WO2017124949A1 - 二氢黄酮衍生物、其制备方法和用途 - Google Patents

二氢黄酮衍生物、其制备方法和用途 Download PDF

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WO2017124949A1
WO2017124949A1 PCT/CN2017/070877 CN2017070877W WO2017124949A1 WO 2017124949 A1 WO2017124949 A1 WO 2017124949A1 CN 2017070877 W CN2017070877 W CN 2017070877W WO 2017124949 A1 WO2017124949 A1 WO 2017124949A1
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group
compound
cell
pharmaceutically acceptable
acceptable salt
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PCT/CN2017/070877
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English (en)
French (fr)
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李林
谷洪顺
张兰
陈溪
尹琳琳
张如意
杨翠翠
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首都医科大学宣武医院
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Priority to US16/071,472 priority Critical patent/US10513512B2/en
Priority to EP17740980.2A priority patent/EP3406611B9/en
Publication of WO2017124949A1 publication Critical patent/WO2017124949A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • 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
    • 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

Definitions

  • the invention relates to the field of medicine, in particular to a dihydroflavone derivative, a preparation method thereof and use thereof.
  • Mental disorder refers to the disorder of brain function, which leads to different degrees of mental disorders such as cognition, emotion, behavior and will.
  • Common mental disorders include schizophrenia, depression, manic depressive disorder (bipolar disorder), anxiety, phobia, obsessive-compulsive disorder, stress-related disorders, and mental disorders associated with various organic lesions. Wait. According to statistics, mental disorders account for more than 15% of the global burden of disease. China's mental illness ranks first in China's total disease burden, accounting for about 20% of the total burden of disease. According to reports, the incidence of mental illness in China has reached 17.5%, and the incidence of severe mental disorders is as high as 1%.
  • DRD2 dopamine type 2 receptor
  • N-methyl-D-aspartic acid (NMDA) receptor antagonists can induce schizophrenia-like effects; substances that enhance NMDA receptor function can improve symptoms in patients with schizophrenia And cognitive function.
  • microglia In the brains of patients with schizophrenia and those at high risk of schizophrenia, immune cells (microglia) are more active, suggesting that the neuroinflammatory response is an important factor in schizophrenia and has become a treatment and prevention of schizophrenia. A new potential target.
  • autopsy studies and special imaging techniques for humans, as well as animal depression models have shown that depression can occur when microglia changes and cannot continue to regulate brain function and behavioral processes. Long-term exposure to chronic, unpredictable psychological stress can also cause changes in the shape and function of microglia, which is also one of the most leading causes of depression in humans.
  • microglia activation and neuroinflammation are neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), cerebrovascular disease, brain trauma, spinal cord injury, demyelinating disease, multiple sclerosis An important pathogenesis of neurological diseases such as encephalomyelitis.
  • the white matter is an important part of the central nervous system. It is the place where the nerve fibers gather.
  • the myelin damage of the central nerve cells causes white matter lesions.
  • Patients with schizophrenia, depression, and other mental disorders, as well as cerebrovascular disease, diabetic neuropathy, and other abnormalities of white matter nerve fibers, such as changes in myelin, axonal disorders, etc., and demyelinating diseases such as multiple sclerosis Symptoms of mental disorders appear. These results indicate that white matter lesions are closely related to the pathogenesis of mental disorders and some neurological diseases.
  • clinically applied antipsychotic drugs can be divided into two categories: one is a first-generation antipsychotic drug that blocks the action of dopamine receptors, and is called a "classic” antipsychotic drug (such as haloperidol). Although they can effectively control the positive symptoms of schizophrenia, they are very effective against cognitive disorders; the other is shared with dopamine receptors and other receptors (such as serotonin receptors and norepinephrine receptors).
  • the drug of action called “non-classical” antipsychotic drugs (such as ziprasidone, risperidone, etc.), although this drug has a certain effect on the positive and negative symptoms of schizophrenia, but similarly, it is Cognitive impairment is less effective.
  • the inventors of the present invention obtain a novel structure of a compound by structural modification of a dihydroflavonoid compound, which can simultaneously act on multiple targets such as a dopaminergic system, a glutamatergic system, a microglia, and a white matter.
  • the invention can effectively improve cognitive function and can be used for preventing or treating mental disorders or nervous system diseases, and the present invention is completed based on the above findings.
  • the object of the present invention is at least one of the following: 1. Providing a novel structure of a dihydroflavone derivative or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a process comprising the same or a pharmaceutically acceptable thereof a pharmaceutical composition of an acceptable salt; 2. Use of the dihydroflavone derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for the preparation of a medicament for preventing or treating a mental disorder or a nervous system disease 3. A method for preventing or treating a mental disorder or a nervous system disease, which comprises administering to a patient in need thereof an effective amount of the dihydroflavone derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition; 4. The dihydroflavone derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating a mental disorder and a nervous system disease.
  • the first aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, halogen (e.g., fluorine or chlorine), cyano, hydroxy, amino, C 1-6 alkane. a group (e.g., methyl), a C1-6 alkoxy group (e.g., methoxy), a C1-6 alkylamino group, and an aryl group, optionally wherein the C1-6 alkyl group, C1-6 alkane The oxy group, the C 1-6 alkylamino group and the aryl group are each independently substituted with one or more substituents selected from halogen (for example, fluorine or chlorine), an amino group and a hydroxyl group;
  • halogen e.g., fluorine or chlorine
  • X is a saturated or partially saturated subchain hydrocarbon group having 2 to 6 carbon atoms, optionally wherein the subchain hydrocarbon group is substituted with a substituent selected from a hydroxyl group or a methyl group;
  • Y is N or C(R), wherein the R group is selected from the group consisting of hydrogen, hydroxy, amino, C 1-6 alkyl;
  • Z is an aryl or heteroaryl group.
  • R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen, halogen (eg, fluoro or chloro), cyano, hydroxy, amino, C 1-6 alkyl (e.g., methyl), C 1-6 alkoxy (e.g., methoxy), C 1-6 alkylamino, and 6-20 membered aryl (e.g., 6-10 membered aryl, such as benzene Or a naphthyl group; the remaining atoms or substituents are as described in the first aspect of the invention.
  • halogen eg, fluoro or chloro
  • cyano cyano
  • hydroxy amino
  • C 1-6 alkyl e.g., methyl
  • C 1-6 alkoxy e.g., methoxy
  • C 1-6 alkylamino e.g., 6-20 membered aryl (e.g., 6-10 membered aryl, such as
  • R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen, halogen (eg, fluoro or chloro), cyano, hydroxy, amino, and C 1-4 alkyl (e.g., methyl); the remaining atoms or substituents are as described in the first aspect of the invention.
  • R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen, halogen (eg, fluoro or chloro), cyano, hydroxy, amino, and C 1-2 alkyl (e.g., methyl); the remaining atoms or substituents are as described in the first aspect of the invention.
  • R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are all hydrogen; the remaining atoms or substituents are as described in the first aspect of the invention.
  • R 3 and R 8 are each independently selected from hydrogen, halogen (eg, fluoro or chloro), C 1-6 alkyl (eg, methyl), and C 1-6 alkoxy. (e.g., methoxy), optionally wherein the C 1-6 alkyl group and the C 1-6 alkoxy group are each independently substituted with one or more substituents selected from the group consisting of halogen, amino and hydroxy;
  • halogen eg, fluoro or chloro
  • C 1-6 alkyl eg, methyl
  • C 1-6 alkoxy e.g., methoxy
  • R 3 is selected from the group consisting of hydrogen, halogen (e.g., fluoro or chloro), C 1-4 alkyl (e.g., methyl), and C 1-4 alkoxy (e.g., methoxy).
  • halogen e.g., fluoro or chloro
  • C 1-4 alkyl e.g., methyl
  • C 1-4 alkoxy e.g., methoxy
  • said C 1-4 alkyl group and C 1-4 alkoxy group are each independently substituted with one or more substituents selected from the group consisting of halogen, amino and hydroxy;
  • R 3 is selected from the group consisting of hydrogen, halogen (eg, fluoro or chloro), C 1-2 alkyl (eg, methyl), and C 1-2 alkoxy (eg, methoxy). ;
  • R 3 is selected from halogen (eg, fluoro or chloro), C 1-2 alkyl (eg, methyl), and C 1-2 alkoxy (eg, methoxy);
  • R 3 is selected from the group consisting of fluoro, methyl and methoxy
  • R 8 is selected from the group consisting of hydrogen, halogen (eg, fluoro or chloro), C 1-2 alkyl (eg, methyl), and C 1-2 alkoxy (eg, methoxy). ;
  • R 8 is selected from halogen (eg, fluoro or chloro), C 1-2 alkyl (eg, methyl), and C 1-2 alkoxy (eg, methoxy);
  • R 8 is selected from the group consisting of fluoro and methoxy
  • X is C 2-6 alkylene (eg, C 2-4 alkylene, further such as 1,2-ethylene, 1,3-propylene or 1, 4-butylene), optionally, the C 2-6 alkylene group is substituted with a substituent selected from a hydroxyl group or a methyl group;
  • X is 1,3-propylene or 1,4-butylene
  • Y is N or C(R), wherein R is selected from hydrogen, hydroxy or methyl;
  • Y is N or CH
  • Z is an aryl or heteroaryl group having from 5 to 20 carbon atoms (eg, from 5 to 15 carbon atoms, such as from 5 to 10 carbon atoms);
  • Z is an aryl group or a 5-20 membered heteroaryl group having 6 to 20 carbon atoms (eg, 6 to 15 carbon atoms, for example, 6 to 10 carbon atoms) ( For example, a 5-15 membered heteroaryl group, for example, a 5-10 membered heteroaryl group);
  • Z is selected from the group consisting of phenyl, naphthyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole , triazazolyl, pyridyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fluorenyl, benzofuranyl, benzothienyl, benzimidazolyl, benzo Pyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolyl, benzopyranyl, benzopyrimidinyl, a quinoxalinyl group, a benzoxazinyl group, a benzotriazinyl group and
  • Z is selected from the group consisting of phenyl and benzoisoxazole.
  • the compound is selected from the group consisting of
  • a second aspect of the present invention provides a process for the preparation of the compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof, which comprises synthesizing a dihydroflavone moiety on the right side of the X group and then passing a A carbon chain of -6 carbon atoms is bonded to a substituted phenyl or 1,2-benzisoxazolyl substituted piperazinyl or piperidinyl group, wherein each atom or substituent is as defined in the first aspect of the invention Said.
  • the method comprises the steps of:
  • PG represents a hydroxy protecting group such as MOM, TMS or TBS
  • L represents a leaving group of a nucleophilic substitution reaction, such as halogen, -OTs, -OCOR (R represents an alkyl group) and the like;
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable Excipients (such as carriers and / or excipients, etc.).
  • the excipient refers to a substance which has been evaluated in terms of safety in addition to the pharmaceutically active ingredient and which is contained in the pharmaceutical preparation.
  • carriers or excipients including but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, sorbus Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, Polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin; the excipient refers to an additive other than the main drug in the pharmaceutical preparation, the nature of which Stable, no
  • the compounds of the present invention are useful for oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, lingual or respiratory administration. Among them, oral administration, parenteral (intravenous, intramuscular or subcutaneous) administration is preferred.
  • the compounds of the present invention can be formulated into any orally acceptable formulation including, but not limited to, tablets, pills, powders, syrups, capsules, aqueous solutions or aqueous suspensions and the like.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule formulation generally comprises lactose and dried cornstarch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some sweeteners, fragrances or colorants may also be added to the above oral formulations.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • a sterile injectable preparation including sterile injectable aqueous or oily suspension or sterile injectable solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
  • a preferred dosage is from 0.001 to 100 mg/kg body weight/day, more preferably from 0.01 mg/kg to 50 mg/kg body weight/day, even more preferably from 0.1 mg/kg to 25 mg/kg body weight/day, optimal.
  • the dose is from 1 mg/kg to 10 mg/kg body weight/day.
  • an effective daily dose can be divided into multiple doses for administration purposes; therefore, a single dose composition can contain such amounts or sub-doses thereof to constitute a daily dose.
  • the frequency of administration of the above compound of formula I can be determined according to the experience of the clinician and factors such as the age, weight, sex, general health of the patient, and the type and severity of the disease, for example, once, twice, three times a day, 4 times, 5 times, etc., or once every 2 days, once every 3 days, once every 1 week, Once every 2 weeks, etc.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention, for use in the treatment or prevention of a psychiatric disorder or a neurological disorder Use of the drug.
