WO2010013302A1 - Spiroaminodihydrothiazine derivative - Google Patents

Spiroaminodihydrothiazine derivative Download PDF

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Publication number
WO2010013302A1
WO2010013302A1 PCT/JP2008/063516 JP2008063516W WO2010013302A1 WO 2010013302 A1 WO2010013302 A1 WO 2010013302A1 JP 2008063516 W JP2008063516 W JP 2008063516W WO 2010013302 A1 WO2010013302 A1 WO 2010013302A1
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group
compound
reaction
substituent
added
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PCT/JP2008/063516
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French (fr)
Japanese (ja)
Inventor
貴史 元木
敏彦 金子
昇 山本
アフザル カーン
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エーザイ・アール・アンド・ディー・マネジメント株式会社
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Priority to PCT/JP2008/063516 priority Critical patent/WO2010013302A1/en
Priority to US13/055,830 priority patent/US8501733B2/en
Priority to JP2010533357A priority patent/JP5444240B2/en
Priority to KR1020107029705A priority patent/KR20110048491A/en
Priority to EP09788008.2A priority patent/EP2318416B1/en
Priority to AU2009277485A priority patent/AU2009277485B2/en
Priority to ES09788008T priority patent/ES2433223T3/en
Priority to PCT/JP2009/063627 priority patent/WO2010013794A1/en
Priority to CN200980129365.1A priority patent/CN102105475B/en
Priority to CA2731209A priority patent/CA2731209A1/en
Publication of WO2010013302A1 publication Critical patent/WO2010013302A1/en
Priority to IL210548A priority patent/IL210548A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a spiroaminodihydrothiazine derivative and its pharmaceutical use. More specifically, it has a amyloid ⁇ (hereinafter referred to as A ⁇ ) protein production inhibitory action or a beta-site amyloid ⁇ precursor protein cleavage enzyme 1 (hereinafter referred to as BACE1) inhibitory action, and is a neurodegenerative disease caused by A ⁇ protein.
  • a ⁇ amyloid ⁇
  • BACE1 beta-site amyloid ⁇ precursor protein cleavage enzyme 1
  • the present invention relates to a spiroaminodihydrothiazine derivative effective for the treatment of Alzheimer-type dementia, Down's syndrome and the like and a pharmaceutical composition containing it as an active ingredient.
  • Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles as well as neuronal degeneration and loss.
  • treatment of Alzheimer's disease is limited to symptomatic treatment with symptom ameliorating agents represented by acetylcholinesterase inhibitors, and no fundamental therapeutic agent that suppresses the progression of the disease has been developed.
  • Development of a method for controlling the onset of the pathological condition is necessary for the creation of a fundamental therapeutic agent for Alzheimer's disease.
  • a ⁇ protein which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in the degeneration / dropout of nerve cells and the development of dementia symptoms (for example, Non-Patent Documents 3 and 4). reference).
  • the main components of the A ⁇ protein are A ⁇ 40 consisting of 40 amino acids and A ⁇ 42 with 2 amino acids added at the C-terminus. These A ⁇ 40 and 42 are highly aggregating (see, for example, Non-Patent Document 5), and are the main constituents of the elderly population (see, for example, Non-Patent Documents 5, 6, and 7).
  • a ⁇ is produced by cleaving APP with beta-secretase (BACE1), followed by cleaving with gamma-secretase. Accordingly, attempts have been made to create inhibitors of gamma secretase and beta secretase for the purpose of suppressing A ⁇ production.
  • BACE1 beta-secretase
  • gamma-secretase inhibitors have been reported in Patent Documents 1 to 13 and Non-Patent Documents 1 and 2 shown below.
  • Patent Document 1 describes the inhibitory activity of aminodihydrothiazine derivatives and beta-secretase. That is, compounds having BACE1 inhibitory activity are described.
  • International Publication No. 2007/049532 Pamphlet U.S. Pat. No. 3,235,551 U.S. Pat. No. 3,227,713 Japanese Patent Application Laid-Open No. 9-067355 International Publication No. 01/187293 Pamphlet International Publication No. 04/014843 Pamphlet JP 2004-149429 A WO 02/96897 pamphlet International Publication No. 04/043916 Pamphlet International Publication No. 2005/058311 Pamphlet International Publication No. 2007/097767 Pamphlet International Publication No.
  • Glenner GG 1 other, Alzheimer's disease: initial report of the purification and physicalization of a novel cerebral vascular bioprotein. 885-890. Masters CL, 5 others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Procedural National Academy of Science USA, 1985, Jun, 82 (12). 4245-4249. Gouras GK, 11 others, Intraneuronal A ⁇ 42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156 (1), p. 15-20.
  • the subject of the present invention is a compound different from the aminodihydrothiazine derivative and the compound having BACE1 inhibitory activity described in Patent Document 1, which has an A ⁇ production inhibitory action or a BACE1 inhibitory action, resulting from A ⁇ . It is an object of the present invention to provide a spiroaminodihydrothiazine compound useful as a prophylactic or therapeutic agent for neurodegenerative diseases represented by Alzheimer-type dementia and a pharmaceutical use thereof.
  • Ring A is a C6-10 aryl group or a 5-10 membered heterocyclic group
  • L is a single bond, an oxygen atom, or a formula —C ( ⁇ O) NR L —
  • R L is a hydrogen atom or a C1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent ⁇ Or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group, each optionally having 1 to 3 substituents selected from the substituent group ⁇
  • Ring B is a C3-8 cycloalkyl group, a C6-10 aryl group or a 5-10 membered heterocyclic group
  • X is a C1-3 alkylene group or C2-3 alkenylene group each optionally having 1 to 3 substituents selected from substituent group ⁇
  • Y represents an oxygen atom, a sulfur atom, a sulfoxide group, a
  • Z is a single bond or a C1-3 alkylene group
  • R 1 and R 2 each independently have a hydrogen atom, a halogen atom, a hydroxy group or a cyano group, or a C 1-6 alkyl group which may have 1 to 3 substituents each selected from substituent group ⁇
  • R 3 may have a hydrogen atom or 1 to 3 substituents each selected from substituent group ⁇ , C 1-6 alkyl group, C 1-6 alkyl carbonyl group, C 6-10 aryl carbonyl group, C 1 A -6 alkylsulfonyl group, a C6-10 arylsulfonyl group, a C3-8 cycloalkyl group, a C6-10 aryl group or a 5-10 membered heterocyclic group
  • R 4 and R 5 each independently have a hydrogen atom, a halogen atom, a hydroxy group or 1 to 3 substituents each selected from substituent group ⁇
  • Substituent group ⁇ hydrogen atom, halogen atom, hydroxy group, oxo group, cyano group, C1-6 alkyl group, trifluoromethyl group, trifluoromethoxy group, C1-6 alkoxy group, C3-8 cycloalkyl group, C3 -8 cycloalkyloxy group, C6-10 aryl group and 5-10 membered heterocyclic group.
  • [6] L is a formula —C ( ⁇ O) NR L — (R L is a C1-6 alkyl group optionally having 1 to 3 substituents selected from a hydrogen atom or a substituent ⁇ .
  • a pharmaceutical composition comprising as an active ingredient the compound according to any one of [1] to [6] above or a pharmaceutically acceptable salt thereof; [8] The pharmaceutical composition 1 according to the above [7] for suppressing amyloid ⁇ protein production; [9] The pharmaceutical composition according to [7] above, for inhibiting beta-site amyloid ⁇ precursor protein-cleaving enzyme 1 (BACE1); [10] The pharmaceutical composition according to any one of [7] to [9] above for treating a neurodegenerative disease; [11] The pharmaceutical composition according to the above [10], wherein the neurodegenerative disease is Alzheimer-type dementia or Down's syndrome.
  • BACE1 beta-site amyloid ⁇ precursor protein-cleaving enzyme 1
  • the structural formula of a compound may represent a certain isomer for convenience, but in the present invention, all geometrical isomers generated in the structure of the compound, optical isomers based on asymmetric carbon, stereo It includes isomers such as isomers and tautomers, and isomer mixtures, and is not limited to the description of the formula for convenience, and may be either isomer or mixture. Accordingly, there may be an optically active substance and a racemate having an asymmetric carbon atom in the molecule. However, the present invention is not limited to these, and both are included.
  • crystal polymorphs may exist, but are not limited in the same manner, and may be any single crystal form or a mixture thereof, and may be a hydrate in addition to an anhydride.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like, preferably a fluorine atom or a chlorine atom.
  • C1-6 alkyl group means an alkyl group having 1 to 6 carbon atoms, and preferred groups include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group.
  • C2-6 alkenyl group refers to an alkenyl group having 2 to 6 carbon atoms, and preferred groups include, for example, a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, and 1-butene-1- Linear or branched alkenyl such as yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl, etc. Groups.
  • C2-6 alkynyl group refers to an alkynyl group having 2 to 6 carbon atoms, and preferred groups include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group And a linear or molecular chain alkynyl group.
  • C1-6 alkylene group means a divalent group derived from the above-defined “C1-6 alkyl group” by removing one arbitrary hydrogen atom. For example, a methylene group, 1,2-ethylene group 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group, hexamethylene group and the like.
  • C2-6 alkenylene group means a divalent group derived by removing one arbitrary hydrogen atom from the above-defined “C2-6 alkenyl group”. For example, 1,2-vinylene group (ethenylene group) ), Propenylene group, butenylene group, pentenylene group, hexenylene group and the like.
  • C2-6 alkynylene group means a divalent group derived by removing one arbitrary hydrogen atom from “C2-6 alkynyl group” as defined above. For example, ethynylene group, propynylene group, butynylene group , A pentynylene group, a hexynylene group, and the like.
  • C 1-6 alkylsulfonyl group refers to a group in which one hydrogen atom is substituted with a sulfonyl group in an alkyl group having 1 to 6 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group.
  • C 1-6 alkylcarbonyl group refers to a group in which one hydrogen atom is substituted with a carbonyl group in an alkyl group having 1 to 6 carbon atoms.
  • a carbonyl group having 1 to 6 carbon atoms Preferably, for example, an acetyl group, a propionyl group, a butyryl group, etc. Can be mentioned.
  • the “C6-10 aryl group” means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group, and among them, a phenyl group is preferable.
  • C6-10 arylcarbonyl group refers to a group in which a carbonyl group is bonded to an aromatic hydrocarbon ring group having 6 to 10 carbon atoms, preferably a benzoyl group, a naphthoyl group, etc., more preferably a benzoyl group. It is.
  • C3-8 cycloalkyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms.
  • Preferred examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclo An octyl group etc. are mentioned.
  • C3-8 cycloalkyloxy group refers to a group in which one hydrogen atom is substituted with an oxygen atom in a cyclic alkyl group having 3 to 8 carbon atoms, such as a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group. Group, cyclohexoxy group, cycloheptyloxy group, cyclooctyloxy group and the like.
  • C3-8 cycloalkylcarbonyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is substituted with a carbonyl group, such as a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentyl group. Examples include carbonyl group, cyclohexylcarbonyl group, cycloheptylcarbonyl group, cyclooctylcarbonyl group and the like.
  • 5-10-membered heterocyclic group refers to a cyclic group containing 5 to 10-membered heteroatoms, preferably, for example, piperidinyl group, pyrrolidinyl group, azepinyl group, azocanyl group, piperazinyl group, 1,4-diazepanyl.
  • the “5-6 membered heteroaryl group” refers to an aromatic cyclic group containing 5 to 6 membered heteroatoms in the “5-10 membered heterocyclic group”, and includes, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group.
  • C1-3 alkylene group examples include a methylene group, an ethylene group, a propylene group, and the like.
  • C2-3 alkenylene group includes vinylene group and propenylene group.
  • Substituent group ⁇ means a hydrogen atom, a halogen atom, a hydroxy group, an oxo group, a cyano group, a C1-6 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a C1-6 alkoxy group, a C3-8 cyclohexane.
  • An alkyl group, a C3-8 cycloalkyloxy group, a C6-10 aryl group and a 5-10 membered heterocyclic group are meant.
  • the spiraminodihydrothiazine derivative of formula (I) of the present invention may be a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt include inorganic acid salts (for example, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, Hydrobromide, hydroiodide, etc.), organic carboxylates (eg acetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonates (eg Methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartate, glutamate, etc.), quaternary amine salts , Alkali metal salts (for example, sodium salts, potassium salt
  • the spiroaminodihydrothiazine derivative or pharmaceutically acceptable salt of the formula (I) of the present invention may be a solvate thereof, and examples of the solvate include a hydrate.
  • Compound (I) is not limited to a specific isomer, but all possible isomers (ketoeenol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) and racemates Is included.
  • the compound (I) in which R 1 is hydrogen includes the following tautomers.
  • X may have 1 to 3 substituents selected from the substituent group ⁇ .
  • a compound which is an alkylene group, in particular, methylene or ethylene which may have 1 to 3 substituents selected from the substituent group ⁇ is preferable.
  • a compound in which Y is an oxygen atom, a sulfur atom, a sulfone group, or a group represented by the formula —NR Y — (R Y is the same as defined above) is preferable.
  • a compound in which L is a group represented by the formula —C ( ⁇ O) NR L — (R L is the same as defined above) is preferable.
  • a compound in which Y is an oxygen atom and Z is a single bond in formula (I); Y is an oxygen atom, and Z has 1 to 3 substituents selected from substituent group ⁇ Preferred is a compound that is C 1-3 alkylene; Y is a sulfur atom or sulfone, and Z is a single bond.
  • Preferred compounds in the present invention include the following compounds. 1) (-)-N- (2'-amino-2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazin] -6-yl) -5-cyano Pyridine-2-carboxamide, 2) N- (2'-amino-2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazin] -6-yl) -5-trifluoromethylpyridine- 2-carboxamide, 3) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -3,5-difluoropyridine- 2-carboxamide, 4) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4
  • the “leaving group” in the raw material compound used for producing the compound of the formula (I) of the present invention described below may be any leaving group used for the nucleophilic substitution reaction, preferably A C 1-6 alkylsulfonyloxy group optionally substituted with 1 to 3 substituents selected from the above substituent group ⁇ ; 1 to 3 substituents selected from the above substituent group ⁇ A C1-6 alkylcarbonyloxy group which may be substituted with a group; an arylsulfonyloxy group which may be substituted with 1 to 3 substituents selected from the above substituent group ⁇ , and the like.
  • Chlorine atom bromine atom, iodine atom, methanesulfonyloxy group, trifluorocarbonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc.
  • This step is a method of obtaining a compound (II) by cyclizing the compound (a-1) with an acid.
  • This reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • 1 equivalent to a large amount of an appropriate acid is added in the presence or absence of a solvent such as benzene, toluene, dichloromethane and the like. It can be carried out with excessive action.
  • a solvent such as benzene, toluene, dichloromethane and the like. It can be carried out with excessive action.
  • an acid can also be used as a solvent.
  • reaction time is not specifically limited, Usually, it is 1 to 72 hours, Preferably it is 1 to 48 hours.
  • the reaction temperature is usually from ice cooling to the reflux temperature of the solvent.
  • Method 1 is a method for producing compound (a-1) in two steps using compound (a-2) as a raw material.
  • a commercially available product can be used as is, or it can be produced from a commercially available product by a known method, and further can be produced using the method described in the production examples in the examples.
  • This step is a step of obtaining a compound (a-3) by an addition reaction of a vinyl lithium reagent, a vinyl Grignard reagent and a compound (a-2) which can be prepared by a commercially available method or a known method.
  • This reaction is described, for example, in J. Org. Am. Chem. Soc. 2006, 128, 9998-9999, J. MoI. Heterocyclic Chem.
  • the reaction can be carried out under the same conditions as described in 1982, 19, 1041-1044, etc.
  • the solvent used in the reaction varies depending on the starting materials and reagents used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent and is always inactive during the reaction.
  • An organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, or a mixed solvent thereof.
  • the reaction time is not particularly limited, but is usually 0.1 to 48 hours, preferably 0.1 to 12 hours.
  • the reaction temperature varies depending on the starting materials, reagents used, etc., but it is preferable to keep the temperature low, for example, from ⁇ 78 ° C. to room temperature in order to minimize the formation of by-products.
  • a Lewis acid such as zinc chloride, TMEDA (tetramethylethylenediamine), or HMPA (hexamethylphosphoramide) as an additive, for example, good results in improving yield and shortening reaction time, etc. May give.
  • Process 2 In this step, compound (a-3) is reacted with thiourea or N-substituted thiourea in the presence of an acid to obtain compound (a-1).
  • the reaction in this step is described in, for example, Russ. J. et al. Org. Chem. , 2006, 42 (1), 42-47.
  • the acid used in this reaction is, for example, acetic acid, trifluoroacetic acid, hydrogen chloride, sulfuric acid or a mixture thereof.
  • the reaction can be carried out by allowing 1 equivalent or more of a thiourea derivative to act on (a-3) without solvent or in an organic solvent such as toluene.
  • the reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
  • the reaction temperature is usually 0 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • Method 2 [Wherein, ring A, R 1 , R 2 , R 3 , R 4 , X, Y, Z have the same meaning as described above. LV represents a leaving group, and R 10 represents a C 1-6 alkyl group. ] Method 2 is a method for producing compound (a-1) in 4 steps using compound (a-2) as a raw material.
  • Process 1 is a step of obtaining compound (a-4) by addition reaction of Peterson reagent, Horner-Wadworth-Emmons reagent and compound (a-2) under the same conditions as in known methods.
  • Peterson reagent and the Horner-Wadsworth-Emmons reagent commercially available products can be used as they are, and can be prepared by methods known to those skilled in the art.
  • a commercially available organometallic reagent for example, an alkyl lithium reagent such as butyl lithium, or an alkoxy potassium or alkoxy sodium such as tert-butoxy potassium with respect to a trialkylsilylacetic acid alkyl compound or a phosphonoacetic acid trialkyl compound
  • an alkyl lithium reagent such as butyl lithium
  • an alkoxy potassium or alkoxy sodium such as tert-butoxy potassium
  • a trialkylsilylacetic acid alkyl compound or a phosphonoacetic acid trialkyl compound It can be prepared by a reagent or a corresponding lithium alkylamide reagent or magnesium alkylamide reagent by proton metal exchange using metal magnesium or metal lithium.
  • the solvent used in this step varies depending on the starting material and the reagent used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent and is always inactive during the reaction.
  • the reaction time is not particularly limited, but is usually 0.1 to 48 hours, preferably 0.1 to 12 hours.
  • the reaction temperature varies depending on the starting materials, reagents used, etc., but it is preferable to keep the temperature low, for example, from ⁇ 78 ° C. to room temperature in order to minimize the formation of by-products.
  • This step is a step of subjecting the ester compound (a-4) to a reduction reaction to obtain an alcohol compound (a-5).
  • the reducing agent used in the reaction include lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride and the like.
  • the reaction temperature is not particularly limited, but is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from ⁇ 78 ° C. to room temperature.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, diethyl ether, toluene, dichloromethane and the like.
  • Step 3 is a step of obtaining compound (a-6) by converting the hydroxyl group of compound (a-5) to a leaving group.
  • the leaving group include the aforementioned leaving groups.
  • the reaction can be carried out under the same conditions as those usually used for the reaction for converting a hydroxyl group into these leaving groups.
  • the leaving group is a halogen atom
  • the compound (a-5) is reacted with, for example, hydrochloric acid, odorous acid, thionyl chloride, thionyl bromide, phosphorus tribromide or tetrahalogenomethane-triphenylphosphine.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include benzene, toluene, xylene, dichloromethane, chloroform and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from ice cooling to the reflux temperature of the solvent.
  • the reaction time is not particularly limited, but is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours.
  • the leaving group is a C 1-6 alkylcarbonyloxy group
  • it can be produced by reacting the compound (a-5) with, for example, trifluoroacetic acid chloride or trifluoroacetic anhydride.
  • the leaving group is a C 1-6 alkylsulfonyloxy group or arylsulfonyloxy group
  • the compound (a-5) is reacted with, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. And can be manufactured.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • tetrahydrofuran, toluene, xylene, dichloromethane, chloroform, N, N-dimethylformamide and the like are used.
  • the reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably -78 ° C to room temperature.
  • a base may give good results such as improved yield.
  • the base to be used is not particularly limited as long as it does not inhibit the reaction, and preferred examples include sodium carbonate, potassium carbonate, triethylamine, pyridine, diisopropylethylamine and the like.
  • Step 4 is a step of obtaining compound (a-1) by reacting compound (a-6) with thiourea or N-substituted thiourea. Specifically, this reaction is carried out in an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, or odorous acid. In the inorganic acid, the compound (a-6) can be reacted with 1 equivalent or more of thiourea or N-methylthiourea.
  • the reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
  • the reaction temperature is usually 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • General production method 2 is a method for producing a compound in which L is —NHCO— in general formula (I) according to the present invention in 6 steps from compound (II) obtained in general production method 1.
  • Compound (II) can be produced from a commercially available product by the above general production method 1, and can also be produced by using the method described in the production examples in the examples. As the compounds (b-5) and (b-6), commercially available products can be used as they are, or they can be produced from commercially available products by methods known to those skilled in the art. Further, description of production examples in Examples It is also possible to manufacture using the method.
  • Process 1 This step is a step of producing compound (b-1) from compound (II). This reaction can be carried out by the following known method 1 or method 2.
  • Method 1 Method in which compound (II) is subjected to acetylation and nitration reaction simultaneously in the system This reaction can be carried out by a method known to those skilled in the art. / Acetic anhydride, fuming nitric acid / acetic anhydride, and the like.
  • the reaction temperature is not particularly limited, but is usually ⁇ 20 ° C. to 50 ° C., preferably ⁇ 20 ° C. to room temperature.
  • Step 2-1 This step is a step of obtaining the corresponding acetyl compound by acetylation reaction of compound (II).
  • Conditions commonly used for acetylation of amino compounds such as T.I. W. T. T. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A.
  • the reaction can be carried out under the same conditions as described in the literature such as 351-352.
  • Examples of the acetylating agent used in the reaction include acetyl chloride and acetic anhydride.
  • the reaction temperature is not particularly limited, but is usually ⁇ 20 ° C. to 150 ° C.
  • Step 2-2 This step is a step of obtaining the compound (b-1) by nitration of the acetyl compound synthesized in the above Step 2-1.
  • This nitration reaction is carried out under conditions generally used for nitration, such as the Chemical Society of Japan, 4th edition, Experimental Chemistry Course Vol. The reaction can be carried out under the same conditions as described in the literature such as 394-404 and (1992).
  • the nitrating agent used in the reaction include concentrated nitric acid, concentrated nitric acid / acetic acid, concentrated nitric acid / concentrated sulfuric acid, potassium nitrate / concentrated sulfuric acid, fuming nitric acid / acetic anhydride, and the like.
  • the reaction temperature is not particularly limited, but is usually ⁇ 20 ° C. to 70 ° C.
  • This step is a step of obtaining compound (b-2) by deacetylation reaction of compound (b-1).
  • This reaction is carried out under conditions generally used for acetyl group deprotection, such as T.P. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A.
  • the reaction can be carried out under the same conditions as described in the literature such as 351-352.
  • the reaction can be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or hydrobromic acid.
  • the reaction solvent is methanol, ethanol, toluene, propanol or the like, and the reaction temperature is not particularly limited, but is usually ⁇ 20 ° C. to 150 ° C., preferably room temperature to solvent reflux temperature.
  • Step 3 is a step of obtaining compound (b-3) by t-butoxycarbonylation of the amino group of compound (b-2).
  • Conditions commonly used for t-butoxycarbonylation of amino compounds such as those described in T.W. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A.
  • the reaction can be carried out under conditions similar to those described in the literature such as 327-330.
  • compound (b-3) can be obtained by reacting compound (b-2) with di-tert-butyl dicarbonate using triethylamine as a base in a solvent such as tetrahydrofuran.
  • Step 4 is a step of obtaining compound (b-4) by reducing compound (b-3).
  • This reaction can be carried out under conditions generally used for reduction of nitro compounds. For example, reduction by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, palladium, ruthenium, rhodium or platinum, iron, etc. Reduction with the metal used, reduction with sodium dithionite and the like can be mentioned. Preferable examples in this case include a reduction reaction with iron under neutral conditions using ammonium chloride.
  • Process 5 This step is a step of obtaining compound (b-7) from compound (b-4).
  • (1) a method of directly condensing compound (b-4) and compound (b-5) using a condensing agent (method (1)), (2) mixed acid of compound (b-5) Method of reacting anhydride with compound (b-4) (method (2)), (3) Method of reacting active ester of compound (b-5) with compound (b-4) (method (3) Or (4) a method of reacting the acid chloride compound (b-6) with the compound (b-4) (method (4)).
  • the compound (b-4) used for these reactions may be free or a salt.
  • Compound (b-7) can be obtained by directly condensing compound (b-4) and compound (b-5) using a condensing agent. This reaction can be carried out by a known method.
  • a condensing agent CDI (N, N′-carbonyldiimidazole), Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethyl Amino)) phosphonium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride), DCC (N, N-dicyclohexylcarbodiimide), diethyl phosphoryl cyanide, PyBOP ( And benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate) and EDC.HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydro
  • the solvent for this reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, dichloromethane, chloroform, N, N-dimethylformamide, toluene, xylene and the like. can give.
  • Compound (b-5) is used in an amount of 1 equivalent to a large excess with respect to compound (b-4). If necessary, 1 equivalent to a large excess of an organic base such as triethylamine may be added.
  • reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours.
  • the reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited, but is preferably ice-cold to the reflux temperature of the solvent.
  • Method (2) Compound (b-5) can be obtained by making compound (b-5) a mixed acid anhydride and then reacting the mixed acid anhydride with compound (b-4).
  • the mixed acid anhydride can be synthesized by a known method, and is performed by reacting the compound (b-5) with a chloroformate such as ethyl chloroformate in the presence of a base such as triethylamine.
  • the chloroformate and base are used in the amounts of 1 equivalent to 2 equivalents based on compound (b-5).
  • the reaction temperature is ⁇ 30 ° C. to room temperature, preferably ⁇ 20 ° C. to room temperature.
  • the step of condensing the mixed acid anhydride and the compound (b-4) is performed by reacting the mixed acid anhydride and the compound (b-4) in a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, or the like. Done.
  • Compound (b-4) is used in an amount of 1 equivalent to a large excess based on the mixed acid anhydride.
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably ⁇ 20 ° C. to room temperature.
  • Compound (b-5) can be obtained by reacting compound (b-5) with active ester and then reacting active ester with compound (b-4).
  • the compound (b-5) and the active ester synthesis reagent are reacted in the presence of a condensing agent such as DCC in a solvent such as 1,4-dioxane, tetrahydrofuran or N, N-dimethylformamide. Is done.
  • a condensing agent such as DCC
  • a solvent such as 1,4-dioxane, tetrahydrofuran or N, N-dimethylformamide.
  • the active ester synthesis reagent include N-hydroxysuccinimide.
  • the active ester synthesis reagent and the condensing agent are used in the amount of 1 to 1.5 equivalents based on compound (b-5).
  • reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours.
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably ⁇ 20 ° C. to room temperature.
  • the step of condensing the active ester with the compound (b-4) is performed by reacting the active ester with the compound (b-4) in a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide or the like. Compound (b-4) is used in an amount of 1 equivalent to a large excess based on the active ester.
  • reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours.
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably ⁇ 20 ° C. to room temperature.
  • the acylation reaction for obtaining the compound (b-7) from the compound (b-4) and the compound (b-6) can be carried out under the same conditions as known generally used conditions.
  • the base used for the reaction include triethylamine, pyridine, potassium carbonate, diisopropylethylamine and the like.
  • the reaction temperature is not particularly limited, but is usually from ⁇ 78 ° C. to the reflux temperature of the solvent, preferably from ⁇ 20 ° C. to room temperature.
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, ether, toluene, dichloromethane and the like.
  • This step is a step of obtaining compound (Ia) by deprotecting the t-butoxycarbonyl group of compound (b-7).
  • Conditions generally used for the deprotection reaction of the t-butoxycarbonyl group such as those described in T.W. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A.
  • the reaction can be carried out under conditions similar to those described in the literature such as 327-330.
  • compound (Ia) can be obtained by reacting trifluoroacetic acid with compound (b-7) in a solvent such as dichloromethane.
  • L is —C ( ⁇ O) NH—
  • R L is a C1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent ⁇ Can be obtained.
  • the compound (Ia) obtained in the general production method 2 is further converted into a C1-6 alkyl halide, a C1-6 alkylcarbonyl halide, a C6-10 aryl.
  • R 3 may have 1 to 3 substituents selected from the substituent group ⁇ and may have a substituent selected from the substituent group ⁇ .
  • C-6-10 arylcarbonyl group optionally having 1 to 3 substituents selected from a -6 alkylcarbonyl group and substituent group ⁇
  • substituent group ⁇ C1-6 alkylsulfonyl group optionally having 1 to 3 substituents selected
  • C6-10 arylsulfonyl group optionally having 1 to 3 substituents selected from substituent group ⁇
  • a C3-10 membered carbocyclic group which may have 1 to 3 substituents selected from the substituent group ⁇ , or 1 to 3 substituents selected from the substituent group ⁇ .
  • Compounds of the invention that are good 5-10 membered heterocyclic groups can be obtained.
  • L 1 represents a single bond or a C 1-6 alkylene group in the compounds (c-4), (c-5) and (c-6), and the compounds (c-8) and (c— 9) represents a single bond or a C1-4 alkylene group
  • L represents a single bond, an oxygen atom, a C1-6 alkylene group, a C2-6 alkenylene group or a C2-6 alkynylene group
  • ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, Z have the same meaning as described above.
  • General production method 3 is a method for producing compound (Ib) in which L is a single bond, double bond, or triple bond in general formula (I) in three steps from compound (II).
  • Compound (II) can be produced from a commercially available product by the general production method 1, and can also be produced by using the method described in the production examples in the examples.
  • compounds (c-4), (c-5), (c-6), (c-7) and (c-8) can be used as they are, or they can be used as they are by commercially known methods. It can also be produced, and further can be produced using the method described in the production examples in the examples.
  • This step is a step of obtaining compound (c-1) by carrying out bromination reaction of compound (II) in the system.
  • This reaction is described, for example, in Holberg, P .; Tedenburg, P .; Rosquivst, S .; Hohansson, A .; M.M. Bioorg. Med. Chem. Lett. ; 15 (3), 747-750 (2005) and the like.
  • Examples of the conditions used for the reaction include bromine / acetic acid, bromine / sodium carbonate / hexane, N-bromosuccinimide / methylene chloride, and the like.
  • the reaction temperature is not particularly limited, but is usually ⁇ 20 ° C. to 50 ° C., preferably ⁇ 20 ° C. to room temperature.
  • Process 2 This step is a step of obtaining compound (c-2) by tert-butoxycarbonylation of compound (c-1) or compound (c-3) when R 3 is a hydrogen atom.
  • This reaction is carried out by reacting compound (c-1) with di-tert-butyl dicarbonate using 4-dimethylaminopyridine as a base in conditions generally used for t-butoxycarbonylation of amide compounds, such as THF. To give compound (c-2) or (c-3).
  • the solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, but is preferably an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, DMF, acetonitrile and the like. Or these mixed solvents are mentioned.
  • the base to be used include triethylamine, 4-dimethylaminopyridine, DBU, or a mixture thereof. These bases are used in a catalytic amount to an excess amount relative to compound (c-1), more preferably 0.1-5 equivalents.
  • Di-tert-butyl dicarbonate is used in an amount of 2 equivalents to an excess amount relative to compound (c-1), more preferably 2-10 equivalents.
  • the reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
  • the reaction temperature is usually from ⁇ 20 ° C. to the reflux temperature of the solvent, more preferably from 0 ° C. to the reflux temperature of the solvent.
  • Step 3 This step comprises compound (c-2) or (c-3) and compound (c-4), (c-5), (c-6), (c-7), (c-8) or (
  • compound (Ib) is obtained by deprotecting the t-butoxycarbonyl group by a coupling reaction with c-9) using a transition metal.
  • This reaction is a coupling reaction using a transition metal (for example, Suzuki-Miyaura reaction, Stille reaction (Still reaction), Sonogashira reaction, Heck reaction (Heck reaction), Buckwald, SL et al., J Am.
  • the reaction can be carried out under conditions usually used in Chem Soc (1999) 121 (18), 4369-4378 and the like.
  • the organometallic catalyst used in this reaction is not particularly limited, but preferably, for example, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), [1,1′-bis (diphenyl) Metal catalysts such as phosphino) ferrocene] palladium (II) dichloride, bis (tert-butylphosphine) palladium (0), palladium (II) acetate, [1,3-bis (diphenylphosphino) propane] nickel (II) Or the mixture of these metal catalysts can be mention
  • the amount of the organometallic catalyst used is about 0.001 to 0.5 equivalent with respect to the raw material.
  • the amount of compound (c-4), (c-5), (c-6), (c-7) or (c-8) used is not particularly limited, but is usually compound (c-2) or ( 1 to 6 equivalents relative to c-3).
  • the solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction.
  • the reaction temperature is not particularly limited, but is usually from ice-cooling to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent, for example.
  • the reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
  • the base or salt is not particularly limited, but preferably sodium carbonate, potassium carbonate, barium hydroxide, cesium carbonate, potassium phosphate, potassium fluoride, or an aqueous solution thereof, and triethylamine, N, N-diisopropylethylamine, Examples include bases such as lithium chloride and copper (I) iodide, and salts.
  • step 3 when R 3 is a hydrogen atom in compound (c-1), a coupling reaction is performed with compound (c-7) without protecting the amino group with a t-butoxycarbonyl group or the like, Compound (Ib) can be synthesized.
  • R 3 when R 3 is a hydrogen atom, the compound (Ib) obtained in the general production method 3 is further converted into a C1-6 alkyl halide, C1-6 alkylcarbonyl halide, C6-10 aryl.
  • a corresponding halogenated compound such as carbonyl halide, C1-6 alkylsulfonyl halide, C6-10 arylsulfonyl halide, C3-10 membered carbocyclic halide, 5-10 membered heterocyclic halide, etc.
  • formula (I) In R 1 , R 3 may have 1 to 3 substituents selected from the substituent group ⁇ and may have a substituent selected from the substituent group ⁇ .
  • C-6-10 arylcarbonyl group optionally having 1 to 3 substituents selected from a -6 alkylcarbonyl group and substituent group ⁇
  • substituent group ⁇ C1-6 alkylsulfonyl group optionally having 1 to 3 substituents selected
  • C6-10 arylsulfonyl group optionally having 1 to 3 substituents selected from substituent group ⁇
  • a C3-10 membered carbocyclic group which may have 1 to 3 substituents selected from the substituent group ⁇ , or 1 to 3 substituents selected from the substituent group ⁇ .
  • Compounds of the invention that are good 5-10 membered heterocyclic groups can be obtained.
  • the compound (Ib) obtained in General Production Method 3 wherein L is a C1-6 alkylene group is compound (c-2) or (c-3) and (c-8) or (c-9)
  • the resulting L is produced by a coupling reaction using a transition metal with C2-6 alkenylene group or C2-6 alkynylene group under the conditions normally used for the reduction reaction, for example, a reaction using a catalyst such as palladium. You can also.
  • the compound of the formula (I) of the present invention thus obtained can be converted into a pharmaceutically acceptable salt by a conventional method as necessary.
  • the production method can be carried out by appropriately combining methods usually used in the field of synthetic organic chemistry. Specific examples include neutralization titration of a free solution of the compound of the present invention with an acid solution. If necessary, the compound of formula (I) of the present invention can be converted into a solvate by subjecting to a solvate formation reaction known per se.
  • the spiroaminodihydrothiazine derivative or a pharmaceutically acceptable salt thereof according to the present invention has a very excellent A ⁇ production inhibitory action or BACE1 inhibitory action, and is a neurodegenerative disease represented by Alzheimer-type dementia caused by A ⁇ . It is extremely useful as a prophylactic or therapeutic agent.
