CA1110248A - Method of producing aminophenyl ether compound - Google Patents

Abstract

SPECIFICATION
TITLE OF THE INVENTION
"METHOD OF PRODUCING
AMINOPHENYL ETHER COMPOUNDS"
ABSTRACT OF THE DISCLOSURE
Method of producing aminophenyl ether compounds or the pharmacologically acceptable salts thereof having the formula wherein X1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), an alkyl group containing from 1 to 20 carbon atoms, a phenyl group or a benzyl group; R3 represents hydrogen atom, a lower alkyl group, or a cyclohexyl group which may have been substituted by lower alkyl group(s); R4 represents hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group; and R5 represents hydrogen atom, an aryl group or the group shown by -COR6 or -CH2R6 (wherein R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 19 carbon atoms, a cyclohexyl group an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group(s), a heterocyclic group which may have been substituted by lower alkyl group, or a bridged hydrocarbon group;) said R2 and R3 may, however, form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl group(s) and said R4 and R5 may from together with the adjacent nitrogen atom a pyrrolidine ring or a piperidine ring.
The above compounds have a hypolipemic activity, a cholesterol and a triglyceride reducing activity, and an activity of increasing high density lipoprotein (HDL) cholesterol, selectively.

Description

~Z~8 r This invention relates to a method of producing the novel aminophenyl ether compounds or the pharmacologically acceptable salts thereof shown by formula I

R2 - C - 0 - ~ N ~ ~ I

wherein Rl represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl groups, an alkyl group containing from 1 to 20 carbon atoms, a phenyl group or a benzyl group; R3 represents hydrogen atom, a lower alkyl group or a cyclohexyl group which may have been substituted by lower alkyl groups R4 represents hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group; and R5 represents hydrogen atom, an aryl group, or the group shown by -COR6 or -CH2R6 (wherein R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 19 carbon atoms, cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl groups, a heter-ocyclic group which may have been substituted by lower alkyl group, . or a bridged hydrocarbon group;) said R2 and R3 may, however, form together with the adjacent carbon atom a cyclohexane ring which may have been substituted by lower alkyl groups and said R4 and R5 may form together with the adjacent nitrogen atom a pyrrolidine ring or a piperidine ring.
When in the aminopheRyl ether compounds shown by formula I

the moiety shown by R2 ~ C - has a di-substituted cyclohexane `__R3 ~- ring, there exist the cis and trans stereoisomers of them, and hence the compounds in this invention include these stereoisomers.
Now, "lower alkyl group" used in this invention includes straight chain or branched alkyl groups containing from 1 to 6 carbon atoms, such as methyl group, ethyl group, isopropyl group, ;, , 1 ~

24~
butyl group, isopentyl group, hexyl group, etc. Also, as "aryl group" in this invention, there are, for example, phenyl group, naphthyl group, etc.; as "aralkyl group", there are for example, benzyl group, phenetyl group, phenylpropyl group, etc.; as "lower alkoxycarbonyl group", there are, for example, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, etc.; and as "aralkenyl group", there are, for example, styryl group, cinnamyl group, etc.; and as "heterocyclic group", there are, for example, pyrrolyl group, furyl group, thienyl group, oxazolynyl group, pyridyl group, thiazolyl group, thiadiazolyl group, dithianyl group, pyrimidinyl group, piperadinyl group, morpholino group, etc.
Furthermore, as l'bridged hydrocarbon group", there are, for example, bicyclononanyl group, bicyclodecanyl group, adamantyl group, - pinanyl group, bornyl group, etc.
As the pharmacologically acceptable salts of the compounds of formula I in this invention, there are salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.; salts with an organic acid such as formic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, benzenesulfonic acid, etc.; and also the quaterary ammonium salts obtained by the reaction with an alkyl halide such as methyl iodide, etc.
The compounds of formula I in this invention have a hypolipermic activity and also a particularly excellent cholesterol and trigly-ceride reducing activity and are effective for the prophylaxis andthe medical treatment of arteriosclerosis such as coronary heart disease.
It is said that arteriosclerosis is caused partially by unusually excessive amount of lipids such as cholesterol, tri-glyceride, etc., in blood. A hypolipemic agent, p-chloro-~henoxy-iso-butyric acid ethyl ester (Clofibrate) has hitherto been used frequently but it has further been desired to develop medicaments having more effective hypolipemic activity and less side effects.
As the result of the inventor's earnest investigations, it has now been found that the compounds described formula I have a cholesterol and triglyceride reducing activity and an effect of elevating high density lipoprotein (HDL) cholesterol, selectively.
It is known that the amount of HDL in blood is lower in arteriosclerosis than in normal state in human and also HDL prevents the excessive accumulation of cholesterol on the arterial wall and promotes the removal of cholesterol from the arterial wall in ex--- perimental animals. Therefore, the increase of HDL cholesterol may be effective for the prophylaxis and the medical treatment of arteriosclerosis. However, the conventional hypolipemic agent such ; as Clofibrate, etc., dose not show an activity of increasing HDL
cholesterol, selectively.
As a compound having the activity increasing ~DL cholesterol, ; N-[p-(l-adamantyloxy)phenyl] piperidine (U-41,792) as described in U.S. Patent No. 4,036,977 is known, but the activity of the compounds in this invention is clearly superior to that of the known compound, as shown below.
Experiment 1.
Three weeks old male Sprague-Dawley rats were fed for 7 days semipurified diet containing 1.5% cholesterol and 0.5% bile acid to induce hypercholesterolemia.
A compound in this invention suspended in an aqueous solution containing 0.25% methyl cellulose was administered to them once a by oral gavage for final four days. After fasted overnight, the animals were anesthetized with ether, and the blood was obtained from the peripheral vascular, and the HDL cholesterol (cholesterol of HDL) in the serum were determined. The results are shown in the following tables. In addition, the determination of the total cholesterol was practiced by the method described in Schettler G
& ~ussel; "Arbeitsmed. Sozialmed, Praventivmed.". 10, 25(1975) and the determination of HDL cholesterol was practiced by the method described in T, T. Ishikawa et al: " ipids", 11, 628(1976~.

,'~ /

-, /
'~ / `

/~

Table 1 Compound Dose Decrease of Increase of (A) (mg/kg/day) cholesterol cholesterol (control=l) (%) of HDL (%) 5 Known : Compound 1 ;. U-41,792* 25 -73 210 19.7 Compounds in the invention (Example ~o.) . 1825 -75 460 30.7 :~ 3125 -80 370 47.3 ;''' ;~. 4725 -80 460 47.7 :. 15 j 53100 -79 440 66 j~ 5425 -76 490 39.3 ;`~ 5525 -76 430 32.4 . 20 7125 -77 450 35.3 7225 -75 420 26.3 (A): Cholesterol of HDL/cholesterol of (VLDL + LDL)*

' 1~ 24~

Table 2 Compound Dose Cholesterol / holesterol (mg/kg/day) of HDL / of (VLDL + LDL)*2 (control = 1) - Known compound 25 19.7 U-41,792 Compounds in the invention ~ (Example No.) ; 1 100 45 18 25 30.7 31 25 47.3 47 25 47.7 54 25 39.3 32.4 71 25 35.3 72 25 26.3 *1: N- p-(l-adamantyloxy)phenyl piperidine (U.S. Patent No. 4,036,977) ~ 0 ~ ~

*2: VLDL: Very low density lipoprotein LDL: Low density lipoproptein __ ; Experiment 2.
By following the same procedure as in Experiment l using five ~- weaks old male Sprague-Dawley rats and the total choleterol in the serum and the HDL cholesterol were determined by the same manners - 5 as in Experiment 1. The results are shown in the following tables.
'' ; Table 3 . Compound in the Dose Decrease of Increase of ,: invention (mgikg/dat) cholesterol HDL (%) (Example No.) (%) ., . 10 31 12.5 -43 119 ,' 25 -69 280 48 12.5 -54 212 . .:
' 25 -68 308 ~-. 49 12.5 -36 154 r ~

' :

Table 4 :.
Compound in the Dose Cholesterol / Cholesterol ~ invention(mg/kg/day) of HDL / of (VLDL + LDI) - (Example No.) ~ control = 1) . 20 31 12.5 2.2 : 25 16.5 48 12.5 5.7 18.8 . 49 12.5 2.5 As is clear from the above-described experimental results, the compounds of formula I in this invention have not only an : excellent cholesterol reducing activity but also make the amount of HDL increasing greatly which is known to promote the removal of choleterol from the arterial wall. Therefore, the compounds in this invention are very effective for the prophylaxis and the medi-cal treatment of arteriosclerosis.
The compounds of formula I in this invention can be formed into various formulations such as powders, granules, tablets, cap-sules, injections, etc., using additivies for formulation gener-ally used. It is preferred that the compounds are administered orally. The doses of the compounds depend upon the condition, age, etc., of the patient but in a case of oral administration, the 10 dose is usually 1-100 mg/kg, preferably about 5-25 mg/kg a day per an adult.
The compounds of formula I in this invention can be prepared ; by various methods and, for example, can be prepared by methods ; 1-5 shown in the following reaction formulae:

~ .
A-OH III (A
strong base ~2 " _R3 Method 1 X ~ No2 IV

(A- ~ ~ NO ) reduction r~
A-O ~ ~H2 II
~ Method 4 Method 2 / \ ~ d ~ R8-X XI
~ 6-COOH VI \ R -X IX ~ ~
/ or its reactive ~ 7 A-O ~ ~R8 ~ derivatives f A-O ~ NH-R7 VII X

A-O ~ NHCO-R6 IA-O ~ N-R ' V \ 7 VIII
R ' Method 5 reduction 7 A-O ~ NHCH -R XII

24~8 That is, the compounds of formula I in this invention include the compounds of formulae II, V, VII, VIII, X and XII.
: The above-described five methods are described below in detail.
Method 1:
- In this invention, the compounds shown by formula II, Rl R - C -- ~ -~H2 II
~ _ R3 : , wherein Rl, R2 and R3 have the same significance as described above, can be obtained by reacting the alcohol compound shown by formula III, ~ R2 - C - OH III

: ~ R3 .;' wherein Rl, R2 and R3 have the same significance as above, and the ? p-halogenonitrobenzene shown by formula IV, ~ 2 IV

wherein X represents halogen atom, in the presence of a strong base and then reducing the product.

