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WO2025011640A1 - Dérivé de mémantine, composition pharmaceutique et utilisation associées - Google Patents

Dérivé de mémantine, composition pharmaceutique et utilisation associées Download PDF

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Publication number
WO2025011640A1
WO2025011640A1 PCT/CN2024/105172 CN2024105172W WO2025011640A1 WO 2025011640 A1 WO2025011640 A1 WO 2025011640A1 CN 2024105172 W CN2024105172 W CN 2024105172W WO 2025011640 A1 WO2025011640 A1 WO 2025011640A1
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Prior art keywords
integer
pharmaceutically acceptable
solvate
stereoisomer
alkyl
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English (en)
Chinese (zh)
Inventor
李德耀
周溢谦
游华金
郭�旗
高波
张礼军
张健存
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Guangzhou Henovcom Bioscience Co Ltd
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Guangzhou Henovcom Bioscience Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61P25/28—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
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to memantine derivatives, stereoisomers, solvates, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, and use of the compounds or compositions in preparing drugs for preventing and/or treating central nervous system diseases.
  • AD Alzheimer's disease
  • the factors that cause AD are very complex, including neurotransmitter factors, genetic factors, environment, age, and other diseases.
  • Research data show that globally, a new dementia patient is diagnosed every 3 seconds. In 2018, about 50 million people in the world suffered from dementia. By 2050, this number will increase to 152 million, which will be three times as much as now. It is estimated that the global social dementia-related costs in 2018 were US$1 trillion, and by 2030, this figure will increase to US$2 trillion. In low-income and middle-income countries, less than 10% of dementia patients are diagnosed, and about 94% of dementia patients are cared for at home.
  • anti-dementia drugs on the market mainly include cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (N-methyl-D-aspartate, NMDA) receptor non-competitive antagonists (memantine).
  • cholinesterase inhibitors donepezil, galantamine, rivastigmine
  • N-methyl-D-aspartate N-methyl-D-aspartate, NMDA receptor non-competitive antagonists
  • Memantine is a non-competitive, moderate affinity, voltage-dependent NMDA receptor antagonist that does not interfere with glutamate activity in the normal brain. Memantine has potential neuroprotective effects on neurodegenerative diseases. Many degenerative diseases involve excessive intracellular calcium influx, which is considered a key early step in glutamate-induced excitotoxicity. Memantine can bind to the cyclohexidine binding site on the NMDA receptor, reduce calcium influx, and inhibit the cytotoxic effects induced by excitatory amino acids.
  • Memantine was developed by Merz, a German company. It was approved by the European Patent Medicines Committee in 2002 and entered the EU market in the same year. In 2003, memantine was approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. In addition, memantine is also used in other types of dementia, such as vascular dementia, mixed dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia, alcohol-related dementia, etc. (3-7).
  • Neurodegenerative diseases such as Alzheimer's disease mainly affect the elderly. The deterioration of their body functions makes it difficult for them to take care of themselves, and they need to be cared for, which brings a huge burden to their families and society. In addition, such diseases require long-term medication. Although memantine is the first choice for the treatment of Alzheimer's disease, it needs to be taken orally twice a day. Due to the physiological characteristics of patients, oral medication is prone to missed doses, resulting in unstable blood drug concentrations and thus affecting the therapeutic effect.
  • a preparation with long-acting effect is prepared to provide a more convenient treatment approach for patients with Alzheimer's disease and neurodegenerative diseases, improve the compliance of patients to receive treatment, ensure the efficacy, reduce the burden on patients and their families, and bring economic benefits to society.
  • the present invention aims at the inconvenience that patients with central nervous system degeneration need to take memantine every day, and provides a memantine derivative with a long-acting effect.
  • the compound of the present invention has low water solubility, can be well prepared into a suspension preparation, has a low dissolution rate in the body, forms a drug reservoir under the skin or in the muscle after a single subcutaneous or intramuscular injection, and the drug is slowly released from the reservoir, which can achieve the effect of drug efficacy lasting for several weeks, reduce the number of medication times for patients, improve the compliance of patients, and also ensure the efficacy, and has a good application prospect.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the memantine derivative with long-lasting effect.
  • Another object of the present invention is to provide the use of the long-acting memantine derivative or its composition in the preparation of a drug for preventing and/or treating central nervous system diseases, especially Alzheimer's disease, Parkinson's disease or brain function recovery treatment of stroke sequelae, etc.
