WO2024012565A1

WO2024012565A1 - Memantine derivative, pharmaceutical composition thereof and use thereof

Info

Publication number: WO2024012565A1
Application number: PCT/CN2023/107438
Authority: WO
Inventors: 李德耀; 周溢谦; 游华金; 郭�旗; 高波; 张礼军; 张健存
Original assignee: 广州市恒诺康医药科技有限公司
Priority date: 2022-07-15
Filing date: 2023-07-14
Publication date: 2024-01-18

Abstract

The present invention provides a memantine derivative or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a use in preparing a drug for preventing and/or treating central nervous system diseases, especially Alzheimer's disease, Parkinson's disease or other neurodegenerative diseases. 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 a living body. After a single administration, it can achieve the effect of drug efficacy lasting for several weeks, thereby reducing the number of medication administrations to a patient. This not only improves patient compliance, but also ensures curative effects, and has good application prospects.

Description

Memantine derivatives, pharmaceutical compositions thereof and uses thereof

Technical field

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.

Background technique

Alzheimer's disease (hereinafter referred to as AD), also known as 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. Although 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.

Contents of the invention

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. In particular, the drug is a long-acting drug.

The above objects of the present invention are achieved through the following solutions:

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):

Among them, n is 1 or 2; m is an integer from 6 to 20.

In some specific embodiments, when n is 1, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

When n is 2, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In some specific embodiments, m is an integer from 6 to 18.

Preferably, m is an integer from 6 to 16.

Preferably, m is an integer from 6 to 14.

Preferably, m is an integer from 8 to 18.

Preferably, m is an integer from 8 to 16.

Preferably, m is an integer from 8 to 14.

Preferably, m is an integer from 10 to 18.

Preferably, m is an integer from 10 to 16.

Preferably, m is an integer from 10 to 14.

In some embodiments, the memantine derivative is selected from one of the following structures:

Another object of the present invention is to provide a composition comprising the above compound or its stereoisomer, solvate, or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients, carriers or diluents.

In some embodiments, the pharmaceutical 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.

Wherein, the drugs for preventing and/or treating central nervous system diseases are long-acting drugs.

Preferably, 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 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.

Pharmaceutical compositions, preparations and uses

When used as medicaments, 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. Typically, 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. In addition, 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). Pharmaceutical 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. In certain embodiments, 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.

In certain embodiments, the 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. In particular embodiments and the present invention, 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. The term "carrier" includes a diluent, 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.

For an individual of about 50-70 kg, 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.

In another aspect, the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in medicine. In a specific embodiment, 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.

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

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.

Description of drawings

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.

Definitions and general terms

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

As used herein, 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. For example, "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. In certain embodiments, 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.

Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be identically or differently substituted at each position.

The term "unsubstituted" means that the specified group carries no substituents.

The term "optionally substituted by" may be used interchangeably with the term "unsubstituted or substituted by", i.e. the structure is unsubstituted or substituted by one or more The 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. , alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, heterocyclyl, oxo (=O), thio (=S), -C (=O) NH-R ^4a , -NHC(=O)-R ^4a , -S(=O) _1- ₂ NH-R ^4b , -NHS(=O) _1-2 -R ^4b , C _1-6 alkyl group, carbonyl group , C _3-6 cycloalkyl, C _6-10 aryl or C _1-9 heteroaryl, etc., wherein R ^4a and R ^4b both have the definitions described in the present invention.

In addition, it should be noted that, unless otherwise clearly stated, the description methods used in the present invention are "each...independently" and "...each/respectively independently" and "...independently" "地" can be interchanged and should be understood in a broad sense. It can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or it can mean that in the same group, the same The specific options expressed between the symbols do not affect each other.

In various parts of this specification, substituents of the compounds disclosed herein are disclosed according to group type or range. In particular, the present invention includes each and every individual subcombination of the individual members of these radical classes and ranges. For example, the term "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.

In various parts of this invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group are to be understood as referring to the linking group. For example, if the structure requires a linking group and 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.

The term "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.

