WO2023116915A1 - Inhibiteur double cible ache/sert, son procédé de préparation et son utilisation - Google Patents

Inhibiteur double cible ache/sert, son procédé de préparation et son utilisation Download PDF

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WO2023116915A1
WO2023116915A1 PCT/CN2022/141611 CN2022141611W WO2023116915A1 WO 2023116915 A1 WO2023116915 A1 WO 2023116915A1 CN 2022141611 W CN2022141611 W CN 2022141611W WO 2023116915 A1 WO2023116915 A1 WO 2023116915A1
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halogens
substituted
alkyl
formula
alkoxy
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PCT/CN2022/141611
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Chinese (zh)
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杨新春
李剑
成佳兴
赵金龙
李晓康
许祥诚
梅丹
陈亮
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珠海市藤栢医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a novel AChE/SERT dual-target inhibitor, a preparation method thereof, a pharmaceutical composition containing this type of compound, and as an acetylcholinesterase inhibitor and a serotonin transporter inhibitor , especially the preparation of medicines for preventing and/or treating Alzheimer's disease, depression, Alzheimer's disease and depression comorbidities.
  • AD Alzheimer's disease
  • dementia dementia
  • senile dementia dementia
  • dementia is a progressive and fatal neurodegenerative disease, clinically manifested as memory dysfunction, aphasia, apraxia, agnosia, visuospatial Generalized dementia manifests as impaired skills, executive dysfunction, and changes in personality and behavior, with psychiatric symptoms such as depression, irritability, and anxiety.
  • psychiatric symptoms such as depression, irritability, and anxiety.
  • 90% of AD patients will be accompanied by neuropsychiatric symptoms, among which depression is one of the most common comorbidities, accounting for about 50% of AD patients, which is 10 times the incidence rate of the general population, and is different from the general population.
  • Patients with depression, AD-depression co-morbidity are more difficult to treat and have higher mortality.
  • depression patients are often accompanied by memory and cognitive impairment. About two-thirds of depressed patients will be accompanied by cognitive impairment. 94% of depressed patients still have cognitive impairment after recovery. Depression is considered to be a prodromal symptom of AD. or risk factors. At present, there are 35 million AD patients and 264 million depression patients in the world. Therefore, the potential number of patients with AD-depression co-morbidity is huge, and the development of related therapeutic drugs has broad market prospects and important social value.
  • AD-depression co-morbidity is still unclear, and there is no targeted treatment.
  • the existing method is to use anti-AD drugs and antidepressants for combined administration.
  • the curative effect of such combination drugs is often poor, and it cannot achieve the effect of single drug in treating a single disease, and because the patients are mainly elderly, it is accompanied by a higher risk of drug-drug interactions.
  • Acetylcholinesterase inhibitors are the most important anti-AD drugs, including Tacrine developed by Warner-Lambert in the United States (later withdrawn due to liver toxicity), Japan's Eisai Pharmaceuticals (Eisai) Donepezil developed by Novartis, Rivastigmine developed by Novartis, Galanthamine developed by Johnson & Johnson, and Huperzine A developed by Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Among them, donepezil is a reversible acetylcholinesterase inhibitor, which increases the concentration of acetylcholine in the synaptic cleft by inhibiting the hydrolysis of acetylcholine by acetylcholinesterase.
  • Antidepressant drugs are mainly selective serotonin reuptake inhibitors (SSRIs), which selectively inhibit the reuptake of serotonin (5-HT) by inhibiting the serotonin transporter (SERT). , Increase the concentration of 5-HT in the synaptic gap in the brain of depressed patients.
  • SSRIs selective serotonin reuptake inhibitors
  • SERT serotonin transporter
  • SSRIs selective serotonin reuptake inhibitors
  • 5-HT serotonin transporter
  • Vilazodone an anti-major depressive drug, has both selective 5-HT reuptake inhibitory activity and 5-HT 1A agonistic activity. Therefore, for the mature targets of AD and depression, the development of drugs that simultaneously increase the levels of acetylcholine and serotonin in the brain may be expected to treat AD-depression co-morbidity.
  • 5-HT 1A agonistic activity may aggravate memory impairment in AD patients.
  • 5-HT 1A receptors affect memory function by affecting the activity of glutamatergic, cholinergic and GABAergic neurons in the cerebral cortex and hippocampal projection areas. Studies have shown that human subjects who take the 5-HT 1A receptor agonist Ipsapirone or the 5-HT 1A receptor partial agonist Tandospirone have impaired verbal memory.
  • 5-HT 1A receptor antagonists can enhance cholinergic transmission and improve cognitive function, such as NAD-299, WAY-100635 and Lecozotan (SRA-333) SR. It has been shown to improve memory in animal models of cognitive impairment.
