JP2003246732A - Neurotmesis remedy comprising 1,2-ethanediol derivative or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a neurotmesis remedy which can accelerate the regeneration of a cut nerve. <P>SOLUTION: A 1,2-ethanediol derivative expressed by general formula 1 or a salt thereof (wherein R<SP>1</SP>is a heterocyclic group which may be substituted; R<SP>2</SP>and R<SP>3</SP>are the same or different from each other and each a hydrogen atom or a lower alkyl group which may be substituted; and n is an integer of 1-6) accelerates the regeneration of the cut nerve and is useful as a remedy for the neurotmesis of which the main complaints are sensory disorder, dyskinesia, digestive tract dysfunction, excretion disorder, sexial function disorder and the like and which are generated by the cutting of peripheral nerves or the damage of the spinal cords caused by traffic accidents, disasters or the like, and by the cutting of visceral nerves caused by surgical operations for visceral disorders. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for nerve rupture, which comprises a 1,2-ethanediol derivative or a salt thereof as an active ingredient and promotes regeneration of a cleaved nerve.

[0002]

2. Description of the Related Art When a peripheral nerve or spinal cord is cut (ruptured) by external force such as a traffic accident, injury, or surgical operation, the body becomes the dominated area of the cut nerve, and sensory disturbance, movement disorder, digestive tract function Disorders, discharge disorders, sexual dysfunction, etc. are known to occur [Axonal Regeneration in the Central Nervous System (Axonal Regene
ration in the central nervous system), Marcel
Marcel Dekker, In
c), pp. 603-647, 2001]. It is known that the peripheral nerve has a high regenerative ability and, after being cut, the peripheral nerve degenerates, but new neurites extend from the cut portion on the central side to establish innervation again. It has also been revealed that similar reactions occur in the spinal cord depending on the conditions.
[From Neuron to Brain
Brain), Third Edition, Sinauer Associates, Inc. (Sinauer)
Associates, Inc), pp. 388-421, 1992].

On the other hand, the 1,2-ethanediol derivatives or salts thereof described in JP-A-3-232830 and JP-A-4-95070 are
It is a compound useful as a brain function improving agent, and particularly (R)-
1- (benzo [b] thiophen-5-yl) -2- [2-
(N, N-Diethylamino) ethoxy] ethanol / hydrochloride
(Hereinafter referred to as T-588) is a preferred compound. And, T-588 exerts a protective action against nerve cell death by amyloid β protein [Society for Neuroscience Abstracts (S
OCIETY FOR NEUROSCIENCE, Abstracts, Vol. 24, Part 1, 228 (1998) and it is known to exert the action enhancing action of nerve growth factor (International Publication WO96 / 12717).

[0004]

[Problems to be Solved by the Invention] Attempts have been made to treat the physical function impaired by the regeneration and repair of nerves by making the most of the regenerative ability of the severed peripheral nerve or spinal cord.
Specific examples include stump junction, nerve transplantation, and filling of cross-linking substances [The Anatomic Record (The Anato
mical Record), Volume 263, pp. 396-404, 2001]. However, it takes a long time for the regenerated nerves to reach the target organ and establish innervation again. Therefore, there is a need for a compound useful as a drug that accelerates the reaction of the body involved in nerve regeneration and shortens the time required for functional recovery.

[0005]

[Means for Solving the Problems] Under such circumstances,
As a result of earnest research, the present inventors have shown the following general formula [1].

