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WO2022122009A1 - Formes cristallines d'un composé dérivé du pyrrole et leur procédé de préparation - Google Patents

Formes cristallines d'un composé dérivé du pyrrole et leur procédé de préparation Download PDF

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Publication number
WO2022122009A1
WO2022122009A1 PCT/CN2021/137015 CN2021137015W WO2022122009A1 WO 2022122009 A1 WO2022122009 A1 WO 2022122009A1 CN 2021137015 W CN2021137015 W CN 2021137015W WO 2022122009 A1 WO2022122009 A1 WO 2022122009A1
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Prior art keywords
crystal form
formula
compound
present
solid
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Chinese (zh)
Inventor
鲁霞
陈智雄
张晓宇
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Crystal Pharmatech Co Ltd
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Crystal Pharmatech Co Ltd
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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
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of chemical medicine, in particular to a crystal form of pyrrole derivative compounds and a preparation method thereof.
  • Orexin receptors include orexin type 1 receptor (OX1R) and orexin type 2 receptor (OX2R).
  • the type 1 receptor is a G protein-coupled receptor expressed in the hypothalamus, which is related to the feeding behavior of animals
  • the type 2 receptor also known as hypocretin receptor
  • hypocretin receptor is mainly distributed in the cerebral cortex, hypothalamus and some areas of the thalamus , involved in the regulation of sleep-wake behavior.
  • Studies have shown that mutations in genes encoding OX2 receptors are related to the onset and development of insomnia and depression.
  • Patent WO2011/050198A1 discloses the compound of formula (I), its synthesis and its use. The disclosed synthesis method needs to be purified by an Agilent HPLC column, and the yield is only 56%. Patent WO2017/156266A1 discloses the use of compounds of formula (I) in the treatment of depression.
  • the present invention provides three crystal forms A, crystal forms C and D of the compound of formula (I) and their preparation methods and uses.
  • the compound of formula (I) is dissolved in an alcoholic solvent, and after dissolving at -30-10° C., it is volatilized at -30-30° C. until a solid is precipitated to obtain crystal form C.
  • the compound represented by formula (I) [2-(4,6-dimethylpyrimidin-2-yl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]
  • the D-type crystal of pyrrol-5-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone, namely crystal form D, is characterized in that, using Cu-K ⁇ radiation, the The X-ray powder diffraction of Form D has characteristic peaks at 2 ⁇ values of 11.3° ⁇ 0.2°, 13.0° ⁇ 0.2° and 19.6° ⁇ 0.2°,
  • the compound of formula (I) is dissolved in ketones and esters solvents, dissolved at -30-10°C, and then volatilized at -30-30°C until a solid is precipitated to obtain crystal form D.
  • a pharmaceutical composition comprising the crystal form described in 1, 3, and 5 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition with OX2 receptor blocking activity comprising the crystal forms described in 1, 3, and 5 above as an active ingredient.
  • a clinical therapeutic drug for insomnia and depression comprising the crystal forms 1, 3, and 5 as an active ingredient.
  • the crystal form A, crystal form C and crystal form D of the compound of formula (I) provided by the present invention have the following advantages: There are advantages in at least one aspect of properties and processing performance, purification, preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations containing the compound of formula (I), which is very important for drug development. Significance.
  • the X-ray powder diffraction of the crystal form A is at one or two or three places in the 2 ⁇ value of 11.5° ⁇ 0.2°, 14.9° ⁇ 0.2°, 19.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 11.5° ⁇ 0.2°, 14.9° ⁇ 0.2°, and 19.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 19.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 23.6° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 19.3° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 11.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, 19.7° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.6° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 11.5° ⁇ 0.2°, 14.3° ⁇ 0.2°, 14.9° ⁇ 0.2°, 17.6° ⁇ 0.2°, 19.3° ⁇ There are characteristic peaks at 0.2°, 19.7° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
  • the ketone solvent is 2-butanone
  • the ether solvent is ethylene glycol dimethyl ether
  • the alkane solvent is n-heptane.
  • the dissolution temperature is 20°C to 30°C.
