WO2023236199A1 - N-(苯甲酰基)-苯丙氨酸类化合物的晶体及其药物组合物、制备方法和用途 - Google Patents

N-(苯甲酰基)-苯丙氨酸类化合物的晶体及其药物组合物、制备方法和用途 Download PDF

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WO2023236199A1
WO2023236199A1 PCT/CN2022/098176 CN2022098176W WO2023236199A1 WO 2023236199 A1 WO2023236199 A1 WO 2023236199A1 CN 2022098176 W CN2022098176 W CN 2022098176W WO 2023236199 A1 WO2023236199 A1 WO 2023236199A1
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formula
compound represented
crystal
ray powder
powder diffraction
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PCT/CN2022/098176
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French (fr)
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詹威强
付凌燕
陈方磊
童欢
吴剑波
何春
徐新良
祝方猛
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杭州普洛药物研究院有限公司
普洛药业股份有限公司
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Priority to PCT/CN2022/098176 priority Critical patent/WO2023236199A1/zh
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    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of crystal drugs, and specifically relates to crystals of N-(benzoyl)-phenylalanine compounds, pharmaceutical compositions containing the crystal drugs, and preparation methods and uses of the crystal drugs, especially (S )-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indole Two crystal forms of pholin]-1'-yl)phenyl)propionic acid, corresponding pharmaceutical compositions, and preparation methods and uses of the two crystal forms.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn’s disease
  • indeterminate colitis For example, during the occurrence and development of IBD, immune cells migrate to the intestine through the interaction of ⁇ 4 ⁇ 7 integrin and its ligand mucosal addressin 1 (MAdCAM-1), and abnormally accumulate in the intestinal mucosa.
  • MAdCAM-1 mucosal addressin 1
  • ⁇ 4 ⁇ 7 integrin controls lymphocyte translocation to intestinal tissue and retention in the intestine through interaction with MAdCAM-1.
  • PCT/CN2021/132456 reports a series of N-( Benzoyl)-phenylalanine compounds, including chemically named (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6',7'-di Compounds of fluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionic acid.
  • the preparation method of this compound is: (S)-2-(2-chloro-6-fluorobenzoylamino)-3-(4-(6',7'-difluoro-2'-oxospiro[ Cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionic acid methyl ester was dissolved in tetrahydrofuran, and then 0.5 mol/L sodium hydroxide aqueous solution was added to the reaction system, and the reaction was carried out at room temperature for 2 hours.
  • the product obtained by the above method is amorphous (as shown in Figure 7). Since amorphous is a relatively unstable solid form in thermodynamics and is prone to transformation or degradation, the chemical purity of the compound is reduced, which in turn affects the quality of the drug. Ultimate quality.
  • the present invention unexpectedly found that the crystal form A of the compound represented by formula (I) and the crystal form B of the compound represented by formula (II) have the properties of high stability, simple preparation process, and suitable for large-scale industrial production.
  • the present invention provides a compound represented by formula (I), which exists in a crystal form with crystalline form A, and the crystallographic parameters of said crystalline form A are as follows:
  • the X-ray powder diffraction (XRPD) pattern of the crystalline form A has 2 ⁇ values of 10.4 ⁇ 0.2°, 13.1 ⁇ 0.2°, 13.6 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.6 ⁇ 0.2°, 20.2 There are characteristic peaks at ⁇ 0.2°, 21.9 ⁇ 0.2°, and 22.1 ⁇ 0.2°. Moreover, the XRPD pattern of the crystal form A has at least three characteristic peaks with excellent peak shape and separation at 2 ⁇ values of 10.4 ⁇ 0.2°, 13.1 ⁇ 0.2°, and 13.6 ⁇ 0.2°.
  • the XRPD pattern of Form A also has 2 ⁇ values of 5.2 ⁇ 0.2°, 12.3 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.7 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.5 ⁇ 0.2°, 28.5 There is a characteristic peak at at least one of ⁇ 0.2° and 33.1 ⁇ 0.2° (eg, 1, 2, 3, 4, 5, 6, 7, or 8).
  • the XRPD pattern of Form A also has at least one (eg, 1, 2 or 3) 2 ⁇ value of 31.6 ⁇ 0.2°, 38.3 ⁇ 0.2°, 40.0 ⁇ 0.2°. Characteristic peaks.
  • the XRPD pattern of Form A is substantially as shown in Figure 1.
  • the differential scanning calorimetry (DSC) spectrum of Form A has an endothermic peak at 236 ⁇ 3°C.
  • thermogravimetric analysis (TGA) pattern of Form A exhibits a weight loss of about 0.2% at 25°C to 120°C.
  • the DSC and TGA patterns of Form A are substantially as shown in Figure 2.
  • the present invention provides a compound represented by formula (II), which exists in a crystal form having crystalline form B, and the crystallographic parameters of said crystalline form B are as follows:
  • the XRPD pattern of the crystal form B has characteristic peaks at 2 ⁇ values of 8.5 ⁇ 0.2°, 11.0 ⁇ 0.2°, and 17.9 ⁇ 0.2°.
  • the XRPD pattern of Form B also has a 2 ⁇ value of at least 14.3 ⁇ 0.2°, 15.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.1 ⁇ 0.2°, 24.4 ⁇ 0.2°, and 25.5 ⁇ 0.2°.
  • One location for example, 1, 2, 3, 4, 5, or 6 has a characteristic peak.
  • the XRPD pattern of Form B also has a 2 ⁇ value of at least 20.8 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.8 ⁇ 0.2°, 28.5 ⁇ 0.2°, and 32.5 ⁇ 0.2°.
  • One location for example, 1, 2, 3, 4, 5, or 6 has a characteristic peak.
  • the XRPD pattern of Form B is substantially as shown in Figure 3.