  • the spiroaminodihydrothiazine derivative or a pharmaceutically acceptable salt thereof according to the present invention can be formulated by a usual method.
  • Preferred dosage forms include, for example, tablets such as tablets, film tablets and sugar-coated tablets, Fine granules, granules, powders, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, poultices, lotions, etc. .
  • These solid preparations such as tablets, capsules, granules and powders are generally 0.01 to 100% by weight, preferably 0.1 to 100% by weight, of the active ingredient of the spiroaminodihydro according to the present invention.
  • Thiazine derivatives or pharmaceutically acceptable salts thereof can be included.
  • ingredients generally used as raw materials for pharmaceutical preparations are blended.
  • excipients for example, commonly used excipients, disintegrants, binders, lubricants, coloring agents, flavoring agents, and if necessary, stabilizers , Emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. are added to prepare a formulation by a conventional method.
  • these components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; cetostearyl alcohol and behenyl alcohol Higher alcohols such as: silicone resin; silicone oil; polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, etc.
  • animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides
  • hydrocarbons such as liquid paraffin, squalane and solid paraffin
  • ester oils such as octyldodecyl myristate and isopropyl myristate
  • Water-soluble such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methylcellulose Molecules; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate Body, purified water and the like.
  • excipient examples include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, and the like
  • binder examples include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, Shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, Calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium and the like are lubricants such as magnesium stearate , Talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., which are allowed to be added to pharmaceuticals as colorants, flavourants include cocoa powder, mint brain, aroma
  • an oral preparation is an active ingredient of the spiroaminodihydrothiazine derivative according to the present invention or a pharmaceutically acceptable salt and excipient thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, After adding a flavoring agent, etc., powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by conventional methods. In the case of tablets and granules, of course, sugar coating and other appropriate coatings may be used if necessary.
  • injectable preparations, etc. a pH adjuster, a solubilizer, an isotonic agent, etc., and a solubilizing agent, a stabilizer, etc., if necessary, are added and formulated in a conventional manner.
  • these injections can take the form which melt
  • These injection solutions can usually contain active ingredients such as 0.01 to 100% by weight, preferably 0.1 to 100% by weight.
  • liquid preparations such as suspensions or syrups for oral administration can contain 0.01 to 100% by weight, preferably 0.1 to 100% by weight of an active ingredient.
  • the production method is not particularly limited, and it can be produced by a conventional method.
  • a base material to be used various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.
  • Chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, and the like can be added.
  • components having differentiation-inducing action, blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and the like can be blended as necessary.
  • the dosage of the spiroaminodihydrothiazine derivative or pharmaceutically acceptable salt thereof according to the present invention depends on the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, etc. Usually, in the case of an adult, about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, more preferably 100 ⁇ g to 1 g is orally administered per day, and about 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, more preferably by injection. Administer 100 ⁇ g to 300 mg once or in several divided doses.
  • Root temperature in the following Examples and Production Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates weight percent unless otherwise specified.
  • Table 1 shows the structural formula and 1H-NMR data.
  • Triethylamine (0.595 ml) was added, and the mixture was further stirred for 40 minutes in an ice bath.
  • an aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction.
  • the aqueous layer was extracted with methylene chloride.
  • the water bath was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate.
  • the pale yellow solid produced when the solvent was distilled off under reduced pressure was recovered with a Kiriyama funnel, and the crude product was purified by silica gel column chromatography to obtain the title compound (644 mg).
  • the obtained residue was dissolved in trifluoroacetic acid (0.49 ml), and trifluoromethanesulfonic acid (0.1 ml) was added in an ice bath. After stirring at the same temperature for 1.5 hours, the mixture was stirred at room temperature for 1.5 hours. After confirming disappearance of the raw materials, the reaction mixture was neutralized by adding it to an aqueous sodium bicarbonate solution cooled in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (58.5 mg).
  • reaction mixture was added to sodium bicarbonate water to stop the reaction.
  • the aqueous layer was extracted with ethyl acetate.
  • the water bath was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate.
  • the title compound (214 mg) obtained by distilling off the solvent under reduced pressure was used in the next reaction as the crude product.
  • compound 5-3 can also be synthesized by the method shown below.
  • (3) Synthesis of 2- (7-fluorochroman-4-ylidene) ethyl-2,2,2-trifluoroacetate (Compound 5-4) Compound 5-1 (1.0 g ) cooled in an ice bath ) In tetrahydrofuran (20 ml) was added triethylamine (1.15 ml). A solution of trifluoroacetic anhydride (1.62 g) in tetrahydrofuran (2.5 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. When the disappearance of the raw materials was confirmed, the reaction mixture was added to sodium bicarbonate water to stop the reaction.
  • the aqueous layer was extracted with ethyl acetate.
  • the water bath was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate.
  • the title compound (1.42 g) obtained by distilling off the solvent under reduced pressure was used in the next reaction without purification.
  • Example 1 ( ⁇ ) -N- [2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl] -5-chloropyridine- Synthesis of 2-carboxamide (Compound 8) (1-1) 6-nitro -2,3,5 ', 6'-tetrahydrospiro [chromene-4,4' - [1,3] thiazin] -2'-amine (Compound 6-2) Fuming nitric acid (specific gravity 1.53, 49.5 ⁇ l) was added dropwise to a solution of compound 1 (280 mg) in acetic anhydride (10.0 ml) in an ice bath.
  • the reaction was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for 3 hours.
  • Acetic anhydride (10.0 ml) was added to the reaction solution, and fuming nitric acid (specific gravity 1.53, 400 ⁇ l) was added.
  • the reaction solution was diluted with ether, aqueous sodium bicarbonate was added, and the mixture was stirred for 1 hour.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure.
  • compound 6-1 can also be synthesized by the following method. To a solution of compound 1 (1.1 g) in pyridine (6 ml) was added acetic anhydride (0.886 ml) at room temperature, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-sodium bicarbonate water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the obtained crude product was purified by NH-silica gel column chromatography, and the N-acetyl form of compound 1 (N- (2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1, 3] thiazin] -2′-yl) acetamide) (1.1 g).
  • Nitric acid specific gravity 1.42, 1.0 ml
  • acetic acid 0.2 ml
  • Nitric acid (3.0 ml) was added to this solution at 50 ° C., and the mixture was stirred at 50 ° C.
  • compound 6-4 can also be synthesized by the following method. Iron (1.05 g) was added to compound 6-3 (510 mg) in ethanol (18 ml) -ammonium chloride aqueous solution (1.8 ml), and the mixture was stirred with heating at 87 ° C. for 0.5 hr. The reaction solution was returned to room temperature, poured into ethyl acetate, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • the reaction was diluted with diethyl ether and quenched with aqueous sodium bicarbonate.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was purified by NH-silica gel column chromatography to obtain the title compound (7.8 mg).
  • Example 3 ( ⁇ )-(6-Amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -2′-yl) carbamate t-butyl (compound 10 )
  • Example 6 Of 6- (5-methoxypyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 21) Composition (1) Synthesis of 6-bromo-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (Compound 20) Compound 1 (560 mg) Bromine (382 mg) was added to an acetic acid (12.0 ml) solution at room temperature and stirred for 30 minutes.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography to obtain the title compound (8.6 mg).
  • Table 4 The compounds listed in Table 4 were synthesized in the same manner as in Example 6 (3).
  • Table 4 shows the structural formula and 1H-NMR data.
  • Example 7 Of 6- (2-fluoropyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 24)
  • Composition 2-Fluoropyridine-3-boronic acid (14.9 mg) was added to a solution of compound 11-2 (26.3 mg) in N, N-dimethylformaldehyde (0.95 ml).
  • 1M aqueous sodium bicarbonate solution (0.14 ml) and palladium-triphenylphosphine (7.8 mg) were added, and the mixture was stirred at 100 ° C. for 12 hours under a nitrogen atmosphere.
  • Example 8 7-Fluoro-6- (2-fluoropyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine ( Synthesis of compound 26) (1) Synthesis compound of 6-bromo-7-fluoro-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (Compound 25) Bromine (12.7 mg) was added to a solution of 6 (20 mg) in acetic acid (1.0 ml) at room temperature and stirred for 30 minutes.
  • reaction mixture was added to sodium bicarbonate water for neutralization.
  • the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained crude product 25 (14.4 mg) was used in the next reaction without purification.
  • 2-Fluoropyridine-3-boronic acid (7.2 mg) was added to a solution of the crude product 13-1 (17 mg) obtained in the above reaction in N, N-dimethylformaldehyde (0.5 ml). Subsequently, 1M aqueous sodium bicarbonate solution (0.05 ml) and palladium-triphenylphosphine (3.8 mg) were added, and the mixture was stirred overnight at 100 ° C. in a nitrogen atmosphere. After confirming disappearance of the raw materials, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
  • Test example 1 Quantification of A ⁇ Peptide in Rat Embryonic Brain-Derived Neuronal Culture
  • Rat Primary Neuronal Culture Embryonic 18-day-old Wistar rats (Charles River Japan, Yokohama, Japan) were isolated and subjected to culture. Specifically, fetuses were aseptically removed from pregnant rats under ether anesthesia. The brain was removed from the fetus and immersed in ice-cold L-15 medium (Invitrogen Corp. Cat # 11415-064, Carlsbad, CA USA or SIGMA L1518, etc.). Cerebral cortex was collected from the isolated brain under a stereomicroscope. Collected cerebral cortical fragments were 0.25% trypsin (Invitrogen Corp.
  • the cells were dispersed by enzyme treatment at 37 ° C. for 30 minutes in an enzyme solution containing Louis, MO, USA). At this time, the enzyme reaction was stopped by adding inactivated horse serum. This enzyme-treated solution was centrifuged at 1500 rpm for 5 minutes, and the supernatant was removed. 5 to 10 ml of a medium was added to the obtained cell mass.
  • the medium includes Neurobasal medium (Invitrogen Corp. Cat # 21103-049, Carlsbad, CA USA), and 2% B27 supplement (Invitrogen Corp.
  • This cell dispersion was filtered through a 40 ⁇ m nylon mesh (Cell Strainer, Cat # .35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to obtain a neuronal cell suspension. .
  • This neuronal cell suspension was diluted with a medium, and a 96-well polystyrene incubator (Falcon Cat # .35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA) previously coated with poly-L or D-lysine.
  • poly-L-lysine coat by the following method, or BIOCOAT TM cell environments Poly-D-lysine cell wall 96-well plate, Cat # .35-6461, Becton DickinNoneFrakinN Labin, USA ) was seeded at 100 ⁇ l / well so that the initial cell density was 5 ⁇ 10 5 cells / cm 2 .
  • Poly-L-lysine coating was performed as follows. A 100 ⁇ g / ml poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) solution was aseptically prepared using 0.15 M Borate buffer (pH 8.5).
  • the solution was added to a 96-well polystyrene incubator at 100 ⁇ g / well and incubated at room temperature for 1 hour or longer, or at 4 ° C. overnight or longer. Thereafter, the coated 96-well polystyrene incubator was washed four or more times with sterilized water, dried, or rinsed with sterile PBS or a medium, and used for cell seeding. The seeded cells were cultured for one day in a 37 ° C. incubator under 5% CO 2 -95% air, and then the entire medium was replaced with fresh Neurobasal / B27 / 2-ME medium, followed by culturing for 3 days.
  • the obtained culture medium was an ELISA sample.
  • the A ⁇ x-42 measurement was not diluted, but the A ⁇ x-40 measurement was diluted 5-fold with the diluent supplied with the ELISA kit and used for each ELISA.
  • MTT dissolution buffer was added thereto at 100 ⁇ l / well, and MTT formazan crystals were well dissolved in a 37 ° C. incubator under 5% CO 2 -95% air, and then the absorbance at 550 nm of each well was measured.
  • MTT lysis buffer was prepared as follows. 100 g SDS (sodium dodecyl sulfate (sodium lauryl sulfate), WAKO 191-07145, Osaka, Japan) was dissolved in a solution obtained by mixing 250 mL each of N, N-dimethylformamide (WAKO 045-02916, Osaka, Japan) and distilled water. .
  • a background (bkg) obtained by adding only a medium and an MTT solution to a well not seeded with cells was set.
  • bkg was subtracted according to the following formula, a ratio (% of CTRL) to a control group (group not treated with drug, CTRL) was calculated, and cell survival activity was compared and evaluated.
  • A550_sample-A550_bkg /) A550_CTRL-bkg) x 100 (A550_sample: 550 nm absorbance of sample well, A550_bkg: 550 nm absorbance of background well, A550_CTRL: 550 nm absorbance of control well)
  • a ⁇ ELISA is a human / rat ⁇ amyloid (42) ELISA kit Wako (# 290-62601) from Wako Pure Chemical Industries, Ltd., and a human / rat ⁇ amyloid (40) ELISA kit Wako ( # 294-62501).
  • the method was performed according to the manufacturer's recommended protocol (the method described in the package insert). However A [beta] calibration curve, beta-amyloid peptide 1-42, rat and beta-amyloid peptide 1-40, rat ( Calbiochem. # 171596 [A ⁇ 42], 171593 [A ⁇ 40]) was prepared using. The results are shown in Table 5 as a percentage (% of CTRL) to the A ⁇ concentration in the medium of the control group.
  • the compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an A ⁇ 42 production reducing action, according to the present invention, neurodegenerative diseases caused by A ⁇ such as Alzheimer's dementia and Down's syndrome in particular.
  • a therapeutic or prophylactic agent can be provided.

Abstract

A compound represented by the general formula (I) [wherein ring A is C6-10 aryl, etc.; L is a single bond, a group represented by the formula -C(=O)NRL- (RL is hydrogen or C1-6 alkyl optionally having one to three substituents selected from a substituent group (α)), etc.; ring B is C6-10 aryl, etc.; X is, e.g., C1-3 alkylene optionally having one to three substituents selected from the substituent group (α); Y is oxygen, etc.; Z is a single bond, etc.; R1 and R2 each independently is hydrogen, etc.; R3 is hydrogen, etc.; R4 and R5each independently is hydrogen, etc.; R6, R7, and R8 each independently is hydrogen, etc.; n is an integer of 1 to 3; and the substituent group (α) includes hydrogen, etc.] or a pharmaceutically acceptable salt of the compound. The compound or salt has Aß production inhibitory activity or BACE1 inhibitory activity. They are useful as a preventive or therapeutic agent for neurodegenerative diseases which are attributable to Aß and represented by dementia of Alzheimer type.

Description

スピロアミノジヒドロチアジン誘導体Spiroaminodihydrothiazine derivatives
　本発明は、スピロアミノジヒドロチアジン誘導体及びその医薬用途に関する。更に詳細には、アミロイドβ（以下、Ａβという。）タンパク産生抑制作用又はベータサイトアミロイドβ前駆体タンパク質開裂酵素１（以下、ＢＡＣＥ１という）阻害作用を有し、Ａβタンパクが原因となる神経変性疾患、特にアルツハイマー型痴呆、ダウン症等の治療に有効なスピロアミノジヒドロチアジン誘導体及びそれを有効成分として含有する医薬組成物に関する。 The present invention relates to a spiroaminodihydrothiazine derivative and its pharmaceutical use. More specifically, it has a amyloid β (hereinafter referred to as Aβ) protein production inhibitory action or a beta-site amyloid β precursor protein cleavage enzyme 1 (hereinafter referred to as BACE1) inhibitory action, and is a neurodegenerative disease caused by Aβ protein. In particular, the present invention relates to a spiroaminodihydrothiazine derivative effective for the treatment of Alzheimer-type dementia, Down's syndrome and the like and a pharmaceutical composition containing it as an active ingredient.
　アルツハイマー病は、神経細胞の変性や、脱落とともに、老人班の形成および神経原繊維変化を特徴とする疾患である。現在、アルツハイマー病の治療は、アセチルコリンエステラーゼ阻害剤に代表される症状改善剤による対症療法に限られていて、病気の進行を抑制する根本療法剤は開発されていない。アルツハイマー病の根本療法剤の創出には、病態の発症原因を制御する方法の開発が必要である。
　アミロイド前駆体タンパク（以下、ＡＰＰという。）の代謝産物であるＡβタンパクは、神経細胞の変性・脱落、さらには痴呆症状の発現に大きくかかわると考えられている（例えば、非特許文献３、４参照）。Ａβタンパクの主成分は、アミノ酸４０個からなるＡβ４０とＣ末が２アミノ酸増えたＡβ４２である。これらのＡβ４０および４２は、凝集性が高く（例えば、非特許文献５参照）、老人班の主要構成成分であり（例えば、非特許文献５、６、７参照）、さらに、家族性アルツハイマー病で見られるＡＰＰおよびプレセネリン遺伝子の変異は、これらのＡβ４０および４２を増加させることが知られている（例えば、非特許文献８、９、１０参照）。したがって、Ａβ４０および４２の産生を低下させる化合物は、アルツハイマー病の進行抑制剤または予防薬として期待されている。
　Ａβは、ＡＰＰがベータセクレターゼ（ＢＡＣＥ１）により切断され、続いてガンマセクレターゼにより切り出されることにより産生する。このことより、Ａβ産生抑制を目的として、ガンマセクレターゼおよびベータセクレターゼの阻害剤の創出が試みられている。既に知られているベータセクレターゼ阻害剤は、以下に示す特許文献１～１３、非特許文献１および２等で報告されており、中でも特許文献１にはアミノジヒドロチアジン誘導体およびベータセクレターゼの阻害活性、すなわちＢＡＣＥ１阻害活性を有する化合物が記載されている。
国際公開第２００７／０４９５３２号パンフレット 米国特許第３２３５５５１号明細書 米国特許第３２２７７１３号明細書 特開平９－０６７３５５号公報 国際公開第０１／１８７２９３号パンフレット 国際公開第０４／０１４８４３号パンフレット 特開２００４－１４９４２９号公報 国際公開第０２／９６８９７号パンフレット 国際公開第０４／０４３９１６号パンフレット 国際公開第２００５／０５８３１１号パンフレット 国際公開第２００７／０９７７６７号パンフレット 国際公開第２００７／０４１４０４号パンフレット 国際公開第２００７／０４１４０５号パンフレット ジャーナル・オブ・ヘテロサイクリック・ケミストリー（Ｊｏｕｒｎａｌ　ｏｆ　Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍｉｓｔｒｙ）、１４巻、７１７頁～７２３頁（１９７７年） ジャーナル・オブ・オーガニック・ケミストリー（Ｊｏｕｒｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ）、３３巻、３１２６頁～３１３２頁（１９６８年） Ｋｌｅｉｎ　ＷＬ，外７名，Ａｌｚｈｅｉｍｅｒ’ｓ　ｄｉｓｅａｓｅ－ａｆｆｅｃｔｅｄ　ｂｒａｉｎ：　Ｐｒｅｓｅｎｃｅ　ｏｆ　ｏｌｉｇｏｍｅｒｉｃ　Ａβ　ｌｉｇａｎｄｓ（ＡＤＤＬｓ）ｓｕｇｇｅｓｔｓ　ａ　ｍｏｌｅｃｕｌａｒ　ｂａｓｉｓ　ｆｏｒ　ｒｅｖｅｒｓｉｂｌｅ　ｍｅｍｏｒｙ　ｌｏｓｓ，Ｐｒｏｃｅｄｉｎｇ　Ｎａｔｉｏｎａｌ　Ａｃａｄｅｍｙ　ｏｆ　Ｓｃｉｅｎｃｅ　ＵＳＡ　２００３，Ｓｅｐ　２；１００（１８），ｐ．１０４１７－１０４２２． Ｎｉｔｓｃｈ　ＲＭ，外１６名，Ａｎｔｉｂｏｄｉｅｓ　ａｇａｉｎｓｔ　β－ａｍｙｌｏｉｄ　ｓｌｏｗ　ｃｏｇｎｉｔｉｖｅ　ｄｅｃｌｉｎｅ　ｉｎ　Ａｌｚｈｅｉｍｅｒ’ｓ　ｄｉｓｅａｓｅ，Ｎｅｕｒｏｎ，２００３，Ｍａｙ　２２；３８，ｐ．５４７－５５４． Ｊａｒｒｅｔｔ　ＪＴ，外２名，Ｔｈｅ　ｃａｒｂｏｘｙ　ｔｅｒｍｉｎｕｓ　ｏｆ　ｔｈｅ　β　ａｍｙｌｏｉｄ　ｐｒｏｔｅｉｎ　ｉｓ　ｃｒｉｔｉｃａｌ　ｆｏｒ　ｔｈｅ　ｓｅｅｄｉｎｇ　ｏｆ　ａｍｙｌｏｉｄ　ｆｏｒｍａｔｉｏｎ：　Ｉｍｐｌｉｃａｔｉｏｎｓ　ｆｏｒ　ｔｈｅ　ｐａｔｈｏｇｅｎｅｓｉｓ　ｏｆ　Ａｌｚｈｅｉｍｅｒｓ’　ｄｉｓｅａｓｅ，Ｂｉｏｃｈｅｍｉｓｔｒｙ，１９９３，３２（１８），ｐ．４６９３－４６９７． Ｇｌｅｎｎｅｒ　ＧＧ，外１名，Ａｌｚｈｅｉｍｅｒ’ｓ　ｄｉｓｅａｓｅ：　ｉｎｉｔｉａｌ　ｒｅｐｏｒｔ　ｏｆ　ｔｈｅ　ｐｕｒｉｆｉｃａｔｉｏｎ　ａｎｄ　ｃｈａｒａｃｔｅｒｉｚａｔｉｏｎ　ｏｆ　ａ　ｎｏｖｅｌ　ｃｅｒｅｂｒｏｖａｓｃｕｌａｒ　ａｍｙｌｏｉｄ　ｐｒｏｔｅｉｎ，Ｂｉｏｃｈｅｍｉｃａｌ　ａｎｄ　ｂｉｏｐｈｙｓｉｃａｌ　ｒｅｓｅａｒｃｈ　ｃｏｍｍｕｎｉｃａｔｉｏｎｓ，１９８４，Ｍａｙ　１６，１２０（３），ｐ．８８５－８９０． Ｍａｓｔｅｒｓ　ＣＬ，外５名，Ａｍｙｌｏｉｄ　ｐｌａｑｕｅ　ｃｏｒｅ　ｐｒｏｔｅｉｎ　ｉｎ　Ａｌｚｈｅｉｍｅｒ　ｄｉｓｅａｓｅ　ａｎｄ　Ｄｏｗｎ　ｓｙｎｄｒｏｍｅ，Ｐｒｏｃｅｄｉｎｇ　Ｎａｔｉｏｎａｌ　Ａｃａｄｅｍｙ　ｏｆ　Ｓｃｉｅｎｃｅ　ＵＳＡ，１９８５，Ｊｕｎ，８２（１２），ｐ．４２４５－４２４９． Ｇｏｕｒａｓ　ＧＫ，外１１名，Ｉｎｔｒａｎｅｕｒｏｎａｌ　Ａβ４２　ａｃｃｕｍｕｌａｔｉｏｎ　ｉｎ　ｈｕｍａｎ　ｂｒａｉｎ，Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐａｔｈｏｌｏｇｙ，２０００，Ｊａｎ，１５６（１），ｐ．１５－２０． Ｓｃｈｅｕｎｅｒ　Ｄ，外２０名，Ｓｅｃｒｅｔｅｄ　ａｍｙｌｏｉｄ　β－ｐｒｏｔｅｉｎ　ｓｉｍｉｌａｒ　ｔｏ　ｔｈａｔ　ｉｎ　ｔｈｅ　ｓｅｎｉｌｅ　ｐｌａｑｕｅｓ　ｏｆ　Ａｌｚｈｅｉｍｅｒ’ｓ　ｄｉｓｅａｓｅ　ｉｓ　ｉｎｃｒｅａｓｅｄ　ｉｎ　ｖｉｖｏ　ｂｙ　ｔｈｅ　ｐｒｅｓｅｎｉｌｉｎ　１　ａｎｄ　２　ａｎｄ　ＡＰＰ　ｍｕｔａｔｉｏｎｓ　ｌｉｎｋｅｄ　ｔｏ　ｆａｍｉｌｉａｌ　Ａｌｚｈｅｉｍｅｒ’ｓ　ｄｉｓｅａｓｅ，Ｎａｔｕｒｅ　Ｍｅｄｉｃｉｎｅ，１９９６，Ａｕｇ，２（８），ｐ．８６４－８７０． Ｆｏｒｍａｎ　ＭＳ，外４名，Ｄｉｆｆｅｒｅｎｔｉａｌ　ｅｆｆｅｃｔｓ　ｏｆ　ｔｈｅ　ｓｗｅｄｉｓｈ　ｍｕｔａｎｔ　ａｍｙｌｏｉｄ　ｐｒｅｃｕｒｓｏｒ　ｐｒｏｔｅｉｎ　ｏｎ　β－ａｍｙｌｏｉｄ　ａｃｃｕｍｕｌａｔｉｏｎ　ａｎｄ　ｓｅｃｒｅｔｉｏｎ　ｉｎ　ｎｅｕｒｏｎｓ　ａｎｄ　ｎｏｎｎｅｕｒｏｎａｌ　ｃｅｌｌｓ，Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｂｉｏｌｏｇｉｃａｌ　Ｃｈｅｍｉｓｔｒｙ，１９９７，Ｄｅｃ　１９，２７２（５１），ｐ．３２２４７－３２２５３． Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles as well as neuronal degeneration and loss. Currently, treatment of Alzheimer's disease is limited to symptomatic treatment with symptom ameliorating agents represented by acetylcholinesterase inhibitors, and no fundamental therapeutic agent that suppresses the progression of the disease has been developed. Development of a method for controlling the onset of the pathological condition is necessary for the creation of a fundamental therapeutic agent for Alzheimer's disease.
Aβ protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in the degeneration / dropout of nerve cells and the development of dementia symptoms (for example, Non-Patent Documents 3 and 4). reference). The main components of the Aβ protein are Aβ40 consisting of 40 amino acids and Aβ42 with 2 amino acids added at the C-terminus. These Aβ40 and 42 are highly aggregating (see, for example, Non-Patent Document 5), and are the main constituents of the elderly population (see, for example, Non-Patent Documents 5, 6, and 7). It is known that the mutation of APP and presenelin gene seen increases these Aβ40 and 42 (see, for example, Non-Patent Documents 8, 9, and 10). Therefore, a compound that decreases the production of Aβ40 and 42 is expected as a progression inhibitor or preventive agent for Alzheimer's disease.
Aβ is produced by cleaving APP with beta-secretase (BACE1), followed by cleaving with gamma-secretase. Accordingly, attempts have been made to create inhibitors of gamma secretase and beta secretase for the purpose of suppressing Aβ production. Known beta-secretase inhibitors have been reported in Patent Documents 1 to 13 and Non-Patent Documents 1 and 2 shown below. Among them, Patent Document 1 describes the inhibitory activity of aminodihydrothiazine derivatives and beta-secretase. That is, compounds having BACE1 inhibitory activity are described.
International Publication No. 2007/049532 Pamphlet U.S. Pat. No. 3,235,551 U.S. Pat. No. 3,227,713 Japanese Patent Application Laid-Open No. 9-067355 International Publication No. 01/187293 Pamphlet International Publication No. 04/014843 Pamphlet JP 2004-149429 A WO 02/96897 pamphlet International Publication No. 04/043916 Pamphlet International Publication No. 2005/058311 Pamphlet International Publication No. 2007/097767 Pamphlet International Publication No. 2007/041404 Pamphlet International Publication No. 2007/041405 Pamphlet Journal of Heterocyclic Chemistry, 14, 717-723 (1977) Journal of Organic Chemistry, 33, 3126-3132 (1968) Klein WL, 7 others, Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) 10417-10422. Nitsch RM, 16 other people, Antibodies against β-amyloid slow cognitive deline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554. Jarret JT, two others, The carboterminous of the β amyloid protein, the clinical for the seed of the asymmetric formation, the implications for the formation. 4693-4697. Glenner GG, 1 other, Alzheimer's disease: initial report of the purification and physicalization of a novel cerebral vascular bioprotein. 885-890. Masters CL, 5 others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Procedural National Academy of Science USA, 1985, Jun, 82 (12). 4245-4249. Gouras GK, 11 others, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156 (1), p. 15-20. Scheuner D, outside 20 people, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2 (8), p. 864-870. Former MS, 4 others, Differential effects of the swedish mutant amyloid prescription for 19 and 19, and the like. 32247-32253.
　本発明の課題は、特許文献１に記載のアミノジヒドロチアジン誘導体およびＢＡＣＥ１阻害活性を有する化合物とは相違する化合物であって、Ａβ産生抑制作用又はＢＡＣＥ１阻害作用を有し、Ａβに起因する、アルツハイマー型痴呆に代表される神経変性疾患の予防剤または治療剤として有用なスピロアミノジヒドロチアジン化合物及びその医薬用途を提供することにある。 The subject of the present invention is a compound different from the aminodihydrothiazine derivative and the compound having BACE1 inhibitory activity described in Patent Document 1, which has an Aβ production inhibitory action or a BACE1 inhibitory action, resulting from Aβ. It is an object of the present invention to provide a spiroaminodihydrothiazine compound useful as a prophylactic or therapeutic agent for neurodegenerative diseases represented by Alzheimer-type dementia and a pharmaceutical use thereof.
　本発明は、
　[１]　式（Ｉ）： 
Figure JPOXMLDOC01-appb-C000002
 ［式中、
　環ＡはＣ６－１０アリール基又は５－１０員複素環基であり、
　Ｌは単結合、酸素原子若しくは式－Ｃ（＝Ｏ）ＮＲＬ－（ＲＬは水素原子又は置換基αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基である。）又は、それぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキレン基、Ｃ２－６アルケニレン基若しくはＣ２－６アルキニレン基であり、
　環ＢはＣ３－８シクロアルキル基、Ｃ６－１０アリール基又は５－１０員複素環基であり、
　Ｘは、それぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－３アルキレン基又はＣ２－３アルケニレン基であり、
　Ｙは、酸素原子、硫黄原子、スルホキシド基、スルホン基又は式―ＮＲＹ－（ＲＹは水素原子又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルカルボニル基、Ｃ３－８シクロアルキルカルボニル基、Ｃ６－１０アリールカルボニル基、Ｃ１－６アルキルスルホニル基、Ｃ６－１０アリールスルホニル基、Ｃ６－１０アリール基若しくは５－６員へテロアリール基である。）で示される基であり、
　Ｚは単結合又はＣ１－３アルキレン基であり、
　Ｒ１及びＲ２は各々独立して水素原子、ハロゲン原子、ヒドロキシ基若しくはシアノ基又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基若しくはＣ１－６アルコキシ基であり、
　Ｒ３は、水素原子又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルカルボニル基、Ｃ６－１０アリールカルボニル基、Ｃ１－６アルキルスルホニル基、Ｃ６－１０アリールスルホニル基、Ｃ３－８シクロアルキル基、Ｃ６－１０アリール基若しくは５－１０員複素環基であり、
　Ｒ４及びＲ５は各々独立して水素原子、ハロゲン原子若しくはヒドロキシ基又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルオキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基若しくは５－１０員複素環基であり、
　Ｒ６、Ｒ７及びＲ８は各々独立して水素原子、ハロゲン原子、ヒドロキシ基若しくはシアノ基又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基若しくは５－１０員複素環基であり、
　ｎは１から３の整数である。
　置換基群α：水素原子、ハロゲン原子、ヒドロキシ基、オキソ基、シアノ基、Ｃ１－６アルキル基、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基及び５－１０員複素環基。］
で示される化合物又はその医薬上許容される塩；
　[２]　Ｘが置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－３アルキレン基である、上記[１]の化合物又はその医薬上許容される塩；
　[３]　Ｙが酸素原子である、上記[１]又は[２]記載の化合物又はその医薬上許容される塩；
　[４]　Ｙが硫黄原子またはスルホン基である、上記[１]又は[２]記載の化合物又はその医薬上許容される塩；
　[５]　Ｙが式―ＮＲＹ－（ＲＹは水素原子又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルカルボニル基、Ｃ３－８シクロアルキルカルボニル基、Ｃ６－１０アリールカルボニル基、Ｃ１－６アルキルスルホニル基、Ｃ６－１０アリールスルホニル基、Ｃ６－１０アリール基若しくは５－６員へテロアリール基である。）で示される基である、上記[１]又は[２]記載の化合物又はその医薬上許容される塩；
　[６]　Ｌが式－Ｃ（＝Ｏ）ＮＲＬ－（ＲＬは水素原子又は置換基αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基である。）で示される基である、上記[１]から[５]のいずれかに記載の化合物又はその医薬上許容される塩；
　[７]　上記[１]から[６]のいずれかに記載の化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物；
　[８]　アミロイドβタンパク質産生を抑制するための上記[７]に記載の医薬組成物1;
　[９]　ベータサイトアミロイドβ前駆体タンパク質開裂酵素１（ＢＡＣＥ１）を阻害するための上記[７]に記載の医薬組成物；
　[１０]　神経変性疾患治療のための上記[７]から[９]のいずれかに記載の医薬組成物；
　[１１]　神経変性疾患がアルツハイマー型痴呆又はダウン症である上記[１０]に記載の医薬組成物
に関する。 The present invention
[1] Formula (I):
Figure JPOXMLDOC01-appb-C000002
 [Where:
Ring A is a C6-10 aryl group or a 5-10 membered heterocyclic group,
L is a single bond, an oxygen atom, or a formula —C (═O) NR L — (R L is a hydrogen atom or a C1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent α Or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group, each optionally having 1 to 3 substituents selected from the substituent group α,
Ring B is a C3-8 cycloalkyl group, a C6-10 aryl group or a 5-10 membered heterocyclic group,
X is a C1-3 alkylene group or C2-3 alkenylene group each optionally having 1 to 3 substituents selected from substituent group α,
Y represents an oxygen atom, a sulfur atom, a sulfoxide group, a sulfone group, or a formula —NR Y — (where R Y is a hydrogen atom or 1 to 3 substituents each selected from substituent group α, C1 -6 alkyl group, C1-6 alkylcarbonyl group, C3-8 cycloalkylcarbonyl group, C6-10 arylcarbonyl group, C1-6 alkylsulfonyl group, C6-10 arylsulfonyl group, C6-10 aryl group or 5-6 Is a member heteroaryl group).
Z is a single bond or a C1-3 alkylene group,
R 1 and R 2 each independently have a hydrogen atom, a halogen atom, a hydroxy group or a cyano group, or a C 1-6 alkyl group which may have 1 to 3 substituents each selected from substituent group α, A C1-6 alkoxy group,
R 3 may have a hydrogen atom or 1 to 3 substituents each selected from substituent group α, C 1-6 alkyl group, C 1-6 alkyl carbonyl group, C 6-10 aryl carbonyl group, C 1 A -6 alkylsulfonyl group, a C6-10 arylsulfonyl group, a C3-8 cycloalkyl group, a C6-10 aryl group or a 5-10 membered heterocyclic group,
R 4 and R 5 each independently have a hydrogen atom, a halogen atom, a hydroxy group or 1 to 3 substituents each selected from substituent group α, a C 1-6 alkyl group, C 1-6 An alkyloxy group, a C3-8 cycloalkyl group, a C3-8 cycloalkyloxy group, a C6-10 aryl group or a 5-10 membered heterocyclic group,
R 6 , R 7 and R 8 may each independently have a hydrogen atom, a halogen atom, a hydroxy group or a cyano group, or 1 to 3 substituents each selected from substituent group α, C 1-6 An alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C3-8 cycloalkyl group, a C3-8 cycloalkyloxy group, a C6-10 aryl group or a 5-10 membered heterocyclic group Yes,
n is an integer of 1 to 3.
