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WO2023080299A1 - Nouveau sel d'un dérivé de l'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant - Google Patents

Nouveau sel d'un dérivé de l'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant Download PDF

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Publication number
WO2023080299A1
WO2023080299A1 PCT/KR2021/016128 KR2021016128W WO2023080299A1 WO 2023080299 A1 WO2023080299 A1 WO 2023080299A1 KR 2021016128 W KR2021016128 W KR 2021016128W WO 2023080299 A1 WO2023080299 A1 WO 2023080299A1
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Prior art keywords
oxy
salt
tetrahydrofuran
phenyl
salt according
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PCT/KR2021/016128
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English (en)
Korean (ko)
Inventor
이기용
권지숙
양혜란
이형준
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일동제약(주)
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Priority to PCT/KR2021/016128 priority Critical patent/WO2023080299A1/fr
Priority to PCT/KR2022/017333 priority patent/WO2023080741A1/fr
Publication of WO2023080299A1 publication Critical patent/WO2023080299A1/fr

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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
    • A61K31/435—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
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel salt of a phenyl propionic acid derivative, which is difficult to prepare by conventional salt preparation processes, a method for preparing the same, and a pharmaceutical composition containing the same.
  • GPR40 is mainly expressed in beta cells and is a member of the G-protein coupled receptor super family. It is included in the rhodopsin family and is a common feature of G-protein coupled receptor (GPCR). It has two cell membrane penetrating domains.
  • the ligand of GPR40 is a medium- to long-chain free fatty acid, and GPR40 is also known as Free Fatty Acid Receptor 1 (FFAR1) based on the interaction with the ligand.
  • FFAR1 Free Fatty Acid Receptor 1
  • GPR40 is involved in insulin secretion in a glucose-dependent manner.
  • GPR40 agonists are attracting attention as a new class of drugs because they secrete insulin in a glucose-dependent manner and there is no risk of hypoglycemia.
  • the compounds disclosed in WO2018/111012 enhance the activity of GPR40 and induce insulin secretion selectively in hyperglycemic situations, thereby minimizing the risk of hypoglycemia due to drug administration. It is expected to show a therapeutically effective effect in the treatment of diabetic patients.
  • the drug In order for a drug to exhibit high pharmacological activity in vivo, the drug must be rapidly released from the digestive tract. This is closely related to the solubility of the drug. The higher the solubility of the drug, the higher the rate of dissolution of the drug and the rate of absorption in the digestive tract. A high effect of can be expected. Therefore, it is required to select the optimal salt form, and in order to prepare a salt with excellent physical properties pharmaceutically, physical and chemical properties such as solubility, stability, hygroscopicity, processability into tablet formulations, purity, or density should be considered. .
  • the problem to be solved by the present invention is ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy)pyridine -3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid.
  • a new salt with improved physicochemical and / or pharmaceutical properties such as solubility (specifically, in vivo solubility) and stability (dissolution stability, storage stability, etc.)
  • solubility specifically, in vivo solubility
  • stability dissolution stability, storage stability, etc.
  • the present invention ( S ) -3- (4 - ((( R ) -7-fluoro-4- (6-((( R ) -tetrahydrofuran-3-yl) oxy Novel salt of )pyridin-3-yl)-2,3-dihydro- 1H -inden-1-yl)oxy)phenyl)hex-4-inoic acid, preparation method thereof, and pharmaceutical composition containing the same as an active ingredient provides
  • the present invention provides ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy)pyridine -3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid.
  • novel salt according to the present invention exhibits excellent physical and chemical properties in various aspects such as stability, in vivo solubility, and bioavailability.
  • these novel salts are in crystalline form.
