WO2020048043A1 - 作为防治精神障碍疾病的苯胺类化合物 - Google Patents

作为防治精神障碍疾病的苯胺类化合物 Download PDF

Info

Publication number
WO2020048043A1
WO2020048043A1 PCT/CN2018/121562 CN2018121562W WO2020048043A1 WO 2020048043 A1 WO2020048043 A1 WO 2020048043A1 CN 2018121562 W CN2018121562 W CN 2018121562W WO 2020048043 A1 WO2020048043 A1 WO 2020048043A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
membered
alkyl
group
Prior art date
Application number
PCT/CN2018/121562
Other languages
English (en)
French (fr)
Inventor
阳怀宇
李扬
郭飞
蒋华良
张乾森
Original Assignee
中国科学院上海药物研究所
绍兴从零医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所, 绍兴从零医药科技有限公司 filed Critical 中国科学院上海药物研究所
Publication of WO2020048043A1 publication Critical patent/WO2020048043A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/14—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/08—Aza-anthracenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention belongs to the technical field of medicine and relates to aniline compounds for preventing and treating mental disorders, pharmaceutically acceptable salts thereof, prodrugs thereof, solvates, deuterates or stereoisomers thereof.
  • the invention also relates to the invention A method for preparing a compound, a pharmaceutical composition and a pharmaceutical preparation containing the compound, and an application of the compound in a medicament for the prevention or treatment of a mental disorder such as depression, anxiety and schizophrenia in a mammal.
  • Depression is a common mental illness.
  • the common manifestations of depression are depression, loss of interest or enjoyment, guilt or lack of self-esteem, sleep and appetite disorders, physical fatigue, and difficulty concentrating. Depression can persist or recur frequently, severely affecting an individual's daily life. When the disease is most severe, patients even have a tendency to commit suicide. Depression has become one of the diseases that seriously affect human health. There are currently an estimated 350 million people with depression worldwide, and more than 800,000 people die of suicide each year due to depression. There are about 90 million people with depression in China, and more than 200,000 people commit suicide each year due to depression. It is estimated that by 2020 depression May become the second largest disease after cardiovascular disease. Treatments for depression include medication, psychotherapy, and physical therapy. 70% of patients with depression can alleviate symptoms after being treated with antidepressants. Therefore, highly effective and safe antidepressants will become a new hotspot in drug development.
  • the pathogenesis of depression is very complex and is closely related to various factors such as genetics, environment, and society.
  • the current mainstream hypotheses about the pathogenesis of depression include the monoamine neurotransmitter hypothesis, neuroplasticity, and neurotrophic imbalance theory.
  • the monoamine neurotransmitter hypothesis is the theoretical basis for the development of first-line clinical antidepressants.
  • the monoamine neurotransmitter hypothesis believes that depression is due to the lack of serotonin, noradrenaline and other monoamine neurotransmitters in the patient's brain.
  • Monoamine neurotransmitters are reduced in the synaptic cleft mainly by two pathways.
  • drugs based on this mechanism are selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, etc.), and tricyclic antidepressants (imipramine, amitriptyline) Lin, clomipramine, etc.), norepinephrine reuptake inhibitors (reboxetine, maprotiline, mianserin, etc.).
  • Another pathway is degradation by monoamine oxidase in the brain.
  • the TREK-1 channel is a dual-porous potassium ion channel (K2P).
  • K2P potassium ion channel
  • TREK-1 channels are abundant in human brain regions such as the hippocampus, cortex, and amygdala, and are highly related to the monoamine neurotransmitter system. Antidepressant animal models and gene knockout studies show that inhibition of TREK-1 channel can treat depression, and TREK-1 channel has become an important target for the design of new antidepressants.
  • the object of the present invention is to provide an aniline compound having TREK-1 inhibitory activity, which is used for preventing and treating depression, depression, anxiety, and schizophrenia.
  • Another object of the present invention is to provide a pharmaceutical composition, a health food composition, or a food composition containing the aniline compound.
  • Another object of the present invention is to provide a method for preparing an aniline compound.
  • Another object of the present invention is to provide a method for preventing or treating a mental disorder.
  • a compound represented by Formula I a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof:
  • Ar 2 is a 6-14 membered aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloalkyl group or a 3-14 membered heterocyclic group;
  • Ar 1 is a 6-14 membered aryl group, a 5-14 membered heteroaryl group, a 3-14 membered cycloalkyl group, or a 3-14 membered heterocyclic group;
  • Ar 3 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogenated C1-C4 alkyl or 3-6 membered cycloalkyl;
  • each R ′ and each R ′′ are independently selected from: H, phenyl substituted or unsubstituted by 1-3 Q4, benzyl substituted or substituted by 1-3 Q4, and substituted by 1-3 Q4.
  • n 0, 1 or 2 and m + n ⁇ 1;
  • R 1 may be the same or different;
  • R 6 may be the same or different;
  • f 0, 1, 2, 3, or 4.
  • f is 1, 2 or 3.
  • the compound represented by the formula I has a structure represented by the general formula (II):
  • R 1 , R 2 , R 3 , R 5 , R 6 , p, and q are as described above.
  • the compound represented by the formula I has a structure represented by the general formula (III):
  • R 1 , R 2 , R 3 , and p are as described above.
  • the compound represented by Formula I has a structure represented by Formula (IV):
  • R 1 , R 2 , R 3 , R 5 , R 6 , p, and q are as described above.
  • the compound represented by the formula I has a structure represented by the general formula (V):
  • R 1 , R 2 , R 3 , and p are as described above.
  • Ar 2 is a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered cycloalkyl group, or a 3-8 membered heterocyclic group;
  • Ar 1 is a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group;
  • Ar 3 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, halogenated C1-C4 alkyl or 3-6 membered cycloalkyl;
  • each R ′ and each R ′′ are independently selected from: H, phenyl, benzyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl; or groups R ′ and R ′′ Connected together to form a 4-6 membered ring;
  • n 0, 1 or 2 and m + n ⁇ 1;
  • R 1 may be the same or different;
  • R 6 may be the same or different;
  • f 0, 1, 2, 3, and 4.
  • Ar 1 is a 6-10 membered aryl group, a 5-8 membered heteroaryl group, a 4-8 membered cycloalkyl group, or a 3-8 membered heterocyclic group.
  • Ar 1 is phenyl, 4-6 membered cycloalkyl, pyridine or pyrimidine.
  • Ar 1 is phenyl, R 1 is hydrogen, Ar 3 is H, and R 3 is hydrogen or chlorine.
  • Ar 2 is a 6-10 membered aryl group. In another preferred example, Ar 2 is phenyl.
  • Ar 3 is H.
  • the carbons to which Ar 1 and Ar 3 are attached together form a phenyl group.
  • R 1 , R 2 , and R 3 are each independently: H, fluorine, chlorine, bromine, C 1-4 alkyl, halogenated C 1-4 alkyl, CN, or C 1-4 alkane Oxygen.
  • R 1 , R 2 , and R 3 are each independently: H, fluorine, chlorine, bromine, C 1-4 alkyl, -CF 3 , -C 2 F 5 , -C 3 F 7 , C 1-4 alkoxy or CN.
  • n is 0, 1 or 2.
  • R 1 may be the same or different.
  • q is 0, 1, 2 or 3, and when p is 2 or 3, R 6 may be the same or different.
  • f is 0, 1, 2 or 3.
  • R 5 is H or mesyl (Ms, Mesyl, Methanesulfonyl).
  • R 6 is Cl. In another preferred example, R 6 is Cl and is located in the para position of N (R 5 ).
  • q is 1 or 2.
  • the compound is:
  • the pharmaceutically acceptable salt is selected from:
  • a salt formed with an inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid;
  • a pharmaceutical composition comprising the compound described in the first aspect, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof; and Pharmaceutically acceptable carrier.
  • the pharmaceutical composition further contains one or more drugs selected from the group consisting of imipramine, amitriptyline, dexipramine, nortriptyline, and doxepin , Protilin, Tramipramine, Maprotiline, Amoxapine, Trazodone, Bupropion, Chloripramine, Fluoxetine, Duloxetine, Etapram , Citalopram, sertraline, paroxetine, fluvoxamine, nafazodone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, Chlorbemide, Kava-Kava, St. John'sWort, s-adenosylmethionine, thyroid-stimulating hormone-releasing hormone, neurokinin receptor antagonists with antidepressant activity, and Triiodothyronine.
  • drugs selected from the group consisting of imipramine, amitrip
  • a third aspect of the present invention there is provided the use of the compound described in the first aspect, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof, for the preparation of prevention and / Or medications for mental disorders.
  • the compounds of the present invention prevent or treat depression, anxiety, and schizophrenia in mammals through the action of TREK-1.
  • a method for treating a mental disorder and administering to a patient in need the compound described in the first aspect, a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated substance Or a stereoisomer thereof.
  • Figure 1 shows the results of single-dose and behavioral tests performed 30 minutes after dosing: forced swimming (a) and open field test (b).
  • FIG. 2 is a graph showing the results of a forced swimming test performed 30 minutes after a single administration.
  • Figure 3 shows the results of behavioral tests performed continuously for 10-12 days and 24 hours after the last dose: a is the result of forced swimming experiment; b is the result of tail suspension experiment; c is the result of open field experiment.
  • Figure 4 shows the results of behavioral tests performed continuously for 10-11 days and 24 hours after the last dose: a is the result of forced swimming test; b is the test result of tail suspension experiment; c is the result of open field experiment.
  • Figure 5 shows the results of forced swimming experiments, where a, b, and c are single administration, continuous administration for 3 days, and continuous administration for 6 days, respectively, and the forced swimming test is performed 24 hours after the last administration.
  • the present inventors prepared a class of compounds having a structure represented by Formula I, and found that they have SIRT1 inhibitory activity.
  • the compound at a low concentration has an inhibitory effect on a series of SIRT1, and the inhibitory activity is quite excellent. Therefore, the compound can be used to treat diseases related to SIRT1 activity or expression, such as degenerative diseases, metabolic diseases, and tumors. Based on this, the present invention has been completed.
  • halogen in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.
  • a fluorine atom and a chlorine atom are preferred.
  • halo in the present invention means that any atom capable of being substituted in the group is replaced by halogen, and can be fully halogenated, that is, all positions where the halogen atom can be substituted in the group.
  • the “C 1-10 alkyl group” in the present invention means a linear or branched alkyl group containing 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like.
  • C 1-7 alkyl and C 1-3 alkyl
  • C 2-10 alkenyl group in the present invention refers to a straight or branched chain or cyclic alkenyl group having 2 to 10 carbon atoms containing double bonds, such as vinyl, 1-propenyl, 2-propene Base, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl 2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butene 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl 2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2- Propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl
  • C 2-10 alkynyl group in the present invention refers to a straight or branched chain alkynyl group having 2 to 10 carbon atoms containing a triple bond, such as ethynyl, 1-propynyl, 2-propynyl , 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl Alkynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl -3-pentynyl, 2-methyl-3-pentyn
  • the “C 1-6 alkoxy group” in the present invention refers to a group in which a “C 1-6 alkyl group” is connected to other structures through an oxygen atom, such as a methoxy group, an ethoxy group, a propoxy group, and a 1-methyl group.
  • C 1-6 alkylcarbonyl means a term “C 1-6 alkyl” group through a carbonyl group is connected to other structures, such as methylcarbonyl group, ethylcarbonyl group, propyl carbonyl group, an isopropyl group Carbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.
  • C 1-6 alkoxycarbonyl group in the present invention is a group in which the term “C 1-6 alkoxy group” is connected to other structures through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyl Oxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentoxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like.
  • a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyl Oxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentoxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like.
  • the "3-14-membered cycloalkyl group” in the present invention refers to a cyclic alkyl group derived from an alkane portion of 3-14 carbon atoms by removing one hydrogen atom, and includes a 3-8-membered monocyclic cycloalkyl group, 6-14 A membered cyclocycloalkyl group, a 7-12 member bridged ring group, and a 7-12 membered spiro group.
  • C 3-8 cycloalkyl, C 3-6 cycloalkyl and C 5-6 cycloalkyl are preferred.
  • the terms "C 3-8 cycloalkyl", “C 3-6 cycloalkyl", and "C 5-6 cycloalkyl” are respectively the following examples containing 3-8, 3-6, 5-6 Specific examples of carbon atoms.
  • 3-8 membered monocyclic cycloalkyl includes 3-8 membered saturated monocyclic cycloalkyl and 3-8 membered partially saturated monocyclic cycloalkyl.
  • a 3-8 membered saturated monocyclic cycloalkyl group means that the monocyclic ring is a fully saturated carbocyclic ring, and examples thereof include, but are not limited to, cyclopropylalkyl, cyclobutyl, cyclopentyl, cyclohexane, and cyclo Heptyl, cyclooctyl, methylcyclopropanyl, dimethylcyclopropanyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentane Methyl, methylcyclohexane, dimethylcyclohexane and the like.
  • a 3-8 member partially saturated monocyclic cycloalkyl group means that the monocyclic ring is a partially saturated carbocyclic ring.
  • Examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1 , 4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl, etc .;
  • C 3-8 cycloalkoxy group in the present invention refers to a group in which the term “C 3-8 cycloalkyl group” is connected to other structures through an oxygen atom, such as cyclopropoxy, cyclobutoxy, 1-methylcyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • the “6- to 14-membered aryl group” in the present invention refers to a cyclic aromatic group having 6 to 14-membered carbon atoms as a ring atom, and includes a 6 to 8-membered monocyclic aryl group and an 8 to 14-membered fused ring aryl group.
  • 6-8 membered monocyclic aryl refers to all unsaturated aryl groups, such as phenyl, cyclooctatetraenyl and the like.
  • An 8-14 membered fused ring aryl group is a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other. At least one ring is a completely unsaturated aromatic ring.
  • 8 to 14-membered unsaturated fused ring aryl, naphthyl, anthracenyl, and phenanthryl, etc. and 8 to 14-membered partially saturated fused ring aryl, such as benzo 3 to 8-membered saturated monocyclic cycloalkyl, Benzo 3-8 member partially saturated monocyclic cycloalkyl, specific examples are 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4 -Dihydronaphthyl and the like.
  • a 6-10 membered aryl group is preferred, and a benzene or benzo 3-8 membered saturated monocyclic cycloalkyl group and a benzo 3-8 member partially saturated monocyclic cycloalkyl group are more preferred.
  • the term "6- to 10-membered aryl group” refers to a specific example of the above-mentioned "aryl group” having 6 to 10 ring atoms.
  • the ring atoms include one or more heteroatoms
  • the "heteroatoms” include, but are not limited to, oxygen atoms, nitrogen atoms, and sulfur atoms.
  • Heteroaryl groups can be bonded via a carbon or heterocyclic atom. Includes 5-8 membered monocyclic heteroaryl and 8-14 member fused heterocyclic aryl.
  • 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, furyl, and thiophene Base, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl , 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazinyl, 1,2,4- Triazinyl, tetrazolyl, oxatriazolyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazine Azinyl,
  • the “3-14 membered heterocyclic group” in the present invention refers to a 3-14 membered cyclic group containing one or more heteroatoms, and the “heteroatom” means N, S, O, SO, and / or SO 2 etc. Includes saturated, partially saturated, unsaturated 3 to 8 membered single heterocyclic groups having 1-4 heteroatoms selected from N, S, O, SO and / or SO 2 and saturated, partially saturated, unsaturated 5 -14 membered double heterocyclyl. Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs.