  • the invention also provides a method of preventing or treating a psychiatric disorder or a neurological disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula I according to the first aspect of the invention or a pharmaceutically acceptable compound thereof Or a pharmaceutical composition according to the third aspect of the invention.
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, spiritual A long animal; among them, a particularly preferred subject is a human.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for use in the prevention or treatment of a psychiatric disorder or a neurological disorder.
  • the mental disorder is selected from the group consisting of schizophrenia, depression, manic depressive disorder (bipolar disorder), cognitive disorder, anxiety disorder, stress related disorder, attention deficit It is associated with hyperactivity disorder, tic disorder, and various mental disorders associated with organic lesions.
  • the mental disorder associated with the various organic lesions is selected from the group consisting of Alzheimer's disease, vascular dementia, mental disorder caused by traumatic brain injury, and mental disorder caused by intracranial infection.
  • the neurological disease is selected from the group consisting of a neurodegenerative disease (Alzheimer's disease, Parkinson's disease), cerebrovascular disease, brain trauma, spinal cord injury, demyelinating disease, multiple sexual sclerosis, inflammatory demyelinating polyneuropathy, leukoencephalopathy caused by ischemia-hypoxic disease, and diabetic neuropathy.
  • a neurodegenerative disease Alzheimer's disease, Parkinson's disease
  • cerebrovascular disease cerebrovascular disease
  • brain trauma spinal cord injury
  • demyelinating disease multiple sexual sclerosis
  • inflammatory demyelinating polyneuropathy inflammatory demyelinating polyneuropathy
  • leukoencephalopathy caused by ischemia-hypoxic disease
  • diabetic neuropathy diabetic neuropathy
  • the invention further provides the use of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for the preparation of a reagent for use in inhibiting small Overactivation or proliferation of glial cells.
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • the microglia are cell lines or cells from a subject.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for use in inhibiting excessive activation or proliferation of microglia .
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vivo method.
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vitro method.
  • the microglia are cell lines or cells from a subject.
  • the invention also provides a method of inhibiting excessive activation or proliferation of microglia comprising administering to a cell an effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a method of the invention
  • a method of inhibiting excessive activation or proliferation of microglia comprising administering to a cell an effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a method of the invention
  • the method is carried out in vivo.
  • the method is carried out in vitro.
  • the microglia are cell lines or cells from a subject.
  • the invention further provides the use of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for the preparation of a reagent for inhibiting cells The activity of the dopamine receptor.
  • the dopamine receptor is a dopamine type 2 receptor.
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for use in inhibiting the activity of a dopamine receptor in a cell.
  • the dopamine receptor is a dopamine type 2 receptor.
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vivo method.
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention also provides a method of inhibiting dopamine receptor activity in a cell comprising administering to the cell an effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a third aspect of the invention Said pharmaceutical composition.
  • the dopamine receptor is a dopamine type 2 receptor.
  • the method is carried out in vivo.
  • the method is in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention further provides the use of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for the preparation of a reagent for enhancing cells Activity of NMDA receptors.
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for use in enhancing the activity of an NMDA receptor in a cell.
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vivo method.
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention also provides a method of enhancing the activity of an NMDA receptor in a cell comprising administering to the cell an effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a third of the invention
  • a method of enhancing the activity of an NMDA receptor in a cell comprising administering to the cell an effective amount of a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a third of the invention
  • the pharmaceutical composition of aspect is provided.
  • the method is carried out in vivo.
  • the method is in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a method of the invention
  • the pharmaceutical composition of the third aspect for use in the preparation of a reagent for increasing the content of myelin basic protein (MBP) in a cell, reducing myelin loss or white matter lesions.
  • MBP myelin basic protein
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention further provides a compound of formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention for use in increasing myelin basic protein (MBP) in a cell Content, reduce myelin loss or white matter lesions.
  • MBP myelin basic protein
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vivo method.
  • the compound, or a pharmaceutically acceptable salt or pharmaceutical composition thereof is for use in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • the invention also provides a method of increasing the content of myelin basic protein (MBP) in a cell, reducing myelin loss or white matter lesions, comprising administering to the cell an effective amount of a compound of formula I according to the first aspect of the invention. Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the invention.
  • MBP myelin basic protein
  • the method is carried out in vivo.
  • the method is in an in vitro method.
  • the cell is a cell line or a cell from a subject.
  • C 1-6 alkyl as used in the present invention means a straight or branched alkyl group having 1 to 6 carbon atoms, such as a C 1-4 alkyl group, a C 1-2 alkyl group, a C 1 alkyl group, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl or C 6 alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, and the like.
  • C 1-6 alkoxy as used in the present invention means a group having a "C 1-6 alkyl-O-" structure in which a C 1-6 alkyl group has the same meaning as described above.
  • Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • C 1-6 alkylamino as used in the present invention means a group having a structure of "C 1-6 alkyl-NH-" wherein the C 1-6 alkyl group has the same meaning as defined above.
  • C 1-4 alkylamino, C 1-2 alkylamino, C 1 alkylamino, C 2 alkylamino, C 3 alkylamino, C 4 alkylamino, C 5 alkylamino or C 6 alkylamino for example, C 1-4 alkylamino, C 1-2 alkylamino, C 1 alkylamino, C 2 alkylamino, C 3 alkylamino, C 4 alkylamino, C 5 alkylamino or C 6 alkylamino.
  • Specific examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, pentylamino, hexylamino, and the like.
  • aryl as used in the present invention means a fused ring having a monocyclic ring (e.g., phenyl), a polycyclic ring (e.g., naphthyl), or at least one of which is aromatic (e.g., 1, 2, 3, 4-tetra An aromatic carbocyclic group of a hydrogen naphthyl group.
  • Specific examples include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, fluorenyl, fluorenyl, and the like.
  • heteroaryl refers to an aromatic cyclic group containing at least one up to four heteroatoms selected from N, O or S, for example 5-20 (for example 5-15) Or 5-10) heteroaryl groups of the ring members.
  • Specific examples include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridyl, pyran , pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, fluorenyl, benzofuranyl, benzothienyl, benzimidazolyl, benzopyrazole, benzoxazolyl, benzo Isoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolyl, benzopyranyl, benzopyrimidinyl, quinoxalinyl, benzoxazinyl, benzene And triazinyl and fluorenyl and the like.
  • saturated or partially saturated subchain hydrocarbon group means a portion remaining after losing two hydrogen atoms on a saturated or partially saturated chain hydrocarbon group, for example, a saturated or partially containing 2 to 6 carbon atoms.
  • a saturated subchain hydrocarbon group for example, an alkylene group having 2 to 6 carbon atoms, for example, an alkylene group having 2 to 4 carbon atoms.
  • Specific examples include, but are not limited to, methylene, ethylene, propylene, butylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-Asia Pentyl, 1,6-hexylene, and the like.
  • halogen as used in the present invention includes fluorine, chlorine, bromine and iodine.
  • the compounds of the invention may contain chiral centers and may exist in different enantiomeric and diastereomeric forms. All optical isomers, or racemic mixtures, of the compounds of the invention are within the scope of the invention.
  • pharmaceutically acceptable generally means pharmaceutically or medically useful, or, although not directly used in pharmacy or medicine, may be utilized as an intermediate in the preparation of a pharmaceutical or medical product, And it is removed by a suitable method before it is finally used in pharmacy or medicine.
  • pharmaceutically acceptable salts include not only pharmaceutically acceptable salts which are useful in the clinic, but also salts which are not directly usable in the clinic but which can be used in the preparation of the compounds of the invention and which are removed in the subsequent processes.
  • pharmaceutically acceptable salt as used in the present invention includes a conventional salt formed with a pharmaceutically acceptable inorganic or organic acid or an inorganic or organic base, and a salt of a quaternary ammonium and an acid.
  • suitable acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, perchlorate, fumarate, acetate, propionate, pyruvate, Succinate, glycolate, formate, Lactate, maleate, tartrate, citrate, pamoate, malonate, glutarate, hydroxymaleate, phenylacetate, glutamate, benzoate , salicylate, fumarate, tosylate, methanesulfonate, naphthalene-2-sulfonate, besylate, hydroxynaphthoate, hydroiodide, malate, hard Fatty acid, citrate, etc.
  • oxalates although not themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts.
  • suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, ammonium, triethylamine, t-butylamine, N,N'-dibenzyl Ethylenediamine salt, procaine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt and N-methylglucamine salt.
  • the subject is a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate Among them, a particularly preferred subject is a human.
  • an effective amount means an amount sufficient to obtain or at least partially obtain a desired effect.
  • a prophylactically effective amount refers to an amount sufficient to prevent, arrest, or delay the onset of a disease
  • a therapeutically effective amount refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art.
  • the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously. and many more.
  • the invention obtains a novel structure of compounds by structural modification of dihydroflavonoids, which can simultaneously act on multiple targets such as dopaminergic system, glutamatergic system, microglia and white matter.
  • the compound has remarkable activity of inhibiting microglia activation and neuroinflammatory activity, antagonizing dopamine type 2 receptor, improving behavioral changes of animal models of various mental disorders, and effectively inhibiting nerves Inflammation and loss of myelin. It is indicated that the compound of the present invention has the effects of improving cognitive function, preventing and treating mental disorders and nervous system diseases, and provides a new idea for the treatment of related diseases.
  • Figure 2 is a graph showing the antagonistic activity of the compounds of the present invention against dopamine receptor 2 (DRD2).
  • Figure 3 is a graph showing the effect of the compound of the present invention on the autonomic activity of MK-801-induced schizophrenia high activity model mice within 270 minutes.
  • Figure 5 is a graph showing the effect of the compound of the present invention on the activity distance of the central region in MK-801-induced schizophrenia high activity model mice within 210 minutes.
  • Figure 8 is a graph showing the effect of the compound of the present invention on the total distance of the spontaneous activity of the market in the Cuprizone model mice within 10 minutes.
  • MBP myelin basic protein
  • Example 2 The operation is the same as in Example 1, using 1,3-dibromopropane as the reactant in step 6); and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoin in step 7)
  • the oxazole is used as a reactant and the resulting product is a yellow oil.
  • Microglia activation and neuroinflammation are important pathogenesis of many diseases of the central nervous system.
  • the proinflammatory substance bacterial endotoxin lipopolysaccharide (LPS) and interferon gamma (interferon- ⁇ , IFN- ⁇ ) can stimulate the body to produce pro-inflammatory cytokines, which trigger the cascade of inflammatory cascades to further activate microglia
  • An inflammatory cell such as a cell releases an inflammatory medium such as nitric oxide (NO) to form an inflammatory network.
  • NO nitric oxide
  • BV2 cells (mouse microglia cell line) in logarithmic growth phase were inoculated into 96-well culture plates (culture medium was 90% DMEM medium + 10% fetal bovine serum), set at 37 ° C, 5% Culture in a CO 2 incubator. After 24 h, different concentrations of the compound were added. After 24 hours of culture, the culture solution was discarded, and LPS (100 ⁇ g/ml) + INF- ⁇ (1 ng/ml) was added for 24 hours, and the supernatant was collected. The stable metabolite of the NO metabolite was used as an indicator for detecting NO, and was measured using a Griess kit.
  • the compound of the present invention can be used for preventing and treating mental disorders such as schizophrenia and depression, as well as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), cerebrovascular diseases, brain trauma, spinal cord injury, and demyelinating diseases. , multiple sclerosis, inflammatory demyelinating polyneuropathy and other neurological diseases.
  • mental disorders such as schizophrenia and depression, as well as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), cerebrovascular diseases, brain trauma, spinal cord injury, and demyelinating diseases.
  • demyelinating diseases such as multiple sclerosis, inflammatory demyelinating polyneuropathy and other neurological diseases.
  • DA hyperprandial
  • Antipsychotic drugs that block dopamine type 2 receptor (DRD2) can effectively control schizophrenia.
  • Positive symptoms By establishing a co-transfected cell line and G ⁇ 16 DRD2, so that DRD2 is activated to cause the activation of G ⁇ 16 protein, and activation of phospholipase C (PLC) inositol 1,4,5-trisphosphate (IP 3) and diacylglycerol (DAG), IP 3 binds to the endoplasmic reticulum and IP 3 receptors on the mitochondria, causing the release of intracellular calcium. Therefore, measuring changes in intracellular calcium can be used as a method of detecting the activation state of DRD2.
