CA1154452A - Benzaminoethylphenoxycyclohexylacetic acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention provides benzaminoethylphenoxy-cyclohexylacetic acid derivatives having the formula wherein R1 represents hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group; n is ; or 2;
and R2 represents hydrogen atom, a lower alkyl group which may be substituted by a phenyl group, a lower alkoxycarbonyl group, a 3,3,5-trimethylcyclohexyloxycarbonyl group or a heterocyclic group; the hexadecyl group; a phenyl group which may be substi-tuted by a lower akkyl group, a lower alkoxy group, a lower al-koxycarbonyl group or a halogen atom; a cyclohexyl group or ?-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacethoxycyclo hexyl group which are useful in antihyperlipidemic agents as well as compositions containing them.

Description

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The present invention relates to benzaminoethylphenoxy-cyclohexylacetic acid derivati~es, to the preparation of such derivatives and to antihyperlipidemic agents comprising such compounds as the active in~redients.
It is known clinically to use Bezafibrate, Clofibrate and analogous compounds; nicotinic acid derivatives; hormones, such as protein assimilation steroids; unsaturated aliphatic acids, such as linoleic acid; cholestylamine and ~-sitosterols as anti-0 hyperlipidemic agents.

; It has now been found that certain oxyacetic acid de-rivatives have desired antihyperlipidemic properties.

The present invention thus provides benzaminoethylphenoxy-cyclohexylacetic acid derivatives which are effective against hyperlipidemia.

The present invention also provides a process for pro-ducing the benzaminoethylphenoxycyclohexylacetic acid derivatives.

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1~54~2 Accoxding to the present invention there is provided benzaminoethylphenoxycyclohexylacetic acid derivatives having the formula ~ ~ CONHCH2CH2 ~ O ~ COOR

wherein Rl represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2; and R represents hydrogen atom, a lower alkyl group which may be substituted by a phenyl group, a lower alkoxycarbonyl group; the 3,3,5-trimethylcyclohexyloxycarbonyl group or a hetero-cycli.c group, the hexadecyl group; a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a : 15 lower alkoxycarbonyl group or a halogen atom; a cyclohexyl group :~ or ~-[4-~4-chlorobenzaminoethyl)phenoxy]-a-cyclohexylacetoxy cyclohexyl group which derivatives have excellent antihyperlipi-demic activity.

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In the formula (I) as R and R , the halogen atom may be a fluorine, chlorine, bromine or iodine atom; the lower alkyl group and the lower alkoxy group may have a straight or branched alkyl group, and the lower alkyl group may be a methyl, ethyl, propyl or butyl group; the lower alkoxy group may be a methoxy, ethoxy, propoxy or butoxy group; the lower alkoxycarbonyl group may be a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl group; the heterocyclic group may be a furyl, thienyl, morphorino, benzothiazole, pyridyl or 3,4-methylene-dioxyphenyl group.

The benzaminoethylphenoxycyclohexlacetic acid derivativeshaving the formula ~ -CONHCH2CH2 ~ O ~ COOR (I) wherein R , R and n are defined above may be produced by react-ing a benzaminoethylphenol compound having the formula (II) 1 ~ -CONHCH2CH2 ~ - OH (II) wherein R and n are defined above with ~-halocyclohexylacetic acid compound having the formula ( II) X-CHCOOR (III) , ~
, 30 wherein X represents a halogen atom and R represents the groups R as defined above; if necessary, followed by hydrolyzing the product or interesterifying the product.

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` The compounds havin~ the formula (IIX) wherein X is -I, -Br, or -Cl are preferably used. In the reaction, an equi-molar amount of the ~-halocyclohexylacetate (III) is usually reacted with the compound (II). However, it :is possible to use an excess of either the compound (II) or the compound (III).
The solvents are organic solvents which are inert under the reaction conditions, such as dimethyl formamide and acetone. A
mixed solvent may be used for the reaction. The reaction may be accelerated by adding a base such as potassium carbonate, sodium carbonate, sodium methylate or sodium ethylate. It is possible to separate the reaction product obtained by reacting the base with the compound (II) from the reaction system and then, to react the compound (III) with the separated reaction product.
The reaction conditions such as temperature, time and pressure may be chosen depending upon the starting materials, the solvent and the base. The reaction is ussually completed, at room tem-perature, in 1 to 2 days or at 100 to 180C for 5 to 20 hours.

