WO2016107222A1 - 一种苯丙氨酸类化合物的盐及其无定形体 - Google Patents

一种苯丙氨酸类化合物的盐及其无定形体 Download PDF

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WO2016107222A1
WO2016107222A1 PCT/CN2015/090095 CN2015090095W WO2016107222A1 WO 2016107222 A1 WO2016107222 A1 WO 2016107222A1 CN 2015090095 W CN2015090095 W CN 2015090095W WO 2016107222 A1 WO2016107222 A1 WO 2016107222A1
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compound
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fluorobenzoyl
phenylamino
ethoxy
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鲁先平
李志斌
宁志强
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深圳微芯生物科技有限责任公司
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system

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  • the invention belongs to the field of chemical pharmacy, in particular to a salt of a phenylalanine compound, and more particularly to an amorphous form of the salt; the invention also relates to a preparation method of the salt and its amorphous form and Use in the manufacture of a medicament for the prevention or treatment of a disease associated with metabolic syndrome.
  • the object of the present invention is to overcome the disadvantages of the prior art and to improve 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)) The stability and bioavailability of oxy)phenyl)propionic acid.
  • the inventors have found through experiments that the sodium and potassium salts of the compounds are unexpectedly stable and have significantly improved bioavailability.
  • the amorphous forms of the sodium and potassium salts have significantly improved stability and bioavailability.
  • the sodium salt and potassium salt of the present invention have a chemical structure as shown in the general formula (I):
  • M is Na or K.
  • the sodium and potassium salts of the present invention can be prepared by the following exemplary preparation methods:
  • M is Na or K.
  • 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)benzene The propionic acid is dissolved in tetrahydrofuran, and a methanol solution containing sodium hydroxide or potassium hydroxide is added thereto, and the reaction is stirred at room temperature for 10 to 30 minutes; concentrated in vacuo to remove tetrahydrofuran and methanol to obtain a concentrate; the concentrate is dissolved in dichloromethane.
  • the sodium salt is preferably in an amorphous form.
  • the X-ray powder diffraction pattern of the amorphous form of the sodium salt is a diffuse taro peak (see Figure 1); in another aspect of the invention, the amorphous form of the sodium salt is in its infrared Characteristic absorption peaks at about 2867, 1618, 1509, 1242, 1154, 851, and 750 cm -1 in the spectrum; in a preferred aspect, the amorphous form of the sodium salt is still about 3364, 3050, 2929, 1598, 1556 Characteristic absorption peaks at 1485, 1459 and 1326 cm -1 (see Fig. 2); in still another aspect of the invention, the differential scanning calorimetry curve of the amorphous form of the sodium salt has an endothermic peak at about 117.3 °C (See Figure 3).
  • the potassium salt is preferably in an amorphous form.
  • the X-ray powder diffraction pattern of the potassium salt amorphous form is a diffuse taro peak (see Figure 4); in another aspect of the invention, the potassium salt amorphous form is in its infrared Characteristic absorption peaks at about 2870, 1617, 1509, 1299, 1177, 852, and 786 cm -1 in the spectrum; in a preferred aspect, the potassium salt amorphous form is still about 3337, 3051, 2931, 1598, 1555 Characteristic absorption peaks at 1485, 1459 and 1326 cm -1 (see Fig. 5); in still another aspect of the invention, the differential scanning calorimetry curve of the amorphous form of the potassium salt has an endothermic peak at about 118.5 °C (See Figure 6).
  • the present inventors have unexpectedly found that the sodium salt amorphous body and the potassium salt amorphous body of the present invention are relatively stable, and are placed under high temperature (60 ° C), high humidity (90%), and intense light irradiation (4500 Lx). In the day, no ordinary crystal transformation phenomenon occurred in the amorphous body, but the original state was maintained, and the content and related substances did not change significantly, indicating that the sodium salt amorphous body and the potassium salt amorphous body of the present invention Particularly suitable for pharmaceutical manufacturing and long-term storage.
  • the sodium salt amorphous body and the potassium salt amorphous body of the present invention have significantly improved bioavailability.
  • Oral administration (20 mg/kg) of SD rats showed that the bioavailability of the sodium salt of the present invention was 6.0 times that of the unsalted free acid, and the bioavailability of the potassium salt of the present invention was unsalted. 7.5 times the free acid.
  • the lithium salt can also increase the bioavailability of the unsalted free acid, the increase in bioavailability is much smaller than that of the sodium salt and the potassium salt.
  • Other common salts e.g., ammonium salts, calcium salts, magnesium salts, etc. are not obtainable by the preparation methods described in the present invention or other common acid-base neutralization processes.
  • the invention provides a pharmaceutical composition comprising said sodium or potassium salt, in particular an amorphous form thereof.
  • the pharmaceutical composition comprises a compound of the formula (1) of the invention and optionally a pharmaceutically acceptable adjuvant.
  • the pharmaceutical excipients include pharmaceutically acceptable excipients and carriers.
  • the compound of the formula (1) is present in its amorphous form.
  • the pharmaceutical composition of the present invention may be various oral solid preparations such as tablets, capsules or granules, powders, powders and the like.
  • the pharmaceutical composition of the present invention may further comprise a second active agent other than the compound of the above formula (1), and the second active agent may be selected from the group consisting of biguanides such as metformin, sulfonylureas such as glibenclamide.
  • biguanides such as metformin, sulfonylureas such as glibenclamide.
  • Urea, glipizide, glimepiride, gliclazone, thiazolidinediones such as rosiglitazone, pioglitazone, alpha-glucosidase inhibitors such as acarbose, voglibose, insulin Secretions such as repaglinide, nateglinide, mitiglinide and the like.
