JPS6129330B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel aminophenyl ether compound represented by formula () and a pharmaceutically acceptable salt thereof. [In the formula, R is a hydrogen atom, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ is a cyclopentyl group or cyclohexyl group that may be substituted with a lower alkyl group, an alkyl group having 1 to 20 carbon atoms, phenyl group or benzyl group, R ₃ is hydrogen atom,
A lower alkyl group, a cyclopentyl group or cyclohexyl group optionally substituted with a lower alkyl group, a phenyl group, or a benzyl group, R ₄ is a hydrogen atom, a lower alkyl group, an aralkyl group, or a lower alkoxycarbonyl group, R ₅ is a hydrogen atom, a lower alkyl group, a COR ₆ (in the formula, R ₆ is a lower alkyl group, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group optionally substituted with a lower alkyl group, or a bridged (represents a hydrocarbon group) However, R ₂ and R ₃ may be combined with adjacent carbon atoms to form a cyclohexane ring which may be substituted with a lower alkyl group, and R ₄ and R ₅ may be combined with adjacent nitrogen atoms. may be used to form a pyrrolidine ring, piperidine ring or morpholine ring. ] In the aminophenyl ether compound represented by formula ()

When the partial structure represented by the formula has a disubstituted cyclohexane ring, cis or trans stereoisomers exist. Here, "halogen atom" means chlorine atom, bromine atom, fluorine atom, etc., and "lower alkyl group"
means 1 carbon number such as methyl group, ethyl group, isopropyl group, butyl group, isopentyl group, hexyl group, etc.
~6 straight chain or branched alkyl groups, "lower alkoxy group" refers to methoxy group, ethoxy group,
It means an alkoxy group having 1 to 6 carbon atoms such as a butoxy group. Further, examples of the "aryl group" include phenyl group, naphthyl group, etc., examples of the "aralkyl group" include benzyl group, phenethyl group, phenylpropyl group, etc., and examples of the "lower alkoxycarbonyl group" include methoxycarbonyl group. Examples of the "aralkenyl group" include a styryl group, a cinnamyl group, and the like. Examples of the "substituted amino group" include lower alkylamino groups such as methylamino, ethylamino, and isobutylamino groups; di-lower alkylamino groups such as dimethylamino, diethylamino, and dibutylamino; As "hydrogen group",
For example, bicyclononyl group, bicyclodecyl group,
Examples include an adamantyl group, a pinanyl group, and a bornyl group. Pharmaceutically acceptable salts of the compound () of the present invention include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, formic acid, lactic acid, oxalic acid, succinic acid,
Examples include acid addition salts with organic acids such as fumaric acid, benzoic acid and benzenesulfonic acid, and quaternary ammonium salts with alkyl halides such as methyl iodide. The compounds of the present invention have lipid-lowering effects, particularly excellent cholesterol- and triglyceride-lowering effects, and are effective in preventing and treating diseases of the cardiovascular system and the like caused by arteriosclerosis. Arteriosclerosis is caused by excess lipids such as cholesterol and triglycerides in the blood, and p-chlorophenoxyisobutyric acid ethyl ester (clofibrate) has been commonly used as a lipid-lowering agent. However, there is a desire to develop a drug that is more effective and has fewer side effects. As a result of extensive research, the present inventors discovered that the compound represented by the above formula () has an excellent effect of lowering cholesterol and triglyceride, and an effect of selectively increasing high-density lipoprotein (HDL) in the blood. I was able to complete it. It is known that the amount of HDL decreases during arteriosclerosis compared to normal levels, and that it prevents excessive accumulation of cholesterol in the arterial walls and promotes the flow of cholesterol from the arterial walls. Increase in HDL is effective in treating and preventing arteriosclerosis. To confirm the effectiveness of the compound of the present invention, male Sprague-Dawley rats, 3 weeks old, were fed a diet containing 1.5% cholesterol and 0.5% bile acid for 7 days, and for the last 4 days, methylcellulose 0.25 The compound of the present invention suspended in an aqueous solution of 1%
Administered once daily by oral probe, after overnight fasting,
It is performed by collecting blood under ether anesthesia and measuring the amount of serum total cholesterol and HDL. Cholesterol measurement is performed by “Schettler, G.