  • the drug is a long-acting drug.
  • R1 and R2 are each independently H, D or C1-4 alkyl
  • Each X is independently a C 1-10 alkyl group or is absent, and each X may be the same or different;
  • W is selected from C 1-30 alkyl, C 1-30 heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-10 aliphatic, C 2-10 heterocyclyl, C 2-10 heterocyclyl, C 1-10 aliphatic, aryl, aryl C 1-10 aliphatic, hetero Aryl or heteroaryl C 1-10 aliphatic.
  • R 1 and R 2 are each independently H, D, methyl, or ethyl.
  • W is selected from C 1-30 alkyl, C 2-30 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-6 aliphatic, C 2-7 heterocyclyl, C 2-7 heterocyclylC 1-6 aliphatic, C 6-10 aryl, C 6-10 arylC 1-6 aliphatic, C 5-9 heteroaryl, or C 5-9 heteroarylC 1-6 aliphatic.
  • W is selected from C 1-22 alkyl, C 2-6 alkenyl, C 6-10 aryl, C 3-7 heterocyclylC 1-6 aliphatic, or C 6-10 arylC 1-6 aliphatic.
  • W is selected from C 1-4 alkyl, C 1-6 alkyl, C 1-8 alkyl, C 1-10 alkyl, C 1-12 alkyl, C 1-16 alkyl, C 1-18 alkyl, C 1-20 alkyl, C 1-22 alkyl, C 2-6 alkenyl, phenylene, C 2-7 heterocyclylC 1-6 aliphatic or C 6-10 arylC 1-6 aliphatic.
  • W is C 2-6 alkenyl.
  • W is selected from C 2-4 alkyl, C 2-6 alkyl, C 2-8 alkyl, C 2-10 alkyl, C 2-12 alkyl, C 2-16 alkyl, C 2-18 alkyl, C 2-20 alkyl, C 2-22 alkyl.
  • W is selected from C 2-4 alkyl, C 2-6 alkyl, C 4-8 alkyl, C 4-10 alkyl, C 4-12 alkyl, C 4-16 alkyl, C 4-18 alkyl, C 4-20 alkyl, C 4-22 alkyl.
  • W is selected from C 2-4 alkyl, C 2-6 alkyl, C 6-8 alkyl, C 6-10 alkyl, C 6-12 alkyl, C 6-16 alkyl, C 6-18 alkyl, C 6-20 alkyl, C 6-22 alkyl.
  • the memantine derivative has the structure shown in the following formula (I-1):
  • n 3.
  • n 4.
  • n is 5.
  • n is an integer from 2 to 18.
  • m is an integer from 2 to 16.
  • m is an integer from 4 to 20.
  • m is an integer from 4 to 18.
  • m is an integer from 4 to 16.
  • m is an integer from 6 to 18.
  • m is an integer from 6 to 16.
  • m is an integer from 2 to 12.
  • m is an integer from 2 to 10.
  • m is an integer from 2 to 8.
  • m is an integer from 4 to 12.
  • m is an integer from 4 to 10.
  • m is an integer from 4 to 8.
  • n 3
  • m 2 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • n 3
  • m 2 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • n 3
  • m 2 3, 4, 5, 6, 7, 8, 9 or 10.
  • n 3
  • m 2 3, 4, 5, 6, 7 or 8.
  • n 3
  • m 4
  • 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 5
  • n 3
  • m 4
  • n 3
  • m 4
  • n 3
  • m 6 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.
  • n 3
  • m 6 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • n 3
  • m 4 or 16
  • n 3 or 16
  • n 3 or 14
  • n 3
  • m 5 7, 9, 11, 13 or 15.
  • n 3
  • m 9 11, 13 or 15.
  • n 4
  • m 2 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • n 4
  • m 4
  • n 4
  • m 4
  • n 4
  • m 4
  • n 4
  • m 6 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.
  • n 4
  • m 6 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • n 4
  • m 4 or 6
  • n 4
  • m 8 10, 12, 14 or 16.
  • n 4
  • m 8 10, 12 or 14.
  • n 4
  • m 5 7, 9, 11, 13 or 15.
  • n 4
  • m 9 11, 13 or 15.
  • n when n is 5, m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • n when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • n when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.
