NO820355L - PROCEDURES FOR THE PREPARATION OF CYCLIC AMINOPHENYL ETHER COMPOUNDS. - Google Patents

Description

The present invention relates to a process for the production of new aminophenyl ether compounds and pharmacologically acceptable salts, thereof of formula I •

wherein R-^ denotes a hydrogen atom or a lower alkyl group, R 2 denotes a cyclohexyl group which may be substituted with lower alkyl groups, an alkyl group containing from 1 to 20 carbon atoms, a phenyl group or a benzyl group; R 3 denotes a hydrogen atom, a lower alkyl group or a cyclohexyl group which may be substituted with a lower alkyl group, R^ denotes a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, and R^ denotes a hydrogen atom, an aryl group or the group shown by -COR ^ or -CI-^Rg where Rg denotes a 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 with lower alkyl groups, a heterocyclic group which may be substituted with lower alkyl group, or a bridged hydrocarbon group, which R2 and R3 can, however, together with the adjacent carbon atom form a cyclohexane ring which can be substituted with lower alkyl groups and which R^ and R^ together with the adjacent nitrogen atom can form a pyrrolidine ring or a piperidine ring- . When in the aminophenyl ether compounds shown by formula I, the group shown at

has a di-substituted cyclohexane ring,

there are cis- and. trans stereoisomers thereof, and the compounds according to the invention include these stereoisomers.

The term "lower alkyl groups" used in this description includes straight-chain or branched alkyl groups containing from 1 to 6 carbon atoms such as methyl group, ethyl group, isopropyl group, biethyl group, isopentyl group, hexyl group, etc. As "aryl group" can be mentioned phenyl group, naphthyl group, etc., such as " aralkyl group" can e.g. mention is made of benzyl group, phenethyl group, phenylpropyl group etc, as "lower alkoxycarbonyl group" can be mentioned methoxycarbonyl group, ethoxy-carbonyl group, butoxycarbonyl group etc, and as "araalkenyl group" can be mentioned styryl group, cyanmyl group etc, and as "heterocyclic group" can be mentioned pyrrolyl group, furyl group, thienyl group, oxazolynyl group, pyridyl group, thiazolyl group, thiadiazolyl group, dithianyl group, pyrimidinyl group, piperadinyl group, morpholine group, etc. As "bridged hydrocarbon group" can e.g. bicyclonohanyl group, bicyclodecanyl group, adamantyl group, pinanyl group, bornyl group are mentioned.

As pharmacologically acceptable salts of the compounds of formula I, mention may be made of 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 quaternary ammonium salts obtained by reaction with an alkyl halide such as methyl iodide etc.

The compounds of formula I have hypoliperemic activity and also particularly good cholesterol- and triglyceride-reducing activity and are effective for prophylactic and medical treatment of arteriosclerosis such as coronary heart disease.

It has been stated that arteriosclerosis is partly caused by an abnormally increasing amount of lipids such as cholesterol, triglycerides, etc., in the blood. A hypolipemic agent, p-chloro.rf enoxy-iso-butyric acid ethyl ester. (Clofibrate) has so far been frequently used, but there is a need to develop drugs with more effective hypolipemic activity and fewer side effects.

It has now been found that the compounds of formula I have a cholesterol and triglyceride reducing activity and an activity in selectively increasing high density lipoprotein (HDL) cholesterol.

It is known that the amount of HDL in blood is lower in arteriosclerosis than in the normal human condition and that HDL also prevents the increasing accumulation of cholesterol on arterial walls and activates the removal of cholesterol from the arterial wall in experimental animals. Therefore, an increase in HDL cholesterol can be effective in the prophylactic and medical treatment of arteriosclerosis. However, the conventional hypolipemic agent such as Clofibrate does not show any activity in raising HDL cholesterol selectively. As a compound exhibiting an activity in raising HDL cholesterol, an N-[p-(1-adamantyloxy)phenyl]piperidine (U-41,792) is disclosed in US Patent 4,036,977, but the activity of the compounds prepared according to the present invention is clearly better than this known compound which will be shown in the following.

Attempt 1

3-week-old male Sprague-Dawley rats were inoculated for 7 days with semipurified diet containing 1.5% cholesterol and 0.5

% bile acid to induce hypercholesterolemia.

A compound prepared according to the invention suspended in an aqueous solution containing 0.25% methylcellulose was administered to these once per day by oral administration in .4

days. After fasting overnight, the animals were anesthetized with ether and the blood was obtained from the peripheral vessels, and HDL bound. cholesterol

(cholesterol of .HDL) in serum was determined. The results are shown in the following table. In addition, total cholesterol was determined according to the method described in Schettler G&Nussel; "Occupational medicine. Sozialmed. Praventivmed.",

10, 25 (1975) and the determination of HDL-bound cholesterol was carried out according to the method described in T.T. Ishikawa et al.,. "Lipids", 11, 628 (1976)..

xl: N-p-(1-adamantyloxy)phenyl-piperidine (US Patent 4,036,977)

-2: VLDL: lipoprotein with very low density

LDL: low-density lipoprotein

Attempt 2

By following the same procedure as in experiment 1 using 4-week-old male Sprague-Dawlay rats, total serum cholesterol and HDL-bound cholesterol were determined in the same way as described in experiment 1. The results are shown in the following tables.

As is clear from the test results stated above, the compounds of formula I not only have an excellent cholesterol-reducing activity but also greatly increase the amount of HDL, which, as is known, activates the removal of cholesterol from the arterial wall. Therefore is. the compounds produced according to the invention are very effective for the prophylactic and medical treatment of arteriosclerosis.

The compounds of formula I can be formed in various formulations such as powders, granules, tablets, capsules, injection solutions etc. using the additives which are usually used for such formulations. It is preferred that. the compounds are administered orally. The doses of the compounds depend on the condition, age etc. of the patient, but in the case of oral administration the dose will usually be 1 - 100 mg/kg, preferably 5 - 25 g/kg per day for one adult patient.

The compounds of formula I can be prepared by different methods and can, for example, be prepared by methods 1-5 shown in the following reaction scheme: .- a

The compounds of formula I thus include the compounds of formula II, V, VII, VIII, X and XII.

The five methods described above are described in detail in what follows.

Progress small t,e_l£

By this method, the compounds shown by

formula II

in which R 1 R 2 and R 3 have the previously indicated meanings, is obtained by reacting the alcohol compound shown by formula III in which R-j^, R 2 and R 3 have the meanings indicated above, and p-halogenitrobenzene shown by formula IV:

wherein X denotes a halogen atom, in the presence of a strong base,

after which the product is reduced.

It is preferred that the reaction is carried out under heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, or a mixed solvent thereof. Preferred examples of. the strong base used in this method is sodium, potassium, lithium, sodium hydride, potassium hydride, lithium hydride etc. In this case it is preferred that the alcohol compound of formula III is reacted with the strong base beforehand and that the product there-. after reacting with the p-halogenitrobenzene of formula IV.