  • Lecozotan developed by Wyeth can significantly improve the task completion efficiency of aged rhesus monkeys and reverse the memory deficits in marmoset monkeys caused by glutamate antagonists, and entered clinical phase II in 2005 for the treatment of mild to moderate AD patients.
  • 5-HT 1A agonistic activity may play a role that is not conducive to disease treatment, and it is urgent to develop a more beneficial treatment for AD-depression co-morbidity.
  • AChE/SERT dual-target inhibitor of the disease may play a role that is not conducive to disease treatment, and it is urgent to develop a more beneficial treatment for AD-depression co-morbidity.
  • the pathological mechanism of AD-depression co-morbidity is complex, the market demand is huge, and the treatment drug is facing a gap.
  • the development of effective treatment drug has important social value and medical value.
  • the resulting drug-drug interaction reduces the difficulty of taking medicine and the physical burden of patients.
  • the object of the present invention is to provide a dual-target inhibitor of acetylcholinesterase (AChE)/serotonin transporter (SERT) with novel structure.
  • AChE acetylcholinesterase
  • SERT serotonin transporter
  • the present invention provides the compound shown in formula I, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I, its tautomer or its stereo isomer), or any of the foregoing (referring to the pharmaceutically acceptable salt of the foregoing compound as shown in formula I, its tautomer, its stereoisomer, or any of the foregoing The solvate of the salt of );
  • each are independently double bonds or single bonds
  • Each R 1 is independently CN, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or C 1 -C 6 alkoxy substituted by 3 halogens;
  • n1 0, 1, 2, 3 or 4;
  • R 2 is H, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens;
  • Each R 3 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens or substituted by 1, 2 or 3 Halogen substituted C 1 -C 6 alkoxy;
  • n2 0, 1, 2, 3 or 4;
  • R 4 is C 6 -C 10 aryl, C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, benzyl, benzyl substituted by 1, 2 or 3 halogens, cyclopentane, substituted by 1, 2 or 3 halogen substituted cyclopentane, cyclohexane, 1, 2 or 3 halogen substituted cyclohexane, "heteroatoms selected from 1, 2 or 3 of N, O and S species, 5-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms", “heteroatoms substituted by 1, 2 or 3 halogens are selected from one or two of N, O and S or 3 kinds, 5-12 membered heterocycloalkyl groups with 1, 2 or 3 heteroatoms", “heteroatoms are selected from 1, 2 or 3 kinds of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered heteroaryls" or "heteroatoms substituted by 1,
  • R 5 is H, halogen, C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted by 1, 2 or 3 halogens Substituted C 1 -C 6 alkoxy; or, R5 is connected to the carbon marked with * to form -(CH 2 ) n2 -; n2 is 0 or 1;
  • n 1, 2, 3, 4, 5 or 6;
  • n1 0, 1, 2 or 3.
  • the compound shown in formula I, its tautomer, its stereoisomer, or any of the foregoing referring to the aforementioned compound shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or
  • Certain groups in the solvate of any of the aforementioned pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are as described in any scheme of the present invention (referred to as "in a certain scheme of the present invention") ,
  • R 1 among the halogen, the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens and the C 1 -C 6 alkoxy substituted by 1, 2 or 3 halogens,
  • the halogen is independently F, Cl, Br or I, such as F.
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens is trifluoromethyl.
  • the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the halogens are independently F, Cl, Br or I, such as F.
  • the halogen in R 3 , is independently F, Cl, Br or I, such as F.
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
  • Aryl is phenyl or naphthyl, eg phenyl.
  • the C 6 -C 10 aryl substituted by 1, 2 or 3 halogens is phenyl substituted by 1, 2 or 3 Fs, for example
  • the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered Heterocycloalkyl" and the "heteroatom” substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 In 5-12 membered heterocycloalkyl", said "heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • Cycloalkyl is independently "a 5-6 membered heterocycloalkyl group with 1 or 2 heteroatoms selected from one or two of N, O and S".
  • the "heteroatom is selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12 membered Heteroaryl" and the "heteroatoms substituted by 1, 2 or 3 halogens are selected from 1, 2 or 3 of N, O and S, 5 with 1, 2 or 3 heteroatoms -12-membered heteroaryl", said "heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3 5-12-membered heteroaryl "independently means "a 5-6 membered heteroaryl group with 1 or 2 heteroatoms selected from one or two of N, O and S".
  • the halogen in R 5 , is independently F, Cl, Br or I, such as F.
  • the C 1 -C 6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
  • the C 1 - C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy .
  • R 1 is independently CN, halogen or C 1 -C 6 alkyl substituted by 1, 2 or 3 halogens; preferably F, CF 3 or CN, more preferably F or CN .
  • m1 is 1.
  • R 2 is H or C 1 -C 6 alkyl, preferably H or methyl, more preferably H.
  • R 3 is halogen, such as F.
  • m2 is 0 or 1.
