JP2001131153A - Dihydroquinoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which has an analgesic action and is useful as an analgesic, especially an analgesic for mitigating neurogenic pain, and to provide a medicinal composition containing the same as an active ingredient. SOLUTION: The dihydroquinoline derivative represented by the general formula (1) (R1, R2 and R6 are each H, a lower alkoxy or a halogen atom; R3 is a lower alkyl; R4 is a phenyl lower alkoxy lower alkyl which has one to three lower alkoxy groups on the phenyl ring, or a phenoxy lower alkyl group which has one to three lower alkoxy groups on the phenyl ring; R5 is phenyl which often has one to three lower alkoxy groups).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel dihydroquinoline derivative.

[0002]

2. Description of the Related Art The derivative of the present invention is a novel compound which has not been described in any literature.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug, particularly a compound having an analgesic action and useful as an analgesic.

[0004] The present inventors have been researching and developing compounds having pharmacological activity useful as pharmaceuticals, and in the course of the treatment, they have a hypoglycemic action and are used as antihyperglycemic agents for the treatment and treatment of diabetes. We succeeded in synthesizing a series of dihydroquinoline compounds effective for prevention, and filed a patent application for an invention relating to the compounds (see Japanese Patent Application Laid-Open No. 9-255658).

[0005] As a result of subsequent studies, the present inventors have found that a series of other novel dihydroquinoline derivatives having a dihydroquinoline skeleton in common with the above-mentioned compounds, but which are clearly distinguished in the 1-position substituent, have been found. With success, they have found that these novel derivatives are essentially different from the hypoglycemic action of the above compounds and have an analgesic action that cannot be predicted from the action. The invention has been completed.

[0006]

According to the present invention, there is provided a novel dihydroquinoline derivative represented by the following general formula (1). General formula (1):

[0007]

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Wherein R ¹ , R ² and R ⁶ each represent a hydrogen atom, a lower alkoxy group or a halogen atom;
³ represents a lower alkyl group, and R ⁴ represents a phenyl lower alkoxy lower alkyl group having 1 to 3 lower alkoxy groups on a phenyl ring or a phenoxy lower alkyl group having 1 to 3 lower alkoxy groups on a phenyl ring. Indicates that
R ⁵ represents a phenyl group which may have 1 to 3 lower alkoxy groups. ]

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1) representing the derivative of the present invention, the following groups can be exemplified as the groups represented by R ^{1 to} R ⁶ .

That is, the lower alkoxy groups represented by R ¹ , R ² and R ⁶ and the lower alkoxy groups as substituents on the phenyl ring represented by R ⁴ and R ⁵ include methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy group, etc.
6 linear or branched alkoxy groups.

The halogen atoms represented by R ¹ , R ² and R ⁶ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The lower alkyl group represented by R ³ includes:
Methyl, ethyl, propyl, butyl, isobutyl, tert
Examples thereof include straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms such as -butyl, pentyl and hexyl groups.

