Lumepirone derivative, pharmaceutical composition and application

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a lumepirone derivative, a pharmaceutical composition and application, the lumepirone derivative is a compound shown in a formula I or a hydrate or a solvate or a pharmaceutically acceptable salt of the compound, # imgabs0 # wherein: R1 is selected from the group consisting of an optionally substituted C1-12 alkyl group, an optionally substituted C2-12 alkenyl group, an optionally substituted C2-12 alkynyl group, an optionally substituted C1-12 alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyl heterocyclic group, an optionally substituted aryl group, or an optionally substituted cycloalkyl heteroaryl group. The lumepirone derivative provided by the invention has good stability.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a lumiperone derivative, a pharmaceutical composition and a use thereof. Background Art

[0002] Lumiperone is a new type of antipsychotic drug with the chemical name 1-(4-fluorophenyl)-4-

[0003] [(6BR,10AS)-2,3,6B,9,10,10A-Hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-DE]quinoxalin-8(7H)-yl]-1-butanone.

[0004] Lumiperone is a dopamine receptor phosphoprotein modulator (DPPM) that can simultaneously and synergistically regulate the transmission of 5-hydroxytryptamine (5-HT), dopamine and glutamine neurotransmitters, thereby exerting a therapeutic effect. Thanks to this unique pharmacological mechanism, lumiperone helps treat schizophrenia or other related mental illnesses and mood disorders, and has good tolerability.

[0005] Currently, lumepirone is available in the United States in oral capsules with specifications of 10.5 mg, 21 mg and 42 mg, which need to be administered daily to maintain its blood concentration. However, due to the need for frequent administration, patients' medication compliance is poor; and oral capsules have defects such as inconvenience in use and difficulty in swallowing; therefore, it is urgent to provide a new lumepirone dosage form to improve patient compliance, which has important clinical significance. Summary of the invention

[0006] In view of the above problems, the present invention unexpectedly discovered through continuous research and experimentation that by modifying lumepirone with appropriate substituents and preparing lumepirone derivatives into suspensions, the purpose of slow release can be achieved while maintaining stability, thereby greatly improving patient compliance.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] The first aspect of the present invention provides a lumiperone derivative, which is a compound represented by formula I or a hydrate or a solvate or a pharmaceutically acceptable salt thereof;

[0009]

[0010] in:

[0011] R 1 Selected from optionally substituted C 1-12 Alkyl, optionally substituted C 2-12 Alkenyl, optionally substituted C 2-12Alkynyl, optionally substituted C 1-12 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylheterocyclyl, optionally substituted aryl or optionally substituted cycloalkylheteroaryl.

[0012] In some preferred embodiments, R 1 Selected from optionally substituted C 1-12 Alkyl, optionally substituted C 2-12 Alkenyl, optionally substituted C 2-12 Alkynyl or optionally substituted C 1-12 Alkoxy.

[0013] Preferably, R 1 C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with halogen, cyano, hydroxy, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl.

[0014] Preferably, R 1 C 2-12 Alkyl, the C 2-12 The alkyl group is optionally substituted with halogen, cyano, hydroxy, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl.

[0015] More preferably, R 1 C 7-12 Alkyl, the C 7-12 The alkyl group is optionally substituted with halogen, cyano, hydroxy, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl.

[0016] More preferably, R 1 C 1 , C 4 or C 8 Alkyl, the C 1 , C 4 or C 8 The alkyl group is optionally substituted with halogen, cyano, hydroxy, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl.

[0017] Most preferably, R 1 It is methyl, butyl or octyl.

[0018] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent.

[0019] As used herein, the term "pharmaceutically acceptable salts" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound and which are not biologically or otherwise undesirable.

[0020] In some preferred embodiments, the pharmaceutically acceptable salt is selected from methanesulfonate, oxalate, aminosalicylate or cyclaminate.

[0021] The term "substituted" used in the present invention, when referring to a chemical group, refers to one or more hydrogen atoms of the chemical group being removed and replaced by a substituent. The term "substituent" used has the common meaning well known in the art and refers to a chemical portion that is covalently attached to or fused to a parent group where applicable.

[0022] The term "C n-m " represents a range of carbon number, wherein n and m are integers and the range of carbon number includes the endpoints (i.e., n and m) and each integer point therebetween.

[0023] The term "alkyl" as used herein, whether as part of another term or used alone, refers to a saturated hydrocarbon group, which may be straight-chain or branched. n-m "Alkyl" refers to an alkyl group having n to m carbon atoms.

[0024] The term "heteroalkyl" used in the present invention refers to an alkyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkyl group can be a carbon radical or a heteroatom radical (i.e., a heteroatom can appear in the middle or at the end of the group), and can be optionally substituted independently by one or more substituents described herein. The term "heteroalkyl" encompasses alkoxy and heteroalkoxy.

[0025] As used herein, the term "alkenyl", whether used as part of another term or alone, refers to an unsaturated hydrocarbon group, which may be straight-chain or branched, having at least one carbon-carbon double bond.

[0026] The term "heteroalkenyl" as used in the present invention refers to an alkenyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkenyl group may be a carbon radical or a heteroatom radical (i.e., the heteroatom may appear in the middle or at the terminal of the group), and may be optionally substituted independently by one or more substituents described herein.

[0027] The term "alkynyl" as used herein, whether as part of other terms or used alone, refers to an unsaturated hydrocarbon group, which may be linear or branched, having at least one carbon-carbon triple bond. In certain embodiments, the alkynyl group contains 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms.

[0028] The term "heteroalkynyl" as used in the present invention refers to an alkynyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O or S. The heteroalkynyl group can be a carbon radical or a heteroatom radical (i.e., the heteroatom can appear in the middle or at the terminal of the group), and can be optionally substituted independently by one or more substituents described herein.

[0029] The term "alkoxy" as used herein, whether used as part of another term or alone, refers to a group represented by the formula "-O-alkyl". n-m "Alkoxy" refers to an alkoxy group in which the alkyl portion has n to m carbon atoms.

[0030] The term "cycloalkyl" used in the present invention refers to a ring system alkyl group consisting of at least 3 atoms. The term "nm-membered cycloalkyl" refers to a cycloalkyl group having n to m members forming the ring. In addition, the ring may also have one or more double bonds, but does not have a completely conjugated system.

[0031] The term "heterocyclic group" used in the present invention refers to a cyclic group in which at least one atom in the ring system is a heteroatom and the remaining ring atoms are carbon atoms. The term "nm-membered heterocyclic group" refers to a heterocyclic group having n to m members forming a ring. The term "heterocyclic group" used in the present invention includes heteroaryl and heterocycloalkyl. In addition, the ring may also have one or more double bonds.

[0032] The term "heterocycloalkyl" used in the present invention refers to a cycloalkyl group in which at least one atom in the ring system is a heteroatom and the remaining ring atoms are carbon atoms. The term "nm-membered heterocycloalkyl" refers to a heterocycloalkyl group having n to m members forming a ring. In addition, the ring may also have one or more double bonds, but does not have a completely conjugated system. In certain embodiments, the heterocycloalkyl group is a saturated heterocycloalkyl group.

