AP188A

AP188A - Novel aryloxy alcohol benzenes, processes for their preparation as well as the pharmaceutical compositions containing them.

Info

Publication number: AP188A
Application number: APAP/P/1990/000223A
Authority: AP
Inventors: Gerald Moinet; Thierry Imvert; Dominique Marais; Jean Louise Vidaluc; Didier Mesangeau
Original assignee: Lipha Lyonnise Ind Pharmaceutique
Priority date: 1989-10-18
Filing date: 1990-10-18
Publication date: 1992-05-01
Also published as: JPH03255043A; CA2028031A1; AU650429B2; HUT57175A; RU2042659C1; PT95624A; OA09465A; AP9000223A0; EP0428423A3; FR2653119A1; ZA908355B; AU6486990A; EP0428423A2; FR2653119B1; HU906498D0; HU212938B

Abstract

This invention has a subject matter novel aryloxy alkylbenzenes, their processes for production and the pharmaceutical compositions containing them.

Description

This invention relates to novel aryloxy alkyl bent of production as well as the pharmaceutical compositions - containing, them.

It has more precisely as subject matter as novel compounds, aryloxyethyl benzene substituted on one or both rings and specifically the aryloxyethyl benzene of the formula I

Ar - CH - CH - 0 - Ar' (I) wherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of

- phenyl derivatives having the formula (Z)p wherein X is a hydroxy, free esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lower alkyl or alkenyl radical

Z is a substituent selected from the group consisting of hydrogen, halogens, hydroxy, a lower alkoxy, an acyloxy, a phenyl lower alkyl, a lower alkyl, a lower alkyl substituted by a ((lower alkyl) oxy carbonyle), a (lower alkyl) substituted by a hydroxy carbonyle, a moiety -CCKCT^)^ CH^ wherein m is an integer of from 1 to 4, a moiety CHOH-(CH2)_m,-CH2 wherein m' is an integer of from 1 to 4 a carboxamido group optionally substituted by one or two lower alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula

AP 0 0 0 1 8 8

wherein A is a free hydroxy or an esterified or etherified hydroxy group

Z is defined as above-given and p is an integer of from 1 to 3 and those of formula (Z)p

wherein A, Z and p are defined as above-given

Ar' is an aromatic mono- or bicyclic radical selected from the consisting of group

- the benzenic derivatives of formula

wherein Y is a hydrogen, a halogen, a (lower alkylene) dioxy, a hydroxy, a lower alkoxy, an acyloxy derivated from an organic carboxylic acid, a lower alkyl, a lower alkyl substituted by a (lower alkoxy) carbonyl, an oxo alkyl chain of the formula ^3 wherein m is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CHOH-(CH) -^,-CH-^ wherein m' is an integer of from 1 to 4

- the naphtalenic derivatives selected from the group consisting of naphtyl derivatives of formula

- »

- 3 wherein Y is defined as above-givent and n is an integer of from 1 to 4

- and the naphtalenic derivatives of formula

wherein Y and n are defined as above-given

R is a hydrogen, a hydroxy, the oxygen of a keto group or a lower alkyl radical

R^ is a hydrogen or a lower alkyl radical

This invention also relates to the optically-active isomers of a compound of formula I when R^ and/or R£ are different than hydrogen and when R is not a keto group.

Further when R and R^ are both substituents, it is possible to create a pair of diastereo isomers erythro and threo and further to resolve it into the optically-active isomers by means of a chiral reagent.

This invention also includes the salts of the compounds of formula I -when X is a hydroxy esterified by sulphuric acid or phosphoric acidwith a mineral or organic base.

Among the compounds of formula I according to this invention, the following groups may be more precisely cited :

- the hydroxyphenyl ethoxy benzenes of formula I_A

x

- 4 wherein X is hydroxy, a hydroxy etherified by a lower alkyl or a lower alkenyl or esterified by an organic carboxylic or sulphonic acid, by phosphoric acid or by phosphoric acid and R, R^, Y, Z, n and p have the above-given definitions and as preferred compounds :

l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane

- the metallic or organic base addition salts of l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane such as the piperazine disalt or the sodium salt l-(2-hydroxy 5-carboxamido phenyl) (4-fluorophenoxy) ethane

wherein the definitions of the substituents X, Y, Z, R, remain unaltered

R^, n and p

- the compounds having the general formula I_c

wherein the definitions of the substituents Ζ, Υ, X, R, R^, n and p remain unaltered

- 5 - the compounds to having the formula Ιθ

wherein Z, Υ, X, R, Rj, n and p are defined as previously given

- the compounds according to this invention having the formula I_E

(Y).

⁽ⁱe’

AP 0 0 0 1 8 8 wherein R, R^, X, Y, Z, n and p have the above-given definitions As far as this invention is concerned, a lower alkyl radical is a hydrocarbon chain which may be straight or branched, having up to 6 carbon atoms such as a methyl, ethyl, isopropryl, secbutyl, tert-butyl, neopentyl or n-hexyl. A lower alkoxy radical includes an alkyl chain defined as above.

Among the various halogens, it may more particularly be cited fluorine or chlorine. However bromine and iodine are also of value.

A lower alkenyl radical is a hydrocarbon chain including a double bond, having from 2 to 6 carbon atoms. As lower alkenyl radicals, it may be cited an allyl, a methallyl, a but-2-enyl radical, an isopropenyl or a

3-methyl but-l-enyl radical.

A lower alkylene dioxy group has from 1 to 4 carbon atoms in the alkylene chain as for example methylenedioxy or ethylenedioxy.

When X and/or Y and /or Z are an acyl moiety, this moiety derives from

- 6 a lower alkyl carboxylic acid such as acetyl, propionyl, dipropyl acetyl, or from an aromatic cyclic acid such as a benzoyl, naphtoyl-1, 2,6-dichlorobenzoyl, 3,4,5-trimethoxybenzoyl, a veratroyl, a syringoyl, a O-carbethoxy syringoyl, a nicotinoyl or a furoyl; or from an aryl lower alkyl carboxylic acid such as a phenoxy acetyl, a dichlorophenoxyacetyl or a p-chlorophenoxy isobutyryl.

