WO2016091079A1 - 多奈哌齐衍生物及其用途 - Google Patents

多奈哌齐衍生物及其用途 Download PDF

Info

Publication number
WO2016091079A1
WO2016091079A1 PCT/CN2015/095647 CN2015095647W WO2016091079A1 WO 2016091079 A1 WO2016091079 A1 WO 2016091079A1 CN 2015095647 W CN2015095647 W CN 2015095647W WO 2016091079 A1 WO2016091079 A1 WO 2016091079A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
compound
donepezil
group
acceptable salt
Prior art date
Application number
PCT/CN2015/095647
Other languages
English (en)
French (fr)
Inventor
刘飞
张翠霞
林成刚
周春燕
陈盼
王薇
王露露
Original Assignee
诺瑞特国际药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 诺瑞特国际药业股份有限公司 filed Critical 诺瑞特国际药业股份有限公司
Priority to US15/533,865 priority Critical patent/US10080746B2/en
Publication of WO2016091079A1 publication Critical patent/WO2016091079A1/zh
Priority to US15/972,500 priority patent/US10632111B2/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a donepezil derivative of the formula (I) or a pharmaceutically acceptable salt thereof, and the use of the compound for the preparation of a medicament for treating a disease caused by abnormal acetylcholinesterase activity .
  • AD Alzheimer's disease
  • donepezil As an acetylcholinesterase inhibitor, donepezil is suitable for Alzheimer's disease (AD) and has the advantages of high efficacy, easy absorption and low toxicity. However, after administration, the blood concentration is rapidly increased, which may cause adverse reactions such as vomiting, diarrhea or insomnia.
  • AD Alzheimer's disease
  • the present invention provides a new class of compounds.
  • the object of the present invention is attained by the following technical means, and the present invention relates to a donepezil derivative of the formula (I) or a pharmaceutically acceptable salt thereof.
  • R is an alkyl group of C 5-17 .
  • the donepezil derivative of the formula (I) or a pharmaceutically acceptable salt thereof is preferably n-pentyl, n-hexane, n-heptyl, n-octyl, n-decyl, N-decyl, n-undecyl, n-tridecyl, n-pentadecyl or n-heptadecyl, R is further preferably n-pentyl, n-hexane, n-heptyl, n-octane
  • the group is a n-decyl group or a n-decyl group, and R is most preferably an n-hexane group, an n-heptyl group, an n-octyl group or a n-decyl group.
  • the present invention also provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease caused by abnormal acetylcholinesterase activity.
  • the disease includes Alzheimer's disease.
  • the method for expressing the number of carbon atoms of a group means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms; the term “or” may be used. Use with the terms “and/or” unless the context clearly dictates otherwise.
  • Alkyl represents a saturated aliphatic hydrocarbon group having the carbon atom, including straight-chain and branched hydrocarbon groups, including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl Base, n-pentyl, n-hexyl and the like.
  • Pharmaceutically acceptable salts represent those salts which retain the biological effectiveness and properties of the parent compound.
  • the salt formation with an acid means that it is obtained by the reaction of the free base of the parent compound with an inorganic acid or an organic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, and the like.
  • Organic acids include, but are not limited to, acetic acid, trichloroacetic acid, dichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, and the like.
  • the present invention also provides a pharmaceutical composition comprising the above respective compounds provided by the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • excipients include, but are not limited to, castor oil, soybean oil, sesame oil, peanut oil, corn oil, cottonseed oil, various types of glycerides.
  • the excipient is preferably castor oil.
  • solubilizers include, but are not limited to, benzyl benzoate, alcohols.
  • the solubilizing agent is preferably benzyl benzoate.
  • analgesics include, but are not limited to, benzyl alcohol.
  • the compounds of the invention are prepared by the following methods.
  • R is an alkyl group of C 5-17 .
