WO2019170009A1 - 一种美金刚帕罗西汀共晶盐及其制备方法、药物组合物、应用 - Google Patents

一种美金刚帕罗西汀共晶盐及其制备方法、药物组合物、应用 Download PDF

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WO2019170009A1
WO2019170009A1 PCT/CN2019/075891 CN2019075891W WO2019170009A1 WO 2019170009 A1 WO2019170009 A1 WO 2019170009A1 CN 2019075891 W CN2019075891 W CN 2019075891W WO 2019170009 A1 WO2019170009 A1 WO 2019170009A1
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paroxetine
memantine
eutectic salt
disease
eutectic
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PCT/CN2019/075891
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English (en)
French (fr)
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王珂
程千流
王宗贵
耿燕
王刚
赵勋
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合肥科大生物技术有限公司
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Priority to JP2020570619A priority Critical patent/JP7049007B2/ja
Priority to EP19764271.3A priority patent/EP3750889B1/en
Priority to US16/978,202 priority patent/US11839607B2/en
Publication of WO2019170009A1 publication Critical patent/WO2019170009A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • A61P25/24—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/38—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the invention relates to the technical field of drug synthesis, and more particularly to a memantine paroxetine co-crystal salt, a preparation method thereof, a pharmaceutical composition and an application thereof.
  • AD Alzheimer's disease
  • senile dementia is a degenerative disease of the central nervous system characterized by decreased daily living ability, behavioral abnormalities, and cognitive dysfunction. Patients with neurodegenerative diseases often have depressive symptoms. According to incomplete statistics, about 25% to 40% of Alzheimer's patients may have depression. Depression and AD promote the development of diseases, and the common initiating factors of depression and AD are mainly chronic chronic stress.
  • Kobayashi et al. proposed the concept of “depression-dementia intermediate state”, and considered that patients who were in the “depression-dementia intermediate state” could prevent or delay the occurrence of AD if they were treated promptly and effectively.
  • the National Institute of Mental Health developed a diagnostic criteria for depression in Alzheimer's patients.
  • patients must have 3 or more depressive symptoms while meeting the diagnostic criteria for AD.
  • depressive symptoms such as depression, insomnia, loss of appetite, decreased excitability of psychomotors, agitation, burnout, decreased social or daily life interests or pleasant reactions, social disengagement or withdrawal, self-denial, helplessness, excessive self-blame, suicidal tendencies, etc.
  • the standard requires patients to have depressive symptoms for more than 2 weeks. It is enough to see that there is a certain clinical feature correlation between Alzheimer's disease and depression.
  • Alzheimer's disease patients, depression patients or a total of patients with both diseases are difficult and hot spots for the development of clinical drugs. They are drugs that are not currently met by clinical treatment, and are also urgently needed for clinical development. Disease has become a major public health problem in the world.
  • AD Alzheimer's disease
  • antidepressants have certain effects in improving and preventing Alzheimer's disease.
  • antidepressants have been frequently used in the adjuvant treatment of Alzheimer's disease, and have achieved certain results.
  • the memantine hydrochloride chemical name is 3,5-Dimethyl-1-aminoadamantane hydrochloride, also known as 3,5-dimethyltricyclo[3.3. 1.1. (3.7)] decane-1-aminohydrochloride (3,5-Dimethyltricyclo (3.3.1.1 (3,7)) decan-1-aminehydrochloride).
  • Its molecular formula is C 12 H 21 N ⁇ HCl, which is a drug for the treatment of dementia developed by Merz, Germany. Its structural formula is as follows:
  • Memantine Hydrochloride is a novel, low-to-moderate, voltage-dependent, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that non-competitively blocks NMDA receptors and reduces valleys.
  • NMDA N-methyl-D-aspartate
  • CPMP European Patent and Drug Administration
  • CPMP European Patent and Drug Administration
  • memantine hydrochloride is also effective in patients with mild to moderate Alzheimer's disease.
  • the recommended dose for the first week is 10 mg/d
  • the maximum daily dose for adults is 20 mg
  • the molecular weight is 215.76, and the free base molecular weight is 179.3.
  • Paroxetine mesylate or paroxetine hydrochloride is used to treat various types of depression, including depression with anxiety and reactive depression. Its molecular formula is: C 20 H 24 FNO 6 S or C 19 H 21 ClFNO 3 , and its structural formula is as follows:
  • the recommended initial dose is 20mg/d, which can be gradually increased, up to 50mg/d.
  • the initial dose is 10mg/d, and the dosage can be increased later.
  • the maximum is 60mg / d; in the treatment of obsessive-compulsive disorder, the initial dose is 20mg / d, the subsequent can be gradually increased, up to 60mg / d.
  • Its molecular weight is 425.47 and the free base molecular weight is 329.37.
  • (NMDA) receptor antagonists and SSRI-type antidepressants can be used for the prevention or adjuvant treatment of Alzheimer's disease. Because the pathogenesis of Alzheimer's disease is very complicated, the cause is not clear, and it cannot be completely controlled by a single treatment. The combination of drugs with different mechanisms may have good effects.
  • the technical problem to be solved by the present invention is how to obtain memantine and paroxetine co-crystal drugs with better therapeutic effect, higher drug bioavailability, lower dosage, and less adverse reactions.
  • a memantine paroxetine eutectic salt characterized in that the memantine paroxetine eutectic salt has the formula C19H20FNO3 ⁇ C12H21N ⁇ H2SO4 ⁇ XH2O, wherein 0 ⁇ X ⁇ 5, the memantine molecule and the paroxetine molecule Combined by non-covalent bonds.
  • the X-ray powder diffraction pattern of the eutectic salt measured by a powder diffractometer includes the following lattice plane spacing They are: 19.06, 7.48, 7.13, 5.86, 4.97, 4.45, 4.20, 3.90, 3.80.
  • the invention also protects the preparation method of the memantine paroxetine co-crystal salt, comprising the following steps:
  • Step 1 The memantine and paroxetine are sequentially dissolved in a solvent of -10 to 25 ° C, and the volume-to-mass ratio of the solvent to paroxetine is (1 to 20 mL): 1 g, and then the concentration is 10% to 80%. Sulfuric acid, stirring and crystallization for 1 to 24 hours, wherein the molar ratio of memantine, paroxetine and sulfuric acid is (0.8 to 1.2): (0.8 to 1.2): (0.8 to 1.2);
  • Step 2 The solid is suction filtered, and dried at 40-80 ° C for 2 to 12 hours to obtain a eutectic salt.
  • the solvent temperature is 0 to 10 °C.
  • volume-to-mass ratio of the solvent to paroxetine in the first step is (3 to 10 mL): 1 g.