An aryl lower alkyl radical is defined as a monocyclic aryl radical bearing a hydrocarbonated side-chain of 1 to 6 carbon atoms such as for example benzyl, phenylethyl, ot-methylphenyl ethyl, 2,6-dichlorobenzyl,

2,3,5-1 r imethoxybenzy1.

When Z is an alkyl carboxylic side chain, the alkyl moiety has from 1 to 4 carbon atom. The carboxylic function may be free or esterified such a (methoxy carbonyl) methyl, an (ethoxy carbonyl) methyl or an (ethoxy carbonyl) ethyl.

The substituent Y may further be an alkyl radical substituted with an oxo group or a hydroxy group. A preferred example of such group is acetyl or hydroxy ethyl.

When R and/or are a lower alkyl radical, they are preferably a methyl or an ethyl.

From all the compound of formula I, mentionned hereabove, the presently preferred compounds are those for which X is a hydroxy, free, esterified, or etherified located in position ortho to the ethyloxy chain and those for which Y is a halogen and most preferably those for which Y is a fluorine.

The significance of Z may very broadly vary. The nature of this substituant is important but the number of the substituents Z plays a more reduced role.

This invention also extend to a process for producing a compound of genec,'ii formula I

- 7 (I)

- Ο \

Ar'-(Y)_n which comprises the steps consisting of

- condensing a phenolic derivative of the formula II

Ar - X (II) (Z)p wherein Ar, X, Z are defined as above-given with an aryl aceto nitrile of the formula III „ 0 CH, CN

Ar' ^*2 (HI) ^<Y)n wherein Ar', Y and n have the above-given definitions in the presence of an acidic catalyst to produce a diaryl ethanone of the formula IV

AP 0 0 0 1 8 8 wherein z, Y, Ar, Ar', n and p have the above-given definitions and X is a free hydroxy rducing the latter by means of an alkali metal mixed hydride in the presence of a metalic catalyst or by reaction with a lower alkyl chloroformate and reduction of the intermediary so-produced compound by means of an alkali metal borohydride to obtain a compound of formula I.

This invention more particularly relates to a process for producing a compound of formula I_A which comprises the steps of condensing a phenol of formula II.

A (Z)p

OH

X

IU_A>

wherein Z, X and p have the above-given defintions with a phenoxyaceto nitrile of the formula

wherein Y and n have the above-given definitions in the presence of an acidic catalyst to produce the ethanone of general formula IV.

O

wherein Z, Y, n and p have the previous definitions and X is a free hydroxyl

- reducing the latter into a compound of general formula I_A by means of an alkali metal mixed hydride in the presence of a metallic catalyst or by reaction with a lower alkyl chloroformate then reduction of the thus-formed intermediary compound with an alkali-metal borohydride which may be alkylated by means of an alkylating reagent in basic

- 9 medium or acylated by meeans of functional derivative of a carboxylic, sulphonic, sulphuric or phosphoric acid.

This process also includes another process for producing a compound of formula I which comprises the steps of blocking the phenolic function of a hydroxy acetophenone of formula V (Z)p - Ar Cf (V)

CO CH₃ wherein Ar, Z and p are defined as previously given and X is a free hydroxyl using a easily-split reagent submitting the so-blocked phenol of formula VI ___OB (Z)p - Ar <7 (VI) — 0 CH₃ wherein B is a leaving group

Z and p have the above-given definitions submitting the latter to the action of a brominating agent to produce an α-bromoketone of formula VII

OB (Z)p - Ar (VII)

CO CH₂ Br wherein Z, Ar, B and p have the above-given meanings

- condensing this derivative with a phenolic derivative of formula

Ar’

AP 0 0 0 1 8 8 wherein Ar', Y and n are defined as previously indicated to produce a phenoxy ethanone of formula VIII (Z)p - Ar (VIII)

- 10 COCH. 0 Ar' - (Y) z n

X wherein the definitions of the substituents Y, Z, Ar, n and p remain unaltered and X is a hydroxy group blocked by an easily-split radical

- submitting the conpound of formula VIII to a hydrogenolysis in the presence of a metallic-catalyst or to an acidolysis to make free the hydroxy group and produce a phenoxy ethanone of formula IX

CH- 0 -, (Z)p - Ar ^z Ar' - (Y) (IX) '--OH ⁿ wherein Z, Y, Ar, Ar', n and p have the above-given meanings

- treating the latter with a reducing agent to produce the hydroxylated derivative thereof of formula X

CHOH - CH- 0 (Z)p - Ar Ar' - (Y) (X)

OH in which Z, Y, n, p, Ar and Ar' are defined as above-indicated and X is a free hydroxyl.

This process particularly applies for producing a compound of formula VIII.

A which comprises the steps of

- blocking the free hydroxyl of a hydroxy acetophenone of formula V_A

X _ »

- 11 with an easily-split blocking reagent

- submitting this blocked phenolic derivative to the action of a brominating agent to produce the corresponding a-bromoketone

- condensing this bromoketone with a phenol of formula

wherein Y and n are defined as previously to obtain a phenoxy ethanone of formula VI_A

(Y) n (VI_A, wherein the meanings of the substituents Z, Y, p and n remain unchanged and X is blocked hydroxyl

AP 0 0 0 1 8 8

- submitting this compound to hydrogenation in the presence of a metallic catalyst or to an acidolysis, to make free the hydroxyl function and obtain a phenoxy ethanone of formula VII_A

wherein X is a hydroxy

,. *

- 12 and Ζ, Y, p and n are defined as previously indicated

- reducing the compound of formula VII_A by means of a reducing agent to produce the corresponding alkanol of formula VIII_A

wherein Ζ, Y, n and p are defined as previously given and X is a free hydroxyl

This invention also relates to another process for producing a compound of formula I wherein R is a lower alkyl radical, which comprises the steps of

- reacting a phenoxy ethanone of formula VIII (Z)p - Ar - CO CH. 0 - Ar' - (Y) (VIII) \_χ ζ n wherein Ζ, Y, Ar, Ar', p and n have the above-given definitions and X is a blocked hydroxy group to the action of a triaryl alkyl phosphonium bromide under the conditions of the Wittig's reaction to produced an ethylenic derivative of formula XI

R

I (Z)p - Ar - C = CH - 0 - Ar' - (Y) (VI) ^X ⁿ wherein Ζ, Y, Ar, Ar', n and p are defined as above-given

X is a blocked hydroxy group and R is a lower alkyl radical

- 13 - submitting this compound to hydrogenation in the presence of a metallic catalyst to produce the «-alkylated derivative of formula I

R

I (Z)p - Ar - CH - CH-, - 0 - Ar' - (Y) (I) \x ^{2 n} wherein Z, Y, Ar, Ar, n and p are defined as previously

X is a free hydroxy group and R is a lower alkyl radical which may, when desired, be alkylated or acylated under the conditions previously defined

This process more particularly applies for producing a compound of formula I_A which comprises the steps of reacting a phenoxy ethanone of formula VI.

