JP2002037730A - Nerve growth factor action enhancer including 1,2-ethane diol derivative or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent for diseases caused by the degeneration of central nervous system. SOLUTION: 1,2-Ethane diol derivatives represented by the general formula (wherein individual signs have the same meanings as described in the specification) or their salts have the effect of enhancing the NGF action and are useful as a therapeutic agent for a variety of diseases caused by the degeneration of central nervous system, for example, senile dementia of Alzheimer type, Huntington's chorea, and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a nerve growth factor (Nerve
Growth Factor; hereinafter referred to as NGF. The present invention relates to a 1,2-ethanediol derivative or a salt thereof which enhances the action of (1).

[0002]

2. Description of the Related Art NGF has effects on the peripheral nervous system, such as maintaining survival of sympathetic nerve cells and sensory nerve cells, and elongating neurites [Physiol. Rev., Vol. 1284-1335 (1980);
Annual Review of Biochemistry (A
nn. Rev. Biochem.), Volume 51, pp. 845-868 (1982)
Year)], and large cell neuroprojection areas (hippocampus, neocortex,
High levels of NGF in the olfactory sense) and in the cell body regions of these nerves (septal area, broker diagonal band, basal ganglia of Meynert) and acting as neurotrophic factors for large cell cholinergic nerves [ The Embo Journal (EMBO J.), Vol. 4, pp. 1389-1393 (1985)] is known. N
GF is used for Alzheimer-type dementia [Scienc
e) Vol. 232, p. 1341 (1986)] and Huntington's chorea [Neurosci. Let
t.), Vol. 40, No. 2, pp. 161-164 (1992)] and various neuropathies ｛diabetic neuropathy [Brain Research (Brain Res.), 634,
7-12 (1994)], Drug-induced neuropathy [Brain Res., 640, 195]
-204 (1994)], etc., and Riley-Day Syndrome [Japanese Clinic, 50, 4, 178-183 (1992)
Year)], traumatic neuropathy [Pharmacol Ther., Vol. 65, No. 1, pp. 1-16 (199)
5 years)], amyotrophic lateral sclerosis (ALS) [Nature
Medicine (Nature Medicine), Vol. 1, No. 2, 168
-P.172 (1995)] and attention has been paid to the relationship with peripheral nerve diseases.

[0003]

Attempts have been made to use NGF or a substance having an NGF-like action for the treatment of the above-mentioned diseases of the central nervous system and peripheral nerves [brain and nerves, Vol. 43, No. 12]. No. 1101-1112 (1991) etc.].
However, all of these substances are proteins, and when used as medicines, there are problems in stability, antigenicity and the like. Therefore, a compound useful as a medicament for enhancing the action of NGF is required.

[0004]

In such a situation,
The present inventors have conducted intensive studies and found that the following general formula

Embedded image

Wherein R ¹ is an optionally substituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group; R ² is a hydrogen atom or a lower alkyl or hydroxyl protecting group; R
³ is a hydrogen atom or a lower alkyl group; n R ⁴ are
Same or different hydrogen atom or lower alkyl group;
n R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group; R ⁶ is an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n is 0 or 1 to An integer of 6 is shown. A 1,2-ethanediol derivative or a salt thereof,
The inventors have found that the action of nerve growth factor is enhanced, and have completed the present invention.

Hereinafter, the present invention will be described in detail. In this specification, unless otherwise specified, each term has the following meaning. A halogen atom is a fluorine atom, a chlorine atom,
A lower alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl,
a C _1-6 alkyl group such as n-butyl, isobutyl, tert-butyl, pentyl and hexyl group; a lower alkenyl group is a C _2-6 alkenyl group such as vinyl, propenyl, butenyl, pentenyl and hexenyl group. A lower alkenyloxy group is C _2-6 alkenyl-
The cycloalkyl group, for example, cyclopropyl, cyclobutyl, C _3-6 cycloalkyl groups such as cyclopentyl and cyclohexyl; an O- group and the lower alkoxy group, a C _1-6 alkyl -O- group; A lower alkylthio group is a C _1-6 alkyl-S- group; a halo-lower alkyl group is a halogen-C _1-6 alkyl group; an aryl group is a phenyl, naphthyl, indanyl and indenyl group; An aryloxy group is an aryl O- group; an ar-lower alkyl group is, for example, an ar-C _1-4 alkyl group such as benzyl, diphenylmethyl, trityl and phenethyl groups; and an ar-lower alkoxy group is _1-4 alkyl -O- group; the ar (lower) alkylthio group, Al C _1-4 alkyl -S- group; the ar (lower) alkenyl group, Al C _2-4 alkenyl A lower alkylenedioxy group, for example, a C _1-4 alkylenedioxy group such as a methylenedioxy and ethylenedioxy group; a lower acyl group, for example, a formyl, acetyl, and butyryl group; the C _1-6 acyl group; and aroyl group, an aryl -CO- group; lower alkylsulfonyl group, C _1-6 alkyl -SO ₂ - groups and; the ar (lower) alkylsulfonyl group, Al C _{1 -6} alkyl-SO ₂ -group; arylsulfonyl group is aryl-SO ₂ -group; arylsulfonylamino group is aryl-SO
_A lower alkylsulfonylamino group;
The C _{1 -6} alkyl -SO ₂ NH- group; and di-lower alkylamino group, for example, dimethylamino, (C _1-6 alkyl) and ₂ N- group such as a diethylamino group; and ammonio groups include, for example, Tri-lower alkylammonio groups such as trimethylammonio and triethylammonio groups;

The nitrogen-containing heterocyclic group includes, for example, pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl,
One of the heteroatoms forming the ring such as quinolyl, quinolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, prenyl and indazolyl groups. A 5- or 6-membered ring, a condensed ring or a bridged ring heterocyclic group which contains the above nitrogen atom and may further contain one or more oxygen atoms or sulfur atoms; The above-mentioned nitrogen-containing heterocyclic groups and, for example, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxali 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl, imidazo [2, 3-
a) pyridyl, benzo [b] piperazinyl, chromenyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, isoindolyl and isoquinolyl groups, which contain one or more oxygen or sulfur atoms as hetero atoms forming the ring. A 5- or 6-membered, fused or bridged heterocyclic group containing at least one heteroatom atom selected from nitrogen, oxygen or sulfur atoms; and a heterocyclic carbonyl group , A heterocyclic -CO- group.

Examples of the substituent of phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl and a heterocyclic group in R ¹ include a halogen atom, an optionally substituted amino, a lower alkyl, an aryl, an ar-lower alkyl and a lower alkyl. Alkoxy, lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, lower alkylthio, lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic groups or protected Amino groups, optionally protected hydroxyl groups, nitro groups, oxo groups and lower alkylenedioxy groups.

Phenyl, naphthyl, indanyl for R ¹ ,
Lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy, aryloxy, carbamoyloxy, lower alkyl thio, lower alkenyl, lower alkenyl, lower alkenyl oxy, ar lower alkyl thio, al As the substituent for the lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic group and the nitrogen-containing heterocyclic group for R ⁶ , a halogen atom, an optionally protected hydroxyl group, A carboxyl group which may be protected, an amino group which may be protected, a lower alkyl group which may be substituted by an optionally protected hydroxyl group, an aryl group which may be substituted by halogen, Optionally substituted aroyl group, lower alkoxy group optionally substituted by lower alkoxy group, halo-lower alkyl group, lower acyl group, ar-lower alkyl group, ar-lower alkenyl group, heterocyclic group, heterocyclic group Examples include a carbonyl group, an oxo group, a lower alkylsulfonyl group and an arylsulfonyl group, which may be substituted with one or more substituents.

