JP2000026424A - Dihydroquinoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound comprising a specific dihydroquinoline derivative, having analgesic actions and useful as a medicine, especially an analgesic agent. SOLUTION: This compound is represented by formula I (R1, R2 and R6 are each H, a lower alkoxy or a halogen; R3 and R4 are each a lower alkyl, an oxo-lower alkyl or the like; R5 is phenyl which can be substituted with 1 to 3 lower alkyls or the like), preferably 7-chloro-1-(4-methoxybenzyl)-3-(methyl- n-propylsulfonio)-2-oxo-1,2-dihydroquinolin-4-olate, etc. The compound represented by formula I is obtained by reacting, e.g. a compound represented by formula II [e.g. 7-chloro-3-(methyl-n-propylsulfonio)-2-oxo-1,2-dihydroquinoline-4-olate] with a compound represented by the formula R5-CH2-X (X is a halogen) (e.g. 4-methoxybenzyl chloride) in the presence of a base such as sodium hydride in an inert solvent such as N,N-dimethylformamide, preferably at a temperature of 0 deg.C to about room temperature.

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 and R ⁴ each represent a lower alkyl group, oxo-lower alkyl group or a hydroxyphenyl group to or bonded to each other showing group forming a 1,4-thioxane ring with the sulfur atom to which they are attached, R ⁵ is substituted A phenyl group which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group and a halogen atom is shown. ]

[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 alkyl group represented by R ^{3 to} R ⁴ or the lower alkyl group as a phenyl substituent in R ⁵ includes carbon such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. Examples include straight-chain or branched-chain alkyl groups of the formulas 1 to 6.

As the lower alkoxy group represented by R ¹ , R ² and R ⁶ , a straight-chain or straight-chain having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. A branched alkoxy group can be exemplified.

The halogen atom represented by R ¹ , R ² and R ⁶ or the halogen atom as a phenyl substituent in R ⁵ includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The hydroxyphenyl groups represented by R ³ and R ⁴ include 2-hydroxyphenyl, 3-hydroxyphenyl and 4-hydroxyphenyl groups.

The oxo-lower alkyl group represented by R ³ and R ⁴ includes 2-oxoethyl, 2-oxopropyl, 3-oxopropyl, 2-oxobutyl, 3-oxobutyl, 4-oxobutyl, 2-oxopentyl,
-Oxopentyl, 4-oxopentyl, 5-oxopentyl, 2-oxohexyl, 3-oxohexyl, 4
Examples thereof include oxoalkyl groups having 1 to 6 carbon atoms, such as -oxohexyl, 5-oxohexyl, and 6-oxohexyl.

Examples of the lower alkoxy group as a phenyl substituent represented by R ⁵ include alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups.

The phenyl group represented by R ⁵ which may have 1 to 3 groups selected from the group consisting of a lower alkyl group, a lower alkoxy group and a halogen atom as a substituent includes an unsubstituted phenyl group. In addition, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,
-Ethylphenyl, 4-propylphenyl, 4-butylphenyl, 4-pentylphenyl, 4-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethyl Phenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-diethylphenyl, 3,4-dipropylphenyl, 3,4-dibutylphenyl, 3,4-dipentylphenyl, 3,4-dihexyl Phenyl, 3,
4,5-trimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3
6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4,5-trimethylphenyl, 3,4,5-
Triethylphenyl, 3,4,5-tripropylphenyl, 3,4,5-tributylphenyl, 3,4,5-tripentylphenyl, 3,4,5-trihexylphenyl, 2-methoxyphenyl, 3-methoxy Phenyl, 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-dibutoxy Phenyl,
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, 3,4,5-tripentyloxyphenyl, 3,4,5-trihexyloxyphenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl,
3-iodophenyl, 4-iodophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, , 5-Dichlorophenyl, 2,6-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 2,4-diiodophenyl, 3,4
5-trichlorophenyl, 2,4,6-trichlorophenyl, 4-methoxy-3-methylphenyl, 4-methoxy-2-methylphenyl, 3-methoxy-2-methylphenyl, 4-methoxy-3,5-dimethyl Phenyl, 4
-Chloro-3-methoxyphenyl, 3-chloro-4-methoxyphenyl, 4-chloro-3-methylphenyl, 3
-Chloro-4-methylphenyl, 4-chloro-3,5-
Examples thereof include dimethoxyphenyl and 4-chloro-3,5-dimethylphenyl.

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.