The reduction can be carried out in a known manner, for example by catalytic reduction in a hydrogen atmosphere using a

catalyst such as Raney nickel catalyst, platinum, palladium, or by reduction under acidic conditions using a

metal such as iron, zinc, tin etc. The catalytic reduction can not only cause reduction of the nitro group but also hydro-

generation of the double bond present in the group

Method 2;

By this method, the compound shown by formula V:

in which R^, R2, R^ and R^ have the meanings given above, is obtained by reacting the compound shown by formula II in method 1: '.• and a carboxylic acid shown by formula VI:

wherein Rg has the above meaning, or its reactive derivative.

It is preferred to carry out 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 these. When using the carboxylic acid of formula VI in this reaction, it is better to carry out the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide. As the reactive derivatives of the carboxylic acid of formula VI, acid halides such as acid chloride, acid bromide etc., mixed acid anhydrides such as benzyl phosphate, alkyl carbonate, pivalic acid etc., active esters such as p-nitrophenyl ester, thiophenyl ester etc. and acid anhydrides can be mentioned .

By this method, the compounds shown by formula VII can:

or formula VIII in which denotes an alkyl group containing from 1 to 20 carbon atoms, an aryl group, an aralkyl group or a lower alkoxycarbonyl group, R^<1> denotes a lower alkyl group, and R-^, and R^ have the meanings given above, obtained by reaction of the compounds shown by formula II in process I: and the compound shown by formula IX

in which R^ and X have the meanings given above.

Preferred examples of the halogen atom are bromine and iodine. It is preferred to carry out the reaction at room temperature or under heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide. dimethyl sulfoxide, dioxane, tetrahydrofuran, pyridine, methanol, ethanol etc., or a mixed solvent of these, in the presence of a basic agent such as sodium carbonate, potassium carbonate .etc.

By this method, the compound shown by formula X:

in which Rg denotes -(CH,,)^- or -(CI^)^- and R-^, R2 and R^ have the above-mentioned meanings, obtained by reacting compounds

the deisen shown by formula II in method 1: and the compound shown by formula XI:

in which Rg and X have de. meanings given above, and are the same reaction conditions as used in method 3.

By this method, the compound can be shown by formula

XII:

wherein R-^, R2, R-j and. R^ has the meanings stated above, erhol- . des by reduction of the compounds shown by formula V:

using a reducing agent such as lithium aluminum hydride, diborane etc., in an organic solvent such as tetrahydrofuran, ether etc. preferably under heating.

Furthermore, the following reactions can be carried out using the compounds obtained by the methods indicated above.

In the following formulas, A denotes

where X has the meaning given above.

If in the above methods cis-compound-

If the alcohol compound of formula III is used, the cis isomer of the compound of formula I is obtained, and if the trans isomer of the alcohol compound of formula III is used, the trans isomer of the compound of formula I is obtained. If a mixture of 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 from each other by ordinary separation procedures such as fractional crystallization.

The following examples illustrate the invention.

Example_el_l

In 120 ml of a mixture of dimethylformamide and benzene in a volume ratio of 1:2, 5.1 g of p-menthen-8-ol were dissolved and, after the addition of 1.6 g of sodium hydride (50% suspension in a mineral oil), the mixture boiled under reflux for 30 minutes. After cooling the reaction mixture, 4.7 g of p-fluoronitrobenzene was added dropwise to the mixture and the resulting mixture was boiled under reflux for 6 hours. After cooling the reaction mixture, 200 ml of benzene were added, the mixture was washed with water and then with an aqueous sodium chloride solution.

The denzen layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled from under reduced pressure. The residue was applied to a silica gel column and the desired product was eluted using an equivalent mixture of benzene and hexane. By distilling off the solvent from the eluate under reduced pressure, 7.2 g of 4-(1-p-menthen-; 8-yloxy)hydrobenzene were 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 was absorbed. After filtering the palladium carbon, the solvent was distilled from , under reduced pressure and the residue was distilled under reduced pressure to give 5.07 g of 4-(p-menthen-8-yloxy)-aniline.

Boiling point: 14 6 - 148° C/0.3 mm Hg Elemental analysis for C^gH^NO:

Calculated: C m',' 68. %, H 10.19 N 5.66 %

Found: C 77.73%, H 10.20%,.- N 5.64%

Example_el_2

In 670 ml of a mixture of dimethylformamide and benzene

in a volume ratio of 1:2, 3.1.2 g of cis-p-menthan-8-ol were dissolved, and after the addition of 8.0 g of sodium hydride (60% suspension in

a mineral oil) the mixture was boiled under reflux for 30 minutes. After cooling, 28.2 g of p-fluoronitrobenzene was added dropwise to the mixture and the resulting mixture was further refluxed for 6 hours. After cooling, 400 ml of benzene was added to the mixture and the resulting mixture was washed with water and an aqueous sodium chloride solution. The benzene layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue formed was placed on a silica gel column and the desired product was eluted using an equivalent mixture of benzene and hexane after which the solvent was distilled from the eluate under reduced pressure to form 49 g of cis- 4-(p-menthan-8-yloxy) nitrobenzene with a boiling point of 18.0 - 183° C/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 a hydrogen atmosphere until a theoretical amount of hydrogen was. been absorbed. After filtration of palladium carbon, the solvent was distilled off under reduced pressure and the residue was distilled off under reduced pressure to give 39.4 g of cis-4-(p-menthan-8-yl-oxy)aniline.

Boiling point: 152 - 154° C/l mm Hg

Elementary analysis for .C-^ 5H25NO: ■-•

Calculated: C 77.68%, H 10.19%, N 5.66%

Found. : C 77.70%, H 10.22. %, N 5.65%<.>"<,>'<1>

Eczema gel_3

Following the same procedure as described in Example 2 using trans-p-menthan-8-ol instead of cis-p-menthan-8-ol, trans-4-(p-menthan-8-yloxy) nitrobenzene obtained with a boiling point of 168 - 171°C/1 mm Hg, and by treating the product as described in Example 2, trans-4-(p-menthan-8-.yloxy)aniline was obtained.

Boiling point: 141 - 143°C/0.6 mm Hg Elemental analysis for C-j^H^NO: Calculated: C 77.68%, H 10.19%, N 5.66% Found: C 77.86%, H 10 .31%, N 5.64%

Example 1_4

In 100 ml of an equivalent mixture of tetrahydrofuran and pyridine, 10 g of 4-(p-menthan-8-yloxy)aniline were dissolved, and after the dropwise addition of 8 ml of acetic anhydride to the solution under ice cooling, the mixture was stirred overnight at room temperature. The reaction mixture was poured into 300 g of ice followed by stirring for 2 hours, after which the precipitated crystals were collected by filtration, washed with water and recrystallized from 50 ml of ethanol to form 6.7 g of white, crystalline 4-(p-menthane) -8-yloxy)-acetanilide.