Examples of the phenyl lower alkoxy lower alkyl group having 1 to 3 lower alkoxy groups on the phenyl ring represented by R ⁴ include 2-methoxybenzyloxymethyl, 3-methoxybenzyloxymethyl, and 4-methoxybenzyl. Oxymethyl, 2- (4-methoxybenzyloxy) ethyl, 3- (4-methoxybenzyloxy)
Propyl, 4- (4-methoxybenzyloxy) butyl, 5- (4-methoxybenzyloxy) pentyl, 6
-(4-methoxybenzyloxy) hexyl, 3,4-
Dimethoxybenzyloxymethyl, 2- (3,4-dimethoxybenzyloxy) ethyl, 3- (3,4-dimethoxybenzyloxy) propyl, 4- (3,4-dimethoxybenzyloxy) butyl, 5- (3,4 -Dimethoxybenzyloxy) pentyl, 6- (3,4-dimethoxybenzyloxy) hexyl, 3,4,5-trimethoxybenzyloxymethyl, 2- (3,4,5-trimethoxybenzyloxy) ethyl, 3- (3,4,5-trimethoxybenzyloxy) propyl, 4- (3,4,5
-Trimethoxybenzyloxy) butyl, 5- (3,
4,5-trimethoxybenzyloxy) pentyl, 6-
(3,4,5-trimethoxybenzyloxy) hexyl, 2- (3,4,5-trimethoxyphenyl) ethoxymethyl, 3- (3,4,5-trimethoxyphenyl)
Propoxymethyl, 4- (3,4,5-trimethoxyphenyl) butoxymethyl, 5- (3,4,5-trimethoxyphenyl) pentyloxymethyl, 6- (3,4
5-trimethoxyphenyl) hexyloxymethyl, 2
-[2- (3,4,5-trimethoxyphenyl) ethoxy] ethyl, 3- [3- (3,4,5-trimethoxyphenyl) propoxy] propyl, 4- [4- (3,4,
5-trimethoxyphenyl) butoxy] butyl, 5-
[5- (3,4,5-trimethoxyphenyl) pentyloxy] pentyl, 6- [6- (3,4,5-trimethoxyphenyl) hexyloxy] hexyl, 2,4,5
-Trimethoxybenzyloxymethyl, 2- (2,4,
5-trimethoxybenzyloxy) ethyl, 3- (2,
4,5-trimethoxybenzyloxy) propyl, 4-
(2,4,5-trimethoxybenzyloxy) butyl,
Examples thereof include 5- (2,4,5-trimethoxybenzyloxy) pentyl and 6- (2,4,5-trimethoxybenzyloxy) hexyl group.

The phenoxy lower alkyl group having 1 to 3 lower alkoxy groups on the phenyl ring represented by R ⁴ includes 2-methoxyphenoxymethyl, 3-methoxyphenoxymethyl, 4-methoxyphenoxymethyl,
2- (4-methoxyphenoxy) ethyl, 3- (4-methoxyphenoxy) propyl, 4- (4-methoxyphenoxy) butyl, 5- (4-methoxyphenoxy) pentyl, 6- (4-methoxyphenoxy) hexyl, 3,
4-dimethoxyphenoxymethyl, 2- (3,4-dimethoxyphenoxy) propyl, 3- (3,4-dimethoxyphenoxy) propyl, 4- (3,4-dimethoxyphenoxy) butyl, 5- (3,4-dimethoxy) Phenoxy) pentyl, 6- (3,4-dimethoxyphenoxy)
Hexyl, 3,4,5-trimethoxyphenoxymethyl, 2- (3,4,5-trimethoxyphenoxy) ethyl, 3- (3,4,5-trimethoxyphenoxy) propyl, 4- (3,4 5- (trimethoxyphenoxy) butyl, 5- (3,4,5-trimethoxyphenoxy) pentyl, 6- (3,4,5-trimethoxyphenoxy)
Hexyl, 2,4,5-trimethoxyphenoxymethyl, 2- (2,4,5-trimethoxyphenoxy) ethyl, 3- (2,4,5-trimethoxyphenoxy) propyl, 4- (2,4 5- (trimethoxyphenoxy) butyl, 5- (2,4,5-trimethoxyphenoxy) pentyl, 6- (2,4,5-trimethoxyphenoxy)
Hexyl, 2,4,6-trimethoxyphenoxymethyl, 2- (2,4,6-trimethoxyphenoxy) ethyl, 3- (2,4,6-trimethoxyphenoxy) propyl, 4- (2,4 6-trimethoxyphenoxy) butyl, 5- (2,4,6-trimethoxyphenoxy) pentyl, 6- (2,4,6-trimethoxyphenoxy)
A hexyl group and the like can be exemplified.

The phenyl group which may have 1 to 3 lower alkoxy groups represented by R ⁵ includes 2-methoxyphenyl, 3-methoxyphenyl,
-Methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2,4
-Dimethoxyphenyl, 2,5-dimethoxyphenyl,
2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-diethoxyphenyl, 3,4-dipropoxyphenyl, 3,4-
Dibutoxyphenyl, 3,4-dipentyloxyphenyl, 3,4-dihexyloxyphenyl, 3,4,5-
Trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6
-Trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 3,4
5-triethoxyphenyl, 3,4,5-tripropoxyphenyl, 3,4,5-tributoxyphenyl, 3,
Examples thereof include a 4,5-tripentyloxyphenyl and a 3,4,5-trihexyloxyphenyl group.