The corresponding carboxylic acids can be obtained by hydrolyzing the benzaminoethylphenoxycyclohexylacetic acid ester (I). The hydrolysis can be carried out by using conventional processes. It is preferable to carry out the hydrolysis under alkaline conditions with an aqueous solution of sodium hydroxide or an alcoholic solution of potassium hydroxide. The resulting benzaminoethylphenoxycyclohexylacetic acid or ester thereof can be converted into the corresponding ester by reacting it with a chlorinating agent such as thionyl chloride and phosphorus trichloride to form the corresponding carboxylic acid chloride and further reacting the produce with a compound having the for-; 30 mula 2 R -OH

wherein R is defined above, in the presence of a base, such as pyridine or triethylamine; or by reacting it with a compound having the formula , .....
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wherein R2 and X are defined ahove; or by reacting it with a compound having the formula R2_oH
in the presence of an esterifying agent such as tosyl acid and tosyl chloride.

The reaction products (I) can be separated and purified by conventional separating methods such as concentration, parti-cularly concentration under reduced pressure; distillation; par-ticularly distillation under a reduced pressure; fractional distillation; the adjustment of alkalinity or acidity; solvent extraction; crystallization; recrystallization; inversion and chromatography.

The benzaminoethylphenoxycyclohexylacetic acid deriva-tives (I) have excellent antihyperlipidemic activity and are ef-fective in practice as an antihyperlipidemic agent for the treat-ment of hyperlipidemia. The benzaminoethylphenoxycyclohexylacetic acid derivatives (I) have low toxicity and do not cause hepatitis which is found in the administration of ethyl-~-(p-chlorophenoxy)-isobutyrate (Clofibrate) or [2-{4-12-(4-chlorobenzamine)-ethyl]-phenoxy}-2-methylpropionic acid](Bezafibrate).
The antihyperlipidemic agents of the present invention comprising the benzaminoethylphenoxycyclohexylacetic acid deri-vatives (I) can be administered orally in the form of tablets, ` capsules, powders or granules; and they can also be administered i~ 30 parenterally in the form of injectable solutions, suppositories or pellets. The benzaminoethylphenoxycyclohexylacetic acid ~, $

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derivative (I~ can be combined with other antihyperlipidemic a~ents, ,a, hypotensive agent or an ~nticoagulant agent. The dose of the benzaminoethylphenoxycyclohexylacetic acid derivative (I) is usually in a range of 25 to 2500 mg., preferably 100 to 1000 S mg. per day per adult inoral dose.

The invention will be further illustrated by the follow-ing examples.

EXAMPLE 1:

Ethyl-~-[4-(4-chlorobenzaminoethyl)phenoxy]-~-cyclohexylacetate: (Compound No. l) ; 15 Into 50 ml. of dimethylformamide containing 3.2 g.(0.0479 mol) of sodium ethylate, ll g. (0.04 mol) of N-(4-chloro-benzoyl)-tyramine was added and further 39.8 g. (0.16 mol) of ethyl ~-bromocyclohexylacetate was added and the mixture was stirred at 170C for 10 hours. After the reaction, dimethyl-formamide was distilled off under a reduced pressure and ice water was added and the reactionproductwas extracted with benzene.
The extracted benzene layer was washed with 2% NaOH aq.sol. and ' then with water and was dehydrated over sodium sulfate and the, benzene was distilled off under a reduced pressure. The residue was recrystallized from a mixed solvent of ethanol and n-hexane ' to obtain 5.7 g. of ethyl ~-[4-(4-chlorobenzaminoethyl)phenoxy]-~; ~-cyclohexylacetate (yield: 35.2%).