  • PLC phospholipase C
  • IP 3 inositol 1,4,5-trisphosphate
  • DAG diacylglycerol
  • Fluo-4/AM is a calcium fluorescent probe indicator used to measure calcium ions. This experiment uses the Fluo-4 fluorescence method to reflect the level of activation of G ⁇ protein by measuring the intensity of fluorescence excited by intracellular calcium ions. If the compound is able to agonize DRD2, the calcium flow response can be increased; conversely, if the compound is capable of antagonizing DRD2, the calcium flow response is reduced.
  • HEK293 cells human embryonic kidney cell line derived from Shanghai Institute of Materia Medica, Chinese Academy of Sciences
  • stably expressing DRD2/G ⁇ 16 were seeded in 96-well plates (90% DMEM medium + 10% fetal bovine serum). Cultivate overnight.
  • the culture solution was aspirated, and freshly prepared dye Fluo-4/AM was added and incubated in a 37 ° C incubator for 40 minutes. The dye was discarded and washed with freshly prepared calcium buffer and replaced with 50 ⁇ l of calcium buffer in which the drug to be tested was dissolved.
  • L Sample indicates the detection signal value of the sample to be tested
  • L Blank indicates the detection signal value of complete inhibition of Eticlopride
  • L Dopamine indicates the detection signal value after the 50 nM agonist Dopamine stimulated the DMSO group.
  • the IC 50 value was calculated by GraphPad Prism.
  • N-methyl-D-aspartic acid (NMDA) receptor antagonists can induce Schizophrenia-like effects.
  • NMDA receptor antagonist dizocilpine (MK-801) was used to induce a highly active schizophrenia model in mice, and the in vivo activities of the compounds P6, P5, P4 and P7 of the present invention were evaluated.
  • mice purchased from Capital Medical University Experimental Animal Center
  • body weight (20 ⁇ 2) g
  • the mice were first adapted to the feeding environment for 1 week and administered by continuous intragastric administration for 3 days.
  • the control group and the model group were given normal saline by intragastric administration, and administered on the 4th day before the test, and then placed in the open field behavior infrared monitoring system instrument.
  • the test was started for 60 minutes, then the control group was intraperitoneally injected with normal saline.
  • the model group and the drug group of the present invention were intraperitoneally injected with the NMDA receptor antagonist dextrozine (MK-801) solution 0.6 mg/kg, and the mice in each group were continuously measured within 210 minutes.
  • Spontaneous activity and central area activities are used to reflect the rapid symptoms of rapid movement in schizophrenia; central activity is used to evaluate the anxiety state of schizophrenia.
  • mice The open field test was used to detect the spontaneous activity of the mice. The results showed that compared with the control group, the total distance of the spontaneous activity and the active distance of the central region in the MK-801 model group were prolonged within 210 minutes; the compound P6 of the present invention P5 and P7 intragastric administration can shorten the spontaneous activity total distance and central activity distance of MK-801 model mice (Fig. 3, Fig. 4, Fig. 5, Table 2). The results suggest that the compounds of the invention can alleviate the positive symptoms and anxiety states of schizophrenia.
  • mice SPF-grade inbred C57BL/6 male mice, weighing (20 ⁇ 2) g, were randomly divided into control group, model group and drug group of the present invention.
  • the mice were first adapted to the feeding environment for 3 days. Then, except for the normal feed, the other groups were given a diet containing 0.2% Cuprizone for modeling. At the same time, each group was intragastrically administered with the corresponding dose of the drug for 5 weeks. Then perform Y-maze and open field behavior tests. Among them, the number of advances in the Y-maze is used to reflect the movement of the mice; the spontaneous alternation of the Y-maze is used to reflect the working memory of the mice; the spontaneous activity of the open field behavior is used to reflect the small The movement of the mouse.
  • EXPERIMENTAL RESULTS The results of the Y-maze test showed that the number of arms in the Cuprizone model mice was increased and the spontaneous alternation was reduced compared with the control group.
  • the administration of the compounds P6 and P5 of the present invention can reduce the progression of the model mice.
  • the number of arms ( Figure 6) increases the spontaneous alternating response ( Figure 7).
  • the results of the open field behavior test showed that the total spontaneous activity of the Cuprizone model mice was prolonged compared with the control group; the intragastric administration of the compounds P6 and P5 of the present invention shortened the total spontaneous activity of the model mice (Fig. 8).
  • the results indicate that the compounds of the present invention can improve the cognitive function and motor behavior of the Cuprizone model mice, and reduce the high activity state of the model mice.
  • MBP Myelin basic protein
  • the compounds of the present invention can be used for the prevention and treatment of schizophrenia, depression and other mental disorders, as well as cerebrovascular diseases, demyelinating diseases, multiple sclerosis, inflammatory demyelinating polyneuropathy, ischemia-anoxic diseases White matter encephalopathy, diabetic neuropathy and other diseases.
  • Iba-1 is capable of specifically labeling microglia.
  • the effects of the compounds of the present invention on Iba-1 marker microglia in the brain of Cuprizone mouse model were studied by immunohistochemistry.
  • Rinse with PBST add biotin-labeled goat anti-rabbit IgG antibody (secondary antibody), and incubate at 37 °C for 2 h.
  • Rinse with PBST add horseradish-labeled streptavidin, and incubate for 3 h at 37 °C.
  • Rinse with PBS, DAB reagent was developed, transparent, and mounted. Iba-1 positive cells were observed under a microscope and counted.
  • the compound of the present invention can be used for preventing and treating mental disorders such as schizophrenia and depression, as well as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), cerebrovascular diseases, brain trauma, spinal cord injury, and demyelinating diseases. , multiple sclerosis, inflammatory demyelinating polyneuropathy and other neurological diseases.
  • mental disorders such as schizophrenia and depression, as well as neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease), cerebrovascular diseases, brain trauma, spinal cord injury, and demyelinating diseases.
  • demyelinating diseases such as multiple sclerosis, inflammatory demyelinating polyneuropathy and other neurological diseases.
  • the present invention provides a novel class of compounds of the formula I which are capable of antagonizing dopamine type 2 receptors, inhibiting microglia activation and neuroinflammatory responses; animal experiments indicate that the compounds of the invention It can reduce the high activity of MK-801 mouse model and relieve its anxiety state; it can improve memory dysfunction, abnormal motor behavior and high activity of Cuprizone model mice, and can inhibit microglia in model mice. Activation and loss of myelin. These results indicate that the compounds of the present invention have utility in the prevention and treatment of a variety of psychiatric disorders and neurological diseases.

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Abstract