  • the crystalline form of tromethamine salt of the present invention has a 2 ⁇ (theta) angle of 6.64 ⁇ 0.2, 10.85 ⁇ 0.2, 13.29 ⁇ 0.2, 16.39 ⁇ 0.2, 18.50 ⁇ 0.2 and 21.21 ⁇ 0.2 degrees in a powder X-ray diffraction (PXRD) graph. It may include three or more diffraction peaks selected from the group consisting of. More specifically, the tromethamine salt crystalline form of the present invention has a 2 ⁇ (theta) angle of 6.64 ⁇ 0.2, 10.85 ⁇ 0.2, 13.29 ⁇ 0.2, 16.39 ⁇ 0.2, 18.50 ⁇ 0.2 and 21.21 ⁇ in a powder X-ray diffraction analysis (PXRD) graph. It may include a diffraction peak with a value of 0.2 degrees.
  • PXRD powder X-ray diffraction analysis
  • the crystalline form of tromethamine salt of the present invention is characterized by having an endothermic transition peak value at 100 to 140 ° C when the heating rate is 10 ° C / min in a differential scanning calorimetry (DSC) graph, preferably 110 ⁇ 2 ° C And characterized in that it has an endothermic transition peak value at 136 ⁇ 2 °C.
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) pattern of less than 1 wt% at 150°C or less. may represent a weight loss of Specifically, the thermogravimetric analysis (TGA) pattern of FIG. 2 may be shown.
  • the present invention also provides ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy) pyridin-3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid.
  • novel salt according to the present invention exhibits excellent physical and chemical properties in various aspects such as stability, in vivo solubility, and bioavailability.
  • these novel salts may be crystalline Form I.
  • Crystalline Form I of the L-lysine salt of the present invention had 2 ⁇ (theta) angles of 7.05 ⁇ 0.2, 7.90 ⁇ 0.2, 11.29 ⁇ 0.2, 14.61 ⁇ 0.2, 15.79 ⁇ 0.2, 16.23 ⁇ 0.2 in a powder X-ray diffraction analysis (PXRD) graph. And it may include three or more diffraction peaks selected from the group consisting of a value of 20.18 ⁇ 0.2 degrees. More specifically, the crystalline form I of the L-lysine salt of the present invention has a 2 ⁇ (theta) angle of 7.05 ⁇ 0.2, 7.90 ⁇ 0.2, 11.29 ⁇ 0.2, 14.61 ⁇ 0.2, 15.79 ⁇ 0.2, diffraction peaks with values of 16.23 ⁇ 0.2 and 20.18 ⁇ 0.2.
  • Crystal type I of the L-lysine salt of the present invention has a differential scanning calorimetry (DSC) graph of 100 to 120 ° C and 210 to 230 ° C, specifically 105 to 115 ° C and 215 to 225 ° C when the heating rate is 10 ° C / min. It is characterized by having an endothermic transition peak value at . Specifically, it is characterized by having an endothermic transition peak value at 215.5 ⁇ 2 ° C. More specifically, it is characterized in that it has endothermic transition peak values at 110.7 ⁇ 2 ° C and 215.5 ⁇ 2 ° C when the heating rate is 10 ° C / min.
  • DSC differential scanning calorimetry
  • these new salts may be crystalline Form II.
  • the L-lysine salt crystalline Form II of the present invention has a 2 ⁇ (theta) angle of 8.07 ⁇ 0.2, 16.22 ⁇ 0.2, 17.84 ⁇ 0.2, 19.42 ⁇ 0.2 and 22.79 ⁇ 0.2 degrees in a powder X-ray diffraction (PXRD) graph. It may include 3 or more diffraction peaks selected from the group. More specifically, L-lysine salt crystalline form II of the present invention has a 2 ⁇ (theta) angle of 8.07 ⁇ 0.2, 16.22 ⁇ 0.2, 17.84 ⁇ 0.2, 19.42 ⁇ 0.2 and 22.79 ⁇ 0.2 in a powder X-ray diffraction analysis (PXRD) graph. values of diffraction peaks.
  • PXRD powder X-ray diffraction analysis
  • the crystalline form II of the L-lysine salt of the present invention has a differential scanning calorimetry (DSC) graph of 160 to 180 ° C and 190 to 210 ° C, specifically 165 to 170 ° C and 195 to 200 ° C when the heating rate is 10 ° C / min. It is characterized by having an endothermic transition peak value at . Specifically, it is characterized by having an endothermic transition peak value at 195.6 ⁇ 2 ° C.
  • the present invention has prepared a novel salt that has never been used in the prior art. Specifically, ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy)pyridin-3-yl) Tromethamine salt and L-lysine salt, which are novel salts of -2,3-dihydro- 1H -inden-1-yl)oxy)phenyl)hex-4-inoic acid, have excellent stability, photostability, thermal stability and pH. The stability is excellent, so it can be maintained stably without changing the content for a long time. Therefore, it can be obtained as a raw material for the new salt of the present invention, and the increase in related substances is remarkably low even during long-term storage, and high purity can be maintained for a long time.
  • novel salt of the present invention can exhibit excellent pharmacological effects by exhibiting excellent solubility values under various pH conditions, particularly bio-relevant media conditions, and can be usefully used as a new active ingredient of pharmaceutical compositions that can treat various indications.
  • FaSSIF gastric fluid
  • FeSSIF artificial intestinal fluid