[Chemical 3] "In the formula, R ¹ represents an optionally substituted heterocyclic group;
R ² and R ³ are the same or different and each is a hydrogen atom or an optionally substituted lower alkyl group; and n is
The integers 1 to 6 are shown respectively. , 1,2-
The ethanediol derivative or a salt thereof has been found to have an action of promoting regeneration of a cleaved (ruptured) nerve, and has 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. The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the lower alkyl group means a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl group. A C _1-6 alkyl group; a lower alkenyl group means a C _2-6 alkenyl group such as vinyl, propenyl, butenyl, pentenyl and hexenyl groups;
The lower alkynyl group is a C _2-6 alkynyl group such as ethynyl, propynyl, butynyl, pentynyl and hexynyl; the lower alkoxy group is methoxy, ethoxy,
C _1-6 alkyloxy groups such as propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy and hexyloxy groups; lower alkenyloxy groups are vinyloxy, propenyloxy, butenyloxy, pentenyloxy and hexenyloxy groups. A C _2-6 alkenyloxy group such as; a lower alkylthio group means methylthio, ethylthio, propylthio,
Isopropylthio, butylthio, isobutylthio, tert
- butylthio, the C _1-6 alkylthio group such as pentylthio and hexylthio; Halo-lower alkyl group, chloromethyl, fluoromethyl, difluoromethyl, halogen -C _1-6 alkyl group such as chloroethyl;

Aryl groups are phenyl, naphthyl, indanyl and indenyl groups; aryloxy groups are phenyloxy, naphthyloxy, indanyloxy and indenyloxy groups; and ar lower alkyl groups are benzyl and diphenyl. Al-C _1-6 alkyl groups such as methyl, trityl and phenethyl groups; and ar-lower alkoxy groups include ar-C _1-6 alkyl-O-groups such as benzyloxy, diphenylmethyloxy and trityloxy; The group is an ar C _1-6 alkyl-S- group such as benzylthio or diphenylmethylthio; the ar lower alkenyl group is an ar C _1-6 alkenyl group such as styryl or cinnamyl; the lower alkylenedioxy group is , for example, C _1-4 a, such as methylenedioxy and ethylenedioxy groups The Kirenjiokishi group;

The lower acyl group is formyl, acetyl,
A C _1-6 acyl group such as butyryl and ethylcarbonyl group; an aroyl group means an arylcarbonyl group such as benzoyl and naphthylcarbonyl group; a lower alkylsulfonyl group means methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, Isopropylsulfonyl,
a C _1-6 alkylsulfonyl group such as n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl or pentylsulfonyl; an ar lower alkylsulfonyl group means an ar C _1-6 alkyl group such as benzylsulfonyl. SO 2 _- group; and arylsulfonyl groups, benzenesulfonyl, p- toluenesulfonyl, aryl -SO such naphthylsulfonyl group ₂ -
Group; an arylsulfonylamino group is an aryl-SO ₂ NH- group such as benzenesulfonylamino, naphthylsulfonylamino and the like; a lower alkylsulfonylamino group is C _1-6 alkyl such as methylsulfonylamino, ethylsulfonylamino and the like. An —SO ₂ NH— group; an ammonio group means a tri-lower alkylammonio group such as a trimethylammonio and triethylammonio group;

The heterocyclic group means pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, homopiperidinyl, morpholyl, thiomorpholyl, tetrahydroquinolinyl, tetrahydroisoquinolyl, quinuclidinyl,
Imidazolinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, quinolyl, quinolidinyl,
Thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, purinyl, furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, isoxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, Benzothiazolyl, quinoxalyl, dihydroquinoxalyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo [b] dioxanyl , Imidazo
Such as [2,3-a] pyridyl, benzo [b] piperazinyl, chromenil, isothiazolyl, isoxazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl, 1,3-benzodioxonyl and 1,4-benzodioxanyl groups. It may contain one or more oxygen atoms or sulfur atoms as a hetero atom forming a ring,
A 5- or 6-membered, condensed or bridged heterocyclic group containing at least one hetero atom selected from nitrogen, oxygen or sulfur atoms; and a heterocyclic carbonyl group is a heterocyclic group. Means the formula -CO- group.

The substituent of the heterocyclic group in R ¹ is a halogen atom, optionally substituted amino, lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy, aryloxy, carbamoyloxy, lower Alkylthio, lower alkenyl, lower alkenyloxy, ar lower alkylthio, ar lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or heterocyclic group or protected amino group, optionally protected hydroxyl group , A nitro group, an oxo group and a lower alkylenedioxy group.