本发明涉及二氢黄酮衍生物、其制备方法和用途，具体涉及如式（I）所示化合物或其药学上可接受的盐、其药物组合物、其制备方法及其预防或治疗精神障碍和神经系统疾病的用途。本发明的化合物具有显著的抑制小胶质细胞活化和神经炎症反应活性，能拮抗多巴胺2型受体，改善多种精神障碍动物模型的行为学变化，能有效抑制神经炎症和髓鞘脱失，可用于精神障碍和神经系统疾病的预防或治疗。

Description

二氢黄酮衍生物、其制备方法和用途 技术领域
本发明涉及医药领域，具体涉及二氢黄酮衍生物、其制备方法和用途。
背景技术
精神障碍是指大脑机能活动发生紊乱，导致认知、情感、行为和意志等精神活动不同程度障碍的总称。常见的精神障碍有精神分裂症，抑郁症，躁狂抑郁性精神障碍(双相障碍)，焦虑症，恐惧症，强迫症，应激相关障碍，以及各种器质性病变伴发的精神障碍等。据统计，精神障碍占全球整个疾病负担的15％以上。我国精神疾病在我国疾病总负担中排名首位，约占疾病总负担的20％。据报道，我国精神疾病发病率已高达17.5％，其中重性精神障碍发病率高达1％。
在发病机制方面，单胺类递质及其受体是精神医学研究得最广泛的神经递质和受体之一。在精神分裂症的发病机制中，主要有多巴胺(DA)活动过度假说、5-羟色胺(5-HT)和去甲肾上腺素(NE)神经通路障碍假说。研究表明，精神分裂症患者的阳性症状(幻觉、妄想等)可能与皮质下边缘系统DA功能亢进有关。通过阻断多巴胺2型受体(DRD2)发挥药理作用的抗精神病药物能有效控制精神分裂症的阳性症状。
谷氨酸和天门冬氨酸是中枢神经系统最常见的兴奋性神经递质。有研究提示精神分裂症和其他精神障碍涉及谷氨酸能传递异常。N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid，NMDA)受体拮抗剂能够诱导精神分裂症样效应；增强NMDA受体功能的物质能够改善精神分裂症患者的症状和认知功能。
现在越来越多的证据表明，炎症和免疫功能异常可能与精神分裂症、抑郁症和其他精神障碍的发生发展有密切关系。在精神分裂症患者和具有精神分裂高风险的患者大脑内，免疫细胞(小胶质细胞)更活跃，表明神经炎性反应是精神分裂的一个重要因素，并成为了治疗和预防精神分裂症的一个新的潜在目标。此外，针对人类的尸检研究及特殊的成像学技术，以及动物抑郁模型研究显示，当小胶质细胞发生改变，无法继续调节脑内功能及行为进程时，即可发生抑郁。长期暴露于慢性的、无法预测的心理应激也可导致小胶质细胞的形状及功能发生改变，而这种应激同样也是导致人类抑郁的最首要原因之一。
已有大量研究表明，小胶质细胞激活和神经炎症是神经退行性疾病(如阿尔茨海默病、帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、脑脊髓炎等神经系统疾病的重要发病机制。
神经白质是中枢神经系统的重要组成部分，是神经纤维聚集的地方，中枢神经细胞的髓鞘损害，会引起白质病变。精神分裂症、抑郁症和其他精神障碍患者，以及脑血管病、糖尿病性神经病等出现白质神经纤维的异常，如髓鞘的变化、轴突的紊乱等，而且多发性硬化等脱髓鞘疾病可出现精神障碍症状。这些结果表明神经白质病变与精神障碍和一些神经系统疾病的发病机制密切相关。
目前，临床上应用的抗精神病药物可分为两类：一类是具有阻断多巴胺受体作用的第一代抗精神病药物，称为“经典”抗精神病药物(如氟哌啶醇等)，它们虽然能有效控制精神分裂症的阳性症状，但对认知障碍的疗效甚差；另一类是与多巴胺受体和其他受体(如5-羟色胺受体、去甲肾上腺素受体)共同作用的药物，称为“非经典”抗精神病药物(如齐拉西酮、利培酮等)，该类药物虽然对精神分裂症的阳性症状和阴性症状有一定疗效，但同样地，其对认知障碍的疗效较差。
综上所述，当前仍缺乏能够改善认知障碍的抗精神病药物，另外，对于能够同时作用在多巴胺能系统、谷氨酸能系统、小胶质细胞、脑白质等精神障碍和神经疾病复杂发病机制多靶点的药物的研究不足。
因此，研制作用在多靶点的抗精神障碍和神经疾病药物对临床治疗具有重要意义。
发明内容
本发明的发明人通过对二氢黄酮类化合物进行结构修饰得到一类结构新颖的化合物，其能够同时作用在多巴胺能系统、谷氨酸能系统、小胶质细胞、脑白质等多靶点，能有效改善认知功能，可用于预防或治疗精神障碍或神经系统疾病，本发明即是基于以上发现而完成。
基于以上发现，本发明的目的在于以下的至少一项：1.提供一类结构新颖的二氢黄酮衍生物或其药学上可接受的盐，其制备方法，以及包含所述衍生物或其药学上可接受的盐的药物组合物；2.提供所述二氢黄酮衍生物或其药学上可接受的盐、药物组合物在制备用于预防或治疗精神障碍或神经系统疾病的药物中的用途；3.提供一种预防或治疗精神障碍或神经系统疾病的方法，其包括向有此需要的患者给予有效量的所述二氢黄酮衍生物或其药学上可接受的盐、药物组合物；4.所述二氢黄酮衍生物或其药学上可接受的盐、药物组合物，其用于预防或治疗精神障碍和神经系统疾病。
更具体地说，本发明第一方面提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2017070877-appb-000001
R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基、C1-6烷基(例如甲基)、C1-6烷氧基(例如甲氧基)、C1-6烷氨基和芳基，任选地，其中所述C1-6烷基、C1-6烷氧基、C1-6烷氨基和芳基各自独立地被一个或多个选自卤素(例如氟或氯)、氨基和羟基的取代基取代；
X为含有2-6个碳原子的饱和或部分饱和的亚链烃基，任选地，其中所述亚链烃基被选自羟基或甲基的取代基取代；
Y为N或C(R)，其中所述R基选自氢、羟基、氨基、C1-6烷基；
Z为芳基或杂芳基。
在本发明的某些优选实施方案中，R1、R2、R4、R5、R6和R7各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基、C1-6烷基(例如甲基)、C1-6烷氧基(例如甲氧基)、C1-6烷氨基和6-20元芳基(例如6-10元芳基，例如苯基或萘基)；其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R1、R2、R4、R5、R6和R7各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基和C1-4烷基(例如甲基)；其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R1、R2、R4、R5、R6和R7各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基和C1-2烷基(例如甲基)；其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R1、R2、R4、R5、R6和R7均为氢；其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R3和R8各自独立地选自氢、卤素(例如氟或氯)、C1-6烷基(例如甲基)和C1-6烷氧基(例如甲氧基)，任选地，其中所述C1-6烷基和C1-6烷氧基各自独立地被一个或多个选自卤素、氨基和羟基的取代基取代；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R3选自氢、卤素(例如氟或氯)、C1-4烷基(例 如甲基)和C1-4烷氧基(例如甲氧基)，任选地，其中所述C1-4烷基和C1-4烷氧基各自独立地被一个或多个选自卤素、氨基和羟基的取代基取代；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R3选自氢、卤素(例如氟或氯)、C1-2烷基(例如甲基)和C1-2烷氧基(例如甲氧基)；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R3选自卤素(例如氟或氯)、C1-2烷基(例如甲基)和C1-2烷氧基(例如甲氧基)；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R3选自氟、甲基和甲氧基；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R8选自氢、卤素(例如氟或氯)、C1-2烷基(例如甲基)和C1-2烷氧基(例如甲氧基)；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R8选自卤素(例如氟或氯)、C1-2烷基(例如甲基)和C1-2烷氧基(例如甲氧基)；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，R8选自氟和甲氧基；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，X为C2-6亚烷基(例如C2-4亚烷基，再例如1,2-亚乙基、1,3-亚丙基或1,4-亚丁基)，任选地，所述C2-6亚烷基被选自羟基或甲基的取代基取代；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，X为1,3-亚丙基或1,4-亚丁基；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，Y为N或C(R)，其中R选自氢、羟基或甲基；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，Y为N或CH；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，Z为含5-20个碳原子(例如5-15个碳原子，再例如5-10个碳原子)的芳基或杂芳基；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，Z为含6-20个碳原子(例如6-15个碳原子，再例如6-10个碳原子)的芳基或5-20元杂芳基(例如5-15元杂芳基，再例如5-10元杂芳基)；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，Z选自苯基、萘基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、吡啶基、吡喃基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并吡唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三氮唑基、喹啉基、苯并吡喃基、苯并嘧啶基、喹喔啉基、苯并哒嗪基、苯并三嗪基和嘌呤基；
其余各原子或取代基如本发明第一方面所述。
在本发明的某些优选实施方案中，Z选自苯基和苯并异噁唑基。
在本发明的某些优选实施方案中，所述化合物选自：
5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮；
5-羟基-2-(4-甲基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮；
5-羟基-2-(4-氟基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮；
5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丙氧基)苯并二氢吡喃-4-酮；
5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丁氧基)苯并二氢吡喃-4-酮；
5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丙氧基)苯并二氢吡喃-4-酮；和
5-羟基-2-(4-氟基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丁氧基)苯并二氢吡喃-4-酮。
本发明第二方面提供了本发明第一方面所述的化合物或其药学上可接受的盐的制备方法，其特征在于，先合成X基团右侧的二氢黄酮部分，然后通过一个含有2-6个碳原子的碳链与取代苯基或1，2-苯并异噁唑基取代的哌嗪基或哌啶基连接而成，其中各原子或取代基定义如本发明第一方面所述。
在本发明的一个实施方案中，所述方法包括以下步骤：
Figure PCTCN2017070877-appb-000002
1)化合物A与乙酰氯经酰基化反应得到化合物B；
2)在化合物B的羟基上引入保护基得化合物C；
3)化合物C与化合物D发生羟醛缩合反应制得化合物E；
4)化合物E经关环反应得化合物F；
5)化合物F脱保护基得化合物G；
6)化合物G与化合物H经亲核取代得到化合物I；
7)化合物I与化合物J经亲核取代得到式I化合物；
其中，PG代表羟基保护基，例如MOM、TMS或TBS等；L表示亲核取代反应的离去基团，例如卤素、-OTs、-OCOR(R代表烷基)等；
其余各原子或取代基定义如本发明第一方面所述。
本发明的第三方面提供了一种药物组合物，其包含本发明第一方面所述的式I化合物或其药学上可接受的盐，以及任选地一种或多种药学上可接受的辅料(如载体和/或赋形剂等)。
在本发明的实施方案中，所述辅料是指除药物活性成分以外，在安全性方面已经进行了合理的评估，且包含在药物制剂中的物质。例如载体或赋形剂，这里的载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂；所述赋形剂是指在药物制剂中除主药以外的附加物，其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂，等等。
本发明的化合物适用于口服、胃肠外(静脉内、肌肉或皮下)，经皮、经舌或呼吸给药等给药途径。其中优选口服、胃肠外(静脉内、肌肉或皮下)的给药方式。
当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、丸剂、散剂、糖浆剂、胶囊、水溶液或水悬浮液等。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
本发明的化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
另外需要指出，本发明化合物的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.001至100mg/kg体重/天，更优选剂量为0.01mg/kg至50mg/kg体重/天，再更优选剂量为0.1mg/kg至25mg/kg体重/天，最优剂量为1mg/kg至10mg/kg体重/天。如果需要，有效的日剂量可出于给药目的分成多剂量；因此，单剂量组合物可含有这种数量或其分剂量，以构成日剂量。上述式I化合物的给药频率可以根据临床医生的经验和诸如患者年龄、体重、性别、一般健康状况以及疾病的类型和严重性等因素来确定，例如每天给予1次、2次、3次、4次、5次等，或者每2天一次、每3天1次、每1周1次、 每2周1次等。
本发明还提供了本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物在制备用于治疗或预防精神障碍或神经系统疾病的药物中的用途。
本发明还提供了一种预防或治疗精神障碍或神经系统疾病的方法，其包括向有此需要的受试者给予有效量的本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物。
在本发明的某些优选实施方案中，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物，其用于预防或治疗精神障碍或神经系统疾病。
在本发明的某些优选实施方案中，所述精神障碍选自精神分裂症、抑郁症、躁狂抑郁性精神障碍(双相障碍)、认知障碍、焦虑症、应激相关障碍、注意缺陷与多动障碍、抽动障碍，以及各种器质性病变伴发的精神障碍等。
在本发明的某些优选实施方案中，所述各种器质性病变伴发的精神障碍选自阿尔茨海默病、血管性痴呆、脑外伤所致精神障碍、颅内感染所致精神障碍、脑肿瘤所致精神障碍、梅毒所致精神障碍、癫痫性精神障碍和HIV/AIDS所致精神障碍。
在本发明的某些优选实施方案中，所述神经系统疾病选自神经退行性疾病(阿尔茨海默病、帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病、缺血-缺氧性病引起的白质脑病和糖尿病性神经病。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物用于制备试剂的用途，所述试剂用于抑制小胶质细胞的过度激活或增殖。
在本发明的某些优选实施方案中，所述试剂用于体内方法中。
在本发明的某些优选实施方案中，所述试剂用于体外方法中。
在本发明的某些优选实施方案中，所述小胶质细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物，其用于抑制小胶质细胞的过度激活或增殖。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中。
在本发明的某些优选实施方案中，所述小胶质细胞为细胞系或来自受试者的细胞。
本发明还提供一种抑制小胶质细胞过度激活或增殖的方法，其包括向细胞施用有效量的本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物。
在本发明的某些优选实施方案中，所述方法在体内进行。
在本发明的某些优选实施方案中，所述方法在体外进行。