The amino group of the substituent for R ¹ and the amino group for R ⁶ may be substituted with an optionally protected hydroxyl group, an optionally protected hydroxy group or an optionally protected carboxyl group. Optionally substituted lower alkyl group, cycloalkyl group, aryl group, lower acyl group, ar-lower alkyl group, heterocyclic group, heterocyclic carbonyl group optionally substituted by oxo group, adamantyl group, lower alkyl Examples include a sulfonyl group and an arylsulfonyl group, which may be substituted with one or more substituents.

The hydroxyl protecting group and the protecting group for the hydroxyl group, the carboxyl group and the amino group in the substituent of R ² include Protective Groups in Organic Synthesis.
Organic Synthesis), [Theodra W. Greene (1981), John Wiley and Sons Inc.]
& Sons. Inc.)]
Protecting groups for carboxyl and amino groups, and especially protecting groups for hydroxyl group include, for example, lower alkyl, lower acyl, tetra-lower alkyl groups such as tetrahydropyranyl and optionally substituted benzyl. Can be

The salt of the 1,2-ethanediol derivative of the general formula [I] may be a pharmaceutically acceptable salt, for example, a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Salts with carboxylic acids such as formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid and aspartic acid; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid And salts with sulfonic acids and salts with alkali metals such as sodium and potassium.

When isomers (for example, optical isomers, geometric isomers and tautomers) exist in the 1,2-ethanediol derivative of the general formula [I] or a salt thereof, the present invention It includes all isomers and includes hydrates, solvates and all crystalline forms.

The 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be prepared by a conventional method using a pharmaceutically acceptable excipient, carrier and diluent. Preparations such as preparations, powders, granules, fine granules, pills, suspensions, emulsions, solutions, syrups and injections can be administered orally or parenterally. Also,
The administration method, dosage and number of administrations can be appropriately selected according to the age, weight and condition of the patient, but in the case of oral administration, usually 0.01 to 500 mg per day is divided into one to several times for an adult. It may be administered.

Next, a method for producing the 1,2-ethanediol derivative of the general formula [I] or a salt thereof will be described. The 1,2-ethanediol derivative of the general formula [I] or a salt thereof is disclosed in JP-A-3-47158 and JP-A-3-197.
No. 422, JP-A-3-232830 or JP-A-4-95070, or a method known per se or an appropriate combination thereof, for example, can be produced by the following production methods. it can.

[0016]

(Equation 1)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and n have the same meaning as described above, and * represents
X ¹ and X ² represent a halogen atom. "

Production Method 1 (1) A compound of the general formula [IV] or a salt thereof can be produced by reacting a compound of the general formula [II] with a compound of the general formula [III]. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene and toluene. These solvents may be used alone or in combination of two or more. In this reaction, the compound of the general formula [III] is used in an amount of 0.8 to 100 moles, preferably 0.8 to 10 moles, per mole of the compound of the general formula [II]. This reaction is usually carried out at -78 ° C to + 100 ° C, preferably -78 ° C to + 50 ° C.
Then, it may be carried out for 5 minutes to 24 hours. The obtained general formula [I
The compound [V] or a salt thereof may be used in the next reaction without isolation. The compound of the general formula [III] used here can be prepared by a method known per se, for example, Brettin de la Societe Simic de France (BuBu)
ll. Soc. Chim. Fr.), 1967 (5), pages 1533-1540.

(2) A compound of the general formula [IV] or a salt thereof is reacted with a compound of the general formula [V] or a salt thereof in the presence or absence of a catalyst and in the presence or absence of a base. Thereby, the compound of the general formula [I] or a salt thereof can be produced. The solvent used in this reaction may be any solvent which does not adversely affect the reaction, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane; ethanol, propanol and butanol. Alcohols; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; and water. These solvents may be used alone or in combination of two or more. Also,
Examples of the catalyst used as needed include potassium iodide and sodium iodide.
The amount of the catalyst used as needed is determined by the general formula [IV]
Is 0.1 to 1-fold the molar amount of the compound or a salt thereof.
Examples of the base used as needed include, for example, triethylamine, diisopropylethylamine,
1,8-diazabicyclo- [5.4.0] undec-7-
Ene (DBU), pyridine, potassium tert-butoxide,
Organic or inorganic bases such as sodium carbonate, potassium carbonate and sodium hydride are mentioned, and the compound of the formula [V] or a salt thereof can also be used as the base. The amount of the compound of the general formula [V] or a salt thereof or the base used if necessary is at least equimolar to the compound of the general formula [IV] or a salt thereof, respectively.
Preferably, it is 1 to 20 moles. This reaction is usually 10
It may be carried out at -150 ° C, preferably 20-100 ° C for 10 minutes to 20 hours. The compounds or bases used in each of the above production methods can also be used as a solvent depending on their properties.

The general formula [II] in the above-mentioned production method,
When isomers (for example, optical isomers, geometric isomers and tautomers) exist in the compounds of [III], [IV] and [V], all of these isomers can be used. Also, hydrates, solvates and all crystalline forms can be used. General formulas [II], [II
Compounds having a hydroxyl group, an amino group or a carboxyl group in the compounds of [I], [IV] and [V]
These hydroxyl group, amino group or carboxyl group are protected with a usual protecting group in advance, and after the reaction,
If necessary, these protecting groups can be eliminated by a method known per se.

Production method 2 (1) A compound of the general formula [IV] is prepared by a method known per se, for example, Modern Synthetic Reactions 2nd edition (Mode
rn Synthetic Reactions Second Edition), [Herbert O. House (1972), WA
Benjamin Incorporated (WA Benjamin,
Inc)], to produce a compound of the general formula [VI] or a salt thereof. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene and toluene. , These solvents
Species or a mixture of two or more kinds may be used. The obtained compound of the general formula [VI] or a salt thereof may be used for the next reaction without isolation.

(2) Compounds of general formula [VI] can be prepared in a manner known per se in the presence or absence of a catalyst and in the presence or absence of a base, for example, by the method known in the art, for example, Tetrahedron Letters, Vol. The compound of general formula [IVa] or a salt thereof can be produced by reduction according to the method described in, for example, No. 29, p. 4102.

(3) Similar to the production method 1 (2), the compound represented by the general formula [IV]
a) is reacted with a compound of the general formula [V] or a salt thereof in the presence or absence of a catalyst and in the presence or absence of a base to give a compound of the general formula [I] A compound or a salt thereof can be produced.
The thus obtained 1,2-ethanediol derivative of the general formula [I] or a salt thereof can be isolated and purified by a usual method such as extraction, crystallization, distillation and column chromatography. In addition, 1, of the general formula [I],
A 2-ethanediol derivative or a salt thereof is, for example,
By appropriately combining known methods such as an oxidation reaction, a reduction reaction, an addition reaction, an acylation reaction, an alkylation reaction, a sulfonylation reaction, a deacylation reaction, a substitution reaction, a dehydration reaction and a hydrolysis reaction, other general formulas It can be derived into a 1,2-ethanediol derivative of [I] or a salt thereof.