Melting point: 103 - 104C
IR Spectrum (KBr):
~(cm ): 3325 (NH), 1740 (C=0), 1640 (C-NH) ~,: O

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- : , In accordallce with the s(lme process, the products shown in T~ble 1 were produced by using the corresponding starting materi-als. The physical properties of the products are also shown in Table : `
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_~ble 1 (R )n ~ CONHCH2CH2~O-C~lCOO~

Comp. (R ) ¦ R I :I\,Ielting _ C-0 _ 2 ¦2 5 89 - 90 1760, 1655 _ _

3 3-Cl C2 5 106 - 107 1755, 1630

4 . 2-F ¦C2H5 85 - 86 1745, 1650 s S 3-F . ~ 104 - 105 1750, 1640 l _ 6 4-F ¦ ' j 111 - 112 1755, 1640 7 2-CH3 ~ 86 - 87 1755, 1630 8 3-CH3 ¦i~ 80 - 81 1740, 1630 '.~ l ~. . 4-CH3 l ' 88- 89 Oil 2-OCH3 l Oil ~/C o 1740,1645 11 3_oCH3 1 ~ 78-79 ! 1740,1640 :~
'' 12 4-OCH3 _ 120 - 121 1755, 1640 13 H " ¦ 95.5 - 97 1755, 1640 ¦ 14 ~ 4- C3H7 =

:t.: 16 4 -t- C4Hg 125 126 1750 : j __ ~ I 17 4-Cl n-C4Hg 92 - 93 1750, 1645 ;~ 18 4-Cl n C16 33109 - 110 1740, i645 .~ ~
51 2-OH C2H5 oil 1750, 16~0 .. .

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S~-[ 4-(4-chlorobenzaminoethyl)phenoxy~-c~-cyclohexylacetatic acid: (Com~ound No, 19) Into 70 ml. of 70% ethanol containing 2 g. of sodium :
hydroxide, 5. 7 g. (O. 0128 mol ) of the ester obtained in Example 1 was dissolved and the mixture was refluxed for 30 minutes and then, the solvent was distilled off under a reduced pressure and then water was added and the mixture was acidified with 5~oHCl and the reaction product was extracted with benzene. The extracted benzene layer was washed with water and dehydrated over sodium sulfate and benzene was distilled off and the residue was recrystallized fromethanol to obtain 3.8 g. of o~-(4-(4-chlorobenzaminoethyl)phen O;- cy cl ohexylacetic aci d (yield: 71.7~o).
Melting point: 187 - 188C
lS IR Spectrum (KBr):

~(cm ): 3320(NH); 1735(C=0); 1640 (CONH) In accordance with the same process, the products shown in Table 2 were produced by using the corresponding starting materials.
The physical properties of the products are also shown in Table 2.
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1159~52 Tab1e 2 (Rl)n \~ CONHCH2CH2~0- CHcc)oR2 Comp . I ( ~1 )n ¦ R2 point( C ) L~R ~ C o ( cm _ 20 2-C1 126 127 1740, 1650 21 1 3-C1 __ 165- 166 1730, 1640 -22 l2-F I !153-154 1740,1650 23 l3-F I I !175-176T1740,1620 24 ¦ 4-F I , ¦ 186 187 ¦ 1740, 1620 25 ¦ 2-CH3 ¦ 138 139 1 1740, 1620 26 ¦ 3-CH3 1 181 182 1 1730, 1620 27 14-CH3 1 !195-1961 1740,1620 28 ¦ 2-OCH3 1 ¦ 124 125 1 1750, 1630 29 ¦ 3-OCH3 1 ¦ 205 206 1 1730, 1720 30 4-OCH3 1 " 1 213~ 1730 31 H I I _ 2 32 ! 4~i~C3H7 ¦ ¦ 1 55 1 56 1 1740, 1640 33 ! 4 n-C4 9 ¦ 1 154 155 1 1740, 1650 34 ¦ 4~t~C4H9 ¦ " ¦ 1 65 166 ~0, 1640 .