在本发明的某些优选实施方案中，所述小胶质细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物用于制备试剂的用途，所述试剂用于抑制细胞中多巴胺受体的活性。
在本发明的某些优选实施方案中，所述多巴胺受体为多巴胺2型受体。
在本发明的某些优选实施方案中，所述试剂用于体内方法中。
在本发明的某些优选实施方案中，所述试剂用于体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物，其用于抑制细胞中多巴胺受体的活性。
在本发明的某些优选实施方案中，所述多巴胺受体为多巴胺2型受体。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供一种抑制细胞中多巴胺受体活性的方法，其包括向细胞施用有效量的本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物。
在本发明的某些优选实施方案中，所述多巴胺受体为多巴胺2型受体。
在本发明的某些优选实施方案中，所述方法在体内进行。
在本发明的某些优选实施方案中，所述方法在体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物用于制备试剂的用途，所述试剂用于增强细胞中NMDA受体的活性。
在本发明的某些优选实施方案中，所述试剂用于体内方法中。
在本发明的某些优选实施方案中，所述试剂用于体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物，其用于增强细胞中NMDA受体的活性。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供一种增强细胞中NMDA受体的活性的方法，其包括向细胞施用有效量的本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物。
在本发明的某些优选实施方案中，所述方法在体内进行。
在本发明的某些优选实施方案中，所述方法在体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第 三方面所述的药物组合物用于制备试剂的用途，所述试剂用于提高细胞中髓鞘碱性蛋白(MBP)的含量、减轻髓鞘脱失或白质病变。
在本发明的某些优选实施方案中，所述试剂用于体内方法中。
在本发明的某些优选实施方案中，所述试剂用于体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物，其用于提高细胞中髓鞘碱性蛋白(MBP)的含量、减轻髓鞘脱失或白质病变。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中。
在本发明的某些优选实施方案中，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
本发明还提供一种提高细胞中髓鞘碱性蛋白(MBP)的含量、减轻髓鞘脱失或白质病变的方法，其包括向细胞施用有效量的本发明第一方面所述的式I化合物或其药学上可接受的盐、或本发明第三方面所述的药物组合物。
在本发明的某些优选实施方案中，所述方法在体内进行。
在本发明的某些优选实施方案中，所述方法在体外方法中。
在本发明的某些优选实施方案中，所述细胞为细胞系或来自受试者的细胞。
以下对本发明的术语进行解释，对于特定的术语，如果本发明中的含义与本领域技术人员通常理解的含义不一致，以本发明中的含义为准；如果在本发明中没有定义，则其具有本领域技术人员通常理解的含义。除非有相反陈述，本发明中使用的术语具有下述含义：
本发明所用术语“C1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如C1-4烷基、C1-2烷基、C1烷基、C2烷基、C3烷基、C4烷基、C5烷基或C6烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等。
本发明中所用术语“C1-6烷氧基”是指具有“C1-6烷基-O-”结构的基团，其中C1-6烷基具有前述相同的含义。例如C1-4烷氧基、C1-2烷氧基、C1烷氧基、C2烷氧基、C3烷氧基、C4烷氧基、C5烷氧基或C6烷氧基。具体的实例包括但不限于甲氧基、乙氧基、丙氧基、 异丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等。
本发明中所用术语“C1-6烷氨基”是指具有“C1-6烷基-NH-”结构的基团，其中C1-6烷基具有前述相同的含义。例如C1-4烷氨基、C1-2烷氨基、C1烷氨基、C2烷氨基、C3烷氨基、C4烷氨基、C5烷氨基或C6烷氨基。具体的实例包括但不限于甲氨基、乙氨基、丙氨基、异丙氨基、丁氨基、叔丁氨基、戊氨基、己氨基等。
本发明中所用术语“芳基”是指具有单环(如苯基)、多环(如萘基)或其中至少一个环具有芳香性的稠合环(如1，2，3，4-四氢萘基)的芳族碳环基。例如含有5-20个(例如5-15个或5-10个)碳原子的芳基。具体的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、茚基、苊基等。
本发明中所用术语“杂芳基”是指含有至少一个至多四个选自N、O或S的杂原子的具有芳香性的环状基团，例如含有5-20个(例如5-15个或5-10个)环成员的杂芳基。具体的实例包括但不限于、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、吡啶基、吡喃基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并吡唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三氮唑基、喹啉基、苯并吡喃基、苯并嘧啶基、喹喔啉基、苯并哒嗪基、苯并三嗪基和嘌呤基等。
本发明中所用术语“饱和的或部分饱和的亚链烃基”是指饱和的或部分饱和的链烃基上失去两个氢原子后剩余的部分，例如含有2-6个碳原子的饱和的或部分饱和的亚链烃基，例如含有2-6个碳原子的亚烷基、例如含有2-4个碳原子的亚烷基。具体的实例包括但不限于亚甲基、亚乙基、亚丙基、亚丁基、1,2-亚乙基、1,3-亚丙基、1,4-亚丁基、1,5-亚戊基、1,6-亚己基等。
本发明所用术语“卤素”包括氟、氯、溴和碘。
本发明的化合物可以含有手性中心，且可以以不同的对映体和非对映体形式存在。本发明化合物的所有旋光异构体，或外消旋混合物均在本发明的保护范围之内。
本发明中所用术语“药学上可接受的”通常是指制药学上或医学上可用的，或者虽然不能直接用于制药学或医学，但是可作为制备制药学或医学产品中间体时可以利用，并在最后用于制药学或医学之前通过适宜的方法脱除的。例如药学上可接受的盐，不但包括可用于临床的药用盐，还包括不能直接用于临床，但可在制备本发明化合物时使用并在随后的工艺过程中脱除的盐。本发明中所用术语“药学上可接受的盐”包括与药学上可接受的无机酸或有机酸或者无机碱或有机碱形成的常规的盐以及季铵与酸形成的盐。合适的酸盐的例子包括但不限于盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、高氯酸盐、富马酸盐、乙酸盐、丙酸盐、丙酮酸盐、琥珀酸盐、羟基乙酸盐、甲酸盐、 乳酸盐、马来酸盐、酒石酸盐、柠檬酸盐、扑酸盐、丙二酸盐、戊二酸盐、羟基马来酸盐、苯乙酸盐、谷氨酸盐、苯甲酸盐、水杨酸盐、富马酸盐、甲苯磺酸盐、甲磺酸盐、萘-2-磺酸盐、苯磺酸盐、羟基萘甲酸盐、氢碘酸盐、苹果酸盐、硬脂酸盐、鞣酸盐等。其它的如草酸盐，虽然其本身并非药学上可接受的，但可以用于制备用作中间体的盐，以获得本发明化合物及其药学上可接受的盐。合适的碱盐的更具体的例子包括钠盐、锂盐、钾盐、镁盐、铝盐、钙盐、锌盐、铵盐、三乙胺盐、叔丁胺盐、N,N'-二苄基乙二胺盐、普鲁卡因盐、氯代普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐和N-甲基葡糖胺盐等。
在本发明的实施方案中，所述受试者为哺乳动物，例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物；其中，特别优选的受试者为人。
本发明中所用术语“有效量”是指，足以获得或至少部分获得期望的效果的量。例如，预防有效量是指，足以预防，阻止，或延迟疾病的发生的量；治疗有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度，患者自己的免疫系统的总体状态，患者的一般情况例如年龄、体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
发明的有益效果
本发明通过对二氢黄酮类化合物进行结构修饰得到一类结构新颖的化合物，其能同时作用在多巴胺能系统、谷氨酸能系统、小胶质细胞和脑白质等多靶点上。在本发明的实施方案中，所述化合物具有显著的抑制小胶质细胞活化和神经炎症反应活性，能拮抗多巴胺2型受体，改善多种精神障碍动物模型的行为学变化，能有效抑制神经炎症和髓鞘脱失。表明本发明的化合物具有改善认知功能，防治精神障碍和神经系统疾病的作用，为相关疾病的治疗提供了一种新的思路。
附图说明
图1为本发明化合物抑制LPS+INF-γ致小胶质细胞(BV2细胞)活化及一氧化氮(NO)过度产生和释放结果，其中每个样品每个浓度平行6孔，实验重复2次，数据以Mean±SE表示；##P<0.01，模型组与对照组相比；*P<0.05，**P<0.01，给药组与模型组相比。
图2为本发明化合物对多巴胺受体2(DRD2)的拮抗活性。
图3为本发明化合物对MK-801致精神分裂症高活动模型小鼠270分钟内自主活动影响的曲线图，小鼠放入旷场行为红外监视系统仪器中开始测试60分钟，然后对照组(Con)腹腔注射生理盐水，模型组(M)和本发明药物组(P4、P5、P6、P7)均腹腔注射MK-801，继续测定各组小鼠210分钟内的自发活动性和中央区活动情况，每10分钟检测一次，每组n＝10。
图4为本发明化合物对MK-801致精神分裂症高活动模型小鼠210分钟内自发活动总路程的影响；数据以Mean±SE表示，每组n＝10；##P<0.01，模型组与对照组相比；*P<0.05本发明药物组与模型组相比。
图5为本发明化合物对MK-801致精神分裂症高活动模型小鼠210分钟内中央区活动距离的影响，数据以Mean±SE表示，每组n＝10；##P<0.01，模型组与对照组相比。
图6为本发明化合物对Cuprizone模型小鼠8分钟内Y-迷宫进臂次数的影响，数据以Mean±SE表示，每组n＝8，*P<0.05；**P<0.01；本发明药物组与模型组相比。
图7为本发明化合物对Cuprizone模型小鼠8分钟内Y-迷宫自发性交替反应的影响，数据以Mean±SE表示，每组n＝8，#P<0.05，模型组与对照组相比；*P<0.05，本发明药物组与模型组相比。
图8为本发明化合物对Cuprizone模型小鼠10分钟内旷场自发活动总路程的影响，数据以Mean±SE表示，每组n＝8，##P<0.01，模型组与对照组相比；*P<0.05，本发明药物组与模型组相比。
图9为本发明化合物对Cuprizone模型小鼠额叶皮质髓鞘碱性蛋白(myelin basic protein，MBP)的影响，其中(A)为MBP蛋白的Western blot代表性图片，小：小剂量组，25mg/kg；大：大剂量组，50mg/kg；(B)为MBP蛋白定量统计结果，数据以Mean±SE表示，n＝4，##P<0.01，与对照组相比；**P<0.01，与模型组相比。
图10为本发明化合物对Cuprizone模型小鼠脑内小胶质细胞的影响(免疫组织化学染色)，数据以Means±SE表示，n＝3，##P<0.01，与对照组相比；*P<0.05，与模型组相比。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得或按照公知教导制备得到的常规产品。
实施例中所述化合物的结构是按照常规的光谱技术(红外、紫外、核磁共振或ESI-MS 质谱)测定的。
A本发明化合物的合成
实施例1：5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮(P1)的合成
Figure PCTCN2017070877-appb-000003
1)将间苯三酚5.0g(40mmol)，溶于50ml二硫化碳和15ml硝基苯的溶液中，加入15.6g(120mmol)无水三氯化铝，室温搅拌10分钟，向反应液中滴加10ml乙酰氯4.23ml(60mmol)的二硫化碳溶液，之后于50℃下加热回流1小时结束反应。减压蒸去二硫化碳，向残留物中加入10ml盐酸和50ml冰水混合物，乙酸乙酯萃取3次(50ml×3)，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸干乙酸乙酯，所得残余物用硅胶拌样，硅胶柱分离。石油醚：乙酸乙酯(2:1)洗脱，得淡黄色固体5.71g，收率85.7％。
2)取第一步产物5.0g，溶于50ml丙酮中，加入无水碳酸钾15g，在室温下缓慢滴加氯甲基甲醚1.58ml，20min滴完，之后于室温下继续搅拌2小时，反应结束。滤掉无水碳酸钾固体，减压蒸去丙酮溶液，残余物中加入20ml水，乙酸乙酯萃取3次(30ml×3)，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸干有机溶剂，所得残余物用硅胶拌样，硅胶柱分离。石油醚：乙酸乙酯(15:1)洗脱，得淡黄色油状物约4.3g，收率56.4％。
3)取第二步产物4g，氢氧化钠10g，甲醇100ml，对甲氧基苯甲醛3.64ml，加热回流5小时，冷至室温，减压蒸干溶剂，加入50ml蒸馏水，2％HCl溶液中和至中性，乙酸乙酯萃取3次(50ml×3)，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压蒸干乙酸乙酯，所得残余物用硅胶拌样，硅胶柱分离。先用石油醚洗脱5个柱体积，再用石油醚：乙酸乙酯(10:1)洗脱，得黄色固体4.98g，收率85.2％。
1H NMR(300MHz，DMSO-d6)：δ＝12.39(br s,1H,OH-5),7.67(d,2H,J＝8.7Hz,Ar-H),7.53(d,2H,J＝9.6Hz,Ar-H),7.01(d,2H,J＝9.0Hz,Ar-H),5.28(s,2H,-OCH2-),5.22(s,2H,-OCH2-),3.81(s,3H,-OCH3),3.40(s,3H,-OCH3),3.40(s,3H,-OCH3).
4)取第三步产物2g，乙酸钠8g，甲醇30ml，加热回流12小时，冷至室温，减压蒸干溶剂，加入30ml蒸馏水，乙酸乙酯萃取3次(20ml×3)，有机层用饱和氯化钠洗 涤，无水硫酸钠干燥，减压蒸干乙酸乙酯，所得残余物用硅胶拌样，硅胶柱分离。先用石油醚：乙酸乙酯(10:1)洗脱4个柱体积，再用石油醚：乙酸乙酯(3:1)洗脱，得无色油状物1.63g，收率81.5％。
1H NMR(300MHz，DMSO-d6)：δ＝7.44(d,2H,J＝8.7Hz,Ar-H),6.97(d,2H,J＝8.7Hz,Ar-H),6.36(d,1H,J＝2.1Hz,H-8),6.33(d,1H,J＝2.4Hz,H-6),5.50(dd,1H,J＝12.9,2.7Hz,H-2),5.23(s,2H,-OCH2-),5.22(s,2H,-OCH2-),3.77(s,3H,-OCH3),3.41(s,3H,-OCH3),3.38(s,3H,-OCH3),3.14(dd,1H,J＝16.2,12.9Hz,H-3α),2.60(dd,1H,J＝16.2,2.7Hz,H-3β).
5)取第四步产物1.5g，甲醇30ml，浓盐酸1ml，加热回流30分钟，冷至室温，减压蒸干溶剂，少量甲醇混悬，倒入100ml冰水混合物中，减压抽滤，滤饼烘干后得白色固体0.87g，收率72.3％。
1H NMR(300MHz，DMSO-d6)：δ＝12.14(br s,1H,OH-5),10.78(br s,1H,OH-7),7.44(d,2H,J＝8.7Hz,Ar-H),6.97(d,2H,J＝8.7Hz,Ar-H),5.90(br s,1H,H-8),5.89(br s,1H,H-6),5.50(dd,1H,J＝12.6,2.7Hz,H-2),3.77(s,3H,-OCH3),3.28(dd,1H,J＝14.1,12.6Hz,H-3α),2.72(dd,1H,J＝14.1,3.0Hz,H-3β).
6)取第五步产物0.8g，无水碳酸钾3g，丙酮20ml，1,4-二溴丁烷1.2g，加热回流3小时，冷至室温，滤掉无水碳酸钾固体，有机层用硅胶拌样，硅胶柱分离，石油醚：乙酸乙酯(15:1)洗脱，得黄色油状物0.61g，收率54.5％。
ESI+-MS：423.1[M+H]+
1H NMR(300MHz，CDCl3)：δ＝12.03(br s,1H,OH-5),7.40(d,2H,J＝8.7Hz,Ar-H),6.97(d,2H,J＝8.7Hz,Ar-H),6.06(d,1H,J＝2.4Hz,H-8),6.04(d,1H,J＝2.4Hz,H-6),5.38(dd,1H,J＝12.9,3.0Hz,H-2),4.04(t,2H,J＝6.0Hz,H-1”),3.85(s,3H,-OCH3),3.49(t,2H,J＝6.0Hz,H-4”),3.11(dd,J＝17.1,12.9Hz,H-3α),2.80(dd,1H,J＝17.1,3.0Hz,H-3β),2.68(m,4H,H2-2”’；H2-6”’),2.49(t,2H,J＝7.2Hz,H-5”’),2.09(m,2H,H-3”),1.96(m,2H,H-2”).
