JPH11335275A - Nitron derivative percutaneous agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent capable of maintaining blood medicament levels for a long time and extending the biological half-life of the levels compared to the case with oral administration or intravenous injection, and useful as a therapeutic agent for neurodegenerative diseases such as nerve retina- degenerative diseases, by including a specific nitron derivative or the like. SOLUTION: This agent is obtained by including a compound of formula I [Ar is a substituted phenyl or the like; (n) is 0-2; W is CH2 NH or CH=N(O); R<1> to R<3> are each (substituted) alkyl or the like; R<4> and R<5> are each H or the like] or a pharmaceutically acceptable salt thereof [pref. α-(2,4- difluorophenyl)-N-t-butynitron]. The compound of formula I is obtained, as a preferable one process, by reaction between a compound of the formula Ar<1> -(CR<4> =CR<5> )n -CHO [Ar<1> is a (substituted) five-membered aromatic heterocyclic ring or the like] (e.g. 2,4-difluorobenzaldehyde) and a compound of formula II. The daily dose of this agent is normally 0.1 mg to 10 g per adult in terms of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a transdermal preparation containing a nitrone derivative and a precursor thereof. More specifically, the present invention relates to a systemic transdermal preparation capable of treating a neurodegenerative disease such as a neuroretinal degenerative disease by transdermally absorbing a nitrone derivative or a pharmaceutically acceptable acid addition salt. About.

[0002]

2. Description of the Related Art Phenyl t-butyl nitrone (PBN)
Such a nitrone derivative has conventionally been used as a spin trapping agent for the purpose of detecting free radicals by ESR (electron spin resonance). J. Org. Chem., 57 , 2
624 (1992) describes the synthesis of a derivative in which one various substituent is introduced into PBN, and its effect as a spin trapping agent. A nitrone derivative such as PBN acts as an antioxidant and is associated with a disorder caused by active oxygen (for example, central nervous system, peripheral nervous system and peripheral organs resulting from ischemia, infection, inflammation, radiation damage, drug poisoning) (WO91 / 5552, WO92 / 22290, WO95 / 17).
876, J. Biol. Chem., 271 , 3097 (1996)). However, it is not described whether such compounds are effective for neuroretinal degenerative diseases. It has also been suggested that free radicals such as active oxygen are involved in retinal damage caused by light (AM Van Der Hagen, et al., J. Am. Opto
m. Assoc., 64 , 871 (1993)). JP-A-54-2324 discloses Nt-butyl-4-chlorobenzylamine, N-
It describes the synthesis of compounds useful as insecticides using t-butyl-2,4-dichlorobenzylamine and the like as synthesis intermediates.

[0003]

An object of the present invention is to provide a neurodegenerative disorder (eg, neurodegenerative disorders caused by stroke, hypoglycemia, cardiac arrest, perinatal asphyxia, spinal cord injury, etc.), epilepsy, It is an object of the present invention to provide a preparation capable of treating Huntington's disease, Parkinson's disease, Alzheimer's disease, diabetic neuropathy, neuroretinal degenerative disease, and the like.

[0004]

As a result of various studies, the present inventors have found that transdermal agents such as nitrone derivatives are useful as therapeutic agents for neurodegenerative diseases such as neuroretinal degenerative diseases. The present inventors have found that the corresponding amine, which is a reduced form of the nitrone derivative, is converted to the nitrone derivative in vivo to show the same effectiveness, and have completed the present invention.

[0005] That is, the present invention is as follows. [1] Equation 1:

Embedded image [In the formula, Ar represents a substituted phenyl or an optionally substituted aromatic heterocyclic group. n represents 0, 1 or 2. W is, -CH ₂ NH- or -CH = N (O) -
Represents R ¹ , R ² and R ³ each independently represent an optionally substituted alkyl, carboxyl, or alkoxycarbonyl. Provided that any ^{two of} R ¹ , R ² and R ³ are bonded to each other to form a cycloalkane ring together with the carbon atom to which they are bonded, or ^three of R ¹ , R ² and R ³ are They may combine with each other to form a bicycloalkane ring or a tricycloalkane ring together with the carbon atoms to which they are attached. The cycloalkane ring, the bicycloalkane ring and the tricycloalkane ring may be substituted. R ⁴ and R ⁵ each independently represent a hydrogen atom or an optionally substituted alkyl. Or a pharmaceutically acceptable salt thereof.

[2] The substituent in the substituted phenyl and the substituted aromatic heterocyclic group is a halogen atom, cyano, nitro,
Alkyl, halogen-substituted alkyl, alkoxy, halogen-substituted alkoxy, alkoxycarbonyl, carbamoyl or alkyl-substituted carbamoyl, wherein the substituent in the substituted alkyl, substituted cycloalkane ring, substituted bicycloalkane ring and substituted tricycloalkane ring is cycloalkyl, heteroalkyl, The transdermal agent according to [1], which is a ring group, alkoxy, alkoxyalkoxy, alkanoyloxy or alkanoylamino. [3] The transdermal agent according to [1] or [2], wherein n is 0. [4] Ar is an optionally substituted 5-membered aromatic heterocyclic group or a compound represented by the formula:

Embedded image (R ⁶ represents a halogen atom, trifluoromethyl, cyano or nitro; R ⁷ represents a hydrogen atom or a substituent; R ⁸ represents a substituent; provided that W is —CH ₂ NH
If-, Ar is not dichlorophenyl. )
The transdermal agent according to any one of [1] to [3], which is a group represented by:

[5] Ar is 2-thienyl or a formula:

Embedded image (R ⁶ has the same meaning as described above. R ⁹ represents a halogen atom, cyano, nitro, alkyl, halogen-substituted alkyl, alkoxy, alkoxycarbonyl, carbamoyl, or alkyl-substituted carbamoyl.) 1) The transdermal preparation according to any one of [3]. [6] The transdermal agent according to any one of [1] to [3], wherein Ar is 2-thienyl or phenyl substituted with 1 to 3 halogen atoms. [7] Ar is 2-thienyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-bromophenyl,
The transdermal agent according to any one of [1] to [3], which is 2,6-difluorophenyl or 2,4-dichlorophenyl. [8] The transdermal agent according to any one of [1] to [7], wherein R ¹ , R ² and R ³ are each independently an optionally substituted alkyl. [9] W is -CH = N (O)-[1]-[8]
The transdermal agent according to any one of the above. [10] α- (2,4-difluorophenyl) -N-
The transdermal agent according to [1], comprising t-butyl nitrone. [11] tapes, patches, ointments, creams,
In the form of a lotion, liquid or gel formulation [1]
-The transdermal preparation according to any of [10].

[12] Formula:

Embedded image And an aldehyde represented by the formula:

Embedded image By reacting a hydroxyamine represented by
formula:

Embedded image A method for producing a compound represented by the formula: [Wherein, n, R ¹ , R ² , R
³ , R ⁴ and R ⁵ are as defined above. Ar ¹ is an optionally substituted 5-membered aromatic heterocyclic group or a compound represented by the formula:

Embedded image (R ⁶ , R ⁷ and R ⁸ are as defined above). ]

[13] The production method according to [12], wherein n is 0. [14] Ar ¹ is 2-thienyl, or a formula:

Embedded image (R ⁶ and R ⁹ are as defined above.) Is a group represented by [12] or method according to [13]. [15] The production method according to [12] or [13], wherein Ar ¹ is 2-thienyl or phenyl substituted with 1 to 3 halogen atoms. [16] The description of [12] or [13], wherein Ar ¹ is 2-thienyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,6-difluorophenyl or 2,4-dichlorophenyl. Manufacturing method. [17] R ¹ , R ² and R ³ are each independently:
The production method according to any one of [12] to [16], which is an alkyl which may be substituted. [18] The method for producing α- (2,4-difluorophenyl) -Nt-butylnitrone according to [12].

[19] Formula:

Embedded image By oxidizing a compound represented by the formula:

Embedded image A method for producing a compound represented by the formula: [Wherein, n, R ¹ , R ² , R
³ , R ⁴ and R ⁵ are as defined above. Ar ¹ has the same meaning as described above. ]

[20] The production method according to [19], wherein n is 0. [21] Ar ¹ is 2-thienyl, or a formula:

Embedded image (R ⁶ and R ⁹ are as defined above.) Is a group represented by [19] or [20] A process according. [22] The production method according to [19] or [20], wherein Ar ¹ is 2-thienyl or phenyl substituted with 1 to 3 halogen atoms. [23] The method according to [19] or [20], wherein Ar ¹ is 2-thienyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,6-difluorophenyl or 2,4-dichlorophenyl. Manufacturing method. [24] R ¹ , R ² and R ³ are each independently:
The production method according to any one of [19] to [23], which is an alkyl which may be substituted. [25] The method for producing α- (2,4-difluorophenyl) -Nt-butylnitrone according to [19].

The aromatic heterocyclic group is, for example, a 5- or 6-membered aromatic ring containing 1-3 atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And a heterocyclic group. Examples of the 5-membered aromatic heterocyclic group include a 5-membered aromatic heterocyclic group containing 1 to 3 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Preferred specific examples thereof include 1 or 2 atoms independently selected from the group consisting of nitrogen, sulfur and oxygen, such as pyrrolyl, thienyl, imidazolyl, pyrazolyl, isothiazolyl and isoxazolyl. And a 5-membered aromatic heterocyclic group containing: Examples of the 6-membered aromatic heterocyclic group include a 6-membered aromatic heterocyclic group containing 1 to 3 nitrogen atoms, and specific examples thereof include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Is mentioned. Examples of the heterocyclic group include an aromatic heterocyclic group and an aliphatic heterocyclic group. As the aliphatic bicyclic group,
Examples thereof include a 5-membered or 6-membered aliphatic heterocyclic group containing 1-3 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Examples of the 5-membered aliphatic heterocyclic group include a 5-membered aliphatic heterocyclic group containing 1 to 3 atoms arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And preferred specific examples include, for example, pyrrolidinyl,
5-membered aliphatic heterocycle containing 1 or 2 atoms independently selected from the group consisting of nitrogen, sulfur and oxygen, such as pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dioxolanyl and the like Groups. As the 6-membered aliphatic heterocyclic group, for example, a 6-membered aliphatic heterocyclic group containing 1-3 atoms independently and arbitrarily selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom Specifically, for example, one or two atoms independently selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom such as piperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl And a 6-membered aliphatic heterocyclic group containing

[0013] Examples of the substituent in the substituted phenyl and the substituted aromatic heterocyclic group include a halogen atom, cyano, nitro, alkyl, halogen-substituted alkyl, alkoxy,
Examples thereof include alkoxycarbonyl, carbamoyl, and alkyl-substituted carbamoyl, which may be independently substituted by one or more. Preferred substituents include electron-withdrawing substituents such as halogen atoms, cyano, nitro, and trifluoromethyl, more preferably halogen atoms, and particularly preferably fluorine atoms. In the substituted phenyl, the number of the substituents is, for example, 1, 2 or 3, preferably 1 or 2, and more preferably 2.
A preferred substitution position of the substituent is 4-position, and when the compound has a plurality of substituents, 2,4-position is mentioned.

Examples of the alkyl include straight-chain or branched-chain alkyl having 6 or less carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, butyl,
-Methylpropyl, pentyl, 1,2-dimethylpropyl, hexyl, 3-ethylbutyl and the like. Examples of the alkoxy include straight-chain or branched-chain alkoxy having 6 or less carbon atoms. Specifically, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy,
-Methylpropoxy, pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 3-ethylbutoxy and the like. Alkoxyalkoxy means alkoxy substituted with alkoxy. Alkoxycarbonyl means carbonyl substituted with alkoxy. The halogen-substituted alkyl and the halogen-substituted alkoxy mean an alkyl and an alkoxy each substituted with one or more halogen atoms, and preferable examples include, for example, trifluoromethyl, trifluoromethoxy and the like, respectively. Examples of the alkanoyl in alkanoyloxy and alkanoylamino include straight-chain or branched-chain alkanoyls having 6 or less carbon atoms, specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-methylbutyryl , Hexanoyl and the like. Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In the alkyl-substituted carbamoyl, it may be independently substituted with 1 or 2 alkyl. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom,
And iodine atoms. Preferred are a fluorine atom, a chlorine atom and a bromine atom, and particularly preferred is a fluorine atom.