The dihydroquinoline derivative represented by the above general formula (1) according to the present invention has an analgesic action and is useful as an analgesic, particularly as an analgesic for alleviating neuropathic pain. Further, the compound of the present invention has a characteristic that it does not show side effects such as dependence, addiction, hallucination and the like as seen in the conventional active ingredients for analgesics, and is particularly effective as an analgesic in these respects.

The compounds of the present invention which are more effective as analgesics include those represented by R ¹ , R ² and R ^{6 in the} general formula (1).
And the substitution positions of the 6-, 7-, and 8-positions, respectively.

In the compound, R¹ , R^Two And R⁶ But
Each is a hydrogen atom or R¹ , R ^Two And R⁶ Each
Is a lower alkoxy group, R¹ And R^Two Is each
A lower alkoxy group and R⁶ Is a hydrogen atom, or
Is R¹ And R⁶ Is a hydrogen atom and R^Two Is haloge
Compounds that are nitro atoms are preferred.

[0019] Particularly Among these preferred compounds, compounds wherein R ⁴ is a tri-lower alkoxyphenyl-lower alkoxy-lower alkyl group or a tri-lower alkoxy phenoxy lower alkyl group; compounds in which R ² is a chlorine atom; R ⁵ is 4
Compounds that are -methoxyphenyl or 3,4,5-trimethoxyphenyl are more preferred.

More preferred specific examples of each group in such a preferred compound include a group in which R ³ is a methyl group and R ⁴ is 2
A-(3,4,5-trimethoxybenzyloxy) ethyl group or a 3- (3,4,5-trimethoxyphenoxy) propyl group.

The most preferred compound is 7-chloro-1
-(4-methoxybenzyl) -3- [methyl-2-
(3,4,5-trimethoxybenzyloxy) ethylsulfonio] -2-oxo-1,2-dihydroquinoline-
4-olate, 7-chloro-1- (4-methoxybenzyl) -3- [methyl-3- (3,4,5-trimethoxyphenoxy) propylsulfonio] -2-oxo-1,
2-dihydroquinoline-4-olate and 7-chloro-
1- (3,4,5-trimethoxybenzyl) -3- [methyl-3- (3,4,5-trimethoxyphenoxy) propylsulfonio] -2-oxo-1,2-dihydroquinoline-4- Olates are included.

The compound of the present invention can be produced by various methods. Examples thereof will be described below with reference to reaction process formulas.

[0023]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above. According to the above scheme, first, compound (2) is reacted with iodobenzene diacetate in the presence of an alkali to obtain compound (3). In the reaction, water, dimethylformamide (DMF) or the like can be suitably used as a solvent, and sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or the like can be used as an alkali. The amount of the alkali and iodobenzene diacetate used is preferably an equimolar amount to a small excess amount based on the starting compounds, respectively. The reaction requires about 1 to 10 hours at a temperature of 0 ° C. to around room temperature. Done.

Next, the compound (1) of the present invention can be obtained by reacting the compound (3) obtained above with a thioether derivative (4). The reaction can be carried out using a lower alcohol-based solvent such as methanol, ethanol and trifluoroethanol and adding an appropriate amount of an acid catalyst such as p-toluenesulfonic acid and acetic acid. The amount of the thioether derivative (4) to be used is preferably about 1 to 10 times the molar amount of the compound (3), and the reaction is completed at room temperature to reflux temperature in about 10 minutes to 24 hours.

The compound (2) as a starting material in the above reaction scheme 1 can be produced, for example, by the method shown in the following reaction scheme 2.

[0027]

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Wherein R ¹ , R ² , R ⁵ and R ⁶ are as defined above. A represents a lower alkyl group, and X represents a halogen atom. That is, first, the compound (5) is reacted with the benzyl halide derivative (6) to obtain the compound (7). The reaction is carried out in an inert solvent such as dimethylformamide (DMF) or dimethylacetamide (DMA) in the presence of an alkali such as sodium hydride, potassium hydride, sodium amide, or sodium ethoxide at 0 ° C. to room temperature. This takes 1 to 20 hours. Here, the use amount of the benzyl halide derivative (6) and the alkali is preferably 1 to a small excess molar amount with respect to the compound (5). Next, compound (2) can be obtained by treating compound (7) obtained above with a base. The treatment reaction is carried out in an inert solvent such as benzene, toluene, xylene and cumene using 1 to excess equivalents of potassium-t-butoxide, sodium ethoxide, sodium hydroxide or the like as a base at a temperature around the boiling point of the solvent. It takes about a minute to 10 hours.