Examples of 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 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 CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1- Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-Methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, C ₁₂ alkyl, C ₁₄ alkyl group, C ₁₆ alkyl, C ₁₈ alkyl, C ₂₀ alkyl, C ₂₂ alkyl, etc.

The term "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”. In one embodiment, 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. Examples of alkenyl groups include, but are not limited to, vinyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), and the like. The alkenyl group may be optionally substituted with one or more substituents described herein.

The term "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. In one embodiment, 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. Examples of 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.

The term "aliphatic" or "aliphatic group" as used herein 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. Unless otherwise specified, 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. In other embodiments, the aliphatic group contains 1-8 carbon atoms. In other embodiments, the aliphatic group contains 1-6 carbon atoms. In other embodiments, the aliphatic group contains 1-4 carbon atoms. In other embodiments, 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.

The term "cycloalkyl" as used herein, unless otherwise stated, refers to a monovalent saturated or partially unsaturated (but non-aromatic) monocyclic or polycyclic hydrocarbon. In some embodiments, the cycloalkyl group can be bridged or non-bridged, spiro or non-spiro, and/or fused or non-fused bicyclic groups. In some embodiments, the cycloalkyl group includes 3-10 carbon atoms, i.e., C ₃ to C ₁₀ cycloalkyl. In some embodiments, 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. In some embodiments, 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. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, deca Hydronaphthyl, or adamantyl. 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.

The terms "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. In some embodiments, the heterocycle contains 1 or 2 heteroatoms, all of which are nitrogen atoms. In some embodiments, 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. In some embodiments, the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some embodiments, 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. The polycyclic heterocyclyl group can be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains heteroatoms. In some embodiments, 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. 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. In some embodiments, such 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-pyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxeptanyl, thieptanyl, oxaza base, diazepine base, thiaza base, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothiophene base, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, cinnolinyl, coumarinyl, decahydroquinolinyl, decahydrisoiso Quinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazine base, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithiodyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl , imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumaryl, isodihydrogen Indolyl (isoindolinyl), 1-oxo-isoindolyl, 1,3-dioxo-isoindolyl, isothiazolidinyl, isoxazolidinyl, 3-oxo -Isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3- Dioxy-hexahydroisoindolyl, oxazolidinone, oxazolidinyl, ethylene oxide, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6- Dioxy-piperidinyl, 4-piperidinonyl, 2-oxypyrrolidinyl, 2,5-dioxopyrrolidyl, quinuclidinyl, tetrahydroisoquinolinyl, 3,5-dioxo- Thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthenyl and 1,3,5-trisulfide Heterocyclohexyl. Examples in which the -CH ₂ - group in the heterocyclyl group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinedione groups. 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.

In one embodiment, 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. Unless otherwise stated, the heterocyclyl group consisting of 3 to 8 atoms may be a carbon group or a nitrogen group, and the -CH ₂ - group may be optionally replaced by -C(=O)-. 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. Examples of 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, oxeptanyl, thieptanyl, oxaza base, diazepine base, thiaza base. Examples in which the -CH ₂ - group in the heterocyclyl group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidine diketone group. 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.

In one embodiment, 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. Unless otherwise stated, the heterocyclyl group consisting of 3 to 6 atoms may be a carbon group or a nitrogen group, and the -CH ₂ - group may be optionally replaced by -C(=O)-. 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.

In another embodiment, 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. Unless otherwise stated, the heterocyclyl group consisting of 5-6 atoms may be a carbon group or a nitrogen group, and the -CH ₂ - group may be optionally replaced by -C(=O)-. 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. Examples of 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, 2-piperidinone, 3,5-dioxopiperidinyl and pyrimidinedione, 1,1-dioxanyl Thiomorpholinyl. The heterocyclyl group composed of 5-6 atoms may be optionally substituted by one or more substituents described in the present invention.

The term "aryl" as used in the present invention, unless otherwise stated, 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. In some embodiments, aryl is phenyl, naphthyl, bicyclo[4.2.0]oct-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl. 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. In some or any embodiments, 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.