  • the normal solvents include halogenated hydrocarbons, alcohols, cyclic ethers, acyclic ethers, ketones, esters and sulfoxide solvents, and the anti-solvents include alkanes, alcohols, esters and acyclic ethers solvent-like.
  • the halogenated hydrocarbon solvents include chloroform, dichloromethane and dibromomethane
  • the alcohol solvent is methanol
  • the cyclic ether solvents include tetrahydrofuran, 2-methyltetrahydrofuran and 1 ,4-dioxane
  • acyclic ether solvent is anisole
  • ketone solvent is acetone
  • ester solvent is ethyl formate
  • sulfoxide solvent is dimethyl sulfoxide
  • the solvent is n-heptane
  • the alcohol solvent is ethanol
  • the ester solvent is isopropyl acetate
  • the acyclic ether solvent is methyl cyclopentyl ether.
  • the temperature of the dissolving, dropping, stirring and precipitation is 5°C to 50°C, for example, 20°C to 30°C.
  • the normal solvents include halogenated hydrocarbons, alcohols, ketones, cyclic ethers, amides and alkyl nitrile solvents, and the anti-solvents include pure water, alkanes and acyclic ethers.
  • the halogenated hydrocarbon solvent is chloroform
  • the alcohol solvent is methanol
  • the ketone solvent is acetone
  • the cyclic ether solvent includes tetrahydrofuran and 1,4-dioxane
  • the amide solvent It is N,N-dimethylformamide
  • the alkyl nitrile solvent is acetonitrile
  • the alkane solvent is n-heptane
  • the acyclic ether solvent includes methyl tert-butyl ether and methyl cyclopentyl ether.
  • the temperature of dissolution, dropwise addition, stirring and precipitation is 20°C to 30°C.
  • the solvent system is a single or mixed solvent of alcohols, ketones, esters, ethers, pure water, alkyl nitriles, and alkanes.
  • alcohol solvents include isopropanol and trifluoroethanol
  • ketone solvents include acetone and methyl isobutyl ketone
  • ester solvents include ethyl acetate, isopropyl acetate Esters and n-butyl acetate
  • ether solvents include methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and ethylene glycol dimethyl ether
  • alkyl nitrile solvents are acetonitrile
  • alkanes include n-heptane and cyclohexane.
  • the mixed solvent includes acetone/n-heptane, tetrahydrofuran/n-heptane, 2-methyltetrahydrofuran/n-heptane, acetonitrile/water, trifluoroethanol/water, tetrahydrofuran/water and Glycol dimethyl ether/cyclohexane.
  • the volume ratio of acetone/n-heptane is 1:3 ⁇ 1, for example, 1:2.
  • the volume ratio of tetrahydrofuran/n-heptane is 1:3-1, for example, 1:2.
  • the volume ratio of 2-methyltetrahydrofuran/n-heptane is 1:5-3, for example, 1:4.
  • the volume ratio of the acetonitrile/water is 2:1 ⁇ 2, for example, 1:1.
  • the volume ratio of the trifluoroethanol/water is 1:3 ⁇ 5, for example, 1:4.
  • the volume ratio of tetrahydrofuran/water is 1:0.5-2, for example 1:1.
  • the volume ratio of ethylene glycol dimethyl ether/cyclohexane is 1:0.5-2, such as 1:1.
  • the dissolution temperature is 40°C to 60°C, eg 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling rate is 0.05 ⁇ 1° C./min.
  • the volatilization temperature is 10°C to 50°C, for example, 20°C to 30°C.
  • the solvent system includes dichloromethane/ethyl acetate, methanol/water, tetrahydrofuran/water, ethylene glycol dimethyl ether/cyclohexane and dichloromethane/methyl isobutyl ketone.
  • the volume ratio of dichloromethane/ethyl acetate is 1:0.5-2, for example, 1:1.
  • the volume ratio of methanol/water is 1:0.5 ⁇ 2, for example, 1:1.
  • the volume ratio of acetonitrile/water is 1:1 ⁇ 3, for example, 1:2.