  • the donepezil used to prepare the compounds of the invention can be purchased commercially or can be prepared according to known methods.
  • the compounds obtained in the present invention were tested for pharmacokinetics in SD rats.
  • the test results confirmed that the compound of the present invention has a long half-life and an advantage of suppressing a rapid increase in blood concentration.
  • Figure 1 shows the relationship between drug concentration and time in plasma after administration of rats in the donepezil group
  • Figure 2 shows the relationship between drug concentration and time in plasma after administration of rats in Compound 1 group
  • Figure 3 is a graph showing the relationship between drug concentration and time in plasma after administration of rats in the compound 3 group
  • Figure 4 is a graph showing the relationship between drug concentration and time in plasma after administration of rats in the compound 4 group
  • Figure 5 shows the relationship between drug concentration and time in plasma after administration of rats in the compound 6 group.
  • the temperature of the system was lowered to -60 to -78 ° C, and the positive acetic anhydride (20.4 g, 200 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran, and then added to a constant pressure dropping funnel, and added at a time, at -60 to -78 ° C.
  • the temperature was naturally raised to room temperature (20 to 30 ° C), and the reaction of the starting material by TLC was completed.
  • the reaction system was placed in an ice water bath, and 250 ml of a saturated ammonium chloride solution was added dropwise.
  • n-hexanoic anhydride (21.4g, 100mmol) was dissolved in 100ml of anhydrous tetrahydrofuran into the constant pressure dropping funnel, quickly added at one time, -60 ⁇ -78 ° C
  • the temperature was naturally raised to room temperature (20 to 30 ° C), and the reaction of the starting material by TLC was completed.
  • the reaction system was placed in an ice water bath, and 250 ml of a saturated ammonium chloride solution was added dropwise.
  • the preparation method was the same as in Example 2, and donepezil (19.0 g, 50.1 mmol) was reacted with phthalic anhydride (22.7 g, 76.2 mmol), followed by treatment, and the insoluble matter was removed by filtration before crystallization, and the crystallization temperature was -15 to -20 ° C to obtain the compound citric acid.
  • the preparation method was the same as that in Example 2, donepezil (2.00 g, 5.27 mmol) and tetradecanoic anhydride (3.50 g, 8.00 mmol), followed by treatment, and the insoluble matter was removed by filtration before crystallization to obtain 1.93 g of donepezil myristate (yield: 62.0%), HPLC (aera): 98.15%.
  • Component Prescription amount Compound 4 100mg Benzyl benzoate 200mg Benzyl alcohol 100mg castor oil 1ml
  • the SD rats were divided into the donepezil group, the compound 1 group, the compound 3 group, the compound 4 group and the compound 6 group according to the gender and body weight.
  • Each group was administered by intramuscular injection (i.m.) at a dose of 90 mg/kg (on donepezil) and the sample was dissolved in an oil solvent at a concentration of 90 mg/ml (on donepezil).
  • venous blood was collected from the fundus venous plexus and placed in a pre-labeled EDTA (4 mM) anticoagulated EP tube, whole blood. After the collection, the cells were placed on ice, and then the plasma was collected by centrifugation at 4 ° C, 8000 rpm, 5 min, transferred to a 96-well plate, and stored at -20 ° C until LC-MS/MS detection.
  • the drug concentration in the plasma of EDTA (4 mM) anticoagulated SD rats was measured using the LC/MS/MS (Agilent 6460) method, and the concentration time curves of the respective groups are shown in Figs.
  • WinNonlin 5.2 software according to the statistical distance theory, the pharmacokinetic parameters of the concentration at each time point after each group administration were calculated. See Table 1 for details.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及通式为(I)的多奈哌齐衍生物或其可药用盐，式中R如正文所述；其制备方法以及含有效剂量的通式(I)化合物或其可药用盐组合物。通式为(I)的化合物或其药用盐在制备用于治疗乙酰胆碱酯酶活性异常引起的疾病中的药物的应用。