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_XA MP l.E 3 Cyclohexyl o~-(4-(4-chlorobenzaminoethyl)phcllox _ ~)(-cyclohexylacetate:(Compound No, 35) Into 6 ml. of pyridine, 1. 65 g. (0. 004 mol ) of ~ (4-chlorobenæaminoethyl)phenoxy)-~(-cyclohexylacetic acid w<-s dissolved, and then, 0. 40 g. (0. 004 mol ) of cyclohexanol was added and then, 0. 95 g, (0. 005 mol ) of tosyl chloride was added and the mixture was heated at 80 - 90C for 2 hours to react them, The reaction mixture was poured into ice water and the precipitate was separated by a filtration and washed withwater and the reaction product was recrys-tallized from a mixed solvent of ethanol and water to obtain 1. 7 g. of the object compound (yield: 86. l~o).
Melting point: 104 - 105C
Spectrum:
~ C-O 1760, 1750, 1650 cm~

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2 -Ethoxycarbonvlphenylo( - ~4 - (4 -chlorobenz -aminoethyl)phenoxy~ -cyclohexylacetate: (Compound No. 36) ; In 15 ml. of dichloroethane, 1. 65 g. (0. 004 mol ) of C~- ~4-(4-chlorobenzaminoethyl)phenoxy~ -cyclohexylacetic acid obtained in E~ample 2 was suspended and then, 2 ml. of thionyl chloride was added. The mixture was refluxed for 1 hour to react them. The solvent was distilled off under a reduced pressure and 10 ml. of dichloroethane was added to the residue and the solvent ^ 25 was distilled off under a reduced pressure. The residue was adn~ixed with 1 ml. of pyridine and 0, 73 g. (0. 0044 mol ) of ethyl . ,, .
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salicylate dissolved in 0. 5 ml. of pyridirle was added to react them for 30 minutes. The reaction mixture was cooled and added into

5%HC1 aqueous solution. The reaction product was extractcd with benzene and the benzene layer was washed with water, with 5~/~ONaOH
aq. sol. and then with water and the benzene laycr W.-IS clchyclr.lted over sodium sulfate. ~enzene was distilled off and the residue was recrystallized from ethanol to obtain 1. 6 g. of the object compound (yield: 71. 5 ~0) .
Melting point: 12 5 - 12 6C
IR Spectrum:
y cBo : 1770, 1740, 1640 cm~1 In accordance with the process of Example 3 or 4, the products shown in Table 3 were produced by using the corresponding starting materials. The physical properties of the products are also shown in Table 3.

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llS~452 T.lbl e 3 (Rl)n ~- CoNI'lcH2cH2~-o-cHcooR

No. ( Rl )n _ __ Mc 1 ~in g _ __ C _0____ 37 ~-C1 _ ~ 148 - 1~9 1775, 1650 38 _ - CH ~ Oil C = 0 1650 39 " ~O2C-~H-O~ 1755, 1740, ll -CH2~ 88 - 89 1765, 1650 _ 41 ~Cl 152 - 153 1775, 1650 42 ~CH3 131 - 13Z 1775, 1650 43 ~______ -C~2~ 122 - 123 1750, 1660 .

44 ~ -CH2~ 133 - 134 1745, 1650 ., Et 1 Z 4 - 1 Z 5 1750, 1660, 46 2 2 ~_~ Oil ~Oil 1750 1159~4S~

rCol-np- ¦ (R1)n R polnt 5~ \/'C=0 ( _ l_ (o 48 I. 3-Cl ~Oil ~Oil 1750 1650 ~ ~coo~ ~ I~c ( I~-o 50 ~ 4-Cl -ÇHCO;?~ 59 - 60 1760, 1655 Preparation 1:

A 400 g. of ethyld~4-(4-chlorobenzaminoethyl)phenoxy3-~-cyclohexylacetate, 400 g. of fine powdery silicondioxide and 185 g.
of corn starch were uniformly mixed and charged in a kneader and 1000 ml. of 3% aqueous solution of hydroxypropyl cellulose was added and the mixture was kneaded. The mixture was granulated by passing it through the 16 mesh screen to form uniform granules which comprises an antihyperlipidemic agent.