[0024]

Now, the production method of the compound of the present invention will be specifically described with reference examples and production examples. The mixing ratios of the solvents are all volume ratios, and the carrier in column chromatography is silica gel (70 to 230 mesh) [Merck]
And the carrier in medium pressure column chromatography is LC S
orb SP-A-Si (manufactured by Chemco) was used. The compound of the general formula [II], which is a raw material for producing the compound of the present invention, is known per se or can be produced by a method known per se or an appropriate combination thereof, for example, according to each of the reference examples shown below. Can be.

Reference Example 1 (1) 25.0 g of 3-fluoro-4-methylaniline was added to water 250
Suspend the mixture in 3 ml, add 34.7 ml of concentrated hydrochloric acid, and cool to 5 ° C. To this solution was added a solution of 15.2 g of sodium nitrite in 20 ml of water for 5 to 10
Add dropwise over 1 hour at ° C. The obtained reaction solution is heated at 50-60 ° C.
Is added dropwise over 1 hour to a solution of 64.0 g of potassium O-ethyl dithiocarbonate in 200 ml of water. After cooling the reaction solution to room temperature, 300 ml of ethyl acetate is added, and the organic layer is separated. The obtained organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. As a result, brown oily O-ethyl dithiocarbonate S- (3-fluoro-4-methyl) is obtained. Obtain phenyl.

(2) O-ethyl dithiocarbonate S- (3-
To a solution of (fluoro-4-methyl) phenyl in 150 ml of methanol was added 22.4 g of potassium hydroxide at room temperature under a nitrogen atmosphere,
After stirring at room temperature for 5 hours, 34.8 ml of bromoacetaldehyde diethyl acetal is added, and the mixture is refluxed for 6 hours. After cooling, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. 300 ml of water and 150 ml of ethyl acetate are added to the obtained residue, the organic layer is separated, washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give an oily 1,1-diethoxy-2.
-(3-Fluoro-4-methylphenylthio) ethane 43.
Get 6g. NMR (CDCl ₃ ) δ value: 1.19 (6H, t, J = 7.0 Hz), 2.22 (3H, d, J = 2.0H)
z), 3.09 (2H, d, J = 5.4Hz), 3.58 (2H, q, J = 7.0Hz), 3.63 (2H,
q, J = 7.0Hz), 4.63 (1H, t, J = 5.4Hz), 6.9-7.3 (3H, m)

(3) 1,1-Diethoxy-2- (3-fluoro-4-methylphenylthio) ethane 43.6 g of toluene
80 ml of 85% phosphoric acid is added to the 400 ml solution and refluxed for 2.5 hours using an azeotropic dehydrator. After cooling, 600 ml of water and 200 ml of ethyl acetate are added to the reaction solution, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.
The obtained residue is subjected to column chromatography [eluent;
Hexane] to give 4-fluoro-5 as a colorless solid.
-Methyl-benzo [b] thiophene and 6-fluoro-5
15.9 g of a mixture of -methyl-benzo [b] thiophene are obtained.

(4) To a solution of 15.9 g of a mixture of 4-fluoro-5-methyl-benzo [b] thiophene and 6-fluoro-5-methyl-benzo [b] thiophene in 160 ml of carbon tetrachloride was added 17 g of N-bromosuccinimide. After adding 0.31 g of 2,2′-azobis (isobutyronitrile) and refluxing for 2 hours. After cooling, the insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue obtained is suspended in 75 ml of acetic acid and 75 ml of water,
After adding 26.8 g of hexamethylenetetramine, the mixture is refluxed for 2 hours. After cooling, 150 ml of water and 200 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue is subjected to medium pressure column chromatography.
Purify with [eluent: hexane: ethyl acetate = 15: 1] to obtain 4
1.71 g of -fluorobenzo [b] thiophen-5-carbaldehyde and 5.82 g of 6-fluorobenzo [b] thiophen-5-carbaldehyde are obtained.

The properties of each compound are as follows. 4-fluorobenzo [b] thiophene-5-carbaldehyde IR (KBr) cm ^-1 : 1684 NMR (CDCl ₃ ) δ value: 7.5-8.1 (4H, m), 10.55 (1H, s) 6-fluoro Benzo [b] thiophen-5-carbaldehyde IR (KBr) cm ^-1 : 1684 NMR (CDCl ₃ ) δ value: 7.3-7.6 (2H, m), 7.67 (1H, d, J = 10.3Hz),
8.34, (1H, d, J = 6.4Hz), 10.46 (1H, s)

Similarly, the following compound is obtained. 7-fluorobenzo [b] thiophene-5-carbaldehyde IR (KBr) cm ^-1 : 1678 NMR (CDCl ₃ ) δ value: 7.2-7.8 (3H, m), 8.16 (1H, s), 10.60 (1H ,
s) · 4-bromobenzo [b] thiophene-5-carbaldehyde ^{IR (KBr) cm -1: 1674} NMR (CDCl 3) δ value: 7.1-8.0 (4H, m), 10.54 (1H, s) · 6- Bromobenzo [b] thiophene-5-carbaldehyde IR (KBr) cm ^-1 : 1681 NMR (CDCl ₃ ) δ value: 7.3-7.6 (2H, m), 8.18 (1H, s), 8.41 (1H,
s), 10.51 (1H, s ) · 4- chlorobenzo [b] thiophene-5-carbaldehyde ^{IR (KBr) cm -1: 1678} NMR (CDCl 3) δ value: 7.3-8.2 (4H, m), 10.66 ( 1H, s) · 6- chlorobenzo [b] thiophene-5-carbaldehyde ^{IR (KBr) cm -1: 1678} NMR (CDCl 3) δ value: 7.2-7.7 (2H, m), 7.98 (1H, s), 8.42 (1H, s)
10.60 (1H, s)

Reference Example 2 (1) Benzo [b] thiophen-5-carbaldehyde
20 ml of ethylene glycol and a catalytic amount of p-toluenesulfonic acid are added to a solution of 5 g of benzene in 100 ml, and the mixture is refluxed for 2 hours using an azeotropic dehydrator. After cooling, 200 ml of water and 100 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is purified by medium pressure column chromatography [eluent: hexane: ethyl acetate = 10: 1] to give a colorless solid.
6.12 g of-(1,3-dioxolan-2-yl) benzo [b] thiophene are obtained. NMR (CDCl ₃ ) δ value: 3.9-4.3 (4H, m), 5.94 (1H, s), 7.2-7.6 (3
H, m), 7.7-8.1 (2H, m)

(2) 5- (1,3-dioxolan-2-
Ill) After cooling a solution of 1.5 g of benzo [b] thiophene in 15 ml of tetrahydrofuran to -40 ° C, 4.55 ml of a 1.6 M n-butyllithium hexane solution is added dropwise at the same temperature. The reaction solution was
After the temperature was raised to 10 ° C, the mixture was cooled again to -40 ° C, and 0.45 ml of methyl iodide was added. After warming to room temperature, 30 ml of water and 30 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue was purified by medium pressure column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give 2-colorless solid.
1.45 g of methyl-5- (1,3-dioxolan-2-yl) benzo [b] thiophene are obtained. NMR (CDCl ₃ ) δ value: 2.55 (3H, s), 3.9-4.3 (4H, m), 5.89 (1H,
s), 6.9-8.0 (4H, m)

