WO2024012565A1 - Dérivé de mémantine, composition pharmaceutique associée et utilisation associée - Google Patents

Dérivé de mémantine, composition pharmaceutique associée et utilisation associée Download PDF

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WO2024012565A1
WO2024012565A1 PCT/CN2023/107438 CN2023107438W WO2024012565A1 WO 2024012565 A1 WO2024012565 A1 WO 2024012565A1 CN 2023107438 W CN2023107438 W CN 2023107438W WO 2024012565 A1 WO2024012565 A1 WO 2024012565A1
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pharmaceutically acceptable
disease
group
integer
memantine
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PCT/CN2023/107438
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English (en)
Chinese (zh)
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李德耀
周溢谦
游华金
郭�旗
高波
张礼军
张健存
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广州市恒诺康医药科技有限公司
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Publication of WO2024012565A1 publication Critical patent/WO2024012565A1/fr

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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 medicinal chemistry, and in particular to memantine derivatives, their stereoisomers, solvates, or pharmaceutically acceptable salts, pharmaceutical compositions containing the compounds, and the use of the compounds or compositions in Use in the preparation of medicines for the prevention and/or treatment of central nervous system diseases.
  • AD Alzheimer's disease
  • senile dementia is a chronic and progressive neurological degenerative disease with insidious onset.
  • the factors that cause AD are very complex, including neurotransmitter factors, genetic factors, environment, age, other diseases, etc.
  • Research data shows that globally, a new patient with dementia is diagnosed every 3 seconds. In 2018, approximately 50 million people worldwide suffered from dementia. By 2050, this number will increase to 152 million. It will be three times as much as it is now. Dementia-related costs to society worldwide are estimated to be US$1 trillion in 2018, rising to US$2 trillion by 2030. In low- and middle-income countries, less than 10% of people with dementia are diagnosed and about 94% of people with dementia are cared for at home.
  • Anti-dementia drugs currently on the market mainly include cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and N-methyl-D-aspartate (NMDA). Body non-competitive antagonist (memantine).
  • Memantine is a noncompetitive, moderate affinity, voltage-dependent NMDA receptor antagonist that does not interfere with glutamate activity in normal brain. Memantine has potential neuroprotective effects in neurodegenerative diseases. Excessive intracellular calcium influx occurs in many degenerative diseases and is considered a critical early step in glutamate-induced excitotoxicity. Memantine can bind to the cyclohexidine binding site on the NMDA receptor, reducing calcium ion influx and inhibiting the cytotoxic effects induced by excitatory amino acids.
  • Memantine was developed by the German company Merz. It was licensed by the European Patented Medicines Committee in 2002 and entered the EU market in the same year. In 2003, memantine was approved by the U.S. 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 elderly patients. The deterioration of body functions makes it difficult for patients to take care of themselves and require care, which places a huge burden on the patients' families and society. In addition, these diseases require long-term medication.
  • memantine is the drug of choice for the treatment of Alzheimer's disease, it needs to be administered orally twice a day. In view of the patient's own physiological characteristics, oral administration is easy to miss, resulting in inconsistent blood drug concentration. Stability affects the therapeutic effect. Therefore, memantine derivatives are synthesized by chemical means and combined with modern preparation technology to prepare long-acting preparations, which provide a more convenient treatment approach for patients with Alzheimer's disease and neurodegenerative diseases and improve patients' compliance with treatment. It ensures the curative effect, reduces the burden on patients and their families, and brings economic benefits to society.
  • the present invention aims at the inconvenience that patients with central nervous system degeneration currently need to take memantine every day, and provides a long-acting Memantine derivatives used.
  • the compound of the present invention has low water solubility, can be well made into a suspension preparation, and has a low dissolution rate in the body. After a single administration by subcutaneous or intramuscular injection, a drug reservoir is formed under the skin or in the muscle, and the drug is slow. Released from the reservoir, the drug effect can last for several weeks, reduce the number of patients taking medication, improve the patient's compliance, and at the same time ensure the efficacy, and has good application prospects.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the memantine derivative with long-acting effect.
  • Another object of the present invention is to provide the memantine derivative or its composition with long-acting effect for the preparation of preparations for preventing and/or treating central nervous system diseases, especially Alzheimer's disease, Parkinson's disease or stroke sequelae. Used in medicines such as brain function recovery treatment.
  • the drug is a long-acting drug.
  • Memantine derivatives or their stereoisomers, solvates, or pharmaceutically acceptable salts, the memantine derivatives have the structure described in the following formula (I-2) or (I-3):
  • n 1, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
  • n 2
  • m 6 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • n is an integer from 6 to 18.
