WO2010090305A1 - 置換アシルグアニジン誘導体 - Google Patents
置換アシルグアニジン誘導体 Download PDFInfo
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- WO2010090305A1 WO2010090305A1 PCT/JP2010/051757 JP2010051757W WO2010090305A1 WO 2010090305 A1 WO2010090305 A1 WO 2010090305A1 JP 2010051757 W JP2010051757 W JP 2010051757W WO 2010090305 A1 WO2010090305 A1 WO 2010090305A1
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- Prior art keywords
- compound
- salt
- group
- cyano
- schizophrenia
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/58—Amidines
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
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- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
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- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/20—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hydrogen atoms and substituted hydrocarbon radicals directly attached to ring carbon atoms
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Definitions
- the present invention relates to a substituted acylguanidine derivative having a drug, particularly a 5-HT 5A receptor-modulating effect, and useful as a therapeutic or prophylactic agent for dementia, schizophrenia and the like.
- 5-HT 5A receptor which is one of serotonin receptor subtypes, plays an important role in dementia and schizophrenia.
- 5-HT 5A receptor increases, also, overactive by LSD is a 5-HT 5A receptor knockout mice have been reported to be inhibited (Neuron, 22, 581-591, 1999).
- 5-HT 5A receptor is highly expressed in human and rodent brains, and in hippocampal CA1, CA3 pyramidal cells, which are involved in memory, and schizophrenia. It has been reported that there is a lot of expression in the frontal cortex (cerebral cortex) that is deeply related to the disease (Molecular Brain Reserch, 56, 1-8, 1998).
- 5-HT 5A receptor polymorphism is associated with schizophrenia (Neuroreport 11, 2017-2020, 2000; Mol. Psychiatr. 6, 217-219, 2001; J. Psychiatr. Res. 38, 371-376, 2004).
- modulating the function of 5-HT 5A receptor leads to improvement of dementia and schizophrenia, and a compound having such a function is desired.
- guanidine derivative represented by the following general formula binds to a 5-HT 5A receptor and is used for the treatment of various central diseases such as neurodegenerative diseases or neuropsychiatric diseases (Patent Literature). 1).
- A is NO 2 , NH 2, etc., B is a hydrogen atom, R w 1 is a hydrogen atom, D is a group represented by A, Q is a disubstituted 5-membered heteroaryl, R 1 , R 2 and R 3 are hydrogen atoms, etc., Z is- (CR z 1 R z 2 ) a- (V z ) b- (CR z 3 R z 4 ) c- , where a and c are 0- 4 and b are 0 or 1, R z 1 , R z 2 , R z 3 and R z 4 are each a hydrogen atom, V z is CO, etc. (Refer to the publication for details.)
- R 1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, or the above structure, etc., n is 1, 2, 3 or 4, Q is independently hydrogen, cycloalkyl, thienyl, furyl, (Pyrazolyl, pyridyl, substituted pyridyl, phenyl, substituted phenyl, etc., X represents hydrogen or alkoxy.
- Patent Document 3 a patent application relating to a compound having a similar structure has been filed by a common applicant. In these publications, there is no description regarding the 5-HT 5A receptor modulating action of the above derivatives or the therapeutic use of dementia schizophrenia.
- Patent Documents 4 to 7 naphthalene derivatives having an Na + / H + exchange mechanism inhibitory action and useful for the treatment of myocardial infarction, angina pectoris and the like have been reported (Patent Documents 4 to 7 and Non-Patent Document 1). None of these documents describes the 5-HT 5A receptor modulating action of naphthalene derivatives or the therapeutic use of dementia and schizophrenia.
- An object of the present invention is to provide an excellent therapeutic or preventive agent for dementia, schizophrenia and the like based on a 5-HT 5A receptor modulating action.
- the present inventors have found a structure in which guanidine is bonded to the 2-position of naphthalene via a carbonyl group and a cyclic group is bonded to the 8-position. Finding that a characteristic acylguanidine derivative has a potent 5-HT 5A receptor modulatory action and an excellent pharmacological action based on this, it can be used as a therapeutic or preventive drug for dementia, schizophrenia, etc. Thus, the present invention has been completed. That is, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- R 1 , R 2 and R 3 are the same or different from each other, H, lower alkyl, halogen, —CN, —OR a , lower alkylene —OR a , R a : H or lower alkyl, R 5 : -CN, -SMe, or -SO n R b , n: 1 or 2 R b : lower alkyl and R 6 : H or halogen.
- R 1 , R 2 and R 3 are the same or different from each other, H, lower alkyl, halogen, —CN, —OR a , lower alkylene —OR a , R a : H or lower alkyl, R 5 : -CN, -SMe, or -SO n R b , n: 1 or 2 R b : lower alkyl and R 6 : H or halogen.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for example, 5-HT 5A receptor
- the pharmaceutical composition which is a modulator and as another example, the pharmaceutical composition which is a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder or attention deficit hyperactivity disorder,
- a pharmaceutical composition which is a preventive or therapeutic agent for dementia or schizophrenia is a preventive or therapeutic agent for dementia or schizophrenia.
- Another aspect of the present invention includes a 5-HT 5A receptor modulator, such as a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder or attention deficit hyperactivity disorder, particularly dementia.
- the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic or therapeutic agent for schizophrenia, and in another embodiment, the compound of the above formula (I) Or a method of preventing or treating dementia, schizophrenia, bipolar disorder or attention deficit hyperactivity disorder, comprising administering to a mammal a therapeutically effective amount of a pharmaceutically acceptable salt thereof, A method for preventing or treating dementia or schizophrenia.
- the compound of the present invention has the advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon. Therefore, the pharmaceutical composition of the present invention is useful for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the prevention or treatment of dementia, schizophrenia, bipolar disorder or attention deficit hyperactivity disorder. It is.
- 5-HT 5A receptor modulator refers to a compound that suppresses 5-HT 5A receptor activation by antagonizing an endogenous ligand (5-HT 5A antagonist), and 5- It is a general term for compounds (5-HT 5A agonists) that exert their actions by sustained activation of the HT 5A receptor.
- “Lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), specifically, methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like.
- C 1-6 linear or branched alkyl having 1 to 6 carbon atoms
- C 1-6 specifically, methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like.
- Another embodiment is C 1-4 alkyl
- yet another embodiment is a methyl, ethyl, n-propyl and isopropyl group.
- “Lower alkylene” means linear or branched C 1-6 alkylene, specifically methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1, 2-dimethylethylene, 1,1,2,2-tetramethylethylene group and the like.
- Another embodiment is C 1-4 alkylene, and still another embodiment is a methylene, ethylene, trimethylene and propylene group.
- Halogen means F, Cl, Br and I.
- Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, which may have a bridge. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group, and the like. Another embodiment is C 3-6 cycloalkyl, and another embodiment is cyclopropyl. It is a group.
- “Monocyclic heteroaryl” is a 5- to 6-membered unsaturated ring group containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. Ring atoms such as sulfur or nitrogen may be oxidized to form oxides or dioxides. Specific examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, thienyl, furyl, pyranyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, tetrazolyl groups, and other embodiments include pyridyl , Pyrimidinyl, thienyl, thiazolyl, pyrazolyl and oxadiazolyl groups, and in yet another embodiment, a pyridyl and thiazolyl group, and in another embodiment, a
- the “saturated or partially unsaturated monocyclic oxygen-containing heterocyclic group” includes a hetero ring group containing one oxygen atom and further containing one hetero atom consisting of nitrogen, oxygen and sulfur. Or a group that is a 3- to 7-membered saturated or partially unsaturated monocycle, such as oxiranyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, dihydropyranyl and 1,4-dioxanyl groups; Is a dihydropyranyl group.