  • R 4 is C 6 -C 10 aryl or C 6 -C 10 aryl substituted by 1, 2 or 3 halogens, preferably phenyl, More preferably phenyl or
  • R 5 is H; or, R 5 is connected with a carbon marked with * to form -CH 2 -.
  • n1 is 0.
  • n 1, 2, 3 or 4.
  • the compound shown in formula I has a structure shown in formula I-A or I-B:
  • n, m1, m2, R 1 , R 2 , R 3 and R 4 are as described in any one of the present invention.
  • the compound shown in formula I is any one of the following compounds:
  • the present invention also provides a preparation method of the compound shown in formula I, which is the following method 1 or method 2:
  • Described method one comprises the steps:
  • X is a halogen
  • Described method two comprises the following steps:
  • n3 n-1 (ie 0, 1, 2, 3, 4 or 5);
  • n, n1, m1, m2, R 1 , R 2 , R 3 , R 4 and R 5 are as described in any one of the present invention.
  • the present invention also provides compounds as shown in formula II:
  • n1, m2, R 3 , R 4 and R 5 are as described in any one of the present invention.
  • the compound shown in formula II is any one of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing referring to the aforementioned formula I
  • the pharmaceutically acceptable salt of the shown compound, its tautomer or its stereoisomer), or any of the foregoing referring to the aforementioned compound shown in formula I, its tautomer, its Stereoisomers or pharmaceutically acceptable salts of any of the foregoing) solvates are active ingredients, and the content thereof is a safe and effective amount.
  • Safe and effective amount means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose.
  • the "one dose” is a tablet.
  • the administration method of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other therapeutic agents.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is generally 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention also provides the compound shown in formula I as described in any one of the present invention, its tautomer, its stereoisomer, or any of the foregoing (referring to the aforementioned compound shown in formula I , its tautomer or its stereoisomer), or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer, its stereoisomer or a pharmaceutically acceptable salt of any of the foregoing), or the use of the pharmaceutical composition, selected from:
  • the present invention also provides a method for preventing and/or treating diseases, which comprises: administering a therapeutically effective amount of a compound represented by formula I as described in any one of the present invention, or its tautomorphism, to a subject in need isomer, its stereoisomer, or a pharmaceutically acceptable salt of any of the foregoing (referring to the aforementioned compound as shown in formula I, its tautomer or its stereoisomer), or any of the foregoing (referring to the solvate of the aforementioned compound shown in formula I, its tautomer, its stereoisomer or any of the aforementioned pharmaceutically acceptable salts), or the pharmaceutical composition, the Disease selected from:
  • a substituent may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond.
  • pharmaceutically acceptable means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • the base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid, arginine) and the like.
  • the compounds of the present invention When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts.
  • base addition salts For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
  • solvate refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric solvent.
  • Solvent molecules in solvates can exist in an ordered or non-ordered arrangement.
  • the solvent includes but not limited to: water, methanol, ethanol and the like.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution through bond formation (chemical combination, etc.) or salt formation (physical combination, etc.) with other chiral compounds.
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • any variable such as halogen
  • the definition at each position of the variable has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 halogens, that is to say, the group may be substituted by up to 3 halogens, the definition of halogen at this position is independent of the definition of halogen at other positions. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • alkoxy refers to the group -ORx , wherein Rx is alkyl as defined above.
  • heterocycloalkyl refers to a group having a specified number of ring atoms (eg, 5-12 members), a specified number of heteroatoms (eg, 1, 2, or 3), a specified type of heteroatom (N, O, and S 1, 2 or 3) of the cyclic group, which is a monocyclic, bridged or spiro ring, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • aryl refers to a C 6 -C 10 aryl group such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic ring groups independently selected from nitrogen, oxygen and sulfur, which are monocyclic or bicyclic, when When bicyclic, at least one ring is aromatic, such as furyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzene Azoxazolyl, benzisoxazolyl, quinolinyl, isoquinolyl, etc.
  • pharmaceutically acceptable carrier refers to the excipients and additives used in the production of medicines and the formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except the active ingredient.
  • Can refer to Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • patient refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • the acetylcholinesterase inhibitor, the serotonin transporter inhibitor or the dual inhibitor of acetylcholinesterase and serotonin transporter can be used in mammalian organisms; it can also be used in vitro, mainly as Experimental purposes, for example: providing comparison as a standard or control sample, or making a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of acetylcholinesterase and/or serotonin transporter.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: the inventors of the present invention have developed a compound as shown in formula I after extensive and in-depth research, which has both acetylcholinesterase inhibitory activity and serotonin transporter inhibitory activity, and has good in vitro And blood-brain barrier permeability in vivo, used for the treatment of Alzheimer's disease, depression, Alzheimer's disease and depression comorbidities, avoiding harmful drug interactions caused by combined drugs, reducing the difficulty of taking drugs and Physical burden.