Melting point: .119 - 120° C

Elemental analysis for C^g^-^NO:

Calculated: C 74.70%, H 9.40%, N 4.84%

Found : C 74.61%, H 9.65%, N 4.73%

By using a similar method as described in example 1 but using other alcohol compounds instead of p-menthen-8-ol in example .1, other aniline derivatives were obtained and these were reacted with acetic anhydride by a similar method as described in example 4 forming of the compounds indicated in examples 5 - 19.

Example_el_5

Alcohol compound used as starting material

Desired connection

4-(p-menthan-3-yloxy)acetanilide

Melting point: 133 - 134° C

Elemental analysis for C^gH^NC^'-

Calculated: C 74.70%, W 9.40%, N 4.84%

Found : C 74 , 45%, H 9.64%, N 4.56%

Eczema gel_6

Alcohol compound used as starting material. 3.,7-dimethyl-3-oxy-1,6-octadiene.

Desired connection

4-(3,7-dimethyioct-3-yloxy)acetanilide Melting point: 50.- 51° C

Elemental analysis for C^gH^NC^:

Calculated: C 74.18%, H 10.03%, N 4.81% Found: C 74.19%, H 9.89%, N 4.54%

Eczema gel_7

Alcohol compound used as starting material

1,1-dimethylpropanol Desired compound

4-(1,1-dimethylpropoxy)acetanilide Melting point: 116 - 117° C

Elemental analysis for C13HigN02:

Calculated: C 70.56 H 8.65%, N.6.33% Found: C 70.54%, H 8.80%, N 6.33%.

Example 8

Alcohol compound used as starting material.

Cyclohexylmethanol.

Desired connection

4-(cyclohexylmethoxy)acetanilide Melting point: 118 - 119° C Elemental analysis for ci5H2iN02:

Calculated-: C.72.84%, H 8.56%, N 5.66%

Found : C 72.66%, H 8.57 N .5.82%

Example_el_9

Alcohol compound as starting material

- 1-cyclohexylethanol Desired compound

4-(1-cyclohexylethoxy)acetanilide Melting point: 94 - 95° C

Elemental analysis for C^l^-jNC^:

Calculated: C 73.53%, H 8.87%, N 5.36% Found C 73.41%, H 9.08%, N 5.30%

Example_el_10

Alcohol compound used as starting material

1-cyclohexy.l-l-methylethanol

Desired connection

4-(1-cyclohexyl-1-methylethoxy)acetanilide Melting point:. 122 - 123° C

Elemental analysis for ci7H25N02:

Calculated: C 74.14%, H 9.15%, N 5.09% Found: C 74.07%, H 9.41%, N 4.93%

Exemgel_ll

Alcohol compound used as starting material

l-toenzyl-l-methylethanol

Desired connection

4-(α,α-dimeth.hylfénethyloxy)acetanilide Melting point: 153 - 154° C.

Elemental analysis for C^gH^NC^:

Calculated: C 76.30%, H 7.47%, N 4.94%

Found : C 76.38 H 7.47%, N 4.91%

Example_el_12

The alcohol compound used as starting material

1-methylcyclohexanoic

Desired connection

4-(1-methylcyclohexyloxy)acetanilide

Melting point: 123 - 124° C Elemental analysis for C^Hj^NC^ :•,

Calculated: C 72.84%, H 8.56%, N 5.66%

.Found: C 73.15%, H 8.65%, N 5.76% Example_el_13 Alcohol compound used as starting material

3-methylmenthol Desired connection

4-(3-methyl-p-menthan-3-yloxy)acetanilide Melting point: 133 134° C

Elemental analysis for C^gl-^gNC^:

Calculated: C 75.21%, H 9.63%, N 4.62%

Found : C 74.69%, H 9.96%, N 4.93%

Example_el_14

Alcohol compound as starting material 1-cyclohexyl-l-phenylethanol Desired compound

4-(α-cyclohexyl-ct-methylbenzyloxy)acetanilide.

Melting point: 102 - 103° C

Elemental analysis for C22<H>27NQ2:

Calculated: C 78.30%, H 8.06%, N 4.15% Found: C 78.01%, H 8.34%, N 4.36%

Eczema gel_15

Alcohol compound used as starting material

dicyclohexylmethanol

Desired connection

4-(dicyclohexylmethoxy)acetanilide Melting point: 187 - 188° C Elemental analysis for C21<H>31N02: Calculated: C 76.55%, H 9.48%, N 4.25% Found: C 76.61%, H.9 .84%, N 4.15%

Eczema gel_16

Alcohol compound used as starting material

α,α-dimethylbenzyl alcohol. Desired connection

4-(a,a-dimethylbenzyloxy)acetanilide Melting point: 130 - 131° C

Elemental analysis for C^H^^NC^:

■Calculated: C 75.81 I, H 7*11 %, N 5.20 % Found : C 76.05 %, H 7.18 %, N 5.44 %

Example_el_17

Alcohol compound used as starting material

cyclohexanol Desired compound. 4-(cyclohexyloxy)acetanilide Melting point: 158 - 159° C Elemental analysis for C^H^NO.,:Calculated: C 72.07%, H 8.21%, N 6.00% Found: C 71.72'% , H 8.30%, N 6.33%

The compounds in Examples 18 and 19 were prepared below

use of isobutyric anhydride or benzoic anhydride instead of acetic anhydride as used in example 4.

Example_el_18

Desired connection

N-isobutyryl-4-(p-menthan-8-yloxy)aniline

Melting point: 127 - 128° C Elemental analysis for C^qH^NC^: Calculated: C 75.67%, H 9.84%, N 4.41% Found: C 75.54%, H 10.10%, N 4.21%

Example_el_19

Desired connection

4-(p-Menthan-8-yloxy) benzanilide

Melting point: 121 - 122° C

Elemental analysis for C^<K>^NC^".

Calculated: C 78.60%,. H 8.32%, N 3.98%

Found : . C 78.31%, H 8.46%, N 3.69%,

Eczema gel_20

In 10 ml of an equivalent mixture of tetrahydrofuran and pyridine, 1 g of 4-(p-menthan-8-yloxy)aniline was dissolved and after

Dropwise addition of 0.65 g of cyclohexylcarbonyl chloride to the solution under ice-cooling, the mixture was stirred overnight at room temperature. The reaction mixture was poured into 60 g of ice

followed by stirring for 2 hours, and the precipitated crystals were collected by filtration, washed with water and recrystallized from 10 ml of ethanol to give 1.02 g of white crystalline N-;«n cyclohexylcarbonyl-4-(p-menthane -8-yloxy)aniline.

Melting point: 171 - 172° C Elemental analysis f or. (-:23^35N<^2 :

Calculated: C 77.27%, H 9.87%, . N 3.92%

Found : C 77.27%, H 10.13%, N 3.74%

By following a similar procedure as described in example 20 using cinnamoyl chloride, 1-adamantanyl carbonyl chloride or N,N-dimethylcarbamoyl chloride instead of cyclohexyl carbonyl chloride according to example 20, the compounds indicated in examples 21-23 were prepared.

