WO2023061372A1 - Sel de malate de dérivé de xanoméline, forme cristalline a, procédé de préparation correspondant et utilisation associée - Google Patents

Sel de malate de dérivé de xanoméline, forme cristalline a, procédé de préparation correspondant et utilisation associée Download PDF

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WO2023061372A1
WO2023061372A1 PCT/CN2022/124662 CN2022124662W WO2023061372A1 WO 2023061372 A1 WO2023061372 A1 WO 2023061372A1 CN 2022124662 W CN2022124662 W CN 2022124662W WO 2023061372 A1 WO2023061372 A1 WO 2023061372A1
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formula
compound
malate
crystal form
preparation
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刘飞
吴刚
李先朝
陈庆
王晓波
赵欣
冷超群
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南京迈诺威医药科技有限公司
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    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a malate salt of a jenomeline derivative, a crystal form A and a preparation method thereof, which also includes the preparation of the malate salt and a crystal form A of a jenomeline derivative
  • a malate salt of a jenomeline derivative a malate salt of a jenomeline derivative
  • a crystal form A a preparation method thereof, which also includes the preparation of the malate salt and a crystal form A of a jenomeline derivative
  • Neurotransmitters are chemical messengers secreted by neurons to facilitate the flow of information and communicate with other cells in the central and peripheral nervous systems, such as muscle or similar nerve cells.
  • Acetylcholine one of the key neurotransmitters in the brain, has two distinct receptor classes: muscarinic receptors (M receptors, G protein-coupled receptors) and nicotinic receptors (N receptors , ion channel receptors).
  • the M receptor family includes five subtypes from M1 to M5, all of which are expressed in the brain and peripheral tissues and play many key physiological roles in cognition, behavior, sensory, motor and autonomic processes. Disruption of M-type receptor signaling leads to memory impairment and cognitive impairment, triggers a variety of diseases including schizophrenia and Alzheimer's disease (AD), and exacerbates psychosis. On the contrary, third-party preclinical and clinical data show that the enhancement of M-type receptor signaling can improve these symptoms. In addition, M-type receptors, especially M1, M2, and M4 receptors, are also considered to be related to analgesia.
  • Xanomeline is a partial agonist of muscarinic receptors, which can produce agonistic effects on all five subtypes of muscarinic receptors without selectivity. Jointly developed and marketed by Eli Lilly and Novo Nordisk, it is mainly used clinically for the treatment of Alzheimer's disease.
  • the chemical name of Normeline is 3-[(4-hexyloxy)-1,2,5 -Thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-picoline, the chemical structure is as follows:
  • Patent document CN94192681.8 discloses that oxalate can be converted into oxalate, but oxalate has potential side effects on the patient's kidney function, so it is not suitable for medicine, especially when treating the elderly. And it is further disclosed that in the series of twelve kinds of pharmaceutically acceptable acids (the name of the specific pharmaceutically acceptable acid is not disclosed), only zomeline tartrate has good bioavailability, good handling properties and reproducible crystal form .
  • the screening of drug salt form is a difficult semi-empirical choice, and the hygroscopicity of the drug will seriously affect the fluidity of the drug, and even affect the stability of the drug.
  • the solubility of drugs has a crucial impact on the preparation of pharmaceuticals, drug dissolution, absorption and so on. But how to improve the solubility of the drug, without the expense of the hygroscopicity of the drug, it is difficult to obtain a candidate drug salt with suitable stability, solubility and hygroscopicity.
  • Xanomeline as an M-receptor activator has shown encouraging therapeutic efficacy in the clinic for the treatment of psychosis and related behavioral symptoms in patients with schizophrenia and AD, but its potential has been limited by cholinergic side effects, including salivation , nausea, dizziness, etc., which are thought to be due to stimulation of M receptors in peripheral nervous tissue.
  • the metabolism of Zanameline in the human body is complex and unpredictable, and Zanameline lacks selectivity for muscarinic receptor subtypes, thus causing difficulties in the drug development of Zanameline.