  • the 5-14 membered bicyclic heterocyclic group includes saturated, partially saturated, unsaturated cyclic, spiro, and bridged rings having 1-4 heteroatoms selected from N, S, O, SO, and / or SO 2 .
  • a 3-8 membered heterocyclic group is preferred, and a saturated, partially saturated, unsaturated 3-8 membered monocyclic heterocyclic group is more preferred.
  • 5-8 membered, 5-7 membered, 5-6 membered heterocyclic groups are more preferred, and saturated, partially saturated, unsaturated 5-8 membered, 5-7 membered, and 5-6 membered heterocyclic groups are more preferred.
  • the "3-8 membered monocyclic heterocyclic group" in the present invention refers to a monocyclic group containing 3-8 ring atoms (including at least one heteroatom selected from N, S, O, SO and / or SO 2 ).
  • Ring heterocyclyl includes 3-8 membered unsaturated monoheterocyclyl, 3-8 member partially saturated monoheterocyclyl and 3-8 member saturated monoheterocyclyl.
  • 3-8-membered unsaturated monoheterocyclyl and 3-8-membered partially saturated monoheterocyclyl refer to 3-8-membered heterocyclic groups having unsaturated bonds in the ring, preferably 5-7-membered unsaturated monoheterocyclyl and 5- to 7-membered partially saturated monoheterocyclyl, specific examples include, but are not limited to, including, but not limited to, for example, the following groups: azacyclobutadiene, 1,2-diazacyclobutene, pyrrole, 4, 5-dihydropyrrole, 2,5-dihydropyrrole, imidazole, 4,5-dihydroimidazole, pyrazole, 4,5-dihydropyrazole, 1,2,3-triazole, 1,2,4 -Triazole, pyridine, 2-pyridone, 4-pyridone, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine,
  • pyrrole dihydropyrrole, imidazole, 4,5-dihydroimidazole, pyrazole, 4,5-dihydropyrazole, pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, 2,5-dihydro Thiophene, 2H-pyran, 2H-pyran-2-one, 3,4-dihydro-2H-pyran, 4H-pyran, 4H-pyran-4-one, 1,4-dioxane Hexadiene, 1,4-dithiacyclohexadiene, 1,4-oxothane hexadiene, oxazole, 4,5-dihydrooxazole, isoxazole, 4,5-dihydro Isoxazole, 2,3-dihydroisoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, thiazole
  • 3-8-membered heterocyclyl, 5-7-membered heterocyclyl, 5-6-membered heterocyclyl refers to 3-8-membered, 5-8-membered, 5 Specific examples of -7 yuan and 5-6 yuan.
  • the "3-8 yuan” in the present invention means 3,4,5,6,7,8 yuan, preferably 5-8 yuan. It is further preferably 5-7 yuan. Even more preferred is 5-6 yuan.
  • the "5-8 yuan” means 5,6,7,8 yuan, and the "5-7 yuan” means 5,5,7 yuan.
  • the "3-8 membered heterocyclic group" includes, but is not limited to, for example, aziridine, azetidine, 1,2-diazetidine, pyrrolidine, imidazolidine, pyridine Zolidine, hydrogenated pyridone, piperidine, piperazine, ethylene oxide, thietane, oxetane, 1,2-dioxetane, thietane, tetrahydrofuran, tetrahydro Thiophene, 1,3-dioxane, 1,3-dithiopentane, tetrahydropyran, 1,4-dioxane, 1,3-dioxane , 1,3-oxothane, oxazolidine, morpholine groups, etc .; among them, aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, hydrogenated pyridone, Piperidine, a
  • haloC 1-4 alkyl refers to the above-mentioned C 1-4 alkyl substituted with the same or different 1-6 of the above-mentioned halogen atoms, such as trifluoromethyl, pentafluoroethyl, or similar groups.
  • C 1-4 acyl refers to a linear or branched acyl group having 1-4 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, or similar groups.
  • aryl refers to a monocyclic to tricyclic aromatic hydrocarbon group, such as phenyl, naphthyl, or similar groups.
  • aralkyl refers to a C 1-6 alkyl substituted with the above-mentioned aryl.
  • aromatic heterocycle containing one to two oxygen or nitrogen refers to a furan ring, a pyridine ring, a pyrimidine ring, a pyrrole ring, a pyrazine ring, a pyridazine ring, a triazine ring, or a similar group.
  • C 3 -C 6 heterocycloalkyl refers to a pyrrole ring, a piperidine ring, a morpholine ring, a piperazine ring, or a similar group.
  • C 5 -C 12 aryl refers to benzyl, phenethyl, naphthyl methylene, or similar groups
  • the present invention also provides a pharmaceutical composition for treating or preventing a mental disorder, comprising: (a) a prophylactic or therapeutically effective amount of the active ingredient of the present invention represented by formula (I); and (b) a pharmaceutically acceptable Carrier, excipient or extended release.
  • the term "containing” means that various ingredients can be used together in the mixture or composition of the present invention. Accordingly, the terms “consisting essentially of” and “consisting of” are included in the term "containing”.
  • a "pharmaceutically acceptable” ingredient is a substance that is suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergies), that is, a reasonable benefit / risk ratio.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspension or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to an animal or human.
  • the carrier can be a liquid or a solid.
  • the pharmaceutical composition contains a safe and effective amount (such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, and more preferably 0.1-90 parts by weight) of the compound represented by the formula (I) Or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.
  • a safe and effective amount such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, and more preferably 0.1-90 parts by weight
  • a pharmaceutically acceptable carrier or excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition according to the present invention contains 0.001 to 99.9% by weight, more preferably 0.01 to 99% by weight, and more preferably 0.1 to 90% by weight of the compound represented by formula (I) or a pharmacological agent thereof.
  • the preferred ratio of the compound of formula (I) to the pharmaceutically acceptable carrier, excipient or slow-release agent is that formula (I) as the active ingredient accounts for more than 65% of the total weight, and the rest accounts for The total weight ratio is 0.5-40%, or more preferably 1-20%, or most preferably 1-10%.
  • the various preparation forms of the pharmaceutical composition of the present invention each contain a unit dose of 0.05 mg-500 mg, preferably 0.5 mg-200 mg, and more preferably 0.1 mg-100 mg of the compound of formula (I), an enantiomer, Racemates, pharmaceutically acceptable salts, or mixtures thereof. .
  • the amount of the active ingredient may generally be a conventional amount or lower in the prior art.
  • the pharmaceutical composition of the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent in.
  • the pharmaceutical composition of the present invention may also be stored in a suitable disinfection device for injection or drip infusion.
  • the pharmaceutical composition may further include an odorant, a fragrance, and the like.
  • the compound of the formula (I) or the pharmaceutical composition comprising the compound of the formula (I) of the present invention can be used clinically in mammals (including humans) through administration routes such as oral, nasal, skin, lung, or gastrointestinal tract.
  • the preferred route of administration is oral.
  • the preferred daily dose is 0.5 mg-200 mg / kg of body weight, taken once or in portions. Regardless of the method of administration, the optimal dosage for an individual should depend on the specific treatment. It usually starts with a small dose and gradually increases the dose until the most suitable dose is found.
  • the effective dose of the active ingredient used may vary with the compound used, the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention is administered at a daily dose of about 1 to 300 mg / kg of animal body weight, satisfactory results can be obtained, preferably at 1-3 divided doses per day, or in a sustained release form. Dosing. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg.
  • a dosage form suitable for oral administration contains about 1-200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide the best therapeutic response. For example, due to the urgent need to treat a condition, several divided doses may be given daily, or the dose may be proportionally reduced.
  • the compound or a pharmaceutically acceptable salt thereof and a composition thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously.
  • preferred pharmaceutical compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules. Oral administration of a pharmaceutical composition is preferred.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, and white clay
  • liquid carriers include: sterile water, polyethylene glycol, non-ionic surfactants, and edible oils (such as corn oil, Peanut oil and sesame oil), as long as it is suitable for the characteristics of the active ingredient and the particular mode of administration required.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also be advantageously included, for example, flavoring agents, pigments, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • the active compound or a pharmaceutically acceptable salt thereof and a composition thereof can also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds can also be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose.
  • Dispersions can also be prepared in glycerol, liquids, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the temporary preparation of sterile injection solutions or dispersions). In all cases, these forms must be sterile and must be fluid to facilitate the discharge of the fluid by the syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, alcohols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a composition thereof may also be administered in combination with other active ingredients or drugs for treating or preventing a mental disorder.
  • other active ingredients or drugs for treating or preventing a mental disorder.
  • two or more drugs are administered in combination, they generally have better effects than the two drugs administered separately.
  • the pharmaceutically acceptable salt of any of the above compounds of the present invention refers to a pharmaceutically acceptable salt, which includes (but is not limited to): (1) a salt formed with the following inorganic acid: such as hydrochloric acid, sulfuric acid, Nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, or arginine.
  • Other salts include salts with alkali or alkaline earth metals, such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates, or other conventional "prodrugs".
  • the compounds of the invention in free form can be converted to the corresponding compounds in the form of salts and vice versa.
  • Compounds of the invention in free or salt form and / or solvate form can be converted to corresponding compounds in free or salt form in unsolvated form; and vice versa.
  • solvate is used herein to describe a molecular complex comprising a compound of the present invention and a stoichiometric one or more pharmaceutically acceptable solvent molecules, such as ethanol.
  • solvent such as water
  • hydrate is used.
  • Prodrugs of the compounds according to the invention are also part of the invention.
  • “Prodrug” means that it can be converted to a compound of formula (I) in vivo by metabolic means (eg, by hydrolysis, reduction, or oxidation).
  • an ester prodrug of a compound of formula (I) can be converted into the parent molecule in vivo by hydrolysis.
  • Examples of ester prodrugs are those described in F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.
  • reference to a compound of formula (I) also includes prodrug forms.
  • the present invention relates to "stereoisomers" of compounds of formula (I).
  • the compounds of the present invention contain one or more asymmetric centers and can therefore be used as racemates and racemic mixtures, single enantiomers, diastereomers Enantiomeric mixtures and single diastereomers.
  • the compounds of the present invention have asymmetric centers. Such asymmetric centers each independently produce two optical isomers.
  • the scope of the present invention includes all possible optical isomers and diastereomeric mixtures and pure or partial Pure compounds.
  • the invention includes all stereoisomeric forms of these compounds.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention may exist as an optical isomer due to the presence of asymmetric carbon atoms.
  • the present invention also includes these optical isomers and mixtures thereof.
  • the structures described herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometrically isomeric (or conformational)) forms of the structures; for example, R and S configuration, Z and E double bond isomers, and Z and E conformation isomers.
  • isomeric e.g., enantiomeric, diastereomeric, and geometrically isomeric (or conformational)
  • Z and E double bond isomers e.g., enantiomeric, diastereomeric, and geometrically isomeric (or conformational)
  • single stereochemical isomers of compounds of the invention and mixtures of enantiomers, diastereomers and geometric isomers (or conformers) are within the scope of the invention.
  • all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the present invention relates to "deuterates" of compounds of formula (I).
  • the compounds of the present invention also include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the structure of the present invention but including the replacement of hydrogen with deuterium or tritium or the replacement of carbon with enriched or carbon are within the scope of the present invention.
  • Such compounds can be used, for example, as analytical tools, probes in biological analysis, or therapeutic agents of the invention.
  • one or more deuterium atoms are included in formula (I).
  • the compounds of the invention have one or more chiral centers.
  • the racemate is obtained synthetically, and the required enantiomerically pure compound can be obtained by chiral resolution: it can be obtained by chromatography with a chiral stationary phase (such as high-pressure preparation liquid phase, supercritical fluid chromatography).
  • Chiral fillers include but are not limited to: Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
  • the compound according to the present invention a pharmaceutically acceptable salt thereof, a prodrug thereof, a solvate thereof, a deuterated substance or a stereoisomer thereof is used for preventing or treating mammals to treat depression, anxiety and depression through the action of TREK-1. And medicine for infectious diseases such as schizophrenia.
  • the present invention further claims a pharmaceutical composition containing any one of the compounds described above, a pharmaceutically acceptable salt thereof, a deuterated product thereof, or a stereoisomer thereof, the composition further comprising one selected from the group consisting of Or multiple drugs: imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protiline, tramipamine, maprotiline, amozapine, trazozole Ketone, bupropion, chlomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nafazodone, Venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, Kava-Kava, St. John's Wort ), S-adenosylmethionine, thyroid-stimulating hormone-releasing hormone, a neuro
  • the compound of the present invention has the following advantages:
  • aniline compounds of the present invention have good inhibitory activity of TREK-1;
  • the aniline compound of the present invention is safe and effective for oral administration.
  • the compound of the present invention has low toxicity and side effects, and a large safety window;
  • the compound of the present invention has a simple preparation process, good physical and chemical properties, stable quality, and is easy for large-scale industrial production.
  • Wild-type (WT) cDNAs of human TREK-1, TREK-2, and TRAAK were subcloned into the pEGFPN1 expression vector, respectively.
  • WT Wild-type cDNAs of human TREK-1, TREK-2, and TRAAK
  • PCR technology and QuickChange XL site-directed mutagenesis kit mutations were introduced into TREK-1 and TRAAK channels, followed by DNA sequencing technology for confirmation.
  • the conditions for cell culture were DMEM / F12 cell culture medium, 10% FBS, 100 ⁇ g / ml penicillin-streptomycin, 5% CO 2 , and the temperature was maintained at 37 ° C.
  • the cells detected in the experiment were cells cultured for 36-96 hours after transfection. Electrophysiological experiments use a whole-cell patch-clamp model.
  • the amplifier model of the experimental recording instrument is Axopatch-200B, and the microscope operating system brand is Olympus. Before the experiment, the electrode was drawn with a Flaming / Brown type micropipette puller electrode puller, and the drawn electrode was polished to obtain a high-impedance seal when performing a whole-cell experiment.
  • the electrode water resistance for whole-cell patch-clamp recording mode is 4-7M ⁇ .
  • Intracellular fluid components mainly include: 140mM KCl, 2mM MgCl2, 10mM EGTA, 1mM CaCl2, 10mM HEPES, and the pH was adjusted to 7.3 with KOH.
  • the extracellular fluid components mainly include: 150mM NaCl, 5mM KCl, 0.5mM CaCl2, 1.2mM MgCl2, 10mM HEPES, and the pH was adjusted to 7.3 with NaOH.
  • the current signal collected in the experiment was filtered using a low-frequency filter with a frequency of 1 kHz.
  • the data is sampled using DigiData 1440A, and the sampling frequency is 10kHz.