Preparation 2:

A 400 g. of ~-~4-(4-chlorobenzaminoethyl)phenoxy~
cyclohexylacetic acid, 400 g~ of lactose and 175 g. of potato starch were uniformly mixed and charged in a kneader and 3% aqueous solution of hydroxypropyl cellulose was added and the mixture was kneaded and granulated by passing through a 16 mesh screen and 0. 3~0 of mag-nesium stearate was added and the mixture was compressed to form tablcts which comprise an antihyperlipidemic agent.

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Te~st 1.

The antihyperlipidemic activity in rats with dictary hyperlipidemia, In the tests, Wister type m~ale rats (weigllt: 1~0 ~:~.) were used in groups of 5 each.
A feed containing 2% of cholesterol, 1% of sodium cholate and 5% of coconut oil was given for ~ days to cause hyperlipiclemia Each active ingredient was suspended in a l% aqueous solution of Tween 80 ( (~) polyoxyethylene sorbitane monoa]kylate) and the suspension was orally administered in a dose of lO0 mg. /kg.
once daily for 4 days starting with the supply of the cholesterol supplemented diet, After 24 hours from the administration, blood was sarnpled and the concentration of total cholesterols in blood-plasma was measured by the method described in Clinical chemistry Vol. 22 page 393 (1968) and the concentration of triglyceride (neutral fat) was measured by Fletcher method (Clinica Chimica Acta)Vol. 10 page 451 (1964).
Percent liver weight was given by extracting liver and measuring each weight of liver and calculating a ratio of the liver weight to a total weight.
As the active ingredients, the compounds of the invention shown in Table and ethyl-~-(p-chlorophenoxy)-isobutylate having the formula CH
Cl4~3O ~-COOC2H5 (Clofibrate) , .

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and 2-~4-~2- (4- chloroben~aln;de)ethyl)pllenoxy~2-methylpropionic acid Cl~CONHCH2cl~2~30-c-coo~l (Bc/afibrF,tc) The test results are shown in Table 4.

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Table 4 (p,o, 100 mg/kg) _ Ant.;hyperlip;deln;c activity(%) Percent weioilt Compoulld No _ _ _ __ inc l e ~lse of _ _ Cholesterol I Triglycerlde ¦liver _ _"lo) 1 44 62 8.8 _ _ ~ . , ,~

___,_____ ... __ 3 33 21 0.9 _ _ ___ _

6 54 45 0

7 42 63 2.1

8 23 42 0

9 14 0 0.5 _ .

_ __ 13 14 72 4.5 _ ~ 15 16 20 0 .

17 53 48 12.8 : 18 47 42 10.3 : 19 46 68 4.5 ~, : 20 1 65 89 1.6 ;

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(p o, 100 mg/kg) Antihyperlipidernic activity % percent weight Compound No. -- I increase of Cholesterol Triglyceride ]iver (~0) 21 57 99 6,2 _ ___ _ 22 41 35 O.9 _ ~_ 23 51 O 9.7 24 65 25 9.6 62 89 10. 2 26 25 64 7,3 27 4. 2 41.1 6.4 _ 54 10.7 31 49 90 9.7 37 42 2.8 36 42 47 3.0 37 39 42 3.9 38 46 50 4.2 39 43 48 3.8 ~.
48 49 4,0 s~ ., ,:

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(p, o, 1 OOmg/kg) C om p o U nd N o C h ol e s t e ro l ~m i c a cti lt~ ~ e ~: ei 41 ____ __________ 1 5.2 42 40 36 3, 8 43 33 37 2, 6 44 . 47 52 4.2 38 41 3. 9 46 41 ^ 42 4. 3 47 32 39 2.9 48 45 50 1 4.2 . 49 42 48 3. 9 40 . 51 0. 9 Clofibrate 38 39 24. 2 Bezafibrate 36 32. 8 `

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Test 2:

In the acute toxicity tests, male mice (weight: 22 to 25 g. ) were used in groups of 10 each.
Each active ingredient was dissolved in olive oil and the solution was orally administrated in a volume corresponding to the body weight.
LD50 was calculated by the area method from the mortal percent after 72 hours from the administration, ' The LD50 of the Compound No. 1, 2, 5, 6 and 19 were respectively greater than 4, 000 mg. /kg.