A

AP 0 0 0 1 8 β wherein Y, Z, n and p have the abobe-given definitions and X is a blocked phenolic group with a triaryl (lower alkyl) phosphonium bromide under the condtions of the Wittig's reaction to produce an ethylenic derivative of formula IX.

A

<^IXA>

tri x

*

- 14 wherein Z, Y, n and p have the above-given definitions

R is a lower alkyl radical and X is blocked phenolic group

- and submitting this latter to hydrogenolysis in the presence of a metallic catalyst to produce an α-alkyl ethoxy derivative of formula I.

A

R

wherein Z, Y, n and p have the above-given definitions

X is a hydroxy and R is a lower alkyl radical which may when desired, be alkylated or acylated under the above-defined conditions.

This invention also includes another process for producing a conpound of formula I which comprises the step of reacting a substituted aryl aldehyde of formula X (Z)p - Ar - CHO (X) wherein Z and p are defined as above and X is a blocked phenolic group with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic conpound of the formula XII (XII) „ *

- 15 (Y) - Ar' - Ο - CH - CH - Ar - Z n s wherein Z, Ar, Ar', X, Y, n and p have the above-given definitions

- hydrogenating the latter by means of hydrogen in the presence of a metallic catalyst into a compound of formula I (Y)„ - Ar' - 0 - H, CH, - Ar - (Z)p (I) wherein the substituents Z, Ar, Ar', Y, n, p and X have the above-given definitions

This invention further includes another process for producing a compound of formula I wherein a substituted benzaldehyde of formula X_A . CHO (Z)p (X_A) wherein Z and p have the above-given definitions and X is a blocked phenolic function is reacted with a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Wittig's reaction to produce an ethylenic derivative of formula XI.

A

AP 0 0 0 1 8 8

wherein Z, Y, n and p have the above-given definitions and X is a blocked phenolic group which is further hydrogenated into a compound of formula I by means „ *

- 16 of hydrogen in the presence of a metallic catalyst.

This invention also includes a process for producing a compound formula I which comprises the steps of blocking the reactive functions of a hydroxy aryl alkanol of formula XIII

R

I (Z)p - Ar - CH - CHOH - R. (XIII)

X wherein Z, Ar, R, R^ have the above-given definitions and X is a free hydroxyl by means of an easily-split reagent, then reacting the thus-blocked derivative with a phenolic derivative of formula XIV ___OH

Ar' —(XIV)

wherein Y, n and Ar' have the above-given definitions _t to produce an aryloxy ethyl arylidenic derivative of formula XV (Z)p - Ar - CH - CH - 0 - Ar' - (Y) (XV) \χ wherein Z, Y, Ar, Ar', n and p have the above-given definitions R and R| the same or different each other are a hydrogen or a lower alkyl radical and X is a blocked phenolic group and to make free the hydroxy function by means of an alkaline agent to produce a compound of formula I

This process more precisely applies for producing a compound of formula I_A which comprises the steps of blocking the reacting functions of a (hydroxyphenyl) ethanol of formula XII_A

- 17 R R.

wherein Z and p are defined as above

X is a hydroxy

R and R^ are a hydrogen or a lower alkyl by means of a ragent, which is easily split, contacting the thus-blocked derivative with a phenol of formula ΧΠΙ_Α

wherein Y and n have the above-given definitions to produce a phenylethoxy phenyl of formula XIV_A

AP 0 0 0 1 8 8 wherein Z, Y, n and p have the above-given definitions

R and R^ are hydrogen or a lower alkyl and X is a blocked phenolic group and making free the hydroxyl function by means of an alkaline agent to product a compound of formula I_A

Thi invention has as a further subject matter the intermediates of formula IX.

A

,. r

- 18 R

X wherein Υ, Ζ, X, R, n and p have the above-given definitions and the compounds of formula XI 1^

CH = CH - O

wherein Ζ, Υ, X, n and p are defined a previously

It is a further subject matter of this invention, the pharmaceutical compositions containing as active ingredient at least one conpound of formula I in admixture or conjunction with an inert non-toxic pharmaceutically-acceptable carrier or vehicle.

The compounds of formula I acccording to this invention show very interesting phamacological properties and namely diuretic, antihypertensive, platelets, anti-aggregating properties and anti-lipoxygenase properties. These vascular properties are very peculiar due to the fact that their site of action is not exclusively renal. The compounds according to this invention inhibit the contractions induced by Noradrenaline and by the potassium salts.

»

- 19 The results of this testing imply the existence of an extra-renal site of action likely vascular, in the mechanism of hypertensive action of the compounds of formula I. The pharmacological testing and the obtained results allow to think that the way of action of the compound of formula I goes through the intra-cellular movement of Calcium into the muscular wall of the vessels.

As a result of the pharmacological properties the compounds according to this invention find a use in human and veterinary therapy as a platelet anti-aggregating mdecine or as an anti-hypertensive medecine. To these ends they are used in the form of pharmaceutical compositions which contain as active ingredient at least one compound of formula I in admixture or conjunction with an inert, non-toxic pharmaceuticallyacceptable vehicle or carrier.

For the therapeutic use, they are manufactured in those forms convenient for administration through parenteral, oral, rectal, permucous or percutaneous ways. It may be cited in this respect the injectible solutes or suspensions packed in ampuls, in multi-dosis flasks, or in the form of auto-injectible syringes, in the form of coated or uncoated tablets, dragees, solft gelatine capsules, powders, rectal suppositories, solutions in a polar solvent, or the transdermal preparations.