It is preferred that the reaction is carried out under heating in an organic solvent such as benzene, toluene, xylene, dimethyl-formamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof. Preferred examples of the strong base used in this invention are sodium, potassium, litium, sodium hydride, .,.

2~8 potassium hydride, lithium hydride, etc. In this case, it is pre-ferred that the alcohol compound of formula III is reacted with the strong base beforehand and then the product is reacted with the p-halogenonitrobenzene of fornula IV.
The reduction can be performed by an ordinary manner, for example, by the catalytic reduction in hydrogen atmosphere using a catalyst such as Raney nickel catalyst, platinum, palladium, etc., or by the reduction under an acidic condition using a metal such as iron, zinc, tin, etc. The catalytic reduction can perform not only the reduction of nitro group but also the hydrogenation of the double bond existing in group IRl ., I I :
~_ R3 Method 2:
In this invention, the compound shown by formula V, ~ R - C - O ~3 NHCo R6 v ~ R3 wherein Rl, R2, R3 and R6 have the same significance as above, can be obtained by reacting the compound shown by formula II in Method 1 R
R - C - O ~ 2 II
\ R3 .''' and the carboxylic acid shown by formula VI, R -COOH VI

2g~8 wherein R6 has the same significance as above, or its reactive derivative thereof.
It is preferred to perform the reaction under cooling or at room temperature in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, pyridine, dioxane, etc., or a mixed solvent of them. Also, in a case of using the carboxylic acid of formula VI in this reaction, it is better to perform the reaction in the presence of a conden-sing agent such as dicyclohexylcarbodiimide. As the reactive derivatives of the carboxylic acid of formula VI, there are acid halides such as acid chloride, acid bromide, etc.,; mixed acid an-hydrides such as benzyl phosphate, alkyl carbonate, pivalic acid, etc.; active esters such as p-nitrophenyl ester, thiophenyl ester, etc.; and acid anhydrides.
Method 3:

R - C - O ~ NHR7 VII

or formula VIII, R2 ~ C - 0 ~ ~ / R7 VILI

wherein R7 represents an alkyl group containing from l to 20 carbon atoms, an aryl group, an aralkyl group, or a lower alkoxycarbonyl group; R7' represents a lower alkyl group; and Rl, R2 and R3 have the same significance as above, can be obtained by reacting the compound shown by formula II in Method l ' 11 2~8 R
R - C - O --~9 NH2 I I

,, ;
and the compound shown by formula IX, ., ~

.~

wherein R7 and X have the same significance as above.

~ lO Preferred examples of the halogen atom in the method are bro-.~.
mine atom and iodine atom. It is preferred to perform the reaction at room temperature or under heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, pyrldine, methanol, ethanol, etc. or a mixed solvent of them, in the presence of a basic agent such as sodium carbonate, potassium carbonate, etc.
Method 4:
In this invention, the compound shown by formula X, Rl N~R 8 X
~ ~ _R3 wherein R8 represents -(CH2)4- or -(CH2)5- and Rl, R2 and R3 have ':
the same significance as above, can be obtained by reacting the compound shown by formula II in Method l R2 ~ C - g ~H2 II

- 3 30 and the compound shown by formula XI, X - R8 ~ X XI

wherein R8 and X have the same significance as above, under the ; same reaction condition as in Method 3.
5 Method 5: -In this invention, the compound shown by formula XII, R
R2 ~ C - o - ~ NHCH2-R6 XII
~ R3 wherein Rl, R2, R3 and R6 have the same significance as above, can be obtained by reducing the compound shown by formula V
.

Rl ! R2 ~ C - 0 ~ \~ NHC0-R6 \ R

using a reducing agent such as lithium aluminum hydride, diborane, etc., in an organic solvent such as tetrahydrofuran, ether, etc., under, preferably, heating.
Furthermore, the following reaction can be performed using the compounds obtained by the above-mentioned methods.
In addition, in the following formulae, A represents .: Rl R2 - C -.

~_ 3 1~48 O ~ CO-lower alkyl ~- alkyl-X
.. 5 ~ (same condition as in Method 3) alkyl A-O ~ N /
CO-lower alkyl wherein X has the same significance as above.
2).
A-O ~/ \> NHCO-aralkenyl .
catalytic reduction : 15 (same condition as in Method 1) ,.' A-O - ~ NHCO-aralkyl 3). A-O ~ ~ ~HCOO-lower alkyl .. 20 reduction ~ / (same condition as in Method 5) : A-O - ~ NHCH3 lower alkyl-COOH
or its reactive derivatives :; ~ ~ (same condition as in Method 2) ~ ~ CO-lower alkyl : ~ ~ CH3 q~2~8 In the above-mentioned methods, if the cis-compound of the alcohol compound of formula III is used, the cis-isomer of the compound of formula I is obtained and if the trans-compound of the alcohol compound of formula III is used, the trans-isomer of the compound of formula I is obtained. Also, if a mixture of the cis-trans isomer of the alcohol compound of formula III is used, a mixture of the cis-trans isomer of the compound of formula I is obtained and in this case, the cis-compound or the trans-compound can be isolated each other by an ordinary separation procedure such as fractional crystallization.
Then, the production methods of the compounds of this inven-tion are described by referring to the following examples.
Example 1 . ' .

CH3 ~ C ~ ~ NH2 ~: .

','' In 120 ml of a mixture of dimethylformamide and benzene in 1 : 2 by volume ratio was dissolved 5.1 g of p-methen-8-ol and after adding thereto 1.6 g of sodium hydride (50~/O suspension in a mineral oil), the mixture was refluxed for 30 minutes. Then, after cooling the reaction mixture, 4.7 g of p-fluoronitrobenzene was added, dropwise to the mixture and the resultant mixture was refluxed for 6 hours. After cooling the reaction mixture, 200 ml of benzene was added thereto, the mixture was washed with water and then an aqueous sodium chloride solution successively.
The benzene layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.
The residue was applied to a silica gel column chromatography and and the desired product was eluted using an equivalent mixture of - benzene and hexane. Then, by distilling off the solvent from the eluate under reduced pressure, 7.2 g of 4-(1-p-menthen-8-yloxy) nitrobenzene was obtained. A mixture of this product and 0.7 g of 10 % palladium carbon in 100 ml of ethyl acetate was shaken under hydrogen until the theoretical amount of hydrogen had been absorbed.
After filtering away palladium carbon, the solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to provide 5.07 g of 4-(p-menthan-8-yloxy)aniline.
Boiling point: 146-148C./0.3 mm Hg Elemental analysis for C16H25NO:
C(%) H(%) N(%) Calculated: 77.68 10.19 5.66 Found: 77.73 10.20 5.64 15 Example 2 CH

~H3O~ O ~ C _ ~ NH2 In 670 ml of a mixture of dimethylformamide and benzene in ; 1 : 2 by volume ratio was dissolved 31.2 g of cis-p-menthan-8-ol and after adding thereto 8.0 g of sodium hydride (60% suspension in a mineral oil), the mixture was refluxed for 30 minutes. After cooling, 28.2 g of p-fluoronitrobenzene was added dropwise to the mixture and the resultant mixture was further refluxed for 6 hours.
After cooling, 400 ml of benzene was added to the mixture and the resultant mixture was washed with water and an a~ueous sodium chlor-ide solution successively. The benzene layer was dried over anhy-drous sodium sulfate. After distilling off the solvent under 29~8 reduced pressure, the residue formed was applied to a silica gel - column chromatography, the desired product was eluted using an equivalent mixture of benzene and hexane, and then the solvent was distilled off from the eluate under reduced pressure to provide 49 g of cis-4-(p-menthan-8-yloxy)nitrobenzene having a boiling point of 180-183C./0.7 mm Hg.
A mixture of 44 g of the product and 2 g of 10 % palladium carbon in 200 ml of ethyl acetate was shaken under hydrogen until a theoretical amount of hydrogen had been absorbed. After filtering away palladium carbon, the solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to provide 39.4 g of cis-4-(p-menthan-8-yloxy)aniline.
Boiling point: 152-154C./l mm Hg Elemental analysis for C16H25NO:
Ct%) H(%) Nt%) Calculated:77.68 10.19 5.66 , Found: 77.70 10.22 5.65 Example 3 CH
CH3 ~ ~ ~ o ~ - NH2 By following the same procedure as in Example 2 using trans-p-menthan-8-ol in place of cis-p-menthan-8-ol, trans-4-(p-menthan-8-yloxy)nitrobenzene having a boiling point of 168-171C./l mm Hg was obtained and by treating the product as in Example 2, trans-4-(p-menthan-8-yloxy)aniline was obtained.
soiling point: 141-143C./0.6 mm Hg Elemental analysis for C16E25N0:

2~8 C(%) H(%) N(%) Calculated: 77.68 10.19 5.66 Found: 77.86 10. 31 5.64 Example 4 , CH3- V - C - O- ~ NHCOCH3 .; CH3 In 100 ml of an equivalent mixture of tetrahydrofuran and py-ridine was dissolved 10 g of 4-(p-menthan-8-yloxy)aniline and after adding dropwise to the solution 8 ml of acetic anhydride under ice-cooling, the mixture was stirred overnight at room temperature.
The reaction mixture was poured over 300 g of ice followed by mix-ing for about 2 hours and crystals precipitated were collected by filtration, washed with water, and recrystallized from 50 ml of ethanol to provide 6.7 g of white crystalline 4-(p-menthan-8-yloxy)-- acetanilide.
,- Melting point: 119-120C.
~ 20 Elemental analysis for C18H27N0:
C(%) H(%) N(%) Calculated: 74.70 9.40 4.84 Found: 74.61 9.65 4.73 By the similar procedure as in Example 1 using other alcohol compounds instead of p-menthen-8-ol in Example 1, aniline deriva-tives were obtained and they were reacted with acetic anhydride by the similar procedure as in Example 4 to provide the compounds of Examples 5-19.
Example 5 Alcohol compound used as starting material

4~Z9~8 OH
CH

Menthol - Desired compound ClH3 ~ lo [~ ~3-- NHCOCH3 CH
/ \

4-(p-Menthan-3-yloxy)acetanilide :.:
~; Melting point 133 - 134C
Elemental analysis for C18H27NO2:
C(%) H(%) N(%) Calculated: 74.70 9.40 4.84 Found: 74.45 9.64 4.56 Example 6 Alcohol compound used as starting material CH3C=CH(CH2)2C -CH=CH2 3,7-Dimethyl-3-oxy-1,6-octadiene - 25 Desired compound f 3 f 3 3 ( 2)3f ~ NHCOCH3 4-(3,7-Dimethyloct-3-yloxy)acetanilide Melting point 50-51C

Z9~8 Elemental analysis for C18H29NO2:
C(%) H(%) N(%) Calculated: 74.18 10.03 4.81 Found: 74.19 9.89 4.54 Example 7 Alcohol compound used as starting material l,l-Dimethylpropanol Desired compound CH

. C2H5C - ~ - NHCOCH3 4-(1,1-Dimethylpropoxy)acetanilide Melting point 116-117C
Elemental analysis for C13HlgNO2:
C(%) H(%) N(%) Calculated: 70.56 8.65 6.33 Found: 70.54 8.80 6.33 Example 8 : Alcohol compound used as starting material ~ CH2 -OH

Cyclohexylmethanol Desired compound i ~ CH2 - O ~ NHCOCH3 4-(Cyclohexylmethoxy)acetanilide Meiting point 118-119C

Elemental analysis for C15H21NO2:
C(%) H(%) N(%) Calculated:72.84 8.56 5.66 Found: 72.66 8.57 5.82 . 5 Example 9 :, .
Alcohol compound used as starting material ~: CH3 ~ CH -OH

l-Cyclohexylethanol Desired compound CH - O ~ NHCOCH3 , .
4~ Cyclohexylethoxy)acetanilide Melting point 94 - 95C
Elemental analysis for C16H23NO2:
; C(%) H(%) N(%) Calculated: 73.53 8.87 5.36 Found: 73.41 9.08 5.30 :: Example 10 Alcohol compound used as starting material : fH3 ~ C -OH

l-Cyclohexyl-l-methylethanol Desired compound -O ~ NHCOCH3 4~ Cyclohexyl-l-methylethoxy)acetanilide Melting point: 122 - 123C
Elemental analysis for C17H25NO2:
C(%) H(%) N(%) . 5 Calculated 74.14 9.15 5.09 Found: 74.07 9.41 4.93 /
~ //
~'" /

4~2 Examplé 11 .~
. , .
Alcohol compound used as starting material l-Benzyl-l-methylethan Desired compound : 10 CH3 - CH2C -o _ ~ NHCOCH3 . CH3 ... 4-(a,a-Dimethylphenethyloxy)acetanilide . Melting point 153 - 154C
. 15 Elemental analysis for C18H21NO2:
C(%) H(%) N(%) Calculated: 76.30 7.47 4.94 Found: 76.38 7.47 4.91 Example 12 Alcohol compound used as starting material H

l-Methylcyclohexanol Desired compound ~ O ~ NHCOCH3 4-(1-Methylcyclohexyloxy)acetanilide Melting point 123 - 124C
Elemental analysis for C15H21NO2:

2~L8 C(%) H(%) N(%) Calculated: 72.84 8.56 5.66 Found: 73.15 8.65 5.76 Example 13 Alcohol compound used as starting material OH
CH
/ \

3-Methylmenthol Desired compound ~ 3 ~ NHCOCH3 CH
~ / \

~ .
4-(3-Methyl-p-menthan-3-yloxy)acetanilide Melting point 133 - 134~C
Elemental analysis for ClgH29N02:
C(%) H(%) N(%) Calculated: 75.21 9.63 4.62 Found: 74.69 9.96 4.93 Example 14 Alcohol compound used as starting material ~ C -OH
,~3 l-Cyclohexyl-l-phenylethanol Desired compound C - O ~ NHCOCH3 ~ 5 ~ 3 4-(a-Cyclohexyl-a-methylbenzyloxy)acetanilide . Melting point 102 - 103C
Elemental analysis for C22H27NO2:
C(%) H(%) N(%) Calculated: 78.30 8.06 4.15 Found: 78.01 8.34 4.36 Example 15 Alcohol compound used as starting material ;. .

~ CH ~ OH
~' ~
- Dicyclohexylmethanol . Desired compound ~ CH- O ~ NHCOCH3 ~J
4-(Dicyclohexylmethoxy)acetanilide Melting point 187 - 188C
: 25 Elemental analysis for C21H31NO2:
C(%) H(%) N(%) Calculated: 76.55 9.48 4.25 Found: 76.61 9.84 4.15 Example 16 Alcohol compound used as start ng material z~ ~

C - OH

a,a-Dimethylbenzylalcohol Desired compound C- O - ~ NHCOCH3 . .
,.'"
4~(a,a-Dimethylbenzyloxy)acetanilide Melting point 130 - 131C
Elemental analysis for Cl7HlgNO2:
C(%) H(%) N(%) ` Calculated: 75.81 7.11 5.20 - 15 Found: 76.05 7.18 5.44 Example 17 Alcohol compound used as starting material OH

Cyclohexanol Desired compound O ~ ~3COC33 4-(Cyclohexyloxy)acetanilide Melting point 158 -159C
; 26 111~2~B

Elemental analysis for Cl4HlgNO2:
C(%) H(%) N(%) Calculated: 72.07 8.21 6.00 Found: 71.72 8.30 6.33 The compounds in Examples 18 and l9 were produced using iso-butyric anhydride or benzoic anhydride instead of acetic anhydride in Example 4.
Example 18 Desired compound ,` 10 CH3 / CH
CH3 - ~ f O ~ NHCOCH \

N-Isobutyryl-4-(p-menthan-8-yloxy)aniline Melting point 127 - 128C
Elemental analysis for C20H3lNO2:
C(%) H(%) N(%) Calculated: 75.679.84 4.41 Found: 75.5410.10 4.21 Example 19 Desired compound H3 ~ C - O ~ NHCO

4-(p-Menthan-8-yloxy)benzanilide Melting point 121 - 122C
Elemental analysis for C23H29NO2:
C(%) H(%) N(%) Calculated: 78.608.32 3.98 Found: 78.318.46 3.69 Example 20 Z9~8 CH3 ~ - ~ ~ NHCO

In 10 ml of an equivalent mixture of tetrahydrofuran and pyri-dine was dissolved 1 g of 4-(p-menthan-8-yloxy)aniline and after adding dropwise 0.65 g of cyclohexylcarbonyl chloride to the solu-tion under ice-cooling, the mixture was stirred overnight at room temperature. The reactiOn mixture was poured over 60 g of ice followed by stirring for about 2 hours and crystals precipitated were collected by filtration, washed with water, and recrystallized from 10 ml of ethanol to provide 1.02 g of white crystalline N-cyclohexylcarbonyl-4-(p-menthan-8-yloxy)aniline.
Melting point: 171-172C
Elemental analysis for C23H35N02:
C(%) H(%) N(%) Calculated: 77.27 9.87 3.92 Found: 77.27 10.13 3.74 By the similar procedure as in Example 20 using cinnamoyl chloride, l-adamantanylcarbonyl chloride or N,N-dimethylcarbamoyl chloride instead of cyclohexylcarbonyl chloride in Example 20, the compounds in Example 21-23 were obtained.
Example 21 Desired compound CH3 ~ C- O ~ ~HCOCH=CH