Examples of the cycloalkane ring include a cycloalkane ring having 3 to 8 carbon atoms, and specific examples include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cycloheptane ring, and a cyclooctane ring. No. Examples of the bicycloalkane ring include a bicycloalkane ring having 7 to 10 carbon atoms, and specific examples include a bicyclo [2.2.1] heptane ring and a bicyclo [2.2.2] octane ring. Examples of the tricycloalkane ring include a tricycloalkane ring having 7 to 13 carbon atoms, and specific examples thereof include an adamantane ring.
Examples of the substituent in the substituted alkyl, substituted cycloalkane ring, substituted bicycloalkane ring and substituted tricycloalkane ring include, for example, cycloalkyl, heterocyclic group, alkoxy, alkoxyalkoxy, alkanoyloxy, alkanoylamino, and the like. And one or more substituents may be substituted.

The pharmaceutically acceptable salts include, for example, addition salts with pharmaceutically acceptable inorganic and organic acids. As the inorganic acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid,
Sulfuric acid and the like. Examples of the organic acid include acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, and the like. In addition, the compound represented by Formula 1 or Formula 2 and a pharmaceutically acceptable salt thereof also include solvates such as hydrates thereof. Compounds of Formula 1 include:
When tautomers exist, these tautomers are also included. When a geometrical isomer is present in the compound of the formula 1, a mixture of these isomers and an isolated isomer are also included.

The compound of the formula 1 can be produced, for example, by the following production method. In the following, W in the formula 1 is -CH ₂ N
The case where H- and the case where -CH = N (O)-will be described separately.

I. When W is -CH ₂ NH-

Embedded image Wherein Ar, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above. An aldehyde of the formula 2 and an amine of the formula 3 are reacted in a suitable organic solvent,
The compound of the formula 4 according to the present invention can be obtained by reductive amination reaction in the presence of a suitable reducing agent (J. Org. Chem., 55 , 1736 (1990)). The reductive amination reaction includes sodium borohydride as a suitable reducing agent,
The reaction can be carried out using a borohydride reagent such as sodium cyanoborohydride or a hydrogenation reaction in the presence of a metal catalyst such as palladium. Suitable organic solvents include, for example, alcoholic solvents such as methanol and ethanol. The reaction temperature is 0
The temperature range is from ° C to room temperature. The compound of formula 5 and the compound of formula 6 are commercially available or can be easily synthesized according to a conventional method.

II. When W is -CH = N (O)-

Embedded image (Wherein Ar, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above). Reaction of the aldehyde of the formula 2 with the hydroxyamine of the formula 5 in a suitable organic solvent Gives the compound of formula 6 according to the present invention. If necessary, an acid may be added as a catalyst. Examples of the organic solvent include toluene, chloroform, ethyl acetate, THF, diethyl ether,
Methanol or ethanol may, for example, be mentioned. Examples of the acid include paratoluenesulfonic acid, trichloroacetic acid,
Examples include protonic acids such as acetic acid, Lewis acids such as phosphorus oxychloride, boron trifluoride, and zinc chloride. The reaction temperature ranges from room temperature to the boiling point of the solvent. The compound of Formula 5 can be easily synthesized according to a conventional method (J. Org. Chem., 57 , 2624 (1992)).
-Hydroxy-t-butylamine can be obtained by reducing 1,1-dimethylnitroethane with zinc in the presence of acetic acid. In addition, the compound of Formula 5 can be generated in the reaction system and the reaction can be carried out as it is.

[0020]

Embedded image (Wherein, Ar, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.) By oxidizing the compound of the formula 4 with an appropriate oxidizing agent, the compound according to the present invention is obtained. 6 can also be obtained (J. Org. Che
m., 55 , 1736 (1990)). The oxidation reaction can be performed using an oxidizing agent such as aqueous hydrogen peroxide in the presence of a catalyst such as sodium tungstate. Suitable organic solvents include, for example, alcoholic solvents such as methanol and ethanol. The reaction temperature ranges from 0 ° C. to the boiling point of the solvent, and preferably room temperature.

The compound of formula 1 can be purified by a conventional method. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic solvents such as toluene, ketone solvents such as acetone, and hydrocarbons such as hexane. Examples thereof include a solvent, water and the like, and a mixed solvent thereof. Further, the compound of formula 1 can be converted into a pharmaceutically acceptable salt according to a conventional method,
Thereafter, recrystallization or the like can be performed.

[0022] The formulation of the transdermal preparation of the present invention may be a dosage form conventionally used as an external preparation, for example, a tape,
It can be used as an external preparation in the form of patches, cataplasms, ointments, creams, lotions, solutions, gels and the like. External preparations of these dosage forms can be produced by an ordinary method using an ordinary adhesive, a base and the like. For example, “Transdermal Application Formulation Development Manual,” edited by Mitsuo Matsumoto (198
5), it can be produced according to the description in Japanese Patent No. 2651616, WO 96/12495, JP-A-9-278651, and the like.

[0023] Examples of the acrylic pressure-sensitive adhesive include (co) polymers mainly composed of alkyl (meth) acrylate. This (co) polymer may be a copolymer of two or more alkyl (meth) acrylates, or a functional monomer copolymerizable with the alkyl (meth) acrylate and a (meth) acrylic monomer. It may be a copolymer with an acid alkyl ester. Examples of the alkyl acrylate include alkyl acrylates esterified with a straight-chain or branched-chain alkyl having 1 to 18 carbon atoms. Specific examples include methyl (meth) acrylate and (meth) acrylate. ) Butyl acrylate, hexyl (meth) acrylate, (meth)
Examples thereof include octyl acrylate, nonyl (meth) acrylate, and decyl (meth) acrylate. Examples of the functional monomer include a monomer having a hydroxyl group (such as hydroxyethyl (meth) acrylate), a monomer having a carboxyl group (such as butyl maleate and crotonic acid), and a monomer having an amide group (such as (meth) acrylamide). And a monomer having an amino group (such as dimethylaminoacrylate) and a monomer having a pyrrolidone ring (such as N-vinyl-2-pyrrolidone).

Examples of the rubber-based adhesive include natural rubber, polyisopropylene rubber, polyisobutylene rubber, styrene
-A rubber-based elastomer such as an isoprene-styrene block copolymer and a styrene-butadiene-styrene block copolymer. Examples of the silicone-based pressure-sensitive adhesive include those mainly containing a silicone rubber such as polydimethylsiloxane and diphenylsiloxane. A microreservoir-type preparation in which a compound of the formula 1 or a pharmaceutically acceptable acid addition salt thereof is dispersed in these adhesives, and a solution of the compound of the formula 1 or a pharmaceutically acceptable acid addition salt thereof is filled. It can be a reservoir-type preparation. A cataplasm containing a pressure-sensitive adhesive containing the compound of the formula 1 or a pharmaceutically acceptable acid addition salt thereof can also be prepared (J. Controlled Release, 29 , 177-185 (199).
Four)).

As bases for ointments and creams, for example, fatty oil, lanolin, petrolatum, paraffin, plastibase, glycols, higher fatty acids, higher alcohols and the like are used. To these bases, stabilizers, preservatives, emulsifiers, suspending agents and the like are added as required. Examples of the base of the lotion include ethanol, glycerin, glycol and the like. As the base of the solution,
For example, ethanol, water, glycol and the like are used. As the base of the gel preparation, for example, in the case of an oily gel, a liquid oil or fat is gelled with a gelling agent, and in the case of an aqueous gel, a gelling agent such as carboxymethyl polymer, hydroxypropylcellulose, or polyvinyl alcohol is used. Used. In reservoir type preparations or lotions,
As the solvent for dissolving the compound of the formula 1 or the pharmaceutically acceptable acid addition salt thereof, for example, the compound of the formula 1 or the pharmaceutically acceptable acid addition salt thereof can be dissolved, and the skin is less irritating. Examples include an organic solvent, a buffer, or a mixed solvent of the organic solvent with water or a buffer.

The transdermal preparation of the present invention may contain, if desired, various pharmacologically acceptable additives within a range not to impair the purpose of the present invention.
For example, stabilizers, antioxidants, fragrances, fillers, or other transdermal absorption enhancers can be added. The dose varies depending on the condition of the patient such as age and body weight, symptoms, and the form of the preparation, but usually 0.1 mg to 10 g / day of the compound of formula 1 is administered to an adult.

[0027]

The present invention will be described in more detail with reference to the following examples.
However, the present invention is not limited to these. Example 1α- (2,4-difluorophenyl) -Nt-butyl
Nitron production  2,4-difluorobenzaldehyde (608.9 mg, 4.28
mmol), 1,1-dimethylnitroethane (881.9 mg, 8.55
 mmol), zinc (840.0 mg, 12.8 mmol) in ethanol (15 m
l) Acetic acid (1.54 g, 25.6 mmol) was added dropwise to the suspension while stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for one day. Cool the reaction to 5 ° C
Then, the zinc acetate was filtered off and the filtrate was concentrated. This is silica
Gel chromatography (hexane / ethyl acetate = 4/1)
did. Yield 852.5 mg (93%)¹ H-NMR (CDCl_Three) 1.62 (s, 9H), 6.80-6.88 (m,
 1H), 6.90-6.98 (m, 1H), 7.79 (s, 1H), 9.38-9.47 (m,
1H)

Embodiment 2α- (2,4-dichlorophenyl) -Nt-butylni
Manufacture of TRON  2,4-dichlorobenzaldehyde (462.1 mg, 2.64 mm
ol), 1,1-dimethylnitroethane (543.1 mg, 5.27 m
mol), zinc (514.8 mg, 7.88 mmol) in ethanol (3.0 m
l) Acetic acid (944.8 mg, 15.7 mmol) was added dropwise to the suspension while stirring at 5 ° C.
After dropping, the mixture was stirred at room temperature for one day. Zinc acetate in the reaction solution
After filtration, the filtrate was concentrated. This is silica gel chromatog
Roughy (hexane / ethyl acetate = 5/1). Yield 436.6 mg (67%)¹ H-NMR (CDCl_Three) 1.62 (s, 9H), 7.30-7.34 (m,
 1H), 7.43 (d, 1H, J = 2.3 Hz), 8.04 (s, 1H), 9.39 (d,
 (1H, J = 8.9 Hz)

Embodiment 3α- (2-methoxyphenyl) -Nt-butylnitro
Manufacturing  2-methoxybenzaldehyde (622.4 mg, 4.57 mmo
l) 1,1-dimethylnitroethane (942.7 mg, 9.14 mmo
l), zinc (896.3 mg, 13.7 mmol) in ethanol (15 ml)
Acetic acid (1.65 g, 27.5 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for one day. Cool the reaction to 5 ° C and add vinegar
The zinc acid was filtered off, and the filtrate was concentrated. This is silica gel
Chromatography (hexane / ethyl acetate = 2/1). Yield 877.2 mg (93%)¹ H-NMR (CDCl_Three) 1.61 (s, 9H), 3.87 (s, 3H),
 6.89 (d, 1H, J = 8.3 Hz), 7.02 (t, 1H, J = 7.9 Hz),
 7.32-7.39 (m, 1H), 8.05 (s, 1H), 9.36 (dd, 1H, J = 1.
7, 7.9 Hz)