As used herein, the term "heteroaryl", unless otherwise specified, 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. In some embodiments, 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. In some embodiments, 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. In certain embodiments, 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. In certain embodiments, 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, thiadiazopyrimidinyl and thienopyridinyl. In certain embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, aridinyl, phenanthrolinyl, phenanthridinyl base and phenazine base. In some or any embodiments, 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 substitution.

"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. Pharmaceutically acceptable 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. Other pharmaceutically acceptable 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 -Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. 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.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

When the solvent is water, the term "hydrate" may be used. In some embodiments, 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.

The term "treating" any disease or condition as used herein, in some embodiments thereof, 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). In other embodiments, "treating" or "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient. In other embodiments, "treating" or "treating" refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both. In other embodiments, "treating" or "treating" refers to preventing or delaying the onset, development, or progression of a disease or disorder.

Detailed ways

The present invention will be further described in detail below with reference to specific examples. The examples are only used to explain the present invention and are not intended to limit the scope of the present invention. The test methods used in the following examples are conventional methods unless otherwise stated; the materials, reagents, etc. used, unless otherwise stated, are commercially available reagents and materials.

Generally, 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.

Those skilled in the art will recognize that the chemical reactions described herein can be suitably used to prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully accomplished by one skilled in the art by modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents in addition to those described herein, or by incorporating The reaction conditions were modified with some routine modifications. In addition, the reactions disclosed in the present invention or the known reaction conditions are also recognized to be suitable for the preparation of other compounds of the present invention.

The examples described below all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification unless otherwise indicated. General reagents are from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory purchased.

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.

The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube over an anhydrous solvent (unless otherwise indicated). The 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. When multiplets occur, the following abbreviations are used: s (singlet), 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).

The measurement conditions for low-resolution mass spectrometry (MS) data are: 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.

Pure compounds were detected using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC) with UV detection at 210nm/254nm.

The following abbreviations are used throughout this disclosure:

Typical synthetic procedures for preparing the compounds disclosed herein are shown in the synthetic scheme below.

Example

Example 1 Preparation of bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methylhexadecanedioate

Step 1) Preparation of N-(4-methoxybenzyl)-memantine hydrochloride

Add memantine (30.51g, 170.15mmol, 1 equivalent) and dichloromethane (300mL) to a 500mL single-neck bottle. After dissolving, add p-methoxybenzaldehyde (24.32g, 178.66mmol, 1.05 equivalent). Add acetic acid dropwise while stirring. (10.21g, 170.15mmol, 1 equivalent), stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (54.09g, 255.23mmol, 1.5 equivalents) was added, and stirring at room temperature was continued overnight. TLC shows that reaction A is basically completed. Add 400 mL of saturated sodium bicarbonate aqueous solution, stir for 10 minutes and separate the liquids. Extract the aqueous phase with dichloromethane (200 mL*1), combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin to dryness. Add methyl tert-butyl ether (500 mL) to dissolve, add 16 mL of concentrated hydrochloric acid dropwise with stirring, and precipitate a white solid. After stirring for 1 hour, filter, wash the filter cake with methyl tert-butyl ether, and dry under vacuum to obtain intermediate 1 (56.45 g). , yield 98.8%), as a white solid.

Step 2) Preparation of chloromethyl ((1r, 3R, 5S, 7r)-3,5-dimethyladamant-1-yl) (4-methoxybenzyl) carbamate

Weigh 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. Dissolve sodium hydroxide (3.57g, 89.30mmol, 1.5 equivalent) in 50mL of water, and add it dropwise to a single-neck bottle. The solid gradually dissolves. After stirring for 30 minutes, separate the liquids. The water phase is extracted with methyl tert-butyl ether (100mL *1), combine the organic phases and transfer to a 1L three-necked flask. Add 200mL water and sodium bicarbonate (12.50g, 148.83mmol, 2.5 equivalents), dissolve, and add chloromethyl chloroformate (11.51g, 89.30mmol, 1.5 equivalents) dropwise while stirring. Control the internal temperature not to exceed 25°C. After the addition is completed, stir at room temperature for 1 hour. TLC shows that the reaction of intermediate 1 is completed. Separate the liquids. Extract the aqueous phase with methyl tert-butyl ether (100mL*1). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin dry to obtain Oily substance. Add 5 mL methyl tert-butyl ether to dissolve, add 100 mL n-heptane dropwise, and precipitate a white solid. Stir overnight and then filter. The filter cake is washed with n-heptane and drained with an oil pump to obtain intermediate 2 (18.50 g, yield 79.3%). , as a white solid.