Description

多奈哌齐衍生物及其用途 技术领域
本发明涉及药物化学领域，具体涉及通式为(I)的多奈哌齐衍生物或其药学上可接受的盐，以及该类化合物在制备用于治疗乙酰胆碱酯酶活性异常引起的疾病中的药物的应用。
背景技术
近年来，伴随人口老龄化的现象，以老年痴呆为主要症状的阿尔兹海默症(AD)的发病率越来越高。而AD患者记忆力差，常有忘吃药、吃错药的现象，还有些AD患者常常不承认自己有病，而拒绝服药，因此迫切需要一种长效的AD治疗药物，可以减少服药次数，改善患者依从性。
多奈哌齐作为一种乙酰胆碱酯酶抑制剂，适用于阿尔兹海默症(AD)，具有高疗效、易吸收、毒性低的优势。但给药后，其血药浓度快速升高，可能引发例如呕吐、腹泻或失眠的不良反应。
为了解决上述问题，本发明提供了一类新化合物。
发明内容
本发明的目的在于提供一类多奈哌齐衍生物或其药学上可接受的盐；本发明的另一目的在于提供一种制备多奈哌齐衍生物或其药学上可接受的盐的方法；本发明的又一目的在于提供该类化合物在制备用于治疗乙酰胆碱酯酶活性异常引起的疾病中的药物的应用。
本发明的目的是由以下技术方案来达到的，本发明涉及通式为(I)的多奈哌齐衍生物或其药学上可接受的盐。
Figure PCTCN2015095647-appb-000001
其中：
R是C5-17的烷基。
根据本发明中通式为(I)的多奈哌齐衍生物或其药学上可接受的盐，R优选为正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基、正十一烷基、正十三烷基、正十五烷基或正十七烷基，R进一步优选为正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基，R最优选为正己烷基、正庚烷基、正辛烷基、正壬烷基。
根据本发明中通式为(I)的多奈哌齐衍生物或其药学上可接受的盐，其优选化合物包括：
Figure PCTCN2015095647-appb-000002
本发明还提供了本发明所述的化合物或其药学上可接受的盐在制备用于治疗由乙酰胆碱酯酶活性异常引起的疾病的药物中的用途。所述的疾病包括阿尔兹海默症。
本发明中，除特别说明外，所用到的术语代表的含义如下所述。
基团碳原子个数表示方法，例如C1-10，是指该基团可以含1个碳原子、2个碳原子、3个碳原子等，直至包含10个碳原子；术语“或”可与术语“和/或”互换使用，除非上下文另有清楚指明。
烷基表示具有所述碳原子的饱和的脂烃基，包括直链和支链烃基，非限制性地包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正己基等。
药学上可接受的盐表示保留母体化合物的生物有效性和性质的那些盐。其中与酸成盐是指，通过母体化合物的游离碱与无机酸或有机酸的反应而得。无机酸包括但不限于盐酸、磷酸和硫酸等。有机酸包括但不限于乙酸、三氯乙酸、二氯乙酸、丙酸、丁酸、马来酸和对甲苯磺酸等。
本发明还提供了一种药用组合物，包括本发明提供的上述各化合物或其药学上可接受的盐和药学上可接受的赋形剂。
赋形剂指的是加入到药用组合物中以进一步便利于给予化合物的惰性物质。赋形剂的实例包括(但不限于)蓖麻油、大豆油、芝麻油、花生油、玉米油、棉籽油、各类甘油酯。赋形剂优选是蓖麻油。
增溶剂的实例包括(但不限于)苯甲酸苄酯、醇类。增溶剂优选是苯甲酸苄酯。
止痛剂的实例包括(但不限于)苯甲醇。
本发明的化合物由下列方法制备。
Figure PCTCN2015095647-appb-000003
R是C5-17的烷基。
用于制备本发明化合物的多奈哌齐可以购自商业，或者可以根据已知的方法制备。
本发明所得化合物进行了SD大鼠体内药动学测试。试验结果证实了，本发明化合物具有半衰期长，抑制血药浓度快速升高的优势。
附图说明
图1显示了多奈哌齐组给药大鼠后血浆中药物浓度和时间的关系；
图2显示了化合物1组给药大鼠后血浆中药物浓度和时间的关系；
图3显示了化合物3组给药大鼠后血浆中药物浓度和时间的关系；
图4显示了化合物4组给药大鼠后血浆中药物浓度和时间的关系；
图5显示了化合物6组给药大鼠后血浆中药物浓度和时间的关系。
