JP2003277357A - New derivative having inhibitory activity against voltage-dependent sodium channel and medicine composition comprising the same as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new derivative having inhibitory activity against a voltage-dependent sodium channel, which is expected to be a therapeutic agent for various diseases associated with a voltage-dependent sodium channel. <P>SOLUTION: The new compound having inhibitory activity against a voltage- dependent sodium channel is represented by general formula (I), formula (II), formula (III) and formula (IV). The medicine composition contains the compound as an active ingredient. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel derivative having a voltage-gated sodium channel inhibitory activity and a pharmaceutical composition containing the derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Voltage-gated sodium channels are complex proteins widely distributed in nerves, skeletal muscles, and cardiomyocytes, and play a major role in the generation and conduction of action potentials. The channel forms a pore 260 kD
33-36k that controls α subunit of a, opening and closing, etc.
It is composed of β ₁ and β ₂ subunits of Da (J. Bio
l. Chem., 259, pp. 1667-1675, 1984.
, And recently β ₃ subunit (Proc. Natl. Acad. Sci. USA, vol. 97, 2308-2).
313, 2000). Further, it is known that subtypes include nerve type and muscle type.

The importance of voltage-gated sodium channels is clear from the fact that conventionally known neurotoxins such as tetrodotoxin and batrachotoxin exert a lethal effect by acting on this channel. Abnormality of channels causes abnormal excitation of nerve cells and is known to cause various diseases such as epilepsy.

Voltage-gated sodium channel inhibitors such as procaine and phenytoin are empirically used as local anesthetics,
It is used as an antiepileptic drug and its mechanism of action is 1
It was revealed in the 980s. Voltage-gated sodium channel inhibitors are still clinically used as local anesthetics, antiarrhythmic drugs, and antiepileptic drugs. However, the efficacy and safety are not satisfactory. For example, among the antiepileptic drugs, carbamazepine and phenytoin can control epileptic seizures in the majority of patients well, but 20 to 40% of these drugs have epilepsy. However, it is still intractable, and is accompanied by many side effects such as cognitive decline, liver damage, and blood damage. Therefore, there is a need for a voltage-gated sodium channel inhibitor that has no side effects and has a wide range of applications.

In recent years, drugs having a voltage-gated sodium channel inhibitory activity include, in addition to the above-mentioned local anesthetics, antiarrhythmic drugs and antiepileptic drugs, pain therapeutic drugs, neuroprotective drugs,
Since it is expected to be effective as a psychotropic drug, the development of these as indications is also in progress.

[0006]

At present, many voltage-gated sodium channel inhibitors are clinically used as local anesthetics, antiarrhythmic drugs, and antiepileptic drugs, but their efficacy and safety have been satisfied. There is nothing yet. Furthermore, although voltage-gated sodium channel inhibitors have been developed as pain therapeutic agents, neuroprotective agents, and psychotropic agents, their clinical use is rare. In view of such circumstances, an object of the present invention is to provide a compound having a voltage-gated sodium channel inhibitory activity and a pharmaceutical composition containing these as an active ingredient.

[0007]

Means for Solving the Problems As a result of intensive studies to find a more effective and safer voltage-gated sodium channel inhibitory active substance, the present inventors have found that an antifungal active substance produced by the genus Aspergius. Reported as (J.Anti
biotics, 41, 1774-1779, 1988.
Year, J. Antibiotics, 42, 1184-1185.
P., 1989) preusin
Was found to have voltage-gated sodium channel inhibitory activity. Furthermore, they have found that a plasmin derivative having various chemical modifications at the 3-position hydroxyl group of plasmin has a voltage-gated sodium channel inhibitory activity and completed the present invention.

That is, the present invention has the following configurations. 1. The following general formula (I)

[Chemical 5] [Wherein R is a hydrogen atom, a linear or branched C ₁ -C ₅ alkoxy group which may have a substituent, a linear or branched C ₁ -C which may have a substituent. ₇ alkylsulfonyloxy group, optionally substituted C _{6 to} C ₁₈
Represents an arylsulfonyloxy group, a linear or branched C ₁ -C ₅ acyloxy group which may have a substituent, and a halogen atom. ] The compound represented by these, or its pharmaceutically acceptable salt. 2. A compound represented by the following formula (II), or a pharmaceutically acceptable salt thereof.