  • m is an integer from 6 to 16.
  • m is an integer from 6 to 14.
  • n is an integer from 8 to 18.
  • n is an integer from 8 to 16.
  • m is an integer from 8 to 14.
  • n is an integer from 10 to 18.
  • m is an integer from 10 to 16.
  • m is an integer from 10 to 14.
  • 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 compound or its stereoisomer, solvate, or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients, carriers or diluents.
  • compositions of the invention further comprise an additional therapeutic agent.
  • the present invention also provides the above-mentioned compound or its stereoisomer, solvate, or pharmaceutically acceptable salt and the use of the above-mentioned pharmaceutical composition in the preparation of medicaments for preventing and/or treating central nervous diseases.
  • the drugs for preventing and/or treating central nervous system diseases are long-acting drugs.
  • the central nervous system disease is brain function damage caused by Alzheimer's disease, Parkinson's disease or stroke sequelae.
  • Another object of the present invention is to provide a method for preventing and/or treating central nervous system diseases, which includes 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 brain function damage caused by Alzheimer's disease, Parkinson's disease or stroke sequelae.
  • the compound of the present invention has low water solubility, can be well made into a suspension preparation, and has a low dissolution rate. After a single administration, the compound can reach The effect lasts for several weeks.
  • the compounds of the invention are generally administered in the form of pharmaceutical compositions.
  • the compositions can be prepared in a manner well known in pharmaceutical technology and comprise at least one compound according to the invention according to formula I, I-1, I-2 or I-3.
  • the compounds of the present invention are administered in a pharmaceutically effective amount.
  • the actual amount of a compound of the invention administered will generally be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound of the invention administered, the age, weight and response of the individual patient, and patient symptoms. severity, etc.
  • the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated into a formulation suitable for a specific route of administration, such as oral administration, parenteral administration, rectal administration, subcutaneous or intramuscular injection, etc.
  • the pharmaceutical compositions of the present invention can be made into solid forms (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid forms (including but not limited to solutions, suspensions or emulsion).
  • compositions may be subjected to conventional pharmaceutical procedures such as sterilization and/or may contain conventional inert diluents, lubricants or buffers and auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers and buffers and the like.
  • compositions for parenteral administration may be emulsions or sterile solutions.
  • propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters may be used as the solvent or carrier, and in some embodiments, ethyl oleate may be used as the solvent or carrier.
  • Said compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersing agents and stabilizing agents. Sterilization can be performed in several ways, in certain embodiments using bacteriological filters, by radiation, or by heat. They may also be prepared in the form of sterile solid compositions, which may be dissolved in sterile water or any other injectable sterile medium at the time of use.
  • compositions provided herein are pharmaceutical compositions or single unit dosage forms.
  • the pharmaceutical compositions and single unit dosage forms provided by the present invention contain a prophylactically or therapeutically effective amount of one or more preventive or therapeutic agents (for example, the compounds provided by the present invention or other preventive or therapeutic agents) and a typical one or A variety of pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other recognized pharmacopeia for use in animals, particularly for use in Drugs for humans.
  • carrier includes a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic agent is administered.
  • adjuvant eg, Freund's adjuvant (complete and incomplete)
  • excipient or vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers may be sterile liquids such as water and oils, including petroleum, animal oils, vegetable oils, or those of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water can be used as a carrier when administering pharmaceutical compositions intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; ed. 22 (September 15, 2012).
  • Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical field. In certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, ethylene glycol Alcohol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to the subject and the specific active ingredient in the dosage form. If desired, the composition or single unit dosage form can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the pharmaceutical composition or combination product of the present invention may 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 0.5-100mg or approximately 1-50mg of active ingredient.
  • the therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age and health of the individual, the condition or disease to be treated, or its severity. A physician, clinician, or veterinarian can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disease or condition.
  • 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 preparations thereof.
  • the compounds of the invention can be used in vitro in the form of solutions, for example aqueous solutions, and in vivo enterally, parenterally (preferably intravenously) in the form of, for example, suspensions or aqueous solutions.
  • In vitro dosage ranges are between about 10-3 molar and 10-9 molar.
  • a therapeutically effective amount in vivo depends on the route of administration and ranges from about 0.1 to about 500 mg/kg or about 1 to about 100 mg/kg.
  • the compounds of the present invention may be administered simultaneously with, before or after one or more other therapeutic ingredients.
