JPH10330380A - Condensed cyclic ethers, production thereof and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new condensed cyclic ether useful for the prevention and treatment of ischemic central nervous system disorders, etc., as an excellent sodium channel adjusting agent, in which carbon atom at 2 position of a condensed cyclic ether is simultaneously substituted by a lower alkyl and a specific group. SOLUTION: This condensed cyclic ether is a compound of formula I [R<1> , R<2> are each H, an acyl, etc.; R<3> to R<5> are each a lower alkyl, a lower alkoxy, etc.; R<6> is a lower alkyl; AR is an aromatic group; ring A is a 5-8 membered heterocycle containing nitrogen; X is a lower alkylene; Y is carbon atom or nitrogen atom; Za is CH2 or formula II (R<7> is H or an aromatic group); Zb is a divalent aliphatic hydrocarbon; (m) is 1-3] or a slat thereof, e.g. 1-[(5- amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-N-(diphen ylmethyl)-4- piperidinamine. In order to obtain the compound, e.g. a compound of formula III (L is an eliminable group) or a salt thereof is reacted with a compound of formula IV or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel condensed cyclic ether having an excellent sodium channel regulating action,
It relates to its production method and agent.

[0002]

BACKGROUND OF THE INVENTION Drugs that modulate voltage-gated sodium channels are known as local anesthetics, antiarrhythmics or anticonvulsants. Recent studies have shown that sodium channel modulators are also effective as therapeutic agents for diseases or disorders of the central nervous system, such as ischemic central nervous system disorders, head trauma, and spinal cord injury (Trens In Pharmacological Science, Volume 16, 309-3
16 pages, 1995). Ischemic or traumatic nerve injury results in sodium ion accumulation in nerve cell bodies or nerve fibers at the site of injury (Stroke, Volume 20, 1377
-1382, 1989), but this storage of sodium causes edema formation, abnormal release of many neurotransmitters such as dopamine and glutamate (Trens in Neuroscience, 16, 415-419, 1993), Enhancement of calcium ion influx by Na ⁺ / Ca ²⁺ exchanger (neuron, vol. 12,
295-300, 1994).
Examples of sodium channel regulators include BW619C8
9. Lifarizine, Riluzo
le) and other compounds are known (Trens in Pharmacological Science, 16, 309-316, 1995)
However, cyclic ethers having an amino group on a condensed ring are not known.

As the cyclic ethers having an amino group on a condensed ring, for example, the following compounds are known. 1) Formula having an inhibitory effect on lipid peroxide production

Embedded image [Wherein, R ¹ and R ² represent a hydrogen atom, an acyl group, an alkoxycarbonyl group, an aliphatic group or an aromatic ring group which may each have a substituent, R ³ , R ⁴ and R ⁵ represent A hydroxyl group which may be acylated, an amino group which may have a substituent, an alkoxy group or an aliphatic group, or two of R ³ , R ⁴ and R ^{5 each} have a carbon homocycle. R ⁶ and R ⁷ may be an aliphatic group which may have a substituent, and at least one of R ⁶ and R ⁷ is a methylene group at the α-position;
R ⁸ and R ⁹ each represent a hydrogen atom or an aliphatic group or an aromatic ring group which may have a substituent.] (JP-A-5-140142, EP
-A-483772). 2) Formula having an inhibitory effect on lipid peroxide production

Embedded image Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a lower alkyl group, and ring A is a lower alkyl group, a lower alkoxy group or a benzene ring substituted with at least one halogen atom. Show. ] (JP-A-6-41123). 3) Crystalline salt of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine having a lipid peroxide production inhibitory action (USP 5,552,552). However, there is no report on the relationship between these compounds and the sodium channel regulating action.

[0004]

Sodium channel modulators which are excellent in sodium channel regulating action, have excellent brain localization and metabolic stability, are diseases and disorders of the central nervous system, such as ischemic central nervous disorder, Central injury (eg, head trauma, spinal cord injury, whiplash etc.), epilepsy, neurodegenerative disease (eg, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neurosis Etc.), vascular dementia (eg, multiple infarct dementia, Binswanger's disease, etc.), manic depression, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine, cerebral edema, etc. . However, at present, no satisfactory compound has been found, and there is an urgent need to develop a compound having an excellent sodium channel regulating activity and sufficiently satisfying as a drug.

[0005]

Means for Solving the Problems As a result of various studies on a compound having a sodium channel regulating action, the present inventors have found that a carbon atom at the 2-position of a condensed cyclic ether has a lower alkyl group and a formula:

Embedded image Wherein each symbol is simultaneously substituted with a group represented by the following formula:

Embedded image [Wherein, R ¹ and R ² are each a hydrogen atom, a lower alkyl or an acyl which may have a substituent, and R ³ , R ⁴ and R ⁵ are a lower alkyl or an each which may have a substituent. Lower alkoxy optionally having a substituent,
Alternatively, R ⁴ and R ⁵ may together form a 5- or 6-membered homocyclic ring, R ⁶ is lower alkyl, Ar is an aromatic group which may have a substituent, and A ring is A 5- to 8-membered nitrogen-containing heterocyclic ring which may have a substituent, X is a lower alkylene which may have a substituent, Y is a carbon atom or a nitrogen atom,

Embedded image (Wherein, R ⁷ represents a hydrogen atom or an aromatic group which may have a substituent, and R ¹⁰ represents a hydrogen atom, a hydrocarbon group which may have a substituent or acyl). Group, Zb
Represents a divalent aliphatic hydrocarbon group which may have a bond or a substituent and may be via an oxygen atom, a nitrogen atom or a sulfur atom, and m represents an integer of 1 to 3] Or a salt thereof (hereinafter abbreviated as compound (I)) for the first time, and a compound containing the compound (I)

Embedded image [In the formula, Q is a hydrogen atom, an aromatic group which may have a substituent, or a formula -Zc-Ar (wherein Zc may have a substituent, and an oxygen atom, a nitrogen atom Or a divalent aliphatic hydrocarbon group which may be via a sulfur atom, Ar is the same as defined above), and the Aa ring contains a 5- to 8-membered group which may have a substituent. Or a salt thereof (hereinafter abbreviated as Compound (Ia)) unexpectedly has an affinity for a sodium channel. It has been found that it has excellent properties as a sodium channel regulator such as sodium chloride and stability, and that it is sufficiently satisfactory as a medicament. Based on these findings, the present invention has been completed.

That is, according to the present invention, (1) compound (I), (2) R ¹ and R ² each represent (i) a hydrogen atom, (ii) a halogen atom, C _3-6 cycloalkyl, C _2-6
Alkynyl, C _2-6 alkenyl, C _6-10 aryl, C
_7-11 aralkyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkyl-carbonyl, C _6-10 aryl-
Carbonyl, C _1-6 alkyl-carbonyloxy, C
_6-10 aryl-carbonyloxy, carboxyl, C
_1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 3- to 6-membered cyclic amino,
C _1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C _1-6 alkylsulfamoyl, di-C _1-6 alkylsulfamoyl, C _1-6 Alkylthio,
C _6-10 arylthio, C _1-6 alkylsulfinyl, C
_6-10 arylsulfinyl, C _1-6 alkylsulfonyl and C _6-10 1 without a substituent selected from arylsulfonyl to 5 optionally having C _1-6 alkyl or (iii) formyl,, C _{1- 6} alkyl-carbonyl, C _6-10
Aryl-carbonyl, C _6-10 aryl-C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C
_6-10 aryl -C _1-6 alkoxy - carbonyl, C _1-6 alkylsulfonyl, C _1-6 alkyl and 1 to 3 have good C _6-10 optionally arylsulfonyl and C _6-10 aryl -C Acyl selected from _1-6 alkylsulfonyl; R ³ , R ⁴ and R ⁵ are each (i) a halogen atom,
C _3-6 cycloalkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _6-10 aryl, C _7-11 aralkyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkyl- Carbonyl, C _6-10 aryl-carbonyl, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino, mono-C _{1 -6}
Alkylamino, di -C _1-6 alkylamino, 3 to 6-membered cyclic amino, C _1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono--C _1-6 Alkylsulfamoyl, di-C _1-6 alkylsulfamoyl,
C _1-6 alkylthio, C _6-10 arylthio, C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl, C _1-6
C which may have 1 to 5 substituents selected from alkylsulfonyl and C _6-10 arylsulfonyl
_1-6 alkyl, or (ii) halogen atom, C _3-6 cycloalkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _6-10
Aryl, C _7-11 aralkyl, C _1-6 alkoxy, C
_6-10 aryloxy, C _1-6 alkyl-carbonyl, C
_6-10 aryl-carbonyl, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino, mono-C _1-6 alkyl Amino, di-C _1-6 alkylamino, 3- to 6-membered cyclic amino, C _1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C _1-6 alkyl Sulfamoyl, di-C _1-6 alkylsulfamoyl, C _1-6 alkylthio, C _6-10 arylthio, C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl, C _1-6 alkylsulfonyl and C _{6 -10} arylsulfonyl 1 substituent selected from nil to 5 optionally having C _1-6 alkoxy, or be adjacent R ⁴ and R ⁵ Together with the two carbon atoms, six-membered aromatic hydrocarbon ring and 5 or form a 5 or 6-membered homocyclic selected from 6-membered cycloalkene; R ⁶ is C _1-6 alkyl; Ar is a halogen Atom, C _1-3
Alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _{1 -6} alkylthio, hydroxy,
Amino, mono--C _1-6 alkylamino, di -C _1-6 alkylamino, C _1-6 alkyl - carbonyl, carboxyl, C _1-6 alkoxy - carbonyl, carbamoyl, mono--C _1-6 alkyl - carbamoyl, 1 to 5 substituents selected from di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo, C _1-6 alkylsulfonyl, C _6-10 aryl and C _6-10 aryloxy;
A 5- to 10-membered aromatic complex containing (i) C _6-14 aryl or (ii) 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. A ring group; A ring is a halogen atom, C _1-3
Alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _{1 -6} alkylthio, hydroxy,
Amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkyl-carbonyl, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, 1 to 3 substituents selected from di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo, C _1-6 alkylsulfonyl, C _6-10 aryl and C _6-10 aryloxy;
A 5- to 8-membered nitrogen-containing heterocyclic ring which may have 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and a nitrogen atom; Atom, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C
_6-14 aryl, nitro, cyano, hydroxy, C _1-6 alkoxy, amino, mono-C _1-6 alkylamino, di-
C _1-6 alkylamino, C _1-6 alkyl-carbonyl, C
_6-10 C _1-6 alkylene optionally having 1 to 3 substituents selected from aryloxy and oxo; Y is (i) a nitrogen atom or (ii) a formula:> C (R ⁸ )-( Where:
R ⁸ is a hydrogen atom, a halogen atom, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio which may be
Hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkyl-carbonyl,
Carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C
A group represented by _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo, C _1-6 alkylsulfonyl, C _6-10 aryl or C _6-10 aryloxy); R ⁷ is a hydrogen atom Or a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, halogen Optionally substituted C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkyl-carbonyl, carboxyl, C
_1-6 alkoxy-carbonyl, carbamoyl, mono-C
_1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo, C
_1-6 alkylsulfonyl, C _6-10 aryl and C _6-10
(I) C _6-14 aryl or (i) each having 1 to 5 substituents selected from aryloxy
i) 5 to 1 containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon atoms
A zero-membered aromatic heterocyclic group; R ¹⁰ represents (i) a hydrogen atom, (ii) a halogen atom, C _3-6 cycloalkyl, C _2-6 alkynyl,
C _2-6 alkenyl, C _6-10 aryl, C _7-11 aralkyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino,
Mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 3- to 6-membered cyclic amino, C _1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, Mono-C
_1-6 alkylsulfamoyl, di -C _1-6 alkylsulfamoyl, C _1-6 alkylthio, C _6-10 arylthio,
C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl, C _1-6 alkylsulfonyl and C _6-10 aryl 1 substituents selected from sulfonyl It may have five each C _1-6 alkyl, C _2-6 alkenyl, C
_2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, or (iii) formyl, C
_1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryl-C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, C _1-10 aryl-C _1-6 alkoxy-carbonyl, C _1-6 alkylsulfonyl, C
_1-6 1 alkyl to 3 have good C _6-10 optionally arylsulfonyl and C _6-10 aryl -C _1-6 acyl selected from alkylsulfonyl; and Zb is halogen atom, nitro, cyano, halogen _Optionally C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono -C _1-6 alkylamino, di-C _1-6 alkylamino, C
_6-14 aryl, C _7-11 aralkyl, C _6-10 aryloxy, oxo, formyl, C _1-6 alkyl-carbonyl,
C _6-10 aryl-carbonyl, C _6-10 aryl-C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-C _1-6 alkoxy-carbonyl,
C _1-6 alkylsulfonyl, C _1-6 alkyl is 1 to 3
C _6-10 arylsulfonyl optionally having
(I) each having 1 to 5 substituents selected from _6-10 aryl-C _1-6 alkylsulfonyl;
C _1-8 alkylene, (ii) C _2-8 alkenylene, (iii)
C _2-8 alkynylene or the formula (iv):-(CH ₂ ) p-M- (CH
₂ ) q- wherein p and q are each an integer of 0 to 8, p + q is an integer of 1 to 8, M is O, S, S
O, SO ₂ or NR ⁹ (R ⁹ is a hydrogen atom, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, C _7-11 aralkyl, formyl, C _1-6 alkyl-carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryl-C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _1-6 alkylsulfonyl, C _1-6 alkyl is 1 to 3
C _6-10 arylsulfonyl or C
_6-10 aryl-C _1-6 alkylsulfonyl)).] The compound according to the above (1),
(3) Za is the formula:

Embedded image Wherein R ⁷ is as defined above, and (4) the compound according to (1), wherein R ¹ and R ² are each a hydrogen atom. , (5) R
³ , the compound according to (1), wherein R ⁴ and R ⁵ are each C _1-6 alkyl; (6) the compound according to (1), wherein R ⁶ is C _1-6 alkyl; (7) Ar is Halogen atom,
The compound according to the above (1), which is a C _6-14 aryl optionally having 1 to 3 substituents selected from C _1-6 alkyl and C _1-6 alkoxy, and (8) ring A is a substituent. (1) the compound according to the above (1), which is a 6-membered nitrogen-containing heterocyclic ring which optionally has (9) the compound according to the above (1), wherein X is methylene; and (10) the compound (1), wherein Y is CH. (11) Za is a compound represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above), the compound according to the above (1), wherein (12) R ⁶ is a C _6-10 aryl _optionally having a substituent. (13) The compound according to (1), wherein R ¹⁰ is a hydrogen atom, (14) the compound according to (1), wherein Zb is a bond, (15) m is 1 compound of (1), wherein it, (16) R ¹ and R ² are each a hydrogen atom;
R ³ , R ⁴ , R ⁵ and R ⁶ are each C _1-6 alkyl; Ar
Is a phenyl optionally having 1 to 3 substituents selected from a halogen atom, C _1-6 alkyl and C _1-6 alkoxy; ring A is a 6-membered nitrogen-containing heterocycle; X is methylene; Y is CH Or N; Za is the formula:

Embedded image (Wherein R ⁷ ′ is a halogen atom, C _1-6 alkyl and C 7
Phenyl optionally having 1 to 3 substituents selected from _1-6 alkoxy, and R ¹⁰ ′ represents a hydrogen atom); Zb is substituted by a bond or C _6-10 aryl is optionally C _1-6 alkylene is, compound of (1) wherein and m is 1 or 2, (17) R
¹ and R ² are each a hydrogen atom; R ³ , R ⁴ , R ⁵ and R ⁶ are each a C _1-6 alkyl; Ar is a C _6-10 aryl optionally substituted with methylenedioxy; Membered nitrogen-containing heterocycle; X is methylene; Y is CH or N;

Embedded image (Wherein, R ^7a represents a hydrogen atom or C _6-10 aryl)
Wherein Zb is (i) C _1-6 alkylene or (ii) C _2-6 alkenylene, each of which may be substituted with a bond or C _6-10 aryl; and (18) R ¹ and R ² are each a hydrogen atom; R ³ , R ⁴ , R ⁵ and R ⁶ are each a C _1-6 alkyl; Ar is a halogen atom, methylenedioxy, C _{1- 6}
Substituent 1 selected from alkyl and C _1-6 alkoxy
A C _6-10 aryl optionally having 3 to 3 ring (s); A ring is a 6-membered nitrogen-containing heterocyclic ring; X is methylene; Y is CH or N;

Embedded image (Wherein R ^7b represents a C _6-10 aryl optionally substituted with a hydrogen atom or a halogen atom, and R ^10a represents a hydrogen atom or a C _7-11 aralkyl); or C _6-10 optionally substituted respectively with an aryl (i) C _1-6 alkylene, (ii) C _2-6 alkenylene or (iii) formula _{:-( CH 2) p'-M '} - (CH ₂ ) q'- (where p 'and q' are each an integer of 0 to 5, and p '
+ Q 'is an integer of 1 to 6, M' represents O or NH)
And the group represented by the above (1), wherein m is 1 or 2.
The compound described in (19) 1-[(5-Amino-2,3-
Dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4
-Piperidineamine, (-)-1-[(5-amino-
2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (+)-1-[(5-amino-2 , 3-Dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, 1-[(5-amino-2,3-dihydro- 7-isopropyl-2,4,6
-Trimethylbenzofuran-2-yl) methyl] -N-
(Diphenylmethyl) -4-piperidineamine, (-)
-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (+) -1-[(5-Amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine or a salt thereof The compound according to the above (1), which is a compound of the formula (20) (i):

Embedded image [Wherein L is a leaving group, and other symbols have the same meanings as described above] or a salt thereof, and a compound represented by the formula:

Embedded image Wherein each symbol is as defined above, or a salt thereof, (ii) a formula:

Embedded image Wherein each symbol is as defined above, or a salt thereof, (a) subject to an alkylation reaction, (b) subjecting to an acylation reaction, or (c) subjecting to a acylation reaction. And
Then, subject to the reduction reaction, the formula (iii):

Embedded image Wherein n is an integer of 1 to 4, and other symbols are as defined above, or a salt thereof and a compound represented by the formula:

Embedded image [In the formula, R ¹¹ is a hydrogen atom or a hydrocarbon group which may have a substituent, Zd may have a substituent, and may be a group which has an oxygen atom, a nitrogen atom or a sulfur atom. A good divalent aliphatic hydrocarbon group, Ar has the same meaning as defined above), or a salt thereof;
Equation (iv):

Embedded image Wherein each symbol is as defined above, or a salt thereof, and a compound represented by the formula:

Embedded image Wherein each symbol is as defined above, or a salt thereof, and if necessary, subjecting the obtained compound to a reduction reaction; or (v)

Embedded image Wherein each symbol is as defined above, or a salt thereof, is subjected to (a) a nitration reaction and then a reduction reaction, or (b) a diazo coupling reaction. And then subjecting the compound to a reduction reaction, (21) a pharmaceutical composition comprising the compound (I), and (22) a pharmaceutical composition comprising a sodium channel regulator. (23) a composition according to (22), which is a preventive or therapeutic agent for ischemic central nervous system disorder, central injury, neurodegenerative disease or cerebral edema, (24) compound (Ia) A sodium channel modulator comprising: (25) (S) -2,
3-dihydro-2,4,6,7-tetramethyl-2-
[(4-phenyl-1-piperidinyl) methyl] -5-
Benzofuranamine, 2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, (-)-2,3-dihydro -7-isopropyl-
2,4,6-trimethyl-2-[(4-phenyl-1-
Piperidinyl) methyl] -5-benzofuranamine,
(+)-2,3-dihydro-7-isopropyl-2,
4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, 7-te
rt-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, (-)-7-tert-butyl-2, 3-dihydro-2,4,6-trimethyl-2
-[(4-phenyl-1-piperidinyl) methyl] -5
-Benzofuranamine, (+)-7-tert-butyl-
2,3-dihydro-2,4,6-trimethyl-2-
[(4-phenyl-1-piperidinyl) methyl] -5-
The regulator according to the above (24), which comprises benzofuranamine or a salt thereof.

In the above formula, R ¹ , R ² , R ³ , R ⁴ or R ⁵
"Lower alkyl optionally having substituent (s)"
Examples of "lower alkyl" include, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
C such as butyl, tert-butyl, pentyl and hexyl
_{And a 1-6} alkyl group.

The "substituent" which the "lower alkyl" may have is, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, C _3-6 cycloalkyl such as cyclohexyl),
Lower alkynyl (eg, C _2-6 alkynyl such as ethynyl, 1-propynyl, propargyl, etc.), lower alkenyl (eg, C _2-6 alkenyl such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.), aryl (eg, , phenyl, C _6-10 aryl such as naphthyl, etc.), aralkyl (e.g. benzyl, alpha-methylbenzyl, etc. C _7-11 aralkyl phenethyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, C _1-6 alkoxy such as isobutoxy, sec-butoxy, tert-butoxy, etc., aryloxy (eg, C _6-10 aryloxy such as phenoxy), lower alkanoyl (eg, acetyl, propionyl, butyryl, isobutyryl and the like) C _1-6 alkyl - carbonyl) Ariruka Boniru (e.g., benzoyl, C _6-10 aryl such as naphthoyl - carbonyl), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, C _1-6 alkyl such as iso-butyryloxy - carbonyloxy, etc.), aryl Carbonyloxy (eg, C _6-10 aryl-carbonyloxy such as benzoyloxy, naphthoyloxy, etc.), carboxyl, lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy) Carbonyl, te
C _1-6 alkoxy-carbonyl such as rt-butoxycarbonyl), carbamoyl, amidino, imino, amino,
Mono-lower alkylamino (eg, mono-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-lower alkylamino (eg, dimethylamino, diethylamino, ethylmethyl) Amino, dipropylamino,
Di-C _1-6 such as diisopropylamino and dibutylamino
Alkylamino), a 3- to 6-membered cyclic amino (for example, aziridinyl) which may contain 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom and one nitrogen atom 3- to 6-membered cyclic aminos such as azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, virazolyl, imidazolidinyl, piperidino, morpholino, thiomorpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl and the like ), Alkylenedioxy (eg, C _1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, monoalkylsulfamoyl (eg, , Methylsulfamoyl, d Mono-C _1-6 alkylsulfamoyl such as tylsulfamoyl, propylsulfamoyl, isopropylsulfamoyl, and butylsulfamoyl; and dialkylsulfamoyl (eg, dimethylsulfamoyl, diethylsulfamoyl, Di-C such as dipropylsulfamoyl and dibutylsulfamoyl
_1-6 such alkylsulfamoyl), lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio, tert-
A C _1-6 alkylthio butylthio), arylthio (e.g., phenylthio, etc. C _6-10 arylthio such as naphthylthio), lower alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propyl-sulfinyl, and butyl sulfinyl C _{1- 6} alkylsulfinyl, arylsulfinyl (eg, C _6-10 arylsulfinyl such as phenylsulfinyl, naphthylsulfinyl), lower alkylsulfonyl (eg, C _1-6 such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.)
Alkylsulfonyl, etc.) and arylsulfonyl (eg, phenylsulfonyl, naphthylsulfonyl, etc.
_6-10 arylsulfonyl) and the like. The "lower alkyl" of the "lower alkyl optionally having substituent (s)" means that the above-mentioned substituent (s) has 1 to 5, preferably 1 to 3 substituent (s) at a substitutable position of the alkyl group. When the number of substituents is two or more, each substituent may be the same or different.

The "acyl" represented by R ¹ or R ² includes, for example, acyl derived from carboxylic acid or sulfonic acid. Preferably, formyl, lower alkylcarbonyl (eg, C _1-6 alkyl-carbonyl such as acetyl, propionyl, butyryl, isobutyryl), arylcarbonyl (eg, C _6-10 aryl-carbonyl such as benzoyl, naphthoyl),
Aralkylcarbonyl (eg, benzylcarbonyl,
C _6-10 aryl-C _1-6 alkyl-carbonyl such as phenethylcarbonyl, naphthylmethylcarbonyl, etc., lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert C _1-6 alkoxy-carbonyl such as -butoxycarbonyl, etc., aralkyloxycarbonyl (eg C _6-10 aryl-C _1-6 alkoxy-carbonyl such as benzyloxycarbonyl), lower alkylsulfonyl (eg, mesyl, ethyl C _1-6 alkylsulfonyl such as sulfonyl and propylsulfonyl),
C _6-10 arylsulfonyl optionally having C _1-6 alkyl (eg, phenylsulfonyl, naphthylsulfonyl, tosyl, etc.), aralkylsulfonyl (eg,
C _6-10 aryl-C _1-6 alkylsulfonyl such as benzylsulfonyl, phenethylsulfonyl and naphthylmethylsulfonyl). R ¹ and R ² are preferably a hydrogen atom, C _1-6 alkyl, C _1-6 alkyl-carbonyl. More preferably, a hydrogen atom, C _1-6
Alkyl. Particularly preferred is a hydrogen atom.

The "lower alkoxy" of the "optionally substituted lower alkoxy" represented by R ³ , R ⁴ or R ⁵ includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyl And C _1-6 alkoxy such as oxy and hexyloxy. As the substituent which the “lower alkoxy” may have, for example, the same substituents as the above-mentioned “lower alkyl” may have the same number. The “5- or 6-membered homocyclic ring” formed by R ⁴ and R ⁵ together with two adjacent carbon atoms includes, for example, a 6-membered aromatic hydrocarbon ring (eg, a benzene ring),
Or a 6-membered cycloalkene (eg, cyclopentene,
Cyclopentadiene, cyclohexene, etc.). R ³ , R ⁴ and R ⁵ are preferably C _1-6 alkyl. R ³ and R ⁴ are more preferably methyl.

The "lower alkyl" represented by R ⁶ includes the "lower alkyl" of the "optionally substituted lower alkyl" represented by R ¹ , R ² , R ³ , R ⁴ or R ^5. ]. R ⁶ is preferably C
_1-6 alkyl. More preferably, it is methyl.
"Aromatic group optionally having substituent (s)" for Ar
Examples of the "aromatic group" include an aromatic hydrocarbon group and an aromatic heterocyclic group. Examples of the "aromatic hydrocarbon group" include a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms.
Specific examples thereof include C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl and anthryl. Among them, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl is preferred. Particularly preferred is phenyl. As the "aromatic heterocyclic group", for example, a 5- to 10-membered monocyclic ring containing one or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom or And the condensed aromatic heterocyclic group. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine,
An aromatic heterocycle such as pyrimidine, pyridazine, indole, isoindole, 1H-indazole, isoquinoline, quinoline, carbazole, isothiazole, isoxazole, or one of these rings (preferably a 5- or 6-membered monocycle) or A monovalent group formed by removing an arbitrary hydrogen atom from a ring formed by condensing with a plurality (preferably one or two, more preferably one) of aromatic rings (eg, benzene ring, pyridine ring, etc.) Is mentioned.
Preferred examples of the “aromatic heterocyclic group” include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,
Quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-
Benzothienyl, benzofuranyl, 2-thienyl, 3-
Thienyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-pyridothiazolyl and the like can be mentioned. More preferably, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,
-In-drill, 3-in-drill and the like.

The “substituent” of the “aromatic group which may have a substituent” represented by Ar includes, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkyl Rangeoxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) ), Optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propyl amino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, dipropylamino, dibutylamino, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), carboxyl, C _1-6 alkoxy-carbonyl (eg, , methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), carbamoyl, mono- -C _1-6 alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di -C _1-6 alkylcarbamoyl (e.g., dimethylcarbamoyl, Diethylcarbamoyl, etc.), C
_6-10 aryl-carbamoyl (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.), sulfo, C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.), C _6-10 aryloxy (eg, phenyloxy,
Naphthyloxy, etc.). When the substituent is C
_{In the case of 1-3} alkylenedioxy, it is desirable to form a ring together with two adjacent carbon atoms.

The above "optionally halogenated C _1-6"
Examples of the “alkyl” include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.) which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). Isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl, etc.), and specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, Propyl, 3,3,3-trifluoropropyl,
Isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluoro Hexyl and the like. Examples of the "optionally halogenated C _1-6 alkoxy optionally", for example, 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine and the like) a C _1-6 alkoxy optionally having And specific examples thereof include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.

The above "optionally halogenated C _1-6"
The “alkylthio” includes, for example, a C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.) which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). , Sec-butylthio, tert-butylthio, etc.), and specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, and pentylthio. , Hexylthio and the like. The "aromatic group" of the "aromatic group optionally having substituent (s)" includes, for example, 1 to 5, preferably 1 to 3 of the above substituents at substitutable positions on the ring. And when the number of substituents is two or more, they may be the same or different. Ar is preferably
C _6-14 aryl _optionally having a substituent (preferably phenyl), 2-pyridyl, 3-pyridyl,
-Pyridyl, 2-indolyl or 3-indolyl, more preferably C _6-10 aryl optionally having substituent (s). The “substituent” is preferably a halogen atom, C _1-6 alkoxy and C _1-6 alkyl. A
r is more preferably a substituent 1 to 3 selected from a halogen atom, C _1-6 alkoxy and C _1-6 alkyl.
C _6-14 aryl (preferably phenyl) which may have a _{single bond} .

As the "5- to 8-membered nitrogen-containing heterocycle" of the "optionally substituted 5- to 8-membered nitrogen-containing heterocycle" for ring A, for example, at least one other than a carbon atom
And a 5- to 8-membered saturated or unsaturated heterocyclic ring containing one nitrogen atom. Specific examples include piperidine, piperazine, 1,2,5,6-tetrahydropyridine, pyrrolidine, 1H-azepine, 1H-2,3-dihydroazepine, 1H-2,3,4,5-tetrahydroazepine, 1H- 2,3,6,7-tetrahydroazepine, 1H-2,3,4,5,6,7-hexahydroazepine, 1H-1,4-diazepine, 1H-2,3-dihydro-1,4-diazepine 1H-2,3,4,5-tetrahydro-1,4-diazepine, 1H-2,3,6
7-tetrahydro-1,4-diazepine, 1H-2,
3,4,5,6,7-hexahydro-1,4-diazepine, 1,2-dihydroazocine, 2,3,4,5-tetrahydroazocine, 1,2,3,4,5,6- Hexahydroazocin, 1,2,3,4,5,6,7,8-octahydroazocin, 1,2-dihydro-1,5-diazocine, 1,2,3,4,5,6- Hexahydro-1,5
-Diazosin, 1,2,3,4,5,6,7,8-octahydro-1,5-diazosin and the like. Of these, a 6-membered nitrogen-containing heterocyclic ring is preferable. More preferred are piperidine and piperazine. As the “substituent” that the “5- to 8-membered nitrogen-containing heterocycle” may have, the “substituent” may be the “aromatic group which may have a substituent” represented by Ar. The same as a good substituent is 1
Up to three are used. When the number of substituents is two or more, each substituent may be the same or different. Ring A is preferably a 6-membered nitrogen-containing heterocyclic ring which may have a substituent, more preferably piperidine or piperazine.