Substituent group α: hydrogen atom, halogen atom, hydroxy group, oxo group, cyano group, C1-6 alkyl group, trifluoromethyl group, trifluoromethoxy group, C1-6 alkoxy group, C3-8 cycloalkyl group, C3 -8 cycloalkyloxy group, C6-10 aryl group and 5-10 membered heterocyclic group. ]
Or a pharmaceutically acceptable salt thereof;
[2] The compound of the above-mentioned [1] or a pharmaceutically acceptable salt thereof, wherein X is a C1-3 alkylene group optionally having 1 to 3 substituents selected from the substituent group α;
[3] The compound according to the above [1] or [2] or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom;
[4] The compound according to the above [1] or [2] or a pharmaceutically acceptable salt thereof, wherein Y is a sulfur atom or a sulfone group;
[5] Y is a formula —NR Y — (R Y is a hydrogen atom or a C1-6 alkyl group, a C1-6 alkylcarbonyl, each optionally having 1 to 3 substituents selected from substituent group α) Group, a C3-8 cycloalkylcarbonyl group, a C6-10 arylcarbonyl group, a C1-6 alkylsulfonyl group, a C6-10 arylsulfonyl group, a C6-10 aryl group, or a 5-6 membered heteroaryl group). A compound or a pharmaceutically acceptable salt thereof according to the above [1] or [2],
[6] L is a formula —C (═O) NR L — (R L is a C1-6 alkyl group optionally having 1 to 3 substituents selected from a hydrogen atom or a substituent α. ) Or a pharmaceutically acceptable salt thereof according to any one of [1] to [5] above, which is a group represented by
[7] A pharmaceutical composition comprising as an active ingredient the compound according to any one of [1] to [6] above or a pharmaceutically acceptable salt thereof;
[8] The pharmaceutical composition 1 according to the above [7] for suppressing amyloid β protein production;
[9] The pharmaceutical composition according to [7] above, for inhibiting beta-site amyloid β precursor protein-cleaving enzyme 1 (BACE1);
[10] The pharmaceutical composition according to any one of [7] to [9] above for treating a neurodegenerative disease;
[11] The pharmaceutical composition according to the above [10], wherein the neurodegenerative disease is Alzheimer-type dementia or Down's syndrome.
　以下に、本願明細書において記載する記号、用語等の意義を説明し、本発明を詳細に説明する。 Hereinafter, the meanings of symbols, terms, and the like described in the present specification will be described, and the present invention will be described in detail.
　本願明細書中においては、化合物の構造式が便宜上一定の異性体を表すことがあるが、本発明には化合物の構造上生ずる総ての幾何異性体、不斉炭素に基づく光学異性体、立体異性体、互変異性体等の異性体及び異性体混合物を含み、便宜上の式の記載に限定されるものではなく、いずれか一方の異性体でも混合物でもよい。したがって、分子内に不斉炭素原子を有し光学活性体及びラセミ体が存在することがあり得るが、本発明においてはそれらに限定されず、いずれもが含まれる。さらに結晶多形が存在することもあるが同様に限定されず、いずれかの単一結晶形またはそれらの混合物であってもよく、無水物以外に水和物であってもよく、いずれも本願の請求の範囲に含まれる。 In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but in the present invention, all geometrical isomers generated in the structure of the compound, optical isomers based on asymmetric carbon, stereo It includes isomers such as isomers and tautomers, and isomer mixtures, and is not limited to the description of the formula for convenience, and may be either isomer or mixture. Accordingly, there may be an optically active substance and a racemate having an asymmetric carbon atom in the molecule. However, the present invention is not limited to these, and both are included. In addition, crystal polymorphs may exist, but are not limited in the same manner, and may be any single crystal form or a mixture thereof, and may be a hydrate in addition to an anhydride. Within the scope of the following claims.
　本明細書において、「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子等を示し、好ましくはフッ素原子、塩素原子である。 In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like, preferably a fluorine atom or a chlorine atom.
　「Ｃ１－６アルキル基」とは、炭素数が１乃至６個のアルキル基を示し、好ましい基としては、例えばメチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、ネオペンチル基、ｎ－ヘキシル基、１－メチルプロピル基、１，２－ジメチルプロピル基、１－エチルプロピル基、１－メチル－２－エチルプロピル基、１－エチル－２－メチルプロピル基、１，１，２－トリメチルプロピル基、１－メチルブチル基、２－メチルブチル基、１，１－ジメチルブチル基、２，２－ジメチルブチル基、２－エチルブチル基、１，３－ジメチルブチル基、２－メチルペンチル基、３－メチルペンチル基等の直鎖又は分枝状アルキル基が挙げられ、より好ましくは、メチル基、エチル基、ｎ－プロピル基が挙げられる。 “C1-6 alkyl group” means an alkyl group having 1 to 6 carbon atoms, and preferred groups include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. , T-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylpropyl, 1,2-dimethylpropyl, 1-ethylpropyl, 1-methyl-2-ethylpropyl Group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2- Examples thereof include linear or branched alkyl groups such as ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group, and 3-methylpentyl group, and more preferably methyl. Group, an ethyl group, and an n- propyl group.
　「Ｃ２－６アルケニル基」とは、炭素数が２乃至６個のアルケニル基を示し、好ましい基としては、例えばビニル基、アリル基、１－プロペニル基、イソプロペニル基、１－ブテン－１－イル基、１－ブテン－２－イル基、１－ブテン－３－イル基、２－ブテン－１－イル基、２－ブテン－２－イル基等の直鎖状又は分枝鎖状のアルケニル基が挙げられる。 The “C2-6 alkenyl group” refers to an alkenyl group having 2 to 6 carbon atoms, and preferred groups include, for example, a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, and 1-butene-1- Linear or branched alkenyl such as yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl, etc. Groups.
　「Ｃ２－６アルキニル基」とは、炭素数が２乃至６個のアルキニル基を示し、好ましい基としては、例えばエチニル基、１－プロピニル基、２－プロピニル基、ブチニル基、ペンチニル基、ヘキシニル基等の直鎖状又は分子鎖状のアルキニル基が挙げられる。 “C2-6 alkynyl group” refers to an alkynyl group having 2 to 6 carbon atoms, and preferred groups include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group And a linear or molecular chain alkynyl group.
　「Ｃ１－６アルキレン基」とは前記定義「Ｃ１－６アルキル基」からさらに任意の水素原子を１個除いて誘導される二価の基を意味し、例えばメチレン基、１，２－エチレン基、１，１－エチレン基、１，３－プロピレン基、テトラメチレン基、ペンタメチレン基、ヘキサメチレン基等が挙げられる。 “C1-6 alkylene group” means a divalent group derived from the above-defined “C1-6 alkyl group” by removing one arbitrary hydrogen atom. For example, a methylene group, 1,2-ethylene group 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group, hexamethylene group and the like.
　「Ｃ２－６アルケニレン基」とは前記定義「Ｃ２－６アルケニル基」からさらに任意の水素原子を１個除いて誘導される二価の基を意味し、例えば１，２－ビニレン基（エテニレン基）、プロペニレン基、ブテニレン基、ペンテニレン基、ヘキセニレン基等が挙げられる。 “C2-6 alkenylene group” means a divalent group derived by removing one arbitrary hydrogen atom from the above-defined “C2-6 alkenyl group”. For example, 1,2-vinylene group (ethenylene group) ), Propenylene group, butenylene group, pentenylene group, hexenylene group and the like.
　「Ｃ２－６アルキニレン基」とは前記定義の「Ｃ２－６アルキニル基」からさらに任意の水素原子を１個除いて誘導される二価の基を意味し、例えばエチニレン基、プロピニレン基、ブチニレン基、ペンチニレン基、ヘキシニレン基等が挙げられる。 “C2-6 alkynylene group” means a divalent group derived by removing one arbitrary hydrogen atom from “C2-6 alkynyl group” as defined above. For example, ethynylene group, propynylene group, butynylene group , A pentynylene group, a hexynylene group, and the like.
　「Ｃ１－６アルキルオキシ基」とは、炭素数１乃至は６個のアルキル基において、一つの水素原子が酸素原子に置換された基を示し、例えばメトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－ブトキシ基、イソブトキシ基、ｓｅｃ－ブトキシ基、ｔ－ブトキシ基、ｎ－ペントキシ基、イソペントキシ基、ｓｅｃ－ペントキシ基、ｔ－ペントキシ基、ｎ－ヘキソキシ基、イソヘキソキシ基、１，２－ジメチルプロポキシ基、２－エチルプロポキシ基、１－メチル－２－エチルプロポキシ基、１－エチル－２－メチルプロポキシ基、１，１，２－トリメチルプロポキシ基、１，１，２－トリメチルプロポキシ基、１，１－ジメチルブトキシ基、２，２－ジメチルブトキシ基、２－エチルブトキシ基、１，３－ジメチルブトキシ基、２－メチルペントキシ基、３－メチルペントキシ基、ヘキシルオキシ基等が挙げられる。 The “C 1-6 alkyloxy group” refers to a group in which one hydrogen atom is substituted with an oxygen atom in an alkyl group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propoxy group, Isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, n-pentoxy group, isopentoxy group, sec-pentoxy group, t-pentoxy group, n-hexoxy group, isohexoxy group, 1, 2-dimethylpropoxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group Group, 2-methyl pentoxy group, 3-methyl pentoxy group, hexyloxy group and the like.
　「Ｃ１－６アルキルスルホニル基」とは、炭素数１乃至は６のアルキル基において、１つの水素原子がスルホニル基に置換された基を示し、例えばメチルスルホニル基、エチルスルホニル基、ｎ－プロピルスルホニル基、イソプロピルスルホニル基、ｎ－ブチルスルホニル基、イソブチルスルホニル基、ｔ－ブチルスルホニル基、ｎ－ペンチルスルホニル基、イソペンチルスルホニル基、ネオペンチルスルホニル基、ｎ－ヘキシルスルホニル基、１－メチルプロピルスルホニル基等が挙げられる。 The “C 1-6 alkylsulfonyl group” refers to a group in which one hydrogen atom is substituted with a sulfonyl group in an alkyl group having 1 to 6 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, an n-propylsulfonyl group. Group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, isopentylsulfonyl group, neopentylsulfonyl group, n-hexylsulfonyl group, 1-methylpropylsulfonyl group Etc.
　「Ｃ１－６アルキルカルボニル基」とは、炭素数１乃至６個のアルキル基において一つの水素原子がカルボニル基で置換された基を示し、好ましくは、例えばアセチル基、プロピオニル基、ブチリル基などが挙げられる。 The “C 1-6 alkylcarbonyl group” refers to a group in which one hydrogen atom is substituted with a carbonyl group in an alkyl group having 1 to 6 carbon atoms. Preferably, for example, an acetyl group, a propionyl group, a butyryl group, etc. Can be mentioned.
　「Ｃ６－１０アリール基」とは、炭素数６乃至１０の芳香族炭化水素環基を示し、例えばフェニル基、ナフチル基等が挙げられ、なかでもフェニル基が好ましい。 The “C6-10 aryl group” means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms, and examples thereof include a phenyl group and a naphthyl group, and among them, a phenyl group is preferable.
　「Ｃ６－１０アリールカルボニル基」とは、炭素数６乃至１０の芳香族炭化水素環基にカルボニル基が結合した基を示し、好ましくはベンゾイル基、ナフトイル基等が挙げられ、より好ましくはベンゾイル基である。 The “C6-10 arylcarbonyl group” refers to a group in which a carbonyl group is bonded to an aromatic hydrocarbon ring group having 6 to 10 carbon atoms, preferably a benzoyl group, a naphthoyl group, etc., more preferably a benzoyl group. It is.
　「Ｃ６－１０アリールスルホニル基」とは、炭素数６乃至１０の芳香族炭化水素環基にスルホニル基が結合した基を示し、好ましくはベンジルスルホニル基、ナフチルスルホニル基等が挙げられ、より好ましくはベンジルスルホニ基である。 The “C6-10 arylsulfonyl group” refers to a group in which a sulfonyl group is bonded to an aromatic hydrocarbon ring group having 6 to 10 carbon atoms, preferably a benzylsulfonyl group, a naphthylsulfonyl group, and the like, more preferably Benzylsulfoni group.
　「Ｃ３－８シクロアルキル基」とは、炭素数３乃至８の環状アルキル基を示し、当該基における好ましい基としては、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基等が挙げられる。 The “C3-8 cycloalkyl group” refers to a cyclic alkyl group having 3 to 8 carbon atoms. Preferred examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclo An octyl group etc. are mentioned.
　「Ｃ３－８シクロアルキルオキシ基」とは、炭素数３乃至８の環状アルキル基において、一つの水素原子が酸素原子に置換された基を示し、例えばシクロプロポキシ基、シクロブトキシ基、シクロペントキシ基、シクロヘキソキシ基、シクロヘプチロキシ基、シクロオクチロキシ基等が挙げられる。 The “C3-8 cycloalkyloxy group” refers to a group in which one hydrogen atom is substituted with an oxygen atom in a cyclic alkyl group having 3 to 8 carbon atoms, such as a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group. Group, cyclohexoxy group, cycloheptyloxy group, cyclooctyloxy group and the like.
　「Ｃ３－８シクロアルキルカルボニル基」とは、炭素数３乃至８の環状アルキル基において、一つの水素原子がカルボニル基に置換された基を示し、例えばシクロプロピルカルボニル基、シクロブチルカルボニル基、シクロペンチルカルボニル基、シクロヘキシルカルボニル基、シクロヘプチルカルボニル基、シクロオクチルカルボニル基等が挙げられる。 The “C3-8 cycloalkylcarbonyl group” refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is substituted with a carbonyl group, such as a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentyl group. Examples include carbonyl group, cyclohexylcarbonyl group, cycloheptylcarbonyl group, cyclooctylcarbonyl group and the like.
　「５－１０員複素環基」とは、総員数５ないし１０員複素原子含有環状基を示し、好ましくは、例えばピペリジニル基、ピロリジニル基、アゼピニル基、アゾカニル基、ピペラジニル基、１，４－ジアゼパニル基、モルホリニル基、チオモルホリニル基、ピロリル基、イミダゾリル基、ピラゾリル基、ピリジニル基、ピリダジニル基、ピリミジニル基、ピラジニル基、トリアゾリル基、トリアジニル基、テトラゾリル基、イソオキサゾリル基、オキサゾリル基、オキサジアゾリル基、イソチアゾリル基、チアゾリル基、チアジアゾリル基、フリル基、チエニル基、キノリニル基、イソキノリニル基、ベンゾフリル基、ベンゾピラニル基、ベンズイミダゾリル基、ベンゾトリアゾリル基、ベンゾイソチアゾリル基、インドリニル基、イソインドリニル基、クロマニル基、イソクロマニル基、１，３－ジオキサインダニル基、１，４－ジオキサテトラリニル基等が挙げられる。 “5-10-membered heterocyclic group” refers to a cyclic group containing 5 to 10-membered heteroatoms, preferably, for example, piperidinyl group, pyrrolidinyl group, azepinyl group, azocanyl group, piperazinyl group, 1,4-diazepanyl. Group, morpholinyl group, thiomorpholinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, triazinyl group, tetrazolyl group, isoxazolyl group, oxazolyl group, oxadiazolyl group, isothiazolyl group, Thiazolyl, thiadiazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, benzofuryl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzoisothiazolyl, indolinyl, isoin Riniru group, chromanyl group, isochromanyl group, 1,3 dioxabicycloctane sign mite group, 1,4-oxa tetralinyl group and the like.
　「５－６員ヘテロアリール基」とは、前記「５－１０員複素環基」のうち、総員数５ないし６員複素原子含有芳香族環状基を示し、例えば、ピロリル基、イミダゾリル基、ピラゾリル基、ピリジニル基、ピリダジニル基、ピリミジニル基、ピラジニル基、トリアゾリル基、トリアジニル基、テトラゾリル基、イソオキサゾリル基、オキサゾリル基、オキサジアゾリル基、イソチアゾリル基、チアゾリル基、チアジアゾリル基、フリル基、チエニル基等が挙げられる。 The “5-6 membered heteroaryl group” refers to an aromatic cyclic group containing 5 to 6 membered heteroatoms in the “5-10 membered heterocyclic group”, and includes, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group. Group, pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, triazinyl group, tetrazolyl group, isoxazolyl group, oxazolyl group, oxadiazolyl group, isothiazolyl group, thiazolyl group, thiadiazolyl group, furyl group, thienyl group, etc. .
　「Ｃ１－３アルキレン基」とは、例えば、メチレン基、エチレン基、プロピレン基等を挙げることがきる。 Examples of the “C1-3 alkylene group” include a methylene group, an ethylene group, a propylene group, and the like.
　「Ｃ２－３アルケニレン基」とは、ビニレン基、プロペニレン基を挙げることがきる。 “C2-3 alkenylene group” includes vinylene group and propenylene group.
　「置換基群α」とは、水素原子、ハロゲン原子、ヒドロキシ基、オキソ基、シアノ基、Ｃ１－６アルキル基、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基及び５－１０員複素環基を意味する。 “Substituent group α” means a hydrogen atom, a halogen atom, a hydroxy group, an oxo group, a cyano group, a C1-6 alkyl group, a trifluoromethyl group, a trifluoromethoxy group, a C1-6 alkoxy group, a C3-8 cyclohexane. An alkyl group, a C3-8 cycloalkyloxy group, a C6-10 aryl group and a 5-10 membered heterocyclic group are meant.
　本発明の式（Ｉ）のスピロアミノジヒドロチアジン誘導体は、医薬上許容される塩でもよい。医薬上許容される塩としては、具体的には、例えば無機酸塩（例えば硫酸塩、硝酸塩、過塩素酸塩、リン酸塩、炭酸塩、重炭酸塩、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩など）、有機カルボン酸塩（例えば酢酸塩、シュウ酸塩、マレイン酸塩、酒石酸塩、フマル酸塩、クエン酸塩など）、有機スルホン酸塩（例えばメタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、カンファースルホン酸塩など）、アミノ酸塩（例えばアスパラギン酸塩、グルタミン酸塩など）、四級アミン塩、アルカリ金属塩（例えばナトリウム塩、カリウム塩など）、アルカリ土類金属塩（例えばマグネシウム塩、カルシウム塩など）などが挙げられる。 The spiraminodihydrothiazine derivative of formula (I) of the present invention may be a pharmaceutically acceptable salt. Specific examples of the pharmaceutically acceptable salt include inorganic acid salts (for example, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, hydrofluoride, hydrochloride, Hydrobromide, hydroiodide, etc.), organic carboxylates (eg acetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonates (eg Methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartate, glutamate, etc.), quaternary amine salts , Alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (for example, magnesium salts, calcium salts, etc.), and the like.
　本発明の式（Ｉ）のスピロアミノジヒドロチアジン誘導体又は医薬上許容される塩は、それらの溶媒和物であってもよく、溶媒和物としては、例えば、水和物などが挙げられる。また、化合物（I）は特定の異性体に限定するものではなく、全ての可能な異性体（ケトーエノール異性体、イミンーエナミン異性体、ジアステレオ異性体、光学異性体および回転異性体等）やラセミ体を含むものである。例えばR１が水素である化合物（I）は以下のような互変異性体を包含する。
Figure JPOXMLDOC01-appb-C000003
 The spiroaminodihydrothiazine derivative or pharmaceutically acceptable salt of the formula (I) of the present invention may be a solvate thereof, and examples of the solvate include a hydrate. Compound (I) is not limited to a specific isomer, but all possible isomers (ketoeenol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) and racemates Is included. For example, the compound (I) in which R 1 is hydrogen includes the following tautomers.
Figure JPOXMLDOC01-appb-C000003
　本発明の式（Ｉ）のスピロアミノジヒドロチアジン誘導体としては、式（Ｉ）において、Ｘが、置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－３アルキレン基、特に、置換基群αから選択される１乃至３の置換基を有していてもよいメチレン又はエチレンである化合物が好ましい。
　また、式（Ｉ）において、Ｙが酸素原子、硫黄原子、スルホン基または式―ＮＲＹ－（ＲＹは前記定義に同じである。）で示される基である、化合物が好ましい。
　また、式（Ｉ）において、Ｌが式－Ｃ（＝Ｏ）ＮＲＬ－（ＲＬは前記定義に同じである。）で示される基である、化合物が好ましい。
　特に、式（Ｉ）においてＹが酸素原子であり、Ｚが単結合である化合物；Ｙが酸素原子であり、Ｚが置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－３アルキレンである化合物；Ｙが硫黄原子またはスルホンであり、Ｚが単結合である化合物が好ましい。 As the spiroaminodihydrothiazine derivative of the formula (I) of the present invention, in the formula (I), X may have 1 to 3 substituents selected from the substituent group α. A compound which is an alkylene group, in particular, methylene or ethylene which may have 1 to 3 substituents selected from the substituent group α is preferable.
In the formula (I), a compound in which Y is an oxygen atom, a sulfur atom, a sulfone group, or a group represented by the formula —NR Y — (R Y is the same as defined above) is preferable.
In the formula (I), a compound in which L is a group represented by the formula —C (═O) NR L — (R L is the same as defined above) is preferable.
In particular, a compound in which Y is an oxygen atom and Z is a single bond in formula (I); Y is an oxygen atom, and Z has 1 to 3 substituents selected from substituent group α Preferred is a compound that is C 1-3 alkylene; Y is a sulfur atom or sulfone, and Z is a single bond.
　本発明において好ましい化合物としては、以下の化合物が挙げられる。
　１）（－）－Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－５－シアノピリジン－２－カルボキサミド、
　２）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－５－トリフルロメチルピリジン－２－カルボキサミド、
　３）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－３，５－ジフルオロピリジン－２－カルボキサミド、
　４）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－５－フルオロピリジン－２－カルボキサミド、
　５）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－５－ブロモピリミジン－２－カルボキサミド、
　６）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，８］４´－［１、３］チアジン］－６－イル）－５－ブロモピリジン－２－カルボキサミド、
　７）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－５－メトキシピラジン－２－カルボキサミド、
　８）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－３，５－ジクロロピリジン－２－カルボキサミド、
９）Ｎ－（２´－アミノ－２、３、５´、６´－テトラヒドロスピロ［クロメン－４，４´－［１、３］チアジン］－６－イル）－３－フルオロピリジン－２－カルボキサミド、
　１０）６－（５－メトキシピリジン－３－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［１、３］チアジン］－２’－アミン、
　１１）６－（３、５－ジクロロフェニル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［１、３］チアジン］－２’－アミン、
　１２）６－（１－メチル－１Ｈ－ピラゾル－４－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［１、３］チアジン］－２’－アミン、
　１３）６－（２－フルオロピリジン－３－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［１、３］チアジン］－２’－アミン、
　１４）６－［（２－アミノピリジン－３－イル）エチニル］－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［１、３］チアジン］－２’－アミン、
　１５）７―フルオロ―６－（２－フルオロピリジン－３－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［１、３］チアジン］－２’－アミン、
より好ましくは、以下の化合物が挙げられる。
　１）（－）－Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－５－シアノピリジン－２－カルボキサミド、
　２）Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－５－トリフルロメチルピリジン－２－カルボキサミド、
　３）Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－３，５－ジフルオロピリジン－２－カルボキサミド、
　４）Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－５－ブロモピリミジン－２－カルボキサミド、
　５）Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－５－ブロモピリジン－２－カルボキサミド、
　６）Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－３，５－ジクロロピリジン－２－カルボキサミド。 Preferred compounds in the present invention include the following compounds.
1) (-)-N- (2'-amino-2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazin] -6-yl) -5-cyano Pyridine-2-carboxamide,
2) N- (2'-amino-2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazin] -6-yl) -5-trifluoromethylpyridine- 2-carboxamide,
3) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -3,5-difluoropyridine- 2-carboxamide,
4) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-fluoropyridine-2- Carboxamide,
5) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-bromopyrimidine-2- Carboxamide,
6) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,8] 4 ′-[1,3] thiazin] -6-yl) -5-bromopyridine- 2-carboxamide,
7) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-methoxypyrazine-2- Carboxamide,
8) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -3,5-dichloropyridine- 2-carboxamide,
9) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -3-fluoropyridine-2- Carboxamide,
10) 6- (5-Methoxypyridin-3-yl) -2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazine] -2'-amine,
11) 6- (3,5-dichlorophenyl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine,
12) 6- (1-Methyl-1H-pyrazol-4-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine ,
13) 6- (2-Fluoropyridin-3-yl) -2, 3, 5 ′, 6′-tetrahydrospiro [chromene-4, 4 ′-[1,3] thiazine] -2′-amine,
14) 6-[(2-Aminopyridin-3-yl) ethynyl] -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine ,
15) 7-Fluoro-6- (2-fluoropyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′- Amines,
More preferably, the following compounds are mentioned.
1) (−)-N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-cyano Pyridine-2-carboxamide,
2) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-trifluoromethylpyridine- 2-carboxamide,
3) N- (2'-amino-2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazin] -6-yl) -3,5-difluoropyridine- 2-carboxamide,
4) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-bromopyrimidine-2- Carboxamide,
5) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-bromopyridine-2- Carboxamide,
6) N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -3,5-dichloropyridine- 2-carboxamide.
　次に、本発明の式（Ｉ）の化合物［以下、化合物（Ｉ）という、他式で表される化合物についても同様に表記する］又はその医薬上許容される塩の製造法について説明する。 Next, a method for producing a compound of the formula (I) of the present invention [hereinafter referred to as a compound represented by another formula (compound (I)]) or a pharmaceutically acceptable salt thereof will be described.
　以下に説明する本発明の式（Ｉ）の化合物を製造する際に用いる原料化合物における「脱離基」とは、求核置換反応に利用される脱離基であればいずれでもよく、好ましくは、例えばハロゲン原子；上記の置換基群αから選択される１乃至３の置換基で置換されてもよいＣ１－６アルキルスルホニルオキシ基；上記の置換基群αから選択される１乃至３の置換基で置換されてもよいＣ１－６アルキルカルボニルオキシ基；上記の置換基群αから選択される１乃至３の置換基で置換されてもよいアリールスルホニルオキシ基等が挙げられ、具体的には、塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基、トリフルオロカルボニルオキシ基、トリフルオロメタンスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基等が挙げられる。 The “leaving group” in the raw material compound used for producing the compound of the formula (I) of the present invention described below may be any leaving group used for the nucleophilic substitution reaction, preferably A C 1-6 alkylsulfonyloxy group optionally substituted with 1 to 3 substituents selected from the above substituent group α; 1 to 3 substituents selected from the above substituent group α A C1-6 alkylcarbonyloxy group which may be substituted with a group; an arylsulfonyloxy group which may be substituted with 1 to 3 substituents selected from the above substituent group α, and the like. Chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, trifluorocarbonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc.
一般的製造法１：
Figure JPOXMLDOC01-appb-C000004
 ［式中、環Ａ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｘ、ＹおよびＺは前記と同じ意味を示す。］
　本工程は、化合物（ａ－１）を酸により閉環し、化合物（ＩＩ）を得る方法である。
　本反応は、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、例えば、ベンゼン、トルエン、ジクロロメタン等の溶媒の存在下または非存在下に適当な酸を１当量～大過剰作用させて行うことができる。さらに酸を溶媒として用いることもできる。使用する酸としては、例えば硫酸、トリフルオロ酢酸、メタンスルホン酸、トリフルオロメタンスルホン酸またはそれらの混合物等があげられる。反応時間は、特に限定されないが、通常、１から７２時間であり、好ましくは１から４８時間である。反応温度は、通常、氷冷～溶媒の還流温度である。 General production method 1 :
Figure JPOXMLDOC01-appb-C000004
 [Wherein, ring A, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y and Z have the same meaning as described above. ]
This step is a method of obtaining a compound (II) by cyclizing the compound (a-1) with an acid.
This reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, 1 equivalent to a large amount of an appropriate acid is added in the presence or absence of a solvent such as benzene, toluene, dichloromethane and the like. It can be carried out with excessive action. Furthermore, an acid can also be used as a solvent. Examples of the acid used include sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and mixtures thereof. Although reaction time is not specifically limited, Usually, it is 1 to 72 hours, Preferably it is 1 to 48 hours. The reaction temperature is usually from ice cooling to the reflux temperature of the solvent.
化合物（ＩＩ）の合成法
　一般的製造法１で用いる化合物（ａ－１）は化合物（ａ－２）から、方法１又は方法２によって合成することができる。
方法１：
Figure JPOXMLDOC01-appb-C000005
 ［式中、各記号は前記と同じ意味を示す。］
　方法１は、化合物（ａ－２）を原料として２工程で化合物（ａ－１）を製造する方法である。化合物（ａ－２）は、市販品をそのまま用いることもでき、市販品から公知の方法で製造することもでき、更に実施例中の製造例の記載の方法を用いて製造することもできる。 Synthesis Method of Compound (II) Compound (a-1) used in General Production Method 1 can be synthesized from Compound (a-2) by Method 1 or Method 2.
Method 1:
Figure JPOXMLDOC01-appb-C000005
 [Wherein each symbol has the same meaning as described above. ]
Method 1 is a method for producing compound (a-1) in two steps using compound (a-2) as a raw material. As compound (a-2), a commercially available product can be used as is, or it can be produced from a commercially available product by a known method, and further can be produced using the method described in the production examples in the examples.
工程１：
　本工程は、市販または公知の方法で調整することができるビニルリチウム試薬、ビニルグリニヤール（Ｇｒｉｇｎａｒｄ）試薬と化合物（ａ－２）の付加反応により化合物（ａ－３）を得る工程である。この反応は、例えば、Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．２００６、１２８、９９９８－９９９９、Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍ．１９８２、１９、１０４１－１０４４、等に記載の条件と同様の条件で反応を行うことができる。反応に用いる溶媒は、出発原料、使用する試薬により異なり、また反応を阻害せず出発物質をある程度溶解し反応中常に不活性なものであれば特に限定されないが、好適には、例えばジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、ベンゼン、トルエン等の有機溶媒、或いはその混合溶媒である。反応時間は、特に限定されないが、通常、０．１～４８時間であり、好ましくは０．１～１２時間である。反応温度は、出発原料、使用する試薬等により異なるが、副生成物の形成を最小限に抑えるために温度を低く、例えば、－７８℃から室温等に保つことが好ましい。
　また、添加剤として、例えば塩化亜鉛等のルイス酸、或いは、ＴＭＥＤＡ（テトラメチルエチレンジアミン），ＨＭＰＡ（ヘキサメチルホスホロアミド）を添加することにより収率の向上や反応時間の短縮等に良好な結果を与えることがある。 Process 1 :
This step is a step of obtaining a compound (a-3) by an addition reaction of a vinyl lithium reagent, a vinyl Grignard reagent and a compound (a-2) which can be prepared by a commercially available method or a known method. This reaction is described, for example, in J. Org. Am. Chem. Soc. 2006, 128, 9998-9999, J. MoI. Heterocyclic Chem. The reaction can be carried out under the same conditions as described in 1982, 19, 1041-1044, etc. The solvent used in the reaction varies depending on the starting materials and reagents used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent and is always inactive during the reaction. An organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, or a mixed solvent thereof. The reaction time is not particularly limited, but is usually 0.1 to 48 hours, preferably 0.1 to 12 hours. The reaction temperature varies depending on the starting materials, reagents used, etc., but it is preferable to keep the temperature low, for example, from −78 ° C. to room temperature in order to minimize the formation of by-products.
Further, by adding a Lewis acid such as zinc chloride, TMEDA (tetramethylethylenediamine), or HMPA (hexamethylphosphoramide) as an additive, for example, good results in improving yield and shortening reaction time, etc. May give.
工程２：
　本工程は、化合物（ａ－３）にチオウレアまたはＮ－置換チオウレアを酸存在下に反応させて、化合物（ａ－１）を得る工程である。
　本工程における反応は、例えば、Ｒｕｓｓ．Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００６、４２（１）、４２－４７に記載の条件と同様の条件で反応を行うことができる。
　本反応で用いる酸は例えば酢酸、トリフルオロ酢酸、塩化水素、硫酸またはそれらの混合物である。反応は無溶媒またはトルエン等の有機溶媒中で（ａ－３）に対して１当量以上のチオウレア誘導体を作用させて反応を行うことができる。反応時間は、特に限定されないが、通常、５分から２４時間であり、好ましくは５分から１２時間である。反応温度は、通常、０℃～１５０℃であり、より好ましくは０℃～１００℃である。 Process 2 :
In this step, compound (a-3) is reacted with thiourea or N-substituted thiourea in the presence of an acid to obtain compound (a-1).
The reaction in this step is described in, for example, Russ. J. et al. Org. Chem. , 2006, 42 (1), 42-47.
The acid used in this reaction is, for example, acetic acid, trifluoroacetic acid, hydrogen chloride, sulfuric acid or a mixture thereof. The reaction can be carried out by allowing 1 equivalent or more of a thiourea derivative to act on (a-3) without solvent or in an organic solvent such as toluene. The reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours. The reaction temperature is usually 0 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
方法２：
Figure JPOXMLDOC01-appb-C000006
 ［式中、環Ａ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｘ、Ｙ、Ｚは前記と同じ意味を示す。ＬＶは脱離基を、Ｒ１０はＣ１－６アルキル基を示す。］
　方法２は、化合物（ａ－２）を原料として４工程で化合物（ａ－１）を製造する方法である。 Method 2:
Figure JPOXMLDOC01-appb-C000006
 [Wherein, ring A, R 1 , R 2 , R 3 , R 4 , X, Y, Z have the same meaning as described above. LV represents a leaving group, and R 10 represents a C 1-6 alkyl group. ]
Method 2 is a method for producing compound (a-1) in 4 steps using compound (a-2) as a raw material.
工程１：
　本工程は、公知の方法と同様の条件でピーターソン試薬、ホーナー・ワズワース・エモンズ試薬と化合物（ａ－２）の付加反応により化合物（ａ－４）を得る工程である。
　ピーターソン試薬、ホーナー・ワズワース・エモンズ試薬は、市販品をそのまま用いることもでき、当業者に公知の方法で調整することができる。具体的には、例えば、トリアルキルシリル酢酸アルキル化合物、またはホスホノ酢酸トリアルキル化合物に対し、市販の有機金属試薬、例えばブチルリチウム等のアルキルリチウム試薬、またはｔｅｒｔ－ブトキシカリウム等のアルコキシカリウム、アルコキシナトリウム試薬、または金属マグネシウムや金属リチウムを用いるプロトン金属交換を行って対応するリチウムアルキルアミド試薬もしくはマグネシウムアルキルアミド試薬により調製することができる。
　本工程において用いる溶媒は、出発原料、使用する試薬により異なり、また反応を阻害せず出発物質をある程度溶解し反応中常に不活性なものであれば特に限定されないが、好適には、例えばジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、ベンゼン、トルエン、メタノール、エタノール等の有機溶媒、或いはその混合溶媒である。反応時間は、特に限定されないが、通常、０．１～４８時間であり、好ましくは０．１～１２時間である。反応温度は、出発原料、使用する試薬等により異なるが、副生成物の形成を最小限に抑えるために温度を低く、例えば、－７８℃から室温等に保つことが好ましい。 Process 1 :
This step is a step of obtaining compound (a-4) by addition reaction of Peterson reagent, Horner-Wadworth-Emmons reagent and compound (a-2) under the same conditions as in known methods.
As the Peterson reagent and the Horner-Wadsworth-Emmons reagent, commercially available products can be used as they are, and can be prepared by methods known to those skilled in the art. Specifically, for example, a commercially available organometallic reagent, for example, an alkyl lithium reagent such as butyl lithium, or an alkoxy potassium or alkoxy sodium such as tert-butoxy potassium with respect to a trialkylsilylacetic acid alkyl compound or a phosphonoacetic acid trialkyl compound It can be prepared by a reagent or a corresponding lithium alkylamide reagent or magnesium alkylamide reagent by proton metal exchange using metal magnesium or metal lithium.
The solvent used in this step varies depending on the starting material and the reagent used, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent and is always inactive during the reaction. , Tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, methanol, ethanol and other organic solvents, or a mixed solvent thereof. The reaction time is not particularly limited, but is usually 0.1 to 48 hours, preferably 0.1 to 12 hours. The reaction temperature varies depending on the starting materials, reagents used, etc., but it is preferable to keep the temperature low, for example, from −78 ° C. to room temperature in order to minimize the formation of by-products.
