WO2020073770A1 - 丁酰胆碱酯酶选择性抑制剂及其制备方法与用途 - Google Patents

丁酰胆碱酯酶选择性抑制剂及其制备方法与用途 Download PDF

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WO2020073770A1
WO2020073770A1 PCT/CN2019/105625 CN2019105625W WO2020073770A1 WO 2020073770 A1 WO2020073770 A1 WO 2020073770A1 CN 2019105625 W CN2019105625 W CN 2019105625W WO 2020073770 A1 WO2020073770 A1 WO 2020073770A1
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arh
compound
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benzo
acetamide
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孙昊鹏
李琦
卢鑫
陈瑶
冯锋
邢帅帅
李启航
曲玮
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • the invention belongs to the field of medicine, and relates to a selective inhibitor of butyrylcholinesterase and a preparation method and application thereof.
  • AD Alzheimer ’s disease
  • AD is a systemic neurodegenerative syndrome with clinical manifestations of central cognitive impairment, mental and motor disorders, etc.
  • AD has posed a huge threat to the health of the elderly and the overall medical resources of society.
  • AD World Alzheimer's Disease Report
  • the global investment in AD treatment has increased by more than 35%.
  • This series of shocking figures clearly reveals the current severe situation in the prevention and treatment of AD, and finding an effective response is urgent and urgent. Therefore, the discovery of effective AD prevention and treatment drugs has important basic research and clinical application value.
  • AD pathological causes of AD are extremely complex, and no clear pathogenic factors have been found so far.
  • the pathological process involves multiple systems and links such as nerves, immunity, and blood circulation.
  • a large number of studies have shown that the occurrence and development of AD are closely related to the following factors: 1) pathological changes and dysfunction of the neurocholinergic system; 2) ⁇ -amyloid ( ⁇ -amyloid) that induces neuronal cell apoptosis , A ⁇ ) tangles and precipitation; 3) Tau protein is excessively phosphorylated to form senile plaque (SP) and neurofibrillary tangles (NFT), which in turn causes the loss of neurons in the brain; 4) causes the brain Inflammatory response to environmental changes in body fluids and the rise in levels of active oxygen free radicals; 5) Disorders of immune regulation in the brain.
  • SP senile plaque
  • NFT neurofibrillary tangles
  • AD N-methyl-D-aspartic receptor
  • drugs are all cholinesterase inhibitors. (Donepezil, Galantamine, Levantine). These marketed drugs are only suitable for the symptomatic treatment of mild to moderate AD, and there is a serious lack of effective drugs for severe AD. At present, the only effective drug for the treatment of severe AD is memantine, but its effect is not satisfactory. The course of AD is long, and many patients with severe AD are still in a situation where no drugs are available.
  • Cholinesterase inhibitors designed based on the central cholinergic hypothesis are still the clinically preferred strategy for AD treatment.
  • the hypothesis believes that AD patients have severely damaged cholinergic neurons, especially in the cortex and hippocampus, Meynert basal nucleus and septum of the forebrain, which results in abnormally reduced levels of acetylcholine (ACh).
  • the pathological features of AD, especially cognitive dysfunction, are closely related.
  • the cholinesterase that is responsible for the hydrolysis of ACh is the key factor to control the level of ACh. Therefore, by inhibiting the activity of cholinesterase, the excitability of the central cholinergic system can be improved, and the learning and memory abilities of the elderly can be improved. To delay the course of AD.
  • Cholinesterase mainly has two members: Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE).
  • AChE Acetylcholinesterase
  • BuChE Butyrylcholinesterase
  • AChE can specifically recognize and hydrolyze ACh, which is a key target for its metabolism. Therefore, existing drugs are also mainly aimed at AChE.
  • donepezil and galantamine are selective AChE inhibitors.
  • BuChE because it is not the main metabolic node of ACh under normal conditions, it is often considered to be a redundant mechanism of AChE formed by the body during natural evolution.
  • the level of AChE decreased by 90% from the normal value, and the function was almost lost.
  • BuChE inhibitors have a strong rationality and important research and application value for the treatment of AD.
  • most existing BuChE inhibitors are accompanied by the emergence of AChE inhibitors. They have the disadvantages of small number, lack of structural novelty and diversity, and poor selectivity. Therefore, the development of highly selective BuChE inhibitors with a completely new framework is of great significance and value.
  • the present invention discloses a class of compounds having anti-Alzheimer's disease as shown in formula (I).
  • n is an integer from 1 to 4;
  • R represents Or R 2 substituted naphthyl or quinoline;
  • R 1 represents optionally substituted hydroxy, halogen, C 1 -C 4 alkyl, halogen substituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 ⁇ C 4 acyl, phenyl, -O (CH 2 ) m O-, cyano, nitro or -NR 3 R 4 , where m is 1 or 2, and R 3 and R 4 each independently represent hydrogen or C 1 ⁇ C 3 alkyl;
  • R 2 represents hydrogen, or optionally substituted C 1 -C 4 alkyl.
  • the compound having anti-Alzheimer's disease or a pharmaceutically acceptable salt thereof preferably n is 1 or 2
  • R represents Or R 2 substituted naphthyl or quinoline
  • R 1 is selected from optionally substituted fluorine, chlorine, bromine, methyl, isopropyl, methoxy, methoxycarbonyl, acetyl, acetamido, phenyl, -OCH 2 O-, cyano, nitro or -NR 3 R 4 , R 3 and R 4 are independently selected from hydrogen or methyl
  • R 2 is selected from hydrogen, methyl or bromine.
  • the compound having anti-Alzheimer's disease represented by formula (I) or a pharmaceutically acceptable salt thereof, further preferably n 1 or 2; R is selected from para-nitro, methyl mono-substituted or meta-position Monosubstituted or polysubstituted phenyl, unsubstituted, methyl or bromo substituted naphthyl or quinoline.
  • the compound having anti-Alzheimer's disease represented by formula (I) is further preferably any of the following compounds:
  • the pharmaceutically acceptable salt of the present invention is selected from hydrochloride, maleate and citrate; the pharmaceutically acceptable salt of the compound represented by formula (I) has the same as the compound represented by formula (I) Or better pharmacodynamic activity.
  • the preparation method of the compound having anti-Alzheimer's disease as shown in formula (I) includes: starting from 2-cyanomethylbenzimidazole, sodium nitrite (1-1.2 times equivalent), Hydroxylamine hydrochloride (2 to 4 times equivalent) reacts in two steps to obtain 4- (1H-benzo [d] imidazol-2-yl) -1,2,5-oxadiazol-3-amine Different ring systems and differently substituted aromatic amines react with (1.3 to 2 equivalents) of chloroacetyl chloride, 3-chloropropionyl chloride, 4-chlorobutyryl chloride or 5-chloropentanoyl chloride to form the corresponding amide intermediates And then 4- (1H-benzo [d] imidazol-2-yl) -1,2,5-oxadiazol-3-amine (1: 0.8 to 1.2 equivalents) The reaction produces a selective butyrylcholinesterase inhibitor with anti-Alzheimer's disease as shown in formula (I).
  • the reaction formula is
  • n is an integer from 1 to 4;
  • R represents Or R 2 substituted naphthyl or quinoline;
  • R 1 represents optionally substituted hydroxy, halogen, C 1 -C 4 alkyl, halogen substituted C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, C 1 ⁇ C 4 acyl, phenyl, -O (CH 2 ) m O-, cyano, nitro or -NR 3 R 4 , where m is 1 or 2, and R 3 and R 4 each independently represent hydrogen or C 1 ⁇ C 3 alkyl;
  • R 2 represents hydrogen, or optionally substituted C 1 -C 4 alkyl.
  • the invention includes the use of the compound in the preparation of a medicament for preventing or treating Alzheimer's disease.
  • the compound of the present invention can be added to a pharmaceutically acceptable carrier to make common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, injections, flavors, sweeteners, liquid or Commonly used pharmaceutical excipients such as solid fillers or diluents.
  • the compound of the present invention can be administered orally or by injection in the clinic.
  • the dose of the compound of the present invention in clinic is 0.01 mg to 1000 mg / day, and may also deviate from this range according to the severity of the disease or the different dosage forms.
  • the present invention provides a series of compounds represented by formula (I), using butyrylcholinesterase inhibitory activity, selective screening, and Morris water maze test as carriers to evaluate compounds of formula (I) for treatment of Alzheimer ’s disease
  • the therapeutic effect of Mercury's disease is found to have good in vitro and in vivo activity and extremely high selectivity, which can be used as a further development by selectively inhibiting butyrylcholinesterase Precursor for the action of Alzheimer's disease.