[Chemical 6] 3. A compound represented by the following formula (III), or a pharmaceutically acceptable salt thereof.

[Chemical 7] 4. A compound represented by the following formula (IV), or a pharmaceutically acceptable salt thereof.

[Chemical 8] 5. A pharmaceutical composition comprising the compound according to any one of 1 to 4 above or at least one of pharmaceutically acceptable salts thereof as an active ingredient. 6. The pharmaceutical composition according to the above 5, which is a local anesthetic, antiarrhythmic drug, antiepileptic drug, pain therapeutic drug, neuroprotective drug, and psychotropic drug. 7. A voltage-gated sodium channel inhibitor containing as an active ingredient at least one of the compound according to any one of 1 to 4 above or a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, lower alkyl means, for example, a methyl group, an ethyl group and the like having 1 carbon atom.
~ 6 straight chain alkyl and branched chain alkyl such as isopropyl, isobutyl, t-butyl, and the like. The alkoxy group is, for example, a C _{1 to} C ₅ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and the like, preferably a methoxy group. The alkylsulfonyloxy group represents, for example, methanesulfonyloxy, ethanesulfonyloxy or the like, and preferably represents a methanesulfonyloxy group. The arylsulfonyloxy group includes phenylsulfonyloxy, tolylsulfonyloxy, xylylsulfonyloxy, biphenylsulfonyloxy and the like, and preferably p-toluenesulfonyloxy group.
The acyloxy group represents, for example, formyloxy, acetoxy and the like, preferably formyloxy group. In the present invention, the phrase “may have a substituent” with respect to a certain functional group means that the functional group may have one or two or more arbitrary substituents. 2
When they have the above substituents, they may be the same or different. Examples of the substituent include a linear or branched C _{1 to} C ₅ alkoxy group, a hydroxyl group, a halogen atom, a nitro group, an amino group, a formyl group, an amide group and the like.

The compounds of general formula (I) provided in the present invention can exist as salts. Examples of the salt include pharmaceutically acceptable salts. Examples of possible salt forms include hydrohalic acid salts such as hydrofluoric acid, hydrochloric acid and hydrobromic acid, sulfates, nitrates,
Inorganic acid salts such as phosphates, perchlorates, carbonates, acetic acid,
Trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid,
Carboxylic acid salts such as lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, malic acid, amino acid salts such as alginic acid, aspartic acid, glutamic acid, methanesulfone Examples thereof include acids and sulfonates such as p-toluenesulfonic acid.

Formula (II), Formula (III) and Formula (IV
Like the compound of the general formula (I), the compound of the above) can be present as a salt, and the specific examples of the possible salt form thereof may be the same as those of the general formula (I).

General formula (I), formula (II), formula (III)
And the compound of formula (IV) has voltage-gated sodium channel inhibitory activity. Therefore, it can be administered as a medicine to animals including humans. Specifically, it is useful as a local anesthetic, antiarrhythmic drug, antiepileptic drug, pain therapeutic drug, neuroprotective drug, psychotropic drug, and the like.

The general formula (I
), The formula (II), the formula (III) and the formula (IV) can be produced by using the following pleucine (a compound in which R is a hydroxyl group in the general formula (I)) and a derivative thereof as starting materials.

[0014]

[Chemical 9]

The starting material, pleucine, is, for example, JP-A-1-299268, J. Antibiotics, Volume 41, 17
74-1779, 1988, J. Antibiotics, 4
Volume 2, pages 1184 to 1185, 1989.

The compound in which R is an alkoxy group in the general formula (I) can be obtained by alkylating the hydroxyl group of pleucine in which R is a hydroxyl group in the general formula (I).
More specifically, a solvent (eg dimethylformamide)
In the presence of 1 to 30 equivalents of a base (eg, sodium hydride), 1 to 20 equivalents of an alkylating agent (eg, methyl iodide) is added, and the mixture is reacted for 30 minutes to 10 hours under cooling to obtain the target compound. Can be obtained.