工程２：
　本工程は、エステル化合物（ａ－４）を還元反応に付し、アルコール化合物（ａ－５）を得る工程である。
　反応に使用される還元剤としては、例えば水素化リチウムアルミニウム、水素化ホウ素リチウム、水素化ジイソブチルアルミニウム等が挙げられる。反応温度は特に限定されないが、通常、－７８℃～溶媒の還流温度であり、好ましくは－７８℃～室温である。反応に使用される溶媒は、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好適には、例えばテトラヒドロフラン、ジエチルエーテル、トルエン、ジクロロメタン等があげられる。 Process 2 :
This step is a step of subjecting the ester compound (a-4) to a reduction reaction to obtain an alcohol compound (a-5).
Examples of the reducing agent used in the reaction include lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride and the like. The reaction temperature is not particularly limited, but is usually from −78 ° C. to the reflux temperature of the solvent, preferably from −78 ° C. to room temperature. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, diethyl ether, toluene, dichloromethane and the like.
工程３：
　本工程は、化合物（ａ－５）の水酸基を脱離基に変換し、化合物（ａ－６）を得る工程である。
　脱離基としては、前記した脱離基をあげることができる。水酸基をこれらの脱離基に変換する反応に通常用いられる条件と同様の条件で反応を行うことができる。例えば脱離基がハロゲン原子の場合には、化合物（ａ－５）を、例えば塩酸、臭酸、塩化チオニル、臭化チオニル、三臭化リンまたテトラハロゲノメタン－トリフェニルホスフィンと反応させることにより製造することができる。反応に使用する溶媒としては、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好ましくは、例えばベンゼン、トルエン、キシレン、ジクロロメタン、クロロホルム等があげられる。反応温度は、通常、－７８℃～溶媒の還流温度であり、好ましくは氷冷～溶媒の還流温度である。反応時間は、特に限定されないが、通常、５分～４８時間であり、好ましくは５分～１２時間である。 Step 3 :
This step is a step of obtaining compound (a-6) by converting the hydroxyl group of compound (a-5) to a leaving group.
Examples of the leaving group include the aforementioned leaving groups. The reaction can be carried out under the same conditions as those usually used for the reaction for converting a hydroxyl group into these leaving groups. For example, when the leaving group is a halogen atom, the compound (a-5) is reacted with, for example, hydrochloric acid, odorous acid, thionyl chloride, thionyl bromide, phosphorus tribromide or tetrahalogenomethane-triphenylphosphine. Can be manufactured. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include benzene, toluene, xylene, dichloromethane, chloroform and the like. The reaction temperature is usually from −78 ° C. to the reflux temperature of the solvent, preferably from ice cooling to the reflux temperature of the solvent. The reaction time is not particularly limited, but is usually 5 minutes to 48 hours, preferably 5 minutes to 12 hours.
　また、脱離基がＣ１－６アルキルカルボニルオキシ基の場合には、化合物（ａ－５）を、例えば塩化トリフルオロ酢酸、無水トリフルオロ酢酸等と反応させて、製造することができる。
　また、脱離基がＣ１－６アルキルスルホニルオキシ基又はアリールスルホニルオキシ基の場合には、化合物（ａ－５）を、例えば塩化メタンスルホニル、塩化ｐ－トルエンスルホニル、無水トリフルオロメタンスルホン酸等と反応させて、製造することができる。
　反応に使用する溶媒としては、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好ましくは、例えばテトラヒドロフラン、トルエン、キシレン、ジクロロメタン、クロロホルム、Ｎ，Ｎ－ジメチルホルムアミド等があげられる。反応温度は、通常、－７８℃～溶媒の還流温度であり、好ましくは－７８℃～室温である。さらに塩基の添加により収率向上等の良好な結果を得ることがある。用いる塩基は反応を阻害しない限りにおいて特に限定されないが、好ましくは、例えば炭酸ナトリウム、炭酸カリウム、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン等があげられる。 When the leaving group is a C 1-6 alkylcarbonyloxy group, it can be produced by reacting the compound (a-5) with, for example, trifluoroacetic acid chloride or trifluoroacetic anhydride.
When the leaving group is a C 1-6 alkylsulfonyloxy group or arylsulfonyloxy group, the compound (a-5) is reacted with, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. And can be manufactured.
The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, for example, tetrahydrofuran, toluene, xylene, dichloromethane, chloroform, N, N-dimethylformamide and the like are used. can give. The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably -78 ° C to room temperature. Furthermore, the addition of a base may give good results such as improved yield. The base to be used is not particularly limited as long as it does not inhibit the reaction, and preferred examples include sodium carbonate, potassium carbonate, triethylamine, pyridine, diisopropylethylamine and the like.
工程４：
　本工程は、化合物（ａ－６）にチオウレアまたはＮ－置換チオウレアを反応させて、化合物（ａ－１）を得る工程である。
　具体的には，本反応は、例えばメタノール、エタノール、１－プロパノール、２－プロパノール、１－ブタノール、テトラヒドロフラン、１，４－ジオキサン、Ｎ，Ｎ‐ジメチルホルムアミド等の有機溶媒中、または臭酸等の無機酸中、化合物（ａ－６）に対して１当量以上のチオウレアまたはＮ－メチルチオウレアを作用させて反応を行うことができる。反応時間は、特に限定されないが、通常、５分から２４時間であり、好ましくは５分から１２時間である。反応温度は、通常、０℃～１５０℃であり、より好ましくは室温～１００℃である。 Step 4 :
This step is a step of obtaining compound (a-1) by reacting compound (a-6) with thiourea or N-substituted thiourea.
Specifically, this reaction is carried out in an organic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, or odorous acid. In the inorganic acid, the compound (a-6) can be reacted with 1 equivalent or more of thiourea or N-methylthiourea. The reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours. The reaction temperature is usually 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
２．一般的製造法２：
Figure JPOXMLDOC01-appb-C000007
 ［式中、環Ａ、環Ｂ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｘ、Ｙ、Ｚは前記と同じ意味を示す。］
　一般的製造法２は、一般的製造法１で得られた化合物（ＩＩ）から６工程で本発明にかかる一般式（Ｉ）において、Ｌが－ＮＨＣＯ－である化合物を製造する方法である。
　化合物（ＩＩ）は、市販品から前記一般的製造法１により製造することができ、更に実施例中の製造例の記載の方法を用いて製造することもできる。また、化合物（ｂ－５）および（ｂ－６）は、市販品をそのまま用いることもでき、市販品から当業者に公知の方法で製造することもでき、更に実施例中の製造例の記載の方法を用いて製造することもできる。 2. General production method 2 :
Figure JPOXMLDOC01-appb-C000007
 [Wherein, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, Z have the same meaning as described above. ]
General production method 2 is a method for producing a compound in which L is —NHCO— in general formula (I) according to the present invention in 6 steps from compound (II) obtained in general production method 1.
Compound (II) can be produced from a commercially available product by the above general production method 1, and can also be produced by using the method described in the production examples in the examples. As the compounds (b-5) and (b-6), commercially available products can be used as they are, or they can be produced from commercially available products by methods known to those skilled in the art. Further, description of production examples in Examples It is also possible to manufacture using the method.
工程１：
　本工程は、化合物（ＩＩ）から化合物（ｂ－１）を製造する工程である。
　この反応は、以下の公知の方法１又は方法２で行うことができる。 Process 1 :
This step is a step of producing compound (b-1) from compound (II).
This reaction can be carried out by the following known method 1 or method 2.
方法１：化合物（ＩＩ）にアセチル化とニトロ化反応を系内で同時に行う方法
　本反応は、当業者に公知の方法により反応することができ、反応に使用される条件としては、例えば濃硝酸／無水酢酸、発煙硝酸／無水酢酸等が挙げられる。反応温度は特に限定されないが、通常、－２０℃から５０℃であり、好ましくは－２０℃～室温である。 Method 1: Method in which compound (II) is subjected to acetylation and nitration reaction simultaneously in the system This reaction can be carried out by a method known to those skilled in the art. / Acetic anhydride, fuming nitric acid / acetic anhydride, and the like. The reaction temperature is not particularly limited, but is usually −20 ° C. to 50 ° C., preferably −20 ° C. to room temperature.
方法２：化合物（ＩＩ）のアセチル化体を単離した後、ニトロ化を行う方法
　工程２－１：本工程は、化合物（ＩＩ）のアセチル化反応により対応するアセチル化合物を得る工程である。アミノ化合物のアセチル化に一般に用いられる条件、例えばＴ．Ｗ．Ｔ．Ｗ．Ｇｒｅｅｎ　ａｎｄ　Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，“Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，Ｓｅｃｏｎｄ　Ｅｄｉｔｉｏｎ”，Ｊｏｈｎ　Ｗｉｌｅｙ＆Ｓｏｎｓ（１９９１），Ｐ．３５１－３５２等の文献記載の条件と同様の条件で反応を行うことができる。反応に使用されるアセチル化剤としては、例えば塩化アセチル、無水酢酸等が挙げられる。反応温度は特に限定されないが、通常、－２０℃～１５０℃である。 Method 2: Method of performing nitration after isolating the acetylated form of compound (II) Step 2-1: This step is a step of obtaining the corresponding acetyl compound by acetylation reaction of compound (II). Conditions commonly used for acetylation of amino compounds, such as T.I. W. T. T. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A. The reaction can be carried out under the same conditions as described in the literature such as 351-352. Examples of the acetylating agent used in the reaction include acetyl chloride and acetic anhydride. The reaction temperature is not particularly limited, but is usually −20 ° C. to 150 ° C.
　工程２－２：本工程は、前記工程２－１で合成したアセチル化合物をニトロ化することにより化合物（ｂ－１）を得る工程である。本ニトロ化反応は、ニトロ化に一般に用いられる条件、例えば日本化学会編、第４版　実験化学講座２０巻、Ｐ．３９４－４０４、（１９９２）等の文献記載の条件と同様の条件で反応を行うことができる。反応に使用されるニトロ化剤としては、例えば濃硝酸、濃硝酸／酢酸、濃硝酸／濃硫酸、硝酸カリウム／濃硫酸、発煙硝酸／無水酢酸等が挙げられる。反応温度は特に限定されないが、通常、－２０℃～７０℃である。 Step 2-2: This step is a step of obtaining the compound (b-1) by nitration of the acetyl compound synthesized in the above Step 2-1. This nitration reaction is carried out under conditions generally used for nitration, such as the Chemical Society of Japan, 4th edition, Experimental Chemistry Course Vol. The reaction can be carried out under the same conditions as described in the literature such as 394-404 and (1992). Examples of the nitrating agent used in the reaction include concentrated nitric acid, concentrated nitric acid / acetic acid, concentrated nitric acid / concentrated sulfuric acid, potassium nitrate / concentrated sulfuric acid, fuming nitric acid / acetic anhydride, and the like. The reaction temperature is not particularly limited, but is usually −20 ° C. to 70 ° C.
工程２：
　本工程は、化合物（ｂ－１）の脱アセチル化反応により化合物（ｂ－２）を得る工程である。本反応は、アセチル基の脱保護反応に一般に用いられる条件、例えばＴ．Ｗ．Ｇｒｅｅｎ　ａｎｄ　Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，“Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，Ｓｅｃｏｎｄ　Ｅｄｉｔｉｏｎ”，Ｊｏｈｎ　Ｗｉｌｅｙ＆Ｓｏｎｓ（１９９１），Ｐ．３５１－３５２等の文献記載の条件と同様の条件で反応を行うことができる。反応は、例えば塩酸、硫酸、臭化水素酸等の酸存在下行うことができる。反応溶媒はメタノール、エタノール、トルエン、プロパノール等であり、反応温度は特に限定されないが、通常、－２０℃から１５０℃であり、好ましくは室温から溶媒還流温度である。 Process 2 :
This step is a step of obtaining compound (b-2) by deacetylation reaction of compound (b-1). This reaction is carried out under conditions generally used for acetyl group deprotection, such as T.P. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A. The reaction can be carried out under the same conditions as described in the literature such as 351-352. The reaction can be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or hydrobromic acid. The reaction solvent is methanol, ethanol, toluene, propanol or the like, and the reaction temperature is not particularly limited, but is usually −20 ° C. to 150 ° C., preferably room temperature to solvent reflux temperature.
工程３：
　本工程は、化合物（ｂ－２）のアミノ基をｔ－ブトキシカルボニル化させることにより化合物（ｂ－３）を得る工程である。
　アミノ化合物のｔ－ブトキシカルボニル化に一般に用いられる条件、例えばＴ．Ｗ．Ｇｒｅｅｎ　ａｎｄ　Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，“Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，Ｓｅｃｏｎｄ　Ｅｄｉｔｉｏｎ”，Ｊｏｈｎ　Ｗｉｌｅｙ＆Ｓｏｎｓ（１９９１），Ｐ．３２７－３３０等の文献記載の条件と同様の条件で反応を行うことができる。例えばテトラヒドロフラン等の溶媒中でトリエチルアミンを塩基として化合物（ｂ－２）とジ－ｔｅｒｔ－ブチル　ジカーボネートを反応させることで化合物（ｂ－３）を得ることができる。 Step 3 :
This step is a step of obtaining compound (b-3) by t-butoxycarbonylation of the amino group of compound (b-2).
Conditions commonly used for t-butoxycarbonylation of amino compounds, such as those described in T.W. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A. The reaction can be carried out under conditions similar to those described in the literature such as 327-330. For example, compound (b-3) can be obtained by reacting compound (b-2) with di-tert-butyl dicarbonate using triethylamine as a base in a solvent such as tetrahydrofuran.
工程４：
　本工程は、化合物（ｂ－３）を還元して、化合物（ｂ－４）を得る工程である。
　本反応は、ニトロ化合物の還元反応に一般的に用いられる条件で反応を行うことができ、例えばラネーニッケル、パラジウム、ルテニウム、ロジウムまたは白金等の貴金属触媒を使用する接触水素化による還元、鉄等を用いた金属による還元、亜二チオン酸ナトリウムによる還元等が挙げられる。この場合に好ましいのは、例えば、塩化アンモニウムを用いる中性条件下での鉄による還元反応等が挙げられる。 Step 4 :
This step is a step of obtaining compound (b-4) by reducing compound (b-3).
This reaction can be carried out under conditions generally used for reduction of nitro compounds. For example, reduction by catalytic hydrogenation using a noble metal catalyst such as Raney nickel, palladium, ruthenium, rhodium or platinum, iron, etc. Reduction with the metal used, reduction with sodium dithionite and the like can be mentioned. Preferable examples in this case include a reduction reaction with iron under neutral conditions using ammonium chloride.
工程５：
　本工程は化合物（ｂ－４）から化合物（ｂ－７）を得る工程である。
　この反応は、（１）化合物（ｂ－４）と化合物（ｂ－５）とを縮合剤を用いて直接縮合させる方法（方法（１））、（２）化合物（ｂ－５）の混合酸無水物と化合物（ｂ－４）とを反応させる方法（方法（２））、（３）化合物（ｂ－５）の活性エステルと化合物（ｂ－４）とを反応させる方法（方法（３））、または（４）酸クロリド化合物（ｂ－６）と化合物（ｂ－４）とを反応させる方法（方法（４））等の公知の方法で行うことができる。
　これらの反応に用いる化合物（ｂ－４）はフリー体であっても塩であってもよい。 Process 5 :
This step is a step of obtaining compound (b-7) from compound (b-4).
In this reaction, (1) a method of directly condensing compound (b-4) and compound (b-5) using a condensing agent (method (1)), (2) mixed acid of compound (b-5) Method of reacting anhydride with compound (b-4) (method (2)), (3) Method of reacting active ester of compound (b-5) with compound (b-4) (method (3) Or (4) a method of reacting the acid chloride compound (b-6) with the compound (b-4) (method (4)).
The compound (b-4) used for these reactions may be free or a salt.
方法（１）：
　化合物（ｂ－４）と化合物（ｂ－５）とを縮合剤を用いて直接縮合させて化合物（ｂ－７）を得ることができる。
　本反応は公知の方法で反応することができ、縮合剤としては、ＣＤＩ（Ｎ，Ｎ’－カルボニルジイミダゾール）、Ｂｏｐ（１Ｈ－１，２，３－ベンゾトリアゾール－１－イルオキシ（トリ（ジメチルアミノ））ホスホニウム　ヘキサフルオロホスフェ－ト）、ＷＳＣ（１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド・塩酸塩）、ＤＣＣ（Ｎ，Ｎ－ジシクロヘキシルカルボジイミド）、ジエチルホスホリルシアニド、ＰｙＢＯＰ（ベンゾトリアゾール－１－イルオキシトリス（ピロリジノ）ホスホニウムヘキサフルオロホスフェート）、ＥＤＣ・ＨＣｌ（１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩）等が挙げられる。
　本反応の溶媒は、反応を阻害しないものであれば特に限定されないが、例えばテトラヒドロフラン、１，４－ジオキサン、酢酸エチル、酢酸メチル、ジクロロメタン、クロロホルム、Ｎ，Ｎ－ジメチルホルムアミド、トルエン、キシレン等があげられる。
　化合物（ｂ－５）は化合物（ｂ－４）に対して１当量から大過剰用いる。また必要に応じて１当量から大過剰の有機塩基、例えばトリエチルアミン等を加えてもよい。
　反応時間は、特に限定されないが、通常、０．５から４８時間であり、好ましくは０．５から２４時間である。反応温度は、使用する原料、溶媒等により異なり特に限定されないが、好ましくは氷冷～溶媒の還流温度である。 Method (1):
Compound (b-7) can be obtained by directly condensing compound (b-4) and compound (b-5) using a condensing agent.
This reaction can be carried out by a known method. As the condensing agent, CDI (N, N′-carbonyldiimidazole), Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethyl Amino)) phosphonium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride), DCC (N, N-dicyclohexylcarbodiimide), diethyl phosphoryl cyanide, PyBOP ( And benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate) and EDC.HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride).
The solvent for this reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, ethyl acetate, methyl acetate, dichloromethane, chloroform, N, N-dimethylformamide, toluene, xylene and the like. can give.
Compound (b-5) is used in an amount of 1 equivalent to a large excess with respect to compound (b-4). If necessary, 1 equivalent to a large excess of an organic base such as triethylamine may be added.
Although reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours. The reaction temperature varies depending on the raw materials and solvent used, and is not particularly limited, but is preferably ice-cold to the reflux temperature of the solvent.
　方法（２）：
　化合物（ｂ－５）を混合酸無水物とした後、該混合酸無水物と化合物（ｂ－４）とを反応させて化合物（ｂ－７）を得ることができる。混合酸無水物は、公知の方法により合成できるが、例えばトリエチルアミン等の塩基存在下、化合物（ｂ－５）および例えばクロロギ酸エチル等のクロロギ酸エステル類を反応させることで行われる。クロロギ酸エステル類および塩基は、化合物（ｂ－５）に対して１当量から２当量用いる。反応温度は－３０℃～室温であり、好ましくは－２０℃～室温である。
　混合酸無水物と化合物（ｂ－４）を縮合させる工程は、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒中、混合酸無水物と化合物（ｂ－４）とを反応させることにより行われる。化合物（ｂ－４）は、混合酸無水物に対して１当量から大過剰を用いる。
　反応時間は、特に限定されないが、通常、０．５から４８時間であり、好ましくは０．５から１２時間である。反応温度は－２０℃～５０℃であり、好ましくは－２０℃から室温である。 Method (2):
Compound (b-5) can be obtained by making compound (b-5) a mixed acid anhydride and then reacting the mixed acid anhydride with compound (b-4). The mixed acid anhydride can be synthesized by a known method, and is performed by reacting the compound (b-5) with a chloroformate such as ethyl chloroformate in the presence of a base such as triethylamine. The chloroformate and base are used in the amounts of 1 equivalent to 2 equivalents based on compound (b-5). The reaction temperature is −30 ° C. to room temperature, preferably −20 ° C. to room temperature.
The step of condensing the mixed acid anhydride and the compound (b-4) is performed by reacting the mixed acid anhydride and the compound (b-4) in a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, or the like. Done. Compound (b-4) is used in an amount of 1 equivalent to a large excess based on the mixed acid anhydride.
The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours. The reaction temperature is −20 ° C. to 50 ° C., preferably −20 ° C. to room temperature.
方法（３）：
　化合物（ｂ－５）を活性エステルとした後、該活性エステルと化合物（ｂ－４）とを反応させて化合物（ｂ－７）を得ることができる。活性エステルを得る工程は、例えば１，４－ジオキサン、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒中、例えばＤＣＣ等の縮合剤存在下、化合物（ｂ－５）および活性エステル合成試薬を反応させることにより行われる。活性エステル合成試薬としては、例えばＮ－ヒドロキシスクシンイミド等が挙げられる。活性エステル合成試薬および縮合剤は化合物（ｂ－５）に対して１当量から１．５当量用いる。反応時間は、特に限定されないが、通常、０．５から４８時間であり、好ましくは０．５から２４時間である。
　反応温度は－２０℃～５０℃であり、好ましくは－２０℃から室温である。
　活性エステルと化合物（ｂ－４）を縮合させる工程は、例えばジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド等の溶媒中、活性エステルと化合物（ｂ－４）とを反応させることにより行われる。化合物（ｂ－４）は、活性エステルに対して１当量から大過剰を用いる。反応時間は、特に限定されないが、通常、０．５から４８時間であり、好ましくは０．５から２４時間である。反応温度は－２０℃～５０℃であり、好ましくは－２０℃から室温である。 Method (3):
Compound (b-5) can be obtained by reacting compound (b-5) with active ester and then reacting active ester with compound (b-4). In the step of obtaining an active ester, the compound (b-5) and the active ester synthesis reagent are reacted in the presence of a condensing agent such as DCC in a solvent such as 1,4-dioxane, tetrahydrofuran or N, N-dimethylformamide. Is done. Examples of the active ester synthesis reagent include N-hydroxysuccinimide. The active ester synthesis reagent and the condensing agent are used in the amount of 1 to 1.5 equivalents based on compound (b-5). Although reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours.
The reaction temperature is −20 ° C. to 50 ° C., preferably −20 ° C. to room temperature.
The step of condensing the active ester with the compound (b-4) is performed by reacting the active ester with the compound (b-4) in a solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide or the like. Compound (b-4) is used in an amount of 1 equivalent to a large excess based on the active ester. Although reaction time is not specifically limited, Usually, it is 0.5 to 48 hours, Preferably it is 0.5 to 24 hours. The reaction temperature is −20 ° C. to 50 ° C., preferably −20 ° C. to room temperature.
　方法（４）：
　化合物（ｂ－４）と化合物（ｂ－６）から化合物（ｂ－７）を得るアシル化反応は、公知の一般的に用いられる条件と同様の条件で行うことができる。
　反応に使用される塩基としては、例えばトリエチルアミン、ピリジン、炭酸カリウム、ジイソプロピルエチルアミン等が挙げられる。反応温度は特に限定されないが、通常、－７８℃～溶媒の還流温度であり、好ましくは－２０℃～室温である。反応に使用される溶媒は、反応を阻害せず出発物質をある程度溶解するものであれば特に限定されないが、好適には、例えば、テトラヒドロフラン、エーテル、トルエン、ジクロロメタン等があげられる。 Method (4):
The acylation reaction for obtaining the compound (b-7) from the compound (b-4) and the compound (b-6) can be carried out under the same conditions as known generally used conditions.
Examples of the base used for the reaction include triethylamine, pyridine, potassium carbonate, diisopropylethylamine and the like. The reaction temperature is not particularly limited, but is usually from −78 ° C. to the reflux temperature of the solvent, preferably from −20 ° C. to room temperature. The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and preferred examples include tetrahydrofuran, ether, toluene, dichloromethane and the like.
工程６：
　本工程は、化合物（ｂ－７）のｔ－ブトキシカルボニル基の脱保護反応により化合物（Ｉ－ａ）を得る工程である。
　ｔ－ブトキシカルボニル基の脱保護反応に一般に用いられる条件、例えばＴ．Ｗ．Ｇｒｅｅｎ　ａｎｄ　Ｐ．Ｇ．Ｍ．Ｗｕｔｓ，“Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ，Ｓｅｃｏｎｄ　Ｅｄｉｔｉｏｎ”，Ｊｏｈｎ　Ｗｉｌｅｙ＆Ｓｏｎｓ（１９９１），Ｐ．３２７－３３０等の文献記載の条件と同様の条件で反応を行うことができる。例えばジクロロメタン等の溶媒中でトリフルオロ酢酸と化合物（ｂ－７）を反応させることで化合物（Ｉ－ａ）を得ることができる。 Process 6 :
This step is a step of obtaining compound (Ia) by deprotecting the t-butoxycarbonyl group of compound (b-7).
Conditions generally used for the deprotection reaction of the t-butoxycarbonyl group, such as those described in T.W. W. Green and P.M. G. M.M. Wuts, “Protective Groups in Organic Chemistry, Second Edition”, John Wiley & Sons (1991), P.A. The reaction can be carried out under conditions similar to those described in the literature such as 327-330. For example, compound (Ia) can be obtained by reacting trifluoroacetic acid with compound (b-7) in a solvent such as dichloromethane.
　かくして得られる、本発明にかかる一般式（Ｉ）において、Ｌが－Ｃ（＝Ｏ）ＮＨ－である化合物に、更に、対応するＣ１－６アルキルハライドを通常の方法で反応させることにより、本発明にかかる一般式（Ｉ）において、Ｌが－Ｃ（＝Ｏ）ＮＲＬ－（ＲＬは置換基αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基である。）である化合物を得ることができる。 The compound thus obtained in the general formula (I) according to the present invention, in which L is —C (═O) NH—, is further reacted with a corresponding C 1-6 alkyl halide by a conventional method. In the general formula (I) according to the invention, L is —C (═O) NR L — (R L is a C1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent α Can be obtained.
　一般式（Ｉ）において、Ｒ３が水素原子の場合、一般的製造法２において得られる化合物（Ｉ－ａ）を、更に、Ｃ１－６アルキルハライド、Ｃ１－６アルキルカルボニルハライド、Ｃ６－１０アリールカルボニルハライド、Ｃ１－６アルキルスルホニルハライド、Ｃ６－１０アリールスルホニルハライド、Ｃ３－１０員炭素環ハライド、５－１０員複素環ハライドなどの対応するハロゲン化化合物などと反応させることにより、式（Ｉ）において、Ｒ３が置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基、置換基群αから選択される置換基を有していてもよいＣ１－６アルキルカルボニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ６－１０アリールカルボニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキルスルホニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ６－１０アリールスルホニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ３－１０員炭素環基又は置換基群αから選択される１乃至３の置換基を有していてもよい５－１０員複素環基である本発明の化合物を得ることができる。 In the general formula (I), when R 3 is a hydrogen atom, the compound (Ia) obtained in the general production method 2 is further converted into a C1-6 alkyl halide, a C1-6 alkylcarbonyl halide, a C6-10 aryl. By reacting with a corresponding halogenated compound such as carbonyl halide, C1-6 alkylsulfonyl halide, C6-10 arylsulfonyl halide, C3-10-membered carbocyclic halide, 5-10-membered heterocyclic halide, etc., formula (I) In R 1 , R 3 may have 1 to 3 substituents selected from the substituent group α and may have a substituent selected from the substituent group α. From a C-6-10 arylcarbonyl group optionally having 1 to 3 substituents selected from a -6 alkylcarbonyl group and substituent group α, and substituent group α C1-6 alkylsulfonyl group optionally having 1 to 3 substituents selected, C6-10 arylsulfonyl group optionally having 1 to 3 substituents selected from substituent group α A C3-10 membered carbocyclic group which may have 1 to 3 substituents selected from the substituent group α, or 1 to 3 substituents selected from the substituent group α. Compounds of the invention that are good 5-10 membered heterocyclic groups can be obtained.
３．一般製造法３：
Figure JPOXMLDOC01-appb-C000008
［式中、Ｌ１は、化合物（ｃ－４）、（ｃ－５）及び（ｃ－６）においては、単結合又はＣ１－６アルキレン基を示し、化合物（ｃ－８）及び（ｃ－９）においては、単結合又はＣ１－４アルキレン基を示し、Ｌは単結合、酸素原子、Ｃ１－６アルキレン基、Ｃ２－６アルケニレン基またはＣ２－６アルキニレン基を示し、環Ａ、環Ｂ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｘ、Ｙ、Ｚは前記と同じ意味を示す。］
　一般的製造法３は、化合物（ＩＩ）から３工程で一般式（Ｉ）において、Ｌが単結合、二重結合、三重結合である化合物（Ｉ－ｂ）を製造する方法である。
　化合物（ＩＩ）は、市販品から前記一般製造法１により製造することができ、更に実施例中の製造例の記載の方法を用いて製造することもできる。また、化合物（ｃ－４）、（ｃ－５）、（ｃ－６）、（ｃ－７）および（ｃ－８）は、市販品をそのまま用いることもでき、市販品から公知の方法で製造することもでき、更に実施例中の製造例の記載の方法を用いて製造することもできる。 3. General production method 3 :
Figure JPOXMLDOC01-appb-C000008
[Wherein, L 1 represents a single bond or a C 1-6 alkylene group in the compounds (c-4), (c-5) and (c-6), and the compounds (c-8) and (c— 9) represents a single bond or a C1-4 alkylene group, L represents a single bond, an oxygen atom, a C1-6 alkylene group, a C2-6 alkenylene group or a C2-6 alkynylene group, and ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, Z have the same meaning as described above. ]
General production method 3 is a method for producing compound (Ib) in which L is a single bond, double bond, or triple bond in general formula (I) in three steps from compound (II).
Compound (II) can be produced from a commercially available product by the general production method 1, and can also be produced by using the method described in the production examples in the examples. In addition, compounds (c-4), (c-5), (c-6), (c-7) and (c-8) can be used as they are, or they can be used as they are by commercially known methods. It can also be produced, and further can be produced using the method described in the production examples in the examples.
工程１：
　本工程は、化合物（ＩＩ）の臭素化反応を系内で行うことにより化合物（ｃ－１）を得る工程である。本反応は、例えば、Ｈｏｌｍｂｅｒｇ，Ｐ．；Ｔｅｄｅｎｂｏｒｇ，　Ｐ．；Ｒｏｓｑｕｖｉｓｔ，　Ｓ．；Ｈｏｈａｎｓｓｏｎ，　Ａ．Ｍ．，Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．；１５（３），７４７－７５０（２００５）等の文献記載の方法と同様の方法で行うことができる。反応に使用される条件としては、例えば臭素／酢酸、臭素／炭酸ナトリウム／ヘキサン、Ｎ－ブロモスクシンイミド／塩化メチレン等が挙げられる。反応温度は特に限定されないが、通常、－２０℃から５０℃であり、好ましくは－２０℃～室温である。 Process 1 :
This step is a step of obtaining compound (c-1) by carrying out bromination reaction of compound (II) in the system. This reaction is described, for example, in Holberg, P .; Tedenburg, P .; Rosquivst, S .; Hohansson, A .; M.M. Bioorg. Med. Chem. Lett. ; 15 (3), 747-750 (2005) and the like. Examples of the conditions used for the reaction include bromine / acetic acid, bromine / sodium carbonate / hexane, N-bromosuccinimide / methylene chloride, and the like. The reaction temperature is not particularly limited, but is usually −20 ° C. to 50 ° C., preferably −20 ° C. to room temperature.
工程２：
　本工程は、化合物（ｃ－１）をｔｅｒｔ－ブトキシカルボニル化することにより化合物（ｃ－２）、或いはＲ３が水素原子の場合に化合物（ｃ－３）を得る工程である。本反応は、アミド化合物のｔ－ブトキシカルボニル化に一般に用いられる条件、例えば、ＴＨＦ等の溶媒中で４－ジメチルアミノピリジンを塩基として化合物（ｃ－１）とジ－ｔｅｒｔ－ブチル　ジカーボネートを反応させることで化合物（ｃ－２）或いは（ｃ－３）を得ることができる。
　本反応に用いられる溶媒は、反応を阻害しないものであれば特に限定されないが、好ましくは、例えば、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン、ジクロロメタン、ＤＭＦ、アセトニトリル等の有機溶媒、或いは、これらの混合溶媒が挙げられる。使用する塩基としては、例えば、トリエチルアミン、４－ジメチルアミノピリジン、ＤＢＵ、或いは、これらの混合物等があげられる。これらの塩基は、化合物（ｃ－１）に対して、触媒量から過剰量用いられ、より好ましくは０．１－５当量である。ジ－ｔｅｒｔ－ブチル　ジカーボネートは、化合物（ｃ－１）に対して２当量から過剰量用いられ、より好ましくは、２－１０当量用いられる。反応時間は、特に限定されないが、通常、５分から２４時間であり、好ましくは５分から１２時間である。反応温度は、通常、－２０℃～溶媒の還流温度であり、より好ましくは０℃～溶媒の還流温度である。 Process 2 :
This step is a step of obtaining compound (c-2) by tert-butoxycarbonylation of compound (c-1) or compound (c-3) when R 3 is a hydrogen atom. This reaction is carried out by reacting compound (c-1) with di-tert-butyl dicarbonate using 4-dimethylaminopyridine as a base in conditions generally used for t-butoxycarbonylation of amide compounds, such as THF. To give compound (c-2) or (c-3).
The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction, but is preferably an organic solvent such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, DMF, acetonitrile and the like. Or these mixed solvents are mentioned. Examples of the base to be used include triethylamine, 4-dimethylaminopyridine, DBU, or a mixture thereof. These bases are used in a catalytic amount to an excess amount relative to compound (c-1), more preferably 0.1-5 equivalents. Di-tert-butyl dicarbonate is used in an amount of 2 equivalents to an excess amount relative to compound (c-1), more preferably 2-10 equivalents. The reaction time is not particularly limited, but is usually 5 minutes to 24 hours, preferably 5 minutes to 12 hours. The reaction temperature is usually from −20 ° C. to the reflux temperature of the solvent, more preferably from 0 ° C. to the reflux temperature of the solvent.
工程３：
　本工程は、化合物（ｃ－２）或いは（ｃ－３）と、化合物（ｃ－４）、（ｃ－５）、（ｃ－６）、（ｃ－７）、（ｃ－８）或いは（ｃ－９）との遷移金属を用いたカップリング反応により、ｔ－ブトキシカルボニル基の脱保護を伴って化合物（Ｉ－ｂ）を得る工程である。本反応は、遷移金属を用いたカップリング反応（例えば、鈴木－宮浦反応、スティル反応（Ｓｔｉｌｌｅ反応）、園頭反応、ヘック反応（Ｈｅｃｋ反応）、Ｂｕｃｋｗａｌｄ、Ｓ．Ｌ．ｅｔ　ａｌ．，Ｊ　Ａｍ　Ｃｈｅｍ　Ｓｏｃ（１９９９）１２１（１８），４３６９－４３７８等に記載の方法等）に通常用いられている条件で反応を行うことができる。 Step 3 :
This step comprises compound (c-2) or (c-3) and compound (c-4), (c-5), (c-6), (c-7), (c-8) or ( In this step, compound (Ib) is obtained by deprotecting the t-butoxycarbonyl group by a coupling reaction with c-9) using a transition metal. This reaction is a coupling reaction using a transition metal (for example, Suzuki-Miyaura reaction, Stille reaction (Still reaction), Sonogashira reaction, Heck reaction (Heck reaction), Buckwald, SL et al., J Am. The reaction can be carried out under conditions usually used in Chem Soc (1999) 121 (18), 4369-4378 and the like.