- R 1 , R 2 and R 3 are the same or different from each other and are H, methyl, F, Cl, CN, —OR a or —CH 2 OR a .
- R a is H, methyl or ethyl, and in another embodiment, is H or methyl.
- R 5 is substituted at the 5- or 7-position of naphthalene.
- the compound wherein n is 2.
- R b is methyl.
- R 6 is H, F or Cl, and in another embodiment, is H or F.
- (11) A compound that is a combination of two or more of the groups described in (1) to (7) above.
- the present invention includes these isomers, separated isomers or mixtures thereof.
- the present invention includes pharmaceutically acceptable prodrugs of the compounds of formula (I).
- a pharmaceutically acceptable prodrug has a group that can be converted into an amino group, OH, CO 2 H, etc. by solvolysis or under physiological conditions. It is a compound that produces a compound. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Can be mentioned.
- the compound of formula (I) may form an acid addition salt or a salt with a base depending on the kind of the substituent, and as long as such a salt is a pharmaceutically acceptable salt, the compound of the present invention is used.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
- Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc.
- salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts.
- organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts.
- various hydrates, solvates and polymorphic substances may exist in the compound of the formula (I) and pharmaceutically acceptable salts thereof. Is included.
- the compound of the formula (I) and pharmaceutically acceptable salts thereof include compounds labeled with various radioactive or non-radioactive isotopes.
- the compound of formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
- an appropriate protecting group a group that can be easily converted into the functional group
- Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group
- examples of protective groups thereof include, for example, “Green's Protective Groups in Organic Synthesis (No. 4) by PGM Wuts and Green (TW Greene)”. Edition, 2006) ”, and these may be appropriately selected depending on the reaction conditions.
- a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
- a prodrug of the compound of the formula (I) can be produced by introducing a specific group at the stage of a raw material or an intermediate, or reacting with the obtained compound of the formula (I) in the same manner as the protective group.
- the reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
- typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
- the manufacturing method of this invention is not limited to the example shown below.
- the compound of the formula (I) can be produced by reacting a carboxylic acid or its reactive derivative (1) with guanidine (2) or a salt thereof. The reaction can be carried out using an equivalent amount of carboxylic acid or its reactive derivative (1) and guanidine (2) or an excess amount of guanidine.
- Aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane or dimethoxyethane (DME), Under cooling in a solvent inert to the reaction such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile or water, or a mixture thereof. It can be carried out under heating, preferably at -20 ° C to 80 ° C.
- the reaction is preferably performed in the presence of a condensing agent.
- a condensing agent N, N'-dicyclohexylcarbodiimide (DCC), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (WSC), 1,1'-carbonyldiimidazole (CDI) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), diphenyl phosphate azide (DPPA), phosphorus oxychloride and the like.
- DCC N, N'-dicyclohexylcarbodiimide
- WSC 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide
- CDI 1,1'-carbonyldiimidazole
- HBTU 1- (1H-benzotriazol-1-yl) -1
- an additive for example, N-hydroxysuccinimide (HONSu) or 1-hydroxybenzotriazole (HOBt)
- the condensing agent is used in an equivalent amount or an excess amount relative to the carboxylic acid.
- an acid halide acid chloride or acid bromide, etc.
- an acid anhydride phenyl chlorocarbonate, p-toluenesulfonic acid, Or mixed acid anhydride or symmetric acid anhydride obtained by reaction with isovaleric acid, etc.
- active ester phenol, HOBt, HONSu, etc.
- Esters, lower alkyl esters, etc. can be produced from carboxylic acids using reactions that are obvious to those skilled in the art.
- organic bases such as base (triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine or 4- (N, N-dimethylamino) pyridine, or inorganic bases such as sodium bicarbonate Etc.) may be advantageous for allowing the reaction to proceed smoothly.
- Pyridine can also serve as a solvent.
- the reaction is preferably carried out at room temperature to heating under reflux.
- the starting compound (1) in the general production method can be produced using a known method or a modified method thereof.
- the raw material compound (1a) can be produced by the reaction route shown below (Method for producing raw material compound).
- Method of raw material compound (Wherein X represents trifluoromethanesulfonyloxy, -B (OH) 2 or -B (OZ) OW, R 11 represents a protecting group for a carboxyl group such as lower alkyl or benzyl, and Lv 2 represents a leaving group.
- Z and W are the same or different from each other and represent lower alkyl, or Z and W together represent lower alkylene.
- Compound (1a) can be obtained by first obtaining compound (4) by a coupling reaction between compound (2) and compound (3), followed by further hydrolysis.
- Examples of the leaving group represented by Lv 2 include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy group and the like.
- Compound (4) is synthesized by using equal amounts of compounds (2) and (3), or an excess of one of them, and using a mixture of these in a solvent inert to the reaction in the presence of a base and a palladium catalyst. This is usually carried out by stirring for 0.1 hour to 5 days under heating and reflux. This reaction is preferably performed in an inert gas atmosphere.
- Examples of the solvent used here are not particularly limited, but include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, DMSO, and mixed solvents thereof.
- As the base inorganic bases such as sodium carbonate, potassium carbonate and sodium hydroxide are preferable.
- As the palladium catalyst tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.
- the coupling reaction can be carried out with reference to the following documents. [Reference] A. d. Meijere and F.
- a compound (1a) can be obtained by performing a hydrolysis reaction of the compound (4).
- the hydrolysis reaction can be carried out with reference to “Green's Protective Groups in Organic Synthesis (4th edition, 2006)” by P. G. M. Wuts and T. W. Greene. (Other manufacturing methods)
- the compounds (2) and (3) described in the above can be manufactured using a known method or a modified method thereof, for example, a method described in a later production example Can be manufactured.
- the compound of formula (I) thus prepared is isolated as a free compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or as a crystalline polymorphic substance. Purified. Pharmaceutically acceptable salts of the compounds of formula (I) can also be prepared using salt making processes well known to those skilled in the art. Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and fractional chromatography. Various isomers can be separated by selecting an appropriate raw material compound or utilizing the difference in physicochemical properties between isomers.
- optical isomers can be stereochemically purified by general optical resolution methods (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Can lead to isomers. Moreover, it can also manufacture from a suitable optically active raw material compound.
- the manufacturing method of the compound of Formula (I) is described as an Example. Moreover, the manufacturing method of the compound used as a raw material is described as a manufacture example. In addition, the manufacturing method of the compound of Formula (I) is not limited only to the manufacturing method of the specific Example shown below, It can manufacture also by the combination of these manufacturing methods, or a well-known manufacturing method.
- Trifluoromethanesulfonic anhydride (462 mg) was added to a mixture of methyl 7-cyano-8-hydroxy-2-naphthalenecarboxylate (240 mg), triethylamine (171 mg) and dichloromethane (20 mL), followed by an additional 17 at room temperature. Stir for hours. The reaction mixture was diluted with water and extracted with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 7-cyano-8- ⁇ [(trifluoromethyl) sulfonyl] oxy ⁇ -2-naphthalenecarboxylate (280 mg). It was.