  • the Differential Scanning Calorimetry (DSC) of Form B has endothermic peaks at 121 ⁇ 3°C and 234 ⁇ 3°C, and an exothermic peak at 133 ⁇ 3°C.
  • thermogravimetric analysis (TGA) pattern of Form B exhibits a weight loss of about 3.6% at 50°C to 150°C.
  • the crystal form B is a monohydrate crystal form.
  • the DSC and TGA patterns of Form B are substantially as shown in Figure 4.
  • the present invention provides a method for preparing the compound represented by formula (I) in the form of a crystal having Form A, which is selected from the group consisting of suspension crystallization methods.
  • the specific steps of the above-mentioned suspension crystallization method include: adding the compound represented by formula (I) in the form of an amorphous substance into a binary mixed solvent to prepare a suspension, and performing solid-liquid separation after stirring at a constant temperature. (Preferably centrifugal separation), and dry the obtained solid (preferably vacuum drying) to obtain the compound represented by formula (I) in the form of a crystal having crystalline form A.
  • the binary mixed solvent includes ethylene glycol monomethyl ether/methyl tert-butyl ether, ethylene glycol dimethyl ether/methyl tert-butyl ether, 4-methyl-2-pentanone /water and acetone/water.
  • the binary mixed solvent is ethylene glycol monomethyl ether/methyl tert-butyl ether or acetone/water, preferably acetone/water.
  • the volume ratio of the two solvents in the binary mixed solvent is 1:3-1:9, preferably 1:4-1:5, more preferably 1:5.
  • the dosage ratio (solid-liquid ratio) of the compound represented by formula (I) in the form of an amorphous substance to the binary mixed solvent is 30-80 mg: 1 ml, preferably 40-80 mg: 1 ml, more preferably 40 mg :1ml.
  • the temperature of the constant temperature stirring is room temperature to 60°C, preferably 50-60°C, more preferably 50°C.
  • the constant temperature stirring time is 4-120 hours, preferably 8-24 hours, more preferably 8 hours.
  • the present invention provides a method for preparing the compound represented by formula (II) in the form of a crystal having Form B, which is selected from the group consisting of a solvent evaporation method and an anti-solvent method.
  • the specific steps of the above solvent evaporation method include:
  • the compound represented by formula (I) in the form of an amorphous substance is added to an alcoholic solvent, dissolved and left to volatilize at room temperature to obtain the compound represented by formula (II) existing in the form of a crystal with crystal form B.
  • the alcoholic solvent is at least one of methanol and ethanol, preferably ethanol.
  • the dosage ratio (solid-liquid ratio) of the compound represented by formula (I) in the form of amorphous substance to the alcohol solvent (solid-liquid ratio) is 20-80 mg:1 ml, preferably 50 mg:1 ml.
  • the specific steps of the above anti-solvent method include:
  • the good solvent is at least one of methanol and ethanol, preferably ethanol.
  • the antisolvent is at least one of cyclohexane and n-heptane, preferably cyclohexane.
  • the dosage ratio (solid-liquid ratio) of the compound represented by formula (I) in the form of an amorphous substance and the good solvent (solid-liquid ratio) is 40-70 mg: 1 ml, preferably 55 mg: 1 ml.
  • the usage ratio (volume ratio) of antisolvent to good solvent is 5-15:1, preferably 10:1.
  • the stirring includes room temperature stirring and optional ice bath stirring; preferably, the room temperature stirring time is 0.5-3 hours, preferably 1 hour.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically and/or therapeutically effective amount of the compound represented by formula (I) with crystal form A and/or the formula (II) with crystal form B.
  • the pharmaceutically acceptable carrier is an inert, non-toxic carrier, which may include pharmaceutically used diluents, binders, disintegrants, glidants, lubricants, coating agents, etc., such as starch. , lactose, powdered cellulose, microcrystalline cellulose, gum arabic, etc.
  • the present invention provides the above-mentioned compound represented by formula (I) with crystal form A and/or the compound represented by formula (II) with crystal form B for preparation and use in the prevention and/or treatment of ⁇ 4 ⁇ 7 integrin-related Use in medicines for diseases.
  • the diseases related to ⁇ 4 ⁇ 7 integrin include autoimmune diseases and inflammatory diseases; preferably, the inflammatory disease is inflammatory bowel disease (IBD), for example, ulcerative colitis (UC), Crohn's disease (CD).
  • IBD inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • the crystal form A of the compound represented by formula (I) and the crystal form B of the compound represented by formula (II) provided by the present invention have the following beneficial effects:
  • Crystal Form A and Crystal Form B of the present invention have good stability
  • the crystalline raw materials provided by the invention have good physical and chemical stability under different storage conditions.
  • the crystalline form A and crystalline form B were placed under the conditions of high temperature 60°C, high humidity 92.5%RH, light 4500lux and accelerated 40°C/75%RH for 15 days respectively.
  • the chemical purity and crystalline form of crystalline form A and crystalline form B There were no obvious changes. This shows that during the storage process of the crystal form A and crystal form B of the present invention and the pharmaceutical preparations containing the crystal form A and the crystal form B, the crystal form A and the crystal form B remain basically unchanged, thereby ensuring the quality of the raw materials and preparations. .
  • Crystal Form A and Crystal Form B of the present invention have low hygroscopicity
  • the weight gain of the crystalline form A of the present invention is 0.09% under the condition of 80% relative humidity, which has no or almost no hygroscopicity; the weight gain of the crystalline form B under the condition of 80% relative humidity is 0.71%, which is slightly hygroscopic. .
  • the solubility of crystal form A and crystal form B of the present invention is good in both FeSSIF (fed state simulated intestinal fluid) and FaSSIF (fasted state simulated intestinal fluid). Good intestinal solubility is conducive to good absorption of drugs in the body, thereby improving the bioavailability and efficacy of drugs.