Among the above compounds, a compound in which R ³ is a lower alkyl group or a group which forms a 1,4-thioxane ring together with a sulfur atom to which R ⁴ is bonded to R ⁴ is preferred.

Among the above preferred compounds, R ³ and R
⁴ is preferably a lower alkyl group, and among these preferred compounds, those in which R ⁵ is a phenyl group having 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom as a substituent are more preferable. preferable.

Among the above preferred compounds, compounds wherein R ⁶ is a hydrogen atom and R ¹ and R ² are each a lower alkoxy group or ^one of R ¹ and R ² is a hydrogen atom and the other is a halogen atom are further mentioned. preferable.

Among the above more preferred compounds, those in which R ³ is a methyl group and R ⁴ is a propyl group are more preferred.

Among the above more preferred compounds, those in which R ⁶ is a hydrogen atom and R ¹ and R ² are each a methoxy group, or those in which R ¹ is a hydrogen atom and R ² is a chlorine atom are even more preferred.

The most preferred compounds are those represented by the formula (1) wherein R ⁵ is a 4-methoxyphenyl group, 3,4,5
-Trimethoxyphenyl group or 2,3-dichlorophenyl group can be exemplified.

The most preferred compounds include, specifically,
7-chloro-1- (3,4,5-trimethoxybenzyl) -3- (methyl-n-propylsulfonio) -2-
Oxo-1,2-dihydroquinoline-4-olate, 7
-Chloro-1- (4-methoxybenzyl) -3- (methyl-n-propylsulfonio) -2-oxo-1,2-
Dihydroquinoline-4-olate, 6,7-dimethoxy-1- (3,4,5-trimethoxybenzyl) -3-
(Methyl-n-propylsulfonio) -2-oxo-
1,2-dihydroquinoline-4-olate, 6,7-dimethoxy-1- (4-methoxybenzyl) -3- (methyl-n-propylsulfonio) -2-oxo-1,2-
Dihydroquinoline-4-olate and 1- (2,3-dichlorobenzyl) -6,7-dimethoxy-3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate Is 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.

[0026]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above. X represents a halogen atom. In the above reaction scheme, the reaction for synthesizing compound (5) from compound (2) via compound (3) can be performed, for example, according to the method described in JP-A-9-255658.

That is, first, a known compound (2) is reacted with iodobenzene diacetate in the presence of an alkali to obtain a compound (3). In the reaction, water can be suitably used as a solvent, and as an alkali, sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Potassium hydrogen carbonate or the like can be used. The amount of the alkali and iodobenzene diacetate used is preferably from equimolar amount to a small excess amount, respectively, based on the starting compound. The reaction is carried out at a temperature near 0 ° C. to room temperature for about 1 to 10 hours.

Next, the compound (3) obtained above can be converted to the compound (5) by reacting it with the thioether derivative (4). The reaction can be carried out by using a lower alcohol such as methanol, ethanol or trifluoroethanol as a solvent and adding an appropriate amount of an acid catalyst such as p-toluenesulfonic acid or 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 in about 10 minutes to 24 hours at room temperature to the reflux temperature of the solvent.

The compound (5) obtained as described above can be converted to the compound (1) of the present invention by reacting the compound (5) with a benzyl halide derivative (6). This reaction is
In an inert solvent such as N, N-dimethylformamide (DMF) or N, N-dimethylacetamide (DMA), in the presence of a base such as sodium hydride, potassium hydride, sodium ethoxide, at 0 ° C. to around room temperature. It is performed under temperature conditions. The amount of the benzyl halide derivative (6) and the base to be used is generally about equimolar to about 5 times the molar amount of the compound (5), respectively, and the reaction is completed in about 0.5 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.

[0032]

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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.

Some of the compounds of the present invention contain a sulfur atom and / or
Alternatively, there are optical isomers having a carbon atom as an asymmetric center, and the present invention includes any of optically active isomers, R-form, S-form and racemic-form. The optically active substance,
It 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 form a general pharmaceutical preparation. 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 usually 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 the case of molding 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 above-mentioned carrier may be, for example, polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, 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 solution, 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 paste, cream, gel or the like, for example, white vaseline, paraffin, glycerin, 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 fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as 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 ingredient 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 administration method of the above-mentioned pharmaceutical composition is not particularly limited, and may be various preparation forms, 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 its usage, the age of the patient, sex and other conditions, 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.

[0049]

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 structures, melting points 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.