(3) A catalytic amount of p-toluenesulfonic acid was added to a solution of 1.5 g of 2-methyl-5- (1,3-dioxolan-2-yl) benzo [b] thiophene in 20 ml of acetone at room temperature. Stir at temperature for 30 minutes. After the reaction, the residue obtained by evaporating the solvent under reduced pressure was added with 20 ml of water and 20 ml of ethyl acetate.
And the organic layer is separated. The obtained organic layer is washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure to give 2-methylbenzo [b] thiophene-5-carbaldehyde as a colorless solid. 1.
Get 15g. IR (KBr) cm ^-1 : 1694 NMR (CDCl ₃ ) δ value: 2.60 (3H, s), 5.89 (1H, s), 7.0-8.4 (4H,
m), 10.10 (1H, s)

Reference Example 3 (1) Benzo [b] thiophene-5-carbaldehyde
1.43 ml of bromine is added dropwise to a solution of 3 g of acetic acid in 30 ml under ice-cooling. After the temperature of the reaction solution is raised to room temperature, the mixture is stirred at the same temperature for 3 hours.
After the reaction, 50 ml of water and 50 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is subjected to medium pressure column chromatography [eluent;
Purification with hexane: ethyl acetate = 20: 1] gives 4.2 g of 3-bromobenzo [b] thiophene-5-carbaldehyde. NMR (CDCl ₃ ) δ value: 7.5-8.4 (4H, m), 10.19 (1H, s)

(2) 3-bromobenzo [b] thiophen-5-carbaldehyde was used instead of benzo [b] thiophen-5-carbaldehyde, and 3-bromo-5-carboxyaldehyde was used in the same manner as in Reference Example 2 (1). (1,3-dioxolane-
2-yl) benzo [b] thiophene is obtained. NMR (CDCl ₃ ) δ value: 3.9-4.2 (4H, m), 5.93 (1H, s), 7.3-8.0 (4
H, m)

(3) 5- (1,3-dioxolan-2-
Yl) 3-bromo- in place of benzo [b] thiophene
5- (1,3-dioxolan-2-yl) benzo [b]
Using thiophene as diethyl ether instead of tetrahydrofuran, 3-methylbenzo [b] thiophene-5-carbaldehyde is obtained in the same manner as in Reference Example 2 (2). NMR (CDCl ₃ ) δ value: 2.51 (3H, s), 7.0-8.4 (4H, m), 10.15 (1H,
s)

Reference Example 4 N-fluorobenzenesulfonimide was used in place of methyl iodide, and 5- (1,3-dioxolan-2-yl) was prepared in the same manner as in Reference Examples 2 (2) and 2 (3). ) 2-Fluorobenzo [b] thiophene-5-carbaldehyde is obtained from benzo [b] thiophene. NMR (CDCl ₃ ) δ value: 6.84 (1 H, d, J = 2.0 Hz), 7.6-8.4 (3 H, m), 1
0.09 (1H, s)

Reference Example 5 5- (1,3-dioxolan-2-yl) benzo [b]
3-bromo-5- (1,3-dioxolan-2-yl) benzo [b] thiophene in place of thiophene, diethyl ether in place of tetrahydrofuran and N-fluorobenzenesulfonimide in place of methyl iodide 3-bromo-5- (1,3-dioxolan-2-yl) benzo [b] thiophene was converted to 3-fluorobenzo [b] thiophene- like in Reference Example 2 (2) and Reference Example 2 (3). This gives 5-carbaldehyde. NMR (CDCl ₃ ) δ value: 6.99 (1H, d, J = 2.0 Hz), 7.7-8.4 (3H, m), 1
0.14 (1H, s)

REFERENCE EXAMPLE 6 (1) To a solution of 2.0 g of 5- (1,3-dioxolan-2-yl) benzo [b] thiophene in 15 ml of tetrahydrofuran at -78 ° C. was added 6.06 ml of a 1.6 M solution of n-butyllithium in hexane.
Is dropped. After the temperature of the reaction solution was raised to -10 ° C,
Cool to ° C. and add 1.55 g of bromine. After warming to room temperature, water 3
0 ml and 30 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue is subjected to medium pressure column chromatography.
Purification with [eluent: toluene] gives 2.45 g of 2-bromo-5- (1,3-dioxolan-2-yl) benzo [b] thiophene as a colorless solid. NMR (CDCl ₃ ) δ value: 3.9-4.3 (4H, m), 5.89 (1H, s), 7.2-8.0 (4
H, m)

(2) To a solution of 2.5 g of 2-bromo-5- (1,3-dioxolan-2-yl) benzo [b] thiophene in 50 ml of toluene, 6.44 g of phenyltri-n-butyltin and tetrakis (triphenylphosphine) palladium were added. (0) Add 0.05 g and reflux for 5 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, 30 ml of water and 30 ml of ethyl acetate were added.
After adding the ml and removing the insoluble matter from the furnace, the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.
The obtained residue is subjected to column chromatography [eluent;
Hexane: ethyl acetate = 20: 1] gives 1.20 g of 2-phenyl-5- (1,3-dioxolan-2-yl) benzo [b] thiophene as a colorless solid.

(3) Reference Example 2 In the same manner as in Example (3), 2-phenylbenzo [b] thiophen-5- was converted from 2-phenyl-5- (1,3-dioxolan-2-yl) benzo [b] thiophene. Obtain carbaldehyde. ^{IR (KBr) cm -1: 1692} NMR (CDCl 3) δ value: 7.2-8.4 (9H, m), 10.13 (1H, s)

Similarly, the following compound is obtained. Obtaining 3-phenylbenzo [b] thiophene-5-carbaldehyde; IR (KBr) cm ^-1 : 1686 NMR (CDCl ₃ ) δ value: 7.3-8.1 (8H, m), 8.37 (1H, m), 10.09 (1H,
s)

Reference Example 7 (1) 4 in place of 3-fluoro-4-methylaniline
Reference Example 1 using methyl-amino-2-methylbenzoate
4- (2,2) in the same manner as in (1) and Reference Example 1 (2).
-Diethoxyethylthio) -2-methyl benzoate is obtained. NMR (CDCl ₃ ) δ value: 1.20 (6H, t, J = 7.0 Hz), 2.57 (3H, s), 3.18
(2H, d, J = 5.4Hz), 3.3-3.8 (4H, m), 3.86 (3H, s), 4.67 (1H, t,
J = 5.4Hz), 7.0-7.3 (2H, m), 7.7-7.9 (1H, m)

(2) 4 instead of 1,1-diethoxy-2- (3-fluoro-4-methylphenylthio) ethane
Using methyl-(2,2-diethoxyethylthio) -2-methylbenzoate, methyl 4-methylbenzo [b] thiophen-5-carboxylate and 6-methylbenzo [b were used in the same manner as in Reference Example 1 (3). To obtain a mixture of methyl thiophene-5-carboxylate.