The "lower alkylene" of the "lower alkylene optionally having substituent (s)" for X is, for example, a divalent group obtained by removing two hydrogen atoms from an alkane having 1 to 6 carbon atoms. Show. As the "lower alkylene",
For example, linear C _1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, butylene, pentylene and the like can be mentioned. Preferably it is methylene or ethylene. More preferably, it is methylene. Examples of the "substituent" that the "lower alkylene" of the "lower alkylene optionally having a substituent" may have include, for example, a halogen atom (for example, fluorine,
Chlorine, bromine, iodine, etc.), C _1-6 alkyl (for example,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc., C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, etc.), C _2-6 alkenyl (eg, vinyl, allyl, 1- Propenyl, 2-butenyl, etc.), C
_2-6 alkynyl (eg, ethynyl, 2-propynyl,
2-butynyl, etc., C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, etc.), nitro, cyano, hydroxy, C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy) , Butoxy, isobutoxy, pentyloxy, hexyloxy, etc.), amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, Ethyl methylamino, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _6-10 aryloxy (eg, phenyloxy, naphthyloxy, etc.), oxo and the like.
The “lower alkylene” of the “lower alkylene optionally having substituent (s)” is the above-mentioned substituent (s) at 1 to 3, preferably 1 to 2 at the substitutable position of the lower alkylene.
And when the number of substituents is two or more, each substituent may be the same or different. X is preferably methylene.

When Y represents a carbon atom, for example, the formula:>
C (R ⁸⁾ - group represented by the like. In the formula, R ⁸ represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine,
Bromine, iodine, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), and optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6
Alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
Di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, dipropylamino,
Dibutylamino, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), carboxyl,
C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl, mono-C _1-6 alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _{1- 6} alkylcarbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, etc.), C _6-10 aryl-carbamoyl (eg, phenylcarbamoyl, naphthylcarbamoyl, etc.), sulfo, C
_1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 aryl (eg, phenyl,
Naphthyl), C _6-10 aryloxy (eg, phenyloxy, naphthyloxy, etc.) and the like. R ⁸
Is preferably a hydrogen atom, cyano, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, pentyl, hexyl, etc.), C
_1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, etc.), hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkyl-carbonyl and the like.

Embedded image Y is preferably CH or N. More preferably, it is CH 2. Examples of the “aromatic group optionally having substituent (s)” for R ⁷ include the same as the “aromatic group optionally having substituent (s)” for Ar. R ⁷ is preferably a hydrogen atom or an optionally substituted C _6-10 aryl. More preferably, it is a C _6-10 aryl _optionally substituted with a halogen atom (for example, phenyl, 1-naphthyl, 2-naphthyl and the like, preferably phenyl).

The "hydrocarbon group" of the "hydrocarbon group which may have a substituent (s)" for R ¹⁰ is a group obtained by removing one hydrogen atom from a hydrocarbon compound. Cyclic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc.)
And the like. Among them, the following chain or cyclic hydrocarbon groups having 1 to 16 carbon atoms are preferred. (I) C _1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (ii)
_C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), (iii) _C2-6 alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl, etc.), (iv )
C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
(V) C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), preferably phenyl, (vi) C _7-16 aralkyl (eg, benzyl, phenethyl, diphenylmethyl) ,
1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl and the like), preferably benzyl. Examples of the “substituent” which the “hydrocarbon group optionally having” may have include the aforementioned R ¹ , R ² , R ³ and R ⁴
Or the same as the substituent which the "lower alkyl optionally having substituent (s)" for R ⁵ may have is 1
From 5 to 5, preferably from 1 to 3, are used. R
^{As the} “acyl” represented by ¹⁰ , the same as the “acyl” represented by R ¹ or R ² can be mentioned. R ¹⁰ is preferably a hydrogen atom or C _7-11 aralkyl.
More preferably, it is a hydrogen atom. Za is preferably
formula:

Embedded image (Wherein each symbol has the same meaning as described above). More preferably, the formula:

Embedded image (Wherein, R ⁷ has the same meaning as described above).

"Oxygen atom, nitrogen atom" of the "divalent aliphatic hydrocarbon group optionally having a substituent and via an oxygen atom, a nitrogen atom or a sulfur atom" for Zb Or the divalent aliphatic hydrocarbon group optionally having a sulfur atom interposed therebetween includes, for example, (i) methylene or (ii) a saturated or unsaturated aliphatic hydrocarbon having a different divalent hydrocarbon group.
Can be formed by removing one hydrogen atom bonded to one carbon atom at a time, and may contain one or two, preferably one oxygen atom, nitrogen atom or sulfur atom at any position between carbon atoms or at a terminal. Shows a divalent group. Among them, those having 1 to 8 carbon atoms are preferable. Specific examples include (i) C _1-8 alkylene (eg, -CH ₂ -,-(CH ₂ ) ₂ -,-
(CH ₂ ) ₃ −, − (CH ₂ ) ₄ −, − (CH ₂ ) ₅ −, − (CH ₂ ) ₆ −, − (C
_{H 2) 7 -, - (} CH 2) 8 - , etc.) (ii) C _2-8 alkenylene (e.g., -CH = CH -, - CH 2 -CH
_{= CH -, - CH 2 -CH} = CH-CH 2 -, - CH 2 -CH 2 -CH = CH
-, - CH = CH-CH 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -CH
₂ -CH = CH- etc.)

Embedded image (Iv) Formula:-(CH ₂ ) p-M- (CH ₂ ) q- (where p and q are each an integer of 0 to 8, p + q is an integer of 1 to 8, M is O, NR ⁹ , S, SO or SO ₂ ). R ⁹ in the formula is a hydrogen atom, C _1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc.), C _3-6 cycloalkyl (for example,
Represents cyclopropyl, cyclobutyl, cyclopentyl, etc., C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, etc.), C _7-11 aralkyl (eg, benzyl, phenethyl, etc.) or acyl. As the “acyl”, those similar to the “acyl” represented by R ¹ or R ² can be mentioned. M is
Preferably is O, NR ^9. Among them, R ⁹ is preferably a hydrogen atom. p and q are each preferably an integer of 0 to 5. More preferably, it is an integer of 0 to 4.

The "substituent" which the "divalent aliphatic hydrocarbon group optionally interposed with an oxygen atom, a nitrogen atom or a sulfur atom" may have, for example, a halogen atom (for example, fluorine, Chlorine, bromine, iodine, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, C
_3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono -C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-C _1-6 alkylamino (eg, dimethylamino, diethylamino, ethylmethylamino, dipropylamino) , Dibutylamino and the like), C _6-14 aryl (for example, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and the like), C _7-11 aralkyl (for example, benzyl, phenethyl and the like), C _6-10 aryloxy (for example, , Phenyloxy, naphthyloxy, etc.), oxo, acyl, etc. No. Examples of the above-mentioned “optionally halogenated C _1-6 alkyl”, “optionally halogenated C _1-6 alkoxy” and “optionally halogenated C _1-6 alkylthio” include the aforementioned Ar And the same as those described in detail for the substituent of the aromatic group represented by. Examples of the “acyl” include those similar to the “acyl” represented by R ¹ or R ² . The substituent is 1 to 1 at a substitutable position.
Five substituents may be substituted, and when the number of substituents is two or more, each substituent may be the same or different. Zb is preferably a bond or C _1-8 alkylene. More preferably, it is a bond.

The "aromatic group optionally having substituent (s)" for Q is the same as the "aromatic group optionally having substituent (s)" for Ar. .
Zc represents a group 2 which may have a substituent and may be via an oxygen atom, a nitrogen atom or a sulfur atom;
As the "valent aliphatic hydrocarbon group", the "divalent aliphatic hydrocarbon which may have a substituent represented by Zb and may be via an oxygen atom, a nitrogen atom or a sulfur atom" And the like. Q is preferably
It is an aromatic group which may have a substituent. As the “optionally substituted 5- to 8-membered nitrogen-containing heterocycle” of the “optionally substituted 5- to 8-membered nitrogen-containing heterocycle or its benzolog-fused ring” represented by the ring Aa Is
Examples of the "5- to 8-membered nitrogen-containing heterocyclic ring which may have a substituent" represented by the ring A include "benzolog condensation of a 5- to 8-membered nitrogen-containing heterocyclic ring which may have a substituent". As the “ring”, the “5- to 8-membered optionally substituted nitrogen-containing heterocyclic ring” represented by the aforementioned ring A can be condensed with one optionally substituted benzene ring. And a condensed ring fused. The "substituent" of the "optionally substituted benzene ring" is a substituent which the "optionally substituted aromatic group" represented by Ar may have The same one as described above is used. The Aa ring is preferably a 6-membered nitrogen-containing heterocycle. More preferably, it is piperidine.

In the formula (I), preferably, R ¹ and R ² are each a hydrogen atom; R ³ , R ⁴ , R ⁵ and R ⁶ are each a C _1-6 alkyl; Ar is a halogen atom, C _1-6 1 to 3 substituents selected from alkyl and C _1-6 alkoxy
A 6-membered nitrogen-containing heterocyclic ring; X is methylene; Y is CH or N;

Embedded image (Wherein R ⁷ ′ is a halogen atom, C _1-6 alkyl and C 7
Phenyl optionally having 1 to 3 substituents selected from _1-6 alkoxy, and R ¹⁰ ′ represents a hydrogen atom); Zb is substituted by a bond or C _6-10 aryl which may also be C _1-6 alkylene; and m is a compound which is 1 or 2. In the formula (I), R
¹ and R ² are each a hydrogen atom; R ³ , R ⁴ , R ⁵ and R ⁶ are each a C _1-6 alkyl; Ar is a halogen atom,
C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _1-6 alkyl-carbonyl, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl , Sulfo, C _1-6 alkylsulfonyl, C _6-10 aryl and C _6-10 aryloxy, which may have 1 to 3 substituents (i) C _6-10 aryl, (i
i) 2-pyridyl, (iii) 3-pyridyl, (iv) 4-pyridyl, (v) 2-indolyl or (vi) 3-indolyl;

Ring A is a 6-membered nitrogen-containing heterocyclic group; X is methylene; Y is CH or N;

Embedded image R ^7b is a C _6-10 aryl optionally substituted with a hydrogen atom or a halogen atom; R ^10a is a hydrogen atom or C _7-11 aralkyl; even if Z ^b is substituted with a bond or C _6-10 aryl, respectively. Good (i) C _1-6 alkylene, (ii)
C _2-6 alkenylene or (iii) formula :-( CH ₂₎ p'-M'-
(CH ₂ ) q′− (where p ′ and q ′ are each 0 to 5)
And p '+ q' is an integer of 1 to 6, M 'represents O or NH); and a compound wherein m is 1 or 2 or a salt thereof. Among them, R ^10a is preferably a hydrogen atom, a compound in which Zb is a bond and m is 1, or a salt thereof. In the formula (I), R ¹ and R ² are each a hydrogen atom; R ³ , R ⁴ , R ⁵ and R ⁶ are each a C _1-6 alkyl; _6-10 aryl; ring A is a 6-membered nitrogen-containing heterocyclic group; X is methylene; Y is CH or N;

Embedded image R ^7a is a hydrogen atom or C _6-10 aryl; Zb is (i) a bond or (ii) C _1-6 alkylene or C _2-6 alkenylene each of which may be substituted with C _6-10 aryl; and m Is preferably a compound or a salt thereof. Alternatively, R ¹ and R ² are each a hydrogen atom; R ³ , R ⁴ , R
⁵ and R ⁶ are each a C _1-6 alkyl; and Ar is a C ₆ which may have 1 to 3 substituents selected from a halogen atom, methylenedioxy, C _1-6 alkyl and C _1-6 alkoxy. _-10 aryl; ring A is a 6-membered nitrogen-containing heterocyclic ring; X is methylene; Y is CH or N;

Embedded image R ^7b is a C _6-10 aryl optionally substituted with a hydrogen atom or a halogen atom; R ^10a is a hydrogen atom or a C _7-11 aralkyl; Zb is a bond or a C _6-10 aryl (I) C _1-6 alkylene, (ii) C _2-6 alkenylene or (iii) a formula each optionally substituted
_{- (CH 2) p'-M} '- (CH 2) q'- ( wherein, p' and q 'integer of 5 to from 0 respectively, and p' + q 'is 1 to 6 integer, M' Is a group represented by O or NH); and a compound wherein m is 1 or 2 or a salt thereof is also preferable.

A preferred specific example of the compound (I) of the present invention is 2-[(4-benzyl-1-piperidinyl) methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5- Benzofuranamine, 1-[(5-amino-
2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (-)-1-[(5-amino-2 , 3-Dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (+)-1-
[(5-amino-2,3-dihydro-2,4,6,7-
Tetramethylbenzofuran-2-yl) methyl] -N-
(Diphenylmethyl) -4-piperidineamine, 1-
[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (-)-1- [(5-Amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl)
-4-piperidineamine, (+)-1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-
Trimethylbenzofuran-2-yl) methyl] -N-
(Diphenylmethyl) -4-piperidineamine, 1-
[(5-amino-7-tert-butyl-2,3-dihydro-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (-)- 1-[(5-amino-7-tert-butyl-2,3-dihydro-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl)
-4-piperidineamine, (+)-1-[(5-amino-7-tert-butyl-2,3-dihydro-2,4,6-
Trimethylbenzofuran-2-yl) methyl] -N-
(Diphenylmethyl) -4-piperidineamine 2-
[[4- (diphenylmethoxy) -1-piperidinyl]
Methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine, 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran -2-yl) methyl] -N- (3,3-diphenylpropyl) -4-piperidineethylamine 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (2-phenylethyl) -1-piperazinyl] methyl] -5-benzofuranamine and salts thereof.

More preferably, 1-[(5-
Amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (-)-1-
[(5-amino-2,3-dihydro-2,4,6,7-
Tetramethylbenzofuran-2-yl) methyl] -N-
(Diphenylmethyl) -4-piperidineamine, (+)
-1-[(5-amino-2,3-dihydro-2,4,
6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, 1-[(5-amino-2,3-dihydro-7-isopropyl-2,4,6 -Trimethylbenzofuran-2-
Yl) methyl] -N- (diphenylmethyl) -4-piperidineamine, (-)-1-[(5-amino-2,3-
Dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (+)-1-[(5
-Amino-2,3-dihydro-7-isopropyl-2,
4,6-trimethylbenzofuran-2-yl) methyl]
—N- (diphenylmethyl) -4-piperidineamine or a salt thereof. In the formula (Ia), R ¹ and R ² are each a hydrogen atom, C _1-6 alkyl or C _1-6 alkyl-carbonyl; R ³ , R ⁴ , R ⁵ and R ⁶ are each a C atom
_6alkyl; Aa ring is fused to a benzene ring optionally may also be 6 or 7-membered nitrogen-containing and heterocyclic group; X is methylene; is Y (i) ^{formula:> C (R 8a) -} ( wherein, R ^8a represents a hydrogen atom or hydroxy) or (ii) N; Q
Is (i) a hydrogen atom, (ii) a halogen or C _1-6
C _6-10 aryl optionally substituted with alkoxy or 6-membered nitrogen-containing aromatic group or (iii) a compound of the formula -Zc'-Ar '
(In the formula, Zc ′ may be each substituted with C _6-10 aryl or oxo, and C _1-6 alkylene or C _2-6 alkenylene which may be via an oxygen atom, and Ar ′ is _{A 6-10} aryl); and m
Is preferably a compound or a salt thereof.

Preferred specific examples of the compound (Ia) include:
(S) -2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, 2,3-dihydro-7
-Isopropyl-2,4,6-trimethyl-2-[(4
-Phenyl-1-piperidinyl) methyl] -5-benzofuranamine, (-)-2,3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl ] -5-benzofuranamine, (+)-2,3-dihydro-7-isopropyl-
2,4,6-trimethyl-2-[(4-phenyl-1-
Piperidinyl) methyl] -5-benzofuranamine, 7
-Tert-butyl-2,3-dihydro-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, (-)-7-tert-
Butyl-2,3-dihydro-2,4,6-trimethyl-
2-[(4-phenyl-1-piperidinyl) methyl]-
5-benzofuranamine, (+)-7-tert-butyl-
2,3-dihydro-2,4,6-trimethyl-2-
[(4-phenyl-1-piperidinyl) methyl] -5-
Examples include benzofuranamine and their salts. Of these, more preferably, (S) -2,3-dihydro-
2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine and salts thereof. Compound (I) and compound (Ia) have stereoisomers, and the present invention includes a case where these isomers are used alone or a mixture thereof.

Compound (I) or compound (I) of the present invention
As the salt of a), for example, pharmacologically acceptable salts and the like are used. Examples include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the salt with an inorganic base include, for example, sodium salt,
Examples thereof include alkali metal salts such as potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and aluminum salts. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine,
Pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,
Salts with N'-dibenzylethylenediamine and the like can be mentioned. Preferred examples of salts with inorganic acids include, for example, hydrochloric acid,
Salts with hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone And salts with acids, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Among them, pharmaceutically acceptable salts are preferable. Examples thereof include compounds having a basic functional group in compound (I) or compound (Ia), for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphorus, and the like. Salts with inorganic acids such as acids, for example, salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid. When having an acidic functional group, for example, an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt,
Ammonium salts and the like.

The method for producing the compound (I) of the present invention is described below. Compound (I) of the present invention can be obtained by a method known per se or a method analogous thereto, or a method represented by the following reaction formula, for example. Compound (Ia) is
A method known per se (JP-A-5-140142, EP-A
-483772, JP-A-6-41123, USP 5,
552, 552) or a method analogous thereto, or a method represented by the following reaction formula, for example. The schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above. The compounds (II) to (XXVIII) in the reaction formulas may include salts, and examples of such salts include the same as the salts of compound (I).

Embedded image

Compound (II) can be prepared by a method known per se, for example, as described in JP-A-5-140142 or Journal of the American Oil Chemistry Society (J. Am. Oi).
l, Chem. Soc.), Vol. 51, 200-203, 1974, or a method analogous thereto. Compound (V) can be produced according to a method known per se, for example, a method described in JP-A-5-140142 or a method analogous thereto. Compound (VI
When the compound (I) is commercially available, a commercially available product can be used as it is, or a method known per se, for example, European Journal of Medicinal Chemistry (Eur.
J. Med. Chem.), 15, 363-370, 1980, JP-A-6
It can be produced according to a method described in JP-A-2-87585, JP-A-2-49726, or a method analogous thereto. Compound (III) (wherein L represents a leaving group) is converted into an alcohol form by directly reducing or esterifying the carboxyl group of compound (II), followed by sulfonic esterification or halogenation. It is manufactured by As the "leaving group" for L, for example, a halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), optionally halogenated C
_1-5 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), arylsulfonyloxy (eg, optionally substituted benzenesulfonyloxy such as p-toluenesulfonyloxy, benzenesulfonyloxy, etc.) Etc.).

Examples of the reducing agent used for reducing the carboxyl group include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, and borane. Borane complexes such as a tetrahydrofuran complex and a borane dimethyl sulfide complex, alkylboranes such as texyl borane and disiamyl borane, and diborane are used. The amount of the reducing agent used is, for example, in the case of metal hydrides, about 0.5 to 10 mol, preferably about 0.5 to 3.0 mol per 1 mol of compound (II).
Mole, in the case of metal hydrogen complex compounds, about 0.5 to 10 moles, preferably about 0.5 to 5.0 moles, per mole of compound (II), in the case of borane complexes, alkylboranes or diborane. , About 1 mole per mole of compound (II).
It is 0 to 10.0 moles, preferably 1.0 to 5.0 moles. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; benzene, toluene, and cyclohexane. And solvents such as hydrocarbons, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and organic acids such as formic acid and acetic acid, or a mixed solvent thereof. The reaction time is generally 1 hour to 100 hours, preferably 1 hour to 50 hours. The reaction temperature is usually 0 to 120 ° C, preferably 20 ° C.
To 80 ° C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

The compound (II) is esterified according to a conventional method used in organic chemistry, and the resulting compound is subjected to reduction. Examples of the reducing agent include metal hydrides such as aluminum hydride and diisobutylaluminum hydride. Hydrides, lithium aluminum hydride, metal hydride complexes such as sodium borohydride, borane complexes such as borane tetrahydrofuran complex, borane dimethyl sulfide complex, alkylboranes such as texyl borane, disiamyl borane, diborane, or for example, Raney nickel, Raney A hydrogenation catalyst such as cobalt is used. The amount of the reducing agent used is, for example, in the case of metal hydrides,
About 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of the ester of the compound (II), and in the case of a metal hydride complex, 1 mol of the ester of the compound (II) About 1.0 to 10 mol, preferably about 1.0 mol
Borane complex, alkyl borane or diborane, about 1.0 to 5.0 mol per 1 mol of the ester of compound (II). In the case of hydrogenation, a hydrogenation catalyst is used. About 10 to the ester form of (II)
To 1000% by weight, preferably about 80 to 300%
% By weight. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene,
Solvents such as hydrocarbons such as cyclohexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as formic acid and acetic acid, and mixed solvents thereof are preferable. The reaction time varies depending on the activity and amount of the catalyst to be used, but is usually from 1 hour to 1 hour.
00 hours, preferably 1 hour to 50 hours. The reaction temperature is usually 0 to 120 ° C, preferably 20 to 80 ° C. When a hydrogenation catalyst is used, the pressure of hydrogen is usually 1 to 100 atm. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

In order to convert the obtained alcohol to a sulfonic acid ester, methanesulfonyl chloride, p
A sulfonating agent such as toluenesulfonyl chloride,
Used with a base as needed. The sulfonating agent is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of the alcohol compound. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, cyclohexane, and hexane; Amides such as dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide and the like. Solvents such as sulfoxides, nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine, and quinoline, and mixed solvents thereof are preferable. Examples of the base optionally used include triethylamine, pyridine and the like. The reaction temperature is about -20 to 150 ° C, preferably 0 ° C.
To 100 ° C. The reaction time is usually from 5 minutes to 24
Time, preferably 10 minutes to 5 hours. Examples of the halogenating agent include thionyl halides such as thionyl chloride and thionyl bromide, phosphoryl halides such as phosphoryl chloride and phosphoryl bromide, phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, and phosphorus tribromide. Phosphorous halides such as, oxalyl halides such as oxalyl chloride,
Phosgene and the like. The halogenating agent is used in an amount of about 1.0 to 30 mol, preferably about 1.0 to 10 mol, per 1 mol of the alcohol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction.
Such a solvent is not particularly limited as long as the reaction proceeds, for example, aromatic hydrocarbons such as benzene and toluene, saturated hydrocarbons such as cyclohexane and hexane, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane. Amides such as ethers, N, N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane or a mixed solvent thereof are preferable. The reaction time is generally 10 minutes to 12 hours, preferably 10 minutes to 5 hours. The reaction temperature is usually -10 to 200
° C, preferably -10 to 120 ° C. The product (III) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (IV) is produced by nitrating compound (III). Examples of the nitrating agent include mixed acids, acetyl nitrate, fuming nitric acid, nitronium tetrafluoroborate (NO ₂ ⁺ BF ₄ ⁻ ), and nitronium trifluoromethanesulfonate (NO ₂ ⁺ CF ₃ SO ₃ ⁻ ). The nitrating agent is used in an amount of about 1.
0 to 50 mol, preferably about 1.0 to 10 mol is used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.For example, organic acids such as acetic acid, acid anhydrides such as acetic anhydride, mineral acids such as sulfuric acid and nitric acid, saturated hydrocarbons such as cyclohexane and hexane, and dichloromethane. , Chloroform, carbon tetrachloride,
Solvents such as halogenated hydrocarbons such as 1,2-dichloroethane or a mixed solvent thereof are preferred. The reaction time is generally 10 minutes to 12 hours, preferably 10 minutes to 5 hours. The reaction temperature is usually -10 to 20
0 ° C, preferably -10 to 120 ° C. The product (IV) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (VI) is produced by reducing compound (IV) and, if desired, subjecting it to alkylation and acylation. Examples of the reducing agent used in the reduction include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, borane tetrahydrofuran complex, borane dimethyl sulfide Borane complexes such as complexes, alkylboranes such as texyl borane and disiamyl borane, diborane or metals such as zinc, aluminum, tin and iron; alkali metals such as sodium and lithium / liquid ammonia (birch reduction)
And the like. As the hydrogenation catalyst, for example, a catalyst such as palladium carbon, platinum oxide, Raney nickel, Raney cobalt and the like are used. The amount of the reducing agent used is, for example, in the case of metal hydrides, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (IV).
Mole, metal-hydrogen complex compound, about 1.0 to 10 mole, preferably about 1.0 to 3.0 mole per mole of compound (IV), in the case of borane complex, alkylborane or diborane. , About 1 per mole of compound (IV).
0 to 5.0 moles, about 1.0 to 20 equivalents, preferably about 1 to 5 equivalents for metals, about 1 to 20 equivalents, preferably about 1 to 5 equivalents when using an alkali metal, for hydrogenation , Palladium carbon, platinum oxide, Raney nickel, Raney cobalt and the like are used in an amount of about 5 to 1000% by weight, preferably about 10 to 300% by weight, based on the compound (IV). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, N,
Solvents such as amides such as N-dimethylformamide and N, N-dimethylacetamide, organic acids such as formic acid and acetic acid, and mixed solvents thereof are preferable. When a Raney nickel or Raney cobalt catalyst is used, amines such as ammonia may be further added to suppress side reactions. The reaction time varies depending on the type and amount of the reducing agent used or the activity and amount of the catalyst, but is usually 1 hour to 100 hours, preferably 1 hour to 50 hours. The reaction temperature is usually 0 to 120 ° C, preferably 20 ° C.
To 80 ° C. When a hydrogenation catalyst is used, the pressure of hydrogen is usually 1 to 100 atm. The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method,
It can be easily purified by separation means such as recrystallization, distillation and chromatography.

The obtained amine compound is subjected to an alkylation reaction if necessary. Compound (VI) (wherein at least one of R ¹ and R ² represents a hydrogen atom) and a corresponding alkylating agent (eg, a corresponding alkyl halide, a sulfonic acid ester of an alcohol, etc.) are optionally used to form a base React in the presence. The alkylating agent is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (VI). As the base, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-hexyldimethylamine
Dimethylaminopyridine, N, N-dimethylaniline,
Tertiary amines such as N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, alkali metal hydrides such as potassium hydride;
Metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (VI). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane,
Nitriles such as acetonitrile and propionitrile,
Solvents such as sulfoxides such as dimethyl sulfoxide or a mixed solvent thereof are preferable. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 2 hours.
4 hours. The reaction temperature is usually -20 to 200 ° C,
Preferably it is 0 to 150 ° C.

Further, the obtained amine compound is subjected to an acylation reaction if necessary. Compound (VI) wherein R ¹ and R ²
At least one of which represents a hydrogen atom) and an acylating agent, if desired, in the presence of a base or an acid. Examples of the acylating agent include a corresponding carboxylic acid or a reactive derivative thereof (eg, acid halide, acid anhydride, ester, and the like). The acylating agent is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (VI). This reaction is advantageously performed without a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, cyclohexane, and hexane; -Dimethylformamide, N, N
-Amides such as dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, acetonitrile, nitriles such as propionitrile, sulfoxides such as dimethylsulfoxide, pyridine, lutidine, Solvents such as nitrogen-containing aromatic hydrocarbons such as quinoline or a mixed solvent thereof are preferable. Examples of the base optionally used include triethylamine, pyridine and the like. Examples of the acid used if desired include methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like. The reaction temperature is about -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 5 hours. The product (VI) can be used in the next reaction as a reaction solution or as a crude product. Can be purified. The above alkylation reaction and acylation reaction may be combined or repeated as desired.

Compound (VI) can also be produced by reacting compound (V) with a halogenating agent. The reaction is carried out, if desired, in the presence of a base or a basic salt, a radical initiator, or the like, or under light irradiation. As a halogenating agent, halogens such as bromine, chlorine, iodine and iodine monochloride, imides such as N-bromosuccinimide, benzyltrimethylammonium dichloroiodate, benzyltrimethylammonium tribromide, bromine addition of tetramethylammonium bromide And halogen adducts such as pyridinium bromide bromide and dioxane dibromide. The halogenating agent is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (V). This reaction is advantageously performed without a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, and propanol, benzene, toluene, and cyclohexane. , Hydrocarbons such as hexane, N, N-dimethylformamide, N, N
Amides such as N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, halogenated hydrocarbons such as tetrachloroethane, acetonitrile, nitriles such as propionitrile, sulfoxides such as dimethyl sulfoxide, Organic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane, nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine, and quinoline, solvents such as water, and a mixed solvent thereof are preferable. Examples of the optionally used base include, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, and cyclohexyl. Tertiary amines such as dimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine. Examples of the optionally used basic salt include, for example, salts such as sodium acetate and potassium acetate. As the radical initiator optionally used, for example, benzoyl peroxide, azobisisobutyronitrile and the like are used. When light irradiation is performed, a halogen lamp or the like is usually used. The reaction temperature is usually -50 to 150
° C, preferably -20 to 100 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 1 hour.
5 hours.

Compound (VI) can also be produced by cyclizing compound (V) by treating it with an organic peracid in the presence of a base, if desired, and subjecting the resulting alcohol to sulfonic acid esterification. . Examples of the organic peracid include m-chloroperbenzoic acid and peracetic acid. Compound (V) 1
The organic peracid is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per mol. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, water, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane, and hexane; Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; dimethyl sulfoxide Organic acids such as sulphoxides, acetic acid, propionic acid, etc.
Solvents such as nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine, and quinoline, and mixed solvents thereof are preferable. As the optionally used base, for example, sodium carbonate, potassium carbonate, cesium carbonate, inorganic bases such as sodium bicarbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, Tertiary amines such as 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine. The reaction temperature is about -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 5 hours.
In the sulfonic acid esterification in the next step, the same conditions as in the production of compound (III) from compound (II) are used.
The product (VI) can be used in the next reaction as a reaction solution or as a crude product. Can be purified.