  • the solvent is one of tetrahydrofuran, acetone, dichloromethane, isopropanol, methanol, ethanol, n-butanol, acetonitrile, diethyl ether or ethyl acetate.
  • the concentration of sulfuric acid in the first step is 30-40%.
  • the invention also protects the use of the eutectic salt described in the preparation or prevention of a disease or condition, Alzheimer's disease, obsessive-compulsive disorder and depression.
  • the present invention also contemplates a pharmaceutical composition
  • a pharmaceutical composition comprising the eutectic salt and at least one pharmaceutically acceptable additive, the pharmaceutically acceptable additive being a diluent, a filler, a disintegrant, a flow aid A lubricant, a binder, an antioxidant, a buffer or a colorant.
  • the disease or condition is Alzheimer's disease, obsessive-compulsive disorder, depression, and Parkinson's disease.
  • the present invention also protects a pharmaceutical composition
  • a pharmaceutical composition comprising the eutectic salt, at least one therapeutic agent, and at least one pharmaceutically acceptable additive, which is donepezil, galantamine or rivastigmine .
  • the disease or condition is Alzheimer's disease, obsessive-compulsive disorder, depression, and Parkinson's disease.
  • compositions of the present invention can be prepared according to well-known methods, which are suitable for gastrointestinal administration (for example, oral or rectal administration) and parenteral administration, to mammals (warm-blooded animals), including humans, said combination
  • the compositions include a therapeutically effective amount of the combination product or a multi-targeted eutectic salt, which may be used alone or in combination with at least one pharmaceutically acceptable carrier, particularly a carrier suitable for gastrointestinal or parenteral application.
  • Typical oral formulations include tablets, capsules, syrups, oral solutions, granules and suspensions.
  • Typical injectable formulations include solutions and suspensions.
  • additives suitable for use in the present invention include, but are not limited to, diluents or fillers, disintegrants, glidants, lubricants, binders, colorants, and combinations thereof, provided they are chemically inert, Thus there is no negative impact on the combined product or multi-targeted eutectic salts, and the amount of each additive in the solid formulation can vary within the conventional range of the art.
  • Examples of typical pharmaceutically acceptable carriers suitable for use in the above formulations are: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and its derivatives, For example, sodium hydroxymethylcellulose, ethylcellulose and methylcellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; a fatty acid alkaline earth metal salt such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants; Glycol polymers; ⁇ -cyclodextrin; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders,
  • compositions for gastrointestinal or parenteral administration are, for example, unit dosage forms such as coated tablets, tablets, capsules or suppositories, and ampoules. They can be prepared according to well known methods, for example, by conventional mixing, granulating, coating, concentrated or freeze drying. Therefore, the pharmaceutical composition for oral administration can be obtained by mixing a linked prodrug, a combination product or a multi-targeted eutectic salt with a solid excipient, and if necessary, granulating the mixture obtained above, and If desired or necessary, the mixture or granules are formed into the tablet core of a tablet or coated tablet after the addition of suitable excipients.
  • the dosage of the active compound in the eutectic salt or pharmaceutical composition depends on a variety of factors, such as the mode of administration, the type of mammal, age and/or individual condition. Dosages for oral administration that set efficacy in animal disease models range from about 0.1 mg/kg/day to about 100 mg/kg/day, and human therapeutic settings range from about 0.1 mg/day to about 200 mg/day.
  • the preferred dosage of the eutectic salt or pharmaceutical composition of the invention is a therapeutically effective dose.
  • the eutectic salt of the present invention is memantine paroxetine sulfate, and the mechanism of action is a 5-HT inhibitor and an NMDA receptor antagonist, and belongs to a multi-target drug.
  • the eutectic salt has the advantages of a multi-target mechanism in the patient population, and has the characteristics of reducing the occurrence of complications, reducing the recurrence rate, improving the quality of life of the patient, and reducing the burden of family care during the treatment process.
  • the eutectic salt of the present invention can also be combined with other drugs having different mechanisms of action to form a compound preparation or a combination application to obtain an unexpected clinical effect.
  • the preliminary pharmacokinetic experiments by testing the memantine paroxetine eutectic salt and memantine showed that the eutectic salt can improve the absorption of the drug, can significantly increase the blood concentration, improve the bioavailability, reduce the dosage and reduce the adverse drug reactions. Provide a material basis.
  • the main pharmacokinetic parameters such as t 1/2 , T max , C max and AUC (0) can be found.
  • the eutectic salt can change the pharmacokinetic parameters of the drug, especially to improve the absorption capacity of memantine in the body, and to reduce the dose when the same blood concentration is reached. May reduce the adverse effects of the drug.
  • the eutectic salt of the invention has the corresponding curative effect through the multi-target mechanism, and can significantly improve the bioavailability of memantine after forming the eutectic salt, and provides a basis for reducing the dosage of the drug and reducing the adverse reaction, and has an important potential. Clinical application value.
  • Example 1 is an X-ray powder diffraction pattern of C 19 H 20 FNO 3 ⁇ C 12 H 21 N ⁇ H 2 SO 4 ⁇ 3H 2 O according to Example 1 of the present invention
  • Fig. 5 is a perspective structural view showing a C 19 H 20 FNO 3 ⁇ C 12 H 21 N ⁇ H 2 SO 4 ⁇ 3H 2 O single crystal according to Example 1 of the present invention.
  • the apparatus for detecting the structure and performance of the eutectic salt in the examples of the present invention is as follows:
  • X-ray powder diffractometer Rigaku TTR III high-power X-ray diffractometer from Japan Science, measuring conditions: Cu target, 40kv, 40mA, 3°-50°, target/filter-copper/Ni filter, current /voltage -40.0mA / 40.0KV, 2 ⁇ angle range: 3 ° -50 °);
  • paroxetine mesylate added 120g (0.282mol) of paroxetine mesylate to the reaction flask, add 1200mL of 1mol / L sodium hydroxide solution, add 1200mL of ethyl acetate, keep the temperature below 30 ° C, stir until clear, no solid, static The layers were separated, and the organic phase was washed three times with water, dried over anhydrous sodium sulfate for 4 h, filtered, and concentrated under reduced pressure, and the obtained paroxetine was used;
  • memantine hydrochloride 60g (0.278mol) memantine hydrochloride was added to the reaction flask, 200mL of 1mol / L sodium hydroxide solution was added, 200mL of dichloromethane was added, the temperature was kept below 30 ° C, stirred until clear, no solid, static standing The organic phase is washed three times with water, dried over anhydrous sodium sulfate for 4 h, filtered and washed, and concentrated under reduced pressure, and the obtained memantine is used;
  • the reaction process is as follows:
  • the C 19 H 20 FNO 3 ⁇ C 12 H 21 N ⁇ H 2 SO 4 ⁇ 3H 2 O eutectic salt prepared in this example has the following structural formula:
  • the sample was analyzed by X-ray diffraction using a Rigaku TTR III high-power X-ray diffractometer from Japan Rigaku.