The substituent for lower alkyl in R ² and R ³ includes a halogen atom, optionally substituted amino, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, Lower alkenyl, lower alkenyloxy, ar lower alkylthio, ar lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino or a heterocyclic group or a protected amino group, optionally protected hydroxyl group, nitro Groups and oxo groups.

Lower alkyl, aryl, ar lower alkyl, lower alkoxy, ar lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl, lower alkenyloxy, ar lower alkylthio in the substituent of the heterocyclic group of R ¹ ; As a substituent for ar lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylamino, arylsulfonylamino and heterocyclic group, a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group, a protected Optionally substituted amino group, lower alkyl group optionally substituted by optionally protected hydroxyl group, aryl group optionally substituted by halogen, aroyl group optionally substituted by halogen, lower alkoxy Replace with group Optionally substituted lower alkoxy group, halo lower alkyl group, lower acyl group, lower alkyl group, lower alkyl group, heterocyclic group, heterocyclic carbonyl group, oxo group, lower alkylsulfonyl group and arylsulfonyl group And may be substituted with one or more of these substituents.

As protective groups for hydroxyl group, carboxyl group and amino group, Protective Groups in Organic Synthesis (Protective Groups)
in Organic Synthesis), Third Edition (Third E
dition) [Theodora W. Green (Theodora W.
Greene) (1999), John Wiley & Sons. In
c.)] and the usual protecting groups for hydroxyl, carboxyl and amino groups.

The salt of the 1,2-ethanediol derivative of the general formula [1] may be any pharmaceutically acceptable salt, such as a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid,
Salts with carboxylic acids such as malic acid, tartaric acid and aspartic acid; methanesulfonic acid, benzenesulfonic acid, p-
Examples thereof include salts with sulfonic acids such as toluenesulfonic acid and naphthalenesulfonic acid, salts with alkaline metals such as sodium and potassium, and the like.

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

1,2- of the general formula [1] which is preferable as a therapeutic agent for nerve tearing which promotes the regeneration of the cleaved nerve of the present invention
The ethanediol derivative or the salt thereof is a benzothiophene group in which R ¹ may be substituted with a halogen atom or an aryl group; a lower alkyl group in which R ² may be substituted with a hydroxyl group, an alkyl group or an aryl group. R ³ is a lower alkyl group which may be substituted with a hydrogen atom or an aryl group, and further,
R ¹ is a benzothiophene group optionally substituted with a halogen atom; R ² is a lower alkyl group optionally substituted with a hydroxyl group; and n is 2.
More specifically, (R) -1- (benzo [b] thiophene-
5-yl) -2- [2- (N, N-diethylamino) ethoxy] ethanol hydrochloride (T-588); 1- (benzo [b]
Thiophen-5-yl) -2- {2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol.
Hydrochloride; (S) -1- (6-Fluorobenzo [b] thiophen-5-yl) -2- {2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol hydrochloride And so on.

The 1,2-ethanediol derivative of the general formula [1] or a salt thereof can be produced by a method known per se or an appropriate combination thereof. Specifically, for example, 1,2-ethanediol derivatives described in JP-A Nos. 3-232830 and 4-95070; International Publication WO99 / 31056.
It can be produced by the production method described in the publication relating to the alkyl ether derivative described in.

When the 1,2-ethanediol derivative of the general formula [1] or a salt thereof is formulated as a therapeutic agent for nerve rupture which promotes the regeneration of a cleaved nerve, a pharmaceutically acceptable excipient, Tablets, capsules, powders, and powders can be prepared by a conventional method by appropriately using formulation aids such as carriers, diluents and stabilizers.
It can be made into a preparation such as granules, fine granules, pills, suspensions, emulsions, solutions, syrups, injections and eye drops. This formulation can be administered orally or parenterally. The administration method, dose and frequency of administration can be appropriately selected according to the patient's age, body weight and symptoms, but in the case of oral administration, it is usually 0.01 to 500 mg per day for an adult.
It may be given in divided doses from several times.