Compound (I) is compound (VI) and compound (VI
It is produced by condensing I). Compound (V
The condensation of I) with compound (VII) can be carried out in the presence of a base, if desired. As the base, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine,
Tributylamine, cyclohexyldimethylamine, 4
-Dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N
Tertiary amines such as methyl morpholine, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium Metal alkoxides such as ethoxide and potassium tert-butoxide; About 1.0 base was added per 1 mol of compound (VI).
To 30 mol, preferably about 1.0 to 10 mol. This reaction is advantageously performed without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, dichloroethane, halogenated hydrocarbons such as chloroform, hexane, aliphatic hydrocarbons such as cyclohexane, toluene,
Aromatic hydrocarbons such as xylene, diethyl ether,
Ethers such as diisopropyl ether, amides such as dimethylformamide and dimethylacetamide, alcohols such as methanol and ethanol, and mixtures thereof are used. The amount of the solvent used is the same as the compound (VI)
Usually 0.2 to 50 milliliters per gram,
Preferably it is 2 to 20 ml. The reaction is
Usually -5 to 200 ° C, preferably 5 to 180 ° C
Done in The reaction time is generally about 5 minutes to 72 hours, preferably about 0.5 to 30 hours. When the reaction temperature is high, a sealed tube (autoclave) is generally used.

Embedded image

Compound (IX) wherein L is as defined above,
r represents 1 or 2), and the compound wherein r = 1 is
In the compound (VI), m = 1, that is, in the compound (VIII) (wherein r has the same meaning as described above)
= 1 by reacting the compound with a cyano compound. Examples of the cyano compound include sodium cyanide, potassium cyanide, and a mixture thereof. Further, hydrogen cyanide in the reaction system, for example, sodium hydroxide, potassium hydroxide, sodium carbonate,
It can also be prepared and used by reaction with an alkali metal salt such as potassium carbonate. The cyano compound is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (VIII). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, N, N-dimethylformamide, N,
Amides such as N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, orthodichlorobenzene, sulfoxides such as dimethylsulfoxide, solvents such as water, or solvents thereof. A mixed solvent is preferred. In the presence of a phase transfer catalyst, water and the above-mentioned solvent which is insoluble or hardly soluble in water can also be used. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts. The phase transfer catalyst is used in an amount of about 0.001-10 mol, preferably about 0.005-0.5 mol, per 1 mol of compound (VIII). The reaction time is usually from 10 minutes to 5 minutes.
0 hours, preferably 30 minutes to 20 hours. The reaction temperature is usually 0 to 200 ° C, preferably 20 to 1 ° C.
50 ° C. The product (IX) can be used as is in the reaction solution or as a crude product in the next reaction. It can be easily purified.

In the compound (X) (wherein r is as defined above), the compound in which r = 1 is obtained by hydrolyzing the compound in which r = 1 in the compound (IX) using an acid or a base. It can be manufactured by decomposition. Acid hydrolysis includes, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., Lewis acids such as boron trichloride and boron tribromide, the combined use of Lewis acids with thiols or sulfides, trifluoroacetic acid, p -Organic acids such as toluenesulfonic acid are used. For alkali hydrolysis, for example, sodium hydroxide, potassium hydroxide, metal hydroxides such as barium hydroxide, sodium carbonate, metal carbonates such as potassium carbonate, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide and organic bases such as triethylamine, imidazole and formamidine are used. These acids and bases are
About 0.1 to 2 per mole of compound (IX)
0 mol, preferably about 0.5 to 12 mol is used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene,
Hydrocarbons such as cyclohexane and hexane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and orthodichlorobenzene; sulfoxides such as dimethyl sulfoxide; solvents such as water; A mixed solvent is preferred. The reaction time is generally 10 minutes to 50 hours, preferably 30 minutes to 40 hours. The reaction temperature is usually 0 to 200 ° C, preferably 20 to 150 ° C.
° C. The product (X) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be separated by separation means such as recrystallization, distillation, and chromatography. It can be easily purified.

The compound of formula (VIII) where r = 2 is converted from the compound of formula (X) where r = 1 in the same manner as in the method for producing compound (III) from compound (II). Can be manufactured. R of the compound (IX)
= 2 corresponds to r =
The compound (VIII) can be produced from the compound (r = 2) in the same manner as the method for producing the compound (IX) where r = 1 from the compound (1). Among the compounds (X), the compound wherein r = 2 is the compound (I)
(X) from r = 1 in the compound (X) to r
In the same manner as in the method for producing the compound where = 1, the compound (IX) can be produced from the compound where r = 2. Compound (XI) (wherein r is as defined above)
Is obtained by condensing compound (VII) with compound (X), a reactive derivative of compound (X) or a salt of compound (X). As the reactive derivative of the compound (X),
Acid halides (eg, acid chlorides, acid bromides, etc.),
Acid amides (e.g., acid amides with pyrazole, imidazole, benzotriazole, etc.), mixed acid anhydrides (e.g., mono C _1-4 alkyl- such as monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monotert-butyl carbonate). Mixed acid anhydride with monocarbonic acid; mixed acid anhydride with mono-C _7-10 aralkyl-carbonic acid such as monobenzylcarbonic acid and mono (p-nitrobenzyl) carbonic acid; acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, Mixed acid anhydrides with C _1-6 aliphatic carboxylic acids such as valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid; benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc. C
_7-11 Mixed acid anhydride with aromatic carboxylic acid; Mixed acid anhydride with organic sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; Mixed acid anhydride with monoallyl carbonic acid Products), acid azides, active esters (e.g., diethoxy phosphate, diphenoxy phosphate, p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-
Ester with hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with 6-chloro-1-hydroxybenzotriazole, 1-hydroxy-1
For example, an ester with H-2-pyridone), an active thioester (for example, 2-pyridylthioester, 2-benzothiazolylthioester, or the like) is used.

Instead of using the reactive derivative of compound (X), compound (X) or a salt of compound (X) may be directly reacted with compound (VII) in the presence of a suitable condensing agent. Examples of the condensing agent include N, N′-disubstituted carbodiimides such as N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride, and N, N′-. Azolides such as carbonyldiimidazole, dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, 2-chloromethylpyridinium iodide, 2-fluoro-1-methyl 2-halogenopyridinium salts such as pyridinium iodide and the like are used. Compound (VII)
Is generally used in an amount of about 1.0 to about 1 mol of the compound (X), the reactive derivative of the compound (X) or 1 mol of the salt of the compound (X).
It is 5.0 moles, preferably about 1.0 to 2.0 moles.
This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, and cyclohexane; and N, N-dimethyl. Formamide, N, N-
Solvents such as amides such as dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethylsulfoxide, and water or Preferred are mixed solvents thereof. When an acid halide, a mixed acid anhydride, an active ester, or the like is used as a reactive derivative of the compound (X), the reaction is carried out in the presence of a deoxidizing agent in order to remove the released acidic substance from the reaction system. It can be carried out. Examples of such a deoxidizing agent include inorganic bases such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, and the like.
It is desirable to add tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine. The reaction time varies depending on the reagents and solvents used, but is usually 30 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually 0 to 100 ° C, preferably 0 to 70 ° C.

The product (XI) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be used for recrystallization, distillation, chromatography and the like. It can be easily purified by separation means. Compound (I) can also be produced by reducing compound (XI). Examples of the reducing agent used in the reduction include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, borane tetrahydrofuran complex, borane dimethyl sulfide For example, borane complexes such as a complex, alkylboranes such as texyl borane and disiamyl borane, and diborane are used. The amount of the reducing agent to be used is, for example, in the case of metal hydrides, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (XI), of the metal hydride complex compound. If the compound (X
I) About 1.0 to 10 mol, preferably about 1.0 to 5.0 mol, per mol of borane complex, alkylborane or diborane, about 1 to 1 mol per mol of compound (XI). The amount is from 1.0 to 10.0 mol, preferably from 1.0 to 7.0 mol. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.For example, solvents such as diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, and hydrocarbons such as cyclohexane, or a solvent thereof. A mixed solvent is preferred. The reaction time is generally 15 minutes to 100 hours, preferably 20 minutes to 50 hours. The reaction temperature is usually 0 to 120 ° C, preferably 10 ° C.
To 80 ° C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Compound (XII) is a compound of the formula (I) wherein Y =
The compound represented by N can be produced by deprotecting a group represented by the formula: -Za-Zb-Ar (wherein each symbol is as defined above). As a method for removing the protecting group, for example, a method of treating with an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a reduction reaction is used. These reactions can be performed by a method known per se, for example, "Protective Groups in Organic Synthesis (Prot.
Effective Groups in Organic Synthesis) Second Edition, John Wi
and ley & Sons, Inc., 1991. The product (XII) can be used in the next reaction as a reaction solution or as a crude product.
It can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. Y = N in compound (I)
Is obtained by subjecting a compound of the formula (XII) wherein Y = N to (i) an alkylation reaction, (ii) an acylation reaction or (iii) an acylation reaction, It can also be produced by subjecting an amide to a reduction reaction. The alkylation reaction is carried out using the compound (V
It is carried out in the same manner as in the method for obtaining compound (I) from I).
The acylation reaction is carried out by converting the compound (X) into a compound (X
It is performed in the same manner as in the method for producing I). The step of subjecting the amide obtained after the acylation reaction to a reduction reaction is carried out in the same manner as in the method for producing the compound (I) from the compound (XI).

Embedded image Compound (XIV) (wherein, n represents an integer of 1 to 4)
Represents the compound (VI) and the compound (XIII) (wherein n has the same meaning as described above), and the compound (VI) and the compound (VI
It can be produced by subjecting to a condensation reaction in the same manner as the condensation reaction with I). When the compound (XIII) is commercially available, a commercially available product can be used as it is, or a method known per se, for example, Journal of Medicinal Chemistry (J. Med. Chem.), 1991, 34, 1073. Can also be produced according to the method described in, for example.

Compound (XV) (wherein n has the same meaning as described above) can be produced by subjecting compound (XIV) to an oxidation reaction known per se. The oxidizing agent used in this reaction includes chromic acids such as chromic anhydride, sodium dichromate, and potassium dichromate; periodic acids such as paraperiodic acid, metaperiodic acid, and sodium metaperiodate; Metal oxides such as manganese, silver oxide and lead oxide, sulfoxides such as dimethylsulfoxide, and dehydrating agents such as oxalyl chloride and N, N'-dicyclohexylcarbodiimide are used in combination.
The amount of the oxidizing agent to be used is about 1 to 1 mol of compound (XIV).
To 30 moles, preferably about 1 to 10 moles. The solvent used in this reaction is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, N, Amides such as N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetone,
Ketones such as methyl ethyl ketone, acetonitrile,
Nitriles such as propionitrile, sulfoxides such as dimethylsulfoxide, solvents such as water, and mixed solvents thereof are preferable. The reaction time is generally 5 minutes to 48 hours, preferably 5 minutes to 16 hours. The reaction temperature is usually -90 to 200 ° C, preferably -80.
To 150 ° C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Compound (I) comprises compound (XV) and compound (X
VI) (wherein, R ¹¹ is a hydrogen atom or a hydrocarbon group which may have a substituent, Zd may have a substituent,
And a divalent aliphatic hydrocarbon group which may be via an oxygen atom, a nitrogen atom or a sulfur atom). Represented by R ¹¹ as "may also be a hydrocarbon optionally having substituent", "optionally substituted hydrocarbon" represented by R ¹⁰
And the same. "A divalent aliphatic hydrocarbon group which may have a substituent and may be via an oxygen atom, a nitrogen atom or a sulfur atom" for Zd
Is the same as the “divalent aliphatic hydrocarbon group which may have a substituent and may be through an oxygen atom, a nitrogen atom, or a sulfur atom” represented by Zb. No. When the aliphatic hydrocarbon group is via an oxygen atom or a sulfur atom, it is preferably contained between carbon atoms.
When the compound (XVI) is commercially available, a commercially available product can be used as it is, or it can be produced according to a method known per se. The amount of compound (XVI) to be used is about 0.5 to 2 mol, preferably 0.8 to 1.5 mol, per 1 mol of compound (XV). Examples of the reducing agent include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride, sodium borohydride and sodium cyanoborohydride, borane tetrahydrofuran complex, borane dimethyl Borane complexes such as sulfide complexes, alkylboranes such as texylborane and disiamylborane, and diborane are used. In this reaction, an acid (for example, hydrogen chloride,
Hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc.). The amount of the reducing agent used is, for example, in the case of metal hydrides, about 0.3 to 10 mol, preferably about 0.3 to 3.0 mol, per 1 mol of compound (XV). In the case, about 0.3 to 10 mol, preferably about 0.5 to 5.0 mol, per 1 mol of the compound (XV), in the case of a borane complex, alkylborane or diborane,
The amount is about 1.0 to 10.0 mol, preferably 1.0 to 3.0 mol, per 1 mol of compound (XV). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; benzene, toluene, and cyclohexane. Hydrocarbons, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, solvents such as water, and mixtures thereof. Reaction time is usually 1
0 minutes to 10 hours, preferably 10 minutes to 2 hours. The reaction temperature is generally -20 to 120C, preferably -10 to 80C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Further, for example, platinum oxide, palladium carbon,
Compound (I) can also be produced by reductively condensing compound (XV) and compound (XVI) using a hydrogenation catalyst such as Raney nickel or Raney cobalt and hydrogen. The amount of the hydrogenation catalyst to be used is about 0.1-1000% by weight, preferably about 1-300% by weight, relative to compound (XV). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, N,
Solvents such as amides such as N-dimethylformamide and N, N-dimethylacetamide, organic acids such as formic acid and acetic acid, and mixed solvents thereof are preferable. The reaction time varies depending on the activity and amount of the catalyst used, but is usually 10 minutes to 100 hours, preferably 10 minutes to 10 hours.
Time. The reaction temperature is usually 0 to 120 ° C, preferably 20 to 80 ° C. When a hydrogenation catalyst is used, the pressure of hydrogen is usually 1 to 100 atm. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Embedded image Compound (XVIII) (wherein R ¹² represents a hydrogen atom or a hydrocarbon group, and n has the same meaning as described above), is obtained by the same method as that for producing compound (I) from compound (VI). The compound (VI) can be produced by condensing compound (VI) with compound (XVII) (wherein each symbol is as defined above).

The “hydrocarbon group” represented by R ¹² includes
Represented by R ¹⁰ include those similar to the "hydrocarbon group" of the "optionally substituted hydrocarbon group". When the compound (XVII) is commercially available, a commercially available product can be used as it is, or a method known per se, for example, Journal of the American Chemical Society (J. Am. Chem. Soc.), 1953, 75 Vol., Page 6249, and the like. Compound (XI
X) (wherein n is as defined above) is a compound (XVI
It is produced by subjecting II) to an acid or alkali hydrolysis reaction. Acid hydrolysis includes, for example, mineral acids such as hydrochloric acid and sulfuric acid, Lewis acids such as boron trichloride and boron tribromide, combined use of Lewis acids with thiol or sulfide, and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid. Is used. Alkali hydrolysis includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, metal carbonates such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Metal alkoxides, organic bases such as triethylamine, imidazole and formamidine. These acids and bases are used in an amount of about 0.5 to 20 mol, preferably about 0.5 to 10 mol, per 1 mol of compound (XVIII).
This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, formic acid, Organic acids such as acetic acid, tetrahydrofuran, dioxane, 1,2-
Ethers such as dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane,
Nitriles such as acetonitrile and propionitrile,
Ketones such as acetone and methyl ethyl ketone, sulfoxides such as dimethyl sulfoxide, solvents such as water, and mixed solvents thereof are preferable. The reaction time is generally 10 minutes to 60 hours, preferably 10 minutes to 12 hours.
Time. The reaction temperature is usually -10 to 200C, preferably 0 to 120C. The product (XIX) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

Compound (XX) (wherein n and Zd have the same meanings as described above) is obtained by converting compound (X) to compound (X
It is obtained by condensing compound (XVI) with compound (XIX), a reactive derivative of compound (XIX) or a salt of compound (XIX) in the same manner as in the method for obtaining I). Compound (I) can also be produced by subjecting compound (XX) to a reduction reaction in the same manner as in the above-mentioned method for obtaining compound (I) from compound (XI).

Embedded image Compound (XXI) (wherein M represents a metal and R ¹³ represents a hydrocarbon group or a silyl group which may have a substituent) is described in a method known per se, for example, in JP-A-5-140142. Or a method analogous thereto. Examples of the “metal” represented by M include an alkali metal such as lithium and sodium, an alkaline earth metal such as magnesium, copper, zinc, boron, aluminum, cerium, and titanium. As the “hydrocarbon group optionally having substituent (s)” for R ¹³ , the same as the “hydrocarbon group optionally having substituent (s)” for R ¹⁰ can be mentioned. Examples of the "silyl group" represented by R ¹³ include tri-C _1-6 alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl.

Compound (XXII) (wherein each symbol has the same meaning as described above) can be prepared by a method known per se, for example, the method of Journal of the American Chemical Society (J. Am. C.).
hem. Soc.), Vol. 109, pp. 5765-5780, 1987, or a method analogous thereto. Compound (XXV) can be produced according to a method known per se, for example, a method described in JP-A-5-140142 or a method analogous thereto. In the compound (XXIII) (wherein each symbol is as defined above), m = 1 and X is methylene are the compounds (XXI) and (XXII) where m = 1 and X are methylene. By condensation with a compound of the formula
Compound (XXI) is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (XXII).
Use 0 mol. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.For example, solvents such as diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, and hydrocarbons such as cyclohexane, or a solvent thereof. A mixed solvent is preferred. The reaction time is generally 10 minutes to 100 hours, preferably 10 minutes to 10 hours. The reaction temperature is usually -100 to 30C, preferably -80 to 20C. In this reaction, an additive may be added, if desired. Examples of the additive include boron trifluoride complexes such as boron trifluoride diethyl ether complex and boron trifluoride dimethyl sulfide complex, and copper salts such as copper (I) iodide. The additive is used in an amount of about 0.1 to 3.0 mol per 1 mol of compound (XXII),
Preferably, about 0.5 to 1.5 mol is used. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. You can also.

In the compound (XXIV) (wherein the symbols have the same meanings as described above), the compound in which m = 1 and X is methylene is the compound (XXIII) in which m = 1 and X is methylene. It is produced by cyclizing a compound with a base. As the base, for example, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, basic salts such as sodium bicarbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, Tertiary amines such as 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine; alkali metal hydrides such as sodium hydride and potassium hydride; Metal amides such as sodium amide, lithium diisopropylamide, and lithium hexamethyldisilazide; and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. The base is added in an amount of about 1.0 to 5.0 based on 1 mol of the compound (XXIII).
Mole, preferably about 1.0 to 2.0 moles. This reaction is advantageously performed using a solvent inert to the reaction.
The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propio Preferred are nitrites such as nitriles, sulfoxides such as dimethyl sulfoxide, solvents such as water, and mixed solvents thereof. The reaction time is generally 5 minutes to 3 hours, preferably 5 minutes to 2 hours. The reaction temperature is generally -20 to 200C, preferably -10 to 120C.

In the compound (III) (wherein the symbols have the same meanings as described above), the compound wherein m = 1 and X is methylene is the compound (XXIV) wherein m = 1 and X is methylene The compound can also be produced by deprotecting R ¹³ of the compound with an acid or base catalyst and simultaneously closing the ring. Examples of the acid catalyst include mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid, organic acids such as acetic acid and trifluoroacetic acid, boron trifluoride diethyl ether complex, Lewis acids such as zinc chloride and tin chloride, p-toluene. And sulfonic acids such as sulfonic acid and methanesulfonic acid. As the base catalyst,
Inorganic bases such as sodium hydroxide and potassium hydroxide,
Basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate; aromatic amines such as pyridine and lutidine; triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N Tertiary amines such as dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium hexane Metal amides such as methyldisilazide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide; The acid or base catalyst is used in an amount of about 0.1 to 30 mol, preferably about 0.5 to 10 mol, per 1 mol of compound (XXIV). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, N,
Amides such as N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform,
Preferred are halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride, nitriles such as acetonitrile and propionitrile, ketones such as acetone and methyl ethyl ketone, solvents such as water, and mixtures thereof. The reaction time is generally 5 minutes to 100 hours, preferably 5 minutes to 3 hours. The reaction temperature is usually -2
It is 0 to 120 ° C, preferably 0 to 80 ° C.
The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. You can also.

Compound (III) (wherein each symbol is as defined above) wherein m = 1 and X is methylene are the same as in the method for producing compound (VI) from compound (V) To a compound (XXV) wherein X is methylene. Compound (XXVI)
Can be produced by condensing compound (III) and compound (VII) in the same manner as in the method for producing compound (I) from compound (VI). Compound (I) is
Production by nitrating compound (XXVI) in the same manner as in the method for obtaining compound (IV) from compound (III), and then reducing the nitro group in the same manner as in the method for obtaining compound (VI) from compound (IV) You can also. Further, the alkylation reaction and the acylation reaction optionally performed on the compound (VI) may be combined with each other as required, or may be repeatedly performed on the compound (I). The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, and chromatography. You can also.

Compound (I) can also be produced by subjecting compound (XXVI) to a diazo coupling reaction and reducing the resulting azo compound. As the diazonium salt, for example, benzenediazonium chloride,
Aryldiazonium salts such as 4-nitrobenzenediazonium chloride, 2,4-dinitrobenzenediazonium chloride, and 4-sulfobenzenediazonium chloride are used. The diazonium salt can be produced according to a method known per se, for example, a method described in JP-A-5-140142 or a method analogous thereto. About 0.8 to 3 mol of a diazonium salt is used per 1 mol of compound (XXIV). The diazo coupling reaction is advantageously performed using a solvent inert to the reaction.
The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, and cyclohexane; and N, N-. Amides such as dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile and propionitrile; acetone and methyl ethyl ketone; Ketones, acetic acid, organic acids such as propionic acid, solvents such as water, or a mixed solvent thereof are preferable. The reaction time is generally 10 minutes to 100 hours, preferably 20 minutes to 30 hours. The reaction temperature is usually
The temperature is 20 to 80 ° C, preferably 0 to 50 ° C.
The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. You can also. For the reduction of the azo compound in the next step, the same conditions as in the method for producing compound (VI) from compound (IV) are used. Further, the alkylation reaction and the acylation reaction optionally performed on the compound (VI) may be combined with each other as required, or may be repeatedly performed on the compound (I). The product can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by separation means such as recrystallization, distillation, and chromatography. You can also. Also, by using the optically active compound (XXII) as a raw material,
Optically active compound (I) can be easily synthesized.

[0056]

Embedded image Compound (XXVII) can be prepared by a method known per se, for example,
It can be manufactured according to the method described in -140142 or the like, or a method analogous thereto. Compound (XXVI
II) (wherein L is as defined above, and m represents 1) can be produced by reacting compound (XXVII) with a halogenating agent. The reaction is carried out, if desired, in the presence of a base or a basic salt, a radical initiator, or the like, or under light irradiation. As halogenating agents, halogens such as bromine, chlorine, iodine and iodine monochloride, imides such as N-bromosuccinimide, benzyltrimethylammonium dichloroiodate, benzyltrimethylammonium tribromide, and bromine addition of tetramethylammonium bromide Body, pyridinium bromide perbromide, dioxane dibromide, and the like, and the like. Compound (XX
VII) About 1.0 to 5.
0 mol, preferably about 1.0 to 2.0 mol.
This reaction is advantageously performed without a solvent or in a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, alcohols such as methanol, ethanol, and propanol, benzene, toluene, and cyclohexane. , Hydrocarbons such as hexane,
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and tetrachloroethane; nitriles such as acetonitrile and propionitrile , Sulfoxides such as dimethyl sulfoxide, organic acids such as acetic acid and propionic acid, nitrated hydrocarbons such as nitromethane, nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine and quinoline, solvents such as water, and mixtures thereof. Solvents and the like are preferred. As the optionally used base, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate,
Aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine And other tertiary amines. Examples of the optionally used basic salt include, for example, salts such as sodium acetate and potassium acetate. As the radical initiator optionally used, for example, benzoyl peroxide, azobisisobutyronitrile and the like are used. When performing light irradiation, a halogen lamp is usually used. The reaction temperature is usually -50 to 150C, preferably -20 to 100C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 15 hours.

Compound (XXVIII) is compound (XXVII)
If desired, the compound can be cyclized by treatment with an organic peracid in the presence of a base, and the resulting alcohol compound can be sulfonic acid esterified. Examples of the organic peracid include m-chloroperbenzoic acid and peracetic acid. The organic peracid is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (XXVII). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, water, ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane, and hexane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane and tetrachloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethylsulfoxide, organic acids such as acetic acid and propionic acid, pyridine, lutidine, and quinoline. Solvents such as nitrogen aromatic hydrocarbons or a mixed solvent thereof are preferred. As the optionally used base, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogencarbonate, pyridine,
Aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N
And tertiary amines such as -dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, and N-methylmorpholine. The reaction temperature is usually -20 to 1
The temperature is 50 ° C, preferably 0 to 100 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 5 hours.
Time. In the sulfonic acid esterification in the next step, the same conditions as in the production of compound (III) from compound (II) are used. The product (XXVIII) can be used in the next reaction as a reaction solution or as a crude product.
It can be easily purified by separation means such as chromatography.

Compound (VI) can also be produced by subjecting compound (XXVIII) to an alkylation reaction in the presence of a protonic acid or Lewis acid. As the alkylating agent,
For example, methanol, ethanol, isopropyl alcohol, alcohols such as tert-butyl alcohol, isopropyl chloride, halogenated hydrocarbons such as tert-butyl chloride, alkenes such as isobutene, isopropyl acetate, tert-butyl acetate, diisopropyl sulfate, p
Esters such as isopropyl toluenesulfonate and isopropyl phosphite, and ethers such as tert-butyl methyl ether. Compound (XXVIII) 1
About 1.0 to 30 moles of the alkylating agent,
Preferably, about 1.0 to 15 mol is used. As the protic acid, concentrated sulfuric acid, trifluoroacetic acid and the like are used. As the Lewis acid, aluminum chloride, aluminum bromide, iron (III) chloride, tin (IV) chloride, titanium tetrachloride, zinc chloride and the like are used. Usually, each of the protonic acid and the Lewis acid is used alone, but they may be combined as desired. When a protonic acid is used, about 1.0 to 200 mol per 1 mol of compound (XXVIII),
Preferably about 1.0 to 100 moles are used. When a Lewis acid is used, about 1.1 mol per mol of compound (XXVIII) is used.
0 to 5.0 moles, preferably about 1.0 to 3.0 moles
Use moles. This reaction is advantageously performed using a solvent inert to the reaction. There is no particular limitation as long as the reaction proceeds as such a solvent, for example, benzene, toluene, xylene, cyclohexane, hydrocarbons such as hexane, dichloromethane, chloroform, carbon tetrachloride,
Preferred are halogenated hydrocarbons such as 1,2-dichloroethane and tetrachloroethane, nitriles such as acetonitrile and propionitrile, nitroalkanes such as nitromethane, and solvents such as carbon disulfide and their mixed solvents. The reaction temperature is usually -20 to 200
° C, preferably from 0 to 150 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 10 minutes to 5 hours. The product (VI) can be used in the next reaction as a reaction solution or as a crude product. It can be purified. In each of the above reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the desired compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the amino-protecting group include formyl and C _1-6 alkyl-carbonyl (for example, acetyl, propionyl and the like) each having a substituent, phenylcarbonyl, C _1-6 alkoxy-carbonyl. (Eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-10 aralkyloxy-carbonyl (eg, benzyloxycarbonyl), trityl, phthaloyl and the like are used.
As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, valeryl, etc.), nitro and the like are used. Is 1 to 3
Individual. Examples of the carboxyl-protecting group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like. Used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, butylcarbonyl, etc.), nitro,
C _1-6 alkyl (eg, methyl, ethyl, tert-butyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.) and the like are used, and the number of substituents is 1 to 3. Examples of the hydroxy-protecting group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-
Butyl, etc.), phenyl, C _7-11 aralkyl (eg,
Benzyl, etc.), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), phenyloxycarbonyl, C _7-11 aralkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, Cyril and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6
Alkyl (eg, methyl, ethyl, tert-butyl, etc.), C _7-11 aralkyl (eg, benzyl, etc.), C
_6-10 aryl (eg, phenyl, naphthyl, etc.), nitro and the like are used, and the number of substituents is 1 to 4.

As a method for removing the protecting group, a method known per se or a method analogous thereto is used.
Base, ultraviolet light, hydrazine, phenylhydrazine, N-
A method of treating with sodium methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or the like, or a reduction reaction is used. In each case,
If desired, known deprotection reactions, acylation reactions,
Alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction,
Compound (I) can be synthesized by performing the carbon chain extension reaction and the substituent exchange reaction each alone or in combination of two or more thereof. For these reactions, for example, the methods described in Shin-Jikken Kagaku Koza, Vol. 14, 15, 1977 (Maruzen Publishing) are employed. When the desired product is obtained in a free state by the above reaction, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. Can also.
The compound (I) thus obtained can be isolated and purified from the reaction solution by a known means such as phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like. When compound (I) exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, or the like, each can be isolated by the above separation and purification means, if desired. When compound (I) is a racemate, it can be separated into an S-form and an R-form by ordinary optical resolution means. Compound (I) may be a hydrate or a non-hydrate.

Compounds (I) and (Ia) of the present invention
Has high affinity for sodium channels, particularly site 2, and has low toxicity and few side effects, and is therefore useful as a safe pharmaceutical. Compound (I) and compound (Ia) can be obtained from mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows,
Acts as a sodium channel modulator on sheep, monkeys, humans, etc., and acts on central nervous system diseases and disorders such as ischemic central nervous system disorders, central trauma (eg, head trauma,
Spinal cord injury, whiplash etc.), epilepsy, neurodegenerative diseases (eg, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neurosis, etc.), vascular dementia (eg, Polyinfarct dementia, Binswanger's disease, etc.), manic depression, depression, schizophrenia, chronic pain,
It is used as a prophylactic and therapeutic agent for trigeminal neuralgia, migraine, cerebral edema and the like. Further, compound (I) and compound (Ia)
Also has excellent antioxidant and dopamine transporter-modulating effects. Used as Of these, ischemic central nervous disorder, central injury, neurodegenerative disease,
It is a prophylactic and therapeutic agent for cerebral edema.