  • the test conditions were: Cu target, 40 kV, 40 mA, 3°-50°, target/filter: copper/Ni filter, current/ Voltage: -40.0 mA / 40.0 KV, 2 ⁇ angle range: 3 ° - 50 °), measured X-ray powder diffraction data Values: 19.0629, 7.4792, 7.1407, 5.9035, 4.9778, 4.4550, 4.1107, 3.8866, 3.7882.
  • the X-ray diffraction pattern is shown in Figure 1.
  • the eutectic salt prepared in this example corresponds to a 2 ⁇ value of 4.6180, 11.8380, 12.3792, 14.9811, 17.785, 19.8835, 21.6020, 22.80, 23.381.
  • the eutectic salt is characterized by infrared absorption spectroscopy obtained by Fourier transform infrared spectroscopy (FT-IR) spectrometry, using the important bands described below (represented by the reciprocal of the wavelength data (cm-1)): Thermo Scientific Instrument Co. USA, Nicolet 8700 Fourier Transform Infrared Spectrometer, test samples were prepared by KBr tableting, main absorption peak position (cm -1 ): 3433 (s), 2920 (s), 1633 (m), 1606 (m), 1511 (m), 1489 (m), 1471 (m), 1226 (m), 1186 (m), 1125 (m), 1038 (m), 933 (m), 835 (m), 620 (m).
  • the infrared spectrum is shown in Figure 2.
  • the samples were measured using a Bruker Avance III 400 superconducting nuclear magnetic resonance spectrometer.
  • the solvent was determined: DMSO-d, internal standard: TMS.
  • NMR 13 C spectral data (ppm): 162.08, 159.68, 153.79, 147.76, 141.21, 139.48, 129.34, 129.26, 115.24, 115.03, 107.82, 105.45, 100.93, 97.68, 68.48, 51.62, 49.58, 46.35, 45.78, 43.83, 41.64, 41.58, 38.79, 38.33, 31.82, 30.48, 29.66, 29.15.
  • the map is shown in Figure 3.
  • the NMR 1 H spectrum data is as follows: 8.32 (Brs, 1H), 7.34 (dd, 2H), 7.08 (t, 2H), 6.67 (d, 1H), 6.38 (d, H), 6.11 (dd, 1H), 5.89 (s, 2H), 4.04 (Brs, 2H), 3.57–3.39 (m, 3H), 3.32 (d, 1H), 2.82 (dt, 3H), 2.60 (s, 1H), 2.25 (d, 1H) , 2.06 (s, 1H), 1.73 (m, 3H), 1.50 (dd, 4H), 1.33 - 1.16 (m, 4H), 1.13 - 1.00 (m, 2H), 0.78 (s, 6H).
  • the map is shown in Figure 4.
  • Test conditions single crystal data single crystal X-ray diffractometer, light source: Temperature: room temperature; ⁇ angle collection range: 3.60 ⁇ 69.44°
  • Crystal shape block crystal
  • the sample was analyzed by X-ray diffraction using a Rigaku TTR III high-power X-ray diffractometer from Japan Rigaku.
  • the test conditions were: Cu target, 40 kV, 40 mA, 3°-50°, target/filter: copper/Ni filter, current/ Voltage: -40.0 mA / 40.0 KV, 2 ⁇ angle range: 3 ° - 50 °), measured X-ray powder diffraction data Values: 19.050, 7.461, 7.147, 5.9091, 4.9849, 4.4568, 4.1587, 3.8983, 3.8052.
  • the eutectic is characterized by infrared absorption spectroscopy obtained by Fourier transform infrared spectroscopy (FT-IR) spectrometry, using the important bands described below (represented by the reciprocal of the wavelength data (cm-1)): Thermo Scientific Instrument Co.
  • FT-IR Fourier transform infrared spectroscopy
  • the samples were measured using a Bruker Avance III 400 superconducting nuclear magnetic resonance spectrometer.
  • the solvent was determined: DMSO-d, internal standard: TMS.
  • NMR 13 C spectral data 160.93, 153.79, 147.77, 141.24, 139.38, 129.36, 115.26, 115.06, 107.80, 105.44, 100.96, 97.68, 68.41, 51.69, 49.61, 46.05, 45.67, 43.65, 41.60, 41.42, 38.50, 38.23, 31.82, 30.06, 29.68, 29.18.
  • the NMR 1 H spectrum data is as follows: 8.35 (Brs, 1H) 7.35 (dd, 2H), 7.09 (t, 2H), 6.68 (d, 1H), 6.39 (d, 1H), 6.12 (dd, 1H), 5.90 (s, 2H), 4.06 (Br, 2H), 3.58-3.40 (m, 3H), 3.33 (d, 1H), 2.83 (dt, 3H), 2.61 (s, 1H), 2.26 (d, 1H), 2.07 (s, 1H), 1.74 (m, 3H), 1.51 (dd, 4H), 1.34-1.17 (m, 4H), 1.14-1.01 (m, 2H), 0.79 (s, 6H).
  • thermoelectric company TQ/Orbitrap XL Fourier transform electrostatic field orbitrap mass spectrometer was used.
  • Test method GB/T 6041-2002 General rules for mass spectrometry. The test results are shown in Table 1.
  • Mass-to-charge ratio (m/z) (measured value) Mass-to-charge ratio (m/z) (theoretical value) Relative abundance (%) Molecular formula 180.17444 180.17468 100.00 C 12 H 22 N 4 330.15002 330.15000 10.19 C 19 H 21 O 3 NF
  • the NMR data are: 1 H NMR (400 MHZ, DMSO-d): 7.37 (2H), 7.13 (2H), 6.70 (1H), 6.42 (1H), 6.14 (1H, 5.93 (2H), 3.54-3.46 (3H), 3.33(1H), 2.86(3H), 2.26(1H), 2.10(1H), 1.75(3H), 1.56(4H), 1.28(4H), 1.14-1.07(2H), 0.82(6H); white prepared Solid X-ray powder diffraction characteristics Values: 19.0648, 7.4908, 7.1171, 5.8144, 4.9614, 4.4404, 4.2498, 3.91010, 3.7913.
  • the powder X-ray diffraction of the memantine paroxetine co-crystal salt obtained in Example 3 has the same characteristics as the eutectic salt of Example 1. value.
  • the hydrogen nuclear magnetic resonance of the memantine paroxetine co-crystal salt obtained in Example 3 had the same absorption peak as in Example 1.