[0033] The term "aryl" or "aromatic group" as used herein, whether as part of another term or used alone, refers to a mono- or poly-carbocyclic ring system radical having alternating double bonds and single bonds between the carbon atoms forming the ring. n-m The term "aryl" refers to an aromatic group having n to m carbon atoms forming a ring.

[0034] The term "heteroaryl" used in the present invention refers to an aryl group in which at least one ring atom in the aromatic ring is a heteroatom and the remaining ring atoms are carbon atoms. The term "nm-membered heteroaryl" refers to a heteroaryl group having n to m ring-forming members.

[0035] The term "n-membered" as used herein, wherein n is an integer, is generally used with a ring system to describe the number of atoms forming the ring in the ring system. For example, phenyl is an example of a 6-membered aryl group, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered aryl group.

[0036] The term "amino" as used herein refers to a 2 " The term "cyano" used in the present invention refers to a group represented by the formula "-CN". The term "hydroxyl" used in the present invention refers to a group represented by the formula "-OH". The term "halogen" used in the present invention refers to an atom selected from fluorine, chlorine, bromine and iodine.

[0037] As used herein, the term "compound" includes all stereoisomers (eg, enantiomers and diastereomers), geometric isomers, tautomers, and isotopes of the depicted structure.

[0038] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended to be included. In certain embodiments, the compounds described herein have an (R)-configuration. In certain embodiments, the compounds described herein have an (S)-configuration.

[0039] The compounds of the present invention also include tautomeric forms. The compounds of the present invention may also include all isotopes of atoms occurring in the intermediates or final compounds.

[0040] The second aspect of the present invention provides a pharmaceutical composition, which includes the above-mentioned lumiperone derivative and is a suspension.

[0041] In some preferred embodiments, the average particle size of the lumiperone derivative is 0.1-100 μm, preferably 0.1-50 μm, preferably 0.1-20 μm, preferably 1-10 μm, preferably 2-4 μm, and most preferably 2.5 μm.

[0042] The term "average particle size" used in the present invention refers to the volume average diameter as measured by the laser light scattering (LLS) method.

[0043] In some preferred embodiments, the particle size distribution of the lumiperone derivative with an average particle size of 2.5 μm is: 95% <20 μm, 90% <15 μm, 50% <10 μm, 10% <2 μm. Preferably, the particle size distribution of the lumiperone derivative with an average particle size of 2.5 μm is: 95% <8 μm, 90% <6 μm, 75% <3 μm, 50% <1.5 μm, 10% <0.5 μm.

[0044] The inventors have found that the smaller the average particle size of the lumiperone derivative, the shorter the time of extended release. Therefore, according to the present invention, when the average particle size is 1 μm, the compound will be released during a period of less than about 3 weeks, preferably about 2 weeks. When the average particle size is greater than 1 μm, the lumiperone derivative will be released during at least 2 weeks, preferably about 3 to 4 weeks, up to 6 weeks or longer. Therefore, according to the present invention, the duration of release can be changed by changing the particle size in the pharmaceutical composition.

[0045] In some preferred embodiments, the content of the lumiperone derivative in the pharmaceutical composition is 1-40% w / v, preferably 1-35% w / v, preferably 1-30% w / v, preferably 1-25% w / v, preferably 1-20% w / v, preferably 1-18% w / v, preferably 1-16% w / v, preferably 1-15% w / v, preferably 2-15% w / v, preferably 3-15% w / v, preferably 4-15% w / v, preferably 5-15% w / v, preferably 6-15% w / v, preferably 7-15% w / v, preferably 8-15% w / v.

[0046] In some preferred embodiments, the pharmaceutical composition further comprises a suspending agent.

[0047] The term "suspending agent" used in the present invention refers to an additive that can increase the viscosity of the dispersion medium to reduce the sedimentation rate of the particles or increase the hydrophilicity of the particles.

[0048] In some preferred embodiments, the suspending agent is selected from one or more combinations of polyethylene glycol 4000, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, gelatin, gum arabic and polylactic acid-glycolic acid copolymer. Preferably, the suspending agent is selected from polyethylene glycol 4000, carboxymethyl cellulose, polylactic acid-glycolic acid copolymer or polyvinyl pyrrolidone.

[0049] In some preferred embodiments, the content of the suspending agent in the pharmaceutical composition is 0.2-10% w / v, preferably 0.2-9% w / v, preferably 0.2-8% w / v, preferably 0.2-7% w / v, preferably 0.2-6% w / v, preferably 0.2-5% w / v, preferably 0.3-5% w / v, preferably 0.4-5% w / v, preferably 0.5-5% w / v, preferably 0.6-5% w / v, preferably 0.7-5% w / v, preferably 0.8-5% w / v, preferably 0.9-5% w / v, preferably 1-5% w / v, preferably 1-4% w / v, preferably 1-3% w / v.

[0050] In some preferred embodiments, the pharmaceutical composition further comprises a stabilizer.

[0051] The term "stabilizer" used in the present invention refers to an additive that can effectively reduce the surface tension of the aqueous suspension solution, prevent particles from aggregating and enlarging, and thus increase the physical stability of the preparation.

[0052] In some preferred embodiments, the stabilizer is selected from one or more combinations of polysorbate 20, polysorbate 40, polysorbate 80, lecithin, polyoxyethylene ether, polyoxypropylene ether, povidone K30 and sodium deoxycholate. Preferably, the stabilizer is polysorbate 20.

[0053] In some preferred embodiments, the content of the stabilizer in the pharmaceutical composition is 0.1-5% w / v, preferably 0.1-4% w / v, preferably 0.1-3% w / v, preferably 0.2-3% w / v, preferably 0.3-3% w / v, preferably 0.4-3% w / v, preferably 0.5-3% w / v, preferably 0.5-2.5% w / v, preferably 0.5-2% w / v, preferably 0.5-1. 8% w / v, preferably 0.5-1.6% w / v, preferably 0.5-1.4% w / v, preferably 0.5-1.2% w / v, preferably 0.6-1.2% w / v, preferably 0.7-1.2% w / v, preferably 0.8-1.2% w / v, preferably 0.9-1.2% w / v, preferably 1-1.2% w / v, and most preferably, the content of the stabilizer in the pharmaceutical composition is 1.1% w / v.

[0054] In some preferred embodiments, the pharmaceutical composition further comprises a buffer salt.

[0055] In some preferred embodiments, the buffer salt is selected from one or more combinations of anhydrous sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate, TRIS buffer, acetic acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid and malic acid. Preferably, the buffer salt is anhydrous sodium dihydrogen phosphate.

[0056] In some preferred embodiments, the content of the buffer salt in the pharmaceutical composition is 0.01-2% w / v, preferably 0.02-2% w / v, preferably 0.03-2% w / v, preferably 0.03-1.8% w / v, preferably 0.03-1.6% w / v, preferably 0.03-1.4% w / v, preferably 0.03-1.2% w / v, preferably 0.03-1% w / v, preferably 0.03-0.8% w / v, preferably 0.03-0.6% w / v, preferably 0.03-0.5% w / v, preferably 0.03-0.4% w / v, preferably 0.03-0.3% w / v, preferably 0.03-0.2% w / v, preferably 0.03-0.1% w / v.

