WO2019242642A1 - Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur d'otr et procédé de préparation associé - Google Patents

Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur d'otr et procédé de préparation associé Download PDF

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WO2019242642A1
WO2019242642A1 PCT/CN2019/091888 CN2019091888W WO2019242642A1 WO 2019242642 A1 WO2019242642 A1 WO 2019242642A1 CN 2019091888 W CN2019091888 W CN 2019091888W WO 2019242642 A1 WO2019242642 A1 WO 2019242642A1
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compound
fluoronaphthalen
methoxymethyl
methoxypyridine
solvent
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PCT/CN2019/091888
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English (en)
Chinese (zh)
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杨俊然
杜振兴
王捷
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980004485.2A priority Critical patent/CN111094272B/zh
Publication of WO2019242642A1 publication Critical patent/WO2019242642A1/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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2 , 4-triazol-4-yl) -2-methoxypyridine pharmaceutically acceptable salt, crystal form and preparation method thereof.
  • PCT / CN2017 / 117421 (application date 2017.12.20) describes a compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methyl (Oxymethyl) -4H-1,2,4-triazol-4-yl) -2-methoxypyridine, as a free base, shows highly selective OTR inhibition and has good brain permeability It can effectively block the downstream function of oxytocin receptor mediated by oxytocin.
  • the compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidine-1- Poly) -5- (methoxymethyl) -4H-1,2,4-triazol-4-yl) -2-methoxypyridine, a polymorphic form of pharmaceutically acceptable salt, suitable for industrial development
  • the production of drugs with good biological activity is of great significance.
  • compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2 , 4-triazol-4-yl) -2-methoxypyridine, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, mesylate, phosphate, lemon Acid, benzoate or fumarate.
  • the chemical ratio of the compound to the acid molecule is about 1: 2 to 2: 1, and may be about 1: 2, 1: 1, 2: 1.
  • the chemical ratio of the compound to hydrogen chloride is about 1: 1.
  • the chemical ratio of the compound to sulfuric acid is about 1: 1 or 2: 1.
  • the chemical ratio of the compound to phosphoric acid is about 1: 1, 2: 1.
  • the chemical ratio of the compound to methanesulfonic acid is about 1: 1.
  • the present disclosure also provides a method for preparing the aforementioned pharmaceutically acceptable salt, including: compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidine-1-yl) -5- ( Step of forming methoxymethyl) -4H-1,2,4-triazol-4-yl) -2-methoxypyridine with an acid.
  • the solvent used for the salt formation described in the present disclosure is at least one selected from the group consisting of water, alcohols, halogenated hydrocarbons, ethers, nitriles, alcohols, esters, or ethers, and is preferably selected from isopropyl alcohol, acetone, and methyl alcohol. At least one of t-butyl ether, acetonitrile, ethanol, ethyl acetate, and water.
  • the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of volatile solvent or stirring crystallization, and filtering.
  • composition comprising a pharmaceutically acceptable salt of the aforementioned compound and a pharmaceutically acceptable excipient, optionally from at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
  • the present disclosure also provides the use of the aforementioned pharmaceutically acceptable salts in the manufacture of a medicament for the treatment or prevention of a disease or condition known or shown to inhibit the effects of oxytocin, said disease or condition being selected from sexual dysfunction, Impaired libido, sexual arousal disorder, orgasmic disorder, painful sexual intercourse, premature ejaculation, prenatal delivery, labor complications, appetite and eating disorders, benign prostatic hyperplasia, premature delivery, dysmenorrhea, congestive heart failure, arterial hypertension, liver Sclerosis, renal hypertension, high intraocular pressure, obsessions and behavioral disorders, and neuropsychiatric diseases are preferably selected from sexual dysfunction, sexual arousal disorder, orgasmic disorder, pain during intercourse, and premature ejaculation.
  • the present disclosure also provides the use of the aforementioned pharmaceutically acceptable salts in the manufacture of a medicament for antagonizing oxytocin.
  • compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2 X-ray powder diffraction pattern of A, 4-triazol-4-yl) -2-methoxypyridine hydrochloride, represented by a diffraction angle of 2 ⁇ , at 6.92, 12.54, 15.23, 16.32, 22.70 There are characteristic peaks at 27.44 and 28.10.
  • the A-form, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle has features at 6.92, 12.54, 15.23, 16.32, 18.89, 19.52, 20.90, 22.70, 27.44, 28.10 peak.