  • Powder X-ray diffraction of the memantine paroxetine co-crystal salt obtained in Example 4 has the same characteristics as in Example 1. value.
  • the hydrogen nuclear magnetic resonance of the memantine paroxetine co-crystal salt obtained in Example 4 had the same absorption peak as in Example 1.
  • Powder X-ray diffraction of the memantine paroxetine eutectic salt obtained in Example 5 has the same characteristics as in Example 1. value.
  • the hydrogen nuclear magnetic resonance of the memantine paroxetine co-crystal salt obtained in Example 5 had the same absorption peak as in Example 1.
  • LC/MS Thermo Finnigan TSQ Quantum, consisting of Surveyor As, Surveyor MS Pump Plus and TSQ Quantum, Thermo Fisher Scientific; Sartorius BP-211D electronic balance; Thermo STRATOS high speed refrigerated centrifuge; Eppendorf PCB-11 Type micro vortex mixer; Milli-Q Grandient pure water meter.
  • Ion detection method multiple reaction monitoring (MRM); ion polarity: positive ion (Positive); ionization mode: electrospray ionization (ESI); ionization voltage (IS): 3000.0V; temperature: 300 ° C; sheath gas : 35; auxiliary gas: 30.
  • MRM multiple reaction monitoring
  • ion polarity positive ion (Positive)
  • ionization mode electrospray ionization (ESI)
  • temperature 300 ° C
  • sheath gas 35
  • auxiliary gas 30.
  • mice Ten rats were randomly divided into two groups, 5 in each group, respectively: group A: memantine hydrochloride 5.6 mg/kg; group B: eutectic salt 17.4 mg/kg;
  • the rats were fasted for 12 h before the experiment, and the test drugs were administered by gavage, and the administration volume was 1 ml/100 g.
  • the administration volume was 1 ml/100 g.
  • the main pharmacokinetic parameters such as t1/2, Tmax, Cmax and AUC (0- ⁇ ) can be found. There was a significant difference; the ratio comparison showed that the t 1/2 time was significantly prolonged to 2.79 times; the T max time was extended to 1.41 times; the C max value was significantly increased to 1.62 times, AUC (0- ⁇ ) , Significantly enhanced, at 4.10 times.

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Abstract

本发明公开了一种美金刚帕罗西汀共晶盐及其制备方法、药物组合物、应用，本发明的共晶盐为美金刚帕罗西汀硫酸水合物，作用机制为5-HT抑制剂和NMDA受体拮抗剂，属于多靶点药物。初步药动学实验表明，共晶盐与美金刚的主要药动学参数如t 1/2、T max、C max和AUC (0 ∞),存在显著性差异；表明共晶盐可以改善药物的吸收，提高血药浓度，改善生物利用度，提高疗效，为减少用药剂量，降低药品不良反应提供物质基础。同时本发明的共晶盐除作为多靶点药物，还可以和其他作用机制不同的药物组成复方制剂或联合应用，以获得意想不到的临床疗效。

Description

一种美金刚帕罗西汀共晶盐及其制备方法、药物组合物、应用 技术领域
本发明涉及药物合成技术领域，更具体涉及一种美金刚帕罗西汀共晶盐及其制备方法、药物组合物、应用。
背景技术
阿尔茨海默病(AD)又称为老年性痴呆，是以日常生活能力下降、行为异常及认知功能障碍为特征的中枢神经系统退行性疾病。神经退行性疾病的患者常并发抑郁症状，据不完全统计约25％～40％的阿尔茨海默病患者可能患有抑郁症。抑郁和AD相互促进疾病的发生发展，而引起抑郁和AD的共同始发因素主要为长期的慢性应激。2011年Kobayashi等提出了“抑郁-痴呆中间状态”的概念，认为处于“抑郁-痴呆中间状态”的患者若得到及时有效治疗，可预防或延缓AD的发生。2002年，美国国立精神卫生院就制定了有关阿尔茨海默症患者抑郁症的诊断标准，其具体要求主要有:患者在符合AD诊断标准的同时，须具有3项或3项以上的抑郁症状，如抑郁情绪、失眠、食欲丧失、精神运动兴奋性下降、激越、倦怠、社会和日常生活兴趣或愉快反应减少、社会脱离或退缩、自我价值否认、无助、过分自责，自杀倾向等。且该标准要求患者的抑郁症状须持续2周以上。足以可见，阿尔茨海默症与抑郁症确实存有一定临床特征相关性。
阿尔茨海默症患者、抑郁症患者或者两者疾病的共患者，对于目前临床药物的开发都是难点和热点，是目前未被临床治疗满足的药物，也是临床急需开发的药物，这两种疾病已成为世界重大公共卫生问题。