  • the statistical analysis and mapping of the data were performed using the software origin 6.0.
  • test compounds of the present invention have good inhibitory activity on TREK-1.
  • the compound of the present invention has good clinical application potential in the therapeutic field related to TREK-1.
  • the experimental animals were 6-week-old C57 mice, male, and C57 mice were purchased from Shanghai Slack Experimental Animal Co., Ltd., weighing 20.45 ⁇ 0.19g. Arrived at the Animal Breeding Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences before the experiment (animal production license: SCXK9 [Shanghai] 2004-0002, use license: SYXK [Shanghai] 2003-0029), and adapted to animal facilities for more than 3 days Only / cage rearing. The rearing environment is 23 ⁇ 0.2 °C at room temperature, and day / night light and dark alternate between 12/12 hours. Before the behavioral test, the animals were moved to the behavioral test operation room 2 hours in advance to adapt to the environment and reduce their tension.
  • test group and test time are shown in Table 2 below.
  • test product freshly prepared before each experiment: Weigh appropriate powders of Example 1, Example 65 before weighing, and accurately weigh 12 mg of each compound, and add 40 ⁇ l of absolute ethanol to each tube to make It was fully dissolved, and then added 50 ⁇ l of tween 80 and mixed, and then made up to 3 ml with 0.9% NaCl, and prepared into a 4 mg / ml solution for use. Similarly, accurately weigh 3 mg of fluoxetine in 3 ml 0.9% NaCl and set aside.
  • mice Before the test, the mice must acclimatize in the operation room for more than 2 hours.
  • mice Weigh the mice before acclimation, and mark the tails.
  • mice Twenty-four hours before the administration, the mice were placed in a cylindrical tank to adapt to the water environment for 10 minutes. On the day of the behavior test, the animals were administered once, and they were administered by gavage 30 minutes before the behavior test. The mice were placed in a cylindrical glass tank with a height of 30 cm and a diameter of 20 cm. The water depth in the tank was 15 cm, so that the animals could not escape the glass tank, and their feet and tails did not touch the bottom of the tank. The water temperature was 23 ° C. -25 ° C. Take a 6-minute video of the mouse after entering the water.
  • Open field test (also called open box test) is a method to evaluate the autonomous behavior, inquiry behavior and anxiety-like behavior of experimental animals in a new environment.
  • the frequency and duration of behaviors such as environment and exploration of new environments reflect the autonomous and inquiry behaviors of experimental animals in unfamiliar environments.
  • Analysis of the results of animal open field experiments can be used to assess depression and anxiety-like behaviors in animals.
  • mice 2 hours before the experiment, place the experimental animals in the behavior room to acclimate. During the experiment, the animals were placed in the center of the bottom surface of a black plastic box (size 100 * 100 * 45cm), and video shooting was performed at the same time. The experiment time was 10 minutes and it was guaranteed to be performed in a quiet environment. Wipe the bottom and inner walls of the open box after each experiment to prevent interference from the remaining information of the previous animal on the next experiment. Using the animal spontaneous activity analysis software to analyze the video, the animal's central area activity time (anxiety-like behavior), total activity distance (exercise ability), wall climbing times (new different environment exploration behavior) and other information can be used to depression the animal Or anxiety-like behavior and extent.
  • the experimental animals were 6-week-old C57 mice, male, and C57 mice were purchased from Shanghai Slack Experimental Animal Co., Ltd., weighing 20.45 ⁇ 0.19g. Arrived at the Animal Breeding Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences before the experiment (animal production license: SCXK9 [Shanghai] 2004-0002, use license: SYXK [Shanghai] 2003-0029), and adapted to animal facilities for more than 3 days Only / cage rearing. The rearing environment is 23 ⁇ 0.2 °C at room temperature, and day / night light and dark alternate between 12/12 hours. Before the behavioral test, the animals were moved to the behavioral test operation room 2 hours in advance to adapt to the environment and reduce their tension.
  • test group and test time are shown in Table 3 below.
  • test products freshly prepared before each experiment: Weigh appropriate amounts of Example 1, Example 65 before weighing, and accurately weigh each compound 3mg, 6mg, and 12mg, and add 60 ⁇ l each Water ethanol was used to fully dissolve it, and after adding 40 ⁇ lween 80 to mix it, the volume was adjusted to 3 ml with 0.9% NaCl, and a 4 mg / ml solution was prepared for use. Similarly, accurately weigh 3 mg of fluoxetine in 3 ml 0.9% NaCl and set aside.
  • mice Before the test, the mice must acclimatize in the operation room for more than 2 hours.
  • mice Weigh the mice before acclimation, and mark the tails.
  • mice Twenty-four hours before the administration, the mice were placed in a cylindrical tank to adapt to the water environment for 10 minutes. On the day of the behavioral test, the animals were administered once, and were administered by gavage 1h and 24h before the behavioral test, respectively. The mice were placed in a cylindrical glass tank with a height of 30 cm and a diameter of 20 cm. The water depth in the tank was 15 cm, so that the animals could not escape the glass tank, and their feet and tails did not touch the bottom of the tank. The water temperature was 23 ° C. -25 ° C. Take a 6-minute video of the mouse after entering the water.
  • the experimental animals were 6-week-old C57 mice, male, and C57 mice were purchased from Shanghai Slack Experimental Animal Co., Ltd., weighing 20.45 ⁇ 0.19g. Arrived at the Animal Breeding Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences before the experiment (animal production license: SCXK9 [Shanghai] 2004-0002, use license: SYXK [Shanghai] 2003-0029), and adapted to animal facilities for more than 3 days Only / cage rearing. The rearing environment is 23 ⁇ 0.2 °C at room temperature, and day / night light and dark alternate between 12/12 hours. Before the behavioral test, the animals were moved to the behavioral test operation room 2 hours in advance to adapt to the environment and reduce their tension.
  • test group and test time are shown in Table 4 below.
  • Dosing frequency is 1 time / day
  • test product freshly prepared before each experiment: Weigh an appropriate amount of the powder of Example 65 before weighing, and accurately weigh the compounds 3mg, 9mg, and 12mg, and add 60 ⁇ l DMSO to each tube to fully dissolve, and then add After 40 ⁇ ltween80 was mixed, the volume was adjusted to 3ml with 1% CMC-Na, and the solutions were prepared into 1mg / ml, 3mg / ml and 4mg / ml, and set aside. Similarly, 3 mg of fluoxetine was accurately weighed into 3 ml of 1% CMC-Na until use.
  • the animals were randomly divided into 5 groups of 10 animals each.
  • the way of administration for each group of animals is shown in the table.
  • mice Before the test, the mice must acclimatize in the operation room for more than 2 hours. The mice were weighed before acclimation and marked at the tail. Forced swimming and open field tests were performed 10 days after continuous dosing and 24 hours after dosing. The tail suspension experiment was performed 12 days after continuous administration and 24 hours after administration (as shown in Table 4 above).
  • mice Twenty-four hours before the administration, the mice were placed in a cylindrical tank to adapt to the water environment for 10 minutes. Animals were dosed continuously for 10 days and forced swimming tests were performed 24 h after the last dose. The mice were individually placed in a cylindrical glass tank with a height of 30 cm and a diameter of 20 cm. The water depth in the tank was 15 cm, so that the animals could not escape the glass tank, and their feet and tails did not touch the bottom of the tank. -25 ° C. Take a 6-minute video of the mouse after entering the water. Since most animals are very active in the first two minutes, the 4 minute immobility time is calculated (determination of immobility: the mouse stops struggling in the water, does not move, and maintains balance or appears Floating limb movements). Mice of each group were operated in parallel.
  • TST Tail Suspension Test
  • mice were placed in the behavior room for adaptation. Animals were administered 12 times in a row, and tail suspension experiments were performed 24 hours after the last administration. During the experiment, the tail of the mouse was taped or clamped about 1 cm away from the end and suspended on a hanging tail test rack about 15 cm from the ground. The rats struggled to overcome the abnormal posture, but after a period of activity, they showed intermittent movements, showing disappointment. The experimental time in each group was 6 minutes. Since most of the mice struggled frequently with excitement in the first two minutes, the immobility time in the next 4 minutes was counted.
  • Open field test (also called open box test) is a method to evaluate the autonomic behavior, inquiry behavior and anxiety-like behavior of experimental animals in a new environment.
  • the frequency and duration of the behaviors of experimental animals in the open box, the fear of the open environment and the exploration of new environments, etc. are used to reflect the experimental and autonomous behavior of experimental animals in unfamiliar environments. Analysis of the results of animal open field experiments can be used to assess depression and anxiety-like behaviors in animals.
  • mice 2 hours before the experiment, place the experimental animals in the behavior room to acclimate. Animals were dosed continuously for 11 days, and open field testing was performed 24 h after the last dose. During the experiment, the animals were placed in the center of the bottom surface of a black plastic box (size 100 * 100 * 45cm), and video shooting was performed at the same time. The experiment time was 10 minutes and it was guaranteed to be performed in a quiet environment. Wipe the bottom and inner walls of the open box after each experiment to prevent interference from the remaining information of the previous animal on the next experiment.
  • the animal spontaneous activity analysis software to analyze the video, the animal's central area activity time (anxiety-like behavior), total activity distance (exercise ability), wall climbing times (new different environment exploration behavior) and other information can be used to depression the animal Or anxiety-like behavior and extent. All data analysis was done using SPSS 22 (for Mac) data processing software. A one-way analysis of variance was used, and the post-hoc LSD method was used to compare and verify the results. Data are expressed as Mean ⁇ sem. One asterisk is marked when p ⁇ 0.05; two asterisks are marked when p ⁇ 0.01; three asterisks are marked when p ⁇ 0.001.
  • Example 65 significantly reduced the immobility time of forced swimming, and the dose-effect relationship was not obvious (a in Figure 3).
  • tail suspension experiments show (b in FIG. 3) that when the dosages are 20 mg / kg and 40 mg / kg, Example 65 significantly reduces the immobility time of the tail suspension of the mice, which also shows a certain amount of effect relationship.
  • Open field experiments (c in FIG. 3) show that Example 65 has no effect on the exercise ability of mice, and the drug is obviously not effective for animals. The results suggest that compared with the clinical first-line antidepressant fluoxetine, Example 65 has a faster onset (onset of 10 days).
  • the experimental animals were 6-week-old C57 mice, male, and C57 mice were purchased from Shanghai Slack Experimental Animal Co., Ltd., weighing 20.45 ⁇ 0.19g. Arrive at the Animal Breeding Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences before the experiment (animal production license: SCXK9 [Shanghai] 2004002, use license: SYXK [ ⁇ ] 2003-0029), and adapt to animal facilities for more than 3 days, 6 animals / Cage rearing.
  • the rearing environment is 23 ⁇ 0.2 °C at room temperature, and day / night light and dark alternate between 12/12 hours. Before the behavioral test, the animals were moved to the behavioral test operation room 2 hours in advance to adapt to the environment and reduce their tension.
  • test group and test time are shown in Table 5.
  • Dosing frequency is 1 time / day
  • test products freshly prepared before each experiment: Weigh the appropriate amount of Example 33 powder before weighing, and accurately weigh the compounds 0.3mg, 0.9mg and 3mg, and add 60 ⁇ l of absolute ethanol to each tube to make it full. Dissolve, add 40 ⁇ ltween 80, mix well, make up to 3ml with 0.9% NaCl, and prepare solutions of 1mg / ml, 3mg / ml and 10mg / ml. Similarly, accurately weigh 3 mg of fluoxetine in 3 ml 0.9% NaCl and set aside.
  • the animals were randomly divided into 5 groups of 10 animals each.
  • the mode of administration for each group of animals is as indicated.
  • mice Before the test, the mice must acclimatize in the operation room for more than 2 hours. The mice were weighed before acclimation and marked at the tail. The forced swimming test was performed 24 hours after a single administration, 3 administrations, 6 administrations, and 10 administrations. The tail suspension and open field experiments were performed 24 h after the 11 doses (as shown in Table 5 above).
  • mice Twenty-four hours before the administration, the mice were placed in a cylindrical tank to adapt to the water environment for 10 minutes. On the day of the behavior test, the animals were administered once, and they were administered intraperitoneally 1 h and 24 h before the behavior test. The mice were individually placed in a cylindrical glass tank with a height of 30 cm and a diameter of 20 cm. The water depth in the tank was 15 cm, so that the animals could not escape the glass tank, and their feet and tails did not touch the bottom of the tank. The water temperature was 23 ° C. -25 ° C. Take a 6-minute video of the mouse after entering the water.
  • TST Tail Suspension Test
  • mice were placed in the behavior room for adaptation. The experiment was performed 1 hour after the last administration. During the experiment, the tail of the mouse was taped or clamped about 1 cm away from the end and suspended on a hanging tail test rack about 15 cm from the ground. The mouse struggled to overcome the abnormal posture. However, after a period of activity, there was intermittent motion, showing disappointment. The experimental time of each group was 6 minutes. Since most of the mice struggled frequently with excitement in the first two minutes, the immobility time in the next 4 minutes was counted.
  • Open field test (also called open box test) is a method to evaluate the autonomic behavior, inquiry behavior and anxiety-like behavior of experimental animals in a new environment.
  • the frequency and duration of the behaviors of experimental animals in the open box, the fear of the open environment and the exploration of new environments, etc. are used to reflect the experimental and autonomous behavior of experimental animals in unfamiliar environments. Analysis of the results of animal open field experiments can be used to assess depression and anxiety-like behaviors in animals.
  • mice 2 hours before the experiment, place the experimental animals in the behavior room to acclimate. During the experiment, the animals were placed in the center of the bottom surface of a black plastic box (size 100 * 100 * 45cm), and video shooting was performed at the same time. The experiment time was 10 minutes and it was guaranteed to be performed in a quiet environment. Wipe the bottom and inner walls of the open box after each experiment to prevent interference from the remaining information of the previous animal on the next experiment. Using the animal spontaneous activity analysis software to analyze the video, the animal's central area activity time (anxiety-like behavior), total activity distance (exercise ability), wall climbing times (new different environment exploration behavior) and other information can be used to depression the animal Or anxiety-like behavior and extent.
  • Example 33 was significant at the doses of 1 mg / kg and 10 mg / kg. Reduce the immobility time of forced swimming, the dose-response relationship is not obvious (a in Figure 4); tail suspension experiments show (b in Figure 4), when the doses are 3mg / kg and 10mg / kg, Example 33 is significantly reduced The immobility time of the tail suspension of the mouse showed a certain amount of effect relationship (see Figure 4). Open field experiments (c in Fig. 4) showed that Example 33 had no effect on the exercise ability of the mice, and the drug had no obvious effect on the animals. The results suggest that compared with the clinical first-line antidepressant fluoxetine, Example 33 has a fast onset (10 days onset) and a low onset dose (see Figures 4 and 5).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明公开了作为防治精神障碍疾病的苯胺类化合物，该类化合物的结构如式I所示，各取代基的定义如说明书和权利要求书所述。本发明还公开了含有该类化合物的药物组合物。本发明的化合物，具有较好的TREK-1的抑制活性，能够用于制备预防和/或治疗精神障碍疾病的药物。