  • n when n is 5, m is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • n when n is 5, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.
  • n when n is 5, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • n when n is 5, m is 4, 6, 8, 10, 12, 14 or 16.
  • n when n is 5, m is 8, 10, 12, 14 or 16.
  • n when n is 5, m is 8, 10, 12 or 14.
  • n when n is 5, m is 5, 7, 9, 11, 13 or 15.
  • n when n is 5, m is 9, 11, 13 or 15.
  • the memantine derivative is selected from one of the following structures:
  • Another object of the present invention is to provide a composition
  • a composition comprising the above-mentioned compound or its stereoisomer, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient, carrier or diluent.
  • compositions described herein further comprise an additional therapeutic agent.
  • the present invention also provides the use of the above compound or its stereoisomer, solvate, or pharmaceutically acceptable salt and the above pharmaceutical composition in the preparation of drugs for preventing and/or treating central nervous system diseases.
  • the drug for preventing and/or treating central nervous system diseases is a long-acting drug.
  • the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.
  • Another object of the present invention is to provide a method for preventing and/or treating central nervous system diseases, comprising administering the above-mentioned compound or its stereoisomer, solvate, or pharmaceutically acceptable salt and the above-mentioned pharmaceutical composition.
  • the central nervous system disease is Alzheimer's disease, Parkinson's disease or brain function damage caused by sequelae of stroke.
  • the compound of the present invention has low water solubility, can be well prepared into a suspension preparation, has a low dissolution rate, and can achieve the effect of drug efficacy lasting for several weeks after a single administration.
  • the compounds of this invention are usually used in the form of pharmaceutical compositions.
  • the composition can be prepared in a manner well known in pharmaceutical technology and comprises at least one compound of the invention according to formula I or formula I-1.
  • the compounds of this invention are used in a pharmaceutically effective amount.
  • the amount of the compounds of this invention actually used will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound of the invention used, the age, body weight and response of individual patients, the severity of the patient's symptoms, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be prepared into a preparation suitable for a specific route of administration, such as oral administration, parenteral administration, rectal administration, subcutaneous or intramuscular injection, etc.
  • the pharmaceutical composition of the present invention can be prepared into a solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or a liquid form (including but not limited to solutions, suspensions or emulsions).
  • the pharmaceutical composition can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricants or buffers and adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • compositions for parenteral administration can be emulsions or sterile solutions.
  • propylene glycol, polyethylene glycol, vegetable oil, particularly olive oil or injectable organic esters can be used as solvents or carriers, and in some embodiments, ethyl oleate is used as solvents or carriers.
  • These compositions can also include adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers.
  • Sterilization can be carried out in several ways, and in certain embodiments, bacteriological filters are used, sterilized by radiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or any other injectable sterile medium when used.
  • the composition provided by the invention is a pharmaceutical composition or a single unit dosage form.
  • the pharmaceutical composition provided by the invention and the single unit dosage form include one or more preventive agents or therapeutic agents (for example, compounds or other preventive agents or therapeutic agents provided by the invention) of a preventive or therapeutically effective amount and one or more typical pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable” refers to a drug for animals, particularly for humans, approved by a regulatory agency of a federal or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias.
  • carrier includes a diluent, adjuvant (for example, Freund's adjuvant (complete and incomplete)), excipient or vehicle used together with a therapeutic agent.
  • a drug carrier can be sterile liquids, such as water and oils, including those of petroleum, animal oils, vegetable oils or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • water can be used as a carrier.
  • Saline solutions and aqueous glucose solutions and glycerol solutions can also be used as liquid carriers, particularly for injection solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).
  • Typical pharmaceutical compositions and dosage forms include one or more adjuvants.
  • suitable adjuvants are well known to those skilled in the art of pharmacy.
  • suitable adjuvants include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talcum powder, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc.
  • a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is applied to a subject and the specific active ingredient in the dosage form.
  • the composition or single unit dosage form may also contain a small amount of a wetting agent or emulsifier, or a pH buffer.
  • the pharmaceutical composition or combination product of the present invention can be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient.
  • the therapeutically effective amount of the compound, pharmaceutical composition, or combination product thereof depends on the species, body weight, age, and individual health condition, the disorder or disease to be treated, or its severity. A physician, clinician, or veterinarian can easily determine the effective amount of each active ingredient necessary for preventing, treating, or inhibiting the progression of a disease or disorder.