Embodiment 4α- (2-fluorophenyl) -Nt-butylnitro
Manufacturing  2-fluorobenzaldehyde (332.3 mg, 2.68 mmo
l) 1,1-dimethylnitroethane (547.5 mg, 5.31 mmo
l), zinc (514.6 mg, 7.87 mmol) in ethanol (3.0 ml)
Acetic acid (940.2 mg, 15.7 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for 6.5 hours. Reaction solution zinc acetate
And the filtrate was concentrated. This is silica gel chromatograph
(Hexane / ethyl acetate = 4/1 to 2/1). Yield 489.0 mg (93%)¹ H-NMR (CDCl_Three) 1.63 (s, 9H), 7.04-7.12 (m,
 1H), 7.18-7.24 (m, 1H), 7.32-7.41 (m, 1H), 7.87 (s,
1H), 9.29-9.36 (m, 1H)

Embodiment 5α- (3-fluorophenyl) -Nt-butylnitro
Manufacturing  3-fluorobenzaldehyde (327.5 mg, 2.64 mmo
l) 1,1-dimethylnitroethane (542.3 mg, 5.26 mmo
l), zinc (517.9 mg, 7.92 mmol) in ethanol (3.0 ml)
Acetic acid (946.2 mg, 15.8 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for 5 hours. Zinc acetate in the reaction solution
After filtration, the filtrate was concentrated. This is silica gel chromatog
Roughy (hexane / ethyl acetate = 2/1). Yield 448.8 mg (87%)¹ H-NMR (CDCl_Three) 1.62 (s, 9H), 7.06-7.13 (m,
 1H), 7.32-7.41 (m, 1H), 7.56 (s, 1H), 7.77 (d, 1H, J
 = 7.9 Hz), 8.33-8.39 (m, 1H)

Embodiment 6α- (4-fluorophenyl) -Nt-butylnitro
Manufacturing  4-fluorobenzaldehyde (325.0 mg, 2.62 mmo
l) 1,1-dimethylnitroethane (542.3 mg, 5.26 mmo
l), zinc (516.0 mg, 7.89 mmol) in ethanol (3.0 ml)
Acetic acid (941.7 mg, 15.7 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for 4.5 hours. Reaction solution zinc acetate
And the filtrate was concentrated. This is silica gel chromatograph
(Hexane / ethyl acetate = 2/1-1/1). Yield 432.1 mg (84%)¹ H-NMR (CDCl_Three) 1.61 (s, 9H), 7.10 (dd, 2H,
 J = 8.7, 8.7 Hz), 7.53 (s, 1H), 8.31-8.36 (m, 2H)

Embodiment 7α- (2,6-difluorophenyl) -Nt-butyl
Nitron production  2,6-difluorobenzaldehyde (374.7 mg, 2.64
mmol), 1,1-dimethylnitroethane (541.6 mg, 5.25
mmol), zinc (517.0 mg, 7.91 mmol) in ethanol (3.0 m
l) Acetic acid (940.5 mg, 15.7 mmol) was added dropwise to the suspension while stirring at 5 ° C.
After dropping, the mixture was stirred at room temperature for 5 hours. Reaction solution zinc acetate
And the filtrate was concentrated. This is silica gel chromatograph
(Hexane / ethyl acetate = 5/2-2/1). Yield 488.2 mg (87%)¹ H-NMR (CDCl_Three) 1.64 (s, 9H), 6.93 (dd, 2H,
 J = 8.2, 8.2 Hz), 7.27-7.38 (m, 1H), 7.58 (s, 1H)

Embodiment 8α- (4- (1-imidazolyl) phenyl) -Nt-
Production of butyl nitrone  1,1-dimethylnitroethane (261.2 mg, 2.53 mmo
l), zinc (247.0 mg, 3.78 mmol) in ethanol (3.0 ml)
Acetic acid (451.8 mg, 7.52 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for 30 minutes. Bring reaction to 5 ° C again
After cooling and stirring, 4- (1-imidazolyl) benzal
Dehydration (216.5 mg, 1.26 mmol) was added dropwise.
Stirred overnight. The zinc acetate in the reaction solution is separated by filtration, and the filtrate is concentrated.
did. This is subjected to silica gel chromatography (chloropho
Lum / methanol = 10/1). Yield 126.5 mg (41%)¹ H-NMR (CDCl_Three) 1.64 (s, 9H), 7.22 (d, 1H,
J = 1.0 Hz), 7.34 (s, 1H), 7.45 (d, 2H, J = 8.7 Hz),
 7.61 (s, 1H), 7.93 (s, 1H), 8.44 (d, 2H, J = 8.7 Hz)

Embodiment 9Production of α- (2-pyridyl) -Nt-butylnitrone  1,1-dimethylnitroethane (545.5 mg, 5.29 mmo
l), zinc (516.6 mg, 7.90 mmol) in ethanol (3.0 ml)
Acetic acid (950.1 mg, 15.8 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for 20 minutes. Bring reaction to 5 ° C again
After cooling and stirring, 2-pyridylaldehyde (283.9 mg,
2.65 mmol) was added dropwise, and the mixture was stirred at room temperature overnight after the addition. reaction
The liquid zinc acetate was filtered off, and the filtrate was concentrated. This is silica
Gel chromatography (ethyl acetate) was performed. Yield 307.1 mg (65%)¹ H-NMR (CDCl_Three) 1.63 (s, 9H), 7.26-7.31 (m,
 1H), 7.76-7.83 (m, 1H), 7.93 (s, 1H), 8.62-8.65 (m,
1H), 9.20-9.24 (m, 1H)

Embodiment 10Production of α- (2-thienyl) -Nt-butylnitrone  Thiophene-2-carbaldehyde (296.7 mg, 2.65 mmo
l), 1,1-dimethylnitroethane (543.9 mg, 5.27 mm
ol), zinc (516.3 mg, 7.90 mmol) in ethanol (3.0 ml)
Acetic acid (946.6 mg, 15.8 mmol) was added dropwise to the suspension while stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for one day. Filter the zinc acetate in the reaction mixture.
Separately, the filtrate was concentrated. This is silica gel chromatograph
Fee (hexane / ethyl acetate = 1/2). Yield 373.9 mg (77%)¹ H-NMR (CDCl_Three) 1.61 (s, 9H), 7.14-7.17 (m,
 1H), 7.43-7.47 (m, 2H), 8.04 (s, 1H)

Embodiment 11Production of α- (2-pyrrolyl) -Nt-butylnitrone  Pyrrole-2-carbaldehyde (277.8 mg, 2.92 mmo
l), 1,1-dimethylnitroethane (601.1 mg, 5.83 mm
ol), zinc (572.5 mg, 8.76 mmol) in ethanol (4.0 ml)
Acetic acid (1.05 g, 17.5 mmol) was added dropwise to the suspension while stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for one day. Filter the zinc acetate in the reaction mixture.
Separately, the filtrate was concentrated. This is silica gel chromatograph
Fee (hexane / ethyl acetate = 1/1-2/3). Yield 421.6 mg (87%)¹ H-NMR (CDCl_Three) 1.57 (s, 9H), 6.30-6.33 (m,
 1H), 6.50-6.53 (m, 1H), 6.93-6.94 (m, 1H), 7.52 (s,
1H), 12.01 (brs, 1H)

Embodiment 12Production of α- (4-pyrazolyl) -Nt-butylnitrone
Construction  1,1-dimethylnitroethane (546.0 mg, 5.29 mmo
l), zinc (515.5 mg, 7.89 mmol) in ethanol (3.0 ml)
Acetic acid (950.0 mg, 15.8 mmol) was added dropwise to the suspension under stirring at 5 ° C.
After the addition, the mixture was stirred at room temperature for 45 minutes. Bring reaction to 5 ° C again
After cooling and stirring, pyrazole-4-carbaldehyde (25
(5.4 mg, 2.66 mmol) and stirred at room temperature for one day.
Was. The zinc acetate of the reaction solution was separated by filtration, and the filtrate was concentrated. this
To silica gel chromatography (chloroform / methano
= 10/1). Yield 226.3 mg (51%)¹ H-NMR (CDCl_Three) 1.60 (s, 9H), 6.56 (d, 1H,
J = 2.0 Hz), 7.64 (d, 1H, J = 2.0 Hz), 7.71 (s, 1H),
 8.43 (brs, 1H)

Embodiment 13α- (2-phenylethenyl) -Nt-butylnitro
Manufacturing  Cinnamaldehyde (769.8 mg, 5.82 mmol), 1,1-di
Methylnitroethane (1.20 g, 11.6 mmol), zinc dust (1.14 g)
g, 17.4 mmol) in ethanol (30 ml)
Under the above, acetic acid (2.10 g, 35.0 mmol) was added dropwise.
After stirring for an hour, the mixture was left for 6 days. Cool the reaction to 5 ° C and add
The zinc was filtered off and the filtrate was concentrated. This is silica gel
Matography (hexane / ethyl acetate = 1/1-acetate
Chill only). Yield 541.4 mg (46%)¹ H-NMR (CDCl_Three) 1.56 (s, 9H), 7.01 (d, 1H,
J = 15.8 Hz), 7.28-7.38 (m, 3H), 7.43-7.58 (m, 4H)

Embodiment 14N- (2,4-difluorophenylmethyl) -N- [di
Methyl (methoxymethyl) methyl] amine  1) 2-t-butoxycarbonylamino-2-methyl-
Synthesis of 1-propanol 2-amino-2-methyl-1-propanol (921.2 mg,
 10.33 mmol) in dichloromethane (5 ml)
0 ° C., and di-t-butyl dicarbonate (Boc_TwoO) (2.104
5 g, 9.64 mmol) in dichloromethane (5 ml) in 30 minutes.
I dropped it. After completion of the dropwise addition, the mixture was brought to room temperature and stirred for 5 hours. Reaction
The solution was added to a saturated aqueous solution of sodium bicarbonate, and extracted three times with ethyl acetate._Four
And dried. The solvent is distilled off to give the crude title compound.
(1.7204 g: 88%).¹ H-NMR (CDCl_Three) 4.63 (br, s, 1H), 4.0 (br,
s, 1H), 3.59 (d, J = 6.3 Hz, 2H), 1.43 (s, 9H), 1.25
(s, 6H) 2) 2-t-butoxycarbonylamino-2-methyl-
Synthesis of 1-methoxypropane THF of 60% sodium hydride (635.7 mg, 15.89 mmol)
(10 ml) The suspension was cooled to 0 ° C by ice cooling, and 2-t-butoxy was added.
Carbonylamino-2-methyl-1-propanol (1.5
398 g, 8.14 mmol) in THF (5 ml) was added dropwise.
While stirring. While maintaining the solution at 0 ° C., methyl iodide (0.50
 ml, 8.03 mmol) in THF (5 ml).
Stirred for hours. Add the reaction solution to water, and add ethyl acetate three times.
Extract and MgSO_FourAnd dried. Solvent is distilled off and silica gel
Chromatography (hexane / ethyl acetate = 5/1-0 /
Purification by 1) gave the title compound (422 mg; 26%).
Obtained.¹ H-NMR (CDCl_Three) 4.75 (br, s, 1H), 3.37 (s,
3H), 3.31 (s, 2H), 1.43 (s, 9H), 1.29 (s, 6H)

3) Synthesis of 2-amino-2-methyl-1-methoxypropane hydrochloride 2-t-butoxycarbonylamino-2-methyl-1-methyl
Methoxypropane (422 mg, 2.08 mmol) in ether (5 ml)
4N Hydrogen chloride-dioxane (5 ml) was added to the solution, and the mixture was stirred for 22 hours. The solvent of the reaction solution was distilled off to obtain a crude title compound (342.1 mg). ¹ H-NMR (CDCl ₃ ) 8.32 (brs, 3H), 3.42 (s, 5
H), 1.46 (s, 6H) 4) N- (2,4-difluorobenzylidene) -N-
[Dimethyl (methoxymethyl) methyl] amine To a solution of the obtained 2-amino-2-methyl-1-methoxypropane hydrochloride in toluene (7 ml) was added 2,4-difluorobenzaldehyde (310 mg, 2.18 mmol) and the mixture was heated to reflux. Then, after stirring for 1 hour while dehydrating with a Dean-Stark trap, triethylamine (1.0 ml) was added and the mixture was stirred for 6 hours. The precipitated hydrochloride was removed by filtration, and the solvent of the reaction solution was distilled off to obtain a crude title compound (547.5 mg). ¹ H-NMR (CDCl ₃ ) 8.51 (s, 1H), 8.02 (t
d, J = 8.6, 6.6 Hz, 1H), 6.93-6.76 (m, 2H), 3.39 (s,
2H), 3.36 (s, 3H), 1.27 (s, 6H)