  • the crystal form A and crystal form B of the present invention have important applications in the preparation of drugs for preventing and/or treating diseases related to ⁇ 4 ⁇ 7 integrin (for example, autoimmune diseases, inflammatory diseases) value.
  • diseases related to ⁇ 4 ⁇ 7 integrin for example, autoimmune diseases, inflammatory diseases
  • Figure 1 is the XPRD pattern of crystal form A of the compound of formula (I) prepared in Example 1.
  • Figure 2 is a DSC/TGA spectrum of crystal form A of the compound of formula (I) prepared in Example 1.
  • Figure 3 is the XPRD pattern of crystal form B of the compound of formula (II) prepared in Example 3.
  • Figure 4 is a DSC/TGA spectrum of crystal form B of the compound of formula (II) prepared in Example 3.
  • Figure 5 is an XPRD pattern of the amorphous powder of the compound of formula (I) prepared in Example 15 of PCT/CN2021/132456.
  • Figure 6 is a DVS spectrum of crystal form A of the compound of formula (I) in Example 6.
  • Figure 7 is the XPRD pattern of the crystal form A of the compound of formula (I) in Example 7 when it was placed under high temperature, high humidity, light and acceleration experiments for 15 days.
  • Figure 8 is the DVS spectrum of crystal form B of the compound of formula (II) in Example 9.
  • Figure 9 is the XPRD pattern of the crystal form B of the compound of formula (II) in Example 10 when it was placed under high temperature, high humidity, light and acceleration experiments for 15 days.
  • the X-ray powder diffraction (XRPD) method used in the present invention is: use a Bruker D8 Advance diffractometer for analysis, use Cu-K ⁇ radiation, and obtain an X-ray powder diffraction pattern under the operating conditions of 40KV and 40Ma. The samples are tested at room temperature, and the samples to be tested are placed on the phosphide silicon wafer. The detailed detection conditions are as follows: scanning in the range of 3-45° with a step size of 0.02° and an exposure time of 0.08 seconds. Use Diffrac.Measurement Center software to collect data and Diffrac.Eva software to process data.
  • the differential scanning calorimetry (DSC) method used in the present invention is: using a TA Discovery 2500 instrument with a thermal analysis controller to perform differential scanning calorimetry. Data were collected and analyzed using trios software. Approximately 1-2 mg was accurately weighed and placed in a punched DSC Tzero sample pan, and a linear heating device of 10°C/min was used for sample analysis from 25°C to 290°C. During use, the DSC furnace chamber was purged with dry nitrogen at a purge rate of 50 ml/min.
  • thermogravimetric analysis (TGA) method used in the present invention is: using a TA Discovery 55 instrument with a thermal analysis controller to perform thermogravimetric analysis. Data were collected and analyzed using trios software. Approximately 2-5 mg of sample is placed in a balanced aluminum sample pan and automatically weighed in a TGA heating furnace. Sample analysis was performed from 25°C to 290°C using a linear heating device at 10°C/min. During use, the DSC chamber is purged with dry nitrogen, the nitrogen purge rate at the sample is 60mL/min, and the nitrogen purge rate at the balance is 40mL/min.
  • the solubility results in the present invention are measured using SHIMADZU LC 2030C 3D Plus high performance liquid chromatography.
  • the chromatographic column model is YMC Pack ODS-AQ C18, 4.6 ⁇ 250mm, 5 ⁇ m, the detection wavelength is 220nm, the flow rate is 1.2ml/min, and the column temperature The temperature was 30°C, and the mobile phase was: 0.1% phosphoric acid water-acetonitrile gradient elution.
  • the hygroscopicity results in the present invention are measured by the DVS Intrinsic dynamic moisture and gas adsorption instrument of the British Surface Measurement Systems company.
  • the humidity change is 50%-95%-0%-50%, and each gradient is within the range of 0% to 90%.
  • the humidity change is 10%, air flow: 200ml/min, temperature: 25°C, test point: take one test point per liter of 10% humidity.
  • test sample a compound of formula (I) that exists in the form of a crystal with Form A
  • test results are shown in Table 4, and the DVS pattern of the hygroscopicity experiment of Form A is shown in Figure 6.
  • Test sample 80%RH weight gain/% Form A 0.09%
  • test samples compounds of formula (I) that exist in the form of crystals with Form A
  • put them into a watch glass spread them into a thin layer ⁇ 5mm thick, and store them at a high temperature of 60°C and a high humidity of 92.5% RH.
  • HPLC detects the purity of the samples and XPRD detects the crystal form of the samples.
  • the test results are shown in Table 5.
  • the XRPD pattern is shown in Figure 7.
  • test sample a compound of formula (II) that exists in the form of a crystal with Form B
  • dynamic moisture adsorption instrument to test its hygroscopicity.
  • Table 7 The DVS diagram of the hygroscopicity experiment of Form B is basically as shown in Figure 8.
  • Test sample 80%RH weight gain/% Form B 0.71%
  • test samples compounds of formula (II) that exist in the form of crystals with Form B
  • put them into a watch glass spread them into a thin layer ⁇ 5mm thick, and store them at a high temperature of 60°C and a high humidity of 92.5% RH.
  • HPLC detects the purity of the sample
  • XPRD detects the crystal form of the sample. The test results are shown in Table 8 and the XRPD pattern is shown in Figure 9.