Step 3) Bis((((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)(4-methoxybenzyl)carbamoyl)oxy)methyl ) Preparation of hexadecanedioic acid ester

Add chloromethyl ((1r, 3R, 5S, 7r)-3,5-dimethyladamantan-1-yl) (4-methoxybenzyl) carbamate (3g, 7.65 mmol, 1 equivalent), hexadecanedioic acid (1.10g, 3.83mmol, 0.5 equivalent), sodium bicarbonate (1.29g, 15.30mmol, 2 equivalents), add tetrahydrofuran (50mL), triethylamine (1.06mL, 7.65 mmol, 1 equivalent), stir at 60°C overnight until TLC shows that the reaction of raw material 1 is complete. Lower the reaction solution to room temperature, spin to dryness, add 100 mL of dichloromethane to dissolve, add 100 mL of 0.5M hydrochloric acid, stir for 5 minutes, separate the liquids, extract the aqueous phase with dichloromethane (50 mL*1), combine the organic phases, and add anhydrous sodium sulfate Dry, filter, and spin to dryness to obtain crude intermediate 3 (3.52 g, yield 92.15%), which is a light yellow oil.

¹ H NMR (500MHz, CDCl ₃ ): δ7.08 (d, J=8.5Hz, 4H), 6.82 (d, J=8.5Hz, 4H), 5.76 (s, 4H), 4.56 (s, 4H), 3.79 (s, 6H), 2.30 (t, J=7.5Hz, 4H), 2.10 (t, J=3.0Hz, 2H), 1.93 (s, 4H), 1.82-1.79 (m, 4H), 1.74-1.72 (m, 4H), 1.59 (s, 4H), 1.31-1.21 (m, 28H), 1.12-1.06 (m, 4H), 0.81 (s, 12H).

Step 4) Preparation of bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methylhexadecanedioate

Place the crude intermediate 3 (3.52g, 3.53mmol) into a 100mL single-neck bottle, add methylene chloride (36mL) to dissolve, and stir under an ice-water bath. Trifluoroacetic acid (4 mL) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature. After about 1 hour, TLC showed that the reaction of Intermediate 1 was completed. Add 100 mL of saturated sodium bicarbonate aqueous solution and stir for 5 minutes. The liquids were separated. The aqueous phase was extracted with dichloromethane (30 mL x 1). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, spin dry, and purify by column chromatography to obtain bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methylhexadecane Diacid ester (1.24g, yield 46.44%) is a white solid.

¹ H NMR (500MHz, CDCl ₃ ): δ5.67 (s, 4H), 4.72 (s, 2H), 2.35 (t, J=7.5Hz, 4H), 2.15 (t, J=3.0Hz, 2H), 1.76 (s, 4H), 1.63-1.55 (m, 12H), 1.37-1.33 (m, 4H), 1.30-1.24 (m, 24H), 1.17-1.12 (m, 4H), 0.85 (s, 12H).

Example 2 Bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-hexadecanedi Preparation of amidodiacetate

According to the synthesis method of Example 1, 2,2'-hexadecanedioic acid is replaced by hexadecanedioic acid to prepare bis(((1r,3R,5S,7r)-3,5-diacetic acid. Methyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-hexadecanediamidodiacetate (1.08 g, yield 45.4%).