[0019]

EXAMPLE The therapeutic agent for nerve rupture of the present invention is described below.
The test examples, examples and formulation examples will be described, but the present invention is not limited thereto. The mixing ratios in the eluents are all volume ratios, and the carrier in column chromatography is silica gel 60, No. 7733.
(Merck) and BW silica gel, BW-127ZH, FL
-100DX (manufactured by Fuji Silysia Chemical Ltd.) was used.

Test Example Action to promote regeneration of cleaved nerve (test compound) Compound A: T-588 Compound B: 1- (benzo [b] thiophen-5-yl) -2
-{2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol hydrochloride compound C :; (S) -1- (6-fluorobenzo [b] thiophen-5-yl)- 2- {2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol hydrochloride

(Test Method) The test is based on the Journal of
Journal of pharmacology and experi
mentaltherapeutics), 290, 348, 1999 and Neuroscience, 88, 25
It was carried out according to the method described on page 7, 1999. That is,
SD rats (male 6 to 7 weeks old, body weight 170 to 280 g) were anesthetized with pentobarbital, the sciatic nerve on the left side was exposed in the thigh, the nerve was separated from the surrounding connective tissue, and about from the gluteal muscle.
1 cm distal side was cut. Both ends of the severed nerve are 8 mm long
In a sterile silicon tube (inner diameter 1.3 mm, outer diameter 1.8 mm),
After 3.5 mm was inserted so that there was a 1 mm gap in the center and fixed, the nerve was returned to the muscle tissue together with the tube, and the incision was sutured. After 7 days, the test compound dissolved in distilled water was orally administered, and thereafter, it was similarly administered once a day for 13 days.

21 days after the nerve was cut, the sciatic nerve was exposed again under pentobarbital anesthesia, the nerves of the thigh and the lower leg were separated from the surrounding connective tissue, and the silicon tube at the cut was removed. The stimulation electrode is placed centrally from the cut site, and the recording electrode is placed on the most distal side of the lower leg, and electrical stimulation is given (vo
ltage 2V, delay 1msec, duration 100μsec) Action potentials were recorded. The recording electrode was gradually moved to the central side, and the distance from the most peripheral point where the action potential was obtained to the cutting site was measured and used as the reproduction distance. Only distilled water was administered to the control group. The sciatic nerve regeneration rate of the test compound was
It was calculated from the following formula. (Regeneration distance of administration group) / (regeneration distance of control group) x 100 (%) The results are shown in Table 1.

[0023]

[Table 1] -------------------------------------------------- --------- Test compound Dose (mg / kg) Regeneration rate (%) -------------------------------------------------- --------- Compound A 10 142 Compound B 1 173 Compound C 1 193 -------------------------------------------------- ---------

Example 1 (1) (S) -2- (6-fluorobenzo [b] thiophen-5-yl)
-2- (1-methoxy-1-methylethoxy) -1-ethanol (1.50
g) tert-butanol (10.4 mL) and N, N-dimethylformamide (3.6 mL) in a solution of tert-butoxy potassium under ice cooling.
(0.92g) and N-methyl-N- [2- (trityloxy) ethyl]
-2-Chloroacetamide (3.11 g) was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 2 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethanol (15m
L), water (1.5 mL) and p-toluenesulfonic acid monohydrate
(0.50 g) was added, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (eluent; chloroform: methanol = 30: 1 to 15: 1) to give a colorless oily (S) -2-
[2- (6-Fluorobenzo [b] thiophen-5-yl) -2-hydroxyethoxy] -N- (2-hydroxyethyl) -N-methylacetamide (1.13 g) was obtained. IR (neat) cm ^-1 : 3368,2935,1643,1452,1113,1078,754