  • Figure 1 shows the effect of compound Ib - 7 on the activity of acetylcholinesterase AChE in mouse brain.
  • Figure 2 shows the experimental results of the antidepressant effect of compound Ib - 7 on tail suspension depression model mice.
  • Figure 3 shows the results of the antidepressant effect of compound Ib - 7 on forced swimming model mice.
  • Figure 4 shows the experimental results of the antidepressant effect of compound Ib - 4 on tail suspension depression model mice.
  • Fig. 5 shows the experimental results of the drug effect of compound Ib - 7 on cognitive impairment model mice.
  • Example 1 The 4-bromoacetophenone in step a in Example 1 was replaced by 5-bromoindanone, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product Ia - 4, a yellow solid, with a yield of 52 %.
  • step a in Example 1 The 4-bromoacetophenone in step a in Example 1 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-formonitrile in step e is replaced by 3 -(3-Bromopropyl)-1H-indole-5-carbonitrile, the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 5, a yellow solid, with a yield of 50%.
  • Example 1 The 4-bromoacetophenone in step a in Example 1 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-formonitrile in step e is replaced by 3 -(2-Bromoethyl)-1H-indole-5-carbonitrile, the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product Ia - 6, a yellow solid, with a yield of 52%.
  • step a The 4-bromoacetophenone in step a is replaced by 5-bromoindanone, and 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidine-4 -yl)-2,3-dihydro-1H-inden-1-one.
  • step a in the above-mentioned Example 1, and it is prepared by Aldol condensation reaction of 4-bromoacetophenone and 1-benzyl-4-piperidinecarbaldehyde.
  • the trichlorosilane was formulated into a 25% (volume ratio) anhydrous dichloromethane solution, and the bottle was sealed for later use.
  • Step b tert-Butyl-4-(4-(3-(1-benzylpiperidin-4-yl)propionyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Synthesis
  • Step d Synthesis of 3-(1-benzylpiperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one
  • Example 11 The 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e of Example 11 was replaced by 3-(3-bromopropyl)-1H-indole-5-carbonitrile, and the rest The required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product I a -8, a yellow solid, with a yield of 54%.
  • Example 11 The 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e of Example 11 was replaced by 3-(2-bromoethyl)-1H-indole-5-carbonitrile, and the rest The required raw materials, reagents and preparation method are the same as in Example 11 to obtain the product Ia - 9, a yellow solid, with a yield of 57%.
  • Example 11 The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (2-Bromoethyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 10, a yellow solid, with a yield of 57%.
  • Example 11 The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (3-Bromopropyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 11, a yellow solid, with a yield of 57%.
  • Example 11 The 4-bromoacetophenone in step a of Example 11 is replaced by 5-bromoindanone, and the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile in step e is replaced by 3- (2-Bromoethyl)-1H-indole-5-carbonitrile, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 11 to obtain the product Ia - 12, a yellow solid, with a yield of 53%.
  • Example 7 3-(1-benzylpiperidin-4-yl)-1-(4-(piperidin-4-yl)phenyl)propan-1-one in Example 7 is replaced by 3-(1-benzyl Piperidin-4-yl)-1-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propan-1-one, the rest of the required raw materials, reagents and preparation methods are the same Example 7, the product Ib - 5 was obtained as a white solid with a yield of 57%.
  • Step b tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step c tert-butyl-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Synthesis of -yl)piperidine-1-carboxylate
  • Step d 2-((1-Benzyl-4-fluoropiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1- Ketone synthesis
  • Step e 3-((4-(2-((1-Benzyl-4-fluoropiperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene-5 Synthesis of -yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step n of Example 19 The benzyl bromide in Step n of Example 19 was replaced by 2-fluorobenzyl bromide, and the remaining raw materials, reagents and preparation methods were the same as in Step n of Example 19 to obtain 350 mg of (E)-5-bromo-2-((4-fluoro -1-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-2,3-dihydro-1H-inden-1-one, white solid, yield 52%.