The compound of the general formula (I) in which R is an alkylsulfonyloxy group or an arylsulfonyloxy group can be prepared by adding a solvent (for example, dichloromethane,
Pyridine) in the presence of 1 to 10 equivalents of a base (eg, triethylamine, pyridine), 1 to 20 equivalents of a sulfonylating agent such as methanesulfonyl chloride or p-toluenesulfonyl chloride, and at room temperature or under cooling.
It can be obtained by reacting for 0 minutes to 5 hours.

The compound of the general formula (I) in which R is an acyloxy group can be obtained by carrying out the Mitsunobu reaction (Synthesis, page 1-28, 1981) using pleucine as a starting material. More specifically, in pleucine, in a solvent (eg, dichloromethane, chloroform), 1
~ 20 equivalents of triphenylphosphine, 1-20 equivalents of azodicarboxylic acid diethyl ester, and 1-20 equivalents of alkylcarboxylic acid (e.g. formic acid, acetic acid) are added,
It can be obtained by cooling and reacting for 30 minutes to 5 hours.

The compound of the general formula (I) in which R is halogen is prepared by adding pleucine in a halogen donating solvent (for example, carbon tetrachloride or carbon tetrabromide) with 1 to 10 equivalents of triphenylphosphine at room temperature to under heating under reflux. It is produced by reacting for 1 to 10 hours.

The compound of the formula (II) has the general formula (I)
Is a compound having an alkylsulfonyloxy group or an arylsulfonyloxy group as a starting material, and a solution of this compound (for example, dimethylsulfoxide-water mixture) is added with 1 to
It can be obtained by adding 20 equivalents of a base (eg sodium hydroxide, potassium hydroxide) and reacting at 60 to 100 ° C. for 5 to 24 hours. Or the general formula (I)
Then, a compound in which R is a halogen is used as a starting material, and a solution of this compound (for example, dimethyl sulfoxide) is added with 1 to 2
It can be obtained by adding an alkaline solution such as a saturated sodium hydroxide aqueous solution corresponding to 0 equivalent and reacting at 60 to 100 ° C. for 5 to 24 hours.

The compound of the general formula (I) in which R is hydrogen can be produced by carrying out a reduction reaction using the compound of the formula (II) as a starting material. More specifically, a metal catalyst (eg, palladium carbon) is added to a compound represented by the formula (II) in a solvent (eg, methanol, ethanol) under a hydrogen atmosphere, and the reaction is performed at room temperature for 10 minutes to 5 hours. Can be obtained by

The compound of formula (III) is
It can be obtained by adding 1 to 10 equivalents of triphenylphosphine and 1 to 10 equivalents of diethyl azodicarboxylic acid in a solvent (for example, carbon tetrachloride) under cooling and reacting at room temperature for 1 to 10 hours.

The compound of the formula (IV) is produced by adding a small amount of thionyl chloride to pleucine in a solvent (for example, pyridine) and reacting at room temperature for 1 to 10 hours.

The general formula (I), the formula (
The compounds II), (III) and (IV) have voltage-gated sodium channel inhibitory activity. Therefore, it can be used as a therapeutic or prophylactic agent for diseases involving voltage-gated sodium channels in humans and non-human animals. Specifically, it is useful as a local anesthetic, antiarrhythmic drug, antiepileptic drug, pain treatment drug, neuroprotective drug, psychotropic drug, and the like.

The pharmaceutical composition containing the compound according to the present invention as an active ingredient can be administered orally or parenterally (for example, by intravenous injection,
Intramuscular injection, subcutaneous administration, rectal administration, transdermal administration, etc.) can be used for administration to humans and non-human animals.