Description

作为防治精神障碍疾病的苯胺类化合物 技术领域
本发明属于医药技术领域，涉及作为防治精神障碍疾病的苯胺类化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体，本发明还涉及所述化合物的制备方法，含有所述化合物的药物组合物和药物制剂，以及所述化合物在用于预防或治疗哺乳动物治疗抑郁症、抑郁焦虑和精神分裂症等精神障碍疾病的药物中的应用。
背景技术
抑郁症是一种常见的精神疾病，抑郁症患者的常见表现为心情郁闷、丧失兴趣或享受感、产生负罪感或自尊心不足、睡眠和食欲紊乱、身体疲倦、注意力不易集中。抑郁症可能长期存在或经常复发，从而严重影响个人的日常生活。当疾病最为严重时，患者甚至有自杀的倾向。抑郁症已成为严重影响人类健康的疾病之一。当前全球估计有3.5亿抑郁症患者，每年逾80万人因抑郁症自杀而死亡，中国的抑郁症患者约有9000万，每年有20多万人因抑郁症而自杀，预计到2020年抑郁症可能成为仅次于心血管疾病的第二大疾病。抑郁症的治疗方法包括药物治疗、心理治疗以及物理治疗等。70％的抑郁症患者经过抗抑郁药物治疗后都可缓解症状，因而高效安全的抗抑郁药物将会成为药物研发的新热点。
抑郁症的发病机制非常复杂，与遗传、环境、社会等各种因素密切相关。当前有关抑郁症的发病机制的主流的假说包括单胺神经递质假说、神经可塑性和神经营养失衡学说，其中单胺神经递质假说是目前临床一线抗抑郁药物的研发理论依据。单胺神经递质假说认为抑郁症是因为病人的脑内缺少5-羟色胺，去甲肾上腺素等单胺类神经递质。单胺类神经递质在神经突触间隙中主要通过两个途径发生减少。一条途径为通过突触前膜的重吸收，因此阻断重吸收过程可以提高神经突触间隙中单胺类神经递质的浓度。目前已上市的抗抑郁药物中基于该机制研发的药物有选择性五羟色胺再摄取抑制药(氟西汀、帕罗西汀、舍曲林等)、三环类抗抑郁药(丙咪嗪、阿米替林，氯丙咪嗪等)、去甲肾上腺素再摄取抑制剂(瑞博西汀、马普替林、米安色林等)。另一条途径为通过脑中的单胺氧化酶降解。1957年，Kline用单胺氧化酶抑制剂用于治疗抑郁症取得了明显的疗效。当前用于临床的单胺氧化酶抑制剂药物有环苯丙胺、苯乙肼和异卡波肼等少数几种。虽然在过去的几十年中抗抑郁药物的研发以及临床的应用有了较大发展，但是由于这些药物会不同程度的影响突触后膜上的受体的功能，从而表现出明显的毒副作用以及起效慢等缺陷。尤其是当前的抗抑郁药物因起效慢，无法满足临床上对抑郁症病人及时和迅速治疗的需要，因此研发新型抗抑郁药物迫在眉睫。
TREK-1通道属于双孔钾离子通道(K2P)。TREK-1通道在人的海马、皮质、杏仁核等脑区大量存在，与单胺神经递质系统高度相关。抗抑郁动物模型和基因敲除研究表明抑制TREK-1通道可以治疗抑郁，TREK-1通道已成为新型抗抑郁药物设计的重要靶标。
发明内容
本发明的目的在于提供一种具有TREK-1抑制活性的苯胺化合物，用于预防和治疗抑郁症、抑郁焦虑和精神分裂症等精神障碍疾病。
本发明的另一目的在于提供包含所述苯胺类化合物的药物组合物、保健品组合物或食品组合物。
本发明的另一目的在于提供苯胺类化合物的制备方法。
本发明的另一目的在于提供预防或治疗精神障碍疾病的方法。
本发明的第一方面，提供一种式I所示化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体：
Figure PCTCN2018121562-appb-000001
Ar 2为6-14元芳基、5-14元杂芳基、3-14元环烷基或3-14元杂环基；
Ar 1为6-14元芳基、5-14元杂芳基、3-14元环烷基或3-14元杂环基；
Ar 3为氢、卤素、C1-C4烷基、C1-C4烷氧基、氰基、卤代C1-C4烷基或3-6元环烷基；
或者Ar 1与Ar 3相连的碳共同形成6-14元芳基；
R 1、R 2、R 3各自独立选自下组：H、被1-3个Q1取代或未取代的C 1-10烷基、被1-3个Q1取代或未取代的C 2-10烯基、被1-3个Q1取代或未取代的C 2-10炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN、被1-3个Q1取代或未取代的3-8元杂环烷基；
R 4为H、＝O、C 1-10烷基、或C 1-10烷氧基；
R 5为H、被1-3个Q1取代或未取代的C 1-10烷基、被1-3个Q1取代或未取代的C 2-10链烯基、被1-3个Q1取代或未取代的C 2-10链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
R 6为H、被1-3个Q1取代或未取代的C 1-10烷基、被1-3个Q1取代或未取代的C 2-10链烯基、被1-3个Q1取代或未取代的C 2-10链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
其中各Q1独立地选自下组：C1-C8烷基、卤素、C3-C6环烷基、C3-C6环烷基C1-C6烷基、-COOR′，-NR′R″，-OR′，-COR′，-CONR′R″，＝O，-SR′，C1-C4卤代烷基、氨基、巯 基、氰基、硝基、羟基、三氟甲基、三氟甲氧基、被1-3个Q2取代或未取代的：含一个至两个氧或者氮的芳香杂环、含一个至两个氧或者氮的杂芳基(C1-C6)烷基、含一个至两个氧或者氮的(C6-C12)稠合杂环基(C1-C6)烷基、C5-C12芳基(C1-C6)烷基、苯氧基、苄氧羰基，其中各Q2独立选自：卤素、氧代、C1-C8烷基、C1-C4烷氧基、C1-C4卤代烷基、氨基、巯基、氰基、硝基、羟基、三氟甲基、三氟甲氧基、被1-3个Q3取代或未取代的苯基或苯氧基，其中各Q3独立选自：卤素、C1-C4卤代烷基、氨基、巯基、氰基、羟基、三氟甲基、三氟甲氧基，
其中，各R′，各R″独立地选自：H，被1-3个Q4取代或未取代的苯基，被1-3个Q4取代或未取代的苄基，被1-3个Q4取代或未取代的C1-10烷基，被1-3个Q4取代或未取代的C2-10链烯基，被1-3个Q4取代或未取代的C2-10链炔基；或者，基团R′和R″连接在一起形成4-7元环，其中各Q4独立选自：卤素、C1-C4卤代烷基、C1-C4卤代烷氧基、C1-C4烷基、C1-C4烷氧基、羧基、＝O、氨基、-NO 2或-CN；
m为0、1或2；n为0、1或2，且m+n≥1；
p为0、1、2、3、4或5，当p为2、3、4或5时，R 1可相同或不同；
q为0、1、2、3、4或5，当q为2、3、4或5时，R 6可相同或不同；
f为0、1、2、3或4。
在另一优选例中，f为1、2或3。
在另一优选例中，式I所示化合物具有通式(II)所示的结构：
Figure PCTCN2018121562-appb-000002
R 1、R 2、R 3、R 5、R 6、p、q的定义如前所述。
在另一优选例中，式I所示化合物具有通式(III)所示的结构：
Figure PCTCN2018121562-appb-000003
其中，R 1、R 2、R 3、p的定义如前所述。
在另一优选例中，式I所示化合物具有通式(IV)所示的结构：
Figure PCTCN2018121562-appb-000004
其中，R 1、R 2、R 3、R 5、R 6、p、q的定义如前所述。
在另一优选例中，式I所示化合物具有通式(V)所示的结构：
Figure PCTCN2018121562-appb-000005
其中，R 1、R 2、R 3、p的定义如前所述。
在另一优选例中，Ar 2为6-10元芳基、5-8元杂芳基、3-8元环烷基或3-8元杂环基；
Ar 1为6-10元芳基、5-8元杂芳基、3-8元环烷基或3-8元杂环基；
Ar 3为氢、卤素、C1-C4烷基、C1-C4烷氧基、氰基、卤代C1-C4烷基或3-6元环烷基；
或者Ar 1与Ar 3相连的碳共同形成苯基；
R 1、R 2、R 3各自独立为：H、氟、氯、溴、被1-3个Q1取代或未取代的C 1-4烷基、被1-3个Q1取代或未取代的C 2-6链烯基、被1-3个Q1取代或未取代的C 2-6链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN、被1-3个Q1取代或未取代的3-8元杂环烷基；
R 4为H、＝O、C 1-4烷基、或C 1-4烷氧基；
R 5为H、被1-3个Q1取代或未取代的C 1-4烷基、被1-3个Q1取代或未取代的C 2-4链烯基、被1-3个Q1取代或未取代的C 2-4链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
R 6为H、被1-3个Q1取代或未取代的C 1-4烷基、被1-3个Q1取代或未取代的C 2-4链烯基、被1-3个Q1取代或未取代的C 2-4链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
其中各Q1独立地选自下组：C1-C8烷基、卤素、C3-C6环烷基、C3-C6环烷基C1-C6烷基、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、C1-C4卤代烷基、氨基、巯基、氰基、硝基、羟基、三氟甲基、三氟甲氧基；
其中，各R′，各R″独立地选自：H、苯基、苄基、C1-4烷基、C2-4链烯基、C2-4链炔基；或者基团R′和R″连接在一起形成4-6元环；
m为0、1或2；n为0、1或2，且m+n≥1；
p为0、1、2、3、4或5，当p为2、3、4或5时，R 1可相同或不同；
q为0、1、2、3、4或5，当q为2、3、4或5时，R 6可相同或不同；
f为0、1、2、3、4。
在另一优选例中，Ar 1为6-10元芳基、5-8元杂芳基、4-8元环烷基或3-8元杂环基。在另一优选例中，Ar 1为苯基、4-6元环烷基、吡啶或嘧啶。在另一优选例中，Ar 1为苯基，R 1为氢，Ar 3为H，R 3为氢或氯。
在另一优选例中，Ar 2为6-10元芳基。在另一优选例中，Ar 2为苯基。
在另一优选例中，Ar 3为H。
在另一优选例中，Ar 1与Ar 3相连的碳共同形成苯基。
在另一优选例中，R 1、R 2、R 3各自独立为：H、氟、氯、溴、C 1-4烷基、卤代C 1-4烷基、CN或C 1-4烷氧基。在另一优选例中，R 1、R 2、R 3各自独立为：H、氟、氯、溴、C 1-4烷基、-CF 3、-C 2F 5、-C 3F 7、C 1-4烷氧基或CN。
在另一优选例中，R 4为H或＝O。
在另一优选例中，R 5为H、C 1-4烷基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3或-CN；其中各R′，各R″独立地选自：H、苯基、苄基、C1-4烷基、C2-4链烯基、C2-4链炔基。
在另一优选例中，R 6为H、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3或-CN；其中各R′，各R″独立地选自：H、苯基、苄基、C1-4烷基、C2-4链烯基、C2-4链炔基。
在另一优选例中，m为1或2。在另一优选例中，n为0、1或2。
在另一优选例中，p为0、1、2或3，当p为2或3时，R 1可相同或不同。
在另一优选例中，q为0、1、2或3，当p为2或3时，R 6可相同或不同。
在另一优选例中，f为0、1、2或3。
在另一优选例中，R 4为H或＝O。在另一优选例中，R 5为H或甲磺酰基(Ms,Mesyl,Methanesulfonyl)。
在另一优选例中，R 6为Cl。在另一优选例中，R 6为Cl，位于N(R 5)的对位。
在另一优选例中，q为1或2。
在另一优选例中，所述化合物为：
Figure PCTCN2018121562-appb-000006
Figure PCTCN2018121562-appb-000007
Figure PCTCN2018121562-appb-000008
Figure PCTCN2018121562-appb-000009
Figure PCTCN2018121562-appb-000010
Figure PCTCN2018121562-appb-000011
Figure PCTCN2018121562-appb-000012
Figure PCTCN2018121562-appb-000013
在另一优选例中，所述药学上可接受的盐选自：
(1)与无机酸形成的盐：无机酸选自盐酸、硫酸、硝酸、磷酸；
(2)与有机酸形成的盐，有机酸选自乙酸、草酸、丁二酸、酒石酸、甲磺酸、马来酸或精氨酸；
(3)与碱金属或碱土金属形成的盐。
本发明的第二方面，提供一种药物组合物，含有第一方面所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体；和药学上可接受的载体。
在另一优选例中，所述的药物组合物中还含有选自以下的一种或多种的药物：丙米嗪、阿米替林、地昔帕明、去甲替林、多塞平、普罗替林、曲米帕明、马普替林、阿莫沙平、曲唑酮、丁氨苯丙酮、氯米帕明(chlomipramine)、氟西汀，度洛西汀，依他普仑，西酞普兰、舍曲林、帕罗西汀、氟伏沙明、萘法唑酮、文拉法辛、米那普仑、瑞波西汀、米氮平、苯乙肼、反苯环丙胺、吗氯贝胺、卡瓦胡椒(Kava-Kava)、圣约翰草(St.John’sWort)、s-腺苷蛋氨酸、促甲状腺激素释放激素、具有抗抑郁剂活性的神经激肽受体拮抗剂和三碘甲腺原氨酸。
本发明的第三方面，提供第一方面所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体的用途，用于制备预防和/或治疗精神障碍疾病的药物。
在另一优选例中，本发明的化合物通过TREK-1作用预防或治疗哺乳动物抑郁症、抑郁焦虑和精神分裂症等疾病。
本发明的第四方面，提供一种治疗精神障碍疾病的方法，向有需要的患者给予第一方面所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一赘述。
附图说明
图1为单次给药，且在给药后的30min进行行为测试的结果图：强迫游泳(a)和旷场实验测试(b)。
图2为单次给药，且在给药后的30min进行强迫游泳测试结果图。
图3为连续给药10-12天，且在末次给药后的24h进行行为学测试的结果图：a为强迫游泳实验结果；b为悬尾实验结果；c为旷场实验结果。
图4为连续给药10-11天，且在末次给药后的24h进行行为学检测的结果图：a为强迫游泳实验结果；b为悬尾实验测试结果；c为旷场实验结果。
图5为强迫游泳实验结果图，其中a、b、c分别为单次给药、连续给药3天以及连续给药6天，且在末次给药后的24h进行强迫游泳测试。
具体实施方式
本发明人基于长期而深入的研究，制备了一类具有式I所示结构的化合物，并发现其具有SIRT1抑制活性。且所述的化合物在低浓度下，即对一系列SIRT1产生抑制作用，抑制活性相当优异，因而可以用于治疗与SIRT1活性或表达量相关的疾病如经退行性疾病、代谢疾病、肿瘤。在此基础上，完成了本发明。
术语说明
本发明所述“卤素”是指氟原子、氯原子、溴原子、碘原子等。优选氟原子和氯原子。
本发明所述“卤代”是指所述基团中任意一个能被取代的原子被卤素所取代，可全卤代，即卤素原子取代基团中所有能被取代的位置。
本发明所述“C 1-10烷基”表示直链或支链的含有1-10个碳原子的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。优选C 1-7烷基、C 1-3烷基。本发明所述“C 1-3烷基”指含有1-3个碳原子上述实施例。
本发明所述“C 2-10烯基”是指含有双键的碳原子数为2-10的直链或支链或环状的烯基，如乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-甲基-1-丙烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、2-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、1-甲基-2-丁烯基、2-甲基-2-丁烯基、3-甲基-2-丁烯基、1-甲基-3-丁烯基、2-甲基-3-丁烯基、3-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1,2-二甲基-1-丙烯基、1,2-二甲基-2-丙烯基、1-乙基-1-丙烯基、1-乙基-2-丙烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、4-甲基-1-戊烯基、1-甲基-2-戊烯基、2-甲基-2-戊烯基、3-甲基-2-戊烯基、4-甲基-2-戊烯基、1-甲基-3-戊烯基、2-甲基-3-戊烯基、3-甲基-3-戊烯基、4-甲基-3-戊烯基、1-甲基-4-戊烯基、2-甲基-4-戊烯基、3-甲基-4-戊烯基、4-甲基-4-戊烯基、1,1-二甲基-2-丁烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-1-丁烯基、1,2-二甲基-2-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-1-丁烯基、1,3-二甲基-2-丁烯基、1,3-二甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-1-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-3-丁烯基、 3,3-二甲基-1-丁烯基、3,3-二甲基-2-丁烯基、1-乙基-1-丁烯基、1-乙基-2-丁烯基、1-乙基-3-丁烯基、2-乙基-1-丁烯基、2-乙基-2-丁烯基、2-乙基-3-丁烯基、1,1,2-三甲基-2-丙烯基、1-乙基-1-甲基-2-丙烯基、1-乙基-2-甲基-1-丙烯基、1-乙基-2-甲基-2-丙烯基、1,3-丁二烯基、1,3-戊二烯基、1,4-戊二烯基、2,4-戊二烯基、1,4-己二烯基、2,4-己二烯基、环戊烯基、1,3-环戊二烯基、环己烯基和1,4-环己二烯基等。双键可任选地为顺式和反式。
本发明所述“C 2-10炔基”是指含有三键的碳原子数为2-10的直链或支链的炔基，如乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-2-丁炔基、1-甲基-3-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-2-戊炔基、4-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1-甲基-4-戊炔基、2-甲基-4-戊炔基、3-甲基-4-戊炔基、1,1-二甲基-2-丁炔基、1,1-二甲基-3-丁炔基、1,2-二甲基-3-丁炔基、2,2-二甲基-3-丁炔基、1-乙基-2-丁炔基、1-乙基-3-丁炔基、2-乙基-3-丁炔基和1-乙基-1-甲基-2-丙炔基等。