- Example 1 A mixture of 8- (2-chloro-6-fluorophenyl) -7-cyano-2-naphthalenecarboxylic acid (75 mg), CDI (52 mg) and DMF (10 mL) was heated and stirred at an oil temperature of 60 ° C. for 30 minutes and then reacted. The mixture was allowed to warm to room temperature and guanidine carbonate (104 mg) was added and stirred for an additional 15 hours. The reaction mixture was diluted with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
- Example compounds shown in Tables 8 to 9 below were produced using the corresponding raw materials.
- Table 10 shows the physical data of the example compounds.
- the compound when 2HCl is described, the compound is 2 Me: methyl, Tf: trifluoromethanesulfonyl, RSyn: production method (the number is the same as the compound having the number as the production example number) It shows that it was manufactured using.)
- PCR2 After the; (protein coding region open reading frame) was cloned from human hippocampus cDNA library acquired human 5-HT 5A receptors in Test Example 1 Human 5-HT 5A receptor forced expression HEK293 cells ORF of (Genbank AF498985). The vector was inserted into a vector (Invitrogen), and Escherichia coli carrying the plasmid was cultured in large quantities. Next, the human 5-HT 5A receptor full-length cDNA sequence was analyzed and recombinantly cultured in the expression vector pCDNA3.1 vector (Invitrogen).
- HEK293 cells Human embryonic kidney-derived cell line HEK293 cells (ATCC) were seeded, and the expression plasmid (1 ⁇ g) obtained above was added along with LIPOFECTAMINE 2000 (Invitrogen; 2 ⁇ l), and the gene was introduced into HEK293 cells. Expression cells were selected with a certain geneticin (G418 sulfate 500 ⁇ g / ml; Kanto Chemical).
- Recombinant cells expressing the gene thus prepared were D-MEM (Dulbecco's modified Eagle medium, Sigma), 10% FCS (Fetal calf serum), 1% Pc./Sm (penicillin / The cells were cultured for 3 days in 500 ⁇ g / ml G418 medium (Streptomycin, Invitrogen).
- D-MEM Dulbecco's modified Eagle medium, Sigma
- FCS Fetal calf serum
- Pc./Sm penicillin /
- the above experimental procedures are in accordance with the manuals for genetic manipulation experiments such as known methods (Sambrook, J. et al, Molecular Cloning-A Laboratory Manual ", Cold Spring Harabor laboratory, NY, 1989) and the instructions attached to the reagents. It was.
- Test Example 2 Human 5-HT 5A receptor binding inhibition test (1) culturing film adjusted human 5-HT 5A receptor forced expression HEK293 cells from human 5-HT 5A receptor forced expression HEK293 cells F500 plate, scraper I've written it. After centrifugation, the precipitate was collected and incubation buffer (50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)) was added. After homogenization, the mixture was further centrifuged, and an incubation buffer was added to the precipitate to suspend well. After repeating this operation, the protein concentration was measured to complete the membrane adjustment.
- incubation buffer 50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)
- the radioactivity remaining on the GF / C filter plate was measured using a top count.
- the compound of Example 1 showed a Ki value of 4.3 nM.
- the compounds of Examples 2, 5 to 10, 12, 14, 18 and 20 have Ki values in the range of 1 nM to 30 nM, and the compounds of Examples 3, 4, 13, 15 to 17, 19 and 21 are 30 nM. And Ki values in the range of 300 nM. From the above, it was confirmed that the compound of the formula (I) has 5-HT 5A receptor affinity.
- Test Example 3 Improving effect on methamphetamine or MK-801-induced momentum increase in mice Known as an animal model of schizophrenia, mice with overactivity induced by methamphetamine (hereinafter abbreviated as MAP) or MK-801
- MAP methamphetamine
- MK-801 The improvement effect of the compound of the formula (I) was evaluated by measuring the momentum of the compound by the emission infrared momentum measurement method.
- Animal species Male ICR mouse (2) Operating procedure The animal was removed from the breeding cage, and the test compound was orally administered and placed in the breeding cage. After 30 minutes, the test compound alone was measured for momentum in a measurement cage.
- MAP 1 mg / kg or MK-801; 0.3 mg / kg, both dissolved in physiological saline
- an exercise sensor using an infrared sensor CompACT AMS Muromachi Machine
- the compound of formula (I) suppresses the increase in the momentum of the mouse induced by the drug.
- the compound of Example 1 significantly suppressed overactivity induced by MK-801 at a dose of 0.03 mg / kg. From the above results, it was confirmed that the compound of the formula (I) has an ameliorating action for schizophrenia.
- Test Example 4 Improvement Effect on Scopolamine-Induced or MK-801-Induced Voluntary Alteration Behavior in Mice The improvement effect on the cognitive impairment of the compound of formula (I) can be evaluated by the well-known test method as a model of short-term learning disorder.
- spontaneous alternation behavior spontaneous alternation behavior
- the ratio with respect to the total number of entries of this behavior number is computed as the spontaneous alternation rate (Alternation rate) by the following formula
- Spontaneous replacement rate (%) number of spontaneous replacement actions / (total number of entries -2) x 100
- the test compound is orally administered 50 minutes before the start of the test, and 0.5 mg / kg scopolamine or 0.15 mg / kg MK-801 (in the normal group, physiological saline) is intraperitoneally administered 30 minutes later.
- the vehicle is orally administered when the test compound is administered.
- physiological saline is administered intraperitoneally at the time of scopolamine administration.
- (3) Data analysis When a significant difference (student T test) is observed between the normal group and the control group in the spontaneous alternation rate (%), it is determined that learning disability is established by scopolamine or MK-801 administration.
- the test compound administration group is subjected to Dunnett's test with respect to the control group to determine whether the test compound has a learning disorder improving effect. Significant differences at each test with p ⁇ 0.05. This test confirms that the compound of formula (I) has an effect on cognitive impairment.
- PPI PCP-induced prepulse inhibition
- Test Example 6 Evaluation of aged rats in water maze learning disorder The improving effect of the compound of formula (I) on dementia is evaluated by a water maze learning disorder model known as a pathological model of dementia. Specifically, the method described in “J Pharmacol Exp Ther, 1996; 279: 1157-73, Yamazaki M. et al.” Is followed. This test confirms that the compound of formula (I) has an effect on dementia.
- the compound of the present invention can be used to treat or prevent diseases involving 5-HT 5A , such as dementia, schizophrenia (positive symptoms, negative symptoms, cognitive impairment, mood disorders, etc.) ), Bipolar disorder, attention deficit / hyperactivity disorder, neurosis (panic disorder, obsessive compulsive disorder, etc.), autism, mood disorder (anxiety disorder, depressive disorder), sleep disorder, neurodegeneration It turns out that it is effective in the treatment or prevention of a disease and cerebral infarction.
- diseases involving 5-HT 5A such as dementia, schizophrenia (positive symptoms, negative symptoms, cognitive impairment, mood disorders, etc.) ), Bipolar disorder, attention deficit / hyperactivity disorder, neurosis (panic disorder, obsessive compulsive disorder, etc.), autism, mood disorder (anxiety disorder, depressive disorder), sleep disorder, neurodegeneration
- Formulations containing one or more of the compounds of formula (I) or salts thereof as active ingredients are generally used methods using pharmaceutical carriers, excipients and the like that are usually used in the art Can be prepared. Administration is orally by tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
- solid composition for oral administration tablets, powders, granules and the like are used.