[0057] In some preferred embodiments, the pharmaceutical composition further comprises a pH adjuster, and the pH adjuster adjusts the pH value of the pharmaceutical composition to 5.0-9.0, preferably 6.0-8.0, preferably 6.0-7.5, preferably 6.0-7.0, and most preferably 7.0.

[0058] In some preferred embodiments, the pH regulator is selected from an acidic pH regulator or an alkaline pH regulator; the acidic pH regulator is selected from one or more combinations of hydrochloric acid, acetic acid, phosphoric acid and citric acid; the alkaline pH regulator is selected from one or more combinations of sodium hydroxide, potassium hydroxide, sodium hydrogen phosphate, calcium carbonate, magnesium oxide and magnesium hydroxide. Preferably, the pH regulator is sodium hydroxide.

[0059] In some preferred embodiments, the pharmaceutical composition further comprises an antioxidant.

[0060] In some preferred embodiments, the antioxidant is selected from one or more combinations of lemon monohydrate, citric acid, sulfites, bisulfites, pyrosulfites, dithiocarbamates, ascorbic acid, ascorbic acid palmitate, hydrogen coumarin, vitamin E, ethanolamine, propyl gallate, butylated hydroxyanisole, di-tert-butylated cresol, nordihydroguaiaretic acid and glutathione. Preferably, the antioxidant is lemon monohydrate.

[0061] In some preferred embodiments, the content of the antioxidant in the pharmaceutical composition is 0.01-3% w / v, preferably 0.01-2.5% w / v, preferably 0.01-2% w / v, preferably 0.01-1.8% w / v, preferably 0.01-1.6% w / v, preferably 0.01-1.4% w / v, preferably 0.01-1.2% w / v, preferably 0.01-1% w / v, preferably 0.02-1% w / v, preferably 0.04-1% w / v, preferably 0.06-1% w / v, preferably 0.08-1% w / v, preferably 0.1-1% w / v.

[0062] In some preferred embodiments, the pharmaceutical composition further comprises a solvent; the solvent is selected from at least one of water for injection, physiological saline and 5% glucose.

[0063] In some preferred embodiments, the pharmaceutical composition may further include an antibacterial agent, a metal ion complexing agent, and an osmotic pressure regulator.

[0064] In some preferred embodiments, the metal ion complexing agent is selected from EDTA (ethylenediaminetetraacetic acid) or EGTA (ethylene glycol bis(2-aminoethyl ether)tetraacetic acid).

[0065] In some preferred embodiments, the pharmaceutical composition may further include a lyoprotectant.

[0066] The pharmaceutical composition in the form of an aqueous solution can be in the form of a lyophilized preparation after freeze-drying with a lyoprotectant.

[0067] The lyophilized agent can be mixed with an aqueous solvent (eg, sterile water for injection, physiological saline or 5% glucose) before use to prepare a suspension aqueous solution, and then injected for administration.

[0068] In some preferred embodiments, the lyoprotectant is selected from one or more combinations of mannitol, sucrose, maltose, xylitol, glucose, starch, sorbitol, lactose, trehalose and glycine.

[0069] In some preferred embodiments, the lyoprotectant is mannitol.

[0070] In some preferred embodiments, the content of the lyoprotectant in the pharmaceutical composition is 1-10% w / v, preferably 1-9% w / v, preferably 1-8% w / v, preferably 1-7% w / v, preferably 1-6% w / v, preferably 1-5% w / v, preferably 2-5% w / v, preferably 3-5% w / v, and preferably 4-5% w / v.

[0071] In some preferred embodiments, the pharmaceutical composition may also be a lyophilized powder.

[0072] In some preferred embodiments, the pharmaceutical composition comprises:

[0073] A. a lumiperone derivative; B. a pharmaceutically acceptable carrier, comprising:

[0074] (a), one or more suspending agents; (b), one or more buffer salts; (c), optionally one or more stabilizers; (d), optionally one or more antioxidants; (e), optionally one or more pH adjusters; C, solvent.

[0075] In some preferred embodiments, the pharmaceutical composition comprises:

[0076] A. a lumiperone derivative; B. a pharmaceutically acceptable carrier comprising: (a) polysorbate 20;

[0077] (b) polyethylene glycol 4000; (c) anhydrous sodium dihydrogen phosphate; (d) citric acid monohydrate; (e) sodium hydroxide; C) water for injection.

[0078] In some preferred embodiments, the pharmaceutical composition comprises:

[0079] A. Lumiperone derivative; B. Pharmaceutically acceptable carrier, including: (a) carboxymethyl cellulose or its sodium salt; (b) mannitol; (c) anhydrous sodium dihydrogen phosphate; (d) sodium hydroxide; C. Water for injection.

[0080] In some preferred embodiments, the pharmaceutical composition comprises:

[0081] A. Lumiperone derivative; B. Pharmaceutically acceptable carrier, comprising: (a) polylactic acid-glycolic acid copolymer; (b) povidone K30; (c) dichloromethane; (d) anhydrous sodium dihydrogen phosphate; (e) sodium hydroxide; C. Water for injection.

[0082] In some preferred embodiments, the pharmaceutical composition is for intramuscular administration or subcutaneous administration, preferably the pharmaceutical composition is for intramuscular administration.

[0083] The preparation method of the above-mentioned pharmaceutical composition comprises the following steps: Lumiperone derivative, suspending agent, buffer salt, stabilizer, antioxidant and pH regulator and solvent are mixed to form a suspension to obtain the pharmaceutical composition.

[0084] In some preferred embodiments, wet grinding, dry grinding, high-pressure homogenization or other pharmaceutically acceptable methods (eg, high shear homogenization and microfluidization) may be used in the process of forming the suspension.

[0085] In some preferred embodiments, sterile wet milling, preferably sterile wet ball milling, can be used in the process of forming the suspension to control the average particle size of the compound of formula I or its hydrate, solvate or pharmaceutically acceptable salt to the desired average particle size.

[0086] The contamination level generated by grinding with 95% ZrO stabilized with magnesium oxide, zirconium silicate and glass grinding media to prepare the pharmaceutical composition in the present invention is acceptable. Further, other grinding media such as polymer beads, stainless steel, titanium, alumina and 95% ZrO stabilized with yttrium can also be used.

[0087] In some preferred embodiments, the grinding media has a particle size of greater than 2.5 g / cm 3 density and comprises 95% ZrO stabilized with magnesium oxide and polymeric beads. Grinding times can vary widely and depend largely on the specific machine tool selected and the processing conditions.

[0088] The process of forming the suspension requires the particle size to be reduced at a temperature at which the drug is not significantly degraded. The processing temperature is less than 30-40°C. If necessary, the processing apparatus can be cooled by conventional cooling equipment.

[0089] In some preferred embodiments, the preparation method may further include: a step of preparing a lyophilized agent, wherein the step of preparing a lyophilized agent includes: mixing the final suspension with a lyophilization protectant, pre-freezing, sublimating, and then obtaining the lyophilized agent.