7)取第六步产物0.6g，无水碳酸钾2g，碘化钾0.5g，乙腈10ml，1-(2-甲氧基苯基)哌嗪0.68g，加热回流2小时，冷至室温，滤掉无水碳酸钾固体，有机层用硅胶拌样，硅胶柱分离，石油醚：乙酸乙酯(2:1)洗脱，得黄色油状物0.15g，收率19.7％。
ESI+-MS：532.9[M+H]+
HR-Q-TOF-MS：533.2712[M+H]+(calcd for C31H36N2O6,533.2646).
1H NMR(300MHz，CDCl3)：δ＝12.04(br s,1H,OH-5),7.40(d,2H,J＝8.7Hz,Ar-H),6.90(m,6H,Ar-H),6.08(d,1H,J＝2.1Hz,H-8),6.05(br s,1H,J＝1.8Hz,H-6),5.38(dd, 1H,J＝12.9,2.7Hz,H-2),4.03(t,2H,J＝6.0Hz,H-1”),3.88(s,3H,-OCH3),3.85(s,3H,-OCH3),3.11(m,5H,H2-4”；H2-3”’；H-3α),2.80(dd,1H,J＝17.1,3.0Hz,H-3β),2.68(m,4H,H2-2”’；H2-6”’),2.49(t,2H,J＝7.2Hz,H-5”’),1.85(m,2H,H-2”),1.70(m,2H,H-3”).13C NMR(300MHz，CDCl3)：δ＝195.9(C-4),167.5(C-7),164.1(C-7”’),162.9(C-5),160.1(C-4’),152.3(C-9),141.4(C-8”’),130.5(C-1’),127.7(C-2’,6’),122.9(C-12”’),121.0(C-10”’),118.2(C-11”’),114.2(C-3’,5’),111.3(C-9”’),103.1(C-10),95.6(C-6),94.6(C-8),79.0(C-2),68.3(C-1”),58.1(C-4”),55.4(2×-OCH3),53.4(C-3”’,5”’),50.6(C-2”’,6”’),43.2(C-3),27.0(C-2”),23.2(C-3”).
实施例2：5-羟基-2-(4-甲基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮(P2)的合成
Figure PCTCN2017070877-appb-000004
操作同实施例1，在步骤3)中使用对甲基苯甲醛作为反应物。
ESI+-MS：517.2[M+H]+
HR-Q-TOF-MS：517.2766[M+H]+(calcd for C31H36N2O5,517.2697).
1H NMR(300MHz，CDCl3)：δ＝12.03(br s,1H,OH-5),7.36(d,2H,J＝8.1Hz,Ar-H),7.26(d,2H,J＝7.8Hz,Ar-H),6.95(m,4H,Ar-H),6.08(d,1H,J＝2.7Hz,H-8),6.06(br s,1H,J＝2.4Hz,H-6),5.40(dd,1H,J＝12.9,3.0Hz,H-2),4.03(t,2H,J＝6.3Hz,H-1”),3.88(s,3H,-OCH3),3.10(m,5H,H2-4”；H2-3”’；H-3α),2.82(dd,1H,J＝17.1,3.0Hz,H-3β),2.69(m,4H,H2-2”’；H2-6”’),2.49(t,2H,J＝7.2Hz,H-5”’),2.40(s,3H,-CH3),1.83(m,2H,H-2”),1.71(m,2H,H-3”).13C NMR(300MHz，CDCl3)：δ＝195.8(C-4),167.5(C-7),164.1(C-7”’),162.9(C-5),152.3(C-9),141.4(C-8”’),138.8(C-4’),135.5(C-1’),129.5(C-2’,6’),126.2(C-3’,5’),122.9(C-12”’),121.0(C-10”’),118.2(C-11”’),111.3(C-9”’),103.1(C-10),95.6(C-6),94.6(C-8),79.1(C-2),68.3(C-1”),58.1(C-4”),55.4(2-OCH3),53.4(C-3”’,5”’),50.6(C-2”’,6”’),43.3(C-3),27.0(C-2”),23.2(C-3”),21.2(-CH3).
实施例3：5-羟基-2-(4-氟基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮(P3)的合成
Figure PCTCN2017070877-appb-000005
操作同实施例1，在步骤3)中使用对氟苯甲醛作为反应物，所得产物P3为黄色油状物。
ESI+-MS：520.8[M+H]+
HR-Q-TOF-MS：521.2506[M+H]+(calcd for C30H33FN2O5,521.2446).
1H NMR(300MHz，CDCl3)：δ＝12.01(br s,1H,OH-5),7.45(m,2H,Ar-H),7.16(m,2H,J＝7.8Hz,Ar-H),6.95(m,4H,Ar-H),6.10(d,1H,J＝2.4Hz,H-8),6.06(d,1H,J＝2.1Hz,H-6),5.40(dd,1H,J＝13.2,3.0Hz,H-2),4.03(t,2H,J＝6.0Hz,H-1”),3.88(s,3H,-OCH3),3.06(m,5H,H2-4”；H2-3”’；H-3α),2.82(dd,1H,J＝17.1,3.3Hz,H-3β),2.68(m,4H,H2-2”’；H2-6”’),2.49(t,2H,J＝7.5Hz,H-5”’),2.40(s,3H,-CH3),1.82(m,2H,H-2”),1.70(m,2H,H-3”).13C NMR(300MHz，CDCl3)：δ＝195.3(C-4),167.6(C-7),164.2(C-7”’),162.6(C-5),152.3(C-9),141.4(C-8”’),134.4(C-4’),134.3(C-1’),128.0(C-2’,6’),122.9(C-12”’),121.0(C-10”’),118.2(C-11”’),116.0(C-3’),115.7(C-3’),111.3(C-9”’),103.0(C-10),95.7(C-6),94.7(C-8),78.5(C-2),68.3(C-1”),58.1(C-4”),55.4(2-OCH3),53.5(C-3”’,5”’),50.6(C-2”’,6”’),43.4(C-3),27.0(C-2”),23.2(C-3”).
实施例4：5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丙氧基)苯并二氢吡喃-4-酮(P6)的合成
Figure PCTCN2017070877-appb-000006
操作同实施例1，在步骤6)中使用1,3-二溴丙烷作为反应物，所得产物P3为黄色油状物。
ESI+-MS：519.0[M+H]+
HR-Q-TOF-MS：519.2548[M+H]+(calcd for C30H34N2O6,519.2490).
1H NMR(300MHz，CDCl3)：δ＝12.04(br s,1H,OH-5),7.40(d,2H,J＝8.4Hz,Ar-H),6.96(m,6H,Ar-H),6.09(br s,1H,H-8),6.08(br s,1H,H-6),5.38(dd,1H,J＝12.9,2.4Hz, H-2),4.08(t,2H,J＝6.0Hz,H-1”),3.88(s,3H,-OCH3),3.85(s,3H,-OCH3),3.11(m,5H,H2-3”；H2-3”’；H-3α),2.80(dd,1H,J＝17.1,3.0Hz,H-3β),2.69(m,4H,H2-2”’；H2-6”’),2.58(t,2H,J＝7.2Hz,H-5”’),2.03(m,2H,H-2”).13C NMR(300MHz，CDCl3)：δ＝196.0(C-4),167.2(C-7),164.1(C-7”’),162.9(C-5),160.1(C-4’),152.2(C-9),140.8(C-8”’),130.4(C-1’),127.7(C-2’,6’),123.3(C-12”’),121.1(C-10”’),118.4(C-11”’),114.2(C-3’,5’),111.2(C-9”’),103.2(C-10),95.6(C-6),94.6(C-8),79.0(C-2),66.4(C-1”),55.4(2×-OCH3),54.8(C-3”),53.2(C-5”’,9”’),49.8(C-2”’,6”’),43.2(C-3),29.7(C-2”).
实施例5：5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丁氧基)苯并二氢吡喃-4-酮(P5)的合成
Figure PCTCN2017070877-appb-000007
操作同实施例1，在步骤7)中使用6-氟-3-(4-哌啶基)-1,2-苯并异噁唑作为反应物，所得产物P5为黄色油状物。
ESI+-MS：560.8[M+H]+
HR-Q-TOF-MS：561.2447[M+H]+(calcd for C32H33FN2O6,561.2395).
1H NMR(300MHz，CDCl3)：δ＝12.05(br s,1H,OH-5),7.40(dd,1H,J＝8.7,5.1Hz,Ar-H),7.44(d,2H,J＝8.7Hz,Ar-H),7.25(dd,2H,J＝8.7,2.1Hz,Ar-H),7.07(dt,1H,J＝9.0,2.1Hz,Ar-H),6.97(d,2H,J＝8.7Hz,Ar-H),6.08(d,1H,J＝2.1Hz,H-8),6.06(br s,1H,J＝2.4Hz,H-6),5.40(dd,1H,J＝13.2,3.0Hz,H-2),4.03(t,2H,J＝6.0Hz,H-1”),3.85(s,3H,-OCH3),3.12(m,4H,H2-4”；H-8”；H-3α),2.81(dd,1H,J＝17.1,3.0Hz,H-3β),2.47(t,2H,J＝7.2Hz,H-6”),2.08(m,6H,H2-7”；H2-9”；H2-10”),1.83(m,2H,H-2”),1.70(m,2H,H-3”).13C NMR(300MHz，CDCl3)：δ＝195.9(C-4),167.5(C-7),164.1(C-6”’),162.9(C-5),161.1(C-9),160.1(C-4’),130.5(C-1’),127.7(C-2’,6’),122.7(C-8”’),122.5(C-6”’),117.3(C-3”’),114.4(C-3’,5’),112.5(C-9”’),112.1(C-9”’),103.1(C-10),97.6(C-7”’),97.2(C-7”’),95.5(C-6),94.6(C-8),79.0(C-2),68.3(C-1”),58.3(C-4”),55.4(-OCH3),53.5(C-6”,10”),43.2(C-3),34.6(C-8”),30.5(C-7”,9”),27.0(C-2”),23.3(C-3”).
实施例6：5-羟基-2-(4-氟基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丁氧基)苯并二氢吡喃-4-酮(P4)的合成
Figure PCTCN2017070877-appb-000008
操作同实施例1，在步骤3)中使用对氟苯甲醛作为反应物；在步骤7)中使用6-氟-3-(4-哌啶基)-1,2-苯并异噁唑作为反应物，所得产物为黄色油状物。
ESI+-MS：548.8[M+H]+
HR-Q-TOF-MS：549.2273[M+H]+(calcd for C31H30F2N2O5,549.2196).
1H NMR(300MHz，CDCl3)：δ＝12.04(br s,1H,OH-5),7.40(dd,2H,J＝8.7,5.1Hz,Ar-H),7.44(m,2H,Ar-H),7.24(dd,2H,J＝8.7,2.1Hz,Ar-H),7.09(m,4H,Ar-H),6.08(d,1H,J＝2.1Hz,H-8),6.05(br s,1H,J＝2.4Hz,H-6),5.40(dd,1H,J＝12.6,3.0Hz,H-2),4.03(t,2H,J＝6.0Hz,H-1”),3.06(m,4H,H2-4”；H-8”；H-3α),2.80(dd,1H,J＝17.1,3.0Hz,H-3β),2.48(t,2H,J＝7.2Hz,H-6”),2.05(m,6H,H2-7”；H2-9”；H2-10”),1.83(m,2H,H-2”),1.70(m,2H,H-3”).13C NMR(300MHz，CDCl3)：δ＝195.9(C-4),167.5(C-7),164.1(C-4”’),162.6(C-5),161.0(C-9),134.3(C-4’),134.3(C-1’),128.0(C-2’,6’),122.7(C-8”’),122.5(C-6”’),117.3(C-9”’),115.9(C-3’),115.7(C-3’),112.5(C-1”’),112.1(C-7”’),103.0(C-10),97.2(C-5”’),95.7(C-6),94.6(C-8),78.5(C-2),68.3(C-1”),58.2(C-4”),53.4(C-6”,10”),30.4(C-7”,9”),43.3(C-3),34.5(C-8”),26.9(C-2”),23.2(C-3”).
实施例7：5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丙氧基)苯并二氢吡喃-4-酮(P7)的合成
Figure PCTCN2017070877-appb-000009
操作同实施例1，在步骤6)中使用1,3-二溴丙烷作为反应物；在步骤7)中使用6-氟-3-(4-哌啶基)-1,2-苯并异噁唑作为反应物，所得产物为黄色油状物。
ESI+-MS：546.9[M+H]+
HR-Q-TOF-MS：547.2309[M+H]+(calcd for C31H31FN2O6,547.2239).
