenyl
methyl
carboxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2024/092233
Other languages
English (en)
French (fr)
Inventor
姚佳琪
杨俊然
杜振兴
王捷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Pharmaceutical Co Ltd
Priority to KR1020257041155A priority Critical patent/KR20260009339A/ko
Priority to CN202480028455.6A priority patent/CN121285544A/zh
Priority to AU2024267706A priority patent/AU2024267706A1/en
Priority to EP24803084.3A priority patent/EP4711355A1/en
Publication of WO2024230805A1 publication Critical patent/WO2024230805A1/zh
Priority to MX2025013356A priority patent/MX2025013356A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention belongs to the pharmaceutical field and relates to a lipoprotein compound crystal form and a preparation method thereof.
  • Lipoprotein (a) is a low-density lipoprotein-like lipid particle, mainly composed of a core rich in cholesterol esters and a unique apolipoprotein (a) [Apo(a)]. It has the characteristics of genetic polymorphism and long-term stability, and is skewed in the population. Studies have found that elevated Lp(a) is associated with an increased risk of cardiovascular events and related revascularization.
  • PCT/CN2022/129479 discloses a novel lipoprotein compound, namely (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (Compound A)
  • the crystal structure of the active pharmaceutical ingredient often affects the chemical and physical stability of the drug. Different crystallization and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other forms of crystals may be produced.
  • amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, easy agglomeration, poor fluidity, etc. Therefore, studying its crystal form is of great significance for the development of drugs suitable for industrial production and with good biological activity.
  • salt formation can improve some undesirable physicochemical or biological properties of drugs. It is of great significance to develop salts having better physicochemical properties or pharmaceutical properties than (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid.
  • the present disclosure provides a crystalline form A of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 8.343, 18.020, and 21.028.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.343, 12.559, 15.612, 18.020, and 21.028.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 2 .
  • the present disclosure provides a crystalline form B of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , with characteristic peaks at 7.794, 15.530, 19.456, 20.559, and 21.500.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.794, 11.832, 15.530, 19.456, 20.559, 21.500, and 29.097.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.794, 11.832, 12.642, 15.530, 19.456, 20.559, 21.500, and 29.097.
  • the X-ray powder diffraction pattern of the B crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 3.
  • the present disclosure provides a crystalline form C of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , with characteristic peaks at 8.547, 8.847, 13.567, 15.576, and 19.169.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.547, 8.847, 10.487, 13.567, 15.576, and 19.169.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.547, 8.847, 10.487, 13.567, 15.576, 19.169, and 21.973.
  • the X-ray powder diffraction pattern of the C crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 4.
  • the present disclosure provides a D-type crystalline compound of (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , with characteristic peaks at 13.834, 16.316, and 20.830.
  • the D crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.928, 13.834, 16.316, and 20.830.
  • the X-ray powder diffraction pattern of the D crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 5.
  • the present disclosure provides the E crystalline form of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , with characteristic peaks at 4.933, 6.545, 8.528, 20.874, and 22.149.
  • the E crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ . There are characteristic peaks at 4.671, 4.933, 6.545, 8.528, 16.262, 20.874, and 22.149.
  • the E crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.671, 4.933, 6.545, 8.528, 13.037, 15.017, 16.262, 20.874, and 22.149.
  • the E crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 20 .
  • the X-ray powder diffraction patterns of the crystal form A, crystal form B, crystal form C, crystal form D and crystal form E of compound A disclosed in the present invention are expressed in terms of a diffraction angle 2 ⁇ , wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the present disclosure also provides a method for preparing the crystalline form of the aforementioned compound A, which is selected from any of the following methods:
  • the method for preparing the crystalline form of the aforementioned Compound A described in the present disclosure further comprises any step of crystallization, filtration, washing or drying.
  • the crystallization includes but is not limited to stirring crystallization (dissolution crystallization, slurry crystallization) and volatile crystallization.
  • the drying method includes but is not limited to forced air drying and vacuum drying.
  • the drying temperature is generally 25°C to 100°C, preferably 30°C to 70°C, such as 40°C, 50°C or 60°C.
  • the method for preparing the aforementioned crystalline form of compound C comprises (a) mixing compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid with one or more solvents selected from water, isopropanol, tetrahydrofuran, ethanol, acetone, and ethyl acetate,
  • the present disclosure also provides a pharmaceutically acceptable salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid.
  • the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, succinate, meglumine, maleate, hippurate, sulfate, phosphate, methanesulfonate, tartrate, fumarate, citrate, sodium, potassium and arginine salts.
  • the chemical ratio of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid to the acid molecule or the base molecule is 1:0.2 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3 or 1:4.
  • the chemical ratio of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid to the acid molecule is 1:1 to 1:4.
  • the chemical ratio of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and the base molecule is 1:1 to 1:3.
  • Some embodiments provide the hydrochloride salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, wherein the chemical ratio of the compound to HCl is 1:1 to 1:3.
  • Some embodiments provide the maleate salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, wherein the chemical ratio of the compound to HCl is 1:1.
  • Some embodiments provide the L-tartrate salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, wherein the chemical ratio of the compound to L-tartaric acid is 1:1.
  • Some embodiments provide the maleate salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, wherein the chemical ratio of the compound to maleic acid is 1:1.
  • Some embodiments provide the meglumine salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, wherein the chemical ratio of the compound to meglumine is 1:1 to 1:2.
  • the present disclosure also provides a method for preparing the aforementioned pharmaceutically acceptable salt, comprising the step of forming a salt of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid with an acid or a base.
  • the acid used in the salt-forming reaction is selected from, but not limited to, HCl, succinic acid, maleic acid, hippuric acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, tartaric acid, fumaric acid and citric acid.
  • the base used in the salt-forming reaction is selected from, but not limited to, meglumine salt, sodium hydroxide, potassium hydroxide, and arginine.
  • the solvent used in the salt-forming reaction is selected from at least one of ethanol, ethyl acetate, tetrahydrofuran, acetonitrile, acetone, methanol, 1,4-dioxane, isopropanol, 2-methyltetrahydrofuran, ethylene glycol, and water.
  • the salt-forming method of the present disclosure further comprises any step of filtering, washing or drying.
  • the present disclosure also provides a potassium salt ⁇ -crystalline form of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , and has characteristic peaks at 5.544, 8.016, and 19.356.
  • the potassium salt ⁇ -crystalline form has characteristic peaks at 5.544, 8.016, 19.356, and 21.537 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the potassium salt ⁇ -crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG6 .
  • the present disclosure also provides a method for preparing the potassium salt ⁇ -crystalline form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and ethanol, and (b) adding a potassium hydroxide aqueous solution and stirring.
  • the present disclosure also provides an alpha crystalline form of the arginine salt of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , having characteristic peaks at 8.191, 10.598, 15.844, 18.447, and 20.119.
  • the arginine salt a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.191, 10.598, 15.844, 18.447, 20.119, and 24.226.
  • the X-ray powder diffraction pattern of the arginine salt a crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG. 7 .
  • the present disclosure also provides a method for preparing the arginine salt a crystal form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and 10% water/tetrahydrofuran, (b) adding an arginine aqueous solution, and stirring.
  • the present disclosure also provides a sodium salt of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, Form I, having an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 13.831 and 18.556.
  • the sodium salt I crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.834, 13.831, 16.194, and 18.556.
  • the sodium salt I crystal form has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ . As shown in Figure 8.
  • the present disclosure also provides a method for preparing the sodium salt I crystal form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and 10% water/tetrahydrofuran, and (b) adding sodium hydroxide solution and stirring.
  • the present disclosure also provides a crystalline form a of the meglumine salt of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , having characteristic peaks at 5.361, 5.879, 7.118, 8.069, 8.827, and 19.069.
  • the meglumine salt a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.361, 5.879, 7.118, 8.069, 8.827, 9.748, 16.230, and 19.069.
  • the meglumine salt a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.361, 5.879, 7.118, 8.069, 8.827, 9.748, 13.795, 16.230, 19.069, 21.864, and 26.223.
  • the X-ray powder diffraction pattern of the meglumine salt form a represented by a diffraction angle 2 ⁇ is shown in FIG9 .
  • the present disclosure also provides a method for preparing the meglumine salt a crystalline form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and ethanol, and (b) adding a meglumine aqueous solution and stirring.
  • the present disclosure also provides a maleate salt form a of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 7.907, 15.612, 19.174, and 20.701.
  • the maleate salt a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG10 .
  • the present disclosure also provides a method for preparing the maleate salt a crystalline form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and 10% water/tetrahydrofuran, (b) adding maleic acid aqueous solution, and stirring.
  • the present disclosure also provides a hippurate salt a crystalline form of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , having characteristic peaks at 5.551, 9.410, 13.522, 14.534, 19.956, 21.337, and 22.945.
  • the hippurate a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.551, 9.410, 11.209, 13.522, 14.175, 14.534, 19.956, 21.022, 21.337, and 22.945.
  • the hippurate a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.551, 9.410, 11.209, 13.522, 14.175, 14.534, 16.709, 19.956, 21.022, 21.337, and 22.945.
  • the hippurate a crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 11 .
  • the present disclosure also provides a method for preparing the hippurate salt a crystalline form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and ethyl acetate, (b) adding a hippuric acid aqueous solution, and stirring.
  • the present disclosure also provides a hippurate ⁇ -crystalline form of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 4.944, 14.737, 17.143, and 20.109.
  • the hippurate ⁇ -crystalline form has characteristic peaks at 4.944, 9.978, 14.737, 17.143, and 20.109 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the hippurate ⁇ -crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 12 .
  • the present disclosure also provides a method for preparing the hippurate ⁇ -crystalline form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and ethyl acetate, (b) adding a hippuric acid aqueous solution, stirring, and drying.
  • the present disclosure also provides a crystalline form a of the hydrochloride salt of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 6.385, 13.533, 16.203, and 21.244.
  • the hydrochloride salt form a has characteristic peaks at 6.385, 8.530, 13.533, 16.203, and 21.244 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the X-ray powder diffraction pattern of the hydrochloride salt form a represented by a diffraction angle of 2 ⁇ is shown in FIG13 .
  • the chemical ratio of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and HCl in the hydrochloride salt form a is 1:1.
  • the present disclosure also provides a method for preparing the hydrochloride salt a crystalline form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and a solvent (1), wherein the solvent (1) is selected from methanol, ethyl acetate, and 1,4-dioxane, and (b) adding a hydrochloric acid aqueous solution and stirring.
  • the present disclosure also provides a hydrochloride salt b form of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , and has characteristic peaks at 8.059, 10.359, 19.412, 20.726, and 21.843.
  • the hydrochloride salt b crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.059, 10.359, 16.017, 17.806, 19.412, 20.726, and 21.843.
  • the X-ray powder diffraction pattern of the hydrochloride salt form b represented by a diffraction angle of 2 ⁇ is shown in FIG. 14 .
  • the chemical ratio of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and HCl in the hydrochloride salt form b is 1:1.
  • the present disclosure also provides a method for preparing the hydrochloride salt b crystal form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and acetonitrile, (b) adding a hydrochloric acid aqueous solution, and stirring.
  • the present disclosure also provides a hydrochloride salt c crystalline form of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ , with characteristic peaks at 9.395, 11.238, 13.495, and 20.153.
  • the hydrochloride salt form c has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 9.395, 11.238, 13.495, 20.153, 21.169, and 23.125.
  • the X-ray powder diffraction pattern of the hydrochloride salt form c represented by a diffraction angle of 2 ⁇ is shown in FIG. 15 .
  • the chemical ratio of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and HCl in the hydrochloride salt c crystal form is 1:1.
  • the present disclosure also provides a method for preparing the hydrochloride salt c crystal form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and 10% water/tetrahydrofuran, (b) adding a hydrochloric acid aqueous solution, and stirring.
  • the present disclosure also provides a hydrochloride salt form d of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , and has characteristic peaks at 8.128, 12.995, 14.962, 16.354, 20.401, and 23.032.