Eczema p_el_21

Desired connection

N-cinnamoyl-4-(p-menthan-8-yloxy)aniline

Melting point: 75 - 76° C

Elemental analysis for C25H3iN02:

Calculated: C 79.54%, H 8.28%, N 3.71%

Found : C 79.31%, H 8.37%, N 3.52%

Example_el_22

N-(adamant-1-yl-carbonyl)-4-(p-menthan-8-yloxy)aniline Melting point: .105 - 106° C

Elemental analysis for C^H^NO^:

Calculated: C 79.19%, H 9.60%, N 3.42%

Found : C 79.32%, H 9.64%, N 3.26%

Example_el_23 ...,

Desired connection

1-(4-(p-menthan-8-yloxy)phenyl]-3,3-dimethylurea Melting point: 112 - 114° C

Elemental analysis for CigH3o<N>2°2<:>

Calculated: C 71.66%, H 9.50%, N 8.80

Found: C 71.56%, H 9.81%, N. 8.65

By a similar procedure as described in example 1. but using other alcohol compounds instead of p-menthan-8-ol according to example 1, aniline derivatives were obtained and these were reacted with N,N-dimethylcarbamoyl chloride or 1-adamantanyl carbonyl chloride in a similar manner as described in example 20 while forming the compounds according to examples 24 - 26.

Example_el_24

Alcohol compound used as starting material

Desired connection

1-14-(p-menthan-3-yloxy).phenyl]-3,3-dimethylurea

Melting point: 154 - 156° C

Elemental analysis for c^<gH3>Q<N2>02:

Calculated: C 71.66%, H 9.50 N 8.80%

Found: C 71, 53 H 9.69%, N 8.58

Example_el_25

Alcohol compound used as starting material

Cyclohexylmethanol Desired compound

1-(4-cyclohexylmethoxyphenyl)-3,5-dimethylurea Melting point: 158 - 159° C

Elemental analysis for c1gH24N2°2:

Calculated: C. 69.53%, H 8.75%, N 10.14% Found: C 69.21%, H 8.81%, N 9.90%

Example_e.l 26

Alcohol compound used as starting material

Desired connection

N-(adamant-1-ylcarbonyl)-4-(p-menthan-3-yloxy)aniline

Melting point: 194 - 195° C

Elemental analysis for C27H39N02:

Calculated: C 79.17%, H 9.60%, N 3.42%

Found : C 79.40%, H 9.86%, N 3.37%

Example_el_2 7

In 10 ml of anhydrous tetrahydrofuran, 2.0 g of 4-(p-.menthan-8-yloxy)aniline was dissolved and after the addition of 5 ml of anhydrous pyridine, 1.55 g of N-decanoyl chloride (CgH19COCl) was added dropwise to the mixture under ice-cooling and the resulting mixture was stirred overnight at room temperature.

The reaction mixture was poured over 50 g of ice followed by stirring for 3 hours. The thus precipitated oily product was then recovered by decantation and dissolved in 100 ml of ether. The ether solution was washed successively with 3% hydrochloric acid, a saturated t anhydrous sodium bicarbonate solution, and then an aqueous sodium chloride solution, dried with anhydrous sodium sulfate after which the solvent was distilled off under reduced pressure to form 3.2 g of crystals of 4-(p-menthan-8 -yloxy)-N-decanoylaniline. On recrystallization of the product from ethanol, white crystals with a melting point of 31 - 32° C were obtained.

Elemental analysis for C2gH^2N02:

Calculated: C 77.75%, H 10.79%, N 3.49%

Found C 77.55%, H 11.07%, N 3.41%

Example_el_28'

By following the same procedure as described in Example 27 using myristoyl chloride • ( C-^^ Hi instead of N-decanoyl chloride, 4-(p-rnenthan-8-yloxy)-N-myristoylaniline was obtained-... .

Melting point: 51 52° C

Elemental analysis for C^gH^NC^:

Calculated: C 78.72%, H 11.23%, N 3.06% Found: C 78.54%, H 11.56% , N 2.90 Example_el_29

By following the same procedure as described in Example -<27 using palmitoyl chloride (C-^H^COCl) instead of N-decanoyl chloride, 4-(p-menthan-8-yloxy)-N-palmitoylaniline was obtained.

Melting point: 61 - 62° C

Elemental analysis for C32H55N02:

Calculated: C 79.12%, H 11.41%, N2.88%

Found : C 79.45%, H 11.79%, N 2.71%

Example_el_3 0

In 20 ml of anhydrous tetrahydrofuran, 2.0 g of 4-(p-menthan-8-yloxy)aniline and 4.5 g of anhydrous stearic acid were suspended and after the dropwise addition of 5 ml of anhydrous pyridine while stirring and ice-cooling, the mixture was stirred overnight at room temperature.

The reaction mixture was poured over .100 g of ice followed by stirring for 2 hours and precipitated white crystals were collected

by filtration, washed three times each time with 50 ml of petroleum ether, and then recrystallized twice with 25 ml of ethanol to give 3.1 g of white crystals of 4-(p-menthan-8-yloxy)-N-stearoylaniline.

Melting point: 72 - 73° C

Elemental analysis for C^Hj-gNC^: ti

Calculated: C 79.47%, H 11.57%, N 2.73%

Found : C 7 9.71%, H 11.93%, N 2.44%

Eczema gel_31

To 150 ml of anhydrous ethanol were added 6.2 g of 4-(p-menthan-8-yloxy)aniline, 7 g of anhydrous potassium carbonate 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 from under reduced pressure until to the residue was added 200 ml of dichloromethane and 150 ml of water. The dichloromethane layer was separated and. washed with water and then with 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. The desired product was then eluted using benzene saturated with ammonia and the solvent was then distilled off under reduced pressure from the eluate to give 5.77 g of crystalline 1-[4-(p-menthan-8-yloxy)phenyl]-piperidine. When the product was recrystallized from ethanol, white crystals with a melting point of 53 - 54° C were obtained.