5) N- (2,4-difluorophenylmethyl) -N- [dimethyl (methoxymethyl) methyl] amine N- (2,4-difluorobenzylidene)-obtained
A methanol (7 ml) solution of N- [dimethyl (methoxymethyl) methyl] amine was cooled to 0 ° C. by ice cooling, sodium borohydride (117.1 mg, 3.09 mmol) was added, and the mixture was stirred for 14 hours while gradually returning to room temperature. . The reaction solution was added to saturated aqueous sodium hydrogen carbonate, and the precipitated white solid was dissolved by adding water, extracted three times with ethyl acetate, and dried over MgSO ₄ . The solvent was distilled off and silica gel chromatography (hexane / hexane
Purification with ethyl acetate / triethylamine = 50/25/1) gave N- (2,4-difluorophenylmethyl) -N- [dimethyl (methoxymethyl) methyl] amine (378.8 mg; 95%, 3 steps). I got ¹ H-NMR (CDCl ₃ ) 7.36 (td, J = 8.6, 6.6 Hz,
1H), 6.87-6.72 (m, 2H), 4.72 (s, 1H), 3.69 (s, 2H),
3.36 (s, 3H), 3.24 (s, 2H), 1.13 (s, 6H)

Embodiment 15α- (2,4-difluorophenyl) -N- [dimethyl
Production of (methoxymethyl) methyl] nitrone  N- (2,4-difluorophenyl) obtained in Example 14
Methyl) -N- [dimethyl (methoxymethyl) methyl
[Amine] (378.8 mg, 1.65 mmol), sodium tungstate
Thorium dihydrate (84.3 mg, 0.256 mmol) in methanol
(5 ml) The solution was cooled to 0 ° C by ice cooling, and 31% hydrogen peroxide solution (43
9.3 mg, 4.00 mmol) was added dropwise. Room temperature gradually after dropping
And stirred for 15 hours. The reaction solution was added to a saturated saline solution,
Extract three times with ethyl acetate, extract MgSO_FourAnd dried. Evaporate the solvent
To silica gel chromatography (toluene / acetic acid
Purification by chill = 5/1) gave the title compound (204.8
 mg; 51%).¹ H-NMR (CDCl_Three) 9.43 (td, J = 8.7, 6.9 Hz,
 1H), 7.77 (s, 1H), 6.97-6.89 (m, 1H), 6.84 (ddd, J =
 11.2, 8.7, 2.6 Hz, 1H), 3.65 (s, 2H), 3.36 (s, 3H),
 1.58 (s, 6H)

Embodiment 16α- (2,4-difluorophenyl) -N- [dimethyl
Production of (methoxymethoxymethyl) methyl] nitrone  1) 2-Methyl-2-nitro-1- (methoxymethoxy)
B) Propane 2-methyl-2-nitro-1-propanol (366.8 mg,
 3.08 mmol) and lithium bromide (60.8 mg, 0.700 mmol).
P-Toluenesulfonic acid in methoxymethane (5 ml) solution
Add monohydrate (56.3 mg, 0.296 mmol) and stir for 24 hours.
Was. The reaction solution was added to water, extracted three times with ether, MgSO_Four
And dried. Solvent is distilled off and silica gel chromatography
(Hexane / ether = 4/1)
Gave the title compound (382.7 mg; 76%).¹ H-NMR (CDCl_Three) 4.61 (s, 2H), 3.81 (s, 2H),
 3.34 (s, 3H), 1.61 (s, 6H) 2) α- (2,4-difluorophenyl) -N- [dimethyl
Tyl (methoxymethoxymethyl) methyl] nitrone 2,4-difluorobenzaldehyde (293.3 mg, 2.06
mmol), 2-methyl-2-nitro-1- (methoxymeth
Xy) propane (382.7 mg, 2.35 mmol), zinc dust (266 m
g, 4.07 mmol) in ethanol (5 ml).
℃ and acetic acid (0.46 ml, 8.0 mmol) was added dropwise. End of dripping
After completion, the temperature was gradually returned to room temperature and stirred for 19 hours. Remove the reaction solution
Filter by light and evaporate the solvent to remove silica gel.
Purify with hexane (hexane / ethyl acetate = 4/1)
Gave the title compound (361.9 mg; 56%).¹ H-NMR (CDCl_Three) 9.43 (td, J = 8.7, 6.9 Hz,
 1H), 7.79 (s, 1H), 6.96-6.89 (m, 1H), 6.84 (ddd, J
= 11.2, 8.7, 2.6 Hz, 1H), 4.61 (s, 2H), 3.81 (s, 2
H), 3.33 (s, 3H), 1.61 (s, 6H)

Embodiment 17α- (2,4-difluorophenyl) -N- [dimethyl
Production of (acetoxymethyl) methyl] nitrone  1) 2-Methyl-2-nitro-1-acetoxypropane 2-methyl-2-nitro-1-propanol (375.4 mg,
 3.15 mmol), triethylamine (0.80 ml, 5.74 mmol)
Acetic anhydride (0.34 ml, 3.60) in dichloromethane (5 ml) solution
mmol) and stirred for 2.5 hours. Evaporate the solvent of the reaction solution
To silica gel chromatography (hexane / ether
To give the title compound (467.8 m
g; 92%).¹ H-NMR (CDCl_Three) 4.40 (s, 2H), 2.08 (s, 3H),
 1.62 (s, 6H) 2) α- (2,4-difluorophenyl)
-N- [dimethyl (acetoxymethyl) methyl] nitro
2,4-difluorobenzaldehyde (428.2 mg, 3.01
mmol), 2-methyl-2-nitro-1-acetoxypro
Bread (467.8 mg, 2.90 mmol), zinc dust (321.7 mg, 4.92 m
mol) of ethanol (5 ml) was brought to 0 ° C by ice cooling,
Acetic acid (0.57 ml, 9.9 mmol) was added dropwise. Gradually after dropping
To room temperature and stirred for 16 hours. Filter the reaction solution through Celite
And the solvent is distilled off.
(Hexane / ethyl acetate = 2/1)
Gave the title compound (380.8 mg; 48%).¹ H-NMR (CDCl_Three) 9.41 (td, J = 8.7, 6.9 Hz,
 1H), 7.75 (s, 1H), 7.00-6.91 (m, 1H), 6.86 (ddd, J =
 11.2, 8.7, 2.6 Hz, 1H), 4.42 (s, 2H), 2.05 (s, 3H),
 1.62 (s, 6H)

Embodiment 18N- (2,4-difluorophenylmethyl) -Nt-
Production of butylamine  1) N- (2,4-difluorobenzylidene) -t-butyl
Tylamine 2,4-difluorobenzaldehyde (431.6 mg, 3.04
mmol) in toluene (5 ml).
l, 6.00 mmol), heat the mixture under reflux and add Dean-Starktrap.
After stirring for 1 hour while dehydrating,
Min (0.63 ml, 6.00 mmol) was added and stirred for 5 hours. Anti
The title compound is obtained by distilling off the solvent of the reaction solution.
Was.¹ H-NMR (CDCl_Three) 8.49 (s, 1H), 8.02 (td, J =
 8.6, 6.6 Hz, 1H), 6.93-6.76 (m, 2H), 1.29 (s, 9H) 2) N- (2,4-difluorophenylmethyl) -N-
t-butylamine obtained N- (2,4-difluorobenzylidene)-
A solution of t-butylamine in methanol (5 ml) was cooled with ice.
0 ° C and sodium borohydride (138.3 mg, 3.65 mmo
l) was added, and the mixture was stirred for 2.5 hours while gradually returning to room temperature.
Add the reaction solution to saturated aqueous sodium hydrogen carbonate and extract three times with ethyl acetate
And MgSO_FourAnd dried. Solvent is distilled off and silica gel
Matography (ethyl acetate / ethanol / triethyl alcohol)
Purification with min = 100/5/1) gave the title compound (5
04.2 mg; 83%, 2 steps).¹ H-NMR (CDCl_Three) 7.41-7.31 (m, 1H), 6.86-6.
73 (m, 2H), 3.73 (s, 2H), 1.42 (br, 1H), 1.17 (s, 9H)

Embodiment 19α- (3,4-difluorophenyl) -Nt-butyl
Nitron production  3,4-difluorobenzaldehyde (289.1 mg, 2.03
mmol), 2-methyl-2-nitropropane (413.5 mg, 4.
01 mmol), zinc dust (399 mg, 6.10 mmol) in ethanol (5
The suspension was cooled to 0 ° C by ice cooling, and acetic acid (0.69 ml, 12.0 m
mol) was added dropwise. After dropping, gradually return to room temperature for 2.5 hours
After stirring for a while, it was left overnight. Celite filtration of the reaction solution
The solvent is distilled off and silica gel chromatography (He
Purification with hexane / ethyl acetate = 10/1)
The title compound (394.2 mg; 91%) was obtained.¹ H-NMR (CDCl_Three) 8.58 (ddd, J = 12.5, 8.2,
2.0 Hz, 1H), 7.78-7.72 (m, 1H), 7.52 (s, 1H), 7.18 (d
t, J = 10.1, 8.4 Hz, 1H), 1.61 (s, 9H)

Embodiment 20α- (2,5-difluorophenyl) -Nt-butyl
Nitron production  2,5-difluorobenzaldehyde (291.5 mg, 2.05
mmol), 2-methyl-2-nitropropane (427.3 mg, 4.
14 mmol), zinc dust (407.3 mg, 6.23 mmol) in ethanol
(5 ml) The suspension was cooled to 0 ° C by ice cooling, and acetic acid (0.69 ml, 12.
0 mmol) was added dropwise. After dropping, gradually return to room temperature and leave at 2:00
After stirring for a while, it was left overnight. Celite filtration of the reaction solution
The solvent is distilled off and silica gel chromatography (He
Purification with hexane / ethyl acetate = 10/1)
The title compound (393 mg; 90%) was obtained.¹ H-NMR (CDCl_Three) 9.16-9.08 (m, 1H), 7.84 (d,
 J = 1.3 Hz, 1H), 7.07-7.01 (m, 2H), 1.62 (s, 9H)

Embodiment 21α- (2,4-difluorophenyl) -N- [dimethyl
Production of (hydroxymethyl) methyl] nitrone  1) N- (2,4-difluorophenylmethyl) -N
-[Dimethyl (t-butyldimethylsiloxymethyl) methyl
Tyl] amine 2,4-difluorobenzaldehyde (1.42 g, 10.0 mm
ol) in toluene (30 ml) solution.
Siloxy-2-methyl-2-propylamine (2.03 g, 1
(0.0 mmol) and heated under reflux, and deaerated by Dean-Stark trap.
The mixture was stirred with water for 6 hours. The solvent of the reaction solution is distilled off,
The residue was converted to a methanol (10 ml) solution by ice cooling at 0 ° C.
Add excess sodium borohydride as
The mixture was stirred while returning to warm temperature until the Schiff base disappeared. Anti
The reaction solution was added to a 1N aqueous solution of sodium hydroxide, and toluene was added.
, And the organic layer is washed with a saturated saline solution._Fourso
Dried. The solvent is distilled off to give the crude title compound.
(2.92 g; 92%, 2 steps).¹ H-NMR (CDCl_Three) 7.40-7.14 (m, 1H), 6.86-
6.72 (m, 2H), 3.67 (d, 2H, J = 9.0 Hz), 3.42 (s, 2
H), 1.91-61 (br, 1H), 1.10 (s, 6H), 0.94 (s, 9H),
0.08 (s, 6H) 2) α- (2,4-difluorophenyl) -N- [dimethyl
Tyl (t-butyldimethylsiloxymethyl) methyl] d
Tolon N- (2,4-difluorophenylmethyl) -N- [di
Methyl (methoxymethyl) methyl] amine (2.0 g, 6.0
8 mmol), sodium tungstate dihydrate (0.080
g, 0.24 mmol) in methanol (10 ml).
° C, and 31% aqueous hydrogen peroxide (2 ml) was added dropwise. Drip end
Thereafter, the mixture was gradually warmed to room temperature and stirred overnight. The reaction solution was saturated saline
Add to water, extract three times with ethyl acetate,_FourAnd dried.
The solvent was distilled off and silica gel chromatography (hexa
Purification by purification in ethyl acetate / ethyl acetate = 5/1)
The compound (1.53 g; 73%) was obtained.¹ H-NMR (CDCl_Three) 9.41 (td, 1H, J = 8.7, 6.
9 Hz), 7.77 (s, 1H), 6.96-6.89 (m, 1H), 6.83 (ddd,
 1H, J = 11.2, 8.7, 2.6 Hz), 3.79 (s, 2H), 1.56
(s, 6H), 0.83 (s, 9H), 0.00 (s, 6H)