  • the object of the present invention is to provide a malate salt of a zanmeline derivative shown in formula I, which can be used for the preparation of medicines for preventing or treating central nervous system disorders and the dissolution of this derivative Improved ability, stable storage, convenient administration, improved drug metabolism, drug toxicity and side effects, and high patient compliance during administration.
  • Another object of the present invention is to provide a crystal form A of the malate salt of phenomeline derivatives shown in formula I, the crystal form A can have excellent thermodynamic stability and mechanical stability, good repeatability, Suitable for commercial mass production.
  • the present invention provides a malate salt of a compound of formula I.
  • the malate salt of the compound of formula I above is shown in formula II, wherein x is selected from 0.5-2.
  • the above-mentioned x is 0.5, 1.0, 1.5, 2.0.
  • x in the compound of formula II above is 1.0.
  • the present invention provides the A crystal form of the malate salt of the compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 14.827 ⁇ 0.2°, 16.796 ⁇ 0.2° , 20.012 ⁇ 0.2° and 21.942 ⁇ 0.2°.
  • the crystal form A of the malate salt of the compound of formula I is the compound of formula II with x being 1.0, and the malic acid therein is L-malic acid.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 14.827 ⁇ 0.2°, 16.796 ⁇ 0.2°, 20.012 ⁇ 0.2°, 21.942 ⁇ 0.2 °, 22.473 ⁇ 0.2° and 25.333 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 13.288 ⁇ 0.2°, 14.827 ⁇ 0.2°, 16.796 ⁇ 0.2°, 20.012 ⁇ 0.2 °, 21.942 ⁇ 0.2°, 22.473 ⁇ 0.2°, and 25.333 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 13.288 ⁇ 0.2°, 14.827 ⁇ 0.2°, 15.399 ⁇ 0.2°, 16.796 ⁇ 0.2 °, 20.012 ⁇ 0.2°, 20.327 ⁇ 0.2°, 21.942 ⁇ 0.2°, 22.473 ⁇ 0.2°, and 25.333 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 13.288 ⁇ 0.2°, 14.827 ⁇ 0.2°, 15.399 ⁇ 0.2°, 16.796 ⁇ 0.2 °, 20.012 ⁇ 0.2°, 20.327 ⁇ 0.2°, 21.942 ⁇ 0.2°, 22.473 ⁇ 0.2°, 24.996 ⁇ 0.2°, 25.333 ⁇ 0.2°, and 27.718 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 12.755 ⁇ 0.2°, 13.288 ⁇ 0.2°, 13.903 ⁇ 0.2°, 14.827 ⁇ 0.2 °, 15.399 ⁇ 0.2°, 16.796 ⁇ 0.2°, 17.686 ⁇ 0.2°, 18.906 ⁇ 0.2°, 20.012 ⁇ 0.2°, 20.327 ⁇ 0.2°, 21.942 ⁇ 0.2°, 22.473 ⁇ 0.2°, 24.996 ⁇ 0.2°, 25.333 ⁇ 0.2 ° and 27.718 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.007 ⁇ 0.2°, 12.755 ⁇ 0.2°, 13.288 ⁇ 0.2°, 13.903 ⁇ 0.2°, 14.827 ⁇ 0.2 °, 15.399 ⁇ 0.2°, 16.796 ⁇ 0.2°, 17.686 ⁇ 0.2°, 18.906 ⁇ 0.2°, 20.012 ⁇ 0.2°, 20.327 ⁇ 0.2°, 20.660 ⁇ 0.2°, 21.942 ⁇ 0.2°, 22.473 ⁇ 0.2°, 24.996 ⁇ 0.2 °, 25.333 ⁇ 0.2°, 27.382 ⁇ 0.2°, and 27.718 ⁇ 0.2°.
  • the above crystal form A has an XRPD pattern as shown in FIG. 1 .
  • the above crystal form A has a DSC spectrum substantially as shown in FIG. 2 .
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 111.03 ⁇ 3°C.
  • the above crystal form A has a TGA curve substantially as shown in FIG. 3 .
  • the present invention also provides a method for preparing malate of the compound of formula I, comprising reacting the compound of formula I with malic acid.