本发明所述“C 1-6烷氧基”指“C 1-6烷基”通过氧原子与其他结构相连接的基团，如甲氧基、乙氧基、丙氧基、1-甲基乙氧基、丁氧基、1-甲基丙氧基、2-甲基丙氧基、1,1-二甲基乙氧基、戊氧基、1-甲基丁氧基、2-甲基丁氧基、3-甲基丁氧基、1,1-二甲基丙氧基、1,2-二甲基丙氧基、2,2-二甲基丙氧基、1-乙基丙氧基、己氧基、1-甲基戊氧基、2-甲基戊氧基、3-甲基戊氧基、4-甲基戊氧基、1,1-二甲基丁氧基、1,2-二甲基丁氧基、1,3-二甲基丁氧基、2,2-二甲基丁氧基、2,3-二甲基丁氧基、3,3-二甲基丁氧基、1-乙基丁氧基、2-乙基丁氧基、1,1,2-三甲基丙氧基、1,2,2-三甲基丙氧基、1-乙基-1-甲基丙氧基和1-乙基-2-甲基丙氧基。术语“C 1-4烷氧基”指上述实例中的含有1-4个碳原子的具体实例。
本发明所述“C 1-6烷基羰基”指术语“C 1-6烷基”通过羰基与其他结构相连接的基团，如甲基羰基、乙基羰基、丙基羰基、异丙基羰基、丁基羰基、异丁基羰基、叔丁基羰基、仲丁基羰基、戊基羰基、新戊基羰基、己基羰基等。
本发明所述“C 1-6烷氧羰基”为术语“C 1-6烷氧基”通过羰基与其他结构相连接的基团，如甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、叔丁氧羰基、仲丁氧羰基、戊氧羰基、新戊氧羰基、己氧羰基等。
本发明所述的“3-14元环烷基”是指3-14个碳原子的烷烃部分去除一个氢原子衍生的环状烷基，包括3-8元单环环烷基、6-14元并环环烷基、7-12元桥环基和7-12元螺环基。优选C 3-8环烷基、C 3-6环烷基和C 5-6环烷基。术语“C 3-8环烷基”、“C 3-6环烷基”、“C 5-6环烷基”分别为下述实例中含有3-8个、3-6个、5-6个碳原子的具体实例。
3-8元单环环烷基，包括3-8元饱和单环环烷基和3-8元部分饱和单环环烷基。3-8元饱和单环环烷基，是指该单环为全部饱和的碳环，其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、甲基环丙烷基、二甲基环丙烷基、甲基环丁烷基、二甲基环丁烷基、甲基环戊烷基、二甲基环戊烷基、甲基环己烷基、二甲基环己烷基等。3-8元部分饱和单环环烷基，是指该单环为部分饱和的碳环，其实例包括但不仅限于环丙烯基、环丁烯基、环戊烯基、环己烯基、1,4-环己二烯基、环庚烯基、1,4-环庚二烯基、 环辛烯基、1,5-环辛二烯基等；
本发明所述的“C 3-8环烷氧基”是指术语“C 3-8环烷基”通过氧原子与其他结构相连接的基团，如环丙氧基、环丁氧基、1-甲基环丁氧基、环戊氧基、环己氧基、环庚氧基、环辛氧基等。
本发明所述的“6-14元芳基”是指环原子为6-14元碳原子的环状芳香基团，包括6-8元单环芳基和8-14元稠环芳基。6-8元单环芳基是指全部不饱和的芳基，例如苯基、环辛四烯基等。8-14元稠环芳基是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的，至少有一个环为全部不饱和的芳香环的环状基团，包括8-14元全部不饱和稠环芳基，萘基、蒽基和菲基等，还包括8-14元部分饱和稠环芳基，例如苯并3-8元饱和单环环烷基、苯并3-8元部分饱和单环环烷基，具体实例如2,3-二氢-1H-茚基、1H-茚基、1,2,3,4-四氢萘基、1,4-二氢萘基等。优选6-10元芳基，进一步优选苯或苯并3-8元饱和单环环烷基、苯并3-8元部分饱和单环环烷基。术语“6-10元芳基”之指上述“芳基”中环原子数为6-10的具体实例。
所述的“5-14元杂芳基”，其环原子除了碳原子外，还包括一个或多个杂原子，所述“杂原子”包括但不限于氧原子、氮原子和硫原子。杂芳基可通过碳或杂环原子键合。包括5-8元单环杂芳基和8-14元稠杂环芳基。5-8元单环杂芳基包括但不限于吡咯基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,2,3-三嗪基、1,2,4-三嗪基、四唑基、噁三唑基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、2H-1,3-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、2H-1,4-噁嗪基、4H-1,4-噁嗪基、异噁嗪基、哒嗪基、嘧啶基和吡嗪基等；8-14元稠杂环芳基包括但不限于苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、喹啉基、异喹啉基、吲嗪基、吲唑基、酞嗪基、喹喔啉基、喹唑啉基、苯并二嗪基、苯并异噁唑基、苯并噁嗪基、苯并咪唑基、吡啶并吡啶基、吡唑并[3,4-b]吡啶基、嘌呤基、吖啶基和呫吨基等。
本发明所述“3-14元杂环基”是指含有一至多个杂原子的3-14元环状基团，所述“杂原子”是指N、S、O、SO和/或SO 2等。包括饱和、部分饱和、不饱和的具有1-4个选自N、S、O、SO和/或SO 2的杂原子的3-8元单杂环基和饱和、部分饱和、不饱和的5-14元双杂环基。还包括上面提及的杂芳基及其二氢化及四氢化类似物。5-14元双杂环基包括饱和、部分饱和、不饱和的具有1-4个选自N、S、O、SO和/或SO 2的杂原子的并环、螺环、桥环。优选3-8元杂环基，进一步优选饱和、部分饱和、不饱和的3-8元单杂环基。更优选5-8元、5-7元、5-6元杂环基，进一步优选饱和、部分饱和、不饱和的5-8元、5-7元、5-6元单杂环基。
本发明所述的“3-8元单杂环基”，是指含有3-8个环原子(其中至少含有一个杂原子，选自N、S、O、SO和/或SO 2)的单环杂环基，包括3-8元不饱和单杂环基、3-8元部分饱和单杂环基和3-8元饱和单杂环基。3-8元不饱和单杂环基和3-8元部分饱和单杂环基，指环中存在不饱和键的3-8元杂环基团，优选5-7元不饱和单杂环基和5-7元部分饱和单杂环基，具体实例包括但不仅限于包括，但不限于，例如下列基团：氮杂环丁二烯、1,2-二氮杂环丁烯、吡咯、4,5-二氢吡咯、2,5-二氢吡咯、咪唑、4,5-二氢咪唑、吡唑、4,5-二氢吡唑、1,2,3-三唑、 1,2,4-三唑、吡啶、2-吡啶酮、4-吡啶酮、哒嗪、嘧啶、吡嗪、1,2,3-三嗪、1,2,4-三嗪、氮杂环庚三烯、1,2-二氮杂环庚三烯、1,3-二氮杂环庚三烯、1,4-二氮杂环庚三烯、氮杂环辛四烯、1,4-二氢-1,4-二氮杂环辛三烯，1,2-二硫杂环丁烯、呋喃、4,5-二氢呋喃、2,5-二氢呋喃、噻吩、2,5-二氢噻吩、4,5-二氢噻吩、1,2-二硫杂环戊烯、1,3-二硫杂环戊烯、2H-吡喃、2H-吡喃-2-酮、3,4-二氢-2H-吡喃、4H-吡喃、4H-吡喃-4-酮、1,4-二氧杂环己二烯、1,4-二硫杂环己二烯、1,4-氧硫杂环己二烯、氧杂环庚三烯、硫杂环庚三烯、1,4-二氧杂环辛三烯，噁唑、4,5-二氢噁唑、2,3-二氢噁唑、异噁唑、4,5-二氢异噁唑、2,3-二氢异噁唑、1,2,3-噁二唑、1,2,5-噁二唑、噻唑、4,5-二氢噻唑、2,3-二氢噻唑、异噻唑、1,2,3-噻二唑、2H-1,2-噁嗪、4H-1,2-噁嗪、6H-1,2-噁嗪、2H-1,3-噁嗪、4H-1,3-噁嗪、5,6-二氢-4H-1,3-噁嗪、6H-1,3-噁嗪、2H-1,4-噁嗪、4H-1,4-噁嗪、2H-1,3-噻嗪、4H-1,3-噻嗪、5,6-二氢-4H-1,3-噻嗪、6H-1,3-噻嗪、2H-1,4-噻嗪、4H-1,4-噻嗪基团等。其中优选氮杂环丁二烯、1,2-二氮杂环丁烯、吡咯、二氢吡咯、咪唑、4,5-二氢咪唑、吡唑、4,5-二氢吡唑、吡啶、2-吡啶酮、4-吡啶酮、哒嗪、嘧啶、吡嗪、氮杂环庚三烯、1,2-二硫杂环丁烯、呋喃、噻吩、2,5-二氢噻吩、1,2-二硫杂环戊烯、2H-吡喃、2H-吡喃-2-酮、3,4-二氢-2H-吡喃、4H-吡喃、4H-吡喃-4-酮、1,4-二氧杂环己二烯、1,4-二硫杂环己二烯、1,4-氧硫杂环己二烯、氧杂环庚三烯、1,4-二氧杂环辛三烯、噁唑、4,5-二氢噁唑、异噁唑、4,5-二氢异噁唑、2,3-二氢异噁唑、1,2,3-噁二唑、1,2,5-噁二唑、噻唑、4,5-二氢噻唑、异噻唑、1,2,3-噻二唑、2H-1,2-噁嗪、4H-1,2-噁嗪、6H-1,2-噁嗪、2H-1,3-噁嗪、4H-1,3-噁嗪、5,6-二氢-4H-1,3-噁嗪、6H-1,3-噁嗪、2H-1,4-噁嗪、4H-1,4-噁嗪、2H-1,3-噻嗪、4H-1,3-噻嗪、5,6-二氢-4H-1,3-噻嗪、6H-1,3-噻嗪、2H-1,4-噻嗪、4H-1,4-噻嗪、吗啉、1,3,4-噻二唑基团。更优选吡咯、二氢吡咯、咪唑、4,5-二氢咪唑、吡唑、4,5-二氢吡唑、吡啶、哒嗪、嘧啶、吡嗪、呋喃、噻吩、2,5-二氢噻吩、2H-吡喃、2H-吡喃-2-酮、3,4-二氢-2H-吡喃、4H-吡喃、4H-吡喃-4-酮、1,4-二氧杂环己二烯、1,4-二硫杂环己二烯、1,4-氧硫杂环己二烯、噁唑、4,5-二氢噁唑、异噁唑、4,5-二氢异噁唑、2,3-二氢异噁唑、1,2,3-噁二唑、1,2,5-噁二唑、噻唑、4,5-二氢噻唑、异噻唑、1,2,3-噻二唑、1,2,4-噻二唑、1,3,4-噻二唑基团等；3-8元饱和单杂环基，是指全部为饱和键的含有杂原子的环状基团，优选5-7元饱和单杂环基，具体实例包括但不仅限于：氮杂环丙烷、氮杂环丁烷、1,2-二氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、氢化吡啶酮、哌啶、哌嗪、环氧乙烷、硫杂环丙烷、氧杂环丁烷、1,2-二氧杂环丁烷、硫杂环丁烷、四氢呋喃、四氢噻吩、1,3-二氧杂环戊烷、1,3-二硫杂环戊烷、四氢吡喃、1,4-二氧杂环己烷、1,3-二氧杂环己烷、1,3-氧硫杂环己烷、噁唑烷、吗啉基团等；其中，优选氮杂环丙烷、氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、氢化吡啶酮、哌啶、哌嗪、环氧乙烷、四氢呋喃、四氢噻吩、1,3-二氧杂环戊烷、1,3-二硫杂环戊烷、四氢吡喃、1,4-二氧杂环己烷、1,3-二氧杂环己烷、1,3-氧硫杂环己烷、噁唑烷、吗啉基团等。
术语3-8元杂环基、5-7元杂环基、5-6元杂环基指上述“3-14元杂环基”中环原子数为3-8元、5-8元、5-7元、5-6元的具体实例。
本发明所述的“3-8元”是指3,4,5,6,7,8元，优选5-8元。进一步优选5-7元。更进一步优选 5-6元。所述的“5-8元”是指,5,6,7,8元，“5-7元”是指,5,6,7元。
本发明所述的“3-8元杂环基”包括，但不限于，例如氮杂环丙烷、氮杂环丁烷、1,2-二氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、氢化吡啶酮、哌啶、哌嗪、环氧乙烷、硫杂环丙烷、氧杂环丁烷、1,2-二氧杂环丁烷、硫杂环丁烷、四氢呋喃、四氢噻吩、1,3-二氧杂环戊烷、1,3-二硫杂环戊烷、四氢吡喃、1,4-二氧杂环己烷、1,3-二氧杂环己烷、1,3-氧硫杂环己烷、噁唑烷、吗啉基团等；其中，优选氮杂环丙烷、氮杂环丁烷、吡咯烷、咪唑烷、吡唑烷、氢化吡啶酮、哌啶、哌嗪、环氧乙烷、四氢呋喃、四氢噻吩、1,3-二氧杂环戊烷、1,3-二硫杂环戊烷、四氢吡喃、1,4-二氧杂环己烷、1,3-二氧杂环己烷、1,3-氧硫杂环己烷、噁唑烷、吗啉基团等；
术语“卤代C 1-4烷基”指被相同或不同的1-6个上述卤原子取代的上述C 1-4烷基，例如三氟甲基、五氟乙基、或类似基团。
术语“C 1-4酰基”指具有1-4个碳原子的直链或支链酰基，例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、或类似基团。
术语“芳基”指单环至三环的芳族烃基，例如苯基、萘基、或类似基团。
术语“芳烷基”指被上述芳基取代的C 1-6烷基。
术语“含一个至两个氧或者氮的芳香杂环”指呋喃环、吡啶环、嘧啶环、吡咯环、吡嗪环、哒嗪环、三嗪环、或类似的基团。
术语“C 3-C 6杂环烷基”指吡咯环、哌啶环、吗啉环、哌嗪环、或类似的基团。
术语“C 5-C 12芳基”指苄基、苯乙基、萘基亚甲基、或类似的基团
本发明还提供治疗或预防精神障碍类疾病的药物组合物，其包含：(a)预防或治疗有效量的式(I)所示的本发明的活性成分；以及(b)药学上可接受的载体、赋形剂或缓释剂。
本发明中，术语“含有”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。
本发明中，“药学上可接受的载体”是用于将本发明的活性物质或其生理上可接受的盐传送给动物或人的药学上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
在本发明中，所述的药物组合物含有安全有效量(如0.001-99.9重量份，更佳地，0.01-99重量份，更优选0.1-90重量份)的式(I)所示的化合物或其药学上可接受的盐；以及药学上可接受的载体或赋形剂，其中组合物的总重量为100重量份。
或者，本发明所述的药物组合物含有0.001-99.9wt％，更佳地，0.01-99重量％，更优选占总重量0.1-90重量％的式(I)所示的化合物或其药学上可接受的盐；以及药学上可接受的载体或赋形剂，其中组合物的总重量为100重量％。
在另一优选例中，式(I)化合物与药学上可接受的载体、赋形剂或缓释剂的优选比例是，式(I)作为活性成分占总重量比65％以上，其余部分占总重量比0.5-40％，或更好为1-20％，或最好为1-10％。
本发明药物组合物的各种制剂形式，其单位剂量每剂包含0.05mg-500mg，优选0.5mg-200mg，更优选0.1mg-100mg所述的式(I)化合物、对映异构体、外消旋体、药学上可接受的盐或它们的混合物。。
当所述的药物组合物中含有额外的治疗或预防精神障碍类疾病的药物活性成分时，该活性成分的用量通常可以是现有技术中的常规用量或更低。
本发明的药物组合物可以是多种形式，如片剂、胶囊、粉末、糖浆、溶液状、悬浮液和气雾剂等，其中式(I)化合物可以存在于适宜的固体或液体载体或稀释液中。本发明的药物组合物也可以储存在适宜的注射或滴注的消毒器具中。该药物组合物中还可包含气味剂、香味剂等。
本发明的式(I)化合物或包含式(I)化合物的药物组合物可通过口、鼻、皮肤、肺或胃肠道等给药途径对哺乳动物(包括人)临床使用。优选的给药途径为口服。优选的每日剂量为0.5mg-200mg/kg体重，一次或分次服用。不管用何种服用方法，个人的最佳剂量应根据具体治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最合适的剂量。
所用的活性成分的有效剂量可随所用的化合物、给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物每天以约1-300mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以1-3次分开的剂量给予，或以缓释形式给药。对大部分大型哺乳动物而言，每天的总剂量约为5-1000mg，较佳地约为10-500mg。适用于内服的剂量形式，包含与固态或液态药学上可接受的载体密切混合的约1-200mg的活性化合物。可调节此剂量方案以提供最佳治疗应答。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。
所述化合物或其药学上可接受的盐及其组合物可通过口服以及静脉内、肌内或皮下等途径给药。从易于制备和给药的立场看，优选的药物组合物是固态组合物，尤其是片剂和固体填充或液体填充的胶囊。药物组合物的口服给药是优选的。
固态载体包括：淀粉、乳糖、磷酸二钙、微晶纤维素、蔗糖和白陶土，而液态载体包括：无菌水、聚乙二醇、非离子型表面活性剂和食用油(如玉米油、花生油和芝麻油)，只要适合活性成分的特性和所需的特定给药方式。在制备药物组合物中通常使用的佐剂也可有利地被包括，例如调味剂、色素、防腐剂和抗氧化剂如维生素E、维生素C、BHT和BHA。
所述活性化合物或其药学上可接受的盐及其组合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂(如羟丙基纤维素)的水中制备这些活性化合物(作为游离碱或药学上可接受的盐)的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下，这些制剂中含有防腐剂以防止微生物的生长。
适应于注射的药物形式包括：无菌水溶液或分散液和无菌粉(用于临时制备无菌注射溶液或分散液)。在所有情况中，这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的，且必须能防止微生物(如细菌和真菌)的污染影响。载体可以是溶剂或分散介质，其中含有如水、醇(如甘油、丙二醇和液态聚乙二醇)、它们的适当混合物和植物油。
式(I)所示的化合物或其药学上可接受的盐及其组合物还可与其它治疗或预防精神障碍类疾病的活性成分或药物联合给药。当两种或两种以上的药物联合给药时，一般具有优于两种药物分别单独给药的效果。
本发明上述任一化合物药学上可接受的盐是指由药学上可接受的盐，所述的盐为包括(但不限于)：(1)与如下无机酸形成的盐：如盐酸、硫酸、硝酸、磷酸；(2)与如下有机酸形成的盐，如乙酸、草酸、丁二酸、酒石酸、甲磺酸、马来酸、或精氨酸。其它的盐包括与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐，以酯、氨基甲酸酯，或其它常规的“前体药物”的形式。
可将游离形式的本发明化合物转化成盐形式的相应化合物，反之亦然。可将游离形式或盐形式和/或溶剂化物形式的本发明化合物转化成非溶剂化物形式的游离形式或盐形式的相应化合物；反之亦然。
所述的“溶剂化物”在本文中用以描述包含本发明的化合物和化学计量(stoichiometric amount)的一种或多种可药用溶剂分子的分子配合物，所述溶剂有，例如乙醇。当所述溶剂为水时，使用术语“水合物”。
本发明涉及的化合物的前药，如酯等也是本发明的一部分。“前药”的含义是可在体内通过代谢方式(例如，通过水解、还原或氧化)转化为式(I)的化合物。例如式(I)化合物的酯前药可通过水解在体内转化为母体分子。酯前药的实例有F.J.Leinweber，Drug Metab.Res.，1987，18，379中记载的那些。如本文使用的，提及式(I)化合物的含义还包括前药形式。
本发明涉及式(I)化合物的“立体异构体”，本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，这类不对称中心各自会独立的产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明包括这些化合物的所有立体异构形式。本发明式(I)化合物或其药学上可接受的盐由于存在不对称碳原子，可以以一种旋光异构体形式存在，因此，本发明还包括这些旋光异构体及其混合物。本文描述的结构也拟包括所述结构的所有异构(例如对映异构、非对映异构和几何异构(或构象异构))形式；例如，关于每一不对称中心的R和S构型、Z和E双键异构体以及Z和E构象异构体。因此，本发明化合物的单一立体化学异构体以及对映异构体、非对映异构体和几何异构体(或构象异构体)的混合物都在本发明的范围内。除非另作规定，否则本发明化合物的所有互变异构形式都在本发明的范围内。