1H NMR(300MHz，CDCl3)：δ＝12.04(br s,1H,OH-5),7.72(dd,1H,J＝8.4,5.1Hz,Ar-H),7.39(d,2H,J＝8.4Hz,Ar-H),7.25(m,1H,Ar-H),7.06(dt,1H,J＝9.0,2.1Hz,Ar-H),6.96(d,2H,J＝8.4Hz,Ar-H),6.10(br s,1H,H-8),6.08(br s,1H,H-6),5.40(dd,1H,J＝12.9,2.1Hz,H-2),4.08(t,2H,J＝6.0Hz,H-1”),3.84(s,3H,-OCH3),3.11(m,4H,H2-3”；H-8”；H-3α),2.81(dd,1H,J＝17.1,2.7Hz,H-3β),2.60(t,2H,J＝7.2Hz,H-5”),2.09(m,8H,H2-2”；H2-6”；H2-8”；H2-9”).13C NMR(300MHz，CDCl3)：δ＝196.0(C-4),167.4(C-7),164.1(C-6”’),162.9(C-5),161.0(C-9),160.0(C-4’),130.4(C-1’),127.7(C-2’,6’),122.7(C-8”’),122.6(C-6”’),117.3(C-3”’),114.2(C-3’,5’),112.5(C-9”’),112.2(C-9”’),103.1(C-10),97.6(C-7”’),95.6(C-6),94.6(C-8),79.0(C-2),66.7(C-1”),55.4(-OCH3),55.0(C-3”),53.5(C-5”,9”),43.2(C-3),34.5(C-7”),30.4(C-6”,8”),30.0(C-2”),26.5(C-3”).
B.本发明化合物的药理研究
实验例1：本发明化合物对LPS+INF-γ致小胶质细胞炎症反应的影响
实验目的：小胶质细胞活化和神经炎症是中枢神经系统许多疾病的重要发病机制。致炎物质细菌内毒素脂多糖(lipopolysaccharides，LPS)以及干扰素γ(interferon-γ，IFN-γ)可刺激机体产生前炎症细胞因子，后者触发瀑布式炎症级联反应，进一步激活小胶质细胞等炎症细胞，释放炎性介质一氧化氮(nitric oxide，NO)等，形成炎症网络。本实验通过建立LPS+INF-γ联合致小胶质细胞(BV2细胞)炎症模型，研究本发明合成的新型化合物对小胶质细胞炎症的抑制作用。
实验方法：取处于对数生长期的BV2细胞(小鼠小胶质细胞系)接种于96孔培养板(培养液为90％DMEM培养基+10％胎牛血清)，置37℃、5％CO2培养箱中培养。24h后，加入不同浓度的化合物，培养24h后弃培养液，加入LPS(100μg/ml)+INF-γ(1ng/ml)作用24h，收集上清液。以NO的稳定性代谢产物亚销酸盐作为检测NO的指标，用Griess试剂盒测定。
实验结果：如图1所示，LPS+INF-γ诱导BV2细胞(小胶质细胞)产生和释放炎性介质NO明显增多。本发明化合物都具有抑制LPS+INF-γ致BV2细胞NO过度生成和释放的作用，表明这些化合物具有明显的拮抗神经炎症的作用。
结果提示本发明化合物可用于防治精神分裂症、抑郁症等精神障碍，以及神经退行性疾病(如阿尔茨海默病、帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病等神经系统疾病。
实验例2：本发明化合物对多巴胺2型受体活性的影响
实验目的：精神分裂症患者的阳性症状(幻觉、妄想等)可能与皮质下边缘系统多巴胺(DA)功能亢进有关，阻断多巴胺2型受体(DRD2)的抗精神病药物能有效控制精神分裂症的阳性症状。通过建立共转DRD2和Gα16的细胞系，使得DRD2被激活后能引起Gα16蛋白的活化，进而激活磷脂酶C(PLC)产生1,4,5-三磷酸肌醇(IP3)和二酰甘油(DAG)，IP3可与细胞内质网和线粒体上的IP3受体结合，从而引起胞内钙的释放。因此，测定胞内钙的变化可以作为检测DRD2活化状态的方法。
Fluo-4/AM是一种钙荧光探针指示剂用来测量钙离子。本实验应用Fluo-4荧光法，通过测量被细胞内钙离子激发的荧光强度来反映Gα蛋白被激活的水平。如果化合物能够激动DRD2，则可以使钙流反应升高；反之，如果化合物能够拮抗DRD2，则使钙流反应降低。
实验方法：将稳定表达DRD2/Gα16的HEK293细胞(人胚肾细胞系，来源于中国科学院上海药物研究所)种于96孔板(培养液为90％DMEM培养基+10％胎牛血清)，培养过夜。吸去培养液，加入新鲜配制的染料Fluo-4/AM，37℃培养箱内孵育40分钟。将染料吸尽弃去，用新鲜配制的钙缓冲液洗一遍后，换上50μl溶解有待测药物的钙缓冲液。用FlexStation II仪检测，第15秒开始由仪器自动加入25μl溶解有已知激动剂的钙缓冲液，最终读取525nm处荧光值(激发波长设为485nm)。以多巴胺(Dopamine)为激动剂，Eticlopride(依替必利，D2受体拮抗剂)为拮抗剂，通过以下公式计算得到各样品各浓度条件下的细胞反应率(％Response)：％Response＝(LSample-LBlank)/(LDopamine-LBlank)。LSample表示待测样品的检测信号值，LBlank表示Eticlopride完全抑制的检测信号值，LDopamine表示50nM激动剂Dopamine刺激DMSO组后的检测信号值。IC50值是通过GraphPad Prism计算得到。
实验结果：从表1和图2看出，本发明化合物P1～P7都具有抑制多巴胺2型受体(DRD2)的活性，并具有一定量效关系。结果提示本发明化合物可用于防治精神分裂症等精神障碍。
表1.本发明部分化合物抑制多巴胺2型受体的IC50值
Figure PCTCN2017070877-appb-000010
Figure PCTCN2017070877-appb-000011
实验例3：本发明化合物对NMDA受体拮抗剂致精神分裂症小鼠模型的影响
实验目的：谷氨酸传递低下是精神分裂症等精神障碍的发病机制之一，N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid，NMDA)受体拮抗剂能够诱导精神分裂症样效应。本实验采用NMDA受体拮抗剂地卓西平(MK-801)诱导小鼠的高活动性精神分裂症模型，对本发明化合物P6、P5、P4、P7进行体内活性评价。
实验方法：选择无特殊病原体SPF级近交系Balb/c雄性小鼠(购自首都医科大学实验动物中心)，体重(20±2)g，随机分为对照组、模型组、本发明药物组。小鼠先适应饲养环境1周，连续灌胃给药3天，其中，对照组和模型组灌胃给予生理盐水，第4天在测试前给药，随后放入旷场行为红外监视系统仪器中开始测试60分钟，然后对照组腹腔注射生理盐水，模型组和本发明药物组腹腔注射NMDA受体拮抗剂地卓西平(MK-801)溶液0.6mg/kg，继续测定各组小鼠210分钟内的自发活动性和中央区活动情况。其中，自发活动用来反映精神分裂症中快速移动的阳性症状；中央区活动情况用来评价精神分裂症的焦虑状态。
实验结果：应用旷场试验检测小鼠自主活动情况，结果显示：与对照组相比，MK-801模型组小鼠210分钟内的自发活动总路程和中央区活动距离延长；本发明化合物P6、P5、P7灌胃给药能够缩短MK-801模型小鼠的自发活动总路程和中央区活动距离(图3，图4，图5，表2)。结果提示本发明化合物可减轻精神分裂症的阳性症状和焦虑状态。
表2.本发明化合物对MK-801致精神分裂症高活动模型小鼠210分钟内自发活动总路程及中央区活动距离的影响(旷场试验)
Figure PCTCN2017070877-appb-000012
数据以Mean±SE表示，每组n＝10；##P<0.01，模型组与对照组相比；*P<0.05，给药组与模型组相比。
实验例4：本发明化合物对Cuprizone小鼠模型行为学变化的影响
实验目的：神经炎症、白质病变、髓鞘脱失是中枢神经系统许多疾病和精神障碍的重要发病机制。Cuprizone(双环己酮草酰二腙)可引起炎症反应、髓鞘脱失、轴突损伤、认知功能损害等变化。本实验应用Y-迷宫和旷场行为试验研究了本发明化合物对Cuprizone小鼠模型记忆功能和运动情况的影响。
实验方法：选择SPF级近交系C57BL/6雄性小鼠，体重(20±2)g，随机分为对照组、模型组、本发明药物组。小鼠先适应饲养环境3天，然后除了对照组给予正常饲料以外，其它各组均给予含0.2％Cuprizone的饲料进行造模，造模的同时各组灌胃相应剂量的药物，连续饲养5周，然后进行Y-迷宫和旷场行为测试。其中，Y-迷宫的进臂次数用来反映小鼠的运动情况；Y-迷宫的自发性交替反应(Alternation)用来反映小鼠的工作记忆情况；旷场行为的自发活动性用来反映小鼠的运动情况。
实验结果：Y-迷宫试验的结果显示，与对照组相比，Cuprizone模型小鼠的进臂次数增高，自发性交替反应减低；本发明化合物P6、P5灌胃给药能够减低模型小鼠的进臂次数(图6)，增高自发性交替反应(图7)。旷场行为试验的结果显示，与对照组相比，Cuprizone模型小鼠的自发活动总路程延长；本发明化合物P6、P5灌胃给药能够缩短模型小鼠的自发活动总路程(图8)。结果表明本发明化合物能够改善Cuprizone模型小鼠的认知功能和运动行为，减低模型小鼠的高活动状态。
实验例5：本发明化合物对Cuprizone小鼠模型髓鞘脱失的影响
实验目的：神经白质病变、髓鞘脱失是中枢神经系统许多疾病和精神障碍的重要发病机制。Cuprizone可引起髓鞘脱失和神经白质病变。髓鞘碱性蛋白(MBP)是轴突髓鞘化的标志性蛋白，是髓鞘的主要组成成分。本实验应用蛋白免疫印迹(western blot)方法研究本发明化合物对Cuprizone模型小鼠脑内MBP含量及髓鞘脱失的影响。
实验方法：Cuprizone小鼠造模与给药方法同实验例4。小鼠进行行为学检测后，腹腔注射10％水合氯醛进行麻醉，取脑，于-80℃保存。Western blot检测：取脑组织用裂解液提取蛋白，测蛋白浓度。进行SDS-PAGE凝胶电泳，转膜，封闭。于4℃冰箱与抗MBP抗体(一抗)孵育过夜。在TBST漂洗后，于4℃冰箱与羊抗鼠IgG抗体(二抗)孵育2h。TBST洗膜后，在暗室中加入ECL发光液，压片，曝光。各蛋白条带的信号强度用FluorChem 8900灰度分析软件进行分析。
实验结果：应用western blot方法检测，结果显示：与对照组相比，Cuprizone模型组小鼠额叶皮层髓鞘碱性蛋白(MBP)含量明显降低；本发明化合物P5、P4能够显著升高模型小鼠的MBP含量，表明具有改善髓鞘脱失的作用(图9)。
结果提示本发明化合物可用于防治精神分裂症、抑郁症和其他精神障碍，以及脑血管病、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病、缺血-缺氧性病引起的白质脑病、糖尿病性神经病等疾病。
实验例6：本发明化合物对Cuprizone小鼠模型小胶质细胞活化的影响
实验目的：小胶质细胞活化和神经炎症是中枢神经系统许多疾病的重要发病机制。Iba-1能够特异标志小胶质细胞。本实验应用免疫组织化学方法研究本发明化合物对Cuprizone小鼠模型脑内Iba-1标志的小胶质细胞的影响。
实验方法：Cuprizone小鼠造模与给药方法同实验例4。小鼠进行行为学检测后，腹腔注射10％水合氯醛进行麻醉。灌注后，取出脑组织，用15％多聚甲醛固定脑组织，然后进行冰冻切片。免疫组织化学染色：冰冻切片用3％的H2O2灭活10min，PBS漂洗；10％的血清封闭，37℃孵育1h。洗出血清，滴加一抗(抗Iba-1抗体)，4℃过夜。用PBST漂洗，滴加生物素标记的羊抗兔IgG抗体(二抗)，37℃孵育2h。用PBST漂洗，滴加辣根酶标记的链酶卵白素三抗，37℃孵育2h。用PBS漂洗，DAB试剂显色，透明，封片。在显微镜下观察Iba-1阳性细胞，计数。
实验结果：免疫组织化学染色结果显示，与正常对照组相比，Cuprizone模型组脑内Iba-1标记的小胶质细胞数量明显增多，表明小胶质细胞活化，出现炎症反应；本发明化合物P6(25、50mg/kg)能够明显减少小胶质细胞数量，表明能够抑制小胶质细胞活化，减轻炎性反应(图10)。
结果提示本发明化合物可用于防治精神分裂症、抑郁症等精神障碍，以及神经退行性疾病(如阿尔茨海默病、帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病等神经系统疾病。
综上所述，本发明提供了一类式I所示的结构新颖的化合物，这些化合物能够拮抗多巴胺2型受体，抑制小胶质细胞激活和神经炎症反应；动物实验结果表明，本发明化合物可降低MK-801小鼠模型的高活动性，并能缓解其焦虑状态；能够改善Cuprizone模型小鼠的记忆功能障碍、异常运动行为和高活动性，并能抑制模型小鼠的小胶质细胞活化和髓鞘脱失。这些结果表明本发明化合物具有防治多种精神障碍和神经系统疾病的用途。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解，根据已经公开的所有教导，对本发明细节进行的各种修改和替换均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (25)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2017070877-appb-100001
    其中：