3) α- (2,4-difluorophenyl) -N
-[Dimethyl (hydroxymethyl) methyl] nitrone α- (2,4-difluorophenyl) -N- [dimethyl (t-butyldimethylsiloxymethyl) methyl] nitrone (688.3 mg, 2.00 mmol) in THF (20 ml) Was cooled to 0 ° C. by ice cooling, and pyridine hydrofluoride (1 ml) was carefully added. The temperature was gradually raised to room temperature, and the mixture was stirred for 7 hours. The reaction solution was added to saturated aqueous sodium hydrogen carbonate, extracted three times with ethyl acetate, and dried over MgSO ₄ . The solvent was distilled off, and the precipitated white crystals were washed with hexane to give the title compound (317.3 mg; 69%). _{^{1 H-NMR (CDCl 3)}} 9.35 (td, 1H, J = 8.7, 6.
9 Hz), 7.73 (s, 1H), 7.01-6.92 (m, 1H), 6.87 (ddd,
1H, J = 11.2, 8.7, 2.6 Hz), 3.94 (t, 1H, J = 5.9 H
z), 3.80 (d, 2H, J = 5.9 Hz), 1.61 (s, 6H)

Embodiment 22α- (2,4-difluorophenyl) -N- [dimethyl
Production of (benzyloxymethyl) methyl] nitrone  1) 2-Methyl-2-nitro-1-benzyloxypropa
2-methyl-2-nitro-1-propanol (2.3975 g,
 20.13 mmol), D of silver (I) oxide (4.6385 g, 20.02 mmol)
Benzyl bromide (2.65 ml, 22.28 mmol) in MF 25 ml suspension
Was added and stirred for 48 hours. The reaction solution was filtered and the filtrate was 5%
Ethyl acetate / toluene
= Extract 3 times with 1/1, MgSO_FourAnd dried. Evaporate the solvent
Purified by silica gel chromatography (toluene only)
This gave the title compound (639.4 mg; 15%).¹ H-NMR (CDCl_Three) 7.38-7.25 (m, 5H), 4.54
(s, 2H), 3.72 (s, 2H), 1.59 (s, 6H) 2) α- (2,4-difluorophenyl) -N- [dimethyl
Tyl (benzyloxymethyl) methyl] nitrone 2,4-difluorobenzaldehyde (443.7 mg, 3.12
mmol), 2-methyl-2-nitro-1-benzyloxyp
Lopan (639.4 mg, 3.06 mmol), zinc dust (326.4 mg, 4.99
(mmol) of ethanol (6 ml) was cooled to 0 ° C by ice cooling,
Acetic acid (0.57 ml, 9.9 mmol) was added dropwise. Gradually after dropping
The mixture was returned to room temperature and stirred for 7 hours. Celite filtration of the reaction solution
The solvent is distilled off and silica gel chromatography (He
By purifying with hexane / ethyl acetate = 10/1-4/1)
Gave the title compound (468.8 mg; 48%).¹ H-NMR (CDCl_Three) 9.43 (td, 1H, J = 8.9, 6.
9 Hz), 7.82 (s, 1H), 7.38-7.25 (m, 5H), 6.99-6.80
(m, 2H), 4.54 (s, 2H), 3.73 (s, 2H), 1.59 (s, 6H)

Embodiment 23α- (2,4-difluorophenyl) -N- [dimethyl
(3,3-ethylenedioxy-1-propyl) methyl]
Nitron production  2,4-difluorobenzaldehyde (290.6 mg, 2.04
mmol), 2- (3-methyl-3-nitrobutyl) -1,
3-dioxolane (776.8 mg, 4.11 mmol), zinc dust (40
(2.7 mg, 6.16 mmol) in 5 ml of ethanol
The temperature was further raised to 0 ° C., and acetic acid (0.69 ml, 12.0 mmol) was added dropwise.
After completion of dropping, gradually return to room temperature and stir for 10 hours, then overnight
I left it. The reaction solution was filtered through celite and the solvent was distilled off.
Silica gel chromatography (hexane / ethyl acetate
= 4/1-1/1) to give the title compound (419.
4 mg; 69%).¹ H-NMR (CDCl_Three) 9.41 (td, 1H, J = 8.6, 6.
9 Hz), 7.72 (s, 1H), 6.96-6.88 (m, 1H), 6.84 (ddd,
 1H, J = 11.2, 8.6, 2.6 Hz), 4.86 (t, 1H, d = 4.6 H
z), 3.99-3.81 (m, 4H), 2.05-1.98 (m, 2H), 1.65-1.5
8 (m, 2H), 1.59 (s, 6H)

Example 24 α- (2-Fluoro-4-methoxyphenyl) -Nt
Preparation of -butylnitrone 1) Methyl 2,4-difluorobenzoate A solution of 2,4-difluorobenzoic acid (1.5808 g, 10.00 mmol) in methanol (15 ml) was cooled to 0 ° C. by ice cooling, and thionyl chloride (1.46 ml, 20.02 mmol) was used. ) In methanol (10 ml) was added dropwise. After completion of the dropwise addition, the temperature was gradually raised to room temperature, followed by stirring for 24 hours. The reaction solution was added to saturated aqueous sodium hydrogen carbonate, extracted three times with ether, and dried over MgSO ₄ . The solvent was distilled off, and the residue was purified by silica gel chromatography (hexane / ether = 5/1) to give the title compound (1.6743 g; 97%). ¹ H-NMR (CDCl ₃ ) 7.99 (td, 1H, J = 8.2, 6.
6 Hz), 6.98-6.84 (m, 2H), 3.93 (s, 3H) 2) Methyl 2-fluoro-4-methoxybenzoate and Methyl 4-fluoro-2-methoxybenzoate Methyl 2,4-difluorobenzoate (1.5249 g, 8.76 mm
ol) in methanol (10 ml) was cooled to 0 ° C. by ice cooling, and sodium methoxide (28% methanol solution) (1.9860 g, 10.29 g
mmol) was added. The mixture was gradually brought to room temperature and stirred for 24 hours. The reaction solution was added to water, extracted three times with ethyl acetate, and dried over MgSO ₄ . By evaporating the solvent and purifying by silica gel chromatography (hexane / ether = 10/1),
The title compounds methyl 2-fluoro-4-methoxybenzoate (618.2 mg; 38%) and methyl 4-fluoro-2-methoxybenzoate (442.2 mg; 27%) were obtained. Methyl 2-fluoro-4-methoxybenzoate ¹ H-NMR (CDCl ₃ ) 7.90 (t, 1H, J = 8.7 Hz),
6.72 (ddd, 1H, J = 8.7, 2.3, 0.7 Hz), 6.64 (dd, 1
H, J = 12.5, 2.3 Hz), 3.90 (s, 3H), 3.85 (s, 3H) Methyl 4-fluoro-2-methoxybenzoate ¹ H-NM
R (CDCl ₃ ) 7.86 (dd, 1H, J = 9.1, 6.8 Hz), 6.
71-6.64 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H)

3) 2-fluoro-4-methoxybenzyl alcohol Lithium aluminum hydride (71.6 mg, 1.89 mmol) T
To a suspension of 3 ml of HF, a solution of methyl 2-fluoro-4-methoxybenzoate (273.3 mg, 1.48 mmol) in 3 ml of THF was added dropwise, and the mixture was stirred for 0.5 hour. A water-THF mixed solution was added dropwise to the reaction solution, and then added to water, and extracted three times with ethyl acetate.
and dried over gSO _4. Evaporation of the solvent gave the crude title compound (240.4 mg;> 99%). _{^{1 H-NMR (CDCl 3)}} 7.29 (t, 1H, J = 8.6 Hz),
6.69 (dd, 1H, J = 8.6, 2.6 Hz), 6.63 (dd, 1H, J =
11.7, 2.6 Hz), 4.68 (d, 2H, J = 5.0 Hz), 3.80 (s,
3H), 1.65 (t, 1H, J = 5.0 Hz)

4) 2-fluoro-4-methoxybenzaldehyde 2-fluoro-4-methoxybenzyl alcohol (346.9
mg, 2.22 mmol) in 8 ml of DMSO, triethylamine (0.92 ml, 6.60 mmol) was added, and pyridine complex of sulfur trioxide (1.0501 g, 6.60 mmol) was slowly added while observing heat generation, followed by stirring for 0.5 hour. The reaction solution was added 5% aqueous potassium hydrogensulfate solution, extracted 3 times with ethyl acetate, MgSO ₄
And dried. The solvent was distilled off, and the residue was purified by silica gel chromatography (hexane / ethyl acetate = 5/1) to give the title compound (301 mg; 88%). ¹ H-NMR (CDCl ₃ ) 10.21 (s, 1H), 7.83 (t, 1
H, J = 8.3 Hz), 6.79 (ddd, 1H, J = 8.3, 2.3, 0.7 H
z), 6.65 (dd, 1H, J = 12.2, 2.3 Hz), 3.88 (s, 3H) 5) α- (2-Fluoro-4-methoxyphenyl) -N
-T-butyl nitrone 2-fluoro-4-methoxybenzaldehyde (301 mg,
The same reaction as in Example 1 was carried out using 1.95 mmol) to give the title compound (373.9 mg; 85%). _{^{1 H-NMR (CDCl 3)}} 9.34 (t, 1H, J = 9.1 Hz),
7.75 (s, 1H), 6.74 (dd, 1H, J = 9.1, 2.6 Hz), 6.6
4 (dd, 1H, J = 13.0, 2.6 Hz), 3.84 (s, 3H), 1.61
(s, 9H)

Embodiment 25α- (4-fluoro-2-methoxyphenyl) -Nt
-Production of butyl nitrone  1) 4-Fluoro-2-methoxybenzyl alcohol T of lithium aluminum hydride (94.6 mg, 2.49 mmol)
The 4-F suspension obtained in Example 23-2) was added to a 3 ml suspension of HF.
Methyl fluoro-2-methoxybenzoate (442.2 mg, 2.40
(mmol) was added dropwise and the mixture was stirred for 1 hour. Anti
The water-THF mixed solution was dropped into the reaction solution, and then added to water.
Extract three times with ethyl acetate, extract MgSO_FourAnd dried. Evaporate the solvent
To give the crude title compound (310.8 mg; 83%).
Was.¹ H-NMR (CDCl_Three) 7.23 (dd, 1H, J = 8.6, 6.
6 Hz), 6.68-6.59 (m, 2H), 4.64 (d, 2H, J = 6.3 H
z), 3.86 (s, 3H), 2.13 (t, 1H, J = 6.3 Hz) 2) 4-fluoro-2-methoxybenzaldehyde 4-fluoro-2-methoxybenzyl alcohol (310.8
 mg, 1.99 mmol) in 7 ml of DMSO.
Min (0.84 ml, 6.03 mmol) and sulfur trioxide pyridine
Dissolve the complex salt (938.6 mg, 5.90 mmol)
It was added clearly and stirred for 1 hour. The reaction solution is 5% hydrogen sulfate
Aqueous solution, extracted three times with ethyl acetate, extracted with MgSO_Fourso
Dried. Solvent is distilled off and silica gel chromatography
-(Hexane / ethyl acetate = 5/1)
Gave the title compound (293.3 mg; 96%).¹ H-NMR (CDCl_Three) 10.36 (d, 1H, J = 0.8 H
z), 7.86 (dd, 1H, J = 8.6, 6.9 Hz), 6.73 (tdd, 1H,
 J = 8.6, 2.3, 0.8 Hz), 6.69 (dd, 1H, J = 10.6, 2.
3 Hz), 3.93 (s, 3H)