  • the hydrochloride salt d form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.128, 12.216, 12.995, 14.962, 16.354, 19.268, 20.401, and 23.032.
  • the hydrochloride salt d crystal form has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ . There are characteristic peaks at 8.128, 12.216, 12.995, 14.962, 16.354, 19.268, 19.965, 20.401, 23.032, and 24.742.
  • the X-ray powder diffraction pattern of the hydrochloride d form represented by a diffraction angle of 2 ⁇ is shown in FIG. 16 .
  • the chemical ratio of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and HCl in the hydrochloride salt d form is 1:1.
  • the present disclosure also provides a method for preparing the hydrochloride salt d form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and 10% water/isopropanol, (b) adding a hydrochloric acid aqueous solution, and stirring.
  • the present disclosure also provides the hydrochloride salt form e of the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , and has characteristic peaks at 9.385, 14.145, 19.709, 20.277, and 21.583.
  • the hydrochloride e crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 9.385, 14.145, 15.451, 19.709, 20.277, 21.583, and 23.684.
  • the hydrochloride e crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 9.385, 14.145, 15.451, 19.709, 20.277, 21.583, 23.187, 23.684, and 24.366.
  • the X-ray powder diffraction pattern of the hydrochloride e crystal form represented by a diffraction angle of 2 ⁇ is shown in FIG. 17 .
  • the chemical ratio of compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and HCl in the hydrochloride e crystal form is 1:1.
  • the present disclosure also provides a method for preparing the hydrochloride e crystal form of the aforementioned compound, comprising the steps of mixing the compound (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid and a solvent (2), wherein the solvent (2) is selected from 10% water/isopropanol, acetonitrile, 10% water/tetrahydrofuran, methanol, isopropanol or a mixed solvent thereof; and (b) adding a hydrochloric acid aqueous solution, stirring, and drying.
  • the crystal form of the pharmaceutically acceptable salt of Compound A disclosed herein has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the method for preparing the crystal form disclosed herein comprises any step of filtration (or centrifugal filtration/centrifugation), washing or drying.
  • the drying method includes but is not limited to forced air drying and vacuum drying.
  • the drying temperature is generally 25°C to 100°C, preferably 30°C to 70°C, such as 40°C, 50°C or 60°C.
  • the present disclosure also provides a pharmaceutical composition, which includes the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal form and a pharmaceutically acceptable excipient.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising mixing the aforementioned crystal form with a pharmaceutically acceptable excipient. Combined steps.
  • the present disclosure also provides use of the aforementioned pharmaceutically acceptable salt, the aforementioned crystal form or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease or condition associated with elevated plasma levels of LP(a).
  • the present disclosure also provides use of the aforementioned pharmaceutically acceptable salt, the aforementioned crystal form or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating cardiovascular diseases.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14 , 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • the numerical values in this disclosure are instrumental measurements or calculated values after instrumental measurements, and there is a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used needs to be considered.
  • the total impurity content which is a value with an error change of no more than plus or minus 10% after measurement, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.
  • the "differential scanning calorimetry or DSC” described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • compositions include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • the "beating” mentioned in the present disclosure refers to a method of purification that utilizes the property that a substance has poor solubility in a solvent, but impurities have good solubility in a solvent. Beating purification can remove color, change the crystal form, or remove a small amount of impurities.
  • the crystalline forms disclosed herein include but are not limited to solvates of Compound A, and the solvents include but are not limited to water.
  • FIG1 is an amorphous XRPD spectrum of compound A.
  • Figure 2 is the XRPD spectrum of Form A of Compound A.
  • FIG3 is an XRPD spectrum of Form B of Compound A.
  • FIG4 is an XRPD spectrum of Form C of Compound A.
  • Figure 5 is an XRPD spectrum of the D crystal form of compound A.
  • Figure 6 is an XRPD spectrum of the ⁇ crystal form of the potassium salt of compound A.
  • FIG. 7 is an XRPD spectrum of Compound A arginine salt form a.
  • FIG8 is an XRPD spectrum of Compound A sodium salt Form I.
  • FIG. 9 is an XRPD spectrum of Compound A meglumine salt Form a.
  • FIG. 10 is an XRPD spectrum of Compound A maleate salt Form a.
  • FIG. 11 is an XRPD spectrum of the hippurate salt form a of Compound A.
  • FIG. 12 is an XRPD spectrum of the ⁇ -form of hippurate salt of Compound A.
  • FIG. 13 is an XRPD spectrum of Compound A hydrochloride Form a.
  • FIG. 14 is an XRPD spectrum of Compound A hydrochloride b crystal form.
  • FIG. 15 is an XRPD spectrum of Compound A hydrochloride Form c.
  • FIG. 16 is an XRPD spectrum of Compound A hydrochloride Form d.
  • Figure 17 is the XRPD spectrum of Compound A hydrochloride Form e.
  • FIG. 18 is an XRPD spectrum of amorphous form of Compound A hydrochloride (1:4).
  • FIG. 19 is an XRPD spectrum of amorphous form of Compound A hydrochloride (1:1).
  • Figure 20 is the XRPD spectrum of Form E of Compound A.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC-MS (Manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (Manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO Q 15 Exactive).
  • HPLC determinations were performed using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48°.
  • DSC is differential scanning calorimetry: the measurement was performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min, 25-300°C or 25-350°C, and a nitrogen purge rate of 50mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min.
  • the specific temperature range refers to the corresponding spectrum, and the nitrogen purge rate is 50mL/min.
  • DVS dynamic moisture adsorption: using Surface Measurement Systems instrinsic, humidity starts from 50%, the humidity range is 0%-95%, the step is 10%, the judgment standard is each gradient mass change dM/dT ⁇ 0.002%, TMAX 360min, two cycles.
  • the known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • Step 1 Preparation of (R)-tert-butyl 3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-(benzyloxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (6a)
  • Step 2 Preparation of (S)-3-(3-(benzyloxy)phenyl)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)propanoic acid (6b)
  • Step 3 Preparation of (R)-tert-butyl 3-((S)-3-(3-(benzyloxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (6c)
  • Step 4 Preparation of (R)-tert-butyl 3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (6d)
  • Step 5 Preparation of (R)-tert-butyl 3-((S)-3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (6e)
  • Step 6 Preparation of (R)-tert-butyl 3-((S)-3-(3-(2-aminoethoxy)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (6f)
  • Step 7 Preparation of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl]-3-oxopropyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (6 g)
  • Step 8 Preparation of (2S)-3-(3- ⁇ [(2- ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenoxy ⁇ ethyl)( ⁇ 3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl ⁇ methyl)amino]methyl ⁇ phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid tetrahydrochloride
  • reaction solution was cooled to room temperature, centrifuged, and the filtrate was purified by reverse phase flash column chromatography (acetonitrile/water) to obtain 4a (270 mg, yield 76%) as a yellow oil.
  • Test Example 1 Test of the compound's inhibitory activity on Lp(a) assembly
  • the present invention utilizes a double antibody ELISA method to detect the assembly efficiency of Apo(a) and ApoB proteins, wherein the antibodies are ApoB-Capture antibody (Mabtech) and Apo(a)-Detector antibody (Abcam); the detection samples are the plasma of human transgenic hApo(a) and hApoB mice, which are diluted 500 times respectively for use.
  • the antibodies are ApoB-Capture antibody (Mabtech) and Apo(a)-Detector antibody (Abcam); the detection samples are the plasma of human transgenic hApo(a) and hApoB mice, which are diluted 500 times respectively for use.
  • reaction solution was added to the ELISA test plate pre-coated with ApoB-Capture antibody, incubated at room temperature for 2 hours, and then the plate was washed 4 times with washing solution; biotin-labeled Apo(a)-Detector antibody was added, incubated at room temperature for 1 hour, the plate was washed and the color substrate TMB solution was added; after incubation at room temperature for 15 minutes, the reaction stop solution was added, and the absorbance at 450nm was immediately detected with an enzyme reader after mixing. Finally, GraphPad Prism 9 software was used for data analysis and IC 50 calculation.
  • 0% inhibition rate of Apo(a) and ApoB protein assembly corresponds to the OD value when the compound concentration is 0 (1% DMSO); 100% inhibition rate of Apo(a) and ApoB protein assembly corresponds to the OD value when only ApoB protein solution (hApoB mouse plasma dilution) is added.
  • IC 50 0.41 nM.
  • Test Example 2 In vivo pharmacokinetic study in beagle dogs
  • Beagle dogs were used as test animals, and the drug concentration in plasma at different time points after oral administration of the disclosed compound to beagle dogs was determined by LC/MS/MS method. The pharmacokinetic behavior of the disclosed compound in beagle dogs was studied, and its pharmacokinetic characteristics were evaluated.
  • Drug preparation Weigh a certain amount of drug and add normal saline to make a 2 mg/mL colorless clear solution.
  • Beagles were intragastrically administered with the disclosed compounds. About 0.6 mL of blood was collected by peripheral venous puncture at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in a tube containing EDTA-K2 and centrifuged at 2000 rpm for 10 minutes at about 4°C to separate the plasma, which was then stored at -75°C.
  • WinNonlin 6.1 software was used to calculate pharmacokinetic parameters using the non-compartmental model method.
  • the pharmacokinetic parameters of the disclosed compounds in beagle dogs are shown in Table 1.
  • the disclosed compounds have better oral absorption, better systemic exposure, longer half-life, and excellent pharmacokinetic characteristics, and oral administration has obvious advantages.
  • Reference 1 is the compound of Example 1 in patent CN114008021, which is obtained according to the preparation method of Example 1 in patent CN114008021.
  • the product was defined as Form B by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG3 , and the positions of its characteristic peaks are shown in Table 3.
  • the product was defined as Form C by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG4 , and the positions of its characteristic peaks are shown in Table 4 .
  • the XRPD spectrum is shown in FIG5 , and the positions of the characteristic peaks are shown in Table 6 .
  • the product is defined as free state D crystal form.
  • the DSC spectrum showed that the endothermic peaks were 65.77 and 256.41°C.
  • the TGA had a weight loss of 9.9% in the range of 31-221°C.
  • the product was defined as potassium salt ⁇ -crystalline form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG6 , and the positions of its characteristic peaks are shown in Table 7.
  • the product was defined as arginine salt a crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG7 , and the positions of its characteristic peaks are shown in Table 8.
  • the product was defined as sodium salt I crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG8 , and the positions of its characteristic peaks are shown in Table 9.
  • the product was defined as meglumine salt a crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG9 , and the positions of its characteristic peaks are shown in Table 10.
  • the product was defined as maleate a crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in FIG10 , and the positions of its characteristic peaks are shown in Table 11.
  • the product was defined as hippurate ⁇ -crystal by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG11 , and the positions of its characteristic peaks are shown in Table 12.
  • the product was defined as hippurate ⁇ -crystal by X-ray powder diffraction analysis.
  • the XRPD spectrum is shown in FIG12 , and the positions of its characteristic peaks are shown in Table 13.
  • the product was defined as hydrochloride a crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 13 and the positions of its characteristic peaks are shown in Table 14.
  • the DSC spectrum shows that the endothermic peaks are 59.78 and 285.05°C. TGA loses 4.4% of its weight in the range of 32-160°C. Ion chromatography shows that the chloride ion content is 4.75%. The DVS hygroscopicity test results show that the weight gain is 30% at 80% RH.
  • the product was defined as hydrochloride b crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 14, and the positions of its characteristic peaks are shown in Table 15.
  • the product was defined as hydrochloride c crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 15, and the positions of its characteristic peaks are shown in Table 16.
  • the DSC spectrum shows that the endothermic peaks are 70.77, 114.11, 147.43, 227.41, and 282.72°C.
  • the TGA shows a weight loss of 3.8% in the range of 32-122°C and a weight loss of 4.2% in the range of 122-225°C.
  • the product was defined as hydrochloride d crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 16, and the positions of its characteristic peaks are shown in Table 17.
  • the DSC spectrum showed that the endothermic peaks were 97.05, 117.48, 142.73, and 284.01°C.
  • the TGA had a weight loss of 6.3% in the range of 33-138°C.
  • the product was defined as hydrochloride e crystal form by X-ray powder diffraction detection.
  • the XRPD spectrum is shown in Figure 17, and the positions of its characteristic peaks are shown in Table 18.
  • the DSC spectrum showed that the endothermic peaks were 76.58, 108.43, 146.76, and 287.37°C.
  • the TGA had a weight loss of 6.1% in the range of 30-161°C.
  • the ion chromatography showed that the chloride ion content was 5.20%.
  • the DVS hygroscopicity test showed that the weight gain was 18% at 80% RH.
  • the DSC spectrum showed that the endothermic peak was 247.23°C and the TGA weight loss was 3.58% in the range of 36-90°C.
  • Test Example 3 Long-term accelerated test
  • Test Example 4 Long-term accelerated test
  • the free state C crystal form of the aforementioned compound A was sealed in an aluminum foil bag (nitrogen-filled for protection) and placed under 25° C./60% RH and 40° C./75% RH conditions to investigate the stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本公开涉及一种脂蛋白化合物晶型及其制备方法。具体而言，本公开提供(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的晶型及其制备方法。