  • the A-form, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is 6.92, 12.54, 15.23, 16.32, 16.63, 18.15, 18.89, 19.52, 20.90, 22.70, 24.93, 25.80 There are characteristic peaks at 27.44 and 28.10.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1.
  • the solvent (I) used in this method has a volume (ml) of 1 to 50 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (I) is preferably from isopropanol / water, ethyl acetate.
  • compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2 X-ray powder diffraction pattern of B-form of 4-triazol-4-yl) -2-methoxypyridine hydrochloride represented by a diffraction angle of 2 ⁇ at 14.62, 15.65, 19.21, 23.66, 24.15 There are characteristic peaks at 25.92 and 27.19.
  • the B-form, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 11.76, 14.62, 15.65, 19.21, 23.66, 24.15, 25.92, 27.19, 28.01,29.54 Characteristic peaks.
  • the B-form, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is 11.76, 14.62, 15.65, 16.43, 18.70, 19.21, 23.66, 24.15, 24.56, 25.60, 25.92, There are characteristic peaks at 27.19, 28.01,29.54.
  • the X-ray powder diffraction pattern of the B-form represented by a diffraction angle of 2 ⁇ is shown in FIG. 2.
  • the solvent (II) used in this method has a volume (ml) of 1 to 50 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (II) is preferably selected from ethanol, acetone, and acetonitrile.
  • the compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1
  • the C-form, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 6.94, 12.54, 16.30, 20.89, 21.51,22.71,24.99, 25.80, 27.45, 28.14 Characteristic peaks.
  • the C-form, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is 6.94, 12.54, 16.30, 18.15, 18.88, 19.50, 20.89, 21.51,22.71,24.78,24.99, There are characteristic peaks at 25.80, 27.45, and 28.14.
  • the X-ray powder diffraction pattern of the crystal form C is shown in FIG. 4.
  • the solvent (III) used in the method has a volume (ml) of 1 to 50 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times, and the solvent (III) is preferably from methyl tert-butyl ether.
  • Also provided in this disclosure is the compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1, 2,4-triazol-4-yl) -2-methoxypyridine sulfate, Form A, X-ray powder diffraction pattern in terms of diffraction angle 2 ⁇ , at 12.66, 18.50, 19.90, 21.64, 23.61 There are characteristic peaks at 24.22 and 26.34.
  • the A-form of the sulfate salt, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 12.66, 14.65, 18.50, 19.90, 21.64, 22.05, 23.61,24.22, 24.75, 26.34 There are characteristic peaks everywhere.
  • the crystalline form A of the sulfate, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 7.28, 12.66, 14.04, 14.65, 17.60, 18.50, 19.90, 21.64, 22.05, 23.61, There are characteristic peaks at 24.22, 24.75, 26.34, and 26.70.
  • the X-ray powder diffraction pattern of the crystalline form A of the sulfate in a diffraction angle 2 ⁇ angle is shown in FIG. 7.
  • the solvent (IV) used in this method has a volume (ml) of 1 to 40 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (IV) is preferably selected from acetonitrile, ethanol, acetone, and ethyl acetate.
  • Also provided in this disclosure is the compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,
  • the B-form of 2,4-triazol-4-yl) -2-methoxypyridine sulfate, the X-ray powder diffraction pattern represented by the diffraction angle of 2 ⁇ , is 11.87, 13.22, 14.62, 15.29, 18.49 There are characteristic peaks at 22.66 and 23.61.
  • the B-form of the sulfate of the compound, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is 11.87, 13.22, 14.62, 15.29, 18.49, 19.89, 21.65, 22.66, 23.61, There are characteristic peaks at 24.18.
  • the B-form of the sulfate of the compound, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is 7.78, 11.87, 12.66, 13.22, 14.62, 15.29, 18.49, 19.89, 21.65, 22.66 There are characteristic peaks at 23.61, 24.18, 24.62, and 26.36.
  • the X-ray powder diffraction pattern of the B-form of the compound sulfate represented by a diffraction angle 2 ⁇ angle is shown in FIG. 9.
  • the solvent (V) used in this method has a volume (ml) of 1 to 40 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40 times; the solvent (V) is preferably from methyl tert-butyl ether.
  • Also provided in this disclosure is the compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1, 2,4-triazol-4-yl) -2-methoxypyridine methanesulfonate Form A, X-ray powder diffraction pattern in terms of diffraction angle 2 ⁇ , at 6.66, 16.81, 16.90, 18.92 There are characteristic peaks at 19.19, 22.92, 24.88.
