WO2018210229A1 - Agoniste du récepteur nicotinique de l'acétylcholine alpha-7 et application de celui-ci - Google Patents

Agoniste du récepteur nicotinique de l'acétylcholine alpha-7 et application de celui-ci Download PDF

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WO2018210229A1
WO2018210229A1 PCT/CN2018/086865 CN2018086865W WO2018210229A1 WO 2018210229 A1 WO2018210229 A1 WO 2018210229A1 CN 2018086865 W CN2018086865 W CN 2018086865W WO 2018210229 A1 WO2018210229 A1 WO 2018210229A1
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acid
mmol
nmr
pharmaceutically acceptable
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Chinese (zh)
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吴凌云
张丽
张鹏
陈兆国
陈曙辉
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南京明德新药研发股份有限公司
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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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of alpha-7 nicotine acetylcholine receptor agonists, in particular to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof, and its medical use.
  • Nicotine acetylcholine receptors belong to the family of ligand-gated cation channels and are regulated by the endogenous agonist acetylcholine. Each receptor is a 5-mer composed of 5 sub-organisms. The homologous or heterologous subunits combine to form different nicotine acetylcholine receptor subtypes, but each subtype has the same basic structural features, and the five subtypes form a water-filled pore structure around a center [Masatomo Ishikawa and Kenji Hashimoto, current Pharmaceutical Design, 2011, 17, 121-129, Caulfield MP. Pharmacol Ther. 1993, 58, 319-79, Jones S, Sudweeks S, Yakel JL. Trends Neurosci. 1999, 22, 555-61]. They display three main functional states when they are affected by agonists: the "shutdown” state, the "channel open” state, and the "shutdown desensitization” state.
  • the a7 nicotine acetylcholine receptor is a homologous subtype and is a well-received target, mainly distributed in the cerebral cortex and hippocampus, which are related to learning, memory and cognition [Seguela P, Wadiche J, Dineley-Miller K, J Neurosci. 1993, 13, 596-604].
  • a7 nicotine acetylcholine receptors have been found around the synapses, where they are responsible for regulating other inputs to neurons and activating various downstream signaling pathways [Berg DK, Conroy WG.J Neurobiol. 2002, 53, 512–23, Shoop RD , Martone ME, Yamada N, et al. J Neurosci.
  • the a7 nicotine acetylcholine receptor not only participates in the process of learning, memory, but also plays an important role in regulating neurotransmitters.
  • the a7 nicotine acetylcholine receptor is highly permeable to calcium ions, is rapidly activated by agonists, and is rapidly desensitized. These characteristics make the a7 nicotine acetylcholine receptors the most potential targets for the repair and improvement of cognitive impairment, such as Alzheimer's disease, psychosis, Parkinson's disease, senile memory loss, and neuropathy. Pain and so on.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • T 1 or T 2 is selected from NH and the other is selected from CH 2 ;
  • R 1 is selected from H or is selected from R 2 -L-;
  • R 2 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 -membered heterocycloalkyl optionally substituted by 1, 2 or 3 R, 6 ⁇ 10-membered aryl, 4-6-membered heteroaryl;
  • L is selected from a single bond, or selected from optionally substituted with 1 or 2 R is: -CH 2 -, or
  • R is selected from halogen, CN, OH, NH 2 , NO 2 , COOH, or C 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R';R' Selected from F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 , N(CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R', C 1-3 heteroalkyl.
  • R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, Me, Et, CF 3 .
  • the above R 2 is selected from C 1-3 alkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, or butyl butyl optionally substituted by 1, 2 or 3 R , azetidinyl, tetrahydropyranyl, phenyl, pyridyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, triazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, 2, 3-Dihydrobenzofuranyl.
  • R 2 is selected from the group consisting of
  • the above L is selected from the group consisting of a single bond and -CH 2 -.
  • R 1 is selected from the group consisting of Me,
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 1 is as defined above.
  • the above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R', C 1-3 heteroalkyl, other variables are as defined above.
  • the above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, Me, Et, CF 3 , and other variables are as defined above.
  • the above R 2 is selected from C 1-3 alkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, or butyl butyl optionally substituted by 1, 2 or 3 R , azetidinyl, tetrahydropyranyl, phenyl, pyridyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, triazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, 2, 3-Dihydrobenzofuranyl, other variables are as defined above.
  • R 2 is selected from the group consisting of Other variables are as defined above.
  • the above L is selected from the group consisting of a single bond and -CH 2 -, and other variables are as defined above.
  • R 1 is selected from the group consisting of Me, Other variables are as defined above.
  • the present invention also provides the use of the above compound, a pharmaceutically acceptable salt thereof and tautomer thereof for the preparation of a medicament for treating diseases such as schizophrenia or senile dementia.
  • novel series of compounds in the present invention have good activity and drug-like properties and have potential as candidate compounds for further clinical studies.
  • C 1-6 is selected from C 1 , C 2 , C 3 , C 4 , C 5 and C 6 ;
  • C 3-6 is selected from C 3 , C 4 , C 5 and C 6 .