Description

一种脂蛋白化合物晶型及其制备方法 技术领域
本公开属于制药领域，涉及一种脂蛋白化合物晶型及其制备方法。
背景技术
脂蛋白(a)[Lp(a)]是一种类低密度脂蛋白的血脂颗粒，主要由富含胆固醇酯的内核和特有的载脂蛋白(a)[Apo(a)]组成，具有基因多态性和长期稳定的特点，在人群中呈偏态分布。有研究发现Lp(a)升高与罹患心血管事件风险增加及相关血运重建有关。
PCT/CN2022/129479公开了一类新型脂蛋白化合物，即(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸(化合物A)
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，研究其晶型对开发适合工业生产且生物活性良好的药物具有重要意义。
另一方面，成盐可改善药物某一些不理想的物理化学或生物学性质。开发出相对于(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸，在理化性质或药学性质方面具有更优异的性质的盐是具有重要意义的。鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，深入研究化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的可药用盐的多晶型，对开发适合工业生产且生物活性良好的药物也是具有重要意义。
发明内容
本公开一方面提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的A晶型,以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.343、18.020、21.028处有特征峰。
在一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.343、12.559、15.612、18.020、21.028处有特征峰。
在另一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
本公开一方面提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的B晶型,以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.794、15.530、19.456、20.559、21.500处有特征峰。
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.794、11.832、15.530、19.456、20.559、21.500、29.097处有特征峰。
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.794、11.832、12.642、15.530、19.456、20.559、21.500、29.097处有特征峰。
在另一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开一方面提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.547、8.847、13.567、15.576、19.169处有特征峰。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.547、8.847、10.487、13.567、15.576、19.169处有特征峰。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.547、8.847、10.487、13.567、15.576、19.169、21.973处有特征峰。
在另一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开一方面提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.834、16.316、20.830处有特征峰。
在一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.928、13.834、16.316、20.830处有特征峰。
在另一些实施方案中，所述D晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开一方面提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.933、6.545、8.528、20.874、22.149处有特征峰。
在一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在 4.671、4.933、6.545、8.528、16.262、20.874、22.149处有特征峰。
在一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.671、4.933、6.545、8.528、13.037、15.017、16.262、20.874、22.149处有特征峰。
在另一些实施方案中，所述E晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
进一步地，本公开所述化合物A的A晶型、B晶型、C晶型、D晶型、E晶型，以衍射角2θ角度表示的X-射线粉末衍射图，其中2θ角度的误差范围为±0.2。
另一方面，本公开还提供制备前述化合物A的晶型的方法，选自如下任一方法，
方法一：
(a)将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与溶剂混合，搅拌溶解或加热溶解，
(b)析晶；
或，方法二：
(a)将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与溶剂混合，搅拌溶解或加热溶解，
(b)加入第二溶剂，搅拌；
或，方法三：
(a)将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与溶剂混合，
(b)搅拌。
在某些实施方案中，本公开所述前述化合物A的晶型制备方法还包析晶、过滤、洗涤或干燥中任一步骤。
在一些实施方案中，所述析晶包括但不限于搅拌析晶(溶析析晶、打浆析晶)和挥发析晶。
在一些实施方案中，所述干燥方式包括但不限于鼓风干燥、真空干燥。干燥温度一般为25℃～100℃，优选30℃～70℃，如40℃、50℃或60℃。
在一些实施方案中，制备前述化合物C晶型的方法，包括(a)将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与水、异丙醇、四氢呋喃、乙醇、丙酮、乙酸乙酯中的一种或多种溶剂混合，
(b)打浆析晶、过滤和干燥。
在一些实施方案中，制备前述化合物E晶型的方法，包括(a)将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与甲醇、乙酸 乙酯/乙醇(v/v＝1:1)，乙腈/甲醇(v/v＝1:1)中的一种溶剂混合，
(b)打浆析晶、过滤和干燥。
另一方面，本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的可药用盐。
在一些实施方案中，其中所述可药用盐选自盐酸盐、琥珀酸盐、葡甲胺盐、马来酸盐、马尿酸盐、硫酸盐、磷酸盐、甲磺酸盐、酒石酸盐、富马酸盐、柠檬酸盐、钠盐、钾盐和精氨酸盐。
在另一些实施方案中，其中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与酸分子或碱分子的化学配比1:0.2～1:5，优选1:0.5、1:1、1:2、1:3或1:4。
在一些实施方案中，其中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与酸分子的化学配比1:1～1:4。
在一些实施方案中，其中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与碱分子的化学配比1:1～1:3。
一些实施方案提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐，其中化合物与HCl的化学配比1:1～1:3。
一些实施方案提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马来酸盐，其中化合物与HCl的化学配比1:1。
一些实施方案提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的L-酒石酸盐，其中化合物与L-酒石酸的化学配比1:1。
一些实施方案提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马来酸盐，其中化合物与马来酸的化学配比1:1。
一些实施方案提供化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的葡甲胺盐，其中化合物与葡甲胺的化学配比1:1～1:2。
本公开还提供制备前述可药盐的方法，所述方法包括化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与酸或碱成盐的步骤。
在一些实施方案中，成盐反应所用的酸选自但不限于HCl、琥珀酸、马来酸、马尿酸、 硫酸、磷酸、甲磺酸、酒石酸、富马酸和柠檬酸。
在一些实施方案中，成盐反应所用的碱选自但不限于葡甲胺盐、氢氧化钠、氢氧化钾和精氨酸。
在一些实施方案中，成盐反应所用的溶剂选自乙醇、乙酸乙酯、四氢呋喃、乙腈、丙酮、甲醇、1，4-二氧六环、异丙醇、2-甲基四氢呋喃、乙二醇、水中的至少一种。
在某些实施方案中，本公开成盐的方法还包括过滤、洗涤或干燥中任一步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的钾盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.544、8.016、19.356处有特征峰。
在一些实施方案中，所述钾盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.544、8.016、19.356、21.537处有特征峰。
在另一些实施方案中，所述钾盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开还提供制备前述化合物的钾盐α晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和乙醇混合，(b)加入氢氧化钾水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的精氨酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.191、10.598、15.844、18.447、20.119处有特征峰。
在一些实施方案中，所述精氨酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.191、10.598、15.844、18.447、20.119、24.226处有特征峰。
在另一些实施方案中，所述精氨酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开还提供制备前述化合物的精氨酸盐a晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和10％水/四氢呋喃混合，(b)加入精氨酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.831、18.556处有特征峰。
在一些实施方案中，所述钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.834、13.831、16.194、18.556处有特征峰。
在另一些实施方案中，所述钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱 如图8所示。
本公开还提供制备前述化合物的钠盐I晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和10％水/四氢呋喃混合，(b)加入氢氧化钠溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的葡甲胺盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.361、5.879、7.118、8.069、8.827、19.069处有特征峰。