- one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
- the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, or a solubilizing agent according to a conventional method. .
- Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol.
- the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances, and preservatives.
- Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions.
- aqueous solvent examples include distilled water for injection or physiological saline.
- water-insoluble solvent examples include propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name).
- Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
- External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
- ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
- ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
- Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods.
- known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
- an appropriate device for inhalation or insufflation can be used.
- a known device such as a metered dose inhalation device or a nebulizer
- the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
- the dry powder inhaler or the like may be for single or multiple administrations, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
- a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
- the appropriate daily dose is about 0.0001 to 100 mg / kg, preferably 0.0001 to 10 mg / kg, more preferably 0.0001 to 1 mg / kg per body weight. Or in 2 to 4 divided doses.
- the appropriate daily dose is about 0.00001-1 mg / kg per body weight, and is administered once a day or divided into multiple times.
- an external preparation or transmucosal agent about 0.0001 to 10 mg / kg per body weight is administered once to several times a day.
- the dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
- the content of the active ingredient in the preparation is 0.0001 to 50%, more preferably 0.001 to 50%.
- the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
- the combination can be administered simultaneously, separately in succession, or at desired time intervals. In the case of simultaneous administration, it can be administered as a combination drug or as a separate preparation.
- the compound of the present invention has a potent 5-HT 5A receptor modulating action and exhibits a good pharmacological action based on this. Therefore, the pharmaceutical composition of the present invention is used for prevention or treatment of diseases involving 5-HT 5A receptor, particularly prevention or treatment of dementia, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder. it can.
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Abstract
Description
例えば、下記一般式で示される誘導体が、抗ウィルス活性を有し、HIVやHCV等の感染症治療に有用であることが報告されている(特許文献2)。
また、同様の構造を有する化合物に関する特許出願が、共通する出願人より出願されている(特許文献3)。これらの公報には、上記誘導体の5-HT5A受容体調節作用、或いは、認知症の統合失調症の治療用途に関する記載は無い。
即ち、本発明は、式(I)の化合物又はその製薬学的に許容される塩に関する。
R1、R2及びR3:同一または互いに異なって、H、低級アルキル、ハロゲン、-CN、-ORa、低級アルキレン-ORa、
Ra:Hまたは低級アルキル、
R5:-CN、-SMe、または、-SOnRb、
n:1または2
Rb:低級アルキル、及び、
R6:Hまたはハロゲン。)
なお、特に記載がない限り、本明細書中のある化学式中の記号が他の化学式においても用いられる場合、同一の記号は同一の意味を示す。
また、本発明の別の態様としては、5-HT5A受容体調節剤、例えば、認知症、統合失調症、双極性障害又は注意欠陥多動性障害の予防または治療剤、殊に、認知症または統合失調症の予防または治療剤の製造のための前記式(I)の化合物またはその製薬学的に許容される塩の使用であり、更に別の態様としては、前記式(I)の化合物またはその製薬学的に許容される塩の治療有効量を哺乳動物に投与することからなる、認知症、統合失調症、双極性障害又は注意欠陥多動性障害の予防または治療方法、殊に、認知症または統合失調症の予防または治療方法である。
本明細書中、「5-HT5A受容体調節剤」とは、内在性リガンドに拮抗することにより5-HT5A受容体活性化を抑制する化合物(5-HT5A拮抗剤)、並びに5-HT5A受容体の持続的な活性化により作用を発現する化合物(5-HT5A作動剤)の総称である。
「低級アルキル」とは、直鎖または分枝状の炭素数が1から6(以後、C1-6と略す)のアルキル、具体的には、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル基等である。別の態様としては、C1-4アルキルであり、さらに別の態様としては、メチル、エチル、n-プロピル及びイソプロピル基である。
「低級アルキレン」とは、直鎖または分枝状のC1-6アルキレン、具体的には、メチレン、エチレン、トリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン、プロピレン、メチルメチレン、エチルエチレン、1,2-ジメチルエチレン、1,1,2,2-テトラメチルエチレン基等である。別の態様としては、C1-4アルキレンであり、さらに別の態様としては、メチレン、エチレン、トリメチレン及びプロピレン基である。
「シクロアルキル」とは、C3-10の飽和炭化水素環基であり、架橋を有していてもよい。具体的には、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、アダマンチル基等であり、別の態様としては、C3-6シクロアルキルであり、さらに別の態様としては、シクロプロピル基である。
(1)
(2)R1、R2及びR3が、同一または互いに異なってH、メチル、F、Cl、CN、-ORaまたは-CH2ORaである化合物。