  • Step b tert-butyl-(E)-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2, Synthesis of 3-dihydro-1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step c tert-butyl-4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)piperidine-1-carboxylate
  • Step d 2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H -Synthesis of inden-1-one
  • Step f 3-((4-(2-((4-fluoro-1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro- Synthesis of 1H-inden-5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step b tert-butyl-(E)-4-(1-oxo-2-(piperidin-4-ylmethylene)-2,3-dihydro-1H-inden-5-yl)-3 , Synthesis of 6-dihydropyridine-1(2H)-carboxylate
  • Step f 3-((4-(2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step a tert-butyl-4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
  • Step b 2-((1-(3-Fluorobenzyl)piperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-indene-1 -Synthesis of ketones
  • Step c 3-((4-(2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step a tert-butyl-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidine-1-carboxylate
  • Step f 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step d Synthesis of 2-((1-benzylpiperidin-4-yl)methyl)-5-(piperidin-4-yl)-2,3-dihydro-1H-inden-1-one
  • Step f 2-((1-benzylpiperidin-4-yl)methyl)-5-(1-((5-fluoro-1H-indol-3-yl)methyl)piperidine-4- Synthesis of -2,3-dihydro-1H-inden-1-one
  • Step a tert-butyl-(E)-4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-1-oxo-2,3-dihydro Synthesis of -1H-inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step b (E)-2-((1-(4-fluorobenzyl)piperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl )-2,3-dihydro-1H-inden-1-one synthesis
  • Step c 3-((4-(2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)-1-oxo-2,3-dihydro-1H-indene- Synthesis of 5-yl)piperidin-1-yl)methyl)-1H-indole-5-carbonitrile
  • Step d (E)-2-((1-Benzyl-4-fluoropiperidin-4-yl)methylene)-5-(1,2,3,6-tetrahydropyridin-4-yl) Synthesis of -2,3-dihydro-1H-inden-1-one
  • 530mg tert-butyl-(E)-4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro-1H -Inden-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added dropwise with stirring, and stirred at room temperature for 1 hour.
  • Step f (E)-3-((4-(2-((1-benzyl-4-fluoropiperidin-4-yl)methylene)-1-oxo-2,3-dihydro- Synthesis of 1H-indol-5-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-indole-5-carbonitrile
  • This effect example shows the activity inhibition experiment and activity results of the compound of the present invention on acetylcholinesterase (AChE).
  • the compound with acetylcholinesterase inhibitory activity can inhibit the hydrolysis of acetylcholine in the brain, thereby increasing the concentration of acetylcholine in the brain, promoting memory cognition, and can be used to improve symptoms and treat AD.
  • the modified Ellman method was used to measure the activity of acetylcholinesterase. Using the cerebral cortex of SD mice as the source of AChE enzyme, thioacetylcholine was added to the reaction template under the optimal enzyme reaction conditions, and the AChE enzyme activity was detected by colorimetry after adding the test substance.
  • the cerebral cortex of SD rats was used as the source of acetylcholinesterase.
  • the sampling method was that after the rats were put to death, the brain was quickly taken out and the cortex was separated on ice, and the brain homogenate was prepared with 75mM phosphate buffer (pH 7.4). Store in a centrifuge tube at -20°C for later use.
  • the solution was diluted with pre-cooled PBS to an absorbance of 0.3-0.35, and 10% volume fraction of butyrylcholinesterase inhibitor OMPA was added to the solution.
  • the experimental operation is as follows: (1) Take a 96-well plate, add 10 ⁇ L of cerebral cortex homogenate, 50 ⁇ L of phosphate buffer (0.1M), and 50 ⁇ L of chromogenic agent 5,5’-dithiobis(2 -nitrobenzoic acid) (DTNB), 109 ⁇ L of deionized water, 30 ⁇ L of the choline substrate thioacetylcholine (S-Ach) at a concentration of 2 mM, and 1 ⁇ L of the compound to be tested (concentration gradient from 1 nM to 10 mM). (2) After reacting at room temperature for 20 minutes, 50 ⁇ L of 3% SDS was added to terminate the reaction.
  • DTNB chromogenic agent 5,5’-dithiobis(2 -nitrobenzoic acid)
  • thioacetylcholine will be decomposed into Thiocholine (Thiocholine) under the action of AChE in the cortex, and then quickly react with the chromogenic agent DTNB to generate a yellow substance 5-mercapto-2-nitrobenzene with a maximum absorption wavelength of 412nm Formate.
  • DTX 880 Beckman Coulter
  • Table 1 The inhibitory activity data of compound of the present invention to acetylcholinesterase
  • This effect example shows the activity inhibition experiment and activity results of the compound of the present invention on serotonin transporter (SERT).
  • SERT serotonin transporter
  • the compound with this activity can increase the concentration of serotonin in the brain by inhibiting the reuptake of serotonin in the brain, and can be used for treating depression or improving AD.
  • human embryonic kidney cells HEK293 were used to express the human 5-HT transporter, and the commercially available kit Neurotransmitter Transporter Uptake Assay Kit (Molecular Devices, Cat. No. R8173) was used for testing.
  • the kit uses fluorescent substrates to simulate monoamine neurotransmitters such as 5-HT, and enters cells through specific transporters such as serotonin transporters, resulting in an increase in the fluorescence intensity of cells.
