WO2006054514A1 - Preventive or therapeutic pharmaceutical composition for neuropathic pain - Google Patents

Abstract

A medicine useful for the prevention or treatment of neuropathic pain. There is provided a preventive or therapeutic pharmaceutical composition for neuropathic pain, comprising as an active ingredient a 3,4-disubstituted phenylethanolaminotetralincarboxamide derivative of the general formula (I) or a pharmacologically acceptable salt thereof. (I) In the formula, A is a lower alkylene; B is an amino, a di-lower-alkyl substituted amino, an alicyclic amino, etc.; n is an integer of 1 or 2; the carbon atom marked with * is a carbon atom of R-configuration or S-configuration, or a carbon atom having the same mixed therein; and the carbon atom marked with (S) is a carbon atom of S-configuration.

Description

 Specification

 Pharmaceutical composition for prevention or treatment of neuropathic pain

 Technical field

 [0001] The present invention relates to a pharmaceutical composition useful for the prevention or treatment of neuropathic pain.

 [0002] More specifically, the present invention relates to a 3,4-disubstituted phenylaminoaminotetralincarboxylic acid amide derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. The present invention relates to a pharmaceutical composition for preventing or treating neuropathic pain.

 Background art

 [0003] Neuropathic pain (Neuropathic Pain) is defined as pain caused by or caused by temporary damage to the nervous system or its abnormal function, and is an anti-inflammatory analgesic or anesthetic / analgesic It is an intractable pain disease that is resistant to. Examples of such diseases include cancer pain, postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, causalgia, and painful diabetic god • Transpathology (also known as diabetic painful neuropathy) It is a thing. In particular, it is speculated that the number of patients with painful diabetic neuropathy among neuropathic pain diseases will increase further as the number of diabetic patients increases as lifestyle changes and the population ages. ing. In these disorders, pain and sensory abnormalities characterized by hyperalgesia, alodynia, occur, and patients continue to experience persistent QOL, often resulting in insomnia, loss of appetite, and reactive depression. It has been reported to be damaged (for example, see Non-Patent Document 1).

 [0004] The pathogenesis of neuropathic pain is still largely unknown. Peripheral and central nerve damage at various levels contributes to the disease, and metabolic abnormalities, nerve fiber blood flow disturbances, nerve fiber Degeneration and synaptic responsive changes overlap in a complex manner, and it is assumed that pain develops.

[0005] Treatment of neuropathic pain is performed by drug therapy and nerve block therapy. Drug treatment includes anticonvulsants, neurotrophic vitamins, non-steroidal anti-inflammatory drugs, Aldose reductase inhibitors, hypoglycemic drugs, lidocaine-like antiarrhythmic drugs, etc. are used. In addition, as a nerve block therapy, an astrocyte block, a continuous epidural block, a nerve root block and the like are used. However, the increased pain sensitivity of neuropathic pain is caused by the imbalance between pain transmission and suppression systems, and these treatments often fail to provide sufficient therapeutic effects. Early development of new drugs is desired.

 [0006] The following general formula

[0007] [Chemical 1]

(In the formula, A is a lower alkylene group, B is an amino group, a di-lower alkylamino group, or a 3- to 7-membered alicyclic anamino group optionally containing an oxygen atom in the ring, and n is Is an integer of 1 or 2, and a carbon atom marked with * indicates an R configuration or S configuration carbon atom or a carbon atom mixed with them, and a carbon atom marked with (S) indicates an S configuration carbon atom. 3, 4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivatives and their pharmacologically acceptable salts are represented by β adrenergic receptors (hereinafter referred to as β AR).

 2 2) It has a stimulating action and exhibits uterine contraction-suppressing action, and is known to be useful as a treatment for premature labor premature labor, bronchodilators, pain relief for urolithiasis, and a calculus promoter. (See Patent Document 1). However, it is not known at all that these compounds are useful for the treatment of neuropathic pain, and they are neither described nor suggested in the literature.