The carriers which are appropriate for such manners of administration are cellulose derivatives, micro-crystalline cellulose, earth-alkaline carbonates, magnesium phosphate, starches, chemically-modified starches or lactose.

For parenteral use, water, aqueous solutions, saline, glucose solutions and the like are the most conveniently used ones. For rectal way of administration, cacao butter or polyethylene glycol stearates are the preferred carriers.

AP 0 0 0 1 Θ 8

- 20 The dosology may vary within broad limits which are a function of the severity of the hypertensive disease, of the weight and the age of the patient and of the way of administration.

A a general rule, the unit dosage may range from 1 to 200 mg per intake and the daily dosage may range from 2 to 500 mg per day in the man.

The manner of administration may also be modulated as a function^ of the duration of the action of the compounds of formula I.

The following examples are merely intended to illustrate the invention without limiting it in any manner.

EXAMPLE I

1—(2—HYDROXY 5—METHOXY PHENYL) 2-FHENQXY ETHANE (Process A)

Step A : l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethanone

To a solution of 32.2 g (0,27 mol) of boron trichloride in 200 ml chloroethane cooled to 0°, they are successively added a solution of 28,4 g (0,23 mol) 4-methoxy phenol in 100 ml dichloroethane, 36,6 g (0,24 mol) phenoxy acetonitrile then 15,2 g (0,11 mol) aluminium chloride while stirring. The mixture is kept under stirring for 20 hours at room temperature. After hydrolysis in acidic conditions for 30 mn, and extraction, it is obtained after crystallisation from methanol, 26 g (ie a yield of 44%) phenoxy acetophenone. The pure compound melts at 128°C.

Step B : l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane To 6,4 g (0,058 mol) of ethyl chloroformate at 0°C one adds a solution of 12.8 g l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethanone obtained at step A in 100 ml tetrahydrofuran in the presence of 6 g (0,058 mol) triethylamine. After one hour contact under stirring at room temperature, the thus formed „ *

- 21 triethylamine hydrochloride which has precipitated is filtered and the filtrate is dropwise added to a solution of

5.6 g (0,15 mol) sodium borohydride in 50 ml water at 5°C for 45 mn. After stirring at room temperature for 1,5 hour the reaction mixture is poured on ice, one proceeds to an acidic hydrolysis with hydrochloric acid then extracts with ether. The ethereous phases are separated, the solvent is evaporated off and 8.4 g of product recovered after purification by distillation under reduced pressure. The yield amounts to 69%. The melting point of the pure compound is 170^eC.

Its piperazine disalt melts at 95^eC

EXAMPLE II

1—(2-METBOKY PHENYL) 2-PHENOKY ETHANE g l-(2-hydroxy phenyl) 2-phenoxy ethane (ie 0,032 mol) and 16 g potassium carbonate (0,117 mol) in 100 ml acetonitrile are added with

4.9 g (0,039 mol) methyl sulphate. The whole mixture is heated to reflux for 5 hours. Thereafter the solvent is evaporated off and the residue extracted, 5,6 g (ie a yield of 80%) of the methoxy derivative are recovered as an only product.

EXAMPLE III l-(2-ACETOXY 5-METHOXY PHENYL) 2-PHENOXY ETHANE

To 4 g (0,016 mol) l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane they are added 1.5 g (0,019 mol) acetyl chloride and 2 g (0,019 mol) triethylamine for acetylation. After stirring of the mixture for 1 hour at room temperature, the mixture is extracted with a solvent to provide 4 g (ie a yield of 85%) of the 2-acetoxylated derivative.

EXAMPLE IV

1—(2-SULFITO CKY PHENYL) 2-( 4-FLUOROPHENOXY) ETHANE AS THE POTASSIUM SALT

AP 0 0 0 1 8 8 „ *

- 22 In a three-neck flask, under Argon atmospher, 6.53 g (0,47 mol) potassium carbonate and 10 g (0,43 mol) l-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanol are introduced with 100 ml acetonitrile. The mixture is stirred for 30 mn at 40°C then 8.97 g (0,645 mol) of the complex (SO^-triethylamine) are added. After stirring the mixture is cooled and the formed sulphate precipitates. After filtration 6.5 g of a white solid are recovered.

Melting point : 163°C

Yield : 42 % _Λ

EXAMPLE V l-(2-PHOSPHCNYLQXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANE

Step A : 2-(4-fluorophenoxy ethyl) phenyl phosphochloridate g (0,043 mol) of l-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethane are dissolved into 36 g POCl^ (0,235mol) and the mixture is heated to the reflux for 2,5 hours in the presence of 0.1 g Aluminium chloride. The mixture is concentrated then distilled. The formed phosphate distillates (Eb θ ₂^ 210 220’C) - 9,71 g of an oily residue are thus recovered (yield - 64 %).

Step B : Hydrolysis of the phosphochloridate g (0,11 mol) of the phosphochloridate are hydrolysed in 10 ml water under stirring at 80°C. The reaction mixture is kept under stirring for three further hours. It is concentrated therafter under reduced pressure until dryness. By scratching in petroleum ether, a white solid weighing 3.1 g is recovered.

Yield : 86 %

MP : 80-82°

EXAMPLE VI

1-(2-HYDROXY PHENYL) 2-( 4-FLUOROPHENOKY) ETHANOL (Process B)

- 23 Step A : 1-(2-benzyloxy phenyl) 2-bromo ethanone

250 g (1,1 mol) of 2-benzyloxy acetophenone are dissolved in 1000 ml of dry tetrahydrofuran, the solution is cooled to O’C and then added portionwise to 500 g (1,32 mol) of phenyl trimethyl anilinium tribromide for 4 hours. The so-formed precipitate is filtered. The mixture is distilled off to dryness and the residue is used as such for the next step of the synthesis.

Weight : about 34 g Yield : 70 %

Step B : 1-(2-benzyloxy phenyl) 2-phenoxy ethanone

125 g of the α-bromoketone obtained in the preceding step are added to 57 g phenol (0,61 mol). 283 g (2 mol) of potassium carbonate in acetonitrile and the whole mixture is heated to reflux for 2 hours. After filtration of the mineral salts and evaporation off of the solvent the residue is taken up dichoroethane, washed with a N solution of sodium hydroxide then with water until the washings are neutral. The solvant is further dried and evaporated until dry to produce 104 g of the phenoxy benzylated derivative.