The compound (1) of the present invention obtained as described above is considered to have the following resonance structure, and can be represented by any of the structural formulas.

[0030]

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The target compound in each step shown in the above reaction scheme can be easily isolated and purified by ordinary separation means. Such means include, for example, adsorption chromatography,
Examples include preparative thin-layer chromatography, recrystallization, and solvent extraction.

The compound of the present invention has an optical isomer having an asymmetric center at a sulfur atom and / or a carbon atom, and the present invention includes any of optically active R-form, S-form and racemic-form. . The optically active substance can be separated by a conventional method, for example, a method using a known optical resolving agent.

The pharmaceutical composition of the present invention is prepared by using the compound represented by the above general formula (1) as an active ingredient together with a suitable pharmaceutically acceptable carrier to give a general pharmaceutical preparation form. Is done.

The carrier used in the pharmaceutical composition of the present invention includes a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant, a lubricant, which are generally used depending on the use form of the preparation. Diluents or excipients such as powders can be exemplified, and these are appropriately selected and used depending on the dosage unit form of the obtained preparation.

As the dosage unit form of the pharmaceutical preparation, various forms can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, Capsules, suppositories, injections (solutions, suspensions, etc.),
Ointments and the like.

In forming into tablets, the above-mentioned carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate and the like. water,
Ethanol, propanol, simple syrup, glucose solution,
Starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, binders such as polyvinylpyrrolidone; carboxymethylcellulose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose,
Disintegrators such as dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate; surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and monoglyceride stearate; sucrose, stearin, cocoa butter , Hydrogenation oils and other disintegration inhibitors; quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate; humectants such as glycerin and starch; starch, lactose, kaolin;
Adsorbents such as bentonite and colloidal silicic acid; lubricating agents such as purified talc, stearates, powdered boric acid, and polyethylene glycol can be used.

Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

When the pill is formed into a pill, the carrier may be, for example, glucose, lactose, starch, cocoa butter,
Excipients such as hardened vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; disintegrating agents such as laminaran and agar can be used.

In shaping into a suppository, the carrier may be, for example, polyethylene glycol, cocoa butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like.

Capsules are prepared according to a conventional method, usually by mixing the compound of the present invention with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like.

When the pharmaceutical composition of the present invention is prepared as an injection, such as a liquid, emulsion or suspension, it is preferable that the composition is sterilized and isotonic with blood. Is, for example, water, ethyl alcohol,
Macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to adjust the isotonic solution may be contained in the preparation, and a usual solubilizing agent, a buffer, a soothing agent and the like may be added. Is also good.

When shaping into the form of an ointment such as a paste, cream, gel or the like, for example, white vaseline, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

Further, the pharmaceutical composition of the present invention may contain a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals, if necessary.

The compound of the present invention represented by the general formula (1) to be contained in the pharmaceutical composition of the present invention (active compound)
The amount of is not particularly limited and is appropriately selected from a wide range,
Usually, it should be contained in the pharmaceutical composition in an amount of about 0.5 to 90% by weight, preferably about 1 to 85% by weight.

The method of administration of the pharmaceutical composition is not particularly limited, and may be various forms of preparation, age, sex and other conditions of the patient,
It is determined according to the degree of the disease. For example, tablets, pills,
Solutions, suspensions, emulsions, granules and capsules are administered orally, injections are administered alone or mixed with normal replacement fluids such as glucose and amino acids, and administered intravenously. It is administered intradermally, subcutaneously or intraperitoneally, and suppositories are rectal.

The dose of the above pharmaceutical composition is appropriately selected depending on the usage, age, sex and other conditions of the patient, the degree of the disease, etc., but the amount of the compound of the present invention, which is usually the active ingredient, is preferably 1 adult per day. Approximately 0.5-20 mg per kg of weight per person,
The dosage is preferably about 1 to 10 mg, and the preparation can be administered once a day or divided into 2 to 4 times a day.

[0047]

The production examples of the compound of the present invention are described below as examples. In addition, a production example of a starting compound (intermediate) for producing the compound of the present invention will be described as a reference example.