  • the preparation method of the A crystal form of the compound malate of the above formula I comprises the following steps:
  • the solvent is selected from ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptyl
  • the solvent is selected from ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptyl
  • One or more mixtures of alkanes, acetonitrile, tetrahydrofuran preferably one or more mixtures of ethanol, isopropanol, ethyl acetate, n-heptane; or
  • the first solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, n-butanol;
  • the second solvent is selected from methyl tert-butyl ether, esters, acetonitrile, alkanes
  • the mixture of one or more than one of them means that the esters are selected from ethyl acetate and/or, the lipids are, for example, isopropyl acetate; the alkanes are selected from n-heptane and/or n-hexane.
  • the heating temperature is 50-80°C, such as 60-70°C.
  • the compound of formula I, malic acid and the solvent used to dissolve the compound or the first solvent are mixed and then stirred.
  • the stirring time may be 1-5 hours, preferably 2-3 hours.
  • the weight/volume ratio (g/mL) of the compound of formula I to the solvent used to dissolve the compound or the first solvent is 1:4-10, preferably 1:6-8, such as 1:6, 1:7 , 1:8.
  • the cooling may be to 0-30°C, preferably to 2-8°C, for example to 5°C. It can be filtered once before cooling.
  • stirring is carried out during the cooling process, and the stirring time may be 6 to 24 hours, preferably 18 hours.
  • the step of washing with a solvent is also included before drying, and the washing solvent is selected from ethanol, isopropanol, n-propanol, One or a mixture of acetone, ethyl acetate, acetonitrile, tetrahydrofuran.
  • the molar ratio of the compound of formula I to malic acid is 1:0.9-1.3, preferably, the molar ratio of the compound of formula I to malic acid is 1:1-1.1, for example 1: 1. 1:1.05, 1:1.1.
  • the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the malate of the compound of formula I or the malate A crystal form of the compound of formula I, and optional pharmaceutically acceptable excipients agent.
  • the present invention provides the malate of the compound of formula I, the malate A crystal form of the compound of formula I above, or the pharmaceutical composition comprising the malate of the compound of formula I, or the malate of the compound of formula I Use of the pharmaceutical composition of crystal form A in the preparation of medicines for treating disorders of the central nervous system.
  • the disorders of the central nervous system include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain and neurodegeneration (eg Dow disease or synucleinopathies).
  • the central nervous system disorder is schizophrenia.
  • the present invention provides a method for treating or preventing central nervous system disorders in mammals (such as humans), the method comprising administering a therapeutically effective amount of malic acid of a compound of formula I to mammals (such as humans) salt, malate A crystal form of the compound of formula I, a pharmaceutical composition comprising the malate salt of the compound of formula I and a pharmaceutical composition comprising the malate A crystal form of the compound of formula I.
  • the disorders of the central nervous system include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain and neurodegeneration (eg Dow disease or synucleinopathies).
  • the central nervous system disorder is schizophrenia.
  • the present invention provides the malate of the compound of formula I for the first time; the malate of the compound of formula I has at least one aspect such as physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, toxic side effect Excellent effect.
  • the crystal form A of the malate salt of the compound of formula I has good stability, low hygroscopicity, good water solubility, small batch-to-batch variation, and good prospects for making a drug.
  • the preparation process of the salt form and crystal form of the present invention is simple and suitable for industrial production.
  • Fig. 1 is the XRPD pattern of A crystal form of compound L-malate of formula I;
  • Fig. 2 is the DSC spectrum of the A crystal form of formula I compound L-malate
  • Fig. 3 is the TGA spectrum of the A crystal form of formula I compound L-malate
  • Fig. 4 is the XRPD patterns of crystal form A of compound L-malate of formula I at high temperature (60° C.) for 0 days, 6 days, 14 days, and 30 days;
  • Fig. 5 is the XRPD patterns of crystal form A of compound L-malate of formula I under high humidity (RH92.5%) conditions at 0 days, 6 days, 14 days, and 30 days;
  • Fig. 6 is the XRPD pattern of crystal form A of L-malate of the compound of formula I under light conditions (4500 ⁇ 500Lux) at 0 days, 6 days, 14 days and 30 days.