  • the crystal form A of the compound mesylate, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 6.66, 11.00, 16.81, 16.90, 18.92, 19.19, 21.06, 22.92, There are characteristic peaks at 23.96, 24.88.
  • the crystal form A of the compound mesylate, the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ angle is at 6.66, 11.00, 14.87, 16.81, 16.90, 18.92, 19.19, 20.27, 21.06. There are characteristic peaks at 22.92, 23.96, 24.88, 27.85, 29.50.
  • the X-ray powder diffraction pattern of the crystal form A of the compound mesylate in the diffraction angle 2 ⁇ angle is shown in FIG. 14.
  • the solvent (VI) used in this method has a volume (ml) of 1 to 40 times the weight (g) of the compound, and can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times; the solvent (VI) is preferably from ethyl acetate, methyl tert-butyl ether.
  • composition comprising a crystalline form of the aforementioned pharmaceutically acceptable salt and a pharmaceutical excipient, optionally from a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions prepared from the aforementioned crystalline forms also provides pharmaceutical compositions prepared from the aforementioned crystalline forms.
  • the present disclosure also provides the use of a crystalline form of the aforementioned pharmaceutically acceptable salt for the manufacture of a medicament for the treatment or prevention of a disease or condition known or shown to inhibit the beneficial effects of oxytocin, said disease or condition being selected from the group consisting of Dysfunction, Loss of libido, Sexual arousal disorder, Orgasmic disorder, Painful intercourse, Premature ejaculation, Prenatal delivery, Complications of delivery, Appetite and eating disorders, Benign prostatic hyperplasia, Preterm delivery, Dysmenorrhea, Congestive heart failure, High arteries Blood pressure, cirrhosis, renal hypertension, high intraocular pressure, obsessions and behavioral disorders, and neuropsychiatric disorders are preferably selected from sexual dysfunction, sexual arousal disorder, orgasmic disorder, pain during intercourse, and premature ejaculation.
  • the present disclosure also provides the use of the aforementioned crystalline form of a pharmaceutically acceptable salt in the manufacture of a medicament for antagonizing oxytocin.
  • Deliquescence Absorb sufficient water to form a liquid
  • Hygroscopicity The moisture gain is less than 15% but not less than 2%;
  • the moisture gain is less than 2% but not less than 0.2%
  • the hygroscopic weight gain is less than 0.2%.
  • 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2, 4-triazol-4-yl) -2-methoxypyridine methanesulfonate has A crystal form 20.0% RH-80.0% RH, and has a hygroscopic weight increase of 0.1061%, with little or no hygroscopicity.
  • the "X-ray powder diffraction pattern" described in this disclosure is obtained using Cu-K ⁇ radiation measurement.
  • ⁇ is the wavelength of X-rays
  • the "2 ⁇ or 2 ⁇ angle" described in this disclosure refers to the diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.30, which can be -0.30, -0.29, -0.28 , -0.27, -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.12,- 0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19,
  • crystal plane spacing or crystal plane spacing (d value) refers to the selection of three non-parallel unit vectors a, b, and c that connect two adjacent lattice points in space.
  • the lattice is divided into juxtaposed parallelepiped units, called the crystal plane spacing.
  • the space lattice is divided according to the determined parallelepiped unit connection to obtain a set of straight grids, which are called space lattices or lattices.
  • the lattice and the lattice reflect the periodicity of the crystal structure with geometric points and lines, respectively. Different crystal planes have different interplanar distances (that is, the distance between two adjacent parallel crystal planes); the unit is Or Egypt.
  • the “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference during the temperature rise or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical change to obtain phase change information of the sample.
  • the drying temperature described in this disclosure is generally 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C, and can be dried at normal pressure or under reduced pressure. Preferably, the drying is performed under reduced pressure.
  • Chemical or biological reagents used in this disclosure can be purchased commercially.
  • Heating rate 10.0 °C / min
  • Heating rate 10.0 °C / min
  • DVS dynamic moisture adsorption
  • the test uses SMS DVA Advantage. At 25 ° C, the humidity is from 0-90%, the step is 10%, the humidity is from 90-95%, and the step is 5%.
  • the judgment criterion is that the mass change dM / dT of each gradient is less than 0.002. T MAX is less than 360min.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR measurement was performed using Bruker AVANCE-400 nuclear magnetic analyzer.