  • the formulation contains from 5 to 50% of a sodium or potassium salt (especially its amorphous form) and from 50 to 95% of a pharmaceutical excipient.
  • the pharmaceutical excipients include a glidant such as talc, magnesium stearate, etc., a disintegrating agent such as sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, etc., a filler such as lactose, Microcrystalline cellulose, starch, etc., and a binder such as hydroxypropyl methylcellulose phthalate.
  • the present invention also provides the use of the sodium or potassium salt of the present invention for the preparation of a medicament for preventing or treating a disease associated with metabolic syndrome.
  • the present invention provides the use of the sodium salt amorphous or potassium salt amorphous body of the present invention for the preparation of a medicament for preventing or treating a disease associated with metabolic syndrome.
  • the invention provides the use of a sodium or potassium salt of the invention, particularly an amorphous form thereof, as a PPAR alpha, PPAR gamma or PPAR sigma agonist.
  • the present invention provides that the sodium or potassium salt of the present invention, especially its amorphous form, can be prepared for prevention or treatment by PPAR ⁇ , PPAR ⁇ . Or use in a medicament for a disease or condition treated by a PPAR serotype agonist.
  • the present invention also demonstrates the unexpected technical effects of the sodium and potassium salts of the present invention by stability test, bioavailability measurement and clinical test, and the stability and bioavailability are significantly improved, and the phase IIb clinical trial further confirms the present invention.
  • the effectiveness and safety of the salts of the invention are significantly improved.
  • Figure 1 is a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy) group according to Example 1 of the present invention.
  • X-ray powder diffraction pattern of sodium phenyl)propionate obtained by irradiation with copper K ⁇ rays.
  • the ordinate is the diffraction intensity expressed in counts per second (cps)
  • the abscissa is the diffraction angle 2 ⁇ expressed in degrees.
  • Figure 2 is a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy) group according to Example 1 of the present invention.
  • Infrared spectrum of phenyl)propionate the ordinate is the light transmittance (T), the unit is the percentage (%); the abscissa is the wave number, the unit is cm -1 .
  • Figure 3 is a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy) group according to Example 1 of the present invention.
  • the differential scanning calorimetry curve of phenyl)propionate the ordinate is the rate of heat change in millijoules per second; the abscissa is the temperature in °C.
  • Figure 4 is a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy) group according to Example 1 of the present invention.
  • X-ray powder diffraction pattern of phenyl) potassium propionate obtained by irradiation with copper K ⁇ rays.
  • the ordinate is the diffraction intensity expressed in counts per second (cps)
  • the abscissa is the diffraction angle 2 ⁇ expressed in degrees.
  • Figure 5 is a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy) group according to Example 1 of the present invention.
  • Infrared spectrum of phenyl) potassium propionate the ordinate is the light transmittance (T), the unit is the percentage (%); the abscissa is the wave number, the unit is cm -1 .
  • Figure 6 is a 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-carbazol-9-yl)ethoxy) group according to Example 1 of the present invention.
  • Differential scanning calorimetry graph of phenyl) potassium propionate the ordinate is the rate of heat change in millijoules per second; the abscissa is the temperature in °C.
  • Control compound 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid, according to The method described in Example 20 of Chinese Patent Application No. 03126974.5 is incorporated herein by reference.
  • Mass spectrometry test conditions Instrument: VG ZAB-HS color-mass spectrometer; analytical method: fast atom bombardment ionization (FAB).
  • Instrument VG ZAB-HS color-mass spectrometer; analytical method: fast atom bombardment ionization (FAB).
  • the obtained sodium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propionate is amorphous
  • the X-ray powder diffraction pattern is a diffuse taro peak (see Figure 1) with an infrared spectrum of about 3364, 3050, 2929, 2867, 1618, 1598, 1556, 1509, 1485, 1459, 1326, 1242, 1154.
  • the obtained potassium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoate is amorphous
  • the X-ray powder diffraction pattern is a diffuse taro peak (see Figure 4) with an infrared spectrum of about 3373, 3051, 2931, 2870, 1617, 1598, 1555, 1509, 1485, 1459, 1326, 1299, 1177.
  • Amorphous 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propionate Prepared according to the preparation method of Example 1 of the present invention, batch number: 20130606, purity (HPLC): 99.61%.
  • Amorphous form of potassium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoate Prepared according to the preparation method of Example 2 of the present invention, batch number: 20130619, purity (HPLC): 99.52%.
  • Determination of the content and related substances Take about 5mg of the sample, accurately weighed, placed in a 100ml volumetric flask, dissolved in the solvent methanol-water-tetrahydrofuran (35:35:30), using the solvent methanol-water-tetrahydrofuran (35:35: 30) Dilute to the mark, shake well, accurately draw 20 ⁇ l, inject into the liquid chromatograph, record the chromatogram, calculate the sample content and related substances according to the area normalization method.
  • Chromatographic conditions instrument: Shimadzu LC-2010A; column: Shim-pack VP-ODS 5 ⁇ m 150L ⁇ 4.6; mobile phase: methanol-water-tetrahydrofuran-acetic acid (35:35:30:0.5); detection wavelength: 256nm; Column temperature: 30 ° C.
  • Crystal form determination X-ray powder diffraction method: Instrument: D/MAX-1200 (Rigaku Corporation, Japan); Radiation source: Cu-K ⁇ (40 kV, 40 mA).
  • Drug 1 (control): 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propene
  • the acid was prepared according to Example 20 of Chinese Patent Application 03126974.5, batch number: T1263-07-12-02, purity (HPLC): 99.34%.
  • Drug 2 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propionate
  • the shaped body was prepared according to the preparation method of Example 1 of the present invention, batch number: 20130606, purity (HPLC): 99.61%.