具体实施方式
为了更详细说明本发明。给出下述制备实例。但本发明的范围并非限定于此。
实施例1
化合物1：乙酸多奈哌齐酯的制备
将多奈哌齐(50.0g，132mmol)加入到2000ml三口圆底烧瓶(配备有氩气保护，温度计，机 械搅拌，恒压滴液漏斗)中，氮气置换，加入无水四氢呋喃600ml搅拌溶解，然后将体系温度冷却至-60～-78℃。将双三甲基硅基胺基锂(200ml，1.0mol/L，200mmol)通过双头针加入到恒压滴液漏斗中，一次性快速加入，-60～-78℃下搅拌15～30分钟后，自然升温到0～10℃。随后将体系温度降至-60～-78℃，将正乙酸酐(20.4g，200mmol)用200ml无水四氢呋喃溶解后加入恒压滴液漏斗中，一次性快速加入，-60～-78℃下搅拌30分钟后，自然升温至室温(20～30℃)，TLC检测原料反应完全。将反应体系于冰水浴下，滴加250ml饱和氯化铵溶液，滴加完成后，分液，再用20％氯化钠溶液250ml洗涤一遍，用饱和氯化钠溶液250ml洗涤，分液，有机相用无水硫酸钠干燥，减压除去溶剂，用500ml异丙醇结晶，得到白色固体41g(收率：73.7％)，HPLC(aera)：95.71％。
质谱(m/z)：[M+H]+＝422.3.
1H-NMR(CDCl3)δ：7.33-7.29(4H，d)，7.25-7.27(1H，m)，6.99(1H，s)，6.62(1H，s)，3.90(3H，s)，3.90(3H，s)，3.50(2H，s)，3.27(2H，s)，2.88-2.91(2H，d)，2.36(3H，s)，2.29-2.31(2H，d)，1.92-1.97(2H，t)，1.66-1.69(2H，d)，1.51-1.52(1H，m)，1.29-1.35(2H，m).
实施例2
化合物2：己酸多奈哌齐酯的制备
将多奈哌齐(25.0g，65.9mmol)加入到1000ml三口圆底烧瓶(配备有氩气保护，温度计，机械搅拌，恒压滴液漏斗)中，氮气置换，加入无水四氢呋喃300ml搅拌溶解，然后将体系冷却至-60～-78℃。将双三甲基硅基胺基锂(100ml，1.0mol/L，100mmol)通过双头针加入到恒压滴液漏斗中，一次性快速加入，-60～-78℃下搅拌15～30分钟后，自然升温到0～10℃。随后将体系温度降至-60～-78℃，然后将正己酸酐(21.4g，100mmol)用100ml无水四氢呋喃溶解加入到恒压滴液漏斗中，一次性快速加入，-60～-78℃下搅拌30分钟后，自然升温至室温(20～30℃)，TLC检测原料反应完全。将反应体系于冰水浴下，滴加250ml饱和氯化铵溶液，滴加完成后，分液，再用20％氯化钠溶液250ml洗涤一遍，用饱和氯化钠溶液250ml洗涤，分液，有机相用无水硫酸钠干燥，减压除去溶剂，得到油状物29.3g(收率：93％)。将油状物用225ml正庚烷加热溶解过滤除去不溶物，然后加入22.5ml乙醇，降温析晶，在-5～-10℃下保温1h，过滤，用冷的正庚烷/乙醇(10∶1)50ml洗涤，抽干，真空干燥得到灰白色固体21.0g(收率：66.7％)，HPLC(aera)：99.08％。
质谱(m/z)：[M+H]+＝478.4.
1H-NMR(CDCl3)δ：7.32-7.31(4H，d)，7.25-7.27(1H，m)，6.98(1H，s)，6.60(1H，s)，3.89(6H，s)，3.49(2H，s)，3.26(2H，s)，2.86-2.89(2H，d)，2.60-2.64(2H，t)，2.28-2.29(2H，d)，1.91-1.93(2H，t)， 1.81-1.84(2H，t)，1.65-1.68(2H，t)，1.20-1.60(7H，m)，0.95-0.97(3H，t).
实施例3
化合物3：庚酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(40.0g，105.4mmol)与庚酸酐(38.82g，242.4mmol)反应，得到庚酸多奈哌齐酯42.30g(收率：81.7％)，HPLC(aera)：98.2％。