N-Cinnamoyl-4-(p-menthan-8-yloxy)aniline Melting point 75 - 76C
Elemental analysis for C25H31N02:

1~ 8 C(%) H(%) N(%) Calculated: 79.54 8.28 3.71 ; Found: 79.31 8.37 3.52 Example 22

5 Desired compound CH3 ~ C- O ~ NHCO

,~
N-(Adamant-l-yl-carbonyl)-4-(p-menthan-8-yloxy)aniline Melting point 105 - 106C
Elemental analysis for C27H39NO2:
C(%) H(%) N(%) Calculated: 79.199.60 3.42 - 15 Found: 79.329.64 3.26 Example 23 Desired compound CH3- ~ f - O ~ NHCON ~

l-[4-(p~menthan-8-yloxy)phenyl]-3,3-dimethylurea Melting point 112 - 114C
: Elemental analysis for ClgH30N2O2:
C(%) H(%) N(%) Calculated: 71.66 9.50 8.80 Found: 71.56 9.81 8.65 By similar procedure as in Example 1 using other alcohol com-pounds instead of p-menthan-8-ol in Example 1, aniline derivatives were obtained and they were reacted with N,N-dimethylcarbamoyl chloride or l-adamantanylcarbonyl chloride by the similar procedure 2~3 as in Example 20 to provide the compounds in Examples 24-26.
Example 24 Alcohol compound used as starting material:

,- 5 ~ ~
I OH
cH
CH3/ \ CH3 '?
Menthol Desired compound O ~ NHCON
CH CH
/ \ 3 1-[4-(p-Menthan-3-yloxy)phenyl]-3,3-dimethylurea Melting point 154 - 156C

Elemental analysis for ClgH30N2O2:
C(%) H(%) N(%) Calculated 71.66 9.50 8.80 Found 71.53 9.69 8.58 Example 25 Alcohol compound used as starting material ~ CH2 - OH

Cyclohexylmethanol Desired Compound ~ CH2 _ O ~
; ~1 30 ~ . .
' 1-(4-Cyclohexylmethoxyphenyl)-3,3-dimethylurea Melting point 158 - 159C
Elemental analysis for C16H24N202:
C(%) H(%) N(%) Calculated: 69.53 8.7510.14 Found: 69.21 8.81 9.90 ExamPle 26 Alcohol compound used as starting material ~, CH

Menthol Desired compound '',. ~
~ 0 ~ NHC0 N-(Adamant-l-ylcarbonyl)-4-(p-menthan-3-yloxy)aniline Melting point 194 - 195C
Elemental analysis for C27H39N02:
C(%) H(%) N(%) 25 Calculated: 79.179.60 3.42 Found: 79.40 9.863.37 Example 27 CH3 ~ C - 0 ~ NHCOCgHlg In 10 ml of anhydrous tetrahydrofuran was dissolved 2.0 g of 4-(p-menthan-8-yloxy)aniline and after adding thereto 5 ml of an-hydrous pyridine, 1.55 g of N-decanoyl chloride (CgH19COCl) was added dropwise to the mixture under ice-cooling, and the resul-tant mixture was stirred overnight at room temperature.
The reaction mixture was poured over 50 g of ice followed by stirring for about 3 hours. Then, the oily product thus precipi-- tated was recovered by decantation and dissolved in 100 ml of ether. The ether solution was washed successively with 3% hydro-chloric acid, a saturated aqueous sodium hydrogencarbonate solu-tion, and then an aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and then thé solvent was distilled off under reduced pressure to provide 3.2 g of the crystals of 4-(p-menthan-8-yloxy)-N-decanoylaniline. By recrystallizing the product from ethanol, the white crystals having a melting point of 31-32C.
was obtained.
Elemental analysis for C26H43~O2:
C(%) H(%) N(%) Calculated: 77.75 10.79 3.49 Found: 77.55 11.07 3.41 Example 28 3 ~ C - o ~ NHCOC13H27 By following the same procedure as in Example 27 using myris-toyl chloride (C13H27COCl) in place of N-decanoyl chloride, 4-(p-; menthan-8-yloxy)-N-myristoylaniline was obtained.

Melting point: 51 - 52C
Elemental analysis for C30H51NO2:
C(%) H(%) N(%) 111~J~2~8 Calculated: 78.72 11.23 3.06 Found: 78.54 11.56 2.90 Example 29 3 ~ ~ C o ~ NHCOC15H

By following the same procedure as in Example 27 using palmi-toyl chloride (C15H31COCl) in place of N-decanoyl chloride, 4-(p-menthan-8-yloxy)-N-palmitoylaniline was obtained.

Melting point: 61 - 62C.

- Elemental analysis for C32H55N02:

- C(%) H(%) ~(%) Calculated: 79.12 11.41 2.88 Found: 79.45 11.79 2.71 Example 30 <~} C --O .~ NHCOC 17H3 5 In 20 ml of anhydrous tetrahydrofuran were suspended 2.0 g of 4-(p-menthan-8-yloxy)aniline and 4.5 g of anhydrous stearic acid and after adding dropwise thereto 5 ml of anhydrous pyridine with stirring under ice-cooling, the mixture was stirred overnight at room temperature.
The reaction mixture was poured over 100 g of ice followed by stirring for about 2 hours and white crystals precipitated were collected by filtration, washed thrice each with 50 ml of petroleum ether, and then recrystallized twice with 25 ml of ethanol to pro-vide 3.1 g of the white crystals of 4-(p-menthan-8-yloxy)-N-stear-oylaniline.

Melting point: 72 - 73C.

Elemental analysis for C34H59NO2:

C(%) H(%) N(%) Calculated: 79.47 11.57 2.73 Found: 79.71 11.93 2.44 Example 31 `~ CH3 CH3 ~ C - 0 - ~ N

, To 150 ml of anhydrous ethanol were added successively 6.2 g of 4-(p-menthan-8-yloxy)aniline, 7 g of anhydrous potassium carbo-nate, and 5.75 g of 1,5-dibromopentane and the mixture was refluxed . .
for 40 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and to the residue were added ; 200 ml of dichloromethane and 150 ml of water. The dichloromethane layer was separated washed with water and then an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was applied to a silica gel column chromatography. The desired - product was then eluted using benzene saturated with ammonia and then the solvent was distilled off under reduced pressure from the eluate to provide 5.77 g of crystalline 1-[4-(p-menthan-8-yloxy)-phenyl]piperidine. When the product was recrystallized from ~- ethanol, the white crystals having a melting point of 53-54C.
were obtained.
Elemental analysis for C21H33NO:
C(%) H(%) N(%) 30Calculated: 79.95 10.54 4.44 79.90 10.83 4.37 By the similar procedure as in Example 1 using other alcohol compounds instead of p-menthan-8-ol in Example 1, aniline deriva-tives were obtained and they were reacted with l,5-dibromopentane by the similar procedure as in Example 31 to provide the compounds in Examples 32-46.
Example 32 Alcohol compound used as starting material OH
CH

MENTHOL

Desired compound ~ 3 ,;' ~1 CH ~ N

1-[4-(p-menthan-3~yloxy)phenyl]piperidine ;~ Melting point 93 - 94C

Elemental analysis for C21H33NO:

C(%) H(%) N(%) Calculated: 79.95 10.54 4.44 .:
Found: 79.91 10.75 4.41 Example 33 Alcohol compound used as starting material CH2 = C - (CH2)3CH(CH2~2OH

2~L8 3,7-dimethyl-7-octen-1-ol - Desired compound (C~2~3CH CH2~2-- 0~

1-[4-(3,7-Dimethyloctyloxy)phenyl]piperidine Boiling point 174 - l78oc/o~4mmHg Elemental analysis for C21H35NO:
C(%) H(%) N(%) Calculated: 79.44 11.11 4.41 Found: 79.40 11.43 4.19 -~ Example 34 ; Alcohol compound used as starting material fH3 OIH

CH3C-= CH(CH2)2CI -CH =CH2 3,7-Dimethyl-3-oxy-1,6-oxtadiene Desired compound CH3CH(CH2)3C - O ~ ~ N

N-[4-(3,7-Dimethyloct-3-yloxy)phenyl]piperidine Boiling point 174 - l76oc/o~5mmHg Elemental analysis for C21H35NO:
C(%) H(%) N(%) Calculated: 79.44 11.11 4.41 Found: 79.74 11.23 4.13 Example 35 Alcohol compound used as starting material CH3(CH2)17 OH
Octadecanol Desired compound 36 CH (CH ) --O ~9 N~/~
N-(4-Octadecanyloxyphenyl)piperidine Melting point 54 - 55C
Elemental analysis for C29H51NO:
C(%) H(%) N(%) Calculated: 81.06 11.96 3.26 Found: 80.92 12.27 3.00 Example 36 Alcohol compound used as starting material fH3 : CH3CH2C OH
~ CH
: 3 1, l-Dimethylpropanol Desired compound CH3CH2C--O ~ N~
: CH3 N-[4-(1, l-Dimethylpropoxy)phenyl]piperidine ~` Boiling point 120 - 122C/lmmHg . 20 Elemental analysis for C16H 2~O:
C(%) H(%) N(%) Calculated: 77.68 10.19 5.66 Found: 77.32 10.24 5.39 ; Example 37 25 Alcohol compound used as starting material Cyclohexylmethanol Desired compound 0 2 ~3 ~C) N-[4-(Cyclohexylmethoxy)phenyl]piperidine -Melting point 63 - 64C
Elemental analysis for C18H27NO:
C(%) H(%) N(%) Calculated: 79.07 9.95 5.12 Found: 78.88 10.22 5.00 Example 38 Alcohol compound used as starting material ~ CH - OH