Elemental analysis for C2^<H>32N0:

Calculated: C 79.95 I, H 10.54%, N 4.44%

Found : C 79.50%, H 10.83 N 4.37%

By a similar procedure as described in example 1 but using other alcohol compounds instead of p-menthan-8-ol according to example 1, aniline derivatives were obtained, and these were reacted with 1,5-dibromopentane in a similar way as described in example 31 while forming the compounds according to examples 32-46.-

Example_el_32

Alcohol compound used as starting material

Desired connection

1-[4-(p-Menthan-3-yloxy)-phenyl]-piperidine

Melting point: 93 - 94° C Elemental analysis for C21H33NO:

Calculated: C 79.95%, H 10.54%, N 4.44%

Found' : C 79.91%, H 10.75 in, N 4.41%

Example_el_33

Alcohol compound used as starting material

3,7-dimethyl-7-octen-l-ol,

Desired connection

1-[4-(3,7-dimethyloctyloxy)phenyl]piperidine Boiling point: .174 - 178°C/0.4 mmHg

Elemental analysis for C2-LH35NO:

Calculated: C 79.44%, H 11.11%, N 4.41% Found: C 79.40 H 11.43%, N 4.19%

Example_el_34

Alcohol compound used as starting material

3,7-dimethyl-3-oxy-1,6-octadiene

Desired connection

N- [4-(3,7-dimethyloct-3-yloxy)phenyl]piperidine Boiling point: 174 - 176°C/0.5 mmHg Elemental analysis for (-21H3 5N<^): Calculated: C 79.44%, H 11.11%, N 4.41% Found : C 79.74%, H 11.23%, N 4.13%

Example_el_3 5

Alcohol compound used as starting material CH3(CH2)1?-OH

Octadecanol

Desired connection

N-(4-octadecanyloxyphenyl)piperidine Melting point: 54 - 55° C.

Elemental analysis for C^H^NO:

Calculated: C 81.06%, H 11.96%, N 3.26% Found: C 80.92%, H 12.27%, N 3.00% Example_el_36 Alcohol compound used as starting material

1,1-dimethylpropanol Desired compound.

N-[4-(1,1-dimethylpropoxy)phenyl]piperidine

Boiling point: 120. - 122°C/1 mmHg

Elemental analysis for C-^gH^NO:

Calculated: C 77.68%, H 10.19%, N 5.66%

Found : C 77.32%, H 10.24%, N 5.39%

Eczema gel_37

Alcohol compound used as starting material

Cyclohexylmethanol Desired compound

N-[4-(cyclohexylmethoxy)phenyl]piperidine Melting point: 63 - 64° C

Elemental analysis for C^g<H>27NO:

Calculated: C 79.07%, H 9.95%, N 5.12% Found: C 78.88%, H 10.22%, N 5.00%

Example_el_38

Alcohol compound used as starting material

1-cyclohexylethanol Desired compound

N-[4-(1-cyclohexylethoxy)phenyl]piperidine

Boiling point: 147 - 148°C/0.3 mmHg

Elemental analysis for C^gh^gNO: Calculated: C 79.39%, H 10.17%, N 4.87% Found: C 79.28%, H 10.51%, N 4.87%

Example_el_39

Alcohol compound used as starting material

1-cyclohexyl-i-methylethanol Desired compound

N-[4-(1-cyclohexyl-1-methylethoxy)phenyl]piperidine

Melting point: 66 - 67° C

Elemental analysis for C2qH^NO:

Calculated: C 79.68%, H 10.36%, N 4.65%

Found : C 79.54%, H 10.58%, N 4.41%

Exemgel 4 0

Alcohol compound used as starting material

1-benzyl-1-methylethanol Desired compound

N-[4-(α,α-dimethylphenethyloxy)phenyl]piperidine

Melting point: 68. - 69° C Elemental analysis for C21H27NO:

Calculated: C 81.51%, H 8.79%, N 4.53%

Found : C 81.33%, H 8.95%, N 4.52%

Example_41

Alcohol compound used as starting material

1-methylcyclohexanol.

Desired connection

N-[4-(1-methylcyclohexyloxy)phenyl]-piperidine hydrochloride Melting point:. 150 - 151° C

Elemental analysis for C^gH2gNOCl:

Calculated: C 69.77%, H 9.1.1%, N 4.52%

Found : C 69.39%, H 9.42%, N 4.64%

Eczema gel_42

Alcohol compound used as starting material

3-Methylmenthol. ; Desired connection

N-[4-(3-methyl-p-menthan-3-yloxy)phenyl]piperidine Boiling point: 140 - 145°C/0.3 mmH

Elementary analysis for £22^ 25®®"'

Calculated: C 80.19%, H 10.71%, N 4.25% Found: C 80.14%, H 10.42%, N 3.92%

Example_el_43

Alcohol compound used as starting material

α-cyclohexyl-α-methylbenzyl alcohol Desired compound.

N-[4-(a-cyclohexyl-a-methylbenzyloxy)phenyl]piperidine Boiling point: 178 - 183°C/0.25 mmH

Elemental analysis for € 2^ 22^''

Calculated: C 82.60%, H 9.15%, N 3.85%

Found : C 82.66%, H 9.35%, N 3.65%

Example_el_44

Alcohol compound used as starting material dicyclohexylmethanol Desired compound

N-(4-dicyclohexylmethoxyphenyl)piperidine Melting point: 57 - 58° C

Elemental analysis for C^^ H^- j^ 1

Calculated: C 81.07%, H 10.49%, N 3.94% Found: C 81.16%, H 10.83%, N 3.75%

Example_el_45

Alcohol compound.used as starting material

α,α-dimethylbenzyl alcohol Desired compound

N-[4-(a,a-dimethylbenzyloxy)phenyl]piperidine Melting point: 92 - 93° C

Elemental analysis for C2QH25NO:

Calculated: C 81.31%, H 8.53%, N 4.74% Found: C 81.09%, H 9.69%, N 4.98%

Example_el_46

Alcohol compound used as starting material

cyclohexanol Desired compound .

N-(4-cyclohexyloxyphenyl)piperidine

Melting point: 50 - 51° C

Elemental analysis for C^7H2^NO:

Calculated: C 78.72%, H 9.71 I, N 5.40%

Found : C 78.51%, H 9.92%, N 5.56%

Example_el_4 7

To 50 ml of anhydrous ethanol was added 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 boiled under reflux for 42 hours. The reaction product was then subjected to extraction and purification as described in example 31, forming 1.1 g of crystalline N-[4-(p-menthan-8-yloxy)phenyl]pyrrolidine.

When the product was recrystallized from ethanol, white crystals with a melting point of 92 - 93° C were obtained.

Elemental analysis for C2qH.^NO:

Calculated: C 79.68%, H 10.36%, N 4.65%

Found : C 79.43%, II 10.65%, N 4.37%

Example_el_48

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 were added to 150 ml of anhydrous ethanol and the mixture was boiled under reflux

for 15 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and 5.00 ml of dichloromethane and 500 ml of water were added to the residue. The dichloromethane layer was separated by decantation, washed with water and then with an aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled from under reduced pressure

and the residue formed was transferred to a silica gel column.

The desired product was then eluted using ben-

zen saturated with ammonia, and the solvent in the eluate was distilled off under reduced pressure to give 23 g of cis-1-[4-(p-menthan-8-yloxy)phenyl]piperidine. When the product was recrystallized from ethanol, white crystals with a melting point of 78 - 79° C were obtained. ■

Elemental analysis for C22H33NO:

Calculated: C 7 9.95%, H 10.54 1, N 4.44 I

Found : C 79.83%, H 10.98%, N 4.36%

Example 49

—————— i

By following the same procedure as described in Example 4 8 using trans-4-(p-menthan-8-yloxy)aniline instead of cis-4-(p-menthan-8-yloxy)aniline, crystals were obtained of trans-1-[4-(p-menthan-8-yloxy)phenyl]piperidine.