  • Figure 1 The time for the mouse to reach the platform
  • Fig. 2 The trajectory of mice reaching the platform (A: control group; B: model group; C: tacrine group; D: compound 1 treatment group; E: compound 6 treatment group; F: compound 7 treatment group; G: Compound 9 treatment group).
  • 2-Methyl-6-aminoquinoline is self-made, the method is: take p-nitroaniline (500mg, 3.65mmol) in an eggplant-shaped bottle, use concentrated hydrochloric acid as a solvent, dropwise add triethylene glycol to the reaction bottle Aldehyde (1.45g, 10.94mmol) was added dropwise, the reaction solution was heated to reflux for 6 hours, and cooled to room temperature; the reaction solution was adjusted to pH 8 with potassium hydroxide, extracted with dichloromethane multiple times, combined organic phases, and washed with saturated brine once The organic phase was dried and separated through a silica gel chromatography column to obtain the intermediate 2-methyl-6-nitroquinoline (460 mg, yield 67.40%).
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced by 2-chloro-N- (quinolin-6-yl) acetamide to obtain a milky white solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-6-yl) acetamide (Compound 2). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 3 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 3-chloro-N- (quinolin-6-yl) propanamide to obtain a milky white solid compound, which is 3- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-6-yl) propionamide (Compound 3). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 1 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 5-chloro-N- (quinolin-6-yl) pentanamide to obtain a light yellow solid compound, which is 5- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-6-yl) pentanamide.
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 4 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (quinolin-5-yl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-5-yl) acetamide (Compound 4). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 5 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (quinolin-4-yl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-4-yl) acetamide (Compound 5). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 6 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (quinolin-3-yl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-3-yl) acetamide (Compound 6). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 7 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (quinolin-2-yl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (quinolin-2-yl) acetamide (compound 7). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 8 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (naphthalene-1-yl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (naphthalen-1-yl) acetamide (Compound 8). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 9 the intermediate 2 in Example 1 is replaced with 2-chloro-N- (naphthalen-2-yl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (naphthalen-2-yl) acetamide (Compound 9).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 10 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N-phenylacetamide to obtain a light yellow solid compound, that is, 2- (2- (4-amino-1,2 , 5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N-phenylacetamide (Compound 10).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 11 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-fluoro-N- (2-chlorophenyl) acetamide to obtain a milky white solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (2-fluorophenyl) acetamide (Compound 11). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 12 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (2-chlorophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (2-chlorophenyl) acetamide (Compound 12). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 13 the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-fluorophenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-fluorophenyl) acetamide (Compound 13).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 14 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced by 2-chloro-N- (3-chlorophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-fluorophenyl) acetamide (Compound 14). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 15 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-bromophenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-fluorophenyl) acetamide (Compound 15). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 16 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-methylphenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-methylphenyl) acetamide (Compound 16).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 17 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3,4,5-trimethoxyphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3,4,5-trimethoxybenzene Group) acetamide (Compound 17).
  • Example 18 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-nitrophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-nitrophenyl) acetamide (Compound 18).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 19 the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-cyanophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-cyanophenyl) acetamide (Compound 19).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-acetamidophenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-acetamidophenyl) acetamide (Compound 22). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-acetylphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-acetylphenyl) acetamide (Compound 20).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 21 the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3-methoxycarbonylphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- ( 4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3-methoxycarbonylphenyl) acetamide (Compound 21) .
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 23 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-chlorophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-chlorophenyl) acetamide (Compound 23). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-bromophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-bromophenyl) acetamide (Compound 24).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 25 the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-methylphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-methylphenyl) acetamide (Compound 25).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with 2-chloro-N- (4-methoxyphenyl) acetamide to obtain a light yellow solid compound, that is, 2- (2- ( 4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-methoxyphenyl) acetamide (Compound 26) .
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 1 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-acetylphenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-acetylphenyl) acetamide (compound 27).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 1 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-acetylphenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-acetylphenyl) acetamide (Compound 28). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 29 the intermediate 2 in Example 1 is replaced by 2-chloro-N- (4-nitrophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-nitrophenyl) acetamide (Compound 29).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 30 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-aminophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4- Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-nitrophenyl) acetamide (Compound 30).
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 1 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-isopropylphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- ( 4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-isopropylphenyl) acetamide.
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 31 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-acetamidophenyl) acetamide to obtain a pale yellow solid compound, which is 2- (2- (4 -Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-acetamidophenyl) acetamide (Compound 31). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 1 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (4-biphenylphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- ( 4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-biphenylphenyl) acetamide.
  • TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 35 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (3,4,5-trimethoxyphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (3,4,5-trimethoxybenzene Group) acetamide (compound 35). TLC detection is a point, there are dark spots under the UV lamp at 254nm, and no fluorescence at 365nm.
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced by 2-chloro-N- (benzo [d] [1,3] dioxol-5-yl) acetamide, Light yellow solid compound, which is 2- (2- (4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (benzene And [d] [1,3] dioxol-5-yl) acetamide (compound 32).
  • Example 33 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (2,3-dimethylphenyl) acetamide to obtain a light yellow solid compound, which is 2- (2 -(4-amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (2,3-dimethylphenyl) acetamide (Compound 33).
  • Example 1 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 is replaced with 2-chloro-N- (2,3-difluorophenyl) acetamide to obtain a light yellow solid compound, which is 2- (2- (4-Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (2,3-difluorophenyl) acetamide (compound 34).
  • Example 2 Referring to the synthesis method of Example 1, the intermediate 2 in Example 1 was replaced with 2-chloro-N- (4-bromonaphthalen-1-yl) acetamide to obtain a light yellow solid compound, which was 2- (2- (4-Amino-1,2,5-oxadiazol-3-yl) -1H-benzo [d] imidazol-1-yl) -N- (4-bromonaphthalen-1-yl) acetamide (compound 36).
  • test compound AChE (EC3.1.1.7, Type VI-S, selected from electric eel), BuChE (EC3.1.1.8, selected from horse serum), 5,5'-disulfide (2- Nitrobenzoic acid) (DTNB), acetylthiocholine (ATC) iodide and butyrylthiocholine (BTC) iodide were purchased from Sigma; positive control tacrine hydrochloride (9-Amino- 1,2,3,4-tetrahydroacridine (hydrochloride hydrate) was purchased from BioTrend.
  • buffer solution 13.6g of potassium dihydrogen phosphate is dissolved in 1L of water, and the pH is adjusted to 8 ⁇ 0.1 with potassium hydroxide. The solution is stored at 4 ° C and set aside.
  • AChE and BuChE solutions Dissolve 5000 units of AChE in 1 mL of 1% gel solution, then dilute with water to 100 mL to prepare an AChE solution with a concentration of 5 units / mL, store at -30 ° C, and reserve for use; Dissolve 5000 units of BuChE in 1 mL of 1% gel solution, then dilute with water to 100 mL to prepare a BuChE solution with a concentration of 5 units / mL, store at -30 ° C, and set aside.
  • Test solution The test compound was dissolved in ethanol to obtain a concentration of 10 -3 M solution (ethanol does not affect the test results), respectively, then diluted with water to obtain a concentration of 10 -4, 10 - 5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 M solution.
  • a represents the inhibition rate of the compound on the target at a concentration of 10 ⁇ M
  • the compounds in Table 1 all showed better inhibitory activity against BuChE (the compound 7 had a BuChE inhibitory activity of 20 nM, and the compound 39 had a BuChE inhibitory activity of 6 nM), but had no inhibitory activity against AChE (at a concentration of 10 ⁇ M). (Inhibition rate is less than 10%), indicating that this series of compounds have extremely high selectivity.
  • 80% of ACh was hydrolyzed by AChE, but BuChE had almost no effect. With the progression of the disease, the level of AChE decreased and the function was almost lost. At this time, the level and function of BuChE increased relatively, replacing AChE as the main ACh Metabolic enzymes.
  • the inhibitory activity of BuChE is particularly important.
  • the development of selective BuChE inhibitors is of great significance.
  • the compounds involved in the present invention have very good inhibitory activity on BuChE and extremely high selectivity, and are expected to produce good therapeutic effects on mild and severe AD.
  • mice Adult male ICR mice (8-10 weeks, body weight 20-25 grams) were purchased from Yangzhou University Medical Center.
  • Scopolamine hydrobromide was purchased from Aladdin Reagent Company (S107418, Shanghai), tacrine (purity> 95%), compound 1, compound 6, compound 7, compound 9.
  • mice were randomly divided into 7 groups (8 mice per group): control group, model group, tacrine group, compound 1 treatment group, compound 6 treatment group, compound 7 treatment group, compound 9 Treatment group.