质谱(m/z)：[M+H]+＝492.4.
1H-NMR(CDCl3)δ：7.32-7.31(4H，d)，7.26-7.27(1H，m)，6.98(1H，s)，6.59(1H，s)，3.89(3H，s)，3.90(3H，s)，3.50(2H，s)，3.26(2H，s)，2.87-2.89(2H，d)，2.60-2.64(2H，t)，2.27-2.29(2H，d)，1.90-1.93(2H，t)，1.80-1.83(2H，t)，1.65-1.68(2H，t)，1.20-1.60(9H，m)，0.90-0.96(3H，t).
实施例4
化合物4：辛酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(46.16g，121.6mmol)与辛酸酐(50.0g，270.4mmol)反应，得到辛酸多奈哌齐酯46.0g(收率：74.8％)，HPLC(aera)：98.51％。
质谱(m/z)：[M+H]+＝506.4.
1H-NMR(CDCl3)δ：7.32-7.31(4H，d)，7.26-7.27(1H，m)，6.98(1H，s)，6.59(1H，s)，3.89(3H，s)，3.90(3H，s)，3.49(2H，s)，3.26(2H，s)，2.86-2.89(2H，d)，2.60-2.63(2H，t)，2.27-2.29(2H，d)，1.90-1.96(2H，t)，1.80-1.83(2H，t)，1.65-1.68(2H，t)，1.10-1.60(11H，m)，0.90-0.96(3H，t).
实施例5
化合物5：壬酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(19.0g，50.1mmol)与壬酸酐(22.7g，76.2mmol)反应，后处理，结晶前过滤除去不溶物，结晶温度-15～-20℃，得到化合物壬酸多奈哌齐酯17.8g(收率：68.3％)，HPLC(aera)：98.15％。
质谱(m/z)：[M+H]+＝520.4.
1H-NMR(CDCl3)δ：7.32-7.31(4H，d)，7.25-7.26(1H，m)，6.98(1H，s)，6.59(1H，s)，3.896(3H，s)，3.889(3H，s)，3.49(2H，s)，3.26(2H，s)，2.86-2.89(2H，d)，2.60-2.63(2H，t)，2.27-2.29(2H，d)，1.91-1.96(2H，t)，1.81-1.85(2H，t)，1.65-1.68(2H，t)，1.18-1.65(13H，m)，0.88-0.91(3H，t).
实施例6
化合物6：癸酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(25.0g，65.9mmol)与癸酸酐(32.6g，100mmol)反应，后处理，结晶前过滤除去不溶物，得到化合物癸酸多奈哌齐酯21.9g(收率：62.2％)，HPLC(aera)：98.15％。
质谱(m/z)：[M+H]+＝534.4.
1H-NMR(CDCl3)δ：7.32-7.31(4H，d)，7.26-7.28(1H，m)，6.98(1H，s)，6.59(1H，s)，3.891(3H，s)，3.899(3H，s)，3.49(2H，s)，3.26(2H，s)，2.86-2.89(2H，d)，2.60-2.63(2H，t)，2.27-2.29(2H，d)，1.90-1.94(2H，t)，1.80-1.83(2H，t)，1.65-1.68(2H，t)，1.30-1.62(15H，m)，0.89-0.93(3H，t).
实施例7
化合物7：十二酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(15.0g，39.5mmol)与十二酸酐(23.0g，60.0mmol)反应，后处理，结晶前过滤除去不溶物，得到十二酸多奈哌齐酯14.3g(收率：64.4％)，HPLC(aera)：98.15％。
质谱(m/z)：[M+H]+＝562.4.