  • the above dosage characteristics can be demonstrated by in vitro and in vivo tests using suitable mammals, such as mice, rats, dogs, monkeys or isolated organs, tissues and their products.
  • suitable mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and their products.
  • the compounds of the present invention can be applied in vitro in the form of solutions, such as aqueous solutions; in vivo in the form of suspensions or aqueous solutions, for example, in the enteral, parenteral (preferably intravenous) application.
  • the in vitro dosage range is between about 10-3 molar concentration and 10-9 molar concentration.
  • the therapeutically effective amount is in the range of about 0.1-500 mg/kg or about 1-100 mg/kg, depending on the route of administration.
  • the compounds of the present invention may be administered simultaneously with one or more other therapeutic ingredients, or before or after them.
  • the compounds of the present invention may be administered separately with another ingredient by the same or different routes of administration, or the two may be administered together in the same pharmaceutical composition.
  • the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which is used in medicine.
  • the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which is used to prevent and/or treat central nervous system diseases in mammals, especially brain function recovery treatment of Alzheimer's disease, Parkinson's disease or stroke sequelae, etc.
  • the present invention has the following beneficial effects:
  • the compound of the present invention After entering the organism, the compound of the present invention can be decomposed into the active ingredient of memantine, and then exert its effect; and the compound of the present invention has low water solubility, can be well prepared into a suspension preparation, has a low dissolution rate in the organism, and after a single subcutaneous or intramuscular injection, a drug reservoir is formed in the subcutaneous or muscle area, and the drug is slowly released from the reservoir without obvious burst release phenomenon.
  • the blood drug concentration is maintained for a long time and is stable, and the effect of drug efficacy lasting for several weeks can be achieved, thereby reducing the number of medication times for patients, improving the compliance of patients, and ensuring the efficacy, and having good application prospects.
  • FIG1 is a time curve of the blood concentration of the original drug of the compound of the present invention after intramuscular injection into rats.
  • Stereoisomers refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed in the present invention can be racemized or enantiomerically enriched.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.
  • “Pharmaceutically acceptable” refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specified substituent.
  • a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represent a linked alkylene group or arylene group, respectively.
  • alkyl or "alkyl group” as used herein refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 30 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-30 carbon atoms. Unless otherwise specified, the alkyl group contains 1-22 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1-4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH2CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2
  • alkenyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 30 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, including "cis” and “trans” orientations, or "E” and “Z” orientations.
  • the alkenyl group contains 2 to 30 carbon atoms; in one embodiment, the alkenyl group contains 2 to 22 carbon atoms; in one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents described herein.
  • alkynyl refers to a straight or branched monovalent hydrocarbon radical containing 2 to 30 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp triple bond.
  • the alkynyl group contains 2 to 30 carbon atoms; In one embodiment, the alkynyl group contains 2-22 carbon atoms; in one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2-4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like.
  • the alkynyl group may be optionally substituted with one or more substituents described herein.
  • aliphatic or "aliphatic group” as used herein refers to a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturations.
  • an aliphatic group contains 1-30 carbon atoms, in some embodiments, an aliphatic group contains 1-20 carbon atoms, in some embodiments, an aliphatic group contains 1-10 carbon atoms, in other embodiments, an aliphatic group contains 1-8 carbon atoms, in other embodiments, an aliphatic group contains 1-6 carbon atoms, in other embodiments, an aliphatic group contains 1-4 carbon atoms, and in other embodiments, an aliphatic group contains 1-3 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, straight chain or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, ethynyl, and the like.
  • cycloalkyl used in the present invention, unless otherwise specified, refers to a monovalent saturated or partially unsaturated (but non-aromatic) monocyclic or polycyclic hydrocarbon.
  • the cycloalkyl group can be a bridged or non-bridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group.
  • the cycloalkyl group includes 3-10 carbon atoms, i.e., C 3 to C 10 cycloalkyl.
  • the cycloalkyl has 3-15 (C 3-15 ), 3-10 (C 3-10 ), 3-7 (C 3-7 ) carbon atoms, 3-6 (C 3-6 ) carbon atoms.
  • the cycloalkyl group is a monocyclic or bicyclic ring. In some embodiments, the cycloalkyl group is a monocyclic ring. In some embodiments, the cycloalkyl group is a bicyclic ring. In some embodiments, the cycloalkyl group is a tricyclic ring. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, or adamantyl.