(3)Raが、H、メチルまたはエチルであり、別の態様としては、Hまたはメチルである(2)に記載の化合物。
(4)R5の置換位置が、ナフタレンの5または7位である化合物。
(5)nが、2である化合物。
(6)Rbが、メチルである化合物。
(7)R6が、H、FまたはClであり、さらに別の態様としては、HまたはFである化合物。
(8)上記(1)及び(2)に記載の基の組み合わせである化合物。
(9)上記(1)、(2)及び(4)に記載の基の組み合わせである化合物。
(10)上記(1)、(2)、(4)及び(7)に記載の基の組み合わせである化合物。
(11)その他、上記(1)~(7)に記載の基のうち二以上の組み合わせである化合物。
(12)7-シアノ-N-(ジアミノメチレン)-8-(2,4,6-トリフルオロフェニル)-2-ナフタミド、7-シアノ-N-(ジアミノメチレン)-8-(2,6-ジフルオロフェニル)-2-ナフタミド、5-シアノ-N-(ジアミノメチレン)-7-フルオロ-8-(2,4,6-トリフルオロフェニル)-2-ナフタミド、8-(2-クロロ-6-フルオロフェニル)-7-シアノ-N-(ジアミノメチレン)-2-ナフタミド、及び、7-シアノ-N-(ジアミノメチレン)-8-(3,5-ジフルオロピリジン-4-イル)-2-ナフタミドからなる群より選択される化合物又はその塩。
更に、本発明には、式(I)の化合物の製薬学的に許容されるプロドラッグも含まれる。製薬学的に許容されるプロドラッグとは、加溶媒分解によりまたは生理学的条件下でアミノ基、OH、CO2H等に変換できる基を有し、投与後、生体内で式(I)の化合物を生成する化合物である。プロドラッグを形成する基としては、例えば、Prog. Med., 5, 2157-2161 (1985)や「医薬品の開発」(廣川書店、1990年)第7巻 分子設計163-198に記載の基が挙げられる。
さらに、式(I)の化合物及びその製薬学的に許容される塩には、各種の水和物や溶媒和物及び結晶多形の物質が存在する場合があり、本発明にはこれらの全てが包含される。また式(I)の化合物及びその製薬学的に許容される塩には、種々の放射性または非放射性同位体でラベルされた化合物も包含される。
式(I)の化合物及びその製薬学的に許容される塩は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料乃至中間体の段階で適当な保護基(容易に当該官能基に転化可能な基)に置き換えておくことが製造技術上効果的な場合がある。このような官能基としては例えばアミノ基、水酸基、カルボキシル基等であり、それらの保護基としては例えば、ウッツ(P. G. M. Wuts)及びグリーン(T. W. Greene)著、「Green's Protective Groups in Organic Synthesis (第4版、2006年)」に記載の保護基等を挙げることができ、これらを反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行った後、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
また、式(I)の化合物のプロドラッグは上記保護基と同様、原料乃至中間体の段階で特定の基を導入、あるいは得られた式(I)の化合物を用い反応を行うことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者により公知の方法を適用することにより行うことができる。
以下、式(I)の化合物の代表的な製造法を説明する。各製法は、当該説明に付した参考文献を参照して行うこともできる。なお、本発明の製造法は以下に示した例には限定されない。
(一般製法)
式(I)の化合物は、カルボン酸またはその反応性誘導体(1)とグアニジン(2)またはその塩とを反応させることにより製造することができる。
反応はカルボン酸またはその反応性誘導体(1)とグアニジン(2)とを等量若しくはグアニジンを過剰量用いて行うことができる。ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン(THF)、ジオキサン若しくはジメトキシエタン(DME)等のエーテル類、N,N-ジメチルホルムアミド(DMF)、ジメチルスルホキシド(DMSO)、N-メチルピロリドン(NMP)、酢酸エチル、アセトニトリルまたは水等の反応に不活性な溶媒中、あるいはそれらの混合液中で、冷却下~加熱下、好ましくは、-20℃~80℃で行うことができる。
原料化合物(1)として、Lv1がOHであるカルボン酸を用いる場合には、縮合剤の存在下で反応を行うことが好ましい。この場合の縮合剤としては、N,N'-ジシクロヘキシルカルボジイミド(DCC)、1-[3-(ジメチルアミノ)プロピル]-3-エチルカルボジイミド(WSC)、1,1'-カルボニルジイミダゾール(CDI)、2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(HBTU)、ジフェニルリン酸アジド(DPPA)、オキシ塩化リン等が挙げられる。場合によっては、更に添加剤(例えば、N-ヒドロキシスクシンイミド(HONSu)または1-ヒドロキシベンゾトリアゾール(HOBt)等)を用いることが好ましい。通常、縮合剤はカルボン酸に対して等量若しくは過剰量用いる。
原料化合物(1)において、Lv1が脱離基であるカルボン酸の反応性誘導体としては、酸ハロゲン化物(酸クロリドまたは酸ブロミド等)、酸無水物(クロロ炭酸フェニル、p-トルエンスルホン酸、またはイソ吉草酸等との反応で得られる混合酸無水物あるいは対称酸無水物)、活性エステル(ニトロ基もしくはフッ素原子等の電子吸引基で置換していてもよいフェノール、HOBt、HONSu等を用いて調製できるエステル)、低級アルキルエステル等が挙げられ、いずれもカルボン酸より当業者に自明な反応を用いて製造することができる。反応性誘導体の種類によっては、塩基(トリエチルアミン、ジイソプロピルエチルアミン(DIPEA)、N-メチルモルホリン、ピリジン若しくは4-(N,N-ジメチルアミノ)ピリジン等の有機塩基類、または炭酸水素ナトリウム等の無機塩基等)の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。ピリジンは溶媒を兼ねることもできる。尚、反応性誘導体として低級アルキルエステルを用いる場合には、反応を室温下~加熱還流下で行うことが好ましい。
(原料化合物の製造法)
化合物(1a)は、化合物(2)と化合物(3)とのカップリング反応により、まず化合物(4)を得た後、さらに加水分解を行うことにより得ることができる。
Lv2で示される脱離基の例としては、ハロゲン、メタンスルホニルオキシ、p-トルエンスルホニルオキシ、トリフルオロメタンスルホニルオキシ基などが含まれる。
化合物(4)の合成は、化合物(2)と(3)を等量、或いは一方を過剰に用い、これらの混合物を、反応に不活性な溶媒中、塩基及びパラジウム触媒の存在下、室温~加熱還流下で、通常0.1時間~5日間撹拌することによって行なわれる。本反応は不活性ガス雰囲気下で行うことが好ましい。ここで用いられる溶媒の例としては、特に限定はされないが、芳香族炭化水素類、エーテル類、ハロゲン化炭化水素類、アルコール類、DMF、DMSO、及びこれらの混合溶媒が挙げられる。塩基としては、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム等の無機塩基が好ましい。パラジウム触媒としては、テトラキス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリフェニルホスフィン)パラジウム、塩化パラジウム-1,1'-ビス(ジフェニルホスフィノ)フェロセン等が好ましい。
カップリング反応は、以下の文献を参照して実施することができる。
〔文献〕
A. d. Meijere及びF. Diederich編、「Metal-Catalyzed Cross-Coupling Reactions」、第1版、VCH Publishers Inc.、1997年
日本化学会編「実験化学講座(第5版)」13巻(2005年)(丸善)
続いて、化合物(4)の加水分解反応を行うことにより化合物(1a)を得ることができる。加水分解反応は、ウッツ(P. G. M. Wuts)及びグリーン(T. W. Greene)著、「Green's Protective Groups in Organic Synthesis (第4版、2006年)」を参照して実施することができる。
(その他の製法)
さらに、上記(原料化合物の製造法)に記載の化合物(2)、(3)は、公知の方法あるいはそれらの変法を用いて製造することができ、例えば、後の製造例に記載の方法によって製造できる。
単離、精製は、抽出、分別結晶化、分画クロマトグラフィー等通常の化学操作を適用して行われる。
各種の異性体は、適当な原料化合物を選択することにより、あるいは異性体間の物理化学的性質の差を利用して分離することができる。例えば、光学異性体は一般的な光学分割法(例えば、光学活性な塩基または酸とのジアステレオマー塩に導く分別結晶化やキラルカラム等を用いたクロマトグラフィー等)により、立体化学的に純粋な異性体に導くことができる。また、適当な光学活性な原料化合物より製造することもできる。