Therefore, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is made into a suitable dosage form depending on the administration route, and specifically, mainly injections such as intravenous injection and intramuscular injection, capsules, Tablets, granules, powders, pills, fine granules,
It can be prepared into oral preparations such as troches, rectal preparations, oily suppositories, aqueous suppositories and the like. These various formulations include commonly used excipients, fillers, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersants, buffers, preservatives, solubilizing agents, preservatives, It can be produced by using a flavoring agent, a soothing agent, a stabilizer and the like. Examples of non-toxic additives that can be used include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or salts thereof, gum arabic, polyethylene glycol. ,
Examples include syrup, petrolatum, glycerin, ethanol, poloethylene glycol, citric acid, sodium chloride, sodium nitrite, sodium phosphate and the like.

The dose as a medicine varies depending on the age, body weight, type and degree of illness and administration route, but when administered orally to humans, it is 0.02 to 20 per day per adult.
0 mg / kg, 0.01 to 1 for intravenous administration
This is administered within the range of 00 mg / kg once a day or divided into several times.

[0028]

The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.

Example 1. 1-Methyl-3-methoxy-5-nonyl
-2- Phenylmethyl -pyrrolidine (Compound 1) Methyl iodide was added to a solution of preusin (50.0 mg) in dimethylformamide (0.5 ml) at 0 ° C under an argon atmosphere.
(16.0 μl) and 60% sodium hydride (121 mg) were added, and the mixture was stirred for 4 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the organic layer was washed with 5% potassium hydrogen sulfate solution, and evaporated under reduced pressure. Preparative thin layer chromatography of the residue (developing solvent chloroform / methanol = 10/1)
Compound 1 (23.9 mg) was obtained after purification. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 3.6 Hz
), 1.28, (14H, m), 1.46 (1H, m), 1.75 (2H, br
-s), 2.03 (2H, m), 2.32 (1H, m), 2.33 (3H, s
), 2.79 (1H, br-d, J = 12.7 Hz), 3.02 (1H, br-d
d, J = 10.0, 12.9 Hz), 3.19 (3H, s), 3.31 (1H,
br-s), 7.19-7.29 (5H, m) FAB-MS (m / z): 332 (M + H) ⁺

Example 2. 1-Methyl-5-nonyl-2- phenyl
Lumethyl-pyrrolidin-3-yl methanesulfonate
Compound 2) Pleucine (222 mg) in dichloromethane (1 ml)
To the mixture were added triethylamine (245 μl) and methanesulfonyl chloride (135 μl), and the mixture was stirred at room temperature for 45 minutes.
The reaction mixture was poured into a 5% aqueous potassium hydrogen sulfate solution, extracted with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent chloroform / acetone = 5/1) to obtain compound 2 (276 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 H
z), 1.28-1.41 (15H, m), 1.77 (1H, m), 1.90 (1
H, ddd, J = 2.4, 7.8, 10.0 Hz), 2.23 (1H, m), 2.35
(3H, s), 2.42 (1H, m), 2.70 (1H, m), 2.80 (3
H, s), 2.95 (1H, d, J = 9.5 Hz), 3.02 (1H, dd, J =
4.6, 14.1 Hz), 4.91 (1H, m), 7.20-7.33 (5H, m
) FAB-MS (m / z): 396 (M + H) ⁺

Example 3. 1-Methyl-5-nonyl-2-phenyl
Methyl-pyrrolidin-3-yl p-toluenesulfonate
(Compound 3) p-toluenesulfonyl chloride (63 mg) was added to a solution of pleucine (51 mg) in pyridine (1 ml), and the mixture was mixed at 0 ° C for 4
Stir for 5 minutes. The reaction mixture was poured into 5% aqueous potassium hydrogen sulfate solution, extracted with chloroform, and the solvent was evaporated under reduced pressure. Preparative thin layer chromatography (hexane)
/ Ethyl acetate = 2/1) and purified by compound 3 (13.7 mg
) Got. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (3H, t, J = 6.6 Hz
), 1.15-1.32 (15H, m), 1.66 (2H, m), 2.11-2.20
(2H, m), 2.27 (3H, s), 2.45 (3H, s), 2.54 (
1H, ddd, J = 5.8, 8.0, 10.5 Hz), 2.84 (1H, s),
2.86 (1H, d, J = 2.4 Hz), 4.83 (1H, m), 7.12-7.
31 (7H, m), 7.73 (2H, d, J = 8.3Hz) FAB-MS (m / z): 472 (M + H) ⁺