¹ H NMR (500MHz, CDCl ₃ ) δ 5.95 (s, 2H), 5.73 (s, 4H), 4.77 (s, 2H), 4.09 (d, J=5.0Hz, 4H), 2.23 (t, J= 7.5Hz, 4H), 2.15 (t, J=2.5Hz, 2H), 1.76 (s, 4H), 1.66-1.55 (m, 12H), 1.37-1.24 (m, 28H), 1.14 (dd, J1=15.0 Hz, J2＝13.5Hz, 4H), 0.85(s, 12H).

Example 3 Bis((((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-tetradecanedi Preparation of amidodiacetate

According to the synthesis method of Example 1, 2,2'-(tetradecanedioylbis(azadiyl))diacetic acid was used instead of hexadecanedioic acid to prepare bis(((1r,3R,5S, 7r)-3,5-Dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-tetradecanediamide diacetate (1.2g, yield 38.9% ).

¹ H NMR (50 (MHz, CDCl ₃ ) δ5.96 (t, J=5.0Hz, 2H), 5.72 (s, 4H), 4.78 (s, 2H), 4.09 (d, J=5.0Hz, 4H) , 2.23 (t, J=7.5Hz, 4H), 2.16-2.14 (m, 2H), 1.76 (s, 4H), 1.66-1.55 (m, 12H), 1.37-1.22 (m, 24H), 1.17-1.12 (m, 4H), 0.85 (s, 12H).

Example 4 Bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-dodecanedi amidodiacetate

According to the synthesis method of Example 1, 2,2'-(dodecanedioyl bis(azadiyl))diacetic acid was used instead of hexadecanedioic acid to prepare bis(((1r,3R,5S, 7r)-3,5-Dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-hexadecanediamidodiacetate (527 mg, yield 27.5%) .

¹ H NMR (500MHz, CDCl ₃ ) δ5.96 (t, J=5.0Hz, 2H), 5.73 (s, 4H), 4.78 (s, 2H), 4.09 (d, J=5.0Hz, 4H), 2.23 (t, J=7.5Hz, 4H), 2.15 (t, J=3.0Hz, 2H), 1.86 (s, 4H), 1.66-1.55 (m, 12H), 1.37-1.24 (m, 20H), 1.15 ( dd, J1＝15.0Hz, J2＝13.0Hz,, 4H), 0.85(s, 12H).

Example 5 Bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-sebacamide Diacetate

According to the synthesis method of Example 1, 2,2'-(sebacylbis(azadiyl))diacetic acid was used instead of tetradecanoic acid to prepare bis(((1r,3R,5S,7r)- 3,5-Dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-sebacamidodiacetate (205 mg, yield 27.4%).

¹ H NMR (500MHz, CDCl ₃ ) δ5.96 (t, J=5.0Hz, 2H), 5.72 (s, 4H), 4.78 (s, 2H), 4.09 (d, J=5.0Hz, 4H), 2.23 (t, J=7.5Hz, 4H), 2.15 (t, J=3.0Hz, 2H), 1.86 (s, 4H), 1.66-1.55 (m, 12H), 1.37-1.23 (m, 16H), 1.15 ( dd, J ₁ =15.0Hz, J ₂ =13.0Hz,, 4H), 0.85 (s, 12H).

Example 6 Bis(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-suberamide Diacetate

According to the synthesis method of Example 1, 2,2'-(suberoylbis(azadiyl))diacetic acid was used instead of tetradecanoic acid to prepare bis(((1r,3R,5S,7r)- 3,5-Dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-suberamide diacetate (217 mg, yield 29.1%).

¹ H NMR (500MHz, CDCl ₃ ) δ6.19 (t, J=5.0Hz, 2H), 5.72 (s, 4H), 4.82 (s, 2H), 4.09 (d, J=5.5Hz, 4H), 2.26 (t, J=7.5Hz, 4H), 2.15 (t, J=3.0Hz, 2H), 1.76 (s, 4H), 1.71-1.53 (m, 12H), 1.37-1.25 (m, 12H), 1.15 ( dd, J1＝14.0Hz, J2＝12.5Hz, 4H), 0.85(s, 12H).