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Abstract

本发明涉及N-(苯甲酰基)-苯丙氨酸类化合物的晶体及其药物组合物、制备方法和用途。具体而言，该化合物如式(I)和式(II)所示，式(I)化合物的晶体具有晶型A，式(II)化合物的晶体具有晶型B，两种晶型稳定性好，制备方法重复性高，操作性强，在预防和/或治疗与α4β7整合素相关的疾病方面具有重要的应用价值。

Description

N-(苯甲酰基)-苯丙氨酸类化合物的晶体及其药物组合物、制备方法和用途 技术领域
本发明属于晶体药物技术领域，具体涉及N-(苯甲酰基)-苯丙氨酸类化合物的晶体，包含该晶体药物的药物组合物，以及该晶体药物的制备方法和用途，特别涉及(S)-2-(2-氯-6-氟苯甲酰氨基)-3-(4-(6',7'-二氟-2'-氧代螺[环丙烷-1,3'-吲哚啉]-1'-基)苯基)丙酸的两种晶型，相应的药物组合物，以及两种晶型的制备方法和用途。
背景技术
炎症性肠病(inflammatory bowel disease，IBD)是一系列主要累及消化道的慢性、炎症性疾病。IBD包括溃疡性结肠炎(ulcerative colitis，UC)、克罗恩病(Crohn’s disease，CD)和未定型结肠炎。例如，在IBD的发生及发展过程中，免疫细胞通过α4β7整合素与其配体黏膜地址素1(MAdCAM-1)的相互作用向肠道部位迁移，并在肠道黏膜层异常聚集。α4β7整合素通过与MAdCAM-1的相互作用来控制淋巴细胞向肠道组织的转移以及在肠道中的滞留。
有人已经提出，抑制整合素与其配体的相互作用是治疗多种自身免疫和炎性疾病的有效方法，并且阻断α4β7-MAdCAM-1相互作用已经显示出对于炎症性肠病(如克罗恩氏病和溃疡性结肠炎)的治疗作用。
PCT/CN2021/132456报道了一系列具有较强的α4β7-MAdCAM-1抑制活性，可用于预防和/或治疗与α4β7整合素相关的疾病(如自身免疫性疾病和炎症性疾病)的N-(苯甲酰基)-苯丙氨酸类化合物，其中包含化学名为(S)-2-(2-氯-6-氟苯甲酰氨基)-3-(4-(6',7'-二氟-2'-氧代螺[环丙烷-1,3'-吲哚啉]-1'-基)苯基)丙酸的化合物。该化合物的制备方法为：将(S)-2-(2-氯-6-氟苯甲酰氨基)-3-(4-(6',7'-二氟-2'-氧代螺[环丙烷-1,3'-吲哚 啉]-1'-基)苯基)丙酸甲酯溶于四氢呋喃，再向反应体系加入0.5mol/L氢氧化钠水溶液，室温反应2h。用2mol/L稀盐酸调节反应体系pH值至1-2，二氯甲烷萃取三次(每次2mL)，合并有机层，有机层分别用水和饱和食盐水洗涤一次，无水硫酸钠干燥，抽滤，减压浓缩，浓缩物通过反相HPLC(含有0.1％甲酸的H 2O/CH 3CN体系)进行纯化，得到式(I)所示化合物。
Figure PCTCN2022098176-appb-000001
通过上述方法得到的产品为无定形物(如图7所示)，由于无定形是热力学中相对不稳定的固体形态，易发生转变或降解等，因而导致化合物的化学纯度降低，进而影响药品的最终品质。
发明内容
针对以上缺陷，本发明出人意料地发现，式(I)所示化合物的晶型A和式(II)所示化合物的晶型B具有稳定性高、制备工艺简便、适合规模化工业生产的性质。
在第一方面，本发明提供了式(I)所示化合物，其以具有晶型A的晶体形式存在，所述晶型A的晶体学参数如下：
使用Cu-Kα辐射，所述晶型A的X射线粉末衍射(XRPD)图谱在2θ值为10.4±0.2°、13.1±0.2°、13.6±0.2°、18.8±0.2°、19.6±0.2°、20.2±0.2°、21.9±0.2°、22.1±0.2°处具有特征峰。并且，所述晶型A的XRPD图谱至少在2θ值为10.4±0.2°、13.1±0.2°、13.6±0.2°处具有峰形及分离度俱佳的三个特征峰。
在一些实施方案中，所述晶型A的XRPD图谱还在2θ值为5.2±0.2°、12.3±0.2°、14.7±0.2°、15.7±0.2°、24.7±0.2°、26.5±0.2°、28.5±0.2°、33.1±0.2°的至少一处(例如，1处、2处、3处、4处、5处、6处、7处或8处)具有特征峰。
在一些实施方案中，所述晶型A的XRPD图谱还在2θ值为31.6±0.2°、38.3±0.2°、40.0±0.2°的至少一处(例如，1处、2处或3处)具有特征峰。
在一些实施方案中，所述晶型A的XRPD图谱基本上如图1所示。
在一些实施方案中，所述晶型A的差示扫描量热分析(DSC)图谱在236±3℃处具有吸热峰。
在一些实施方案中，所述晶型A的热重分析(TGA)图谱在25℃-120℃下显示出约0.2％的失重。
在一些实施方案中，所述晶型A的DSC和TGA图谱基本上如图2所示。
在第二方面，本发明提供了式(II)所示化合物，其以具有晶型B的晶体形式存在，所述晶型B的晶体学参数如下：
使用Cu-Kα辐射，所述晶型B的XRPD图谱在2θ值为8.5±0.2°、11.0±0.2°、17.9±0.2°处具有特征峰。
在一些实施方案中，所述晶型B的XRPD图谱还在2θ值为14.3±0.2°、15.5±0.2°、19.3±0.2°、20.1±0.2°、24.4±0.2°、25.5±0.2°的至少一处(例如，1处、2处、3处、4处、5处或6处)具有特征峰。
在一些实施方案中，所述晶型B的XRPD图谱还在2θ值为20.8±0.2°、22.7±0.2°、23.9±0.2°、24.8±0.2°、28.5±0.2°、32.5±0.2°的至少一处(例如，1处、2处、3处、4处、5处或6处)具有特征峰。
在一些实施方案中，所述晶型B的XRPD图谱基本上如图3所示。
在一些实施方案中，所述晶型B的差示扫描量热分析图(DSC)在121±3℃和234±3℃处具有吸热峰，在133±3℃处具有放热峰。