 In addition, βAR stimulators improve neuronal blood flow in diabetic neuropathy model rats

2

 (See Non-Patent Document 2). However, AR stimulants are neuropathic

 2

 No analgesic action has been reported for pain. In addition, βAR stimulants are high

 2

It has been suggested that the dose may cause an increase in blood glucose level in diabetic patients, and has been studied as a pain treatment for diabetic neuropathy. [0009] Patent Document 1: Pamphlet of International Publication No. 97-30023

 Non-Patent Document 1: Katsuyuki Moriwaki et al., Pain Clinic, May 2000, 21st volume, separate volume, p. S 101 -S107

 Non-Patent Document 2: Mary A. Cotteri, Masahiro, European Journal of Pharmacology, 1998, 343, p. 217-223

 Disclosure of the invention

 Problems to be solved by the invention

An object of the present invention is to provide a medicament for treating neuropathic pain.

 Means for solving the problem

 As a result of intensive studies in view of the above problems, the present inventors have surprisingly found that the compound represented by the general formula (I) is a streptozotocin (hereinafter referred to as STZ) -induced diabetic rat. In the Seltzer model rat, it has been found that it has an action to reduce neuropathic pain, and has led to the present invention.

 That is, the present invention provides:

 [1] A neurogenic agent comprising a 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for the prevention or treatment of sexual pain;

 [2] The 3,4-disubstituted phenylethanolinoreaminotetralin carboxylic acid amide derivative represented by the general formula (I) is represented by (1) -2-[(2S) -2-([((2R) _ 2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yloxy) one N, N-dimethylacetamide or its The pharmaceutical composition according to the above [1], which is a pharmacologically acceptable salt;

 (3) The neuropathic pain is painful diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, Kausanoregi, cancer pain, or chronic pain after surgery or trauma. The pharmaceutical composition according to the above [1] or [2];

 [4] Used in combination with one or more drugs selected from neurotrophic vitamins, non-steroidal anti-inflammatory drugs, aldose reductase inhibitors, lidocaine-like antiarrhythmic drugs, antidepressants, and anticonvulsants A pharmaceutical composition according to any one of the above [1] to [3];

Corrected jar (parent [5] A neurogenic cause comprising administering an effective amount of the 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. For preventing or treating sexual pain;

 [6] A 3,4-disubstituted phenylethanolaminotetralincarboxylic acid amide derivative represented by the above general formula (I) or its pharmacology for producing a preparation for the prevention or treatment of neuropathic pain Use of chemically acceptable salts;

 The invention's effect

 [0013] The pharmaceutical composition of the present invention is a representative model for evaluation of drug efficacy against neuropathic pain, and exhibits an extremely high nociceptive threshold value increasing effect in STZ-induced diabetic rats and Seltzer model rats. It is useful for prevention or treatment.

 Brief Description of Drawings

 FIG. 1 shows analgesic effects (STZ-induced diabetic rats) upon repeated administration of Compound 1. The horizontal axis in the figure represents each administration group: Normal represents a normal group; Control represents a control group; the number represents the dose of Compound 1 (mg / kg). * * Indicates P <0.01 (significant difference from control group (Steel test)); # # indicates p 0.01 (significant difference from control group (Aspin-Welch t test)); Show.

 FIG. 2 shows the analgesic effect (Seltzer model) upon single administration of Compound 1. The horizontal axis of the figure shows each administration group (Normal is a normal group). * * Indicates P 0.01 (significant difference from the pre-drug value (test of two paired groups)); # indicates P <0. 05 (normal group and nerve ligation group before drug administration) Significant differences (Aspin-Welch t test) are shown respectively.

 FIG. 3 shows analgesic effect (Seltzer model) after repeated administration of Compound 1. The horizontal axis in the figure shows each application group (Normal and Control have the same meaning as described above). * * Indicates Ρ <0 · 01 (significant difference (Aspin-Welch's t-test) with respect to the control group).

 BEST MODE FOR CARRYING OUT THE INVENTION

[0015] Although the mechanism of the compound represented by the general formula (I) showing the action of increasing nociceptive threshold in STZ-induced diabetic rats and the like is not clear, the compound power β represented by the general formula (I) AR stimulation

 2 It has not only an action but also an adrenergic receptor (hereinafter called AR) stimulation action.

 twenty two

It is speculated. Therefore, α A stimulating action is preferable. Α A The binding ability to R is preferably an IC value of 10 mol / L or less.