[0051]

Reference Example 1 Production of 7-chloro-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate 8.3 g of sodium carbonate was dissolved in 400 ml of water, and 7-chloro-4 was added to the aqueous solution. -Hydroxy-2-oxo-
14.5 g of 1,2-dihydroquinoline was dissolved, 24.0 g of iodobenzene diacetate was further added at room temperature, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the precipitated crystals were collected by filtration, washed with methanol, and dried under reduced pressure at 60 ° C. for 5 hours to give 28.1 g of crystals of the target compound (melting point: 16
3-165 ° C). This is designated as compound (1). ^{1 H-NMR (δ: ppm} ) [DMSO-d _6]; 7.12 (1H,
d, J = 7.4), 7.17-7.29 (2H, m), 7.36-7.61 (4H, m), 7.80-
7.99 (3H, m), 10.80 (1H, s) In the same manner as above, the following compounds (2) to (5) were produced. (2) 2-oxo-3-phenyliodonium-1,2-
Dihydroquinoline-4-olate Melting point: 244 to 246 ° C ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 7.01 (1H, d
d, J = 6.9,7.4), 7.17 (1H, d, J = 8.4), 7.32-7.50 (4H, m),
7.81 (2H, d, J = 7.4), 7.89 (1H, d, J = 6.9), 10.63 (1H, s) (3) 6-chloro-2-oxo-3-phenyliodonium-1,2-dihydroquinoline -4-olate (4) 6,7-dimethoxy-2-oxo-3-phenyliodonium-1,2-dihydroquinoline-4-olate (5) 6,7,8-trimethoxy-2-oxo-3-phenyl Iodonium-1,2-dihydroquinoline-4-olate

[0052]