在一些实施方案中，所述葡甲胺盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.361、5.879、7.118、8.069、8.827、9.748、16.230、19.069处有特征峰。
在一些实施方案中，所述葡甲胺盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.361、5.879、7.118、8.069、8.827、9.748、13.795、16.230、19.069、21.864、26.223处有特征峰。
在另一些实施方案中，所述葡甲胺盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本公开还提供制备前述化合物的葡甲胺盐a晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和乙醇混合，(b)加入葡甲胺水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马来酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.907、15.612、19.174、20.701处有特征峰。
在另一些实施方案中，所述马来酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
本公开还提供制备前述化合物的马来酸盐a晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和10％水/四氢呋喃混合，(b)加入马来酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马尿酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.551、9.410、13.522、14.534、19.956、21.337、22.945处有特征峰。
在一些实施方案中，所述马尿酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.551、9.410、11.209、13.522、14.175、14.534、19.956、21.022、21.337、22.945处有特征峰。
在一些实施方案中，所述马尿酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.551、9.410、11.209、13.522、14.175、14.534、16.709、19.956、21.022、21.337、22.945处有特征峰。
在另一些实施方案中，所述马尿酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本公开还提供制备前述化合物的马尿酸盐a晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和乙酸乙酯混合，(b)加入马尿酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马尿酸盐β晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.944、14.737、17.143、20.109处有特征峰。
在一些实施方案中，所述马尿酸盐β晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.944、9.978、14.737、17.143、20.109处有特征峰。
在另一些实施方案中，所述马尿酸盐β晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
本公开还提供制备前述化合物的马尿酸盐β晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和乙酸乙酯混合，(b)加入马尿酸水溶液，搅拌、干燥的步骤。本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.385、13.533、16.203、21.244处有特征峰。
在一些实施方案中，所述盐酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.385、8.530、13.533、16.203、21.244处有特征峰。
在另一些实施方案中，所述盐酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
在另一些实施方案中，所述盐酸盐a晶型中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1。
本公开还提供制备前述化合物的盐酸盐a晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和溶剂(1)混合，所述溶剂(1)选自甲醇、乙酸乙酯、1,4-二氧六环，(b)加入盐酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.059、10.359、19.412、20.726、21.843处有特征峰。
在一些实施方案中，所述盐酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.059、10.359、16.017、17.806、19.412、20.726、21.843处有特征峰。
在另一些实施方案中，所述盐酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
在另一些实施方案中，所述盐酸盐b晶型中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1。
本公开还提供制备前述化合物的盐酸盐b晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和乙腈混合，(b)加入盐酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐c晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.395、11.238、13.495、20.153处有特征峰。
在一些实施方案中，所述盐酸盐c晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.395、11.238、13.495、20.153、21.169、23.125处有特征峰。
在另一些实施方案中，所述盐酸盐c晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
在另一些实施方案中，所述盐酸盐c晶型中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1。
本公开还提供制备前述化合物的盐酸盐c晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和10％水/四氢呋喃混合，(b)加入盐酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐d晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.128、12.995、14.962、16.354、20.401、23.032处有特征峰。
在一些实施方案中，所述盐酸盐d晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.128、12.216、12.995、14.962、16.354、19.268、20.401、23.032处有特征峰。
在一些实施方案中，所述盐酸盐d晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱， 在8.128、12.216、12.995、14.962、16.354、19.268、19.965、20.401、23.032、24.742处有特征峰。
在另一些实施方案中，所述盐酸盐d晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
在另一些实施方案中，所述盐酸盐d晶型中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1。
本公开还提供制备前述化合物的盐酸盐d晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和10％水/异丙醇混合，(b)加入盐酸水溶液，搅拌的步骤。
本公开还提供了化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐e晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.385、14.145、19.709、20.277、21.583处有特征峰。
在一些实施方案中，所述盐酸盐e晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.385、14.145、15.451、19.709、20.277、21.583、23.684处有特征峰。
在一些实施方案中，所述盐酸盐e晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.385、14.145、15.451、19.709、20.277、21.583、23.187、23.684、24.366处有特征峰。
在另一些实施方案中，所述盐酸盐e晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
在另一些实施方案中，所述盐酸盐e晶型中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1。
本公开还提供制备前述化合物的盐酸盐e晶型的方法，包括将化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸和溶剂(2)混合，所述溶剂(2)选自10％水/异丙醇、乙腈、10％水/四氢呋喃、甲醇、异丙醇或其混合溶剂；(b)加入盐酸水溶液，搅拌、干燥的步骤。
进一步地，本公开所述化合物A可药用盐的晶型，以衍射角2θ角度表示的X-射线粉末衍射图，其中2θ角度的误差范围为±0.2。在某些实施方案中，本公开成晶型制备方法包括过滤(或离心过滤/离心)、洗涤或干燥中任一步骤。
在一些实施方案中，所述干燥方式包括但不限于鼓风干燥、真空干燥。干燥温度一般为25℃～100℃，优选30℃～70℃，如40℃、50℃或60℃。
另一方面，本公开还提供一种药物组合物，其包括前述晶型和药学上可接受的赋形剂。
本公开还提供一种药物组合物，由前述晶型和药学上可接受的赋形剂制备得到。
本公开还提供了一种药物组合物的制备方法，包括前述晶型与药学上可接受的赋形剂混 合的步骤。
本公开还提供了前述可药用盐，前述晶型或前述药物组合物在制备用于预防和/或治疗与LP(a)血浆水平升高相关的疾病或病症的药物中的用途。
本公开还提供了前述可药用盐，前述晶型或前述药物组合物在制备用于预防和/或治疗心血管疾病的药物中的用途。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中数值为仪器测量值或仪器测量后计算值，存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。当然需要考虑该数值所用之处的上下文，例如，总杂质的含量，该数值为测量后误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开中所述的“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本公开所述的晶型包括但不限于化合物A的溶剂合物，所述的溶剂包括但不限于水。
附图说明
图1为化合物A的无定型XRPD谱图。
图2为化合物A的A晶型XRPD谱图。
图3为化合物A的B晶型XRPD谱图。
图4为化合物A的C晶型XRPD谱图。
图5为化合物A的D晶型XRPD谱图。图6为化合物A钾盐α晶型的XRPD谱图。
图7为化合物A精氨酸盐a晶型的XRPD谱图。
图8为化合物A钠盐晶型I的XRPD谱图。
图9为化合物A葡甲胺盐a晶型的XRPD谱图。
图10为化合物A马来酸盐a晶型的XRPD谱图。
图11为化合物A马尿酸盐a晶型的XRPD谱图。
图12为化合物A马尿酸盐β晶型的XRPD谱图。
图13为化合物A盐酸盐a晶型的XRPD谱图。
图14为化合物A盐酸盐b晶型的XRPD谱图。
图15为化合物A盐酸盐c晶型的XRPD谱图。
图16为化合物A盐酸盐d晶型的XRPD谱图。
图17为化合物A盐酸盐e晶型的XRPD谱图。
图18为化合物A盐酸盐(1:4)无定型的XRPD谱图。
图19为化合物A盐酸盐(1:1)无定型的XRPD谱图。