  • the cycloalkyl When the cycloalkyl is substituted, it can be substituted independently with one or more substituents described herein on any ring, i.e., on any aromatic or non-aromatic ring contained by the cycloalkyl.
  • heterocyclyl and “heterocycle” are used interchangeably in this application and, unless otherwise specified, refer to a monovalent monocyclic non-aromatic ring system and/or a polycyclic ring system comprising at least one non-aromatic ring; wherein one or more (in certain embodiments, 1, 2, 3 or 4) of the non-aromatic monocyclic atoms are independently selected from O, S(O) 0-2 and N heteroatoms.
  • the heterocyclic ring comprises 1 or 2 heteroatoms, and the heteroatoms are all nitrogen atoms.
  • the heterocyclic ring comprises 1 or 2 heteroatoms, and the remaining ring atoms are all carbon atoms; and wherein one or more (in some embodiments, 1, 2, 3 or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S (O) 0-2 and N heteroatoms, and the remaining ring atoms are all carbon atoms.
  • the heterocyclic ring comprises 1 or 2 heteroatoms, and the heteroatoms are all nitrogen atoms.
  • the heterocyclic ring is polycyclic and comprises one heteroatom in a non-aromatic ring, or comprises one heteroatom in an aromatic ring, or comprises two heteroatoms in an aromatic ring, or comprises two heteroatoms, one of which is in an aromatic ring, and the other is in a non-aromatic ring.
  • the heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7 or 5-6 ring atoms.
  • the heterocyclic group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • the heterocyclyl group can be a bridged or non-bridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group.
  • One or more nitrogen atoms and sulfur atoms can be optionally oxidized, one or more nitrogen atoms can be optionally quaternized, one or more carbon atoms can be optionally quaternized. Replacement.
  • Some rings can be partially or completely saturated, or aromatic, provided that the heterocycle is non-completely aromatic.
  • the monocyclic heterocycle and polycyclic heterocycle can be connected to the main structure on any heteroatom or carbon atom that leads to a stable compound.
  • the polycyclic heterocyclic group can be connected to the main structure through any ring thereof, including any aromatic ring or non-aromatic ring, regardless of whether the ring contains a heteroatom.
  • the heterocyclic group is a "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group containing at least one ring heteroatom as described in the present invention, or 2) a saturated or partially unsaturated (but non-aromatic) monovalent bicyclic group or tricyclic group, wherein at least one ring contains at least one heteroatom as described in the present invention.
  • heterocyclic and heterocycloalkyl When heterocyclic and heterocycloalkyl are substituted, they can be substituted on any ring, i.e., on any aromatic or non-aromatic ring contained by heterocyclic and heterocycloalkyl.
  • heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothio
  • heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described herein.
  • the heterocyclic group is a 3-8-atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can be optionally oxidized to S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to N-oxide.
  • heterocyclic groups of 3-8 atoms include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, ox
  • heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group consisting of 3 to 8 atoms may be optionally substituted by one or more substituents described herein.
  • the heterocyclic group is a heterocyclic group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can be optionally oxidized to S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to N-oxide.
  • the heterocyclic group of 3-6 atoms can be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a 5-6 atom heterocyclic group, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can be optionally oxidized to S-oxide.
  • the nitrogen atom of the ring can be optionally oxidized to N-oxide.
  • Examples of 5-6 atom heterocyclic groups include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane, dithiolanyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidone, 3,5-di
  • aryl refers to a monovalent C6 -C14 carbocyclic ring system comprising at least one aromatic ring, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic.
  • the aryl group may be attached to the main structure through any of its rings, i.e., any aromatic or non-aromatic ring.
  • the aryl group is phenyl, naphthyl, bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl.
  • the aryl group When the aryl group is substituted, it may be substituted on any ring, i.e., on any aromatic or non-aromatic ring comprised by the aryl group.
  • the aryl group is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl.
  • the aryl group may be independently and optionally substituted by one or more substituents described herein.
  • heteroaryl refers to a monovalent monocyclic or polycyclic aromatic group, wherein at least one (in certain embodiments, 1, 2, 3 or 4) ring atom is independently selected from the heteroatoms of O, S(O) 0-2 and N in the ring.