[0090] In some preferred embodiments, during the preparation of a lyophilized agent, the freeze-drying cycle includes the following stages: freezing, primary drying, and optional secondary drying.

[0091] In some preferred embodiments, the freezing stage comprises cooling the formulation to -40°C or lower at a suitable cooling rate.

[0092] In some preferred embodiments, the primary drying is performed at a temperature below 0° C. and under a suitable vacuum and duration, and the secondary drying is performed at a temperature above 0° C. and under a suitable vacuum and duration.

[0093] In some preferred embodiments, the lumiperone derivative in the lyophilized agent has a polymorphic form, preferably an anhydrate, a monohydrate or a mixture thereof.

[0094] The present invention also provides the use of the above compound or its hydrate, solvate or pharmaceutically acceptable salt, or the above pharmaceutical composition in the preparation of a drug for treating schizophrenia and / or bipolar I or II related depressive episodes.

[0095] Compared with the prior art, the present invention has the following beneficial effects:

[0096] (1) The present invention first discovered that by modifying lumepirone with appropriate substituents, the purpose of slow release can be achieved while maintaining stability.

[0097] (2) The pharmaceutical composition provided by the present invention has good stability and can be released continuously for at least 1 month or longer. The drug can maintain an effective concentration in the body for a longer period of time, thereby reducing the frequency of administration and greatly improving patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 Lumeperone 1 H-NMR spectrum;

[0099] Figure 2 Butyllumepirone 1 H-NMR spectrum;

[0100] Figure 3 Octyllumepirone 1 H-NMR spectrum;

[0101] Figure 4 This is the particle size distribution diagram of octinyllumepirone suspension;

[0102] Figure 5 This is the particle size distribution diagram of octinyllumepirone suspension after being placed for 3 weeks;

[0103] Figure 6 is the particle size distribution diagram of butyllumepirone suspension;

[0104] Figure 7 This is the particle size distribution diagram of butyllumepirone suspension after being placed for 3 weeks. DETAILED DESCRIPTION

[0105] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0106] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0107] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0108] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0109] The terms “include,” “comprising,” “have,” “containing,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0110] In the following examples, unless otherwise specified, all raw materials used were commercially available or prepared by conventional methods in the art.

[0111] The abbreviations or chemical formulas of the raw materials used in the following examples are as follows:

[0112] EtOH: ethanol; HCl: hydrochloric acid; TFA: trifluoroacetic acid; TESH: triethylsilane; ClCOOMe: methyl chloroformate; Na 2 CO 3 : sodium carbonate; KI: potassium iodide; K 2 CO 3 :sodium carbonate;CuI:copper iodide;DMEDA:N,N'-dimethylethylenediamine;KOH:potassium hydroxide;n-BuOH:n-butanol;dioxane / toluene:dioxane / toluene;TEA:triethylamine;DCM:dichloromethane;MeOH:methanol;Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium; THF: tetrahydrofuran.

[0113] Example 1 Synthesis of Lumeperone

[0114] Step 1:

[0115]

[0116] Take a 1L three-necked flask, add 500mL of ethanol, 2-bromophenylhydrazine hydrochloride (50g, 224mmol), 4-piperidone hydrochloride hydrate (36g, 234mmol), and concentrated hydrochloric acid (25mL, 300mmol) in sequence, and react at 70°C for 12h. After the reaction is completed, cool and filter, and the filter cake is compound 1 (61.1g, yield 94.6%).

[0117] Step 2:

[0118]

[0119] Take a 1L three-necked flask, add 400mL of TFA, add compound 1 (48.8g, 170mmol), add triethylsilane (170mL, 1mol) under nitrogen protection and ice bath, then heat the reaction to 35°C and react overnight. After the reaction is completed, reduce the pressure and concentrate to the remaining brown oil, add 300mL of petroleum ether for washing, discard the supernatant, then add 400mL of dichloromethane to dilute, add 2NNaOH under ice bath, adjust pH=12, extract with water and dichloromethane, dry and concentrate to obtain brown compound 2 (38.3g, yield 89%).

[0120] Step 3:

[0121]

[0122] Compound 2 (36.6 g, 144 mmol) was dissolved in 200 mL of ethanol, and S-mandelic acid (23.6 g, 155 mmol) was added under stirring at 50°C, and stirred to dissolve. The temperature was gradually lowered, and a white solid was precipitated after cooling to room temperature. After standing at 10°C for 1 h, the mixture was filtered to obtain a white solid compound 3 (20.2 g, yield 34%, ee>99%).

[0123] Step 4:

[0124]

[0125] Compound 3 (15 g, 37 mmol) and sodium carbonate (8.7 g, 81 mmol) were added to 80 mL of THF in sequence, and methyl chloroformate (3.36 mL, 44 mmol) was added at room temperature and reacted for 30 min. The mixture was filtered and dried to give a white solid compound 4 (11 g, yield 91%).

[0126] Step 5:

[0127]

[0128] Compound 4 (6.5 g, 20 mmol) and 50 mL of dioxane were added to the reaction flask, and K 2 CO3 (4.2g, 30mmol), 2-chloro-N-methylethylamine hydrochloride (2.9g, 22mmol), KI (3.3g, 20mmol), react at 100℃ for 12h, then cool the reaction to 40℃, add CuI (0.76g, 4mmol) and N,N'-dimethylethylenediamine (1.06g, 120mmol) in sequence under nitrogen protection, the reaction solution turns blue, and react at 100℃ for 10h. After the reaction, filter with diatomaceous earth and evaporate under reduced pressure to obtain compound 5 (4.4g, yield 74%).

[0129] Step 6:

[0130]

[0131] Compound 5 (4.4 g, 15 mmol) was dissolved in 50 mL of n-butanol, and then KOH (10.0 g, 178 mmol) was added to the reaction solution. The mixture was reacted at 120°C for 5 h. After the reaction, the mixture was extracted with water and dichloromethane, dried and concentrated to obtain compound 6 (2.8 g, yield 90%).

[0132] Compound 6 (2.8 g, 12.2 mmol), 4-chloro-4'-fluoro-butyrophenone (18.3 mmol), KI (18.3 mmol), and TEA (48.8 mmol) were dissolved in dioxane / toluene (1:1, 120 mL), and the mixture was reacted at 100°C for 7 h. After the reaction, the mixture was filtered and concentrated. The concentrate was extracted with water and dichloromethane, and separated and purified using DCM:MeOH=50:1 to obtain the target compound 7 (2 g, yield 42%). The target compound 7 is lumepirone, and its NMR spectrum is as follows: Figure 1 shown.

[0133] Example 2 Synthesis of Butyllumepirone

[0134] Step 1:

[0135]

[0136] Take a 1L three-necked flask, add 500mL of ethanol, 2-bromophenylhydrazine hydrochloride (50g, 224mmol), 4-piperidone hydrochloride hydrate (36g, 234mmol), and concentrated hydrochloric acid (25mL, 300mmol) in sequence, and react at 70℃ for 12h. After the reaction, cool and filter. The filter cake is compound 1 (61.1g, yield 94.6%).