(3) 0.37 g of lithium aluminum hydride
Was suspended in 20 ml of tetrahydrofuran, and then suspended under ice-cooling.
A solution of 2 g of a mixture of methyl methylbenzo [b] thiophen-5-carboxylate and methyl 6-methylbenzo [b] thiophen-5-carboxylate in 20 ml of tetrahydrofuran is added dropwise. After the temperature was raised to room temperature, 30 ml of water and 30 ml of ethyl acetate were added, followed by filtration, and the organic layer was separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography [eluent: hexane: ethyl acetate = 10: 1] to obtain colorless solids of 4-methylbenzo [b] thiophene-5-methanol and 6-methylbenzo [b] thiophene-5. 1.7 g of a mixture of methanol are obtained.

(4) 1.7 g of a mixture of 4-methylbenzo [b] thiophen-5-methanol and 6-methylbenzo [b] thiophen-5-methanol was dissolved in 17 ml of chloroform, and 4.1 g of manganese dioxide was added at room temperature for 1 hour. Reflux. After the reaction, insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue was purified by medium pressure column chromatography [eluent; hexane: toluene = 1: 1] to give 0.65 g of colorless solid 4-methylbenzo [b] thiophene-5-carbaldehyde and 6-colorless solid 6-methylbenzene. Methyl benzo [b]
0.48 g of thiophene-5-carbaldehyde is obtained. The properties of each compound are as follows. 4-methylbenzo [b] thiophene-5-carbaldehyde IR (KBr) cm ^-1 : 1673 NMR (CDCl ₃ ) δ value: 2.95 (3H, s), 7.5-7.9 (4H, m), 10.50 (1H,
s) 6-methylbenzo [b] thiophene-5-carbaldehyde IR (KBr) cm ^-1 : 1696 NMR (CDCl ₃ ) δ value: 2.77 (3H, s), 7.2-7.6 (2H, m), 7.75 ( 1H,
s), 8.26 (1H, s), 10.35 (1H, s)

Reference Example 8 In the same manner as in Reference Example 6, 6-methoxybenzo [b] thiophen-5-carbaldehyde is obtained from 4-amino-2-methoxybenzoic acid. NMR (CDCl ₃₎ δ value: 3.99 (3H, s), 7.33 (2H, m), 7.42 (1H, s), 8.
28 (1H, s), 10.56 (1H, s)

REFERENCE EXAMPLE 9 (1) To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran was added dropwise at −20 ° C. 9.19 ml of a 1.6 M n-butyllithium n-hexane solution. After stirring at the same temperature for 1 hour, -7
After cooling to 0 ° C., a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is added dropwise at the same temperature over 30 minutes. After the temperature of the reaction solution was raised to -40 ° C, it was cooled again to -70 ° C, and 0.97 ml of methyl iodide was added at the same temperature. After warming to room temperature, 80 ml of water and 80 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to give 4-bromo-2,6-difluorotoluene as a colorless oil.
1.98 g are obtained. NMR (CDCl ₃ ) δ value: 2.23 (3H, t, J = 1.5 Hz), 7.00 (2H, d, J = 6.3 H
z)

(2) A solution of 1.98 g of 4-bromo-2,6-difluorotoluene in 20 ml of tetrahydrofuran at -70 ° C.
5.7 ml of 1.6 M n-butyllithium n-hexane solution is added dropwise. After stirring for 1 hour at the same temperature, 2,2,2 ', 2'-
A solution of 2.88 g of tetraethoxydiethyldisulfide in 5 ml of tetrahydrofuran is added dropwise. After heating to room temperature, water 80m
l and 80 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 20: 1] to give 1,1-diethoxy-2- (3,5-difluoro-4) as a colorless oil.
2.1 g of -methylphenylthio) ethane are obtained. NMR (CDCl ₃ ) δ value: 1.20 (3H, t, J = 7.0 Hz), 1.23 (3H, t, J = 7.2H)
z), 2.1 (3H, t, J = 1.7Hz), 3.10 (2H, d, J = 5.6Hz), 3.4-3.9 (4
H, m), 4.64 (1H, t, J = 5.6Hz), 6.87 (2H, d, J = 7.6Hz)

(3) Instead of 1,1-diethoxy-2- (3-fluoro-4-methylphenylthio) ethane, 1,1-diethoxy-2- (3,5-difluoro-4-methylphenylthio) Using ethane, 4,6-difluoro-5-methylbenzo [b] in the same manner as in Reference Example 1 (3)
Obtain thiophene. NMR (CDCl ₃ ) δ value: 2.31 (3H, t, J = 1.9 Hz), 7.2-7.5 (3H, m)

(4) A solution of 0.48 g of 4,6-difluoro-5-methylbenzo [b] thiophene in 5 ml of carbon tetrachloride,
After adding 0.92 g of N-bromosuccinimide and 0.01 g of 2,2'-azobis (isobutyronitrile), the mixture is refluxed for 16 hours. After cooling, the insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by column chromatography [eluent: hexane] to give 0.18 g of 5-bromomethyl-4,6-difluorobenzo [b] thiophene as a colorless solid. NMR (CDCl ₃ ) δ value: 4.67 (2H, t, J = 1.2 Hz), 7.2-7.5 (3H, m)

(5) 0.23 g of potassium acetate was added to a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzo [b] thiophene in 5 ml of N, N-dimethylformamide, and the solution was added at 60 ° C. for 1 hour.
Stir for hours. After cooling to room temperature, 10 ml of water and 10 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer was washed successively with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to give a colorless oil.
-Acetoxymethyl-4,6-difluorobenzo [b]
0.14 g of thiophene is obtained. NMR (CDCl ₃ ) δ value: 2.07 (3H, S), 5.31 (2H, t, J = 1.2 Hz), 7.3-
7.6 (3H, m)

(6) 0.14 g of 5-acetoxymethyl-4,6-difluorobenzo [b] thiophene in 5 ml of methanol
After adding 0.03 g of potassium hydroxide to the solution at room temperature, the mixture is stirred at the same temperature for 30 minutes. After the reaction, water 10 ml and ethyl acetate 10 ml
And the organic layer is separated. The obtained organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove colorless oily 5-hydroxymethyl-4,6-difluorobenzo [b. 0.12 g of thiophene is obtained. NMR (CDCl ₃ ) δ value: 4.88 (2H, bs), 7.2-7.6 (3H, m)

(7) To a solution of 0.22 ml of oxalyl chloride in 10 ml of methylene chloride was added -0.35 ml of dimethyl sulfoxide at -78 ° C, followed by a solution of 0.20 g of 5-hydroxymethyl-4,6-difluorobenzo [b] thiophene in 3 ml of methylene chloride. Is dropped. After stirring at the same temperature for 1 hour, triethylamine
Add 0.70 ml. After warming to room temperature, 10 ml of water and 10 ml of ethyl acetate are added, and the organic layer is separated. The obtained organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography [eluent: hexane]. Purification yields 0.20 g of 4,6-difluorobenzo [b] thiophene-5-carbaldehyde as a colorless solid. IR (KBr) cm ^-1 : 1696 NMR (CDCl ₃ ) δ value: 7.4-7.6 (3H, m), 10.49 (1H, s)

Production Example 1 (1) To a solution of 1.6 g of 6-fluorobenzo [b] thiophene-5-carbaldehyde in 30 ml of tetrahydrofuran was added
10 ml of a 1.6 M solution of 2-chloroethoxymethylmagnesium chloride in tetrahydrofuran is added dropwise at 30 ° C. over 10 minutes, and the resulting mixture is stirred under ice-cooling for 1 hour. The reaction mixture was then introduced into a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 2 g of ammonium chloride, and p
After adjusting to H2, the mixture is stirred at the same temperature for 5 minutes. Next, the reaction mixture is adjusted to pH 6 with a saturated aqueous solution of sodium hydrogen carbonate, and then the organic layer is separated. The separated organic layer is sequentially washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 4: 1) to give oily 2- (2-chloroethoxy) -1- ( 1.3 g of 6-fluorobenzo [b] thiophen-5-yl) ethanol are obtained.