  • the specific experimental methods are as follows: (1) Cell plating: Thaw the cells and culture them for 3-4 days. After passage, cells were cultured for another 3 days in the cell culture incubator. Cells were collected by centrifugation at 1000 rpm for five minutes after digestion with trypsin-EDTA. Resuspend cells in 10 mL medium. Pipette cells to prevent adhesion. cell counts. Dilute the cells with medium to 1 million cells/mL, plant 20,000 cells per well, and incubate at 37°C/5% CO 2 for 16–20 hours. (2) Transport experiment: configure 20mM HEPES HBSS solution containing 0.1% BSA as diluent and working solution. Positive compounds were serially diluted 4 times to 10 concentrations, with the highest concentration being 2 ⁇ M.
  • the compounds of the present invention have potent serotonin transporter inhibitory activity, wherein the inhibitory activity of some preferred compounds is lower than 10nM (better than positive control citalopram hydrobromide), illustrating the present invention
  • the compounds can be developed into serotonin transporter inhibitors antidepressants or anti-AD drugs. Since the compound of the present invention has the inhibitory activity of acetylcholinesterase and five serotonin transporter, it is a kind of multi-target drug which is expected to treat AD-depression co-morbidity.
  • This effect example shows the agonistic activity test and activity results of the compound of the present invention on 5-HT 1A receptors.
  • the human 5-HT 1A receptor was overexpressed using HEK293 cells.
  • the culture medium is DMEM medium containing 50 mg/mL G418 and 10% FBS, cultured under the condition of 5% CO 2 /37°C. When the cells grow to 70%, digest the cells, resuspend the cells with buffer after centrifugation, and incubate in a 384-well plate for 16-20 hours.
  • Table 3 Agonistic activity data of compounds of the present invention on 5-HT 1A
  • comparative compound A comes from "Design Synthesis and Activity Research of Multi-target Anti-AD Active Compounds and Research on Synthesis Methodology of 3-aryl-3-oxindolinone", Li Xiaokang, East China University of Science and Technology, 2018.
  • the EC50 of most compounds of the present invention to the 5-HT 1A receptor is more than several hundred nanomoles, which is more than a hundred times different from the positive control, and compared with the AChE/SERT activity of the compound itself. The difference is quite large, indicating that the compound of the present invention basically eliminates the agonistic activity of 5-HT 1A and avoids memory damage that may be caused by 5-HT 1A receptor stimulation.
  • Effect Example 4 This effect example shows the inhibitory experiment and activity results of the compound of the present invention on the activity of acetylcholinesterase in mouse brain.
  • the compound with acetylcholinesterase inhibitory activity can inhibit the hydrolysis of acetylcholine in the brain, thereby increasing the concentration of acetylcholine in the brain, promoting memory cognition, and can be used to improve symptoms and treat AD.
  • the AChE inhibition experiment in the mouse brain is a fast and efficient experiment, which is used to evaluate the inhibitory activity of the test compound on the activity of AChE in the animal brain, and can also reflect the brain-penetrating ability of the compound.
  • the experimental animals were ICR mice, male, weighing about 17–21 g. Weigh a certain amount of compound and dissolve it in PEG400, vortex to dissolve it, then add HS-15 and mix evenly to form a transparent and clear solution. It was orally administered at a dose of 0.3 mg/kg-30 mg/kg, and the solvent control group was given the corresponding solvent control. After administration, the appearance and state of the mice were observed to judge whether there were peripheral cholinergic side effects such as salivation, sweating, and convulsions.
  • mice were killed by denecking at the sampling point (0.5-24 hours), and the brain was quickly taken out, and the hemibrain was diluted into a homogenate with pre-cooled phosphate buffer solution, and the butyrylcholinesterase inhibitor OMPA was added, and then Add thioacetylcholine (S-Ach) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTBN) and react at room temperature for 20 minutes. No brain homogenate was added to blank wells. After the experiment, SDS was added to each well to terminate the reaction, and an appropriate amount of enzyme was added to the blank well.
  • S-Ach thioacetylcholine
  • DTBN 5,5'-dithiobis(2-nitrobenzoic acid)
  • the inhibitory rate of the compound to AChE was calculated by detecting the absorbance of each well.
  • the calculated inhibition rate and the corresponding concentration were nonlinearly fitted to calculate the IC 50 value of the compound against AChE in the mouse brain.
  • the values in Table 4 are the activity of acetylcholinesterase in the mouse brain 1 hour and 6 hours after administration.
  • the solvent control group (control group) is the 20% PEG400 solution that does not contain compound, is set as 100%, and all the other groups are percentage values (Mean ⁇ SD) compared with the solvent control group, *P ⁇ 0.05 (with the solvent control group group), **P ⁇ 0.01 (compared with solvent control group).
  • Table 5 Effect of 1 mg/kg preferred compound Ib - 7 on the activity of acetylcholinesterase in the ICR mouse brain
  • the values in Table 5 are the activity of acetylcholinesterase in the mouse brain after administration for 0.5-24 hours.
  • the solvent control group is deionized water, which is set as 100%, and all the other groups are percentage values (Mean ⁇ SD) compared with the solvent control group, *P ⁇ 0.05 (compared with the solvent control group), **P ⁇ 0.01 (compared with the solvent control group).