  • the compounds of the present invention may be administered separately from another ingredient by the same or different routes of administration, or both may be administered together in the same pharmaceutical composition.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in medicine.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for the prevention and/or treatment of central nervous system diseases in mammals, in particular Alzheimer's disease, Parkinson's disease or Brain function recovery treatment for stroke sequelae, etc.
  • the present invention has the following beneficial effects:
  • the compound of the present invention After the compound of the present invention enters the organism, it can be decomposed into the active component of memantine and then exert its effect; and the compound of the present invention has low water solubility, can be well made into a suspension preparation, and has low dissolution in the organism.
  • Speed after a single dose of subcutaneous or intramuscular injection, a drug reservoir is formed under the skin or in the muscle. The drug is slowly released from the reservoir, which can achieve the effect of lasting for several weeks, reduce the number of patients taking medication, and improve the patient's compliance. While being safe, it also ensures curative effect and has good application prospects.
  • Figure 1 is a blood drug concentration-time curve of the original drug after intramuscular injection administration of the compound of the present invention to rats.
  • the articles “a,””an,” and “the” are intended to include “at least one” or “one or more” unless otherwise stated or there is an obvious conflict from the context. Therefore, as used herein, these articles refer to articles of one or more than one (ie at least one) object.
  • a component refers to one or more components, i.e. there may be more than one component being considered in the context adopted or used in the implementation of the embodiment.
  • Stereoisomers refer to compounds that have the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in a racemic or enantioenriched form, such as (R)-, (S)- or (R,S)-configuration form exist.
  • each asymmetric atom has at least a 50% enantiomeric excess, at least a 60% enantiomeric excess, at least a 70% enantiomeric excess, in the (R)- or (S)-configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • “Pharmaceutically acceptable” refers to compounds, raw materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reaction or reasonable concern. The benefit/risk ratio is proportional to other issues and complications and is effective for its intended purpose.
  • 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.
  • the substituents may be identically or differently substituted at each position.
  • substituents described in the present invention are substituted.
  • the substituents described in the present invention include, but are not limited to H, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 and haloalkyl.
  • substituents of the compounds disclosed herein are disclosed according to group type or range.
  • the present invention includes each and every individual subcombination of the individual members of these radical classes and ranges.
  • C 1-6 alkyl refers specifically 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 variables listed for that group are to be understood as referring to the linking group.
  • the Markush group definition for the variable lists “alkyl” or “aryl,” it will be understood that “alkyl” or “aryl” respectively Represents an attached alkylene group or arylene group.
  • alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 30 carbon atoms, wherein the alkyl group can be optional is substituted with one or more substituents described in the present invention. Unless otherwise specified, alkyl groups contain 1 to 30 carbon atoms. Unless otherwise specified, alkyl groups contain 1 to 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 to 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, -CH 2 CH (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 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 linear or branched monovalent hydrocarbon group containing 2 to 30 carbon atoms, which has at least one unsaturated site, that is, a carbon-carbon sp2 double bond, which includes "cis” and “trans” ” positioning, or the positioning of “E” and “Z”.
  • the alkenyl group contains 2-30 carbon atoms; in one embodiment, the alkenyl group contains 2-22 carbon atoms; in one embodiment, the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2-4 carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents described herein.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group containing 2 to 30 carbon atoms, which has at least one unsaturated site, that is, a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-30 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 refers to a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation.
  • an aliphatic group contains 1-30 carbon atoms, with some embodiments having an aliphatic group containing 1-20 carbon atoms, and some embodiments having an aliphatic group containing 1-10 carbon atoms. Carbon atoms.
  • the aliphatic group contains 1-8 carbon atoms.
  • the aliphatic group contains 1-6 carbon atoms.
  • the aliphatic group contains 1-4 carbon atoms.
  • the aliphatic group contains 1-3 carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl or alkynyl groups such as methyl, ethyl, propyl, isopropyl, butyl, Tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, ethynyl, etc.
  • cycloalkyl refers to a monovalent saturated or partially unsaturated (but non-aromatic) monocyclic or polycyclic hydrocarbon.
  • the cycloalkyl group can be bridged or non-bridged, spiro or non-spiro, and/or fused or non-fused bicyclic groups.
  • the cycloalkyl group includes 3-10 carbon atoms, i.e., C 3 to C 10 cycloalkyl.
  • the cycloalkyl group 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 monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. 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, deca Hydronaphthyl, or adamantyl.