メチル 7-フルオロ-8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(9.21g)、臭化第二銅(20.4g)およびTHF(300mL)の混合物を油温60℃で6日間撹拌した。反応混合物を室温に戻し、不溶物をろ別後、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-ブロモ-7-フルオロ-8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(13.6g)を得た。
メチル 7-ブロモ-7-フルオロ-8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(13.6g)、臭化リチウム(7.8g)およびDMF(100mL)の混合物を油温100℃で10時間加熱撹拌した。反応混合物を氷冷し、水で希釈後、析出物を濾取することにより,メチル 7-フルオロ-8-ヒドロキシ-2-ナフタレンカルボキシラート(8.7g)を得た。
メチル 7-(メチルスルファニル)-8-(2,4,6-トリフルオロフェニル)-2-ナフタレンカルボキシラート(220mg)、およびジクロロメタン(15mL)の混合物中に、0℃でm-クロロ過安息香酸(含有量約70%,1.05g)を加え、16時間撹拌した。反応混合物をチオ硫酸ナトリウム水溶液で希釈後、酢酸エチルで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-(メチルスルホニル)-8-(2,4,6-トリフルオロフェニル)-2-ナフタレンカルボキシラート(221mg)を得た。
メチル 7-シアノ-8-(2,6-ジフルオロ-4-ホルミルフェニル)-2-ナフタレンカルボキシラート(168mg)、水素化ほう素ナトリウム(18mg)、THF(10mL)およびメタノール(20mL)の混合物を室温で3時間撹拌した。反応混合物を水で希釈後、酢酸エチルで抽出した。有機層を水洗および乾燥後、減圧下濃縮することにより、メチル 7-シアノ-8-[2,6-ジフルオロ-4-(ヒドロキシメチル)フェニル]-2-ナフタレンカルボキシラート(227mg)を得た。
メチル 7-シアノ-8-(2,6-ジフルオロフェニル)-2-ナフタレンカルボキシラート(129mg)、1M水酸化ナトリウム水溶液(2mL)、THF(10mL)およびメタノール(10mL)の混合物を室温で6時間撹拌した。反応混合物を減圧下濃縮し、得られた残渣を1M塩酸で中和後、析出物を濾取することにより、7-シアノ-8-(2,6-ジフルオロフェニル)-2-ナフタレンカルボン酸(110mg)を得た。
メチル 7-フルオロ-8-ヒドロキシ-2-ナフタレンカルボキシラート(460mg)、メタノール(20mL)およびジクロロメタン(20mL)の混合物中に、0℃で過臭化臭化ピリジニウム(702mg)を加え、室温で1時間撹拌した。反応混合物を水で希釈後、酢酸エチルで抽出した。有機層を水洗および乾燥後、減圧下濃縮することにより、メチル 5-ブロモ-7-フルオロ-8-ヒドロキシ-2-ナフタレンカルボキシラート(610mg)を得た。
メチル 7-ブロモ-8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(6.88g)、メチルメルカプタン ナトリウム塩(1.7g)およびDMF(100mL)の混合物を室温で3時間撹拌した。反応混合物を水で希釈後、酢酸エチルで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-(メチルスルファニル)-8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(3.97g)を得た。
メチル 7-シアノ-8-ヒドロキシ-2-ナフタレンカルボキシラート(240mg)、トリエチルアミン(171mg)およびジクロロメタン(20mL)の混合物中に、トリフルオロメタンスルホン酸無水物(462mg)を加えた後、室温でさらに17時間撹拌した。反応混合物を水で希釈後、クロロホルムで抽出し、有機層を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-シアノ-8-{[(トリフルオロメチル)スルホニル]オキシ}-2-ナフタレンカルボキシラート(280mg)を得た。
メチル 7-ブロモ-8-ヒドロキシ-2-ナフタレンカルボキシラート(10.2g)、シアン化亜鉛(含有率60%,7.1g)、トリス(ジベンジリデンアセトン)ジパラジウム(0) (1.66g)、1,1'-ビス(ジフェニルホスフィノ)フェロセン(2.0g)およびN-メチル-2-ピロリドン(100mL)の混合物を油温150℃で3時間加熱撹拌した。反応を室温に冷却し、水および酢酸エチルで希釈後、不溶物を濾別した。ろ液を分液操作し、有機層を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-シアノ-8-ヒドロキシ-2-ナフタレンカルボキシラート(5.89g)を得た。
メチル 7-シアノ-8-{[(トリフルオロメチル)スルホニル]オキシ}-2-ナフタレンカルボキシラート(300mg)、ビス(ピナコラト)ジボロン(223mg)、塩化ビス(トリフェニルホスフィン)パラジウム(29mg)、トリフェニルホスフィン(22mg)および酢酸カリウム(246mg)および1,4-ジオキサン(5mL)の混合物を油温100℃で18時間加熱撹拌した。反応混合物を室温に戻し、不溶物を濾別後、ろ液を減圧下濃縮した。得られた残渣を水で希釈後、酢酸エチルで抽出し、有機層を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-シアノ-8-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-2-ナフタレンカルボキシラート(181mg)を得た。
メチル 8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(3.0g)、1-フルオロ-4-ヒドロキシ-1,4-ジアゾニアビシクロ[2,2,2]オクタンビス(テトラフルオロホウ酸塩)(5.2g)およびメタノール(140mL)の混合物を加熱還流下で3時間撹拌した。反応混合物を減圧下濃縮後、ジクロロメタンで希釈し、不溶物を濾別した。ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-フルオロ-8-オキソ-5,6,7,8-テトラヒドロナフタレン-2-カルボキシラート(2.8g)を得た。
N,N,N',N'-テトラメチルエチレンジアミン(1.5g)およびジエチルエーテル(40mL)の混合物中に、アルゴンガス雰囲気下、-78℃でn-ブチルリチウム(1.55Mヘキサン溶液,7.5mL)を加え、同温で30分間撹拌した。反応混合物中に3,5-ジフルオロピリジン(1.2g)およびジエチルエーテル(10mL)の混合物をゆっくり加え、同温で2時間撹拌した。さらに反応混合物中にヨウ素(4.0g)を加え、同温で1時間撹拌後、室温に戻した。反応混合物を水で希釈後、生じた固体を濾別し、濾液をジエチルエーテルで抽出し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、3,5-ジフルオロ-4-ヨードピリジン(820mg)を得た。
メチル 7-シアノ-8-{[(トリフルオロメチル)スルホニル]オキシ}-2-ナフタレンカルボキシラート(250mg)、2,6-ジフルオロフェニルほう酸(165mg)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(102mg)、フッ化セシウム(211mg)および1,2-ジメトキシエタン(15mL)の混合物をアルゴン雰囲気中、加熱還流下で1日間撹拌した。反応混合物を室温に戻し、水で希釈後、酢酸エチルで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-シアノ-8-(2,6-ジフルオロフェニル)-2-ナフタレンカルボキシラート(134mg)を得た。
メチル 7-シアノ-8-{[(トリフルオロメチル)スルホニル]オキシ}-2-ナフタレンカルボキシラート(400mg)、2,6-ジフルオロ-4-ホルミルフェニルほう酸ピナコールエステル(448mg)、酢酸パラジウム(II)(25mg)、りん酸三カリウム(994mg)、2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピルビフェニル(106mg)およびトルエン(5mL)の混合物をアルゴンガス雰囲気下、油温100℃で3時間加熱撹拌した。反応混合物を室温に戻し、水で希釈後、酢酸エチルで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、メチル 7-シアノ-8-(2,6-ジフルオロ-4-ホルミルフェニル)-2-ナフタレンカルボキシラート(168mg)を得た。
8-(2-クロロ-6-フルオロフェニル)-7-シアノ-2-ナフタレンカルボン酸(75mg)、CDI(52mg)およびDMF(10mL)の混合物を油温60℃で30分間加熱撹拌後、反応混合物を室温に戻し、炭酸グアニジン(104mg)を加えて、さらに15時間撹拌した。反応混合物を重曹水で希釈後、酢酸エチルで抽出し、飽和塩化ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=20/1)で精製し、さらに4M塩化水素/1,4-ジオキサン溶液で処理し、酢酸エチルで加熱洗浄することにより、8-(2-クロロ-6-フルオロフェニル)-7-シアノ-N-(ジアミノメチレン)-2-ナフタミド塩酸塩(40mg)を得た。