抑郁症与AD之间具备一定共病基础，近年来，临床研究表明部分抗抑郁药可用于改善AD患者伴发的抑郁症状，并进一步改善痴呆症状，其中主要有SSRIs类抗抑郁药、天然抗抑郁药等。目前，有相关研究表明抗抑郁药具有一定改善和预防阿尔茨海默症作用，而近年来临床上也常将抗抑郁药应用于辅助治疗阿尔茨海默症，且取得一定成效。
盐酸美金刚化学名称为3，5-二甲基-1-氨基-金刚烷盐酸盐(3,5-Dimethyl-1-aminoadamantane hydrochloride)，又名3，5-二甲基三环[3.3.1.1.(3.7)]癸烷-1-氨基盐酸盐(3,5-Dimethyltricyclo(3.3.1.1(3,7))decan-1-aminehydrochloride)。其分子式为C 12H 21N·HCl，是由德国Merz公司研制的治疗痴呆症药物，其结构式如下：
Figure PCTCN2019075891-appb-000001
盐酸美金刚是一种新型、低中度亲和力、电压依赖、非竞争性N-甲基-D-天冬氨酸(NMDA)受体拮抗药，可非竞争性阻滞NMDA受体，降低谷氨酸引起的NMDA受体过度兴奋，防止细胞凋亡，改善记忆，是新一代改善认知功能的药物。2002年2月，欧洲专利药品委员会(CPMP)批准其用于中、重度阿尔茨海默病患者的治疗，同年8月在德国上市，2003年10月17日被美国食品与药品监督管理局(FDA)批准用于治疗中、重度阿尔茨海默病患者。进一步的研究表明，盐酸美金刚对轻、中度阿尔茨海默病患者也有效。第一周建议用量为10mg/d，成人每日最大剂量为20mg，其分子量为215.76，游离碱分子量为179.3。
甲磺酸帕罗西汀或盐酸帕罗西汀用于治疗各种类型的抑郁症，包括伴有焦虑的抑郁症及反应性抑郁症。其分子式为：C 20H 24FNO 6S或C 19H 21ClFNO 3，其结构式如下：
Figure PCTCN2019075891-appb-000002
甲磺酸帕罗西汀在治疗重性抑郁障碍时，推荐的初始剂量为20mg/d，后续可逐步增加，最多为50mg/d；在治疗惊恐障碍时，初始剂量为10mg/d，后期可增加用量，最多为60mg/d；在治疗强迫症时，初始剂量为20mg/d，后续可逐步增加，最多为60mg/d。其分子量为425.47，游离碱分子量为329.37。当美金刚与帕罗西汀以1:1的摩尔比结合时，用于药物制剂，符合单独制剂的用量区间。
所以，(NMDA)受体拮抗药和SSRI类抗抑郁药可以用以阿尔茨海默病的防治或辅助治疗。由于阿尔茨海默症的发病机制十分复杂，病因尚未明确，靠单一治疗无法完全控制，采用作用机制不同的药物联合应用，可能具有良好的效果。
发明内容
本发明所要解决的技术问题在于如何获取更好疗效、更高药物生物利用度、更低使用剂量、更少不良反应的美金刚与帕罗西汀共晶药物。
本发明是通过以下技术方案解决上述技术问题的：
一种美金刚帕罗西汀共晶盐，其特征在于，所述美金刚帕罗西汀共晶盐的分子式为C19H20FNO3·C12H21N·H2SO4·XH2O，其中0≤X≤5，所述美金刚分子与帕罗西汀分子通过非共价键结合。
进一步地，所述X＝3。
进一步地，所述共晶盐经粉末衍射仪测定的X-射线粉末衍射图谱包括下列晶格平面间隔
Figure PCTCN2019075891-appb-000003
为：19.06、7.48、7.13、5.86、4.97、4.45、4.20、3.90、3.80。
本发明还保护所述的美金刚帕罗西汀共晶盐的制备方法，包括以下步骤：
步骤一、将美金刚、帕罗西汀依次溶于-10～25℃溶剂中，所述溶剂与帕罗西汀的体积质量比为(1～20mL)：1g，然后滴加浓度为10％～80％的硫酸，搅拌析晶1～24h，其中美金刚、帕罗西汀、硫酸三者的摩尔比为(0.8～1.2):(0.8～1.2):(0.8～1.2)；
步骤二、抽滤固体，在40～80℃条件下干燥2～12h，得到共晶盐。
进一步地，所述步骤一中溶剂温度为0～10℃。
进一步地，所述步骤一中溶剂与帕罗西汀的体积质量比为(3～10mL)：1g。
进一步地，所述溶剂为四氢呋喃、丙酮、二氯甲烷、异丙醇、甲醇、乙醇、正丁醇、乙腈、乙醚、乙酸乙酯中的一种。
进一步地，所述步骤一中硫酸浓度为30～40％。
本发明还保护所述的共晶盐在制备或预防疾病或病症中的应用，所述疾病或病症为阿尔茨海默病、强迫症和抑郁症。
本发明还保护一种药物组合物，其包含所述的共晶盐和至少一种药学上可接受的添加剂，所述药学上可接受的添加剂为稀释剂、填充剂、崩解剂、助流剂、润滑剂、粘合剂、抗氧剂、缓冲剂或着色剂。
进一步地，所述疾病或病症为阿尔茨海默病、强迫症、抑郁症和帕金森症。
本发明还保护一种药物组合物，其包含所述的共晶盐、至少一种治疗药物和至少一种药学上可接受的添加剂，所述治疗药物为多奈哌齐、加兰他敏或卡巴拉汀。
进一步地，所述疾病或病症为阿尔茨海默病、强迫症、抑郁症和帕金森症。
本发明药用组合物可以根据众所周知的方法制备，它们适用于胃肠给药(例如口服或直肠给药)和胃肠外给药，给予哺乳动物(温血动物)，包括人，所述组合物包括治疗有效量的组合产品或多靶点作用的共晶盐，它们可以单独使用或与至少一种药学上可接受的载体(特别是适用于胃肠或肠胃外应用的载体)组合使用。典型的口服制剂包括片剂、胶囊、糖浆、口服液、颗粒剂和悬浮液。典型的注射制剂包括溶液剂和悬浮液。适用于本发明的药学上可接受的添加剂包括但不限于稀释剂或填充剂、崩解剂、助流剂、润滑剂、粘合剂、着色剂及其组合，前提是它们是化学惰性的，因而不会对组合产品或多靶点作用的共晶盐产生负面影响，固体制剂中每一种添加剂的量可以在本领域常规范围内改变。适用于上述制剂的典型的药学上可接受的载体的实例为:糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羟甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和阴离子表面活性剂；乙二醇聚合物；β-环糊精；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
用于胃肠或肠胃外给药的药物制剂为例如单位剂型，例如包衣片剂、片剂、胶囊或栓剂以及安瓿。它们可以根据众所周知的方法制备，例如，采用传统的混合、制粒、包衣、浓解或冷冻干燥。所以，用于口服的药用组合物可以通过将连接的前药、组合产品或多靶点作用的共晶盐与固体赋形剂混合而获得，如果需要，将上述获得的混合物制粒，并且如果需要或必须，在加入适当的辅料后， 将所述混合物或颗粒制成片剂或包衣片剂的片芯。
所述的共晶盐或药用组合物中的活性化合物的剂量取决于多种因素，例如，给药的模式、哺乳动物的种类、年龄和/或个体情况。在动物疾病模型中设定疗效的口服给药的剂量范围自约0.1mg/kg/天至约100mg/kg/天，人类治疗设定的剂量范围自约0.1mg/天至约200mg/天。本发明的共晶盐或药用组合物优选的剂量为治疗有效剂量。
本发明相比现有技术具有以下优点：
本发明共晶盐为美金刚帕罗西汀硫酸盐，作用机制为5-HT抑制剂和NMDA受体拮抗剂，属于多靶点药物。该共晶盐为针对患者人群除了多靶点的作用机制优势外，在治疗过程中具有减少患者并发症的发生，降低复发率，提高患者生活质量，减轻家庭护理负担等特点。同时本发明的共晶盐除作为多靶点药物，还可以和其他作用机制不同的药物组成复方制剂或联合应用，以获得意想不到的临床疗效。