  • the volume ratio of the dichloromethane/methyl isobutyl ketone is 1:0.5-2, such as 1:1.
  • the alcoholic solvent includes ethanol and isopropanol.
  • the inorganic acid includes hydrochloric acid and sulfuric acid.
  • the alkaline aqueous solution includes an aqueous solution of potassium carbonate, sodium hydroxide and sodium bicarbonate.
  • the temperature of the dissolution, dropwise addition, stirring and precipitation is 20°C to 30°C.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 6.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, and 26.1° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 6.5° ⁇ 0.2°, 12.9° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 8.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 8.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.9° ⁇ 0.2° 0.2°, 14.7° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, 26.1° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.5° ⁇ 0.2°, 8.0° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.8° ⁇ 0.2°, 12.9° ⁇ 0.2° There are characteristic peaks at 0.2°, 14.7° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.6° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form C is shown in FIG. 5 .
  • the compound of formula (I) is dissolved in an alcohol solvent, and volatilized under a certain temperature condition until a solid is precipitated to obtain crystal form C.
  • the alcohol solvent is methanol.
  • the volatilization temperature is -20°C to 30°C, for example, -20°C.
  • the X-ray powder diffraction of the crystal form D has one or two or three 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, and 10.6° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form D has characteristic peaks at 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, and 10.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form D has one or two or three 2 ⁇ values of 9.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 21.4° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form D has characteristic peaks at 2 ⁇ values of 9.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form D has 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 9.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.3° ⁇ 0.2°, 13.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.4° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form D has 2 ⁇ values of 6.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 9.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.3° ⁇ There are characteristic peaks at 0.2°, 13.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form D is shown in FIG. 9 .
  • the compound of formula (I) is dissolved in a ketone and ester solvent system, and volatilized under certain temperature conditions until a solid is precipitated to obtain crystal form D.
  • the ketone solvent is acetone
  • the ester solvent is ethyl formate.
  • the volatilization temperature is -30°C to 30°C, for example, -20°C.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is 200-1500 rev/min, preferably 300-1000 rev/min , the mechanical stirring is preferably 100 to 300 rpm.
  • the above crystals of the present invention can be used for the preparation of pharmaceutical compositions, which contain the above crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above crystal of the present invention can be used to prepare a pharmaceutical composition having OX2 receptor blocking activity, which comprises the above crystal of the present invention as an active ingredient.
  • the above-mentioned crystal of the present invention can be used to prepare a therapeutic drug for insomnia or depression, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the present invention also provides a pharmaceutical composition comprising any one of the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition with OX2 receptor blocking activity, which contains any one of the above-mentioned crystals of the present invention as an active ingredient.
  • the present invention provides a therapeutic drug for insomnia or depression, which contains any one of the above-mentioned crystals of the present invention as an active ingredient.
  • crystalline or “polymorphic form” means as evidenced by the characterization of the X-ray diffraction pattern shown.
  • X-ray diffraction patterns generally vary with the conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor.
  • the relative intensities of the diffraction peaks in the X-ray diffraction pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, the error of these angles should also be taken into account, usually an error of ⁇ 0.2° is allowed.
  • the overall shift of the peak angle will be caused, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not necessarily have to be exactly the same as the X-ray diffraction pattern in the examples mentioned here, and the "same X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and some variability in peak intensity is allowed. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention.
  • Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the crystalline form of the present invention is pure, single, substantially free of admixture with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly construed as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can be based on specific technical environments, without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles. In the present invention, such a range of fluctuations that can be foreseen by those skilled in the art is often represented by the term "about”.
  • room temperature generally refers to 22°C to 28°C unless otherwise specified.
  • PSD particle size distribution
  • PLM Polarized Light Microscope
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert 3 X-ray powder diffractometers of Panalytical Corporation.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of the thermogravimetric analysis of the present invention are as follows:
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL for testing.