    R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基、C1-6烷基(例如甲基)、C1-6烷氧基(例如甲氧基)、C1-6烷氨基和芳基，任选地，其中所述C1-6烷基、C1-6烷氧基、C1-6烷氨基和芳基各自独立地被一个或多个选自卤素(例如氟或氯)、氨基和羟基的取代基取代；
    X为含有2-6个碳原子的饱和或部分饱和的亚链烃基，任选地，其中所述亚链烃基被选自羟基或甲基的取代基取代；
    Y为N或C(R)，其中所述R基选自氢、羟基、氨基、C1-6烷基；
    Z为芳基或杂芳基。
  2. 权利要求1的化合物或其药学上可接受的盐，其中，R1、R2、R4、R5、R6和R7各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基、C1-6烷基(例如甲基)、C1-6烷氧基(例如甲氧基)、C1-6烷氨基和6-20元芳基(例如6-10元芳基，例如苯基或萘基)；
    优选地，R1、R2、R4、R5、R6和R7各自独立地选自氢、卤素(例如氟或氯)、氰基、羟基、氨基和C1-4烷基(例如甲基)；
    优选地，R1、R2、R4、R5、R6和R7均为氢。
  3. 权利要求1或2的化合物或其药学上可接受的盐，其中，R3选自氢、卤素(例如氟或氯)、C1-6烷基(例如甲基)和C1-6烷氧基(例如甲氧基)，任选地，其中所述C1-6烷基和C1-6烷氧基各自独立地被一个或多个选自卤素、氨基和羟基的取代基取代；
    优选地，R3选自氢、卤素(例如氟或氯)、C1-4烷基(例如甲基)和C1-4烷氧基(例如甲氧基)，任选地，其中所述C1-4烷基和C1-4烷氧基各自独立地被一个或多个选自卤素、氨基和羟基的取代基取代；
    优选地，R3选自氢、卤素(例如氟或氯)、C1-2烷基(例如甲基)和C1-2烷氧基(例如甲氧基)；
    优选地，R3选自氟、甲基和甲氧基。
  4. 权利要求1-3任一项的化合物或其药学上可接受的盐，其中，R8选自氢、卤素(例如氟或氯)、C1-6烷基(例如甲基)和C1-6烷氧基(例如甲氧基)，任选地，其中所述C1-6烷基和C1-6烷氧基各自独立地被一个或多个选自卤素、氨基和羟基的取代基取代；
    优选地，R8选自氢、卤素(例如氟或氯)、C1-2烷基(例如甲基)和C1-2烷氧基(例如甲氧基)；
    优选地，R8选自氟和甲氧基。
  5. 权利要求1-4任一项的化合物或其药学上可接受的盐，其中，Y为N或C(R)，R选自氢、羟基或甲基；
    优选地，Y为N或CH。
  6. 权利要求1-5任一项的化合物或其药学上可接受的盐，其中，X为C2-6亚烷基(例如C2-4亚烷基，再例如1,2-亚乙基、1,3-亚丙基或1,4-亚丁基)，任选地，所述C2-6亚烷基被选自羟基或甲基的取代基取代；
    优选地，X为1,3-亚丙基或1,4-亚丁基。
  7. 权利要求1-6任一项的化合物或其药学上可接受的盐，其中Z为含5-20个碳原子(例如5-15个碳原子，再例如5-10个碳原子)的芳基或杂芳基；
    优选地，所述芳基或杂芳基选自苯基、萘基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、吡啶基、吡喃基、嘧啶基、吡嗪基、哒嗪基、三嗪基、吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并吡唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三氮唑基、喹啉基、苯并吡喃基、苯并嘧啶基、喹喔啉基、苯并哒嗪基、苯并三嗪基和嘌呤基。
  8. 权利要求1的化合物或其药学上可接受的盐，其中所述化合物选自：
    5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮；
    5-羟基-2-(4-甲基苯基)-7-(4-(4-(2-甲氧基苯一基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮；
    5-羟基-2-(4-氟基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)苯并二氢吡喃-4-酮；
    5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丙氧基)苯并二氢吡喃-4-酮；
    5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丁氧基)苯并二氢吡喃-4-酮；
    5-羟基-2-(4-甲氧基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丙氧基)苯并二氢吡喃-4-酮；和
    5-羟基-2-(4-氟基苯基)-7-(4-(4-(6-氟-苯并[d]异噁唑-3-基)哌啶-1-基)丁氧基)苯并二氢吡喃-4-酮。
  9. 药物组合物，其包含权利要求1-8任一项的化合物或其药学上可接受的盐，以及任选地一种或几种药学上可接受的辅料(如载体和/或赋形剂)。
  10. 权利要求1所述的化合物或其药学上可接受的盐的制备方法，其包括以下步骤：
    Figure PCTCN2017070877-appb-100002
    1)化合物A与乙酰氯经酰基化反应得到化合物B；
    2)在化合物B的羟基上引入保护基得化合物C；
    3)化合物C与化合物D发生羟醛缩合反应制得化合物E；
    4)化合物E经关环反应得化合物F；
    5)化合物F脱保护基得化合物G；
    6)化合物G与化合物H经亲核取代得到化合物I；
    7)化合物I与化合物J经亲核取代得到式I化合物；
    其中，PG代表羟基保护基，例如MOM、TMS或TBS等；L表示亲核取代反应的离去基团，例如卤素、-OTs、-OCOR(R代表烷基)等；
    其余各原子或取代基定义如权利要求1所述。
  11. 权利要求1-8任一项所述的化合物或其药学上可接受的盐或者权利要求9的药物组合物在制备用于预防或治疗精神障碍或神经系统疾病的药物中的用途；优选地，所述精神障碍选自精神分裂症、抑郁症、躁狂抑郁性精神障碍(双相障碍)、认知障碍、焦虑症、应激相关障碍、注意缺陷与多动障碍、抽动障碍，以及各种器质性病变伴发的精 神障碍；优选地，所述各种器质性病变伴发的精神障碍选自阿尔茨海默病、血管性痴呆、脑外伤所致精神障碍、颅内感染所致精神障碍、脑肿瘤所致精神障碍、梅毒所致精神障碍、癫痫性精神障碍、HIV/AIDS所致精神障碍；优选地，所述神经系统疾病选自神经退行性疾病(例如阿尔茨海默病或帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病、缺血-缺氧性病引起的白质脑病和糖尿病性神经病。
  12. 权利要求1-8任一项所述的化合物或其药学上可接受的盐或者权利要求9的药物组合物，其用于预防或治疗精神障碍或神经系统疾病；优选地，所述精神障碍选自精神分裂症、抑郁症、躁狂抑郁性精神障碍(双相障碍)、认知障碍、焦虑症、应激相关障碍、注意缺陷与多动障碍、抽动障碍，以及各种器质性病变伴发的精神障碍；优选地，所述各种器质性病变伴发的精神障碍选自阿尔茨海默病、血管性痴呆、脑外伤所致精神障碍、颅内感染所致精神障碍、脑肿瘤所致精神障碍、梅毒所致精神障碍、癫痫性精神障碍、HIV/AIDS所致精神障碍；优选地，所述神经系统疾病选自神经退行性疾病(例如阿尔茨海默病或帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病、缺血-缺氧性病引起的白质脑病和糖尿病性神经病。
  13. 一种预防或治疗精神障碍或神经系统疾病的方法，其包括向有此需要的受试者施用有效量的权利要求1-8任一项所述的化合物或其药学上可接受的盐或者权利要求9的药物组合物；优选地，所述精神障碍选自精神分裂症、抑郁症、躁狂抑郁性精神障碍(双相障碍)、认知障碍、焦虑症、应激相关障碍、注意缺陷与多动障碍、抽动障碍，以及各种器质性病变伴发的精神障碍；优选地，所述各种器质性病变伴发的精神障碍选自阿尔茨海默病、血管性痴呆、脑外伤所致精神障碍、颅内感染所致精神障碍、脑肿瘤所致精神障碍、梅毒所致精神障碍、癫痫性精神障碍、HIV/AIDS所致精神障碍；优选地，所述神经系统疾病选自神经退行性疾病(例如阿尔茨海默病或帕金森病)、脑血管病、脑创伤、脊髓损伤、脱髓鞘病、多发性硬化、炎症性脱髓鞘性多发性神经病、缺血-缺氧性病引起的白质脑病和糖尿病性神经病。
  14. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物用于制备试剂的用途，所述试剂用于抑制小胶质细胞的过度激活或增殖；
    优选地，所述试剂用于体内方法中；
    优选地，所述试剂用于体外方法中；
    优选地，所述小胶质细胞为细胞系或来自受试者的细胞。
  15. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物，其用于抑制小胶质细胞的过度激活或增殖；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中；
    优选地，所述小胶质细胞为细胞系或来自受试者的细胞。
  16. 一种抑制小胶质细胞过度激活或增殖的方法，其包括向细胞施用有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物；
    优选地，所述方法在体内进行；
    优选地，所述方法在体外进行；
    优选地，所述小胶质细胞为细胞系或来自受试者的细胞。
  17. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物用于制备试剂的用途，所述试剂用于抑制细胞中多巴胺受体的活性；
    优选地，所述多巴胺受体为多巴胺2型受体；
    优选地，所述试剂用于体内方法中；
    优选地，所述试剂用于体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  18. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物，其用于抑制细胞中多巴胺受体的活性；
    优选地，所述多巴胺受体为多巴胺2型受体；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  19. 一种抑制细胞中多巴胺受体活性的方法，其包括向细胞施用有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物；
    优选地，所述多巴胺受体为多巴胺2型受体；
    优选地，所述方法在体内进行；
    优选地，所述方法在体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  20. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物用于制备试剂的用途，所述试剂用于增强细胞中NMDA受体的活性；
    优选地，所述试剂用于体内方法中；
    优选地，所述试剂用于体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  21. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物，其用于增强细胞中NMDA受体的活性；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  22. 一种增强细胞中NMDA受体的活性的方法，其包括向细胞施用有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物；
    优选地，所述方法在体内进行；
    优选地，所述方法在体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  23. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物用于制备试剂的用途，所述试剂用于提高细胞中髓鞘碱性蛋白(MBP)的含量、减轻髓鞘脱失或白质病变；
    优选地，所述试剂用于体内方法中；
    优选地，所述试剂用于体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  24. 权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物，其用于提高细胞中髓鞘碱性蛋白(MBP)的含量、减轻髓鞘脱失或白 质病变；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体内方法中；
    优选地，所述化合物或其药学上可接受的盐或药物组合物用于体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
  25. 一种提高细胞中髓鞘碱性蛋白(MBP)的含量、减轻髓鞘脱失或白质病变的方法，其包括向细胞施用有效量的权利要求1-8任一项所述的式I化合物或其药学上可接受的盐、或权利要求9所述的药物组合物；
    优选地，所述方法在体内进行；
    优选地，所述方法在体外方法中；
    优选地，所述细胞为细胞系或来自受试者的细胞。
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