Example 7 Bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-terephthalamide diacetate

According to the synthesis method of Example 1, 2,2'-terephthalamidodiacetic acid was used instead of myristanoic acid to prepare bis(((1r,3R,5S,7r)-3,5-dimethyl Adamantan-1-yl)carbamoyl)oxy)methyl-2,2'-terephthalamidodiacetate (408 mg, yield 50.3%).

¹ H NMR (500MHz, CDCl ₃ ) δ7.84 (s, 4H), 6.84 (t, J=5.0Hz, 2H), 5.77 (s, 4H), 4.81 (s, 2H), 4.29 (d, J= 5.0Hz, 4H), 2.15 (t, J=3.0Hz, 2H), 1.77 (s, 4H), 1.61-1.56 (m, 8H), 1.37-1.24 (m, 8H), 1.18-1.12 (m, 4H ), 0.85(s, 12H).

Example 8 Bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-hexadecanedi Amidodipropionate

According to the synthesis method of Example 1, 2,2'-(hexadecanedioylbis(azadiyl))dipropionic acid was used instead of myristanoic acid to prepare bis(((1r,3R,5S, 7r)-3,5-Dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-hexadecanediamidodipropionate (0.65g, yield 38.4% ).

MS(m/z): 900[M+H] ⁺ .

Example 9 Bis(((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-tetradecanedi Amidodipropionate

According to the synthesis method of Example 1, 2,2'-(tetradecanedioylbis(azadiyl))dipropionic acid was used instead of myristanoic acid to prepare bis(((1r,3R,5S, 7r)-3,5-Dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-tetradecanediamide dipropionate (0.53g, yield 36.2% )

MS(m/z): 872[M+H] ⁺ .

Example 10 Bis(((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-dodecanedi Amidodipropionate

According to the synthesis method of Example 1, 2,2'-(dodecanedioyl bis(azadiyl))dipropionic acid was used instead of myristanoic acid to prepare bis(((1r,3R,5S, 7r)-3,5-Dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-dodecanediamidodipropionate (0.55g, yield 38.1% ).

MS(m/z): 844[M+H] ⁺ .

Example 11 Bis((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-sebacamide dipropionate

According to the synthesis method of Example 1, 2,2'-(sebacylbis(azadiyl))dipropionic acid was used instead of tetradecanoic acid to prepare bis(((1r,3R,5S,7r) -3,5-dimethyladamant-1-yl)carbamoyl)oxy)methyl-2,2'-sebacamidedipropionate (0.55g, yield 38.1%).

MS(m/z): 815[M+H] ⁺ .

Example 12 Bis((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-suberamide dipropionate

According to the synthesis method of Example 1, 2,2'-(suberoylbis(azadiyl))dipropionic acid was used instead of myristanoic acid to prepare bis(((1r,3R,5S,7r) -3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methyl-2,2'-suberamidodipropionate (0.35g, yield 27.3%).

MS(m/z): 787[M+H] ⁺ .

Example 13 ((((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)carbamoyl)oxy)methylbenzoate

According to the synthesis method of Example 1, 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%).

¹ H NMR (500MHz, CDCl ₃ ): δ8.09 (d, J=7.5Hz, 2H), 7.58 (t, J=7.5Hz, 1H), 7.45 (t, J=7.5Hz, 2H), 5.92 ( s, 2H), 4.76 (s, 1H), 2.14 (s, 1H), 1.77 (s, 2H), 1.60-1.58 (m, 4H), 1.27 (dd, J ₁ =20.5Hz, J ₁ =12.0Hz , 4H), 1.17-1.11 (m, 2H), 0.85 (s, 6H).

Example 14 Preparation of pharmacokinetic samples

Accurately weigh an appropriate amount of the compound of the present invention and place it in a 10 mL vial. Add blank matrix solution and 20 g of zirconia beads (0.6 to 0.8 mm) for vortex grinding. After grinding, transfer the suspended sample, dilute it with blank matrix solution, and distribute it into 5 mL vials to prepare a suspension of about 30 mg/mL. After measuring the content, it is used for pharmacokinetic experiments in rats.