  • the heteroaryl group is connected to the rest of the molecule through any atom in the ring system, where the valence rules permit.
  • each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and/or 1 to 4 N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom.
  • the heteroaryl has 5-20, 5-15, or 5-10 ring atoms. When the heteroaryl is substituted, it may be on any ring.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolo
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, furidinyl, phenanthrolinyl, phenanthridinyl, and phenazinyl.
  • heteroaryl is phenylene, naphthylene, pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene, thiazolylene, benzothiazolyl, benzo[d]isothiazolyl, imidazo[1,2-a]pyridinyl, quinolinyl, 1H-indolyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, or pyrazolo[1,5-a]pyridinyl; each of which is optionally substituted with 1, 2, 3, or 4 groups as defined throughout
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • salts formed by non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates
  • organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionat
  • Salts obtained by reaction with an appropriate base include alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol.
  • hydrate refers to an association formed by the solvent molecule being water.
  • the term "hydrate” may be used.
  • one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.
  • the term “treating" any disease or condition refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in Formula I, II or III.
  • the following reaction schemes and examples are provided to further illustrate the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.
  • the chromatographic column used was a silica gel column, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant.
  • 1 H NMR spectra were recorded using a Bruker 400 MHz or 500 MHz NMR spectrometer. 1 H NMR spectra were recorded using CDCl 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).
  • the low resolution mass spectrometry (MS) data were measured using Thermo LTQ (column model: Zorbax SB-C18, 2.1x30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5%-95% (CH 3 CN containing 0.1% formic acid) in H 2 O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.
  • Memantine (30.51 g, 170.15 mmol, 1 equivalent) and dichloromethane (300 mL) were added to a 500 mL single-mouth bottle, and p-anisaldehyde (24.32 g, 178.66 mmol, 1.05 equivalent) was added after dissolution, and acetic acid (10.21 g, 170.15 mmol, 1 equivalent) was added dropwise under stirring, and stirred at room temperature for 1 hour.
  • Sodium triacetoxyborohydride 54.09 g, 255.23 mmol, 1.5 equivalent was added, and stirring was continued at room temperature overnight. TLC showed that the reaction of A was basically completed.
  • N-(4-methoxybenzyl)-memantine hydrochloride (20 g, 59.53 mmol, 1 equivalent) into a 500 mL single-mouth bottle, add 150 mL of water and 200 mL of methyl tert-butyl ether, and the solid will not dissolve.
  • Dissolve sodium hydroxide (3.57 g, 89.30 mmol, 1.5 equivalent) in 50 mL of water and add dropwise to the single-mouth bottle. The solid will gradually dissolve.
  • Separate the liquid extract the aqueous phase with methyl tert-butyl ether (100mL*1), combine the organic phases, and transfer to a 1L three-necked flask.
  • reaction solution is cooled to room temperature, filtered, the filter cake is washed with ethyl acetate (30 mL * 2), the filtrate is combined, concentrated, and then dissolved with dichloromethane (180 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and pumped dry to obtain intermediate 3 (Int3, 4.02 g, yield 100%) as a white foam solid.
  • Memantine (30.51 g, 170.15 mmol, 1 equivalent) and dichloromethane (300 mL) were added to a 500 mL single-mouth bottle, and p-anisaldehyde (24.32 g, 178.66 mmol, 1.05 equivalent) was added after dissolution, and acetic acid (10.21 g, 170.15 mmol, 1 equivalent) was added dropwise under stirring, and stirred at room temperature for 1 hour.
  • Sodium triacetoxyborohydride 54.09 g, 255.23 mmol, 1.5 equivalent was added, and stirring was continued at room temperature overnight. TLC showed that the reaction of A was basically completed.
  • N-(4-methoxybenzyl)-memantine hydrochloride (20g, 59.53mmol, 1 equivalent) and place it in a 500mL single-necked bottle, add 150mL water and 200mL methyl tert-butyl ether, and the insoluble solid.
  • Dissolve sodium hydroxide (3.57g, 89.30mmol, 1.5 equivalent) in 50mL water and add it dropwise to the single-necked bottle. The solid gradually dissolves. After stirring for 30 minutes, separate the liquids, extract the aqueous phase with methyl tert-butyl ether (100mL*1), combine the organic phases, and transfer them to a 1L three-necked bottle.