图20为化合物A的E晶型XRPD谱图。
具体实施方式
通过以下实施例和实验例进一步详细说明本公开。这些实施例和实验例仅用于说明性目的，并不用于限制本公开的范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q 15Exactive)。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Thermo U3000高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，射线：单色Cu-Ka射线扫描方式：θ/2θ，扫描范围：3-48°。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，25-300℃或25-350℃，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱，氮气吹扫速度50mL/min。
DVS为动态水分吸附：采用Surface Measurement Systems instrinsic，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT≤0.002％，TMAX 360min，循环两圈。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学30科技(Accela ChemBio Inc)、达瑞化学品等公司
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系， B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸四盐酸盐
步骤1：(R)-3-((S)-1-((S)-4-苄基-2-氧代噁唑烷-3-基)-3-(3-(苄氧基)苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6a)的制备
氮气氛下，将1b(10.0g,25.74mmol)溶于四氢呋喃(10mL)，降温至-30℃，滴加1M双(三甲基硅基)酰胺锂四氢呋喃溶液(31mL，31mmol)，加完后反应30分钟；滴加3-苄氧基溴苄(8.56g,30.89mmol)的四氢呋喃(15mL)溶液，反应1小时，升温至0℃-5℃反应过夜。加饱和氯化铵溶液(50mL)，甲基叔丁基醚萃取(50mL×2)，饱和氯化钠溶液洗涤(70mL)，无水硫酸钠干燥，过滤，减压浓缩，所得残余物柱层析纯化(石油醚：乙酸乙酯＝4:1)，得标题产物6a(7.08g，产率：47.0％)。
步骤2：(S)-3-(3-(苄氧基)苯基)-2-((R)-1-(叔丁氧羰基)吡咯烷-3-基)丙酸(6b)的制备
将6a(7g,11.983mmol)溶于四氢呋喃(70mL)，水(35mL)，加双氧水(30％)(4.07g, 35.95mmol)，氢氧化锂一水合物(431mg,17.97mmol)，室温反应过夜。2M氢氧化钠溶液调节pH至＞13，甲基叔丁基醚萃取(50mL×2)，水相用2M盐酸溶液调节pH至＜3，甲基叔丁基醚萃取(50mL×2)，饱和氯化钠溶液洗涤(70mL)，无水硫酸钠干燥，过滤，减压浓缩至干，得产物6b粗品3.11g，产物不经纯化直接进行下一步反应。
步骤3：(R)-3-((S)-3-(3-(苄氧基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6c)的制备
将上步粗品6b(3.1g,7.29mmol)溶于2-甲基四氢呋喃(60mL)，后加2-叔丁基-1,3-二异丙基异脲(5.84g,29.14mmol)，升温至65℃反应过夜。过滤，滤液减压浓缩至干，所得残余物柱层析纯化(石油醚：乙酸乙酯＝5:1)，得产物6c(2.5g,两步产率：43.3％)。
步骤4：(R)-3-((S)-1-(叔丁氧基)-3-(3-羟基苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6d)的制备
氢气氛下，将6c(2.5g,5.19mmol)溶于MeOH(40mL)，加Pd/C(0.80g)，室温反应过夜，过滤，减压浓缩得产物6d(1.78g,产率：87.6％)。
步骤5：(R)-3-((S)-3-(3-(2-(((苄氧基)羰基)氨基)乙氧基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6e)的制备
将6d(400mg,0.99mmol)，N-(2-溴乙基)氨基甲酸苄酯(280mg,1.09mmol)，碳酸铯(803mg,2.47mmol)加入到N，N-二甲基甲酰胺(8mL)中，升温至80℃反应3小时。加水(40mL)，乙酸乙酯萃取(30mL×2)，饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，加压浓缩得残余物，柱层析纯化(石油醚：乙酸乙酯＝8:1)，得产物6e(300mg，产率53.5％)。
步骤6：(R)-3-((S)-3-(3-(2-氨基乙氧基)苯基)-1-(叔丁氧基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(6f)的制备
氢气氛下，将6e(300mg,0.528mmol)溶于MeOH(5mL)，加Pd/C(100mg)，室温反应过夜。过滤，减压浓缩得到产物6f(150mg，产率65.4％)。
步骤7：(3R)-3-[(2S)-1-(叔丁氧基)-3-(3-{[(2-{3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-氧代丙基]苯氧基}乙基)({3-[(2S)-3-(叔丁氧基)-2-[(3R)-1-[(叔丁氧基)羰基]吡咯烷-3-基]-3-氧代丙基]苯基}甲基)氨基]甲基}苯基)-1-氧代丙烷-2-基]吡咯烷-1-羧酸叔丁酯(6g)的制备
冰浴下，将6f(150mg,0.35mmol)和4a(278.6mg,0.69mmol)溶于异丙醇(6mL)，加1滴冰醋酸，保温反应30分钟。加入三乙酰氧基硼氢化钠(292.6mg,1.38mmol)，缓慢升至室温，反应过夜。饱和碳酸氢钠溶液调节pH至8-9，乙酸乙酯萃取(40mL×2)，饱和氯化钠溶液洗涤(60mL)，无水硫酸钠干燥，过滤，浓缩得粗品480mg,制备液相纯化得到产物6g(250mg，产率59.9％)。
步骤8：(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸四盐酸盐的制备
将6g(100mg,0.083mmol)加入到4M盐酸二氧六环溶液(4mL)，室温搅拌过夜。倾出 上清液，得固体，固体用乙酸乙酯洗涤，冻干，得标题产物(50mg，产率68.5％)。经X-射线粉末衍射检测，X-射线粉末衍射谱图无明显特征峰，如图18所示，定义为无定型。
MS m/z(ESI):741.3[M+H]+。
1H NMR(400MHz,D2O):δ7.42-7.16(m,9H),6.86(d,J＝7.6Hz,1H),6.70(dd,J＝8.3,2.6Hz,1H),6.65(s,1H),4.43(s,4H),4.14-3.97(m,2H),3.62-3.45(m,5H),3.45-3.30(m,3H),3.29-3.14(m,3H),3.07-2.98(m,3H),2.93-2.63(m,9H),2.61-2.39(m,3H),2.24-2.02(m,3H),1.78-1.64(m,3H)。
取按上述实施例制备盐酸盐1g，加入碳酸氢钠水溶液(4eq.5.4mmol，约0.45g碳酸氢钠)，搅拌2-4小时，经反相色谱柱C18(乙腈/水为1:9至1:1梯度洗脱)，冻干，得(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸(化合物A)。经X-射线粉末衍射检测，X-射线粉末衍射谱图无明显特征峰，如图1所示，定义为无定型。
中间体1b制备:(R)-3-(2-((S)-4-苄基-2-氧代噁唑烷-3-基)-2-氧代乙基)吡咯烷-1-羧酸叔丁酯(1b)的制备
将原料(R)-N-叔丁氧羰基-3-四氢吡咯乙酸1a(9g,39mmol)溶于无水四氢呋喃(100mL)，冷却至0℃，加入三乙胺(13.6mL,98mmol)，0℃下搅拌反应5分钟。加入新戊酰氯(5.8g，47.1mmol)，加入过程中温度不超过10℃，搅拌反应15分钟后，加入氯化锂(1.9g，47.1mmol)和溶有(S)-4-苄基-2-噁唑烷酮(6.9g，39mmol)的四氢呋喃溶液(100mL)。反应液升至室温，搅拌24小时。加入2M盐酸水溶液(500mL)，分离得到有机相，浓缩，剩余物经硅胶快速柱层析(石油醚/乙酸乙酯)纯化得到油状液体1b(12.5g,收率82％)。
MS(ESI):m/z＝411.1[M+Na]+。
中间体4a制备：(R)-3-((S)-1-(叔丁氧基)-3-(3-甲酰基苯基)-1-氧代丙烷-2-基)吡咯烷-1-羧酸叔丁酯(4a)的制备
将按照专利WO2020247429中Preparation 16制备的3a，N-甲酰基糖精(428mg，2.0mmol)，醋酸钯(40mg，0.2mmol)，1,4-双(二苯基膦)丁烷(83mg，0.2mmol)，三乙基硅烷(0.24mL，1.5mmol)加入微波反应管中，然后加入N,N-二甲基甲酰胺(6mL)。置换氮气后，75℃反应过夜。LCMS监测反应完成后，将反应液冷却至室温，离心过滤，滤液经反相快速柱层析(乙腈/水)纯化得到黄色油状4a(270mg，收率76％)。
MS(ESI):m/z＝404.5[M+H]+。
测试例1：化合物抑制Lp(a)的组装活性测试
本公开利用双抗体ELISA方法检测Apo(a)与ApoB蛋白的组装效率，抗体分别是ApoB-Capture抗体(Mabtech)和Apo(a)-Detector抗体(Abcam)；检测样本分别是人转基因hApo(a)和hApoB小鼠的血浆，分别稀释500倍使用。
实验步骤：分别将等量的Apo(a)和ApoB血清与梯度浓度稀释(最高浓度100nM，3倍梯度稀释)的待测化合物混合，将混合液放在37℃培养箱里孵育2小时，然后加入终浓度为150mM的EACA终止反应。将反应后溶液加入预先包被ApoB-Capture抗体的ELISA检测板中，室温孵育2小时，然后利用洗涤液洗板4次；加入生物素标记的Apo(a)-Detector抗体，室温孵育1小时后，洗板并加入显色底物TMB溶液；室温孵育15分钟后，加入反应终止液，混匀后即刻用酶标仪检测450nm处的吸光值。最后，利用GraphPad Prism 9软件进行数据分析和IC50的计算。
Apo(a)与ApoB蛋白组装的0％抑制率对应着化合物浓度为0(1％DMSO)时的OD值；Apo(a)与ApoB蛋白组装的100％抑制率对应着只加ApoB蛋白溶液(hApoB小鼠的血浆稀释液)时的OD值。IC50＝0.41nM。
测试例2：比格犬体内药代动力学实验
以比格犬为受试动物，应用LC/MS/MS法测定比格犬灌胃给予本公开化合物后不同时刻血浆中的药物浓度。研究本公开化合物在比格犬体内的药代动力学行为，评价其药动学特征。
试验动物：每组健康8～36月雄性比格犬2条
药物配制：称取一定量药物，加生理盐水配成2mg/mL的无色澄清溶液。
给药：比格犬禁食过夜后灌胃给药，参照物1和实施例6化合物给药剂量均为10mg/kg。
操作：比格犬灌胃给药本公开化合物，给药后0.25、0.5、1、2、4、6、8、24小时由外周静脉穿刺采血约0.6mL，置于含EDTA-K2的试管中，4℃左右，2000转每分钟离心10分钟分离得到血浆，于-75℃保存。
测定不同采血时间点比格犬血浆中待测化合物含量：取给药后各时刻采取的比格犬血浆33μL(30μL血浆和3μL空白)加入到18μL浓度为6％的高氯酸溶液，涡旋混合30秒，4℃温度下，3900转每分钟离心15分钟，然后加入含内标地塞米松的碱化后(氨水调pH为10-11)乙腈溶液200μL沉淀蛋白，涡旋混合30秒，4℃、3900转每分钟离心15分钟，血浆样品取上清液，加水稀释3倍，取8μL进行LC/MS/MS分析。
药代动力学参数结果
LC/MS/MS分析检测血药浓度后，采用WinNonlin 6.1软件，非房室模型法计算药动学参数。本公开化合物的比格犬药代动力学参数如下表1。
表1 本公开化合物的比格犬口服药代动力学参数
结论：本公开化合物口服吸收更优，系统暴露量更佳，半衰期长，具有优异的药代动力学特征，口服给药具有明显优势。
参照物1为专利CN114008021中的实施例1化合物，按照专CN114008021中的实施例1的制备方法获得。
实施例2：化合物A的A晶型的制备
取化合物A(按照实施例1方法制备)5mg，置于93％RH条件下放置。经X-射线粉末衍射检测，将该产物定义为晶型A，XRPD谱图如图2，其特征峰位置如表2所示
表2
实施例3：化合物A的B晶型的制备
取化合物A(按照实施例1方法制备)100mg，加入1.0mL水，室温打浆，离心后得到产物。
经X-射线粉末衍射检测，将该产物定义为B晶型，XRPD谱图如图3，其特征峰位置如表3所示。
表3