Pharmacokinetic experiments of the compound of Example 15 in rats

Take the suspensions of Examples 2, 4, 7, 10 and 13 prepared according to the method of Example 14, according to the dosage of 30.75mg/kg (based on memantine), 3 animals for each compound, SD rat muscle For injection administration, take whole blood at 1h, 4h, 8h, 24h, 48h, 72h, 120h, 168h, 216h, 288h, 360h time points, 0.2mL/time point, add K ₂ EDTA/heparin sodium for anticoagulation, add Stabilizer BNPP, centrifuge within 30 minutes to collect plasma for testing. The results are shown in Table 1 and Figure 1.

Table 1 Memantine plasma concentration (ng/mL) at different time points after intramuscular injection administration of compound suspension of the present invention to rats

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.

From the data in Table 1 and Figure 1, it can be seen that after injection of the compound of Example 13, there was an obvious burst release phenomenon within 24 hours, and more than 168 hours after injection, the blood concentration dropped rapidly, indicating that after injection of the compound of Example 13, There are obvious fluctuations in the blood drug concentration in animals, and within 288 hours after injection, the maximum concentration and the minimum concentration differ significantly, making it difficult to ensure long-term stability of the blood drug concentration. The compounds of Examples 2, 4, 8 and 11 showed no obvious burst release 24 hours after injection. Within 380 hours of injection, the blood concentration was relatively stable and the fluctuation range was small. It was easier to ensure the long-lasting stability of the blood concentration and was suitable for Developed as a long-acting formulation.

In short, 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.

All publications, patents and patent applications cited in this specification are hereby incorporated by reference as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. Although the claimed subject matter has been described in terms of various examples/embodiments, those skilled in the art will recognize that various modifications/modifications, substitutions, omissions and changes can be made without departing from the spirit of the invention /Variety. Accordingly, the scope of the claimed subject matter is intended to be limited only by the scope of the appended claims, including equivalents thereof.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and do not limit the protection scope of the present invention. For those of ordinary skill in the art, based on the above descriptions and ideas, they can also make There are other variations or modifications in different forms, and it is not necessary and impossible to exhaustively enumerate all implementations here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

Memantine derivatives or their stereoisomers, solvates, or pharmaceutically acceptable salts, characterized in that the memantine derivatives have a structure represented by the following formula (I-2) or (I-3) :

Among them, n is 1 or 2; m is an integer from 6 to 20.
The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein m is 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19 or 20.
The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein m is an integer from 6 to 18;

Preferably, the m is an integer from 6 to 16;

Preferably, m is an integer from 6 to 14.
The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein m is an integer from 8 to 18;

Preferably, the m is an integer from 8 to 16;

Preferably, m is an integer from 8 to 14.
The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to claim 1, wherein m is an integer from 10 to 18;

Preferably, the m is an integer from 10 to 16;

Preferably, m is an integer from 10 to 14.
The memantine derivative or its stereoisomer, solvate, or pharmaceutically acceptable salt according to any one of claims 1 to 5, characterized in that the memantine derivative is selected from one of the following structures:
Pharmaceutical composition, characterized in that the pharmaceutical composition contains the compound according to any one of claims 1 to 6 or its stereoisomer, solvate, or pharmaceutically acceptable salt, and a pharmaceutically acceptable salt thereof. Acceptable excipients, carriers or diluents.
The compound of any one of claims 1 to 6 or its stereoisomer, solvate, or pharmaceutically acceptable salt and the pharmaceutical composition of claim 7 are used in the preparation of prevention and/or treatment of central nervous system Use in medicines for neurological diseases;

Preferably, the drug for preventing and/or treating central nervous system diseases is a long-acting drug;

Preferably, the central nervous system disease is brain function damage caused by Alzheimer's disease, Parkinson's disease or stroke sequelae.
A method of preventing and/or treating central nervous system diseases, characterized by comprising administering the compound of any one of claims 1 to 6 or its stereoisomer, solvate, or pharmaceutically acceptable salt and the pharmaceutical composition of claim 7.
The treatment method according to claim 9, characterized in that the central nervous system disease is brain function damage caused by Alzheimer's disease, Parkinson's disease or stroke sequelae.