本发明涉及式(I)化合物的“氘代物”，本发明化合物的结构也包括不同之处仅在于存在一个或一个以上同位素富集的原子的化合物。举例来说，具有本发明的结构但包括氢经氘或氚置换或碳经富集或的碳置换的化合物在本发明的范围内。此类化合物可用作例如分析工具、生物分析中的探针或本发明的治疗剂。在一些实施例中，式(I)中的包含一个或一个以上氘原子。
本发明的化合物有1个或者更多的手性中心。合成得到的是消旋体，所需要的对映体纯的化合物可以通过手性拆分的方法得到：可以通过具有手性固定相的色谱法(像高压制备 液相、超临界流体色谱)。手性填料包括但不限于：Chiralcel OJ-H,Chiralpak AD-H,Chiralpak IA,Chiralpak AS-H。
本发明所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体用于通过TREK-1作用预防或治疗哺乳动物治疗抑郁症、抑郁焦虑和精神分裂症等疾病感染性疾病的药物中的应用。
本发明进一步要求保护含有上面所述的任一化合物、其药学上可接受的盐、其氘代物或其立体异构体的药物组合物，所述的组合物中还含有选自以下的一种或多种的药物：丙米嗪、阿米替林、地昔帕明、去甲替林、多塞平、普罗替林、曲米帕明、马普替林、阿莫沙平、曲唑酮、丁氨苯丙酮、氯米帕明(chlomipramine)、氟西汀，度洛西汀，依他普仑，西酞普兰、舍曲林、帕罗西汀、氟伏沙明、萘法唑酮、文拉法辛、米那普仑、瑞波西汀、米氮平、苯乙肼、反苯环丙胺、吗氯贝胺、卡瓦胡椒(Kava-Kava)、圣约翰草(St.John’sWort)、s-腺苷蛋氨酸、促甲状腺激素释放激素、具有抗抑郁剂活性的神经激肽受体拮抗剂和三碘甲腺原氨酸。
本发明化合物与最接近的现有技术相比，具有以下优点：
(1)本发明苯胺类化合物具有较好的TREK-1的抑制活性；
(2)本发明苯胺类化合物口服安全有效。
(3)本发明化合物毒性和副作用较低，安全窗口大；
(4)本发明化合物制备工艺简单，理化性质好，质量稳定，易于进行大规模工业生产。
以下将以实施例进一步说明本发明。这些实施例仅用于举例说明本发明，但不以任何方式限制本发明。实施例中的所有参数及其余说明，除另外说明之外，都是以质量为依据的。实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
实施例1 2-((4-氯苯基)胺基)-1-(7-苯基-3,4-二氢异喹啉-2(1H)-基)乙基-1-酮(化 合物1)的制备
Figure PCTCN2018121562-appb-000014
向50毫升单口瓶中加入3.5克(16.7mmol,1eq)，7-苯基-1，2,3,4-四氢异喹啉，5.89毫升(33.5mmol，2eq)DIPEA,30毫升二氯甲烷，2.2毫升(25mmol,1.5eq)溴乙酰溴，室温搅拌半小时。乙酸乙酯-水洗涤，浓缩过柱，得到2.5克橙色油状物。H-NMR(400MHZ,CDCl 3),δ7.56-7.24(8H),4.84-4.60(s,2H,),4.00(s,2H,),3.90-3.75(t,2H),3.06-2.95(t,2H)
Figure PCTCN2018121562-appb-000015
向100毫升单口瓶加入2.5克(7.3mmol,1eq)上步产物,1.12g(8.7mmol)对氯苯胺，2.0克(14.6mmol)碳酸钾，30毫升乙腈，回流3小时，冷却到室温，加入30克水，析出固体，抽滤，得到3克类白色固体。过柱纯化得到1.5克。
H-NMR(400MHZ,CDCl 3)：δ7.56-7.47(m,7H),7.28(m,1H,),7.18(m,2H,),6.61(m,2H),4.8-4.6(s,2H),3.88(s,2H),4.0-3.7(t,2H),3.1-2.9(t,2H)。
实施例2-实施例32
参考实施例1的方法，制备化合物2-32
Figure PCTCN2018121562-appb-000016
Figure PCTCN2018121562-appb-000017
Figure PCTCN2018121562-appb-000018
实施例33 N-(4-氯苯基)-N-(2-氧代-2-(7-苯基-3,4-二氢异喹啉-2(1H)基)乙 基)甲磺酰胺(化合物33)的制备
Figure PCTCN2018121562-appb-000019
步骤1.
将对氯苯胺(1mmol)、吡啶(160mg，1.00mmol)溶于二氯甲烷(10mL)中，0℃条件下将甲基磺酰氯(1.00mmol)慢慢滴加入反应液中。1小时后，TLC监测反应结束。反应液倒入冰水中，分离出有机相，水相用二氯甲烷萃取，合并的有机相，水洗，饱和盐水洗，无水硫酸钠干燥，浓缩得到粗品为淡黄色油状物。
步骤2.
将2-溴-1-(3,4-二氢异喹啉-2(1H)-基)乙-1-酮(462mg，1.82mmol)、N-(4-氯苯基)甲磺酰胺(450mg，粗品)、无水碳酸钾(500mg，3.63mmol)加入乙腈中(10mL)，使反应液升温80℃反应5小时。TLC监测反应结束。反应液降至室温，反应液倒入冰水中，分离出有机相，水相用乙酸乙酯萃取，合并的有机相，水洗，饱和盐水洗，无水硫酸钠干燥，浓缩。粗品硅胶柱层析纯化(石油醚/乙酸乙酯＝4/1)得到目标产物(80mg，12％)为淡黄色油状物。
1H NMR(400MHz,CDCl 3):δ7.55-7.45(m,3H),7.34-7.30(m,2H),7.11-7.01(m,2H),4.75-4.55(m,4H),3.86-3.62(m,2H),3.17-3.16(m,3H),2.96-2.85(m,2H)。
步骤3.
Figure PCTCN2018121562-appb-000020
将N-(2-(8-溴-3,4-二氢异喹啉-2(1H)-基)-2-氧代乙基)-N-(4-氯苯基)甲磺酰胺(300mg，0.66mmol)、苯硼酸(80mg，0.66mmol)、碳酸钾(272mg，1.97mmol)和Pd(dppf)Cl 2(24mg，0.03mmol)溶解在DMF(10mL)中，使反应液在氮气保护条件下升温90℃反应3小时。TLC监测反应结束。反应液降至室温后倒入冰水中，用乙酸乙酯萃取，合并有机相水洗，饱和NaCl水溶液，无水硫酸钠干燥、浓缩。粗品硅胶层析纯化(石油醚/乙酸乙酯＝5/1)得到N-(4-氯苯基)-N-(2-氧代-2-(8-苯基-1,2,3,4-四氢吡啶-2-基)乙基)甲磺酰胺(200mg，67％)为淡黄色固体。
1H NMR(400MHz,CDCl 3):δ7.57-7.51(m,4H),7.46-7.42(m,3H),7.39-7.31(m,4H),7.24-7.13(m,1H),4.79-4.60(m,4H),3.88-3.63(m,2H),3.19(s,3H),2.99-2.92(m,2H)。
实施例34-实施例64
参考实施例33的方法，制备化合物34-64
Figure PCTCN2018121562-appb-000021
Figure PCTCN2018121562-appb-000022
Figure PCTCN2018121562-appb-000023
实施例65 4-氯-N-(2-(7-苯基-3,4-二氢异喹啉-2(1H)基)乙基)苯胺(化合物65) 的制备
Figure PCTCN2018121562-appb-000024
向50毫升单口瓶中加入60毫克(1.6mmol,2eq)氢化铝锂,6毫升四氢呋喃，加入300毫克(0.8mmol,1eq)化合物1,66℃回流4小时。依次加入1毫升水，2毫升氢氧化钠溶液，1毫升水，搅拌。过滤，浓缩，过柱得到产物。
1H NMR(400MHz,CDCl3):δ7.60-7.58(m,2H),7.48-7.44(m,3H),7.39-7.37(m,1H),7.29-7.25(m,3H),7.17-7.14(m,2H),6.66-6.59(m,2H),3.87(m,2H),3.35-3.32(m,2H),3.04-3.02(m,2H),2.97-2.94(m,4H)。
实施例66-实施例96
参考实施例65的方法，制备化合物66-96。
Figure PCTCN2018121562-appb-000025
Figure PCTCN2018121562-appb-000026
Figure PCTCN2018121562-appb-000027
Figure PCTCN2018121562-appb-000028
实施例97 4-氯-N-(2-(7-苯基-3,4-二氢异喹啉-2(1H)基)乙基)苯胺(化合物97) 的制备
Figure PCTCN2018121562-appb-000029
向50毫升单口瓶依次加入200毫克实施例65的化合物(0.53mmol,1eq),10毫升吡啶，6.5毫克(0.053mmol,0.1eq)DMAP,125mg(1.06mmol,2eq)甲磺酰氯。室温搅拌2小时，乙酸乙酯-水洗涤3次，过柱得类白色固体180毫克。
1H NMR(400MHz,CDCl3):δ7.60-7.58(m,2H),7.44-7.35(m,8H),7.39-7.37(m,1H),7.28-7.27(m,1H),3.97-3.93(m,2H),3.76(m,2H),2.98-2.94(m,5H),2.86-2.83(m,2H)，2.72-2.69(m,2H)。
实施例98-实施例128
参考实施例97的方法，制备化合物98-128
Figure PCTCN2018121562-appb-000030
Figure PCTCN2018121562-appb-000031
Figure PCTCN2018121562-appb-000032
Figure PCTCN2018121562-appb-000033
实施例129
Figure PCTCN2018121562-appb-000034
向50毫升单口瓶中加入200毫克(0.53mmol,1eq)实施例1的化合物,6mL丙酮，0.23克(1.06mmol,2eq)碳酸钾，0.23克(1.6mmol,3eq)碘甲烷，室温搅拌过夜。
1H NMR(400MHz,CDCl 3):δ7.60-7.58(m,2H),7.48-7.45(m,3H),7.39-7.37(m,1H),7.29-7.27(m,2H),7.19-7.17(m,2H),6.67-6.65(m,2H),4.83-4.73(m,2H),4.24-4.21(m,2H),3.94-3.74(m,2H),3.08(s,3H),3.00-2.94(m,2H)。
实验例130  体外活性检测
细胞转染与培养
人源TREK-1，TREK-2以及TRAAK的野生型(WT)cDNA分别被亚克隆到pEGFPN1表达载体中。利用PCR技术以及QuickChange XL定点突变试剂盒，在TREK-1以及TRAAK通道上引入突变，随后利用DNA测序技术进行确证。
构建好的的质粒被转染到CHO细胞中，并按照文献中报道的方式进行培养(Li,Y.,Langlais,P.,Gamper,N.,Liu,F.&Shapiro,M.S.Dual phosphorylations underlie modulation of unitary KCNQ K+channels by Src tyrosine kinase.J.Biol.Chem.279,45399-45407(2004))。
细胞培养的条件为DMEM/F12细胞培养基，10％FBS，100μg/ml青霉素-链霉素，5％CO 2，温度保持在37℃。
电生理实验以及数据分析
实验检测的细胞为转染后培养36-96小时的细胞。电生理实验采用全细胞膜片钳模式。实验记录仪器的放大器型号为Axopatch-200B，显微操作系统品牌为奥林巴斯。实验之前用Flaming/Brown type micropipette puller电极拉制仪拉制电极，并将拉制好的电极进行抛光以使进行全细胞实验时得到高阻抗封接。用于全细胞膜片钳记录模式的电极入水电阻为4-7MΩ。细胞内液成分主要包括：140mM KCl,2mM MgCl2,10mM EGTA,1mM CaCl2,10mM HEPES,并用KOH将pH调至7.3。细胞外液成分主要包括：150mM NaCl,5mM KCl,0.5mM CaCl2,1.2mM MgCl2,10mM HEPES,并用NaOH将pH调至7.3。实验所采集的电流信号使用频率为1kHz的低频滤波器进行过滤。数据的采样采用DigiData 1440A，采样的频率为10kHz。数据的统计分析与作图采用软件origin 6.0。
计算不同药物浓度下的电流值I/不加药物的电流值I 0：数值越低，说明抑制活性越好。结果如下表。
表1 化合物对TREK-1的抑制活性
Figure PCTCN2018121562-appb-000035
实验结果表明，本发明供试化合物对TREK-1都有较好的抑制活性。本发明化合物在与TREK-1相关的治疗领域具有较好的临床应用潜力。
实验例131
抗抑郁研究(急性给药)
实验动物为6周龄C57小鼠，雄性，C57种小鼠购自上海斯莱克实验动物有限公司，体重20.45±0.19g。实验前到达中国科学院上海药物研究所动物饲养中心(动物生产许可证:SCXK9[沪]2004-0002，使用许可证：SYXK[沪]2003-0029)，并在动物设施中适应3天以上，6只/笼饲养。饲养环境为室温23±0.2℃，12/12小时昼夜明暗交替。行为学测试前，动物先提前2小时移至行为测试操作间，使之适应该环境，降低其紧张感。
试验分组及测试时间如下表2所示。
表2 实验分组及测试时间
Figure PCTCN2018121562-appb-000036
行为学试验
1)供试品配制(每次实验前新鲜配制)：分别成称量前称取适量实施例1、实施例65粉末，分别精密称量各种化合物12mg，各管均加入40μl无水乙醇使之充分溶解，再加入50μl tween 80混匀后，分别用0.9％NaCl定容到3ml，配成4mg/ml溶液，待用。同样，精密称量氟西汀3mg定容于3ml 0.9％NaCl，待用。
2)动物随机分成7组，每组10只动物。每组动物的给药方式如表示。
3)受试前，小鼠须在操作间适应2小时以上。
4)适应前小鼠称重，并尾部标记。
5)强迫游泳测试在单次给药后的30min进行(如表2示)。
强迫游泳实验(FST)
在给药前24小时，小鼠放入圆柱型缸内适应水中环境10min。行为测试当天，动物给药1次，分别在行为测试前30min灌胃给药。将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎，不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
旷场试验(OFT)
旷场实验(open field test)又称敞箱实验，是评价实验动物在新异环境中自主行为、探究行为与焦虑样行为的一种方法以实验动物在敞箱之中的正常活动、惧怕空旷环境和探索新环境等行为的发生频率和持续时间等，来反应实验动物在陌生环境中的自主行为与探究行为。分析动物旷场实验结果可对动物进行抑郁及焦虑样行为评估。
实验操作：实验前2小时将实验动物放于行为室适应。实验时将动物放于黑色塑料箱(大小为100*100*45cm)底面中心，同时进行视频拍摄，实验时间10分钟并保证在安静的环境下进行。每次实验后擦拭敞箱底部及内壁，防止上次动物余留信息对下次实验的干扰。利用动物自发活动分析软件对视频进行分析，得出动物的中央区域活动时间(焦虑样行为)、活动总路程(运动能力)、爬壁次数(新异环境探索行为)等信息，可以对动物抑郁或焦虑样行为及程度进行评判。
所有数据分析采用spss 22(for mac)数据处理软件完成。使用单因素方差分析，采用post-hoc LSD法多重比较校验结果。数据用Mean±sem表示。p<0.05时标记一个星号；p<0.01时标记两个星号；p<0.001时标记三个星号。
结果如图1所示。化合物实施例1和实施例65在口服剂量为40mg/kg时，均能显著降低小鼠强迫游泳的不动时间(图1中a)，初步提示化合物实施例1和实施例65可能具有抗抑郁活性。旷场实验提示(图1中b)，实施例1和实施例65对动物的运动能力无明显影响，且没有表现类似镇定的作用。
实施例132
抗抑郁量效关系研究(急性给药)
实验动物为6周龄C57小鼠，雄性，C57种小鼠购自上海斯莱克实验动物有限公司，体重20.45±0.19g。实验前到达中国科学院上海药物研究所动物饲养中心(动物生产许可证:SCXK9[沪]2004-0002，使用许可证：SYXK[沪]2003-0029)，并在动物设施中适应3天以上，6只/笼饲养。饲养环境为室温23±0.2℃，12/12小时昼夜明暗交替。行为学测试前，动物先提前2小时移至行为测试操作间，使之适应该环境，降低其紧张感。
试验分组及测试时间如下表3所示。
表3 试验分组及测试时间
Figure PCTCN2018121562-appb-000037
行为学试验
1)供试品配制(每次实验前新鲜配制)：分别成称量前称取适量实施例1、实施例65，分别精密称量各种化合物3mg、6mg和12mg，各管均加入60μl无水乙醇使之充分溶解，再加入40μltween 80混匀后，分别用0.9％NaCl定容到3ml，配成4mg/ml溶液，待用。同样，精密称量氟西汀3mg定容于3ml 0.9％NaCl，待用。
2)动物随机分成8组，每组9只动物。每组动物的给药方式如上表示。
3)受试前，小鼠须在操作间适应2小时以上。
4)适应前小鼠称重，并尾部标记。
5)强迫游泳测试在单次给药后的30min进行(如上表3示出)。
强迫游泳实验(FST)
在给药前24小时，小鼠放入圆柱型缸内适应水中环境10min。行为测试当天，动物给药1次，分别在行为测试前1h和24h灌胃给药。将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎，不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
所有数据分析采用spss 22(for mac)数据处理软件完成。使用单因素方差分析，采用post-hoc LSD法多重比较校验结果。数据用Mean±sem表示。p<0.05时标记一个星号；p<0.01时标记两个星号；p<0.001时标记三个星号。
前期结果已经提示(图1)，化合物实施例1和实施例65在口服剂量为40mg/kg时具抗抑郁效果显著。本研究使小鼠口服剂量10mg/kg、20mg/kg和40mg/kg，研究化合物抗抑郁效果是否呈量效关系，结果提示(图2)口服实施例1和实施例65化合物抗抑郁效果显著，而且实施例65化合物呈明显的量效关系。
实施例133  抗抑郁量效关系研究(亚慢性给药)