Reference Example 2 Preparation of 7-chloro-3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate The compound obtained in Reference Example 1 in 30 ml of trifluoroethanol. (1) 7.6 g, methyl-n-propyl sulfide 2.1 g and p-toluenesulfonic acid 100 mg were dissolved and stirred at 70 ° C. for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol: chloroform = 1: 15).
The obtained crystals were washed with diethyl ether to obtain 4.1 g of the desired compound as crystals (melting point: 219 to 221 ° C).
This is designated as compound (6). ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 0.97 (3
(H, t, J = 7.4), 1.43-1.70 (2H, m), 3.09 (3H, s), 3.20-3.33
(1H, m), 3.89-4.01 (1H, m), 7.04 (1H, d, J = 8.4), 7.16 (1
H, s), 7.82 (1H, d, J = 8.4), 10.56 (1H, s) In the same manner as above, the following compounds (7) to (16) were produced. (7) 6-chloro-3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate Melting point: 210-212 ° C ¹ H-NMR (δ: ppm) [DMSO −d ₆ ]; 0.97 (3H,
t, J = 7.4), 1.41-1.70 (2H, m), 3.09 (3H, s), 3.22-3.37 (1
H, m), 3.90-4.01 (1H, m), 7.14 (1H, d, J = 8.9), 7.45 (1H,
d, J = 8.9), 7.75 (1H, s), 10.59 (1H, s) (8) 7-Chloro-3- (ethyl-methylsulfonio)-
2-oxo-1,2-dihydroquinoline-4-olate Melting point: 217-219 ° C. ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 1.17 (3H,
t, J = 7.4), 3.09 (3H, s), 3.29-3.45 (1H, m), 3.85-3.99 (1
H, m), 7.05 (1H, d, J = 8.4), 7.16 (1H, s), 7.82 (1H, d, J = 8.
4), 10.57 (1H, s) (9) 6,7-dimethoxy-3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate Melting point: 161-163 ° C ^{1 H-NMR (δ: ppm} ) [DMSO-d _6]; 0.96 (3H,
t, J = 7.4), 1.40-1.70 (2H, m), 3.07 (3H, s), 3.14-3.28 (1
H, m), 3.75 (3H, s), 3.77 (3H, s), 3.92-4.03 (1H, m), 6.6
8 (1H, s), 7.28 (1H, s), 10.20 (1H, s) (10) 3- (ethyl-methylsulfonio) -6,7-dimethoxy-2-oxo-1,2-dihydroquinoline- 4-
Olato Melting point: 192 to 194 ° C. ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 1.15 (3H,
t, J = 7.4), 3.07 (3H, s), 3.25-3.40 (1H, m), 3.75 (3H, s),
3.77 (3H, s), 3.81-3.99 (1H, m), 6.69 (1H, s), 7.28 (1H,
s), 10.21 (1H, s) (11) 3- (n-butyl-methylsulfonio) -6,7-
Dimethoxy-2-oxo-1,2-dihydroquinoline-
4-olate Melting point: 198-200 ° C ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 0.85 (3H,
t, J = 7.2), 1.29-1.55 (4H, m), 3.08 (3H, s), 3.18-3.31 (1
H, m), 3.75 (3H, s), 3.77 (3H, s), 3.93-4.05 (1H, m), 6.6
9 (1H, s), 7.28 (1H, s), 10.21 (1H, s) (12) 3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate Melting point 158-160 ° C ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 0.97 (3H,
t, J = 7.2), 1.45-1.70 (2H, m), 3.09 (3H, s), 3.20-3.34 (1
H, m), 3.92-4.04 (1H, m), 7.01 (1H, dd, J = 7.2,7.9), 7.11
(1H, d, J = 7.9), 7.40 (1H, dd, J = 7.2,7.9), 7.82 (1H, d, J =
7.9), 10.43 (1H, s) (13) 6,7,8-Trimethoxy-3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate Melting point: 190-90 193 ° C. ¹ H-NMR (δ: ppm) [DMSO-d ₆ ]; 0.96 (3H,
t, J = 7.4), 1.40-1.70 (2H, m), 3.08 (3H, s), 3.15-3.30 (1
H, m), 3.79 (3H, s), 3.80 (3H, s), 3.82 (3H, s), 3.90-4.0
3 (1H, m), 7.17 (1H, s), 9.46 (1H, s) (14) 6,7-dimethoxy-3- [methyl- (4-oxopentyl) sulfonio] -2-oxo-1,2 -Dihydroquinoline-4-olate (15) 3-[(4-hydroxyphenyl) -methylsulfonio] -6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-4-olate (16) 6 7-dimethoxy-3- (1,4-thioxane-
1-io) -2-oxo-1,2-dihydroquinoline-
4-Olate In a similar manner, the following compounds (17) to (30) can be synthesized. (17) 3- [methyl- (4-oxopentyl) sulfonio] -2-oxo-1,2-dihydroquinoline-4-olate (18) 6-chloro-3- [methyl- (4-oxopentyl) sulfonio 2-oxo-1,2-dihydroquinoline-4-olate (19) 7-chloro-3- [methyl- (4-oxopentyl) sulfonio] -2-oxo-1,2-dihydroquinoline-4- Olate (20) 3- (1,4-thioxan-1-io) -2-oxo-1,2-dihydroquinoline-4-olate (21) 6-chloro-3- (1,4-thioxan-1- (Io) -2-oxo-1,2-dihydroquinoline-4-olate (22) 7-chloro-3- (1,4-thioxan-1-io) -2-oxo-1,2-dihydroquinoline-4 -Olate (23) 3-[(4-hydroxyphenyl) -Methylsulfonio] -2-oxo-1,2-dihydroquinoline-4-
Olate (24) 6-chloro-3-[(4-hydroxyphenyl)-
Methylsulfonio] -2-oxo-1,2-dihydroquinoline-4-olate (25) 7-chloro-3-[(4-hydroxyphenyl)-
Methylsulfonio] -2-oxo-1,2-dihydroquinoline-4-olate (26) 3- (ethyl-methylsulfonio) -2-oxo-
1,2-dihydroquinoline-4-olate (27) 6-chloro-3- (ethyl-methylsulfonio)-
2-oxo-1,2-dihydroquinoline-4-olate (28) 3- (n-butyl-methylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate (29) 6-chloro- 3- (n-butyl-methylsulfonio) -2-oxo-1,2-dihydroquinoline-4-olate (30) 7-chloro-3- (n-butyl-methylsulfonio) -2-oxo-1 , 2-Dihydroquinoline-4-olate

[0053]

Example 1 7-Chloro-1- (4-methoxybenzyl) -3- (methyl-n-propylsulfonio) -2-
Preparation of oxo-1,2-dihydroquinoline-4-olate 270 mg of 60% sodium hydride was dissolved in 10 ml of DMF and cooled to 0 ° C. 1.3 g of the compound (5) obtained in Reference Example 2 was added thereto, and the mixture was stirred at 0 ° C. for 10 minutes, subsequently, 1.4 g of 4-methoxybenzyl chloride was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added, and the mixture was extracted three times with 30 ml of chloroform. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol: chloroform = 1: 20), and the obtained crystals were washed with diethyl ether-n-hexane.
1.49 g of crystals of the target compound were obtained.