MP : 141°C Yield : 80 %

Step C : l-(2-hydroxy phenyl) 2-phenoxy ethane g (0,164 mol) of phenoxy benzylated derivative of step B are let to be hydrogenated under an atmospher of hydrogen in ethanol (1000 ml), preferably in the presence of 3 g of palladized charcoal at 10%. After absorption of the required amount of hydrogen, the catalyst is separated by filtration, Ethanol is evaporated off and the dry residue is crystallized to provide 34,7 g of phenolic derivative melting at 120°C.

The yield amounts to 92%

8 V 0 0 0 dV

.. *

- 24 Step D : 1-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanol

To a solution of 5 g (0,02 mol) of 1-(2-hydroxy phenyl) 2-(4-fluorophenoxy) ethanone in methanol cooled to 0°, they are added dropwise 0.760 g (0.02 mol) of sodium borohydride. After return to room temperature, at the end of one hour,the reaction mixture is concentrated and poured on ice then is acidified at pH 4. The whole mixture is extracted with ether to recover 4.5 g of the hydroxy ethylated derivative as an oily residue.

The yield amounts to 90%

EXAMPLE VII

2-(2-HYDROXY PHENYL) 3-PHENOXY PROPANE

A solution of 53,5 g of triphenyl methyl phosphonium in 500 ml tetrahydrofuran under atmospher of argon, is added to 112,5 ml of a

1,6 M solution of butyl lithium in hexane at room temperature. After 4 hours of steering, l-(benzyloxy phenyl) 2-phenoxy ethanone dissolved in tetrahydrofuran is added dropwise and the mixture is heated over a night at reflux temperature.

After concentration of the solvent, the mixture is poured into water and is extracted with ether. The residue recovered after evaporating off the solvent, is submitted to a flash-chromatography on silica, with a mixture of eluents (Petroleum ether/isopropyl ether 90:10) to recover 37 g of propenylated derivative which melts at 57°C.

g of propenylated derivative is hydrogenated under hydrogen atmospher in the presence of palladized charcoal at 10% Palladium, in 400 ml ethanole under vigorous stirring at atmospheric pressure and at 50°C, for 20 hours.

After having separated the catalyst by filtration and evaporation of the filtrate, 16 g of 2-(2-hydroxy phenyl) 3-phenoxy propane are recovered (yield : 75%)

EXAMPLE VIII

1-(3—METHOXY 4-HYDROXY PHENYL) 2-(4-FLUOROPHENOXY) ETHANE _ »

- 25 Preparation of (chloromethyl) 4-fluorophenoxy ether :

g (0,47 mol), of 4-fluoroanisole are heated with 97 g (0,47 mol) phosphorous pentachloride at 120^eC for 2 hours then the temperature is increased to 140® then to 160° as PCl^ distillates. One maintains still 2 further hours at this temperature after the distillation of PCl^ is achieved, then one distillates under reduced pressure (15 mm Hg) at a temperature of 100® to obtain 47 g of the chlorinated ether. The yield amounts to 75%.

Preparation of triphenyl 4-fluoroxy methyl) phosphonium chloride :

In 300 ml benzene, 42 g of chloromethylated ether (0,26 mol) and 81 g of triphenyl phosphine are introduced and the whole mixture is heated to reflux for a night. Afer evaporation of benzene, the salt of phosphonium is allowed to crystallyse from ether. 62 g of salt of phosphonium are recovered, melting at 248®C. The yield amounts to 57%.

Step A : 1-(3-methoxy 4-benzyloxy phenyl) 2-4-fluorophenoxy) ethene

12.2 g (0,029 mol) (4-fluorophenoxy methyl) triphenyl phosphonium chloride are dissolved in 100 ml tetrahydrofuran and the solution is cooled to 78®C under atmospher of argon. To this, 16 ml of a 1,6 H (i.e 0,026 mol) solution of butyl lithium in hexane are added dropwise. After 1 hour standing at this temperature, 5 g (0,02 mol) of 3-methoxy 4-benzyloxy benzaldehyde are added then the mixture is allowed to revert to room temperature in two hours. The mixture is then poured on ice, made acidic at pH 4 and extracted with ether. After evaporation of the solvent, the residue is filtered on silica and 6,2 g (86%) of the phenoxy ethene are recovered.

Step B : 1-( 3-methoxy 4-hydroxyphenyl) 2-( 4-fluorophenoxy) ethane

8.2 g (0,0225 mol) of phenoxy ethenic derivative of step A is put in a vessel for hydrogenation under atmospher of hydrogen, in ethanol, in the presence of 2 g of palladized charcoal at 10%. The mixture is kept under vigourous stirring

AP 0 0 0 1 8 8

- 26 for 12 hours. After filtration of the catalyst and having evaporated off the solvent, the residue is chromatographied on silica and after elution by a mixture of petroleum ether/ethyl acetate (90:10) to provide after evaporation of the solvent, 3.5 g of the saturated derivative in the form of an oily product

Yield :60 %

EXAMPLE IX (Method B)

1-(3-HYDRCKY PHENYL) 2-(4-FLUDROPHENQXY ETHANE)

Step A : l-(2-methyl sulphonyloxy ethyl) 3-(methylsulphonyloxy) benzene g (0,21 mol) of (3-hydroxy phenyl) ethanol in anhydrous pyridine are added dropwise to 41 ml (0,525 mol) methyl sulphonyl chloride at O^eC, under stirring

After return to room temperature and standing at this temperature for 1,5 hour, the mixture is poured on ice. It is acidified then extracted with methylene chloride. The extract is washed with water until neutral, dried on sodium sulphate and evaporated to dryness. 53 g of di-methyl sulphonate are obtained. Yield : 86%

Step B : 1-( 3-methyl sulphonyloxy phenyl) 2-(4-fluorophenoxy) ethane A mixture made of 53 g (0,18 mol) of the dimethyl sulphonate of step A, 24,4 g (0,217 mol) of 4-fluorophenol and 28,8 g (0,217 mol) potassium carbonate are introduced into 350 ml acetone and heated to reflux under stirring for 9 hours. The mineral salts are thereafter filtered and the filtrate is evaporated off. The residue is taken up in water and extracted with ether. The organic phases are separated, washed with sodium hydroxide then with water until neutral and dried on sodium sulphate. The ethereous solution is evaporated off to obtain 46 g of dry residue (i.e a yield of 83%) of (3-methyl sulphonyl phenyl) 2-(4-fluorophenoxy) ethane, pure enough for the progress of the synthesis.