实验动物为6周龄C57小鼠，雄性，C57种小鼠购自上海斯莱克实验动物有限公司，体重20.45±0.19g。实验前到达中国科学院上海药物研究所动物饲养中心(动物生产许可证:SCXK9[沪]2004-0002，使用许可证：SYXK[沪]2003-0029)，并在动物设施中适应3天以上，6只/笼饲养。饲养环境为室温23±0.2℃，12/12小时昼夜明暗交替。行为学测试前，动物先提前2小时移至行为测试操作间，使之适应该环境，降低其紧张感。
试验分组及测试时间如下表4所示。
表4 试验分组及测试时间
Figure PCTCN2018121562-appb-000038
Figure PCTCN2018121562-appb-000039
给药频率为1次/天
行为学试验
供试品配制(每次实验前新鲜配制)：分别成称量前称取适量实施例65粉末，分别精密称量化合物3mg、9mg以及12mg，各管均加入60μl DMSO使之充分溶解，再加入40μltween80混匀后，分别用1％CMC-Na定容到3ml，配成1mg/ml、3mg/ml和4mg/ml溶液，待用。同样，精密称量氟西汀3mg定容于3ml 1％CMC-Na，待用。
动物随机分成5组，每组10只动物。每组动物的给药方式如表所示。
受试前，小鼠须在操作间适应2小时以上。适应前小鼠称重，并尾部标记。强迫游泳和旷场测试在连续给药后10天，并在给药后的24小时进行。悬尾实验在连续给药后12天，并在给药后的24小时进行(如上表4示出)。
强迫游泳实验(FST)
在给药前24小时，小鼠放入圆柱型缸内适应水中环境10min。动物连续给药10天，并在最后一次给药后的24h进行强迫游泳测试。将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎，不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
悬尾实验(FST)
悬尾实验(Tail suspension test,TST)的原理是利用小鼠尾部绑定以后，因企图逃脱而挣扎，但又因无法逃脱而放弃挣扎，进入因失望或绝望而抑郁的不动状态。实验过程中动物的不动时间可以反映抑郁状态，而抗抑郁药物、兴奋药物能明显地缩短和改变其状态。所以TST是一种经典而又能快速评价抗抑郁药物、兴奋药物、镇静药物药效的方法。悬尾实验的不动时间反映动物在不可逃避条件下的绝望行为，是抗抑郁药效评估的常用方法，也是抑郁症状中的常见行为，以此表明化合物的抗抑郁效果。
实验操作：实验前2小时将小鼠放入行为室进行适应。动物连续给药12次，末次给药后24小时后进行悬尾实验，实验时将小鼠尾部距末端约1cm处用胶带或夹子，倒吊于距地面15cm左右的悬尾试验架上，小鼠为克服不正常体位而挣扎活动，但活动一段时间后，出现间断性不动，显示失望状态，各组实验时间为6分钟。由于前两分钟小鼠大多因兴奋而挣扎频繁，统计其后4分钟不动时间。
旷场试验(OFT)
旷场实验(open field test)又称敞箱实验，是评价实验动物在新异环境中自主行为、探究行为与焦虑样行为的一种方法。以实验动物在敞箱之中的正常活动、惧怕空旷环境和探索新环境等行为的发生频率和持续时间等，来反应实验动物在陌生环境中的自主行为与探究行为。分析动物旷场实验结果可对动物进行抑郁及焦虑样行为评估。
实验操作：实验前2小时将实验动物放于行为室适应。动物连续给药11天，并在最后一次给药后的24h进行旷场测试。实验时将动物放于黑色塑料箱(大小为100*100*45cm)底面中心，同时进行视频拍摄，实验时间10分钟并保证在安静的环境下进行。每次实验后擦拭敞箱底部及内壁，防止上次动物余留信息对下次实验的干扰。利用动物自发活动分析软件对视频进行分析，得出动物的中央区域活动时间(焦虑样行为)、活动总路程(运动能力)、爬壁次数(新异环境探索行为)等信息，可以对动物抑郁或焦虑样行为及程度进行评判。所有数据分析采用spss 22(for mac)数据处理软件完成。使用单因素方差分析，采用post-hoc LSD法多重比较校验结果。数据用Mean±sem表示。p<0.05时标记一个星号；p<0.01时标记两个星号；p<0.001时标记三个星号。
通过给药10-12天给药结果显示：10-12天给药(1次/日)，并在末次给药后的24小时进行强迫游泳和悬尾测试，结果显示在给药剂量为2mg/kg和40mg/kg时，实施例65显著降低强迫游泳的不动时间，量效关系不明显(图3中a)。类似地，悬尾实验显示(图3中b)在给药剂量为20mg/kg和40mg/kg时，实施例65显著降低小鼠悬尾的不动时间，也呈一定量效果关系。旷场实验显示(图3中c)，实施例65对小鼠的运动能力无影响，且药物对动物也明显无镇定做用。结果提示与临床一线抗抑郁药氟西汀比较，实施例65起效快(10天起效)。
实施例134 抗抑郁研究(亚慢性给药)
实验动物为6周龄C57小鼠，雄性，C57种小鼠购自上海斯莱克实验动物有限公司，体重20.45±0.19g。实验前到达中国科学院上海药物研究所动物饲养中心(动物生产许可证:SCXK9[沪]2004002，使用许可证：SYXK[沪]2003-0029)，并在动物设施中适应3天以上，6只/笼饲养。饲养环境为室温23±0.2℃，12/12小时昼夜明暗交替。行为学测试前，动物先提前2小时移至行为测试操作间，使之适应该环境，降低其紧张感。
试验分组及测试时间如下表5。
表5 试验分组及测试时间
Figure PCTCN2018121562-appb-000040
给药频率为1次/天
行为学试验
供试品配制(每次实验前新鲜配制)：分别成称量前称取适量实施例33粉末，分别精密称量化合物0.3mg、0.9mg以及3mg，各管均加入60μl无水乙醇使之充分溶解，再加入40μltween 80混匀后，分别用0.9％NaCl定容到3ml，配成1mg/ml、3mg/ml和10mg/ml溶液，待用。同样，精密称量氟西汀3mg定容于3ml 0.9％NaCl，待用。
动物随机分成5组，每组10只动物。每组动物的给药方式如表示。
受试前，小鼠须在操作间适应2小时以上。适应前小鼠称重，并尾部标记。强迫游泳测试在单次给药、3次给药后、6次给药以及10次给药后的24小时进行。悬尾和旷场实验在11次给药后的24h进行(如上表5示出)。
强迫游泳实验(FST)
在给药前24小时，小鼠放入圆柱型缸内适应水中环境10min。行为测试当天，动物给药1次，分别在行为测试前1h和24h腹腔给药。将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎，不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
悬尾实验(FST)
悬尾实验(Tail suspension test,TST)的原理是利用小鼠尾部绑定以后，因企图逃脱而挣扎，但又因无法逃脱而放弃挣扎，进入因失望或绝望而抑郁的不动状态。实验过程中动物的不动时间可以反映抑郁状态，而抗抑郁药物、兴奋药物能明显地缩短和改变其状态。所以TST是一种经典而又能快速评价抗抑郁药物、兴奋药物、镇静药物药效的方法。悬尾实验的不动时间反映动物在不可逃避条件下的绝望行为，是抗抑郁药效评估的常用方法，也是抑郁症状中的常见行为，以此表明化合物的抗抑郁效果。
实验操作：实验前2小时将小鼠放入行为室进行适应。末次给药1小时后进行实验，实验时将小鼠尾部距末端约1cm处用胶带或夹子，倒吊于距地面15cm左右的悬尾试验架上，小鼠为克服不正常体位而挣扎活动，但活动一段时间后，出现间断性不动，显示失望状态，各组实验时间为6分钟。由于前两分钟小鼠大多因兴奋而挣扎频繁，统计其后4分钟不动时间。
旷场试验(OFT)
旷场实验(open field test)又称敞箱实验，是评价实验动物在新异环境中自主行为、探究行为与焦虑样行为的一种方法。以实验动物在敞箱之中的正常活动、惧怕空旷环境和探索新环境等行为的发生频率和持续时间等，来反应实验动物在陌生环境中的自主行为与探究行为。分析动物旷场实验结果可对动物进行抑郁及焦虑样行为评估。
实验操作：实验前2小时将实验动物放于行为室适应。实验时将动物放于黑色塑料箱(大小为100*100*45cm)底面中心，同时进行视频拍摄，实验时间10分钟并保证在安静的环境下进行。每次实验后擦拭敞箱底部及内壁，防止上次动物余留信息对下次实验的干扰。利 用动物自发活动分析软件对视频进行分析，得出动物的中央区域活动时间(焦虑样行为)、活动总路程(运动能力)、爬壁次数(新异环境探索行为)等信息，可以对动物抑郁或焦虑样行为及程度进行评判。
所有数据分析采用spss 22(for mac)数据处理软件完成。使用单因素方差分析，采用post-hoc LSD法多重比较校验结果。数据用Mean±sem表示。p<0.05时标记一个星号；p<0.01时标记两个星号；p<0.001时标记三个星号。
通过给药10-11天给药结果显示：
10-11天给药(1次/日)，并在末次给药后的24小时进行强迫游泳和悬尾测试，结果显示在给药剂量为1mg/kg和10mg/kg时，实施例33显著降低强迫游泳的不动时间，量效关系不明显(图4中a)；悬尾实验表明(图4中b)，在给药剂量为3mg/kg和10mg/kg时，实施例33显著降低小鼠悬尾的不动时间，呈一定量效果关系(如图4)。旷场实验显示(图4中c)，实施例33对小鼠的运动能力无影响，且药物对动物也无明显镇定做用。结果提示与临床一线抗抑郁药氟西汀比较，实施例33起效快(10天起效)，且起效剂量低(如图4和图5)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 式I所示化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体：
    Figure PCTCN2018121562-appb-100001
    Ar 2为6-14元芳基、5-14元杂芳基、3-14元环烷基或3-14元杂环基；
    Ar 1为6-14元芳基、5-14元杂芳基、3-14元环烷基或3-14元杂环基；
    Ar 3为氢、卤素、C1-C4烷基、C1-C4烷氧基、氰基、卤代C1-C4烷基或3-6元环烷基；
    或者Ar 1与Ar 3相连的碳共同形成6-14元芳基；
    R 1、R 2、R 3各自独立选自下组：H、被1-3个Q1取代或未取代的C 1-10烷基、被1-3个Q1取代或未取代的C 2-10烯基、被1-3个Q1取代或未取代的C 2-10炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN、被1-3个Q1取代或未取代的3-8元杂环烷基；
    R 4为H、＝O、C 1-10烷基、或C 1-10烷氧基；
    R 5为H、被1-3个Q1取代或未取代的C 1-10烷基、被1-3个Q1取代或未取代的C 2-10链烯基、被1-3个Q1取代或未取代的C 2-10链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
    R 6为H、被1-3个Q1取代或未取代的C 1-10烷基、被1-3个Q1取代或未取代的C 2-10链烯基、被1-3个Q1取代或未取代的C 2-10链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
    其中各Q1独立地选自下组：C1-C8烷基、卤素、C3-C6环烷基、C3-C6环烷基C1-C6烷基、-COOR′，-NR′R″，-OR′，-COR′，-CONR′R″，＝O，-SR′，C1-C4卤代烷基、氨基、巯基、氰基、硝基、羟基、三氟甲基、三氟甲氧基、被1-3个Q2取代或未取代的：含一个至两个氧或者氮的芳香杂环、含一个至两个氧或者氮的杂芳基(C1-C6)烷基、含一个至两个氧或者氮的(C6-C12)稠合杂环基(C1-C6)烷基、C5-C12芳基(C1-C6)烷基、苯氧基、苄氧羰基，其中各Q2独立选自：卤素、氧代、C1-C8烷基、C1-C4烷氧基、C1-C4卤代烷基、氨基、巯基、氰基、硝基、羟基、三氟甲基、三氟甲氧基、被1-3个Q3取代或未取代的苯基或苯氧基，其中各Q3独立选自：卤素、C1-C4卤代烷基、氨基、巯基、氰基、羟基、三氟甲基、三氟甲 氧基，
    其中，各R′，各R″独立地选自：H，被1-3个Q4取代或未取代的苯基，被1-3个Q4取代或未取代的苄基，被1-3个Q4取代或未取代的C1-10烷基，被1-3个Q4取代或未取代的C2-10链烯基，被1-3个Q4取代或未取代的C2-10链炔基；或者，基团R′和R″连接在一起形成4-7元环，其中各Q4独立选自：卤素、C1-C4卤代烷基、C1-C4卤代烷氧基、C1-C4烷基、C1-C4烷氧基、羧基、＝O、氨基、-NO 2或-CN；
    m为0、1或2；n为0、1或2，且m+n≥1；
    p为0、1、2、3、4或5，当p为2、3、4或5时，R 1可相同或不同；
    q为0、1、2、3、4或5，当q为2、3、4或5时，R 6可相同或不同；
    f为0、1、2、3、4。
  2. 如权利要求1所述的化合物，其特征在于，式I所示化合物具有通式(II)所示的结构：
    Figure PCTCN2018121562-appb-100002
    R 1、R 2、R 3、R 5、R 6、p、q的定义如权利要求1所述。
  3. 如权利要求1所述的化合物，其特征在于，式I所示化合物具有通式(III)所示的结构：
    Figure PCTCN2018121562-appb-100003
    其中，R 1、R 2、R 3、p的定义如权利要求1所述。
  4. 如权利要求1所述的化合物，其特征在于，式I所示化合物具有通式(IV)所示的结构：
    Figure PCTCN2018121562-appb-100004
    其中，R 1、R 2、R 3、R 5、R 6、p、q的定义如权利要求1所述。
  5. 如权利要求1所述的化合物，其特征在于，式I所示化合物具有通式(V)所示的结构：
    Figure PCTCN2018121562-appb-100005
    其中，R 1、R 2、R 3、p的定义如权利要求1所述。
  6. 如权利要求所述1的化合物，其特征在于，Ar 2为6-10元芳基、5-8元杂芳基、3-8元环烷基或3-8元杂环基；
    Ar 1为6-10元芳基、5-8元杂芳基、3-8元环烷基或3-8元杂环基；
    Ar 3为氢、卤素、C1-C4烷基、C1-C4烷氧基、氰基、卤代C1-C4烷基或3-6元环烷基；
    或者Ar 1与Ar 3相连的碳共同形成苯基；
    R 1、R 2、R 3各自独立为：H、氟、氯、溴、被1-3个Q1取代或未取代的C 1-4烷基、被1-3个Q1取代或未取代的C 2-6链烯基、被1-3个Q1取代或未取代的C 2-6链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN、被1-3个Q1取代或未取代的3-8元杂环烷基；
    R 4为H、＝O、C 1-4烷基、或C 1-4烷氧基；
    R 5为H、被1-3个Q1取代或未取代的C 1-4烷基、被1-3个Q1取代或未取代的C 2-4链烯基、被1-3个Q1取代或未取代的C 2-4链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
    R 6为H、被1-3个Q1取代或未取代的C 1-4烷基、被1-3个Q1取代或未取代的C 2-4链烯基、被1-3个Q1取代或未取代的C 2-4链炔基、卤素、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、-SO 3R′、-SO 2NR′R″、-SOR′、-SO 2R′、-NO 2、-OCF 3、-CN或被1-3个Q1取代或未取代的3-8元杂环烷基；
    其中各Q1独立地选自下组：C1-C8烷基、卤素、C3-C6环烷基、C3-C6环烷基C1-C6烷基、-COOR′、-NR′R″、-OR′、-COR′、-CONR′R″、＝O、-SR′、C1-C4卤代烷基、氨基、巯基、氰基、硝基、羟基、三氟甲基、三氟甲氧基；
    其中，各R′，各R″独立地选自：H、苯基、苄基、C1-4烷基、C2-4链烯基、C2-4链炔基；或者基团R′和R″连接在一起形成4-6元环；
    m为0、1或2；n为0、1或2，且m+n≥1；
    p为0、1、2、3、4或5，当p为2、3、4或5时，R 1可相同或不同；
    q为0、1、2、3、4或5，当q为2、3、4或5时，R 6可相同或不同；
    f为0、1、2、3、4。
  7. 如权利要求1所述的化合物，其特征在于，所述化合物为：
    Figure PCTCN2018121562-appb-100006
    Figure PCTCN2018121562-appb-100007
    Figure PCTCN2018121562-appb-100008
    Figure PCTCN2018121562-appb-100009
    Figure PCTCN2018121562-appb-100010
    Figure PCTCN2018121562-appb-100011
    Figure PCTCN2018121562-appb-100012
  8. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-7任一项所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体；和药学上可接受的载体。
  9. 如权利要求8所述的药物组合物，其特征在于，所述的药物组合物中还含有选自以下的一种或多种的药物：丙米嗪、阿米替林、地昔帕明、去甲替林、多塞平、普罗替林、曲米帕明、马普替林、阿莫沙平、曲唑酮、丁氨苯丙酮、氯米帕明(chlomipramine)、氟西汀，度洛西汀，依他普仑，西酞普兰、舍曲林、帕罗西汀、氟伏沙明、萘法唑酮、文拉法辛、米那普仑、瑞波西汀、米氮平、苯乙肼、反苯环丙胺、吗氯贝胺、卡瓦胡椒(Kava-Kava)、圣约翰草(St.John’sWort)、s-腺苷蛋氨酸、促甲状腺激素释放激素、具有抗抑郁剂活性的神经激肽受体拮抗剂和三碘甲腺原氨酸。
  10. 如权利要求1-7任一项所述的化合物、其药学上可接受的盐、其前体药物、其溶剂化物、氘代物或其立体异构体的用途，其特征在于，用于制备预防和/或治疗精神障碍疾病的药物。
PCT/CN2018/121562 2018-09-06 2018-12-17 作为防治精神障碍疾病的苯胺类化合物 WO2020048043A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811038093.1 2018-09-06
CN201811038093.1A CN110878048B (zh) 2018-09-06 2018-09-06 作为防治精神障碍疾病的苯胺类化合物