  • a cycloalkyl group When a cycloalkyl group is substituted, it can be independently substituted on any ring, that is, on any aromatic or non-aromatic ring comprised by the cycloalkyl group, with one or more of the substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably in this application and, unless otherwise stated, refer to a monovalent monocyclic non-aromatic ring system and/or a polycyclic ring system containing at least one non-aromatic ring; where One or more (in certain embodiments, 1, 2, 3, or 4) of the non-aromatic single ring atoms are heteroatoms independently selected from O, S(O), O-2, and N, and the The remaining ring atoms are all carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3 or 4) of the ring atoms of the polycyclic system are independently selected from O, S ( O) The heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
  • the heterocycle contains 1 or 2 heteroatoms, all of which are nitrogen atoms.
  • the heterocyclyl is polycyclic and contains one heteroatom in a non-aromatic ring, one heteroatom in an aromatic ring, two heteroatoms in an aromatic ring, or two One of the heteroatoms is in the aromatic ring and the other is in the nonaromatic ring.
  • the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
  • the heterocyclyl group can be bridged or non-bridged, spiro or non-spiro, and/or fused or non-fused bicyclic groups.
  • One or more nitrogen atoms and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally quaternized. replace.
  • Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
  • the monocyclic heterocycles and polycyclic heterocycles can be attached to the main structure at any heteroatom or carbon atom resulting in a stable compound.
  • heterocyclyl is a "heterocycloalkyl" which is 1) a saturated or partially unsaturated (but non-aromatic) ring containing at least one ring heteroatom as described herein.
  • valent monocyclic group or 2) 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.
  • heterocyclyl and heterocycloalkyl When heterocyclyl and heterocycloalkyl are substituted, they may be substituted on any ring, that is, on any aromatic or non-aromatic ring comprised by heterocyclyl and heterocycloalkyl.
  • heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentanyl base, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-
  • Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane groups and 1,1-dioxothiomorpholinyl groups.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • the heterocyclyl group is a heterocyclyl group composed of 3-8 atoms, 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 ring sulfur atoms may optionally be oxidized to S-oxide.
  • the nitrogen atoms of the ring may optionally be oxidized to N-oxygen compounds.
  • heterocyclyl groups composed of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazine base, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl
  • Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane groups and 1,1-dioxothiomorpholinyl groups.
  • the heterocyclyl group composed of 3 to 8 atoms may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclyl group is a heterocyclyl group composed 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 atoms of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atoms of the ring may optionally be oxidized to N-oxygen compounds.
  • the heterocyclyl group composed of 3 to 6 atoms may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclyl group is a heterocyclyl group composed of 5-6 atoms, 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 atoms of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atoms of the ring may optionally be oxidized to N-oxygen compounds.
  • heterocyclic groups composed of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine base, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 - Thiazolidinyl, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithialkyl, thioxanyl,
  • aryl refers to a monovalent C 6 -C 1 4 carbocyclic ring system containing at least one aromatic ring, wherein the aromatic ring system is a monocyclic ring, a bicyclic ring, or a tricyclic ring. ring.
  • the aryl group can be attached to the main structure through any ring thereof, ie, any aromatic or non-aromatic ring.
  • aryl is phenyl, naphthyl, bicyclo[4.2.0]oct-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl.
  • an aryl group When an aryl group is substituted, it may be substituted on any ring, ie, on any aromatic or non-aromatic ring comprised by the aryl group.
  • the aryl group is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl.
  • the aryl groups may independently be optionally substituted with one or more substituents described herein.
  • heteroaryl refers to a monovalent monocyclic or polycyclic aromatic group in which at least one (in certain embodiments, 1, 2, 3, or 4) Ring atoms are heteroatoms independently selected from O, S(O) 0-2 , and N in the ring.
  • the heteroaryl group is attached to the rest of the molecule through any atom in the ring system whose valency 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 combinations thereof, provided that each ring The total number of heteroatoms is 4 or less, and each ring contains at least 1 carbon atom.
  • the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. When a heteroaryl group is substituted, it can be substituted on either ring.
  • monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, Pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuryl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzo Thiazolyl, benzo Thienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridyl, imidazothiazolyl, indoxyl, indolyl, indazolyl, isobenzofuranyl, isobenzene Thiophenyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinine Phyllinyl, quinoxalinyl, quinazolinyl, thiadia
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, aridinyl, phenanthrolinyl, phenanthridinyl base and phenazine base.