Example 4 1-Methyl-5-nonyl-2- phenyl
Lumethyl-pyrrolidin-3-yl formate (Compound 4) Preucine (188.2 mg) in dichloromethane (3 ml
), Triphenylphosphine (1.56 g) at 0 ° C, 40%
Azodicarboxylic acid diethyl ester-toluene solution (2.
6 ml) and formic acid (225 μl) were added, and the mixture was stirred for 50 minutes. The reaction mixture was poured into water, extracted with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent hexane, 1%-, 3%-, 5%-, 10% -acetone-hexane, the target compound was eluted with 3% -acetone-hexane) to give compound 4 ( 99.3 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.6 Hz
), 1.15-1.33 (16H, m), 1.63 (1H, m), 1.68 (1
H, m), 1.80 (1H, dd, J = 6.1, 12.2 Hz), 2.33 (3
H, s), 2.45 (1H, m), 2.68 (1H, m), 2.95 (1H,
dd, J = 8.3, 16.8 Hz), 4.98 (1H, br-d, J = 7.1 Hz
), 7.18-7.30 (5H, m), 7.77 (1H, s) FAB-MS (m / z): 346 (M + H) ⁺

Example 5. 3-Chloro-1-methyl-5-nonyl-
2- Phenylmethyl- pyrrolidine (Compound 5) Triphenylphosphine (133.5 mg) was added to carbon tetrachloride solution (1 ml) of pleucine (53.7 mg) and the mixture was mixed at 60 ° C for 3
The mixture was stirred for 45 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent chloroform / acetone = 50/1) to obtain Compound 5 (47.4 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.6 Hz
), 1.15-1.35 (15H, m), 1.65 (1H, m), 1.84 (1
H, ddd, J = 7.6, 9.3, 16.8 Hz), 2.07 (1H, ddd, J =
3.4, 6.5, 13.6 Hz), 2.34 (3H, s), 2.63 (1H, m
), 2.76 (1H, dd, J = 8.1, 15.3 Hz), 2.86 (1H,
d, J = 5.1 Hz), 2.89 (1H, dd, J = 3.4,3.4 Hz), 3.
92 (1H, ddd, J = 3.7, 3.7, 7.6 Hz), 7.20-7.31 (5
H, m) FAB-MS (m / z): 336 (M + H) ⁺

Example 6. 1-Methyl-5-nonyl-2- phenyl
Rumethyl-2,5-dihydro-1H-pyrrole (Compound 6) 0.1 ml of water and sodium hydroxide (261.6 mg) were added to a dimethylsulfoxide solution (0.6 ml) of the compound 2 (266.6 mg) obtained in Example 2 above. In addition, the mixture was stirred at 60 ° C. for 8 hours and 40 minutes. The reaction mixture was poured into 5% aqueous potassium hydrogen sulfate solution, extracted with chloroform, and the solvent was evaporated under reduced pressure. Preparative thin layer chromatography (developing solvent chloroform /
Acetone = 3/1) for purification to obtain Compound 6 (40.9 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz
), 1.22-1.40 (15H, m), 1.53 (1H, m), 2.42 (3
H, s), 2.58 (1H, dd, J = 8.8, 12.9 Hz), 2.91 (1
H, dd, J = 4.9, 12.9 Hz), 3.29 (1H, m), 3.49 (1
H, m), 5.59 (1H, d, J = 6.1 Hz), 5.67 (1H, d, J
= 6.1 Hz), 7.18-7.31 (5H, m) FAB-MS (m / z): 300 (M + H) ⁺

Example 7. 1-Methyl-5-nonyl-2- phenyl
Rumethyl-2,5-dihydro-1H-pyrrole (compound 6) To the dimethyl sulfoxide solution (5 ml) of the compound 5 (328.6 mg) obtained in Example 5 above was added 26.7N sodium hydroxide aqueous solution (400 μl), The mixture was stirred at 75 ° C for 17 hours.
Then, the reaction mixture was poured into water, extracted with chloroform, and the solvent was evaporated under reduced pressure. Preparative thin layer chromatography of the residue (developing solvent chloroform / acetone = 10 /
Purification in 1) provided compound 6 (181.9 mg).