  • Tacrine, compound 1, compound 6, compound 7 and compound 9 were dissolved in CMC-Na solution (0.5g CMC-Na, 100mL distilled water) and administered by intragastric administration (15mg / kg body weight).
  • mice in the model group, tacrine group, compound 1 treatment group, compound 6 treatment group, compound 7 treatment group, and compound 9 treatment group were intraperitoneally injected with scopolamine (1 mg / kg), and control group mice were intraperitoneally injected with physiological saline.
  • the water maze was used to test the cognitive function and memory ability of mice.
  • the trajectory of mice in the model group is significantly more chaotic than that in the blank group; the path of mice in the tacrine group is less chaotic than the model group, indicating that he Klin improved the memory and cognitive function of mice; the trajectories of mice in the compound 1 treatment group, compound 6 treatment group, compound 7 treatment group, and compound 9 treatment group reached the platform were significantly less chaotic than the model group. It is superior to the tacrine group, indicating that compound 1, compound 6, compound 7, and compound 9 have a significant effect on improving memory and cognitive function in mice, and are superior to tacrine.

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Abstract

公开了式(I)所示的丁酰胆碱酯酶选择性抑制剂及其制备方法与在制备预防或治疗阿尔茨海默氏病药物中的应用。以丁酰胆碱酯酶抑制活性、选择性的筛选以及Morris水迷宫实验为载体来评价式(I)所示的化合物治疗阿尔茨海默氏病(尤其是中重度阿尔茨海默氏病)，发现具有良好的体外、体内活性和极高的选择性，可作为进一步开发通过选择性抑制丁酰胆碱酯酶来发挥开阿尔茨海默氏病作用的前体物质。（I）

Description

丁酰胆碱酯酶选择性抑制剂及其制备方法与用途 技术领域
本发明属于医药领域，涉及丁酰胆碱酯酶选择性抑制剂及其制备方法与用途。
背景技术
阿尔茨海默氏病(Alzheimer’s disease,AD)是一种系统性的大脑神经退行综合征，临床表现为中枢认知功能减退、精神及运动障碍等。当前，伴随着人口老龄化已成为全球性问题，AD对于老年人的生命健康以及社会整体医疗资源都已经构成了巨大的威胁。据《2016年世界阿尔茨海默氏病报告》统计，2015年全球AD患者已有4680万人，而到2050年，这个数字将达到1.32亿。在过去的五年里，全球在AD治疗方面的资金投入增幅超过35％，2015年已达8180亿美元，2018年将突破万亿美元。这一串触目惊心的数字，清楚地揭示了目前防治AD的严峻形势，寻找有效的应对之道，已是迫在眉睫、刻不容缓。因此，发现有效的AD防治药物，具有重要的基础研究与临床应用价值。
AD的病理成因极为复杂，至今仍未发现明确的致病因素，其病理进程涉及神经、免疫以及血液循环等多个系统和环节。大量研究表明，AD的发生与发展与如下几个因素紧密相关：1)神经胆碱能系统的病理性改变及功能紊乱；2)诱导神经元细胞凋亡的β-淀粉样蛋白(β-amyloid,Aβ)缠结、沉淀；3)Tau蛋白过度磷酸化，形成老年斑(senile plaque,SP)、神经元纤维缠结(neurofibrillary tangles,NFT)，进而造成脑内神经元丧失；4)引起脑部体液内环境变化的炎症反应及活泼氧自由基水平的上升；5)脑内免疫调节的紊乱。但是无论是哪种学说，目前都未阐明其与AD之间明确的因果关系，这也直接阻碍了抗AD药物的研发。
尽管目前已经提出了多种治疗AD的潜在策略，但是均处于基础研究阶段。目前临床上有效的药物除了美金刚为N-甲基-D-天冬氨酸受体(N-methyl-D-aspartic acid receptor,NMDAR)阻滞剂外，其他均为胆碱酯酶抑制剂(多奈哌齐、加兰他敏、利凡斯的明)。这些上市的药物仅适用于轻、中度AD的对症治疗，对重度AD有效的药物严重匮乏。目前对重度AD治疗唯一有效的药物为美金刚，然而其效果也不尽如人意。AD病程漫长，许多重度AD患者目前仍处于无药可用的境地。
以中枢胆碱能假说为基础而设计的胆碱酯酶抑制剂仍然是AD治疗的临床首选策略。该假说认为，AD患者脑内胆碱能神经元受损严重，尤其是皮质和海马、前脑Meynert基底核和隔区等部位，这导致了乙酰胆碱(acetylcholine,ACh)水平异常降低，后者与AD的病理特征尤其是认知功能障碍存在紧密关联。而负责水解ACh的胆碱酯酶则是控制ACh水平的关键因素，因此通过抑制胆碱酯酶的活性，可提高中枢胆碱能系统的兴奋性，改善老年人的学习与记忆能力，进而起到延缓AD病程的作用。胆碱酯酶主要有两个成员：乙酰胆碱酯酶(Acetylcholinesterase,AChE)和丁酰胆碱酯酶(Butyrylcholinesterase,BuChE)。目前现有的大多数研究认为，AChE可特异性识别并水解ACh，是其代谢的关键靶标，因此现有的药物也主要针对于AChE，例如多奈哌齐和加兰他敏均是选择性AChE抑制剂。而对于BuChE，由于在正常状态下它并非ACh的主要代谢节点，常常被认为可能是机体在自然进化过程中形成的AChE的冗余机制。然而，在AD病理情况下，由于胆碱神经元受损严重，AChE的水平相对正常值下降了90％，功能几乎丧失，而此时BuChE的水平及功能则提升至正常水平的105～165％，取代AChE成为水解ACh的主要代谢酶。因此对于重度AD的治疗，其关键不在于AChE，而在于BuChE。抗AD药物虽然非常关注药物的中枢靶向性，但仍然难以做到完全的组织选择性，因此，选择性AChE抑制剂或是非选择性胆碱酯酶抑制剂，都具有外周胆碱能样副作用。而多项研究表明，BuChE敲除鼠生长发育正常，无论是中枢还是外周均 无异常，可见其生物效应强度远低于AChE，因此可以推断，选择性BuChE抑制剂引起的胆碱能副作用明显较低，在AD治疗的药物安全性方面也更具有优势。
综上所述，通过特异性抑制BuChE对于治疗AD具有极强的合理性和重要的研究与应用价值。然而现有的BuChE抑制剂大多是伴随着AChE抑制剂的出现而出现的，它们具有数量少，缺乏结构新颖性与多样性，选择性差等缺点。因此开发具有全新骨架的高选择性BuChE抑制剂就具有重要的意义和价值。
发明内容
本发明公开了一类如式(I)所示的具有抗阿尔茨海默氏病的化合物。
本发明结构式如下：
Figure PCTCN2019105625-appb-000001
其中n为1～4的整数；R代表
Figure PCTCN2019105625-appb-000002
或R 2取代的萘基或喹啉；
其中R 1代表任意取代的羟基、卤素、C 1～C 4烷基、卤素取代的C 1～C 4烷基、C 1～C 4烷氧基、C 1～C 4烷氧羰基、C 1～C 4酰基、苯基、-O(CH 2) mO-、氰基、硝基或-NR 3R 4，其中，m为1或2，R 3、R 4各自独立地代表氢或C 1～C 3烷基；
R 2代表氢、或任意取代的C 1～C 4烷基。
如式(I)所示的具有抗阿尔茨海默氏病的化合物或其药学上可接受的盐，优选n为1或2，R代表
Figure PCTCN2019105625-appb-000003
或R 2取代的萘基或喹啉，R 1选自任意取代的氟、氯、溴、甲基、异丙基、甲氧基、甲氧羰基、乙酰基、乙酰氨基、苯基、-OCH 2O-、氰基、硝基或-NR 3R 4，R 3、R 4独立的选自氢或甲基；R 2选自氢、甲基或溴。
式(I)所示的具有抗阿尔茨海默氏病的化合物或其药学上可接受的盐，进一步优选n＝为1或2；R选自对位硝基、甲基单取代或间位单取代或多取代苯基、未取代、甲基或溴取代的萘基或喹啉。
式(I)所示的具有抗阿尔茨海默氏病的化合物更进一步优选以下任意化合物：
Figure PCTCN2019105625-appb-000004
本发明所述的药学上可接受的盐选自盐酸盐、马来酸盐、枸橼酸盐；式(I)所示化合物药学上可接受的盐具有与式(I)所示化合物同样或更好的药效活性。