1H-NMR(CDCl3)δ：7.32-7.30(4H，d)，7.26-7.27(1H，m)，6.98(1H，s)，6.59(1H，s)，3.890(3H，s)，3.899(3H，s)，3.50(2H，s)，3.26(2H，s)，2.87-2.90(2H，d)，2.59-2.63(2H，t)，2.27-2.29(2H，d)，1.91-1.97(2H，t)，1.79-1.83(2H，t)，1.65-1.68(2H，t)，1.28-1.49(19H，m)，0.90-0.92(3H，t).
实施例8
化合物8：十四酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(2.00g，5.27mmol)与十四酸酐(3.50g，8.00mmol)反应，后处理，结晶前过滤除去不溶物，得到十四酸多奈哌齐酯1.93g(收率：62.0％)，HPLC(aera)：98.15％。
质谱(m/z)：[M+H]+＝590.5.
1H-NMR(CDCl3)δ：7.32-7.30(4H，d)，7.26-7.27(1H，m)，6.98(1H，s)，6.59(1H，s)，3.890(3H，s)，3.899(3H，s)，3.51(2H，s)，3.26(2H，s)，2.87-2.90(2H，d)，2.60-2.63(2H，t)，2.27-2.29(2H，d)，1.91-1.97(2H，t)，1.81-1.83(2H，t)，1.65-1.68(2H，t)，1.28-1.49(23H，m)，0.88-0.92(3H，t).
实施例9
化合物9：棕榈酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(30.0g，79.1mmol)与棕榈酸酐(58.7g，119mmol)反应，后处理，结晶前过滤除去不溶物，得到棕榈酸多奈哌齐酯38.0g(收率：79.5％)，HPLC(aera)：98.15％。
质谱(m/z)：[M+H]+＝618.5.
1H-NMR(CDCl3)δ：7.32-7.31(4H，d)，7.25-7.27(1H，m)，6.98(1H，s)，6.59(1H，s)，3.90(3H，s)，3.89(3H，s)，3.49(2H，s)，3.26(2H，s)，2.86-2.89(2H，d)，2.60-2.63(2H，t)，2.28-2.29(2H，d)，1.90-1.96(2H，t)，1.80-1.83(2H，t)，1.65-1.68(2H，t)，1.28-1.55(29H，m)，0.88-0.92(3H，t).
实施例10
化合物10：硬脂酸多奈哌齐酯的制备
制备方法同实施例2，多奈哌齐(2.00g，5.27mmol)与硬脂酸酐(4.40g，8.00mmol)反应，后处理，结晶前过滤除去不溶物，得到硬脂酸多奈哌齐酯2.13g(收率：62.6％％)，HPLC(aera)：98.15％。
质谱(m/z)：[M+H]+＝646.5.
1H-NMR(CDCl3)δ：7.32-7.30(4H，d)，7.25-7.27(1H，m)，6.98(1H，s)，6.59(1H，s)，3.890(3H，s)，3.898(3H，s)，3.50(2H，s)，3.26(2H，s)，2.87-2.89(2H，d)，2.60-2.63(2H，t)，2.27-2.29(2H，d)，1.91-1.96(2H，t)，1.81-1.83(2H，t)，1.66-1.68(2H，t)，1.28-1.60(31H，m)，0.88-0.92(3H，t).
实施例11
处方：
组分 处方量
化合物4 100mg
苯甲酸苄酯 200mg
苯甲醇 100mg
蓖麻油 1ml
制备方法：
将处方量的化合物4，苯甲醇和苯甲酸苄酯溶解于蓖麻油中，搅拌至药物完全溶解，用0.22μm滤膜过滤除菌，压塞，轧盖，得到油性制剂。
实施例12
本发明化合物给药大鼠后的药动学性质
本实施例中所使用的为雄性SD大鼠(SPF级)，年龄9个月，体重180～220g，购自上海斯莱克实验动物有限责任公司。整个实验过程中，大鼠自由进食进水。