3) α- (4-Fluoro-2-methoxyphenyl) -Nt-butylnitrone 4-fluoro-2-methoxybenzaldehyde (293.3 m
g, 1.90 mmol) to carry out the same reaction as in Example 1 to obtain the title compound (405.7 mg; 95%). ¹ H-NMR (CDCl ₃ ) 9.44 (dd, 1H, J = 8.9, 7.
3 Hz), 7.95 (s, 1H), 6.71 (td, 1H, J = 8.9, 2.3 H
z), 6.60 (dd, 1H, J = 10.8, 2.3 Hz), 3.87 (s, 3H),
1.54 (s, 9H)

Embodiment 26α- (4-trifluoromethylphenyl) -Nt-butyl
Production of tilnitron  4-trifluoromethylbenzaldehyde (343.7 mg, 1.9
7 mmol) and the same reaction as in Example 1 was carried out.
Gave the title compound (445.2 mg; 92%).¹ H-NMR (CDCl_Three) 8.39 (d, 2H, J = 8.4 Hz),
 7.66 (d, 2H, J = 8.4Hz), 7.62 (s, 1H), 1.63 (s, 9
H)

Embodiment 27α- (4-bromophenyl) -Nt-butylnitrone
Manufacturing of  Use 4-bromobenzaldehyde (372.2 mg, 2.01 mmol)
By performing the same reaction as in Example 1, the title compound was obtained.
(492.1 mg; 96%).¹ H-NMR (CDCl_Three) 8.17 (dd, 2H, J = 6.8, 1.
7 Hz), 7.54 (dd, 2H, J = 6.8, 2.0 Hz), 7.51 (s, 1
H), 1.61 (s, 9H)

Embodiment 28α- (4-methoxyphenyl) -Nt-butylnitro
Manufacturing  Using p-anisaldehyde (274.9 mg, 2.02 mmol,
The same reaction as in Example 1 was carried out to give the title compound (41
2.4 mg; 98%).¹ H-NMR (CDCl_Three) 8.29 (d, 2H, J = 9.1 Hz),
 7.47 (s, 1H), 6.93 (d, 2H, J = 9.1 Hz), 3.85 (s,
3H), 1.61 (s, 9H)

Embodiment 29α- (4-trifluoromethoxyphenyl) -Nt-
Production of butyl nitrone  4- (trifluoromethoxy) -benzaldehyde (293.2 m
g, 1.54 mmol) in the same manner as in Example 1.
And gave the title compound (353.9 mg; 88%).¹ H-NMR (CDCl_Three) 8.36 (d, 2H, J = 9.2 Hz),
 7.56 (s, 1H), 7.25 (d, 2H, J = 9.2 Hz), 1.62 (s, 9
H)

Embodiment 30N- (4-cyanophenylmethyl) -Nt-butyla
Production of min  4-cyanobenzaldehyde (392.9 mg, 3.00 mmol), t
-Butylamine (227.3 mg, 3.10 mmol) in 1,2-dichloromethane
Loetane To a 10 ml solution add sodium triacetoxyborohydride.
Thorium (0.8567 g, 4.04 mmol) was added and stirred for 3 hours.
After that, acetic acid (0.17 ml, 2.95 mmol) was added and 2.5 more
Stirred for hours. The reaction solution is added to a saturated aqueous solution of sodium bicarbonate, and ethyl acetate is added.
Extraction three times with MgSO_FourAnd dried. Distilling off the solvent
Gave the crude title compound (595.3 mg).¹ H-NMR (CDCl_Three) 7.60 (d, 2H, J = 8.4 Hz),
 7.47 (d, 2H, J = 8.4Hz), 3.79 (s, 2H), 1.17 (s, 9
H)

Example 31α- (4-cyanophenyl) -Nt-butylnitrone
Manufacturing of  N- (4-cyanophenylmethyl) obtained in Example 30
L) -Nt-butylamine (595.3 mg), tungsten
Metabolic acid sodium dihydrate (105.7 mg, 0.320 mmol)
Knol 5 ml solution to 0 ° C by ice cooling, 31% hydrogen peroxide
Water (786.2 mg, 7.17 mmol) was added dropwise. Gradually after dropping
The mixture was stirred at room temperature for 14 hours. Add the reaction solution to water and add acetic acid
Extract three times with ethyl and extract MgSO_FourAnd dried. Evaporate the solvent
Silica gel chromatography (hexane / ethyl acetate
= 2/1-1/1) to give the title compound (272.
3 mg; 45%, two steps).¹ H-NMR (CDCl_Three) 8.37 (d, 2H, J = 8.6 Hz),
 7.68 (d, 2H, J = 8.6Hz), 7.62 (s, 1H), 1.62 (s, 9
H)

Embodiment 32α- (2-chloro-4-fluorophenyl) -Nt-
Production of butyl nitrone  2-chloro-4-fluorobenzaldehyde (316.6 mg,
 (2.00 mmol) and perform the same reaction as in Example 1.
Gave the title compound (387.8 mg; 84%).¹ H-NMR (CDCl_Three) 9.48 (dd, 1H, J = 8.9, 6.
6 Hz), 8.02 (s, 1H), 7.17 (dd, 1H, J = 8.3, 2.6 H
z), 7.10-7.01 (m, 1H), 1.63 (s, 9H)

Embodiment 33α- (4-fluoro-2-trifluoromethylphenyi
F) Production of -Nt-butylnitrone  4-fluoro-2-trifluoromethylbenzaldehyde
(286.2 mg, 1.49 mmol) in the same manner as in Example 1.
Reaction afforded the title compound (310.8 mg; 79%).
Was.¹ H-NMR (CDCl_Three) 9.57 (dd, 1H, J = 8.9, 5.
8 Hz), 7.88 (s, 1H), 7.42 (dd, 1H, J = 8.9, 3.0 H
z), 7.35-7.26 (m, 1H), 1.61 (s, 9H)

Embodiment 34α- (2-fluoro-4-trifluoromethylphenyi
F) Production of -Nt-butylnitrone  2-fluoro-4-trifluoromethylbenzaldehyde
(291.3 mg, 1.52 mmol) and the same reaction as in Example 1.
Reaction afforded the title compound (347.2 mg; 87%).
Was.¹ H-NMR (CDCl_Three) 9.46 (t, 1H, J = 7.6 Hz),
 7.89 (s, 1H), 7.48 (d, 1H, J = 7.6 Hz), 7.34 (d,
1H, J = 10.9 Hz), 1.63 (s, 9H)

Embodiment 35N- (2,4-difluorophenylmethyl) -N-cycl
Production of rohexylamine  1) N- (2,4-difluorobenzylidene) -cyclo
Hexylamine 2,4-difluorobenzaldehyde (0.4353 g, 3.06
mmol) and cyclohexylamine (0.69 ml, 6.03 mmol).
And performing the same reaction as in Example 18-1).
To give the crude title compound.¹ H-NMR (CDCl_Three) 8.54 (s, 1H), 7.99 (td, 1
H, J = 8.9, 6.6 Hz), 6.94-6.85 (m, 1H), 6.81 (ddd,
 1H, J = 10.6, 8.9, 2.6 Hz), 3.23 (tt, 1H, J = 10.
4, 4.1 Hz), 1.9-1.0 (m, 10H) 2) N- (2,4-difluorophenylmethyl) -N-
t-Butylamine N- (2,4-difluoro) obtained in Example 35-1)
Example using (benzylidene) -cyclohexylamine
By performing the same reaction as in 18-2), the crude title compound is obtained.
I got something.¹ H-NMR (CDCl_Three) 7.36-7.26 (m, 1H), 6.87-
6.74 (m, 2H), 3.81 (s, 2H), 2.49-2.40 (m, 1H), 1.9-
1.0 (m, 10H)

Embodiment 36α- (2,4-difluorophenyl) -N-cyclohex
Manufacture of silnitron  N- (2,4-difluoro) obtained in Example 35-2)
(Phenylmethyl) -Nt-butylamine
The same reaction as in Example 15 was carried out to give the title compound (0.2
966 g; 41%, 3 steps).¹ H-NMR (CDCl_Three) 9.37 (td, 1H, J = 8.6, 6.
9 Hz), 7.66 (s, 1H), 6.97-6.90 (m, 1H), 6.83 (ddd,
 1H, J = 11.2, 8.6, 2.6 Hz), 3.88 (tt, 1H, J = 11.
2, 4.1 Hz), 2.1-1.2 (m, 10H)

Embodiment 37α- (4-chlorophenyl) -Nt-butylnitrone
Manufacturing of  4-chlorobenzaldehyde (0.2819 g, 2.01 mmol)
And performing the same reaction as in Example 1 to give the title
The compound (0.3830 g; 90%) was obtained.¹ H-NMR (CDCl_Three) 8.25 (d, 2H, J = 8.6 Hz),
 7.53 (s, 1H), 7.38 (d, 2H, J = 8.6 Hz), 1.61 (s,
9H)

Embodiment 38α- (4-chloro-2-fluorophenyl) -Nt-
Production of butyl nitrone  1) 4-chloro-2-fluorobenzyl alcohol 4-chloro-2-fluorobenzoic acid (0.5259 g, 3.01 mm
ol) and performing the same reaction as in Example 24-3).
Gave the title compound (0.4984 g;> 99%).¹ H-NMR (CDCl_Three) 7.38 (t, 1H, J = 8.3 Hz),
 7.15 (dd, 1H, J = 8.3, 2.0 Hz), 7.09 (dd, 1H, J =
 9.9, 2.0 Hz), 4.73 (br, d, J = 3.6 Hz, 2H), 1.79
(br, 1H) 2) 4-chloro-2-fluorobenzaldehyde 4-chloro-2-fluorobenzyl alcohol (0.4907
g, 3.06 mmol) and the same reaction as in Example 24-4).
To give the title compound (0.3052 g, 63%).
Was.¹ H-NMR (CDCl_Three) 10.31 (d, 1H, J = 0.7 H
z), 7.83 (dd, 1H, J = 8.2, 7.3 Hz), 7.31-7.20 (m,
2H) 3) α- (4-chloro-2-fluorophenyl) -N-
t-butyl nitrone 4-chloro-2-fluorobenzaldehyde (0.2966 g,
 (1.87 mmol) to perform the same reaction as in Example 1.
Gave the title compound (0.3292 g, 77%).¹ H-NMR (CDCl_Three) 9.33 (t, 1H, J = 8.6 Hz),
 7.80 (s, 1H), 7.19 (dd, 1H, J = 8.6, 2.0 Hz), 7.1
1 (dd, 1H, J = 10.9, 2.0 Hz), 1.61 (s, 9H)

Embodiment 39α- (4-bromo-2-fluorophenyl) -Nt-
Production of butyl nitrone  4-bromo-2-fluorobenzaldehyde (0.3051 g,
 Perform the same reaction as in Example 1 using 1.50 mmol)
Gave the title compound (0.3716 g, 90%).¹ H-NMR (CDCl_Three) 9.26 (t, 1H, J = 8.6 Hz),
 7.80 (s, 1H), 7.38-7.33 (m, 1H), 7.27 (dd, 1H, J
= 10.6, 2.0 Hz), 1.61 (s, 9H)