Example 8. 1-Methyl-5-nonyl-2- phenyl
Lumethyl-pyrrolidine (Compound 7) Compound 6 (28.1 mg) obtained in Example 6 or 7 above.
10% Palladium carbon was added to the methanol solution (1 ml) of and the mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere. The reaction mixture was filtered, the filtrate was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent chloroform / acetone = 3/1) to obtain compound 7 (15.2 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (3H, t, J = 6.8 Hz
), 1.21-1.39 (16H, m), 1.46 (1H, m), 1.63 (1
H, m), 1.70 (1H, m), 1.79 (1H, m), 2.12 (1H,
m), 2.36 (3H, s), 2.40 (1H, m), 2.45 (1H, m
), 3.08 (1H, dd, J = 3.2, 12.4 Hz), 7.18-7.30 (
5H, m) TSP-MS (m / z): 302 (M + H) ⁺

Example 9. 3-N- [N, N'-di (ethoxycarbo)
Nyl) hydrazino] -1-methyl-5-nonyl-2-phenylmethyl
Le-pyrrolidine (Compound 8) Preucine (17.3 mg) in carbon tetrachloride (0.5 ml)
Triphenylphosphine (72.2 mg), 40% azodicarboxylic acid diethyl ester-toluene solution (120 μ
l) was added, and the mixture was gradually warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into a 5% aqueous potassium hydrogen sulfate solution, extracted with chloroform, and the solvent was evaporated under reduced pressure. Preparative thin layer chromatography of the residue (developing solvent chloroform / acetone =
5/1) to obtain the compound 8 (18.1 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.88 (3H, t, J = 6.6 Hz
), 1.15-1.30 (16H, m), 1.33 (6H, t, J = 7.3 Hz
), 1.62 (1H, br-s), 1.80 (1H, br-s), 1.96 (1
H, br-s), 2.30 (3H, br-s), 2.42 (1H, br-s),
2.60 (1H, br-s), 3.04 (1H, br-s), 4.14 (1H, b
rs), 4.32 (4H, q, J = 7.1 Hz), 7.18-7.28 (5H,
m) FAB-MS (m / z): 476 (M + H) ⁺

Example 10. Bis (1-methyl-5-nonyl-2)
-Phenylmethyl-pyrrolidin-3-yl) sulfite
Compound 9) 0.1 ml of thionyl chloride was added to a pyridine solution (0.5 ml) of preucine (18.1 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a 5% aqueous potassium hydrogen sulfate solution, extracted with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent chloroform / acetone = 10/1) to obtain Compound 9 (19.6 mg). ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (6H, t, J = 6.6 Hz
), 1.20-1.35 (30H, m), 1.67-1.75 (4H, m), 2.11
(2H, m), 2.22 (3H, s), 2.24 (3H, s), 2.27-2.
36 (2H, m), 2.50-2.57 (2H, m), 2.77-2.91 (3H,
m), 2.98 (1H, dd, J = 8.3, 14.1 Hz), 4.64 (1H,
m), 4.71 (1H, m), 7.18-7.31 (10H, m) FAB -MS (m / z): 681 (M + H) ⁺

Test Example Batrachotoxin Binding Inhibitory Activity The voltage-dependent sodium channel inhibitory activity was measured as the binding inhibition activity of batrachotoxin to the channel as shown below.