(2) 2- (2-chloroethoxy) -1-
A mixture of 0.61 g of (6-fluorobenzo [b] thiophen-5-yl) ethanol, 3 ml of a 50% aqueous solution of diethylamine, 0.45 mg of potassium iodide and 20 ml of ethanol is refluxed for 3 hours. Then, 3 ml of a 50% aqueous solution of diethylamine is added to the reaction mixture, and the resulting mixture is refluxed for another 3 hours. The solvent is distilled off under reduced pressure, 30 ml of ethyl acetate and 30 ml of water are added to the obtained residue, the pH is adjusted to 1.5 with 6N hydrochloric acid, and the aqueous layer is separated. The separated aqueous layer was washed with 10 ml of ethyl acetate, 30 ml of ethyl acetate was added, and the pH was adjusted to 10.5 with potassium carbonate.
After adjusting to, the organic layer is separated. The separated organic layer is washed with water
After washing sequentially with 10 ml and 10 ml of a saturated saline solution, it is dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 6 ml of ethanol.
0.6 ml of N-dry hydrogen chloride-ethanol solution and 6 ml of diethyl ether are added, and the resulting mixture is stirred at room temperature for 1 hour. The precipitated crystals are collected by filtration, washed with 2 ml of a mixture of diethyl ether-ethanol (1: 1), and dried to give 2-
[2- (N, N-diethylamino) ethoxy] -1-
0.28 g of the hydrochloride of (6-fluorobenzo [b] thiophen-5-yl) ethanol is obtained. Melting point: 125-126 ° C NMR (DMSO-d ₆ ) δ value: 1.18 (6H, t, J = 7.3 Hz), 2.9-4.0 (10H,
m), 5.0-5.4 (1H, m), 5.6-5.8 (1H, m), 7.4-8.2 (4H, m)

Similarly, the following compound is obtained.・ 2- [2- (N, N-diethylamino) ethoxy]-
Hydrochloride of 1- (4-fluorobenzo [b] thiophen-5-yl) ethanol Melting point: 127-128 ° C NMR (DMSO-d ₆ ) δ value: 1.18 (6H, t, J = 7.3 Hz), 2.9- 4.1 (10H,
m), 5.1-5.4 (1H, m), 5.6-5.8 (1H, m), 7.4-8.0 (4H, m) -2- [2- (N, N-diethylamino) ethoxy]-
1- (7-Fluorobenzo [b] thiophen-5-yl) ethanol hydrochloride Melting point: 119-120 ° C NMR (DMSO-d ₆ ) δ value: 1.15 (6H, t, J = 7.3 Hz), 2.8- 4.0 (10H,
m), 4.7-5.1 (1H, m), 5.6-5.9 (1H, m), 7.1-8.0 (4H, m) -2- [2- (N, N-diethylamino) ethoxy]-
1- (2-Fluorobenzo [b] thiophen-5-yl) ethanol hydrochloride Melting point: 130-131 ° C. NMR (DMSO-d ₆ ) δ value: 1.17 (6H, t, J = 7.3 Hz), 2.8- 4.0 (10H,
m), 4.86 (1H, m), 5.6-5.9 (1H, m), 7.1-8.0 (4H, m) 2- [2- (N, N-diethylamino) ethoxy]-
1- (3-Fluorobenzo [b] thiophen-5-yl) ethanol hydrochloride Melting point: 106-107 ° C NMR (DMSO-d ₆ ) δ value: 1.17 (6H, t, J = 7.3 Hz), 2.8- 4.0 (10H,
m), 4.8-5.2 (1H, m), 5.4-6.0 (1H, m), 7.4-8.2 (4H, m) -2- [2- (N, N-diethylamino) ethoxy]-
1- (2-methylbenzo [b] thiophen-5-yl)
Ethanol hydrochloride Melting point: 136-137 ° C NMR (DMSO-d ₆ ) δ value: 1.18 (6H, t, J = 7.3 Hz), 2.54 (3H, s), 2.8
-4.0 (10H, m), 4.7-5.0 (1H, m), 5.3-5.8 (1H, m), 7.0-8.0 (4
H, m)

.2- [2- (N, N-diethylamino)
1/2 fumarate of ethoxy] -1- (3-methylbenzo [b] thiophen-5-yl) ethanol Melting point: 137-138 ° C NMR (DMSO-d ₆ ) δ value: 0.99 (6H, t, J = 7.3Hz), 2.3-3.1 (9H, m),
3.4-3.8 (4H, m), 4.2-5.1 (3H, m), 6.53 (1H, s), 7.2-8.0 (4H, m
m) ・ 2- [2- (N, N-diethylamino) ethoxy]-
1- (4-methylbenzo [b] thiophen-5-yl)
Ethanol hydrochloride Melting point: 189-190 ° C NMR (DMSO-d ₆ ) δ value: 1.17 (6H, t, J = 7.2 Hz), 2.57, (3H, s), 2.
8-4.0 (10H, m), 4.9-5.3 (1H, m), 5.4-5.7 (1H, m), 7.2-8.0 (4
H, m) -2- [2- (N, N-diethylamino) ethoxy]-
1- (6-methylbenzo [b] thiophen-5-yl)
Ethanol hydrochloride Melting point: 144-145 ° C NMR (DMSO-d ₆ ) δ value: 1.17 (6H, t, J = 7.2 Hz), 2.41, (3H, s), 2.
7-4.1 (10H, m), 4.8-5.3 (1H, m), 5.4-5.8 (1H, m), 7.2-8.1 (4
H, m) 1- (4-chlorobenzo [b] thiophen-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride Melting point: 148-149 ° C NMR (DMSO- d ₆ ) δ value: 1.17 (6H, t, J = 7.2Hz), 2.8-4.1 (10H,
m), 5.1-5.4 (1H, m), 5.7-6.0 (1H, m), 7.3-8.2 (4H, m) 1- (6-chlorobenzo [b] thiophen-5-yl) -2- [2 -(N, N-diethylamino) ethoxy] ethanol hydrochloride Melting point: 140-141 ° C NMR (DMSO-d ₆ ) δ value: 1.17 (6H, t, J = 7.2 Hz), 2.6-4.1 (10H,
m), 5.0-5.4 (1H, m), 5.7-6.1 (1H, m), 7.3-8.2 (4H, m)