在一些实施方案中，所述晶型B的热重分析(TGA)图谱在50℃- 150℃下显示出约3.6％的失重。结合DSC的分析，所述晶型B为一水合物晶型。
在一些实施方案中，所述晶型B的DSC和TGA图谱基本上如图4所示。
在第三方面，本发明提供了上述以具有晶型A的晶体形式存在的式(I)所示化合物的制备方法，其选自悬浮转晶法。
在一些实施方案中，上述悬浮转晶法的具体步骤包括：将以无定形物形式存在的式(I)所示化合物加入到二元混合溶剂中配制成悬浮液，恒温搅拌后进行固液分离(优选离心分离)，将得到的固体进行干燥(优选真空干燥)，得到以具有晶型A的晶体形式存在的式(I)所示化合物。
在一些实施方案中，所述二元混合溶剂包括乙二醇单甲醚/甲基叔丁基醚、乙二醇二甲醚/甲基叔丁基醚、4-甲基-2-戊酮/水和丙酮/水。
在一些实施方案中，所述二元混合溶剂为乙二醇单甲醚/甲基叔丁基醚或丙酮/水，优选丙酮/水。
在一些实施方案中，所述二元混合溶剂中两种溶剂的体积比为1:3-1:9，优选1:4-1:5，更优选1:5。
在一些实施方案中，以无定形物形式存在的式(I)所示化合物与二元混合溶剂的用量比(固液比)为30-80mg:1ml，优选40-80mg:1ml，更优选40mg:1ml。
在一些实施方案中，所述恒温搅拌的温度为室温至60℃，优选50-60℃，更优选50℃。
在一些实施方案中，所述恒温搅拌的时间为4-120小时，优选8-24小时，更优选8小时。
在第四方面，本发明提供了上述以具有晶型B的晶体形式存在的式(II)所示化合物的制备方法，其选自溶剂挥发法和反溶剂法。
在一些实施方案中，上述溶剂挥发法的具体步骤包括：
将以无定形物形式存在的式(I)所示化合物加入到醇类溶剂中， 溶解后于室温静置挥发，得到以具有晶型B的晶体形式存在的式(II)所示化合物。
在一些实施方案中，所述醇类溶剂为甲醇、乙醇中的至少一种，优选乙醇。
在一些实施方案中，以无定形物形式存在的式(I)所示化合物与醇类溶剂的用量比(固液比)为20-80mg:1ml，优选50mg:1ml。
在一些实施方案中，上述反溶剂法的具体步骤包括：
将以无定形物形式存在的式(I)所示化合物加入到良溶剂中，溶解后加入到反溶剂中，搅拌后进行固液分离(优选离心分离)，将得到的固体进行干燥(优选真空干燥)，得到以具有晶型B的晶体形式存在的式(II)所示化合物。
在一些实施方案中，所述良溶剂为甲醇、乙醇中的至少一种，优选乙醇。
在一些实施方案中，所述反溶剂为环己烷、正庚烷中的至少一种，优选环己烷。
在一些实施方案中，以无定形物形式存在的式(I)所示化合物与良溶剂的用量比(固液比)为40-70mg:1ml，优选55mg:1ml。
在一些实施方案中，反溶剂与良溶剂的用量比(体积比)为5-15:1，优选10:1。
在一些实施方案中，所述搅拌包括室温搅拌和任选的冰浴搅拌；优选地，所述室温搅拌的时间为0.5-3小时，优选1小时。
在第五方面，本发明提供了一种药物组合物，其包含预防和/或治疗有效量的上述具有晶型A的式(I)所示化合物和/或具有晶型B的式(II)所示化合物，以及至少一种药学上可接受的载体。
优选地，所述药学上可接受的载体为惰性、无毒载体，其可以包括药学上所使用的稀释剂、粘合剂、崩解剂、助流剂、润滑剂、包裹剂等，例如淀粉、乳糖、粉状纤维素、微晶纤维素、***胶等。
在第六方面，本发明提供上述具有晶型A的式(I)所示化合物和/或具有晶型B的式(II)所示化合物在制备用于预防和/或治疗与α4β7整合素相关的疾病的药物中的用途。
所述与α4β7整合素相关的疾病包括自身免疫性疾病、炎症性疾病；优选地，所述炎症性疾病为炎症性肠病(IBD)，例如，溃疡性结肠炎(UC)、克罗恩病(CD)。
本发明提供的式(I)所示化合物的晶型A和式(II)所示化合物的晶型B具有以下有益效果：
(1)本发明的晶型A和晶型B具有良好的稳定性
本发明提供的晶型原料药在不同的储存条件下均具有良好的物理、化学稳定性。所述晶型A和晶型B分别在高温60℃、高湿92.5％RH、光照4500lux以及加速40℃/75％RH条件下放置15天，晶型A和晶型B的化学纯度及晶型均无明显变化。这表明本发明的晶型A和晶型B及包含晶型A和晶型B的药物制剂在储存过程中，晶型A和晶型B基本保持不变，从而保证了原料药和制剂的质量。
(2)本发明的晶型A和晶型B具有低的引湿性
本发明的晶型A在80％相对湿度条件下的增重为0.09％，属于无或几乎无引湿性；晶型B在80％相对湿度条件下的增重为0.71％，属于略有引湿性。这表明本发明晶型A和晶型B不易受高湿度影响而潮解，从而提高了药物的稳定性、加工时的流动性和均匀性等，提高了药物制剂的质量。
(3)本发明的晶型A和晶型B具有良好的溶解度
本发明的晶型A和晶型B在FeSSIF(进食状态模拟肠液)和FaSSIF(禁食状态模拟肠液)中的溶解度均较好。良好的肠内溶解度有利于药物在体内的良好吸收，从而提高了药物的生物利用度以及疗效。
(4)本发明的晶型A和晶型B的制备工艺重现性好，操作简便，适合工业化生产。
综上所述，本发明的晶型A和晶型B在制备用于预防和/或治疗与α4β7整合素相关的疾病(例如，自身免疫性疾病、炎症性疾病)的药物中具有重要的应用价值。
附图说明
图1为实施例1制备的式(I)化合物的晶型A的XPRD图谱。
图2为实施例1制备的式(I)化合物的晶型A的DSC/TGA图谱。
图3为实施例3制备的式(II)化合物的晶型B的XPRD图谱。
图4为实施例3制备的式(II)化合物的晶型B的DSC/TGA图谱。
图5为PCT/CN2021/132456中实施例15制备的式(I)化合物的无定形粉末的XPRD图谱。
图6为实施例6中式(I)化合物的晶型A的DVS图谱。
图7为实施例7中式(I)化合物的晶型A在高温、高湿、光照和加速实验下放置15天的XPRD图谱。
图8为实施例9对式(II)化合物的晶型B的DVS图谱。