REx:製造例番号、Ex:実施例番号、Str:構造式、Dat:物理学的データ(ESI+: ESI-MS[M+H]+; ESI-:ESI-MS[M-H]-; EI+:EI[M]+;A/E+:APCIとESIの同時測定(陽イオン); A/E-:APCIとESIの同時測定(陰イオン); NMR:CDCl3またはDMSO-d6中の1HNMRにおけるピークのδ(ppm))、Sal:塩(空欄または無記載はフリー体であることを示し、酸成分の前の数字はモル比を示す。例えば2HClが記載されている場合、その化合物が2塩酸塩であることを示す。)Me:メチル、Tf:トリフルオロメタンスルホニル、RSyn:製造方法(数字は、当該化合物が、その番号を製造例番号として有する化合物と同様の方法により、対応する原料を用いて製造したことを示す。)。
本発明化合物の薬理活性は、以下の試験により確認した。
試験例1 ヒト5-HT5A受容体強制発現HEK293細胞の取得
ヒト5-HT5A受容体(Genbank AF498985)のORF(open reading frame;蛋白質コード領域)をヒト海馬cDNAライブラリーよりクローニングしたのちpCR2.1ベクター(Invitrogen)に挿入し、そのプラスミドを持った大腸菌を大量培養した。次に、ヒト5-HT5A受容体全長cDNA配列解析し、発現ベクターであるpCDNA3.1ベクター(Invitrogen)に組み替え大量培養した。ヒト胎児腎由来株化細胞HEK293細胞(ATCC)を播種し、上記で得られた発現プラスミド(1μg)をLIPOFECTAMINE 2000(Invitrogen; 2μl)とともに加え、HEK293細胞に遺伝子を導入した後、薬剤耐性マーカーであるGeneticin(G418 sulfate 500μg/ml; 関東化学)で発現細胞の選別をした。この様にして作製された当該遺伝子を発現する組換え細胞をD-MEM(ダルベッコ改変イーグル培地, シグマ), 10% FCS(Fetal calf serum:牛胎児血清), 1% Pc./Sm(ペニシリン/ストレプトマイシン, Invitrogen社), 500μg/ml G418 培地により3日間培養を行った。以上の実験操作は、公知の方法(Sambrook, J. et al, Molecular Cloning-A Laboratory Manual", Cold Spring Harabor laboratory, NY, 1989)等の遺伝子操作実験マニュアルや試薬等に添付の指示書に従った。
(1)ヒト5-HT5A受容体強制発現HEK293細胞からの膜調整
ヒト5-HT5A受容体強制発現HEK293細胞をF500プレートで培養し、スクレイパーでかきとった。遠心後、沈殿物を集め、インキュベーションバッファー(50mM トリス (HCl) PH7.4、10mM MgSO4、0.5mM EDTA(エチレンジアミン四酢酸))を加えた。ホモジナイズ後、さらに遠心し、沈殿物にインキュベーションバッファーを加えよく懸濁させた。この操作を繰り返した後、タンパク濃度を測定し、膜調整完了とした。
(2)ヒト5-HT5A受容体結合阻害実験
被検化合物および100μMの5-CT(5-カルボキサミドトリプタミン)のDMSO溶液を2μl/ウェルで96ウェルプレートに加え、インキュベーションバッファーに懸濁し、200μg / mlに調製したヒト5-HT5A受容体強制発現HEK293細胞膜を100 μl/ウェルで加えた。室温で15分インキュベーション後、[3H]5-CT溶液(2nM [3H]5-CT, インキュベーションバッファー) を100 μl/ウェルで加えた。
別途、100 μlを液体シンチレーションバイアルに分注し、アクアゾールII(Aquasol II:登録商標)を2ml加え攪拌した後、液体シンチレーションカウンターで放射活性を測定した。37℃で60分インキュベーションを行った。反応混合物を0.2% ポリエチレンイミンで前処理した96 ウェル GF/C フィルタープレートに吸引し、氷冷50mM トリス (pH7.5) バッファーで6回洗浄した。GF/C フィルタープレートを乾燥させた。
マイクロシンチPS(MicroscintTMPS:登録商標)を40 μl/ウェルで添加した。トップカウントにてGF/C フィルタープレート上に残存する放射活性を測定した。
各実験における被検化合物による[3H]5-CT結合阻害活性は、DMSOのみを加えた時の放射活性を0%、1μM 5-CTを加えた時の放射活性を100%阻害として、IC50値を算出した。別途、スキャッチャード解析より求めた[3H]5-CTのKd値より、Ki値を以下の式より算出した。
Ki=IC50(1+添加したリガンド濃度/Kd (4.95nM))
本試験の結果、本発明医薬の有効成分である式(I)の化合物は強いヒト5-HT5A受容体結合阻害活性を有することが判明した。
例えば、実施例1の化合物は4.3nMのKi値を示した。また、実施例2、5~10、12、14、18及び20の化合物は1nMから30nMの範囲内のKi値を、実施例3、4、13、15~17、19及び21の化合物は30nMから300nMの範囲内のKi値をそれぞれ示した。
以上のことから、式(I)の化合物が5-HT5A受容体親和性を有することが確認された。
統合失調証の動物モデルとして知られる、メタンフェタミン(以下MAPと略)又はMK-801により過活動を惹起したマウスを用い、化合物投与下の運動量を放出赤外線運動量測定法で測定することにより、式(I)の化合物の改善効果を評価した。
(1)動物
種:雄ICRマウス
(2)操作手順
飼育ケージから動物を取り出し被験化合物を経口投与したのち飼育用ケージに入れた。30分後に、測定用ケージに入れて、被験化合物単独の運動量を測定した。さらに30~90分後、動物を取り出し運動量を増加させる薬物(MAP;1mg/kgまたはMK-801;0.3mg/kg、ともに生理食塩水に溶解)を腹腔内投与し、赤外線センサーによる運動量測定装置(CompACT AMS 室町機械)を用いて一定時間(60分間)の運動量を測定した。
(3)解析
ノーマルマウス(生理食塩水投与マウス)と運動量を増加させる薬剤を投与したマウスにおいては、それぞれの間隔においてスチューデントT検定(Student's T test)で判定した。被験化合物を投与した群においては、溶媒(vehicle)群とダネット検定(Dunnett's T test)をおこない、検定した。判定は、有意に(P<0.05)差があったときに効果があるとした。
本試験の結果、式(I)の化合物は、薬物により誘発されたマウスの運動量増加を抑制することが判明した。例えば、実施例1の化合物は、MK-801により誘発された過活動を0.03mg/kgの投与量で有意に抑制した。
以上の結果から、式(I)の化合物が統合失調症の改善作用を有することが確認された。
試験例4 マウスでのスコポラミン誘発またはMK-801誘発自発交替行動に対する改善効果
式(I)の化合物の認知障害に対する改善効果を、短期学習障害のモデルとして周知の首記の試験法により評価できる。
(1)動物
種:雄ddYマウス
(2)測定方法
3方向に同じ長さのアームをもつ迷路(Y-maze)のアームの一端にマウスを入れて8分間自由に探索させ、この間のアームへのエントリー数をカウントする。また、連続して3つの異なるアームにエントリーした場合を自発交替行動(Spontaneous alternation behavior)とし、この行動数の総エントリー数に対する割合を自発交替率(Alternation rate)として、以下の式により算出する。
自発交替率(%) =自発交替行動数/ (総エントリー数-2)×100
被験化合物は試験開始50分前に経口投与し、その30分後に0.5 mg/kgスコポラミンまたは0.15 mg/kg MK-801 (通常群においては生理食塩水)を腹腔内投与する。なお、ノーマル群(生理食塩水を投与した群)と対照群(0.5 mg/kgスコポラミンまたは0.15 mg/kg MK-801を投与した群)においては、被験化合物投与時に溶媒(vehicle)を経口投与する。ノーマル群においては、スコポラミン投与時に生理食塩水を腹腔内投与する。
(3)データ解析
自発交替率(%)においてノーマル群と対照群の間に有意な差(スチューデントT検定)が認められる場合、スコポラミンまたはMK-801投与による学習障害成立と判断する。対照群に対する被験化合物投与群のダネット検定を行うことで、被験化合物の学習障害改善作用の有無を判定する。各検定においてp<0.05で有意な差とする。
本試験により、式(I)の化合物が認知障害に効果を有することが確認できる。
ヒトに音刺激を与えると驚愕反応が起こるが、健常人では、この驚愕反応は、その音刺激に先行して弱い音刺激を与えることにより抑制される。統合失調症の患者ではこの抑制機能が低下している。ラットにPCP(フェンサイクリジン)を投与すると、ヒトの統合失調症と似た症状が起きることが知られており、統合失調症の認知障害に含まれる情報処理障害を評価する病態モデルとして知られている。