Nussel；Arbeitsmed.Sozialmed.
Praventivmed.10, 25 (1975)”, and HDL was measured using the method described in “TTIshikawa
etal; Lipids, 11628 (1976). In this experiment, the compound of the present invention was administered to rats at a dose of 10 to 25 mg/Kg (daily dose).
was found to be significantly effective. The compound of the present invention can be made into formulations such as powders, granules, tablets, capsules, and injections using commonly used formulation additives. The administration method is preferably oral, and the dosage varies depending on the patient's symptoms, age, etc., but in the case of oral administration,
Usually 1-100mg/Kg per day for adults, preferably 5-25
It is about mg/Kg. The compound () of the present invention can be produced by various methods, and for example, it can be produced by methods 1 to 5 shown in the following reaction formula. First method Formula () of the compound () of the present invention (In the formula, R, R ₁ , R ₂ and R ₃ have the same meanings as above.) The compound represented by the formula () (In the formula, R ₁ ' is a hydrogen atom, a lower alkyl group, or a lower alkenyl group, and R ₂ ' is an alkyl group or alkenyl group having 1 to 20 carbon atoms, a phenyl group, a benzyl group, or a lower alkyl group or A cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, or a cyclohexenyl group, each of which may be substituted with a lower alkenyl group, and R ₃ ' is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group, a benzyl group, or a lower alkyl group. represents a cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, or a cyclohexenyl group, each of which may be substituted with a group or a lower alkenyl group.However, R ₂ ' and R ₃ ' together with the adjacent carbon atoms represent a lower A cyclohexane ring or a cyclohexene ring which may be substituted with an alkyl group or a lower alkenyl group, respectively, may be formed.) and an alcohol compound represented by the formula () (In the formula, X represents a halogen atom, and R represents the same meaning as above.) By reacting p-halogenonitrobenzene represented by the formula in the presence of a strong base, and then reducing the product. I can do it. This reaction is preferably carried out in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof under heating. As the strong base, for example, sodium, potassium, lithium, sodium hydride, potassium hydride, lithium hydride, etc. are suitable, and the alcohol compound (2) is reacted with these strong bases before p-halogenonitrobenzene (2). It is preferable to react with Reduction can be carried out by conventional methods, for example by catalytic reduction using Raney nickel, platinum, palladium, etc. as catalysts in a hydrogen atmosphere, or by reducing iron, iron, etc. under acidic conditions.
This can be carried out by reduction using a metal such as zinc or tin. This catalytic reduction not only reduces nitro groups but also

Hydrogenation of the double bond present in the formula is also possible. Second method Formula () of the compound of the present invention (In the formula, R, R ₁ , R ₂ , R ₃ and R ₆ have the same meanings as above.) The compound represented by the formula is a compound obtained by the first method. It can be obtained by reacting with a carboxylic acid represented by the formula () R ₆ -COOH () (in the formula, R ₆ represents the same meaning as above) or a reactive derivative thereof. This reaction is preferably carried out in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, pyridine, dioxane, etc., or a mixed solvent thereof, under cooling or at room temperature. When using the carboxylic acid (2), the reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide. Examples of reactive derivatives of carboxylic acids include acid halides such as acid chloride and acid bromide, mixed acid anhydrides with benzyl phosphoric acid, alkyl carbonic acid, pivalic acid, etc., p-nitrophenyl ester, thiophenyl ester, etc. Examples include active esters and acid anhydrides. Third method Among the compounds of the present invention, formula () or expression() (In the formula, R ₇ is a lower alkyl group, an aryl group, an aralkyl group, or a lower alkoxycarbonyl group,