  • the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD).
  • the internal standard was four.
  • Methylsilane (TMS) Methylsilane
  • Figure 1 XRPD pattern of Form A of the hydrochloride salt.
  • Figure 2 XRPD pattern of Form B of the hydrochloride salt.
  • FIG. 3 TGA pattern of Form B of the hydrochloride salt.
  • Figure 4 XRPD pattern of Form C of the hydrochloride salt.
  • Figure 5 DSC pattern of Form C of the hydrochloride salt.
  • FIG. 6 TGA pattern of Form C of the hydrochloride salt.
  • Figure 7 XRPD pattern of Form A of sulfate.
  • Figure 8 TGA pattern of Form A of sulfate.
  • Fig. 9 XRPD pattern of Form B of sulfate.
  • Figure 10 TGA pattern of Form B of sulfate.
  • Figure 11 XRPD pattern of Form A of formate.
  • Figure 12 DSC pattern of Form A of formate.
  • FIG. 13 TGA pattern of Form A of formate.
  • Figure 14 DVS spectrum of the hydrochloride salt B form.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography, a developing agent used in the reaction, a column chromatography eluent system for purifying compounds, and a thin-layer chromatography developing system including: A: methylene chloride / Methanol system, B: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Example 1 Compound 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2, Preparation of 4-triazol-4-yl) -2-methoxypyridine
  • Step 1 3- (6-Fluoro-3,4-dihydronaphthalen-1-yl) azetidine-1-carboxylic acid tert-butyl ester 1c
  • 3-iodoazetidine-1-carboxylic acid tert-butyl ester 1b (1134.58mg, 4.01mmol, prepared by a known method "Organic Letters, 2014, 16 (23), 6160-6163"), iodine (39.12 mg, 0.15 mmol), zinc (604.65 mg, 9.25 mmol) were added to the reaction flask, protected by argon, and reacted for 0.5 hours.
  • Step 4 3- (6-fluoronaphthalen-1-yl) -N- (6-methoxypyridin-3-yl) azetidine-1-thioamide
  • Step 5 (E) -3- (6-fluoronaphthalen-1-yl) -N- (6-methoxypyridin-3-yl) azetidin-1-thioimidate 1h
  • Test Example 1 Determination of human OTR inhibitory activity
  • Oxytocin (synthesized by Jill Biochemical Co., Ltd.)
  • pcDNA3.1-hOTR (NM-000706) (Synthesized and constructed into pcDNA3.1 plasmid by Jin Weizhi Biotechnology Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human OTR stable transfected cells were seeded in a 96-well plate at a density of 25,000 cells / well.
  • Test Example 2 Determination of human V1aR inhibitory activity
  • pcDNA3.1-V1aR (NM-000706) (Synthesized and constructed into pcDNA3.1 plasmid by Jin Weizhi Biotechnology Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human-derived V1aR stable transfected cells were seeded in a 96-well plate at a density of 25,000 cells / well.
  • Compounds were prepared as 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , and 10 1 nM, 1 ⁇ l was added to each well, and the cells were incubated at room temperature for 10 minutes. Detection was performed with a flexstation 3 microplate reader, and 50 ⁇ l of 3 nM vasopressin peptide was automatically added by the machine, and the value was immediately read at 494/516 nM.
  • the IC 50 value of the compound can be the fluorescence value corresponding to different concentrations.
  • the IC 50 calculated by Graphpad Prism 4.5 nM, which indicates that the compound has a weak inhibitory effect on human V1aR activity and that it has a selective inhibitory effect on OTR activity.
  • Test Example 3 Determination of Inhibitory Activity of Compounds on Human V1bR
  • pcDNA3.1-V1bR (NM-000706) (Synthesized and constructed into pcDNA3.1 plasmid by Jin Weizhi Biotechnology Co., Ltd.)
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • HEK293 / human V1bR pool cells were seeded in 96-well plates at a density of 25,000 cells / well.
  • the compound was formulated into 10 6 , 10 5 , 10 4 , 10 3 , 10 2 , and 10 1 nM, 1 ⁇ l was added to each well, and the mixture was incubated at room temperature for 10 minutes.
  • Detection was performed with a flexstation 3 microplate reader, and 50 ⁇ l of 3 nM vasopressin peptide was automatically added by the machine, and the value was immediately read at 494/516 nM.
  • the IC 50 value of the compound can be the fluorescence value corresponding to different concentrations.