通过测试美金刚帕罗西汀共晶盐及美金刚的初步药动学实验表明，共晶盐可以改善药物的吸收，可以显著提高血药浓度，改善生物利用度，为减少用药剂量，降低药品不良反应提供物质基础。经比对相同摩尔剂量美金刚帕罗西汀共晶盐与盐酸美金刚的主要药动学参数及其比值，可以发现，主要药动学参数如t 1/2、T max、C max和AUC (0-∞),存在显著性差异；其比值对比发现：t 1/2时间显著延长，为2.79倍；T max时间延长，为1.41倍；C max数值显著增大，为1.62倍，AUC (0-∞),显著增强，为4.10倍。该结果提示我们在相同给药剂量下，共晶盐可以改变药物的药动学参数，尤其是可以提高美金刚在体内的吸收能力，在达到相同血药浓度情况下，可以降低给药剂量，可能降低药物的不良反应。
故本发明共晶盐通过多靶点机制产生相应的疗效，同时在形成共晶盐后可以显著提高美金刚的 药物生物利用度，为降低药物使用剂量，降低不良反应提供基础，具有重要潜在的临床应用价值。
附图说明
图1为本发明实施例1的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O的X-射线粉末衍射图谱；
图2为本发明实施例1的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O的红外图谱；
图3为本发明实施例1的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O的核磁共振碳谱图；
图4为本发明实施例1的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O的核磁共振氢谱图；
图5为本发明实施例1的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O单晶的立体结构图。
具体实施方式
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
本发明实施例中检测共晶盐结构及性能的仪器如下：
1、X射线粉末衍射仪，日本理学公司Rigaku TTR III型大功率X射线衍射仪,测条件：Cu靶，40kv，40mA，3°-50°，靶/滤波片-铜/Ni滤波片，电流/电压-40.0mA/40.0KV，2θ角范围：3°-50°)；
2、傅里叶变换红外光谱仪，美国热电仪器公司(Thermo Scientific Instrument Co.U.S.A)，Nicolet 8700傅里叶变换红外光谱仪；
3、Bruker Avance III 400超导核磁共振仪，测定溶剂：DMSO-d，内标：TMS；
4、热电公司TQ/Orbitrap XL傅立叶变换静电场轨道阱质谱仪。
实施例1制备C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O
将120g(0.282mol)甲磺酸帕罗西汀加入到反应瓶中，加入1200mL的1mol/L的氢氧化钠溶液， 加入1200mL的乙酸乙酯，保持温度在30℃以下，搅拌至澄清无固体，静置分层，有机相使用水洗三次，加入无水硫酸钠干燥4h，过滤洗涤、减压浓缩，得到的帕罗西汀备用；
将60g(0.278mol)盐酸美金刚加入到反应瓶中，加入200mL的1mol/L的氢氧化钠溶液，加入200mL的二氯甲烷，保持温度在30℃以下，搅拌至澄清无固体，静置分层，有机相使用水洗三次，加入无水硫酸钠干燥4h，过滤洗涤，减压浓缩，得到的美金刚备用；
将77.4g(0.2350mol)帕罗西汀使用387mL四氢呋喃溶解，转移到反应瓶中，加入42.1g(0.235mol)美金刚，搅拌均匀。冰水浴，保持温度为0～10℃，搅拌滴加33％的硫酸69.5g(0.235mol)。加完后，5℃左右搅拌析晶4h，过滤，得到的固体于50℃鼓风8h，得到白色固体117.1g，收率82.1％。
反应流程示意图如下：
Figure PCTCN2019075891-appb-000004
本实施例制备的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O共晶盐具有如下结构式：
Figure PCTCN2019075891-appb-000005
对本实施例制备的产品进行性能表征：
1、X-射线粉末衍射表征
样品使用日本理学公司Rigaku TTR III型大功率X射线衍射仪进行X-衍射分析,测试条件：Cu靶，40kv，40mA，3°-50°，靶/滤波片：铜/Ni滤波片，电流/电压：-40.0mA/40.0KV，2θ角范围：3°-50°)，测得的X-射线粉末衍射数据
Figure PCTCN2019075891-appb-000006
值：19.0629，7.4792，7.1407，5.9035，4.9778，4.4550，4.1107，3.8866，3.7882。X-衍射图谱见图1。如图1所示，本实施例制备的共晶盐对应2θ值为4.6180，11.8380，12.3792，14.9811，17.7805，19.8995，21.6020，22.80，23.381。
2、红外光谱表征
该共晶盐通过用傅里叶变换红外光谱法(FT-IR)光谱仪而得到的红外吸收光谱定性，采用下面所述的重要波段(以波长数据的倒数(cm-1)表示)定性:美国热电仪器公司(Thermo Scientific Instrument Co.U.S.A)，Nicolet 8700傅里叶变换红外光谱仪，测试样品用KBr压片制样，主要吸收峰位置(cm -1)：3433(s)，2920(s)，1633(m)，1606(m)，1511(m)，1489(m)，1471(m)，1226(m)，1186(m)，1125(m)，1038(m)，933(m)，835(m)，620(m)。红外图谱见图2。
3、核磁共振谱表征
样品采用BrukerAvance III 400超导核磁共振仪进行测定，测定溶剂：DMSO-d，内标：TMS。
核磁共振 13C谱数据(ppm):162.08,159.68,153.79,147.76,141.21,139.48,129.34,129.26,115.24,115.03,107.82,105.45,100.93,97.68,68.48,51.62,49.58,46.35,45.78,43.83,41.64,41.58,38.79,38.33,31.82,30.48,29.66,29.15。图谱见图3。
核磁共振 1H谱数据如下：8.32(Brs,1H),7.34(dd,2H),7.08(t,2H),6.67(d,1H),6.38(d,H),6.11(dd,1H),5.89(s,2H),4.04(Brs,2H),3.57–3.39(m,3H),3.32(d,1H),2.82(dt,3H),2.60(s,1H),2.25(d,1H),2.06(s,1H),1.73(m,3H),1.50(dd,4H),1.33–1.16(m,4H),1.13–1.00(m,2H),0.78(s,6H)。图谱见图4。
为进一步说明本发明的美金刚帕罗西汀共晶盐的结构特征，取1g白色固体共晶盐，用100mL二氯甲烷溶解后，室温放置缓慢析晶，析出后过滤，得到透明块状结晶，所得的块状结晶分别进行单晶结构测试、X-射线粉末衍射、红外、核磁、质谱表征，表征结果如下：