  • Fig. 7 is the pharmacokinetic curve of the compound of formula I in rat plasma after oral administration of crystal form A of compound L-malate of formula I (sample of Example 2) and compound of formula I (sample of Example 1).
  • rt stands for room temperature
  • aq stands for aqueous solution
  • DCM dichloromethane
  • THF tetrahydrofuran
  • MeOH stands for methanol
  • EtOH stands for ethanol
  • IPA isopropanol
  • DSC differential scanning calorimeter
  • TGA thermogravimetric analysis
  • 1 H-NMR hydrogen nuclear magnetic resonance spectrum
  • XRPD X-ray powder diffraction
  • eq stands for molar equivalent.
  • Powder X-ray diffraction also known as "X-ray powder diffraction", X-ray powder diffractometer, XRPD
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Phototube voltage 40kV
  • phototube current 40mA
  • the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensities of the bands (especially at low angles) may vary. Varies due to the effect of preferred orientation due to differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic of the targeted crystal, and when judging whether it is the same as a known crystal, more attention should be paid to the relative positions of the peaks rather than their relative intensities. Furthermore, for any given crystal there may be slight errors in the position of the peaks, as is well known in the art of crystallography.
  • the position of the peak can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of their XRPD spectra are similar on the whole, and the relative intensity error may be large.
  • Measurement variance associated with such X-ray powder diffraction analysis results arises from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, ( d) operator errors (including errors in determining peak positions), and (e) properties of the species (eg, preferred orientation errors). Calibration errors and sample height errors often cause all peaks to shift in the same direction. Small differences in sample height will result in large shifts in XRPD peak positions when using flat supports. Systematic studies have shown that a sample height difference of 1 mm can result in a peak shift in 2 ⁇ of up to 1°.
  • shifts can be identified from the X-ray diffraction pattern and can be eliminated by compensating for them (using a system calibration factor for all peak position values) or recalibrating the instrument. Measurement errors from different instruments can be corrected for by applying system calibration factors to make peak positions consistent, as described above.
  • Differential thermal analysis also known as “differential scanning calorimetry”, Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/ minN2 , heat the sample from 25°C to 300°C at a heating rate of 10°C/min.
  • DSC differential scanning calorimetry
  • the error of thermal transition temperature and melting point is typically within about 5°C, usually within about 3°C, when we say that a compound has a given DSC peak or melting point, this means ⁇ 5°C of the DSC peak or melting point.
  • DSC provides an auxiliary method for distinguishing between different crystals. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be pointed out that for mixtures, the DSC peak or melting point may vary in a larger range. In addition, since the melting process of the substance is accompanied by decomposition, the melting temperature is related to the heating rate.
  • TGA Thermal Gravimetric Analyzer
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/ minN2 , heat the sample from room temperature to 350°C at a heating rate of 10°C/min.
  • the instrument used is Waters ARC 2998HPLC; Chromatographic column: Agilent Poroshell bonus-RP 4.6 ⁇ 100mm, 2.7 ⁇ m;
  • the measurement conditions are as follows:
  • Mobile phase A 0.2% phosphoric acid aqueous solution
  • the inventor found that the hygroscopicity of the drug will seriously affect the fluidity of the drug, and even affect the stability of the drug.
  • the solubility of drugs has a crucial impact on the preparation of pharmaceuticals, drug dissolution, absorption and so on. But how to improve the solubility of the drug, without the expense of the hygroscopicity of the drug, it is difficult to obtain a drug candidate salt with suitable drug stability, solubility and hygroscopicity.
  • the inventor unexpectedly found that the malate of the compound of formula I has a higher melting point as determined by DSC, and the stability experiment confirmed that the malate of the compound of formula I has higher stability.
  • the malate salt of the compound of formula I has low hygroscopicity and moderate solubility.
  • the combination of high stability, low hygroscopicity and appropriate solubility of compound malate of formula I is unexpected, which makes compound malate of formula I (especially compound L-malate of formula I) suitable for the preparation of oral solid dosage forms , especially the preparation of tablets.