.2- [2- (N, N-diethylamino)
Ethoxy] -1- (2-phenylbenzo [b] thiophen-5-yl) ethanol hydrochloride Melting point: 131-135 ° C. NMR (DMSO-d ₆ ) δ value: 1.18 (6H, t, J = 7.1 Hz) , 2.8-4.2 (10H,
m), 4.7-5.1 (1H, m), 7.2-8.1 (9H, m) 2- [2- (N, N-diethylamino) ethoxy]-
1- (3-phenylbenzo [b] thiophen-5-yl) ethanol hydrochloride Melting point: 158-160 ° C NMR (DMSO-d ₆ ) δ value: 1.14 (6H, t, J = 7.2 Hz), 2.8- 4.2 (10H,
m), 4.7-5.1 (1H, m), 7.2-8.2 (9H, m) 2- [2- (N, N-diethylamino) ethoxy]-
1- (6-Methoxybenzo [b] thiophen-5-yl) ethanol hydrochloride Melting point: 161-162 ° C. NMR (DMSO-d ₆ ) δ value: 1.19 (6H, t, J = 7.3 Hz), 2.8- 4.2 (10H,
m), 3.87 (3H, s), 5.1-5.3 (1H, m), 7.2-7.6 (3H, m), 7.92 (1H,
s) 1- (4,6-difluorobenzo [b] thiophene-
1/2 fumarate salt of 5-yl) -2- [2- (N, N-diethylamino) ethoxy] ethanol Melting point: 135-136 ° C NMR (DMSO-d ₆ ) δ value: 0.92 (6H, t, J = 7.0Hz), 2.4-2.9 (6H, m),
3.4-3.9 (4H, m), 5.1-5.5 (3H, m), 6.50 (1H, s), 7.4-7.9 (3H,
m) 1- (4-bromobenzo [b] thiophen-5-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol hydrochloride Melting point: 150-151 ° C NMR (DMSO-d ₆ ) δ value: 1.35 (6H, t, J = 7.5Hz), 2.8-4.2 (10H,
m), 5.2-5.6 (2H, m), 7.3-7.4 (4H, m)

1- (6-bromobenzo [b] thiophen-5-yl) -2- [2- (N, N-diethylamino) ethoxy] ethanol hydrochloride Melting point: 153-154 ° C. NMR (DMSO-d ₆ ) δ value: 1.41 (6H, t, J = 7.5Hz), 2.6-4.2 (10H,
m), 5.3-5.6 (2H, m), 7.2-7.5 (2H, m), 7.99 (1H, s), 8.17 (1H,
s) 2- [2- (N, N-di-n-propylamino) ethoxy] -1- (6-fluorobenzo [b] thiophene-
5-yl) ethanol Melting point: 143-144 ° C NMR (DMSO-d ₆ ) δ value: 0.95 (6H, t, J = 7.0 Hz), 1.4-2.2 (4H, m),
2.8-3.4 (6H, m), 3.5-4.2 (4H, m), 5.1-5.5 (2H, m), 7.1-7.6
(3H, m), 8.0-8.2 ( 1H, s) · 1- (6- fluoro-benzo [b] thiophen-5-yl) -2- (1-piperazinyl) ethanol mp: 172-174 ℃ NMR (CDCl ₃ ) δ value: 1.4-2.4 (6H, m), 2.6-4.2 (11H, m), 5.2-5.
4 (1H, m), 7.1-7.6 (3H, m), 7.9-8.2 (1H, m) 1- (6-Fluorobenzo [b] thiophen-5-yl) -2- (1-morpholinyl) ethanol Melting point: 198-200 ° C NMR (DMSO-d ₆ ) δ value: 2.6-4.8 (15H, m), 4.9-5.3 (1H, m), 7.4-
8.2 (4H, m)

Production Example 2 (1) To a solution of 8.73 ml of oxalyl chloride in 90 ml of methylene chloride, 14.2 ml of dimethyl sulfoxide was added dropwise at -70 ° C. over 30 minutes. After stirring at the same temperature for 10 minutes, a solution of 2- (2-chloroethoxy) -1- (6-fluorobenzo [b] thiophen-5-yl) ethanol (11 g) in methylene chloride (90 ml) is added dropwise at the same temperature over 30 minutes. . After stirring at the same temperature for 30 minutes, 50.2 ml of triethylamine is added dropwise. After the temperature was raised to room temperature, 200 ml of diethyl ether was added, the insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. 200 ml of water and 200 ml of ethyl acetate are added to the obtained residue, the pH is adjusted to 1 with 1N hydrochloric acid, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Diethyl ether 50 was added to the obtained residue.
ml, and the insolubles were collected by filtration to give a colorless solid 2- (2-
9.5 g of chloroethoxy) -1- (6-fluorobenzo [b] thiophen-5-yl) ethanone are obtained.

(2) 2- (2-chloroethoxy) -1-
A solution of (6-fluorobenzo [b] thiophen-5-yl) ethanone (4.5 g) in tetrahydrofuran (45 ml) at -10 ° C at (R) -5,5-diphenyl-2-methyl-3,4-propano-1,3,3. After adding 0.46 g of 2-oxazaborolidine, 9.9 ml of a 1M boranetetrahydrofuran solution is added dropwise. After heating to room temperature, stirring at the same temperature for 1.5 hours, water 100 ml
And 100 ml of ethyl acetate, and the organic layer is separated. The obtained organic layer is sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 10: 1) to give oily (+)-2- (2-chloroethoxy) -1- (6-fluorobenzo [ b] thiophen-5-yl) ethanol
Get 4.5g.

(3) In the same manner as in Production Example 1 (2), (+)
-2- (2-chloroethoxy) -1- (6-fluorobenzo [b] thiophen-5-yl) ethanol to (+)-1- (6-fluorobenzo [b] thiophene-
This gives the hydrochloride salt of 5-yl) -2- [2- (N, N-diethylamino) ethoxy] ethanol. Melting point: 138-139 ° C. [α] D + 40.8 (C = 1.40, CH ₃ OH) In the same manner, the following compound is obtained. -(-)-1- (6-fluorobenzo [b] thiophen-5-yl) -2- [2- (N, N-diethylamino)
[Ethoxy] ethanol hydrochloride. Melting point: 138-139 ° C. [α] D-40.3 (C = 1.13, CH ₃ OH) The effect of enhancing the NGF action of the 1,2-ethanediol derivative of the general formula [1] or a salt thereof will be described below.

[Neurite Outgrowth Action] (Specimen Compound) The specimen compounds are disclosed in JP-A-3-47158, JP-A-3-232830 and JP-A-4-234.
The compound of Japanese Patent No. 95070 and the compound of Production Example 1-2 (Tables 1 to 6) are used. Production example 1-2 among them
Table 7 shows the physical property values (melting points) of the compounds other than the above. The compound is dissolved in water or dimethyl sulfoxide.

[0065]

[Table 1]

[0066]

[Table 2]

[0067]

[Table 3]

[0068]

[Table 4]

[0069]

[Table 5]

[0070]

[Table 6]

[0071]

[Table 7]

(Test cells) PC12 cells [rat adrenal medulla pheochromocytoma (NGF-responsive cells)] (Test medium) 10% heat immobilized (56 ° C., 30 minutes) horse serum (Schmidt Biotechnology), 5% heat immobilization (56
(° C, 30 minutes) RPMI 1640 medium (manufactured by Nissui Pharmaceutical) containing fetal calf serum (manufactured by Gibco) and 60 μg / ml kanamycin sulfate is used. (Test method) PC12 cells were cultured in the above medium at 8 × 10 ³ cells / m
2ml / wel to a 6-well plate (Falcon)
l, then add 2.5S-NG to 100ng / ml.
F (manufactured by Wako) [dissolved in phosphate buffered saline containing 0.1% bovine serum albumin] and a test compound at a final concentration of 10 ^-5 M, and added in an incubator at 5% CO ₂ at 37 ° C. Incubate with After 5 days of culture, three fields of view are arbitrarily selected under a phase-contrast microscope, the cells are observed, and the ratio of cells that have extended neurites beyond the diameter of the cell body and those that are not are calculated.
The ratio of the control group to which no test compound is added is defined as 100%. Table 8 shows the results.