图9为实施例10对式(II)化合物的晶型B在高温、高湿、光照和加速实验下放置15天的XPRD图谱。
具体实施方式
本发明所用X射线粉末衍射(XRPD)方法为：使用Bruker D8Advance衍射仪进行分析，使用Cu-Kα辐射，在40KV和40Ma的操作条件下，获得X射线粉末衍射图。样品在室温条件下测试，把需要检测的样品放在磷化硅片上。详细检测条件如下：在3-45°的范围内以0.02°步长进行扫描，曝光时间为0.08秒。使用Diffrac.Measurement Center软件收集数据，Diffrac.Eva软件处理数据。
本发明所用差示扫描量热分析(DSC)方法为：使用带有热分析控制器的TA Discovery 2500仪器进行差示扫描量热。收集数据并使用trios 软件进行分析。将约1-2mg经精准称重后置于扎孔的DSC Tzero样品盘中，使用10℃/min的线性加热装置，从25℃至290℃进行样品分析。在使用期间，将DSC炉室用干燥氮气吹扫，吹扫速度为50ml/min。
本发明所用热失重分析(TGA)方法为：使用带有热分析控制器的TA Discovery 55仪器进行热失重。收集数据并使用trios软件进行分析。将约2-5mg样品置于已平衡的铝制样品盘中，在TGA加热炉内自动称量。使用10℃/min的线形加热装置，从25℃至290℃进行样品分析。在使用期间，将DSC小室用干燥氮气吹扫，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。
本发明中的溶解度结果采用SHIMADZU LC 2030C 3D Plus高效液相色谱仪测定，色谱柱型号为YMC Pack ODS-AQ C18，4.6×250mm，5μm，检测波长为220nm，流速为1.2ml/min，柱温为30℃，流动相为：0.1％磷酸水-乙腈梯度洗脱。
本发明中的引湿性结果采用英国Surface Measurement Systems公司DVS Intrinsic型动态水分与气体吸附仪测定，湿度变化为50％-95％-0％-50％，在0％至90％范围内每个梯度的湿度变化量为10％，气流：200ml/min,温度：25℃，测试点：每升10％湿度取一个测试点。
以下将结合具体实施例来说明本发明的技术方案。本领域一般技术人员可以理解的是，下列实施例仅是为了进一步详细叙述本发明，而并不限制本发明的范围。除非另有限定，下列实施例中使用的药品、试剂、材料、仪器等均可通过常规商业手段获得。
实施例1晶型A的制备
称取40mg样品(以无定形物形式存在的式(I)化合物)，加入0.1ml的乙二醇单甲醚和0.4ml的甲基叔丁基醚，配制成悬浮液，50℃悬浮搅拌1天，离心分离悬浮液，固体在室温下真空干燥，得到晶型A，其XRPD图谱如图1所示，DSC和TGA图谱如图2所示。
表1
编号 衍射角2θ d值 强度％
1 5.152° 17.13880 18.6
2 10.447° 8.46068 75.4
3 12.311° 7.18391 28.3
4 13.082° 6.76188 74.2
5 13.597° 6.50719 69.1
6 14.719° 6.01349 18.4
7 15.693° 5.64239 36.6
8 18.808° 4.71426 64.6
9 18.843° 4.70576 62.5
10 19.574° 4.53153 100.0
11 20.190° 4.39473 88.4
12 21.858° 4.06293 76.9
13 22.092° 4.02047 86.4
14 22.109° 4.01731 82.9
15 24.743° 3.59529 21.7
16 26.537° 3.35628 19.4
17 28.451° 3.13468 18.6
18 31.641° 2.82551 7.9
19 33.108° 2.70355 11.9
20 38.296° 2.34842 7.4
21 40.004° 2.25201 6.7
实施例2晶型A的制备
称取504mg样品(以无定形物形式存在的式(I)化合物)，在12.6ml的丙酮/水(V/V＝1:5)混合溶剂中，50℃悬浮搅拌8小时，将得到的白色悬浊液离心分离，并将固体在50℃下真空干燥，得到晶型A。经测试，其XRPD图谱与图1基本相同。
实施例3晶型B的制备
将20mg样品(以无定形物形式存在的式(I)化合物)加入到0.4ml的乙醇中，溶解后于室温静置挥发5天，得到晶型B，其XRPD图谱如图3所示，DSC和TGA图谱如图4所示。
经实验测定后证实，晶型B在150℃以上能够转为晶型A。 表2
编号 衍射角2θ d值 强度％
1 4.084 21.61671 1.3
2 8.142 10.85096 2.0
3 8.530 10.35778 52.0
4 11.029 8.01590 100.0
5 12.155 7.27595 0.8
6 14.269 6.20208 18.0
7 14.957 5.91853 2.2
8 15.493 5.71464 17.8
9 16.208 5.46414 0.5
10 17.023 5.20444 2.9
11 17.852 4.96469 30.3
12 18.647 4.75470 2.9
13 19.279 4.60019 19.7
14 19.669 4.50997 0.8
15 20.108 4.41232 11.3
16 20.822 4.26266 5.7
17 21.051 4.21681 0.9
18 21.628 4.10559 4.5
19 22.084 4.02189 2.5
20 22.268 3.98905 1.8
21 22.676 3.91821 5.4
22 22.841 3.89022 1.9
23 23.153 3.83845 1.9