Melting point: 62 - 63° C

Elemental analysis for ^I^^^Cm

Calculated: C 79, 95 l, I-l 10.54%, N 4.44%

Found C 80.00%, H 10.87%, N 4 , 39% ?h§S2E§I_å5

In 47 ral of a 95% ethanol solution of 1 normal potassium hydroxide, 2.1 g of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline were dissolved and the solution was boiled under reflux for 6 hours. Then the ethanol was distilled from under reduced pressure from the reaction mixture and to the residue formed 50 ml of ether and 50 ml of water were added followed by extraction

with ether. The extract was washed with water and then with one

aqueous sodium chloride solution and after drying over anhydrous magnesium sulfate, the ether was distilled from the reaction mixture to give 1.7.5 g of trans-4-(p-menthan-8-yloxy) aniline.

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 boiled under reflux for 16 hours... When treating the reaction product as described in example 48 , 0.95 g of crystals of trans-1-[4-(p-menthan-8-yloxy)phenyl)-piperidine were obtained.

Melting point: 62 - 63° C.

Infrared absorption spectra, nuclear magnetic resonance spectrum ("'"H, "^C), and mass spectrum of the crystals were in good agreement with the spectra of the crystals obtained in Example 49.

Eczema gel_51

By following the same procedure as described in Example 50 using cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline instead of trans-N-ethoxycarbonyl-4-(p-menthan-8- yloxy)-aniline, crystals of cis-1-[4-(p-menthan-8-yloxy)phenyl]-piperidine were obtained.

Melting point: 78 79° C.

The infrared absorption spectrum, k nuclear magnetic

1 12 response spectrum (H, C), and mass spectrum of the crystals agreed with those for crystals obtained in example 48.

Example_el_52

To 100 ml of anhydrous ethanol, 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 successively added, and after reaction for 4 hours at room temperature, the mixture was then boiled under reflux for 40 hours. The reaction mixture was then subjected to extraction and purification as described in Example 31 to yield 0.95 g of oily N-benzyl-4-(p-menthan-8-yloxy)-aniline. The product was dissolved in 25 ml ..anhydrous; ether, and after adding 1 ml of 5 normal hydrochloric acid under cooling, the mixture was cooled to give 0.8 g of N-berizyl-4-(p-menthan-8-yloxy)-aniline hydrochloride. When the hydrochloride product was recrystallized from a mixture of dichloromethane and ethyl acetate, white crystals with a melting point of 137 - 138° C were obtained.

Elemental analysis for C22H3 2N(-)C1:

Calculated: C 73 , 87%', . H 8 , 63 N 3.75%

Found : C 7 3.55%, H 8.72%, N 3.54%

Example_el_53

By following the same procedure as described in Example 52 using 1-bromobutane instead of benzyl bromide, N-butyl-4-(p-menthan-8-yloxy)aniline hydrochloride was obtained.

Melting point: 138 - 139° C

Elemental analysis for C2qH34NOC1:

Calculated: C 7 0.66%, H 10.08%, N 4.12%

Found : C 70.46%, H 10.28%, N 3.91%

Eczema gel_54

5 g of 4-(p-menthan-8-yloxy)aniline was dissolved in 50 ml of anhydrous pyridine and then 4 ml of ethyl chlorocarbonate was added dropwise to the solution with stirring and ice-cooling. After further stirring the mixture overnight at 4°C, the reaction mixture was poured into 300 ml of ice water and the oily product formed was extracted with ether. The extract was washed successively with water, 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 crystals formed were recrystallized from 20 ml of methanol to give 3.5 g of white crystalline N-ethoxycarbonyl-4-(p-menthan-8-yToxy) aniline.

Melting point 65 - 66° C

Elemental analysis for C^H^NO^".

Calculated: C 71.44%, H 9.15%, H 4.38%

Found : C 71.46%, H 9.37%, H 4 , 54

From recrystallization of the mother liquor was additionally 1.5

g of the desired product obtained.

£!S§ÉfI!Bei 55

In a mixture of 40 ml of anhydrous pyridine and 100 ml of anhydrous dichloromethane, 21 g of trans-4-(p-menthan-8-yloxy)aniline were dissolved, after which 18.5 g of ethyl chlorocarbonate were added dropwise to the solution with stirring and ice-cooling. After further stirring the mixture overnight at 4° C., the reaction mixture was poured into 300 ml of ice-water and the formed dichloromethane layer was recovered. The aqueous layer was re-extracted with 80 ml of dichloromethane and the extract was combined with the dichloromethane solution recovered earlier, and the mixture was washed successively with water, 2% hydrochloric acid, water and then an aqueous sodium chloride solution and,,( dried over anhydrous magnesium sulfate. The solvent was there-

after distilled from under reduced pressure and the crystals formed were recrystallized from 80 ml of methanol to give 19.5 g of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline.

Melting point: 76 - 77° C

Elemental analysis for C^gl^gNO^:

Calculated: C 71.44%, H 9.15%, N 4.38%

Found: C 71.87%, H 9.43%, N 4.35

Example_el_56

By following the same procedure as described in Example 5.5 using cis-4-(p-menthan-8-yloxy)aniline instead of trans-4-(p-menthan-8-yloxy)aniline, cis-N -ethoxy-carbonyl-4-(p-menthan-8-yloxy)aniline with crystallization methanol obtained.

On drying the product under reduced pressure to remove the methanol, cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline was obtained as an oily material.

Elemental analysis for C^gH^NO^:

Calculated: C 71.44%, H 9.1%, N 4.38%

Found': C 71.15%, H'9.37%, N 4.36%

Nuclear Magnetic Resonance Spectrum (CDCl-j) (Internal Standard TMS) Example 57 ,

2.0 g of 4-(p-menthan-8-yloxy) aniline, 1.2 g of anhydrous potassium carbonate and 2.6 g of hexadecyl bromide (C^^H^^Br) were successively added to 100 ml of anhydrous ethanol and the mixture was cooked under reflux for 48 hours. After cooling the reaction mixture

the solvent was distilled off under reduced pressure, the residue was dissolved in 160 ml of dichloromethane and 100 ml of water, and the dichloromethane layer was separated. The dichloromethane 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 residue formed was transferred to a silica gel column. The desired product was eluted using

benzene saturated with ammonia, and the solvent was distilled from the eluate under reduced pressure to give 1.6 g of N-hexa-decyl-4-(p-menthan-8-yloxy)aniline. Upon recrystallization of the pro-

extracted from ethyl acetate, white crystals with a melting point of 42 - 43° C were obtained.