如式(I)所示的具有抗阿尔茨海默氏病的化合物的制备方法，包括：以2-氰甲基苯并咪唑为起始原料，经亚硝酸钠(1～1.2倍当量)、盐酸羟胺(2～4倍当量)两步反应得到4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺
Figure PCTCN2019105625-appb-000005
不同环系、不同取代的芳胺分别与(1.3～2倍当量的)氯乙酰氯、3-氯丙酰氯、4-氯丁酰氯或5-氯戊酰氯反应形成相应的酰胺中间体
Figure PCTCN2019105625-appb-000006
而后和4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺
Figure PCTCN2019105625-appb-000007
(1：0.8～1.2当量)反应制备得到如式(I)所示的具有抗阿尔茨海默氏病的选择性丁酰胆碱酯酶 抑制剂。反应式如下：
Figure PCTCN2019105625-appb-000008
其中n为1～4的整数；R代表
Figure PCTCN2019105625-appb-000009
或R 2取代的萘基或喹啉；
其中R 1代表任意取代的羟基、卤素、C 1～C 4烷基、卤素取代的C 1～C 4烷基、C 1～C 4烷氧基、C 1～C 4烷氧羰基、C 1～C 4酰基、苯基、-O(CH 2) mO-、氰基、硝基或-NR 3R 4，其中，m为1或2，R 3、R 4各自独立地代表氢或C 1～C 3烷基；
R 2代表氢、或任意取代的C 1～C 4烷基。
本发明包括所述的化合物在制备预防或治疗阿尔茨海默氏病药物中的应用。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。一种预防或治疗阿尔茨海默氏病药用组合物，含有本发明所述的式(I)所示的化合物。
有益效果：
本发明提供了一系列式(I)所示的化合物，以丁酰胆碱酯酶抑制活性、选择性的筛选以及Morris水迷宫实验为载体来评价式(I)所示的化合物治疗阿尔茨海默氏病的疗效(尤其是中重度阿尔茨海默氏病)，发现其具有良好的体外、体内活性和极高的选择性，可作为进一步开发通过选择性抑制丁酰胆碱酯酶来发挥开阿尔茨海默氏病作用的前体物质。
附图说明
图1小鼠到达平台时间；
图2小鼠到达平台经过的轨迹(A:对照组；B：模型组；C：他克林组；D：化合物1处理组；E：化合物6处理组；F：化合物7处理组；G：化合物9处理组)。
具体实施方式
实施例1
(1)4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺(中间体1)的合成
取2-氰甲基苯并咪唑(1g,6.36mmol)于茄形瓶中，用醋酸(10ml)溶解，冰浴下滴加亚硝酸钠(0.44g,6.36mmol)的水溶液，有固体生成，冰浴中搅拌40分钟后抽滤，滤饼用水洗一次，乙醚洗两次。另取一茄形瓶，冰浴中加入盐酸羟胺(0.53g,7.63mmol)，加入水作溶剂，加入氢氧化钾(0.54g,9.54mmol)，而后再加入二甘醇二甲醚(6ml)，最后加入上一步滤饼，将反应体系回升至室温后开始加热，回流6小时，冷却至室温；有大量金粉色晶体析出，抽滤，滤饼用水洗一次，乙醚洗两次，干燥，得到中间体4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺(1.01g,产率为78.90％)。 1H NMR(300MHz,DMSO-d6):δ13.66(s,1H,NH),7.68(s,2H,NH2),7.32(q,J＝3.09Hz,2H,ArH),6.81(s,2H,ArH).MS(ESI):calcd. forC 9H 8N 5O[M+H] +202.0723 found 202.0720.
(2)2-氯-N-(2-甲基喹啉-6-基)乙酰胺(中间体2)的合成
取2-甲基-6-氨基喹啉(200mg,1.26mmol)于茄形瓶中，用氯仿(5ml)溶解，加入碳酸氢钠(127.44mg,1.52mmol)，室温搅拌15分钟后向反应瓶中缓慢滴加氯乙酰氯(214.16mg,1.90mmol)的氯仿溶液，室温搅拌4小时。加水萃取，收集合并有机相，用无水硫酸钠干燥，减压除去溶剂，得白色固体2-氯-N-(2-甲基喹啉-6-基)乙酰胺(243.89mg,产率为82.21％)。 1H NMR(300MHz,DMSO-d6):δ11.30(s,1H,N HCO),9.00(s,1H,ArH),8.70(s,1H,ArH),8.39(s,1H,ArH),8.15(s,1H,ArH),7.90(s,1H,ArH),4.42(s,2H,C H 2),2.93(s,3H,C H 3).MS(ESI):MS(ESI):calcd.for C 12H 12ClN 2O[M+H] +235.0905 found 235.0638.
注：2-甲基-6-氨基喹啉为自制，方法为：取对硝基苯胺(500mg,3.65mmol)于茄形瓶中，用浓盐酸作为溶剂，向反应瓶中滴加三聚乙醛(1.45g,10.94mmol)，滴毕，加热反应液回流6小时，冷却至室温；反应液用氢氧化钾调pH至8，二氯甲烷萃取多次，合并有机相，饱和食盐水洗一次，有机相干燥，经硅胶层析柱分离得到中间体2-甲基-6-硝基喹啉(460mg,产率为67.40％)。其中，硅胶柱层析的洗脱剂为二氯甲烷。 1H NMR(300MHz,DMSO-d6):δ8.99(d,J＝2.46Hz,1H,ArH)，8.57(d,J＝8.46Hz,1H,ArH),8.41(dd,J＝9.21,2.58Hz,1H,ArH),8.09(d,J＝9.24Hz,1H,ArH),7.62(d,J＝8.49Hz,1H,ArH),2.72(s,3H,C H 3).MS(ESI):calcd.for C 10H 9N 2O 2[M+H] +190.0692 found 190.0690.
取上述2-甲基-6-硝基喹啉(500mg,2.66mmol)于茄形瓶中，加乙醇溶解，向反应瓶中滴加浓度9M的盐酸(20ml)，而后逐滴滴加氯化亚锡(2.02g,10.63mmol)的乙醇溶液。滴毕，加热回流反应液5小时，冷却至室温；将乙醇除掉，剩下的溶液冰浴下用氢氧化钠固体调pH至9，奶白色乳浊液用乙酸乙酯萃取五次，合并有机相，加入硅藻土搅拌过夜，次日抽滤，将滤液旋干，得到白色固体，即中间体2-甲基-6-氨基喹啉(363.29mg,产率为86.43％)。 1H NMR(300MHz,DMSO-d6):δ7.83(d,J＝8.43Hz,1H,ArH),7.61(d,J＝8.91Hz,1H,ArH),7.16(q,J＝8.40Hz,2H,ArH),6.77(d,J＝1.98Hz,1H,ArH),5.44(s,2H,N H 2),2.53(s,3H,C H 3).MS(ESI):calcd.for C 10H 9N 2O 2[M+H] +160.0950 found 159.0922.
(3)2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2-甲基喹啉-6-基)乙酰胺的合成
取2-氯-N-(2-甲基喹啉-6-基)乙酰胺(中间体2,194.41mg,0.83mmol)于茄形瓶中，加入DMF(6ml)溶解，而后先后加入碳酸铯(269.91mg,0.83mmol)和4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺(中间体1,150mg,0.75mmol)，70℃反应9小时后，加水析出大量固体，抽滤，乙酸乙酯洗两次，甲醇洗两次，干燥滤饼，得白色固体，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2-甲基喹啉-6-基)乙酰胺(化合物1,230mg,产率为77.24％)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.88(s,1H,N HCO),8.26(s,1H,ArH),8.11(d,J＝8.40Hz,1H,ArH),7.88(t,J＝6.69Hz,3H,ArH,N H 2),7.76(d,J＝9.18Hz,1H,ArH),7.34-7.48(m,3H,ArH),7.05(s,2H,ArH),5.67(s,2H,C H 2),2.62(s,3H,C H 3).MS(ESI):calcd.for C 21H 17N 7O 2[M+H +]400.1520 found 400.1522.
实施例2
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-6-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(喹啉-6-基)乙酰胺，得奶白色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-6-基)乙酰胺(化合物2)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.95(s,1H N HCO),8.80(s,1H,ArH),8.33(s,1H,ArH),8.24(d,J＝8.34Hz,1H,ArH),8.02(d,J＝9.39Hz,1H,ArH),7.91-7.81(m,3H,ArH,N H 2)7.49-7.38(m, 3H,ArH),7.05(s,2H,ArH),5.69(s,2H,C H 2).MS(ESI):calcd.for C 20H 15N 7O 2[M+H +]386.1365 found 386.1359.