- 27 Step C : 1-(3-hydroxy phenyl) 2-(4-fluorophenoxy) ethane g (0,148 mol) of the methyl sulphonate of step B are allowed to be saponified by reflux in 2000 ml of a 2N solution of sodium hydroxide for 16 hours. After cooling, one acidifies with 5N ClH, extracts with ether and dries on sodium sulphate. The solvent is evaporated off and 25 g of crude product substantially containing a 3-hydroxy styrenic derivative are recovered. Using the Flash Chromatography and the elution with a mixture of petroleum ether/isopropyl ether (80:20) 11,68 g of pure (3-hydroxy phenyl) 2-(4-fluorophenyl) ethane are obtained as a crystaline form

MP : 64°

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EXAMPLE X

TABLETS WITH 100 MG OF l-(2-HYDRGXY PHENYL) 2-( 4-FLUOROPHENOXY) ETHANE

- active ingredient ................ 100 g

- wheat starch ..................... 45 g

- Ma'is starch ...................... 55 g

- microcristalline cellulose powder. 12 g

- ethyl cellulose .................. 8 g

- magnesium stearate ............... 5 g for 1000 tablets finished at an average weight of 0.225 g

Pharmacological study of the compounds according to this invention :

A - DIURETIC ACTION

1. in the mice The compounds of formula I have been given to batches of 12 male mice weighing between 25 and 30 g each. The mice, divided by pairs, are prior syhmitt-pd to a load of liquid, constituted by the administration of the compound to be tested under a volume of 25 ml per kg, followed by administration of saline a 9 %₀, the total volume to be given, being of 1 ml per mouse.

The diuresis is studied for 4 hours. The urinary volume is measured every hour. Potassium and sodium are dosed by spectrophotometry on the pooled urines.

2. in the rat

An overload of liquid is obtained in the rats of male sex weighing between 200 and 250 g and fastened for 18 hours before the testing.

The animals are located each in an individual cage for diuresis and receive by oral way an overload of 20 mlAg of saline at 0,9% containing the compound of formula I to be tested. The diuresis is measured for 5 hours. The volumes of urine are determined every hour. Dosages of sodium and potassium are performed by spectrophotometry.

Table I collects the main results obtained during this testing.

- 41 TABLE

PRODUCT of exaiqple
Diuretic power en % R - RAT	Ratio Na/K en % R - RAT
S - MICE Minimal doses in i	(X) active xj/kg PO	S - MICE Minimal a< doses in mg,	(x, rtive dtg PO
ex	25	R (12)	190 %	R (12)	46	%
S (25)	10 %	S (25)	50	%
ex	26	R (50)	250 *	R (50)	40	%
S (100)	30 %	S (100)	210	%
ex	30	R (12)	170 %	R (12)	40	%
S (25)	40 %	S (25)	210	%
ex	36	R (100)	140 %	R (100)	65	%
S (100)	40 %	S (100)	180	%
ex	42	R (12)	190 *	R (12)	60	%
S (100)	Inactive	Inactive
ex	169	R (12)	70 %	R (12)	85	%
S (100)	Inactive	S (100)	Inactive
ex	46	R : Inactive	R : Inactive
S : Inactive	S : Inactive
ex	46	R (25)	80 %	R (25)	80	%
S (100)	20 %	S (100)	130	%
ex	172	R (25)	80 %	R (25)	160	%
S (100)	68 %	S (100)	208	%
ex	56	R : Inactive	R : Inactive
S : Inactive	S : Inactive
ex	107	R (25)	140 %	R (25,	60	%
S (100)	80 *	S (100)	220	%
ex	134	R (6)	100 %	R (6)	50	%
S (25)	40 %	S (25)	140	%
ex	139	R (25)	32 %	R (25)	80	%
S (25)	40 %	S (25)	80	%
ex	163	R (6)	260 *	R (6)	53	%
S (25)	34 %	S (25)	134	%
FUROSEMIDE	R (12) S (25)	30 % 120 %	R (12) S (25)	10 320	% %

8 V 0 0 0 dV

BAD ORIGINAL $

- 42 Β - ΑΝΠ-HYPERTENSIVE ACTION IN THE UNANESTHETIZED RAT

This study has been carried out in batches of males rats SHR (strain OKAMOTO) 16 weeks old. The arterial systolic pressure has be measured by the sphygomanometric process using an electrospohygmograph NARCO (biosystems) type PE 300. The determinations of the blood pressure have been performed 24 hours after the administration of a compound of formula I to be tested. The arterial systolic pressure is calculated from the average of 6 to 8 measurements.

The obtained results are gathered in Table II

It thus appears that the kinetic of the anti-hypertensive action is dissociated from that of the diuretic effect.

♦

- 43 TABLE II

PRODUCT	ANTI-HYPERTENSIVE ACTIVITY STUDIED in the RAT
A - Acute C - chronic (x) » dosis studied in MG/kg ΡΌ	Variation of the anti-hypertensive effect 24 heures after administration of the product
ex 25	not tested	not tested
ex 26	not tested	not tested
ex 30	A - (7,5) A » (30) C - (15)	- 11 mmHg - 30 mmHg - 16 mmHg
ex 36	A - (100) C - (100)	not active - 20 mnHg
ex 42	not tested	not tested
ex 169	not tested	not tested
ex 46	not tested	not tested
ex 48	A (60)	- 24 mmHg
ex 172	A - (60)	- 16 mmHg
ex 56	not tested	not tested
ex 107	not tested	not tested
ex 134	A - (15) A - (60) C - (30)	- 11 nmHg - 37 mmHg - 26 mmHg
ex 139	A (60)	- 12 mmHg
ex 163	A - (10) A - (60)	- 19 mmHg - 33,5 mmHg
FUROSEMIDE	FUROSEMIDE (60) HYDROCHLOROTHIAZIDE (60)	FUROSEMIDE not active HYDROCHLOROTHIAZIDE not active

AP 0 0 0 1 8 8

BAD ORIGINAL $

C - BLOOD PLATELETS ΑΝΠ-AGGREGATING EFFECT

These studies have been carried out on plasmas reach in platelets, coming from rat blood. The aggregation is induced by adding Adenosine diphosphoric acid (ADP). The nephelometric curves showing the aggregation are obtained using an aggregometer type BORN, plasma being incubated at 37° under continuous stirring at 100 RPM (cf. Bom G.V.fc, and CROSS J, J.Physiol. 168 (1962) 178).