  • the IC 50 calculated by Graphpad Prism software is 26 ⁇ M, which shows that the compound has no obvious inhibitory effect on human V1bR activity, which indicates that it has selective inhibitory effect on OTR activity.
  • Test Example 4 Determination of human-derived V2R inhibitory activity
  • HEK293 cells (Cat. No. GNHu18, Chinese Academy of Sciences Cell Bank)
  • Agonist 460 ⁇ M vasopressin mother solution, first made up to 2 ⁇ M with DMSO, and then diluted to 0.5 nM concentration with experimental buffer 2.
  • the first spot is 20 ⁇ l of stock stock solution (2848nM). From the second spot, it is diluted 4 times with experimental buffer 1 in sequence, for a total of 11 concentrations.
  • Standard curve wells need to add 5 ⁇ l / well of experimental buffer 2.
  • PheraStar multi-functional microplate reader reads HTRF signals.
  • Test Example 5 Determination of brain permeability of rats
  • the brain permeation activity of the compounds in this disclosure on rats is determined by the following experimental methods:
  • each compound has a concentration of 2-3 samples. Cover the 96-well bottom plate with a sealing tape, and place the entire bottom plate in a thermal mixer, equilibrate at 37 ° C for 4 h at a speed of 400 rpm.
  • the LC / MS / MS method was used to determine the peak area ratio of the total drug (brain homo chamber) and free drug (buffer chamber) to the internal standard, and calculate the free percentage (f u brain hom %).
  • the compounds in this disclosure have good brain permeability.
  • Example 2 Using SD male rats as test animals, the compounds of Example 2, Example 17, Compound 34, Compound 37, Compound 38, and Example 2 were administered orally to rats by LC / MS / MS.
  • the pharmacokinetic behavior of the compounds in the present disclosure in rats was studied and their pharmacokinetic characteristics were evaluated.
  • Example 2 The compound of Example 2, the compound of Example 17, the compound of Example 34, the compound of Example 37, the compound of Example 38, the compound of Example 39, the compound of Example 42 and the compound of Example 43.
  • SD rats were fasted orally after fasting overnight.
  • the doses were 30.0 mg / kg and the volume was 10.0 mL / kg.
  • Rats were administered with the compound of Example 2, the compound of Example 17, the compound of Example 34, the compound of Example 37, the compound of Example 38, the compound of Example 39, the compound of Example 42 and the compound of Example 43 by intragastric administration, before administration And 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after administration, 0.2 mL of blood was collected from the orbit, placed in a heparinized tube, centrifuged at 4 ° C, 3500 rpm for 10 minutes to separate the plasma, and at -20 ° C Store and eat 2 hours after administration.
  • Determining the content of test compound in rat plasma after drug administration at different concentrations Take 50 ⁇ L of rat plasma at each time after administration, add 50 ⁇ L of internal standard solution camptothecin (100 ng / mL), 150 ⁇ L of acetonitrile, vortex Spin-mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 3 ⁇ L of the supernatant from the plasma sample for LC / MS / MS analysis.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.86%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • the XRPD spectrum of this crystalline sample is shown in Figure 1.
  • the melting peak point is around 183.41 ° C.
  • the characteristic peak positions are shown in Table 1 below:
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 7.83%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • the ion chromatography (HPIC) test result of the obtained product showed that the chloride ion content was 6.76%, indicating that the molar ratio of the compound to hydrochloric acid in the salt was about 1: 1.
  • the XRPD spectrum of this crystal sample is shown in Figure 4, the DSC spectrum is shown in Figure 5, the TGA spectrum is shown in Figure 6, and the melting peak point is around 170.63 ° C.
  • the characteristic peak positions are shown in Table 3 below:
  • Example 8 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2,4 -Triazol-4-yl) -2-methoxypyridine-sulfate Form A
  • Example 13 5- (3- (3- (6-fluoronaphthalen-1-yl) azetidin-1-yl) -5- (methoxymethyl) -4H-1,2,4 -Triazol-4-yl) Form A of 2-methoxypyridine methanesulfonate
  • the XRPD spectrum of this crystalline sample is shown in Figure
  • the DSC spectrum is shown in Figure
  • the TGA spectrum is shown in Figure
  • the melting peak point is around 207.46 ° C
  • its characteristic peak position is shown in Table 6 below:
  • the hydrochloride A crystal sample is between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.769%, and the moisture gain is less than 2% but Not less than 0.2%, the sample is slightly hygroscopic. Under normal storage conditions (that is, 60% humidity at 25 ° C), water absorption is about 1.675%; under accelerated test conditions (that is, 70% humidity), water absorption is about 1.738%; under extreme conditions (that is, 90% humidity), water absorption is about 1.860 %.