  • Drug 3 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoate
  • the shaped body was prepared according to the preparation method of Example 2 of the present invention, batch number: 20130619, purity (HPLC): 99.52%.
  • Drug 4 lithium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoate,
  • test drugs were added to water, ultrasonically dispersed or dissolved, and the concentration was 4 mg/mL.
  • Eight SD rats were intragastrically administered at a dose of 20 mg/kg, 0.5 h, 1 h, and 1.5 h after administration, respectively.
  • 0.5 mL of blood was collected from the fundus venous plexus, and the blood concentration-time curve and drug exposure (AUC 0-t ) of each test drug administered by gavage were determined.
  • Drug 1 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propene acid;
  • Drug 2 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propionate Shaped body
  • Drug 3 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoate Shaped body
  • Drug 4 lithium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoate.
  • the results in Table 2 show that the bioavailability of the sodium salt amorphous body of the present invention is 6.0 times that of the unsalted free acid, and the bioavailability of the potassium salt amorphous body of the present invention is the unsalted free acid. 7.5 times.
  • the lithium salt can also increase the bioavailability of the unsalted free acid, the increase in bioavailability is much smaller than that of the sodium salt and the potassium salt. It is apparent that the bioavailability of the sodium salt amorphous body and the potassium salt amorphous body of the present invention is greatly improved with respect to the unsalted free acid and the lithium salt.
  • Example 5 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid Preparation of sodium amorphous tablets
  • Example 7 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid Preparation of capsules of sodium amorphous body
  • Example 8 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid Preparation of granules of sodium amorphous body
  • Example 11 2-(2-(4-Fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid Preparation of granules of potassium amorphous body
  • Example 12 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propanoic acid Phase IIb clinical trial of sodium amorphous tablets in the treatment of type 2 diabetes
  • Test drug sodium 2-(2-(4-fluorobenzoyl)phenylamino)-3-(4-(2-(9H-indazol-9-yl)ethoxy)phenyl)propionate
  • the tablet of the shaped body was prepared according to the preparation method of Example 3 of the present invention, and the specification was 8 mg/tablet.
  • Control drug pioglitazone tablets, commercially available drugs, manufacturer is Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., specification: 15mg/tablet.
  • a multi-center, randomized, double-blind, positive drug parallel control design was used. It is planned to enroll 200 patients with type 2 diabetes who have not been treated with hypoglycemic drugs. They are randomly divided into four groups of 50 patients each with oral 2-(2-(4-fluorobenzoyl)phenylamino). Tablets of -3-(4-(2-(9H-carbazol-9-yl)ethoxy)phenyl)propionate amorphous tablets 32 mg, 40 mg and 48 mg and 30 mg of pioglitazone tablets, taken once a day, For 16 consecutive weeks.