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • the particle size distribution results described in the present invention were collected on Microtrac's Model S3500 laser particle size analyzer.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the described laser particle size analyzer are as follows:
  • Particle Size Distribution Volume Distribution Acquisition time: 10 seconds
  • Dispersion medium Isopar G
  • Granularity Coordinates Standard Collection times: 3 times
  • Transparency Transparent Residuals: enabled
  • Flow Rate 60%*
  • Ultrasonic power 30 watts
  • Ultrasound time Ultrasound 30s
  • the intrinsic dissolution rate data described in the present invention were collected on the Agilent 708DS type dissolution apparatus of Agilent. Described inherent dissolution test conditions are as follows:
  • the polarized light microscope photos described in the present invention were collected at room temperature by a Zeiss microscope Axio Scope.A1 equipped with an Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of compound (I) used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2011/050198A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 3, the XRPD pattern of the solid obtained in Example 4 is shown in FIG. 1 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 2 to 4 , respectively.
  • the sample is at about 11.5° ⁇ 0.2°, about 14.3° ⁇ 0.2°, about 14.9° ⁇ 0.2°, about 17.6° ⁇ 0.2°, about 18.2° ⁇ 0.2°, about 19.3° ⁇ 0.2°, about 19.7° ⁇ 0.2 °, about 21.9° ⁇ 0.2°, about 22.3° ⁇ 0.2°, about 23.6° ⁇ 0.2°, and about 26.9° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction data of the sample of Example 4 are shown in Table 4.
  • Diffraction angle 2 ⁇ d value strength% 30.71 2.91 1.72 31.83 2.81 4.31 32.54 2.75 1.98 33.54 2.67 0.72 34.62 2.59 1.70 36.98 2.43 0.92 38.04 2.37 2.60
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 7, and the X-ray powder diffraction data of the sample of Example 25 are shown in Table 8.
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 9, and the X-ray powder diffraction data of the sample of Example 35 is shown in Table 10.
  • the solids obtained in this example are all crystal form A.
  • the detailed test conditions involved in this example are shown in Table 11, and the X-ray powder diffraction data of the sample of Example 37 is shown in Table 12.
  • Diffraction angle 2 ⁇ d value strength% 18.27 4.86 2.80 18.60 4.77 6.71 19.31 4.60 6.81 19.75 4.49 4.73 21.87 4.06 12.53 22.32 3.98 100.00 23.67 3.76 14.54 24.63 3.61 7.33 25.08 3.55 1.79 26.44 3.37 6.57 26.95 3.31 29.76 27.22 3.28 14.26 30.19 2.96 1.89 31.83 2.81 6.96 34.66 2.59 1.19 37.99 2.37 4.46
  • Example 39 Preparation of crystal form A (rapid evaporation method at room temperature)
  • Diffraction angle 2 ⁇ d value strength% 18.59 4.77 16.01 19.29 4.60 20.25 19.72 4.50 26.36 21.87 4.06 30.17 22.28 3.99 93.13 23.20 3.83 14.38 23.60 3.77 28.87 24.56 3.63 15.28 25.11 3.55 6.24 26.42 3.37 9.19 26.92 3.31 27.97 27.20 3.28 23.93 30.15 2.96 5.79 31.82 2.81 11.89 33.63 2.67 8.25 34.25 2.62 4.50 37.94 2.37 4.24
  • the sample is at about 6.5° ⁇ 0.2°, about 8.0° ⁇ 0.2°, about 9.9° ⁇ 0.2°, about 10.8° ⁇ 0.2°, about 12.9° ⁇ 0.2°, about 14.7° ⁇ 0.2°, about 16.1° ⁇ 0.2 °, about 17.5° ⁇ 0.2°, about 19.6° ⁇ 0.2°, about 21.6° ⁇ 0.2°, and about 26.1° ⁇ 0.2° have characteristic peaks. Its X-ray powder diffraction data are shown in Table 16.
  • Diffraction angle 2 ⁇ d value strength% 18.31 4.85 5.80 18.60 4.77 24.70 19.58 4.53 75.40 20.47 4.34 7.45 21.39 4.15 21.12 22.83 3.90 11.51 23.61 3.77 11.58 24.70 3.60 24.80 26.23 3.40 53.27 27.26 3.27 23.41 27.97 3.19 8.56 31.73 2.82 7.27
  • the XRPD pattern of the solid obtained in Example 45 is shown in FIG. 9 , and the TGA, DSC, and 1 H NMR are shown in FIGS. 10 to 12 , respectively.