このPCP誘発プレパルス抑制障害モデルを用いて、式(I)の化合物の統合失調症に対する改善効果を評価する。具体的には、「ニューロサイコファーマコロジー(Neuropsychopharmacology, 1989;2:61-66, Mansbach, R.S. and Geyer, M.A.)及びブレインリサーチ(Brain Research, 1998;781:227-235)」記載の方法に従う。
本試験により、式(I)の化合物が統合失調症の認知障害に含まれる情報処理障害に対しても効果を有することを確認できる。
式(I)の化合物の認知症に対する改善作用を、認知症の病態モデルとして公知の水迷路学習障害モデルにより評価する。具体的には、「ジャーナル オブ ファーマコロジー アンド エクスペリメンタル セラピューティックス(J Pharmacol Exp Ther, 1996;279:1157-73, Yamazaki M. et al.」記載の方法に従う。
本試験により、式(I)の化合物が認知症に効果を有することが確認できる。
投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、または、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤またはエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水またはエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
非経口投与のための注射剤は、無菌の水性または非水性の溶液剤、懸濁剤または乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水または生理食塩液が含まれる。非水溶性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコールまたはオリーブ油のような植物油、エタノールのようなアルコール類、またはポリソルベート80(局方名)等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、または溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合または照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水または無菌の注射用溶媒に溶解または懸濁して使用することもできる。
吸入剤や経鼻剤等の経粘膜剤は固体、液体または半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、pH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入または吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独でまたは処方された混合物の粉末として、もしくは医薬的に許容し得る担体と組み合わせて溶液または懸濁液として投与することができる。乾燥粉末吸入器等は、単回または多数回の投与用のものであってもよく、乾燥粉末または粉末含有カプセルを利用することができる。あるいは、適当な駆出剤、例えば、クロロフルオロアルカン、ヒドロフルオロアルカンまたは二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。
Claims (12)
- R1、R2及びR3が、同一または互いに異なって、H、メチル、F、Cl、CN、-ORaまたは-CH2ORaである請求の範囲2記載の化合物又はその塩。
- R5の置換位置が、ナフタレンの5または7位である請求の範囲4記載の化合物又はその塩。
- R6が、H、FまたはClである請求の範囲5記載の化合物又はその塩。
- 7-シアノ-N-(ジアミノメチレン)-8-(2,4,6-トリフルオロフェニル)-2-ナフタミド、7-シアノ-N-(ジアミノメチレン)-8-(2,6-ジフルオロフェニル)-2-ナフタミド、5-シアノ-N-(ジアミノメチレン)-7-フルオロ-8-(2,4,6-トリフルオロフェニル)-2-ナフタミド、8-(2-クロロ-6-フルオロフェニル)-7-シアノ-N-(ジアミノメチレン)-2-ナフタミド、及び、7-シアノ-N-(ジアミノメチレン)-8-(3,5-ジフルオロピリジン-4-イル)-2-ナフタミドからなる群より選択される請求の範囲1記載の化合物又はその塩。
- 請求の範囲1記載の化合物又はその塩と、製薬学的に許容される担体とからなる医薬組成物。
- 5-HT5A受容体調節剤である、請求の範囲8記載の医薬組成物。
- 認知症、統合失調症、双極性障害又は注意欠陥多動性障害の予防又は治療剤である請求の範囲9に記載の医薬組成物。
- 認知症、統合失調症、双極性障害又は注意欠陥多動性障害の予防又は治療剤の製造のための、請求の範囲1に記載の誘導体又はその塩の使用。
- 請求の範囲1に記載の誘導体又はその塩の治療有効量を患者に投与することを含む、認知症、統合失調症、双極性障害又は注意欠陥多動性障害の予防又は治療方法。
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EP10738633A EP2394988A4 (en) | 2009-02-09 | 2010-02-08 | SUBSTITUTED ACYLGUANIDINE DERIVATIVE |
US13/148,448 US20120041036A1 (en) | 2009-02-09 | 2010-02-08 | Substituted acylguanidine derivatives (as amended) |
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WO2011016504A1 (ja) * | 2009-08-06 | 2011-02-10 | アステラス製薬株式会社 | 含窒素環アシルグアニジン誘導体 |
WO2012105588A1 (ja) | 2011-02-02 | 2012-08-09 | アステラス製薬株式会社 | テトラヒドロイソキノリン誘導体 |
WO2012108490A1 (ja) * | 2011-02-09 | 2012-08-16 | アステラス製薬株式会社 | イソキノリンアミド誘導体 |
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WO2015110370A1 (en) * | 2014-01-22 | 2015-07-30 | F. Hoffmann-La Roche Ag | Fluoro-naphthyl derivatives |
CN113416149B (zh) * | 2021-08-03 | 2023-04-18 | 贵州大学 | 一种氮杂环卡宾催化合成的联芳基类轴手性化合物及其制备方法 |
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JP2008543886A (ja) * | 2005-06-24 | 2008-12-04 | バイオトロン リミテッド | 抗ウイルス化合物および方法 |
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Cited By (8)
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WO2011016504A1 (ja) * | 2009-08-06 | 2011-02-10 | アステラス製薬株式会社 | 含窒素環アシルグアニジン誘導体 |
US8853242B2 (en) | 2009-08-06 | 2014-10-07 | Astellas Pharma Inc. | Nitrogenous-ring acylguanidine derivative |
WO2012105588A1 (ja) | 2011-02-02 | 2012-08-09 | アステラス製薬株式会社 | テトラヒドロイソキノリン誘導体 |
CN103339109A (zh) * | 2011-02-02 | 2013-10-02 | 安斯泰来制药有限公司 | 四氢异喹啉衍生物 |
US8962612B2 (en) | 2011-02-02 | 2015-02-24 | Astellas Pharma Inc. | Tetrahydroisoquinoline derivative |
CN103339109B (zh) * | 2011-02-02 | 2015-04-29 | 安斯泰来制药有限公司 | 四氢异喹啉衍生物 |
JP5870937B2 (ja) * | 2011-02-02 | 2016-03-01 | アステラス製薬株式会社 | テトラヒドロイソキノリン誘導体 |
WO2012108490A1 (ja) * | 2011-02-09 | 2012-08-16 | アステラス製薬株式会社 | イソキノリンアミド誘導体 |
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EP2394988A1 (en) | 2011-12-14 |
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