1、单晶结构测试
测试条件：单晶数据单晶X射线衍射仪，光源：
Figure PCTCN2019075891-appb-000007
温度：室温；θ角收集范围：3.60～69.44°
数据和参数:
分子式：各单位分子式：C 19H 2,1FNO 3，C 12H 22N，O 4S，3(H 2O)；总分子式：C 31H 49FN 2O 10S
分子量：660.78
结晶颜色：无色
结晶形状：块状晶体
晶系：正交晶系
空间群：P212121
晶胞参数：a＝7.2618(1)
b＝11.9317(1)
c＝38.3731(4)
alpha＝90
beta＝90
gamma＝90
Z(单位晶胞内不对称单位的数量)：4
计算强度：1.320g/cm 3
根据委托单位提供的晶体成份及分子式为C 31H 49FN 2O 10S，在测量的单晶衍射数据基础上，通过WinGX(v1.80.05)软件解析和精修得到的晶体可能空间结构如图5所示。
2、X-射线粉末衍射表征
样品使用日本理学公司Rigaku TTR III型大功率X射线衍射仪进行X-衍射分析,测试条件：Cu靶，40kv，40mA，3°-50°，靶/滤波片：铜/Ni滤波片，电流/电压：-40.0mA/40.0KV，2θ角范围：3°-50°)，测得的X-射线粉末衍射数据
Figure PCTCN2019075891-appb-000008
值：19.050，7.461，7.147，5.9091，4.9849，4.4568，4.1587，3.8983，3.8052。
3、红外光谱表征
该共晶物通过用傅里叶变换红外光谱法(FT-IR)光谱仪而得到的红外吸收光谱定性，采用下面所述的重要波段(以波长数据的倒数(cm-1)表示)定性:美国热电仪器公司(Thermo Scientific Instrument Co.U.S.A)，Nicolet 8700傅里叶变换红外光谱仪，测试样品用KBr压片制样，主要 吸收峰位置(cm-1)：3432(s)，2920(s)，1633(m)，1606(m)，1510(m)，1489(m)，1471(m)，1186(m)，1125(m)，1038(m)，933(m)，620(m)，较之于物理混合物的红外吸收光谱有非常明显的光谱峰和位移。
4、核磁共振谱表征
样品采用BrukerAvance III 400超导核磁共振仪进行测定，测定溶剂：DMSO-d，内标：TMS。
核磁共振 13C谱数据(ppm):160.93,153.79,147.77,141.24,139.38,129.36,115.26,115.06,107.80,105.44,100.96,97.68,68.41,51.69,49.61,46.05,45.67,43.65,41.60,41.42,38.50,38.23,31.82,30.06,29.68,29.18。
核磁共振 1H谱数据如下：8.35(Brs,1H)7.35(dd,2H),7.09(t,2H),6.68(d,1H),6.39(d,1H),6.12(dd,1H),5.90(s,2H),4.06(Br,2H),3.58-3.40(m,3H),3.33(d,1H),2.83(dt,3H),2.61(s,1H),2.26(d,1H),2.07(s,1H),1.74(m,3H),1.51(dd,4H),1.34-1.17(m,4H),1.14-1.01(m,2H),0.79(s,6H)。
5、质谱表征：
采用热电公司TQ/Orbitrap XL傅立叶变换静电场轨道阱质谱仪，测试方法：GB/T 6041-2002质谱分析方法通则。测试结果见表1。
表1样品质谱图中主要裂解碎片峰的位置及相对丰度
质荷比(m/z)(测定值) 质荷比(m/z)(理论值) 相对丰度(％) 分子式
180.17444 180.17468 100.00 C 12H 22N 4
330.15002 330.15000 10.19 C 19H 21O 3NF
由上述的表征数据可以看出，本实施例制备的C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O具有与单晶相同的物相与结构，与美金刚与帕罗西汀两种活性成分通过简单的物料混合得到的混合物的物相和结构截然不同。
实施例2制备C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O
分别取50g甲磺酸帕罗西汀和30g盐酸美金刚，按照实施例1的方法制备帕罗西汀和美金刚；
将15.98g(0.0485mol)帕罗西汀加入到80mL四氢呋喃，搅拌溶解均匀，加入8.70g(0.0485mol)美金刚，搅拌均匀；保持溶液温度0～10℃，向溶液中滴加33％的硫酸14.4g(0.0485mol)，加完后，搅拌析晶2h，过滤，得到的固体于50℃鼓风干燥6h，得到白色固体21.2g。
核磁数据为： 1HNMR(400MHZ,DMSO-d):7.37(2H),7.13(2H),6.70(1H),6.42(1H),6.14(1H,5.93(2H),3.54-3.46(3H),3.33(1H),2.86(3H),2.26(1H),2.10(1H),1.75(3H),1.56(4H),1.28(4H),1.14-1.07(2H),0.82(6H)；制备的白色固体的X-射线粉末衍射特征
Figure PCTCN2019075891-appb-000009
值：19.0648、7.4908、7.1171、5.8144、4.9614、4.4404、4.2498、3.9010、3.7913。
实施例3制备C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O
分别取50g甲磺酸帕罗西汀和30g盐酸美金刚，按照实施例1的方法制备帕罗西汀和美金刚；
将12.35g(0.0375mol)帕罗西汀加入到62mL丙酮，搅拌溶解均匀，加入6.72g(0.0375mol)美金刚，搅拌均匀；保持溶液温度0～10℃，向溶液中滴加33％的硫酸11.13g(0.0375mol)，加完后，搅拌析晶2h，过滤，得到的固体于50℃鼓风干燥6h，得到白色固体10.34g。
实施例3所得的美金刚帕罗西汀共晶盐的粉末X-射线衍射具有和实施例1的共晶盐相同的特征
Figure PCTCN2019075891-appb-000010
值。
实施例3所得的美金刚帕罗西汀共晶盐的氢核磁共振具有和实施例1相同的吸收峰。
实施例4制备C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O
分别取50g甲磺酸帕罗西汀和30g盐酸美金刚，按照实施例1的方法制备帕罗西汀和美金刚；
将9.80g(0.0298mol)帕罗西汀加入到49mL二氯甲烷，搅拌溶解均匀，加入5.34g(0.0298mol)美金刚，搅拌均匀；保持溶液温度0～10℃，向溶液中滴加33％的硫酸8.85g(0.0298mol)，加完后，搅拌析晶2h，过滤，得到的固体于50℃鼓风干燥6h，得到白色固体6.38g。
实施例4所得的美金刚帕罗西汀共晶盐的粉末X-射线衍射具有和实施例1相同的特征