R ₇ ' represents a lower alkyl group, aryl group or aralkyl group, and R, R ₁ , R ₂ and R ₃ have the same meanings as above. ) is a compound obtained by the first method and a compound represented by the formula () R ₇ -X () (wherein X represents a halogen atom and R ₇ represents the same meaning as above). Preferred halogen atoms are bromine and iodine atoms. This reaction is carried out in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, pyridine, anhydrous methanol, anhydrous ethanol, etc., or a mixed solvent thereof at room temperature or under heating. Preferably, this is carried out in the presence of a deoxidizing agent. Fourth method Among the compounds of the present invention, formula () (In the formula, R ₈ is −(CH ₂ ) ₄ −, −(CH ₂ ) ₅ − or −
_{CH2CH2OCH2CH2- , and} R, _R1 , _R2 and _R3 have _the same meanings as above. ) is a compound obtained by the first method and a compound represented by the formula (XI) X-R ₈ -X (XI) (in the formula, R ₈ and You can get it by twisting it. Fifth method Among the compounds of the present invention, formula (XII) (In the formula, R, R ₁ , R ₂ , R ₃ and R ₆ have the same meanings as above.) The compound represented by () can be obtained by reducing the compound in an organic solvent such as tetrahydrofuran or ether using a reducing agent such as lithium aluminum hydride or diborane, preferably under heating. Using the compound obtained by the above method, the following reactions can be further carried out. (In the structural formula below, A is

Represents [formula]. ) (1) (R, R ₆ and R ₇ ' in the above formula have the same meanings as above.) (2) (R and R ₆ in the above formula have the same meanings as above.) (3) (R in the above formula has the same meaning as above.) (4) (In the above formula, R and R ₆ have the same meanings as above.) The production of the compounds of the present invention will be explained below with reference to Examples. Example 1 5.1 g of α-terpineol was dissolved in 120 ml of a dimethylformamide-benzene mixture (volume ratio 1:2), 1.6 g of sodium hydride (50% suspension in mineral oil) was added, heated under reflux for 30 minutes, then cooled and p- 4.7 g of fluoronitrobenzene was added dropwise, and the mixture was heated under reflux for 6 hours. After cooling the reaction solution, 200 ml of benzene was added and washed with water and brine, and the benzene layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The target product was eluted using a mixture of equal volumes of benzene and hexane as an eluent. When the solvent of the eluate was distilled off under reduced pressure, 4-(1 7.2 g of -p-menthen-8-yloxy)nitrobenzene were obtained. Dissolve this in 100ml of ethyl acetate and
% palladium on carbon was added, and the mixture was stirred and reacted in a hydrogen atmosphere until the theoretical amount of hydrogen was absorbed. After removing the palladium on carbon, the solvent was distilled off under reduced pressure, and the residue was rectified under reduced pressure to obtain 4-(p-
5.07 g of menthan-8-yloxy)aniline were obtained. Boiling point 146-148℃/0.3mmHg Elemental analysis value (as C ₁₆ H ₂₅ NO) C (%) H (%) N (%) Theoretical value 77.68 10.19 5.66 Experimental value 77.73 10.20 5.64 Example 2 6.2 g of 4-(p-menthan-8-yloxy)aniline, 7 g of anhydrous potassium carbonate and 1.5-
Dibromopentane 5.75g and absolute ethanol 150ml
were sequentially added to the mixture and heated under reflux for 40 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and dichloromethane was added to the residue.
200 ml and 150 ml of water were added. The dichloromethane layer was separated, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
The target product was eluted using benzene saturated with ammonia as an eluent, and the solvent of the eluate was distilled off under reduced pressure to obtain 5.77 g of crystalline 1-[4-(p-menthan-8-yloxy)phenyl]piperidine. It was done. When this substance is recrystallized with ethanol, the melting point is 53.
White crystals at ~54°C were obtained. Elemental analysis value (as C ₂₁ H ₃₃ NO) C (%) H (%) N (%) Theoretical value 79.95 10.54 4.44 Experimental value 79.90 10.83 4.37 Other alcohol compounds were used in place of α-terpineol in Example 1. The mixture was treated in the same manner as in Example 1 to obtain an aniline derivative, and then reacted with 1,5-dibromopentane in the same manner as in Example 2 to produce the compounds of Examples 3 to 17.