~ l-Cyclohexylethanol - Desired compound CH

CH - O ~ N

N-[4-(1-Cyclohexylethoxy)phenyl]piperidine Boiling point 147 - 148C/0.3mmHg A Elemental analysis for ClgH29NO:
C(%) H(%) N(%) ", Calculated: 79.39 10.17 4.87 Found: 79.28 10.51 4.87 ; Example 39 Alcohol compound used as starting material ~ C - OH

Cyclohexyl-l-methylethanol Desired compound Z~8 ~~ ~
:: CH3 N-[4-(1-Cyclohexyl-l-methylethoxy)phenyl]piperidine Melting point 66 - 67C
Elemental analysis for C20H31NO:
C(%) H(%) N(%) Calculated: 79.68 10.36 4.65 Found: 79.54 10.58 4.41 Example 40 Alcohol compound used as starting material CH
: 1 3 ~ CH C - OH
~ 21 . CH3 Benzyl-l-methylethan Desired compound : CH3 '~ ~ CH2C - ~ N

N-[4-(a,a-Dimethylphenethyloxy)phenyl]piperidine Melting point 68 - 69C
Elemental analysis for C21H27NO:
C(%) H(%) N(%) Calculated: 81.51 8.79 4.53 Found: 81.33 8.95 4.52 Example 41 Alcohol compound used as starting material ~ CH3 OH

2~3 l-Methylcyclohexanol Desired compound O ~ ~ .~Cl N-[4-(1-Methylcyclohexyloxy)phenyl]piperidine hydrochloride - Melting point 150 - 151C
Elemental analysis for C18H28NOCl:
C(%) H(%) N(%) ; Calculated: 69.77 9.11 4.52 Found: 69.39 9.42 4.64 Example_42 Alcohol compound used as starting material ~, CH

~ OH
/CH \

,:
3-Methylmenthol Desired compound C~_ N-[4-(3-Methyl-p-menthan-3-yloxy)phenyl]piperidine 25 Boiling point 140 - 145C~0.3mmHg Elemental analysis for C22H35N0:
C(%) H(%) N(%) Calculated: 80.19 10.71 4.25 Found: 80.14 10.42 3.92 Example 43 2,~

Alcohol compound used as starting material C - OH
~3 a-Cyclohexyl-a-methylbenzylalcohol Desired compound C - O ~ N
,, ~
N-[4-(a-Cyclohexyl-a-methylbenzyloxy)phenyl]piperidine Boiling point 178 - 183C/0.25mmHg Elemental analysis for C25H33NO:
C(%) H(%) N(%) . 15 Calculated: 82.60 9.15 3.85 Found: 82.66 9.35 3.65 Example 44 Alcohol compound used as starting material ~ CH - OH
Dicyclohexylmethanol Desired compound ~ CH ~ O ~ N ~

N-(4-Dicyclohexylmethoxyphenyl)piperidine Melting point 57 - 58C
Elemental analysis for C24~37NO:

2~8 C(%) H(%) N(%) Calculated: 81.07 10.49 3.94 Found: 81.16 10.83 3.73 Example 45 Alcohol compound used as starting material ~ .

C OH
,,~, I
; CH3 a,a-Dimethylbenzylalcohol '~ 10 Desired compound C - O ~ ~ N

; :
N-[4-(a,a-Dimethylbenzyloxy)phenyl]piperidine Melting point 92 - 93C
Elemental analysis for C20H25NO:
C(%) H(%) N(%) ' Calculated: 81.31 8.53 4.74 Found: 81.09 9.69 4.98 Example 46 Alcohol compound used as starting material .
~OE~

Cyclohexanol Desired compound ~ - ~ N

~`:

~$~2~18 .
N-(4-Cyclohexyloxyphenyl)piperidine Melting point 50 - 51C
Elemental analysis for C17H25N0:
C(%) H(%) N(%) Calculated: 78.72 9.71 5.40 Found: 78.51 9.92 5.56 Example 47 CH3 ~ I ~ ¦

To 50 ml of anhydrous ethanol were added successively 1.23 g of 4-(p-menthan-8-yloxy)aniline, 1.4 g of anhydrous potassium carbonate, and 1.1 g of 1,4-dibromobutane and the mixture was re-fluxed for 42 hours. Then, the reaction product was subjected to the extraction and purification procedures as in Example 31 to - provide 1.1 g of crystalline N-[4-(p-menthan-8-yloxy)phenyl]pyrro-lidine. When the product was recrystallized from ethanol, the white crystals having a melting point of 92-93C. were obtained.
Elemental analysis for C20H31N0:
C(%) H(%) N(%) Calculated: 79.68 10.36 4.65 Found: 79.43 10.65 4.37 Example 48 CH3~ ~ ~6 C - 0 ~ N

To 150 ml of anhydrous ethanol were added successively 30 g of cis-4-(p-menthan-8-yloxy)aniline, 25.2 g of anhydrous potassium carbonate, and 33.5 g of 1,5-dibromopentane and the mixture was refluxed for 15 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and to the resi-due was added 500 ml of dichloromethane and 500 ml of water. The dichloromethane layer was separated by decantation, washed with water and then an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue formed was applied to silica gel column chromatography. Then, the desired product was eluted using benzene saturated with ammonia and the solvent of the eluate was distilled off under reduced pressure to provide 23 g of cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine. When the product was recry-stallized from ethanol, the white cr~stals having a melting point of 78-79C were obtained.
Elemental analysis for C21H33NO:
C(%) H(%) N(%) .. . .
15 Calculated 79.95 10.54 4.44 Found 79.83 10.98 4.36 Example 49 : F 3 C--O ~3 By following the same procedure as in Example 48 using trans-4-(p-menthan-8-yloxy)aniline in place of cis-4-(p-menthan-8-yloxy)-aniline, the crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]-piperidine were obtained.
Melting point 62-63C.
Elemental analysis for C2lH33NO:

C(%) H(%) N(%) Calculated 79.95 10.54 4.44 Found 80.00 10.87 4.39 Example 50 ~ 44 CH ~ O --- C - ~ -In 47 ml of a 95% ethanol solution of 1 normal potassium hydroxide was dissolved 2.1 g of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline and the solution was refluxed for 6 hours.
Then, ethanol was distilled off under reduced pressure from the reaction mixture and to the residue formed were added 50 ml of ether and 50 ml of water followed by extraction with ether. The extract was washed with water and then an aqueous sodium chloride solution and after drying over anhydrous magnesium sulfate, ether was distilled off from the reaction mixture to provide 1.75 g of trans-4-(p-menthan-8-yloxy)aniline.
; 15 To 50 ml of anhydrous ethanol was added 1.7 g of the product together with 2 g of anhydrous potassium carbonate and 1.7 g of 1,5-dibromopentane and the mixture was refluxed for 16 hours.
Then, by treating the reaction product as in Example 48, 0.95 g of the crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained.
Melting point: 62-63C.
The infrared absorption spectra, nuclear magnetic resonance spectra ( H, C), and the mass spectra of the crystals coincided well with these spectra of the crystals obtained in Example 49.
Example 51 CH3 ~ O ~ I - O

By following the same procedure as in Example 50 using cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline in place of trans-N-. _.....

i ``/!

Z4~
ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline, the crystals of cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine were obtained.
Melting point: 78-79C
The infrared absorption spectra, nuclear magnetic resonance spectra ( H, C), and mass spectra of the crystals coincided well with those of the crystals obtained in Example 48.
Example 52 ~;~ CH3 CH3 ~ } C - 0 ~ NHCH2 ~ .HCl To 100 ml of anhydrous ethanol were added successively 2.5 g of 4-(p-menthan-8-yloxy)aniline, 1.4 g of anhydrous potassium car-bonate, and 1.7 g of benzyl bromide and after causing reaction for 4 hours at room temperature, the mixture was then refluxed for 40 hours. Then, the reaction mixture was subjected to the extraction and purification procedures as in Example 31 to provide 0.95 g of oily N-benzyl-4-(p-menthan-8-yloxy)aniline. The product was dis-solved in 25 ml of anhydrous ether and after adding thereto 1 ml of 5 normal hydrochloric acid under cooling, the mixture was allowed to cool to provide 0.8 g of hydrochloride of ~-benzyl-4-(p-menthan-8-yloxy)aniline. When the product hydrochloride was recry-stallized from a mixture of dichloromethane and ethyl acetate, the white crystalline having a melting point of 137-138C. was obtained.
Elemental analysis for C23H32NOCl:
C(%) H(%) N(%) Calculated: 73.87 8.63 3.75 Found: 73.55 8.72 3.54 Example 53 CH3 ~ C 0 ~ ( 2)3 3 2~L8 : -.
- By following the same procedure as in Example 52 using 1-bromobutane in place of benzyl bromide, N-butyl-4-(p-menthan-8-yloxy)aniline.hydrochloride was obtained.
- Melting point: 138-139C.
Elemental analysis for C20H34NOCl:
C(%) H(%) N(%) Calculated: 70.66 10.08 4.12 Found: 70.46 10.28 3.91 Example 54 CH3 - O _ C 0 ~ - NHCOOC2H5 In 50 ml of anhydrous pyridine was dissolved 5 g of 4-(p-menthan-8-yloxy)aniline and then 4 ml of ethyl chlorocarbonate was added dropwise to the solution with stirring under ice-cooling.
After further stirring the mixture overnight at 4C., the reaction mixture was poured into 300 ml of ice-water and the oily product .:.
- formed was extracted with ether. The extract was washed success-ively with wate~, 2% hydrochloric acid, water, and then an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure and the crys-tals formed were recrystallized from 20 ml of methanol to provide 3.5 g of white crystalline N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline.
¦ 25 Melting point: 65-66C
Elemental analysis for ClgH29NO3:
C(%) H(%) N(%) Calculated: 71.44 9.15 4.38 Found: 71.46 9.37 4.54 In addition, from the recrystallization mother liquor, 1.5 g Z~L8 of the desired product could further be obtained.