  • HbA1c test drugs 32mg, 40mg and 48mg group and the control drug pioglitazone 30mg group after treatment, the plasma levels of HbA1c decreased by 1.07%, 1.32%, 1.12% and 1.06%, respectively, the test drug three dose group treatment.
  • the level of plasma HbA1c was significantly reduced, both greater than 1%, reaching or slightly stronger than the efficacy of 30 mg of pioglitazone.
  • the plasma LDL-C levels in each group were 0.21 mmol/L, 0.08 mmol/L, -0.06 mmol/L, and 0.23 mmol/L, respectively, compared with the baseline levels before treatment.
  • the tablets of the present invention were dose-dependent on LDL-C levels. Reduce the trend. Further analysis of patients with high LDL-C baseline levels ( ⁇ 3.37 mmol/L) found that the two high-dose groups of the present invention reduced TG levels, with the 40 mg dose group (-0.39 mmol/L) and the 48 mg dose group. (-0.29 mmol/L) slightly superior or equivalent to pioglitazone group (-0.23 mmol/L).

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Abstract

提供了一种通式(I)的苯丙氨酸类化合物的盐、无定形形式、其制备方法和应用，所述盐可用于制备治疗与代谢综合征相关的疾病的药物。

Description

一种苯丙氨酸类化合物的盐及其无定形体 技术领域
本发明属于化学制药领域，具体涉及一种苯丙氨酸类化合物的盐，更具体涉及所述盐的无定形体形式；本发明还涉及所述盐及其无定形体形式的制备方法及其在制备用于预防或治疗与代谢综合征相关的疾病的药物中的用途。
背景技术
2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸是一种对于代谢性疾病和病症有治疗和预防活性的苯丙氨酸类化合物，其化学结构式如下：
Figure PCTCN2015090095-appb-000001
在中国专利申请CN03126974.5和美国专利申请US7,268,157中均记载了该化合物的药理活性。2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸具有选择性激活PPAR-α、PPAR-γ和PPAR-δ的能力，可以用于治疗与代谢综合症相关的疾病，如糖尿病。本领域中已知，PPAR-α、PPAR-γ和PPAR-δ作为核受体超家族的成员。近年来，核受体家族在代谢性疾病领域受到广泛的关注，已有研究证明，它们与糖尿病、脂肪肝等疾病的发生发展密切相关，也被称为代谢性核受体。已有报道表明，PPAR-α、PPAR-γ和PPAR-δ的激动剂在预防和治疗人和动物的代谢综合征方面有很好的效果(WO 00//08002、WO01/57001A1、US6054453、EP088317B1、WO97/25042、WO02/26729A2和US 6353018B1)。因此，开发新的具有PPAR-α、PPAR-γ和PPAR-δ激动剂性能的化合物对于代谢异常疾病的治疗具有非常重要的意义。这些代谢异常疾病包括例如糖尿病、高血压、肥胖、胰岛素抵抗、高甘油三酯血症、高血糖、高胆固醇、动脉粥样硬化、冠心病其它心血管病等代谢综合征。
然而，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的稳定性较差，其在高温(60℃)、高湿(90％)和强光照射(4500Lx)下放置10 天，含量明显降低，有关物质明显增加，这表明2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸在药物制造、贮存和运输过程中易分解，影响该药物的安全性和有效性，限制了其在制备用于治疗与代谢综合征相关的药物中的应用。
此外，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸在水中的溶解度极小，几乎不溶解，生物利用度较低。这极大地影响了其治疗效果。
因此，改善其稳定性和生物利用度具有极其重要的意义。
发明内容
本发明的目的在于克服现有技术的缺点，改善2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的稳定性和生物利用度。
本发明人经过试验，发现所述化合物的钠盐和钾盐出乎意料地稳定并具有显著提高的生物利用度。特别地，所述钠盐和钾盐的无定形形式具有显著提高的稳定性和生物利用度。
本发明所述的钠盐和钾盐，其化学结构如通式(I)所示：
Figure PCTCN2015090095-appb-000002
其中，M为Na或K。
本发明所述的钠盐和钾盐可通过以下的示例性制备方法制得：
Figure PCTCN2015090095-appb-000003
其中，M为Na或K。
在示例性的实施方案中，将2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸溶于四氢呋喃，加入溶有氢氧化钠或氢氧化钾的甲醇溶液，室温搅拌反应10～30min；真空浓缩，除去四氢呋喃和甲醇，得浓缩物；将浓缩物溶于二氯甲烷，在室温和搅拌下滴加到异丙醚或无水乙醚中，离心分离，收集固体，于60～105℃真空干燥3～20h，即得2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的钠盐或钾盐。
其中，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸与四氢呋喃的重量比为1:25～1:30，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸与氢氧化钠或氢氧化钾的摩尔比为1:0.95～1:1.05，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸与二氯甲烷的重量比为1:2.50～1:2.80，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸与异丙醚的重量比为1:20～1:30；氢氧化钠或氢氧化钾与甲醇的重量比为1:15～1:25。
本发明所述的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的钠盐优选为无定形形式。在本发明的一个方面，所述钠盐无定形形式的X-射线粉末衍射图为弥散型馒头峰(见图1)；在本发明的另一个方面，所述钠盐无定形形式在其红外光谱中在约2867、1618、1509、1242、1154、851和750cm-1处有特征吸收峰；在一个优选的方面，所述钠盐无定形形式还在约3364、3050、2929、1598、1556、1485、1459和1326cm-1处有特征吸收峰(见图2)；在本发明的又一个方面，所述钠盐无定形形式的差示扫描量热曲线在约117.3℃处有吸热峰(见图3)。