24 23.937 3.71461 7.6
25 24.386 3.64715 22.9
26 24.845 3.58076 9.7
27 25.516 3.48812 14.1
28 26.426 3.37010 3.3
29 26.895 3.31230 1.7
30 27.809 3.20551 1.5
31 28.510 3.12830 5.0
32 29.411 3.03447 0.7
33 29.845 2.99134 1.5
34 30.083 2.96815 3.4
35 30.398 2.93817 4.8
36 31.196 2.86479 2.4
37 32.317 2.76796 2.6
38 32.533 2.75006 8.4
39 33.429 2.67838 0.5
40 33.674 2.65941 0.8
41 34.340 2.60935 4.6
42 35.598 2.51995 0.5
43 36.176 2.48100 0.7
44 36.550 2.45650 1.5
45 36.915 2.43302 0.4
46 37.669 2.38604 0.7
47 38.760 2.32134 0.6
48 39.047 2.30496 2.3
49 40.013 2.25150 0.9
50 41.122 2.19332 1.9
51 41.504 2.17402 0.4
52 41.872 2.15575 2.1
53 42.946 2.10428 0.5
54 43.621 2.07326 1.8
实施例4晶型B的制备
将20mg样品(以无定形物形式存在的式(I)化合物)加入到0.35ml的乙醇中，溶解后，将样品溶液加入到3ml的环己烷中，室温搅拌1h后冰浴搅拌，离心分离，将固体在室温下真空干燥，得到晶型B。经测试，其XRPD图谱与图4基本相同。
实施例5晶型A的溶解度
将20mg样品(以具有晶型A的晶体形式存在的式(I)化合物)加入到10ml锥形管中，分别加入4ml的水或生物介质(FeSSIF(pH5.0)或FaSSIF(pH6.5))，37℃恒温浴振摇24h，振摇速度1000rpm，分别在0.5h、2h和24h取样，将样品经水系微孔滤膜过滤，弃去初滤液，即得供试品溶液。
取供试品溶液(20μL)，采取HPLC检测，通过标准曲线法计算样品浓度，具体结果见下表。
表3.晶型A在不同介质中的溶解度测试结果
Figure PCTCN2022098176-appb-000002
结论：由表3可知，晶型A在FeSSIF和FaSIF中的溶解度相对较好。
实施例6晶型A的引湿性
取供试品(以具有晶型A的晶体形式存在的式(I)化合物)适量， 采用动态水分吸附仪测试其引湿性。实验结果如表4所示，晶型A的引湿性实验DVS图谱如图6所示。
表4.本发明晶型A的引湿性测试结果
供试样品 80％RH的增重/％
晶型A 0.09％
实验结论：由表4以及图6可知，晶型A在80％RH下增重为0.09％。根据引湿性增重的界定标准，属于无或几乎无引湿性，表明本发明的晶型A不易受高湿度影响而潮解。
实施例7晶型A的稳定性
取一批供试品(以具有晶型A的晶体形式存在的式(I)化合物)适量，放入表面皿中，摊成≤5mm厚的薄层，于高温60℃、高湿92.5％RH下、光照4500lux以及加速40℃/75％RH条件下分别放置15天，于第7天、15天取样，观察样品颜色变化，HPLC检测样品纯度，XPRD检测样品晶型，试验结果见表5，XRPD图谱见图7。
表5.晶型A及无定形的稳定性测试结果
Figure PCTCN2022098176-appb-000003
由表5及图7可知，在高温60℃、高湿92.5％RH下、光照4500lux以及加速40℃/75％RH的条件下放置15天，晶型A的纯度及晶型均无明显变化，并且与无定形相比，本发明的晶型A具有更好的稳定性，适合药用。
实施例8晶型B的溶解度
将20mg样品(以具有晶型B的晶体形式存在的式(II)化合物)加 入到10ml锥形管中，分别加入4ml的水或生物介质(FeSSIF(pH5.0)或FaSSIF(pH6.5))，37℃恒温浴振摇24h，振摇速度1000rpm，分别在0.5h、2h和24h取样，将样品经水系微孔滤膜过滤，弃去初滤液，即得供试品溶液。
取供试品溶液(20μL)，采取HPLC检测，通过标准曲线法计算样品浓度，具体结果见下表。
表6.晶型B在不同介质中的溶解度测试结果
Figure PCTCN2022098176-appb-000004
结论：由表6可知，晶型B在FeSSIF和FaSIF中的溶解度也相对较好。
实施例9晶型B的引湿性
取供试品(以具有晶型B的晶体形式存在的式(II)化合物)适量，采用动态水分吸附仪测试其引湿性。实验结果如表7所示，晶型B的引湿性实验DVS图基本如图8所示。
表7.本发明晶型B的引湿性测试结果
供试样品 80％RH的增重/％
晶型B 0.71％
实验结论：由表7以及图8可知，晶型B在80％湿度下增重为0.71％。根据引湿性增重的界定标准，属于略有引湿性，表明本发明的晶型B不易受高湿度影响而潮解。
实施例10晶型B的稳定性
取一批供试品(以具有晶型B的晶体形式存在的式(II)化合物)适量，放入表面皿中，摊成≤5mm厚的薄层，于高温60℃、高湿92.5％RH下、光照4500lux以及加速40℃/75％RH条件下分别放置15天，于第15天取样，观察样品颜色变化，HPLC检测样品纯度，XPRD检测样品晶型，试验结果见表8，XRPD图谱见图9。
表8.晶型B的稳定性测试结果
Figure PCTCN2022098176-appb-000005
由表8及图9可知，在高温60℃、高湿92.5％RH下、光照4500lux以及加速40℃/75％RH的条件下放置15天，晶型B的纯度及晶型均无明显变化，并且与无定形相比，本发明的晶型B也具有更好的稳定性，适合药用。