　本反応に用いられる有機金属触媒としては特に限定されないが、好ましくは、例えばテトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、［１，１´－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド、ビス（ｔｅｒｔ－ブチルホスフィン）パラジウム（０）、酢酸パラジウム（ＩＩ）、［１，３－ビス（ジフェニルホスフィノ）プロパン］ニッケル（ＩＩ）等の金属触媒或いは、これら金属触媒の混合物をあげることができる。有機金属触媒の使用量は、原料に対して約０．００１～０．５当量である。化合物（ｃ－４）、（ｃ－５）、（ｃ－６）、（ｃ－７）或いは（ｃ－８）の使用量は、特に限定されないが、通常、化合物（ｃ－２）或いは（ｃ－３）に対して１～６当量である。本反応に用いられる溶媒は、反応を阻害しないものであれば特に限定されないが、好ましくは、例えばベンゼン、トルエン、キシレン、Ｎ，Ｎ－ジメチルホルムアミド、１－メチル－２－ピロリドン、テトラヒドロフラン、１，２－ジメトキシエタン、１，４－ジオキサン、アセトニトリル、プロピオニトリル等をあげることができる。反応温度は特に限定されないが、通常、氷冷～溶媒の還流温度であり、好ましくは、例えば、室温～溶媒の還流温度である。反応時間は、特に限定されないが、通常、０．５～４８時間であり、好ましくは０．５～２４時間である。 The organometallic catalyst used in this reaction is not particularly limited, but preferably, for example, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), [1,1′-bis (diphenyl) Metal catalysts such as phosphino) ferrocene] palladium (II) dichloride, bis (tert-butylphosphine) palladium (0), palladium (II) acetate, [1,3-bis (diphenylphosphino) propane] nickel (II) Or the mixture of these metal catalysts can be mention | raise | lifted. The amount of the organometallic catalyst used is about 0.001 to 0.5 equivalent with respect to the raw material. The amount of compound (c-4), (c-5), (c-6), (c-7) or (c-8) used is not particularly limited, but is usually compound (c-2) or ( 1 to 6 equivalents relative to c-3). The solvent used in this reaction is not particularly limited as long as it does not inhibit the reaction. Preferably, for example, benzene, toluene, xylene, N, N-dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, 1, Examples thereof include 2-dimethoxyethane, 1,4-dioxane, acetonitrile, propionitrile and the like. The reaction temperature is not particularly limited, but is usually from ice-cooling to the reflux temperature of the solvent, and preferably from room temperature to the reflux temperature of the solvent, for example. The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 24 hours.
　さらに本反応を塩基或いは塩の共存下に行うことで収率向上等のより好ましい結果を得ることがある。かかる塩基或いは塩としては特に限定はされないが、好ましくは炭酸ナトリウム、炭酸カリウム、水酸化バリウム、炭酸セシウム、リン酸カリウム、フッ化カリウム、或いはそれらの水溶液、およびトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、塩化リチウム、ヨウ化銅（Ｉ）等の塩基、或いは塩があげられる。 Further, by carrying out this reaction in the presence of a base or a salt, a more favorable result such as an improvement in yield may be obtained. The base or salt is not particularly limited, but preferably sodium carbonate, potassium carbonate, barium hydroxide, cesium carbonate, potassium phosphate, potassium fluoride, or an aqueous solution thereof, and triethylamine, N, N-diisopropylethylamine, Examples include bases such as lithium chloride and copper (I) iodide, and salts.
　工程３において、化合物（ｃ－１）でＲ３が水素原子である場合には、アミノ基をｔ－ブトキシカルボニル基等で保護することなく、化合物（ｃ－７）とカップリング反応を行い、化合物（Ｉ－ｂ）を合成することができる。 In step 3, when R 3 is a hydrogen atom in compound (c-1), a coupling reaction is performed with compound (c-7) without protecting the amino group with a t-butoxycarbonyl group or the like, Compound (Ib) can be synthesized.
　一般式（Ｉ）において、Ｒ３が水素原子の場合、一般的製造法３において得られる化合物（Ｉ－ｂ）を、更に、Ｃ１－６アルキルハライド、Ｃ１－６アルキルカルボニルハライド、Ｃ６－１０アリールカルボニルハライド、Ｃ１－６アルキルスルホニルハライド、Ｃ６－１０アリールスルホニルハライド、Ｃ３－１０員炭素環ハライド、５－１０員複素環ハライドなどの対応するハロゲン化化合物などと反応させることにより、式（Ｉ）において、Ｒ３が置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基、置換基群αから選択される置換基を有していてもよいＣ１－６アルキルカルボニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ６－１０アリールカルボニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキルスルホニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ６－１０アリールスルホニル基、置換基群αから選択される１乃至３の置換基を有していてもよいＣ３－１０員炭素環基又は置換基群αから選択される１乃至３の置換基を有していてもよい５－１０員複素環基である本発明の化合物を得ることができる。 In the general formula (I), when R 3 is a hydrogen atom, the compound (Ib) obtained in the general production method 3 is further converted into a C1-6 alkyl halide, C1-6 alkylcarbonyl halide, C6-10 aryl. By reacting with a corresponding halogenated compound such as carbonyl halide, C1-6 alkylsulfonyl halide, C6-10 arylsulfonyl halide, C3-10 membered carbocyclic halide, 5-10 membered heterocyclic halide, etc., formula (I) In R 1 , R 3 may have 1 to 3 substituents selected from the substituent group α and may have a substituent selected from the substituent group α. From a C-6-10 arylcarbonyl group optionally having 1 to 3 substituents selected from a -6 alkylcarbonyl group and substituent group α, and substituent group α C1-6 alkylsulfonyl group optionally having 1 to 3 substituents selected, C6-10 arylsulfonyl group optionally having 1 to 3 substituents selected from substituent group α A C3-10 membered carbocyclic group which may have 1 to 3 substituents selected from the substituent group α, or 1 to 3 substituents selected from the substituent group α. Compounds of the invention that are good 5-10 membered heterocyclic groups can be obtained.
一般製造法３において得られる化合物（Ｉ－ｂ）のＬがＣ１－６アルキレン基である化合物は、化合物（ｃ－２）或いは（ｃ－３）と（ｃ－８）或いは（ｃ－９）との遷移金属を用いたカップリング反応により、生成したＬがＣ２－６アルケニレン基又はＣ２－６アルキニレン基を還元反応に通常用いられている条件、例えば、パラジウム等の触媒を用いる反応で製造することもできる。 The compound (Ib) obtained in General Production Method 3 wherein L is a C1-6 alkylene group is compound (c-2) or (c-3) and (c-8) or (c-9) The resulting L is produced by a coupling reaction using a transition metal with C2-6 alkenylene group or C2-6 alkynylene group under the conditions normally used for the reduction reaction, for example, a reaction using a catalyst such as palladium. You can also.
　かくして得られる本発明の式（Ｉ）の化合物は、必要に応じて、常法により、医薬上許容される塩とすることができる。その製造法は、有機合成化学分野で通常用いられる方法などを適宜組み合わせて行うことができる。具体的には、本発明化合物の遊離型の溶液を酸溶液で中和滴定することなどが挙げられる。また、必要に応じて、それ自体周知の溶媒和物形成反応に付すことにより、本発明の式（Ｉ）の化合物を溶媒和物に変換することができる。 The compound of the formula (I) of the present invention thus obtained can be converted into a pharmaceutically acceptable salt by a conventional method as necessary. The production method can be carried out by appropriately combining methods usually used in the field of synthetic organic chemistry. Specific examples include neutralization titration of a free solution of the compound of the present invention with an acid solution. If necessary, the compound of formula (I) of the present invention can be converted into a solvate by subjecting to a solvate formation reaction known per se.
　本発明に係るスピロアミノジヒドロチアジン誘導体又はその医薬上許容される塩は、極めて優れたＡβ産生抑制作用又はＢＡＣＥ１阻害作用を有し、Ａβに起因する、アルツハイマー型痴呆に代表される神経変性疾患の予防剤または治療剤として極めて有用である。 The spiroaminodihydrothiazine derivative or a pharmaceutically acceptable salt thereof according to the present invention has a very excellent Aβ production inhibitory action or BACE1 inhibitory action, and is a neurodegenerative disease represented by Alzheimer-type dementia caused by Aβ. It is extremely useful as a prophylactic or therapeutic agent.
　本発明に係るスピロアミノジヒドロチアジン誘導体又はその医薬上許容される塩は、通常の方法により製剤化が可能であり、好ましい剤形としては、例えば、錠剤、フィルム錠や糖衣錠等の被覆錠剤、細粒剤、顆粒剤、散剤、カプセル剤、シロップ剤、トローチ剤、吸入剤、坐剤、注射剤、軟膏剤、点眼剤、点鼻剤、点耳剤、パップ剤、ローション剤等が挙げられる。
　これらの錠剤、カプセル剤、顆粒剤、粉末などの固形製剤は、一般的には０．０１～１００重量％、好ましくは０．１～１００重量％の有効成分である本発明に係るスピロアミノジヒドロチアジン誘導体又はその医薬上許容される塩を含むことができる。 The spiroaminodihydrothiazine derivative or a pharmaceutically acceptable salt thereof according to the present invention can be formulated by a usual method. Preferred dosage forms include, for example, tablets such as tablets, film tablets and sugar-coated tablets, Fine granules, granules, powders, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, nasal drops, ear drops, poultices, lotions, etc. .
These solid preparations such as tablets, capsules, granules and powders are generally 0.01 to 100% by weight, preferably 0.1 to 100% by weight, of the active ingredient of the spiroaminodihydro according to the present invention. Thiazine derivatives or pharmaceutically acceptable salts thereof can be included.
　製剤化には、一般に医薬品製剤の原料として用いられる成分を配合し、例えば、通常用いられる賦形剤、崩壊剤、結合剤、滑沢剤、着色剤、矯味矯臭剤や、必要により安定化剤、乳化剤、吸収促進剤、界面活性剤、ｐＨ調整剤、防腐剤、抗酸化剤等を添加して常法により製剤化を行う。これらの成分としては、例えば、大豆油、牛脂、合成グリセライド等の動植物油；流動パラフィン、スクワラン、固形パラフィン等の炭化水素；ミリスチン酸オクチルドデシル、ミリスチン酸イソプロピル等のエステル油；セトステアリルアルコール、ベヘニルアルコール等の高級アルコール；シリコン樹脂；シリコン油；ポリオキシエチレン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン硬化ひまし油、ポリオキシエチレンポリオキシプロピレンブロックコポリマー等の界面活性剤；ヒドロキシエチルセルロース、ポリアクリル酸、カルボキシビニルポリマー、ポリエチレングリコール、ポリビニルピロリドン、メチルセルロース等の水溶性高分子；エタノール、イソプロパノール等の低級アルコール；グリセリン、プロピレングリコール、ジプロピレングリコール、ソルビトール等の多価アルコール；グルコース、ショ糖等の糖；無水ケイ酸、ケイ酸アルミニウムマグネシウム、ケイ酸アルミニウム等の無機粉体、精製水等が挙げられる。賦形剤としては、例えば乳糖、コーンスターチ、白糖、ブドウ糖、マンニトール、ソルビット、結晶セルロース、二酸化ケイ素等が、結合剤としては、例えばポリビニルアルコール、ポリビニルエーテル、メチルセルロース、エチルセルロース、アラビアゴム、トラガント、ゼラチン、シェラック、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ポリプロピレングリコール・ポリオキシエチレン・ブロックポリマー、メグルミン等が、崩壊剤としては、例えば澱粉、寒天、ゼラチン末、結晶セルロース、炭酸カルシウム、炭酸水素ナトリウム、クエン酸カルシウム、デキストリン、ペクチン、カルボキシメチルセルロース・カルシウム等が、滑沢剤としては、例えばステアリン酸マグネシウム、タルク、ポリエチレングリコール、シリカ、硬化植物油等が、着色剤としては医薬品に添加することが許可されているものが、矯味矯臭剤としては、ココア末、ハッカ脳、芳香散、ハッカ油、竜脳、桂皮末等が用いられる。もちろん、これらの添加剤成分に限定される訳ではないことは言うまでもない。 For formulation, ingredients generally used as raw materials for pharmaceutical preparations are blended. For example, commonly used excipients, disintegrants, binders, lubricants, coloring agents, flavoring agents, and if necessary, stabilizers , Emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. are added to prepare a formulation by a conventional method. Examples of these components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; cetostearyl alcohol and behenyl alcohol Higher alcohols such as: silicone resin; silicone oil; polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, etc. Agent: Water-soluble, such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methylcellulose Molecules; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as anhydrous silicic acid, magnesium aluminum silicate and aluminum silicate Body, purified water and the like. Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, and the like, and examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, Shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, Calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium and the like are lubricants such as magnesium stearate , Talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., which are allowed to be added to pharmaceuticals as colorants, flavourants include cocoa powder, mint brain, aroma powder, mint oil, dragonfly, For example, cinnamon powder is used. Of course, it goes without saying that the present invention is not limited to these additive components.
　例えば経口製剤は、有効成分である本発明に係るスピロアミノジヒドロチアジン誘導体又はその医薬上許容される塩と賦形剤、さらに必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤等を加えた後、常法により散剤、細粒剤、顆粒剤、錠剤、被覆錠剤、カプセル剤等とする。錠剤・顆粒剤の場合には、糖衣、その他必要により適宜コーティングすることはもちろん差支えない。
　例えばシロップ剤や注射用製剤等の場合は、ｐＨ調整剤、溶解剤、等張化剤等と、必要に応じて溶解補助剤、安定化剤等を加えて、常法により製剤化する。また、これらの注射剤は予め溶解したものの他、粉末のまままたは適当な添加物を加えたものを用時溶解する形態も取ることができる。これらの注射液は、通常０．０１～１００重量％、好ましくは０．１～１００重量％等の有効成分を含むことができる。さらには、経口投与の懸濁剤またはシロップ剤等の液剤は、通常０．０１～１００重量％、好ましくは０．１～１００重量％等の有効成分を含むことができる。
　例えば、外用剤の場合は、特に製法が限定されず、常法により製造することができる。使用する基剤原料としては、医薬品、医薬部外品、化粧品等に通常使用される各種原料を用いることが可能で、例えば動植物油、鉱物油、エステル油、ワックス類、高級アルコール類、脂肪酸類、シリコン油、界面活性剤、リン脂質類、アルコール類、多価アルコール類、水溶性高分子類、粘土鉱物類、精製水等の原料が挙げられ、必要に応じ、ｐＨ調整剤、抗酸化剤、キレート剤、防腐防黴剤、着色料、香料等を添加することができる。さらに、必要に応じて分化誘導作用を有する成分、血流促進剤、殺菌剤、消炎剤、細胞賦活剤、ビタミン類、アミノ酸、保湿剤、角質溶解剤等の成分を配合することもできる。 For example, an oral preparation is an active ingredient of the spiroaminodihydrothiazine derivative according to the present invention or a pharmaceutically acceptable salt and excipient thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, After adding a flavoring agent, etc., powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by conventional methods. In the case of tablets and granules, of course, sugar coating and other appropriate coatings may be used if necessary.
For example, in the case of syrups, injectable preparations, etc., a pH adjuster, a solubilizer, an isotonic agent, etc., and a solubilizing agent, a stabilizer, etc., if necessary, are added and formulated in a conventional manner. Moreover, these injections can take the form which melt | dissolves at the time of use with the powder or the thing which added the suitable additive other than what melt | dissolved beforehand. These injection solutions can usually contain active ingredients such as 0.01 to 100% by weight, preferably 0.1 to 100% by weight. Furthermore, liquid preparations such as suspensions or syrups for oral administration can contain 0.01 to 100% by weight, preferably 0.1 to 100% by weight of an active ingredient.
For example, in the case of an external preparation, the production method is not particularly limited, and it can be produced by a conventional method. As a base material to be used, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used. For example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids , Silicone oil, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water, etc., and pH adjusters, antioxidants as necessary Chelating agents, antiseptic / antifungal agents, coloring agents, fragrances, and the like can be added. Furthermore, components having differentiation-inducing action, blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and the like can be blended as necessary.
　本発明に係るスピロアミノジヒドロチアジン誘導体又はその医薬上許容される塩の投与量は、症状の程度、年齢、性別、体重、投与形態・塩の種類、疾患の具体的な種類等に応じて異なるが、通常、成人の場合は１日あたり経口投与で約３０μｇ～１０ｇ、好ましくは１００μｇ～５ｇ、さらに好ましくは１００μｇ～１ｇを、注射投与で約３０μｇ～１ｇ、好ましくは１００μｇ～５００ｍｇ、さらに好ましくは１００μｇ～３００ｍｇをそれぞれ１回又は数回に分けて投与する。 The dosage of the spiroaminodihydrothiazine derivative or pharmaceutically acceptable salt thereof according to the present invention depends on the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, etc. Usually, in the case of an adult, about 30 μg to 10 g, preferably 100 μg to 5 g, more preferably 100 μg to 1 g is orally administered per day, and about 30 μg to 1 g, preferably 100 μg to 500 mg, more preferably by injection. Administer 100 μg to 300 mg once or in several divided doses.
　以下、本発明を製造例、実施例及び試験例により詳細に説明する。しかし、本発明はこれらに限定されることはない。また、製造例および実施例において使用される略語は当業者に周知の慣用的な略語である、いくつかの略語は以下に示す。
ＴＨＦ；テトラヒドロフラン
ＤＭＦ；Ｎ，Ｎ－ジメチルホルムアミド
ＴＦＡ；トリフルオロ酢酸
ＥＤＣ・ＨＣｌ；１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩
ｐＴＬＣ；分取薄層クロマトグラフィー
ＬＣ－ＭＳ；液体クロマトグラフィー－マススペクトルメトリー
ＰｙＢＯＰ；ベンゾトリアゾール－１－イルオキシトリス（ピロリジノ）ホスホニウムヘキサフルオロホスフェート
　プロトン核磁気共鳴スペクトルの化学シフトは、テトラメチルシランに対するδ単位（ｐｐｍ）で記録、カップリング定数はヘルツ（Ｈｚ）で記録されている。パターンは、ｓ；シングレット、ｄ；ダブレット、ｔ；トリプレット、ｂｒ；ブロード。 Hereinafter, the present invention will be described in detail with reference to production examples, examples and test examples. However, the present invention is not limited to these. Abbreviations used in the production examples and examples are conventional abbreviations well known to those skilled in the art. Some abbreviations are shown below.
THF; tetrahydrofuran DMF; N, N-dimethylformamide TFA; trifluoroacetic acid EDC · HCl; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride pTLC; preparative thin layer chromatography LC-MS; liquid chromatography Graphy-mass spectrometry PyBOP; Benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate The chemical shift of the proton nuclear magnetic resonance spectrum is recorded in δ units (ppm) relative to tetramethylsilane, and the coupling constant is Hertz ( Hz). The patterns are: s; singlet, d: doublet, t: triplet, br: broad.
　以下の実施例及び製造例中の「室温」は通常約１０℃から約３５℃を示す。％は特記しない限り重量パーセントを示す。 “Room temperature” in the following Examples and Production Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates weight percent unless otherwise specified.
製造例１
８－フルオロクロマン－４－オン（化合物１－３）の合成
Figure JPOXMLDOC01-appb-C000009
 （１）３－（２－フルオロフェノキシ）プロピオン酸(化合物１－２)の合成
　（１－１）窒素雰囲気下、５０％水素化ナトリウム（３．２２ｇ）のＮ，Ｎ－ジメチルホルムアミド（１００ｍｌ）溶液に、氷浴にて冷却しながら、２－フルオロフェノール（化合物１－１、３．０ｇ）のＮ，Ｎ－ジメチルホルムアミド（７．０ｍｌ）溶液を加えた。同温度にて３０分間撹拌した後、３－ブロモ－プロピオン酸（４．９１ｇ）のＮ，Ｎ－ジメチルホルムアミド（８．０ｍｌ）溶液を加えた。自然に室温に戻し、同温度にて２４時間撹拌した。１Ｎ塩酸（１００ｍｌ）を加え、ｐＨ１－２に調整して反応停止させた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣に２０％酢酸エチル－ヘキサン混合溶媒を加えて結晶化し標題化合物を得た（１．５３ｇ）。 Production Example 1
Synthesis of 8-fluorochroman-4-one (compound 1-3)
Figure JPOXMLDOC01-appb-C000009
 (1) Synthesis of 3- (2-fluorophenoxy) propionic acid (compound 1-2) (1-1) 50% sodium hydride (3.22 g) in N, N-dimethylformamide (100 ml) under nitrogen atmosphere To the solution, a solution of 2-fluorophenol (Compound 1-1, 3.0 g) in N, N-dimethylformamide (7.0 ml) was added while cooling in an ice bath. After stirring at the same temperature for 30 minutes, a solution of 3-bromo-propionic acid (4.91 g) in N, N-dimethylformamide (8.0 ml) was added. The mixture was naturally returned to room temperature and stirred at the same temperature for 24 hours. 1N hydrochloric acid (100 ml) was added to adjust the pH to 1-2 to stop the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized by adding 20% ethyl acetate-hexane mixed solvent to give the title compound (1.53 g).
　（１－２）別法として、以下の方法により標題化合物を合成した。
　化合物１－１（２．２０ｇ）のテトラヒドロフラン（１００ｍｌ）溶液に、室温にてカリウム－ｔ－ブトキシド（２．４２ｇ）を加えた。同温度にて５分間撹拌した後、ｂｅｔａ－プロピオラクトン（２．７１ｍｌ）を加えた。発熱したため、氷浴に移し、同温度にて１時間撹拌した。さらに室温にて４時間撹拌した後に、１Ｎ塩酸を加えて酸性とし、反応停止させた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣に２０％酢酸エチル－ヘキサン混合溶媒を加えて結晶化し標題化合物を得た（１．４４ｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）（ｐｐｍ）：２．７３（ｔ，Ｊ＝６．０Ｈｚ，２Ｈ），４．２４（ｔ，Ｊ＝６．０Ｈｚ，２Ｈ），６．９０－７．００（ｍ，１Ｈ），７．０９－７．２４（ｍ，３Ｈ），１２．４１（ｂｒ．ｓ．，１Ｈ）． (1-2) As an alternative method, the title compound was synthesized by the following method.
To a solution of compound 1-1 (2.20 g) in tetrahydrofuran (100 ml) was added potassium tert-butoxide (2.42 g) at room temperature. After stirring at the same temperature for 5 minutes, beta-propiolactone (2.71 ml) was added. Since it generated heat, it was transferred to an ice bath and stirred at the same temperature for 1 hour. After further stirring at room temperature for 4 hours, 1N hydrochloric acid was added to acidify the reaction and the reaction was stopped. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized by adding 20% ethyl acetate-hexane mixed solvent to give the title compound (1.44 g).
1H NMR (400 MHz, DMSO-d6) (ppm): 2.73 (t, J = 6.0 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 6.90-7.00 (M, 1H), 7.09-7.24 (m, 3H), 12.41 (br.s., 1H).
（２）化合物１－３の合成
　化合物１－２（４５０ｍｇ）にポリリン酸（７．０ｇ）を加え、１００度で３．５時間撹拌した。熱源を切り、７５度まで温度を下げたところで、激しく撹拌しながら、砕氷を反応混合物に少しずつ加えた。室温に戻ったところで、反応液を氷水に加えた。水層をジエチルエーテルで抽出し、有機層を重曹水、続いて飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し標題化合物を得た（２７３ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．８９（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），４．６６（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），６．９８（ｔｄ，Ｊ＝４．４，８．０Ｈｚ，１Ｈ），７．２９－７．３４（ｍ，１Ｈ），７．７１（ｄｔ，Ｊ＝１．５，８．０Ｈｚ，１Ｈ）． (2) Synthesis of Compound 1-3 Polyphosphoric acid (7.0 g) was added to Compound 1-2 (450 mg) and stirred at 100 ° C. for 3.5 hours. When the heat source was turned off and the temperature was lowered to 75 ° C., crushed ice was added to the reaction mixture little by little with vigorous stirring. When the temperature returned to room temperature, the reaction solution was added to ice water. The aqueous layer was extracted with diethyl ether, and the organic layer was washed with aqueous sodium bicarbonate followed by saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (273 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 2.89 (t, J = 6.4 Hz, 2H), 4.66 (t, J = 6.4 Hz, 2H), 6.98 (td, J = 4.4, 8.0 Hz, 1 H), 7.29-7.34 (m, 1 H), 7.71 (dt, J = 1.5, 8.0 Hz, 1 H).
　同様にして表１に記載の化合物を合成した。表１に構造式及び１Ｈ－ＮＭＲデータを示す。 In the same manner, the compounds shown in Table 1 were synthesized. Table 1 shows the structural formula and 1H-NMR data.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
製造例２
２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］　チアジン］－２’－アミン（化合物１）の合成
Figure JPOXMLDOC01-appb-C000011
 （１）４－ビニル－クロマン－４－オール（化合物２－２）の合成　
　ビニルマグネシウムクロライド（１．４８Ｍテトラヒドロフラン溶液；２９．７ｍｌ）に塩化亜鉛（４６１ｍｇ）を加え室温で１時間撹拌した。反応液を０度に冷却した後、化合物２－１（５．００ｇ）のテトラヒドロフラン（２０．０ｍｌ）溶液を滴下した。反応液を同温で５時間撹拌した。原料の消失を確認した後、反応混合物に塩化アンモニウム水溶液を加えた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（５．３７ｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．９９（ｄｄｄ，Ｊ＝２．４，４．８，１３．６Ｈｚ，１Ｈ），２．１２（ｍ，１Ｈ），４．２６（ｄｄｄ，Ｊ＝４．０，４．８，８．８Ｈｚ，１Ｈ），４．３５（ｄｔ，Ｊ＝２．８，１０．８Ｈｚ，１Ｈ），５．３１（ｄｄ，Ｊ＝１．６，１０．６Ｈｚ，１Ｈ），５．４７（ｄｄ，Ｊ＝１．６，１６．８Ｈｚ，１Ｈ），６．０１（ｄｄ，１０．６，１６．８Ｈｚ，１Ｈ），６．８５（ｄｄ，Ｊ＝１．２，８．４Ｈｚ，１Ｈ），６．９０（ｄｔ，Ｊ＝１．２，７．６Ｈｚ，１Ｈ），７．２０（ｄｄｄ，Ｊ＝１．６，７．６，８．４Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝１．６，７．６Ｈｚ，１Ｈ）． Production Example 2
Synthesis of 2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 1)
Figure JPOXMLDOC01-appb-C000011
 (1) Synthesis of 4-vinyl-chroman-4-ol (compound 2-2)
Zinc chloride (461 mg) was added to vinylmagnesium chloride (1.48 M tetrahydrofuran solution; 29.7 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was cooled to 0 ° C., a solution of compound 2-1 (5.00 g) in tetrahydrofuran (20.0 ml) was added dropwise. The reaction was stirred at the same temperature for 5 hours. After confirming disappearance of the raw materials, an aqueous ammonium chloride solution was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (5.37 g).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.99 (ddd, J = 2.4, 4.8, 13.6 Hz, 1H), 2.12 (m, 1H), 4.26 (Ddd, J = 4.0, 4.8, 8.8 Hz, 1H), 4.35 (dt, J = 2.8, 10.8 Hz, 1H), 5.31 (dd, J = 1.6 , 10.6 Hz, 1H), 5.47 (dd, J = 1.6, 16.8 Hz, 1H), 6.01 (dd, 10.6, 16.8 Hz, 1H), 6.85 (dd, J = 1.2, 8.4 Hz, 1H), 6.90 (dt, J = 1.2, 7.6 Hz, 1H), 7.20 (ddd, J = 1.6, 7.6, 8,. 4 Hz, 1 H), 7.28 (dd, J = 1.6, 7.6 Hz, 1 H).
（２）２－［２－クロマン－（４Ｅ）－イリデンエチル］－イソチオウレア（化合物２－３）の合成　
　化合物２－２（５．３０ｇ）の酢酸（２８．０ｍｌ）溶液に、チオウレア（２．７５ｇ）を加えた。室温で４時間撹拌した後、不溶物を綿栓濾過で除き、濾液をエーテル（２００ｍｌ）に滴下した。０度に冷却し、４時間撹拌した。さらに一晩静置して固体を熟成させた。グラスフィルターで生成した固体を除き、濾液の溶媒を減圧留去した。残渣の油状物質に酢酸エチルを加え、重曹水で中和した後、生じた白色固体をグラスフィルターで回収し、水で洗浄した。得られた固体を乾燥させることで標題化合物を得た（３．１０ｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ（ｐｐｍ）：２．７４（ｍ，２Ｈ），３．７４（ｍ，２Ｈ），４．１７（ｍ，２Ｈ），６．１８（ｍ，１Ｈ），６．８３（ｍ，１Ｈ），６．９０（ｍ，１Ｈ），７．１６（ｍ，１Ｈ），７．５９（ｍ，１Ｈ）． (2) Synthesis of 2- [2-chroman- (4E) -ylideneethyl] -isothiourea (compound 2-3)
To a solution of compound 2-2 (5.30 g) in acetic acid (28.0 ml), thiourea (2.75 g) was added. After stirring at room temperature for 4 hours, insolubles were removed by cotton plug filtration, and the filtrate was added dropwise to ether (200 ml). Cool to 0 degrees and stir for 4 hours. Further, the solid was aged by allowing to stand overnight. The solid produced by the glass filter was removed, and the solvent of the filtrate was distilled off under reduced pressure. Ethyl acetate was added to the residual oily substance and neutralized with aqueous sodium bicarbonate, and the resulting white solid was collected with a glass filter and washed with water. The obtained solid was dried to give the title compound (3.10 g).
1 H-NMR (400 MHz, DMSO-d 6 ) δ (ppm): 2.74 (m, 2H), 3.74 (m, 2H), 4.17 (m, 2H), 6.18 (m, 1H), 6.83 (m, 1H), 6.90 (m, 1H), 7.16 (m, 1H), 7.59 (m, 1H).
（３）化合物１の合成
　化合物２－３（１．００ｇ）のトリフルオロ酢酸（５．００ｍｌ）溶液に氷浴下、トリフルオロメタンスルホン酸（１．００ｍｌ）を滴下した。室温まで昇温し、２時間撹拌した。反応混合物を氷浴下、重曹水に滴下し、中和した。水層を酢酸エチルで抽出し、有機層を重曹水および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を減圧留去した。残渣をＮＨ－シリカゲルカラムクロマトグラフィーで精製し標題化合物を得た（３００ｍｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．９２（ｄｄｄ，Ｊ＝３．０，４．８，１４．０Ｈｚ，１Ｈ），１．９５（ｄｄｄ，Ｊ＝４．０，６．６，１４．０Ｈｚ，１Ｈ），２．０７（ｄｄｄ，Ｊ＝４．２，９．６，１４．０Ｈｚ，１Ｈ），２．２３（ｄｄｄ，Ｊ＝４．２，１０．８，１４．０Ｈｚ，１Ｈ），３．０４（ｄｄｄ，Ｊ＝４．２，６．６，１２．８Ｈｚ，１Ｈ），３．１１（ｄｄｄ，Ｊ＝４．０，９．６，１２．８Ｈｚ，１Ｈ），４．２４（ｄｄｄ，Ｊ＝３．０，１０．８，１１．６Ｈｚ，１Ｈ），４．３３（ｄｄｄ，Ｊ＝４．２，４．８，１１．６Ｈｚ，１Ｈ），６．８１（ｄｄ，Ｊ＝１．４，８．１Ｈｚ，１Ｈ），６．８９（ｄｔ，Ｊ＝１．４，７．２Ｈｚ，１Ｈ），７．１２（ｄｄｄ，Ｊ＝１．６，７．２，８．１Ｈｚ，１Ｈ），７．１５（ｄｄ，Ｊ＝１．６，７．６Ｈｚ，１Ｈ）． (3) Synthesis of Compound 1 To a solution of Compound 2-3 (1.00 g) in trifluoroacetic acid (5.00 ml) was added dropwise trifluoromethanesulfonic acid (1.00 ml) in an ice bath. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was neutralized by adding dropwise to an aqueous sodium bicarbonate solution in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (300 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.92 (ddd, J = 3.0, 4.8, 14.0 Hz, 1H), 1.95 (ddd, J = 4.0, 6.6, 14.0 Hz, 1H), 2.07 (ddd, J = 4.2, 9.6, 14.0 Hz, 1H), 2.23 (ddd, J = 4.2, 10.8, 14.0 Hz, 1H), 3.04 (ddd, J = 4.2, 6.6, 12.8 Hz, 1H), 3.11 (ddd, J = 4.0, 9.6, 12.8 Hz, 1H), 4.24 (ddd, J = 3.0, 10.8, 11.6 Hz, 1H), 4.33 (ddd, J = 4.2, 4.8, 11.6 Hz, 1H), 6 .81 (dd, J = 1.4, 8.1 Hz, 1H), 6.89 (dt, J = 1.4, 7.2 Hz, 1H), 7.12 (ddd, J = 1.6, .2,8.1Hz, 1H), 7.15 (dd, J = 1.6,7.6Hz, 1H).
製造例３
Ｎ－（２´―アミノ（６－ニトロ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）トリフルオロアセトアミド（化合物２）の合成
Figure JPOXMLDOC01-appb-C000012
 （１）２，２，２－トリフルオロ－Ｎ－（４－オキソクロマン－６－イル）アセタミド（化合物３－３）の合成
　化合物３－１（１．０ｇ）をアセトン（５０ｍｌ）に溶解した。二塩化スズ－２水和物（３．６６ｇ）を加え、終夜加熱還流した。反応の完結を確認した後、反応混合物を室温まで冷却した。溶媒を減圧下留去した後、反応混合物に重曹水を加え、塩化メチレンにて抽出した。水槽を酢酸エチルにて再度抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製した。得られた生成物（４６４ｍｇ）を、塩化メチレン（１４ｍｌ）に溶解し、氷浴下においてトリエチルアミン（０．５７ｍｌ）と無水トリフルオロ酢酸（０．５７ｍｌ）を加え、同温度で２０分間撹拌した。トリエチルアミン（０．５９５ｍｌ）を加え、さらに氷浴下４０分間撹拌した。原料の消失を確認したら反応混合物に塩化アンモニウム水溶液を加え反応停止させた。水層を塩化メチレンで抽出した。水槽をさらに酢酸エチルで抽出し、併せた有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去時に生じた淡黄色固体を桐山ロートで回収し、粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（６４４ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）（ｐｐｍ）：２．８２（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），４．５５（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），７．１１（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．７９（ｄｄ，Ｊ＝９．０，２．８Ｈｚ，１Ｈ），８．１０（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），１１．３０（ｓ，１Ｈ） Production Example 3
N- (2′-amino (6-nitro-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) trifluoroacetamide (compound 2 ) Synthesis
Figure JPOXMLDOC01-appb-C000012
 (1) Synthesis of 2,2,2-trifluoro-N- (4-oxochroman-6-yl) acetamide (Compound 3-3) Compound 3-1 (1.0 g) was dissolved in acetone (50 ml). Tin dichloride dihydrate (3.66 g) was added, and the mixture was heated to reflux overnight. After confirming the completion of the reaction, the reaction mixture was cooled to room temperature. After the solvent was distilled off under reduced pressure, sodium bicarbonate water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The water bath was extracted again with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained product (464 mg) was dissolved in methylene chloride (14 ml), triethylamine (0.57 ml) and trifluoroacetic anhydride (0.57 ml) were added in an ice bath, and the mixture was stirred at the same temperature for 20 minutes. Triethylamine (0.595 ml) was added, and the mixture was further stirred for 40 minutes in an ice bath. When the disappearance of the raw materials was confirmed, an aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction. The aqueous layer was extracted with methylene chloride. The water bath was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The pale yellow solid produced when the solvent was distilled off under reduced pressure was recovered with a Kiriyama funnel, and the crude product was purified by silica gel column chromatography to obtain the title compound (644 mg).