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[Table] Example 18 4-(p-menthan-8-yloxy)aniline
1.23 g of anhydrous potassium carbonate, 1.4 g of anhydrous potassium carbonate, and 1.1 g of 1,4-dibromobutane were sequentially added to 50 ml of absolute ethanol, and the mixture was heated under reflux for 42 hours. The same extraction and purification operations as in Example 2 were then performed. Crystalline N-[4-(p-
1.1 g of menthan-8-yloxy)phenylpyrrolidine were obtained. When this product was recrystallized from ethanol, white crystals with a melting point of 92-93°C were obtained. Elemental analysis value (as C ₂₀ H ₃₁ NO) C (%) H (%) N (%) Theoretical value 79.68 10.36 4.65 Experimental value 79.43 10.65 4.37 Example 19 Mix 10 g of 4-(p-menthan-8-yloxy)aniline with equal amounts of tetrahydrofuran and pyridine.
Dissolve in 100ml, add 8ml of acetic anhydride dropwise under ice cooling,
Stir overnight at room temperature. Pour the reaction solution into 300g of ice, stir for about 2 hours, remove the precipitated crystals,
After washing with water and recrystallizing with 50 ml of ethanol, white crystalline 4-(p-menthan-8-yloxy) was obtained.
6.7 g of acetanilide was obtained. Melting point 119-120℃ Elemental analysis value (as C ₁₈ H ₂₇ NO) C (%) H (%) N (%) Theoretical value 74.70 9.40 4.84 Experimental value 74.61 9.65 4.73 Instead of α-terpineol in Example 1, other The alcohol compound was treated in the same manner as in Example 1 to obtain an aniline derivative, and then Example
Compounds of Examples 20 to 32 were produced by reacting acetic anhydride in the same manner as in Example 19.

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[Table] Compounds of Examples 33 and 34 were produced using isobutyric anhydride and benzoic anhydride in place of acetic anhydride in Example 19.

[Table] Example 35 A mixture of 1 g of 4-(p-menthan-8-yloxy)aniline and equal amounts of tetrahydrofuran and pyridine
The solution was dissolved in 10 g, 0.65 g of cyclohexylcarbonyl chloride was added dropwise under ice, and the mixture was stirred overnight at room temperature. Pour the reaction solution into 60 g of ice, stir for about 2 hours, collect the precipitated crystals, wash with water, and recrystallize with 10 ml of ethanol to obtain white crystals of N-cyclohexylcarbonyl-4-(p-menthane-8-
1.02 g of yloxy)aniline was obtained. Melting point 171-172℃ Elemental analysis value (as C ₂₃ H ₃₅ NO ₂ ) C (%) H (%) N (%) Theoretical value 77.27 9.87 3.92 Experimental value 77.27 10.13 3.74 Instead of cyclohexyl carbonyl chloride in Example 35, Compounds of Examples 36 to 38 were produced using cinnamyl carbonyl chloride, 1-adamantanyl carbonyl chloride, and N.N-dimethylcarbamoyl chloride.

[Table] Instead of α-terpineol in Example 1, another alcohol compound was used and treated in the same manner as in Example 1 to obtain an aniline derivative, and then N.N.
-Dimethylcarbamoyl chloride or 1-adamantane carbonyl chloride was reacted in the same manner as in Example 35 to produce the compounds of Examples 39 to 41.

[Table] Example 42 N-cinnamoyl-4- obtained in Example 36
(p-menthan-8-yloxy)aniline 750mg
was dissolved in 20 ml of absolute ethanol, 350 mg of 10% palladium on carbon was added, and the mixture was stirred and reacted in a hydrogen atmosphere until the theoretical amount of hydrogen was absorbed. After removing the palladium on carbon, the solvent was distilled off under reduced pressure and the residue was
Recrystallization from 85% ethanol gives white crystalline 4.
-(p-menthan-8-yloxy)-N-(3-
0.7 g of phenylpropionyl)aniline was obtained. Melting point 96-97℃ Elemental analysis value (as C ₂₅ H ₃₃ NO ₂ ) C (%) H (%) N (%) Theoretical value 79.11 8.76 3.69 Experimental value 78.99 8.91 3.68 Example 43 2.5 g of 4-(p-menthan-8-yloxy)aniline, 1.4 g of anhydrous potassium carbonate, and 1.7 g of benzyl bromide were sequentially added to 100 ml of absolute ethanol.