 50

 As the compound represented by the general formula (I),

 (—) — 2 — [(2S) — 2 — [[(2R) — 2-Hydroxy-1- (4-hydroxy-1-hydroxymethylphenyl) ethyl] amino] -1,1,2,3,4-tetrahydronaphthalene _7_iloxy] _N, N-dimethylacetamide 0.5 sulfate monohydrate (hereinafter referred to as Compound 1);

2- [(2S) -2-[[(2RS) _2-Hydroxyl 2_ (4-hydroxy_ 3-hydroxymethylphenyl) ethyl] amino] -1,1,2,3,4-tetrahydronaphthalene _7_yloxy]- N, Ν-dimetinoreacetamide;

 2-[(2S) -2-[[(2RS) _2-Hydroxyl 2_ (4-hydroxy_ 3-hydroxymethylphenyl) ethyl] amino] -1,1,2,3,4-tetrahydronaphthalene _7_yloxy] acetamide ;

 4- [2- [(2S) -2-[[(2RS) _2-Hydroxyl 2_ (4-hydroxy_ 3-hydroxymethylphenyl) ethyl] amino] 1, 2, 3, 4 Tetrahydronaphthalene-7-yloxy] Acetinole] monoreforin;

1- [2-[(2S) -2-[[(2RS) -2 Hydroxy-1- (4-hydroxy-3 hydroxymethylphenyl) ethyl] amino] 1, 2, 3, 4 Tetrahydronaphthalene-7

1- [2-[(2S) -2-[[(2RS) -2 Hydroxy-1- (4-hydroxy-3 hydroxymethylphenyl) ethyl] amino] 1, 2, 3, 4 Tetrahydronaphthalene-7

(1) -1 [2-[(2S) -2-[[(2R) -2 Hydroxy-2- (4-hydroxy-3 hydroxymethylphenyl) ethyl] amino] 1,1,2,3,4-tetrahydro Naphthalene 1-7

(-)-l- [2-[(2S) _2 _ [[(2S) _2—Hydroxyl 2_ (4-hydroxy _3-hydroxymethylphenyl) ethyl] amino] -1,1, 2, 3, 4— Tetrahydronaphthalene 1-7

(-)-2-[(2S) _2 _ [[(2S) _2-Hydroxyl 2_ (4-hydroxy _3-hydroxymethylphenyl) ethyl] amino] 1,1,2,3,4-tetrahydronaphthalene _7_il Xyl] N, N dimethylacetamide;

 4-([(2S) -2-([(2RS) -2-hydroxy-1- (4-hydroxy-1-hydroxymethylphenyl) ethyl] amino] 1, 2, 3, 4-tetrahydronaphthalene-7-yloxy] _N , N_dimethylbutyric acid amide;

 (-) -4- [2- [(2S) _2 _ [[(2R) _2-Hydroxyl 2_ (4-hydroxy _3-hydroxymethylphenyl) ethyl] amino] 1,1, 2, 3, 4 Tetrahydronaphthalene mono 7-yloxy] acetyl] morpholine;

 (-)-l- [2-[(2S) _2 _ [[(2R) _2—Hydroxyl 2_ (4-hydroxy _3-hydroxymethylphenyl) ethyl] amino] 1,1, 2, 3, 4— Tetrahydronaphthalene-7-yloxy] acetyleno] piperidine;

 (-)-2-[(2S) _2 _ [[(2R) _2-Hydroxy-1 2_ [4-hydroxy-1 3_ (2-hydroxychetyl) phenyl] ethyl] amino] -1,1,2,3,4-tetrahydronaphthalene _7_ iloxy] N, N dimethylacetamide;

 (1) -2-[(2S) -2-([(2S) -2 Hydroxy-2- [4-hydroxy-3- (2 hydroxychetyl) phenyl] amino] 1, 2, 3, 4-tetrahydronaphthalene 7-Iloxy] N, N dimethylacetamide;

 2 — [(2S) —2 — [[(2RS) -2 Hydroxy-1- [4-hydroxy-1-3- (2 hydroxysityl) phenyl] ethyl] amino] 1, 2, 3, 4-tetrahydronaphthalene-7 —Iloxy] N, N dimethylacetamide;

 (1) 1 1 [2-[(2S) -2] [[(2R) -2 Hydroxy-2- [4-hydroxy-3- (2hydroxyethyl) phenyl] ethyl] amino] 1, 2, 3, 4 Tetrahydro Naphthalene