Example 55 3 O ~ - ~HCooc2H5 In a mixture of 40 ml of anhydrous pyridine and 100 ml of anhydrous dichloromethane was dissolved 21 g of trans-4-(p-menthan-8-yloxy)aniline and then 18.5 g of ethyl chlorocarbonate was added dropwise to the solution with stirring under ice-cooling. After further stirring the mixture overnight at 4C., the reaction mix-ture was poured into 300 ml of ice-water and the dichloromethane layer formed was recovered. The aqueous layer was re-extracted with 80 ml of dichloromethane and the extract was combined with the dichloromethane solution recovered previously and the mixture was washed successively with water, 2% hydrochloric acidl water, and then an aqueous sodium chloride solution and dried over anhy-drous magnesium sulfate. The solvent was then distilled off under reduced pressure and the crystals formed were recrystallized from 20 80 ml of methanol to provide 19.5 g of trans-~-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline.
Melting point: 76-77C.
Elemental analysis for ClgH29NO3:
C(%) H(%) ~(%) Calculated: 71.44 9.15 4.38 Found: 71.87 9.43 4.35 Example 56 CH3~ O ~ C - O ~ HCOOC2H5 1~ 2~L8 .
By following the same procedure as in Example 55 using cis-4-(p-menthan-8-yloxy)aniline in place of trans-4-(p-menthan-8-yloxy)-aniline, cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline having methanol of crystallization were obtained.
By drying the product under reduced pressure to remove meth-anol, cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline was obtained as the oily materialO
Elemental analaysis for ClgH29N03:
C(%) H(%) N(%) 10Calculated: 71.44 9.1 4.38 Found: 71.15 9.37 4.36 ~uclear magnetic resonance spectra (CDC13) (Internal standard TMS) ~(ppm.): 0.99 ( _ 3 O

1.20 ( ~ C- , 6H, s) 1.30 (CH3-CH2-0-, 3H, t) H ~E
1.0-2.1 ( H~ H , lOH, m) H' ~ H
H' IH
H H

4.24 (CH3-C_2-0-, 2H, q) 256.72 (-NHC0-, lH, s) H H

6.95, 7.3 ( ~ , 4H, A2B2q) Example 57 H H

CH3 ~ CH 16 33 2~8 , . , To 100 ml of anhydrous ethanol were added successively 2.0 g of 4-(p-menthan-8-yloxy)aniline, 1.2 g of anhydrous potassium carbonate, and 2.6 g of hexadecyl bromide (C16H33Br) and the mix-ture was refluxed for 48 hours. After cooling the reaction mix-ture, the solvent was distilled off under reduced pressure, theresidue was dissolved in 160 ml of dichloromethane and 100 ml of water, and the dichloromethane layer was separated. The dichloro-methane solution was washed with water and then an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure and the resi-due formed was applied to a silica gel column chromatography. The desired product was eluted using benzéne saturated with ammonia and the solvent was distilled off from the eluate under reduced pressure to provide 1.6 g of N-hexadecyl-4-(p-menthan-8-yloxy)-aniline, By recrystallizing the product from ethyl acetate, the white crystals having a melting point of 42-43C. were obtained.
; Elemental analysis for C32H57NO:
C(%) H(%) ~(%) Calculated. 81.46 12.18 2.97 Found: 81.20 12.42 2.69 By the similar procedure as in Example 1 using other alcohol : compound instead of p-menthan-8-ol of Example 1, aniline deriva-tives were obtained and they were reacted with hexadecyl bromide by the similar procedure as in Example 57 to provide the compounds in Examples 58-61.
Example 58 Alcohol compound used as starting material ~ 'OH
CH

Menthol Desired compound ~3 ~ O ~ NHC16H33 /CH

N-Hexadecyl-4-(p-menthan-3-yloxy)aniline Melting point 43 - 44C
Elemental analysis for C32H57NO:
C(%) H(%) N(%) Calculated: 81.46 12.18 2.97 Found: 81.68 12.53 3.13 Example 59 Alcohol compound used as starting material C - OH

. .
l-Cyclohexyl-l-methylethanol Desired compound 4-(1-Cyclohexyl-l-methylethoxy)-N-hexadecylaniline Melting point 31 - 32C
Elemental analysis for C31H55NO:
C(%) H(%) N(%) Calculated: 81.32 12.11 3.06 . ~
81.00 12.65 3.17 Example 60 Alcohol compound used as starting material ~ CH-OH
~' l-Cyclohexylethanol Desired compound 10 ~ CH - O- ~ 16 33 :' , 4-(1-Cyclohexylethoxy)-N-hexadecylaniline Melting point 32 - 33C
; Elemental analysis for C30H53NO:
- 15 C(%) H(%) N(%) . Calculated: 81.19 12.04 3.16 ::~ Found: 81.15 12.55 3.16 ... .
Example 61 Alcohol compound used as starting material l-Benzyl-l-methylethanol Desired compound ~ CH2 C o ~3 N 16 33 N-Hexadecyl-4-(a~a-dimethylphenethyloxy)aniline Melting point 45 - 46C
Elemental analysis for C32H51NO:

C(%) H(%) N(%) Calculated: 82.52 11.04 3.01 :
;:
- 5 Found: 82.56 11.46 3.02 Example 62 CH

CH3 ~ C O - ~ N .HCl ' 10 In 80 ml of anhydrous ethanol was dissolved 2.5 g of 4-(p-menthan-8-yloxy)aniline and then after adding thereto 2.8 g of anhydrous potassium carbonate, a solution of 2.8 g of methyl - iodide in 10 ml of anhydrous ethanol was added dropwise to the ~ 15 mixture with stirring at room temperature. After refluxing the , :, - mixture overnight, the solvent was distilled off under reduced pressure and the residue was extracted with dichloromethane. The extract was washed with water and then an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was ex-- tracted with ether, insoluble ammonium salts were removed, and after distilling off ether, the oily material obtained was applied to a silica gel column chromatography. Then, the desired product was eluted using benzene saturated with ammonia and the solvent was distilled off from the eluate under reduced pressure. The re-maining oily material was dissolved in 50 ml of dry ether and 1 ml of a mixture of 5 normal hydrochloric acid and ethanol was added to the solution, whereby 1.8 g of crystalline 4-(p-menthan-8-yloxy)-N,N-dimethylaniline hydrochloride was obtained. By recrystallizing the product from a mixture of dlchloromethane and ethyl acetate, 2~8 the white crystals having a melting point 148-149C. were obtained.
Elemental analysis for Cl8H30NOCl:
C(%) ff(%) N(%) Calculated: 69.32 9.70 4.49 Found: 69.02 9.92 4.51 Example 63 .. I
CH3- ~ C - 0 ~ 2 3 A solution of 580 mg of 4-(p-menthan-8-yloxy)acetanilide in ; lO ml of anhydrous tetrahydrofuran was added dropwise with stirring to a suspension of 100 mg of lithium aluminum hydride in 1 ml of anhydrous tetrahydrofuran and the mixture was refluxed for 5 hours.
To the reaction mixture were added successively 0.1 ml of water, 0.1 ml of an aqueous 15% sodium hydroxide solution, and 0.3 ml of water under cooling and after filtering away insoluble matters~
the solvent was distilled off under reduced pressure. The residue formed was applied to a silica gel column chromatography and then the desired product was eluted using ammonia-saturated benzene.