实施例3
3-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-6-基)丙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为3-氯-N-(喹啉-6-基)丙酰胺，得奶白色固体化合物，即为3-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-6-基)丙酰胺(化合物3)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.40(s,1H,N HCO),8.76(dd,J＝1.56,4.14Hz,1H,ArH),8.21-8.25(m,2H,ArH),7.91(d,J＝9.06Hz,1H,ArH),7.65(d,J＝8.13Hz,1H,ArH),7.81(d,J＝7.89Hz,1H,ArH)7.65(dd,J＝2.28,9.06Hz,1H,ArH),7.47(q,J＝3.54Hz,1H,ArH),7.40(d,J＝7.26Hz,1H,ArH)7.32(t,J＝7.38Hz,1H,ArH),7.01(s,2H,N H 2),5.02(t,J＝6.66Hz,2H,C H 2Cl),3.03(t,J＝6.54Hz,2H,C H 2CO).HR-MS(ESI):calcd.for C 21H 17N 7O 2[M+H +]400.1522 found 400.1523.
实施例4
5-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-6-基)戊酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为5-氯-N-(喹啉-6-基)戊酰胺，得淡黄色固体化合物，即为5-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-6-基)戊酰胺。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.36(s,1H,N HCO),8.76(d,J＝3.99Hz,1H,ArH),8.37(s,1H,ArH),8.25(d,J＝8.52Hz,1H,ArH),7.94(d,J＝8.79Hz,1H,ArH),7.84(d,J＝8.31Hz,2H,ArH),7.77(d,J＝9.09Hz,1H,ArH),7.48-7.34(m,3H,ArH,N H 2),7.04(s,2H,ArH),4.73(t,J＝7.05Hz,2H,C H 2N),2.45(t,J＝6.78Hz,2H,C H 2CONH),1.94-1.85(m,2H,C H 2CH 2N),1.74-1.65(m,2H,C H 2C H 2CONH).MS(ESI):calcd.for C 23H 21N 7O 2[M+H +]428.1835 found 428.1836.
实施例5
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-5-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(喹啉-5-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-5-基)乙酰胺(化合物4)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.68(s,1H,N HCO),8.95(s,1H,ArH),8.63(d,J＝8.25Hz,1H,ArH),7.90(d,J＝6.51Hz,1H,ArH),7.75(d,J＝7.26Hz,1H,ArH),7.71(s,2H,N H 2),7.63(q,J＝4.29Hz,1H,ArH),7.48(t,J＝7.35Hz,1H,ArH),7.40(t,J＝7.32Hz,1H,ArH),7.03(s,2H,ArH),5.78(s,2H,C H 2).MS(ESI):calcd.for C 20H 15N 7O 2[M+H +]386.1360 found 386.1297.
实施例6
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-4-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(喹啉-4-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-4-基)乙酰胺(化合物5)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.92(s,1H,N HCO),8.97(d,J＝8.03Hz,1H,ArH),8.64(d,J＝8.25Hz,1H,ArH),7.97(d,J＝7.91Hz,1H,ArH),7.91-7.83(m,3H,ArH,N H 2),7.65(t,J＝7.25Hz,1H,ArH),7.55(t,J＝7.05Hz,1H,ArH),7.49-7.38(m,2H,ArH),7.05(s,2H,ArH),5.73(s,2H,C H 2).MS(ESI):calcd.for C 20H 15N 7O 2[M+H +]386.1360 found 386.1287.
实施例7
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-3-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(喹啉-3-基)乙酰胺，得 淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-3-基)乙酰胺(化合物6)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ11.12(s,1H,N HCO),8.97(d,J＝2.43Hz,1H,ArH),8.64(d,J＝2.19Hz,1H,ArH),7.93(d,J＝8.28Hz,1H,ArH),7.91-7.86(m,3H,ArH,N H 2),7.65(t,J＝6.90Hz,1H,ArH),7.58(t,J＝7.05Hz,1H,ArH),7.49-7.38(m,2H,ArH),7.04(s,2H,ArH),5.71(s,2H,C H 2).MS(ESI):calcd.for C 20H 15N 7O 2[M+H +]386.1360 found 386.1358.
实施例8
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-2-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(喹啉-2-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(喹啉-2-基)乙酰胺(化合物7)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ11.46(s,1H,N HCO),8.33(d,J＝9.03Hz,1H,ArH),8.10(d,J＝8.76Hz,1H,ArH),7.88(dd,J＝9.21,16.30Hz,3H,ArH),7.74(t,J＝8.28Hz,1H),7.36-7.54(m,3H,ArH),7.01(s,2H,ArH),6.84(s,1H,ArH),5.75(s,2H,C H 2).MS(ESI):calcd.for C 20H 15N 7O 2[M+H +]386.1360 found 386.1361.
实施例9
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(萘-1-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(萘-1-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(萘-1-基)乙酰胺(化合物8)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.47(s,1H,N HCO),8.23(d,J＝7.59Hz,1H,ArH),7.86(m,3H,ArH),7.79(d,J＝7.92Hz,1H,ArH),7.54-7.65(m,3H,ArH),7.48(t,J＝7.68Hz,2H,ArH),7.40(t,J＝7.92Hz,2H,ArH)6.99(s,2H,N H 2),5.78(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 21H 16N 6O 2[M+H +]385.1413 found 385.1409.
实施例10
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(萘-2-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(萘-2-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(萘-2-基)乙酰胺(化合物9)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.81(s,1H,N HCO),8.25(d,J＝1.65Hz,1H,ArH),7.91-7.83(m,4H,ArH,N H 2),7.77(d,J＝7.83Hz,ArH),7.61(dd,J＝2.07 8.85Hz,1H,ArH),7.48-7.38(m,4H,ArH),7.05(s,2H,ArH),5.67(s,2H,C H 2Cl).
实施例11
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-苯基乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-苯基乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-苯基乙酰胺(化合物10)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.51(s,1H N HCO),7.88(d,J＝7.83Hz,1H,ArH),7.81(d,J＝7.89Hz,1H,ArH),7.85(s,1H,ArH),7.55(s,1H,ArH),7.39-7.47(m,2H,ArH),7.32(t,J＝7.68Hz,2H,ArH),7.07(t,J＝7.29Hz,1H,ArH),6.98(s,2H,N H 2),6.81(s,1H,ArH),5.69(s,2H,C H 2).HR-MS(ESI):calcd.for C 17H 14N 6O 2[M+H +]335.1521 found 334.1245.
实施例12
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2-氟苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氟-N-(2-氯苯基)乙酰胺，得 奶白色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2-氟苯基)乙酰胺(化合物11)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6)：δ10.42(s,1H,NHCO),8.33(dd,J＝7.92,12.66Hz,1H,ArH),7.38-7.49(m,2H,ArH),7.32(t,J＝7.68Hz,1H,ArH),7.17(s,2H,ArH),7.41(d,J＝8.04Hz,ArH),7.03(s,2H,NH2),5.69(s,2H,CH2).HR-MS(ESI):calcd.for C 17H 13FN 6O 2[M+H +]353.1157 found 353.1164.
实施例13
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2-氯苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(2-氯苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2-氯苯基)乙酰胺(化合物12)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.09(s,1H,N HCO),7.84(dd,J＝7.53,16.88Hz,2H,ArH),7.67(d,J＝8.03Hz,1H,ArH),7.36-7.53(m,3H,ArH,N H 2),7.31(t,J＝7.55Hz,1H,ArH),7.20(t,J＝7.68Hz,1H,ArH),6.96(s,2H,ArH),5.68(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 17H 13ClN 6O 2[M+H +]369.0867 found 369.0862.
实施例14
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氟苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-氟苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氟苯基)乙酰胺(化合物13)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.99(s,1H,N HCO),7.86(dd,J＝7.29,12.51Hz,2H,ArH),7.54(d,J＝11.4Hz,1H,ArH),7.34-7.47(m,4H,ArH,N H 2),7.02(s,2H,ArH),6.87-6.94(m,1H,ArH),5.62(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 18H 16N 6O 2[M+H +]353.1162 found 353.1171.
实施例15
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氯苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-氯苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氟苯基)乙酰胺(化合物14)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ11.12(s,1H,N HCO),8.61(s,1H,ArH),7.86-7.98(m,4H,ArH),7.66(t,J＝8.19Hz,1H,ArH),7.40-7.51(m,2H,ArH),7.06(s,2H,N H 2),5.67(s,2H,C H 2).HR-MS(ESI):calcd.for C 17H 13ClN 6O 2[M+H +]369.0861 found 369.0863.
实施例16
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-溴苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-溴苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氟苯基)乙酰胺(化合物15)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.81(s,1H,N HCO),7.85-7.94(m,3H,ArH),7.39-7.53(m,3H,ArH),7.30-7.35(m,2H,ArH),7.06(s,2H,N H 2)5.63(s,2H,C H 2).HR-MS(ESI):calcd.for C 17H 13ClN 6O 2[M+H +]415.0356 found 415.1521.