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Claims (50)

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

1. A process for producing a benzaminoethylphenoxy-cyclohexylacetic acid derivative having the formula (I) wherein R1 represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2;
and R represents hydrogen atom, a lower alkyl group which may be substituted by a phenyl group, a lower alkoxycarbonyl group, 3,3,5-trimethylcyclohexyloxycarbonyl group or a heterocyclic group; the hexadecyl group; a phenyl group which may be substi-tuted by a lower alkyl group, a lower alkoxy group, a lower al-koxycarbonyl group or a halogen atom; a cyclohexyl group or .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetoxycyclohexyl group which comprises reacting a benzaminoethylphenol compound having the formula (II) ( I I ) wherein R and n are defined above, with .alpha.-halocyclohexylacetic acid compound having the formula (III) ( I I I ) wherein X represents a halogen atom; and R3 represents the groups R2 defined above and when required hydrolyzing or interesterify-ing the product obtained.

2. The process according to claim 1, wherein the reac-tion is carried out in the presence of a base in an inert sol-vent.

3. A benzaminoethylphenoxycyclohexylacetic acid deri-vative having the formula wherein Rl represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2; and R2 represents hydrogen atom, a lower alkyl group which may be substituted by a phenyl group, a lower alkoxycarbonyl group, a 3,3,5-trimethylcyclohexyloxycarbonyl group or a hetero-cyclic group; the hexadecyl group; a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a halogen atom; a cyclohexyl group or .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetoxycyclo-hexyl group whenever prepared or produced by the process as claimed in claim 1 or 2 or a chemical equivalent thereof.

4. A process according to claim 1, wherein R represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2; and R represents a lower alkyl group.

5. A derivative of formula I given in claim 1, in which Rl and R2 are as in claim 4, whenever prepared or produced by the process as claimed in claim 4 or an obvious chemical equivalent thereof.

6. A process according to claim 1, wherein R represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2; R2 represents a hexadecyl group or a lower alkyl group substituted by a phenyl group, a lower alkoxycarbonyl group, a 3,3,5-trimethylcyclohexyloxy carbonyl group or a heterocyclic group selected from furyl, thienyl, morpholino, benzothiazole, pyridyl or 3,4-methylene dioxy phenyl.

7. A derivative of formula I given in claim 1, in which Rl and R2 are as in claim 6, whenever prepared or produced by the process as claimed in claim 6 or an obvious chemical equivalent thereof.

8. A process according to claim 1, wherein R1 represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2; and R2 represents hydrogen atom.

9. A derivative of formula I given in claim 1, in which R1 and R2 are as in claim 8, whenever prepared or produced by the process as claimed in claim 6 or an obvious chemical equivalent thereof.

10. A process according to claim 1, wherein R1 represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group, a lower alkoxy group; n is 1 or 2; R2 represents phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a halogen atom.

11. A derivative of formula 1 given in claim 1, in which R1 and R2 are as in claim 10, whenever prepared or produced by the process as claimed in claim 10 or an obvious chemical equivalent thereof.

12. A process according to claim 1, wherein R1 represents hydrogen atom, a halogen atom, hydroxyl group, a lower alkyl group or a lower alkoxy group; n is 1 or 2; and R2 represents hydrogen atom, a lower alkyl group which may be substituted by a phenyl group, a lower alkoxycarbonyl group, a 3,3,5-trimethylcyclo-hexyloxycarbonyl group or a heterocyclic group selected from the group consisting of furyl, thienyl, morphoeino, benzothiazole, pyridyl or 3,4-methylenedioxyphenyl, the hexadecyl group, a phenyl group which may be substituted by a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a halogen atom; a cyclohexyl group or .alpha.-[4-(4-chlorobenaminoethyl)phenoxy]-.alpha.-cyclohexylacetoxycyclohexyl group.

13. A derivative of formula 1 given in claim 1, in which R1 and R2 are as in claim 12, whenever prepared or produced by the process as claimed in claim 12 or an obvious chemical equivalent thereof.