  • the novel salt since the novel salt exhibits high bioavailability when administered orally, it can exhibit excellent therapeutic effects even when taken in a small amount, thereby significantly improving the patient's medication convenience.
  • novel salt of the present invention has a rapid onset of action, has a thermodynamically stable form, is very advantageous in processing and storage of pharmaceuticals, and is easy to formulate, and maintains the same state after preparation, so that the content of the preparation Uniformity can be stably maintained for a long period of time, so it can be easily applied to mass production.
  • step (3) filtering and drying the product of step (2);
  • the single organic solvent is methanol, ethanol, 2-propanol, normal propanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran and acetonitrile It is preferably one selected from the group consisting of, and may be more preferably ethanol.
  • ethanol is used, there is an advantage in that a crystalline form of tromethamine salt can be stably prepared and yield reduction can be minimized.
  • the mixed solvent is (a) methanol, ethanol, 2-propanol, normal propanol, acetone, methyl ethyl ketone, acetonitrile, methyl acetate, ethyl acetate, tetrahydrofuran, and 2-methyl It is a mixed solvent of at least one solvent selected from the group consisting of tetrahydrofuran and (b) at least one solvent selected from the group consisting of water, normal heptane, normal hexane, and diisopropyl ether.
  • the mixing ratio of the mixed solvent may be 1:1 to 1:20 by volume.
  • step (1) may be performed at a temperature of 20 to 40 ° C., preferably at room temperature.
  • Tromethamine in step (1) is ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy ) Pyridin-3-yl) -2,3-dihydro-1 H -inden-1-yl) oxy) phenyl) hex-4-inoic acid It is preferably used in 0.5 to 2.0 equivalents based on 1.0 equivalents, 0.7 It is more preferable to use it in an amount of 1.3 to 1.3 equivalents.
  • step (2) the mixture is cooled to a temperature of 0 to 10 ° C.
  • the mixture may be dried at a temperature of 20 to 70 ° C. or evaporated under a nitrogen flow in step (3). there is.
  • step (3) filtering and drying the product of step (2);
  • the single organic solvent or mixed solvent is as described above.
  • the single organic solvent may be ethanol
  • the mixed solvent may be a mixture of 2-isopropanol (IPA) and water.
  • step (1) may be performed at a temperature of 20 to 40 ° C., preferably at room temperature.
  • the L-lysine salt of step (1) is ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl) Oxy) pyridin-3-yl) -2,3-dihydro-1 H -inden-1-yl) oxy) phenyl) hex-4-inoic acid is preferably used in an amount of 0.5 to 2.0 equivalents relative to 1.0 equivalents, More preferably, it is used in an amount of 0.7 to 1.3 equivalents.
  • step (2) the mixture is cooled to a temperature of 0 to 10 ° C.
  • the mixture may be dried at a temperature of 20 to 70 ° C. or evaporated under a nitrogen flow in step (3). there is.
  • the present invention is ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy) represented by Formula 1 below
  • a pharmaceutical composition comprising the tromethamine salt of pyridin-3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid is provided:
  • novel salts according to the present invention are excellent in stability, photostability, thermal stability, and pH stability, and exhibit excellent in vivo solubility in bio-relevant media conditions close to the in vivo environment, thereby exhibiting excellent pharmacological effects.
  • the pharmaceutical composition of the present invention treats "metabolic disorders", particularly obesity, type 2 diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia and dyslipidemia. It can be usefully used for any one or more treatments selected from the group consisting of
  • the present invention is ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy) represented by Formula 1 below tromethamine salt of pyridin-3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid; and a pharmaceutically acceptable carrier.
  • composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the novel salt as an active ingredient for administration.
  • a pharmaceutically acceptable carrier may be a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and, if necessary, antioxidants and buffers. , bacteriostatic agents and other conventional additives may be added.
  • compositions for injections such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
  • the composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository or the like.
  • These formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on each disease or component It can be.
  • composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically applied) according to the desired method, and the dosage is determined according to the patient's weight, age, sex, and health condition. , the range varies depending on the diet, administration time, administration method, excretion rate, and severity of the disease.
  • the daily dosage of the novel salt of the present invention is about 0.5 to 1000 mg/kg, preferably 1 to 100 mg/kg, and can be administered once or several times a day in divided doses.
  • the pharmaceutical composition of the present invention may further contain at least one active ingredient exhibiting the same or similar efficacy in addition to the novel salt.
  • the present invention is ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy) represented by Formula 1 below
  • a pharmaceutical composition for preventing or treating metabolic diseases comprising tromethamine salt of pyridin-3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid to provide:
  • the present invention relates to the above ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy)pyridin-3-yl )-2,3-dihydro- 1H -inden-1-yl)oxy)phenyl)hex-4-inoic acid tromethamine salt and/or ( S )-3-(4-((( R ) -7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro-1 H -inden-1-yl)
  • a method for treating a metabolic disease comprising administering to a subject in need thereof a therapeutically effective amount of an L-lysine salt of oxy)phenyl)hex-4-inoic acid.
  • Subjects requiring this are mammals including humans, including mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice.
  • therapeutically effective amount refers to the amount of the new salt or pharmaceutical composition containing the same effective for preventing or treating metabolic diseases, such as the amount of the new salt administered to a subject to be treated, prevent occurrence or recurrence of disease, alleviate symptoms, impair direct or indirect pathological consequences, prevent metastasis, slow progression, alleviate or palliate the condition, or improve prognosis amounts of the pharmaceutical composition comprising the above-mentioned salts that improve That is, the therapeutically effective amount can be interpreted as encompassing all doses in which symptoms of metabolic diseases are improved or cured by the pharmaceutical composition.
  • the method for preventing or treating a metabolic disease of the present invention includes not only treating the disease itself prior to the onset of symptoms, but also inhibiting or avoiding its symptoms, by administering the above-mentioned salt or a pharmaceutical composition containing the same.
  • the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dosing will vary according to the age, weight and response of the individual patient. A suitable dosage regimen can be readily selected by those skilled in the art who take these factors into account.
  • the method of treating metabolic diseases of the pharmaceutical composition of the present invention may further include administration of a therapeutically effective amount of an additional active agent useful for the treatment of the disease together with the above-mentioned salt, and the additional active agent is the present invention It may exhibit a synergistic effect or a supplementary effect with the above-mentioned salts, which are active ingredients according to.
  • the present invention also relates to ( S )-3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3 for the preparation of a medicament for the treatment of metabolic diseases). -yl)oxy)pyridin-3-yl)-2,3-dihydro-1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid tromethamine salt and/or ( S )- 3-(4-((( R )-7-fluoro-4-(6-((( R )-tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro -1 H -inden-1-yl)oxy)phenyl)hex-4-inoic acid L-lysine salt is provided.
  • the above-mentioned salts for the preparation of pharmaceuticals can be mixed with acceptable adjuvants, diluents, carriers, etc., and can be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
  • novel salt according to the present invention has excellent stability and can be used as an active ingredient in a pharmaceutical composition through improved solubility (particularly, solubility in vivo) and bioavailability as well as improved stability of the formulation.
  • Example 1 is a PXRD (powder X-ray diffraction analysis) graph of the tromethamine salt compound represented by Formula 1 prepared in Example 1 of the present invention.
  • Figure 2 is a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) pattern analysis graph of the tromethamine salt compound represented by Formula I prepared in Example 1 of the present invention.
  • Figure 3 is a PXRD (powder X-ray diffraction analysis) graph of the crystalline form I compound of L-lysine salt represented by Formula II prepared in Example 3 of the present invention.