[0054]

Examples 2 to 24 Using the compounds of (6) to (16) of Reference Example 2 as raw materials, the compounds shown in Table 1 were produced in the same manner as in Example 1.

In the same manner, the compounds shown in Table 2 can be produced.

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

[Table 4]

[0060]

[Table 5]

[0061]

[Table 6]

[0062]

[Table 7]

[0063]

[Table 8]

[0064]

[Table 9]

[0065]

[Table 10]

[0066]

[Table 11]

[0067]

[Table 12]

[0068]

[Table 13]

[0069]

[Table 14]

[0070]

[Table 15]

[0071]

[Table 16]

[0072]

[Table 17]

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

[0074]

[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% of 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. 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.

[0079]

[Table 18]

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

[0081]

Formulation Example 1 Preparation of Tablet Using the compound of the present invention obtained in Example 10 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 10 600 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) 3 g) That is, the compound of the present invention, lactose, corn starch and carboxymethylcellulose calcium obtained in Example 10 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.

[0082]

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 (12)

[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, and R ³ and R ⁴ each represent a lower alkyl group, an oxo lower alkyl group or a hydroxyphenyl group, or R ⁵ represents a group which forms a 1,4-thioxane ring together with a sulfur atom to which they are bonded, R ⁵ is a lower alkyl group as a substituent,
And a phenyl group which may have 1 to 3 groups selected from the group consisting of a lower alkoxy group and a halogen atom. ] 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 compound of the general formula (1) according to claim 1, wherein R ³ is a lower alkyl group or a group which forms a 1,4-thioxane ring together with a sulfur atom to which R ⁴ is bonded. The dihydroquinoline derivative according to claim 2, which is represented. 4. The dihydroquinoline derivative according to claim ^3, wherein R ³ and R ⁴ are each a lower alkyl group, represented by the general formula (1). 5. The general formula (1) according to claim 1, wherein R ⁵ is a phenyl group having 1 to 3 substituents selected from the group consisting of a lower alkoxy group and a halogen atom.
The dihydroquinoline derivative according to claim 3, which is represented by the formula: 6. The method according to claim 1, wherein R ⁶ is a hydrogen atom and R ¹ and R ² are each a lower alkoxy group, or ^one of R ¹ and R ² is a hydrogen atom and the other is a halogen atom. The dihydroquinoline derivative according to any one of claims 3 to 5, which is represented by formula (1). 7. The dihydroquinoline derivative according to any one of claims 4 to 6, wherein R ³ is a methyl group and R ⁴ is a propyl group. 8. R ⁶ is a hydrogen atom, R ¹ and R ² are each a methoxy group, or R ¹ is a hydrogen atom and R ²
Is a chlorine atom. The dihydroquinoline derivative according to any one of claims 4 to 7, which is represented by the general formula (1) according to claim 1. 9. R ⁵ is 4-methoxyphenyl group, 3,
The dihydroquinoline derivative according to any one of claims 4 to 8, which is a 4,5-trimethoxyphenyl group or a 2,3-dichlorophenyl group, and is represented by the general formula (1) according to claim 1. 10. A 7-chloro-1- (3,4,5-trimethoxybenzyl) -3- (methyl-n-propylsulfonio) -2-oxo-1,2-dihydroquinoline-4.
-Olate, 7-chloro-1- (4-methoxybenzyl) -3- (methyl-n-propylsulfonio) -2-
Oxo-1,2-dihydroquinoline-4-olate,
6,7-dimethoxy-1- (3,4,5-trimethoxybenzyl) -3- (methyl-n-propylsulfonio)
-2-oxo-1,2-dihydroquinoline-4-olate, 6,7-dimethoxy-1- (4-methoxybenzyl) -3- (methyl-n-propylsulfonio) -2-
Oxo-1,2-dihydroquinoline-4-olate and 1- (2,3-dichlorobenzyl) -6,7-dimethoxy-3- (methyl-n-propylsulfonio) -2-oxo-1,2- The dihydroquinoline derivative according to claim 9, which is selected from dihydroquinoline-4-olate. 11. A pharmaceutical composition comprising the dihydroquinoline derivative according to claim 1 and a pharmaceutically acceptable carrier. 12. An analgesic comprising the dihydroquinoline derivative according to claim 1 as an active ingredient.