(2) (S) -2- [2- (6-Fluorobenzo [b] thiophen-5-yl) -2-hydroxyethoxy] -N- (2-hydroxyethyl) -N-methylacetamide ( To a solution of 1.13 g) in tetrahydrofuran (11 mL) was added dropwise a 1 mol / L tetrahydrofuran solution (10.4 mL) of borane-tetrahydrofuran complex at 5 ° C, and the mixture was stirred at room temperature for 18 hours. 6 mol / L hydrochloric acid (1.5 mL) was added dropwise to the reaction mixture, the mixture was refluxed for 1 hour, water and ethyl acetate were added, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer, the pH was adjusted to 10.5 with a 5 mol / L aqueous sodium hydroxide solution, and the organic layer was separated. After washing the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent; chloroform: methanol = 20: 1 to 10: 1) to give colorless oil (S) -1- (6-fluorobenzo [b] thiophen-5-yl). -2-
{2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol (0.88 g) was obtained. IR (neat) cm ^-1 : 3384,2872,1451,1121,754 NMR (CDCl ₃ ) δ value: 2.39 (3H, s), 2.6-2.8 (4H, m), 3.2-4.2 (6
H, m), 5.2-5.4 (1H, m), 7.33 (1H, d, J = 3Hz), 7.42 (1H, d, J = 3H
z), 7.58 (1H, d, J = 3Hz), 7.99 (1H, d, J = 7Hz)

Example 2 1- (Benzo [b] thiophen-5-yl) -2- (2-chloroethoxy) ethanol (0.80 g) of N, N-dimethylformamide (5 m
Methylethanolamine (0.66 mL) and potassium carbonate (0.56 g) were added to the (L) solution, and the mixture was stirred at 80 ° C for 6 hr. Water and methylene chloride were added to the reaction mixture, and the pH was adjusted to 1 with 6 mol / L hydrochloric acid.
After adjusting to, the aqueous layer was separated. Ethyl acetate was added to the aqueous layer, the pH was adjusted to 11 with a 5 mol / L sodium hydroxide aqueous solution, and then the organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Column chromatography of the residue (eluent: chloroform to chloroform: methanol = 4
0: 1) and oily 1- (benzo [b] thiophen-5-yl) -2- {2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol (0.43 g) was obtained. IR (neat) cm ^-1 : 3372,2878,1121,1048,703 NMR (CDCl ₃ ) δ value: 2.38 (3H, s), 2.5-2.9 (4H, m), 3.5-4.0 (6
H, m), 4.9-5.1 (1H.m), 7.2-7.5 (3H, m), 7.7-8.0 (2H, m)

Example 3 The following compound was obtained in the same manner as in Example 2.・ 1- (Benzo [b] thiophen-5-yl) -2- {2- [N-methyl-N-
(2-Propinyl) amino] ethoxy} ethanol ・ 1- (benzo [b] thiophen-5-yl) -2- {2- [N- (2-propynyl) amino] ethoxy} ethanol IR (neat) cm ^-1 : 3295,2861,1438,1116,1090,704 NMR (CDCl ₃ ) δ value: 2.23 (1H, t, J = 2Hz), 2.91 (2H, t, J = 6Hz),
3.44 (2H, d, J = 2Hz), 3.5-3.9 (4H, m), 5.00 (1H, dd, J = 3,8H
z), 7.30 (1H, d, J = 5Hz), 7.37 (1H, d, J = 7Hz), 7.44 (1H, d, J = 5
Hz), 7.83 (1H, d, J = 7Hz), 7.86 (1H, s) ・ 1- (benzo [b] thiophen-5-yl) -2- [2- (N-benzyl-
N-ethylamino) ethoxy] ethanol NMR (CDCl ₃ ) δ value: 1.11 (3H, t, J = 7Hz), 2.59 (2H, t, J = 7Hz),
2.70 (2H, t, J = 6Hz), 3.4-3.9 (4H, m), 3.67 (2H, s), 4.99 (1H,
dd, J = 3,8Hz), 7.2-7.5 (8H, m), 7.83 (1H, d, J = 7Hz), 7.87 (1
H, s) ・ 2- [2- (N-benzyl-N-methylamino) ethoxy] -1- (2-
Phenylbenzo [b] thiophen-5-yl) ethanol NMR (CDCl ₃ ) δ value: 2.31 (3H, s), 2.66 (2H, t, J = 6Hz), 3.4-3.
9 (4H, m), 3.62 (2H, s), 5.01 (1H, dd, J = 3,8Hz), 7.2-7.6 (10
H, m), 7.6-7.9 (4H, m)