Claims (10)

  1. 一种式(I)所示化合物，
    Figure PCTCN2022098176-appb-100001
    其以具有晶型A的晶体形式存在，使用Cu-Kα辐射，其X射线粉末衍射图谱在2θ值为10.4±0.2°、13.1±0.2°、13.6±0.2°、18.8±0.2°、19.6±0.2°、20.2±0.2°、21.9±0.2°、22.1±0.2°处具有特征峰。
  2. 根据权利要求1所述的式(I)所示化合物，其特征在于，
    其X射线粉末衍射图谱在2θ值为5.2±0.2°、12.3±0.2°、14.7±0.2°、15.7±0.2°、24.7±0.2°、26.5±0.2°、28.5±0.2°、33.1±0.2°中的至少一处具有特征峰；
    优选地，其X射线粉末衍射图谱在2θ值为31.6±0.2°、38.3±0.2°、40.0±0.2°中的至少一处具有特征峰；
    更优选地，其X射线粉末衍射图谱基本上如图1所示。
  3. 根据权利要求1或2所述的式(I)所示化合物，其特征在于，
    其差示扫描量热分析图谱在236±3℃处具有吸热峰；
    优选地，其差示扫描量热分析图谱基本上如图2所示；和/或，
    其热重分析图谱在25℃-120℃下显示出约0.2％的失重；
    优选地，其热重分析图谱基本上如图2所示。
  4. 一种式(II)所示化合物，
    Figure PCTCN2022098176-appb-100002
    其以具有晶型B的晶体形式存在，使用Cu-Kα辐射，其X射线粉末衍射图谱在2θ值为8.5±0.2°、11.0±0.2°、17.9±0.2°处具有特征峰。
  5. 根据权利要求4所述的式(II)所示化合物，其特征在于，
    其X射线粉末衍射图谱在2θ值为14.3±0.2°、15.5±0.2°、19.3±0.2°、20.1±0.2°、24.4±0.2°、25.5±0.2°的至少一处具有特征峰；
    优选地，其X射线粉末衍射图谱在2θ值为20.8±0.2°、22.7±0.2°、23.9±0.2°、24.8±0.2°、28.5±0.2°、32.5±0.2°的至少一处具有特征峰；
    更优选地，其X射线粉末衍射图谱基本上如图3所示。
  6. 根据权利要求4或5所述的式(II)所示化合物，其特征在于，
    其差示扫描量热分析图谱在121±3℃和234±3℃处具有吸热峰，在133±3℃处具有放热峰；
    优选地，其差示扫描量热分析图谱基本上如图4所示；和/或，
    其热重分析图谱在50℃-150℃下显示出约3.6％的失重；
    优选地，其热重分析图谱基本上如图4所示。
  7. 一种根据权利要求1-3中任一项所述的式(I)所示化合物的制备方法，其选自悬浮转晶法。
  8. 一种根据权利要求4-6中任一项所述的式(II)所示化合物的制 备方法，其选自溶剂挥发法和反溶剂法。
  9. 一种药物组合物，其包含预防和/或治疗有效量的根据权利要求1-3中任一项所述的式(I)所示化合物和/或根据权利要求4-6中任一项所述的式(II)所示化合物，以及至少一种药学上可接受的载体。
  10. 根据权利要求1-3中任一项所述的式(I)所示化合物和/或根据权利要求4-6中任一项所述的式(II)所示化合物在制备用于预防和/或治疗与α4β7整合素相关的疾病的药物中的用途；
    优选地，所述与α4β7整合素相关的疾病包括自身免疫性疾病、炎症性疾病。
PCT/CN2022/098176 2022-06-10 2022-06-10 N-(苯甲酰基)-苯丙氨酸类化合物的晶体及其药物组合物、制备方法和用途 WO2023236199A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030220318A1 (en) * 2000-09-29 2003-11-27 Ajinomoto Co. Inc New phenylalanine derivatives
WO2008064823A1 (en) * 2006-11-27 2008-06-05 Ucb Pharma, S.A. Bicyclic and heterobicyclic derivatives, processes for preparing them and their uses
JP2016037467A (ja) * 2014-08-07 2016-03-22 味の素株式会社 スルホンアミド誘導体及びその医薬用途
CN114222730A (zh) * 2019-08-14 2022-03-22 吉利德科学公司 用于抑制α4β7整合素的化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030220318A1 (en) * 2000-09-29 2003-11-27 Ajinomoto Co. Inc New phenylalanine derivatives
WO2008064823A1 (en) * 2006-11-27 2008-06-05 Ucb Pharma, S.A. Bicyclic and heterobicyclic derivatives, processes for preparing them and their uses
JP2016037467A (ja) * 2014-08-07 2016-03-22 味の素株式会社 スルホンアミド誘導体及びその医薬用途
CN114222730A (zh) * 2019-08-14 2022-03-22 吉利德科学公司 用于抑制α4β7整合素的化合物

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