14. A process according to claim 1, which comprises heating a mixture of N-(4-chlorobenzoyl)-tyramine and ethyl .alpha.-bromocyclohexylacetate in the presence of sodium ethylate in diemthyl formamide at a temperature of 170°C.

15. Ethyl .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 14 or an obvious chemical equivalent thereof.

16. A process according to claim 1, which comprises heating a mixture of N-(2-chlorobenzoyl)-tyramine and ethyl .alpha.-bromocyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

17. Ethyl .alpha.-[4-(2-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 16 or an obvious chemical equivalent thereof.

18. A process according to claim 1, which comprises heating a mixture of N-3-chlorobenzoyl)-tyramine and ethyl .alpha.-cyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

19. Ethyl .alpha.-[4-(3-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 18 or an obvious chemical equivalent thereof.

20. A process according to claim 1, which comprises heating a mixture of N-(2-fluorobenzoyl)-tyramine and ethyl .alpha.-cyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

21. Ethyl .alpha.-[4-(2-fluorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 20 or an obvious chemical equivalent thereof.

22. A process according to claim 1, which comprises heating a mixture of N-(3-fluorobenzoyl)-tyramine and ethyl .alpha.-cyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

23. Ethyl .alpha.-[4-(3-fluorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 22 or an obvious chemical equivalent thereof.

24. A process according to claim 1, which comprises heating a mixture of N-(4-fluorobenzoyl)-tyramine and ethyl .alpha.-cyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

25. Ethyl .alpha.-[4-(4-fluorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 24 or an obvious chemical equivalent thereof.

26. A process according to claim 1, which comprises heating a mixture of N-(2-methylbenzoyl)-tyramine and ethyl .alpha.-cyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

27. Ethyl .alpha.-[4-(2-methylbenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 26 or an obvious chemical equivalent thereof.

28. A process according to claim 1, which comprises heating a mixture of N-(3-methoxybenzoyl)-tyramine and ethyl a-cyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

29. Ethyl .alpha.-[4-(3-methoxybenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 28 or an obvious chemical equivalent thereof.

30. A process according to claim 1, which comprises heating a mixture of N-(4-chlorobenzoyl)-tyramine and n-butyl .alpha.-bromocyclohexylacetate in the presence of sodium ethylate in dimethyl formamide at a temperature of 170°C.

31. N-butyl .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 30 or an obvious chemical equivalent thereof.

32. A process according to claim 14, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

33. .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 32 or an obcious chemical equivalent thereof.

34. A process according to claim 16, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

35. .alpha.-[4-(2-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 34 or an obvious chemical equivalent thereof.

36. A process according to claim 18, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

37. .alpha.-[4-(3-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 36 or an obvious chemical equivalent thereof.

38. A process according to claim 20, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

39. .alpha.-[4-(2-fluorobenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 38 or an obvious chemical equivalent thereof.

40. A process according to claim 22, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

41. .alpha.-[4-(3-fluorobenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 40 or an obvious chemical equivalent thereof.

42. A process according to claim 24, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

43. .alpha.-[4-(3-fluorobenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 42 or an obvious chemical equivalent thereof.

44. A process according to claim 26, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

45. .alpha.-[4-(2-methylbenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 44 or an obvious chemical equivalent thereof.

46. A process according to claim 28, in which the pro-duct obtained is refluxed in ethanolic sodium hydroxide.

47. .alpha.- [4-(3-methoxybenzaminoethyl)phenoxy]-.alpha.-cyclo-hexylacetic acid whenever prepared or produced by the process as claimed in claim 46 or an obvious chemical equivalent thereof.

48. A process according to claim 32, in which the .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetic acid so obtained is heated with tosyl chloride in pyridyl methyl alcohol.

49. A process according to claim 32, in which the .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetic acid so obtained is refluxed with thionyl chloride in dichloromethane and heating the carboxylic acid chloride soobtained in the presence of pyri-dine with pyridyl methyl alcohol.

50. Pyridylmethyl .alpha.-[4-(4-chlorobenzaminoethyl)phenoxy]-.alpha.-cyclohexylacetate whenever prepared or produced by the process as claimed in claim 48 or 49 or an obvious chemical equivalent thereof.