*

Table III collects the obtained results with the many tested compounds of formula I bad ORIGINAL

Ill

- * _ 45 TABLE

PLATELETS ΑΝΠ^AGGREGATING ACTIVITY IN VITRO (Aggrating agent is ADP)

PRODUCT	V at 50	M at 50
TICLOPIDINE	0,75 mM	0,85 mM
Ex 56	0,45	0,30
Ex 30	0,5^-1	0,8
Ex 174	0,55	0,40
Ex 90	0,60	0,50
Ex 82	0,65	0,55
Ex 52	0,70	0,75
Ex 64	0,70	0,50
Ex 78	0,70	0,70
Ex 58	0,75	0,60
Ex 129	0,8	0,6
Ex 84	0,8	0,75
Ex 102	1,0	0,7
Ex 42	1,0	1,2
Ex 172	1,0	0,95
Ex 86	1,25	1,55
Ex 134	1,5	1,3
Ex 81	1,6	1
Ex 12	1,95	1,60
Ex 100		1,1
Ex 169	> 2	inactive
Ex 54	> 2	inactive
Ex 36	> 2	inactive

AP 0 0 0 1 8 8 f

These results are confirmed by the results obtained ex vivo in the rats receiving for 3 days a conpound of formula I by oral way.

It is stated an inhibiting efect on the platlets aggregation which is evidenced by a dobblening of the dosis of ADP needed in respect of the dosis given to the controls for obtaining an aggregation of 50%.

Ticlopidine tested as reference substance at the same dosis, give about the same results. ^;

D - ACTION CN THE SYSTEMS OF TRANSPCREATICN OF SODIUM AH) POTASSIUM IONS IN THE HUMAN ERYTHROCYTS

This action has been studied according to the method described by

G. GARAY and cowork in Naunyn-Schmideberg's Arch. Pharmakol. 334 (1986) 202 and in Bioch. Pharm. 33 (1984) 2013.

The following results have been obtained and are collected in Table IV. They appear to be better than those obtained with Furosemide and

XIPAMIDE.

_ 47 _

TABLE

IV

PHARMACOLOGICAL ACTION ON THE TRANSPORT SYSTEMS of Na+ and K⁺ of the human erythrocyts

PRODUCTS	EFFECT ON THE TRANSPORT Na-K IC 50 fOl	EFFECT CN THE ANION EKCHANSH IC 50 fM
ex 25	> 600	120
ex 26	70	40
ex 30	170	4
ex 36	> 600	0,8
ex 42	40	12
ex 169	not active	not active
ex 46	95	200
ex 41	= 400	200
ex 172	= 400	75
ex 56	95	200
ex 107	not tested	not tested
ex 134	not active	not active
ex 139	not tested	not tested
ex 163	not tested	not tested
BUMETANIDE	0,66	300
FUROSEMIDE	37	200
XIPAMIDE	-	25

AP 0 0 0 1 8 8

-48 E - STUDY CN THE IMPACT OF ΊΉΕ COMPOUNDS OF FORMULA I ON THE POTASSIUM CHAM4ELS IN THE AORTA USING A MEASURE OF THE EFFLUX OF RUBIDIUM

The action of the compounds of formula I on the potassium Channels has been determined using Rubidium (Rb⁺) which is the homolog of potassium. The entry of Rb⁺ in pieces of aorta has been studied in initial speed after 5 mn and at 37°C. The content in Rb⁺ and K⁺ have measured using an apparatus of atomic absorption or by a high-performance flamrae photometer.

As an example, the compounds of example 1 and 4 have been studied using a dose-effect curve.

RESULTS

Figures 1 and 2 collect the obtained results.

The compound of example 1 has a very clear positive effect on the opening of the potassium channels. Its activity is far*higher than that of PINACIDIL but slightly weaker than that of CHROMAKALIM.

Compound of ex 1 is less active on the opening of potassium channels. On the other part, in contrast of Cromakalim and Pinacidil, the opening effect on the potassium channels of the compound of ex.l is not antagonized by GLIBENCLAMIDE. The same compound in contrast with those agents acting on the opening of the potassium channels -is glibenclamido-resistent- Its mechanism of action is not bound to the ATP-dependent potassium channel.

F - MEASUREMENT OF THE VASOCCNSTRICTICN INDUCED BY POTASSIUM CHLORIDE

a) Method

A vasoconstriction is caused in male rats of Wistar strain, weighing 200to 350 g by increasing doses of potassium chloride ranging from 20 to 60 mM.

_ 49 _

The rats are thereafter beheaded at the thoracic aorta and the diameter of the vessels is measured.

Curves 1 and 2 gather the obtained results compound of example 1 as the piperazine disalt shows an antagonist efect merely on the contraction induced by the weakest dosis of potassium chloride (C1K at 20 mM).

/

The mean inhibitory dosis (IC^q) has been calculated at 22 μΜ. The contraction induced by the highest dosis of potassium chloride (60 mM) is antagonized only by a strong dosis of the compound of example (IC_5Q - 1,12 mM)

It thus appears that it exists a dissociation of the vaso-relaxing effect of the compound of example 1 after , vaso-constriction by potassium chloride depending on the utilized concentration as it has been previously shown only with the potassium agonists. In contrast thereof the calcium inhibitors induce a decontracting effect at both concentrations of the vaso-constricting agent to be administered.

G - ANTI-LIPCKYGENASE EFFECT

The anti-lipoxygenase effect has been studied using soja lipoxygenase in accordance to the method discribed by W.L SMITH and W.E LANDS (J. Biol. Chem. 247 (1972) 1038).