  • heteroaryl is phenylene, naphthylene, pyridylene, pyrimidinyl, pyrazinylene, pyridazinylene, thiazolylene, benzothiazolyl, benzo[ d] Isothiazolyl, imidazo[1,2-a]pyridyl, quinolyl, 1H-indolyl, pyrro[1,2-b]pyridazinyl, benzofuranyl, benzo[b ]Thienyl, 1H-indazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[1,5-a]pyrimidine base, imidazo[1,2-b]pyridazinyl, or pyrazolo[1,5-a]pyridinyl; each of which is optionally defined by 1, 2, 3 or 4 throughout this specification group
  • “Pharmaceutically acceptable salts” used in the present invention refer to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as documented in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetate, Acid salts, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, are used to obtain these salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glyceryl phosphate Salt, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactouronate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamate, pectate, persulfate, 3 -Phenylprop
  • Salts obtained by reaction with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 alkyl) 4 salts.
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and others.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • 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 of solvent molecules with water.
  • hydrate When the solvent is water, the term "hydrate" may be used.
  • a compound molecule of the present invention can be combined with one water molecule, such as a monohydrate; in other embodiments, a compound molecule of the present invention can be combined with more than one water molecule, such as a dihydrate substances, and in some embodiments, one molecule of a compound of the present invention may be associated with less than one water Molecules combine, such as hemihydrates. It should be noted that the hydrates described herein retain the biological effectiveness of the non-hydrated form of the compound.
  • any disease or condition as used herein means ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof).
  • “treating” or “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient.
  • “treating” or “treating” refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both.
  • “treating” or “treating” refers to preventing or delaying the onset, development, or progression of a disease or disorder.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless further stated, wherein the substituents are defined as shown in formula I, II or III.
  • the following reaction schemes and examples serve to further illustrate the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether are obtained by refluxing and drying with metallic sodium.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying 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 are plugged with appropriate rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.
  • the chromatographic column uses a silica gel column.
  • Silica gel 200-300 mesh was purchased from Qingdao Ocean Chemical Factory.
  • 1 H NMR spectra were recorded using a Bruker 400MHz or 500MHz nuclear magnetic resonance spectrometer.
  • 1 H NMR spectrum uses CDCl 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and TMS (0ppm) or chloroform (7.26ppm) as the reference standard.
  • TMS 0.01 ppm or chloroform (7.26ppm) as the reference standard.
  • s spacinglet
  • d doublet
  • t triplet
  • m multiplet
  • br broadened) Peak
  • dd doublet of doublets, double doublet
  • dt doublet oftriplets, double triplet
  • Coupling constant expressed in Hertz (Hz).
  • Thermo LTQ column model: Zorbax SB-C18, 2.1 x 30mm, 3.5 micron, 6min, flow rate 0.6mL/min.
  • Mobile phase 5%-95% (( The ratio of CH 3 CN with 0.1% formic acid in (H 2 O with 0.1% formic acid), using electrospray ionization (ESI) at 210 nm/254 nm, with UV detection.
  • N-(4-methoxybenzyl)-memantine hydrochloride (20g, 59.53mmol, 1 equivalent) into a 500mL single-neck bottle, add 150mL water, 200mL methyl tert-butyl ether, and remove insoluble solution.
  • Diacid ester (1.24g, yield 46.44%) is a white solid.
  • benzoic acid was used instead of myristanoic acid to prepare bis(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl )oxy)methylbenzoate (338 mg, yield 39.0%).
  • Tests have shown that the compound of the present invention has a low dissolution rate, and can achieve drug effects that last for several weeks after a single administration.
  • the compound of the present invention has low water solubility and can be well made into a suspension preparation for subcutaneous or intramuscular injection. It has a short onset time and a long maintenance time of drug effect, and has good clinical application prospects.

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Abstract

La présente invention concerne un dérivé de mémantine ou un stéréo-isomère, un solvate ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique de celui-ci, et une utilisation dans la préparation d'un médicament 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 de la présente invention présente une faible solubilité dans l'eau, peut être bien converti en une préparation en suspension, et présente un faible taux de dissolution dans un corps vivant. Après une seule administration, il peut exercer l'effet d'une efficacité du médicament durant plusieurs semaines, ce qui permet de réduire le nombre d'administrations de médicament à un patient. Ceci améliore non seulement l'observance du patient, mais assure également des effets curatifs, et présente de bonnes perspectives d'application.
PCT/CN2023/107438 2022-07-15 2023-07-14 Dérivé de mémantine, composition pharmaceutique associée et utilisation associée WO2024012565A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100144868A1 (en) * 2005-01-21 2010-06-10 Ramot At Aviv University Ltd. Novel Neuroprotective Compounds and Uses Thereof
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100144868A1 (en) * 2005-01-21 2010-06-10 Ramot At Aviv University Ltd. Novel Neuroprotective Compounds and Uses Thereof
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

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