  • the desorption process of the sample and the adsorption process basically coincide; the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form does not change before and after DVS.
  • the hydrochloride salt B crystal sample is between 20.0% RH-80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.0641%, and the moisture gain is less than 0.2%.
  • the sample has no or almost no hygroscopicity; under normal storage conditions (ie, 25 ° C humidity 60%), water absorption is about 0.0361%; under accelerated test conditions (ie, humidity 70%), water absorption is about 0.0446%; in extreme conditions (ie 90% humidity), water absorption is about 0.0947%
  • the desorption process of the sample and the adsorption process basically coincide; the DVS spectrum is shown in the figure, and the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form has not changed before and after DVS.
  • Methanesulfonic acid A sample at 25 ° C, between 20.0% RH and 80.0% RH. As the humidity increases, the water absorption also increases, the weight change is 0.1061%, and the moisture gain is less than 0.2%. This sample has no or almost no hygroscopicity; under normal storage conditions (that is, 25 ° C humidity 60%), water absorption is about 0.0993%; under accelerated test conditions (that is, humidity 70%), water absorption is about 0.1154%; in extreme conditions (that is Humidity is 90%), and water absorption is about 0.1755%.
  • the desorption process of the sample and the adsorption process basically coincide; the X-ray powder diffraction comparison chart before and after DVS shows that the crystal form does not change before and after DVS.
  • the salt crystal form was placed flat and open, and the stability of the sample was examined under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH 75%, RH 92.5%). 30 days.
  • Form B (Example 4) was placed at 25 ° C, 60% RH and 40 ° C, 75% RH to investigate its stability.
  • the long-term / accelerated stability experiment shows that the hydrochloride crystal form B is left under the condition of long-term accelerated stability, its crystal form has not changed, and it has good physical stability. At the same time, there is no growth in the related substances, and it has excellent chemistry. stability.

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Abstract

L'invention concerne un sel pharmaceutiquement acceptable et une forme cristalline d'un inhibiteur D'OTR ainsi qu'un procédé de préparation associé. En particulier, l'invention concerne un sel pharmaceutiquement acceptable et une forme cristalline d'un inhibiteur d'OTR, 5-(3-(3-(6-fluoronaphthalèn-1-yl)azétidin-1-yl)-5-(méthoxyméthyl)-4H-1,2,4-triazol-4-yl)-2-méthoxypyridine ainsi qu'un procédé de préparation associé. Le sel pharmaceutiquement acceptable améliore la vitesse de dissolution de l'alcali libre de l'inhibiteur d'OTR et la stabilité physique ou chimique de celui-ci, est de grande importance dans le développement d'un médicament approprié pour une production industrielle et ayant une bonne activité biologique.
PCT/CN2019/091888 2018-06-20 2019-06-19 Sel pharmaceutiquement acceptable et forme cristalline d'un inhibiteur d'otr et procédé de préparation associé WO2019242642A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111474202A (zh) * 2020-04-09 2020-07-31 集美大学 生物体液中代谢物分析用内标液及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028452A1 (fr) * 2003-09-22 2005-03-31 Pfizer Limited Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine
CN101107243A (zh) * 2005-01-20 2008-01-16 辉瑞有限公司 作为催产素拮抗剂的取代三唑衍生物
WO2018113694A1 (fr) * 2016-12-21 2018-06-28 江苏恒瑞医药股份有限公司 Dérivé de triazole du groupe azacyclobutyle à cycle condensé, son procédé de préparation et son utilisation en médecine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005028452A1 (fr) * 2003-09-22 2005-03-31 Pfizer Limited Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine
CN101107243A (zh) * 2005-01-20 2008-01-16 辉瑞有限公司 作为催产素拮抗剂的取代三唑衍生物
WO2018113694A1 (fr) * 2016-12-21 2018-06-28 江苏恒瑞医药股份有限公司 Dérivé de triazole du groupe azacyclobutyle à cycle condensé, son procédé de préparation et son utilisation en médecine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111474202A (zh) * 2020-04-09 2020-07-31 集美大学 生物体液中代谢物分析用内标液及其应用

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