Compound (I) and compound (Ia) have low toxicity, and can be used as is or in a manner known per se in the form of a pharmaceutical composition containing a pharmacologically acceptable carrier, such as tablets (sugar-coated tablets, film-coated tablets). Powders, granules, capsules, (including soft capsules),
It can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) as a liquid, injection, suppository, sustained release agent and the like. The content of compound (I) or compound (Ia) in the pharmaceutical composition or preparation of the present invention is about 0.01 to 100% by weight of the whole composition or preparation.
The dose varies depending on the administration subject, administration route, disease and the like. For example, when administered as an injection to an adult as a therapeutic agent for head trauma, the active ingredient (compound (I) or (Ia)) is used as an active ingredient. About 0.05 to 30 mg /
kg body weight, preferably about 0.1 to 20 mg / kg body weight, more preferably about 0.1 to 5 mg / kg body weight, particularly preferably about 0.1 to 2 mg / kg body weight, once or several times a day. Administration. Furthermore, other active ingredients (for example, antithrombotic agents such as argatroban, thrombolytic agents such as urokinase and tissue plasminogen activator, platelet aggregation inhibitors such as ozagrel, anticoagulants such as heparin, cimetidine and famotidine and the like) Histamine receptor blockers, antiparkinson drugs such as dopamine, levodopa, hydantoin anticonvulsants such as phenytoin, mephenytoin, etotoin, barbital anticonvulsants such as phenobarbital, mehobarbital, metalbital or anesthetics, diltiazem, etc. A calcium antagonist,
Imipenem / cilastatin sodium, glycerol, etc.). The other active ingredient and compound (I) or (Ia) are mixed according to a method known per se, and a pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule), liquid, injection, Suppositories, sustained-release preparations, etc.).

The pharmacologically acceptable carriers which may be used in the production of the pharmaceutical composition or preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, and include, for example, excipients in solid preparations. Examples include excipients, lubricants, binders and disintegrants, or solvents, dissolution aids, suspending agents, isotonic agents, buffers and soothing agents in liquid preparations. If necessary, conventional additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. As an excipient, for example, lactose,
White sugar, D-mannitol, starch, corn starch,
Examples include crystalline cellulose and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,
Examples include ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Examples include hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

[0065]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Formulation Examples and Experimental Examples, which are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. The following reference examples, "room temperature" in the examples
Usually indicates about 10 ° C to 35 ° C. % Indicates weight percent unless otherwise specified. However, the yield shows mol / mol%. As the basic silica gel, NH-DM1020 manufactured by Fuji Silysia Chemical Ltd. was used. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet dd: double doublet dt: double triplet br: broad (Broad) J: coupling constant Hz: Herz CDCl ₃ : heavy chloroform DMSO-d ₆ : heavy dimethyl sulfoxide CD ₃ OD: heavy methanol ¹ H-NMR: proton nuclear magnetic resonance

[0066]

【Example】

Reference Example 1 2,3-dihydro-2-[[4- (4-methoxyphenyl) -1-piperazinyl] methyl] -2,4,6,7-
Tetramethyl-5-benzofuranamine trihydrochloride 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 1.5 g, 1
A mixture of 2.0 g of-(4-methoxyphenyl) piperazine and 1.6 g of triethylamine was stirred at 180 ° C. for 15 hours in a sealed tube under an argon atmosphere. After cooling the reaction solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 9: 1), and then converted to a hydrochloride with a 4N ethanol solution of hydrogen chloride. This was recrystallized from ethanol to obtain 0.53 g of the title compound. Yield 2
0%. Melting point 194-196 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.62 (3H,
s), 2.08 (3H, s), 2.25 (6H, s),
3.05 (1H, d, J = 16.2 Hz), 3.34-
5.63 (11H, m), 3.71 (3H, s), 6.
88 (2H, d, J = 9.0 Hz), 7.05 (2H,
d, J = 9.0 Hz), 9.92 (2H, brs).

Reference Example 2 2-[[4- (2-chlorophenyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine dihydrochloride 2 -Bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 1.4 g, 1
A suspension of 1.4 g of-(2-chlorophenyl) piperazine hydrochloride and 2.1 g of potassium carbonate in 15 mL of N, N-dimethylformamide was stirred at 145 ° C for 20 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate and silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-[[4- (2
-Chlorophenyl) -1-piperazinyl] methyl)]-
2,3-dihydro-2,4,6,7-tetramethyl-5
-Benzofuranamine was obtained. This was dissolved in methanol, and an excess amount of a 10% hydrogen chloride-methanol solution was added. The obtained solution was concentrated under reduced pressure, and crystallized from ethanol / diethyl ether to obtain 1.0 g of the title compound.
Yield 44%. Melting point 167-171 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.61 (3H,
s), 2.07 (3H, s), 2.23 (3H, s),
2.25 (3H, s), 3.06 (1H, d, J = 1
6.6 Hz), 3.1-3.9 (11H, m), 7.0
−7.25 (2H, m), 7.3 to 7.5 (2H,
m).

Reference Example 3 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-pyridyl) -1-piperidinyl] methyl] -5-benzofuranamine 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 0.85 g,
Under nitrogen atmosphere, a mixture of 0.97 g of 4- (4-piperidinyl) pyridine and 1.3 mL of triethylamine was added.
The mixture was stirred at 180 ° C. for 15 hours in a sealed tube. After adding a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 20: 1), and crystallized from ethyl acetate / hexane to obtain 0.77 g of the title compound. Yield 70
%. 126-128 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.45 (3H, s),
1.5-1.9 (4H, m), 2.0-2.5 (3H,
m), 2.08 (6H, s), 2.11 (3H, s),
2.52 (1H, d, J = 13.9 Hz), 2.61
(1H, d, J = 13.9 Hz), 2.83 (1H, d, J = 13.9 Hz)
d, J = 15.4 Hz), 2.95-3.3 (2H,
m), 3.13 (1H, d, J = 15.4 Hz), 7.
1-7.2 (2H, m), 8.45-8.55 (2H,
m).

Reference Example 4 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N-Phenyl-4-piperidineamine The title compound was obtained in the same manner as in Reference Example 3 using N-phenyl-4-piperidineamine. Yield 69%. 116-118 ° C (crystallized from ethyl acetate / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.2-1.6 (2H,
m), 1.43 (3H, s), 1.9-2.2 (2H,
m), 2.07 (6H, s), 2.09 (3H, s),
2.2-2.45 (2H, m), 2.50 (1H, d,
J = 13.8 Hz), 2.58 (1H, d, J = 13.3 Hz).
8 Hz), 2.8-2.95 (1H, m), 2.81
(1H, d, J = 15.0 Hz), 3.0-3.35
(2H, m), 3.11 (1H, d, J = 15.0H
z), 6.5-6.7 (3H, m), 7.1-7.2
(2H, m).

Reference Example 5 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
4- (4-chlorophenyl) -4-piperidinol 2-bromomethyl-2,3-dihydro-2,4,6,7
A suspension of 1.4 g of tetramethyl-5-benzofuranamine and 1.3 g of 4- (4-chlorophenyl) -4-hydroxypiperidine in 10 mL of xylene was stirred under a nitrogen atmosphere at 120 ° C. for 1.5 hours, and then for 16 hours Heated to reflux. Further, 0.85 g of 4- (4-chlorophenyl) -4-hydroxypiperidine was added, and the mixture was heated under reflux for 24 hours. The reaction mixture was cooled, and the solid was filtered and washed with diethyl ether. The filtrate was extracted with 1N hydrochloric acid, and the aqueous layer was made weakly acidic by adding a saturated aqueous solution of sodium hydrogen carbonate. The aqueous layer was washed with diethyl ether and made weakly basic with a saturated aqueous solution of sodium hydrogen carbonate. This was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from diethyl ether / hexane to give 0.58 g of the title compound. Yield 28%. 118-120 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.45 (3H, s),
1.5-1.8 (2H, m), 1.9-2.2 (2H,
m), 2.07 (6H, s), 2.10 (3H, s),
2.5-2.7 (4H, m), 2.7-2.9 (1H,
m), 2.83 (1H, d, J = 15.4 Hz), 2.
9-3.05 (1H, m), 3.13 (1H, d, J =
15.4 Hz), 7.29 (2H, d, J = 8.8H)
z), 7.42 (2H, d, J = 8.8 Hz).

Reference Example 6 N- [2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] benzofuran-5-yl] acetamide 2,3 -Dihydro-2,4,6,7-tetramethyl-2
-[(4-phenyl-1-piperidinyl) methyl] -5
0.9 g of sodium carbonate was added to a suspension of 1.3 g of benzofuranamine dihydrochloride in 10 mL of tetrahydrofuran under ice cooling.
A 5 mL solution of 5 g of water was added and stirred for 5 minutes. 0.26 mL of acetyl chloride was added dropwise thereto, and the resulting mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / diisopropyl ether to give 1.1 g of the title compound. 90% yield. 94-96 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.4-1.5 (3H,
m), 1.6-1.9 (4H, m), 2.0-2.7.
(17H, m), 2.81 (1H, d, J = 15.4H)
z), 2.9-3.3 (3H, m), 6.5-6.7.
(1H, m), 7.1-7.4 (5H, m).

Reference Example 7 N- [2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperazinyl) methyl] benzofuran-5-yl] acetamide hydrochloride In the same manner as in Example 6, 2,3-dihydro-2,
4,6,7-tetramethyl-2-[(4-phenyl-1
-Piperazinyl) methyl] -5-benzofuranamine using N- [2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperazinyl)
Methyl] benzofuran-5-yl] acetamide was obtained. 94% yield. This is dissolved in tetrahydrofuran,
After dilution with methanol, an excess amount of a 10% hydrogen chloride-methanol solution was added. The obtained solution was concentrated under reduced pressure, and crystallized from ethanol / diethyl ether to obtain the title compound. Melting point 195-199 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.62 (3H,
s), 1.97 (3H, s), 1.99 (3H, s),
2.02 (3H, s), 2.05 (3H, s), 3.0
1 (1H, d, J = 15.8 Hz), 3.1-4.2
(11H, m), 6.85 (1H, t, J = 7.1H
z), 6.99 (2H, d, J = 8.2 Hz), 7.2
6 (2H, t, J = 7.7 Hz), 9.11 (0.5
H, s), 10.5-10.9 (0.5H, br).

Reference Example 8 N-ethyl-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)
Methyl] -5-benzofuranamine N- [2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] benzofuran-5-yl] acetamide. 56g
0.11 g of lithium aluminum hydride was added little by little to a solution of the above in 8 mL of tetrahydrofuran under ice-cooling. The resulting mixture was heated at reflux for 30 hours. The reaction mixture was cooled on an ice bath, and 0.42 g of Hyflo Super Cell (trade name) was used.
And ethyl acetate were added. Further, 0.2 mL of water was added and the mixture was vigorously stirred, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 0.35 g of the title compound. 63% yield. 84-86 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.20 (3H, t, J
= 7.1 Hz), 1.46 (3H, s), 1.6-1.
9 (4H, m), 2.08 (3H, s), 2.15 (3
H, s), 2.18 (3H, s), 2.2-2.6 (3
H, m), 2.52 (1H, d, J = 14.0 Hz),
2.61 (1H, d, J = 14.0 Hz), 2.75 −
3.1 (4H, m), 3.09 (1H, d, J = 15.
4Hz), 3.15-3.3 (1H, m), 7.1-
7.4 (5H, m).

Reference Example 9 N-ethyl-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperazinyl)
Methyl] -5-benzofuranamine trihydrochloride N- [2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperazinyl) was prepared in the same manner as in Reference Example 8. ) Methyl] benzofuran-5-yl] acetamide to give N-ethyl-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperazinyl) methyl]- 5-benzofuranamine was obtained. This was dissolved in methanol, and an excess amount of a 10% hydrogen chloride-methanol solution was added. The obtained solution was concentrated under reduced pressure, and crystallized from ethanol / diethyl ether to obtain the title compound. Yield 64%. 210-216 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.33 (3H,
t, J = 7.1 Hz), 1.64 (3H, s), 2.0
8 (3H, s), 2.32 (3H, s), 2.35 (3
H, s), 3.0-3.9 (13H, m), 3.07.
(1H, d, J = 16.0 Hz), 6.86 (1H,
t, J = 7.2 Hz), 7.00 (2H, d, J = 8.
0 Hz), 7.26 (2H, t, J = 7.7 Hz).

Reference Example 10 2,3-dihydro-2,4,6,7-tetramethyl-2
-[(2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl) methyl] -5-benzofuranamine dihydrochloride In the same manner as in Reference Example 3, 2,3,4,5- Using tetrahydro-1H-3-benzazepine, 2,3-dihydro-2,4,6,7-tetramethyl-2-[(3H
-1,2,4,5-tetrahydro-3-benzazepin-3-yl) methyl] -5-benzofuranamine. This was dissolved in methanol, and an excess amount of a 10% hydrogen chloride-methanol solution was added. The obtained solution was concentrated under reduced pressure, and crystallized from methanol / diethyl ether to obtain the title compound. Yield 71%. 180-183 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.64 (3H,
s), 2.09 (3H, s), 2.24 (6H, s),
3.0-3.9 (11H, m), 3.08 (1H, d,
J = 16.6 Hz), 7.19 (4H, s).

Reference Example 11 4-benzyloxypiperidine hydrochloride 4-hydroxy-1-piperidinecarboxylic acid tert-
Sodium hydride (66% liquid paraffin dispersion) was added to a solution of 5.0 g of butyl in 50 mL of tetrahydrofuran.
g was added and stirred at room temperature for 10 minutes. 3.6 mL of benzyl bromide was added to this mixture, and the mixture was heated under reflux for 1 hour.
The reaction mixture was poured into an aqueous ammonium chloride solution and extracted twice with ethyl acetate. Wash the combined organic layers with water and saturated aqueous sodium chloride, dry over magnesium sulfate,
Filtration and concentration under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate, and 15 mL of 4N hydrogen chloride-ethyl acetate solution was added.
Stirred at room temperature for 2 hours. The precipitated solid was collected to obtain 4.4 g of the title compound. Yield 77%. 134-139 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.9-2.3 (4H,
m), 3.1-3.5 (4H, m), 3.7-3.8
(1H, m), 4.52 (2H, s), 7.2-7.4
5 (5H, m), 9.2-9.7 (2H, br).

Reference Example 12 4-[(3-Phenyl-2-propenyl) oxy] piperidine hydrochloride The title compound was prepared in the same manner as in Reference Example 11 using 3-bromo-1-phenyl-1-propene. I got Yield 4
2%. Melting point 211-213 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ 1.9-2.3 (4H,
m), 3.1-3.5 (4H, m), 3.7-3.8
(1H, m), 4.15 (2H, dd, J = 5.8,
1.3 Hz), 6.24 (1H, dt, J = 16.2)
5.8 Hz), 6.60 (1H, d, J = 16.2H)
z), 7.2-7.5 (5H, m), 9.2-9.8
(2H, br).

Reference Example 13 2,3-dihydro-2,4,6,7-tetramethyl-2
-[(1-Piperazinyl) methyl] -5-benzofuranamine trihydrochloride 2,3-dihydro-2,4,6,7-tetramethyl-2
-[(4-benzyl-1-piperazinyl) methyl] -5
-12 g of benzofuranamine, 10% palladium on carbon 1
g (50% water content) and 150 mL of ethanol were stirred at 50 ° C. for 15 hours under a hydrogen atmosphere of 5 atm. After cooling the reaction solution, the catalyst was filtered and the filtrate was concentrated. The residue was recrystallized from ethyl acetate / isopropyl ether to give 7.1 g of the free base of the title compound. Yield 8
0%. The free base was converted into a hydrochloride with a 4.8N hydrogen chloride ethanol solution, and the resulting compound was recrystallized from methanol / ethyl acetate to obtain the title compound. Melting point 228-231 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.53 (3H,
s), 2.05 (3H, s), 2.24 (6H, s),
2.8-4.5 (12H, m), 9.2-10.0 (3
H, br s).

Reference Example 14 A mixture of 5.0 g of 1- [2- (diphenylmethoxy) ethyl] piperazine benzhydrol, 3.5 g of 1- (2-hydroxyethyl) piperazine, 14 g of camphor-10-sulfonic acid and 80 mL of toluene Was heated and refluxed for 6 hours with a water removal device attached. 1N hydrochloric acid was added to the reaction solution to separate into two layers. The aqueous layer was made basic with a 5N aqueous sodium hydroxide solution, then saturated with sodium chloride, and extracted with chloroform. The extract was washed with a small amount of saturated saline and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 1.9 g of the title compound. Yield 24%. This compound was used for the next reaction without further purification. Oily. ¹ H-NMR (CDCl ₃ ) δ 2.42-2.54 (4
H, m), 2.60 (2H, t, J = 6.0 Hz),
2.89 (4H, t, J = 5.0 Hz), 3.60 (2
H, t, J = 6.0 Hz), 5.37 (1H, s),
7.20-7.38 (10H, m).

Reference Example 15 3- (diphenylmethoxy) propyl bromide benzhydrol 5.0 g, 3-bromo-1-propanol 3.8 g, camphor-10-sulfonic acid 1.0 g
And a mixture of 80 mL of toluene was heated to reflux for 2 hours with a water removal device attached. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain 7.0 g of the title compound. Yield 85%. Oily. ¹ H-NMR (CDCl ₃ ) δ 2.16 (2H, qui
ntet, J = 6.0 Hz), 3.58 (4H, t, J)
= 6.0 Hz), 5.36 (1H, s), 7.20-
7.38 (10H, m).

Reference Example 16 1- [3- (Diphenylmethoxy) propyl] piperazine 20 g of piperazine was dissolved in 20 mL of ethanol by heating, and a solution of 7.0 g of 3- (diphenylmethoxy) propyl bromide in 20 mL of ethanol was added dropwise. , 70
Stirred at C for 1 hour. Saturated saline was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated saline to remove the starting material piperazine, and then dried over anhydrous magnesium sulfate. This was concentrated under reduced pressure to obtain 7.1 g of the title compound. Yield 99%. This compound was used for the next reaction without further purification. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.75-1.92 (2
H, m), 2.38-2.50 (6H, m), 2.88
(4H, t, J = 5.0 Hz), 3.50 (2H, t,
J = 6.2 Hz), 5.33 (1H, s), 7.18−
7.41 (10H, m).

Reference Example 17 4- (diphenylmethoxy) butyl chloride In the same manner as in Reference Example 15, benzhydrol
The title compound was obtained from -chloro-1-butanol. 90% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.52-1.84 (4
H, m), 3.45 (2H, t, J = 6.0 Hz),
3.53 (2H, t, J = 6.6 Hz), 5.32 (1
H, s), 7.15-7.44 (10H, m).

Reference Example 18 1- [4- (Diphenylmethoxy) butyl] piperazine In the same manner as in Reference Example 16, the title compound was obtained from 4- (diphenylmethoxy) butyl chloride and piperazine. Yield 54%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.36-1.52 (2
H, m), 1.60-1.73 (2H, m), 2.28
-2.42 (6H, m), 2.88 (4H, t, J =
4.8 Hz), 3.45 (2H, t, J = 6.6H)
z), 5.33 (1H, s), 7.20-7.40 (1
0H, m).

Reference Example 19 5- (Diphenylmethoxy) pentyl chloride In the same manner as in Reference Example 15, benzhydrol
The title compound was obtained from -chloro-1-butanol. 96% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.45-1.85 (6
H, m), 3.46 (2H, t, J = 6.2 Hz),
3.53 (2H, t, J = 6.6 Hz), 5.33 (1
H, s), 7.18-7.42 (10H, m).

Reference Example 20 1- [5- (Diphenylmethoxy) pentyl] piperazine In the same manner as in Reference Example 16, the title compound was obtained from 5- (diphenylmethoxy) pentyl chloride and piperazine. Yield 93%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.34-1.55 (4
H, m), 1.58-1.74 (2H, m), 2.26
-2.42 (6H, m), 2.89 (4H, t, J =
5.0 Hz), 3.44 (2H, t, J = 6.4H)
z), 5.32 (1H, s), 7.18-7.42 (1
0H, m).

Reference Example 21 6- (Diphenylmethoxy) hexyl chloride In the same manner as in Reference Example 15, benzhydrol
The title compound was obtained from -chloro-1-hexanol. Yield 88%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.40-1.51 (4
H, m), 1.60-1.85 (4H, m), 3.45
(2H, t, J = 6.4 Hz), 3.52 (2H, t,
J = 6.8 Hz), 5.33 (1H, s), 7.20−
7.36 (10H, m).

Reference Example 22 1- [6- (Diphenylmethoxy) hexyl] piperazine In the same manner as in Reference Example 16, the title compound was obtained from 6- (diphenylmethoxy) hexyl chloride and piperazine. 94% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.22-1.54 (6
H, m), 1.58-1.71 (2H, m), 2.25
-2.42 (6H, m), 2.89 (4H, t, J =
4.8 Hz), 3.41-3.49 (2H, m), 5.
32 (1H, s), 7.19-7.39 (10H,
m).

Reference Example 23 A mixture of 3.7 g of 4-[(diphenylmethoxy) methyl] piperidine benzhydrol, 2.3 g of 4-piperidinemethanol, 7.0 g of camphor-10-sulfonic acid and 30 mL of toluene was treated with a water removing apparatus. And heated to reflux for 2 hours. After cooling the reaction solution, 35 mL of a 1 N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give the title compound 5.3
g was obtained. 94% yield. This compound was used for the next reaction without further purification. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.08-1.32 (2
H, m), 1.72-1.88 (3H, m), 2.61
(2H, dt, J = 2.2 Hz, 12.0 Hz), 3.
04-3.15 (2H, m), 3.29 (2H, d, J
= 6.0 Hz), 5.31 (1H, s), 7.15-
7.40 (10H, m).

Reference Example 24 4- [2- (diphenylmethoxy) ethyl] piperidine In the same manner as in Reference Example 23,
-The title compound was obtained from piperidine ethanol. Yield 9
4%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.06-1.28 (2
H, m), 1.54-1.71 (3H, m), 2.52
-2.63 (4H, m), 3.02-3.14 (2H,
m), 3.48 (2H, t, J = 6.2 Hz), 5.3
1 (1H, s), 7.20-7.40 (10H, s).

Reference Example 25 4- [3- (Diphenylmethoxy) propyl] piperidine In the same manner as in Reference Example 23, benzhydrol and 1
The title compound was obtained from-(tert-butoxycarbonyl) -4-piperidinepropanol. 90% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 0.99-1.19 (2
H, m), 1.21-1.38 (2H, m), 1.60
-1.75 (3H, m), 1.97 (2H, s), 2.
55 (2H, dt, J = 2.0 Hz, 12.0 Hz),
3.03-3.10 (2H, m), 3.43 (2H,
t, J = 6.4 Hz), 5.33 (1H, s), 7.1
7-7.37 (10H, m).

Reference Example 26 1- (2-Phenylethyl) piperazine In the same manner as in Reference Example 16, the title compound was obtained from β-phenethyl bromide and piperazine. Yield 92%. Oily. ¹ H-NMR (CDCl ₃ ) δ 2.47-2.63 (6
H, m), 2.76-2.91 (2H, m), 2.93
(4H, t, J = 4.8 Hz), 7.18-7.35
(5H, m).

Reference Example 27 4- [Bis (4-fluorophenyl) methoxy] -piperidine 3.0 g of 4-hydroxypiperidine, 6.2 g of 4,4'-difluorobenzhydrol, and p-toluenesulfonic acid monohydrate A suspension of 6.3 g of the product in 30 mL of toluene was heated to reflux for 1 hour using a water removal device. The reaction mixture was washed with a 1N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 9.8 g of a mixture containing the title compound as an oil. This was used for the next reaction without further purification.

Reference Example 28 2,3-Dihydro-2-[[4- (4-methoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7
-Tetramethyl-5-benzofuranamine In the same manner as in Example 10 described below, 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuran The title compound was obtained using the amine and p-anisic acid. Yield 67%. 120-123 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.06 (9H, s), 2.30-2.70 (6H,
m), 2.82 (1H, d, J = 15.6 Hz), 3.
11 (1H, d, J = 15.6 Hz), 3.20-3.
80 (6H, m), 3.83 (3H, s), 6.90
(2H, d, J = 8.8 Hz), 7.36 (2H, d,
J = 8.8 Hz).

Reference Example 29 2,3-Dihydro-2-[[4- (3-methoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7
-Tetramethyl-5-benzofuranamine In the same manner as in Example 10 described later, 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuran The title compound was obtained using the amine and m-anisic acid. 73% yield. 95-98 ° C (recrystallized from ethyl acetate / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.06 (9H, s), 2.30-2.70 (6H,
m), 2.82 (1H, d, J = 15.0 Hz), 3.
11 (1H, d, J = 15.0 Hz), 3.20-3.
80 (6H, m), 3.82 (3H, s), 6.91-
6.97 (3H, m), 7.28-7.40 (1H,
m).

Reference Example 30 2,3-dihydro-2-[[4- (2-methoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7
-Tetramethyl-5-benzofuranamine 2,3-dihydro-2,4,4 by the same method as in Example 10 described later.
The title compound was obtained using 6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine and o-anisic acid. Yield 42%. 128-131 ° C (recrystallized from ethyl acetate / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.06 (9H, s), 2.30-2.70 (5H,
m), 2.82 (1H, d, J = 15.0 Hz), 3.
00-3.80 (8H, m), 3.81 (3H, s),
6.85-7.01 (2H, m), 7.20-7.40
(2H, m).

Reference Example 31 2-[[4- (3,4-dimethoxybenzoyl) -1-]
Piperazinyl] methyl] -2,3-dihydro-2,4,
6,7-Tetramethyl-5-benzofuranamine By the same method as in Example 10 described later, 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl]- 5-benzofuranamine and 3,4
-The title compound was obtained using dimethoxybenzoic acid. Yield 74%. 113-116 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.07 (9H, s), 2.40-2.80 (6H,
m), 2.83 (1H, d, J = 14.8 Hz), 3.
11 (1H, d, J = 14.8 Hz), 3.20-3.
80 (6H, m), 3.89 (3H, s), 3.90
(3H, s), 6.84 (1H, d, J = 9.2H
z), 6.90-7.00 (2H, m).

Reference Example 32 2-[[4- (4-Chlorobenzoyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,6,7-
Tetramethyl-5-benzofuranamine In the same manner as in Example 10 described later, 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine And 4-chlorobenzoic acid to give the title compound. Yield 64%. 136-138 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.06 (9H, s), 2.30-2.70 (6H,
m), 2.86 (1H, d, J = 14.3 Hz), 3.
11 (1H, d, J = 14.3 Hz), 3.30-3.
80 (6H, m), 7.30-7.40 (4H, m).

Reference Example 33 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-Methylbenzoyl) -1-piperazinyl] methyl] -5-benzofuranamine By the same method as in Example 10 described later, 2,3-dihydro-2,4,6,7-tetramethyl The title compound was obtained using -2-[(1-piperazinyl) methyl] -5-benzofuranamine and 4-methylbenzoic acid. Yield 53%. 131-133 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.07 (9H, s), 2.38 (3H, s), 2.4
0-2.80 (6H, m), 2.84 (1H, d, J =
14.6 Hz), 3.12 (1H, d, J = 14.6H)
z), 3.20-3.90 (6H, m), 7.10-
7.40 (4H, m).

Reference Example 34 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-Nitrobenzoyl) -1-piperazinyl] methyl] -5-benzofuranamine By the same method as in Example 10 described later, 2,3-dihydro-2,4,6,7-tetramethyl The title compound was obtained using -2-[(1-piperazinyl) methyl] -5-benzofuranamine and 4-nitrobenzoic acid. Yield 51%. 154-158 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.43 (3H, s),
2.06 (9H, s), 2.40-2.80 (6H,
m), 2.84 (1H, d, J = 15.2 Hz), 3.
12 (1H, d, J = 15.2 Hz), 3.20-3.
85 (6H, m), 7.55 (2H, d, J = 8.8H
z), 8.27 (2H, d, J = 8.8 Hz).

Reference Example 35 1.9 g of lithium aluminum hydride in 4,4-diphenyl-1-butanol was suspended in 70 mL of ice-cooled diethyl ether, and a solution of 6.0 g of 4,4-diphenylbutyric acid in 50 mL of diethyl ether was further added. It was dropped. After completion of the dropwise addition, the reaction solution was heated under reflux for 2 hours, and then allowed to cool. 1.9 mL of water, 1.9 mL of a 15% aqueous sodium hydroxide solution, and 5.7 mL of water were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered, and the filtrate was concentrated to obtain 5.6 g of the title compound. Yield 99%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.20 (1H, br
s), 1.40-1.70 (2H, m), 2.10-
2.19 (2H, m), 3.65 (2H, t, J = 6.
6Hz), 3.91 (1H, t, J = 7.8Hz),
7.10-7.40 (10H, m).

Reference Example 36 4,4-diphenylbutyl methanesulfonate 5.6 g of ice-cooled 4,4-diphenyl-1-butanol
11 mL of triethylamine and 2.9 mL of methanesulfonyl chloride were sequentially added dropwise to a solution of 100 mL of dichloroethane. After stirring for 30 minutes, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 7.5 g of the title compound. Yield 99%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.73 (2H, m),
2.18 (2H, dt, J = 7.9, 7.8 Hz),
2.95 (3H, s), 3.91 (1H, t, J = 7.
9Hz), 4.22 (2H, t, J = 6.3Hz),
7.10-7.40 (10H, m).

Reference Example 37 A solution of 7.5 g of 5,4-diphenylvaleronitrile 4,4-diphenylbutyl methanesulfonate and 2.5 g of sodium cyanide in 70 mL of dimethyl sulfoxide was stirred at 60 ° C. for 15 hours. After allowing to cool, the reaction solution was poured into water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 5.8 g of the title compound quantitatively. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.50-1.72 (2
H, m), 2.19 (2H, dt, J = 7.9, 7.8)
Hz), 2.34 (2H, t, J = 7.1 Hz), 3.
91 (1H, t, J = 7.9 Hz), 7.10-7.4
0 (10H, m).