Embodiment 40N- (2,4-difluorophenylmethyl) -N- (1
-Methylcyclopropyl) amine  1) 1-methylcyclopropanecarbamic acid-t-butyl
1-methylcyclopropanecarboxylic acid (1.0337 g, 10.32
 mmol) in 15 ml of t-butanol.
(1.70 ml, 12.2 mmol), diphenylphosphate azide (3,032
(4 g, 11.02 mmol) and stirred for 1 hour, then distilled for 5 hours
did. After the reaction solvent was distilled off under reduced pressure, the residue was added to saturated aqueous sodium hydrogen carbonate,
The mixture was extracted three times with ethyl acetate and dried over magnesium sulfate. Dissolution
The solvent is distilled off, and silica gel chromatography (hexane
/ Ethyl acetate = 5/1) to give the title compound
(0.5896 g, 33%).¹ H-NMR (CDCl_Three) 4.84 (br, 1H), 1.44 (s, 9
H), 1.34 (s, 3H), 0.76-0.70 (m, 2H), 0.60-0.54 (m,
 2H) 2) 1-methylcyclopropylamine hydrochloride 1-methylcyclopropanecarbamate-t-butyl
(0.5896 g, 3.44 mmol) in 5 ml of diethyl ether
Add 4N-hydrochloric acid-dioxane solution (5 ml) and stir for 3 hours
And left overnight. The precipitated white crystals are collected by filtration, and
After washing with chill ether and drying,
The title compound (0.3452 g, 93%) was obtained.¹ H-NMR (CDCl_Three) 8.54 (br, 3H), 1.54 (s, 3
H), 1.22-1.17 (m, 2H), 0.70-0.64 (m, 2H) 3) N- (2,4-difluorophenylmethyl) -N-
(1-methylcyclopropyl) amine 1-methylcyclopropylamine hydrochloride (0.2155 g, 2.0
0 mmol), 2,4-difluorobenzaldehyde (0.2859
 g, 2.01 mmol), triethylamine (0.56 ml, 4.0 mmol)
Was added to a suspension of 6 ml of 1,2-dichloroethane
Add sodium borohydride (0.6351 g, 3.00 mmol)
And stirred overnight. Add the reaction solution to saturated aqueous sodium bicarbonate
After stirring briefly, extract three times with ethyl acetate and add sodium sulfate.
Dried. The title compound can be obtained by evaporating the solvent.
And a mixture of imines (0.4241 g). This
To a temperature of 0 ° C with ice cooling as a 5 ml
Thorium (0.1165 g, 3.08 mmol) was added. Gradually room temperature
And stirred for 2 hours. Add the reaction solution to saturated aqueous sodium bicarbonate
After stirring for a while, extract with ethyl acetate three times,
Dried with thorium. The solvent is distilled off,
The title compound (0.3799 g, 96%) was obtained.¹ H-NMR (CDCl_Three) 7.30 (td, 1H, J = 8.2, 6.
6 Hz), 6.86-6.72 (m, 2H), 3.83 (s, 2H), 1.32 (s, 3
H), 0.61-0.56 (m, 2H), 0.41-0.36 (m, 2H)

Embodiment 41α- (2,4-difluorophenyl) -N- (1-methyl
Production of rucyclopropyl) nitrone  N- (2,4-difluoro) obtained in Example 40-3)
Phenylmethyl) -N- (1-methylcyclopropyl)
As in Example 15 using amine (0.3799 g, 1.93 mmol).
The title compound (0.1966 g, 48
%).¹ H-NMR (CDCl_Three) 9.35 (td, 1H, J = 8.7, 6.
9 Hz), 7.86 (s, 1H), 6.99-6.90 (m, 1H), 6.85 (ddd,
 1H, J = 11.0, 8.6, 2.5 Hz), 1.76 (s, 3H), 1.50 (b
r t, 2H, J = 6 Hz), 0.89 (ddd, 2H, J = 7.6, 5.1,
1.3 Hz)

Embodiment 42N- (2,4-difluorophenylmethyl) -N-
Production of (1,1-dimethylpropyl) amine  2,4-difluorobenzaldehyde (1.4203 g, 9.99
mmol) in methanol (15 ml).
Lumin (1.17 ml, 10.0 mmol) was added and the exotherm subsided.
Sodium borohydride (0.2538 g, 4.04 m
mol), and the mixture was stirred for 6 hours.
Add sodium iodide (0.5037 g, 8.02 mmol) and stir overnight.
Stirred. Add the reaction solution to saturated aqueous sodium bicarbonate and stir for a while.
After that, methanol was distilled off under reduced pressure and extracted three times with ethyl acetate.
And dried over magnesium sulfate. To remove the solvent
Thus, the crude title compound (1.9854 g, 93%) was obtained.¹ H-NMR (CDCl_Three) 7.39 (td, 1H, J = 8.4, 6.
6 Hz), 6.88-6.74 (m, 2H), 3.70 (s, 2H), 1.51 (q, 2
H, J = 7.5 Hz), 1.13 (s, 6H), 0.90 (t, 3H, J = 7.5
Hz)

Embodiment 43α- (2,4-difluorophenyl) -N- (1,1-
Production of dimethylpropyl) nitrone  N- (2,4-difluorophenyl) obtained in Example 43
Methyl) -N- (1,1-dimethylpropyl) amine
(1.9854 g, 9.31 mmol) and the same reaction as in Example 15.
Reaction yielded the title compound (1.4634 g, 69%).
Was.¹ H-NMR (CDCl_Three) 9.43 (td, 1H, J = 8.8, 6.
9 Hz), 7.71 (s, 1H), 6.98-6.90 (m, 1H), 6.85 (ddd,
 1H, J = 11.1, 8.7, 2.4 Hz), 1.92 (q, 2H, J = 7.4 H
z), 1.57 (s, 6H), 0.87 (t, 3H, J = 7.4 Hz)

Embodiment 44N-t-butyl-5-chloro-2-pyridylnitrone
Manufacture  1) 5-chloro-2- (1,2-dihydroxyethyl) pi
Lysine tributyl (vinyl) tin (6.33 g, 20.0 mmol), 2.5
-Dichloropyridine (2.96 g, 20.0 mmol) in toluene (30
 ml) solution to tetrakis (triphenylphosphine) para
Add indium (0) (0.46 g, 0.4 mmol) and heat to reflux for 3 hours
did. Transfer the reaction solution to ammonium fluoride aqueous solution (100 ml)
Ethyl acetate (30 ml) was added, and the mixture was stirred for 1 hour. Precipitation
The precipitated white precipitate was removed by filtration, and the aqueous layer was separated with ethyl acetate.
Extract three times and combine the organic layers with Na_TwoSO_FourAnd dried. Siri
Kagel chromatography (hexane / ethyl acetate = 10
/ 1-2 / 1), and the solvent is distilled off at normal pressure.
Oil containing 3.6 g of chloro-2-vinylpyridine as solvent
As obtained. 1.69 g of this was cooled under ice cooling to ADmix-α.
(14 g) in a mixed solution of t-butanol / water (1: 1, 100 ml)
The mixture was gradually heated to room temperature and stirred overnight. Cool the reaction solution with ice
Add sodium post sulfite (15g) and stir at room temperature for 1 hour
Extracted with ethyl acetate, Na_TwoSO_FourAnd dried. Distill solvent
After removal, silica gel chromatography (chloroform / me
Title compound
(1.05 g; 60%).¹ H-NMR (CDCl_Three) 8.52 (d, J = 2.4 Hz, 1H),
 7.71 (dd, J = 8.6, 2.4 Hz, 1H), 7.35 (d, J = 8.6 H
z, 1H), 4.81 (dd, J = 5.7, 3.7 Hz, 1H), 3.93 (dd, J
 = 11.7 Hz, 3.7 Hz, 1H), 3.9 (br, 1H), 3.76 (dd, J =
 11.7, 5.7 Hz, 1H), 2.45 (br, 1H). 2) 5-Chloro-2-pyridinecarboxaldehyde 5-chloro-2- (1,2-dihydroxyethyl) pyridi
(0.44 g, 2.5 mmol) in chloroform solution (7 ml)
Aqueous sodium bicarbonate 0.4 ml, sodium periodate (1.07 g, 5.0 mmo
l) was added and the mixture was stirred at room temperature for 1 hour. Magnesium sulfate
After stirring for 1 hour, the mixture was filtered, and the solvent was distilled off from the filtrate.
This gave the title compound (0.32 g, 90%).¹ H-NMR (CDCl_Three) 10.06 (d, J = 0.6 Hz, 1
H), 8.75 (dd, J = 2.0, 0.6 Hz, 1H), 7.94 (dd, J =
8.3, 0.6 Hz, 1H), 7.87 (ddd, J = 8.3, 2.0, 0.6Hz,
1H). 3) Nt-butyl-5-chloro-2-pyridylnitro
2-methyl-2-nitropropane (0.52 g, 5.0 mmol),
To an ethanol suspension (3 ml) of zinc dust (0.49 g, 7.5 mmol)
Acetic acid (0.86 ml, 15 mmol) was added dropwise under ice cooling, and the mixture was allowed to reach room temperature.
The temperature was gradually raised and stirred for 1 hour. 5-chloro-2-pyridi
Ethanol of carboxaldehyde (0.32 g, 2.3 mmol)
Solution (2 ml), stirred overnight, filtered through celite, and the solvent was removed.
The solvent was distilled off under reduced pressure. Silica gel chromatography (hex
And ethyl acetate = 4/1) to give the title
The compound (0.36 g, 75%) was obtained.¹ H-NMR (CDCl_Three) 9.21 (d, J = 8.5 Hz, 1H),
 8.57 (d, J = 2.7, 1H), 7.90 (s, 1H), 7.76 (dd, J
= 8.5, 2.7 Hz, 1H), 1.63 (s, 9H).

The structures of the compounds obtained in Examples 1 to 44 are shown below.

Embedded image

[0078]

Embedded image

[0079]

Embedded image

[0080]

Embedded image

Embodiment 45Example 18 Compound of Example 1 in vivo of Compound of Example 18
Metabolism to  6-week-old Wistar male rats (Charles River Japan)
And bred for 1 week at constant temperature and humidity. Example
Compound 18 was suspended at 10 mg / ml in 0.5% MC solution and
It was administered intraperitoneally under ether anesthesia (50 mg / kg, 5 ml / kg,
n = 3). 30 minutes and 6 hours after administration, ether anesthesia
The whole blood was collected from the descending and descending aorta. Blood is Separapid Chi
Tube (coagulation-promoting type with serum separating agent)
The serum was obtained, and the compound of Example 18 in the serum was obtained.
The concentration of the compound of Example 1 (μg / ml) was
Analyzed by chromatography. Table 1 shows the results.

[Table 1] 30 minutes later 6 hours later ――――――――――――――――――――――――――――――― Concentration of the compound of Example 18 13. 9 2.14 Concentration of compound of Example 1 0.42 1.67

It has been known that extra-retinal granule cells are degenerated and shed by continuously irradiating albino rats with white light for a certain period of time (LM Rapp, et al., New Y.
ork: Plenum, 135 (1980)). The effectiveness of the transdermal agent of the present invention can be evaluated using the retinal protective action in a retinal disorder model (rat) by continuous light irradiation based on this experiment. Specifically, the following tests show the effectiveness of the present invention.