实施例17
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-甲基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-甲基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-甲基苯基)乙酰胺(化合物16)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.49(s,1H,N HCO),7.85(dd,J＝7.23,17.22Hz,2H,ArH),7.33-7.47(m,4H,ArH,N H 2),7.17-7.22(t,J＝7.68Hz,1H,ArH),7.02(s,2H,ArH),6.89(d,J＝7.53Hz,1H,ArH),5.58(s,2H,C H 2Cl),2.26(s,3H,C H 3).HR-MS(ESI):calcd.for C 18H 16N 6O 2[M+H +]349.1383 found 349.1413.
实施例18
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-甲氧基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3,4,5-三甲氧基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3,4,5-三甲氧基苯基)乙酰胺(化合物17)。 1H NMR(300MHz,DMSO-d6):δ10.57(s,1H,N HCO),7.85(dd,J＝7.41,15.02Hz,2H,ArH),7.48-7.36(m,2H,ArH),7.29(t,J＝2.13Hz,1H,ArH),7.23(t,J＝8.13Hz,1H,ArH),7.11(d,J＝8.07Hz,1H,ArH),7.03(s,2H,ArH),6.65(dd,J＝2.34,7.92Hz,1H,ArH),5.59(s,2H,C H 2Cl).
实施例19
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-硝基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-硝基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-硝基苯基)乙酰胺(化合物18)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.80(s,1H,N HCO),7.88(dd,J＝7.89,21.44Hz,1H,ArH),7.79(s,1H,ArH),7.39-7.50(m,4H,ArH),7.17(d,J＝7.80Hz,1H,ArH),7.05(s,2H,N H 2),5.63(s,2H,C H 2).HR-MS(ESI):calcd.for C 17H 13ClN 6O 2[M+H +]380.1102 found 380.1106.
实施例20
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氰基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-氰基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-氰基苯基)乙酰胺(化合物19)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ11.01(s,1H,N HCO),7.88(dd,J＝7.89,21.44Hz,1H,ArH),7.79(s,1H,ArH),7.39-7.50(m,4H,ArH),7.17(d,J＝7.80Hz,1H,ArH),7.05(s,2H,N H 2),5.63(s,2H,C H 2).HR-MS(ESI):calcd.for C 17H 13ClN 6O 2[M+H +]380.1102 found 380.1106.
实施例21
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-乙酰氨基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-乙酰氨基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-乙酰氨基苯基)乙酰胺(化合物22)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.61(s,1H,N HCO),9.97(s,1H,ArH),7.95(s,1H,ArH),7.88(dd,J＝7.50,12.81Hz,2H,ArH),7.44-7.50(m,1H,ArH),7.37-7.43(m,1H,ArH),7.30-7.33(m,1H,ArH),7.20-7.28(m,2H,ArH),7.05(s,2H,N H 2),5.61(s,2H,C H 2),2.05(s,3H,C H 3).HR-MS(ESI):calcd.for C 19H 17N 7O 3[M+H +]392.1466 found 392.1476.
实施例22
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-乙酰基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-乙酰基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-乙酰基苯基)乙酰胺(化合物20)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.85(s,1H,N HCO),8.21(s,1H,ArH),7.87(dd,J＝8.58, 20.55Hz,3H,ArH),7.71(d,J＝7.62Hz,1H,ArH),7.41-7.53(m,3H,ArH),7.07(s,2H,N H 2),5.64(s,2H,C H 2),2.56(s,3H,C H 3).HR-MS(ESI):calcd.for C 19H 16N 6O 3[M+H +]377.1357 found 377.1362.
实施例23
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-甲氧羰基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3-甲氧羰基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3-甲氧羰基苯基)乙酰胺(化合物21)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.84(s,1H,N HCO),8.29(s,1H,ArH),7.79-7.90(m,3H,ArH),7.67(d,J＝7.83Hz,1H,ArH),7.37-7.51(m,3H,ArH),7.03(s,2H,N H 2),5.62(s,2H,C H 2),3.83(s,3H,C H 3).HR-MS(ESI):calcd.for C 19H 16N 6O 4[M+H +]393.1306 found 393.1314.
实施例24
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-氯苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-氯苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-氯苯基)乙酰胺(化合物23)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.71(s,1H,N HCO),7.86(dd,J＝8.13,11.36Hz,2H,ArH),7.57-7.36(m,4H,ArH,N H 2),7.02(s,2H,ArH),5.59(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 17H 13ClN 6O 2[M+H +]369.0867 found 369.0866.
实施例25
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-溴苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-溴苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-溴苯基)乙酰胺(化合物24)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.70(s,1H,N HCO),7.85(dd,J＝7.59,13.50Hz,2H,ArH),7.60(d,J＝8.85Hz,2H,ArH),7.45-7.36(m,4H,ArH,N H 2),7.01(s,2H,ArH),5.59(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 17H 13BrN 6O 2[M+H +]415.0341 found 415.0338.
实施例26
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-甲基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-甲基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-甲基苯基)乙酰胺(化合物25)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.46(s,1H,N HCO),7.85(dd,J＝7.44,15.95Hz,2H,ArH),7.36-7.47(m,4H,ArH,N H 2),7.12(d,J＝8.34Hz,2H,ArH),7.02(s,2H,ArH),5.57(s,2H,C H 2Cl),2.25(s,3H,C H 3).HR-MS(ESI):calcd.for C 18H 17N 5O 2[M+H +]349.1408 found 349.1397.
实施例27
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-甲氧基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-甲氧基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-甲氧基苯基)乙酰胺(化合物26)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.41(s,1H,N HCO),7.84(dd,J＝7.26,16.38Hz,2H,ArH), 7.48(d,J＝9.09Hz,ArH),7.03(s,2H,N H 2),6.89(d,J＝9.09Hz,2H,ArH),5.56(s,2H,C H 2Cl),3.72(s,3H,OC H 3).HR-MS(ESI):calcd.for C 18H 16N 6O 3[M+H +]365.1362 found 365.1357.
实施例28
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-乙酰基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-乙酰基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-乙酰基苯基)乙酰胺(化合物27)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.87(s,1H,N HCO),7.94(d,J＝8.76Hz,2H,ArH),7.86(dd,J＝7.44,14.81Hz,2H,ArH),7.71(d,J＝8.79Hz,2H,ArH),7.37-7.48(m,2H,ArH),7.01(s,2H,N H 2),5.63(s,2H,C H 2Cl),2.53(s,3H,C H 3).HR-MS(ESI):calcd.for C 19H 12N 6O 3[M+H +]377.1362 found 377.1356.
实施例29
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-甲氧羰基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-乙酰基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-乙酰基苯基)乙酰胺(化合物28)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.87(s,1H,N HCO),7.93(d,J＝8.79Hz,2H,ArH),7.85(dd,J＝7.53,15.90Hz,2H,ArH),7.71(d,J＝8.88Hz,2H,ArH),7.36-7.48(m,2H,ArH),6.98(s,2H,N H 2),5.63(s,2H,C H 2Cl),3.83(s,3H,C H 3).HR-MS(ESI):calcd.for C 19H 16N 6O 4[M+H +]393.1311 found 393.1307.
实施例30
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-硝基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-硝基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-硝基苯基)乙酰胺(化合物29)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ11.20(s,1H,N HCO),8.24(d,J＝9.27Hz,2H,ArH),7.81-7.90(m,4H,ArH,N H 2),7.37-7.48(m,2H,ArH),7.01(s,2H,ArH),5.66(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 17H 13N 7O 4[M+H +]380.1107 found 380.1108.
实施例31
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-氨基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-氨基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-硝基苯基)乙酰胺(化合物30)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.48(s,1H,N HCO),7.85(d,J＝7.05Hz,1H,ArH),7.87(d,J＝7.77Hz,1H,ArH),7.37-7.43(m,3H,ArH,N H 2),7.18(d,J＝5.79Hz,2H,ArH),6.94(s,2H,ArH),6.50(d,J＝5.82Hz,1H,ArH)5.51(s,2H,C H 2Cl),4.81(s,2H,N H 2).HR-MS(ESI):calcd.for C 18H 16N 6O 2[M+H +]350.1365 found 350.1349.
实施例32
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-异丙基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-异丙基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-异丙基苯基)乙酰胺。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.47(s,1H,N HCO),7.84(dd,J＝7.53,17.40Hz,2H,ArH),7.38-7.49(m, 4H,ArH,N H 2),7.19(s,1H,ArH),7.16(s,1H,ArH),7.02(s,2H,ArH),5.57(s,2H,C H 2Cl),2.79-2.88(m,1H,C H),1.18(s,3H,C H 3),1.16(s,3H,C H 3).HR-MS(ESI):calcd.for C 18H 16N 6O 2[M+H +]377.2726 found 377.1703.