Reference Example 38 5,5-Diphenylvaleric acid 5,5-Diphenylvaleronitrile 6.5 g in a methanol 30 mL solution, water 80 mL, sodium hydroxide 10 g
Was added and heated under reflux for 72 hours. After cooling, the reaction solution was washed with diethyl ether and further adjusted to pH = 1 with concentrated hydrochloric acid. The acidic solution was extracted with diethyl ether, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
Concentrated. The residue was recrystallized to give 5.5 g of the title compound.
I got 86% yield. 87-90 ° C (recrystallized from diethyl ether / hexane). ¹ H-NMR (DMSO-d ₆ ) δ 1.30-1.50
(2H, m), 1.95-2.09 (2H, m), 2.
23 (2H, t, J = 7.6 Hz), 3.92 (1H,
t, J = 7.6 Hz), 7.12-7.35 (10H,
m).

Reference Example 39 Ethyl 4-[(diphenylmethyl) amino] -1-piperidinecarboxylate A solution of 5.0 g of 1,1-diphenylmethylamine and 4.7 g of 1-ethoxycarbonyl-4-piperidone in 70 mL of toluene was prepared. The mixture was heated and refluxed for 4 hours with a water removal device attached. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50 mL of ethanol. After cooling with ice, 2.1 g of sodium cyanoborohydride and a small amount of bromocresol green were added. A 4N ethanol solution of hydrogen chloride was added dropwise until the reaction solution turned yellow.
Stirred for 0 minutes. The reaction solution was poured into an excess aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 65: 3).
Purification in 5) gave 8.4 g of the title compound. Yield 91
%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 1.20-1.38 (2
H, m), 1.24 (3H, t, J = 7.0 Hz),
1.87-1.96 (2H, m), 2.54-2.66
(1H, m), 2.70-2.84 (2H, m), 3.
99-4.17 (2H, m), 4.10 (2H, q, J
= 7.0 Hz), 5.02 (1H, s), 7.19-
7.41 (10H, m).

Reference Example 40 Ethyl N- (diphenylmethyl) -4-piperidineamine dihydrochloride 42 g of ethyl 4-[(diphenylmethyl) amino] -1-piperidinecarboxylate and 50 g of sodium hydroxide
Was heated to reflux for 24 hours. Water was added to the reaction solution, and extracted with chloroform. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. This was concentrated under reduced pressure to obtain N- (diphenylmethyl) -4-piperidineamine. This was converted into a hydrochloride with a 4N ethanol solution of hydrogen chloride, and the precipitated crystals were collected by filtration and dried to obtain 31 g of the title compound. 73% yield. Melting point 228-234 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.91 to 2.08
(2H, m), 2.40-2.50 (2H, m), 2.
78-2.90 (2H, m), 3.07-3.41 (3
H, m), 5.75 (1H, brs), 7.34-
7.47 (6H, m), 7.87 (4H, d, J = 6.
6 Hz), 9.16 (2H, brs), 10.44
(2H, brs).

Reference Example 41 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
4-Piperidineethanol By the same method as in Example 1 described below, 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-
The title compound was obtained from 5-benzofuranamine and 4-piperidineethanol. Yield 88%. 94-95 ° C (recrystallized from ethyl acetate / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.20-1.63 (7
H, m), 1.42 (3H, s), 1.98-2.18.
(2H, m), 2.07 (6H, s), 2.09 (3
H, s), 2.46 (1H, d, J = 13.8 Hz),
2.54 (1H, d, J = 13.8 Hz), 2.76 −
2.88 (2H, m), 2.06-3.14 (2H,
m), 3.67 (2H, t, J = 6.6 Hz).

Reference Example 42 [2,3-dihydro-2-[[4- (2-hydroxyethyl) -1-piperidinyl] methyl] -2,4,6,7
Tert-butyl-tetramethylbenzofuran-5-yl] carbamate 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
3.1 g of 4-piperidineethanol and dite dicarbonate
To a solution of 2.1 g of rt-butyl in 20 mL of tetrahydrofuran was added 10 mL of a 1 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 95: 5) to obtain 3.9 g of the title compound. Yield 98%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.20-1.65 (7
H, m), 1.41 (3H, s), 1.50 (9H,
s), 2.05-2.21 (2H, m), 2.06 (3
H, s), 2.10 (3H, s), 2.12 (3H,
s), 2.43-2.58 (2H, m), 2.73-
2.90 (2H, m), 3.01-3.13 (2H,
m), 3.68 (2H, t, J = 6.6 Hz), 5.7
8 (1H, brs).

Reference Example 43 [2-[[4- (Formylmethyl) -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamic acid
rt-butyl 2.4 mL of oxalyl chloride was added dropwise to a solution of 2.6 mL of dimethyl sulfoxide in 40 mL of dichloromethane at -78 ° C under an argon atmosphere, followed by stirring for 20 minutes. To this, [2,3-dihydro-2-[[4- (2-hydroxyethyl) -1-piperidinyl] methyl] -2,4,6,7
A solution of 3.6 g of tert-butyl-tetramethylbenzofuran-5-yl] carbamate in 10 mL of dichloromethane was added dropwise, and the mixture was further stirred for 1 hour. After adding 8.0 mL of triethylamine to the reaction solution, it was returned to room temperature, made basic with an aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate) to obtain 3.0 g of the title compound. Yield 85%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.20-2.25 (7
H, m), 1.41 (3H, s), 1.50 (9H,
s), 2.05 (3H, s), 2.09 (3H, s),
2.12 (3H, s), 2.30-2.36 (2H,
m), 2.51 (2H, s), 2.72-2.88 (2
H, m), 3.02-3.13 (2H, m), 5.77.
(1H, brs), 9.76 (1H, s).

Reference Example 44 [2-[[4- [2-[(diphenylmethyl) amino]]]
Ethyl] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5
-Yl] tert-butyl [2-[[4- (formylmethyl) -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamine Acid te
A solution of 1.5 g of rt-butyl and 0.60 mL of 1,1-diphenylmethylamine in 20 mL of ethanol was stirred under ice cooling for 30 minutes. 0.26 g of sodium cyanoborohydride and a small amount of bromocresol green were added thereto, and then a 4N ethanol solution of hydrogen chloride was added until the reaction solution turned yellow. After stirring for 1 hour, the reaction solution was poured into an excess aqueous sodium hydrogen carbonate solution. This was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 4: 1 to ethyl acetate) to obtain 1.6 g of the title compound. Yield 77%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.20-1.78 (7
H, m), 1.40 (3H, s), 1.50 (9H,
s), 2.00-2.21 (2H, m), 2.04 (3
H, s), 2.09 (3H, s), 2.12 (3H,
s), 2.41-2.60 (4H, m), 2.72-
2.84 (2H, m), 2.98-3.12 (2H,
m), 4.79 (1H, s), 5.77 (1H, br)
s), 7.18-7.40 (10H, m).

Reference Example 45 [2-[[4- [2-[(3,3-diphenylpropyl) amino] ethyl] -1-piperidinyl] methyl]-
Tert-Butyl 2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamate [2-[[4- (Formylmethyl) -1-] Piperidinyl] methyl] -2,3-
Tert-butyl dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamate and (3,3
The title compound was obtained from -diphenylpropyl) amine.
97% yield. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 1.20-1.60 (9
H, m), 1.40 (3H, s), 1.50 (9H,
s), 2.04 (3H, s), 2.08 (3H, s),
2.11 (3H, s), 2.23-2.70 (8H,
m), 2.72-2.86 (2H, m), 2.98-
3.11 (2H, m), 3.97 (1H, t, J = 7.
8Hz), 5.79 (1H, brs), 7.13-
7.30 (10H, m).

Reference Example 46 1-[(5-amino-2,4,6,7-tetramethyl-
2,3-dihydrobenzofuran-2-yl) methyl]-
Ethyl 4-piperidinecarboxylate 2-bromomethyl-2,3-dihydro-2,4,6,7
8.4 g of tetramethyl-5-benzofuranamine, 14 g of ethyl isonipecotate, and 20 mL of xylene
Was stirred at 180 ° C. for 15 hours in a sealed tube under a nitrogen atmosphere. Take the supernatant of the reaction mixture and add this solution to water,
The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtered and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1 followed by 2: 1) and crystallized from hexane to obtain 2.9 g of the title compound. Yield 27%. 74-76 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.24 (3H, t, J
= 7.1 Hz), 1.41 (3H, s), 1.6-1.
9 (4H, m), 1.9-2.3 (3H, m), 2.0
7 (6H, s), 2.09 (3H, s), 2.46 (1
H, d, J = 13.7 Hz), 2.54 (1H, d, J)
= 13.7 Hz), 2.79 (1H, d, J = 15.4)
Hz), 2.8-2.95 (1H, m), 3.0-3.
2 (1H, m), 3.10 (1H, d, J = 15.4H)
z), 4.12 (2H, q, J = 7.1 Hz).

Reference Example 47 1-[(5-amino-2,4,6,7-tetramethyl-
2,3-dihydrobenzofuran-2-yl) methyl]-
Sodium 4-piperidinecarboxylate 1-[(5-amino-2,4,6,7-tetramethyl-
2,3-dihydrobenzofuran-2-yl) methyl]-
Ethyl 4-piperidinecarboxylate 10 g ethanol 4
5.7 mL of 5N aqueous sodium hydroxide solution in 0 mL solution
Was added and stirred at room temperature under a nitrogen atmosphere for 2 hours. The precipitated solid was collected by filtration and washed with diethyl ether to obtain 7.5 g of the title compound. Yield 75%. The filtrate was concentrated under reduced pressure, and the solid was sufficiently washed with diethyl ether to obtain an additional 1.4 g. Yield 14%. These were used for the next reaction without further purification. 237-241 ° C. ¹ H-NMR (CD ₃ OD) δ 1.35 (3H, s),
1.5-1.9 (4H, m), 1.9-2.2 (3H,
m), 2.02 (3H, s), 2.05 (6H, s),
2.49 (2H, s), 2.76 (1H, d, J = 1
5.3 Hz), 2.8-3.0 (1H, m), 3.0-
3.2 (1H, m), 3.12 (1H, d, J = 15.
3 Hz).

Reference Example 48 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidinecarboxamide 1-[(5-amino-2,4,6,7-tetramethyl-
2,3-dihydrobenzofuran-2-yl) methyl]-
0.89 g of sodium 4-piperidinecarboxylate N,
0.35 g of triethylamine hydrochloride was added to 10 mL of N-dimethylformamide suspension, and the mixture was stirred at room temperature for 5 minutes. After adding 0.34 g of 1-hydroxybenzotriazole and 0.46 g of 1,1-diphenylmethylamine to the obtained mixture, 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride
48 g were added. This mixture is heated at room temperature under a nitrogen atmosphere for 23 hours.
Stirred for hours. Water was added to the reaction mixture, and ethyl acetate was added.
Extracted times. Wash the combined organic layers with water and saturated aqueous sodium chloride, dry over magnesium sulfate, filter,
It was concentrated under reduced pressure. The residue was recrystallized from methanol / diisopropyl ether to give the title compound (0.71 g). Yield 57%. Melting point 175-177 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ 1.40 (3H, s),
1.4-2.3 (7H, m), 2.06 (6H, s),
2.08 (3H, s), 2.46 (1H, d, J = 1
3.9 Hz), 2.55 (1H, d, J = 13.9H)
z), 2.79 (1H, d, J = 14.8 Hz), 2.
9-3.4 (4H, m), 3.10 (1H, d, J = 1
4.8 Hz), 6.01 (1H, d, J = 7.9H)
z), 6.24 (1H, d, J = 7.9 Hz), 7.1
-7.4 (10H, m).

Reference Example 49 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (2,2-Diphenylethyl) -4-piperidinecarboxamide The title compound was obtained in the same manner as in Reference Example 48 using 2,2-diphenylethylamine. Yield 62%. 168-170 ° C (recrystallized from tetrahydrofuran / methanol). ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, s),
1.4-2.2 (7H, m), 2.06 (3H, s),
2.07 (3H, s), 2.08 (3H, s), 2.4
3 (1H, d, J = 14.1 Hz), 2.52 (1H,
d, J = 14.1 Hz), 2.78 (1H, d, J = 1)
5.0 Hz), 2.8-3.5 (4H, m), 3.08
(1H, d, J = 15.0 Hz), 3.88 (2H, d
d, J = 8.0, 5.5 Hz), 4.18 (1H, t,
J = 8.0 Hz), 5.38 (1H, brt, J =
5.5 Hz), 7.1-7.4 (10H, m).

Reference Example 50 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (3,3-diphenylpropyl) -4-piperidinecarboxamide dihydrochloride 1-[(5-amino-2,3-dihydro-) using 3,3-diphenylpropylamine in the same manner as in Reference Example 48. 2,4,6,7-tetramethylbenzofuran-2
-Yl) methyl] -N- (3,3-diphenylpropyl) -4-piperidinecarboxamide. This was dissolved in methanol, an excess 10% hydrogen chloride-methanol solution was added dropwise, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethanol / diethyl ether to give the title compound. Yield 52%. Melting point 166-171 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.57 (3H,
s), 1.7-2.6 (7H, m), 2.05 (3H,
s), 2.23 (6H, s), 2.8-3.8 (10
H, s), 3.98 (1H, t, J = 7.7 Hz),
7.1-7.4 (10H, m), 8.05 (1H, br
s), 9.4-10.6 (4H, m).

Reference Example 51 Ethyl 4- [benzyl (3,3-diphenylpropyl) amino] -1-piperidinecarboxylate (4.9 g) amine and 4.9 g of 1-ethoxycarbonyl-4-piperidone A solution of 0 g of toluene in 100 mL was heated and refluxed for 2 hours with a water removal device attached. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 80 mL of ethanol. After cooling this with ice, 1.8 g of sodium cyanoborohydride and a small amount of bromcresol green were added. A 4 N ethanol solution of hydrogen chloride was added dropwise until the reaction solution turned yellow, and the mixture was further stirred for 30 minutes after completion of the addition. The reaction solution was poured into an excess aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave ethyl 4-[(3,3-diphenylpropyl) amino] -1-piperidinecarboxylate. This is treated with N, N-dimethylformamide 80
Then, 2.8 mL of benzyl bromide and 3.2 g of potassium carbonate were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 7: 3) to obtain 7.8 g of the title compound. 73% yield from (3,3-diphenylpropyl) amine. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.18-1.40 (5
H, m), 1.59-1.68 (2H, m), 2.10
-2.20 (2H, m), 2.40-2.62 (5H,
m), 3.60 (2H, s), 3.90-4.17 (5
H, m), 7.10-7.35 (15H, m).

Reference Example 52 N-benzyl-N- (3,3-diphenylpropyl)-
According to a method similar to that of 4-piperidineamine Reference Example 40,
The title compound was obtained from ethyl 4- [benzyl (3,3-diphenylpropyl) amino] -1-piperidinecarboxylate. Yield 99%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.22-1.43 (2
H, m), 1.63-1.75 (2H, m), 2.08
−2.19 (2H, m), 2.40-2.61 (5H,
m), 3.02-3.08 (2H, m), 3.62 (2
H, s), 3.97 (1H, t, J = 7.4 Hz),
7.10-7.36 (15H, m).

Reference Example 53 N- (2-cyanomethyl-2,3-dihydro-2,4,
6,7-tetramethylbenzofuran-5-yl) formamide N- (2-bromomethyl-2,3-dihydro-2,4,
6,7-tetramethylbenzofuran-5-yl) formamide (20 g) and sodium cyanide (17 g) in dimethyl sulfoxide (100 mL) were added under an argon atmosphere.
Stirred at 100 ° C. for 13 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / diisopropyl ether to give the title compound (14 g). 86% yield. 183-185 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.66 (3H, s),
2.08-2.17 (9H, m), 2.73-2.75
(2H, m), 3.03-3.22 (2H, m), 6.
65-6.76 (1H, m), 7.96 (0.4H,
d, J = 12.2 Hz), 8.41 (0.6 H, d, J)
= 1.4 Hz).

Reference Example 54 N- (2-cyanomethyl-2,3-dihydro-2,4,5-amino-2,3-dihydro-2,4,6,7-tetramethyl-2-benzofuranacetic acid
To a solution of 6,7-tetramethylbenzofuran-5-yl) formamide (14 g) in methanol (50 mL) was added a 4.6 N aqueous sodium hydroxide solution (120 mL), and the mixture was heated and refluxed under an argon atmosphere for 40 hours. The reaction solution was neutralized with concentrated hydrochloric acid and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from chloroform / diisopropyl ether to obtain 11 g of the title compound. 82% yield. Melting point 186-188 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.43 (3H,
s), 1.95 (9H, s), 2.60 (2H, s),
2.84 (1H, d, J = 15.6 Hz), 3.18
(1H, d, J = 15.6 Hz).

Reference Example 55 5-[(tert-butoxycarbonyl) amino]-
2,3-dihydro-2,4,6,7-tetramethyl-2
-Benzofuranacetic acid 5-amino-2,3-dihydro-2,4,6,7-tetramethyl-2-benzofuranacetic acid 8.3 g of tetrahydrofuran in a 50 mL suspension of ditert-butyl dicarbonate 7.6 g of tetrahydrofuran A 5 mL solution and 34 mL of a 1 N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, made acidic with a 0.5 M aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3),
11 g of the title compound were obtained. Yield 92%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.50-1.53 (9
H, m), 1.58 (3H, s), 2.08-2.09
(6H, m), 2.13 (3H, s), 2.78 (2
H, br s), 2.98 (1H, d, J = 15.4H)
z), 3.25 (1H, d, J = 15.4 Hz), 5.
80 (1H, s).

Reference Example 56 [2,3-dihydro-2- (2-hydroxyethyl)-
Tert-Butyl 2,4,6,7-tetramethylbenzofuran-5-yl] carbamate 5-[(tert-butoxycarbonyl) amino] -2,3-dihydro-2,4,6,7 under ice-cooling. -50m of tetrahydrofuran of tetramethyl-2-benzofuranacetic acid
To the L solution, 64 mL of a 1 M borane tetrahydrofuran complex tetrahydrofuran solution was added dropwise, and the mixture was added at room temperature to 12 mL.
Stirred for hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
2: 1) to give 7.8 g of the title compound. Yield 76%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.47 (3H, s),
1.50 (9H, s), 1.89-2.16 (2H,
m), 2.07 (3H, s), 2.10 (3H, s),
2.13 (3H, s), 2.35 (1H, br s),
2.91 (1H, d, J = 15.4 Hz), 3.06
(1H, d, J = 15.6 Hz), 3.71-3.97
(2H, m), 5.79 (1H, br s).

Reference Example 57 [2- (2-bromoethyl) -2,3-dihydro-2,
Tert-Butyl 4,6,7-tetramethylbenzofuran-5-yl] carbamate [2,3-dihydro-2- (2-hydroxyethyl)-
To a solution of 7.7 g of tert-butyl 2,4,6,7-tetramethylbenzofuran-5-yl] carbamate and 8.0 g of carbon tetrabromide in 80 mL of tetrahydrofuran,
Under ice cooling, 6.3 g of triphenylphosphine was added, and 30
Stirred for minutes. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3 to 4: 1) to obtain 7.5 g of the title compound. 82% yield. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 1.44 (3H, s),
1.50 (9H, s), 2.07 (3H, s), 2.0
8 (3H, s), 2.13 (3H, s), 2.26-
2.35 (2H, m), 2.88 (1H, d, J = 1)
5.8 Hz), 3.01 (1H, d, J = 15.8H)
z), 3.40-3.49 (2H, m), 5.77 (1
H, br s).

Reference Example 58 [2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,
Tert-butyl 7-tetramethylbenzofuran-5-yl] carbamate [2- (2-bromoethyl) -2,3-dihydro-2,
1.2 g of tert-butyl 4,6,7-tetramethylbenzofuran-5-yl] carbamate, 0.85 g of 4- (diphenylmethoxy) piperidine and 0.44 g of potassium carbonate in a 20 mL suspension of N, N-dimethylformamide Was stirred at 60 ° C. for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 98: 2 to 95: 5) to obtain 1.6 g of the title compound. Yield 92%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, s),
1.50 (9H, s), 1.66-1.96 (6H,
m), 2.03-2.20 (2H, m), 2.06 (3
H, s), 2.07 (3H, s), 2.12 (3H,
s), 2.40-2.48 (2H, m), 2.70-
2.80 (2H, m), 2.82 (1H, d, J = 1
5.4 Hz), 3.01 (1H, d, J = 15.4H)
z), 3.35-3.50 (1H, m), 5.51 (1
H, s), 5.76 (1H, brs), 7.20-
7.36 (10H, m).

Reference Example 59 [2- [2- [4-[(Diphenylmethoxy) methyl] methyl]
-1-piperidinyl] ethyl] -2,3-dihydro-
Tert-butyl 2,4,6,7-tetramethylbenzofuran-5-yl] carbamate [2- (2-bromoethyl) -2,3-dihydro-2,4,6 , 7-Tetramethylbenzofuran-5-yl] carbamic acid tert-
The title compound was obtained from butyl and 4-[(diphenylmethoxy) methyl] piperidine. 82% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.18-1.50 (2
H, m), 1.40 (3H, s), 1.50 (9H,
s), 1.60-1.97 (7H, m), 2.07 (6
H, s), 2.12 (3H, s), 2.41-2.50.
(2H, m), 2.78-3.04 (4H, m), 3.
29 (2H, d, J = 6.4 Hz), 5.30 (1H,
s), 5.76 (1H, br s), 7.20-7.3.
7 (10H, m).

Reference Example 60 [2- [2- [4- [2- (diphenylmethoxy) ethyl] -1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran- [Tert-butyl 5-yl] carbamate [2- (2-bromoethyl) -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamine was prepared in the same manner as in Reference Example 58. Acid tert-
The title compound was obtained from butyl and 4- [2- (diphenylmethoxy) ethyl] piperidine. Yield 83%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.18-1.70 (4
H, m), 1.39 (3H, s), 1.49 (9H,
s), 1.80-2.00 (7H, m), 2.07 (6
H, s), 2.11 (3H, s), 2.35-2.50.
(2H, m), 2.78-3.05 (4H, m), 3.
40-3.52 (2H, m), 5.30 (1H, s),
5.77 (1H, brs), 7.19-7.38 (1
0H, m).

Reference Example 61 2-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
2H-isoindole-1,3-dione 2-bromomethyl-2,3-dihydro-2,4,6,7
A suspension of 2.0 g of -tetramethyl-5-benzofuranamine and 2.2 g of potassium phthalimide in 20 mL of N, N-dimethylacetamide was heated under reflux in a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / diisopropyl ether to give 1.4 g of the title compound. Yield 56
%. 147-150 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.52 (3H, s),
1.98 (3H, s), 2.03 (3H, s), 2.0
8 (3H, s), 2.93 (1H, d, J = 15.8H)
z), 3.0-3.4 (2H, br), 3.26 (1
H, d, J = 15.8 Hz), 3.86 (1H, d, J)
= 13.9 Hz), 3.95 (1H, d, J = 13.9)
Hz), 7.6-7.9 (4H, m).

Reference Example 62 2,3-dihydro-2,4,6,7-tetramethyl-2
-[(1,2,3,4-tetrahydroisoquinoline-2
-Yl) methyl] -5-benzofuranamine oxalate 2-bromomethyl-2,3-dihydro-2,4,6,7
-1.4 g of tetramethyl-5-benzofuranamine,
A suspension of 1.3 g of 1,2,3,4-tetrahydroisoquinoline and 1.4 g of potassium carbonate in 10 mL of N, N-dimethylacetamide was heated under reflux in a nitrogen atmosphere for 15 hours. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1,
2,3,4-Tetrahydroisoquinolin-2-yl) methyl] -5-benzofuranamine was obtained. This was dissolved in ethanol, and one equivalent of an oxalic acid-ethanol solution was added. This mixture was dissolved under heating and concentrated under reduced pressure, and the precipitated crystals were collected to obtain 1.5 g of the title compound. Yield 68
%. 153-156 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.41 (3H,
s), 1.99 (6H, s), 2.02 (3H, s),
2.7-3.2 (6H, m), 2.84 (1H, d, J
= 15.8 Hz), 3.11 (1H, d, J = 15.8)
Hz), 3.89 (1H, d, J = 15.4 Hz),
4.00 (1H, d, J = 15.4 Hz), 6.95−
7.2 (4H, m).

Reference Example 63 2-[[4- (2,3-dihydro-2-oxo-1H-
Benzimidazol-1-yl) -1-piperidinyl]
Methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine dihydrochloride 2-bromomethyl-2,3-dihydro-2,4,6,7
A suspension of 1.4 g of tetramethyl-5-benzofuranamine and 2.3 g of 4- (2-keto-1-benzimidazolinyl) piperidine in 20 mL of xylene was placed in a sealed tube under a nitrogen atmosphere at 180 ° C. for 15 minutes. Stirred for hours. The reaction mixture was cooled, and the solid was filtered and washed with diethyl ether.
The filtrate was washed with water and extracted with 1N hydrochloric acid. The aqueous layer was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate.
Extracted times. The combined organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and silica gel (eluted with ethyl acetate), and concentrated under reduced pressure. The residue was crystallized from ethanol to give 2-[[4- (2,3-dihydro-
2-oxo-1H-benzimidazol-1-yl)-
1-piperidinyl] methyl] -2,3-dihydro-2,
1.2 g of 4,6,7-tetramethyl-5-benzofuranamine was obtained. 55% yield. This was dissolved by heating in tetrahydrofuran, diluted with methanol, and an excess amount of a 10% hydrogen chloride-methanol solution was added. The obtained solution was concentrated under reduced pressure, and crystallized from methanol / diethyl ether to obtain the title compound. 202-208 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.5-2.3 (3
H, m), 1.65 (3H, m), 2.07 (3H,
s), 2.22 (3H, s), 2.25 (3H, s),
2.8-3.2 (3H, m), 3.07 (1H, d, J
= 16.4 Hz), 3.2-3.7 (4H, m), 3.
8-4.0 (1H, m), 4.4-4.7 (1H,
m), 6.9-7.1 (3H, m), 7.6-7.8
(1H, m), 9.5-10.1 (2H, br), 1
0.7-11.0 (1H, m).

Reference Example 64 2-[[4-[(9-Fluorenyl) oxy] -1-piperidinyl] methyl] -2,3-dihydro-2,4,
6,7-Tetramethyl-5-benzofuranamine oxalate By the same method as in Example 1 described later, 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-
5-benzofuranamine and 4-[(9-fluorenyl)
Oxy] piperidine to 2-[[4-[(9-fluorenyl) oxy] -1-piperidinyl] methyl] -2,3
-Dihydro-2,4,6,7-tetramethyl-5-benzofuranamine was obtained. 63% yield. A portion was converted to oxalate and then recrystallized from ethanol to obtain the title compound. 121-123 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.36 (3H,
s), 1.63 (2H, br s), 1.86-2.0
6 (2H, m), 1.96 (9H, s), 2.50-
3.12 (8H, m), 3.72 (1H, brs),
5.62 (1H, s), 7.27-7.45 (4H,
m), 7.59 (2H, d, J = 6.8 Hz), 7.7
9 (2H, d, J = 7.4 Hz).

Reference Example 65 4-[(9-Fluorenyl) oxy] piperidine The title compound was obtained from 9-fluorenol and 4-piperidinol in the same manner as in Reference Example 23. Yield 3
8%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 1.45-1.68 (2
H, m), 1.75-1.90 (2H, m), 2.50
-2.62 (2H, m), 3.04-3.18 (2H,
m), 3.45-3.58 (1H, m), 5.62 (1
H, s), 7.22-7.40 (4H, m), 7.56.
-7.67 (4H, m).

Reference Example 66 2-bromo-3- (methoxymethoxy) -1,4,5-
Trimethylbenzene 60% sodium hydride (2.1 g) was added to a suspension of N, N-dimethylformamide (20 mL) in a nitrogen stream under ice-cooling.
A solution of 10 g of -bromo-3,5,6-trimethylphenol in 50 mL of N, N-dimethylformamide was added dropwise,
The mixture was stirred for 10 minutes. To this, 3.9 mL of chloromethyl methyl ether 5N, N-dimethylformamide 5
The mL solution was added dropwise and the mixture was stirred for another 30 minutes.
Ice water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3) to obtain 12 g of the title compound. Yield 99%. Oily. ¹ H-NMR (CDCl ₃ ) δ 2.20 (3H, s),
2.24 (3H, s), 2.34 (3H, s), 3.6
6 (3H, s), 5.04 (2H, s), 6.85 (1
H, s).

Reference Example 67 (R) -1-[[2- (methoxymethoxy) -3,4,4
6-trimethylphenyl] methyl] -1-methyloxirane 2-bromo-3- (methoxymethoxy) -1,4,5-
Trimethylbenzene 3.0 g tetrahydrofuran 30
7.0 mL of 1.6 Mn-butyllithium hexane solution was added dropwise to the mL solution at -78 ° C, and the mixture was stirred for 15 minutes. This is followed by (R) -methylglycidyltosylate 2.8
g and boron trifluoride diethyl ether complex 1.5 m
L was added and the mixture was stirred for another 15 minutes. After returning the reaction solution to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 4-methylbenzenesulfonic acid (R) -2-hydroxy-3- [2- (methoxymethoxy) -3,4,6.
-Trimethylphenyl] -2-methylpropyl was obtained.
This was dissolved in methanol (20 mL), and potassium carbonate (1.6 g) was added thereto under ice cooling, followed by stirring for 30 minutes. Ethyl acetate and water were added to the reaction solution, and two layers were separated. The aqueous layer was extracted with ethyl acetate. The extract and the previous organic layer were combined. This was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain 0.73 g of the title compound. 2-bromo-3-
25% yield from (methoxymethoxy) -1,4,5-trimethylbenzene. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.35 (3H, s),
2.15 (3H, s), 2.20 (3H, s), 2.2
6 (3H, s), 2.44 (1H, d, J = 5.2H)
z), 2.50 (1H, d, J = 5.2 Hz), 3.0
0-3.15 (2H, m), 3.61 (3H, s),
4.88-4.95 (2H, m), 6.78 (1H,
s).