Example 4 1- (Benzo [b] thiophen-5-yl) -2- {2- [N- (2-propynyl) amino] ethoxy} ethanol (0.74 g) of N, N-dimethylformamide ( Ethyl bromide (0.21 mL) and potassium carbonate (0.41 g) were added to the 4 mL) solution, and the mixture was stirred at room temperature for 18 hours.
Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. After sequentially washing the organic layer with water and saturated saline,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: hexane: ethyl acetate = 1: 1 to 1: 3) to give an oily 1- (benzo [b] thiophen-5-yl) -2- {2- [ N-ethyl-N- (2-propynyl) amino] ethoxy} ethanol (0.67 g) was obtained. NMR (CDCl ₃ ) δ value: 1.12 (3H, t, J = 7Hz), 2.21 (1H, t, J = 2Hz),
2.5-3.0 (4H, m), 3.4-3.9 (4H, m), 3.52 (2H, d, J = 2Hz), 4.98
(1H, dd, J = 3,8Hz), 7.2-7.5 (3H, m), 7.7-8.1 (2H, m)

Example 5 The following compounds were obtained in the same manner as in Example 4.・ 1- (Benzo [b] thiophen-5-yl) -2- {2- [N-benzyl-
N- (2-propynyl) amino] ethoxy} ethanol NMR (CDCl ₃ ) δ value: 2.27 (1H, t, J = 2Hz), 2.84 (2H, t, J = 6Hz),
3.43 (2H, d, J = 2Hz), 3.5-3.9 (4H, m), 3.72 (2H, s), 5.00 (1H,
dd, J = 3,8Hz), 7.2-7.5 (8H, m), 7.7-8.1 (2H, m)

Example 6 (1) A solution of 2- (benzo [b] thiophen-5-yl) -2- (tetrahydro-2H-pyran-2-yloxy) -1-ethanol (1.00 g) in toluene (2 mL) In addition, 1-bromo-3-chloropropane (1.78m
L), tetra-n-butylammonium hydrogensulfate (0.06 g) and 50% aqueous sodium hydroxide solution (4 mL) were added, and the mixture was stirred and refluxed for 5 hr. After cooling, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent; hexane: ethyl acetate = 10: 1) to give colorless oily 2- [1- (benzo [b] thiophen-5-yl) -2.
-(3-Chloropropoxy) ethoxy] tetrahydro-2H-pyran (0.99 g) was obtained.

(2) 2- [1- (benzo [b] thiophen-5-yl) -2- (3-chloropropoxy) ethoxy] tetrahydro-2H
To a solution of -pyran (0.49g) in N, N-dimethylformamide (4.9mL) was added methylethanolamine (0.22mL) and potassium carbonate (0.38g), and the mixture was stirred at 80 ° C for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Residue
(0.52 g) in methanol (5.2 mL) and 2 mol / L hydrochloric acid (2.6 mL)
Was added, and the mixture was stirred at room temperature for 4 days. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 2 mol / L aqueous sodium hydroxide solution.
After adjusting to 13, the organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography (eluent: chloroform: methanol = 1
0: 1) and colorless oily 1- (benzo [b] thiophene-
5-yl) -2- {3- [N- (2-hydroxyethyl) -N-methylamino] propoxy} ethanol (0.20 g) was obtained. IR (neat) cm ⁻¹ : 3398,2856,1087,704 NMR (CDCl ₃ ) δ value: 1.80 (2H, qn, J = 6Hz), 2.28 (3H, s), 2.55
(4H, t, J = 5Hz), 3.3-3.8 (6H, m), 5.02 (1H, dd, J = 3,9Hz), 7.3
0 (1H, d, J = 7Hz), 7.37 (1H, d, J = 6Hz), 7.44 (1H, d, J = 6Hz), 7.
83 (1H, d, J = 7Hz), 7.86 (1H, s)