[0073]

[Table 8]

Formulation Example 1 (tablet) 2- [2- (N, N-diethylamino) ethoxy] -1
A tablet containing 50 mg of the hydrochloride salt of (-benzo [b] thiophen-5-yl) ethanol (Compound No. 1) is prepared by the following method using the following formulation. Per tablet: (1) Compound of compound No. 1 (50 mg), lactose (20 mg),
Kollidon CL (Basuf) (15 mg), corn starch (30 mg), Avicel PH101 [Asahi Kasei Corporation] (50 m
g)｝ (2) ｛Polyvinylpyrrolidone K-90 (5 mg), light anhydrous silicic acid (18 mg), magnesium stearate (2 mg)｝ 190 mg in total A mixture of the above component (1) is polyvinylpyrrolidone K-90.
After drying at 60 ° C., the component (2) is mixed and the mixture is compressed into a round tablet having a weight of 190 mg and a diameter of 8 mm.

Formulation Example 2 (Capsule) 2- [2- (N, N-diethylamino) ethoxy] -1
-A capsule containing 50 mg of the hydrochloride salt of (benzo [b] thiophen-5-yl) ethanol (Compound No. 1),
It is prepared by the following method using the following formulation. Per capsule: (1) ｛Compound No. 1 (50 mg), lactose (20 mg),
Corn starch (53 mg), Kollidon CL (manufactured by BASF) (2 mg)｝ (2) ｛polyvinylpyrrolidone K-90 (5 mg), Avicel PH302 (manufactured by Asahi Kasei Corporation) (18 mg), magnesium stearate (2 mg)｝ 150 mg in total The mixture of the above component (1) was mixed with polyvinylpyrrolidone K-90.
After drying at 60 ° C., the component (2) is mixed, and 150 mg per capsule is filled into a No. 3 gelatin capsule to obtain a capsule.

[0076]

The 1,2-ethanediol derivative of the general formula [I] or a salt thereof has an effect of enhancing NGF action,
It is useful as a therapeutic agent for various diseases caused by degeneration of the central nervous system, for example, Alzheimer's dementia, Huntington's disease, and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/496 A61K 31/496 31/5377 31/5377 A61P 5/00 A61P 5/00 25/14 25 / 14 25/28 25/28 C07D 307/79 C07D 307/79 333/54 333/54 // C07C 43/178 C07C 43/178 C C07D 409/12 C07D 409/12 F term (reference) 4C037 PA01 4C063 AA01 BB07 CC94 DD81 EE01 4C086 AA01 AA02 BA06 BB03 BC54 MA01 MA04 NA06 NA07 NA13 ZA02 ZA16 ZC03 4C206 AA01 AA02 FA05 KA01 KA04 MA01 MA04 NA06 NA07 ZA16 ZC03 4H006 AA01 AB21 BJ50 BM30 BM71 BN10 BP10

Claims (9)

[Claims] 1. A compound of the general formula Wherein R ¹ is an optionally substituted phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic group; R ² is a hydrogen atom or a lower alkyl or hydroxyl protecting group; R ³ is N hydrogen atoms or a lower alkyl group; n R ^{4 s} may be the same or different and represent a hydrogen atom or a lower alkyl group; n R ⁵
Is the same or different and is a hydrogen atom or a lower alkyl group; R ⁶ is an optionally substituted amino or nitrogen-containing heterocyclic group or an ammonio group; and n is 0 or an integer of 1 to 6, Shown respectively. 1,
A nerve growth factor action enhancer containing a 2-ethanediol derivative or a salt thereof. 2. R ¹ is an optionally substituted phenyl group; R ² is a hydrogen atom or a hydroxyl protecting group; n R ⁴ are the same or different and are a hydrogen atom or a lower alkyl group; R ⁵ is a hydrogen atom; and R ⁶ is an optionally substituted amino or benzothienylmethylamino group, and the effect of nerve growth factor containing a 1,2-ethanediol derivative or a salt thereof according to claim 1 is enhanced. Agent. 3. R ¹ is a phenyl group, a halogen-substituted phenyl group, a lower alkyl-substituted phenyl group or a lower alkyl-substituted biphenyl group; R ² is a hydrogen atom; n R ⁴ are
Are n R ^5, a hydrogen atom; a hydrogen atom R ⁶ is, the action of nerve growth factor containing 1,2-ethanediol derivative or its salt according to claim 2, wherein an amino group which may be substituted Enhancer. 4. R ¹ is an optionally substituted naphthyl group; R ² is a hydrogen atom or a hydroxyl protecting group; n R ⁴ are the same or different and are a hydrogen atom or a lower alkyl group; R ⁵ is a hydrogen atom; R ⁶ is an optionally substituted amino, pyrrolyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolyl,
The nerve growth factor action enhancer containing a 1,2-ethanediol derivative or a salt thereof according to claim 1, which is a quinolizinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolyl or thiadiazolyl group or an ammonio group. 5. R ¹ is a naphthyl group; R ² is a hydrogen atom;
R ¹ is a hydrogen atom; n R ⁴ is a hydrogen atom; R ⁶ is an amino group which may be substituted;
A nerve growth factor action enhancer containing a 2-ethanediol derivative or a salt thereof. 6. The nerve growth factor action-enhancing agent comprising the 1,2-ethanediol derivative or a salt thereof according to claim 1, wherein R ¹ is an optionally substituted heterocyclic group. 7. R ¹ is a halogen atom, lower alkyl,
A benzothienyl, benzofuranyl or 2,3-dihydrobenzothienyl group optionally substituted with a lower alkoxy or phenyl group; R ² is a hydrogen atom; R ³ is a hydrogen atom; n R ⁴ and n R ⁵ is a hydrogen atom; R ⁶
Is a lower alkyl group, an aroyl group which may be substituted with a lower alkylenedioxy group, an ar lower alkyl group which may be substituted with a lower alkoxy group and an aryl group which may be substituted with a halo lower alkyl group. The nerve growth factor action enhancer containing a 1,2-ethanediol derivative or a salt thereof according to claim 6, which is an amino, pyrrolidinyl, piperazinyl, tetrahydropyridyl or morpholinyl group optionally substituted with a selected group. 8. A benzothienyl group, wherein R ¹ is optionally substituted with a halogen atom or a lower alkyl group;
8. The nerve growth factor action enhancer comprising a 1,2-ethanediol derivative or a salt thereof according to claim 7, wherein ⁶ is an amino group optionally substituted with a lower alkyl group; and n is 2. 9. R ¹ is optionally substituted by a halogen atom benzo [b] thiophen-5-yl group; R ⁶ is,
9. The 1,2- according to claim 8, which is a di-lower alkylamino group.
A nerve growth factor action enhancer containing an ethanediol derivative or a salt thereof.