1H NMR (400 MHz, DMSO-d6) (ppm): 2.82 (t, J = 6.5 Hz, 2H), 4.55 (t, J = 6.5 Hz, 2H), 7.11 (d, J = 9.0 Hz, 1H), 7.79 (dd, J = 9.0, 2.8 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H), 11.30 (s, 1H)
（２）Ｎ－｛４－［２－カルバミミドイルスルファニル－エチ－（Ｅ）－リデン］－クロマン－６－イル｝２，２，２－トリフルオロアセトアミド（化合物３－５）の合成
　化合物３－３（１５０ｍｇ）のテトラヒドロフラン（１０．０ｍｌ）を－７８度に冷却し、ビニルマグネシウムクロライド（１．６Ｍテトラヒドロフラン溶液；１．０９ｍｌ）を滴下した。同温で１時間撹拌後、室温にて５時間撹拌した。原料の消失を確認後、反応混合物に塩化アンモニウム水溶液を加え反応停止させた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物３－４（１７８ｍｇ）は精製することなく、次反応に用いた。
　化合物３－４（１７８ｍｇ）の酢酸（２．０ｍｌ）溶液に、チオウレア（６６ｍｇ）を加えた。５０度で５時間撹拌した後、室温にて終夜撹拌した。溶媒を減圧留去した後に、残渣の油状物質に酢酸エチルを加え、重曹水で中和した。水層を酢酸エチルで抽出し、有機層を重曹水および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を減圧留去した。残渣に酢酸エチルとジエチルエーテルを加え、生じた淡黄色固体を桐山ロートで回収し、酢酸エチルとジエチルエーテル混合溶媒にて洗浄した。得られた固体を乾燥させることで標題化合物を得た（２６ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）（ｐｐｍ）：２．７４（ｍ，２Ｈ），４．１１（ｄ，Ｊ＝７．７Ｈｚ，２Ｈ），４．１８（ｍ，　，２Ｈ），６．０７（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．４５（ｄｄ，Ｊ＝２．４，８．８Ｈｚ，１Ｈ），７．９２（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ） (2) Synthesis of N- {4- [2-carbamimidoylsulfanyl-eth- (E) -lidene] -chroman-6-yl} 2,2,2-trifluoroacetamide (Compound 3-5) Compound 3 -3 (150 mg) of tetrahydrofuran (10.0 ml) was cooled to -78 degrees, and vinylmagnesium chloride (1.6 M tetrahydrofuran solution; 1.09 ml) was added dropwise. After stirring at the same temperature for 1 hour, the mixture was stirred at room temperature for 5 hours. After confirming disappearance of the raw materials, an aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product 3-4 (178 mg) was used in the next reaction without purification.
To a solution of compound 3-4 (178 mg) in acetic acid (2.0 ml) was added thiourea (66 mg). After stirring at 50 degrees for 5 hours, the mixture was stirred overnight at room temperature. After the solvent was distilled off under reduced pressure, ethyl acetate was added to the residual oily substance and neutralized with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate and diethyl ether were added to the residue, and the resulting pale yellow solid was collected with a Kiriyama funnel and washed with a mixed solvent of ethyl acetate and diethyl ether. The obtained solid was dried to give the title compound (26 mg).
1 H NMR (400 MHz, DMSO-d 6 ) (ppm): 2.74 (m, 2H), 4.11 (d, J = 7.7 Hz, 2H), 4.18 (m,, 2H), 6 .07 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 2.4, 8.8 Hz, 1H), 7. 92 (d, J = 2.4 Hz, 1H)
（３）化合物２の合成
　化合物（３－５）（２５．０ｍｇ）のトリフルオロ酢酸（０．４５９ｍｌ）溶液に、氷浴下トリフルオロメタンスルホン酸（０．０４５９ｍｌ）を加えた。同温度にて１．５時間撹拌した後、室温にて１．５時間撹拌した。原料の消失を確認した後、反応混合物を、氷浴にて冷却した重曹水に加え中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗生成物を塩化メチレン溶液から結晶化することで標題化合物を得た（６．６ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．０７－２．１４（ｍ，１Ｈ），２．２６（ｄｄｄ，Ｊ＝３．９，７．９，１４．４Ｈｚ，１Ｈ），２．４２－２．５３（ｍ，２Ｈ），３．１４－３．２９（ｍ，２Ｈ），４．２３－４．３２（ｍ，１Ｈ），４．３４－４．４６（ｍ，１Ｈ），６．８７（ｄ，Ｊ＝８．９Ｈｚ，１Ｈ），７．３５（ｄ，Ｊ＝２．６Ｈｚ，１Ｈ），７．５３（ｄｄ，Ｊ＝８．９，２．６Ｈｚ，１Ｈ）． (3) Synthesis of Compound 2 To a solution of compound (3-5) (25.0 mg) in trifluoroacetic acid (0.459 ml) was added trifluoromethanesulfonic acid (0.0459 ml) in an ice bath. After stirring at the same temperature for 1.5 hours, the mixture was stirred at room temperature for 1.5 hours. After confirming disappearance of the raw materials, the reaction mixture was neutralized by adding it to an aqueous sodium bicarbonate solution cooled in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from a methylene chloride solution to give the title compound (6.6 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 2.07-2.14 (m, 1H), 2.26 (ddd, J = 3.9, 7.9, 14.4 Hz, 1H), 2. 42-2.53 (m, 2H), 3.14-3.29 (m, 2H), 4.23-4.32 (m, 1H), 4.34-4.46 (m, 1H), 6.87 (d, J = 8.9 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.53 (dd, J = 8.9, 2.6 Hz, 1H).
製造例４
８－フルオロ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－２´－アミン（化合物３）の合成
Figure JPOXMLDOC01-appb-C000013
 （１）（８－フルオロクロマン－４－イリデン）酢酸エチル（化合物４－２）の合成
　ドライアイス－アセトン浴にて－７８度に冷却した、ジシクロヘキシルアミン（５４５．７ｍｇ）のテトラヒドロフラン（１３．０ｍｌ）溶液に、Ｎ－ブチルリチウム－ヘキサン溶液（１．６Ｎ、１．８８ｍｌ）を加えた。同温度にて１０分間撹拌した後に、エチル（トリメチルシリル）アセテート（４８２．３ｍｇ）のテトラヒドロフラン（２．５ｍｌ）溶液を加えた。－７８度にて１０分間撹拌した後に、化合物４－１（２５０．０ｍｇ）のテトラヒドロフラン（２．５ｍｌ）溶液を加えた。－７８度にて１時間撹拌した後、室温戻しさらに３時間撹拌した。原料の消失を確認した後、反応混合物を、飽和食塩水に加えた。水層を酢酸エチルで抽出、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（１６２ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：１．２９（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），２．６７（ｔｄ，Ｊ＝１．３，５．９Ｈｚ，２Ｈ），４．２２（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．４４－４．４９（ｍ，２Ｈ），５．７６（ｓ，１Ｈ），６．７８（ｔｄ，Ｊ＝５．１，８．１Ｈｚ，１Ｈ），７．０６（ｄｄｄ，Ｊ＝１．５，８．１，１０．９Ｈｚ，１Ｈ），７．５７（ｄｔ，Ｊ＝１．５，８．１Ｈｚ，１Ｈ）． Production Example 4
Synthesis of 8-fluoro-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 3)
Figure JPOXMLDOC01-appb-C000013
 (1) Synthesis of ethyl (8-fluorochroman-4-ylidene) acetate (Compound 4-2) Dicyclohexylamine (545.7 mg) in tetrahydrofuran (13.0 ml) cooled to -78 degrees in a dry ice-acetone bath ) To the solution was added N-butyllithium-hexane solution (1.6N, 1.88 ml). After stirring at the same temperature for 10 minutes, a solution of ethyl (trimethylsilyl) acetate (482.3 mg) in tetrahydrofuran (2.5 ml) was added. After stirring at −78 ° C. for 10 minutes, a solution of compound 4-1 (250.0 mg) in tetrahydrofuran (2.5 ml) was added. After stirring at −78 ° C. for 1 hour, the mixture was returned to room temperature and further stirred for 3 hours. After confirming disappearance of the raw materials, the reaction mixture was added to saturated brine. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (162 mg).
1 H NMR (400 MHz, CDCl 3 ) (ppm): 1.29 (t, J = 7.1 Hz, 3H), 2.67 (td, J = 1.3, 5.9 Hz, 2H), 4.22 (Q, J = 7.1 Hz, 2H), 4.44-4.49 (m, 2H), 5.76 (s, 1H), 6.78 (td, J = 5.1, 8.1 Hz, 1H), 7.06 (ddd, J = 1.5, 8.1, 10.9 Hz, 1H), 7.57 (dt, J = 1.5, 8.1 Hz, 1H).
（２）（８－フルオロクロマン－４－イリデン）エタノール（化合物４－３）の合成
　窒素雰囲気下、氷浴にて冷却した水素化リチウムアルミニウム（５２．１ｍｇ）のジエチルエーテル（８．０ｍｌ）溶液に、化合物４－２（１６２ｍｇ）のジエチルエーテル（４．０ｍｌ）溶液を２分間かけて滴下した。同温度にて２時間撹拌した後、反応混合物に酢酸エチルゆっくりと滴下した。次に、水を加え１時間撹拌した。水層を酢酸エチルで抽出し、有機層を重曹水、続いて飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物は精製することなく、次反応に用いた。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．６１－２．６５（ｍ，２Ｈ），４．４３（ｂｒｔ，Ｊ＝５．２Ｈｚ，２Ｈ），４．５２（ｄ，Ｊ＝６．４Ｈｚ，２Ｈ），５．６５（ｔ，Ｊ＝６．４Ｈｚ，１Ｈ），６．７８－６．８５（ｍ，１Ｈ），６．９４（ｂｒｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．０２（ｂｒｔ，Ｊ＝９．５Ｈｚ，１Ｈ）． (2) Synthesis of (8-fluorochroman-4-ylidene) ethanol (Compound 4-3) Lithium aluminum hydride (52.1 mg) in diethyl ether (8.0 ml) cooled in an ice bath under a nitrogen atmosphere A solution of compound 4-2 (162 mg) in diethyl ether (4.0 ml) was added dropwise over 2 minutes. After stirring at the same temperature for 2 hours, ethyl acetate was slowly added dropwise to the reaction mixture. Next, water was added and stirred for 1 hour. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium bicarbonate followed by saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was used for the next reaction without purification.
1H NMR (400 MHz, CDCl 3 ) (ppm): 2.61-2.65 (m, 2H), 4.43 (brt, J = 5.2 Hz, 2H), 4.52 (d, J = 6. 4 Hz, 2H), 5.65 (t, J = 6.4 Hz, 1H), 6.78-6.85 (m, 1H), 6.94 (brd, J = 7.6 Hz, 1H), 7. 02 (brt, J = 9.5 Hz, 1H).
（３）化合物３の合成
　化合物４－３（１９．６ｍｇ）の４８％臭化水素（２．０ｍｌ）溶液に、室温にてチオウレア（７．７ｍｇ）を加え、５０度にて２時間撹拌した。原料の消失を確認した後、反応混合物を、氷浴にて冷却した重曹水に加え中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残渣をトリフルオロ酢酸（０．４９ｍｌ）に溶解した後に、氷浴下トリフルオロメタンスルホン酸（０．１ｍｌ）を加えた。同温度にて１．５時間撹拌した後、室温にて１．５時間撹拌した。原料の消失を確認した後、反応混合物を、氷浴にて冷却した重曹水に加え中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＮＨ－シリカゲルカラムクロマトグラフィーで精製し標題化合物を得た（５８．５ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：１．９３－２．０１（ｍ，２Ｈ），２．０５－２．１４（ｍ，１Ｈ），２．２８（ｄｄｄ，Ｊ＝４．２，１０．５，１４．２Ｈｚ，１Ｈ），３．０２－３．０９（ｍ，１Ｈ），３．０９－３．１７（ｍ，１Ｈ），４．３２（ｔｄ，Ｊ＝２．９，１１．０Ｈｚ，１Ｈ），４．４５（ｔｄ，Ｊ＝４．５，１１．０Ｈｚ，１Ｈ），６．７９－６．８６（ｍ，１Ｈ），６．９２－６．９９（ｍ，２Ｈ）． (3) Synthesis of Compound 3 To a 48% hydrogen bromide (2.0 ml) solution of compound 4-3 (19.6 mg) was added thiourea (7.7 mg) at room temperature, and the mixture was stirred at 50 degrees for 2 hours. . After confirming disappearance of the raw materials, the reaction mixture was neutralized by adding it to an aqueous sodium bicarbonate solution cooled in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (0.49 ml), and trifluoromethanesulfonic acid (0.1 ml) was added in an ice bath. After stirring at the same temperature for 1.5 hours, the mixture was stirred at room temperature for 1.5 hours. After confirming disappearance of the raw materials, the reaction mixture was neutralized by adding it to an aqueous sodium bicarbonate solution cooled in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (58.5 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 1.93-2.01 (m, 2H), 2.05-2.14 (m, 1H), 2.28 (ddd, J = 4.2) 10.5, 14.2 Hz, 1H), 3.02-3.09 (m, 1H), 3.09-3.17 (m, 1H), 4.32 (td, J = 2.9, 11 0.0 Hz, 1H), 4.45 (td, J = 4.5, 11.0 Hz, 1H), 6.79-6.86 (m, 1H), 6.92-6.99 (m, 2H) .
製造例５
Ｎ－｛４－［７－フルオロクロマン－（４Ｅ）－イリデン］エチル｝イソチオウレア（化合物５－３）の合成
Figure JPOXMLDOC01-appb-C000014
 （１）４－クロロ－７－フルオロ－４－ビニルクロマン（化合物５－２）の合成
　氷浴にて冷却された、実施例４に準じて７－フルオロクロマン－４－オンから合成した化合物５－１（２００ｍｇ）のテトラヒドロフラン（３．０ｍｌ）溶液に、トリエチルアミン（０．１９ｍｌ）を加えた。同温度にて、メタンスルホニルクロリド（１７７ｍｇ）のテトラヒドロフラン（２．０ｍｌ）溶液を滴下し、１．５時間撹拌した。原料の消失を確認したら反応混合物を重曹水に加え反応停止させた。水層を酢酸エチルで抽出した。水槽をさらに酢酸エチルで抽出し、併せた有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた標題化合物（２１４ｍｇ）は粗生成物のまま、次反応に用いた。 Production Example 5
Synthesis of N- {4- [7-fluorochroman- (4E) -ylidene] ethyl} isothiourea (Compound 5-3)
Figure JPOXMLDOC01-appb-C000014
 (1) 4-chloro-7-fluoro-4-Binirukuroman cooled by (Compound 5-2) Synthesis ice bath, the compound was synthesized from 7-fluoro-4-one according to Example 4 5 -1 (200 mg) in tetrahydrofuran (3.0 ml) was added triethylamine (0.19 ml). At the same temperature, a solution of methanesulfonyl chloride (177 mg) in tetrahydrofuran (2.0 ml) was added dropwise and stirred for 1.5 hours. When the disappearance of the raw materials was confirmed, the reaction mixture was added to sodium bicarbonate water to stop the reaction. The aqueous layer was extracted with ethyl acetate. The water bath was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The title compound (214 mg) obtained by distilling off the solvent under reduced pressure was used in the next reaction as the crude product.
（２）２－｛２－［７－フルオロクロマン－（４Ｅ）－イリデン］エチル｝－イソチオウレア（化合物５－３）の合成
　（２－１）化合物５－２（２１４ｍｇ）をエタノール（６．０ｍｌ）に溶解した。チオウレア（１５３ｍｇ）を加えて、１０時間加熱還流した。原料の消失を確認したら、溶媒を減圧留去した。残渣をＬＣＭＳで精製し、標題化合物を得た（３３ｍｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．７４（ｍ，２Ｈ），４．０５（ｄ，Ｊ＝７．９Ｈｚ，２Ｈ），４．２０（ｔ，Ｊ＝５．８Ｈｚ，２Ｈ），６．１３（ｔ，Ｊ＝７．９Ｈｚ，１Ｈ），６．７２（ｄｄ，Ｊ＝２．７，１０．３Ｈｚ，１Ｈ），６．７８（ｄｄｄ，Ｊ＝２．７，８．６，９．０Ｈｚ，１Ｈ），７．６７（ｄｄ，Ｊ＝６．７，８．９Ｈｚ，１Ｈ）． (2) Synthesis of 2- {2- [7-fluorochroman- (4E) -ylidene] ethyl} -isothiourea (Compound 5-3) (2-1) Compound 5-2 (214 mg) was added to ethanol (6. 0 ml). Thiourea (153 mg) was added and the mixture was heated to reflux for 10 hours. When the disappearance of the raw materials was confirmed, the solvent was distilled off under reduced pressure. The residue was purified by LCMS to give the title compound (33 mg).
1 H-NMR (400 MHz, CDCl 3 ) (ppm): 2.74 (m, 2H), 4.05 (d, J = 7.9 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.13 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 2.7, 10.3 Hz, 1H), 6.78 (ddd, J = 2.7, 8 .6, 9.0 Hz, 1 H), 7.67 (dd, J = 6.7, 8.9 Hz, 1 H).
　（２－２）別法として、化合物５－３は以下に示す方法でも合成することができる。
Figure JPOXMLDOC01-appb-C000015
 （３）２－（７－フルオロクロマン－４－イリデン）エチル－２，２，２－トリフルオロアセテート（化合物５－４）の合成
　氷浴にて冷却された、化合物５－１（１．０ｇ）のテトラヒドロフラン（２０ｍｌ）溶液に、トリエチルアミン（１．１５ｍｌ）を加えた。無水トリフルオロ酢酸（１．６２ｇ）のテトラヒドロフラン（２．５ｍｌ）溶液を滴下し、同温度にて１時間撹拌した。原料の消失を確認したら反応混合物を重曹水に加え反応停止させた。水層を酢酸エチルで抽出した。水槽をさらに酢酸エチルで抽出し、併せた有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた標題化合物（１．４２ｇ）は精製せずに次反応に用いた。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．６４（ｍ，２Ｈ），４．３６（ｍ，２Ｈ），５．１５（ｄ，Ｊ＝７．１Ｈｚ，２Ｈ），５．５５（ｔ，Ｊ＝７．１Ｈｚ，１Ｈ），５．６０（ｄｄ，Ｊ＝２，７，１０．１Ｈｚ，１Ｈ），６．６６（ｄｄｄ，Ｊ＝２．６，８．３，８．７Ｈｚ，１Ｈ），７．０８（ｄｄ，Ｊ＝６．４，８．７Ｈｚ，１Ｈ）． (2-2) Alternatively, compound 5-3 can also be synthesized by the method shown below.
Figure JPOXMLDOC01-appb-C000015
 (3) Synthesis of 2- (7-fluorochroman-4-ylidene) ethyl-2,2,2-trifluoroacetate (Compound 5-4) Compound 5-1 (1.0 g ) cooled in an ice bath ) In tetrahydrofuran (20 ml) was added triethylamine (1.15 ml). A solution of trifluoroacetic anhydride (1.62 g) in tetrahydrofuran (2.5 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. When the disappearance of the raw materials was confirmed, the reaction mixture was added to sodium bicarbonate water to stop the reaction. The aqueous layer was extracted with ethyl acetate. The water bath was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate. The title compound (1.42 g) obtained by distilling off the solvent under reduced pressure was used in the next reaction without purification.
1 H-NMR (400 MHz, CDCl 3 ) (ppm): 2.64 (m, 2H), 4.36 (m, 2H), 5.15 (d, J = 7.1 Hz, 2H), 5.55 (T, J = 7.1 Hz, 1H), 5.60 (dd, J = 2, 7, 10.1 Hz, 1H), 6.66 (ddd, J = 2.6, 8.3, 8.7 Hz) , 1H), 7.08 (dd, J = 6.4, 8.7 Hz, 1H).
（４）化合物５－３の合成
　化合物５－４（１．４１ｇ）をエタノール（２０ｍｌ）に溶解した。チオウレア（０．９２ｇ）を加えて、１時間加熱還流した。原料の消失を確認したら、溶媒を減圧留去した。残渣をＬＣＭＳで精製し、化合物５－３を化合物５－５との混合物（９：１）として得た（０．９６ｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．７４（ｍ，２Ｈ），４．０５（ｄ，Ｊ＝７．９Ｈｚ，２Ｈ），４．２０（ｔ，Ｊ＝５．８Ｈｚ，２Ｈ），６．１３（ｔ，Ｊ＝７．９Ｈｚ，１Ｈ），６．７２（ｄｄ，Ｊ＝２．７，１０．３Ｈｚ，１Ｈ），６．７８（ｄｄｄ，Ｊ＝２．７，８．６，９．０Ｈｚ，１Ｈ），７．６７（ｄｄ，Ｊ＝６．７，８．９Ｈｚ，１Ｈ）． (4) Synthesis of Compound 5-3 Compound 5-4 (1.41 g) was dissolved in ethanol (20 ml). Thiourea (0.92 g) was added and heated to reflux for 1 hour. When the disappearance of the raw materials was confirmed, the solvent was distilled off under reduced pressure. The residue was purified by LCMS to give compound 5-3 as a mixture (9: 1) with compound 5-5 (0.96 g).
1 H-NMR (400 MHz, CDCl 3 ) (ppm): 2.74 (m, 2H), 4.05 (d, J = 7.9 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.13 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 2.7, 10.3 Hz, 1H), 6.78 (ddd, J = 2.7, 8 .6, 9.0 Hz, 1 H), 7.67 (dd, J = 6.7, 8.9 Hz, 1 H).
　製造例２から４に記載の方法と同様にして表２に記載の化合物を合成した。表２に構造式及び１Ｈ－ＮＭＲデータを示す。 The compounds listed in Table 2 were synthesized in the same manner as described in Production Examples 2 to 4. Table 2 shows the structural formula and 1H-NMR data.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
実施例１
（±）－Ｎ－［２’－アミノ－２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］チアジン］－６－イル］－５－クロロピリジン－２－カルボキサミド（化合物８）の合成
Figure JPOXMLDOC01-appb-C000017
 （１－１）６－ニトロ－２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］チアジン］－２’－アミン（化合物６－２）
　化合物１（２８０ｍｇ）の無水酢酸（１０．０ｍｌ）溶液に氷浴下、発煙硝酸（比重１．５３、４９．５μｌ）を滴下した。反応液を同温で１時間撹拌した後、室温まで昇温し３時間撹拌した。反応液に無水酢酸（１０．０ｍｌ）を追加した後、発煙硝酸（比重１．５３、４００μｌ）を加えた。反応の完結を確認した後、反応液をエーテルで希釈し重曹水を加えて１時間撹拌した。水層を酢酸エチルで抽出し、有機層を重曹水および飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し化合物６－１を８－ニトロ体との混合物として得た（３６０ｍｇ）。
　得られたニトロ体の混合物（３３０ｍｇ）にエタノール（１０．０ｍｌ）および濃硫酸（３３０μｌ）を加え、８時間加熱還流した。反応の完結を確認した後、反応混合物を室温まで冷却した。反応混合物に重曹水を加えて中和し、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をＮＨ－シリカゲルカラムクロマトグラフィーで精製し、標題化合物を得た（８２．０ｍｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：２．０２（ｍ，３Ｈ），２．２２（ｍ，１Ｈ），３．０５（ｍ，１Ｈ），３．１５（ｍ，１Ｈ），４．３２（ｍ，１Ｈ），４．４５（ｍ，１Ｈ），６．８９（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），８．０３（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），８．１３（ｓ，１Ｈ）． Example 1
(±) -N- [2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl] -5-chloropyridine- Synthesis of 2-carboxamide (Compound 8)
Figure JPOXMLDOC01-appb-C000017
 (1-1) 6-nitro -2,3,5 ', 6'-tetrahydrospiro [chromene-4,4' - [1,3] thiazin] -2'-amine (Compound 6-2)
Fuming nitric acid (specific gravity 1.53, 49.5 μl) was added dropwise to a solution of compound 1 (280 mg) in acetic anhydride (10.0 ml) in an ice bath. The reaction was stirred at the same temperature for 1 hour, then warmed to room temperature and stirred for 3 hours. Acetic anhydride (10.0 ml) was added to the reaction solution, and fuming nitric acid (specific gravity 1.53, 400 μl) was added. After confirming completion of the reaction, the reaction solution was diluted with ether, aqueous sodium bicarbonate was added, and the mixture was stirred for 1 hour. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 6-1 as a mixture with the 8-nitro compound (360 mg).
Ethanol (10.0 ml) and concentrated sulfuric acid (330 μl) were added to the resulting mixture of nitro compounds (330 mg), and the mixture was heated to reflux for 8 hours. After confirming the completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was neutralized with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (82.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 2.02 (m, 3H), 2.22 (m, 1H), 3.05 (m, 1H), 3.15 (m, 1H) , 4.32 (m, 1H), 4.45 (m, 1H), 6.89 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 8 .13 (s, 1H).
（１－２）別法として、化合物６－１は以下の方法によっても合成することができる。
　化合物１（１．１ｇ）のピリジン（６ｍｌ）溶液に、室温で無水酢酸（０．８８６ｍｌ）を加え、混合物を室温で１２時間攪拌した。反応液を氷－重曹水に注ぎ、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥させた。乾燥剤を濾去し、ろ液を減圧下濃縮した。得られた粗生成物をＮＨ－シリカゲルカラムクロマトグラフィーで精製し化合物１のＮ－アセチル体（N－（２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－２´－イル）アセトアミド）（１．１ｇ）を得た。
　上記のように得られるＮ－アセチル体（１．３ｇ）の酢酸（０．２ｍｌ）溶液に室温で、硝酸（比重１．４２、１．０ｍｌ）を加えた。混合物を５０℃で３０分攪拌した。この溶液に５０℃で硝酸（３．０ｍｌ）を加え、混合物を５０℃で３０分攪拌した。さらに５０℃で硝酸（２．０ｍｌ）を加え、５０℃で３０分攪拌した。反応液を氷－重曹水にゆっくり加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥させた。乾燥剤を濾去し、ろ液を減圧下濃縮した。粗生成物をＮＨ－シリカゲルカラムクロマトグラフィーで精製し、化合物６－１（０．９３ｇ）を８－ニトロ体との混合物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：２．００－２．４０（ｍ、４Ｈ），２．０３（ｓ，３Ｈ，８－異性体），２．０６（ｓ，３Ｈ，６－異性体），２．９５－３．１０（ｍ，２Ｈ），４．１３－４．６０（ｍ，２Ｈ），６．９０－６．９５（ｍ，１Ｈ，６－異性体），６．９９（ｔ，Ｊ＝８．０Ｈｚ，１Ｈ，８－異性体），７．３６（ｄｄ，Ｊ＝１．６，８．０Ｈｚ，１Ｈ，８－異性体），７．７４（ｄｄ，Ｊ＝１．６，８．０Ｈｚ，１Ｈ，８－異性体），８．０３－８．１０（ｍ，２Ｈ，６－異性体）． (1-2) Alternatively, compound 6-1 can also be synthesized by the following method.
To a solution of compound 1 (1.1 g) in pyridine (6 ml) was added acetic anhydride (0.886 ml) at room temperature, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-sodium bicarbonate water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by NH-silica gel column chromatography, and the N-acetyl form of compound 1 (N- (2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1, 3] thiazin] -2′-yl) acetamide) (1.1 g).
Nitric acid (specific gravity 1.42, 1.0 ml) was added to an acetic acid (0.2 ml) solution of the N-acetyl compound (1.3 g) obtained as described above at room temperature. The mixture was stirred at 50 ° C. for 30 minutes. Nitric acid (3.0 ml) was added to this solution at 50 ° C., and the mixture was stirred at 50 ° C. for 30 minutes. Furthermore, nitric acid (2.0 ml) was added at 50 ° C., and the mixture was stirred at 50 ° C. for 30 minutes. The reaction mixture was slowly added to ice-sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain compound 6-1 (0.93 g) as a mixture with the 8-nitro form.
1 H-NMR (CDCl 3 ) δ: 2.00-2.40 (m, 4H), 2.03 (s, 3H, 8-isomer), 2.06 (s, 3H, 6-isomer) 2.95-3.10 (m, 2H), 4.13-4.60 (m, 2H), 6.90-6.95 (m, 1H, 6-isomer), 6.99 (t , J = 8.0 Hz, 1H, 8-isomer), 7.36 (dd, J = 1.6, 8.0 Hz, 1H, 8-isomer), 7.74 (dd, J = 1.6). , 8.0 Hz, 1H, 8-isomer), 8.03-8.10 (m, 2H, 6-isomer).
（２）（６－ニトロ－２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］チアジン］－２’－イル）カルバミン酸ｔ－ブチルエステル（化合物６－３）
　化合物６－２（８２．０ｍｇ）をテトラヒドロフラン（５．００ｍｌ）に溶解し、トリエチルアミン（６３１μｌ）を加えた。次いで反応液に二炭酸ジ－ｔ－ブチル（１９２ｍｇ）を加え、室温で４日間撹拌した。反応の完結を確認したら反応液を減圧留去し、残渣をＮＨ－シリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（１１０ｍｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．４８（ｓ，９Ｈ），２．００－２．３０（ｍ，４Ｈ），３．０２（ｍ，１Ｈ），３．１４（ｍ，１Ｈ），４．３９（ｍ，２Ｈ），６．９３（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），８．０８（ｄｄ，Ｊ＝２．８，９．２Ｈｚ，１Ｈ），８．１４（ｍ，１Ｈ）． (2) (6-Nitro-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -2′-yl) carbamic acid t-butyl ester (Compound 6) -3)
Compound 6-2 (82.0 mg) was dissolved in tetrahydrofuran (5.00 ml), and triethylamine (631 μl) was added. Next, di-t-butyl dicarbonate (192 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. When the completion of the reaction was confirmed, the reaction solution was distilled off under reduced pressure, and the residue was purified by NH-silica gel column chromatography to obtain the title compound (110 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.48 (s, 9H), 2.00-2.30 (m, 4H), 3.02 (m, 1H), 3.14 ( m, 1H), 4.39 (m, 2H), 6.93 (d, J = 9.2 Hz, 1H), 8.08 (dd, J = 2.8, 9.2 Hz, 1H), 8. 14 (m, 1H).
（３－１）（±）－（６－アミノ－２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］チアジン］－２’－イル）カルバミン酸ｔ－ブチルエステル（化合物６－４）
　化合物６－３（１１０ｍｇ）をエタノール（２０．０ｍｌ）に溶解し、亜二チオン酸ナトリウム（２５３ｍｇ）の水溶液を室温で滴下した。反応液に、更に亜二チオン酸ナトリウム（２５３ｍｇ）の水溶液を加えて室温で撹拌した。さらにＮ，Ｎ－ジメチルホルムアミド（２０．０ｍｌ）を加えた。反応の完結を確認した後、余剰のエタノールを減圧留去した。残渣に水を加え、水層を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去し、残渣をＮＨ－シリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（１０．０ｍｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．４６（ｓ，９Ｈ），２．０５（ｍ，１Ｈ），２．１５（ｄｄｄ，Ｊ＝４．０，６．４，１４．０Ｈｚ，１Ｈ），２．２６（ｍ，１Ｈ），２．３８（ｄｄｄ，Ｊ＝４．０，１０．０，１４．０Ｈｚ，１Ｈ）、３．１０（ｍ，２Ｈ），４．２０（ｍ，２Ｈ），６．５９（ｍ，２Ｈ），６．６８（ｍ，１Ｈ）． (3-1) (±)-(6-Amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -2′-yl) carbamic acid t -Butyl ester (compound 6-4)
Compound 6-3 (110 mg) was dissolved in ethanol (20.0 ml), and an aqueous solution of sodium dithionite (253 mg) was added dropwise at room temperature. An aqueous solution of sodium dithionite (253 mg) was further added to the reaction solution, and the mixture was stirred at room temperature. Further N, N-dimethylformamide (20.0 ml) was added. After confirming completion of the reaction, excess ethanol was distilled off under reduced pressure. Water was added to the residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by NH-silica gel column chromatography to obtain the title compound (10.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.46 (s, 9H), 2.05 (m, 1H), 2.15 (ddd, J = 4.0, 6.4, 14 .0Hz, 1H), 2.26 (m, 1H), 2.38 (ddd, J = 4.0, 10.0, 14.0Hz, 1H), 3.10 (m, 2H), 4.20 (M, 2H), 6.59 (m, 2H), 6.68 (m, 1H).
（３－２）別法として、化合物６－４は以下の方法によっても合成できる。
　化合物６－３（５１０ｍｇ）のエタノール（１８ｍｌ）－塩化アンモニウム水溶液（１．８ｍｌ）に、鉄（１．０５ｇ）を加え、８７℃で０．５時間加熱攪拌した。反応液を室温に戻し、反応液を酢酸エチルに注ぎ、不溶物をろ去した。濾液を減圧下濃縮した。残渣に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮し、標記化合物（０．４０ｇ）を得た。。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．４６（ｓ，９Ｈ），２．０５（ｍ，１Ｈ），２．１５（ｄｄｄ，Ｊ＝４．０，６．４，１４．０Ｈｚ，１Ｈ），２．２６（ｍ，１Ｈ），２．３８（ｄｄｄ，Ｊ＝４．０，１０．０，１４．０Ｈｚ，１Ｈ）、３．１０（ｍ，２Ｈ），４．２０（ｍ，２Ｈ），６．５９（ｍ，２Ｈ），６．６８（ｍ，１Ｈ）． (3-2) As an alternative method, compound 6-4 can also be synthesized by the following method.
Iron (1.05 g) was added to compound 6-3 (510 mg) in ethanol (18 ml) -ammonium chloride aqueous solution (1.8 ml), and the mixture was stirred with heating at 87 ° C. for 0.5 hr. The reaction solution was returned to room temperature, poured into ethyl acetate, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.40 g). .
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.46 (s, 9H), 2.05 (m, 1H), 2.15 (ddd, J = 4.0, 6.4, 14 .0Hz, 1H), 2.26 (m, 1H), 2.38 (ddd, J = 4.0, 10.0, 14.0Hz, 1H), 3.10 (m, 2H), 4.20 (M, 2H), 6.59 (m, 2H), 6.68 (m, 1H).