本发明所述的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的钾盐优选为无定形形式。在本发明的一个方面，所述钾盐无定形形式的X-射线粉末衍射图为弥散型馒头峰(见图4)；在本发明的另一个方面，所述钾盐无定形形式在其红外光谱中在约2870、1617、1509、1299、1177、852和786cm-1处有特征吸收峰；在一个优选的方面，所述钾盐无定形形式还在约3373、3051、2931、1598、1555、1485、1459和1326cm-1处有特征吸收峰(见图5)；在本发明的又一个方面，所述钾盐无定形形式的差示扫描量热曲线在约118.5℃处有吸热峰(见图6)。
本发明人出乎意料地发现，本发明的钠盐无定形体和钾盐无定形体相当稳定，其在高温(60℃)、高湿(90％)和强光照射(4500Lx)下放置10天，均未发生无定形体常见的转晶现象，而是仍保持其原有状态，其含量和有关物质也未发生明显改变，这表明本发明的钠盐无定形体和钾盐无定形体特别适合药剂制造和长期储存。
本发明所述的钠盐无定形体和钾盐无定形体具有显著提高的生物利用度。用SD大鼠灌胃给药(20mg/kg)表明，本发明所述的钠盐的生物利用度是未成盐的游离酸的6.0倍，本发明所述的钾盐的生物利用度是未成盐的游离酸的7.5倍。锂盐虽然也能提高未成盐的游离酸的生物利用度，但生物利用度提高的幅度远小于钠盐和钾盐。其他常见的盐(如铵盐、钙盐、镁盐等)采用本发明所述的制备方法或其他常见的酸碱中和工艺均无法获得。
在本发明的一个方面，本发明提供了包含所述的钠盐或钾盐(特别是其无定形体)的药物组合物。所述药物组合物包含本发明的通式(1)化合物以及任选的药用辅料。所述药用辅料包括可药用的赋形剂和载体。特别优选地，所述通式(1)化合物以其无定形形式存在。本发明的药物组合物可以是各种口服固体制剂，如片剂、胶囊剂或颗粒剂、粉剂、散剂等。另外，本发明的药物组合物还可包含除上述通式(1)化合物以外的第二活性剂，所述联用的第二活性剂可选自双胍类如二甲双胍，磺脲类如格列本脲、格列吡嗪、格列美脲、格列喹酮，噻唑烷二酮类如罗格列酮、吡格列酮，α-糖苷酶抑制剂如阿卡波糖、伏格列波糖，胰岛素促泌剂如瑞格列奈、那格列奈、米格列奈等。
优选地，所述制剂含5～50％的钠盐或钾盐(特别是其无定形体)以及50～95％的药用辅料。所述药用辅料，包括助流剂如滑石粉、硬脂酸镁等，崩解剂如羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素等，填充剂如乳糖、微晶纤维素、淀粉等，以及粘合剂如邻苯二甲酸羟丙基甲基纤维素酯等。
本发明还提供了本发明所述的钠盐或钾盐在制备用于预防或治疗与代谢综合征相关的疾病的药物中的用途。在一个方面，本发明提供了本发明所述的钠盐无定形体或钾盐无定形体在制备用于预防或治疗与代谢综合征相关的疾病的药物中的用途。在另一方面，本发明提供了本发明所述的钠盐或钾盐特别是其无定形体作为PPARα、PPARγ或PPARσ激动剂的用途。特别地，本发明提供了本发明所述的钠盐或钾盐尤其是其无定形体在制备用于预防或治疗可由PPARα、PPARγ 或PPARσ激动剂治疗的疾病或病症的药物中的用途。
本发明还通过稳定性试验、生物利用度测定和临床试验证明了本发明钠盐和钾盐的出乎意料的技术效果，稳定性和生物利用度得到显著提高，IIb期临床试验进一步证实了本发明所述盐的有效性和安全性。
附图说明
图1是根据本发明实施例1的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠的X-射线粉末衍射图，其通过用铜Kα射线照射获得。在X-射线粉末衍射图中，纵坐标为用计数/秒(cps)表示的衍射强度，横坐标为用度表示的衍射角2θ。
图2是根据本发明实施例1的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠的红外光谱图，纵坐标为透光率(T)，单位为百分率(％)；横坐标为波数，单位为cm-1。
图3是根据本发明实施例1的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠的差示扫描量热曲线图，纵坐标为热量变化率，单位为毫焦/秒；横坐标为温度，单位为℃。
图4是根据本发明实施例1的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾的X-射线粉末衍射图，其通过用铜Kα射线照射获得。在X-射线粉末衍射图中，纵坐标为用计数/秒(cps)表示的衍射强度，横坐标为用度表示的衍射角2θ。
图5是根据本发明实施例1的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾的红外光谱图，纵坐标为透光率(T)，单位为百分率(％)；横坐标为波数，单位为cm-1。
图6是根据本发明实施例1的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾的差示扫描量热曲线图，纵坐标为热量变化率，单位为毫焦/秒；横坐标为温度，单位为℃。
具体实施方式
下面结合实例进一步阐明本发明的内容，但本发明的保护范围并不仅仅局限于这些实例。本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位或百分比，均是为了提供明白无误的书面参考。本 领域熟练技术人员在实践本专利时，基于本发明的教导和原则，使用在此范围之外或有别于单个数值的温度、浓度、数量等，仍然可以得到预期的结果。
对照化合物和试验仪器：
对照化合物：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸，按照中国专利申请03126974.5实施例20所述方法进行制备，该专利申请内容通过引用并入本文。
X-射线粉末衍射测试条件：仪器：D/MAX-1200(日本Rigaku公司)；辐射源：Cu-Kα(40kV、40mA)。
红外光谱测试条件：仪器：Spectrum65(美国Perkin Elmer公司)；KBr压片法。
差示扫描量热分析测试条件：仪器：DSC 204(德国Netzsch公司)；升温速率：10℃/min；氮气流速：20mL/min。
质子核磁共振测试条件：仪器：AV-400(德国Bruker公司)；溶剂：DMSO-d6。
含量和有关物质测定条件：仪器：岛津LC-2010A；色谱柱：Shim-pack VP-ODS5μm 150L×4.6；流动相：甲醇-水-四氢呋喃-醋酸(35:35:30:0.5)；检测波长：256nm；柱温：30℃。
质谱测试条件：仪器：VG ZAB-HS色质联用仪；分析方法：快原子轰击电离(FAB)。
实施例1：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠的制备
Figure PCTCN2015090095-appb-000004
在50L塑料桶中加入487.4g(12.18mol)NaOH和10.85kg无水甲醇，室温搅拌溶解。在300L不锈钢反应釜(内衬聚四氟乙烯)中加入184kg四氢呋喃和6.90kg(12.06mol)2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙 酸，室温搅拌溶解，向反应釜中加入上述溶有氢氧化钠的甲醇溶液，加完后继续搅拌30min。真空浓缩，除去四氢呋喃和甲醇，得浓缩物。将浓缩物溶于18.29kg二氯甲烷，在室温和搅拌下滴加到149kg异丙醚中，离心分离，收集固体，于105℃真空干燥3h，得2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠，重量6.92kg，收率96.6％。1H NMR(DMSO-d6)δ2.88(dd,1H,CH2)，3.03(dd,1H,CH2)，3.86(m,1H,CH)，4.25(t,2H,CH2)，4.73(t,2H,CH2)，6.36(t,1H,Ar-H)，6.59(d,2H,Ar-H)，6.65(d,1H,Ar-H)，7.00(d,2H,Ar-H)，7.18(m,2H,Ar-H)，7.21(m,2H,Ar-H)，7.31(m,2H,Ar-H)，7.43(m,2H,Ar-H)，7.55(m,2H,Ar-H)，7.64(d,2H,Ar-H)，8.13(d,2H,Ar-H)，8.73(d,1H,NH)。元素分析(C36H28FN2NaO4·0.5H2O)计算值：C 71.63，H 4.83，N 4.64；实测值：C 71.62，H 4.89，N 4.56。