  • solubility of the active ingredient is of great importance for the choice of dosage form because the dosage form has a direct effect on bioavailability.
  • it is generally considered to be advantageous to have a higher solubility of the active ingredient because it leads to increased bioavailability.
  • the inventors have discovered the A crystal form of malate of the compound of formula I, which has advantages in at least one of physical stability, thermodynamic stability and mechanical stability; the prepared formula I compound malate
  • the crystal form A of the acid salt has a suitable crystal size and is suitable for industrial production and preparation.
  • a crystalline form of malate A of the compound of formula I can significantly improve the water solubility of the compound of formula I, and has good stability and extremely low hygroscopicity, which is beneficial for making oral solid preparations.
  • the preparation made of malate of the compound of formula I can maintain the effective physiological concentration of the free base of formula I in the body for a long time and is convenient to administer, so it has the advantages of improving the compliance of patients and the like.
  • 3-Pyridinecarbaldehyde (6.00g, 56.02mmol, 1.0eq), glacial acetic acid (3.36g, 56.02mmol, 1.0eq) and 6mL of pure water were successively added into a 100mL single-port reaction flask, and stirred and mixed at room temperature.
  • step 3 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (intermediate 3)
  • Step 5 Preparation of iodide-1-deuteromethyl-3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (intermediate 5)
  • Step 6 the preparation of deuterated phenomeline (compound of formula I)
  • the obtained white solid was submitted for inspection by XRPD, DSC and TGA. After testing, it was found that the obtained white solid existed in the form of crystals, and the obtained crystal form was named as the compound of formula I L-malate A crystal form, referred to as A crystal form.
  • the XRPD pattern, DSC pattern and TGA pattern of the obtained crystal form A are basically shown in Fig. 1 , Fig. 2 and Fig. 3 respectively.
  • the peak positions and intensities of the characteristic peaks are shown in Table 2;
  • the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 3, and the error range of the 2 ⁇ value is ⁇ 0.2°.
  • Embodiment 7 the preparation of formula I compound nitrate
  • Solubility measurement experiment results the solubility of the compound L-malate of the formula I is 40.48 mg/mL, and the solubility of the compound L-malate of the formula I is better.
  • formula I compound L-malate has higher fusing point (promptly having higher stability), lower hygroscopicity, and suitable solubility is arranged, and this makes formula I compound malate be suitable for preparing oral Preparation of solid dosage forms, especially tablets.
  • Test example 2 The physical stability research of the prepared salt of embodiment 2,7-10
  • the formula I compound L-malate A crystal form (the sample obtained in Example 2), the formula I compound nitrate (the sample obtained in Example 7), the formula I compound succinate (the sample obtained in Example 8), the formula I Compound p-toluenesulfonate (samples obtained in Example 9), compound tartrate of formula I (samples obtained in Example 10) are respectively exposed and laid flat, and placed under high temperature (60° C.), high humidity (RH92.5%), light Carry out the stability test of sample under (4500 ⁇ 500Lux) condition, measure in different sampling time (0 day, 6 days, 14 days, 30 days) in the sample active substance (formula I compound or phenomeline) and related substances content, as shown in Table 6.
  • nitrate of the compound of formula 1 is liquid under high temperature conditions, and its physical properties are unstable. NA means not determined.
  • the crystal form A of compound L-malate of formula I of the present invention has very low impurity content, and has very good stability under high temperature, high humidity and light conditions, and has a good prospect for pharmaceutical preparation;
  • the malate A crystal form of the compound of formula I is more stable under light conditions than other salt forms, which is convenient for the storage of raw materials and pharmaceutical preparations.
  • Test example 3 Toxic and side effects research of different salt types
  • Zanomeline is an M receptor activator, which can not only act on the central nervous system, but also stimulate M receptors in peripheral nervous tissue, resulting in cholinergic side effects, such as salivation, nausea , dizziness, etc.