The structure, melting point and ¹
The 1 H-NMR spectrum data is shown in Table 1. still,
^{The 1} H-NMR spectrum was measured using TMS (tetramethylsilane) as an internal standard. The measurement solvent is DMSO (dimethyl sulfoxide)-unless otherwise specified.
Using the d _6.

[0049]

Reference Example 1 7-chloro-4-hydroxy-1- (4-
Preparation of methoxybenzyl) -2-oxo-1,2-dihydroquinoline A suspension of 2.9 g of sodium hydride in 100 ml of DMF was added under ice-cooling to 15.0 g of 2-acetylamino-4-chloroform. Add methyl benzoate and stir for 10 minutes,
Further, 11.4 g of 4-methoxybenzyl chloride was added, and the mixture was stirred at room temperature for 2 hours. Water is added to the reaction mixture,
The mixture was extracted twice with 200 ml of ethyl acetate.
Washed three times with 0 ml of water. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 1) to obtain 18.0 g of 2
-[Acetyl- (4-methoxybenzyl) amino] -4
-An oil of methyl chlorobenzoate was obtained.

[0050] ^{1 H-NMR (δ: ppm} ); 1.83 (3H,
s), 3.76 (3H, s), 3.79 (3H, s), 4.37 (1H, d, J = 14.3), 5.0
9 (1H, d, J = 14.3), 6.78 (2H, d, J = 8.9), 6.93 (1H, s), 7.07
(2H, d, J = 8.9), 7.39 (1H, d, J = 8.4), 7.89 (1H, d, J = 8.4)
(CDCl ₃ ) 18.0 g of the compound obtained above was dissolved in 200 ml of xylene, 14.5 g of potassium-t-butoxide was added, and the mixture was stirred at 130 ° C. for 1 hour. 200 m of water
The extract was neutralized with citric acid. The precipitated crystals were collected by filtration and washed sequentially with methanol and diethyl ether to give 13.2 g of crystals of the desired compound (melting point: 287).
２290 ° C.). This is designated as compound (1).

¹ H-NMR (δ: ppm); 3.71 (3H,
s), 5.38 (2H, s), 5.98 (1H, s), 6.88 (2H, d, J = 8.7), 7.14
(2H, d, J = 8.7), 7.23 (1H, d, J = 8.4), 7.40 (1H, s), 7.89 (1
H, d, J = 8.4), 11.69 (1H, brs) In the same manner as above, the following compounds (2) to (7) were produced. (2) 4-hydroxy-6,7-dimethoxy-2-oxo-1- (3,4,5-trimethoxybenzyl) -1,2
-Dihydroquinoline Melting point: 246 to 249 ° C ¹ H-NMR (δ: ppm); 3.61 (3H, s), 3.67 (6H,
s), 3.78 (6H, s), 5.40 (2H, s), 5.88 (1H, s), 6.66 (2H, s)
s), 6.93 (1H, s), 7.28 (1H, s), 11.34 (1H, brs) (3) 1-benzyl-4-hydroxy-6,7,8-trimethoxy-2-oxo-1,2- Dihydroquinoline Melting point: 254 to 257 ° C. ¹ H-NMR (δ: ppm); 3.75 (3H, s), 3.84 (6H,
s), 5.58 (2H, s), 5.93 (1H, s), 6.98-7.35 (6H, m), 11.52
(1H, brs) (4) 7-chloro-4-hydroxy-2-oxo-1-
(3,4,5-trimethoxybenzyl) -1,2-dihydroquinoline Melting point: 245 to 248 ° C. ¹ H-NMR (δ: ppm); 3.62 (3H, s), 3.68 (6H,
s), 5.37 (2H, s), 5.98 (1H, s), 6.57 (2H, s), 7.26 (1H, d,
J = 8.4), 7.49 (1H, s), 7.90 (1H, d, J = 8.4), 11.70 (1H, br
s) (5) 7-chloro-1- (3,4-dimethoxybenzyl)
-4-Hydroxy-2-oxo-1,2-dihydroquinoline Melting point: 259 to 262 ° C ¹ H-NMR (δ: ppm); 3.69 (3H, s), 3.71 (3H,
s), 5.37 (2H, s), 5.98 (1H, s), 6.60 (1H, d, J = 8.4), 6.85
(1H, d, J = 8.4), 6.97 (1H, s), 7.24 (1H, d, J = 8.4), 7.43 (1
H, s), 7.89 (1H, d, J = 8.4), 11.70 (1H, brs) (6) 1-benzyl-7-chloro-4-hydroxy-2-
Oxo-1,2-dihydroquinoline Melting point: 285-288 ° C. ¹ H-NMR (δ: ppm); 5.46 (2H, s), 5.99 (1H,
s), 6.57 (2H, s), 7.11-7.39 (7H, m), 7.90 (1H, d, J = 8.
4), 11.72 (1H, brs) (7) 4-Hydroxy-2-oxo-1- (3,4,5-
Trimethoxybenzyl) -1,2-dihydroquinoline Melting point: 262 to 265 ° C. ¹ H-NMR (δ: ppm); 3.61 (3H, s), 3.67 (6H,
s), 5.37 (2H, s), 5.99 (1H, s), 6.55 (2H, s), 7.21 (1H, d
d, J = 6.9,7.9), 7.40 (1H, d, J = 8.4), 7.52 (1H, dd, J = 6.9,
8.4) 、 7.91 (1H, d, J = 7.9) 、 11.56 (1H, brs)