实施例4：化合物A的C晶型制备
将化合物A(按照实施例1方法制备)100mg，加入1.0mL水，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为C晶型，XRPD谱图如图4，其特征峰位置如表4所示。
表4
实施例5：化合物A的C晶型制备
将化合物A(按照实施例1方法制备)10mg，加入表5所示0.1mL溶剂，室温打浆，离心，固体干燥后得到产物。
表5
实施例6：化合物A的C晶型制备
将化合物A(按照实施例1方法制备)5mg，加入0.3mL四氢呋喃/乙酸乙酯(v/v＝2:1)，加入1.2mL水，室温打浆，离心，固体干燥后得到产物。
实施例7：化合物A的D晶型制备
将化合物A(按照实施例1方法制备)50mg，加入0.5mL 10％水/四氢呋喃，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图如图5，其特征峰位置如表6所示，将该产物定义为游离态D晶型。
DSC谱图显示，吸热峰峰值65.77、256.41℃。TGA在31-221℃范围内失重9.9％。
表6
实施例8：钾盐α晶型制备
将化合物A 10mg，加入0.2mL乙醇中，再加入28μL 2M氢氧化钾水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为钾盐α晶型，XRPD谱图如图6，其特征峰位置如表7所示。
表7
实施例9：精氨酸盐a晶型制备
将化合物A 5mg，加入0.1mL 10％水/四氢呋喃中，再加入14μL 1M精氨酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为精氨酸盐a晶型，XRPD谱图如图7，其特征峰位置如表8所示。
表8

实施例10：钠盐I晶型制备
将化合物A 10mg，加入0.2mL 10％水/四氢呋喃中，再加入8μL 2M氢氧化钠水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为钠盐I晶型，XRPD谱图如图8，其特征峰位置如表9所示。
表9
实施例11：葡甲胺盐a晶型制备
将化合物A 10mg，加入0.2mL乙醇中，再加入57μL 1M葡甲胺水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为葡甲胺盐a晶型，XRPD谱图如图9，其特征峰位置如表10所示。
表10

实施例12：钠盐无定型制备
将化合物A 5mg，加入0.1mL乙酸乙酯中，再加入7μL 2M氢氧化钠水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无明显特征峰，该产物为钠盐无定型。
实施例13：精氨酸盐无定型制备
将化合物A 5mg，加入0.1mL乙酸乙酯中，再加入14μL 1M精氨酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无明显特征峰，该产物为精氨酸盐无定型。
实施例14：葡甲胺盐无定型制备
将化合物A 5mg，加入0.1mL乙醇中，再加入14μL 1M葡甲胺水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无明显特征峰，该产物为葡甲胺盐无定型。
实施例15：马来酸盐a晶型制备
将化合物A 10mg，加入0.2mL 10％水/四氢呋喃中，再加入14μL 1M马来酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为马来酸盐a晶型，XRPD谱图如图10，其特征峰位置如表11所示。
表11
实施例16：马尿酸盐α晶型制备
将化合物A 5mg，加入0.1mL乙酸乙酯中，再加入14μL 1M马尿酸水溶液，室温打浆，离心，得到产物。
经X-射线粉末衍射检测，将该产物定义为马尿酸盐α晶型，XRPD谱图如图11，其特征峰位置如表12所示。
表12

实施例17：马尿酸盐β晶型制备
将化合物A 5mg，加入0.1mL乙酸乙酯中，再加入14μL 1M马尿酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为马尿酸盐β晶型，XRPD谱图如图12，其特征峰位置如表13所示。
表13