  • Figure 4 is a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) pattern analysis graph of the crystalline form I compound of L-lysine salt represented by Formula II prepared in Example 3 of the present invention.
  • Example 5 is a PXRD (powder X-ray diffraction analysis) graph of the crystalline form II compound of L-lysine salt represented by Formula II prepared in Example 5 of the present invention.
  • Figure 6 is a differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) pattern analysis graph of the crystalline form II compound of L-lysine salt represented by Formula II prepared in Example 5 of the present invention.
  • XRPD spectra were collected in transmission mode on a Panalytical X'pert Pro or Empyrean instrument with an X'celerator detector using the standard Aptuit method. The above data were evaluated using HighScore Plus or Data Viewer software. The parameters used in the measurement are as follows.
  • VT-XRPD XRPD values were collected in the reflection mode of a Panalytical Empyrean instrument with an Anton-Paar CHC+ or CHC+ MHG chamber with a Pixel3D detector under controlled environmental conditions. The above data were evaluated using HighScore Plus software. The parameters used for measurement are as follows.
  • DSC Different Scanning Calorimeter
  • TGA Thermogravimetric Analysis
  • Instrumental parameters Value Balance purge gas [mL/min] 10 Sample purge gas [mL/min] 25 Gas Nitrogen Temperature-Time-Rate Typically from room temperature to 350°C at 10°C/in Typical sample amount [mg] Usually from 2 mg to 20 mg Pan [Pt/Al] Sealed Aluminum (punched)
  • Example 2 The next day sampling confirmed the presence of the crystalline form prepared in Example 1, and the solid was isolated by filtration on a filter syringe and dried overnight in a vacuum oven at 25 ° C for about 15 minutes at about 150 mbar (4.78 g, 85% yield).
  • the salt was prepared by the same procedure by changing the solvent condition to 7.0 ml of ethanol.
  • the salt was prepared by the same procedure by changing the solvent condition to 7.0 ml of ethanol.
  • a 46 wt% choline hydroxide solution (49.1 ⁇ L) in water was added so that the API and Molar ratio was 1:1, and stirred at room temperature for 1-3 days. Then, the solution was isolated by filtration or centrifugation and after aging at 4° C. for one day, the solution was evaporated under a nitrogen flow at RH ⁇ 15%.
  • the salt was prepared by the same procedure by changing the solvent conditions to acetone, ethanol, ethyl acetate and 2-isopropanol/water (90:10).
  • the conditions of the biological medium are as follows:
  • the saturated solution was placed under stirring at 37 °C and measured at 4 and 24 hours. Samples were prepared at approximately 10 mg/ml, and the pH of the monitored solution was checked at each time point for each condition. In addition, 1 ml was taken at each test time point, centrifuged at 14500 rpm for 10 minutes, and the supernatant was collected and analyzed by HPLC/2506 method and XRPD.
  • Solubility in FaSSIF was confirmed to be very high for both the tromethamine salt and the L-lysine salt. This action shows that the effect of gastric tromethamine salt and L-lysine salt on potential effects by food is low, so that high solubility can be exhibited and bioavailability and the like can be excellent.

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Abstract

La présente invention concerne un nouveau sel de l'acide (S)-3-(4-(((R)-7-fluoro-4-(6-(((R)-tétrahydrofuran-3-yl)oxy)pyridin-3-yl)-2,3-dihydro-1H-indén-1-yl)oxy)phényl)hex-4-ynoïque, le nouveau sel ayant d'excellentes propriétés de solubilité in vivo, de stabilité, de biodisponibilité, etc.; un procédé de production de ce sel; et une composition pharmaceutique le contenant.
PCT/KR2021/016128 2021-11-08 2021-11-08 Nouveau sel d'un dérivé de l'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant WO2023080299A1 (fr)

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PCT/KR2021/016128 WO2023080299A1 (fr) 2021-11-08 2021-11-08 Nouveau sel d'un dérivé de l'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant
PCT/KR2022/017333 WO2023080741A1 (fr) 2021-11-08 2022-11-07 Nouveau sel d'un dérivé d'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant

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PCT/KR2021/016128 WO2023080299A1 (fr) 2021-11-08 2021-11-08 Nouveau sel d'un dérivé de l'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant

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PCT/KR2022/017333 WO2023080741A1 (fr) 2021-11-08 2022-11-07 Nouveau sel d'un dérivé d'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant

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