Test Example 1Pharmacological effects on white light continuous irradiation damage  8 weeks old male SD rats (Charles River Japan)
And bred in a one-week light / dark cycle (8: 00-20: 00 light period)
After breeding, bred for 2 days in a white light continuous irradiation obstacle device
Was. The white light continuous irradiation obstruction device is
Manufactured from an acrylic plate with a length of 1020mm, width of 425mm and height of 520mm
It is a breeding box with a closed lid. White fireflies from the top inside the device
Irradiation was performed continuously for 24 hours using a light lamp. At this time the average in the device
Illuminance is 174.2 foot candle. After two days of breeding,
The kit was placed in a dark room and allowed to dark adapt for 1-4 hours. Rat
Under pentobarbital anesthesia, fixation on brain fixation device, mydriasis
Put the medicine on the eye, put the electrode on the cornea, the center of the forehead, and the lower part of the earlobe
Response potential to light stimulus of constant intensity
roretinogram). Extraretinal granule cells (light receiving
Retinal disorders due to the amplitude of the a-wave of ERG derived from
The degree of harm was evaluated. The test substance should be placed directly in the obstacle device.
Intraperitoneal administration at the same time before and the next day
evaluated. Using the four experimental rats described above,
The compound of the invention is suspended in a 0.5% methylcellulose (MC) solution
Alternatively, it was dissolved and administered intraperitoneally twice at a dose of 50 mg / kg.
Similarly, in the MC administration group, 0.5% MC was intraperitoneally administered and the control group was administered.
Used rats raised on a 12-hour light-dark cycle. Obstacle
The degree of recovery from harm is expressed as% recovery, and the result is
Are shown in Table 2. % Recovery = (ac) ÷ (bc) × 100 a: amplitude of a-wave of test compound administration group b: amplitude of a-wave of control group c: amplitude of a-wave of MC administration group

[Table 2] Compound% recovery (Mean ± SEM) Number of cases ―――――――――――――――――――――――――――――― PBN 15.4 ± 6.38 Compound of Example 1 105.0 ± 8.0 4 Compound of Example 2 36.4 ± 5.2 4 Compound of Example 10 22.2 ± 8.1 4 Compound of Example 18 24.8 ± 5.3 4 Compound of Example 26 40.1 ± 7.2 4 Compound of Example 27 58.0 ± 14.7 4

Test Example 2Pharmacological effects of transdermal agents on white light continuous irradiation damage  Wistar male rats (Charles River Japan) for 7 weeks
And purchased in a weekly light / dark cycle (8: 00-20: 00 light period)
After breeding, bred for 2 days in the white light continuous irradiation obstacle device.
Was. Preparation Example 1 Hair on the back of the rat was removed with a hair clipper
Ointment 1.10g 35cm^TwoWas transdermally administered over a wide area. Rat
The inner surface is all mirrored 1020 mm long, 425 mm wide, 520 mm high
About 2000 lux in a breeding box with a lid made of acrylic plate
Light was irradiated continuously for 2 days and bred. Then, the rat is darkened.
Adapted for 4 hours in room. Rats with ketamine,
Under silane anesthesia, fix on a brain fixation device
Attach the poles to the cornea, the center of the forehead, and the tail,
The response potential to violence was measured by ERG. Epiretinal condyle
To the amplitude of a-wave of ERG derived from granule cells (photoreceptor cells)
The degree of retinal damage was evaluated more. Ointment as a comparison
A light-impaired group that was subjected to the same operation without skin administration and a 12-hour light
A control group raised on a dark cycle was used. Times for obstacles
The degree of recovery is expressed as% recovery, and the results are shown in Table 3.
Was. % Recovery = (ac) ÷ (bc) × 100 a: Amplitude of a-wave of the ointment administration group of Formulation Example 1 b: Amplitude of a-wave of control group c: Amplitude of a-wave of light-impaired group

[Table 3] Group a-wave amplitude% recovery (Mean ± SEM) Number of cases ―――――――――――――――――――――――――――――― Group 297.4 ± 9.2 3 Light damage group 85.8 ± 6.6 3 Ointment group 192.3 ± 21.1 50.3 ± 4.7 3 From the above results, it is clear that administration of the dermal agent suppresses the decrease in a-wave amplitude due to light irradiation by about 50%. Became.

Formulation Example 1Manufacture of ointments  0.10 g of the compound of Example 1 and 50 W of Plastibase (registered trademark)
Mark: Bristol-Myers Squibb) 1.00g mixed
Then, an ointment was produced.

Formulation Example 2Manufacture of gel preparation  Add 140 g of hot water to 60 g of polyvinyl alcohol (PVA).
Then, stir vigorously until the PVA melts. Cool to room temperature
After rejection, 2.0 g of the compound of Example 1 was mixed to obtain a gel preparation.
You.

Formulation Example 3Production of cream  10 g of stearic acid, 15 g of stearyl alcohol and propyl
0.1 g of paraben is heated to 70 ° C. and melted (1 liquid).
Separately, methyl paraben 0.1 g, propylene glycol 30 g,
Heat 0.1 g of potassium hydroxide and 44.2 g of purified water to 70 ° C,
Mix uniformly (2 liquids). Emulsification while adding one liquid to two liquids
Then, when it becomes uniform, cool it. Cooled to 40 ° C
At this time, cooling while mixing 1.0 g of the compound of Example 1
And get a cream.

Formulation Example 4Production of lotion  1 mL polyethylene glycol 400 and 9 mL purification
Mix the water. 1.0 g of the compound of Example 1 was added to the aqueous solution.
Then, mix uniformly to obtain a lotion.

Formulation Example 5Manufacture of tapes  3.5 g of octyl (meth) acrylate, isopropa
6.5 g of phenol and 1.0 g of the compound of Example 1 were mixed and uniformly distributed.
Sprinkle. Apply this solution to a silicon-coated paper
Spread to 100μm and dry to form a tape
Get.

[0090]

EFFECT OF THE INVENTION The nitrone derivative transdermal preparation of the present invention is useful as a therapeutic agent for neuroretinal degenerative diseases and the like. The transdermal agent can maintain the drug concentration in blood for a longer period of time and can prolong the biological half-life as compared with oral or intravenous injection administration. The transdermal preparation is a pain-free, simple and non-invasive drug administration preparation, which can reduce or eliminate gastrointestinal irritation and other side effects related to oral administration, and relates to an invasive administration method such as a needle. Patient anxiety is resolved.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/38 601 A61K 31/38 601 31/40 31/40 31/415 601 31/415 601 31/44 31/44 C07C 291 / 04 C07C 291/04 C07D 207/335 C07D 207/335 231/12 231/12 A // C07D 233/61 102 233/61 102 333/20 333/20 333/20 (72) Inventor Hiroki Ogawa Kanda, Chiyoda-ku, Tokyo 3-11, Surugadai, Sumitomo Pharmaceutical Co., Ltd. (72) Ryu Nagata, Inventor 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi Sumitomo Pharmaceutical Co., Ltd. Sumitomo Pharmaceutical Co., Ltd. 3-chome No. 98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Tatsuya Fujibayashi 3-1-198 Kasuganaka, Konohana-ku, Osaka-shi 1-3, Ichikuragakiuchi No. 45 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Akihiko Sano 1-345 Kuragakiuchi, Ibaraki-shi, Osaka

Claims (25)

[Claims] 1. The formula: embedded image [In the formula, Ar represents a substituted phenyl or an optionally substituted aromatic heterocyclic group. n represents 0, 1 or 2. W is, -CH ₂ NH- or -CH = N (O) -
Represents R ¹ , R ² and R ³ each independently represent an optionally substituted alkyl, carboxyl, or alkoxycarbonyl. Provided that any ^{two of} R ¹ , R ² and R ³ are bonded to each other to form a cycloalkane ring together with the carbon atom to which they are bonded, or ^three of R ¹ , R ² and R ³ are They may combine with each other to form a bicycloalkane ring or a tricycloalkane ring together with the carbon atoms to which they are attached. The cycloalkane ring, the bicycloalkane ring and the tricycloalkane ring may be substituted. R ⁴ and R ⁵ each independently represent a hydrogen atom or an optionally substituted alkyl. Or a pharmaceutically acceptable salt thereof. 2. The substituent in the substituted phenyl and the substituted aromatic heterocyclic group is a halogen atom, cyano, nitro, alkyl, halogen-substituted alkyl, alkoxy, halogen-substituted alkoxy, alkoxycarbonyl, carbamoyl or alkyl-substituted carbamoyl. The transdermal agent according to claim 1, wherein the substituent in the alkyl, substituted cycloalkane ring, substituted bicycloalkane ring and substituted tricycloalkane ring is cycloalkyl, heterocyclic group, alkoxy, alkoxyalkoxy, alkanoyloxy or alkanoylamino. 3. The transdermal preparation according to claim 1, wherein n is 0. 4. Ar is an optionally substituted 5-membered aromatic heterocyclic group or a compound represented by the formula: (R ⁶ represents a halogen atom, trifluoromethyl, cyano or nitro; R ⁷ represents a hydrogen atom or a substituent; R ⁸ represents a substituent; provided that W is —CH ₂ NH
If-, Ar is not dichlorophenyl. )
The transdermal agent according to any one of claims 1 to 3, which is a group represented by the following formula: 5. Ar is 2-thienyl or a compound of the formula: (R ⁶ has the same meaning as in claim 4. R ⁹ is
Represents a halogen atom, cyano, nitro, alkyl, halogen-substituted alkyl, alkoxy, alkoxycarbonyl, carbamoyl or alkyl-substituted carbamoyl. The transdermal agent according to any one of claims 1 to 3, which is a group represented by the formula: 6. Ar is 2-thienyl or phenyl substituted with 1 to 3 halogen atoms.
4. The transdermal agent according to any one of 3. 7. The method according to claim 1, wherein Ar is 2-thienyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,6-difluorophenyl or 2,4-dichlorophenyl. The transdermal agent according to the description. 8. The transdermal agent according to claim ¹ , wherein R ¹ , R ² and R ³ are each independently an optionally substituted alkyl. 9. The method according to claim 1, wherein W is —CH ＝ N (O) —.
The transdermal agent according to any of -8. 10. An α- (2,4-difluorophenyl)
The transdermal agent according to claim 1, comprising -Nt-butyl nitrone. 11. The transdermal preparation according to claim 1, which is in the form of a tape, patch, ointment, cream, lotion, liquid or gel preparation. 12. The formula: embedded image And an aldehyde represented by the formula: By reacting a hydroxyamine represented by
Formula: A method for producing a compound represented by the formula: [Wherein, n, R ¹ , R ² , R
³ , R ⁴ and R ⁵ have the same meaning as in claim 1. Ar ¹ is an optionally substituted 5-membered aromatic heterocyclic group or a compound represented by the formula: (R ⁶ , R ⁷ and R ⁸ have the same meanings as in claim 4). ] 13. The method according to claim 12, wherein n is 0. 14. Ar ¹ is 2-thienyl or a compound of the formula: 14. The method according to claim 12, wherein R ⁶ and R ⁹ are the same as defined in claim 5. 15. The method according to claim 12, wherein Ar ¹ is 2-thienyl or phenyl substituted with 1 to 3 halogen atoms. 16. The method according to claim 12, wherein Ar ¹ is 2-thienyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,6-difluorophenyl or 2,4-dichlorophenyl. Manufacturing method. 17. The method according to claim ¹² , wherein R ¹ , R ² and R ³ are each independently an optionally substituted alkyl.
7. The method according to any one of the above items 6. 18. The method for producing α- (2,4-difluorophenyl) -Nt-butylnitrone according to claim 12. 19. A compound of the formula: By oxidizing a compound represented by the formula: A method for producing a compound represented by the formula: [Wherein, n, R ¹ , R ² , R
³ , R ⁴ and R ⁵ have the same meaning as in claim 1. Ar ¹ has the same meaning as in claim 12. ] 20. The method according to claim 19, wherein n is 0. 21. Ar ¹ is 2-thienyl, or a compound of the formula: 21. The method according to claim 19, wherein R ⁶ and R ⁹ are the same as defined in claim 5. 22. The method according to claim 19, wherein Ar ¹ is 2-thienyl or phenyl substituted with 1 to 3 halogen atoms. 23. The method according to claim 19, wherein Ar ¹ is 2-thienyl, 2,4-difluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2,6-difluorophenyl or 2,4-dichlorophenyl. Manufacturing method. It is 24. R ^1, R ² and R ^3, each independently, claims 19-2 is alkyl which may be substituted
3. The production method according to any one of 3. 25. The method for producing α- (2,4-difluorophenyl) -Nt-butylnitrone according to claim 19.