Figure PCTCN2019075891-appb-000011
值。
实施例4所得的美金刚帕罗西汀共晶盐的氢核磁共振具有和实施例1相同的吸收峰。
实施例5制备C 19H 20FNO 3·C 12H 21N·H 2SO 4·3H 2O
分别取50g甲磺酸帕罗西汀和30g盐酸美金刚，按照实施例1的方法制备帕罗西汀和美金刚；
将11.25g(0.0342mol)帕罗西汀加入到57mL异丙醇，搅拌溶解均匀，加入6.13g(0.0342mol)美金刚，搅拌均匀；保持溶液温度0～10℃，向溶液中滴加33％的硫酸10.16g(0.0342mol)，加完后，搅拌析晶2h，过滤，得到的固体于50℃鼓风干燥6h，得到白色固体9.74g。
实施例5所得的美金刚帕罗西汀共晶盐的粉末X-射线衍射具有和实施例1相同的特征
Figure PCTCN2019075891-appb-000012
值。
实施例5所得的美金刚帕罗西汀共晶盐的氢核磁共振具有和实施例1相同的吸收峰。
实施例6美金刚帕罗西汀共晶盐药动学实验
1、实验目的
利用LC-MS/MS方法测定大鼠血浆中美金刚帕罗西汀共晶盐药动学参数
2、实验材料
2.1主要试剂
实施例1制备的美金刚帕罗西汀共晶盐；盐酸美金刚；地塞米松(中检所)；甲酸铵；甲醇均为色谱纯(Merck公司)；甲酸均为色谱纯(Aladdin公司)；乙腈均为色谱纯(Merck公司)；实验用水为去离子纯化水。
2.2动物
SD大鼠，SPF级，雄性，体重200～250g，购自浙江省实验动物中心，生产许可证号：SCXK(浙)2014-0001。
3、仪器与设备
液质联用仪：Thermo Finnigan TSQ Quantum，由Surveyor As，Surveyor MS Pump Plus和TSQ Quantum组成，赛默飞世尔科技公司；Sartorius BP-211D电子天平；Thermo STRATOS高速冷冻离心机；Eppendorf PCB-11型微型涡旋混合仪；Milli-Q Grandient纯水仪。
4、色谱-质谱条件
4.1色谱条件：
色谱柱：Waters Cortecs C18(2.1mm×50mm,2.7μm)；柱温：35℃；流动相：乙腈-10mm甲酸铵含0.1％甲酸(10:90)；流速：0.2mL·min -1；进样量：5μL。
4.2质谱条件：
离子检测方式：多重反应监测(MRM)；离子极性：正离子(Positive)；离子化方式：电喷雾离子化(ESI)；离子化电压(IS)：3000.0V；温度：300℃；鞘气：35；辅气：30。检测结果见表2。
表2
Figure PCTCN2019075891-appb-000013
5、大鼠血样收集
10只大鼠随机分为2组，每组5只，分别为：A组：盐酸美金刚5.6mg/kg；B组：共晶盐17.4mg/kg；
实验前大鼠禁食12h，灌胃给予受试药物，给药体积均为1ml/100g。分别于给药前及给药后5、10、20、40、60、120、180、240、360、480min，经眼底静脉丛采血0.5ml，肝素抗凝,4000rpm离心10min，分离血浆,用于美金刚浓度检测。
表3大鼠给药后估算的美金刚与共晶盐与药动学参数
Figure PCTCN2019075891-appb-000014
Figure PCTCN2019075891-appb-000015
7、结果讨论
经比对相同摩尔剂量美金刚帕罗西汀共晶盐与盐酸美金刚的主要药动学参数及其比值，可以发现，主要药动学参数如t1/2、Tmax、Cmax和AUC(0-∞),存在显著性差异；其比值对比发现：t 1/2时间显著延长，为2.79倍；T max时间延长，为1.41倍；C max数值显著增大，为1.62倍，AUC (0-∞), 显著增强,为4.10倍。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (13)

  1. 一种美金刚帕罗西汀共晶盐，其特征在于，所述美金刚帕罗西汀共晶盐的分子式为C 19H 20FNO 3·C 12H 21N·H 2SO 4·XH 2O，其中0≤X≤5，所述美金刚分子与帕罗西汀分子通过非共价键结合。
  2. 根据权利要求1所述的一种美金刚帕罗西汀共晶盐，其特征在于，所述X＝3。
  3. 根据权利要求2所述的一种美金刚帕罗西汀共晶盐，其特征在于，所述共晶盐经粉末衍射仪测定的X-射线粉末衍射图谱包括下列晶格平面间隔
    Figure PCTCN2019075891-appb-100001
    为：19.06、7.48、7.13、5.86、4.97、4.45、4.20、3.90、3.80。
  4. 一种如权利要求1至3任一所述的美金刚帕罗西汀共晶盐的制备方法，其特征在于，包括以下步骤：
    步骤一、将美金刚、帕罗西汀依次溶于-10～25℃溶剂中，所述溶剂与帕罗西汀的体积质量比为(1～20mL)：1g，然后滴加浓度为10％～80％的硫酸，搅拌析晶1～24h，其中美金刚、帕罗西汀、硫酸三者的摩尔比为(0.8～1.2):(0.8～1.2):(0.8～1.2)；
    步骤二、抽滤固体，在40～80℃条件下干燥2～12h，得到共晶盐。
  5. 根据权利要求4所述的美金刚帕罗西汀共晶盐的制备方法，其特征在于，所述步骤一中溶剂温度为0～10℃。
  6. 根据权利要求4所述的美金刚帕罗西汀共晶盐的制备方法，其特征在于，所述步骤一中溶剂与帕罗西汀的体积质量比为(3～10mL)：1g。
  7. 根据权利要求4至6任一所述的美金刚帕罗西汀共晶盐的制备方法，其特征在于，所述溶剂为四氢呋喃、丙酮、二氯甲烷、异丙醇、甲醇、乙醇、正丁醇、乙腈、乙醚、乙酸乙酯中的一种。
  8. 根据权利要求4所述的美金刚帕罗西汀共晶盐的制备方法，其特征在于，所述步骤一中硫酸浓度 为30～40％。
  9. 权利要求1或2或3所述的共晶盐在制备或预防疾病或病症中的应用，所述疾病或病症为阿尔茨海默病、强迫症和抑郁症。
  10. 一种药物组合物，其包含权利要求1或2或3所述的共晶盐和至少一种药学上可接受的添加剂，所述药学上可接受的添加剂为稀释剂、填充剂、崩解剂、助流剂、润滑剂、粘合剂、抗氧剂、缓冲剂或着色剂。
  11. 权利要求10所述的药物组合物在制备或预防疾病或病症中的应用，所述疾病或病症为阿尔茨海默病、强迫症、抑郁症和帕金森症。
  12. 一种药物组合物，其包含权利要求1或2或3所述的共晶盐、至少一种治疗药物和至少一种药学上可接受的添加剂，所述治疗药物为多奈哌齐、加兰他敏或卡巴拉汀。
  13. 权利要求12所述的药物组合物在制备或预防疾病或病症中的应用，所述疾病或病症为阿尔茨海默病、强迫症、抑郁症和帕金森症。
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JP7049007B2 (ja) 2022-04-06
EP3750889A1 (en) 2020-12-16
US20210038590A1 (en) 2021-02-11
JP2021516261A (ja) 2021-07-01
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