  • the sample is at about 6.5° ⁇ 0.2°, about 7.1° ⁇ 0.2°, about 8.6° ⁇ 0.2°, about 9.0° ⁇ 0.2°, about 10.6° ⁇ 0.2°, about 11.3° ⁇ 0.2°, about 13.0° ⁇ 0.2 °, about 16.0° ⁇ 0.2°, about 18.0° ⁇ 0.2°, about 19.6° ⁇ 0.2°, and about 21.4° ⁇ 0.2° have characteristic peaks.
  • Its X-ray powder diffraction data are shown in Table 19.
  • the crystal form A, crystal form C and crystal form D of the present invention are respectively prepared into suspensions with FaSSIF (artificial intestinal fluid in fasting state) and pure water, and filtered after equilibration for 1 hour, 2 hours, 4 hours and 24 hours to obtain saturated solution.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the test results are shown in Table 20, and the solubility curves are shown in Figures 13 to 14, respectively.
  • the test results show that the crystal form A, crystal form C and crystal form D of the present invention have good solubility in FaSSIF and pure water.
  • Example 51 Comparative study on hygroscopicity
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • wet weight gain is less than 0.2%

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Abstract

La présente invention concerne des formes cristallines d'un composé dérivé du pyrrole et leur procédé de préparation. L'invention concerne trois formes cristallines, la forme cristalline A, la forme cristalline C et la forme cristalline D, d'un composé représenté par la formule (I), leur procédé de préparation et leur utilisation. La forme cristalline A, la forme cristalline C et la forme cristalline D du composé représenté par la formule (I) selon l'invention présentent des avantages selon au moins un aspect parmi la solubilité, le point de fusion, la stabilité, la dissolution, l'hygroscopicité, l'adhérence, la fluidité, la biodisponibilité et l'aptitude au traitement, la purification, la production de la préparation, la sécurité, etc. La présente invention concerne une nouvelle et meilleure solution de préparation de compositions pharmaceutiques contenant le composé représenté par la formule (I), et présente une grande importance pour le développement de médicaments.
PCT/CN2021/137015 2020-12-11 2021-12-10 Formes cristallines d'un composé dérivé du pyrrole et leur procédé de préparation Ceased WO2022122009A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102781942A (zh) * 2009-10-23 2012-11-14 詹森药业有限公司 用作食欲肽受体调节剂的二取代八氢吡咯并[3, 4-c]吡咯
US9586962B2 (en) * 2011-04-20 2017-03-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo [3,4-C] pyrroles as orexin receptor modulators
CN108883110A (zh) * 2016-03-10 2018-11-23 詹森药业有限公司 使用食欲素-2受体拮抗剂治疗抑郁症的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102781942A (zh) * 2009-10-23 2012-11-14 詹森药业有限公司 用作食欲肽受体调节剂的二取代八氢吡咯并[3, 4-c]吡咯
US9586962B2 (en) * 2011-04-20 2017-03-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo [3,4-C] pyrroles as orexin receptor modulators
CN108883110A (zh) * 2016-03-10 2018-11-23 詹森药业有限公司 使用食欲素-2受体拮抗剂治疗抑郁症的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MICHAEL A. LETAVIC, PASCAL BONAVENTURE, NICHOLAS I. CARRUTHERS, CHRISTINE DUGOVIC, TATIANA KOUDRIAKOVA, BRIAN LORD, TIMOTHY W. LOV: "Novel Octahydropyrrolo[3,4- c ]pyrroles Are Selective Orexin-2 Antagonists: SAR Leading to a Clinical Candidate", JOURNAL OF MEDICINAL CHEMISTRY, vol. 58, no. 14, 23 July 2015 (2015-07-23), US , pages 5620 - 5636, XP055493378, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.5b00742 *

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