Publications (1)

Publication Number Publication Date
WO2020048043A1 true WO2020048043A1 (zh) 2020-03-12

Family

ID=69721586

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/121562 WO2020048043A1 (zh) 2018-09-06 2018-12-17 作为防治精神障碍疾病的苯胺类化合物

Country Status (2)

Country Link
CN (1) CN110878048B (zh)
WO (1) WO2020048043A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114053256B (zh) * 2020-07-30 2023-07-18 中国科学院上海药物研究所 一种预防和治疗精神障碍性疾病的化合物及其应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029666A1 (en) * 1997-12-05 1999-06-17 Smithkline Beecham Plc Arylpiperazine and arylpiperidine derivatives, their preparation and their use as combined 5-ht1a, 5-ht1b and 5-ht1d receptor antagonists
WO2000006575A2 (en) * 1998-07-28 2000-02-10 Smithkline Beecham Plc Azabicyclic compounds
US20110130384A1 (en) * 2008-06-25 2011-06-02 Takeda Pharmaceutical Company Limited Amide compound
WO2011143145A1 (en) * 2010-05-11 2011-11-17 Sanofi Substituted n-alkyl and n-acyl tetrahydro-isoquinoline derivatives, preparation and therapeutic use thereof
CN103209964A (zh) * 2010-08-13 2013-07-17 Abbvie德国有限责任两合公司 苯烷基胺衍生物、含其的药物组合物及其在治疗中的用途
CN107789354A (zh) * 2016-08-31 2018-03-13 中国科学院上海药物研究所 预防和治疗抑郁症的化合物及其应用
CN109020887A (zh) * 2017-06-10 2018-12-18 绍兴从零医药科技有限公司 作为防治精神障碍疾病的酰胺类化合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007098169A1 (en) * 2006-02-21 2007-08-30 Amgen Inc. Cinnoline derivatives as phosphodiesterase 10 inhibitors
JP2010514682A (ja) * 2006-12-20 2010-05-06 アストラゼネカ・アクチエボラーグ 化合物及びその使用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999029666A1 (en) * 1997-12-05 1999-06-17 Smithkline Beecham Plc Arylpiperazine and arylpiperidine derivatives, their preparation and their use as combined 5-ht1a, 5-ht1b and 5-ht1d receptor antagonists
WO2000006575A2 (en) * 1998-07-28 2000-02-10 Smithkline Beecham Plc Azabicyclic compounds
US20110130384A1 (en) * 2008-06-25 2011-06-02 Takeda Pharmaceutical Company Limited Amide compound
WO2011143145A1 (en) * 2010-05-11 2011-11-17 Sanofi Substituted n-alkyl and n-acyl tetrahydro-isoquinoline derivatives, preparation and therapeutic use thereof
CN103209964A (zh) * 2010-08-13 2013-07-17 Abbvie德国有限责任两合公司 苯烷基胺衍生物、含其的药物组合物及其在治疗中的用途
CN107789354A (zh) * 2016-08-31 2018-03-13 中国科学院上海药物研究所 预防和治疗抑郁症的化合物及其应用
CN109020887A (zh) * 2017-06-10 2018-12-18 绍兴从零医药科技有限公司 作为防治精神障碍疾病的酰胺类化合物

Also Published As

Publication number Publication date
CN110878048A (zh) 2020-03-13
CN110878048B (zh) 2023-03-17

Similar Documents

Publication Publication Date Title
CN103702561B (zh) 阿片样物质受体配体以及使用和制备其的方法
RU2535667C2 (ru) Энантиомеры спиро-оксиндольных соединений и их применение в качестве терапевтических средств
BG108487A (bg) Заместени с триамид индоли, бензофурани и бензотиофени като инхибитори на микрозомния триглицерид пренасящ протеин (mtp) и/или секрецията на аполипопротеин б (аро в)
TW200900058A (en) N-(heteroaryl)-1-heteroaryl-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic application
CA2934553A1 (en) Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
CN103917534B (zh) 作为h3受体抑制剂的包含哌啶和哌嗪环的氨基甲酸酯/脲衍生物
CA3129117A1 (en) Charged ion channel blockers and methods for use
CN110121502A (zh) 一种抗抑郁化合物及其制备方法和应用
ES2953926T3 (es) Agonistas 5-HT2A para el tratamiento de la depresión
US20170100389A1 (en) Tetrahydroprotoberbine compounds and uses thereof in the treatment of neurological, psychiatric and neurodegenerative diseases
CN109020887B (zh) 作为防治精神障碍疾病的酰胺类化合物
WO2016088813A1 (ja) 新規ジアザビシクロ［２．２．２］オクタン誘導体
US20240166599A1 (en) Indole derivatives as serotonergic agents useful for the treatment of disorders related thereto
WO2020048043A1 (zh) 作为防治精神障碍疾病的苯胺类化合物
EP3638238A1 (en) Methods of treating metabolic diseases with fused bicyclic pyrazoles
ES2511065T3 (es) Nuevo compuesto imidazopiridina
EP2948143A1 (en) Use of phenoxypropylamine compounds to treat depression
CN102234284B (zh) 含氟的噻氯匹啶类似物及其制备方法和用途
CN111548313A (zh) 预防和治疗慢性疼痛药物的胍类化合物
WO2018102824A1 (en) Methods for treating neurodegenerative disease
WO2024008166A1 (zh) 一类α,β-不饱和酰胺类化合物及其制备方法、药物组合物和用途
CN110467597B (zh) 芳烷环胺类衍生物及其在多靶点抗抑郁症药物中的应用
JP2018048093A (ja) モルヒナン誘導体及びその医薬用途
EP3569233A1 (en) Therapeutic agent for non-motor symptoms associated with parkinson&#39;s disease
CN117886714A (zh) 丙氨酸衍生物、其制备方法及医药用途

Legal Events

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

Ref document number: 18932654

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18932654

Country of ref document: EP

Kind code of ref document: A1