实施例33
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-乙酰氨基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-乙酰氨基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-乙酰氨基苯基)乙酰胺(化合物31)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.48(s,1H,N HCOCH 2),9.89(s,1H,N HCOCH 3),7.81-7.88(m,2H,ArH),7.38-7.49(m,6H,ArH,N H 2),7.02(s,2H,ArH),5.57(s,2H,C H 2Cl),2.02(s,3H,C H 3).HR-MS(ESI):calcd.for C 18H 16N 6O 2[M+H +]392.1471 found 392.1453.
实施例34
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-联苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-联苯基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-联苯基苯基)乙酰胺。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.70(s,1H,N HCO),7.87(t,J＝8.64Hz,2H,ArH),7.70-7.63(m,6H,ArH,ArH),7.49-7.33(m,5H,ArH),7.04(s,2H,ArH),5.62(s,2H,C H 2Cl).
实施例35
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3,4,5-三甲氧基苯基)乙酰胺
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(3,4,5-三甲氧基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(3,4,5-三甲氧基苯基)乙酰胺(化合物35)。TLC检测为一点，紫外灯254nm下有暗斑，365nm下无荧光。 1H NMR(300MHz,DMSO-d6):δ10.43(s,1H,N HCO),7.87(d,J＝7.26Hz,1H,ArH),7.78(d,J＝7.47Hz,1H,ArH),7.36-7.48(m,2H,ArH),6.96(s,4H,ArH,N H 2),5.57(s,2H,C H 2Cl),3.72(s,6H,OC H 3,OC H 3),3.63(s,3H,OC H 3).HR-MS(ESI):calcd.for C 18H 16N 6O 2[M+H +]425.1573 found 425.1558.
实施例36
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(苯并[d][1,3]二氧杂环戊烯-5-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(苯并[d][1,3]二氧杂环戊烯-5-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(苯并[d][1,3]二氧杂环戊烯-5-基)乙酰胺(化合物32)。 1H NMR(300MHz,DMSO-d6):δ10.49(s,1H,N HCO),7.84(dd,J＝7.62,15.69Hz,2H,ArH),7.47-7.36(m,2H,ArH),7.24(d,J＝1.95Hz,1H,ArH),7.02(s,2H,N H 2),6.97(dd,J＝2.07,8.40Hz,1H,ArH),6.87(d,J＝8.4Hz,1H,ArH),5.98(s,2H,OC H 2O)5.55(s,2H,C H 2Cl).HR-MS(ESI):calcd.for C 18H 14N 6O 4[M+H +]379.1149 found 379.1158.
实施例37
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2,3-二甲基苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(2,3-二甲基苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2,3-二甲基苯基)乙酰胺(化合物33)。 1H NMR(300MHz,DMSO-d6):δ9.94(s,1H,N HCO),7.86(dd,J＝4.74,7.82Hz,2H,ArH),7.48(t,J＝6.90Hz,1H,ArH),7.36(t,J＝6.87Hz,1H, ArH),7.08(t,J＝3.18Hz,1H,ArH),7.01-7.04(m,4H,ArH,N H 2),5.62(s,2H,C H 2Cl),2.24(s,3H,C H 3),2.13(s,3H,C H 3).HR-MS(ESI):calcd.for C 19H 18N 6O 2[M+H +]363.1564 found 363.1574.
实施例38
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2,3-二氟苯基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(2,3-二氟苯基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(2,3-二氟苯基)乙酰胺(化合物34)。 1H NMR(300MHz,DMSO-d6):δ10.66(s,1H N HCO),7.90(t,J＝8.34Hz,1H,ArH),7.69(t,J＝7.65Hz,1H,ArH),7.40-7.52(m,2H,ArH),7.21(dd,J＝9.18,15.80Hz,2H,ArH),7.05(s,2H,N H 2),5.73(s,2H,C H 2).HR-MS(ESI):calcd.for C 17H 12F 2N 6O 2[M+H +]379.1149 found 379.1158.
实施例39
2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-溴萘-1-基)乙酰胺的合成：
参考实施例1的合成方法，实施例1中的中间体2替换为2-氯-N-(4-溴萘-1-基)乙酰胺，得淡黄色固体化合物，即为2-(2-(4-氨基-1,2,5-噁二唑-3-基)-1H-苯并[d]咪唑-1-基)-N-(4-溴萘-1-基)乙酰胺(化合物36)。 1H NMR(300MHz,DMSO-d6):δ10.65(s,1H N HCO),8.33(dd,J＝4.38,5.64Hz,1H,ArH),8.17(dd,J＝2.40,6.44Hz,1H,ArH),7.92(d,J＝8.16Hz,1H,ArH),7.87(dd,J＝3.06,8.02Hz,2H,ArH),7.72-7.76(m,2H,ArH),7.58(d,J＝8.07Hz,1H,ArH),7.48(t,J＝7.98Hz,1H,ArH),7.41(d,J＝8.04Hz,1H,ArH),7.04(s,2H,N H 2),5.79(s,2H,C H 2).HR-MS(ESI):calcd.for C 21H 15BrN 6O 2[M+H +]463.0513 found 463.0513.
实施例1-39中合成的化合物结构式
Figure PCTCN2019105625-appb-000010
Figure PCTCN2019105625-appb-000011
Figure PCTCN2019105625-appb-000012
Figure PCTCN2019105625-appb-000013
Figure PCTCN2019105625-appb-000014
Figure PCTCN2019105625-appb-000015
下面是本发明部分化合物药效学试验及结果：
胆碱酯酶抑制活性的测定：
药品与试剂：待测化合物、AChE(E.C.3.1.1.7,Type VI-S,选自电鳗)、BuChE(E.C.3.1.1.8,选自马血清)、5,5’-二硫双(2-硝基苯甲酸)(DTNB)、乙酰硫代胆碱(ATC)碘化物以及丁酰硫代胆碱(BTC)碘化物均购于西格玛公司；阳性对照他克林盐酸盐(9-Amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate)购自BioTrend公司。
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：
(1)配制缓冲液：13.6g磷酸二氢钾溶于1L水中，以氢氧化钾调节pH＝8±0.1。溶液于4℃保存，备用。
(2)配制0.01M DTNB溶液：将0.396g DTNB及0.15g碳酸氢钠溶于100mL水中制得0.01M DTNB溶液，于-30℃保存，备用。
(3)配制0.075M ATC、BTC溶液：将0.217g ATC溶于10mL水中制得0.075M ATC及BTC溶液，于-30℃保存，备用；将0.237g BTC溶于10mL水中制得0.075M BTC溶液，于-30℃保存，备用。
(4)配制AChE、BuChE溶液：将5000单位的AChE溶于1mL 1％的凝胶溶液中，然后用水稀释至100mL制得浓度为5单位/mL的AChE溶液，于-30℃保存，备用；将5000单位的BuChE溶于1mL 1％的凝胶溶液中，然后用水稀释至100mL制得浓度为5单位/mL的BuChE溶液，于-30℃保存，备用。
(5)配制受试物溶液：将受试化合物溶于乙醇中以制得浓度为10 -3M的溶液(乙醇不影响测试结果)，然后用水稀释分别制得浓度为10 -4、10 -5、10 -6、10 -7、10 -8、10 -9、10 -10M的溶液。