[0052]

Reference Example 2 7-chloro-1- (4-methoxybenzyl) -2-oxo-3-phenyliodonium-1,2
Preparation of -dihydroquinoline-4-olate 4.6 g of sodium carbonate was dissolved in 150 ml of water, and the aqueous solution of the compound (1) prepared in Reference Example 1 was dissolved in DM.
A 100 ml solution of F was added, and 13.3 g of iodobenzene diacetate was further added at room temperature, followed by stirring at room temperature for 2 hours. After completion of the reaction, the precipitated crystals were collected by filtration, washed successively with water and diethyl ether, and dried under reduced pressure at 50 ° C. for 5 hours to obtain 20.4 g of crystals of the target compound (melting point: 144 to 14).
5 ° C.). This is designated as compound (8).

[0053] ^{1 H-NMR (δ: ppm} ); 3.70 (3H,
s), 5.37 (2H, s), 6.86 (2H, d, J = 8.7), 7.07-7.18 (3H,
m), 7.28 (1H, s), 7.37-7.56 (3H, m), 7.85 (2H, d, J = 8.
2), 8.02 (1H, d, J = 8.4) In the same manner as above, the following compounds (9) to (14) were produced. (9) 6,7-dimethoxy-2-oxo-3-phenyliodonium-1- (3,4,5-trimethoxybenzyl) -1,2-dihydroquinoline-4-olate Melting point: 120-122 ° C ¹ H -NMR (δ: ppm); 3.59 (3H, s), 3.60 (6H,
s), 3.75 (6H, s), 5.37 (2H, s), 6.63 (2H, s), 6.83 (1H,
s), 7.35-7.55 (4H, m), 7.84 (2H, d, J = 7.4) (10) 1-benzyl-6,7,8-trimethoxy-2-oxo-3-phenyliodonium-1,2- Dihydroquinoline-4-olate Melting point: 86-89 ° C ¹ H-NMR (δ: ppm); 3.38 (3H, s), 3.72 (3H,
s), 3.80 (3H, s), 5.58 (2H, s), 7.01-7.52 (9H, m), 7.82
(2H, d, J = 7.2) (11) 7-chloro-2-oxo-3-phenyliodonium-1- (3,4,5-trimethoxybenzyl) -1,
2-dihydroquinoline-4-olate Melting point: 126-128 ° C ¹ H-NMR (δ: ppm); 3.60 (9H, s), 5.36 (2H,
s), 6.53 (2H, s), 7.12 (2H, d, J = 8.4), 7.33-7.42 (3H,
m), 7.46-7.55 (1H, m), 7.86 (2H, d, J = 7.4), 8.00 (1H, d, J
= 8.4) (12) 7-chloro-1- (3,4-dimethoxybenzyl)
-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate Melting point: 150-151 ° C ¹ H-NMR (δ: ppm); 3.61 (3H, s), 3.68 (3H,
s), 5.35 (2H, s), 6.66 (1H, d, J = 8.4), 6.84 (1H, d, J = 8.
4) 、 6.87 (1H, s) 、 7.19 (1H, d, J = 8.4) 、 7.29 (1H, s) 、 7.33
-7.54 (3H, m), 7.85 (2H, d, J = 7.4), 8.01 (1H, d, J = 8.4) (13) 1-benzyl-7-chloro-2-oxo-3-phenyliodonium-1 , 2-Dihydroquinoline-4-olate Melting point: 129-131 ° C ¹ H-NMR (δ: ppm); 5.45 (2H, s), 7.03-7.31
(7H, m), 7.37-7.57 (3H, m), 7.86 (2H, d, J = 7.9), 8.04 (1
(H, d, J = 8.4) (14) 2-oxo-3-phenyliodonium-1-
(3,4,5-trimethoxybenzyl) -1,2-dihydroquinoline-4-olate Melting point: 138 to 141 ° C. ¹ H-NMR (δ: ppm); 3.58 (3H, s), 3.59 (6H,
s), 5.35 (2H, s), 6.51 (2H, s), 7.07 (1H, dd, J = 7.4,7.
4), 7.32-7.53 (4H, m), 7.85 (2H, d, J = 7.9), 8.04 (1H, d,
(J = 7.9)