Example 7 (S) -1- (6-Fluorobenzo [b] thiophen-5-yl) -2- {2-
[N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol (0.88 g) in ethyl acetate (4.4 mL) solution, 3.87 mol /
L dry hydrogen chloride-ethyl acetate solution (0.94 mL) was added, and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried (S) -1- (6-fluorobenzo [b] thiophen-5-yl) -2- {2- [N- (2-hydroxy Ethyl) -N-methylamino] ethoxy} ethanol hydrochloride (0.58 g) was obtained. Melting point: 136-137 ° C IR (KBr) cm ^-1 : 3384,1451,1140,1078 NMR (DMSO-d ₆ ) δ value: 2.78 (3H, s), 2.9-4.0 (10H, m), 5.0-5.2
(1H, m), 7.47 (1H, d, J = 5Hz), 7.73 (1H, d, J = 5Hz), 7.87 (1H,
d, J = 11Hz), 8.01 (1H, d, J = 7Hz), 10.0 (1H, brs)

Example 8 In the same manner as in Example 7, the following compound was obtained.・ 1- (Benzo [b] thiophen-5-yl) -2- {2- [N- (2-hydroxyethyl) -N-methylamino] ethoxy} ethanol ・ Hydrochloride melting point: 113-115 ℃ IR (KBr ) cm ^-1 : 3362,1432,1121,1090,710,698 NMR (DMSO-d ₆ ) δ value: 2.77 (3H, s), 3.1-3.5 (4H, m), 3.5-4.0
(6H, m), 4.8-5.0 (1H, m), 7.37 (1H, d, J = 8Hz), 7.44 (1H, d, J =
5Hz), 7.75 (1H, d, J = 5Hz), 7.95 (1H, d, J = 8Hz), 7.99 (1H, s) ・ 1- (benzo [b] thiophen-5-yl) -2- {2 -[N-methyl-N-
(2-Propinyl) amino] ethoxy} ethanol / hydrochloride Melting point: 159-161 ° C IR (KBr) cm ^-1 : 3380,2638,1465,1150,1124,1089,710,698 NMR (DMSO-d ₆ ) δ value: 2.50 (1H, t, J = 2Hz), 2.77 (3H, s), 3.2-
3.5 (2H, m), 3.57 (2H, d, J = 6Hz), 3.7-4.0 (4H, m), 4.08 (2H,
d, J = 2Hz), 4.88 (1H, t, J = 6Hz), 7.39 (1H, d, J = 8Hz), 7.44 (1
H, d, J = 5Hz), 7.75 (1H, d, J = 5Hz), 7.90 (1H, s), 7.94 (1H, d, J
= 8Hz) ・ 1- (benzo [b] thiophen-5-yl) -2- {2- [N-ethyl-N-
(2-Propinyl) amino] ethoxy} ethanol / hydrochloride Melting point: 59-61 ° C IR (KBr) cm ^-1 : 3396,2625,1436,1124,1090,1047,710 NMR (DMSO-d ₆ ) δ value: 1.20 (3H, t, J = 7Hz), 2.50 (1H, t, J = 2H
z), 3.1-3.4 (4H, m), 3.57 (2H, d, J = 6Hz), 3.7-4.0 (2H, m), 3.
9-4.2 (2H, m), 4.88 (1H, t, J = 6Hz), 7.39 (1H, d, J = 8Hz), 7.44
(1H, d, J = 5Hz), 7.74 (1H, d, J = 5Hz), 7.90 (1H, s), 7.94 (1H,
d, J = 8Hz) ・ 2- [2- (N-benzyl-N-methylamino) ethoxy] -1- (2-
Phenylbenzo [b] thiophen-5-yl) ethanol / hydrochloride Melting point: 167-169 ° C IR (KBr) cm ^-1 : 3254,2632,1451,1133,756,698 NMR (CDCl ₃ ) δ value: 2.7-3.5 ( 5H, m), 3.5-4.1 (4H, m), 4.1-4.5
(2H, m), 5.1-5.3 (1H, m), 7.2-7.9 (14H, m)