(_) _ 1_ [2 _ [(23) _2 _ [[(21 _2_hydroxy_2_ [4_hydroxy_3_ (2-hydroxyethyl) phenyl] ethyl] amino) 1,1,2,3,4-tetrahydronaphthalene -7-yloxy] acetyl] piperidine;

(-) -4- [2- [(2S) _2 _ [[(2R) _2-hydroxy _2_ [4-hydroxy _3_ (2-hydroxyethyl) phenyl] ethyl] amino] 1, 1, 2, 3, 4 Tetrahydronaphthalene-7_yloxy] acetyl] morpholine; (—) — 2 — [(2S) — 2 — [[(2R) —2 Hydroxy-1- (4-hydroxy-1-hydroxymethylphenyl) ethyl] amino] 1, 2, 3, 4 Tetrahydronaphthalene-7 yloxy ] N, N dimethylacetamide 0 · 5 sulfate;

 (-)-2-[(2S) _2 _ [[(2R) _2-Hydroxy-l 2_ (4-hydroxy_ 3-hydroxymethylphenyl) ethyl] amino] -l, 2,3,4-tetrahydronaphthalene_7_iloxy _N, N-dimethylacetamide 0.5L-tartrate;

 (-)-2-[(2S) _2 _ [[(2R) _2-Hydroxy-l 2_ (4-hydroxy_ 3-hydroxymethylphenyl) ethyl] amino] -l, 2,3,4-tetrahydronaphthalene_7_iloxy _N, N-dimethylacetamide 0.5D-tartrate;

 (-)-l- [2-[(2S) _2 _ [[(2R) _2—Hydroxyl 2_ (4-hydroxy _3-hydroxymethylphenyl) ethyl] amino] 1,1, 2, 3, 4— Tetrahydronaphthalene mono 7-yloxy] acetyl] pyrrolidine 0.5 sulfate;

 (1) -1 [2-[(2S) -2-[[(2R) -2 Hydroxy-2- (4-hydroxy-3 hydroxymethylphenyl) ethyl] amino] 1, 1, 2, 3, 4 Tetrahydronaphthalene 1-yloxy] acetyl] pyrrolidine 0.5L tartrate;

 (1) -1 [2-[(2S) -2-[[(2R) -2 Hydroxy-2- (4-hydroxy-3 hydroxymethylphenyl) ethyl] amino] 1, 1, 2, 3, 4 Tetrahydronaphthalene 1-yloxy] acetyl] pyrrolidine 0.5D tartrate;

 (1) -2-[(2S) -2-[[(2R) -2 Hydroxy-2- [4-hydroxy-3- (2 hydroxyxethyl) phenyl] amino] 1, 2, 3, 4-tetrahydronaphthalene 7-Iloxy] -N, N dimethylacetamide 0 · 5 sulfate;

 (-) -4- [2- [(2S) _2 _ [[(2R) _2-hydroxy _2_ [4-hydroxy _3_ (2-hydroxyethyl) phenyl] ethyl] amino] 1, 1, 2, 3, 4 Tetrahydronaphthalene_7_yloxy] acetyl] morpholine 0.5 sulfate; and the like. These compounds can be easily produced by methods described in the literature (for example, see Patent Document 1).

Since the compound represented by the general formula (I) exhibits a significant nociceptive threshold increasing action in STZ-induced diabetic rats and Seltzer model rats, it prevents or treats neuropathic pain. Useful for medical treatment. Neuropathic pain includes, for example, painful diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, kausanoregy, cancer pain or chronic pain after surgery or trauma .

[0018] The pharmaceutical composition of the present invention comprises necessary excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents,? Various dosage forms can be produced by conventional methods by mixing or diluting and dissolving the preparation carrier such as L-agent, dispersant, stabilizer and solubilizing agent as appropriate.

 [0019] The dosage form of the pharmaceutical composition of the present invention includes, for example, oral administration agents such as powders, granules, fine granules, dry syrups, tablets, capsules; injections, patches, suppositories, etc. Examples include parenteral agents, and oral agents are preferred.

 [0020] The pharmaceutical composition of the present invention may be used in combination with other medicaments having a symptom-relieving action for neuropathic pain as required! /. Other drugs that relieve symptoms of neuropathic pain include, for example, a neurotrophic vitamin (vitamin B), non-steroidal anti-inflammation

 12

 Drugs (indomethacin, diclofenac, etc.), aldose reductase inhibitors (epalrestat), lidocaine-like antiarrhythmic drugs (mexiletine, lidocaine, etc.), antidepressants (imipramine, ami, tryptine, mianserin, etc.), anticonvulsants (carbamazepine) , Phenytoin, etc.).