Elemental analysis for C32H57^0:

Calculated: C 81.46%, H 12.18%, N 2.97

Found : C 81.20%, H 12.42%, N 2.69%

By similar procedures as in example 1 using other alcohol compounds instead of p-menthan-8-ol according to example, aniline derivatives were obtained and these were reacted with hexadecyl bromide in a similar manner as described in example 57 to form the compounds according to example 58 - 61.

Example_el_58

Alcohol compound used as starting material

Desired connection

N-hexadecyl-4-(p-menthan-3-yloxy)aniline

Melting point: 43 - 44° C

Elemental analysis for C321,57NO:

Calculated: C 81.46%, H 12.18%, N 2.97%

Found C 81.68%, H 12.53%, N 3.13%

Example_el_59

Alcohol compound used as starting material 1-cyclohexyl-1-methylethanol Desired compound

4-(1-cyclohexyl-1-methylethoxy)-N^hexadecylaniline Melting point: 31 - 32° C.

Elemental analysis for C31H55NO:

Calculated: C 81.32%, H 12.11%, N 3.06% Found: C 81.00%, H.12.65%, N 3.17%

Example_el_60

Alcohol compound used as starting material

1-cyclohexylethanol Desired compound

4-(1-cyclohexylethoxy)-N-hexadecylaniline Melting point: 32 - 33° C

Elemental analysis for C^gH^NO:

Calculated: C 8o.19%, H 12.04%, N 3.16%

Found : C 81.15%, H 12.55%, ■ N 3.16%

Example_el_61

Alcohol compound used as starting material

1-benzyl-l-methylethanol •

Desired connection

N-hexadecyl-4-(a,a-dimethylphenethyloxy)aniline Melting point: 45 - 46° C

Elemental analysis for ^32H5iN0:

Calculated: C 82.52%, H 11.04%, N 3.01%

Found : C 82.56 H 11.46%, N 3.02%

Example_62

2.5 g of 4-(p-menthan-.8-yloxy)aniline were dissolved in 80 ml of anhydrous ethanol and after adding 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 mixture with stirring at room temperature. After boiling under reflux 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 extracted with ether, insoluble ammonium salts were removed, and after distilling off the ether, the oily material was transferred to a silica gel column. Then, the desired product was eluted using benzene saturated with ammonia and the solvent was distilled from the eluate under reduced pressure. The remaining 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 recrystallization of the product from a mixture of dichloromethane. and .- a ethyl acetate, white crystals with a melting point of 148 -r 149° D were obtained.

Elemental analysis for C^qH^qNOCI:

Calculated: C 69.32%, H 9.70%, N 4.49%

Found. : C 69.02%, H 9.92%, N 4.51%

Example_el_6 3

A solution of 580 mg of 4-(p-menthan-8-yloxy)acetanilide in 10 ml of anhydrous tetrahydrofuran was added dropwise with stirring

to a suspension of 100 mg. lithium aluminum hydride in 1 ml of anhydrous tetrahydrofuran, and the mixture was refluxed for 5 hours. 0.1 ml was successively added to the reaction mixture. water, 0.1 ml of an aqueous 15% sodium hydroxide solution and 0.3 ml of water under cooling, and after filtering insoluble constituents, the solvent was distilled from under reduced pressure.

The residue formed was transferred to a silica gel column and the desired product was eluted using ammonia-saturated benzene. The eluate was concentrated under reduced pressure and distilled under reduced pressure to give 300 mg of N-ethyl-4-(p-menthan-8-yloxy)aniline.

Melting point: 143 - 145°C/0.35 mmHg

Elemental analysis for C^g<H>^NQ:

Calculated: C 78.49%, H 10.61%, N 5.09%

Found : C 78.31%, H 10.75%, N 5.41%

Example 64

In a mixture of 225 ml of anhydrous pyridine and 450 ml of anhydrous tetrahydrofuran, 49.5 g of 4-(p-menthan-8-yloxy)'-aniline (cis-isomer: trans-isomer = 45:55) were dissolved and after the dropwise addition of 48 g of ethyl chlorocarbonate to the solution with stirring and ice-cooling, the mixture was stirred overnight at 4° C. The reaction mixture was poured into 1 liter of ice water and extracted with 500 ml of ether. The extract was washed successively with water, 4% hydrochloric acid, water, an aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The 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 to give 31 g of N-ethoxycarbonyl-4-(p-menthan- 8-yloxy)aniline containing a large part of the trans isomer. The crystals were recrystallized three times from methanol in an amount of 2-3 times its volume, forming 14.5 g of trans-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)-aniline.

Melting point:' 75 - 76° C

The purity of the trans isomer was determined to be 98.9% at . nuclear magnetic resonance spectrum, infrared absorp

tion spectrum, '''H. nuclear magnetic resonance spectrum and mass spectrum of the product agreed well with these spectra for the pure material.

Example_el_65

The mother liquors formed in the preparation of the crystals 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 recrystallized four times from methanol in an amount 3 times its volume, forming 16.2 g of methanol-containing crystals of cis-N-,ethoxycarbonyl-4-(p-menthan-8-yloxy)anil in. The product was left under reduced pressure to remove the methanol, whereby oily cis-N-ethoxycarbonyl-4-(p-menthan-8-yloxy)aniline was obtained.

The purity of the cis isomer was determined to be 80% 13

at C.nuclear magnetic resonance spectrum.

Example_e.l_66

A solution of 2.57 g of 4-(p-menthan-8-yloxy)-N-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 and ice-cooling , and the mixture was refluxed for 6 hours. After ice-cooling, 0.3 ml of water, 0.3 ml of aqueous 15% sodium hydroxide solution and then 1.0 ml of water were added with stirring. After further stirring the mixture for approx. After 30 minutes, insoluble components were filtered off, and the filtrate was concentrated under reduced pressure. The resulting concentrate 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. The solvent was then distilled off under reduced pressure, and the resulting residue was transferred to a silica gel column. The desired product was eluted with ammonia-saturated benzene, and the solvent was distilled from the eluate under reduced pressure to give 1.49 g of crystals of 4-(p-menthan-8-yloxy)-N-octa-decylaniline. On recrystallization of the product from ethanol, white crystals with a melting point of 38 - 39° C were obtained.

Elemental analysis for C^Hg-^NO:

Calculated: C 81.70%, H 12.30%, N 2.80%

Found : C 81.49%, H 12.73%, N 2.85%

By similar procedure as described in example 66

using compounds obtained in examples 27 and 28

instead of 4-(p-menthan-8-yloxy)-N-stearoylaniline in Example 66, the compounds of Examples 67 and 68 were obtained.