  • reaction solution was cooled to room temperature, filtered, the filter cake was washed with an appropriate amount of dichloromethane, the filtrate was combined, and dried, and the concentrate was purified by column chromatography (dichloromethane-methanol gradient elution) to obtain intermediate 2-3 (2.23 g, yield 55.2%) as a white solid.
  • reaction solution Slowly pour the reaction solution into 100 mL of saturated sodium bicarbonate aqueous solution and 100 mL of dichloromethane and stir for 5 minutes, stand and separate, collect the organic phase, dry over anhydrous sodium sulfate, filter, spin dry, and purify the concentrate by column chromatography (dichloromethane-methanol gradient elution) to obtain compound 1 (915 mg, yield 53.2%) as a white solid.
  • Example 19 The suspension prepared in Example 19 was used for animal experiments. Three animals were tested for each compound. SD rats were intramuscularly injected with whole blood at 1h, 2h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, 168h, 216h, 264h, and 336h, respectively. 0.3mL/time point was added, K2EDTA /heparin sodium was added for anticoagulation, and stabilizer BNPP was added. Plasma was collected by centrifugation within 30 minutes for testing, and the blood drug concentration and duration results were obtained after intramuscular injection in mice.
  • the test shows that the compound of the present invention has a low dissolution rate, and after a single administration, the drug effect can be sustained for several weeks.
  • the compound of the present invention is released smoothly in the animal body, without obvious burst release, and the blood drug concentration is stable with a small fluctuation range. Over a long period of time, the blood drug concentration is persistent and stable, and it is suitable for development as a long-acting preparation.
  • the compound of the present invention has low water solubility and can be well prepared into a suspension preparation for subcutaneous or intramuscular injection. It has a short onset time and a long duration of drug efficacy and has a good prospect for clinical application.

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Abstract

La présente invention concerne un dérivé de mémantine ou un stéréoisomère, un solvate ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique associée, et leur utilisation dans la préparation de médicaments pour la prévention et/ou le traitement de maladies du système nerveux central, en particulier la maladie d'Alzheimer, la maladie de Parkinson ou d'autres maladies neurodégénératives. Le composé selon la présente invention a une faible solubilité dans l'eau et peut ainsi être préparé dans de bonnes formulations en suspension. Le composé a un faible taux de dissolution dans un corps vivant, et simplement par une seule administration, peut atteindre une efficacité de médicament durant plusieurs semaines, réduisant ainsi le nombre de fois d'administration pour des patients, améliorant la conformité des patients tout en garantissant les effets curatifs, et ayant de bonnes perspectives d'application.
PCT/CN2024/105172 2023-07-13 2024-07-12 Dérivé de mémantine, composition pharmaceutique et utilisation associées Pending WO2025011640A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573375A (zh) * 2016-10-20 2018-01-12 成都苑东生物制药股份有限公司 一种美金刚衍生物及其制备方法
CN108892771A (zh) * 2018-06-27 2018-11-27 湖南华腾制药有限公司 一种多臂型peg化美金刚衍生物及其制备
CN109152752A (zh) * 2016-05-07 2019-01-04 广东东阳光药业有限公司 一种金刚烷胺类化合物及其制备方法和用途
WO2020069353A1 (fr) * 2018-09-27 2020-04-02 Graybug Vision, Inc. Composés et compositions pour administration oculaire
WO2024012565A1 (fr) * 2022-07-15 2024-01-18 广州市恒诺康医药科技有限公司 Dérivé de mémantine, composition pharmaceutique associée et utilisation associée

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109152752A (zh) * 2016-05-07 2019-01-04 广东东阳光药业有限公司 一种金刚烷胺类化合物及其制备方法和用途
CN107573375A (zh) * 2016-10-20 2018-01-12 成都苑东生物制药股份有限公司 一种美金刚衍生物及其制备方法
CN108892771A (zh) * 2018-06-27 2018-11-27 湖南华腾制药有限公司 一种多臂型peg化美金刚衍生物及其制备
WO2020069353A1 (fr) * 2018-09-27 2020-04-02 Graybug Vision, Inc. Composés et compositions pour administration oculaire
WO2024012565A1 (fr) * 2022-07-15 2024-01-18 广州市恒诺康医药科技有限公司 Dérivé de mémantine, composition pharmaceutique associée et utilisation associée

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