Reference Example 68 (S) -2,3-Dihydro-2,4,6,7-tetramethyl-2-benzofuranmethanol (R) -1-[[2- (methoxymethoxy) -3,4,4
A mixture of 1 mL of trifluoroacetic acid and 1 mL of water was added dropwise to a solution of 0.60 g of 6-trimethylphenyl] methyl] -1-methyloxirane in 5 mL of tetrahydrofuran under ice cooling, followed by stirring for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to give the title compound (0.41 g) as a solid. Yield 83%. ¹ H-NMR (CDCl ₃ ) δ 1.44 (3H, s),
2.08 (3H, s), 2.15 (3H, s), 2.2
0 (3H, s), 2.80 (1H, d, J = 15.4H)
z), 3.13 (1H, d, J = 15.4 Hz);
55-3.73 (2H, m), 6.51 (1H, s).
This compound was used for the next reaction without further purification.

Reference Example 69 Methanesulfonic acid (S)-(2,3-dihydro-2,
4,6,7-Tetramethylbenzofuran-2-yl) methyl tetrahydrofuran (S) -2,3-dihydro-2,4,6,7-tetramethyl-2-benzofuranmethanol 0.40 g and triethylamine 0.41 mL 5m
0.17 mL of methanesulfonyl chloride in an L solution under ice cooling
Was added dropwise and the mixture was stirred for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline,
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give 0.43 g of the title compound. Yield 78%. [Α] _D + 1.4 ° (c 0.41, ethanol). Mp 70-71 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.52 (3H, s),
2.05 (3H, s), 2.15 (3H, s), 2.1
9 (3H, s), 2.88 (1H, d, J = 15.6H)
z), 3.02 (3H, s), 3.13 (1H, d, J
= 15.6 Hz), 4.26 (2H, s), 6.52
(1H, s).

Reference Example 70 (S) -1-[(2,3-dihydro-2,4,6,7-
Tetramethylbenzofuran-2-yl) methyl] -N-
(Diphenylmethyl) -4-piperidineamine methanesulfonic acid (S)-(2,3-dihydro-2,
0.34 g of 4,6,7-tetramethylbenzofuran-2-yl) methyl, 0.73 g of N- (diphenylmethyl) -4-piperidinamine and 0.38 g of potassium carbonate
Of N, N-dimethylacetamide was stirred at 177 ° C. for 6 hours under an argon atmosphere. Water was added to the reaction solution, which was extracted with diisopropyl ether. The organic layer was washed with water and extracted with 1N hydrochloric acid. The aqueous layer was made basic with a 2N aqueous sodium hydroxide solution and then extracted with diisopropyl ether. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain 0.49 g of the title compound. 79% yield. [Α] _D + 3.0 ° (c 0.20, ethanol). Oily. ¹ H-NMR (CDCl ₃ ) δ 1.25-1.52 (2
H, m), 1.41 (3H, s), 1.80-1.96.
(2H, m), 2.00-2.23 (2H, m), 2.
03 (3H, s), 2.13 (3H, s), 2.18
(3H, s), 2.31-2.56 (3H, m), 2.
71-2.87 (2H, m), 2.95-3.08 (2
H, m), 5.00 (1H, s), 6.46 (1H,
s), 7.16-7.39 (10H, m).

Reference Example 71 1-[(2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine 2-bromomethyl- 2,3-dihydro-2,4,6,7
1.0 g of tetramethylbenzofuran, 1.5 g of N- (diphenylmethyl) -4-piperidinamine and 0.77 g of potassium carbonate in N, N-dimethylacetamide 4
The mL suspension was stirred at 177 ° C. for 4 hours under an argon atmosphere. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 3) to give 1.5 g of the title compound. 97% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.25-1.50 (2
H, m), 1.41 (3H, s), 1.78-1.96.
(2H, m), 2.01-2.22 (2H, m), 2.
03 (3H, s), 2.13 (3H, s), 2.18
(3H, s), 2.31-2.57 (3H, m), 2.
71-2.86 (2H, m), 2.96-3.07 (2
H, m), 5.01 (1H, s), 6.46 (1H,
s), 7.16-7.39 (10H, m).

Reference Example 72 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[1,2,3,6-tetrahydro-4- (3-indolyl) -1-pyridyl] methyl] -5-benzofuranamine 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 0.85 g,
3- (1,2,3,6-tetrahydro-4-pyridyl)
1.1 g of -1H-indole, and 0.1 g of potassium carbonate.
A suspension of 83 g of N, N-dimethylacetamide in 6 mL was heated to reflux for 7.5 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to a column chromatography on a basic silica gel (hexane: ethyl acetate = 1: 1), and recrystallized from acetone / diisopropyl ether to obtain 0.99 g of the title compound. 82% yield. Melting point 169-173 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ 1.49 (3H, s),
2.08 (3H, s), 2.09 (3H, s), 2.1
4 (3H, s), 2.50-2.65 (2H, m),
2.66 (1H, d, J = 13.9 Hz), 2.75
(1H, d, J = 13.9 Hz), 2.75-3.06
(3H, m), 3.21 (1H, d, J = 15.4H)
z), 3.23-3.51 (2H, m), 6.15-
6.24 (1H, m), 7.06-7.29 (3H,
m), 7.35-7.40 (1H, m), 7.86-
7.94 (1H, m), 8.08 (1H, brs).

Reference Example 73 A suspension of 8.2 g of 1-phenyl-1H-indole indole, 12 g of potassium carbonate, and 2.7 g of copper (I) iodide in 70 mL of bromobenzene was heated under reflux in a nitrogen atmosphere for 3 hours. 11 g of copper (I) iodide was added thereto, and the mixture was further heated and refluxed for 6 hours. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5).
0: 1 to 20: 1) to give 8.4 g of the title compound. Yield 62%. Oily. ¹ H-NMR (CDCl ₃ ) δ 6.68 (1H, dd,
J = 3.2, 0.8 Hz), 7.11-7.27 (2
H, m), 7.29-7.43 (2H, m), 7.44.
−7.63 (5H, m), 7.65−7.72 (1H,
m).

Reference Example 74 1-phenyl-3- (1,2,3,6-tetrahydro-
4-pyridyl) -1H-indole 4-piperidone monohydrate hydrochloride 8.2 g of acetic acid 15 mL
Then, a 30 mL solution of trifluoroacetic acid was heated to 110 ° C., and a solution of 3.1 g of 1-phenyl-1H-indole in 15 mL of acetic acid was added dropwise over 25 minutes under a nitrogen atmosphere. The mixture was stirred at 120 ° C. for 30 minutes, cooled and poured into ice. While cooling, concentrated aqueous ammonia was added to neutralize the mixture, and extracted three times with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.8 g of the title compound.
I got This was used for the next reaction without further purification. 63% yield. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 2.48-2.66 (2
H, m), 3.21 (2H, t, J = 5.7 Hz),
3.53-3.94 (3H, m), 6.23-6.34
(1H, m), 7.00-7.70 (9H, m), 7.
80-8.04 (1H, m).

Reference Example 75 Bis [2,3-dihydro-2,4,6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4- (1
-Phenyl-3-indolyl) -1-pyridyl] methyl] -5-benzofuranamine] trioxalate In the same manner as in Reference Example 72, 1-phenyl-3-
(1,2,3,6-tetrahydro-4-pyridyl) -1
2,3-Dihydro-2,4, H-indole
6,7-tetramethyl-2-[[1,2,3,6-tetrahydro-4- (1-phenyl-3-indolyl) -1
-Pyridyl] methyl] -5-benzofuranamine in 61% yield. A part of this was converted to oxalate to give the title compound. Amorphous. ¹ H-NMR (DMSO-d ₆ ) δ 1.48 (3H,
s), 1.99 (6H, s), 2.05 (3H, s),
2.64-2.90 (2H, m), 2.89 (1H,
d, J = 15.4 Hz), 3.05-3.48 (5H,
m), 3.62-3.95 (2H, m), 6.27 (1
H, br s), 7.14-7.30 (2H, m),
7.37-7.67 (6H, m), 7.79 (1H,
s), 7.93-8.02 (1H, m).

Reference Example 76 2,3-dihydro-2-[[4- (3-indolyl)-
1-piperidinyl] methyl] -2,4,6,7-tetramethyl-5-benzofuranamine hydrochloride 2,3-dihydro-2,4,6,7-tetramethyl-2
Under a hydrogen atmosphere, a mixture of 0.40 g of [[1,2,3,6-tetrahydro-4- (3-indolyl) -1-pyridyl] methyl] -5-benzofuranamine and 80 mg of platinum oxide in 2 mL of tetrahydrofuran and 4 mL of methanol was used. Stirred at 60 ° C. for 2 hours. After cooling, the catalyst is filtered,
The filtrate was concentrated under reduced pressure. The residue was dissolved in methanol, and an excess of 10% hydrogen chloride-methanol solution was added. A part of the solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 0.20 g of the title compound. Yield 44%. 236-242 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.54 (3H, b
rs), 1.86-2.40 (5H, m), 1.99.
(3H, s), 2.01 (6H, s), 2.70-3.
90 (7H, m), 2.94 (1H, d, J = 16.0)
Hz), 4.50-5.50 (2H, br), 6.92
−7.19 (3H, m), 7.35 (1H, d, J =
8.0 Hz), 7.50-7.76 (1H, m), 9.
40-10.20 (1H, br), 10.89 (1H, br)
brs).

Reference Example 77 2,3-Dihydro-2,4,6,7-tetramethyl-2
-[[4- (1-Phenyl-3-indolyl) -1-piperidinyl] methyl] -5-benzofuranamine oxalate 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[1,2,3,6-tetrahydro-4- (1-phenyl-3-indolyl) -1-pyridyl] methyl] -5
-0.36 g of benzofuranamine and 72 m of platinum oxide
g of tetrahydrofuran 2 mL and methanol 4 mL
The mixture was stirred at 60 ° C. for 3.5 hours under a hydrogen atmosphere. After cooling, the catalyst was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 2,3-dihydro-2,4,4.
6,7-tetramethyl-2-[[4- (1-phenyl-
3-indolyl) -1-piperidinyl] methyl] -5-
Benzofuranamine was obtained. This was dissolved in methanol, and one equivalent of a methanol solution of oxalic acid was added, followed by concentration under reduced pressure. Ethanol and diethyl ether were added to the residue, and the precipitated powder was collected by filtration to obtain 0.10 g of the title compound. Yield 24%. Amorphous. ¹ H-NMR (DMSO-d ₆ ) δ 1.49 (3H,
s), 1.84-2.36 (5H, m), 1.97 (3
H, s), 1.99 (3H, s), 2.01 (3H,
s), 2.90-3.70 (6H, m), 2.91 (1
H, d, J = 16.0 Hz), 3.12 (1H, d, J)
= 16.0 Hz), 7.08-7.26 (2H, m),
7.32-7.69 (6H, m), 7.48 (1H,
s), 7.76 (1H, d, J = 7.8 Hz).

Reference Example 78 N- [2,3-dihydro-2- (iodomethyl) -2,
4,6-Trimethylbenzofuran-5-yl] formamide N- [4-hydroxy-2,6-dimethyl-3- (2-
Methyl-2-propenyl) phenyl] formamide 16
g and 9.3 g of calcium carbonate in 60 mL of tetrahydrofuran and 60 mL of methanol were gradually added with 27 g of benzyltrimethylammonium dichloroiodate, followed by stirring at room temperature for 10 minutes. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a 10% aqueous sodium hydrogen sulfite solution, water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / diisopropyl ether to give 23 g of the title compound. Yield 93%. 135-138 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.66, 1.67 (3
H, s), 2.13, 2.17 (3H, s), 2.2
1, 2.24 (3H, s), 2.97 (1H, d, J =
15.7 Hz), 3.24 (1H, d, J = 15.7H)
z), 3.43, 3.44 (2H, s), 6.53,
6.54 (1H, s), 6.58-6.87 (1H,
m), 8.00 (0.45H, d, J = 12.2H)
z), 8.41 (0.55H, J = 1.4Hz).

Reference Example 79 N- [2,3-dihydro-2- (iodomethyl) -7-
Isopropyl-2,4,6-trimethylbenzofuran-
5-yl] formamide N- [2,3-dihydro-2- (iodomethyl) -2,
20 mL of concentrated sulfuric acid was added dropwise to a mixture of 6.9 g of 4,6-trimethylbenzofuran-5-yl] formamide and 10 mL of 2-propanol on a water bath, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured onto ice and extracted twice with a mixed solvent of tetrahydrofuran / diisopropyl ether (1: 2). The combined organic layer was washed with saturated sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 7.3 g of the title compound. 94% yield. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 1.27, 1.28 (3
H, d, J = 6.6 Hz), 1.30, 1.32 (3
H, d, J = 6.8 Hz), 1.64, 1.67 (3
H, s), 2.09, 2.13 (3H, s), 2.1
9, 2.23 (3H, s), 2.93 (1H, d, J =
15.8 Hz), 3.04-3.27 (2H, m),
3.44, 3.45 (2H, s), 6.72 (0.5
H, br s), 6.81 (0.5H, br d, J =
12.2 Hz), 7.97 (0.5 H, d, J = 12.
2Hz), 8.41 (0.5H, d, J = 1.6H)
z).

Reference Example 80 2,3-Dihydro-2- (iodomethyl) -7-isopropyl-2,4,6-trimethyl-5-benzofuranamine N- [2,3-dihydro-2- (iodomethyl) -7 −
Isopropyl-2,4,6-trimethylbenzofuran-
5-yl] formamide 7.3 g methanol 40 mL
10 mL of concentrated hydrochloric acid was added to the solution, and the mixture was heated under reflux under a nitrogen atmosphere for 1.5 hours. 20 g of sodium hydrogen carbonate was added to the reaction mixture.
Was added to a water / ethyl acetate suspension for neutralization, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to give 5.7 g of the title compound. Yield 84%. 84-86 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.29 (3H, d, J
= 7.0 Hz), 1.31 (3H, d, J = 7.0H)
z), 1.62 (3H, s), 2.06 (3H, s),
2.13 (3H, s), 2.92 (1H, d, J = 1
5.8 Hz), 3.11-3.27 (2H, m),
42 (2H, s).

Reference Example 81 2,3-Dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl)
Methyl] -5-benzofuranamine 2,3-dihydro-2- (iodomethyl) -7-isopropyl-2,4,6-trimethyl-5-benzofuranamine 1.1 g, 4-phenylpiperidine 0.87 g and potassium carbonate 0 A 0.83 g suspension of N, N-dimethylacetamide in 6 mL was heated to reflux for 4.5 hours. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography (hexane:
Ethyl acetate = 30: 1 followed by 10: 1) and recrystallized from ethyl acetate / hexane to give 0.55 g of the title compound. Yield 47%. 128-131 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.27 (3H, d, J
= 6.8 Hz), 1.28 (3H, d, J = 6.8H)
z), 1.39 (3H, s), 1.66-1.87 (4
H, m), 2.07 (3H, s), 2.10-2.55
(3H, m), 2.13 (3H, s), 2.60 (2
H, s), 2.72 (1H, d, J = 15.0 Hz),
3.00-3.28 (4H, m), 7.12-7.37
(5H, m).

Reference Example 82 N- [2,3-dihydro-2- (iodomethyl) -2,
4,6,7-tetramethylbenzofuran-5-yl] formamide N- [4-hydroxy-2,3,6-trimethyl-5-
(2-Methyl-2-propenyl) phenyl] formamide in a suspension of 187 g of calcium carbonate and 104 g of calcium carbonate in 600 mL of tetrahydrofuran and 600 mL of methanol was added benzyltrimethylammonium dichloroiodate.
07 g was added little by little, and the mixture was stirred at room temperature for 10 minutes. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was ethyl acetate 8
It was dissolved in 00 mL and 400 mL of water, the organic layer was separated, and the aqueous layer was extracted with 400 mL of ethyl acetate. The combined organic layers were combined with 400 g of a 10% aqueous sodium bisulfite solution and 300 g of water.
The mixture was washed with 300 mL of a saturated aqueous solution of sodium hydrogencarbonate and 300 mL of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / diisopropyl ether to give 271 g of the title compound. 94% yield. 145-147 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.66, 1.67 (3
H, s), 2.05-2.20 (9H, m), 2.98
(1H, d, J = 15.9 Hz), 3.24 (1H,
d, J = 15.9 Hz), 3.42, 3.43 (2H,
s), 6.63-8.82 (1H, m), 7.96.
(0.45H, d, J = 12.0Hz), 8.41
(0.55H, d, J = 1.2Hz).

Reference Example 83 2,3-Dihydro-2- (iodomethyl) -2,4
6,7-tetramethyl-5-benzofuranamine N- [2,3-dihydro-2- (iodomethyl) -2,
10 mL of concentrated hydrochloric acid was added to a suspension of 6.5 g of 4,6,7-tetramethylbenzofuran-5-yl] formamide in 40 mL of methanol, and the mixture was refluxed under a nitrogen atmosphere for 1.5 hours. The reaction mixture was added to a suspension of 12 g of sodium hydrogencarbonate in water / ethyl acetate to neutralize, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether / hexane and recrystallized from ethyl acetate / hexane to give 5.5 g of the title compound. Yield 91%. 105-107 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.64 (3H, s),
2.07 (6H, s), 2.12 (3H, s), 2.9
8 (1H, d, J = 15.6 Hz), 3.25 (1H, d, J = 15.6 Hz)
d, J = 15.6 Hz), 3.41 (2H, s).

Example 1 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (2-phenylethyl) -1-piperidinyl] methyl] -5-benzofuranamine 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 1.5 g, 4
A mixture of 2.0 g of-(2-phenylethyl) piperidine and 5.3 g of triethylamine was stirred at 180 ° C. for 15 hours in a sealed tube under an argon atmosphere. After cooling the reaction solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and recrystallized from diisopropyl ether to give the title compound (0.88 g). Yield 42%. 91-92 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.17-1.35
(3H, m), 1.42 (3H, s), 1.48-1.
70 (4H, m), 1.99-2.17 (2H, m),
2.07 (6H, s), 2.10 (3H, s), 2.4
5 (1H, d, J = 13.8 Hz), 2.53 (1H,
d, J = 13.8 Hz), 2.55-2.65 (2H,
m), 2.79 (1H, d, J = 15.2 Hz), 2.
82-2.92 (1H, m), 3.06-3.14 (1
H, m), 3.10 (1H, d, J = 15.2 Hz),
7.13-7.20 (3H, m), 7.22-7.31
(2H, m).

Example 2 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (3-Phenylpropyl) -1-piperidinyl] methyl] -5-benzofuranamine In the same manner as in Example 1, 2-bromomethyl-2,
The title compound was obtained from 3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4- (3-phenylpropyl) piperidine. Yield 42%. 79-80 ° C (recrystallized from diisopropyl ether / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.15-1.30 (5
H, m), 1.41 (3H, s), 1.52-1.67.
(4H, m), 1.98-2.17 (2H, m), 2.
06 (3H, s), 2.07 (3H, s), 2.09
(3H, s), 2.44 (1H, d, J = 13.6H)
z), 2.53 (1H, d, J = 13.6 Hz), 2.
57 (2H, t, J = 7.6 Hz), 2.78 (1H,
d, J = 15.0 Hz), 2.81-2.88 (1H,
m), 3.00-3.10 (1H, m), 3.09 (1
H, d, J = 15.0 Hz), 7.13-7.21 (3
H, m), 7.22-7, 30 (2H, m).

Example 3 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-phenylbutyl) -1-piperidinyl] methyl] -5-benzofuranamine In the same manner as in Example 1, 2-bromomethyl-2,
The title compound was obtained from 3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4- (4-phenylbutyl) piperidine. Yield 62%. 70-71 ° C (recrystallized from pentane). ¹ H-NMR (CDCl ₃ ) δ 1.10-1.39 (7
H, m), 1.41 (3H, s), 1.51-1.65.
(4H, m), 1.98-2.18 (2H, m), 2.
06 (3H, s), 2.07 (3H, s), 2.09
(3H, s), 2.44 (1H, d, J = 13.8H)
z), 2.52 (1H, d, J = 13.8 Hz);
59 (2H, t, J = 7.4 Hz), 2.79 (1H,
d, J = 15.2 Hz), 2.83-2.88 (1H,
m), 3.00-3.10 (1H, m), 3.10 (1
H, d, J = 15.2 Hz), 7.12-7.20 (3
H, m), 7.23-7.30 (2H, m).

Example 4 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4-[(3,4-Methylenedioxyphenyl) methyl] -1-piperazinyl] methyl] -5-benzofuranamine trihydrochloride 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 1.5 g, 1
A mixture of 2.5 g of-[(3,4-methylenedioxyphenyl) methyl] piperazine and 1.6 g of triethylamine was stirred at 180 ° C. for 15 hours in a sealed tube under an argon atmosphere. After cooling the reaction solution, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. After the extract was washed with saturated saline, it was dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 95: 5), and then converted to a hydrochloride with a 4N ethanol solution of hydrogen chloride. This was recrystallized from ethanol to obtain 1.2 g of the title compound. Yield 41%. Melting point 216-218 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.51 (3H,
s), 2.03 (3H, s), 2.22 (3H, s),
2.23 (3H, s), 2.96 (1H, d, J = 1
6.8 Hz), 3.25 (1H, d, J = 16.8H)
z), 3.40 (10H, brs), 4.25 (2
H, s), 6.06 (2H, s), 6.97 (1H,
d, J = 8.0 Hz), 7.08 (1H, d, J = 8.
0 Hz), 7.29 (1H, s), 9.85 (2H, b
rs).

Example 5 2-[(4-benzyl-1-piperidinyl) methyl]-
2,3-dihydro-2,4,6,7-tetramethyl-5
-Benzofuranamine 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 0.85 g,
A mixture of 1.1 g of 4-benzylpiperidine and 1.3 mL of triethylamine was placed in a sealed tube under a nitrogen atmosphere for 18 hours.
Stirred at 0 ° C. for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (hexane: ethanol = 10: 1), and crystallized from hexane to obtain 0.86 g of the title compound. Yield 78%. Mp 71-73 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.1-1.7 (5H,
m), 1.41 (3H, s), 1.9-2.2 (2H,
m), 2.06 (9H, s), 2.3-2.6 (4H,
m), 2.7-2.9 (1H, m), 2.79 (1H,
d, J = 15.4 Hz), 3.0-3.2 (1H,
m), 3.10 (1H, d, J = 15.4 Hz), 7.
1-7.3 (5H, m).

Example 6 2-[(4-benzyl-1-piperazinyl) methyl]-
2,3-dihydro-2,4,6,7-tetramethyl-5
-Benzofuranamine trihydrochloride In the same manner as in Example 5, 2-[(4-benzyl-1-piperazinyl) methyl] -2,3-dihydro-2,4,6,7 using 1-benzylpiperazine. -Tetramethyl-5-benzofuranamine was obtained. This was dissolved in methanol, an excess amount of a 10% hydrogen chloride-methanol solution was added and mixed, and the precipitated crystals were collected by filtration to obtain the title compound. Yield 78%. 210-215 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.50 (3H,
s), 2.02 (3H, s), 2.22 (3H, s),
2.23 (3H, s), 2.97 (1H, d, J = 1)
6.1 Hz), 3.0-4.2 (10H, m), 3.2
5 (1H, d, J = 16.1 Hz), 4.35 (2H,
s), 7.4-7.5 (3H, m), 7.55-7.7.
(2H, m), 9.6-10.2 (2H, br).

Example 7 2-[(4-benzyloxy-1-piperidinyl) methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine 4-benzyloxypiperidine hydrochloride 2.0 g was suspended in ethyl acetate, neutralized with a 1 N aqueous solution of sodium hydroxide, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 0.5 mL of toluene of the obtained 4-benzyloxypiperidine
2-Bromomethyl-2,3-dihydro-2,4, was added to the solution.
6,7-tetramethyl-5-benzofuranamine 1.1
g and 2.8 mL of triethylamine were added, and the mixture was stirred at 180 ° C. for 15 hours in a sealed tube under a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
The mixture was subjected to 1) and crystallized from ethyl acetate / hexane to obtain 1.1 g of the title compound. Yield 67%. 85-86 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.42 (3H, s),
1.5-2.1 (4H, m), 2.07 (6H, s),
2.09 (3H, s), 2.1-2.45 (2H,
m), 2.47 (1H, d, J = 13.8 Hz), 2.
56 (1H, d, J = 13.8 Hz), 2.7-3.1
(2H, m), 2.80 (1H, d, J = 15.4H)
z), 3.10 (1H, d, J = 15.4 Hz);
3-3.45 (1H, m), 4.53 (2H, s),
7.2-7.4 (5H, m).

Example 8 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4-[(3-Phenyl-2-propenyl) oxy] -1-piperidinyl] methyl] -5-benzofuranamine In the same manner as in Example 7, 4-[(3-phenyl-
The title compound was obtained using [2-propenyl) oxy] piperidine hydrochloride. Yield 71%. 77-79 ° C (crystallized from diethyl ether / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.4-2.0 (4H,
m), 1.42 (3H, s), 2.07 (6H, s),
2.10 (3H, s), 2.1-2.4 (2H, m),
2.48 (1H, d, J = 13.8 Hz), 2.56
(1H, d, J = 13.8 Hz), 2.7-3.1 (2
H, m), 2.80 (1H, d, J = 15.4 Hz),
3.10 (1H, d, J = 15.4 Hz), 3.25−
3.45 (1H, m), 4.16 (2H, dd, J =
5.9, 1.1 Hz), 6.29 (1H, dt, J = 1)
5.8, 5.9 Hz), 6.60 (1H, d, J = 1)
5.8 Hz), 7.15-7.45 (5H, m).

Example 9 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4-[(3-phenylpropyl) oxy] -1-
Piperidinyl] methyl] -5-benzofuranamine 2,3-dihydro-2,4,6,7-tetramethyl-2
-1.2 g of [[4-[(3-phenyl-2-propenyl) oxy] -1-piperidinyl] methyl] -5-benzofuranamine and 0.23 g of 5% palladium on carbon (50% water-containing product) in 10 mL of tetrahydrofuran The suspension was stirred at room temperature under a hydrogen atmosphere for 1 hour. The catalyst was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane to give 0.36 g of the title compound. Yield 31%. Melting point 53-54
° C (crystallized from hexane). ¹ H-NMR (CDCl ₃ ) δ 1.4-1.7 (2H,
m), 1.42 (3H, s), 1.7-2.0 (4H,
m), 2.07 (6H, s), 2.10 (3H, s),
2.1-2.4 (2H, m), 2.47 (1H, d, J
= 14.0 Hz), 2.56 (1H, d, J = 14.0)
Hz), 2.69 (2H, t, J = 7.5 Hz), 2.
7-3.1 (2H, m), 2.80 (1H, d, J = 1
5.4 Hz), 3.10 (1H, d, J = 15.4H)
z), 3.1-3.3 (1H, m), 3.42 (2H,
t, J = 6.4 Hz), 7.1-7.35 (5H,
m).

Example 10 2,3-Dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-phenylbutyryl) -1-piperazinyl] methyl] -5-benzofuranamine 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.22 g and 1-hydroxybenzotriazo 0.13 g of 4-phenylbutyric acid in 0.13 g of N, N-dimethylformamide solution (5 mL)
C., and the mixture was stirred for 5 minutes and further stirred at room temperature for 2 hours.
This was added to a solution of 0.20 g of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine in N, N-dimethylformamide (2 mL). C. and stirred for another 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 2) to give the title compound 0.1.
22 g were obtained. Yield 74%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.42 (3H, s),
1.97 (2H, m), 2.05 (3H, s), 2.0
7 (6H, s), 2.30 (2H, t, J = 8.0H)
z), 2.4-2.8 (10H, m), 2.80 (1
H, d, J = 15.1 Hz), 3.10 (1H, d, J)
= 15.1 Hz), 3.32 (2H, t, J = 4.8H)
z), 3.57 (2H, t, J = 5.0 Hz), 7.1
-7.3 (5H, m).

Example 11 2,3-Dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-phenylbutyl) -1-piperazinyl] methyl] -5-benzofuranamine trihydrochloride 2,3
-Dihydro-2,4,6,7-tetramethyl-2-
A mixture of 0.47 g of [[4- (4-phenylbutyryl) -1-piperazinyl] methyl] -5-benzofuranamine, 83 mg of lithium aluminum hydride, and 7 mL of tetrahydrofuran was heated to reflux for 1 hour under an argon atmosphere. After cooling, the reaction solution was poured into crushed ice and extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from hexane / diisopropyl ether to give the free base of the title compound in 0.1 ml.
35 g were obtained. Yield 76%. The free base is further added to 4.
The hydrochloride was converted to a hydrochloride with 8N hydrogen chloride ethanol solution, and methanol was added.
The residue was recrystallized from di- / diisopropyl ether to obtain 0.12 g of the title compound. Yield 21%. 190-193 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.49 (3H,
s), 1.5-1.8 (4H, m), 2.05 (3H,
s), 2.22 (6H, s), 2.59 (2H, m),
2.8-3.7 (14H, m), 7.1-7.3 (5
H, m), 9.7-9.9 (2H, brs).

Example 12 2,3-Dihydro-2,4,6,7-tetramethyl-2
-[[4- (3-Phenylpropionyl) -1-piperazinyl] methyl] -5-benzofuranamine In the same manner as in Example 10, 2,3-dihydro-
The title compound was obtained from 2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine and 3-phenylpropionic acid. 73% yield. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.41 (3H, s),
2.07 (9H, s), 2.4-3.1 (12H,
m), 3.33 (2H, t, J = 5.1 Hz), 3.5
8 (2H, t, J = 5.1 Hz), 7.1-7.3 (5
H, m).

Example 13 2,3-dihydro-2,4,6,7-tetramethyl-2
-[[4- (3-Phenylpropyl) -1-piperazinyl] methyl] -5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2,3-dihydro-
2,4,6,7-tetramethyl-2-[[4- (3-phenylpropionyl) -1-piperazinyl] methyl]-
The title compound was obtained from 5-benzofuranamine. Yield 1
9%. 200-202 ° C (recrystallized from methanol / diethyl ether). ¹ H-NMR (DMSO-d ₆ ) δ 1.49 (3H,
s), 2.03 (5H, m), 2.22 (6H, s),
2.64 (2H, t, J = 7.7 Hz), 2.8-3.
7 (14H, m), 7.1-7.4 (5H, m), 9.
7-9.9 (2H, brs).