 Example

 Hereinafter, the present invention will be described in more detail based on experimental examples, but the present invention is not limited to the contents.

 [0022] [Test Example 1] Nociceptive threshold measurement test in STZ-induced diabetic rats (single dose test)

 STZ (50 mgZkg) was administered intravenously to induce diabetes in male SD rats. The test drug was administered 14 days after ST Z administration (10 patients in each group). As the test drug, Compound 1 (0.3, 1, 3 and 10 mg / kg) was used. Vehicle (0.5% methylcellulose) was administered to normal and control groups. The nociceptive threshold for pressure stimulation of the rat right hind limb before and 1 hour after administration of the test drug was measured by the Randall-Selitto method and compared with the control group.

 [0023] [Test Example 2] Nociceptive threshold measurement test in STZ-induced diabetic rats (repeated dose test)

 STZ (50 mgZkg) was administered intravenously to induce diabetes in male SD rats. STZ

(Paper 11191) From the day after the administration, the test drug was orally administered once a day for a total of 14 times (9 to 10 patients in each group). The normal group and the control group were administered with vehicle (0.5% methylcellulose). Randall-Selitto method was used to measure the nociceptive threshold for pressure stimulation of the rat right hind limb before administration (before administration of study drug) and after administration (1 hour after administration of study drug), and compared with the control group. Went.

[0024] [Test Example 3] Nociceptive threshold measurement test in Seltzer model rats

 Using 10 male 9-week-old SD rats, the right sciatic nerve was exposed under pentovanolebital (Nembutal injection (registered trademark)) anesthesia, and the nerve ligation group (7 cases) had a dorsal 1Z2 Was ligated with 5-0 nylon thread. The normal group (3 cases) only exposed the sciatic nerve. Three weeks after the production of the model, the vehicle (0.5% methylcellulose) was orally administered to the control group, and the test drug was orally administered to the nerve ligation group. The nociceptive threshold for pressure stimulation of the rat right hind limb was measured by Randall-Selitto method before administration (before administration of test drug) and after administration (1 hour after administration of test drug), and a comparison test before and after administration was performed.

 [0025] [Test Example 4] Nociceptive threshold measurement test in Seltzer model rats (repeated dose test)

 Thirty 7-week-old male SD rats were used, and the right sciatic nerve was exposed under pentovanolebital (Nembutal injection (registered trademark)) anesthesia, and the nerve ligation group (20 cases) was dorsal 1 / 2 was ligated with 6-0 silk thread. In the normal group (10 cases), only the sciatic nerve was exposed. From the day after the model was prepared, various test drugs were orally administered once a day for a total of 14 times. The vehicle (0.5% methylcellulose) was orally administered to the normal group and the control group, and the test drug was orally administered to the nerve ligation group. One hour after the last administration, the nociceptive threshold for pressure stimulation of the rat right hind limb was measured by the Randall-Selitto method, and compared with the control group.

 [0026] [Test Example 5] a AR and AR receptor binding test

 twenty two

 Rat cerebral cortex membrane preparation (AR) and pregnancy uterine fascia preparation (AR)

 twenty two

Then, ³ H_p-aminoclonidine and ³ H-dihydroalprenolol receptor binding tests were performed (3 cases each). The binding inhibition rate (IC value) of Compound 1 with respect to the binding ability of both receptors of the tracer was calculated, and the binding ability of Compound 1 to HI AR and / 3 AR was determined. So

 50 2 2

As a result, Compound 1, against AR and / 3 AR, respectively 5. 8x10- ⁷ mol / L and

 twenty two

1. The binding affinity (IC value) at a concentration of 4xlO_ ⁸ molZL was shown.

 50

[Example 1] Analgesic effect after single administration of Compound 1 (STZ-induced diabetic rats) According to the method of Test Example 1, the anti-nociceptive effect of Compound 1 (0.3, 1, 3 and lOmgZkg, oral administration) was examined. Table 1 shows the nociceptive threshold (mean soil standard error) after administration in each administration group. In the table, # indicates P, 0.05: significant difference from the control group (Aspin-Welch t test); * indicates P <0.05, significant difference from the control group (Steel test), respectively.