  • the AChE activity in the data in Table 4 has a value higher than 100% because of the low AChE activity in the hippocampus of a mouse in the control group, which belongs to individual differences. , but it does not affect the experimental conclusion.
  • Compound Ib -7 can significantly inhibit the activity of AChE in the mouse brain endocortex and hippocampus at a dose of 5 mg/kg orally, and the inhibitory activity is dose-dependent and time-dependent .
  • the inhibitory activity is dose-dependent and time-dependent .
  • the AChE activities in the hippocampus and cortex were inhibited to 23.0% and 27.8%, respectively.
  • Ib - 7 can reduce the AChE activity in the mouse brain endocortex to 49.49% at a dose of 1 mg/kg orally, and has no peripheral cholinergic side effects.
  • the values in Table 6 are the activity of acetylcholinesterase in the mouse brain 24 hours after administration.
  • the solvent control group (control group) is the 20% PEG400 solution that does not contain compound, is set as 100%, and all the other groups are percentage values (Mean ⁇ SD) compared with the solvent control group, *P ⁇ 0.05 (with the solvent control group group), **P ⁇ 0.01 (compared with solvent control group), ***P ⁇ 0.005 (compared with solvent control group).
  • compound Ib - 4 can significantly inhibit the activity of AChE in the mouse brain endocortex and hippocampus at an oral dose of 1 mg/kg, and the inhibitory activity is dose-dependent. After oral administration of 10 mg/kg Ib -4 for 24 hours, it inhibited the AChE activity in the hippocampus and cortex of the mouse brain to 36.87% and 34.00%, respectively.
  • the tail-suspension test is a classic, fast and convenient test for evaluating the efficacy of antidepressants, and it belongs to the behavioral hopelessness model.
  • the experimental principle is to carry out short-term and inescapable acute stress on mice by tail suspension, so that the mice enter a static state of giving up resistance, so as to establish a mouse depression model.
  • Forced swimming is also a classic model of behavioral desperation. Mice try to escape but cannot escape, so they give up struggling and enter a unique state of depression and immobility. During the experiment, the immobility time of animals is recorded to reflect the state of depression.
  • Antidepressant drugs have the effect of reversing this static state and promoting related behaviors such as escaping in mice, so they can reduce the immobility time of mice, and the antidepressant effect of drugs can be effectively evaluated by measuring the immobility time of mice. effect.
  • compounds Ib -7 and Ib -4 with strong dual-target inhibitory activities of AChE and serotonin transporter were selected for experiments. The experiment adopts the tail suspension test method reported by Steru et al., or the forced swimming method, and evaluates the antidepressant efficacy of the compound by examining whether the administration of the test compound can significantly shorten the immobility time of the tail suspension mice.
  • mice with an average body weight of 20-25 g and 5-6 weeks old were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd. They were fed with free access to water and pre-acclimated to the environment for one week. Before the experiment, number the tails of the mice and group them into groups of 10, and weigh them. The experiment was divided into solvent control group, positive drug vilazodone group and test compound group. On the day of the experiment, the test drug solution was prepared. First, the test compound was dissolved in PEG400, and then 20% HS-15 physiological saline solution was added to form a clear and uniform solution. The final liquid composition is 25% PEG400+15% HS+60% saline.
  • the solvent control group was given 0.9% physiological saline, and the positive drug and test compound group were prepared with the above method and administered orally. According to the order of mouse numbering, the two mice were given medicine at an interval of 8 minutes, and then returned to the original cage, and the tail suspension test was carried out 1 hour later.
  • the tail suspension test was carried out 1 hour later.
  • the experiment video was recorded for 6 minutes. After the completion, the mice were removed, put into the original cage, and the tail suspension box was wiped with alcohol to remove the animal smell.
  • the experimental animals were placed in a glass cylinder filled with water, and the water temperature was controlled at about 25°C (up and down not exceeding 1°C), and the liquid level was adjusted according to the size of the experimental animals, generally about 18cm.
  • Experimental video 6 Minutes change the water to start the next group after completing one group each time, so as to avoid the influence of mouse smell on the experiment.
  • the experiment adopts a double-blind system, that is, the operator who administers the drug and performs the tail suspension test and the statistician of the immobility time need to be different personnel and do not know each other.
  • the statistician counts the immobility time of the mouse in the last 4 minutes of the 6-minute video recording, and can divide the mouse's motor behavior (the subjective and obvious escape behavior) into (1) the action of running forward or backward; 2) The body twists, trying to grab the suspension; (3) The body shakes, swings, and twitches. After the recording was completed, the average immobility time of mice in each group was statistically plotted.
  • the compound I b -7 with strong dual-target inhibitory activity of AChE and serotonin transporter was selected for antidepressant efficacy experiment.