[0137] Step 2:

[0138]

[0139] Take a 1L three-necked flask, add 400mL of TFA, add compound 1 (48.8g, 170mmol), add triethylsilane (170mL, 1mol) under nitrogen protection and ice bath, then heat the reaction to 35°C and react overnight. After the reaction is completed, reduce the pressure and concentrate to the remaining brown oil, add 300mL of petroleum ether for washing, discard the supernatant, then add 400mL of dichloromethane for dilution, add 2N NaOH under ice bath, and adjust pH=12. After extraction with water and dichloromethane, dry and concentrate to obtain brown compound 2 (38.3g, yield 89%).

[0140] Step 3:

[0141]

[0142] Compound 2 (36.6 g, 144 mmol) was dissolved in 200 mL of ethanol, and S-mandelic acid (23.6 g, 155 mmol) was added under stirring at 50°C, and the mixture was stirred to dissolve. The temperature was gradually lowered, and a white solid was precipitated after cooling to room temperature. After standing at 10°C for 1 h, the mixture was filtered to obtain a white solid compound 3 (20.2 g, yield 34%, ee>99%).

[0143] Step 4:

[0144]

[0145] Compound 3 (15 g, 37 mmol) and sodium carbonate (8.7 g, 81 mmol) were added to 80 mL of THF in sequence, and methyl chloroformate (3.36 mL, 44 mmol) was added at room temperature and reacted for 30 min. The mixture was filtered and dried to give a white solid compound 4 (11 g, yield 91%).

[0146] It should be noted that steps 1 to 4 in this embodiment of the present invention and steps 1 to 4 in Example 1 are produced in the same batch.

[0147] Step 5:

[0148]

[0149] Compound 4 (26 g, 80 mmol), benzophenone imine (16 g, 88 mmol), sodium tert-butoxide (15.1 g, 157 mmol), binaphthylphosphine ligand (BINAP, 1.53 g, 2.5 mmol), and toluene (300 mL) were added into a 1 L three-necked round-bottom flask, and nitrogen was bubbled. The temperature of the system was gradually raised to 60 ° C, stirred for a period of time, and then cooled to room temperature;

[0150] Under nitrogen atmosphere, Pd was added 2 (dba) 3(830 mg, 0.80 mmol), then the system was gradually heated to 105 ° C, the reaction was allowed to proceed overnight, and then the system was cooled and diluted with tert-butyl methyl ether (1.25 L), the resulting suspension was filtered through a layer of diatomaceous earth, and then evaporated to dryness under vacuum to obtain compound 5 (31.5 g, yield 93%), which was a brown foamy solid.

[0151] 1H-NMR(DMSO-d6,500MHz)δ7.68(d,J=7.4Hz,2H),7.52(m,1H),7.45(m,2H),7.34-7.2 7(m,3H),7.22-7.14(m,2H),6.64(d,J=7.3Hz,1H),6.29(t,J=7.5Hz,1H),6.11(d,J=7. 8Hz,1H),5.23(s,1H),4.04-3.97(m,2H),3.82(m,1H),3.63(m,1H),3.42(m,1H),3.23- 3.12(m,2H),2.97(m,1H),1.81-1.74(m,1H),1.70-1.64(m,1H),1.15(t,J=7.0Hz,3H).

[0152] MS (ESI) m / z 426.2 [M+H]+.

[0153] Step 6:

[0154]

[0155] The reaction mixture of compound 5 (63 g, 148 mmol), ethyl bromoacetate (22 mL, 198 mmol), sodium carbonate (22.6 g, 213 mmol) and potassium iodide (30.9 g, 186 mmol) in acetone (1.5 L) was refluxed for 16 h, the system was cooled to room temperature, concentrated to remove acetone, and the residue was diluted with dichloromethane (700 mL), then washed with water (500 mL) and brine (200 mL) in sequence, and dried over sodium sulfate. Concentration gave an oil, which was subsequently dissolved in tetrahydrofuran (400 mL), followed by addition of 2 mol / L hydrochloric acid (140 mL) in portions at room temperature. After completion of the reaction (about 1.5 h), tetrahydrofuran was removed under reduced pressure, and the residue was treated with 1 mol / L hydrochloric acid (200 mL). After filtration, the resulting brown solid was dissolved in dichloromethane (250 mL), washed with brine (150 mL), and dried over sodium sulfate. The solvent was evaporated, and the residue was subjected to flash column chromatography to give compound 6 (32.5 g, yield 73%).

[0156] 1H NMR (CDCl 3,300MHz)9.46(s,1H),6.85(d,J=7.0Hz,1H),6.78-6.67(m,2H),4.23-3.81(m,5H),3 .48-3.27(m,3H),3.26-3.08(m,1H),2.76(br,1H),1.94(br,1H),1.35-1.21(m,3H).

[0157] MS (ESI) m / z 302.3 [M+H] +.

[0158] Step 7:

[0159]

[0160] Compound 6 (17.3 g, 57.5 mmol), potassium carbonate (15.8 g, 114 mmol), iodobutane (21.2 g, 115 mmol) and acetone (500 mL) were added to a reaction flask, the system was heated to reflux and reacted for 5.5 h, then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was treated with water (200 mL) and then extracted with dichloromethane (3×200 mL). The combined organic phases were washed with brine (2×200 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain compound 7 (18 g, crude yield 87.71%), which was used in the next reaction without further purification.

[0161] Borane-tetrahydrofuran solution (1.0 M tetrahydrofuran in the solution, 125 mL, 125 mmol) was slowly added to a suspension of the above intermediate 7 (18 g, 50 mmol) in tetrahydrofuran (180 mL) at 0°C. After the addition, the reaction mixture was refluxed for 3 h, then cooled in an ice-water bath, and 6N hydrochloric acid (150 mL) was added dropwise. After removing tetrahydrofuran under reduced pressure, 2N sodium hydroxide was added to adjust the pH to 9. The mixture was extracted with dichloromethane (500 mL), and the dichloromethane layer was washed with brine and water in turn, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain compound 8 (16 g, yield 92.51%) as a thick oil.

[0162] Step 8:

[0163]

[0164] Compound 8 (5.3 g, 15 mmol) was dissolved in 50 mL of n-butanol, and then KOH (10.0 g, 178 mmol) was added to the reaction solution, and the mixture was reacted at 120° C. for 5 h. After the reaction, the mixture was extracted with water and dichloromethane, dried and concentrated to obtain compound 9 (3.3 g, 78.80%). Compound 9 (3.3 g, 12.2 mmol), 4-chloro-4'-fluoro-phenylbutyronone (18.3 mmol), KI (18.3 mmol) and TEA (48.8 mmol) were dissolved in dioxane / toluene (1:1, 120 mL), and the mixture was reacted at 100° C. for 7 h. After the reaction, the mixture was filtered and concentrated. The concentrate was extracted with water and dichloromethane, and purified by column chromatography to obtain the target compound 10 (3 g, yield 56.64%), i.e. butyllumepirone, whose NMR spectrum is shown as follows: Figure 2 shown.