The reaction was allowed to proceed at room temperature for 4 hours, and then heated under reflux for 40 hours. The same extraction and purification operations as in Example 2 yielded oily N-benzyl-4-(p-menthane-8-
0.95 g of yloxy)aniline was obtained. This product was dissolved in 25 ml of anhydrous ether, and while cooling, 1 ml of 5N hydrochloric acid was added and left to cool, yielding 0.8 g of hydrochloride. This was recrystallized from a dichloromethane-ethyl acetate mixture to obtain a white crystalline hydrochloride with a melting point of 137-138°C. Elemental analysis value (as C ₂₃ H ₃₂ NOCl) C (%) H (%) N (%) Theoretical value 73.87 8.63 3.75 Experimental value 73.55 8.72 3.54 Example 44 When the same treatment was performed using 1-bromobutane instead of benzyl bromide in Example 43, N-butyl-4-(p-menthan-8-yloxy)aniline hydrochloride was obtained. Melting point 138-139℃ Elemental analysis value (as C ₂₀ H ₃₄ NOCl) C (%) H (%) N (%) Theoretical value 70.66 10.08 4.12 Experimental value 70.46 10.28 3.91 Example 45 5 g of 4-(p-menthan-8-yloxy)aniline was dissolved in 50 ml of anhydrous pintane, and 4 ml of ethyl chlorocarbonate was added dropwise while stirring under ice cooling. 4
After stirring overnight at ℃, the reaction solution was poured into 300 ml of ice water, the resulting oil was extracted with ether, the extract was washed successively with water, 2% hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate. . The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from 20 ml of methanol to give white crystals of N-ethoxycarbonyl-4-(p
3.5 g of -menthan-8-yloxy)aniline were obtained. Melting point 65-66℃ Elemental analysis value (as C ₁₉ H ₂₉ NO ₃ ) C (%) H (%) N (%) Theoretical value 71.44 9.15 4.38 Experimental value 71.46 9.37 4.54 In addition, 1.5 g of target material was obtained from the recrystallization mother liquor I was able to get Example 46 To a suspension of 0.5 g of lithium aluminum hydride and 6 ml of anhydrous tetrahydrofuran, while stirring,
N-ethoxycarbonyl-4-(p-menthane-
A solution of 3.2 g of 8-yloxy)aniline dissolved in 60 ml of anhydrous tetrahydrofuran was added dropwise over about 2 hours, and then heated under reflux for 5 hours. After cooling the reaction solution on ice, add 0.6 ml of water and 15% aqueous sodium hydroxide solution.
ml and 2 ml of water were added little by little. After removing the insoluble materials, the solvent was distilled off under reduced pressure, and the residue was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the target product was eluted using ammonia-saturated benzene as an eluent. The solvent of the eluate was distilled off under reduced pressure, and the remaining oil was rectified under reduced pressure to obtain 4-(p-menthane-
Boiling point at which 1.22g of (8-yloxy)-N-methylaniline was obtained 148-151℃/0.6mmHg Elemental analysis value (as C ₁₇ H ₂₇ NO) C (%) H (%) N (%) Theoretical value 78.11 10.41 5.36 Experimental value 78.08 10.80 5.51 Example 47 Dissolve 430 mg of N-methyl-4-(p-menthan-8-yloxy)aniline in 5 ml of anhydrous tetrahydrofuran, 300 mg of acetic anhydride, and 0.8 mg of anhydrous pyridine.
ml and stirred overnight at room temperature. Pour the reaction solution into ice water.
Pour the obtained white crystals into 30 ml of petroleum ether.