  • the toxic and side effects of each compound were evaluated by observing the salivation of SD rats in each group. According to the experimental results, it can be seen that the cholinergic side effect of the crystal form A of the compound L-malate of formula I is small and has good safety.
  • mice male SD rats (weight 180-220g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0006), formula I compound L-malate A crystal Type (Example 2), formula I compound (Example 1), purified water (self-made).
  • mice 6 male SD rats were randomly divided into 2 groups (3 rats in each group), free to drink water during the test period, fasted for more than 12 hours before administration, and fed 4 hours after administration.
  • Oral gavage administration two groups of SD rats were given formula I compound malate A crystal form A aqueous solution and formula I compound aqueous solution at a dose of 30 mg/kg (calculated as free base).
  • 0min before administration 15min, 30min, 45min, 1.0h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 10h after administration
  • blood samples were collected into K 2 EDTA anticoagulant tubes, and temporarily stored on ice until centrifugal.
  • Plasma needs to be centrifuged within 60 minutes after blood collection (at 2-8°C, centrifuge at 8000rpm for 5min), after centrifugation, transfer the plasma to a 96-well plate or centrifuge tube, transport it in an ice box, and store it at ⁇ -15°C for LC-MS/MS detection.
  • the LC-MS/MS bioanalysis method was used to detect the drug concentration in SD rat plasma, and the non-compartmental model was used to analyze the blood drug concentration-time data using WinNonlin TM (Version8.3, Certara, USA) to evaluate its SD rat pharmacokinetic (PK) characteristics in vivo, the data are shown in Table 10.

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Abstract

La présente invention relève du domaine de la chimie médicinale et, concerne en particulier, un sel de malate d'un dérivé de xanoméline, le sel de malate ayant une structure telle que représentée dans la formule (I). Le sel de malate du composé de formule (I) a d'excellents effets sur au moins un aspect de la stabilité physique, la solubilité, l'hygroscopicité, l'activité biologique, la sécurité, la biodisponibilité, les effets toxiques et secondaires, etc.
PCT/CN2022/124662 2021-10-14 2022-10-11 Sel de malate de dérivé de xanoméline, forme cristalline a, procédé de préparation correspondant et utilisation associée WO2023061372A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013168A1 (fr) * 1994-10-31 1996-05-09 Eli Lilly And Company Procede de traitement de l'anxiete
CN1208348A (zh) * 1995-12-07 1999-02-17 伊莱利利公司 治疗疼痛的方法
WO2020172516A1 (fr) * 2019-02-22 2020-08-27 Karuna Therapeutics, Inc. Composés et méthodes à base de xanoméline deutérée permettantle traitement de troubles neurologiques
WO2021097427A1 (fr) * 2019-11-15 2021-05-20 Karuna Therapeutics, Inc. Dérivés de xanoméline et méthodes de traitement de troubles neurologiques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5043345A (en) * 1989-02-22 1991-08-27 Novo Nordisk A/S Piperidine compounds and their preparation and use
EP0703915B1 (fr) * 1993-06-04 2000-09-27 Novo Nordisk A/S Xamoneline tartrate
DE69430816T2 (de) * 1993-08-19 2002-12-19 Novo Nordisk A/S, Bagsvaerd Verwendung von Piperidin-Derivaten in der Behandlung von Schizophrenie
WO2012033956A1 (fr) * 2010-09-08 2012-03-15 Mithridion, Inc. Composés et compositions améliorant la cognition, méthodes de préparation et méthodes de traitement

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013168A1 (fr) * 1994-10-31 1996-05-09 Eli Lilly And Company Procede de traitement de l'anxiete
CN1208348A (zh) * 1995-12-07 1999-02-17 伊莱利利公司 治疗疼痛的方法
WO2020172516A1 (fr) * 2019-02-22 2020-08-27 Karuna Therapeutics, Inc. Composés et méthodes à base de xanoméline deutérée permettantle traitement de troubles neurologiques
WO2021097427A1 (fr) * 2019-11-15 2021-05-20 Karuna Therapeutics, Inc. Dérivés de xanoméline et méthodes de traitement de troubles neurologiques

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