[0054]

Example 1 7-Chloro-1- (4-methoxybenzyl) -3- [methyl-2- (3,4,5-trimethoxybenzyloxy) ethylsulfonio] -2-oxo-
Production of 1,2-dihydroquinoline-4-olate In 15 ml of trifluoroethanol, 2.0 g of the compound (8) produced in the above Reference Example 2 and methyl [2- (3,4,
1.3 g of [5-trimethoxybenzyloxy) ethyl] sulfide and 50 mg of paratoluenesulfonic acid were dissolved and stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure,
The residue was subjected to silica gel column chromatography (eluent ...
Purification was performed with chloroform: ethanol = 20: 1), and the obtained crystals were washed with diethyl ether to obtain 1.9 g of crystals of the target compound.

[0055]

Examples 2 to 21 The compounds shown in Table 1 were produced in the same manner as in Example 1 except that the compounds (8) to (14) of Reference Example 2 were used as raw materials.

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

[Table 4]

[0060]

[Table 5]

[0061]

[Table 6]

[0062]

[Table 7]

[0063]

[Table 8]

Examples of pharmacological tests performed on the compounds of the present invention and examples of preparation of pharmaceutical preparations utilizing the compounds of the present invention are described below.

[0065]

[Pharmacological test example 1] D. First, the pain threshold of the left hind footpad of each rat was determined using a pressure-stimulated analgesic effect measuring device (manufactured by Unicom) using the Randall-Selit method [Randall, LO and Sellitto, JJ, Ar
ch.Int.Pharmacodyn., 111, 409 (1957)]. The obtained value is referred to as “previous value”.

One hour after the above measurement, the experimental group was treated with a 5% gum arabic suspension of the compound of the present invention, and the control group was treated with 5% gum arabic.
% Arabic gum solution (not containing the compound of the present invention) in an amount of 10 ml / kg (active ingredient dose: 10 mg / kg)
After 1 hour, 25 ng / 0.1 ml of a physiological saline solution of substance P was subcutaneously injected into the left hind footpad of each rat.

Next, at a predetermined time after the substance P injection (specifically, as shown in Table 3), the pain threshold value of the left hind footpad of each group of rats was measured in the same manner as described above, and this was measured as “ Later value ".

From the measured values (after value and before value) of each group, the pain threshold recovery rate (%) was calculated according to the following equation. Pain threshold recovery rate (%) = [(Tb-Cb) / (Ca-C
b)] × 100 Tb represents the mean value of the experimental group, Cb represents the mean value of the control group,
a shows a control group average before value.

The obtained result (maximum recovery rate)
It is shown in the table.

[0070]

[Table 9]

From the above Table 3, it is clear that the compound of the present invention has an excellent analgesic effect.