Rat forebrain was homogenized in a 10-fold volume of 0.32 M sucrose solution using a Teflon (registered trademark) -glass homogenizer, and the resulting homogenate was diluted to 1000
Centrifuge at xg for 10 minutes. The supernatant was centrifuged at 39000 xg for 20 minutes to obtain a precipitate. The precipitate is added to the assay buffer (50 mM Hepes / Tris (pH 7.4), 130 mM choline chloride, 5.5 mM glucose, 0.8 mM magnesium sulfate,
It was washed by centrifugation with 5.4 mM potassium chloride). Do this operation 2
The membrane fraction finally obtained was used as a voltage-gated sodium channel membrane fraction.

The binding inhibition experiment was carried out by using the obtained membrane fraction and the radioligand [ ³ H] -batracotoxinin A 20-α-benzoate, [benzoyl-2,5- ³ H]-(49.0 Ci / mmol). It was done using. In the presence of the test compound, 100 μl of assay buffer containing 1 mg / ml bovine serum albumin, 1 μM tetrodotoxin, and 0.03 mg / ml scorpion venom contained the membrane fraction (protein amount 50
μg) and a final concentration of 10 nM [ ³ H] -batracotoxinin A 2
Add 0-α-benzoate, [benzoyl-2,5- ³ H]-,
Incubated at 37 ° C for 90 minutes. Unifilter GF /
It was filtered with a B filter (manufactured by Packard) and washed 3 times with 200 μl of assay buffer. After drying at 50 ° C. for 1 hour, 30 μl of Microscint 20 (manufactured by Packard) was added as a scintillator, and the radioactivity was measured using Top Count (manufactured by Packard). Non-specific binding was determined by adding a large excess of veratridine (final concentration 0.3 mM). The binding inhibition rate of batrachotoxin in the presence of the test compound was calculated by the following formula.

[Formula 1]

The batrachotoxin binding inhibition rate of the test compound was measured by the above method, and the concentration at which it inhibited 50% (IC
₅₀ ) was defined as batrachotoxin binding inhibitory activity. The results are shown in Table 1.

【table 1】

The compounds of the present invention showed voltage-gated sodium channel inhibitory activity as shown in Table 1.

[0044]

INDUSTRIAL APPLICABILITY The novel derivative of the present invention has a voltage-gated sodium channel inhibitory activity as shown in Test Examples, and a pharmaceutical composition containing these as an active ingredient is associated with voltage-gated sodium channel. It is effective against various diseases, such as local anesthetics, antiarrhythmic drugs, antiepileptic drugs, pain treatment drugs, neuroprotective drugs, and psychotropic drugs.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 25/08 A61P 25/08 25/18 25/18 29/00 29/00 43/00 111 43/00 111 C07D 207/10 C07D 207/10 207/12 207/12 207/14 207/14 207/20 207/20 F term (reference) 4C069 AA12 AB03 BB02 BB08 BC05 BC19 BC34 4C086 AA01 AA02 AA03 BC06 BC07 MA01 MA04 NA14 ZA01 ZA06 ZA08 ZA18 ZA36 ZC02

Claims (7)

[Claims] 1. The following general formula (I): [Wherein R is a hydrogen atom, a linear or branched C ₁ -C ₅ alkoxy group which may have a substituent, a linear or branched C ₁ -C which may have a substituent. ₇ alkylsulfonyloxy group, optionally substituted C _{6 to} C ₁₈
Represents an arylsulfonyloxy group, a linear or branched C ₁ -C ₅ acyloxy group which may have a substituent, and a halogen atom. ] The compound represented by these, or its pharmaceutically acceptable salt. 2. A compound represented by the following formula (II), or a pharmaceutically acceptable salt thereof. [Chemical 2] 3. A compound represented by the following formula (III):
Or a pharmaceutically acceptable salt thereof. [Chemical 3] 4. A compound represented by the following formula (IV), or a pharmaceutically acceptable salt thereof. [Chemical 4] 5. A pharmaceutical composition containing as an active ingredient at least one of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. 6. A local anesthetic, an antiarrhythmic drug, an antiepileptic drug, a pain therapeutic drug, a neuroprotective drug, and a psychotropic drug.
The pharmaceutical composition according to. 7. A voltage-gated sodium channel inhibitor containing as an active ingredient at least one of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.