所得2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠为无定形体，其X-射线粉末衍射图为弥散型馒头峰(见图1)，其红外光谱在约3364、3050、2929、2867、1618、1598、1556、1509、1485、1459、1326、1242、1154、851和750cm-1处有特征吸收峰(见图2)，其差示扫描量热曲线在约117.3℃处有吸热峰(见图3)。
实施例2：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾的制备
Figure PCTCN2015090095-appb-000005
在100mL单口瓶中加入0.495g(8.84mmol)KOH和10mL无水甲醇，室温搅拌溶解。在300mL反应瓶中加入5.00g(8.74mmol)2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸和150ml四氢呋喃，室温搅拌溶解，加入上述溶有氢氧化钾的甲醇溶液，加完后继续搅拌30min。真空浓缩，除去四氢呋喃和甲醇，得浓缩物。将浓缩物溶于10mL二氯甲烷，在室温和搅拌下滴加到 150mL无水乙醚中，过滤，收集固体，于60℃真空干燥10h，得2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾，重量4.50g，收率84.4％。1H NMR(DMSO-d6)δ2.86(dd,1H,CH2)，3.02(dd,1H,CH2)，3.80(m,1H,CH)，4.24(t,2H,CH2)，4.72(t,2H,CH2)，6.36(t,1H,Ar-H)，6.59(m,3H,Ar-H)，7.01(d,2H,Ar-H)，7.25(m,4H,Ar-H)，7.31(m,2H,Ar-H)，7.43(m,2H,Ar-H)，7.55(m,2H,Ar-H)，7.63(d,2H,Ar-H)，8.13(d,2H,Ar-H)，8.75(d,1H,NH)。元素分析(C36H28FN2KO4·0.5H2O)计算值：C 69.77，H 4.72，N 4.52；实测值：C 69.60，H 4.94，N 4.46。
所得2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾为无定形体，其X-射线粉末衍射图为弥散型馒头峰(见图4)，其红外光谱在约3373、3051、2931、2870、1617、1598、1555、1509、1485、1459、1326、1299、1177、852和786cm-1处有特征吸收峰(见图5)，其差示扫描量热曲线在约118.5℃处有吸热峰(见图6)。
实施例3：稳定性试验
1、受试样品
2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸：按照中国专利申请03126974.5实施例20进行制备，批号：T1263-07-12-02，纯度(HPLC)：99.34％。
2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体：按照本发明实施例1的制备方法进行制备，批号：20130606，纯度(HPLC)：99.61％。
2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体：按照本发明实施例2的制备方法进行制备，批号：20130619，纯度(HPLC)：99.52％。
2、试验方案
依据《中国药典》2010年版二部附录XIX C进行高温(60℃)、高湿(90％)和强光(4500lx)影响因素试验。对于2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸样品，分别于第0天和第10天取样，测定样品的含量和有关物质；对于2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯 基)丙酸钠无定形体样品和2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体样品，分别于第0天和第10天取样，测定样品的含量、有关物质和晶型。
含量和有关物质测定：取样品约5mg，精密称定，置于100ml容量瓶中，用溶剂甲醇-水-四氢呋喃(35:35:30)溶解，用溶剂甲醇-水-四氢呋喃(35:35:30)稀释至刻度，摇匀，精密吸取20μl，注入液相色谱仪，记录色谱图，按面积归一法计算样品的含量和有关物质。色谱条件：仪器：岛津LC-2010A；色谱柱：Shim-pack VP-ODS 5μm 150L×4.6；流动相：甲醇-水-四氢呋喃-醋酸(35:35:30:0.5)；检测波长：256nm；柱温：30℃。
晶型测定：X-射线粉末衍射法：仪器：D/MAX-1200(日本Rigaku公司)；辐射源：Cu-Kα(40kV、40mA)。
3、试验结果
试验结果见表1。
表1稳定性试验结果
Figure PCTCN2015090095-appb-000006
表1结果表明，2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸的稳定性较差，其在高温(60℃)、高湿(90％)和强光照射(4500Lx)下放置10天后，含量明显降低，有关物质明显增加，尤其对光最为敏感。而2-(2-(4- 氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体和2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体均出乎意料地稳定，其在高温(60℃)、高湿(90％)和强光照射(4500Lx)下放置10天，均未发生无定形体常见的转晶现象，而是仍保持其原有状态，其含量和有关物质也未发生明显改变。
实施例4：生物利用度测定
1、受试动物
SD大鼠，雄性，体重180～200g。
2、受试药物
药物1(对照)：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸，按照中国专利申请03126974.5实施例20进行制备，批号：T1263-07-12-02，纯度(HPLC)：99.34％。
药物2：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体，按照本发明实施例1的制备方法进行制备，批号：20130606，纯度(HPLC)：99.61％。
药物3：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体，按照本发明实施例2的制备方法进行制备，批号：20130619，纯度(HPLC)：99.52％。
药物4：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸锂，采用与本发明实施例2类似的方法进行制备，以氢氧化锂代替氢氧化钾。产品批号：20130630，纯度(HPLC)：99.38％，FAB-MS(m/z)：579(M+1)。
3、试验方案