Example 14 2-[[4- (2,2-diphenylethyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,6
7-Tetramethyl-5-benzofuranamine In the same manner as in Example 11, 2-[[4- (2,2
-Diphenylacetyl) -1-piperazinyl] methyl]
-2,3-dihydro-2,4,6,7-tetramethyl-
The title compound was obtained from 5-benzofuranamine. Yield 7
9%. 130-132 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, s),
2.06 (3H, s), 2.07 (6H, s), 2.1
0-2.70 (10H, m), 2.78 (1H, d, J
= 15.4 Hz), 2.96 (2H, d, J = 7.4H)
z), 3.10 (1H, d, J = 15.4 Hz), 4.
20 (1H, t, J = 7.4 Hz), 7.00-7.4
0 (10H, m).

Example 15 2-[[4- (3,3-diphenylpropionyl) -1
-Piperazinyl] methyl] -2,3-dihydro-2,
4,6,7-Tetramethyl-5-benzofuranamine In the same manner as in Example 10, 2,3-dihydro-
The title compound was obtained from 2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine and 3,3-diphenylpropionic acid. Yield 72
%. 77-78 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.40 (3H, s),
2.07 (3H, s), 2.09 (6H, s), 2.0
0-2.60 (6H, m), 2.81 (1H, d, J =
15.0 Hz), 3.03 (2H, d, J = 7.4H)
z), 3.06 (1H, d, J = 15.0 Hz);
31 (2H, t, J = 4.6 Hz), 3.52 (2H,
t, J = 4.6 Hz), 4.66 (1H, t, J = 7.
4 Hz), 7.10-7.40 (10H, m).

Example 16 2-[[4- (3,3-diphenylpropyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4
6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2-[[4- (3,3
-Diphenylpropionyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine to give the free base of the title compound. Yield 78%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.41 (3H, s),
2.07 (6H, s), 2.09 (3H, s), 2.3
0-2.80 (14H, m), 2.79 (1H, d, J
= 15.4 Hz), 3.11 (1H, d, J = 15.4)
Hz), 3.97 (1H, m), 7.10-7.40
(10H, m). This free base was further converted to a hydrochloride with a 4.8N hydrogen chloride ethanol solution and recrystallized from methanol / diisopropyl ether to obtain the title compound. 200-203 ° C.

Example 17 2-[[4- (Diphenylmethoxy) -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine oxalate Reference Example In a similar manner to 3, using 4- (diphenylmethoxy) piperidine, 2-[(4-diphenylmethoxy-1-piperidinyl) methyl] -2,3-dihydro-
2,4,6,7-Tetramethyl-5-benzofuranamine was obtained. This was dissolved in ethanol and 1 equivalent of oxalic acid / ethanol solution was added. The mixture was dissolved by heating, cooled, and crystallized by adding diethyl ether to obtain the title compound. Yield 26%. 173-175 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.41 (3H,
s), 1.6-2.1 (4H, m), 1.96 (9H,
s), 2.7-3.4 (8H, m), 3.4-3.6.
(1H, m), 5.64 (1H, s), 7.15-7.
3 (10H, m).

Example 18 2-[[4- (2,2-diphenylacetyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4
6,7-Tetramethyl-5-benzofuranamine In the same manner as in Example 10, 2,3-dihydro-
The title compound was obtained from 2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine and 2,2-diphenylacetic acid. Yield 67%. 113-115 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.38 (3H, s),
2.05 (3H, s), 2.06 (6H, s), 2.1
0-2.70 (6H, m), 2.79 (1H, d, J =
15.4 Hz), 3.08 (1H, d, J = 15.4H)
z), 3.00-3.80 (2H, brs), 3.3
9 (2H, t, J = 4.8 Hz), 3.65 (2H,
t, J = 4.8 Hz), 5.19 (1H, s), 7.1
0-7.40 (10H, m).

Example 19 2-[[4- [2- (diphenylmethoxy) ethyl]-
1-piperazinyl] methyl] -2,3-dihydro-2,
4,6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 4, 2-bromomethyl-2,
3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1- [2- (diphenylmethoxy)
The title compound was obtained from [ethyl] piperazine. Yield 33
%. 173-176 ° C (recrystallized from ethanol / diethyl ether). ¹ H-NMR (DMSO-d ₆ ) δ 1.54 (3H,
s), 2.03 (3H, s), 2.24 (6H, s),
2.95-3.78 (16H, m), 5.57 (1H,
s), 7.25-7.44 (10H, m).

Example 20 2-[[4- [3- (diphenylmethoxy) propyl]
-1-piperazinyl] methyl] -2,3-dihydro-
2,4,6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 4, 2-bromomethyl-2,
3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1- [3- (diphenylmethoxy)
[Propyl] piperazine to give the title compound. Yield 54
%. 193-196 ° C (recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.54 (3H,
s), 2.05 (5H, br s), 2.24 (6H,
s), 2.95-3.63 (16H, m), 5.48.
(1H, s), 7.34-7.36 (10H, m).

Example 21 2-[[4- [4- (diphenylmethoxy) butyl]-
1-piperazinyl] methyl] -2,3-dihydro-2,
4,6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 4, 2-bromomethyl-2,
3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1- [4- (diphenylmethoxy)
[Butyl] piperazine to give the title compound. Yield 43
%. 203-205 ° C (recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.54 (3H,
s), 1.62 (2H, br s), 1.80 (2H, brs).
br s), 2.05 (3H, s), 2.23 (3H,
s), 2.24 (3H, s), 2.94-3.58 (1
6H, m), 5.44 (1H, s), 7.20-7.3.
8 (10H, m).

Example 22 2-[[4- [5- (diphenylmethoxy) pentyl]
-1-piperazinyl] methyl] -2,3-dihydro-
2,4,6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 4, 2-bromomethyl-2,
3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1- [5- (diphenylmethoxy)
[Pentyl] piperazine provided the title compound. Yield 45
%. 186-189 ° C (decomposition, recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.31-1.70
(6H, m), 1.53 (3H, s), 2.05 (3
H, s), 2.24 (6H, s), 2.94-3.58
(16H, m), 5.42 (1H, s), 7.20-
7.39 (10H, m).

Example 23 2-[[4- [6- (diphenylmethoxy) hexyl]
-1-piperazinyl] methyl] -2,3-dihydro-
2,4,6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 4, 2-bromomethyl-2,
The title compound was obtained from 3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1- [6- (diphenylmethoxy) hexyl] piperazine. Yield 60%. 183-186 ° C (decomposition, recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.35-1.71
(8H, m), 1.53 (3H, s), 2.05 (3
H, s), 2.23 (6H, s), 2.96-3.60.
(16H, m), 5.41 (1H, s), 7.20-
7.39 (10H, m).

Example 24 2-[[4-[(diphenylmethoxy) methyl] -1-]
Piperidinyl] methyl] -2,3-dihydro-2,4,
6,7-tetramethyl-5-benzofuranamine oxalate 2-bromomethyl-2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine 1.5 g, 4
-[(Diphenylmethoxy) methyl] piperidine 3.0
g and 7.4 mL of triethylamine were stirred at 180 ° C. for 15 hours in a sealed tube under an argon atmosphere.
Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2-[[4-[(diphenylmethoxy) methyl].
-1-piperidinyl] methyl] -2,3-dihydro-
2.4 g of 2,4,6,7-tetramethyl-5-benzofuranamine was obtained. 95% yield. Oxalic acid 0.4
After addition of 5 g, recrystallization from ethanol gave 1.8 g of the title compound. Yield 58%. 125-127 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.36-1.79
(5H, m), 1.39 (3H, s), 1.96 (9
H, s), 2.60-3.34 (10H, m), 5.4.
0 (1H, s), 7.21-7.34 (10H, m).

Example 25 2-[[4- [2- (diphenylmethoxy) ethyl]-
1-piperidinyl] methyl] -2,3-dihydro-2,
4,6,7-Tetramethyl-5-benzofuranamine oxalate In the same manner as in Example 24, 2-bromomethyl-
2,3-dihydro-2,4,6,7-tetramethyl-5
The title compound was obtained from -benzofuranamine and 4- [2- (diphenylmethoxy) ethyl] piperidine. Yield 32%. 107-110 ° C (recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.36-1.72
(7H, m), 1.43 (3H, s), 1.96 (9
H, s), 2.70-2.88 (3H, m), 3.00.
-3.25 (4H, m), 3.38-3.45 (3H,
m), 5.40 (1H, s), 7.20-7.39 (1
0H, m).

Example 26 2-[[4- [3- (diphenylmethoxy) propyl]
-1-piperidinyl] methyl] -2,3-dihydro-
2,4,6,7-Tetramethyl-5-benzofuranamine oxalate In the same manner as in Example 24, 2-bromomethyl-
2,3-dihydro-2,4,6,7-tetramethyl-5
-The title compound was obtained from -benzofuranamine and 4- [3- (diphenylmethoxy) propyl] piperidine.
Yield 40%. 109-111 ° C (recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.22-1.80
(9H, m), 1.40 (3H, s), 1.98 (9
H, s), 2.65-3.40 (10H, m), 5.4.
0 (1H, s), 7.20-7.38 (10H, m).

Example 27 2,3-Dihydro-2,4,6,7-tetramethyl-2
-[[4- (2-Phenylethyl) -1-piperazinyl] methyl] -5-benzofuranamine In the same manner as in Example 1, 2-bromomethyl-2,
The title compound was obtained from 3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 1- (2-phenylethyl) piperazine. Yield 50%. 99-100 ° C (recrystallized from diisopropyl ether / pentane). ¹ H-NMR (CDCl ₃ ) δ 1.33 (3H, s),
1.98 (6H, s), 2.00 (3H, s), 2.3
8-2.75 (15H, m), 3.04 (1H, d, J
= 15.0 Hz), 7.08-7.19 (5H, m).

Example 28 2-[[4- [Bis (4-fluorophenyl) methoxy] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuran Amine oxalate 3.8 g of 4- [bis (4-fluorophenyl) methoxy] -piperidine obtained in Reference Example 27, 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl- A suspension of 1.4 g of 5-benzofuranamine and 1.4 g of potassium carbonate in 10 mL of N, N-dimethylacetamide was heated under reflux in a nitrogen atmosphere for 15 hours. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 followed by 1: 1) to give 2-[[4- [bis (4-fluorophenyl) methoxy] -1-piperidinyl] methyl] -2, 3-Dihydro-2,4,6,7-tetramethyl-5-benzofuranamine was obtained. This was dissolved in ethanol, and one equivalent of an oxalic acid-ethanol solution was added. The mixture was dissolved under heating, concentrated under reduced pressure, and recrystallized from methanol to obtain 1.5 g of the title compound. Yield 52%. Melting point 181-185 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.40 (3H,
s), 1.6-2.1 (4H, m), 1.96 (9H,
s), 2.6-3.3 (8H, m), 3.3-3.6.
(1H, m), 5.68 (1H, s), 7.15 (4
H, t, J = 9.0 Hz), 7.39 (4H, dd, J
= 8.6, 5.6 Hz).

Example 29 2,3-Dihydro-2-[[4- (4-methoxybenzyl) -1-piperazinyl] methyl] -2,4,6,7-
Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2,3-dihydro-2
-[[4- (4-methoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7-tetramethyl-5-
The title compound was obtained from benzofuranamine. Yield 85
%. 197-202 ° C (recrystallized from water / ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.48 (3H,
s), 2.03 (3H, s), 2.23 (6H, s),
2.70-4.40 (17H, m), 6.99 (2H,
d, J = 8.8 Hz), 7.53 (2H, d, J = 8.
8 Hz), 9.80 (2H, brs).

Example 30 2,3-Dihydro-2-[[4- (3-methoxybenzyl) -1-piperazinyl] methyl] -2,4,6,7-
Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2,3-dihydro-2
-[[4- (3-Methoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7-tetramethyl-5-
The title compound was obtained from benzofuranamine. Yield 74
%. 196-199 ° C (recrystallized from water / ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.54 (3H,
s), 2.04 (3H, s), 2.24 (6H, s),
2.97 (1H, d, J = 16.2 Hz), 3.20 −
4.50 (16H, m), 7.01 (1H, d, J =
8.0 Hz), 7.18 (1H, d, J = 7.0H)
z), 7.30-7.46 (2H, m), 9.90 (2
H, br s).

Example 31 2,3-Dihydro-2-[[4- (2-methoxybenzyl) -1-piperazinyl] methyl] -2,4,6,7-
Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2,3-dihydro-2
-[[4- (2-methoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7-tetramethyl-5-
The title compound was obtained from benzofuranamine. Yield 67
%. 202-204 ° C (recrystallized from methanol / ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.54 (3H,
s), 2.03 (3H, s), 2.24 (6H, s),
2.70-3.80 (10H, m), 3.86 (3H,
s), 4.10-4.70 (4H, m), 7.00-
7.20 (2H, m), 7.40-7.70 (2H,
m), 9.83 (2H, brs).

Example 32 2-[[4- (3,4-Dimethoxybenzyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,
6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2,3-dihydro-2
The title compound was obtained from-[[4- (3,4-dimethoxybenzoyl) -1-piperazinyl] methyl] -2,4,6,7-tetramethyl-5-benzofuranamine. Yield 77%. 176-179 ° C (recrystallized from water / ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.49 (3H,
s), 2.03 (3H, s), 2.22 (6H, s),
2.70-4.40 (20H, m), 6.98 (1H,
d, J = 7.6 Hz), 7.08 (1H, d, J = 7.
6Hz), 7.39 (1H, s), 9.80 (2H, b
rs).

Example 33 2-[[4- (4-Chlorobenzyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine trihydrochloride According to a method similar to that in Example 11, 2-[[4- (4-chlorobenzoyl) -1-piperazinyl] methyl] -2,
The title compound was obtained from 3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine. Yield 91%. 198-200 ° C (recrystallized from water / ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.43 (3H,
s), 2.02 (3H, s), 2.20 (3H, s),
2.22 (3H, s), 2.70-4.40 (14H,
m), 7.54 (2H, d, J = 7.6 Hz), 7.6
3 (2H, d, J = 7.6 Hz), 9.75 (2H, b
rs).

Example 34 2,3-Dihydro-2,4,6,7-tetramethyl-2
-[[4- (4-Methylbenzyl) -1-piperazinyl] methyl] -5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2,3-dihydro-
2,4,6,7-tetramethyl-2-[[4- (4-methylbenzoyl) -1-piperazinyl] methyl] -5-
The title compound was obtained from benzofuranamine. Yield 36
%. 183-186 ° C (recrystallized from water / ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.50 (3H,
s), 2.00 (3H, s), 2.20 (6H, s),
2.34 (3H, s), 2.80-4.20 (12H,
m), 4.28 (2H, s), 7.25 (2H, d, J
= 7.6 Hz), 7.49 (2H, d, J = 7.6H)
z), 9.78 (2H, br s).

Example 35 2-[[4- (4,4-Diphenylbutyryl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,
6,7-Tetramethyl-5-benzofuranamine In the same manner as in Example 10, 2,3-dihydro-
2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine and 4,4
-The title compound was obtained using diphenylbutyric acid. Yield 29
%. 135-138 ° C (recrystallized from ethyl acetate / diisopropyl ether). ¹ H-NMR (CDCl ₃ ) δ 1.41 (3H, s),
2.07 (9H, s), 2.10-2.70 (10H,
m), 2.80 (1H, d, J = 14.7 Hz), 3.
09 (1H, d, J = 14.7 Hz), 3.10-3.
40 (4H, m), 3.55 (2H, t, J = 5.2H
z), 3.95 (1H, t, J = 7.7 Hz), 7.1
0-7.70 (10H, m).

Example 36 2-[[4- (4,4-diphenylbutyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4,6
7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2-[[4- (4,4
-Diphenylbutyryl) -1-piperazinyl] methyl]
-2,3-dihydro-2,4,6,7-tetramethyl-
The title compound was obtained from 5-benzofuranamine. Yield 5
4%. 190-192 ° C (recrystallized from methanol / diethyl ether). ¹ H-NMR (DMSO-d ₆ ) δ 1.50 (3H,
s), 1.55-1.65 (2H, m), 2.03 (5
H, br s), 2.23 (6H, s), 2.60 −
4.30 (15H, m), 7.10-7.40 (10
H, m), 9.70-10.00 (2H, br s).

Example 37 2-[[4- (5,5-Diphenylvaleryl) -1-piperazinyl] methyl] -2,3-dihydro-2,4
6,7-Tetramethyl-5-benzofuranamine In the same manner as in Example 10, 2,3-dihydro-
2,4,6,7-tetramethyl-2-[(1-piperazinyl) methyl] -5-benzofuranamine and 5,5
-The title compound was obtained using diphenylvaleric acid. Yield 8
6%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.41 (3H, s),
1.50-1.70 (2H, m), 2.20-2, 70
(21H, m), 2.81 (1H, d, J = 15.4H)
z), 3.09 (1H, d, J = 15.4 Hz);
28 (2H, t, J = 4.8 Hz), 3.53 (2H,
t, J = 4.8 Hz), 3.90 (1H, t, J = 8.
2Hz), 7.20-7.40 (10H, m)

Example 38 2-[[4- (5,5-Diphenylpentyl) -1-piperazinyl] methyl] -2,3-dihydro-2,4
6,7-Tetramethyl-5-benzofuranamine trihydrochloride In the same manner as in Example 11, 2-[[4- (5,5
-Diphenylvaleryl) -1-piperazinyl] methyl]
-2,3-dihydro-2,4,6,7-tetramethyl-
The title compound was obtained from 5-benzofuranamine. Yield 8
6%. 177-181 ° C (recrystallized from methanol / diethyl ether). ¹ H-NMR (DMSO-d ₆ ) δ 1.05-1.25
(2H, m), 1.44 (3H, s), 1.60-1.
80 (2H, m), 1.90-2.10 (5H, m),
2.21 (6H, s), 2.40-4.00 (15H,
m), 7.10-7.40 (10H, m), 9.75
(2H, brs).

Example 39 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (Diphenylmethyl) -4-piperidinamine In the same manner as in Example 1, 2-bromomethyl-2,
3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and N- (diphenylmethyl) -4
-The title compound was obtained using piperidineamine. Yield 3
8%. 128-129 ° C (recrystallized from ethyl acetate / hexane). ¹ H-NMR (CDCl ₃ ) δ 1.25-1.49 (2
H, m), 1.39 (3H, s), 1.79-1.92.
(2H, m), 2.00-2.19 (2H, m), 2.
05 (3H, s), 2.06 (3H, s), 2.08
(3H, s), 2.30-2.54 (3H, m), 2.
73-2.84 (2H, m), 2.96-3.11 (2
H, m), 5.00 (1H, s), 7.17-7.39.
(10H, m).

Example 40 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidineamine trihydrochloride 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
1. N- (diphenylmethyl) -4-piperidineamine
2 g of the compound was converted into a hydrochloride with a 4 N ethanol solution of hydrogen chloride and then recrystallized from ethanol / diethyl ether to obtain 2.5 g of the title compound. Yield 87%. 200-203 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ 1.57 (3H,
s), 2.04 (3H, s), 2.18-2.59 (4
H, m), 2.23 (6H, s), 2.98-3.76.
(9H, m), 5.74 (1H, s), 7.30-7.
44 (6H, m), 7.86-7.90 (4H, m).

Example 41 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidineethylamine trihydrochloride [2-[[4- [2-[(diphenylmethyl) amino]]
Ethyl] -1-piperidinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5
[Nyl] -tert-butylcarbamate (1.6 g) in ethanol (3 mL) was treated with 4N hydrogen chloride in ethanol (10)
mL was added and stirred at room temperature for 15 hours. The reaction was basified with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1-
[(5-amino-2,3-dihydro-2,4,6,7-
Tetramethylbenzofuran-2-yl) methyl] -N-
1.3 g of (diphenylmethyl) -4-piperidineethylamine were obtained. 97% yield. This was converted into a hydrochloride with an ethanol solution of hydrogen chloride, and recrystallized from ethanol / diethyl ether to obtain 1.3 g of the title compound. Yield 7
6%. 197-199 [deg.] C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ 1.50-1.80
(7H, m), 1.57 (3H, s), 2.04 (3
H, s), 2.24 (6H, s), 2.80-3.75
(10H, m), 5.60 (1H, brs), 7.3
8-7.58 (6H, m), 7.78 (4H, d, J =
7.8 Hz).

Example 42 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (3,3-diphenylpropyl) -4-piperidineethylamine trihydrochloride In the same manner as in Example 41, [2-[[4- [2-
[(3,3-diphenylpropyl) amino] ethyl]-
1-piperidinyl] methyl] -2,3-dihydro-2,
The title compound was obtained from tert-butyl 4,6,7-tetramethylbenzofuran-5-yl] carbamate. Yield 23%. 180-181 ° C (recrystallized from ethanol / diethyl ether). ¹ H-NMR (DMSO-d ₆ ) δ 1.58 (3H,
s), 1.77 (9H, br s), 2.05 (3H,
s), 2.23 (6H, s), 2.73-3.69 (1
2H, m), 4.10-4.14 (1H, m), 7.1
8-7.32 (10H, m).

Example 43 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidinemethylamine dihydrochloride 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
To a solution of 1.3 g of N- (diphenylmethyl) -4-piperidinecarboxamide in 20 mL of tetrahydrofuran was added 17 mL of a 1M borane tetrahydrofuran complex solution in tetrahydrofuran under ice-cooling, and the mixture was refluxed for 23 hours under a nitrogen atmosphere. The reaction mixture was ice-cooled, 12 mL of 5N hydrochloric acid was added dropwise, and the mixture was concentrated under reduced pressure. The residue was neutralized by adding sodium hydrogen carbonate, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethanol = 1
0: 1) to give 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-
Yl) methyl] -N- (diphenylmethyl) -4-piperidinemethylamine 0.89 g. Yield 68%. This was dissolved in methanol, an excess 10% hydrogen chloride-methanol solution was added dropwise, and the mixture was concentrated under reduced pressure to obtain the title compound. Amorphous. ¹ H-NMR (DMSO-d ₆ ) δ 1.3-2.2 (5
H, m), 1.48 (3H, s), 1.98 (3H,
s), 2.00 (6H, s), 2.3-3.7 (10
H, m), 4.0-4.3 (1H, br), 5.48
(1H, brs), 7.2-7.6 (6H, m),
7.6-7.9 (4H, m).

Example 44 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (2,2-diphenylethyl) -4-piperidinemethylamine trihydrochloride 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
To a solution of N- (2,2-diphenylethyl) -4-piperidinecarboxamide (1.0 g) in tetrahydrofuran (20 mL) was added dropwise a 1 M borane tetrahydrofuran complex tetrahydrofuran solution (12 mL) under ice-cooling, and the mixture was refluxed for 6 hours under a nitrogen atmosphere. The reaction mixture is ice-cooled and 8 mL of 5N hydrochloric acid
And the mixture obtained is stirred.
g of water / diisopropyl ether suspension for neutralization, and extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Dissolve the residue in methanol,
10 mL of 5N hydrochloric acid was added, and the mixture was heated under reflux for 1 hour. The reaction mixture is ice-cooled and 20 mL of 5N aqueous sodium hydroxide solution
And extracted three times with diethyl ether. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate: triethylamine = 30: 10: 1 followed by 20: 1)
0: 1) to give 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-
Yl) methyl] -N- (2,2-diphenylethyl)-
4-Piperidine methylamine was obtained. This was dissolved in methanol, an excess amount of a 10% hydrogen chloride-methanol solution was added dropwise, and the obtained mixture was concentrated under reduced pressure to give the title compound (0.7%).
4 g were obtained. Yield 61%. Amorphous. ¹ H-NMR (DMSO-d ₆ ) δ 1.4-2.3 (5
H, m), 1.57 (3H, s), 2.04 (3H,
s), 2.23 (6H, s), 2.6-3.8 (12
H, m), 4.6-4.8 (1H, m), 7.1-7.
5 (10H, m), 8.9-9.2 (2H, br),
9.5-10.1 (3H, br), 10.3-10.6
(1H, br).

Example 45 1-[(5-Amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (3,3-diphenylpropyl) -4-piperidinemethylamine dihydrochloride 1-[(5-amino-
2,3-Dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (3,3-diphenylpropyl) -4-piperidinecarboxamide (free base of Reference Example 50) The compound was obtained. Yield 46
%. 168-172 ° C (crystallized from methanol / diethyl ether). ¹ H-NMR (DMSO-d ₆ ) δ 1.3-2.2 (5
H, m), 1.46 (3H, brs), 1.98 (9
H, s), 2.3-3.5 (14H, m), 4.09
(1H, t, J = 7.5 Hz), 7.1-7.4 (10
H, m).

Example 46 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N-benzyl-N- (3,3-diphenylpropyl)-
4-Piperidineamine trihydrochloride In the same manner as in Example 1, 2-bromomethyl-2,
From 3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and N-benzyl-N- (3,3-diphenylpropyl) -4-piperidineamine,
[(5-amino-2,3-dihydro-2,4,6,7-
Tetramethylbenzofuran-2-yl) methyl] -N-
Benzyl-N- (3,3-diphenylpropyl) -4-
Piperidineamine was obtained. Yield 60%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.39 (3H, s),
1.45-1.61 (4H, m), 1.97-2.18
(4H, m), 2.05 (3H, s), 2.07 (3
H, s), 2.08 (3H, s), 2.37-2.54
(5H, m), 2.72-2.89 (2H, m), 3.
02-3.10 (2H, m), 3.58 (2H, s),
3.94 (1H, t, J = 7.6 Hz), 7.11-
7.30 (15H, m). The obtained 1-[(5-amino-2,3-dihydro-2,
4,6,7-Tetramethylbenzofuran-2-yl) methyl] -N-benzyl-N- (3,3-diphenylpropyl) -4-piperidineamine (1.0 g) was converted to the hydrochloride salt with a 4N ethanol solution of hydrogen chloride. After recrystallization from ethanol / diethyl ether, 0.65 g of the title compound was obtained. Yield 53%. Melting point 185-187 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.59 (3H,
s), 1.93-2.55 (6H, m), 2.06 (3
H, s), 2.24 (6H, s), 2.76-3.60.
(9H, m), 3.79-3.94 (3H, m), 4.
23-4.49 (2H, m), 7.16-7.23 (1
0H, m), 7.38-7.42 (3H, m), 7.6
6-7.71 (2H, m).

Example 47 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (3,3-diphenylpropyl) -4-piperidineamine trihydrochloride 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N-benzyl-N- (3,3-diphenylpropyl)-
To a solution of 1.5 g of 4-piperidineamine in 50 mL of ethanol was added 0.30 g of 5% palladium carbon (50% water-containing product), and the mixture was stirred at 40 ° C for 6 hours under 5 atm of hydrogen. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to give 1-[(5
-Amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (3
3-Diphenylpropyl) -4-piperidineamine
2 g were obtained. 94% yield. This was converted to a hydrochloride with a 4 N ethanol solution of hydrogen chloride, and then recrystallized from ethanol / diethyl ether to obtain 1.3 g of the title compound. 82% yield. 187-189 [deg.] C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ 1.58 (3H,
s), 2.02-2.26 (4H, m), 2.05 (3
H, s), 2.23 (6H, s), 2.78 (2H, b
rs), 3.00-3.55 (10H, m), 3.7.
7-3.91 (1H, m), 4.14 (1H, t, J =
7.6 Hz), 7.20-7.33 (10H, m).

Example 48 2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7
-Tetramethyl-5-benzofuranamine oxalate In the same manner as in Example 41, [2- [2- [4-
(Diphenylmethoxy) -1-piperidinyl] ethyl]
Tert-Butyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamate to 2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethyl] -2 , 3-dihydro-2,4,
6,7-Tetramethyl-5-benzofuranamine was obtained. Yield 84%. The obtained compound was converted into oxalate and then recrystallized from ethanol to obtain the title compound. Yield 45%. 137-139 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.31 (3H,
s), 1.62-2.01 (6H, m), 1.94 (6
H, s), 1.96 (3H, s), 2.77-3.20.
(8H, m), 3.53 (1H, brs), 5.65
(1H, s), 7.20-7.38 (10H, m).

Example 49 2- [2- [4-[(diphenylmethoxy) methyl]-
1-piperidinyl] ethyl] -2,3-dihydro-2,
4,6,7-Tetramethyl-5-benzofuranamine dioxalate In the same manner as in Example 48, [2- [2- [4-
[(Diphenylmethoxy) methyl] -1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] carbamic acid
The title compound was obtained from rt-butyl. Yield 20%. 160-162 ° C (recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.28-1.66
(2H, m), 1.36 (3H, s), 1.84-2.
10 (5H, m), 1.99 (9H, s), 2.81-
3.16 (6H, m), 3.25-3.30 (2H,
m), 3.41-3.56 (2H, m), 5.43 (1
H, s), 7.20-7.37 (10H, m).

Example 50 2- [2- [4- [2- (Diphenylmethoxy) ethyl] -1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7-tetramethyl-5 Benzofuranamine oxalate [2- [2- [4-
[2- (Diphenylmethoxy) ethyl] -1-piperidinyl] ethyl] -2,3-dihydro-2,4,6,7-
Tetramethylbenzofuran-5-yl] carbamic acid t
The title compound was obtained from tert-butyl. Yield 54%. 119-121 ° C (recrystallized from ethanol). ¹ H-NMR (DMSO-d ₆ ) δ 1.24-2.10.
(9H, m), 1.34 (3H, s), 1.96 (6
H, s), 1.98 (3H, s), 2.79-3.14.
(6H, m), 3.36-3.43 (4H, m), 5.
41 (1H, s), 7.20-7.38 (10H,
m).

Example 51 N- [2-[[4- [4- (Diphenylmethoxy) butyl] -1-piperazinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran 5-yl] acetamide 2-[[4- [4- (diphenylmethoxy) butyl]-
1-piperazinyl] methyl] -2,3-dihydro-2,
To a suspension of 0.60 g of 4,6,7-tetramethyl-5-benzofuranamine trihydrochloride in 10 mL of tetrahydrofuran, 8 mL of a 1 N aqueous sodium hydroxide solution and 0.10 mL of acetic anhydride were added under ice-cooling for 1 hour. Stirred. Water was added to the reaction solution, which was extracted with ethyl acetate. After the extract was washed with saturated saline, dried over anhydrous magnesium sulfate,
Concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to obtain 0.48 g of the title compound. Yield 93%. Oily. ¹ H-NMR (CDCl ₃ ) δ 1.42 (3H, s),
1.62 (4H, brs), 2.05-2.82 (25
H, m), 3.08-3.17 (1H, m), 3.41
-3.47 (2H, m), 5.32 (1H, s), 6.
58-6.62 (1H, m), 7.20-7.33 (1
0H, m).