ml to obtain 350 mg of white crystalline 4-(p-menthan-8-yloxy)-N-methylacetanilide. Melting point 70-71℃ Elemental analysis value (as C ₁₉ H ₂₉ NO ₂ ) C (%) H (%) N (%) Theoretical value 75.21 9.63 4.62 Experimental value 75.01 9.96 4.41 Example 48 Dissolve 1 g of 4-(p-menthan-8-yloxy)acetanilide in 20 ml of absolute ethanol,
0.4 g of tert-butoxypotassium and 0.6 g of benzyl bromide were added, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was treated with dichloromethane and water. The dichloromethane layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography, and the desired product was eluted using ammonia-saturated benzene as an eluent. The solvent of the eluate was distilled off under reduced pressure, and the resulting syrupy substance was rectified under reduced pressure to obtain 1.15 g of N-benzyl-4-(p-menthan-8-yloxy)acetanilide. Boiling point 195-200℃/0.6mmHg Elemental analysis value (as C ₂₅ H ₃₃ NO ₂ ) C (%) H (%) N (%) Theoretical value 79.11 8.76 3.69 Experimental value 79.49 8.96 3.94 Example 49 2.5 g of 4-(p-menthan-8-yloxy)aniline was dissolved in 80 ml of absolute ethanol, 2.8 g of anhydrous potassium carbonate was added, and a solution of 2.8 g of methyl iodide dissolved in 10 ml of absolute ethanol was added dropwise while stirring at room temperature. . After heating under reflux overnight, the solvent was distilled off under reduced pressure, and the mixture was extracted with dichloromethane. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The acid distillate was extracted with ether, insoluble ammonium salts were removed, and the ether was removed. The resulting oil was subjected to silica gel column chromatography, and the target product was eluted using ammonia-saturated benzene as the eluent. . The eluate was distilled off under reduced pressure, and the remaining oil was dissolved in dry ether 50%.
ml and add 1 ml of 5N hydrochloric acid-ethanol mixture to obtain crystalline 4-(p-menthan-8-yloxy)-N·N-dimethylaniline hydrochloride 1.8
g was obtained. When this was recrystallized from a dichloromethane-ethyl acetate mixture, white crystals with a melting point of 148-149°C were obtained. Elemental analysis value (as C ₁₈ H ₃₀ NOCl) C (%) H (%) N (%) Theoretical value 69.32 9.70 4.49 Experimental value 69.02 9.92 4.51 Example 50 4-(p-menthan-8-yloxy)-N・N
- Residue 1 obtained by treating an ether solution containing dimethylaniline hydrochloride with aqueous sodium bicarbonate
g was dissolved in 30 ml of absolute ethanol, 5 ml of methyl iodide was added, and the mixture was heated under reflux overnight. After distilling off the solvent and excess methyl iodide under reduced pressure, the residue was extracted with dichloromethane, and the extract was washed with water and brine.
It was dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, excess ether was added, the precipitate was collected, and recrystallized from a dichloromethane-ether mixture to give white crystalline 4-(p-menthane-8-
0.9 g of N.N.N-trimethylanilinium iodide was obtained. Melting point 179-180℃ Elemental analysis value (as C ₁₉ H ₃₂ NOI) C (%) H (%) N (%) Theoretical value 54.68 7.73 3.36 Experimental value 54.34 7.91 3.25 Example 51 A solution of 580 mg of 4-(p-menthan-8-yloxy)acetanilide dissolved in 10 ml of anhydrous tetrahydrofuran was added to lithium aluminum hydride.
The mixture was added dropwise to a suspension of 100 mg and 1 ml of anhydrous tetrahydrofuran while stirring. Heating under reflux for 5 hours, cooling and adding 0.1 ml of water and 0.1 ml of 15% aqueous sodium hydroxide solution.