  • the experiment set up solvent control group normal saline, 10mL/kg
  • vilazodone multiple administration group (15mg/kg, once a day, continuous administration for 5 days
  • vilazodone Single administration group (30mg/kg, administration once)
  • Ib -7 multi-administration group (3mg/kg, once a day, continuous administration for 5 days) carried out mouse tail suspension behavior experiment, by mice
  • the degree of reduction of immobility time reflects the antidepressant efficacy of the compound, and the experimental results are shown in FIG. 2 .
  • **P ⁇ 0.01 compared with solvent control group).
  • the preferred compound Ib - 7 can significantly reduce the immobility time of tail-suspension mice at a dose of 3 mg/kg orally for 5 consecutive days, indicating that it has antidepressant effects and is expected to be used for the treatment of depression .
  • the experiment set solvent control group normal saline
  • vilazodone multiple administration group 10mg/kg, once a day, continuous administration for 7 days
  • Ib -7 multiple administration group Drug group (0.1mg/kg, once a day, continuously administered for 7 days), I b -7 multiple administration group (0.3mg/kg, once a day, continuously administered for 7 days) and I b -7 repeatedly administered
  • the drug group 1.0 mg/kg, once a day, administered continuously for 7 days
  • the experimental results are shown in Figure 3.
  • the preferred compound Ib - 7 can significantly reduce the immobility time of forced swimming mice under the dose of 0.1-1.0mg/kg orally administered for 7 consecutive days, indicating that it has antidepressant effects and is expected to be used in Treat depression.
  • the scopolamine-induced cognitive impairment animal model is a classic pharmacological model commonly used to evaluate drug candidates against Alzheimer's disease.
  • As an M-choline receptor blocker scopolamine has similar affinity with various subtypes of M-receptors, can hinder the combination of acetylcholine and M-receptors in the brain, and mainly acts on the acquisition stage of memory, thereby affecting the transmission of information. It can lead to impairment of learning and memory functions, which can be used as one of the classic methods for modeling Alzheimer's disease. Studies have proved that a single administration of scopolamine can be used as a model of learning and memory impairment, which can cause functional changes, and the damage of this model is reversible.
  • a model was established by administering 1 mg/kg scopolamine, and 22-25 g C57 mice were used as experimental subjects to receive the test compound once to observe whether the animals could improve the memory impairment caused by scopolamine.
  • the target compound was dissolved with 20% PEG400 to prepare a clear oral reagent, the dosage was 0.1-5 mg/kg, and donepezil hydrochloride 10 mg/kg was used as a positive control group.
  • 1 mg/kg scopolamine was injected intraperitoneally 30 minutes after compound administration, and the behavior of the test mice was observed by Y maze/water maze experiment 30 minutes later.
  • compound I b -7 which has strong dual-target inhibitory activity of AChE and serotonin transporter, was selected for cognitive impairment model experiments.
  • compound Ib - 4 with strong activity was selected for pharmacokinetic properties and blood-brain distribution ratio experiments.
  • oral administration of compound I b -4 (10 mg/kg) or intravenous injection of compound I b -4 (2 mg/kg) to ICR mice plasma and brain tissue were collected at different time points, and the ICR mice were detected The concentration of the test substance in plasma and brain tissue, and calculate the relevant parameters.
  • the experimental results are shown in Table 7 and Table 8. As shown in Table 7, the oral bioavailability of compound Ib -4 was 35.83. It can be seen from Table 8 that the plasma drug concentration of compound Ib - 4 reached a peak rapidly after oral administration, and continued to decline slowly after 0.5 hours.
  • the concentration of compound Ib -4 in the brain first increased gradually, reached the peak at 16-24 hours, and then decreased slowly and was gradually excreted by metabolism.
  • the brain-to-blood ratio of Compound Ib -4 was greater than 1, indicating that Compound Ib -4 has a good ability to penetrate the blood-brain barrier.
  • the oral plasma metabolic half-life of compound Ib -4 is 23.97 hours longer, so once-a-day administration can be considered.

Abstract

Sont divulgués un inhibiteur double cible AChE/SERT, son procédé de préparation et son utilisation, et en particulier un composé tel que représenté dans la formule I, un tautomère de celui-ci, un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de l'un quelconque des précédents, ou un solvate de l'un quelconque des précédents. Le composé a à la fois une activité inhibitrice de l'acétylcholinestérase et une activité inhibitrice du transporteur de la sérotonine, a une bonne perméabilité de la barrière hémato-encéphalique in vitro et in vivo, et est utilisé pour traiter la maladie d'Alzheimer, la dépression et la comorbidité entre la maladie d'Alzheimer et la dépression, ce qui permet d'éviter des interactions médicamenteuses nuisibles provoquées par une administration combinée, et de réduire la difficulté d'administration et la charge physique des patients.
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