[0165] Example 3 Synthesis of Octyllumepirone

[0166] Step 1:

[0167]

[0168] Take a 1L three-necked flask, add 500mL of ethanol, 2-bromophenylhydrazine hydrochloride (50g, 224mmol), 4-piperidone hydrochloride hydrate (36g, 234mmol), and concentrated hydrochloric acid (25mL, 300mmol) in sequence, and react at 70℃ for 12h. After the reaction, cool and filter. The filter cake is compound 1 (61.1g, yield 94.6%).

[0169] Step 2:

[0170]

[0171] Take a 1L three-necked flask, add 400mL of TFA, add compound 1 (48.8g, 170mmol), add triethylsilane (170mL, 1mol) under nitrogen protection and ice bath, then heat the reaction to 35°C and react overnight. After the reaction is completed, reduce the pressure and concentrate to the remaining brown oil, add 300mL of petroleum ether for washing, discard the supernatant, then add 400mL of dichloromethane to dilute, add 2N NaOH under ice bath, adjust pH=12, extract with water and dichloromethane, dry and concentrate to obtain brown compound 2 (38.3g, yield 89%).

[0172] Step 3:

[0173]

[0174] Compound 2 (36.6 g, 144 mmol) was dissolved in 200 mL of ethanol, and S-mandelic acid (23.6 g, 155 mmol) was added under stirring at 50°C, and the mixture was stirred to dissolve. The temperature was gradually lowered, and a white solid was precipitated after cooling to room temperature. After standing at 10°C for 1 h, the mixture was filtered to obtain a white solid compound 3 (20.2 g, yield 34%, ee>99%).

[0175] Step 4:

[0176]

[0177] Compound 3 (15 g, 37 mmol) and sodium carbonate (8.7 g, 81 mmol) were added to 80 mL of THF in sequence, and methyl chloroformate (3.36 mL, 44 mmol) was added at room temperature and reacted for 30 min. The mixture was filtered and dried to give a white solid compound 4 (11 g, yield 91%).

[0178] Step 5:

[0179]

[0180] Compound 4 (26 g, 80 mmol), benzophenone imine (16 g, 88 mmol), sodium tert-butoxide (15.1 g, 157 mmol), binaphthylphosphine ligand (BINAP, 1.53 g, 2.5 mmol), and toluene (300 mL) were added into a 1 L three-necked round-bottom flask, and nitrogen was bubbled. The temperature of the system was gradually raised to 60 ° C, stirred for a period of time, and then cooled to room temperature;

[0181] Under nitrogen atmosphere, Pd was added 2 (dba) 3 (830 mg, 0.80 mmol), then the system was gradually heated to 105 ° C, the reaction was allowed to proceed overnight, and then the system was cooled and diluted with tert-butyl methyl ether (1.25 L), the resulting suspension was filtered through a layer of diatomaceous earth, and then evaporated to dryness under vacuum to obtain compound 5 (31.5 g, yield 93%), which was a brown foamy solid.

[0182] 1H-NMR(DMSO-d6,500MHz)δ7.68(d,J=7.4Hz,2H),7.52(m,1H),7.45(m,2H),7.34-7.2 7(m,3H),7.22-7.14(m,2H),6.64(d,J=7.3Hz,1H),6.29(t,J=7.5Hz,1H),6.11(d,J=7. 8Hz,1H),5.23(s,1H),4.04-3.97(m,2H),3.82(m,1H),3.63(m,1H),3.42(m,1H),3.23- 3.12(m,2H),2.97(m,1H),1.81-1.74(m,1H),1.70-1.64(m,1H),1.15(t,J=7.0Hz,3H).

[0183] MS (ESI) m / z 426.2 [M+H]+.

[0184] Step 6:

[0185]

[0186] The reaction of compound 5 (63 g, 148 mmol), ethyl bromoacetate (22 mL, 198 mmol), sodium carbonate (22.6 g, 213 mmol) and potassium iodide (30.9 g, 186 mmol) in acetone (1.5 L) was refluxed for 16 h. The system was cooled to room temperature, concentrated to remove acetone, and the residue was diluted with dichloromethane (700 mL), then washed with water (500 mL) and brine (200 mL) in sequence, and dried over sodium sulfate, and concentrated to obtain an oily substance, which was subsequently dissolved in tetrahydrofuran (400 mL), and then 2 mol / L hydrochloric acid (140 mL) was added in batches at room temperature. After the reaction was completed (about 1.5 h), tetrahydrofuran was removed under reduced pressure, and the residue was treated with 1 mol / L hydrochloric acid (200 mL). After filtration, the resulting brown solid was dissolved in dichloromethane (250 mL), washed with brine (150 mL), and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to flash column chromatography to obtain Compound 6 (32.5 g, yield 73%).

[0187] 1H NMR(CDCl3,300MHz)9.46(s,1H),6.85(d,J=7.0Hz,1H),6.78-6.67(m,2H),4.23-3.81(m, 5H),3.48-3.27(m,3H),3.26-3.08(m,1H),2.76(br,1H),1.94(br,1H),1.35-1.21(m,3H).

[0188] MS (ESI) m / z 302.3 [M+H] +.

[0189] It should be noted that steps 1 to 6 in this embodiment of the present invention and steps 1 to 6 in Example 2 are produced in the same batch.

[0190] Step 7:

[0191]

[0192] Compound 6 (10.0 g, 33.18 mmol), potassium carbonate (9.2 g, 66.36 mmol), iodooctane (15.9 g, 66.36 mmol), and acetone (500 mL) were added to a reaction flask. The system was heated to reflux, reacted for 5.5 h, and then cooled to room temperature. After the solvent was removed under reduced pressure, the residue was treated with water (200 mL) and then extracted with dichloromethane (3×200 mL). The combined organic phase was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain compound 7 (11 g, crude yield 80.15%), which was used for the next step without further purification.

[0193] To a suspension of the above intermediate (11 g, 50 mmol) in tetrahydrofuran (180 mL), borane-tetrahydrofuran solution (1.0 M tetrahydrofuran in the solution, 66.5 mL, 66.5 mmol) was slowly added at 0°C. After the addition, the reaction mixture was refluxed for 3 h, then cooled in an ice-water bath, and 6N hydrochloric acid (150 mL) was added dropwise. After removing tetrahydrofuran under reduced pressure, 2N sodium hydroxide was added to adjust the pH to 9. The mixture was extracted with dichloromethane (500 mL), and the dichloromethane layer was washed with brine and water in turn, dried over anhydrous sodium sulfate, and then evaporated to dryness to give compound 8 (9 g, yield 84.68%) as a thick oil.

[0194] Step 8:

[0195]

[0196] Compound 8 (8.0 g, 20.02 mmol) was dissolved in 50 mL of n-butanol, and then KOH (10.0 g, 178 mmol) was added to the reaction solution, and the mixture was reacted at 120° C. for 5 h. After the reaction, the mixture was extracted with water and dichloromethane, dried, and concentrated to obtain compound 9 (5.2 g, 79.3%). Compound 9 (5.2 g, 15.88 mmol), 4-chloro-4'-fluoro-phenylbutyronone (23.82 mmol), KI (23.82 mmol), and TEA (63.52 mmol) were dissolved in dioxane / toluene (1:1, 120 mL), and the mixture was reacted at 100° C. for 7 h. After the reaction, the mixture was filtered and concentrated, and the concentrate was extracted with water and dichloromethane. The target compound 10 (4.0 g, yield 51.24%) was obtained by column chromatography separation and purification, i.e., octylumepirone, whose NMR spectrum is shown as follows: Figure 3 shown.