ml and 0.3 ml of water were sequentially added to remove insoluble matter, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the target product was eluted using ammonia-saturated benzene as an eluent. The eluate is concentrated under reduced pressure and then rectified under reduced pressure to obtain N
300 mg of -ethyl-4-(p-menthan-8-yloxy)aniline was obtained. Melting point 143-145℃/0.35mmHg Elemental analysis value (as C ₁₈ H ₂₉ NO) C (%) H (%) N (%) Theoretical value 78.49 10.61 5.09 Experimental value 78.31 10.75 5.41 Example 52 31.28 g of cis-p-menthan-8-ol was added to a dimethylformamide-benzene mixture (volume ratio 1:
2) Dissolved in 670 ml, added 8.0 g of sodium hydride (60% suspension in mineral oil), heated under reflux for 30 minutes, cooled, added dropwise 28.2 g of p-fluoronitrobenzene, and heated under reflux for 6 hours. After cooling the reaction solution, 400 ml of benzene was added, washed with water and an aqueous sodium chloride solution, and the benzene layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and the target product was eluted using a mixture of equal volumes of benzene and hexane. When the solvent of the eluate was distilled off under reduced pressure, cis-
49 g of 4-(p-menthan-8-yloxy)nitrobenzene (boiling point 180-183°C/0.7 mmHg) was obtained. Dissolve 44g of this product in 200ml of ethyl acetate,
2 g of 10% palladium on carbon was added and reacted under pressure in a hydrogen atmosphere with stirring until the theoretical amount of hydrogen was absorbed. After removing the palladium on carbon, the solvent was distilled off under reduced pressure, and the residue was rectified under reduced pressure to obtain 39.4 g of cis-4-(p-menthan-8-yloxy)aniline. Boiling point 152-154℃/1mmHg Elemental analysis value (as C ₁₆ H ₂₅ NO) C (%) H (%) N (%) Theoretical value 77.68 10.19 5.66 Experimental value 77.70 10.22 5.65 Example 53 cis-4-(p-menthan-8-yloxy)
30g of aniline, 25.2g of anhydrous potassium carbonate and
33.5g of 1.5-dibromopentane in absolute ethanol
The mixture was sequentially added to 150 ml and heated under reflux for 15 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and 500 ml of dichloromethane and 500 ml of water were added to the residue. The dichloromethane layer was separated, washed with water and an aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and the target product was eluted using benzene saturated with ammonia as an eluent. When the solvent of the eluate was distilled off under reduced pressure, crystalline cis- 1-[4
-(p-menthan-8-yloxy)phenyl]
23 g of piperidine was obtained. When this product was recrystallized from ethanol, white crystals with a melting point of 78-79°C were obtained. Elemental analysis value (as C ₂₁ H ₃₃ NO) C (%) H (%) N (%) Theoretical value 79.95 10.54 4.44 Experimental value 79.83 10.98 4.36 Example 54 In Example 52, cis-p-menthane-8-
trans-p-menthane-8- instead of ol
trans-4-(p-menthane-
8-yloxy)nitrobenzene (boiling point 168-171
C/1 mmHg) and treated in the same manner as in Example 52 to obtain trans-4-(p-menthan-8-yloxy)aniline. Boiling point 141-143℃/0.6mmHg Elemental analysis value (as C ₁₆ H ₂₅ NO) C (%) H (%) N (%) Theoretical value 77.68 10.19 5.66 Experimental value 77.86 10.31 5.64 Example 55 In Example 53, cis-4-(p-menthane-
trans-8-yloxy)aniline instead of
Using 4-(p-menthan-8-yloxy)aniline, a trans-
Crystals of 1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained. Melting point 62-63℃ Elemental analysis value (as C ₂₁ H ₃₃ NO) C (%) H (%) N (%) Theoretical value 79.95 10.54 4.44 Experimental value 80.00 10.87 4.39 Example 56 21 g of trans-4-(p-menthan-8-yloxy)aniline was dissolved in a mixture of 40 ml of anhydrous pyridine and 100 ml of anhydrous dichloromethane, and 18.5 g of ethyl chlorocarbonate was added dropwise while stirring under ice cooling. 4
After stirring at °C overnight, the reaction solution was poured into 300 ml of ice water, and the dichloromethane layer was separated. The aqueous layer was re-extracted with 80 ml of dichloromethane, and the extract was separated first. This was combined with a dichloromethane solution, washed successively with water, 2% hydrochloric acid, water, and an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the resulting crystals were mixed with methanol 80
19.5 g of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline was obtained. Melting point 76-77℃ Elemental analysis value (as C ₁₉ H ₂₉ NO ₃ ) C (%) H (%) N (%) Theoretical value 71.44 9.15 4.38 Experimental value 71.87 9.43 4.35 Example 57 In Example 56, trans-4-(p-menthan-8-yloxy)aniline was replaced by cis-
Using 4-(p-menthan-8-yloxy)aniline, cis-N-
Ethoxycarbonyl-4-(p-menthane-8-
Methanol-containing crystals of yloxy)aniline were obtained. After drying this product under reduced pressure to remove methanol, cis-N-ethoxycarbonyl-4-(p
-menthan-8-yloxy)aniline was obtained as an oil. Elemental analysis value (as C ₁₉ H ₂₉ NO ₃ ) C (%) H (%) N (%) Theoretical value 71.44 9.15 4.38 Experimental value 71.15 9.37 4.36 Nuclear magnetic resonance spectrum (CDCl ₃ ) (internal standard
TMS) δ (ppm): 0.99 (

[Formula] 3H, d) 1.20 (

[Formula] 6H, s) 1.30 (CH ₃ -CH ₂ -O-, 3H, t) 1.0-2.1 (

[Formula] 10H, m) 4.24 (CH ₃ -CH ₂ -O-, 2H, q) 6.72 (-NHCO-, 1H, s) 6.95, 7.3 (

[Formula] 4H, A ₂ B ₂ q) Example 58 trans-N-ethoxycarbonyl-4-(p
- Menthan-8-yloxy)aniline 2.1g in 1N potassium hydroxide-95% ethanol solution 47
ml and heated under reflux for 6 hours. Ethanol was distilled off from the reaction solution under reduced pressure, and 50 ml of ether was added to the residue.