实验开始前，所用溶液均加温至室温，并将AChE，BuChE溶液用水稀释一倍制成浓度为2.5单位/mL的酶溶液。用空白缓冲液(3mL)测得背景紫外吸收。先将100μL受试化合物溶液、100μL DTNB溶液、100μL酶溶液加至3mL缓冲液中，待加入20μL ATC或BTC溶液触发反应后立即计时并同时快速混匀测试溶液，2min后于412nm波长下测量紫外吸收度。空白对照组用等容积的水代替受试物溶液测得。所有测试均平行操作三次。以空白对照组的紫外吸收值作为100％，记录受试化合物在各个浓度下的吸光度(OD值)，所得结果 用GraphPad Prism TM(GraphPad Software,San Diego,CA,USA)软件以非线性衰退分析模式(non-linear regression analysis model)计算得相应的IC 50值，如表1所示。
Figure PCTCN2019105625-appb-000016
表1 各化合物对eqBuChE的测试结果
Figure PCTCN2019105625-appb-000017
Figure PCTCN2019105625-appb-000018
Figure PCTCN2019105625-appb-000019
Figure PCTCN2019105625-appb-000020
a表示化合物在10μM浓度下对靶标的抑制率
表1中的化合物都表现出了对BuChE较好的抑制活性(其中化合物7的BuChE抑制活性为20nM，化合物39的BuChE抑制活性更好达到了6nM)，对AChE没有抑制活性(10μM浓度下的抑制率小于10％)，说明该系列化合物有极高的选择性。在AD早期，80％的ACh由AChE负责水解，BuChE几乎无作用，随着病程的加重，AChE的水平下降，功能几乎丧失，此时，BuChE的水平及功能相对提升，取代AChE成为ACh的主要代谢酶。因此，对于重度AD的治疗，BuChE的抑制活性尤为重要。为防止化合物对外周AChE造成影响而产生不必要的外周胆碱样副作用，开发选择性BuChE抑制剂具有重大意义。本发明所涉及化合物对BuChE有很好的抑制活性和极高的选择性，有望对轻度及重度AD产生很好的疗效。
Morris水迷宫研究小鼠行为学研究
仪器：Panlab SMART 3.0行为学视频分析仪
动物：成年雄性ICR小鼠(8-10周，体重20-25克)购自扬州大学医学中心。
试剂：氢溴酸东莨菪碱购自阿拉丁试剂公司(S107418，上海)，他克林(纯度>95％)，化合物1、化合物6、化合物7、化合物9。
实验方法：将56只小鼠随机分为7组(每组8只小鼠)：对照组，模型组，他克林组，化合物1处理组，化合物6处理组、化合物7处理组、化合物9处理组。将他克林，化合物1，化合物6，化合物7，化合物9分别溶于CMC-Na溶液(0.5g CMC-Na，100mL蒸馏水)，进行灌胃给药(15mg/kg体重)。30min后，模型组，他克林组，化合物1处理组，化合物6处理组、化合物7处理组、化合物9处理组小鼠腹腔注射东莨菪碱(1mg/kg)，对照组小鼠腹腔注射生理盐水。通过水迷宫测试小鼠的认知功能和记忆能力。在一个圆形水池(直径120cm，高60cm)中固定一个逃生平台(直径10cm)，平台上固定一个5cm高的小旗子，水池中填充高度为40cm的水，并且保持温度在25℃组成水迷宫。服药第1-2天将小鼠放在逃生平台进行训练，第3-5天将平台放置到水下1cm，对小鼠进行训练，最后一天(第6天)将平台移走，对小鼠进行评估，记录小鼠到达平台所在位置的时间，轨迹及速度。实验结果如表2、图1、图2所示。
表2 小鼠到达平台所在位置时间
Figure PCTCN2019105625-appb-000021
####表示有显著性差异，P值<0.0001； **表示有显著性差异，P值<0.01； ***表示有显著性差异，P值<0.001； ****表示有显著性差异，P值<0.0001；
结果分析：结合表2、图1、图2可知，与对照组相比，模型组小鼠到达平台的平均时间有显著性提高，表明东莨菪碱会导致小鼠记忆缺陷，同时表明造模成功。相对于模型组，他克 林组所耗时间和距离都显著降低，表明他克林对于小鼠的记忆和认知功能有明显改善。而化合物1处理组、化合物6处理组、化合物7处理组、化合物9处理组的小鼠到达平台时间和距离都显著低于模型组，并且低于他克林组，表明化合物1、化合物6、化合物7、化合物9对小鼠记忆和认知功能都有所改善，并且效果都优于他克林。除此之外，从图2A-G中可以看出，模型组小鼠的轨迹相对于空白组明显更混乱；他克林组小鼠经过的路径相比较模型组混乱度有所降低，表明他克林对于小鼠的记忆和认知功能有所改善；化合物1处理组、化合物6处理组、化合物7处理组、化合物9处理组小鼠到达平台所经过的轨迹混乱程度明显低于模型组，并优于他克林组，说明化合物1、化合物6、化合物7、化合物9对小鼠的记忆和认知功能改善效果比较明显，且要优于他克林。

Claims (9)

  1. 一类如式(I)所示的化合物或其药学上可接受的盐：
    Figure PCTCN2019105625-appb-100001
    其中n为1～4整数；R代表
    Figure PCTCN2019105625-appb-100002
    或R 2取代的萘基或喹啉，
    其中，R 1代表任意取代的羟基、卤素、C 1～C 4烷基、卤素取代的C 1～C 4烷基、C 1～C 4烷氧基、C 1～C 4烷氧羰基、C 1～C 4酰基、苯基、-O(CH 2) mO-、氰基、硝基或-NR 3R 4，其中，m为1或2，R 3、R 4各自独立地代表氢或C 1～C 3烷基；
    R 2代表氢、卤素或任意取代的C 1～C 4烷基。
  2. 根据权利要求1所述的一类如式(I)所示的化合物或其药学上可接受的盐，其特征在于n为1、2整数，R代表
    Figure PCTCN2019105625-appb-100003
    或R 2取代的萘基或喹啉，其中，R 1选自任意取代的氟、氯、溴、甲基、异丙基、甲氧基、甲氧羰基、乙酰基、乙酰氨基、苯基、-OCH 2O-、氰基、硝基或-NR 3R 4，R 3、R 4独立的选自氢或甲基；R 2选自氢、甲基或溴。
  3. 根据权利要求2所述的一类如式(I)所示的化合物或其药学上可接受的盐，其特征在于n＝为1、2整数，R选自对位硝基、甲基单取代或间位单取代或多取代苯基、未取代、甲基或溴取代的萘基或喹啉。
  4. 根据权利要求2所述的一类如式(I)所示的化合物或其药学上可接受的盐，其特征在于所述的化合物选自以下任意一种化合物：
    Figure PCTCN2019105625-appb-100004
  5. 根据权利要求1所述的一类如式(I)所示的化合物或其药学上可接受的盐，其特征在于所述的药学上可接受的盐选自盐酸盐、马来酸盐、枸橼酸盐；式(I)所示化合物药学上可接受的盐具有与式(I)所示化合物同样或更好的药效活性。
  6. 权利要求1所述的如式(I)所示的化合物的制备方法，其特征在于包括：以2-氰甲基苯并咪唑为起始原料，经亚硝酸钠、盐酸羟胺两步反应得到4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺
    Figure PCTCN2019105625-appb-100005
    不同环系、不同取代的芳胺分别与氯乙酰氯、3-氯丙酰氯、4-氯丁酰氯或5-氯戊酰氯反应形成相应的酰胺中间体
    Figure PCTCN2019105625-appb-100006
    而后和4-(1H-苯并[d]咪唑-2-基)-1,2,5-噁二唑-3-胺
    Figure PCTCN2019105625-appb-100007
    反应制备得到如式(I)所示的具有抗阿尔茨海默氏病的选择性丁酰胆碱酯酶抑制剂，反应路线如下：
    Figure PCTCN2019105625-appb-100008
    其中n为1～4整数；R代表
    Figure PCTCN2019105625-appb-100009
    或R 2取代的萘基或喹啉，
    R 1代表任意取代的羟基、卤素、C 1～C 4烷基、卤素取代的C 1～C 4烷基、C 1～C 4烷氧基、C 1～C 4烷氧羰基、C 1～C 4酰基、苯基、-O(CH 2) mO-、氰基、硝基或-NR 3R 4，其中，m为1或2，R 3、R 4各自独立地代表氢或C 1～C 3烷基；
    R 2代表氢、或任意取代的C 1～C 4烷基。
  7. 权利要求1所述的式(I)所示的化合物或其药学上可接受的盐在制备预防或治疗阿尔茨海默氏病药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于所述的药物以式(I)所示的化合物或其药学上可接受的盐为有效成分或主要有效成分，与药学上可接受的载体制成药物制剂；所述的药物制剂为片剂、胶囊、粉剂、糖浆、液剂、悬浮剂或针剂。
  9. 一种预防或治疗阿尔茨海默氏病药用组合物，其特征在于含有权利要求1-4中任意一项所述的式(I)所示的化合物。
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CN113004252B (zh) * 2019-12-20 2023-06-09 江苏先声药业有限公司 一种芳基并咪唑类衍生物及其用途
CN111423429A (zh) * 2020-05-19 2020-07-17 江西科技师范大学 苯并咪唑联呋咱类系列化合物及其合成方法
CN112920178A (zh) * 2021-01-29 2021-06-08 中国药科大学 具有苯并咪唑结构的化合物及其制备方法与用途
CN113292523A (zh) * 2021-02-24 2021-08-24 中国药科大学 一类选择性丁酰胆碱酯酶抑制剂或其可药用盐及其制备方法与用途
CN112979546B (zh) * 2021-02-25 2023-01-31 中国药科大学 一类丁酰胆碱酯酶选择性抑制剂及其制备方法与用途
CN113956249B (zh) * 2021-11-04 2024-02-02 中国药科大学 脑靶向AChE抑制剂前药及其制备方法与应用

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