采用随机区组设计的分组，根据性别及体重，对试验用SD大鼠进行分组，分为多奈哌齐组、化合物1组、化合物3组、化合物4组及化合物6组。各组以肌肉注射(i.m.)的方式给药，给药剂量设为90mg/kg(以多奈哌齐计)，样品以90mg/ml(以多奈哌齐计)的浓度溶于油溶剂中。
给药后4h，8h，24h(2day)，3day，4day，5day，7day，9day，12day，眼底静脉丛采集静脉血0.5ml置于事先标号的EDTA(4mM)抗凝的EP管中，全血采集后放置在冰上，随即在4℃、8000rpm、5min条件下离心收集血浆，转移至96孔板中，于-20℃保存至LC-MS/MS检测。 使用LC/MS/MS(Agilent6460)方法测定EDTA(4mM)抗凝的SD大鼠血浆中的药物浓度，各组的浓度时间曲线如图1～5所示。采用WinNonlin5.2软件，按统计距理论分别求算各组给药后，各时间点浓度的相关药动学参数。详见表1。
表1
Figure PCTCN2015095647-appb-000004
其中Cmax和Tmax均以实测值表示。
t1/2用公式t1/2＝0.693/λz计算；λz系对数浓度-时间曲线末端直线部份求得的末端消除速率常数，可用对数浓度-时间曲线末端直线部分的斜率求得。
结论：由上述试验结果可知，本发明化合物具有半衰期长，抑制血药浓度快速升高的优势。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 式(I)化合物或其药学上可接受的盐：
    Figure PCTCN2015095647-appb-100001
    其中：
    R是C5-17的烷基。
  2. 根据权利要求1所述的化合物或其药学上接受的盐，其特征在于，所述R选自正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基、正十一烷基、正十三烷基、正十五烷基或正十七烷基。
  3. 根据权利要求1所述的化合物或其药学上接受的盐，其特征在于，所述R选自正戊烷基、正己烷基、正庚烷基、正辛烷基、正壬烷基、正癸烷基，优选自正己烷基、正庚烷基、正辛烷基、正壬烷基。
  4. 化合物或其药学上可接受的盐，其特征在于，所述化合物选自：
    Figure PCTCN2015095647-appb-100002
  5. 权利要求1～3中任意一项所述化合物或其药学上可接受的盐在制备用于治疗由乙酰胆碱酯酶活性异常引起的疾病的药物中的用途。
  6. 根据权利要求4所述的用途，其特征在于，所述疾病是阿尔兹海默症。
  7. 一种药物组合物，其特征在于，包含权利要求1～3中任意一项所述化合物或其药学上可接受的盐和药学上可接受的赋形剂。
  8. 根据权利要求8所述的组合物，其特征在于，所述赋形剂选自蓖麻油、大豆油、芝麻油、花生油、玉米油、棉籽油或各类甘油酯中的一种或多种，优选自蓖麻油。
  9. 根据权利要求8或9所述的组合物，其特征在于，还含有增溶剂，所述增溶剂选自苯甲酸苄酯或醇类中的一种或多种，优选自苯甲酸苄酯。
  10. 根据权利要求8～10任意一项所述的组合物，其特征在于，还含有止痛剂，所述止痛剂选自苯甲醇。
PCT/CN2015/095647 2014-12-11 2015-11-26 多奈哌齐衍生物及其用途 WO2016091079A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/533,865 US10080746B2 (en) 2014-12-11 2015-11-26 Donepezil derivative and use thereof
US15/972,500 US10632111B2 (en) 2014-12-11 2018-05-07 Donepezil derivative and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410777222.4A CN105732478B (zh) 2014-12-11 2014-12-11 多奈哌齐衍生物及其用途
CN201410777222.4 2014-12-11