分别将受试药物加入水中，超声分散或溶解，浓度为4mg/mL，用8只SD大鼠灌胃给药，给药剂量为20mg/kg，分别在给药后0.5h、1h、1.5h、2h、3h、4h、6h、9h、12h和24h从眼底静脉丛采血0.5mL，测定各受试药物灌胃给药的血药浓度-时间曲线和药物暴露量(AUC0-t)。
以药物1为对照，分别计算药物2、3、4的相对生物利用度：
F(相对)＝AUC0-t(药物2、3或4)/AUC0-t(药物1)(倍)
4、试验结果
试验结果见表2。
表2生物利用度测定结果
Figure PCTCN2015090095-appb-000007
*注：药物1：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸；
药物2：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体；
药物3：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体；
药物4：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸锂。
表2结果表明，本发明所述的钠盐无定形体的生物利用度是未成盐的游离酸的6.0倍，本发明所述的钾盐无定形体的生物利用度是未成盐的游离酸的7.5倍。锂盐虽然也能提高未成盐的游离酸的生物利用度，但生物利用度提高的幅度远小于钠盐和钾盐。显然，相对于未成盐的游离酸以及锂盐，本发明的钠盐无定形体和钾盐无定形体的生物利用度大大提高。
实施例5：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的片剂的制备
处方(1000片)：
Figure PCTCN2015090095-appb-000008
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体、微晶纤维素、淀粉和碳酸氢钠，混合均匀，加入适量5％邻 苯二甲酸羟丙基甲基纤维素酯(溶剂为70％乙醇)制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，加入处方量的硬脂酸镁，混合均匀，压片即得。
实施例6：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的片剂的制备
处方(1000片)：
Figure PCTCN2015090095-appb-000009
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体、微晶纤维素、羧甲基淀粉钠和碳酸氢钠，混合均匀，加入适量15％淀粉浆制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，加入处方量的硬脂酸镁，混合均匀，压片即得。
实施例7：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的胶囊剂的制备
处方(1000粒)：
Figure PCTCN2015090095-appb-000010
Figure PCTCN2015090095-appb-000011
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体、微晶纤维素、乳糖、羧甲基淀粉钠和碳酸氢钠，混合均匀，加入适量15％淀粉浆制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，加入处方量的硬脂酸镁，混合均匀，灌装胶囊即得。
实施例8：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的颗粒剂的制备
处方(1000袋)：
Figure PCTCN2015090095-appb-000012
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体、可溶性淀粉、乳糖、微晶纤维素和羧甲基淀粉钠，混合均匀，加入适量15％淀粉浆制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，分装即得。
实施例9：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体的片剂的制备
处方(1000片)：
Figure PCTCN2015090095-appb-000013
Figure PCTCN2015090095-appb-000014
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体、微晶纤维素、羧甲基淀粉钠和碳酸氢钠，混合均匀，加入适量15％淀粉浆制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，加入处方量的硬脂酸镁，混合均匀，压片即得。
实施例10：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体的胶囊剂的制备
处方(1000粒)：
Figure PCTCN2015090095-appb-000015
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体、微晶纤维素、乳糖、羧甲基淀粉钠和碳酸氢钠，混合均匀，加入适量15％淀粉浆制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，加入处方量的硬脂酸镁，混合均匀，灌装胶囊即得。
实施例11：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体的颗粒剂的制备
处方(1000袋)：
Figure PCTCN2015090095-appb-000016
Figure PCTCN2015090095-appb-000017
称取处方量的2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钾无定形体、可溶性淀粉、乳糖、微晶纤维素和羧甲基淀粉钠，混合均匀，加入适量15％淀粉浆制软材，用20目筛制湿颗粒，于60℃干燥，用20目筛整粒，分装即得。
实施例12：含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的片剂治疗2型糖尿病的IIb期临床试验
1、受试药物
试验药物：2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的片剂，按照本发明实施例3的制备方法制备，规格：8mg/片。
对照药物：吡格列酮片，市售药物，生产厂家为杭州中美华东制药有限公司，规格：15mg/片。
2、试验方案
采用多中心、随机、双盲、阳性药平行对照设计。计划入组200名未经过降糖药物治疗的2型糖尿病患者，随机分入四个试验组，每组50人，分别口服含2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的片剂32mg、40mg和48mg及吡格列酮片30mg，每天服药1次，连续16周。
3、疗效试验结果
实际试验入组200例患者，进入全分析集(FAS)的病例数总数197例，其中测试药物32mg、40mg和48mg组以及对照药物吡格列酮30mg组分别为48例、50例、50例和49例；符合方案集(PPS)病人总计172例，各组分别41、48、44和39例。各组患者分别服药2-(2-(4-氟苯甲酰基)苯基氨基)-3-(4-(2-(9H-咔唑-9-基)乙氧基)苯基)丙酸钠无定形体的片剂32mg、40mg和48mg及吡格列酮片30mg 16周。计算相关评价指标在治疗16周后与基线值的水平变化，总结疗效结果如下：