[0197] Application Example 1 Preparation of Lumiperone Suspension by Media Grinding

[0198] The following steps were used to prepare the lumiperone suspension (144 mg lumiperone / 2 mL, 144 mg / bottle):

[0199] Add the following ingredients to a 3 L glass jacketed container maintained at 15°C (±5°C) to form a sterile primary suspension:

[0200] Lumiperone 7.2 g;

[0201] Carboxymethyl cellulose 1.25 g;

[0202] Mannitol 6g;

[0203] Anhydrous sodium dihydrogen phosphate 0.05g;

[0204] Sodium hydroxide solution, 1N q.s., adjust pH to 7;

[0205] Water for injection, USP qs, up to 110 g;

[0206] The preliminary suspension was mixed at 75 ± 25 rpm for 0.5 h, then at 400 ± 100 rpm for another 1 h, followed by media milling: the media milling was operated under the following conditions:

[0207] Grinding container: Water-jacketed 0.6L stainless steel container;

[0208] Cooling temperature: 15℃(±5℃);

[0209] Stirring speed: 2500rpm;

[0210] Grinding media: 500mL very high density zirconium oxide beads;

[0211] Suspension flow rate: 10L / H;

[0212] Grinding time: 6min;

[0213] The particle size distribution of the suspension after media grinding was evaluated using a Malvern 3000 laser particle size analyzer, and it was determined that lumepirone had an average particle size of 2.5 μm and the following particle size distribution: 10% < 0.4 μm, 50% < 1.6 μm, 75% < 3.3 μm, 90% < 5.9 μm, and 95% < 7.6 μm, to obtain a lumepirone suspension.

[0214] Application Example 2 Preparation of Lumiperone Suspension by High-Pressure Homogenization

[0215] The following steps were used to prepare the lumiperone suspension (50 mg lumiperone / 2 mL, 50 mg / bottle):

[0216] Add the following ingredients to a 3 L glass jacketed container maintained at 15°C (±5°C) to form a sterile primary suspension:

[0217] Lumiperone 2.5 g;

[0218] Polysorbate 201g;

[0219] Polyethylene glycol 40002g;

[0220] Citric acid monohydrate 0.5 g;

[0221] Anhydrous sodium dihydrogen phosphate 0.05g;

[0222] Sodium hydroxide solution, 1N q.s., adjust pH to 7;

[0223] Water for injection, USP qs, up to 110 g;

[0224] The preliminary suspension was mixed at 800 rpm for 0.5 h, then at 400 ± 100 rpm for another 1 h, followed by high pressure homogenization grinding, which was performed under the following conditions:

[0225] Container: Waterjacketed 0.6L stainless steel container;

[0226] Homogenizing pressure: 120±20mpa;

[0227] Suspension flow rate: 10L / H;

[0228] Grinding time: 10min;

[0229] The particle size distribution after high pressure homogenization grinding was evaluated using a Malvern 3000 laser particle size analyzer, and it was determined that lumepirone had an average particle size of 2.5 μm and the following particle size distribution: 10% < 0.4 μm, 50% < 1.6 μm, 75% < 3.3 μm, 90% < 5.9 μm, and 95% < 7.6 μm, to obtain a lumepirone suspension.

[0230] Application Example 3 Preparation of Lumiperone Microsuspension by Self-microemulsification

[0231] The following steps were used to prepare the lumiperone suspension (144 mg lumiperone / 2 mL, 144 mg / bottle):

[0232] Add the following ingredients to a 3 L glass jacketed container maintained at 15°C (±5°C) to form a sterile primary suspension:

[0233] Lumiperone 7.2 g;

[0234] PLGA (poly(lactic-co-glycolic acid)) 110001 g;

[0235] Povidone K302g;

[0236] Dichloromethane 0.5 g;

[0237] Anhydrous sodium dihydrogen phosphate 0.05g;

[0238] Sodium hydroxide solution, 1N q.s., adjust pH to 7;

[0239] Water for injection, USP qs, up to 110 g;

[0240] After adding dichloromethane to prepare a suspension, the dichloromethane was removed and the sample existed in solid form. The remaining excipients were added and the preliminary suspension was mixed at 75±25 rpm for 2 hours, and then mixed at 400±100 rpm for another hour. After mixing, a self-microemulsion was formed. The sample was taken out and the particle size distribution was evaluated using a Malvern ZetasizerLab potentiometric analyzer to determine that lumepirone had an average particle size of 370 nm, thereby obtaining a lumepirone suspension.

[0241] Application Example 4: Preparation of Octyllumepirone Microsuspension by Self-microemulsification

[0242] The following steps were used to prepare octinyllumepirone suspension (144 mg octinyllumepirone / 2 mL, 144 mg / bottle):

[0243] Add the following ingredients to a 3 L glass jacketed container maintained at 15°C (±5°C) to form a sterile primary suspension:

[0244] Octyllumepirone 7.2 g;

[0245] Polysorbate 201g;

[0246] Polyethylene glycol 40002g;

[0247] Citric acid monohydrate 0.5 g;

[0248] Anhydrous sodium dihydrogen phosphate 0.05g;

[0249] Sodium hydroxide solution, 1N q.s., adjust pH to 7;

[0250] Water for injection, USP qs, up to 110 g;

[0251] The preliminary suspension was mixed at 75±25 rpm for 2 h, and then at 400±100 rpm for another 1 h. After mixing, a self-microemulsion was formed. The suspension was taken out and the particle size distribution was evaluated using a Malvern ZetasizerLab potentiometric analyzer to determine that the octyllumepirone had an average particle size of 325 nm. The octyllumepirone suspension was obtained. Figure 4 This is the particle size distribution diagram of octinyllumepirone suspension.

[0252] The suspension was left for 3 weeks (25° C.), and the particle size distribution was evaluated using a Malvern ZetasizerLab potentiometric analyzer. It was determined that after being left at room temperature for 3 weeks, octylumepirone had an average particle size of 465 nm. Figure 5 This is the particle size distribution diagram of octinyllumepirone suspension after being placed for 3 weeks.

[0253] Application Example 5: Butyllumepirone microsuspension prepared by self-microemulsification

[0254] The following steps were used to prepare butyllumepirone suspension (144 mg butyllumepirone / 2 mL, 144 mg / bottle):

[0255] Add the following ingredients to a 3 L glass jacketed container maintained at 15°C (±5°C) to form a sterile primary suspension:

[0256] Butyllumepirone 7.2 g;

[0257] Polysorbate 201g;

[0258] Polyethylene glycol 40002g;

[0259] Citric acid monohydrate 0.5 g;

[0260] Anhydrous sodium dihydrogen phosphate 0.05g;

[0261] Sodium hydroxide solution, 1N q.s., adjust pH to 7;

[0262] Water for injection, USP qs, up to 110 g;

[0263] The preliminary suspension was mixed at 75±25 rpm for 2 h and then at 400±100 rpm for another 1 h.