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/533,865 A-371-Of-International US10080746B2 (en) 2014-12-11 2015-11-26 Donepezil derivative and use thereof
US15/972,500 Continuation US10632111B2 (en) 2014-12-11 2018-05-07 Donepezil derivative and use thereof

Publications (1)

Publication Number Publication Date
WO2016091079A1 true WO2016091079A1 (zh) 2016-06-16

Family

ID=56106678

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/095647 WO2016091079A1 (zh) 2014-12-11 2015-11-26 多奈哌齐衍生物及其用途

Country Status (4)

Country Link
US (2) US10080746B2 (zh)
CN (1) CN105732478B (zh)
TW (1) TWI607993B (zh)
WO (1) WO2016091079A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102227100B1 (ko) * 2020-08-14 2021-03-12 주식회사 종근당 도네페질 에테르 팔미테이트 또는 이의 약제학적으로 허용가능한 염

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106474058B (zh) 2015-08-31 2020-01-07 南京诺瑞特医药科技有限公司 具有延长的保质期的阿立哌唑可注射悬浮液制剂
CN110548005B (zh) * 2018-05-30 2021-08-31 南京诺瑞特医药科技有限公司 含有多奈哌齐衍生物的缓释注射制剂
KR101980534B1 (ko) * 2019-04-05 2019-05-21 주식회사 종근당 도네페질 미리스틸옥시메틸에테르 또는 이의 약제학적으로 허용가능한 염
KR20220059300A (ko) * 2020-11-02 2022-05-10 주식회사 종근당 인덴 유도체 프로드럭의 산부가염 및 이의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007052541A1 (en) * 2005-11-02 2007-05-10 Eisai R & D Management Co., Ltd. Prodrug of donepezil hydrochloride
WO2012046062A1 (en) * 2010-10-05 2012-04-12 Shire, Llc Use of prodrugs to avoid gi mediated adverse events

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007052541A1 (en) * 2005-11-02 2007-05-10 Eisai R & D Management Co., Ltd. Prodrug of donepezil hydrochloride
WO2012046062A1 (en) * 2010-10-05 2012-04-12 Shire, Llc Use of prodrugs to avoid gi mediated adverse events

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102227100B1 (ko) * 2020-08-14 2021-03-12 주식회사 종근당 도네페질 에테르 팔미테이트 또는 이의 약제학적으로 허용가능한 염
WO2022035048A1 (ko) * 2020-08-14 2022-02-17 주식회사 종근당 도네페질 에테르 팔미테이트 또는 이의 약제학적으로 허용가능한 염

Also Published As

Publication number Publication date
TWI607993B (zh) 2017-12-11
CN105732478A (zh) 2016-07-06
CN105732478B (zh) 2020-04-24
US20180250278A1 (en) 2018-09-06
US10080746B2 (en) 2018-09-25
TW201636325A (zh) 2016-10-16
US10632111B2 (en) 2020-04-28
US20170319561A1 (en) 2017-11-09

Similar Documents

Publication Publication Date Title
WO2016091079A1 (zh) 多奈哌齐衍生物及其用途
ES2964818T3 (es) Profármacos de abiraterona
WO2017012556A1 (zh) 一种芳基丙酸类化合物及其制药用途
JPS5995269A (ja) 抗てんかん性医薬品
KR20150125663A (ko) 사이클로스포린 a 스테로이드 켤레물
AU2016370499B2 (en) Amorphous onapristone compositions and methods of making the same
US8987263B2 (en) Basic esters of fatty alcohols and their use as anti-inflammatory or immunomodulatory agents
TW202104186A (zh) 多奈派齊肉豆蔻基氧基甲基醚或其之藥理容許鹽
WO2019228477A1 (zh) 含有多奈哌齐衍生物的缓释注射制剂
TW201103911A (en) Novel fumarate salts of a histamine H3 receptor antagonist
EP2226329A1 (en) Metal-containing platensimycin analogues
JP6356218B2 (ja) 抗腫瘍活性を有する７−α−［９−（４，４，５，５，５−ペンタフルオロペンチルスルフィニル）ノニル］−エストラ−１，３，５（１０）−トリエン−３，１７β−ジオールのエステル誘導体及びその調製方法
CN114989138A (zh) 沃诺拉赞盐及其晶型、制备方法和用途
ES2566671T3 (es) Cristal de sal de un compuesto de piridina fusionado
DE1967080C3 (de) t-(3,4-Methylendioxybeiizoyl)-2methyl-5-methoxy-3-indolylessigsäureester, Verfahren zu ihrer Herstellung und Arzneipräparate
JP2005511611A (ja) インテグリン受容体拮抗薬のアミン塩
US4218447A (en) Acyl derivatives of hellebrigenin
Jay et al. Methods and pharmaceutical compositions for decorporation of radioactive compounds
WO2019110006A1 (zh) 抗疼痛化合物及其制备方法
JP2021503474A (ja) 局所麻酔薬
CS221527B2 (en) Method of preparation of n-/1-methyl-2-pyrrolidinylmethyl/2,3-dimethoxy-5-methylsulphamoylbenzamide
KR102119619B1 (ko) 아민염과 그 결정
WO2022022677A1 (zh) 多种功效的吡嗪类化合物及其制备方法和应用
WO2023086438A1 (en) Prodrugs of neurosteroid analogs and uses thereof
JPH03181419A (ja) イミダゾピリジンを含有する麻酔薬

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15866933

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15533865

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15866933

Country of ref document: EP

Kind code of ref document: A1