  • C 1-6 alkyl or C 1-6 heteroalkyl, C 3-6 cyclic or 3- to 6-membered heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then carried out by methods known in the art.
  • the diastereomers are resolved and then recovered to give the pure enantiomer.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • heterocycloalkyl means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom group, which contains a carbon atom and 1, 2, 3 or 4 independently selected from N, Ring heteroatoms of O and S.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). If the resulting compound is stable, the heterocycloalkyl groups described herein can undergo substitutions at the carbon or nitrogen position.
  • the nitrogen atom in the heterocycloalkyl group is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other.
  • Another preferred embodiment is that the total number of S and O atoms in the heterocycloalkyl group does not exceed one.
  • Bridged rings are also included in the definition of heterocycloalkyl.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms.
  • the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Identification index (d2) The ratio of the time difference between the exploration time of the new and old objects (exploring new things time – exploring old things) and the total exploration time (the total exploration time of new and old things) in each group of rats in the test phase.
  • Figure 1 Comparison of the recognition indices of new and old things in each group of rats 15 minutes after training.
  • A-2A (2.00 g, 13.0 mmol) solution of phosphorus oxychloride (21 mL) was stirred at 80 ° C for 5 hours.
  • the reaction mixture was slowly added to water (50 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Filtration and concentration of the filtrate under reduced pressure afforded A-2B (2.10 g).
  • MS-ESI calcd for [M+H] + 173.
  • Iron powder (3.24 g, 57.9 mmol) was added to a solution of A-2C (1.32 g, 5.80 mmol) in acetic acid (40 mL) and stirred at 70 ° C for 3 hr.
  • the reaction mixture was concentrated under reduced vacuolululululululululululululululululululululululululululululu X 1) Washing, drying with anhydrous sodium sulfate, filtration, EtOAc (EtOAc) ).
  • MS-ESI calcd for [M+H] + 153.
  • A-1 (500 mg, 2.54 mmol) and 37B (518 mg, 2.54 mmol) were dissolved in anhydrous dioxane (10 mL), and anhydrous potassium phosphate (1.80 g, 5.08 mmol), (1R) 2R)-cyclohexane-1,2-diamine (29.0 mg, 0.254 mmol) and cuprous iodide (4.8 mg, 0.0250 mmol).
  • the reaction solution was stirred at 110 ° C for 12 hours.
  • the in vitro activity of the compound against the cloned human nicotine acetylcholine receptor was tested.
  • the human nicotine acetylcholine receptor (AChR) ⁇ 7 (encoded by the CHRNA7 gene) and the human chaperone protein RIC-3 (encoded by the RIC3 gene) are stably co-expressed in CHO cells using the Fluo-8 calcium kit or fluorescent imaging plate. The reader reads the information.
  • Test board quality control results are shown in Table 2 (highest value. response; lowest value. response; Z-mass and signal window). The data shows that the test data obtained by this test method is reliable.
  • the test substance defaulted to the positive control acetylcholine (ACh) in the activity assay.
  • ACh positive control acetylcholine
  • the default allosteric modulator PNU-120596 the nicotine acetylcholine ⁇ 7 receptor is rapidly desensitized, it is difficult to observe the agonistic effect of any agonist. Therefore, 1 ⁇ M PNU-120596 was added to the agonist acetylcholine or test article to be tested.
  • the signal caused by the positive control and allosteric modulator PNU-120596 (30 ⁇ M acetylcholine + 1 ⁇ M PNU-120596) was set to an activation rate of 100%.
  • the signal caused by the negative control (1 ⁇ M PNU-120596) was set to an activation rate of 0%.
  • the test compound was classified into the nicotine acetylcholine ⁇ 7 receptor agonistic percentage as follows: + activation rate ⁇ 10%, ++ activation rate 10%-40%, +++ activation rate 40%-70%, ++++ activation rate 70%- 100%, the results are shown in Table 1.
  • Example 37 In vivo activity assay was detected by a NOR (New Object Recognition Memory Experiment) model. Male Wistar rats of 6-8 weeks were used and divided into 3 groups, respectively, a blank control group, Example 37 (1 mpk), and Example 37 (3 mpk), 8-10 rats per group, administered 2 hours before the test.
  • NOR New Object Recognition Memory Experiment
  • ⁇ Train (Trial1): Put the rat in the bucket and explore for 3 minutes.
  • Trial 2 15 minutes and 24 hours after training, replace one of the toys with a new toy and place the rat in the bucket for free to explore for 3 minutes.
  • Example 37 has obvious in vivo effects and can improve or improve the cognitive ability and memory of Wistar rats.
  • the compounds of the invention are effective in vitro and in vivo.
  • Example 37 1mpk group significantly delayed amnesia compared with the control group, the recognition index d2 was higher than the control group, with a significant difference p ⁇ 0.05;
  • Example 37 3mpk group can delay forgetting and recognition compared with the control group The index d2 was higher than the control group, but there was no significant difference, as shown in Figure 1-2.
  • *p ⁇ 0.05 identification index (d2) (exploring new things time – exploring old things time)/new and old The total exploration time of things.

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Abstract

L'invention concerne une série d'agonistes du récepteur nicotinique de l'acétylcholine alpha-7, et en particulier des composés de formule (I), des sels pharmaceutiquement acceptables ou des tautomères de ceux-ci, et leurs utilisations pharmaceutiques.
PCT/CN2018/086865 2017-05-18 2018-05-15 Agoniste du récepteur nicotinique de l'acétylcholine alpha-7 et application de celui-ci WO2018210229A1 (fr)

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