 [0028] As a result, in each administration group of Compound 1, the nociceptive threshold after administration increased in a dose-dependent manner, and administration of Compound 1 with 3 and lOmgZkg showed a clear analgesic effect.

 [0029] [Table 1] Table 1 Nociceptive threshold in STZ-induced diabetic rats (single administration)

[Example 2] Analgesic effect after repeated administration of Compound 1 (STZ-induced diabetic rats)

 According to the method of Test Example 2, the analgesic effect of repeated administration of Compound 1 (0.3, 1, 3, and 10 mg / kg, oral administration) was examined. Figure 1 shows the nociceptive threshold (mean value ± standard error) after administration in each administration group.

 [0031] As a result, repeated oral administration of Compound 1 for 14 days showed a clear increase in noxious threshold from a dose of 0.3 mg / kg in a dose-dependent manner. Repeated administration of Compound 1 showed an even stronger nociceptive threshold effect compared to a single dose, improving to the same level of nociceptive threshold as the normal group.

 [Example 3] Analgesic effect after single administration of Compound 1 (Seltzer model)

 According to the method of Test Example 3, the analgesic effect of Compound 1 (10 mg / kg, oral administration) was examined. Figure 2 shows the nociceptive threshold (average soil standard error) before and after administration in each group.

[0033] As a result, the nociceptive threshold of the right hind limb in the nerve ligation group was positive after 3 weeks of model preparation. It was significantly lower than that of the normal group. Compound 1 treatment significantly improved the nociceptive threshold of the nerve ligation group compared to pre-dose.

 [0034] [Example 4] Analgesic effect of compound 1 repeated administration (Seltzer model)

 According to the method of Test Example 4, the analgesic effect of repeated administration of Compound 1 (10 mg / kg, oral administration) was examined. Figure 3 shows the nociceptive threshold (average soil standard error) before and after administration in each group.

 [0035] As a result, repeated administration of Compound 1 for 14 days significantly improved the right hindlimb nociceptive threshold compared to that of the control group.

[0036] As described above, the compound represented by the general formula (I) of the present invention exhibits a significant nociceptive threshold increasing action in STZ-induced diabetic rats and Seltzer model rats, and prevents neuropathic pain. Or it is very useful for treatment.

 Industrial applicability

[0037] The pharmaceutical composition of the present invention is extremely useful as a preventive or therapeutic agent for neuropathic pain.

Claims

Scope of request  General formula

(In the formula, A is a lower alkylene group, B is an amino group, a di-lower alkylamino group, or a 3- to 7-membered alicyclic anamino group optionally containing an oxygen atom in the ring, and n is Is an integer of 1 or 2, a carbon atom marked with * indicates a carbon atom in R configuration or S configuration or a carbon atom mixed with them, and a carbon atom marked with (S) is a carbon atom in S configuration Or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof as an active ingredient. A therapeutic pharmaceutical composition. '  [2] The 3,4-disubstituted phenylethanolaminotetralin carboxylic acid amide derivative represented by the general formula (I) is represented by (_)-2 — [(2S) -2 — [[(2R) -2 —Hydroxy-2_ (4-hydroxy-3-hydroxymethylphenyl) ethinole] amino] -1,2,3,4-tetrahydronaphthalene-1-7-yloxy] _N, N-dimethylacetamide or pharmacologically The pharmaceutical composition according to claim 1, which is an acceptable salt.  [3] The neuropathic pain is painful diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, causalgia, cancer pain or chronic pain after surgery or trauma. The pharmaceutical composition according to 1 or 2.  [4] Neurotrophic vitamins, non-steroidal anti-inflammatory drugs, aldose reductase inhibitors, lidocaine-like antiarrhythmic drugs, antidepressants, anticonvulsant drugs in combination with one or more selected drugs The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is used.  [5] 3,4-Disubstituted phenylethanolaminotetralin canolebon acid represented by the general formula (I) Corrected form (rules am). A method for preventing or treating neuropathic pain, comprising administering an effective amount of an amide derivative or a pharmacologically acceptable salt thereof.  A 3,4-disubstituted phenolinoethanolaminotetralincarboxylic acid amide derivative represented by the general formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a preparation for the prevention or treatment of neuropathic pain Use of salt. Corrected 'paper rules'