Example_el_67

Alcohol compound used as starting material 4-(p-menthan-8-yloxy)-N-decanoylaniline

(product obtained in example 27)

Desired connection

N-decyl-4-(p-menthan-8-yloxy)aniline Boiling point: 172 - 175°C/0.2 mmHg Elemental analysis for C2gH4t.NO: Calculated: C 80.56 %, H 11.70 i, N 3 ,61 * Found : C. 80.35%, H 12 , 06 N 3.67%

Example_el_68

Alcohol compound used as starting material 4-(p-menthan-8-yloxy)-N-myristoylaniline

(product obtained in example 28)

Desired connection

4-(p-menthan-8-yloxy)-N-tetradecylaniline Melting point: 195 - 200°C/0.25 mmHg Elemental analysis for C^qH^^NO: Calculated: C 81.20% , H 12.04%, N 3.16% Found : C 8.1.01%, H 12.40%, N 3.17%

Example 69

In 20 ml of anhydrous ethanol, 1 g of 4-(p-menthan-8-yloxy)acetanilide was dissolved, and after the addition of 0.4 g of potassium tertiary 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 dichloromethane and water.

The formed dichloromethane layer was separated, washed with water and then with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting oily material was transferred to a silica gel column. The desired product was eluted with ammonia-saturated benzene, the solvent was distilled from the eluate under reduced pressure, and the syrupy material was distilled under reduced pressure to give 1.15 g of N-benzyl-4-(p-menthan-8- yloxy) acetanilide...

Boiling point: 195 - 200°C/0.6 mmHg

Elemental analysis for C25H33NO2:

Calculated: C 79.11 I, H 8.76 I, N 3", 69% Found : C 79.49%, H 8.96%, N 3.94%

Eczema gel_70

1

750 mg of N-cinnamoyl-4-(p-menthan-8-yloxy)aniline obtained in example 21 were dissolved in 20 ml of anhydrous ethanol, and after the addition of 350 mg of 10% palladium carbon, the mixture was stirred in a hydrogen atmosphere until a theoretical amount of hydrogen had been absorbed. After filtration of palladium carbon, the solvent was distilled under reduced pressure and the residue formed was recrystallized from 85% ethanol to form 0.7 g of white crystalline. 4-(p-Menthan-8-yloxy)-N-(3-phenylpropionylDaniline).

Melting point: 96 - 97° C

Elemental analysis for C25H33N02:

Calculated: C.79.11%, H 8.76%, N 3.69%

Found : C 78.99%, H 8.91%, N 3.68%

Example_71

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 anhydrous. tetrahydrofuran with stirring over 2 hours, and the mixture was then 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 successively added to the mixture. After filtration of insolubles, 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 then distilled off under reduced pressure. The residue was transferred to a silica gel column and the desired product was eluted using ammonia-saturated benzene. The solvent in the eluate was evaporated under reduced pressure, and the remaining oily product was distilled under reduced pressure to give 1.22 g of 4-(p-menthan-8-yloxy)-N-methylaniline.

Boiling point: 14 8 - 151°C/0.6 mm Hg

Elemental analysis for C^I-^^NO:

Calculated: C 78.11%, H 10.41%, N 5.36%

Found : C 78.08%, H 10.80%, N 5.51%

Example_el_72

1.5 ml of anhydrous tetrahydrofuran was dissolved in 430 mg of N-methyl-4-(p-menthan-8-yloxy)aniline, and after addition of .300 mg of acetic anhydride and 0.8 ml of anhydrous pyridine, the resulting mixture was stirred overnight at room temperature . Reaction mixture-. was poured over 30 ml of ice water and the crystals obtained were recrystallized from 5 ml of petroleum ether to form 350 mg

white crystalline 4-(p-menthan-8-yloxy)-N-methylacetanilide.

■ i.

Melting point: 70 - 71° C Elemental analysis for C-^gl^.gNC^: '.'

Calculated: C.75.21%, H 9.63%, N 4.62%

Found : C 75.01%, H 9.96%, N 4 , 41%

Example_73

In 30 ml of anhydrous ethanol was dissolved 1 g of 4-(p-menthan-8-yloxy)-N,N-dimethylaniline which had been freed from its hydrochloride according to Example 62, and after addition of 5 ml of methyl iodide, the mixture was boiled under reflux over the night. The solvent and excess methyl iodide were distilled from under reduced

pressure, and the residue formed was extracted with dichloromethane. The extract was washed with water and then an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, excess ether was added to the concentrate and the precipitate formed was collected by filtration and recrystallized from a mixture of dichloromethane and ether to give 0.9 g of white crystalline 4-(p-menthan-8- • yloxy)-N,N,N-trimethylanilinium iodide.

Melting point: 179 - 180° C

Elemental analysis for C^gH-^NOI:

Calculated: C 54.68%, H 7.73%, N 3.36%

Found : C 54.34%, H 7.91%, N 3.25%

Example_el_74

In a solution of 1.6 g of nicotinic acid and 1.31 g of triethylamine in 30 ml of methylene chloride, 1.4 g of ethyl chlorocarbonate was added dropwise while stirring and cooling. A solution of 2.5 g of cis-4-(p-menthan-8-yloxy)aniline in 20 ml of methylene chloride was added dropwise to the resulting solution. 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 residue formed was transferred to a silica gel column. The desired product was eluted using chloroform and the solvent was distilled from the eluate. When the residue was recrystallized from ethanol, 2.3 g were obtained

white crystals of cis-4-(p-menthan-8-yloxy)-N-nicotinoylaniline.

Melting point: 122 - 123° C

Elemental analysis for (-:22H28N2(*l2:

Calculated: C 74.96%, H 8.01%, N 7.95%

Found : C 74.53%, H 7.98%, N 7.99%

Example 75

Pills

1000 tablets for oral use, each containing 100 mg, ,1-[4-(p-menthan-8-yloxy)phenyl]piperidine, were prepared from the following ingredients:

1-[4-(p-Menthan-8-yloxy)phenyl]piperidine: 100 g

Methyl cellulose J.P.: 6.5 g

Lactose: 25 g

Talc: 5 g

Calcium stearate: 3.5 g

1-[4-(p-menthan-8-yloxy)phenyl]piperidine was granulated,

with 7.5 g% w/v aqueous solution of methylcellulose, passed through a No. 8 sieve and dried1 carefully-. The dried granules were passed through a No. 12 sieve, mixed with talc/lactose and stearate and pressed into tablets...

Claims (1)

Process for the preparation of a cyclic aminophenyl- ether compound of general formula , wherein represents a hydrogen atom or a lower alkyl group; R 2 denotes a cyclohexyl group which may be substituted with lower alkyl groups, an alkyl group containing from 1 to 20 carbon atoms, a phenyl group, or a benzyl; R^ denotes a hydrogen atom, a lower alkyl group, or a cyclohexyl group which may be substituted with lower alkyl, and n is 4 or 5, and where R., and R^ together with the adjacent nitrogen atom may form a cyclohexane ring which may be substituted with lower alkyl, characterized in that a compound of formula in which R 1 , R 2 and R 2 have the meanings given above, is reacted with a compound of formula in which X denotes a halogen atom and n has the meaning given above.