实施例18：硫酸盐无定型制备
将化合物A 5mg，加入0.1mL 10％水/四氢呋喃中，再加入8μL 1.8M硫酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无特征峰，该产物为硫酸盐无定型。
实施例19：磷酸盐无定型制备
将化合物A 5mg，加入0.1mL乙醇中，再加入10μL 1.5M磷酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无特征峰，该产物为磷酸盐无定型。
实施例20：甲磺酸盐无定型制备
将化合物A 5mg，加入0.1mL乙醇中，再加入9μL 1.5M甲磺酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无特征峰，该产物为甲磺酸盐无定型。
实施例21：马来酸盐无定型制备
将化合物A 5mg，加入0.1mL乙醇中，再加入14μL 1M马来酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无特征峰，该产物为马来酸盐无定型。
实施例22：富马酸盐无定型制备
将化合物A 5mg，加入0.1mL乙醇中，再加入21μL 0.7M富马酸甲醇溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无特征峰，该产物为富马酸盐无定型。
实施例23：柠檬酸盐无定型制备
将化合物A 5mg，加入0.1mL乙醇中，再加入14μL 0.7M柠檬酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，XRPD谱图无特征峰，该产物为柠檬酸盐无定型。
实施例24：盐酸盐(1:1)a晶型制备
将化合物A 10mg，加入0.07mL甲醇中，再加入9μL 5M盐酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐a晶型，XRPD谱图如图13，其特征峰位置如表14所示。
DSC谱图显示，吸热峰值59.78、285.05℃。TGA在32-160℃范围内失重4.4％。经离子色谱检测，氯离子含量为4.75％。DVS引湿性测试结果显示80％RH下吸湿增重30％。
表14
实施例25：盐酸盐(1:1)a晶型制备
将化合物A 10mg，加入0.07mL乙酸乙酯中，再加入9μL 5M盐酸水溶液，室温打浆，离心，固体干燥后得到目标产物。
实施例26：盐酸盐(1:1)a晶型制备
将化合物A 10mg，加入0.07mL 1,4-二氧六环中，再加入9μL 5M盐酸水溶液，室温打浆，离心，固体干燥后得到目标产物。
实施例27：盐酸盐b晶型制备
将化合物A 10mg，加入0.07mL乙腈中，再加入9μL 5M盐酸水溶液，室温打浆，离心，得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐b晶型，XRPD谱图如图14，其特征峰位置如表15所示。
表15
实施例28：盐酸盐(1:1)c晶型制备
将化合物A 10mg，加入0.07mL 10％水/四氢呋喃(v/v)中，再加入9μL 5M盐酸水溶液，室温打浆，离心得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐c晶型，XRPD谱图如图15，其特征峰位置如表16所示。
DSC谱图显示，吸热峰峰值70.77、114.11、147.43、227.41、282.72℃。TGA在32-122℃范围内失重3.8％，在122-225℃范围内失重4.2％。
表16
实施例29：盐酸盐(1:1)d晶型制备
将化合物A 10mg，加入0.07mL 10％水/异丙醇中，再加入9μL 5M盐酸水溶液，室温打浆，离心得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐d晶型，XRPD谱图如图16，其特征峰位置如表17所示。
DSC谱图显示，吸热峰峰值97.05、117.48、142.73、284.01℃。TGA在33-138℃范围内失重6.3％。
表17

实施例30：盐酸盐(1:1)e晶型制备
将化合物A 100mg，加入0.6mL 10％水/异丙醇中，再加入27μL 5M盐酸水溶液，室温打浆，离心，固体干燥后得到产物。
经X-射线粉末衍射检测，将该产物定义为盐酸盐e晶型，XRPD谱图如图17，其特征峰位置如表18所示。
DSC谱图显示，吸热峰峰值76.58、108.43、146.76、287.37℃。TGA在30-161℃范围内失重6.1％。
经离子色谱检测，氯离子含量为5.20％。DVS引湿性测试结果显示80％RH下吸湿增重18％。
表18
实施例31：盐酸盐e晶型制备
将化合物A 10mg，加入0.6mL乙腈中，再加入2.7μL 5M盐酸水溶液，室温打浆，离心，固体干燥后得到目标产物。
实施例32：盐酸盐e晶型制备
将化合物A 100mg，加入0.6mL 10％水/四氢呋喃(v/v)中，再加入27μL 5M盐酸水溶液，室温打浆，离心，固体干燥后得到目标产物。
实施例33：盐酸盐e晶型制备
将化合物A 2g，加入6.0mL水和10.0mL甲醇，加入540μL 5M盐酸水溶液，将溶液加入到20.0mL异丙醇中，室温打浆，离心，固体干燥后得到目标产物。
实施例34：盐酸盐(1:1)无定型制备
将化合物A的盐酸盐d晶型125mg，加入2.5mL乙腈，室温打浆，离心，固体干燥后得到目标产物。经X-射线粉末衍射检测，该产物为一盐酸盐无定型，XRPD谱图如图19。
实施例35：盐酸盐(1:4)无定型制备
将化合物A实施例1制备得到的四盐酸盐样品5mg，加入表19所示溶剂，室温打浆，观察析晶，如有固体出现，离心，干燥得固体产物。经X-射线粉末衍射检测，相关数据如表19所示。
表19

注：a样品的XRPD谱图如图18，DVS引湿性测试结果显示80％RH下吸湿增重34％。
实施例35：晶型E制备
取化合物A(按照实施例1方法制备)10mg，加入0.5ml甲醇，25℃打浆4天，固体离心、干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为晶型E，XRPD谱图如图20，其特征峰位置如表20所示。
DSC谱图显示，吸热峰峰值247.23℃。TGA在36-90℃范围内失重3.58％。
表20
实施例36：晶型E制备
取化合物A(按照实施例1方法制备)10mg，加入0.5ml甲醇，50℃打浆1天，固体离心、干燥，得到目标产物。
实施例37：晶型E制备
称取式(I)所示化合物约10mg，溶于0.5mL乙酸乙酯/乙醇(v/v＝1:1)中搅拌，反应液25℃打浆4天，固体离心、干燥，得到目标产物。
实施例38：晶型E制备
称取式(I)所示化合物约10mg，溶于0.5mL乙腈/甲醇(v/v＝1:1)中搅拌，反应液25℃打浆4天，固体离心、干燥，得到目标产物。
实施例39：晶型E制备
称取式(I)所示化合物约10mg，溶于0.5mL乙腈/甲醇(v/v＝1:1)中搅拌，反应液50℃打浆1天，固体离心、干燥，得到目标产物。
测试例3：长期加速试验
将前述化合物A盐酸盐(1:1)a晶型、化合物A盐酸盐(1:1)e晶型、化合物A盐酸盐(1:4)无定型和化合物A盐酸盐(1:1)无定型用铝箔袋密封，分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表21盐酸盐(1:1)a晶型长期/加速稳定性
表22盐酸盐(1:1)e晶型长期/加速稳定性
表23盐酸盐(1:4)无定型长期/加速稳定性
表24盐酸盐(1:1)无定型长期/加速稳定性
结论：长期加速实验表明：在25℃/60％RH和40℃/75％RH条件下6个月盐酸盐(1:1)e晶型的物理化学稳定性均良好，盐酸盐(1:1)a晶型、盐酸盐(1:1)无定型和盐酸盐(1:4)无定型稳定性略差。
测试例4：长期加速试验
将前述化合物A游离态C晶型用铝箔袋密封(充氮保护)，分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表25游离态C晶型长期/加速稳定性
结论：长期加速实验表明：在25℃/60％RH和40℃/75％RH条件下6个月游离态C晶型的物理化学稳定性均良好。

Claims (28)