（４）化合物８の合成
　５－クロロピリジン－２－カルボン酸（５．８６ｍｇ）にトルエン（３．００ｍｌ）を加えて懸濁させた。Ｎ，Ｎ－ジメチルホルムアミドを一滴加えた後、塩化チオニル（１．００ｍｌ）を加えた。反応混合物を１２０℃まで加温し、同温で１時間撹拌した。室温まで冷却した後、溶媒を減圧留去することで５－クロロピリジン－２－カルボン酸クロライドを得た。得られた酸クロライドをテトラヒドロフラン（１．００ｍｌ）に懸濁させ、化合物６－４（１０．０ｍｇ）のテトラヒドロフラン（２．００ｍｌ）溶液に、氷浴下滴下した。同温でピリジン（１１．３μｌ）を滴下した後、室温まで昇温し３０分間撹拌した。反応の完結を確認した後、重曹水を加えて反応を停止させた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥させ、溶媒を減圧留去した。得られた残渣をジクロロメタン（２．００ｍｌ）に溶解し、トリフルオロ酢酸（０．４０ｍｌ）を加えて室温で３時間撹拌した。反応の完結を確認した後、ジエチルエーテルで希釈し、重曹水を加えて反応を停止させた。水層を酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去し、残渣をＮＨ－シリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（７．８ｍｇ）。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．９５（ｄｄｄ，Ｊ＝２．８，５．２，１４．０Ｈｚ，１Ｈ），２．０２（ｄｄｄ，Ｊ＝４．４，６．２，１４．０Ｈｚ，１Ｈ），２．１１（ｄｄｄ，Ｊ＝４．４，９．６，１４．０Ｈｚ，１Ｈ），２．２４（ｄｄｄ，Ｊ＝４．０，１０．０，１４．０Ｈｚ，１Ｈ），３．０８－３．２０（ｍ，２Ｈ），４．２４（ｄｔ，Ｊ＝２．８，１１．２Ｈｚ，１Ｈ），４．３４（ｄｔ，Ｊ＝４．８，１０．８Ｈｚ，１Ｈ），６．８５（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５０（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．５７（ｄｄ，Ｊ＝２．４，８．８Ｈｚ，１Ｈ），７．８６（ｄｄ，Ｊ＝２．０，８．４Ｈｚ，１Ｈ），８．２４（ｄｄ，Ｊ＝０．８，８．４Ｈｚ，１Ｈ），８．５５（ｄｄ，Ｊ＝０．８，２．０Ｈｚ，１Ｈ），９．７０（ｓ，１Ｈ）． (4) Synthesis of Compound 8 Toluene (3.00 ml) was added to 5-chloropyridine-2-carboxylic acid (5.86 mg) and suspended. A drop of N, N-dimethylformamide was added followed by thionyl chloride (1.00 ml). The reaction mixture was warmed to 120 ° C. and stirred at the same temperature for 1 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure to obtain 5-chloropyridine-2-carboxylic acid chloride. The obtained acid chloride was suspended in tetrahydrofuran (1.00 ml) and added dropwise to a solution of compound 6-4 (10.0 mg) in tetrahydrofuran (2.00 ml) in an ice bath. After dropwise addition of pyridine (11.3 μl) at the same temperature, the mixture was warmed to room temperature and stirred for 30 minutes. After confirming the completion of the reaction, sodium bicarbonate water was added to stop the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (2.00 ml), trifluoroacetic acid (0.40 ml) was added, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction, the reaction was diluted with diethyl ether and quenched with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by NH-silica gel column chromatography to obtain the title compound (7.8 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.95 (ddd, J = 2.8, 5.2, 14.0 Hz, 1H), 2.02 (ddd, J = 4.4) 6.2, 14.0 Hz, 1H), 2.11 (ddd, J = 4.4, 9.6, 14.0 Hz, 1H), 2.24 (ddd, J = 4.0, 10.0, 14.0 Hz, 1H), 3.08-3.20 (m, 2H), 4.24 (dt, J = 2.8, 11.2 Hz, 1H), 4.34 (dt, J = 4.8) , 10.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 2.4). 8.8 Hz, 1H), 7.86 (dd, J = 2.0, 8.4 Hz, 1H), 8.24 (dd, J = 0.8, 8.4 Hz, 1H), 8.55 (dd , = 0.8,2.0Hz, 1H), 9.70 (s, 1H).
実施例２
（－）－Ｎ－［２’－アミノ－２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］チアジン］－６－イル］－５－クロロピリジン－２－カルボキサミド　（化合物９）の合成
Figure JPOXMLDOC01-appb-C000018
 　化合物８（６ｍｇ）をダイセル製ＣＨＩＲＡＬＰＡＫＴＭ　ＯＤ－Ｈ（２ｃｍ×２５ｃｍ，移動相；ヘキサン：エタノール＝８：２，流速：２０ｍｌ／分）で分取した。保持時間２２．５分から２５．０分の成分を回収した後、ＮＨ－シリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（２．０ｍｇ；＞９９％ｅｅ）。
ＥＳＩ－ＭＳ；ｍ／ｚ３８９［Ｍ＋　＋Ｈ］．１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．９５（ｄｄｄ，Ｊ＝２．８，５．２，１４．０Ｈｚ，１Ｈ），２．０２（ｄｄｄ，Ｊ＝４．４，６．２，１４．０Ｈｚ，１Ｈ），２．１１（ｄｄｄ，Ｊ＝４．４，９．６，１４．０Ｈｚ，１Ｈ），２．２４（ｄｄｄ，Ｊ＝４．０，１０．０，１４．０Ｈｚ，１Ｈ），３．０８－３．２０（ｍ，２Ｈ），４．２４（ｄｔ，Ｊ＝２．８，１１．２Ｈｚ，１Ｈ），４．３４（ｄｔ，Ｊ＝４．８，１０．８Ｈｚ，１Ｈ），６．８５（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５０（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．５７（ｄｄ，Ｊ＝２．４，８．８Ｈｚ，１Ｈ），７．８６（ｄｄ，Ｊ＝２．０，８．４Ｈｚ，１Ｈ），８．２４（ｄｄ，Ｊ＝０．８，８．４Ｈｚ，１Ｈ），８．５５（ｄｄ，Ｊ＝０．８，２．０Ｈｚ，１Ｈ），９．７０（ｓ，１Ｈ）． Example 2
(−) — N- [2′-Amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl] -5-chloropyridine— Synthesis of 2-carboxamide (Compound 9)
Figure JPOXMLDOC01-appb-C000018
 Compound 8 (6 mg) was fractionated with CHIRALPAK ™ OD-H (2 cm × 25 cm, mobile phase; hexane: ethanol = 8: 2, flow rate: 20 ml / min) manufactured by Daicel. After collecting the components having a retention time of 22.5 to 25.0 minutes, the title compound was obtained by purification by NH-silica gel column chromatography (2.0 mg;> 99% ee).
ESI-MS; m / z 389 [M + + H]. 1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.95 (ddd, J = 2.8, 5.2, 14.0 Hz, 1H), 2.02 (ddd, J = 4.4) 6.2, 14.0 Hz, 1H), 2.11 (ddd, J = 4.4, 9.6, 14.0 Hz, 1H), 2.24 (ddd, J = 4.0, 10.0, 14.0 Hz, 1H), 3.08-3.20 (m, 2H), 4.24 (dt, J = 2.8, 11.2 Hz, 1H), 4.34 (dt, J = 4.8) , 10.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 2.4). 8.8 Hz, 1H), 7.86 (dd, J = 2.0, 8.4 Hz, 1H), 8.24 (dd, J = 0.8, 8.4 Hz, 1H), 8.55 (dd , = 0.8,2.0Hz, 1H), 9.70 (s, 1H).
実施例３
（－）－（６－アミノ－２，３，５’，６’－テトラヒドロスピロ［クロメン－４，４’－［１，３］チアジン］－２’－イル）カルバミン酸ｔ－ブチル（化合物１０）の合成
Figure JPOXMLDOC01-appb-C000019
 　実施例１の（３）で得られた化合物６－４（０．５７ｇ）をダイセル製ＣＨＩＲＡＬＰＡＫＴＭ　ＯＪ－Ｈ（２ｃｍ×２５ｃｍ，移動相；ヘキサン：エタノール＝６：４，流速：１０ｍｌ／分）で分取した。保持時間２８－３４分の成分を集め、標題化合物（０．２２ｇ，９７％ｅｅ）を得た。 Example 3
(−)-(6-Amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -2′-yl) carbamate t-butyl (compound 10 )
Figure JPOXMLDOC01-appb-C000019
 Compound 6-4 (0.57 g) obtained in (3) of Example 1 was added to Daicel CHIRALPAK ™ OJ-H (2 cm × 25 cm, mobile phase; hexane: ethanol = 6: 4, flow rate: 10 ml / min) Sorted by The components with a retention time of 28-34 minutes were collected to give the title compound (0.22 g, 97% ee).
実施例４
（－）－Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－５－シアノピリジン－２－カルボキサミド（化合物１１）の合成
Figure JPOXMLDOC01-appb-C000020
 （１）メチル　５－シアノピリジン－２－カルボキシラート（化合物９－２）の合成
　化合物９－１（２．８ｇ）とシアン化銅（３．６ｇ）のＮＭＰ（３０ｍｌ）混合液を１７０度で１．５時間加熱攪拌した。反応液に室温で、水を加え、不溶物を濾過で除いた。濾液を酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製し標題化合物（９２０ｍｇ）を得た。
　１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：４．０６（ｓ，３Ｈ），８．１６（ｄｄ，Ｊ＝２．０，８．０Ｈｚ，１Ｈ），８．２７（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），９．０１（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ）． Example 4
(-)-N- (2'-amino-2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazin] -6-yl) -5-cyanopyridine- Synthesis of 2-carboxamide (compound 11)
Figure JPOXMLDOC01-appb-C000020
 (1) Synthesis of methyl 5-cyanopyridine-2-carboxylate (compound 9-2) NMP (30 ml) of compound 9-1 (2.8 g) and copper cyanide (3.6 g) was mixed at 170 ° C. The mixture was heated and stirred for 1.5 hours. Water was added to the reaction solution at room temperature, and insoluble materials were removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (920 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 4.06 (s, 3H), 8.16 (dd, J = 2.0, 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H).
（２）５－シアノピリジン－２－カルボン酸（化合物９－３）の合成
　化合物９－２（９２０ｍｇ）と５Ｎ水酸化ナトリウム水溶液（２．２６ｍｌ）のエタノール（３０ｍｌ）溶液を室温で１０分間攪拌した。反応液に室温で、５Ｎ塩酸（５．２ｍｌ）を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮し標題化合物（８００ｍｇ）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯｄ６）δ（ｐｐｍ）：８．１８（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），８．５１（ｄｄ，Ｊ＝２．０，８．０Ｈｚ，１Ｈ），９．１２－９．１８（ｍ，１Ｈ）． (2) Synthesis of 5-cyanopyridine-2-carboxylic acid (Compound 9-3) Compound 9-2 (920 mg) and 5N aqueous sodium hydroxide solution (2.26 ml) in ethanol (30 ml) were stirred at room temperature for 10 minutes. did. 5N Hydrochloric acid (5.2 ml) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (800 mg).
1 H-NMR (400 MHz, DMSOd 6 ) δ (ppm): 8.18 (d, J = 8.0 Hz, 1H), 8.51 (dd, J = 2.0, 8.0 Hz, 1H), 9 .12-9.18 (m, 1H).
（３）｛６－［（５－シアノピリジン－２－カルボニル）アミノ］－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－２´－イル｝カルバミン酸ｔｅｒｔ－ブチルエステル（化合物９－４）の合成
　実施例３で得た化合物１０（２５．０ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．０６２４ｍｌ）、５－シアノピリジン－２－カルボン酸（化合物９－３）（１６．９ｍｇ）のジクロロメタン（５．０ｍｌ）溶液に、ＰｙＢＯＰ（７４．５ｍｇ）を室温で加えた。混合物を室温で１時間攪拌した。反応液を重曹水に注ぎ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（３５ｍｇ）を得た。
ＥＳＩ－ＭＳ；ｍ／ｚ４８０［Ｍ＋＋Ｈ］． (3) {6-[(5-Cyanopyridine-2-carbonyl) amino] -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2 ′ Synthesis of —yl} carbamic acid tert-butyl ester (Compound 9-4) Compound 10 (25.0 mg) obtained in Example 3, N, N-diisopropylethylamine (0.0624 ml), 5-cyanopyridine-2- To a solution of carboxylic acid (Compound 9-3) (16.9 mg) in dichloromethane (5.0 ml) was added PyBOP (74.5 mg) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (35 mg).
ESI-MS; m / z 480 [M + + H].
（４）化合物１１の合成
　化合物９－４（３５ｍｇ）のジクロロメタン（３．０ｍｌ）溶液に、トリフルオロ酢酸（１．０ｍｌ）を加え、反応液を室温で１．５時間撹拌した。反応液を重曹水に注ぎ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮した。粗生成物をＮＨ－シリカゲルカラムクロマトグラフィーで精製し、標題化合物（２６．１ｍｇ）を得た。
ＥＳＩ－ＭＳ；ｍ／ｚ３８０［Ｍ＋＋Ｈ］．
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．９０－２．１５（ｍ，３Ｈ），２．２４（ｄｄｄ，Ｊ＝４．０，１０．４，１４．０Ｈｚ，１Ｈ），３．０５－３．２（ｍ，２Ｈ），４．２５（ｄｔ，Ｊ＝３．２，１０．８Ｈｚ，１Ｈ），４．３５（ｄｔ，Ｊ＝４．８，１０．８Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５０（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），７．５８（ｄｄ，Ｊ＝２．８，８．８Ｈｚ，１Ｈ），８．１９（ｄｄ，Ｊ＝２．０，８．０Ｈｚ，１Ｈ），８．４２（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），８．８８（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），９．７４（ｓ，１Ｈ）． (4) Synthesis of Compound 11 To a solution of Compound 9-4 (35 mg) in dichloromethane (3.0 ml) was added trifluoroacetic acid (1.0 ml), and the reaction solution was stirred at room temperature for 1.5 hours. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (26.1 mg).
ESI-MS; m / z 380 [M + + H].
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.90-2.15 (m, 3H), 2.24 (ddd, J = 4.0, 10.4, 14.0 Hz, 1H) , 3.05-3.2 (m, 2H), 4.25 (dt, J = 3.2, 10.8 Hz, 1H), 4.35 (dt, J = 4.8, 10.8 Hz, 1H) ), 6.86 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.58 (dd, J = 2.8, 8.8 Hz, 1H) , 8.19 (dd, J = 2.0, 8.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H), 9.74 (s, 1H).
実施例５
Ｎ－（２´－アミノ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－６－イル）－５－トリフルロメチルピリジン－２－カルボキサミド（化合物１２）の合成
Figure JPOXMLDOC01-appb-C000021
 （１）｛６－［（５－トリフルオロメチルピリジン－２－カルボニル）アミノ］－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－２´－イル｝カルバミン酸ｔｅｒｔ－ブチル（化合物１０－１）の合成
　化合物１０（２０．０ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．０４９９ｍｌ）、５－トリフルオロメチルピリジン－２－カルボン酸（１３．５ｍｇ）のジクロロメタン（３．０ｍｌ）溶液に、ＰｙＢＯＰ（５９．６ｍｇ）を室温で加えた。混合物を室温で１時間攪拌した。反応液を重曹水に注ぎ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮した。粗生成物をシリカゲルカラムクロマトグラフィーで精製し、標題化合物（３０ｍｇ）を得た。
ＥＳＩ－ＭＳ；ｍ／ｚ５２３［Ｍ＋＋Ｈ］． Example 5
N- (2′-amino-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -6-yl) -5-trifluoromethylpyridine-2- Synthesis of carboxamide (compound 12)
Figure JPOXMLDOC01-appb-C000021
 (1) {6-[(5-Trifluoromethylpyridine-2-carbonyl) amino] -2,3,5 ', 6'-tetrahydrospiro [chromene-4,4'-[1,3] thiazine]- Synthesis of tert-butyl 2′-yl} carbamate (Compound 10-1) Compound 10 (20.0 mg), N, N-diisopropylethylamine (0.0499 ml), 5-trifluoromethylpyridine-2-carboxylic acid ( PyBOP (59.6 mg) was added to a solution of 13.5 mg) in dichloromethane (3.0 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (30 mg).
ESI-MS; m / z 523 [M + + H].
（２）化合物１２の合成
　化合物１０－１（３０ｍｇ）のジクロロメタン（３．０ｍｌ）溶液に、トリフルオロ酢酸（０．８５７ｍｌ）を加え、反応液を室温で１．５時間撹拌した。反応液を重曹水に注ぎ、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾去し、ろ液を減圧下濃縮した。粗生成物をＮＨ－シリカゲルカラムクロマトグラフィーで精製し、標題化合物（１３．０ｍｇ）を得た。
ＥＳＩ－ＭＳ；ｍ／ｚ４２３［Ｍ＋＋Ｈ］．
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ（ｐｐｍ）：１．９０－２．１６（ｍ，３Ｈ），２．２４（ｄｄｄ，Ｊ＝４．４，１０．４，１４．０Ｈｚ，１Ｈ），３．０６－３．２２（ｍ，２Ｈ），４．２５（ｄｔ，Ｊ＝２．８，１１．２Ｈｚ，１Ｈ），４．３５（ｄｔ，Ｊ＝４．８，１１．２Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．５８（ｄｄ，Ｊ＝２．４，８．８Ｈｚ，１Ｈ），８．１５（ｄｄ，Ｊ＝１．６，８．０Ｈｚ，１Ｈ），８．４２（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），８．８７（ｓ，１Ｈ），９．８０（ｓ，１Ｈ）． (2) Synthesis of Compound 12 To a solution of Compound 10-1 (30 mg) in dichloromethane (3.0 ml) was added trifluoroacetic acid (0.857 ml), and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (13.0 mg).
ESI-MS; m / z 423 [M + + H].
1 H-NMR (400 MHz, CDCl 3 ) δ (ppm): 1.90-2.16 (m, 3H), 2.24 (ddd, J = 4.4, 10.4, 14.0 Hz, 1H) 3.06-3.22 (m, 2H), 4.25 (dt, J = 2.8, 11.2 Hz, 1H), 4.35 (dt, J = 4.8, 11.2 Hz, 1H) ), 6.86 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.58 (dd, J = 2.4, 8.8 Hz, 1H) , 8.15 (dd, J = 1.6, 8.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.87 (s, 1H), 9.80 (s, 1H).
　実施例５と同様にして表３に記載の化合物を合成した。表３に構造式及び１Ｈ－ＮＭＲデータを示す。 In the same manner as in Example 5, the compounds listed in Table 3 were synthesized. Table 3 shows the structural formula and 1H-NMR data.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
実施例６
６－（５－メトキシピリジン－３－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［1、3］チアジン］－２’－アミン（化合物２１）の合成
Figure JPOXMLDOC01-appb-C000023
 （１）６－ブロモ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－２´－アミン（化合物２０）の合成
　化合物１（５６０ｍｇ）の酢酸（１２．０ｍｌ）溶液に、室温にて臭素（３８２ｍｇ）を加えて３０分間撹拌した。原料の消失を確認した後、反応混合物を氷浴にて冷却した１０％水酸化ナトリウム水溶液に加え中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（５８０ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：１．９３（ｄｄｄ，Ｊ＝３．０，５．０，１４．１Ｈｚ，１Ｈ），２．００－２．０５（ｍ，２Ｈ），２．２２（ｄｄｄ，Ｊ＝４．１，１０．３，１４．１Ｈｚ，１Ｈ），３．０２－３．０９（ｍ，１Ｈ），３．１０－３．１８（ｍ，１Ｈ），４．１８－４．２５（ｍ，１Ｈ），４．３３（ｄｄｄ，Ｊ＝４．４，４．７，１１．３Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２０－７．２４（ｍ，１Ｈ），７．２５（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）． Example 6
Of 6- (5-methoxypyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 21) Composition
Figure JPOXMLDOC01-appb-C000023
 (1) Synthesis of 6-bromo-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (Compound 20) Compound 1 (560 mg) Bromine (382 mg) was added to an acetic acid (12.0 ml) solution at room temperature and stirred for 30 minutes. After confirming disappearance of the raw materials, the reaction mixture was neutralized by adding to a 10% aqueous sodium hydroxide solution cooled in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (580 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 1.93 (ddd, J = 3.0, 5.0, 14.1 Hz, 1H), 2.00-2.05 (m, 2H), 2. 22 (ddd, J = 4.1, 10.3, 14.1 Hz, 1H), 3.02-3.09 (m, 1H), 3.10-3.18 (m, 1H), 4.18 -4.25 (m, 1H), 4.33 (ddd, J = 4.4, 4.7, 11.3 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 7. 20-7.24 (m, 1H), 7.25 (d, J = 2.4 Hz, 1H).
（２）ジ－ｔｅｒｔ－ブチル（６－ブロモ－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［1、3］チアジン］－２’－イル）イミダゾジカルボネート（化合物１１－１）、およびｔｅｒｔ－ブチル（６－ブロモ－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［1、3］チアジン］－２’－イル）カルボネート（化合物１１－２）の合成
　化合物２０（１３９mg) を塩化メチレン（１５ｍｌ）に溶解し、二炭酸ジ－ｔ－ブチル（３８７ｍｇ）を加えた。次いでＮ，Ｎ－ジメチルアミノピリジン（２１７ｍｇ）を加え、室温で３．５時間間撹拌した。原料の消失を確認した後、反応混合物を飽和塩化アンモニウム水溶液に加えた。水層を塩化メチレンで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製することで化合物１１－１と１１－２を得た［（１１－１）１４４ｍｇ、（１１－２）５２．３ｍｇ］。
化合物１１－１の１Ｈ　ＮＭＲ（４００ＭＨｚ，ＭＥＴＨＡＮＯＬ－ｄ４）（ｐｐｍ）：１．５９（ｓ，１８Ｈ），１．８７－１．９８（ｍ，２Ｈ），２．０６－２．１７（ｍ，２Ｈ），２．３７（ｔｄ，Ｊ＝４．０，１４．６Ｈｚ，１Ｈ），３．２１（ｔｄ，Ｊ＝４．２，１２．９Ｈｚ，１Ｈ），３．４５（ｄｔ，Ｊ＝３．６，１２．９Ｈｚ，１Ｈ），４．２８－４．３７（ｍ，１Ｈ），６．８０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．２６（ｄｄ，Ｊ＝２．４，８．７Ｈｚ，１Ｈ）．
化合物１１－２の１Ｈ　ＮＭＲ（４００ＭＨｚ，ＭＥＴＨＡＮＯＬ－ｄ４）（ｐｐｍ）：１．６０（ｓ，９Ｈ），２．０３－２．１２（ｍ，１Ｈ），２．１８－２．２９（ｍ，１Ｈ），３．１６－３．２３（ｍ，１Ｈ），３．３６－３．４３（ｍ，１Ｈ），４．３１－４．３７（ｍ，２Ｈ），６．８０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２６（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．３２（ｄｄ，Ｊ＝２．４，８．７Ｈｚ，１Ｈ）． (2) Di-tert-butyl (6-bromo-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -2′-yl) imidazodicarbonate ( Compound 11-1), and tert-butyl (6-bromo-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazin] -2′-yl) carbonate ( Synthesis of Compound 11-2) Compound 20 (139 mg) was dissolved in methylene chloride (15 ml), and di-t-butyl dicarbonate (387 mg) was added. Next, N, N-dimethylaminopyridine (217 mg) was added, and the mixture was stirred at room temperature for 3.5 hours. After confirming disappearance of the raw materials, the reaction mixture was added to a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compounds 11-1 and 11-2 [(11-1) 144 mg, (11-2) 52.3 mg].
1H NMR (400 MHz, METHANOL-d4) (ppm) of Compound 11-1: 1.59 (s, 18H), 1.87-1.98 (m, 2H), 2.06-2.17 (m, 2H), 2.37 (td, J = 4.0, 14.6 Hz, 1H), 3.21 (td, J = 4.2, 12.9 Hz, 1H), 3.45 (dt, J = 3 .6, 12.9 Hz, 1H), 4.28-4.37 (m, 1H), 6.80 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 2.4, 8.7 Hz, 1H).
1H NMR (400 MHz, METHANOL-d4) (ppm) of Compound 11-2: 1.60 (s, 9H), 2.03-2.12 (m, 1H), 2.18-2.29 (m, 1H), 3.16-3.23 (m, 1H), 3.36-3.43 (m, 1H), 4.31-4.37 (m, 2H), 6.80 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 2.4, 8.7 Hz, 1H).
（３）化合物２１の合成
　化合物１１－１（２５ｍｇ）のＮ，Ｎ－ジメチルホルムアルデヒド（２ｍｌ）溶液に、３－メトキシ－５－（４、４、５、５－テトラメチル－１、３、２－ジオキサボロラン－２－イル）ピリジン（１４．９ｍｇ）を加えた。続いて１Ｍ重曹水溶液（０．１２ｍｌ）と、パラジウム－トリフェニルホスフィン（２．８ｍｇ）を加え、窒素雰囲気下、１００度で１２時間撹拌した。原料の消失を確認した後、反応混合物に水を加えた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（８．６ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．１１－２．２６（ｍ，２Ｈ），２．３７－２．５３（ｍ，２Ｈ），３．１３－３．２９（ｍ，２Ｈ），３．９２（ｓ，３Ｈ），４．２７－４．３６（ｍ，１Ｈ），４．４０－４．４７（ｍ，１Ｈ），６．９３－６．９８（ｍ，１Ｈ），７．３６－７．４４（ｍ，３Ｈ），８．２３（ｂｒ．ｓ．，１Ｈ），８．３７（ｂｒ．ｓ．，１Ｈ）． (3) Synthesis of Compound 21 To a solution of compound 11-1 (25 mg) in N, N-dimethylformaldehyde (2 ml), 3-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2 -Dioxaborolan-2-yl) pyridine (14.9 mg) was added. Subsequently, 1M aqueous sodium bicarbonate solution (0.12 ml) and palladium-triphenylphosphine (2.8 mg) were added, and the mixture was stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. After confirming disappearance of the raw materials, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (8.6 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 2.11-2.26 (m, 2H), 2.37-2.53 (m, 2H), 3.13-3.29 (m, 2H) , 3.92 (s, 3H), 4.27-4.36 (m, 1H), 4.40-4.47 (m, 1H), 6.93-6.98 (m, 1H), 7 36-7.44 (m, 3H), 8.23 (br.s., 1H), 8.37 (br.s., 1H).
　実施例６の（３）と同様にして表４に記載の化合物を合成した。表４に構造式及び１Ｈ－ＮＭＲデータを示す。 The compounds listed in Table 4 were synthesized in the same manner as in Example 6 (3). Table 4 shows the structural formula and 1H-NMR data.
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
実施例７
６－（２－フルオロピリジン－３－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［1、3］チアジン］－２’－アミン（化合物２４）の合成
Figure JPOXMLDOC01-appb-C000025
 　化合物１１－２（２６．３ｍｇ）のＮ，Ｎ－ジメチルホルムアルデヒド（０．９５ｍｌ）溶液に、２－フルオロピリジン－３－ボロン酸（１４．９ｍｇ）を加えた。続いて１Ｍ重曹水溶液（０．１４ｍｌ）と、パラジウム－トリフェニルホスフィン（７．８ｍｇ）を加え、窒素雰囲気下、１００度で１２時間撹拌した。原料の消失を確認した後、反応混合物に水を加えた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（１３．０ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．０４－２．１８（ｍ，２Ｈ），２．２９－２．３７（ｍ，１Ｈ），２．４６（ｄｄｄ，Ｊ＝４．０，１０．７，１４．４Ｈｚ，１Ｈ），３．１８－３．２４（ｍ，２Ｈ），４．３１（ｄｔ，Ｊ＝２．８，１１．４Ｈｚ，１Ｈ），４．４４－４．４７（ｍ，１Ｈ），６．９５（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２４－７．２６（ｍ，１Ｈ），７．３６－７．４２（ｍ，２Ｈ），７．８８（ｄｄｄ，Ｊ＝１．７，７．６，９．９Ｈｚ，１Ｈ），８．１５（ｄｔ，Ｊ＝１．７，４．６Ｈｚ、１Ｈ）． Example 7
Of 6- (2-fluoropyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 24) Composition
Figure JPOXMLDOC01-appb-C000025
 2-Fluoropyridine-3-boronic acid (14.9 mg) was added to a solution of compound 11-2 (26.3 mg) in N, N-dimethylformaldehyde (0.95 ml). Subsequently, 1M aqueous sodium bicarbonate solution (0.14 ml) and palladium-triphenylphosphine (7.8 mg) were added, and the mixture was stirred at 100 ° C. for 12 hours under a nitrogen atmosphere. After confirming disappearance of the raw materials, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (13.0 mg).
1 H NMR (400 MHz, CDCl 3 ) (ppm): 2.04-2.18 (m, 2H), 2.29-2.37 (m, 1H), 2.46 (ddd, J = 4.0) , 10.7, 14.4 Hz, 1H), 3.18-3.24 (m, 2H), 4.31 (dt, J = 2.8, 11.4 Hz, 1H), 4.44-4. 47 (m, 1H), 6.95 (d, J = 8.6 Hz, 1H), 7.24-7.26 (m, 1H), 7.36-7.42 (m, 2H), 7. 88 (ddd, J = 1.7, 7.6, 9.9 Hz, 1H), 8.15 (dt, J = 1.7, 4.6 Hz, 1H).
実施例８
７―フルオロ―６－（２－フルオロピリジン－３－イル）－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［1、3］チアジン］－２’－アミン（化合物２６）の合成
Figure JPOXMLDOC01-appb-C000026
 （１）６－ブロモ－７－フルオロ－２，３，５´，６´－テトラヒドロスピロ［クロメン－４，４´－［１，３］チアジン］－２´－アミン（化合物２５）の合成
　化合物６（２０ｍｇ）の酢酸（１．０ｍｌ）溶液に、室温にて臭素（１２．７ｍｇ）を加えて３０分間撹拌した。原料の消失を確認した後、反応混合物を重曹水に加え中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物２５（１４．４ｍｇ）は精製することなく、次の反応に用いた。
１Ｈ　ＮＭＲ　（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：１．８７－１．９９（ｍ，２Ｈ），１．９９－２．２８（ｍ，２Ｈ），２．９７－３．０８（ｍ，１Ｈ），３．０８－３．１７（ｍ，１Ｈ），４．１６－４．２８（ｍ，１Ｈ），４．３０－４．３９（ｍ，１Ｈ），６．６２（ｄ，Ｊ＝９．７Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）． Example 8
7-Fluoro-6- (2-fluoropyridin-3-yl) -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine ( Synthesis of compound 26)
Figure JPOXMLDOC01-appb-C000026
 (1) Synthesis compound of 6-bromo-7-fluoro-2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (Compound 25) Bromine (12.7 mg) was added to a solution of 6 (20 mg) in acetic acid (1.0 ml) at room temperature and stirred for 30 minutes. After confirming the disappearance of the raw materials, the reaction mixture was added to sodium bicarbonate water for neutralization. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product 25 (14.4 mg) was used in the next reaction without purification.
1H NMR (400 MHz, CDCl 3 ) (ppm): 1.87-1.99 (m, 2H), 1.99-2.28 (m, 2H), 2.97-3.08 (m, 1H) 3.08-3.17 (m, 1H), 4.16-4.28 (m, 1H), 4.30-4.39 (m, 1H), 6.62 (d, J = 9. 7 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H).
（２）化合物２６の合成
　化合物２５（１４．４mg) を塩化メチレン（３．０ｍｌ）に溶解し、二炭酸ジ－ｔ－ブチル（４７．５ｍｇ）を加えた。次いでＮ，Ｎ－ジメチルアミノピリジン（２６．５ｍｇ）を加え、室温で６時間間撹拌した。原料の消失を確認した後、反応混合物を飽和塩化アンモニウム水溶液に加えた。水層を塩化メチレンで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた粗生成物１３－１（１７ｍｇ）は精製することなく、次の反応に用いた。
上記反応で得られた粗生成物１３－１（１７ｍｇ）のＮ，Ｎ－ジメチルホルムアルデヒド（０．５ｍｌ）溶液に、２－フルオロピリジン－３－ボロン酸（７．２ｍｇ）を加えた。続いて１Ｍ重曹水溶液（０．０５ｍｌ）と、パラジウム－トリフェニルホスフィン（３．８ｍｇ）を加え、窒素雰囲気下、１００度で終夜撹拌した。原料の消失を確認した後、反応混合物に水を加えた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（１．７ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：２．００－２．１８（ｍ，２Ｈ），２．２６－２．５１（ｍ，２Ｈ），３．１４－３．２５（ｍ，２Ｈ），４．２７－４．３６（ｍ，１Ｈ），４．４２－４．４８（ｍ，１Ｈ），６．７０（ｄ，Ｊ＝１１．１Ｈｚ，１Ｈ），７．２２（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．２５－７．３４（ｍ，１Ｈ），７．８６－７．９２（ｍ，１Ｈ），８．２１（ｂｒｄ，Ｊ＝４．９Ｈｚ，１Ｈ）． (2) Synthesis of Compound 26 Compound 25 (14.4 mg) was dissolved in methylene chloride (3.0 ml), and di-t-butyl dicarbonate (47.5 mg) was added. Next, N, N-dimethylaminopyridine (26.5 mg) was added, and the mixture was stirred at room temperature for 6 hours. After confirming disappearance of the raw materials, the reaction mixture was added to a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product 13-1 (17 mg) was used in the next reaction without purification.
2-Fluoropyridine-3-boronic acid (7.2 mg) was added to a solution of the crude product 13-1 (17 mg) obtained in the above reaction in N, N-dimethylformaldehyde (0.5 ml). Subsequently, 1M aqueous sodium bicarbonate solution (0.05 ml) and palladium-triphenylphosphine (3.8 mg) were added, and the mixture was stirred overnight at 100 ° C. in a nitrogen atmosphere. After confirming disappearance of the raw materials, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (1.7 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 2.00-2.18 (m, 2H), 2.26-2.51 (m, 2H), 3.14-3.25 (m, 2H) , 4.27-4.36 (m, 1H), 4.42-4.48 (m, 1H), 6.70 (d, J = 11.1 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.25-7.34 (m, 1H), 7.86-7.92 (m, 1H), 8.21 (brd, J = 4.9 Hz, 1H).
実施例９
６－［（２－アミノピリジン－３－イル）エチニル］－２、３、５’、６’－テトラヒドロスピロ［クロメン－４、４‘－［1、3］チアジン］－２’－アミン（化合物２７）の合成
Figure JPOXMLDOC01-appb-C000027
 （１）３－［（トリメチルシリル）エチニル］ピリジン－２－アミン（化合物１４－２）の合成
　化合物１４－１（２００ｍｇ）をテトラヒドロフラン（１．２ｍｌ）とトリエチルアミン（７ｍｌ）の混合溶媒に溶解した。エチニル（トリメチル）シラン（２２７ｍｇ）、ヨウ化銅（Ｉ）（８．８ｍｇ）と、ジクロロパラジウム－トリフェニルホスフィン（３２．５ｍｇ）を加えて封管した。混合物を９０度にて２２時間撹拌した後に、反応混合物を水に加えて反応を停止した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（２４４ｍｇ）。
１Ｈ　ＮＭＲ　（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：０．２６（ｓ，９Ｈ），５．０８（ｂｒ．ｓ．，２Ｈ），６．６２（ｂｒ．ｓ．，１Ｈ），７．５４ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），８．０５（ｂｒ．ｓ．，１Ｈ）． Example 9
6-[(2-Aminopyridin-3-yl) ethynyl] -2,3,5 ′, 6′-tetrahydrospiro [chromene-4,4 ′-[1,3] thiazine] -2′-amine (compound 27) Synthesis
Figure JPOXMLDOC01-appb-C000027
 (1) Synthesis of 3-[(trimethylsilyl) ethynyl] pyridin-2-amine (Compound 14-2) Compound 14-1 (200 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.2 ml) and triethylamine (7 ml). Ethynyl (trimethyl) silane (227 mg), copper (I) iodide (8.8 mg) and dichloropalladium-triphenylphosphine (32.5 mg) were added and sealed. After the mixture was stirred at 90 degrees for 22 hours, the reaction was quenched by adding the reaction mixture to water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (244 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 0.26 (s, 9H), 5.08 (br.s., 2H), 6.62 (br.s., 1H), 7.54d, J = 7.2 Hz, 1H), 8.05 (br.s., 1H).
（２）３－エチニルピリジン－２－アミン（化合物１４－３）の合成
　化合物１４－２（２４４ｍｇ）をメタノール（１５．０ｍｌ）に溶解した。炭酸カリウム（２１２．６ｍｇ）を加え、室温にて２時間撹拌した。反応混合物を水に加えて、水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することで標題化合物を得た（９３．５ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：３．４２（ｓ，１Ｈ），５．０８（ｂｒ．ｓ．，２Ｈ），６．６３（ｄｄ，Ｊ＝５．２，７．４Ｈｚ，１Ｈ），７．５８（ｄｄ，Ｊ＝７．４，１．６Ｈｚ，１Ｈ），８．０８（ｂｒ．ｓ．，１Ｈ）． (2) Synthesis of 3-ethynylpyridin-2-amine (Compound 14-3) Compound 14-2 (244 mg) was dissolved in methanol (15.0 ml). Potassium carbonate (212.6 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was added to water, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (93.5 mg).
1H NMR (400 MHz, CDCl 3 ) (ppm): 3.42 (s, 1H), 5.08 (br.s., 2H), 6.63 (dd, J = 5.2, 7.4 Hz, 1H ), 7.58 (dd, J = 7.4, 1.6 Hz, 1H), 8.08 (br.s., 1H).