50 ml of water was added and the reaction product was extracted with ether. The extract was washed with water and an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the ether was distilled off to give trans-4-(p-menthane-
1.75 g of 8-yloxy)aniline were obtained. 1.7 g of this product, 2 g of anhydrous potassium carbonate, 1.5 g
- Absolute ethanol with 1.7 g of dibromopentane
50 ml and heated under reflux for 16 hours, and the reaction solution was diluted with Example 53.
When treated in the same manner as above, 0.95 g of crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained. Melting point: 62-63° C. The infrared absorption spectrum, nuclear magnetic resonance spectrum ( ¹ H, ¹³ C), and mass spectrum of this crystal were in good agreement with the spectra of the crystal obtained in Example 55. Example 59 In Example 58, trans-N-ethoxycarbonyl-4-(p-mendan-8-yloxy)-
Using cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline instead of aniline, the same treatment as in Example 58 was carried out to obtain cis-1-[4-(p-menthane-8-yloxy)aniline. -yloxy)phenyl]piperidine crystals were obtained. Melting point: 78-79°C The infrared absorption spectrum, nuclear magnetic resonance spectrum ( ¹ H, ¹³ C), and mass spectrum of this crystal were in good agreement with the spectra of the crystal obtained in Example 53.

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom, R ₁ is a hydrogen atom or a lower alkyl group, R ₂ is a cyclopentyl group or a cyclohexyl group that may be substituted with a lower alkyl group; an alkyl group having 1 to 20 carbon atoms, phenyl group or benzyl group, R ₃ is hydrogen atom,
A lower alkyl group, a cyclopentyl group or cyclohexyl group optionally substituted with a lower alkyl group, a phenyl group, or a benzyl group, R ₄ is a hydrogen atom, a lower alkyl group, an aralkyl group, or a lower alkoxycarbonyl group, R ₅ is a hydrogen atom, a lower alkyl group, the formula -COR ₆ (in the formula, R ₆ is a lower alkyl group, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group optionally substituted with a lower alkyl group, or a bridged (represents a hydrocarbon group) However, R ₂ and R ₃ may be combined with adjacent carbon atoms to form a cyclohexane ring which may be substituted with a lower alkyl group, and R ₄ and R ₅ may be combined with adjacent nitrogen atoms to form a cyclohexane ring which may be substituted with a lower alkyl group. They may be combined to form a pyridine ring, piperidine ring or morpholine ring. ] The aminophenyl ether compound represented by these, or its pharmacologically acceptable acid addition salt or quaternary ammonium salt with an alkyl halide. 2 R is a hydrogen atom, R ₁ and R ₃ are lower alkyl groups, R ₂ is a cyclohexyl group substituted with a lower alkyl group, and R ₄ and R ₅ are combined with the adjacent nitrogen atom to form a piperidine ring. A compound according to claim 1. 3. The compound according to claim 1, wherein R and R ₄ are hydrogen atoms, R ₁ and R ₃ are lower alkyl groups, R ₂ is a cyclohexyl group substituted with a lower alkyl group, and R ₅ is an acetyl group.