[0264] After mixing, a self-microemulsion is formed. The mixture is taken out and the particle size distribution is evaluated using a Malvern ZetasizerLab potentiometric analyzer to determine that the butyl lumepirone has an average particle size of 274 nm, thereby obtaining a butyl lumepirone suspension. Figure 6 This is the particle size distribution diagram of butyllumepirone suspension.

[0265] The suspension was left for 3 weeks (25° C.), and the particle size distribution was evaluated using a Malvern ZetasizerLab potentiometric analyzer. It was determined that after being left at room temperature for 3 weeks, the butyllumepirone had an average particle size of 306 nm. Figure 7 This is the particle size distribution diagram of butyllumepirone suspension after being placed for 3 weeks.

[0266] Application Example 6 Human Pharmacokinetic (PK) Data: Single-dose IM Long-acting Study in Patients

[0267] The lumepirone suspension prepared in Example 1 was administered intramuscularly to patients diagnosed with chronic stable schizophrenia or schizoaffective disorder. The study design included administration of a single dose of the suspension to all subjects, 72, 144 and 288 mg / kg per patient. Samples for PK analysis were collected until the lumepirone plasma concentration was below the lower limit of quantitation (LLQ) in 2 consecutive observations.

[0268] In subjects 2 and 3 given the 72 mg / kg suspension, and in subjects 4 and 5 given the 144 mg / kg suspension, plasma levels of lumepirone showed a rapid onset of release and a sustained release for at least 30 days.

[0269] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A lumiperone derivative, characterized in that: It is a compound represented by formula I or a hydrate or a solvate or a pharmaceutically acceptable salt thereof; in: R1 is selected from optionally substituted C 1-12 Alkyl, optionally substituted C 2-12 Alkenyl, optionally substituted C 2-12 Alkynyl, optionally substituted C 1-12 alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylheterocyclyl, optionally substituted aryl or optionally substituted cycloalkylheteroaryl.

2. The lumiperone derivative according to claim 1, characterized in that R1 is selected from optionally substituted C 1-12 Alkyl, optionally substituted C 2-12 Alkenyl, optionally substituted C 2-12 Alkynyl or optionally substituted C 1-12 Alkoxy, preferably, R1 is C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with halogen, cyano, hydroxy, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl.

3. The lumiperone derivative according to claim 2, characterized in that R1 is C 2-12 Alkyl, the C 2-12 The alkyl group is optionally substituted with halogen, cyano, hydroxy, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl. Preferably, R1 is C 7-12 Alkyl, the C 7-12 The alkyl group is optionally substituted by halogen, cyano, hydroxyl, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl, preferably, R1 is C1, C4 or C8 alkyl, and the C1, C4 or C8 alkyl group is optionally substituted by halogen, cyano, hydroxyl, amino, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl, preferably, R1 is methyl, butyl or octyl.

4. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the lumiperone derivative according to any one of claims 1 to 3, and the pharmaceutical composition is a suspension; the average particle size of the lumiperone derivative is 0.1-100 μm, preferably 0.1-50 μm, and preferably 0.1-20 μm.

5. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition further comprises a suspending agent; the suspending agent is selected from one or more combinations of polyethylene glycol 4000, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, gelatin, gum arabic and polylactic acid-glycolic acid copolymer, preferably, the suspending agent is selected from polyethylene glycol 4000, carboxymethyl cellulose, polylactic acid-glycolic acid copolymer or polyvinyl pyrrolidone; The content of the suspending agent in the pharmaceutical composition is 0.2-10% w / v, preferably 0.2-9% w / v, preferably 0.2-8% w / v, preferably 0.2-7% w / v, preferably 0.2-6% w / v, preferably 0.2-5% w / v, preferably 0.3-5% w / v, preferably 0.4-5% w / v, preferably 0.5-5% w / v, preferably 0.6-5% w / v, preferably 0.7-5% w / v, preferably 0.8-5% w / v, preferably 0.9-5% w / v, preferably 1-5% w / v, preferably 1-4% w / v, preferably 1-3% w / v.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition further comprises a stabilizer; the stabilizer is selected from one or more combinations of polysorbate 20, polysorbate 40, polysorbate 80, lecithin, polyoxyethylene ether, polyoxypropylene ether, povidone K30 and sodium deoxycholate, preferably, the stabilizer is polysorbate 20; The content of the stabilizer in the pharmaceutical composition is 0.1-5% w / v, preferably 0.1-4% w / v, preferably 0.1-3% w / v, preferably 0.2-3% w / v, preferably 0.3-3% w / v, preferably 0.4-3% w / v, preferably 0.5-3% w / v, preferably 0.5-2.5% w / v, preferably 0.5-2% w / v, preferably 0.5-1.8% w / v, preferably 0.5-1.6% w / v, preferably 0.5-1.4% w / v, preferably 0.5-1.2% w / v, preferably 0.6-1.2% w / v, preferably 0.7-1.2% w / v, preferably 0.8-1.2% w / v, preferably 0.9-1.2% w / v, preferably 1-1.2% w / v.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition further comprises a buffer salt; the buffer salt is selected from one or more combinations of anhydrous sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate, TRIS buffer, acetic acid, succinic acid, adipic acid, tartaric acid, ascorbic acid, benzoic acid and malic acid, preferably, the buffer salt is anhydrous sodium dihydrogen phosphate; The content of the buffer salt in the pharmaceutical composition is 0.01-2% w / v, preferably 0.02-2% w / v, preferably 0.03-2% w / v, preferably 0.03-1.8% w / v, preferably 0.03-1.6% w / v, preferably 0.03-1.4% w / v, preferably 0.03-1.2% w / v, preferably 0.03-1% w / v, preferably 0.03-0.8% w / v, preferably 0.03-0.6% w / v, preferably 0.03-0.5% w / v, preferably 0.03-0.4% w / v, preferably 0.03-0.3% w / v, preferably 0.03-0.2% w / v, preferably 0.03-0.1% w / v.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition further comprises a pH adjuster, and the pH value of the pharmaceutical composition is adjusted by the pH adjuster to 5.0-9.0, preferably 6.0-8.0, preferably 6.0-7.5, preferably 6.0-7.0, and most preferably 7.

0.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition also includes an antioxidant; the antioxidant is selected from one or more combinations of lemon monohydrate, citric acid, sulfites, bisulfites, pyrosulfites, dithiocarbamates, ascorbic acid, ascorbic acid palmitate, hydrogen coumarin, vitamin E, ethanolamine, propyl gallate, butylated hydroxyanisole, di-tert-butylated cresol, nordihydroguaiaretic acid and glutathione. Preferably, the antioxidant is lemon monohydrate.

10. Use of the lumiperone derivative according to any one of claims 1 to 3 or the pharmaceutical composition according to claims 4 to 9 in the preparation of a medicament for treating schizophrenia and / or depressive episodes associated with bipolar I or II.

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