  1. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的A晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.343、18.020、21.028处有特征峰，优选在8.343、12.559、15.612、18.020、21.028处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  2. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的B晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.794、15.530、19.456、20.559、21.500处有特征峰，优选在7.794、11.832、15.530、19.456、20.559、21.500、29.097处有特征峰，更优选在7.794、11.832、12.642、15.530、19.456、20.559、21.500、29.097处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  3. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的C晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.547、8.847、13.567、15.576、19.169处有特征峰，优选在8.547、8.847、10.487、13.567、15.576、19.169处有特征峰，更优选在8.547、8.847、10.487、13.567、15.576、19.169、21.973处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  4. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的D晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.834、16.316、20.830处有特征峰，优选在7.928、13.834、16.316、20.830处有特征峰，更以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  5. 根据权利要求1-4任一项所述的晶型，其特征在于所述2θ值误差范围为±0.2。
  6. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的可药用盐，其特征在于，所述可药用盐选自盐酸盐、琥珀酸盐、葡甲胺盐、马来酸盐、马尿酸盐、硫酸盐、磷酸盐、甲磺酸盐、酒石酸盐、富马酸盐、柠檬酸盐、钠盐、钾盐和精氨酸盐。
  7. 根据权利要求6所述的可药用盐，其特征在于，化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基 -2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与酸分子或碱分子的化学配比1:0.2～1:5，优选1:0.5、1:1、1:2、1:3或1:4。
  8. 根据权利要求6或7所述的可药用盐，其特征在于，化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1、1:2或1:3。
  9. 制备权利要求6或7所述的可药用盐的方法，其特征在于，包括化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与酸或碱成盐的步骤。
  10. 根据权利要求6所述的方法，其特征在于，成盐反应所用的溶剂选自乙醇、乙酸乙酯、四氢呋喃、乙腈、丙酮、甲醇、1，4-二氧六环、2-甲基四氢呋喃、乙二醇、异丙醇、水中的至少一种。
  11. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的钾盐α晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.544、8.016、19.356处有特征峰，优选在5.544、8.016、19.356、21.537处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  12. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的精氨酸盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.191、10.598、15.844、18.447、20.119处有特征峰，优选在8.191、10.598、15.844、18.447、20.119、24.226处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  13. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的钠盐I晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在13.831、18.556处有特征峰，优选在7.834、13.831、16.194、18.556处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
  14. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷 -3-基]丙酸的葡甲胺盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.361、5.879、7.118、8.069、8.827、19.069处有特征峰，优选在5.361、5.879、7.118、8.069、8.827、9.748、16.230、19.069处有特征峰，更优选在5.361、5.879、7.118、8.069、8.827、9.748、13.795、16.230、19.069、21.864、26.223处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
  15. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马来酸盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.907、15.612、19.174、20.701处有特征峰，优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
  16. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马尿酸盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.551、9.410、13.522、14.534、19.956、21.337、22.945处有特征峰，优选在5.551、9.410、11.209、13.522、14.175、14.534、19.956、21.022、21.337、22.945处有特征峰，更优选在5.551、9.410、11.209、13.522、14.175、14.534、16.709、19.956、21.022、21.337、22.945处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
  17. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的马尿酸盐β晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.944、14.737、17.143、20.109处有特征峰，优选在4.944、9.978、14.737、17.143、20.109处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
  18. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.385、13.533、16.203、21.244处有特征峰，优选在6.385、8.530、13.533、16.203、21.244处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
  19. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐b晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.059、10.359、19.412、20.726、21.843处有特征峰，优选在8.059、10.359、16.017、17.806、19.412、20.726、21.843处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如 图14所示。
  20. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐c晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.395、11.238、13.495、20.153处有特征峰，优选在9.395、11.238、13.495、20.153、21.169、23.125处有特征峰，更优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
  21. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐d晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在8.128、12.995、14.962、16.354、20.401、23.032处有特征峰，优选在8.128、12.216、12.995、14.962、16.354、19.268、20.401、23.032处有特征峰，更优选在8.128、12.216、12.995、14.962、16.354、19.268、19.965、20.401、23.032、24.742处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
  22. 化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸的盐酸盐e晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在9.385、14.145、19.709、20.277、21.583处有特征峰，优选在9.385、14.145、15.451、19.709、20.277、21.583、23.684处有特征峰，更优选在9.385、14.145、15.451、19.709、20.277、21.583、23.187、23.684、24.366处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
  23. 根据权利要求10-22任一项所述的晶型，其特征在于所述2θ值误差范围为±0.2。
  24. 根据权利要求18-22所述的晶型，其中化合物(2S)-3-(3-{[(2-{3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯氧基}乙基)({3-[(2S)-2-羧基-2-[(3R)-吡咯烷-3-基]乙基]苯基}甲基)氨基]甲基}苯基)-2-[(3R)-吡咯烷-3-基]丙酸与HCl的化学配比1:1。
  25. 一种药物组合物，其包括如权利要求1-5或10-23任一项所述的晶型，和药学上可接受的赋形剂。
  26. 一种药物组合物，由如权利要求1-5或10-24任一项所述的晶型和药学上可接受的赋形剂制备得到。
  27. 权利要求6或7所述的可药用盐，或权利要求1-5或10-24任一项所述的晶型，或权利 要求25或26所述的药物组合物在制备用于预防和/或治疗与LP(a)水平升高相关的疾病或病症的药物中的用途。
  28. 权利要求6或7所述的可药用盐，或权利要求1-5或10-24任一项所述的晶型，或权利要求25或26所述的药物组合物在制备用于预防和/或治疗心血管疾病的药物中的用途。
PCT/CN2024/092233 2023-05-11 2024-05-10 一种脂蛋白化合物晶型及其制备方法 Ceased WO2024230805A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1020257041155A KR20260009339A (ko) 2023-05-11 2024-05-10 지질단백질 화합물의 결정형 및 이의 제조방법
CN202480028455.6A CN121285544A (zh) 2023-05-11 2024-05-10 一种脂蛋白化合物晶型及其制备方法
AU2024267706A AU2024267706A1 (en) 2023-05-11 2024-05-10 Crystal form of lipoprotein compound and preparation method therefor
EP24803084.3A EP4711355A1 (en) 2023-05-11 2024-05-10 Crystal form of lipoprotein compound and preparation method therefor
MX2025013356A MX2025013356A (es) 2023-05-11 2025-11-07 Forma cristalina del compuesto de lipoproteína y método de preparación de la misma

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202310529962.5 2023-05-11
CN202310529962 2023-05-11
CN202410340638.3 2024-03-25
CN202410340638 2024-03-25

Publications (1)

Publication Number Publication Date
WO2024230805A1 true WO2024230805A1 (zh) 2024-11-14

Family

ID=93431363

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/092233 Ceased WO2024230805A1 (zh) 2023-05-11 2024-05-10 一种脂蛋白化合物晶型及其制备方法

Country Status (7)

Country Link
EP (1) EP4711355A1 (zh)
KR (1) KR20260009339A (zh)
CN (1) CN121285544A (zh)
AU (1) AU2024267706A1 (zh)
MX (1) MX2025013356A (zh)
TW (1) TW202444710A (zh)
WO (1) WO2024230805A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025108255A1 (zh) * 2023-11-20 2025-05-30 上海齐鲁制药研究中心有限公司 一种多环类衍生物、其制备方法和应用
WO2025237188A1 (zh) * 2024-05-14 2025-11-20 石家庄以岭药业股份有限公司 一种LP(a)抑制剂化合物及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068412A1 (en) * 2003-12-24 2005-07-28 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
WO2005068410A1 (en) * 2003-12-24 2005-07-28 Esperion Therapeutics, Inc. Ether compounds and compositions for cholesterol management and related uses
WO2020247429A1 (en) 2019-06-07 2020-12-10 Eli Lilly And Company Pyrrolidine compounds
WO2023078333A1 (zh) * 2021-11-03 2023-05-11 上海拓界生物医药科技有限公司 一种取代的苯丙酸衍生物及其用途一种取代的苯丙酸衍生物及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005068412A1 (en) * 2003-12-24 2005-07-28 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
WO2005068410A1 (en) * 2003-12-24 2005-07-28 Esperion Therapeutics, Inc. Ether compounds and compositions for cholesterol management and related uses
WO2020247429A1 (en) 2019-06-07 2020-12-10 Eli Lilly And Company Pyrrolidine compounds
CN114008021A (zh) 2019-06-07 2022-02-01 伊莱利利公司 吡咯烷化合物
WO2023078333A1 (zh) * 2021-11-03 2023-05-11 上海拓界生物医药科技有限公司 一种取代的苯丙酸衍生物及其用途一种取代的苯丙酸衍生物及其用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4711355A1

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025108255A1 (zh) * 2023-11-20 2025-05-30 上海齐鲁制药研究中心有限公司 一种多环类衍生物、其制备方法和应用
WO2025237188A1 (zh) * 2024-05-14 2025-11-20 石家庄以岭药业股份有限公司 一种LP(a)抑制剂化合物及其应用

Also Published As

Publication number Publication date
CN121285544A (zh) 2026-01-06
KR20260009339A (ko) 2026-01-19
AU2024267706A1 (en) 2025-11-27
EP4711355A1 (en) 2026-03-18
TW202444710A (zh) 2024-11-16
MX2025013356A (es) 2026-02-03

Similar Documents

Publication Publication Date Title
CN105682656B (zh) 调节法尼醇x受体的组合物和方法
CN105209437B (zh) 心肌肌球蛋白激动剂的盐和制备盐的方法
WO2024230805A1 (zh) 一种脂蛋白化合物晶型及其制备方法
US9221815B2 (en) Solid state form of vemurafenib choline salt
KR20210013554A (ko) Tlr7/tlr8 억제제의 결정질 형태
CN120166990A (zh) α-1抗胰蛋白酶的调节剂
WO2025157260A1 (zh) G12d抑制剂化合物的可药用盐及其晶型
US9440971B2 (en) Solid state forms of vemurafenib hydrochloride
EP3430004B1 (en) Solid state forms of nilotinib salts
TW202120509A (zh) 活化素受體樣激酶抑制劑之鹽及晶體形式
US11059810B2 (en) Pharmaceutically acceptable salt as renal outer medullary potassium channel inhibitor
US20240317764A1 (en) Salts and solid forms of a compound having apj receptor activity
WO2025002355A9 (zh) 一种jak2抑制剂的晶型及制备方法
CN115141132B (zh) 吡咯酰胺化合物的晶型及其制备方法和用途
WO2023236877A1 (zh) 苯并[c]色满化合物的可药用盐、其多晶型及用途
WO2019019851A1 (zh) 钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用
CN111094272B (zh) 一种otr抑制剂的可药用盐、晶型及制备方法
US20260098027A1 (en) Pharmaceutically acceptable salt and crystal form of tetrahydronaphthalene derivative, and preparation method
TW202342446A (zh) Lta4h抑制劑的晶型
WO2019015640A1 (zh) 一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和用途
TW202446373A (zh) 二氧代哌啶化合物或其可藥用鹽的無定形物、結晶、製備方法和用途
US20220235030A1 (en) Selective histamine h3 antagonist acid addition salts and process for the preparation thereof
WO2025180350A1 (zh) 化合物盐的晶型及其制备方法和用途
WO2025157261A1 (zh) G12d抑制剂化合物晶型及其制备方法
TW201713647A (zh) １－（４－（２－（（１－（３，４－二氟苯基）－１ｈ－吡唑－３－基）甲氧基）乙基）呱嗪－１－基）乙酮鹽

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24803084

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: MX/A/2025/013356

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2025565648

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2025565648

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: AU2024267706

Country of ref document: AU

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112025024440

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2024267706

Country of ref document: AU

Date of ref document: 20240510

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020257041155

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2024803084

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

WWP Wipo information: published in national office

Ref document number: 1020257041155

Country of ref document: KR

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

WWP Wipo information: published in national office

Ref document number: MX/A/2025/013356

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2024803084

Country of ref document: EP

Effective date: 20251211

WWP Wipo information: published in national office

Ref document number: 2024803084

Country of ref document: EP