[0072]

Formulation Example 1 Preparation of Tablet Using the compound of the present invention obtained in Example 11 as an active ingredient, a tablet containing 300 mg per tablet (2000
Tablets) were prepared according to the following formulation: Compound of the present invention obtained in Example 11 600 g Lactose (Japanese Pharmacopoeia) 67 g Corn starch (Japanese Pharmacopoeia) 33 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 25 g Methylcellulose (Japanese Pharmacopoeia) 12 g Magnesium stearate (Japan Pharmacopoeia) 3g) That is, the compound of the present invention, lactose, corn starch and carboxymethylcellulose calcium obtained in Example 11 were sufficiently mixed according to the above-mentioned formulation, and the mixture was granulated using an aqueous methylcellulose solution, and passed through a 24-mesh sieve.
This was mixed with magnesium stearate and pressed into tablets to obtain the desired tablets.

[0073]

Formulation Example 2 Preparation of Capsules Using the compound of the present invention obtained in Example 1 as an active ingredient,
Hard gelatin capsules (2000 capsules) containing 200 mg per capsule were prepared according to the following formula. Compound of the present invention obtained in Example 1 400 g Microcrystalline cellulose (Japanese Pharmacopoeia) 60 g Corn starch (Japanese Pharmacopoeia) 34 g Talc (Japanese Pharmacopoeia) 4 g Magnesium stearate (Japanese Pharmacopoeia) 2 g After finely pulverizing each component and mixing them into a uniform mixture, the mixture was filled into a gelatin capsule for oral administration having desired dimensions to obtain a desired capsule.

Claims (10)

[Claims] 1. A compound of the general formula [Wherein, R ¹ , R ² and R ⁶ each represent a hydrogen atom, a lower alkoxy group or a halogen atom, R ³ represents a lower alkyl group, and R ⁴ represents 1 to 3 lower alkoxy groups on a phenyl ring. Represents a phenyl lower alkoxy lower alkyl group having a phenyloxy lower alkyl group having 1 to 3 lower alkoxy groups on the phenyl ring, and R ⁵ represents a phenyl group having 1 to 3 lower alkoxy groups. . ] The dihydroquinoline derivative represented by these. 2. The dihydroquinoline derivative represented by the general formula (1) according to claim 1, wherein the substitution positions of R ¹ , R ² and R ⁶ are respectively 6-position, 7-position and 8-position. 3. The dihydroquinoline derivative according to claim 2, wherein R ⁴ is a tri-lower alkoxyphenyl lower-alkoxy lower alkyl group or a tri-lower alkoxyphenoxy lower alkyl group. 4. R¹ , R^Two And R⁶ Are each a hydrogen atom
Or R¹ , R ^Two And R⁶ Are low-grade alkoxy
Is a group, R¹ And R^Two Are each lower alkoxy
And R⁶ Is a hydrogen atom, or R¹ And R⁶ 
Is a hydrogen atom and R^Two Is a halogen atom
4. The dihydroquinoline derivative according to claim 2 or 3. 5. The dihydroquinoline derivative according to claim 4, wherein R ² is a chlorine atom. 6. R ⁵ is a 4-methoxyphenyl group or 3,
The dihydroquinoline derivative according to claim 5, which is a 4,5-trimethoxyphenyl group. 7. and by R ³ is a methyl group R ⁴ is 2- (3,
4,5-trimethoxybenzyloxy) ethyl group or 3
The dihydroquinoline derivative according to claim 6, which is a-(3,4,5-trimethoxyphenoxy) propyl group. 8. 8-Chloro-1- (4-methoxybenzyl) -3- [methyl-2- (3,4,5-trimethoxybenzyloxy) ethylsulfonio] -2-oxo-
1,2-dihydroquinoline-4-olate, 7-chloro-1- (4-methoxybenzyl) -3- [methyl-3-
(3,4,5-trimethoxyphenoxy) propylsulfonio] -2-oxo-1,2-dihydroquinoline-4
-Olate and 7-chloro-1- (3,4,5-trimethoxybenzyl) -3- [methyl-3- (3,4,5-
Trimethoxyphenoxy) propylsulfonio] -2-
The dihydroquinoline derivative according to claim 7, which is selected from oxo-1,2-dihydroquinoline-4-olate. 9. A pharmaceutical composition comprising the dihydroquinoline derivative according to claim 1 and a pharmaceutically acceptable carrier. 10. An analgesic containing the dihydroquinoline derivative according to claim 1 as an active ingredient.