(1)主要疗效指标HbA1c 测试药物32mg、40mg和48mg组以及对照药物吡格列酮30mg组患者治疗后的血浆HbA1c水平分别平均下降1.07％、1.32％、1.12％及1.06％，测试药物三个剂量组治疗后的血浆HbA1c水平具有显著意义的降低，均大于1％，达到或略强于吡格列酮30mg的疗效。16周治疗后，各组中达到HbA1c<6.5％标准的患者比例相当，达到<7.0％标准的患者比例在该片剂40mg和48mg组中略高于吡格列酮组；各组HbA1c降低≥0.5％的患者比例约为60-72％之间，其中40mg组略高于吡格列酮组。这些数据提示，在入组人群中治疗16周后已经产生明显疗效。
(2)次要疗效指标空腹血糖 四组患者治疗16周后的空腹血糖水平均具有显著意义的降低，较治疗前基线水平分别平均下降1.65mmol/L、2.06mmol/L、1.67mmol/L及2.27mmol/L。PPS集分析结果与FAS集结果趋于一致。
(3)次要疗效指标餐后2h血糖 四组患者治疗16周后的餐后2h血糖水平均有显著意义的降低，较治疗前基线水平分别平均下降2.47mmol/L、2.15mmol/L、2.66mmol/L及3.30mmol/L。PPS集分析结果与FAS集结果趋于一致。
(4)次要疗效指标血脂指标四组患者治疗16周后的血浆HDL-C较治疗前的基线水平分别平均升高0.14mmol/L、0.12mmol/L、0.11mmol/L及0.16mmol/L。TC水平变化分别平均为0.47mmol/L、0.11mmol/L、-0.08mmol/L及0.16mmol/L，本发明片剂对TC水平呈现剂量依赖性的降低趋势。针对TC基线水平偏高(≥5.18mmol/L)的患者进一步分析发现，本发明片剂的三剂量组均可显著降低TC水平，其中48mg剂量组(-0.56mmol/L)略优于吡格列酮组(-0.37mmol/L)。各组患者血浆TG较治疗前基线水平的变化分别平均为0.33mmol/L、-0.30mmol/L、-0.39mmol/L及-0.24mmol/L，本发明片剂对TG水平呈现剂量依赖性的降低趋势。针对TG基线水平偏高(≥1.70mmol/L)的患者的进一步分析发现，本发明片剂的两个高剂量组可显著降低TG水平，其中40mg剂量组(-0.92mmol/L)和48mg剂量组(-0.77mmol/L)略优于吡格列酮组(-0.48mmol/L)。各组血浆LDL-C较治疗前基线水平变化分别平均为0.21mmol/L、0.08mmol/L、-0.06mmol/L及0.23mmol/L，本发明片剂对LDL-C水平呈现剂量依赖性的降低趋势。针对LDL-C基线水平偏高(≥3.37mmol/L)患者进一步分析发现，本发明片剂的二个高剂量组可降低TG水平，其中40mg剂量组(-0.39mmol/L)和48mg剂量组(-0.29mmol/L)略优或相当于吡格列酮组(-0.23mmol/L)。
4、安全性评价结果
SS集共200例病例。本发明的片剂32mg、40mg和48mg三组及吡格列酮30mg组不良事件发生率分别为24％(12例)、22％(11例)、24％(12例)及12％(6例)，组间差异无统计学意义(P>0.05)。不良事件主要是白细胞减少、水肿、尿白细胞升高等。本发明的片剂各组的不良事件以轻度为主，比率分别为86.67％、64.29％、71.43％；吡格列酮30mg组的不良事件以中度为主，比率为72.73％。试验过程中未出现体重增加，仅少数患者出现轻度或中度水肿。本次临床试验结果显示本发明的片剂无明显安全性问题，评价结果与吡格列酮相当。

Claims (16)

  1. 通式(I)所示的化合物：
    Figure PCTCN2015090095-appb-100001
    其中，M为Na或K。
  2. 如权利要求1所述的通式(I)化合物，其中M为Na。
  3. 如权利要求1所述的通式(I)化合物，其中M为K。
  4. 权利要求2所述的通式(I)化合物，其为无定形形式，其具有如图1所示的X-射线粉末衍射图。
  5. 权利要求4所述的通式(I)化合物，其红外光谱在约2867、1618、1509、1242、1154、851和750cm-1处有特征吸收峰。
  6. 权利要求5中的通式(I)化合物，其红外光谱还在约3364、3050、2929、1598、1556、1485、1459和1326cm-1处有特征吸收峰。
  7. 权利要求2、4、5或6中任一项所述的通式(I)化合物，其差示扫描量热曲线在约117.3℃处有吸热峰。
  8. 权利要求3所述的通式(I)化合物，其为无定形形式，其具有如图4所示的X-射线粉末衍射图。
  9. 权利要求8所述的通式(I)化合物，其红外光谱在约2870、1617、1509、1299、1177、852和786cm-1处有特征吸收峰。
  10. 权利要求9中的通式(I)化合物，其红外光谱还在约3373、3051、2931、1598、1555、1485、1459和1326cm-1处有特征吸收峰。
  11. 权利要求3、8、9或10中任一项所述的通式(I)化合物，其差示扫描量热曲线在约118.5℃处有吸热峰。
  12. 一种药物组合物，其包含权利要求1至11中任一项所述的通式(1)化合物以及任选的可药用赋形剂和/或载体。
  13. 权利要求12的药物组合物，其还包含第二治疗剂。
  14. 权利要求13至14中任一项的药物组合物，其为选自片剂、胶囊剂、颗粒剂、粉剂和散剂的形式。
  15. 权利要求1至11中任一项所述的通式(1)化合物在制备用于预防或治疗与代谢综合征相关的疾病的药物中的用途。
  16. 权利要求15的用途，其中所述与代谢综合征相关的疾病是可由PPARα、PPARγ或PPARσ激动剂治疗的疾病或病症。
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WO2019214482A1 (zh) * 2018-05-09 2019-11-14 深圳微芯生物科技股份有限公司 一种苯基氨基丙酸钠衍生物、其制备方法和应用
CN110467560A (zh) * 2018-05-09 2019-11-19 深圳微芯生物科技股份有限公司 一种苯基氨基丙酸钠衍生物、其制备方法和应用
JP2021523897A (ja) * 2018-05-09 2021-09-09 シンセン チップスクリーン バイオサイエンセズ カンパニー リミテッド フェニルアミノプロピオン酸ナトリウム誘導体、その製造方法及び応用
RU2759745C1 (ru) * 2018-05-09 2021-11-17 Шэньчжэнь Чипскрин Байосайенсиз Ко., Лтд. Производное фениламинопропионата натрия, способ его получения и его применение
AU2019267849B2 (en) * 2018-05-09 2021-11-18 Shenzhen Chipscreen Biosciences, Co., Ltd. Phenyl amino sodium propionate derivative, preparation method therefor and application thereof
JP7047136B2 (ja) 2018-05-09 2022-04-04 シンセン チップスクリーン バイオサイエンセズ カンパニー リミテッド フェニルアミノプロピオン酸ナトリウム誘導体、その製造方法及び応用
US11981638B2 (en) 2018-05-09 2024-05-14 Shenzhen Chipscreen Biosciences Co., Ltd. Phenyl amino sodium propionate derivative, preparation method therefor and application thereof

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