The eluate was concentrated under reduced pressure and distilled under reduced pressure to provide 300 mg of N-ethyl-4-(p-menthan-8-yloxy)aniline.
Melting point: 143-145C./0.35 mm Hg Elemental analysis for C18H29N0:
C(%) H(%) N(%) Calculated: 78.49 10.61 5.09 Found: 78.31 10.75 5.41 Example 64 Q2~8 CH3 O ---C-- ~ NHCOOC2H5 -~ 5 In a mixture of 225 ml of anhydrous pyridine and 450 ml of anhydrous tetrahydrofuran was dissolved 49.5 g of 4-(p-menthan-8-yloxy)aniline (cis-isomer : trans-isomer = 45 : 55) and after - adding dropwise 48 g of ethyl chlorocarbonate to the solution with stirring under ice-cooling, the mixture was stirred overnight at 4C. The reaction mixture was poured into 1 liter of ice-water and extracted with 500 ml of ether. The extract was washed succ-essively with water, 4% hydrochloric acid, water, an aqueous sodium hydrogencarbonate solution, and water and dried over anhy-drous magnesium sulfate. Ether was distilled off under reduced pressure, the residue formed was allowed to stand under ice-cooling and the crystals formed were recrystallized from methanol in an amount of 4 times the volume thereof to provide 31 g of N-ethoxy-carbonyl-4-(p-menthan-8-yloxy)aniline containing a large proportion of the trans-isomer. The crystals were repeatedly recrystallized thrice from methanol in an amount of 2-3 times the volume thereof to provide 14.5 g of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-- aniline.
; Melting point: 75-76C
The purity of the trans-isomer thus obtained was confirmed to be 98.9% by the C. nuclear magnetic resonance spectra the infrared absorption spectra, the H.nuclear magnetic resonance spectra, and the mass spectra of the product coincided well with these spectra of the pure material.
Example 65 2~3 ..

H3 O ~ C 0 ~ NHCOOC2H5 The mother liquors formed in the case of obtaining the crys-tals of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline in Example 64 were combined with each other, methanol was distilled off under reduced pressure, and the residue formed was recrystal-lized repeatedly four times from methanol of an amount of 3 times the volume thereof to provide 16.2 g of the methanol-containing crystals of cis-~-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline.
The product was allowed to stand under reduced pressure to remove methanol, whereby oily cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline was obtained.
The purity of the cis-isomer thus obtained was confirmed to be 80% by the C.nuclear magnetic resonance spectra.
Example 66 ., CH

CH3 ~ C - - ~ ~8 37 ., A solution of 2.57 g of 4-(p-menthan-8-yloxy)-~-stearoyl-aniline in 25 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of 0.25 g of lithium aluminum hydride in 3 ml of anhydrous tetrahydrofuran with stirring under ice-cooling, and the mixture was refluxed for 6 hours. After ice-cooling the reac-tion mixture, 0.3 ml of water, 0.3 ml of an aqueous 15% sodium hydroxide solution, and then 1.0 ml of water were added successively to the mixture with stirring. After further stirring the mixture for about 30 minutes, insoluble matters were filtered away and the 2~8 filtrate was concentrated under reduced pressure. The concentrate obtained was dissolved in 50 ml of ether and after washing the solution with a saturated aqueous sodium chloride solution, the solution was dried over anhydrous sodium sulfate. Then, the sol-vent was distilled off under reduced pressure and the residue for-med was applied to a silica gel column chromatography. The desired product was eluted with ammonia-saturated benzene and the solvent was distilled off from the eluate under reduced pressure to provide 1.49 g of the crystals of 4-(p-menthan-8-yloxy)-N-octadecylaniline.
By recrystallizing the product from ethanol, the white crystals having melting point 38-39C. were obtained.
Elemental analysis for C34H61N0:
- C(%) H(%) N(%) .~:
Calculated: 81.70 12.30 2.80 ` 15 Found: 81.49 12.73 2.85 By the similar procedure as in Example 66 using the compounds obtained in Examples 27 and 28 instead of 4-(p-menthan-8-yloxy)-N-stearoylaniline in Example 66, the compounds in Examples 67 and 68 were obtained.

- 20 Example 67 Alcohol compound used as starting material 4-(p-Menthan-8-yloxy)-N-decanoylaniline ; (product obtained in Example 27) Desired compound CH

3 O ~ 10 21 N-Decyl-4-(p-menthan-8-yloxy)aniline Boiling point 172 - 175C/0.2mmHg 2~8 .~

Elemental analysis for C26H45NO:
C(%) H(%) N(%) Calculated 80.56 11.70 3.61 Found 80.35 12.06 3.67 Example 68 . .
Alcohol compound used as starting material 4-(p-Menthan-8-yloxy)-N-myristoylaniline (product obtained in Example 28) Desired compound CH

3 ~ C - o ~ HC14H29 .,~
4-(p-Menthan-8-yloxy)-N-tetradecylaniline ; 15 Boiling point 195-200C/0.25mmHg Elemental analysis for C30H53NO:
C(%) H(%) N(%) Calculated81.20 12.04 3.16 Found 81.01 12.40 3.17 20 Example 69 CH3 ~ 1 3 / CH

In 20 ml of anhydrous ethanol was dissolved 1 g of 4-(p-men-than-8-yloxy)acetanilide and after adding thereto 0.4 g of potas-sium tert-butoxide and 0.6 g of benzyl bromide, the mixture was stirred for 24 hours at room temperature. The solvent was distilled off under reduced pressure and the residue was treated with di-chloromethane and water. The dichloromethane layer formed was ,~ .
~ ~ 58 L~

2~8 . ~
separated washed with water and then an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure and the oily material obtained was applied to a silica gel column chromatography. The desired product was eluted with ammonia-saturated benzene, the solvent was distilled from the eluate under reduced pressure, and the syrupy material obtained was distilled under reduced pressure to provide 1.15 g of N-benzyl-4-(p-menthan-8-yloxy)acetanilide.
; Boiling point: 195-200C./0.6 mm Hg Elemental analysis for C25H33NO2:
C(%) H(%) N(%) Calculated: 79.11 8.76 3.69 ; Found: 79.49 8.96 3.94 Example 70 CH3 -- ~ C - O - ~ NHCOCH2CH2 -n 20 ml of anhydrous ethanol was dissolved 750 mg of N-cin-namoyl-4-(p-menthan-8-yloxy)aniline obtained in Example 21 and after adding thereto 350 mg of lOo/o palladium carbon, the mixture - was stirred in a hydrogen atmosphere until a theoretical amount of hydrogen had been absorbed. After filtering away palladium carbon, the solvent was distilled under reduced pressure and the residue formed was recrystallized from 85% ethanol to provide 0.7 g of white crystalline 4-(p-menthan-8-yloxy)-N-(3-phenylpropionyl)-; aniline.
Melting point: 96-97C.

Elemental analysis for C25H33N02:
30 C(%) H(%) N(%) 2qt8 Calculated: 79.11 8.76 3.69 Found: 78.99 8.91 3.68 Example 71 CH3 - O ---C - O ~ NHCH3 .
A solution of 3.2 g of N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline in 60 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of 0.5 g of lithium aluminum hydride in 6 ml of anhy-drous tetrahydrofuran with stirring over a period of about 2 hours ; and then the mixture was refluxed for 5 hours. After ice-cooling the reaction mixture, 0.6 ml of water, 1 ml of an aqueous 15%
sodium hydroxide solution, and then 2 ml of water were added succ-essively to the mixture little by little. After filtering away insoluble matters, the solvent was distilled off under reduced pre- ~ -ssure and the residue was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was applied to a silica gel column chromatography and the desired product was eluted using ammonia-saturated benzene. The solvent of the eluate was evaporated under reduced pressure and the remain-ing oily product was distilled under reduced pressure to provide -` 1.22 g of 4-(p-menthan-8-yloxy)-N-methylaniline.
Boiling point: 148-151C./0.6 mm Hg : Elemental analysis for C17H27N0:
C(%) H(%) N(%) Calculated:78.11 10.41 5.36 Found: 78.08 10.80 5.51 30 Example 72 Z~
:

CH8 ~ C - O ~ COCH3 In 5 ml of anhydrous tetrahydrofuran was dissolved 430 mg of N-methyl-4-(p-menthan-8-yloxy)aniline and after adding thereto 300 mg of acetic anhydride and 0,8 ml of anhydrous pyridine, the resul-tant mixture was stirred overnight at room temperature. The reac-tion mixture was poured into 30 ml of ice-water and the white crys-tals obtained were recrystallized from 5 ml of petroleum ether to provide 350 mg of white crystalline 4-(p-menthan-8-yloxy)-N-methyl-acetanilide.
~- Melting point 70-71C
Elemental analysis for ClgH29NO2:
C(%) H(~) N(~) Calculated 75.21 9.63 4.62 Found 75.01 9.96 4.41 Example 73 3 ~ C - O ~ N+ CH3 CH3 \ CH3 :
In 30 ml of anhydrous ethanol was dissolved 1 g of 4-(p-menthan-8-yloxy)-N,N-dimethylaniline, which was freed from its hydrochloride of above described Ex. 62 and after adding thereto 5 ml of methyl iodide, the mixture was refluxed overnight. The solvent and excessive methyl iodide were distilled off under redu-ced pressure and the residue formed was extracted with dichloro-methane. The extract was washed with water and then an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
.~
~ 61 2~L8 The solution was concentrated under reduced pressure, excessive ether was added to the concentrate, and the precipitates formed ; were collected by filtration and recrystallized from a mixture of dichloromethane and ether to provide 0.9 g of white crystalline 4-(p-menthan-8-yloxy)-~,~,N-trimethylanilinium iodide.
Melting point: 179-180C.
Elemental analysis for ClgH32NOI:
C(%) H(%) N(%) Calculated: 54.68 7.73 3.36 Found: 54.34 7.91 3.25 - Example 74 3 O I ~ ~ NHC - 4 In a solution of 1.6 g of nicotinic acid and 1.31 g of tri-ethylamine in 30 ml of methylene chloride was added dropwise 1.4 g of ethyl chlorocarbonate with stirring under cooling. To the - solution formed was added dropwise for the reaction a solution of 20 2.5 g of cis-4-(p-menthan-8-yloxy)aniline in 20 ml of methylene chloride. After stirring the mixture to cause reaction for 30 minutes at the same temperature, the reaction mixture was poured into ice-water. The organic layer formed was washed successively with aqueous 5 % sodium carbonate solution and aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate.
the solvent was distilled off under reduced pressure and the resi-due formed was applied to a silica gel column chromatography. The desired product was eluted using chloroform and the solvent was distilled off from the eluate. When the residue was re~ystallized from ethanol, 2.3 g of white crystals of cis-4-(p-menthan-8-yloxy)-2~L?3 , . ~
; N-nicotinoylaniline were obtained.
-~ Melting point: 122-123C.
Elemental analysis for C22H28N2O2:
C(%) H(%) N(%) ~` 5 Calculated: 74.96 8.01 7.95 Found: 74.53 7.98 7.99 f, Example 75 : Tablets One thousand tablets for oral use, each containing 100 mg of 1-[4-(p-menthan-8-yloxy)phenyl]piperidine, are prepared from the following ingredients:
1-[4-(p-menthan-8-yloxy)phenyl]piperidine: 100 Gm Methylcellulose J.P.: 6.5 Gm Lactotose: 25 Gm Talc: 5 Gm Calcium Stearate: 3.5 Gm The 1-[4-(p-menthane-8-yloxy)phenyl]piperidine is granulated with 7.5 % w/v aqueous solution of methylcellulose, passed through a No. 8 screen and dried carefully. The dried granules are passed through a No. 12 screen, mixed with the talc, lactose and stearate and compressed into tablets.

'' ' :
,':, ~ 25 :

:::

:' SUPPLEMENTARY DISCLOSURE
By following the same procedure as in Example 55, the following compounds were obtained.
Example 76 CH3~ C - O ~ NHC
; CH3 .

Melting point 133-134C (recrystallization from E+OH) Elemental analysis for C23H29NO2:
C(%) H(%) N(%) Calculated 78.60 8.32 3.98 - Found 78.54 8.54 4.03 ~- Example 77 CH

3 ~ I ~ HCOCH3 : .

Melting point: 109-110C (recrystallization from E+OH) Elemental analysis for C18H27NO2 C(%) H(%) N(%) Calculated 74.70 9.40 4.84 Found 74.33 9.63 4.86 By following the same procedure as in Example 56, the following compounds were obtained.
Example 78 CH3 - ~ C O ~ NHCO

!~

Melting point: 123-124C (recrystallization from E+OH) Elemental analysis for C23H27NO2 C(%) H(%) N(%) Calculated 78.60 8.32 3.98 :: 5 Found 78.83 8.48 4.04 Example 79 CH
CH3 ~ ~ C - O ~ NHCOCH3 Melting point: 144-145~C (recrystallization from E+OH) ; Elemental analysis for C18H27NO2 C(%) H(%) N(%) Calculated 74.70 9.40 4.84 Found 74.59 9.60 4.84 :

~ , 65

Claims (8)

THE EMDODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of producing an aminophenyl ether compound represented by the formula:
or the pharmacologically acceptable salts thereof wherein R1 represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s); R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group; R4 represents hydrogen atom, a lower alkyl group, an aralkyl group or a lower alkoxycarbonyl group; and R5 represents hydrogen atom or the group shown by -COR6 or -CH2R6 (wherein R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 20 carbon atoms, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group(s), a heterocyclic group which may have been substituted by lower alkyl group or a bridged polycyclic hydrocarbon group), which comprises selecting a process from the group of processes consisting of:
(i) reacting the alcohol compound represented by the formula:
wherein R1, R2 and R3 have the same singificance as above and the p-halogenonitrobenzene represented by the formula:
wherein X represents halogen atom in the presence of a strong base and then reducing the product; or reacting further the reduction product and a compound selected from (a) the compounds shown by the formula R6COOH (wherein R6 has the same significance as above) or the reactive derivatives thereof, (b) the compounds shown by R7 - X (wherein R7 represents an alkyl group containing from 1 to 20 carbon atoms, an aralkyl group or a lower alkoxycarbonyl group and X
represents halogen atom);
(ii) where a compound of the formula:
wherein R1, R2 and R3 are as defined above, is required reacting the alcohol compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the p-halogenitrobenzene represented by the formula:
wherein X represents halogen atoms in the presence of a strong base and then reducing the product;
(iii) where a compound of the formula wherein R1, R2, R3, and R6 are as defined above, is required, reacting the compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the compound represented by the formula:

wherein R6 has the same significance as above or the reactive derivative thereof;
(iv) where a compound of the formula:
wherein R1, R2 and R3 are as defined above and R7 represents an alkyl group containing from 1 to 20 carbon atoms, an aralkyl group, or a lower alkoxycarbonyl group, is required reacting the compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the compound represented by the formula:

wherein X represetns halogen atom and R7 has the same significance as above; or (v) where a compound of the formula:
wherein R1, R2, R3 and R6 are as defined above, is required reducing the compound represented by the formula:
wherein R1, R2, R3 and R6 have the same significance as above.
(vi) where a compound of the formula:
wherein R7, is lower alkyl and R1, R2 and R3 are as defined above, is required, reacting a compound of the formula and a compound of the formula:
R7' - X
wherein X is halogen.

2. A method of producing an aminophenyl ether compound represented by the formula:
or the pharmacologically acceptable salts thereof wherein R1 represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s); R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group; R4 represents hydrogen atom, a lower alkyl group, an aralkyl group, or a lower alkoxycarbonyl group; and R5 represents hydrogen atom or the group shown by -COR6 or -CH2R6 (wherein R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 20 carbon atoms, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group(s), a heterocyclic group which may have been substituted by lower alkyl group or a bridged polycyclic hydrocarbon group), which comprises reacting the alcohol compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the p-halogenonitrobenzene represented by the formula:
wherein X represents halogen atom in the presence of a strong base and then reducing the product; or reacting further the reduction product and a compound selected from (a) the compounds shown by formula R6COOH (wherein R6 has the same significance as above) or the reactive derivatives thereof, and (b) the compounds shown by R7X (wherein R7 represents an alkyl group containing from 1 to 20 carbon atoms, an aralkyl group, or a lower alkoxycarbonyl group and X represents halogen atom).

3. A method of producing a compound represented by the formula:
wherein R1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s), and R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group which comprises reacting the alcohol compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the p-halogenonitrobenzene represented by the formula:
wherein X represents halogen atom in the presence of a strong base and then reducing the product.

4. A method of producing a compound represented by the formula:
wherein R1 represents hydrogen atom, or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s); R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group; and R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 20 carbon atoms, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group(s), a heterocyclic group which may have been substituted by lower alkyl group, or a bridged polycyclic hydrocarbon group, which comprises reacting the compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the compound represented by the formula:

wherein R6 has the same significance as above or the reactive derivative thereof.

5. A method of producing a compound represented by the formula:
wherein R1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s); R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group; and R7 represents an alkyl group containing from 1 to 20 carbon atoms, an aralkyl group, or a lower alkoxycarbonyl group, which comprises reacting the compound represented by the formula:
wherein R1, R2 and R3 have the same significance as above and the compound represented by the formula:

Wherein X represents halogen atom and R7 has the same significance as above.

6 A method of producing a compound of the formula:
wherein R7, is lower alkyl, R1 represents hydrogen atom or a lower alkyl group; R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s) and R3 represents hydrogen, atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group, is required, reacting a compound of the formula:
and a compound of the formula:
R7' - X
wherein X is halogen

7. A method of producing a compound represented by the formula:
wherein R1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group which may have been substituted by lower alkyl group(s); R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group, and R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 20 carbon atoms, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group(s), a heterocyclic group which may have been substituted by lower alkyl group, or a bridged polycyclic hydrocarbon group, which comprises reducing the compound represented by the formula:
wherein R1, R2, R3 and R6 have the same significance as above.

8. Aminophenyl ether compounds represented by the formula:
wherein R1 represents hydrogen atom or a lower alkyl group;
R2 represents a cyclohexyl group, which may have been substituted by lower alkyl group(s); R3 represents hydrogen atom, a lower alkyl group, a cyclohexyl group which may have been substituted by lower alkyl group(s) or a phenyl group;
R4 represents hydrogen atom, a lower alkyl group, an arylkyl group or a lower alkoxycarbonyl group; and R5 represents hydrogen atom, or the group shown by -COR6 or -CH2R6 (wherein R6 represents hydrogen atom, an amino group, an alkyl group containing from 1 to 20 carbon atoms, a cyclohexyl group, an aryl group, an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group(s), a heterocyclic group which may have been substituted by lower alkyl group, or a bridged polycyclic hydrocarbon group) and the pharmacologically acceptable salts thereof, when prepared by the process of claim 1.