（３）化合物２７の合成
　化合物１４－３（３０ｍｇ）と実施例１１－１で得られた化合物２０（４０ｍｇ）をテトラヒドロフラン（２ｍｌ）とトリエチルアミン（２ｍｌ）の混合溶媒に溶解した。ヨウ化銅（Ｉ）（１．２ｍｇ）と、ジクロロパラジウム－トリフェニルホスフィン（４．５ｍｇ）を加えて封管し、９０度にて２２時間撹拌した。反応混合物を水に加えて反応を停止した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。得られた粗生成物をＮＨ－シリカゲルカラムクロマトグラフィーとＮＨ－シリカゲルＴＬＣで精製することで標題化合物を得た（１２．５ｍｇ）。
ＥＳＩ－ＭＳ；ｍ／ｚ　３５１［Ｍ＋＋Ｈ］
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：１．９２－２．１２（ｍ，３Ｈ），２．２５（ｄｄｄ，Ｊ＝４．０，１０．５，１４．２Ｈｚ，１Ｈ），３．０２－３．１０（ｍ，１Ｈ），３．１１－３．２０（ｍ，１Ｈ），４．２６（ｔｄ，Ｊ＝２．９，１１．２Ｈｚ，１Ｈ），４．３８（ｄｔ，Ｊ＝４．６，１１．２Ｈｚ，１Ｈ），５．０５（ｂｒ．ｓ．，２Ｈ），６．６３（ｄｄ，Ｊ＝５．０，７．５Ｈｚ，１Ｈ），６．８１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．２９（ｄｄ，Ｊ＝２．０，８．４Ｈｚ，１Ｈ），７．３４（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．５７（ｄｄ、Ｊ＝１．６，７．５Ｈｚ，１Ｈ），７．９７８．０５（ｍ，１Ｈ）． (3) Synthesis of Compound 27 Compound 14-3 (30 mg) and Compound 20 (40 mg) obtained in Example 11-1 were dissolved in a mixed solvent of tetrahydrofuran (2 ml) and triethylamine (2 ml). Copper (I) iodide (1.2 mg) and dichloropalladium-triphenylphosphine (4.5 mg) were added and sealed, and the mixture was stirred at 90 degrees for 22 hours. The reaction mixture was added to water to stop the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by NH-silica gel column chromatography and NH-silica gel TLC to obtain the title compound (12.5 mg).
ESI-MS; m / z 351 [M + + H]
1H NMR (400 MHz, CDCl 3 ) (ppm): 1.92-2.12 (m, 3H), 2.25 (ddd, J = 4.0, 10.5, 14.2 Hz, 1H), 3. 02-3.10 (m, 1H), 3.11-3.20 (m, 1H), 4.26 (td, J = 2.9, 11.2 Hz, 1H), 4.38 (dt, J = 4.6, 11.2 Hz, 1H), 5.05 (br.s., 2H), 6.63 (dd, J = 5.0, 7.5 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 2.0, 8.4 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 1.6, 7.5 Hz, 1H), 7.978.05 (m, 1H).
実施例１０
２，３，５´，６´－テトラヒドロスピロ［１，３－チアジン－４，４´－チオクロメン］－２－アミン（化合物２８）の合成
Figure JPOXMLDOC01-appb-C000028
 （１）（２Ｅ）－２－（２，３－ジヒドロ－４Ｈ－チオクロメン－４－イリデン）エチル　カルバミミドチオエート（化合物１５－３）の合成
　ビニルマグネシウムクロライド（１．６Ｍテトラヒドロフラン溶液；２．７５ｍｌ）に塩化亜鉛（４６．１ｍｇ）を加え室温で１時間撹拌した。混合物を０度に冷却し、化合物１５－１（５５５ｍｇ）のテトラヒドロフラン（２．０ｍｌ）を滴下した。同温で５時間撹拌した。原料の消失を確認したら反応混合物に塩化アンモニウム水溶液を加え反応停止させた。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して粗生成物を得た（６６５ｍｇ）。この粗生成物を酢酸（５．０ｍｌ）に溶解した後に、チオウレア（３３４ｍｇ）を加えた。室温で終夜撹拌した後、不溶物を綿栓濾過で除き、濾液をジエチルエーテルに滴下した。０度に冷却し撹拌した。グラスフィルターで固体を除き、濾液の溶媒を減圧留去した。残渣の油状物質に酢酸エチルを加え、重曹水で中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去している間に、固体が生じた。濃縮を止めて、ヘキサン・ジエチルエーテル混合溶媒を加え、生じた固体を桐山ロートで回収し、ジエチルエーテルで洗浄した。得られた固体を乾燥させることで標題化合物を得た（６６．５ｍｇ）。
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＭｅＯＤ）（ｐｐｍ）：２．９６－３．０１（ｍ，２Ｈ），３．０５－３．１０（ｍ，２Ｈ），４．０８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），６．０９（ｔ，Ｊ＝８．０Ｈｚ，１Ｈ），７．０７７．２０（ｍ，３Ｈ），７．５０（ｄｄ，Ｊ＝１．３，７．９Ｈｚ，１Ｈ）． Example 10
Synthesis of 2,3,5 ′, 6′-tetrahydrospiro [1,3-thiazine-4,4′-thiochromene] -2-amine (Compound 28)
Figure JPOXMLDOC01-appb-C000028
 (1) Synthesis of (2E) -2- (2,3-dihydro-4H-thiochromene-4-ylidene) ethyl carbamimidothioate (Compound 15-3) Vinylmagnesium chloride (1.6 M tetrahydrofuran solution; (75 ml) was added with zinc chloride (46.1 mg) and stirred at room temperature for 1 hour. The mixture was cooled to 0 ° C., and tetrahydrofuran (2.0 ml) of compound 15-1 (555 mg) was added dropwise. Stir at the same temperature for 5 hours. When the disappearance of the raw materials was confirmed, an aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (665 mg). The crude product was dissolved in acetic acid (5.0 ml) and thiourea (334 mg) was added. After stirring overnight at room temperature, the insoluble material was removed by cotton plug filtration, and the filtrate was added dropwise to diethyl ether. Cooled to 0 degrees and stirred. The solid was removed with a glass filter, and the solvent of the filtrate was distilled off under reduced pressure. Ethyl acetate was added to the residual oily substance and neutralized with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. A solid formed while the solvent was removed under reduced pressure. The concentration was stopped, a mixed solvent of hexane / diethyl ether was added, and the resulting solid was collected with a Kiriyama funnel and washed with diethyl ether. The obtained solid was dried to give the title compound (66.5 mg).
1 H NMR (400 MHz, MeOD) (ppm): 2.96-3.01 (m, 2H), 3.05-3.10 (m, 2H), 4.08 (d, J = 8.0 Hz, 2H), 6.09 (t, J = 8.0 Hz, 1H), 7.077.20 (m, 3H), 7.50 (dd, J = 1.3, 7.9 Hz, 1H).
（２）化合物２８の合成
　化合物１５－３（５０ｍｇ）をトリフルオロ酢酸（０．４６ｍｌ）に溶解した後に、氷浴下トリフルオロメタンスルホン酸（０．１ｍｌ）を加えた。同温度にて０．５時間撹拌した後、室温にて３．０時間撹拌した。原料の消失を確認した後、反応混合物を、氷浴にて冷却した重曹水に加え中和した。水層を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をＮＨ－シリカゲルカラムクロマトグラフィー、次にシリカゲルＴＬＣで精製し標題化合物を得た（１．６ｍｇ）。
ＥＳＩ－ＭＳ；ｍ／ｚ　２５１［Ｍ＋＋Ｈ］
１Ｈ　ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）（ｐｐｍ）：１．８７－１．９５（ｍ，１Ｈ），２．２４－２．３５（ｍ，３Ｈ），２．９２－２．９８（ｍ，２Ｈ），３．０７－３．１３（ｍ，１Ｈ），３．１４－３．２４（ｍ，１Ｈ），７．０７－７．１２（ｍ，１Ｈ），７．１３－７．１５（ｍ，２Ｈ），７．１９（ｂｒｄ，Ｊ＝１．３Ｈｚ，１Ｈ）． (2) Synthesis of Compound 28 Compound 15-3 (50 mg) was dissolved in trifluoroacetic acid (0.46 ml), and trifluoromethanesulfonic acid (0.1 ml) was added in an ice bath. After stirring at the same temperature for 0.5 hours, the mixture was stirred at room temperature for 3.0 hours. After confirming disappearance of the raw materials, the reaction mixture was neutralized by adding it to an aqueous sodium bicarbonate solution cooled in an ice bath. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by NH-silica gel column chromatography and then by silica gel TLC to give the title compound (1.6 mg).
ESI-MS; m / z 251 [M + + H]
1H NMR (400 MHz, CDCl 3 ) (ppm): 1.87-1.95 (m, 1H), 2.24-2.35 (m, 3H), 2.92-2.98 (m, 2H) , 3.07-3.13 (m, 1H), 3.14-3.24 (m, 1H), 7.07-7.12 (m, 1H), 7.13-7.15 (m, 2H), 7.19 (brd, J = 1.3 Hz, 1H).
試験例１
ラット胎仔脳由来神経細胞培養におけるＡβペプチド定量
（１）ラット初代神経細胞培養
　胎生１８日齢のＷｉｓｔａｒ系ラット（Ｃｈａｒｌｅｓ　Ｒｉｖｅｒ　Ｊａｐａｎ，Ｙｏｋｏｈａｍａ，Ｊａｐａｎ）より大脳皮質を単離し培養に供した。具体的には、エーテル麻酔下、妊娠ラットより無菌的に胎仔を摘出した。胎仔より脳を摘出し、氷冷Ｌ－１５ｍｅｄｉｕｍ（Ｉｎｖｉｔｒｏｇｅｎ　Ｃｏｒｐ．　Ｃａｔ　＃１１４１５－０６４，Ｃａｒｌｓｂａｄ，ＣＡ　ＵＳＡ　あるいは　ＳＩＧＭＡ　Ｌ１５１８など）に浸した。その摘出脳から、実体顕微鏡下で大脳皮質を採取した。採取した大脳皮質断片を、０．２５％ｔｒｙｐｓｉｎ（Ｉｎｖｉｔｒｏｇｅｎ　Ｃｏｒｐ．　Ｃａｔ　＃１５０５０－０６５，Ｃａｒｌｓｂａｄ，ＣＡ　ＵＳＡ）および０．０１％ＤＮａｓｅ）Ｓｉｇｍａ　Ｄ５０２５，Ｓｔ．　Ｌｏｕｉｓ，ＭＯ，ＵＳＡ）を含有した酵素溶液中、３７℃下３０分間の酵素処理することにより、細胞を分散させた。この際、酵素反応は非働化済みウマ血清を加えることで停止させた。この酵素処理溶液を１５００ｒｐｍにて５分間遠心分離し、上清を除いた。得られた細胞塊に培地を５～１０ｍｌ加えた。培地にはＮｅｕｒｏｂａｓａｌ　ｍｅｄｉｕｍ（Ｉｎｖｉｔｒｏｇｅｎ　Ｃｏｒｐ．　Ｃａｔ　＃２１１０３－０４９，Ｃａｒｌｓｂａｄ，ＣＡ　ＵＳＡ）に、２％　Ｂ２７　ｓｕｐｐｌｅｍｅｎｔ（Ｉｎｖｉｔｒｏｇｅｎ　Ｃｏｒｐ．　Ｃａｔ　＃１７５０４－０４４，Ｃａｒｌｓｂａｄ，ＣＡ　ＵＳＡ）と２５μＭ２－ｍｅｒｃａｐｔｏｅｔｈａｎｏｌ（２－ＭＥ，ＷＡＫＯ　Ｃａｔ　＃１３９－０６８６１，Ｏｓａｋａ，Ｊａｐａｎ）と０．５ｍＭＬ－ｇｌｕｔａｍｉｎｅ（Ｉｎｖｉｔｒｏｇｅｎ　Ｃｏｒｐ．　Ｃａｔ　＃２５０３０－０８１，Ｃａｒｌｓｂａｄ，ＣＡ　ＵＳＡ）およびＡｎｔｉｂｉｏｔｉｃｓ―Ａｎｔｉｍｙｃｏｔｉｃｓ（Ｉｎｖｉｔｒｏｇｅｎ　Ｃｏｒｐ．　Ｃａｔ　＃１５２４０－０６２，Ｃａｒｌｓｂａｄ，ＣＡ　ＵＳＡ）を添加したもの（Ｎｅｕｒｏｂａｓａｌ／Ｂ２７／２－ＭＥ）を用いた。但し、アッセイの際は、２－ＭＥのみを添加しない培地（Ｎｅｕｒｏｂａｓａｌ／Ｂ２７）を用いた。培地が加えられた細胞塊を、緩やかなピペッティング操作により細胞を再分散させた。この細胞分散液を、４０μｍナイロンメッシュ（セルストレーナー、Ｃａｔ　＃．３５－２３４０，Ｂｅｃｔｏｎ　Ｄｉｃｋｉｎｓｏｎ　Ｌａｂｗａｒｅ，Ｆｒａｎｋｌｉｎ　Ｌａｋｅｓ，ＮＪ、ＵＳＡ）でろ過し、細胞塊を除くことにより、神経細胞懸濁液を得た。この神経細胞懸濁液を培地にて希釈し、予めｐｏｌｙ－ＬあるいはＤ－ｌｙｓｉｎｅにてコーティングされた９６ｗｅｌｌポリスチレン製培養器（Ｆａｌｃｏｎ　Ｃａｔ　＃．３５－３０７５，Ｂｅｃｔｏｎ　Ｄｉｃｋｉｎｓｏｎ　Ｌａｂｗａｒｅ，Ｆｒａｎｋｌｉｎ　Ｌａｋｅｓ，ＮＪ，ＵＳＡを以下の方法でｐｏｌｙ－Ｌ－ｌｙｓｉｎｅコートを施したもの、あるいはＢＩＯＣＯＡＴＴＭ　ｃｅｌｌ　ｅｎｖｉｒｏｎｍｅｎｔｓ　Ｐｏｌｙ－Ｄ－ｌｙｓｉｎｅ　ｃｅｌｌ　ｗａｒｅ　９６－ｗｅｌｌ　ｐｌａｔｅ，Ｃａｔ　＃．３５－６４６１，Ｂｅｃｔｏｎ　Ｄｉｃｋｉｎｓｏｎ　Ｌａｂｗａｒｅ，Ｆｒａｎｋｌｉｎ　Ｌａｋｅｓ，ＮＪ，ＵＳＡ）に初期細胞密度が５ｘ１０５　ｃｅｌｌｓ／ｃｍ２になるように１００μｌ／ｗｅｌｌにて播種した。Ｐｏｌｙ－Ｌ－ｌｙｓｉｎｅコーティングは以下のように行った。０．１５Ｍ　Ｂｏｒａｔｅ　ｂｕｆｆｅｒ（ｐＨ８．５）を用いて１００μｇ／ｍｌのｐｏｌｙ－Ｌ－ｌｙｓｉｎｅ（ＳＩＧＭＡ　Ｐ２６３６，Ｓｔ．　Ｌｏｕｉｓ，ＭＯ，ＵＳＡ）溶液を無菌的に調製した。その溶液を１００μｇ／ｗｅｌｌにて９６ｗｅｌｌポリスチレン製培養器に添加し、室温１時間以上、あるいは４℃一晩以上、インキュベートした。その後、コーティングした９６ｗｅｌｌポリスチレン製培養器は、滅菌水を用いて４回以上洗浄した後、乾燥させるか、あるいは無菌ＰＢＳあるいは培地などを用いてすすいだ後に、細胞播種に用いた。播種した細胞は、５％ＣＯ２－９５％ａｉｒ下、３７℃インキュベーター中にて一日培養した後、培地全量を新鮮なＮｅｕｒｏｂａｓａｌ／Ｂ２７／２―ＭＥ培地と交換し、引き続き３日間培養した。 Test example 1
Quantification of Aβ Peptide in Rat Embryonic Brain-Derived Neuronal Culture (1) Rat Primary Neuronal Culture Embryonic 18-day-old Wistar rats (Charles River Japan, Yokohama, Japan) were isolated and subjected to culture. Specifically, fetuses were aseptically removed from pregnant rats under ether anesthesia. The brain was removed from the fetus and immersed in ice-cold L-15 medium (Invitrogen Corp. Cat # 11415-064, Carlsbad, CA USA or SIGMA L1518, etc.). Cerebral cortex was collected from the isolated brain under a stereomicroscope. Collected cerebral cortical fragments were 0.25% trypsin (Invitrogen Corp. Cat # 15050-065, Carlsbad, CA USA) and 0.01% DNase) Sigma D5025, St. The cells were dispersed by enzyme treatment at 37 ° C. for 30 minutes in an enzyme solution containing Louis, MO, USA). At this time, the enzyme reaction was stopped by adding inactivated horse serum. This enzyme-treated solution was centrifuged at 1500 rpm for 5 minutes, and the supernatant was removed. 5 to 10 ml of a medium was added to the obtained cell mass. The medium includes Neurobasal medium (Invitrogen Corp. Cat # 21103-049, Carlsbad, CA USA), and 2% B27 supplement (Invitrogen Corp. Cat # 17504-044, Carlsbad, CA USA) WAKO Cat # 139-06861, Osaka, Japan) and 0.5 mM L-glutamine (Invitrogen Corp. Cat # 25030-081, Carlsbad, CA USA) and Antibiotics-AntimericCat. ) Neurobasal / B27 / 2-ME) was used. However, in the assay, a medium (Neurobasal / B27) to which only 2-ME was not added was used. The cells were redispersed in the cell mass to which the medium was added by a gentle pipetting operation. This cell dispersion was filtered through a 40 μm nylon mesh (Cell Strainer, Cat # .35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to obtain a neuronal cell suspension. . This neuronal cell suspension was diluted with a medium, and a 96-well polystyrene incubator (Falcon Cat # .35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA) previously coated with poly-L or D-lysine. Or poly-L-lysine coat by the following method, or BIOCOAT ™ cell environments Poly-D-lysine cell wall 96-well plate, Cat # .35-6461, Becton DickinNoneFrakinN Labin, USA ) Was seeded at 100 μl / well so that the initial cell density was 5 × 10 5 cells / cm 2 . Poly-L-lysine coating was performed as follows. A 100 μg / ml poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) solution was aseptically prepared using 0.15 M Borate buffer (pH 8.5). The solution was added to a 96-well polystyrene incubator at 100 μg / well and incubated at room temperature for 1 hour or longer, or at 4 ° C. overnight or longer. Thereafter, the coated 96-well polystyrene incubator was washed four or more times with sterilized water, dried, or rinsed with sterile PBS or a medium, and used for cell seeding. The seeded cells were cultured for one day in a 37 ° C. incubator under 5% CO 2 -95% air, and then the entire medium was replaced with fresh Neurobasal / B27 / 2-ME medium, followed by culturing for 3 days.
（２）化合物添加
　培養４日目に薬物添加を以下の通りに行った。培地全量を抜き取り、２－ＭＥを含まない、２％Ｂ－２７を含有するＮｅｕｒｏｂａｓａｌ　ｍｅｄｉｕｍ（Ｎｅｕｒｏｂａｓａｌ／Ｂ２７）を１８０μｌ／ｗｅｌｌ加えた。試験化合物のジメチルスルホキシド（以下ＤＭＳＯと略す）溶液をＮｅｕｒｏｂａｓａｌ／Ｂ２７にて最終濃度の１０倍になるように希釈した。この希釈液を２０μｌ／ｗｅｌｌ添加し、よく混和した。最終ＤＭＳＯ濃度は１％以下とした。また対照群にはＤＭＳＯのみを添加した。 (2) Compound addition On the fourth day of compound addition culture, drug addition was performed as follows. The whole medium was extracted and Neurobasal medium (Neurobasal / B27) containing 2% B-27 without 2-ME was added at 180 μl / well. A dimethyl sulfoxide (hereinafter abbreviated as DMSO) solution of the test compound was diluted with Neurobasal / B27 so that the final concentration was 10 times. This diluted solution was added at 20 μl / well and mixed well. The final DMSO concentration was 1% or less. Only DMSO was added to the control group.
（３）サンプリング
　化合物添加後３日間培養し、培地全量を回収した。得られた培地は、ＥＬＩＳＡサンプルとした。Ａβｘ－４２測定には希釈せずに、Ａβｘ－４０測定にはＥＬＩＳＡキット付属の希釈液にて５倍希釈して各ＥＬＩＳＡに供した。 (3) After culturing for 3 days after the addition of the sampling compound, the whole amount of the medium was recovered. The obtained culture medium was an ELISA sample. The Aβx-42 measurement was not diluted, but the Aβx-40 measurement was diluted 5-fold with the diluent supplied with the ELISA kit and used for each ELISA.
（４）細胞生存の評価
　細胞生存は以下の方法でＭＴＴアッセイにより評価した。培地回収後のｗｅｌｌに温めた培地を１００μｌ／ｗｅｌｌ加え、さらにＤ－ＰＢＳ（－）（ＤＵＬＢＥＣＣＯ’Ｓ　ＰＨＯＳＰＨＡＴＥ　ＢＵＦＦＥＲＥＤ　ＳＡＬＩＮＥ、ＳＩＧＭＡ　Ｄ８５３７、Ｓｔ．　Ｌｏｕｉｓ，ＭＯ，ＵＳＡ）に溶解した８　ｍｇ／ｍｌのＭＴＴ（ＳＩＧＭＡ　Ｍ２１２８，Ｓｔ．　Ｌｏｕｉｓ，ＭＯ，ＵＳＡ）溶液を８　μｌ／ｗｅｌｌにて添加した。この９６　ｗｅｌｌポリスチレン製培養器を、５％ＣＯ２－９５％ａｉｒ下、３７℃インキュベーター中にて２０分間インキュベートした。そこへＭＴＴ溶解バッファーを１００μｌ／ｗｅｌｌ加え、５％ＣＯ２－９５％ａｉｒ下、３７℃インキュベーター中にてＭＴＴフォルマザン結晶をよく溶解させた後、各Ｗｅｌｌの５５０ｎｍの吸光度を測定した。ＭＴＴ溶解バッファーは以下の通りに調製した。Ｎ，Ｎ－ジメチルホルムアミド（ＷＡＫＯ　０４５－０２９１６，Ｏｓａｋａ，Ｊａｐａｎ）と蒸留水を２５０ｍＬずつ混合した溶液に、１００ｇＳＤＳ（ドデシル硫酸ナトリウム（ラウリル硫酸ナトリウム）、ＷＡＫＯ　１９１－０７１４５，Ｏｓａｋａ，Ｊａｐａｎ）を溶解した。さらに、この溶液に濃塩酸および酢酸を各３５０μｌ添加することにより、溶液の最終ｐＨを４．７程度にした。
　測定の際、細胞を播種しないｗｅｌｌに培地とＭＴＴ溶液のみを加えたものをバックグラウンド（ｂｋｇ）として設定した。各測定値は、以下の数式に従い、ｂｋｇを差し引き、対照群（薬物処理しなかった群、ＣＴＲＬ）に対する比率（％ｏｆＣＴＲＬ）を算出し、細胞生存活性を比較・評価した。
％　ｏｆ　ＣＴＲＬ　＝）　Ａ５５０＿ｓａｍｐｌｅ　－　Ａ５５０＿ｂｋｇ）／）Ａ５５０＿ＣＴＲＬ　－ｂｋｇ）　ｘ　１００
（Ａ５５０＿ｓａｍｐｌｅ：　サンプルｗｅｌｌの５５０　ｎｍ吸光度、Ａ５５０＿ｂｋｇ：　バックグラウンドｗｅｌｌの５５０　ｎｍ吸光度、Ａ５５０＿ＣＴＲＬ：対照群ｗｅｌｌの５５０　ｎｍ吸光度） (4) Evaluation of cell survival Cell survival was evaluated by the MTT assay by the following method. 100 μl / well of the warmed medium was added to the well after the medium was collected, and further 8 mg / ml MTT dissolved in D-PBS (−) (DULBECCO'S PHOSPHATE BUFFERED SALINE, SIGMA D8537, St. Louis, MO, USA). (SIGMA M2128, St. Louis, MO, USA) solution was added at 8 μl / well. This 96-well polystyrene incubator was incubated for 20 minutes in a 37 ° C. incubator under 5% CO 2 -95% air. MTT dissolution buffer was added thereto at 100 μl / well, and MTT formazan crystals were well dissolved in a 37 ° C. incubator under 5% CO 2 -95% air, and then the absorbance at 550 nm of each well was measured. MTT lysis buffer was prepared as follows. 100 g SDS (sodium dodecyl sulfate (sodium lauryl sulfate), WAKO 191-07145, Osaka, Japan) was dissolved in a solution obtained by mixing 250 mL each of N, N-dimethylformamide (WAKO 045-02916, Osaka, Japan) and distilled water. . Further, 350 μl of concentrated hydrochloric acid and acetic acid were added to this solution to bring the final pH of the solution to about 4.7.
At the time of measurement, a background (bkg) obtained by adding only a medium and an MTT solution to a well not seeded with cells was set. For each measured value, bkg was subtracted according to the following formula, a ratio (% of CTRL) to a control group (group not treated with drug, CTRL) was calculated, and cell survival activity was compared and evaluated.
% Of CTRL =) A550_sample-A550_bkg) /) A550_CTRL-bkg) x 100
(A550_sample: 550 nm absorbance of sample well, A550_bkg: 550 nm absorbance of background well, A550_CTRL: 550 nm absorbance of control well)
（５）Ａβ　ＥＬＩＳＡ
　Ａβ　ＥＬＩＳＡは和光純薬工業株式会社（Ｗａｋｏ　Ｐｕｒｅ　Ｃｈｅｍｉｃａｌ　Ｉｎｄｕｓｔｒｉｅｓ，Ｌｔｄ．）のヒト／ラットβアミロイド（４２）ＥＬＩＳＡキットワコー（＃２９０－６２６０１）、およびヒト／ラットβアミロイド（４０）ＥＬＩＳＡキットワコー（＃２９４－６２５０１）を用いた。方法はメーカー推奨のプロトコール（添付文書に記載の方法）にて行った。但しＡβ検量線は、ｂｅｔａ－ａｍｙｌｏｉｄ　ｐｅｐｔｉｄｅ　１－４２，ｒａｔおよびｂｅｔａ－ａｍｙｌｏｉｄ　ｐｅｐｔｉｄｅ　１－４０，ｒａｔ（Ｃａｌｂｉｏｃｈｅｍ．　＃１７１５９６［Ａβ４２］，１７１５９３［Ａβ４０］）を用いて作製した。結果は、対照群の培地中Ａβ濃度に対する百分率（％　ｏｆ　ＣＴＲＬ）にて表５に示した。 (5) Aβ ELISA
Aβ ELISA is a human / rat β amyloid (42) ELISA kit Wako (# 290-62601) from Wako Pure Chemical Industries, Ltd., and a human / rat β amyloid (40) ELISA kit Wako ( # 294-62501). The method was performed according to the manufacturer's recommended protocol (the method described in the package insert). However A [beta] calibration curve, beta-amyloid peptide 1-42, rat and beta-amyloid peptide 1-40, rat ( Calbiochem. # 171596 [Aβ 42], 171593 [Aβ 40]) was prepared using. The results are shown in Table 5 as a percentage (% of CTRL) to the Aβ concentration in the medium of the control group.
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
　表５の結果から明らかなように、本発明化合物は、Ａβ４２産生低下作用が確認された。 As is clear from the results in Table 5, the compound of the present invention was confirmed to have an Aβ42 production lowering effect.
　本発明の一般式（Ｉ）の化合物またはその医薬上許容される塩は、Ａβ４２産生低下作用を有するので、本発明によれば、特にアルツハイマー型痴呆、ダウン症等のＡβが原因となる神経変性疾患の治療剤または予防剤を提供することができる。 Since the compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an Aβ42 production reducing action, according to the present invention, neurodegenerative diseases caused by Aβ such as Alzheimer's dementia and Down's syndrome in particular. A therapeutic or prophylactic agent can be provided.

Claims (11)

  1. 　式（Ｉ）： 
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    　環ＡはＣ６－１０アリール基又は５－１０員複素環基であり、
    　Ｌは単結合、酸素原子若しくは式－Ｃ（＝Ｏ）ＮＲＬ－（ＲＬは水素原子又は置換基αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基である。）又は、それぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキレン基、Ｃ２－６アルケニレン基若しくはＣ２－６アルキニレン基であり、
    　環ＢはＣ３－８シクロアルキル基、Ｃ６－１０アリール基又は５－１０員複素環基であり、
    　Ｘは、それぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－３アルキレン基又はＣ２－３アルケニレン基であり、
    　Ｙは、酸素原子、硫黄原子、スルホキシド基、スルホン基又は式―ＮＲＹ－（ＲＹは水素原子又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルカルボニル基、Ｃ３－８シクロアルキルカルボニル基、Ｃ６－１０アリールカルボニル基、Ｃ１－６アルキルスルホニル基、Ｃ６－１０アリールスルホニル基、Ｃ６－１０アリール基若しくは５－６員へテロアリール基である。）で示される基であり、
    　Ｚは単結合又はＣ１－３アルキレン基であり、
    　Ｒ１及びＲ２は各々独立して水素原子、ハロゲン原子、ヒドロキシ基若しくはシアノ基又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基若しくはＣ１－６アルコキシ基であり、
    　Ｒ３は、水素原子又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルカルボニル基、Ｃ６－１０アリールカルボニル基、Ｃ１－６アルキルスルホニル基、Ｃ６－１０アリールスルホニル基、、Ｃ３－８シクロアルキル基、Ｃ６－１０アリール基若しくは５－１０員複素環基であり、
    　Ｒ４及びＲ５は各々独立して水素原子、ハロゲン原子若しくはヒドロキシ基又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基若しくは５－１０員複素環基であり、
    　Ｒ６、Ｒ７及びＲ８は各々独立して水素原子、ハロゲン原子、ヒドロキシ基若しくはシアノ基又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基若しくは５－１０員複素環基であり、
    　ｎは１から３の整数である。
    　置換基群α：水素原子、ハロゲン原子、ヒドロキシ基、オキソ基、シアノ基、Ｃ１－６アルキル基、トリフルオロメチル基、トリフルオロメトキシ基、Ｃ１－６アルコキシ基、Ｃ３－８シクロアルキル基、Ｃ３－８シクロアルキルオキシ基、Ｃ６－１０アリール基及び５－１０員複素環基。］
    で示される化合物又はその医薬上許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    Ring A is a C6-10 aryl group or a 5-10 membered heterocyclic group,
    L is a single bond, an oxygen atom, or a formula —C (═O) NR L — (R L is a hydrogen atom or a C1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent α Or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group, each optionally having 1 to 3 substituents selected from the substituent group α,
    Ring B is a C3-8 cycloalkyl group, a C6-10 aryl group or a 5-10 membered heterocyclic group,
    X is a C1-3 alkylene group or C2-3 alkenylene group each optionally having 1 to 3 substituents selected from substituent group α,
    Y represents an oxygen atom, a sulfur atom, a sulfoxide group, a sulfone group, or a formula —NR Y — (where R Y is a hydrogen atom or 1 to 3 substituents each selected from substituent group α, C1 -6 alkyl group, C1-6 alkylcarbonyl group, C3-8 cycloalkylcarbonyl group, C6-10 arylcarbonyl group, C1-6 alkylsulfonyl group, C6-10 arylsulfonyl group, C6-10 aryl group or 5-6 Is a member heteroaryl group).
    Z is a single bond or a C1-3 alkylene group,
    R 1 and R 2 each independently have a hydrogen atom, a halogen atom, a hydroxy group or a cyano group, or a C 1-6 alkyl group which may have 1 to 3 substituents each selected from substituent group α, A C1-6 alkoxy group,
    R 3 may have a hydrogen atom or 1 to 3 substituents each selected from substituent group α, a C 1-6 alkyl group, a C 1-6 alkyl carbonyl group, a C 6-10 aryl carbonyl group, C 1 A -6 alkylsulfonyl group, a C6-10 arylsulfonyl group, a C3-8 cycloalkyl group, a C6-10 aryl group or a 5-10 membered heterocyclic group,
    R 4 and R 5 each independently have a hydrogen atom, a halogen atom, a hydroxy group, or 1 to 3 substituents each selected from substituent group α, a C 1-6 alkyl group, C 1-6 An alkoxy group, a C3-8 cycloalkyl group, a C3-8 cycloalkyloxy group, a C6-10 aryl group or a 5-10 membered heterocyclic group,
    R 6 , R 7 and R 8 may each independently have a hydrogen atom, a halogen atom, a hydroxy group or a cyano group, or 1 to 3 substituents each selected from substituent group α, C 1-6 An alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkoxy group, a C3-8 cycloalkyl group, a C3-8 cycloalkyloxy group, a C6-10 aryl group or a 5-10 membered heterocyclic group Yes,
    n is an integer of 1 to 3.
    Substituent group α: hydrogen atom, halogen atom, hydroxy group, oxo group, cyano group, C1-6 alkyl group, trifluoromethyl group, trifluoromethoxy group, C1-6 alkoxy group, C3-8 cycloalkyl group, C3 -8 cycloalkyloxy group, C6-10 aryl group and 5-10 membered heterocyclic group. ]
    Or a pharmaceutically acceptable salt thereof.
  2. 　Ｘが置換基群αから選択される１乃至３の置換基を有していてもよいＣ１－３アルキレン基である、請求項１記載の化合物又はその医薬上許容される塩。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a C1-3 alkylene group optionally having 1 to 3 substituents selected from substituent group α.
  3. 　Ｙが酸素原子である、請求項１又は２記載の化合物又はその医薬上許容される塩。 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom.
  4. 　Ｙが硫黄原子またはスルホン基である、請求項１又は２記載の化合物又はその医薬上許容される塩。 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is a sulfur atom or a sulfone group.
  5. 　Ｙが式―ＮＲＹ－（ＲＹは水素原子又はそれぞれ置換基群αから選ばれる１乃至３の置換基を有していてもよい、Ｃ１－６アルキル基、Ｃ１－６アルキルカルボニル基、Ｃ３－８シクロアルキルカルボニル基、Ｃ６－１０アリールカルボニル基、Ｃ１－６アルキルスルホニル基、Ｃ６－１０アリールスルホニル基、Ｃ６－１０アリール基若しくは５－６員へテロアリール基である。）で示される基である、請求項１又は２記載の化合物又はその医薬上許容される塩。 Y is a formula —NR Y — (R Y is a hydrogen atom or a C1-6 alkyl group, a C1-6 alkylcarbonyl group, C3 which may have 1 to 3 substituents each selected from substituent group α, A -8 cycloalkylcarbonyl group, a C6-10 arylcarbonyl group, a C1-6 alkylsulfonyl group, a C6-10 arylsulfonyl group, a C6-10 aryl group or a 5-6 membered heteroaryl group). A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  6. 　Ｌが式－Ｃ（＝Ｏ）ＮＲＬ－（ＲＬは水素原子又は置換基αから選択される１乃至３の置換基を有していてもよいＣ１－６アルキル基である。）で示される基である、請求項１から５のいずれかに記載の化合物又はその医薬上許容される塩。 L is represented by the formula —C (═O) NR L — (R L is a hydrogen atom or a C1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent α). The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof,
  7. 　請求項１から６のいずれかに記載の化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
  8. 　アミロイドβタンパク質産生を抑制するための請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7 for suppressing amyloid β protein production.
  9. 　ベータサイトアミロイドβ前駆体タンパク質開裂酵素１（ＢＡＣＥ１）を阻害するための請求項７に記載の医薬組成物。 The pharmaceutical composition according to claim 7, for inhibiting beta-site amyloid β precursor protein-cleaving enzyme 1 (BACE1).
  10. 　神経変性疾患治療のための請求項７から９のいずれかに記載の医薬組成物。 10. A pharmaceutical composition according to any one of claims 7 to 9 for treating neurodegenerative diseases.
  11. 　神経変性疾患がアルツハイマー型痴呆又はダウン症である請求項１０に記載の医薬組成物。 The pharmaceutical composition according to claim 10, wherein the neurodegenerative disease is Alzheimer-type dementia or Down's syndrome.
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