Example 52 2-[[4- [4- (diphenylmethoxy) butyl]-
1-piperazinyl] methyl] -N-ethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine trihydrochloride N- [2-[[4- [4- (diphenylmethoxy) ) Butyl] -1-piperazinyl] methyl] -2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl] acetamide 0.48 g of tetrahydrofuran 20
To the mL solution was added lithium aluminum hydride (64 mg), and the mixture was refluxed for 15 hours under an argon atmosphere. After adding a small amount of water to the reaction solution, ethyl acetate, anhydrous magnesium sulfate and Hyflo Super Cell (trade name) were added, and the mixture was filtered. After the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate: methanol =
95: 5) to give 2-[[4- [4- (diphenylmethoxy) butyl] -1-piperazinyl] methyl]-
0.32 g of N-ethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine was obtained.
Yield 68%. The obtained compound was converted into a hydrochloride with a 4 N ethanol solution of hydrogen chloride, and then recrystallized from ethanol / diethyl ether to obtain 0.32 g of the title compound. 55% yield. 156-158 ° C. ¹ H-NMR (DMSO-d ₆ ) δ 1.33 (3H,
t, J = 7.2 Hz), 1.57-1.63 (5H,
m), 1.73-1.85 (2H, m), 2.05 (3
H, s), 2.30 (3H, s), 2.33 (3H,
s), 2.98-3.60 (18H, m), 5.44.
(1H, s), 7.22-7.40 (10H, m).

Example 53 1-[(5-Amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- [bis (4-fluorophenyl) methyl] -4-piperidineamine Under an argon atmosphere, 1.4 g of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine, N- [bis (4-fluorophenyl)
Methyl] -4-piperidineamine 4.5 g and potassium carbonate 1.4 g in N, N-dimethylacetamide 20 m
The L suspension was stirred at 172 ° C. for 4.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
Concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel; ethyl acetate, and basic silica gel;
After purification with hexane: ethyl acetate = 9: 1 to 85:15), recrystallization from ethyl acetate / hexane gave 0.97 g of the title compound. Yield 39%. 133-134 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.24-1.47 (2
H, m), 1.40 (3H, s), 1.78-1.91.
(2H, m), 1.96-2.18 (2H, m), 2.
05 (3H, s), 2.07 (3H, s), 2.08
(3H, s), 2.23-2.55 (3H, m), 2.
74-2.96 (2H, m), 2.95-3.12 (2
H, m), 4.97 (1H, s), 6.97 (4H,
t, J = 8.8 Hz), 7.20-7.40 (4H,
m).

Example 54 1-[(5-Amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- [bis (4-methoxyphenyl) methyl] -4-piperidinamine In the same manner as in Example 53, 2-bromomethyl-
2,3-dihydro-2,4,6,7-tetramethyl-5
The title compound was obtained from -benzofuranamine and N- [bis (4-methoxyphenyl) methyl] -4-piperidineamine. 43% yield. 109-111 ° C. ¹ H-NMR (CDCl ₃ ) δ 1.25-1.46 (2
H, m), 1.40 (3H, s), 1.76-2.55
(9H, m), 2.05 (3H, s), 2.07 (3
H, s), 2.08 (3H, s), 2.72-2.86
(2H, m), 2.96-3.12 (2H, m), 3.
77 (6H, s), 4.92 (1H, s), 6.82
(4H, d, J = 8.8 Hz), 7.26 (4H, d,
J = 8.8 Hz).

Example 55 (R) -1-[(5-amino-2,3-dihydro-2,
4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidineamine was subjected to high performance liquid chromatography (column; CHIRALCE).
L OD (20 × 250 mm) (trade name; Daicel (manufactured by Daicel));
5: 5, flow rate: 8.0 mL / min, column temperature: 30
C) to give the title compound. [Α] _D -21.4 ° (c 0.496, ethanol).

Example 56 (S) -1-[(4-amino-2,3-dihydro-2,
4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine 1-[(5-amino-2,3-dihydro-2,4,6,
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidineamine was subjected to high performance liquid chromatography (column; CHIRALCE).
L OD (20 × 250 mm) (trade name; Daicel (manufactured by Daicel)), mobile phase; hexane: 2-propanol = 9
5: 5, flow rate: 8.0 mL / min, column temperature: 30
C) to give the title compound. [Α] _D + 21.5 ° (c 0.549, ethanol).

Example 57 (R) -1-[(5-amino-2,3-dihydro-2,
4,6,7-Tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidineamine sulfate (R) -1-[(5-amino-2,3-dihydro-2,
4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine 3.5 g of methanol 15 mL and ethyl acetate 5
After adding 7.5 mL of 2N aqueous sulfuric acid to the mL solution, the mixture was concentrated under reduced pressure. 15 mL of methanol was added to the residue and left for 18 hours. The precipitated crystals were collected by filtration, dried, and recrystallized from methanol / water to give the title compound (3.5 g).
I got Yield 76%. [Α] _D -8.0 ° (c 0.51, ethanol). Melting point 154-156 [deg.] C. ¹ H-NMR (DMSO-d ₆ ) δ 1.33 (3H,
s), 1.52-2.20 (4H, m), 1.95 (9
H, s), 2.15-2.30 (1H, s), 2.58
-2.82 (4H, m), 2.97-3.25 (4H,
m), 5.52 (1H, brs), 7.28-7.4.
2 (6H, m), 7.52-7.58 (4H, m).

Example 58 (S) -1-[(5-amino-2,3-dihydro-2,
4,6,7-Tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidineamine sulfate (S) -1-[(5-amino- The title compound was obtained from 2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine and a 2N aqueous sulfuric acid solution. Yield 68%. [Α] _D + 8.5 ° (c 0.52, ethanol). 155-157 ° C (recrystallized from methanol / water). ¹ H-NMR (DMSO-d ₆ ) δ 1.34 (3H,
s), 1.53-2.07 (4H, m), 1.95 (9
H, s), 2.23 (1H, brs), 2.59-
2.81 (4H, m), 2.99-3.28 (4H,
m), 5.52 (1H, brs), 7.28-7.4.
3 (6H, m), 7.52-7.57 (4H, m).

Example 59 (S) -1-[(5-amino-2,3-dihydro-2,
4,6,7-Tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine 0.14 g of 4-nitroaniline was dissolved in 3 mL of 2N hydrochloric acid by heating and then cooled with ice. Sodium nitrite 72
A 0.5 mL solution of mg water was added dropwise and stirred for 15 minutes.
The obtained aqueous solution of 4-nitrobenzenediazonium chloride was treated with (S) -1-[(2,3-dihydro-2,4,6,6).
7-tetramethylbenzofuran-2-yl) methyl]-
N- (diphenylmethyl) -4-piperidineamine
To a solution of 43 g of acetic acid in 3 mL was added with cooling and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into a saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained (S) -1-[[2,
3-dihydro-2,4,6,7-tetramethyl-5
(4-nitrophenylazo) benzofuran-2-yl]
Methyl] -N- (diphenylmethyl) -4-piperidineamine in 30 mL of ethanol and Raney nickel (NDHT-90, manufactured by Kawaken Fine Chemical Co., Ltd.) 0.6
g was added and the mixture was stirred for 1 hour at room temperature under 5 atm of hydrogen. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 1) gave 0.32 of the title compound.
g was obtained. Yield 71%. ¹ H-NMR (CDCl ₃ ) δ 1.25-1.52 (2
H, m), 1.40 (3H, s), 1.78-2.20.
(4H, m), 2.05 (3H, s), 2.06 (3
H, s), 2.08 (3H, s), 2.30-2.54
(3H, m), 2.72-2.83 (2H, m), 2.
95-3.11 (2H, m), 5.01 (1H, s),
7.15-7.40 (10H, m).

Example 60 1-[(5-Amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidine Amine 2,3-dihydro-2- (iodomethyl) -7-isopropyl-2,4,6-trimethyl-5-benzofuranamine 1.1 g, N- (diphenylmethyl) -4-piperidineamine 1.4 g and potassium carbonate A suspension of 0.83 g of N, N-dimethylacetamide in 6 mL was heated to reflux for 4.5 hours. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to a column chromatography on a basic silica gel (hexane: ethyl acetate = 20: 1 followed by 5: 1) to obtain 1.4 g of the title compound. Yield 91
%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ 1.20-1.50
(2H, m), 1.25 (3H, d, J = 7.4H
z), 1.26 (3H, d, J = 6.8 Hz), 1.3
3 (3H, s), 1.70-2.55 (5H, m),
2.04 (3H, s), 2.12 (3H, s), 2.5
1 (2H, s), 2.67 (1H, d, J = 15.0H
z), 2.78-3.29 (3H, m), 3.12 (1
H, d, J = 15.0 Hz), 5.01 (1H, s),
7.12-7.47 (10H, m).

Tables 1 to 5 show the structural formulas of the compounds obtained in Examples 1 to 60.

[Table 1]

[0210]

[Table 2]

[0211]

[Table 3]

[0212]

[Table 4]

[0213]

[Table 5]

Formulation Example 1 The compound obtained in Example 5 was dissolved in physiological saline containing 30% (w / v) polyethylene glycol 400 to prepare a 0.01% solution of the compound. Each 10 mL was dispensed into a vial. An intravenous solution was prepared containing 1 mg of compound per vial.

Formulation Example 2 (S) -2,3-Dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine dihydrochloride 30% (w /
v) The compound was dissolved in a physiological saline solution containing polyethylene glycol 400 to prepare a 0.01% solution of the compound. After sterile filtration, 10 mL of the solution was dispensed into vials. An intravenous solution was prepared containing 1 mg of compound per vial.

Formulation Example 3 (1) Compound obtained in Example 5 1.0 g (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g Using a mixture of 1.0 g of the compound obtained in Example 5, 60.0 g of lactose and 35.0 g of corn starch in 30 mL of a 10% by weight aqueous gelatin solution (3.0 g as gelatin),
After granulating through a 1 mm mesh sieve, it was dried at 40 ° C. and sieved again. The granules obtained were mixed with 2.0 g of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain 1000 coated tablets. Formulation Example 4 The compound obtained in Example 40 was dissolved in physiological saline containing 30% (w / v) polyethylene glycol 400 to prepare a 0.01% solution of the compound. Was dispensed. An intravenous solution was prepared containing 1 mg of compound per vial.

Experimental Example 1 Binding Experiment to Sodium Channel Using Rat Cerebral Cortex Specimens Wistar rats (10-15 weeks old) were used in the experiments. Immediately after decapitation of the rat, the cerebral cortex was excised and homogenized in an approximately 10-fold volume of ice-cold 0.32 M sucrose, 5 mM potassium hydrogen phosphate (pH 7.4, 4 ° C.) using a homogenizer. Then, 1,000x
and centrifuged at 20,000 × g for 1 minute.
Centrifugation was performed for 5 minutes to obtain a precipitate. This precipitate is added to 0.32
The suspension was washed with M sucrose buffer and washed again at 20,000 × g for 1 hour.
After centrifugation for 5 minutes, the residue was collected. The obtained membrane sample was added to an assay buffer (50 mM HE) containing no sodium.
PES, 5.4 mM KCl, 0.8 mM MgSO ₄ , 5.5
mM glucose, 130 mM choline chloride (pH 7.
4)). The binding reaction was performed using the test compound, 1 μM tetrodotoxin, 100 μg / mL scorpion toxin and 5 nM.
[ ³ H] batracotoxinin A20-α-benzoate (34.0 Ci /
mmol) was added to 0.2 mL of the assay buffer, to which 0.2 mL of the above-mentioned membrane specimen suspension was added, and the final volume was 0.4 mL.
The reaction was carried out in a thermostat at 37 ° C. for 1 hour. The reaction solution was immediately suction-filtered onto a CF / B filter, and the washing solution (5
mM HEPES, 1.8 mM CaCl ₂ , 0.8 mM MgS
O ₄ , 130 mM choline chloride and 0.01% BSA (p
H7.4, 4 ° C)) 3 times with 2 mL. 4 mL of a scintillator was added to this filter, and measurement was performed with a liquid scintillation counter. To see non-specific binding, 0.3 mM veratridine was added. The test compound had a final concentration of 0.03, 0.1,
Added to a 0.3, 1, 3, 10 and 30 [mu] M, IC ₅₀ values were determined from the inhibition rate. The results are shown below. Compound IC ₅₀ ( μM) Example 1 0.22 Example 2 0.28 Example 3 0.26 Example 4 0.28 Example 5 0.52 Example 6 0.79 Example 17 0.32 Example 24 0.41 Example 25 0.34 Example 26 0.22 Example 27 0.20 Example 28 0.22 Example 29 0.21 Example 30 0.39 Example 31 0.49 Example 32 0 .25 example 33 0.31 example 34 0.42 example 40 0.16 example 41 0.14 example 42 0.16 example 8 0.64 example 10 0.4 7 from this, compound ( It can be seen that I) and (Ia) have an affinity for sodium channels.

[0218]

The compound (I) and the compound (I) of the present invention
a) is the sodium channel, especially site 2
It acts as a sodium channel modulator and has central nervous system diseases and disorders such as ischemic central nervous system disorders and central trauma (eg, head injury). Head injury, spinal cord injury, whiplash, etc.), epilepsy, neurodegenerative diseases (eg, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Huntington's chorea, Parkinson's disease, diabetic neuropathy, etc.), vascular dementia (Eg, multiple infarct dementia, Binswanger's disease, etc.), manic depression, depression, schizophrenia, chronic pain, trigeminal neuralgia, migraine, cerebral edema, etc., and are used as preventive and therapeutic agents. Further, since compound (I) and compound (Ia) also have excellent antioxidant activity and dopamine transporter regulating activity, in addition to the above diseases, ischemic cardiovascular diseases (eg, myocardial infarction, angina pectoris, etc.), It is also useful as a preventive and therapeutic agent for curing and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 307/81 C07D 307/81 407/12 307 407/12 307

Claims (25)

[Claims] [Claim 1] The formula: [Wherein, R ¹ and R ² are each a hydrogen atom, a lower alkyl or an acyl which may have a substituent, and R ³ , R ⁴ and R ⁵ are a lower alkyl or an each which may have a substituent. Lower alkoxy optionally having a substituent,
Alternatively, R ⁴ and R ⁵ may together form a 5- or 6-membered homocyclic ring, R ⁶ is lower alkyl, Ar is an aromatic group which may have a substituent, and A ring is A 5- to 8-membered nitrogen-containing heterocyclic ring which may have a substituent, X is a lower alkylene which may have a substituent, Y is a carbon atom or a nitrogen atom, (Wherein, R ⁷ represents a hydrogen atom or an aromatic group which may have a substituent, and R ¹⁰ represents a hydrogen atom, a hydrocarbon group which may have a substituent or acyl). Group, Zb
Represents a divalent aliphatic hydrocarbon group which may have a bond or a substituent and may be via an oxygen atom, a nitrogen atom or a sulfur atom, and m represents an integer of 1 to 3] Or a salt thereof. 2. R ¹ and R ² are each (i) a hydrogen atom,
(Ii) halogen atom, C _3-6 cycloalkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _6-10 aryl, C _7-11 aralkyl, C _1-6 alkoxy, C _6-10 aryloxy,
C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, amidino, imino,
Amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 3- to 6-membered cyclic amino, C _1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, Sulfamoyl,
Mono-C _1-6 alkylsulfamoyl, di-C _1-6 alkylsulfamoyl, C _1-6 alkylthio, C _6-10 arylthio, C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl, C _{1 -6alkylsulfonyl} and _C6-10
C _1-6 alkyl optionally having 1 to 5 substituents selected from arylsulfonyl, or (iii) formyl, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C _6-10 Aryl-C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-
C _1-6 alkoxy-carbonyl, C _1-6 alkylsulfonyl, C _1-6 optionally having 1 to 3 C _1-6 alkyl
_6-10 arylsulfonyl and C _6-10 aryl-C _1-6
An acyl selected from alkylsulfonyl; R ³ , R ⁴ and R ⁵ are each (i) a halogen atom, C _3-6 cycloalkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _6-10 aryl, C _{7 -11} aralkyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy Carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 3- to 6-membered cyclic amino, C _1-3 alkyl dioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono--C _1-6 alkylsulfamoyl, di -C _1-6 alkylsulfamoyl C _1-6 alkylthio, C _6-10 arylthio, C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl,, 1 to substituents selected from C _1-6 alkylsulfonyl and C _6-10 arylsulfonyl 5 Yes C _1-6 alkyl, or (ii) a halogen atom, C _3-6 cycloalkyl, C _2-6 alkynyl, C _2-6 alkenyl, C _6-10 aryl, C _7-11 aralkyl, _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C _1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, carboxyl, C _{1 -6} alkoxy - carbonyl, carbamoyl, amidino, imino, amino, mono--C _1-6 alkylamino, di -C _1-6 alkylamino, 3 to 6-membered cyclic amino, C _1-3 alkylenedioxy, hydrin Roxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C _1-6 alkylsulfamoyl, di-C _1-6 alkylsulfamoyl, C _1-6 alkylthio, C _6-10 arylthio, C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl, C _1-6 alkylsulfonyl and C _6-10 aryl 1 substituents selected from sulfonyl to 5 optionally having C _1-6 alkoxy, or, R ⁴ and R ⁵ together with two adjacent carbon atoms form a 6-membered aromatic hydrocarbon ring and 5 or 6
R ⁶ is a C _1-6 alkyl; Ar is a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino Di-C _1-6 alkylamino, C _1-6 alkyl-carbonyl, carboxyl,
C _1-6 alkoxy-carbonyl, carbamoyl, mono-
C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo,
C _1-6 alkylsulfonyl, C _6-10 aryl and C
(I) C _6-14 aryl optionally having 1 to 5 substituents selected from _6-10 aryloxy or (ii) heteroatom selected from nitrogen, sulfur and oxygen in addition to carbon A 5- to 10-membered aromatic heterocyclic group containing 1 to 4 atoms; a ring A being a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _{3 -6} cycloalkyl, optionally halogenated C _1-6 alkoxy optionally, a C _1-6 alkylthio which may be halogenated, hydroxy, amino, mono--C _1-6 alkylamino, di -C _1-6 Alkylamino, C _1-6 alkyl-carbonyl, carboxyl,
C _1-6 alkoxy-carbonyl, carbamoyl, mono-
C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo,
C _1-6 alkylsulfonyl, C _6-10 aryl and C
_{6-10 optionally} having 1 to 3 substituents selected from aryloxy, including 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon and nitrogen 5 to 8 membered nitrogen-containing heterocyclic ring; X is a halogen atom, C _1-6 alkyl, C _3-6 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-14
Aryl, nitro, cyano, hydroxy, C _1-6 alkoxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _1-6 alkyl-carbonyl, C _6-10
C _1-6 alkylene _optionally having 1 to 3 substituents selected from aryloxy and oxo; Y is (i)
A nitrogen atom or formula (ii):> C (R ⁸ ) — wherein R ⁸ is a hydrogen atom, a halogen atom, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl; Alkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di-C _1-6
Alkylamino, C _1-6 alkyl-carbonyl, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl , Sulfo, C _1-6 alkylsulfonyl, C _6-10 aryl or C _6-10 aryloxy);
R ⁷ is a hydrogen atom or a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, optionally halogenated C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _{1 -6} alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino,
Mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkyl-carbonyl, carboxyl, C _1-6
Alkoxy-carbonyl, carbamoyl, mono-C _1-6
Alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, C _6-10 aryl-carbamoyl, sulfo, C
_1-6 alkylsulfonyl, C _6-10 aryl and C _6-10
(I) C _6-14 aryl or (i) each having 1 to 5 substituents selected from aryloxy
i) 5 to 1 containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon atoms
A zero-membered aromatic heterocyclic group; R ¹⁰ represents (i) a hydrogen atom, (ii) a halogen atom, C _3-6 cycloalkyl, C _2-6 alkynyl,
C _2-6 alkenyl, C _6-10 aryl, C _7-11 aralkyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C
_1-6 alkyl-carbonyloxy, C _6-10 aryl-carbonyloxy, carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, amidino, imino, amino,
Mono-C _1-6 alkylamino, di-C _1-6 alkylamino, 3- to 6-membered cyclic amino, C _1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, Mono-C
_1-6 alkylsulfamoyl, di -C _1-6 alkylsulfamoyl, C _1-6 alkylthio, C _6-10 arylthio,
C _1-6 alkylsulfinyl, C _6-10 arylsulfinyl, C _1-6 alkylsulfonyl and C _6-10 aryl 1 substituents selected from sulfonyl It may have five each C _1-6 alkyl, C _2-6 alkenyl, C
_2-6 alkynyl, C _3-6 cycloalkyl, C _6-14 aryl or C _7-16 aralkyl, or (iii) formyl, C
_1-6 alkyl-carbonyl, C _6-10 aryl-carbonyl, C _6-10 aryl-C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, C _6-10 aryl-C _1-6 alkoxy-carbonyl, C _1-6 alkylsulfonyl, C
_1-6 1 alkyl to 3 have good C _6-10 optionally arylsulfonyl and C _6-10 aryl -C _1-6 acyl selected from alkylsulfonyl; and Zb is halogen atom, nitro, cyano, halogen _Optionally C _1-6 alkyl, C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono -C _1-6 alkylamino, di-C _1-6 alkylamino, C
_6-14 aryl, C _7-11 aralkyl, C _6-10 aryloxy, oxo, formyl, C _1-6 alkyl-carbonyl,
C _6-10 aryl-carbonyl, C _6-10 aryl-C _1-6
Alkyl-carbonyl, C _1-6 alkoxy-carbonyl, C _6-10 aryl-C _1-6 alkoxy-carbonyl,
C _1-6 alkylsulfonyl, C _1-6 alkyl is 1 to 3
C _6-10 arylsulfonyl optionally having
(I) each having 1 to 5 substituents selected from _6-10 aryl-C _1-6 alkylsulfonyl;
C _1-8 alkylene, (ii) C _2-8 alkenylene, (iii)
C _2-8 alkynylene or the formula (iv):-(CH ₂ ) p-M- (CH
₂ ) q- wherein p and q are each an integer of 0 to 8, p + q is an integer of 1 to 8, M is O, S, S
O, SO ₂ or NR ⁹ (R ⁹ is a hydrogen atom, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-14 aryl, C _7-11 aralkyl, formyl, C _1-6 alkyl-carbonyl, C
_6-10 aryl-carbonyl, C _6-10 aryl-C _1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl,
C _1-10 aryl-C _1-6 alkoxy-carbonyl, C _1-6
Alkylsulfonyl, C _6-10 arylsulfonyl optionally having 1 to 3 C _1-6 alkyl or C _{6-10
Represents} an aryl-C _1-6 alkylsulfonyl))
The compound according to claim 1, which is a group represented by the formula: (3) Za is a compound represented by the formula: The compound according to claim 1, wherein R ⁷ is a group represented by the formula (1). 4. The compound according to claim 1, wherein R ¹ and R ² are each a hydrogen atom. 5. The compound according to claim 1, wherein R ³ , R ⁴ and R ⁵ are each C _1-6 alkyl. 6. The compound according to claim 1, wherein R ⁶ is C _1-6 alkyl. 7. The compound according to claim 1, wherein Ar is C _6-14 aryl optionally having 1 to 3 substituents selected from a halogen atom, C _1-6 alkyl and C _1-6 alkoxy. . 8. The compound according to claim 1, wherein ring A is a 6-membered nitrogen-containing heterocyclic ring which may have a substituent. 9. The compound according to claim 1, wherein X is methylene. 10. The compound according to claim 1, wherein Y is CH. (11) Za is a compound represented by the formula: (Wherein each symbol has the same meaning as described in claim 1). 12. C _6-10 wherein R ⁷ may have a substituent.
The compound according to claim 1, which is aryl. 13. The compound according to claim 1, wherein R ¹⁰ is a hydrogen atom. 14. The compound according to claim 1, wherein Zb is a bond. 15. The compound according to claim 1, wherein m is 1. 16. R ¹ and R ² are each a hydrogen atom;
R ³ , R ⁴ , R ⁵ and R ⁶ are each C _1-6 alkyl; Ar
Is a phenyl optionally having 1 to 3 substituents selected from a halogen atom, C _1-6 alkyl and C _1-6 alkoxy; ring A is a 6-membered nitrogen-containing heterocycle; X is methylene; Y is CH Or N; Za is a compound of the formula: (Wherein R ⁷ ′ is a halogen atom, C _1-6 alkyl and C 7
Phenyl optionally having 1 to 3 substituents selected from _1-6 alkoxy, and R ¹⁰ ′ represents a hydrogen atom); Zb is substituted by a bond or C _6-10 aryl the compound of claim 1 wherein and m is 1 or 2; a a C _1-6 alkylene optionally be. 17. R ¹ and R ² are each a hydrogen atom;
R ³ , R ⁴ , R ⁵ and R ⁶ are each C _1-6 alkyl; Ar
Is a C _6-10 aryl _optionally substituted by methylenedioxy; ring A is a 6-membered nitrogen-containing heterocycle; X is methylene; Y is C
H or N; (Wherein, R ^7a represents a hydrogen atom or C _6-10 aryl)
A group represented by the formula: wherein Zb is (i) C _1-6 alkylene or (ii) C _2-6 alkenylene, each of which may be substituted with a bond or C _6-10 aryl; and m is 1. 2. The compound according to 1. 18. R ¹ and R ² are each a hydrogen atom;
R ³ , R ⁴ , R ⁵ and R ⁶ are each C _1-6 alkyl; Ar
Is a C _6-10 aryl optionally having 1 to 3 substituents selected from a halogen atom, methylenedioxy, C _1-6 alkyl and C _1-6 alkoxy; X is methylene; Y is CH or N; (Wherein R ^7b represents a C _6-10 aryl optionally substituted with a hydrogen atom or a halogen atom, and R ^10a represents a hydrogen atom or a C _7-11 aralkyl); or C _6-10 optionally substituted respectively with an aryl (i) C _1-6 alkylene, (ii) C _2-6 alkenylene or (iii) formula _{:-( CH 2) p'-M '} - (CH ₂ ) q'- (where p 'and q' are each an integer of 0 to 5, and p '
+ Q 'is an integer of 1 to 6, M' represents O or NH)
The compound according to claim 1, wherein m is 1 or 2. 20. 1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine; (-)-1-[(5-amino-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-
2-yl) methyl] -N- (diphenylmethyl) -4-
Piperidineamine, (+)-1-[(5-amino-2,
3-dihydro-2,4,6,7-tetramethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl)
-4-piperidineamine, 1-[(5-amino-2,3
-Dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (-)-1-
[(5-amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl) -4-piperidinamine, (+)-1- [(5-Amino-2,3-dihydro-7-isopropyl-2,4,6-trimethylbenzofuran-2-yl) methyl] -N- (diphenylmethyl)
The compound according to claim 1, which is -4-piperidineamine or a salt thereof. (20) Formula (i): [Wherein L is a leaving group, and other symbols are as defined in claim 1] or a salt thereof and a compound represented by the formula: (Wherein each symbol is as defined in claim 1) or a salt thereof, (ii) a compound represented by the following formula: Wherein each symbol is as defined in claim 1 or a salt thereof, (a) subject to an alkylation reaction, (b) subjecting to an acylation reaction, or (c) acylating Subjecting to a reaction and then to a reduction reaction, formula (iii): Wherein n is an integer of 1 to 4, and other symbols are as defined in claim 1. or a salt thereof and a compound represented by the formula: [Wherein, R ¹¹ is a hydrogen atom or a hydrocarbon group which may have a substituent, Zd may have a substituent, and may have a substituent via an oxygen atom, a nitrogen atom or a sulfur atom. A good divalent aliphatic hydrocarbon group, Ar has the same meaning as in claim 1] or a compound thereof, or a salt thereof. Wherein each symbol is as defined above, or a salt thereof, and a compound represented by the formula: Wherein each symbol is as defined above, or a salt thereof, and if necessary, subjecting the obtained compound to a reduction reaction; or (v) a compound represented by the formula: Wherein each symbol is as defined in claim 1, or a salt thereof is subjected to (a) nitration reaction,
2. The method for producing a compound according to claim 1, wherein the compound is subjected to a reduction reaction or (b) a diazo coupling reaction and then a reduction reaction. 21. A pharmaceutical composition comprising the compound according to claim 1. 22. The composition according to claim 21, wherein the pharmaceutical composition is a sodium channel modulator. 23. The composition according to claim 22, which is a preventive or therapeutic agent for ischemic central nervous system disorder, central injury, neurodegenerative disease or cerebral edema. 24. The formula: [In the formula, Q is a hydrogen atom, an aromatic group which may have a substituent or a formula -Zc-Ar (wherein Zc may have a substituent, and an oxygen atom, a nitrogen atom Or a divalent aliphatic hydrocarbon group which may be via a sulfur atom, Ar is a group represented by the same meaning as in claim 1), and the Aa ring may have a substituent. A sodium channel regulator comprising an 8-membered nitrogen-containing heterocycle or a benzolog fused ring thereof, and other symbols having the same meanings as defined in claim 1] or a salt thereof. 25. (S) -2,3-dihydro-2,4,
6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, 2,
3-dihydro-7-isopropyl-2,4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, (-)-2,3-dihydro-7-isopropyl- 2,4,6-trimethyl-2
-[(4-phenyl-1-piperidinyl) methyl] -5
-Benzofuranamine, (+)-2,3-dihydro-7
-Isopropyl-2,4,6-trimethyl-2-[(4
-Phenyl-1-piperidinyl) methyl] -5-benzofuranamine, 7-tert-butyl-2,3-dihydro-
2,4,6-trimethyl-2-[(4-phenyl-1-
Piperidinyl) methyl] -5-benzofuranamine,
(-)-7-tert-butyl-2,3-dihydro-2,
4,6-trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine, (+)
-7-tert-butyl-2,3-dihydro-2,4,6-
25. The regulator according to claim 24, comprising trimethyl-2-[(4-phenyl-1-piperidinyl) methyl] -5-benzofuranamine or a salt thereof.