Example 9 1- (Benzo [b] thiophen-5-yl) -2- {3- [N- (2-hydroxyethyl) -N-methylamino] propoxy} ethanol (0.2
A 4.76 mol / L dry hydrogen chloride-ethyl acetate solution (0.16 mL) was added to an ethyl acetate (2 mL) solution of 0 g), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure to give a colorless oily 1-
(Benz [b] thiophen-5-yl) -2- {3- [N- (2-hydroxyethyl) -N-methylamino] propoxy} ethanol / hydrochloride (0.20 g) was obtained. IR (KBr) cm ^-1 : 3334,1115,708 NMR (CDCl ₃ ) δ value: 1.8-2.2 (2H, m), 2.84 (3H, s), 2.8-3.6 (8
H, m), 3.6-3.9 (2H, m), 4.8-5.1 (1H, m), 7.1-7.4 (2H, m), 7.4
0 (1H, d, J = 5Hz), 7.77 (1H, d, J = 8Hz), 7.81 (1H, s), 9.6 (1H, b
rs)

Next, formulation examples are shown. Formulation Example 1 Ingredients [T-588 50 mg, lactose 20 mg, Kollidon CL (Basuf Co.) 15 mg, corn starch 25 mg, Avicel PH 101
(Asahi Kasei) 40mg] polyvinylpyrrolidone K90
After kneading with an 8% aqueous solution of, and drying at 60 ° C., components [polyvinylpyrrolidone K90 5 mg, light anhydrous silicic acid 18 mg,
Magnesium stearate 2mg] and mixed 1 tablet weight 17
It is compressed into a circular tablet having a diameter of 5 mm and a diameter of 8 mm to obtain a tablet containing 50 mg of T-588.

Formulation Example 2 A mixture of the components [T-588 50 mg, lactose 20 mg, corn starch 53 mg, Kollidon CL 2 mg] was kneaded with an 8% aqueous solution of polyvinylpyrrolidone K90 and dried at 60 ° C., and then the component [polyvinylpyrrolidone K90 was used. 5 mg, Avicel PH 302 18 mg, and magnesium stearate 2 mg] are mixed, and 150 mg per capsule is filled in a No. 3 gelatin capsule to obtain a capsule.

[0037]

Industrial Applicability The 1,2-ethanediol derivative of the general formula [1] or a salt thereof has an action of promoting the regeneration of cut nerves, and the peripheral nerves are affected by external forces such as traffic accidents, injuries and surgical operations. Alternatively, it is useful as a therapeutic agent for nerve rupture which is caused by sensory disturbance, movement disorder, gastrointestinal dysfunction, excretion disorder, and sexual dysfunction which occurs when the spinal cord is cut.

Claims (3)

[Claims] 1. A general formula: "In the formula, R ¹ represents an optionally substituted heterocyclic group;
R ² and R ³ are the same or different and each is a hydrogen atom or an optionally substituted lower alkyl group; and n is
The integers 1 to 6 are shown respectively. , 1,2-
A therapeutic agent for nerve rupture containing an ethanediol derivative or a salt thereof. 2. R ¹ is a benzothiophene group optionally substituted with a halogen atom or an aryl group; R ² is a lower alkyl group optionally substituted with a hydroxyl, lower alkynyl or aryl group; R ³ is A therapeutic agent for nerve rupture containing a 1,2-ethanediol derivative or a salt thereof according to claim 1, which is a lower alkyl group which may be substituted with a hydrogen atom or an aryl group. 3. A general formula: "In the formula, R ^1a is a benzothiophene group optionally substituted with a halogen atom or an aryl group; R ^2a is a lower alkyl group substituted with a hydroxyl, lower alkynyl or aryl group; R ³ is a hydrogen atom or A lower alkyl group optionally substituted with an aryl group; and n is 1 to
The integers of 6 are shown. And a 1,2-ethanediol derivative represented by the formula or a salt thereof.