AP 0 0 0 1 8 8

The following results vhich have been obtained are gathered in Table V

TABLE V

PRODUCT	ΑΝΠ-LIPOTYGENASE ACTIVITY
IC 50 pM
ex 25	6
ex 26	6
ex 30	= 100
ex. 36	Inactive
ex 42	not tested
ex 169	In&eti1£>
ex 46	0,7
ex 48	30
ex 172	not tested
ex 56	25
ex 107	7
ex 134	> 166
ex 139	not tested
ex 163	not tested
NDGA	0,5

Claims

WHAT IS CLAIMED IS

1·- Novel derivatives of phenoxyethyl benzene having the formula I

R R,

I f

Ar - CE - CH - 0 - Ar' (I) vherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of

- phenyl derivatives having the formula vherein X is a hydroxy free, esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lover alkyl or alkenyl radical

Z is a substituent selected from the group consisting of hydrogen, halogens, hydroxy a lover alkoxy» an acyloxy, a phenyl lover alkyl, a lover alkyl, a lover alkyl substituted by a [(lover alkyl) oxycarbonyl, a (lover alkyl) substituted by a hydroxy carbonyl, a moiety CO(CH₂)_B CH₃ vherein m is an integer of from 1 to 4, a moiety CB0H-(CB₂)_b,-CH₃ vherein a' is an integer of from 1 to 4, a carboxamido group optionally substituted by one or tvo lover alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula

AP 0 0 0 1 8 8 vherein A is a free hydroxy or an esterified or etherified hydroxy

- 40 Z is defined as above-given and p is an ineger of from 1 to 3 and those of formula (2),

A vherein A, Z and p are defined as above-given

Ar' is an aromatic mono- or bicyclic radical selected from the group consisting of

- the benzenic derivatives of formula

V’· vherein 7 is a hydrogen, a halogen, a (lover alkylene)dioxy, a hydroxy, a lover alkoxy, an acyloxy derivated from in organic carboxylic acid, a lover alkyl, a lover alkyl substituted by a (lover alkyl) carbonyle, an oxo alkyl chain of the formula C0(CH₃)_a CHj vherein a is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CHOH-(CH₃)_a,-CH₃ vherein m' is an integer of from 1 to 4.

- the naphtalenic derivatives selected from the group consisting of naphtyl derivatives of formula vherein 7 is defined as above-given

-Aland n is an integer of from 1 to 4

- and the naphtalenic derivatives of formula vherein 7 and n are defined as above-given

R is a hydrogen, a hydroxy, the oxygene of a keto group of a lover alkyl radical is a hydrogen or a lover alkyl radical
2*- The optically active forms the compounds of claim 1° having the formula I

Ar - CH - CH - 0 - Ar' (I) vherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of

- phenyl derivatives having the formula

AP 0 0 0 1 8 8 vherein X is a hydroxy free, esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid, or etherified by a lover alkyl or alkenyl radical

Z is a substituent selected from the group consisting of hydrogen, halogens, hydroxy a lover alkoxy, an acyloxy, a phenyl lover alkyl, a lover alkyl, a lover alkyl substituted by a [(lover alkyl) oxycarbonylL, a (lover alkyl) substituted by a hydroxy carbonyl, a moiety CO(CH₂)_B CH, vherein m is an integer of from 1

- 42 .to 4, a moiety CH0H-(CH₂)_B,-CH₃ vherein m' is an integer of from 1 to 4, a carboxamido group optionally substituted by one or two lever alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula vherein A is a free hydroxy or an esterified or etherified hydroxy

Z is defined as above-given and p is an Integer of from 1 to 3 and those of formula vherein A, Z and p are defined as above-given

Ar' is an aromatic mono- or bicydic radical selected from the group cconsisting of

- the benzenic derivatives of formula vherein Y is a hydrogen, a halogen, a (lover alkylene)dioxy, a hydroxy, a lover alkoxy, an acyloxy derivated from in organic carboxylic acid, a lover alkyl, a lover alkyl substituted by a (lover alkyl) carbonyle, an oxo alkyl chain of the formula C0(CH₂)_b CH₃ vherein n is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CH0H-(CH₂)_B,-CH₃ vherein m' is an

- 43 integer of from 1 to 4.

- the naphtalenic derivatives selected, from the group consisting of naphtyl derivatives of formula vherein Y is defined as above-given and n is an integer of from 1 to 4

- and the naphtalenic derivatives of formula vherein Y and n are defined as above-given

R is a hydrogen, a hydroxy, the oxygene of a keto group or a lover alkyl radical

R_t is a hydrogen or a lover alkyl radical vith the restriction that E or R_x are different than hydrogen and represent either a hydroxy or a lover alkyl radical.
3*- The base addition salt of a compound of formula I according to claim 1° vith an alkali metal, an earth-alkali metal or an organic base, vhen X is a hydroxy esterified by a polyhydroxylic acid selected from the group consisting of sulphuric acid and phosphoric acid
4·- The compounds of formula I according to any of claims 1 to 3’ having the general formula I_A

AP 0 0 0 1 8 8 vhereir. X is hydrcxy, a hydroxy etherified by a lover alkyl of a lover alkenyl or esterified by an organic carboxylic or sulphonic acid, by phosphoric acid or by phosphoric acid and R, R_x, Υ, Ζ, n and p have the above-given definitions
5*- A compound according to any of claims 1 to 4’ being l-(2-hydroxy
6-methoxy phenyl) 2-phenoxy ethane.

6*- A compound according to any of claims 1 to 5° selected from the group consisting of the metallic and the organic base adition salts of l-(2-hydroxy 5-methoxy phenyl) 2-phenoxy ethane.
7*- A compound according to any of claims 1 to 4* being l-(2-hydroxy 5-carboxamido phenyl) (4-fluorophenoxy) ethane.
8*- The compounds of formula I according to any of claims 1 to 3' having the general formula I, vherein the definitions of the substituents X, Y, Z, R, R_x, n and p are the same as in claim 1°
9°- The compounds according to any of claims 1 to 3° having the generale formula I_c vherein the definitions of the substituents Z, Y, X, R, R_x, n and p the same as in claim 1°
10*- The compounds according to any of the claims 1 to 3* having the formula I_s according to any of claims 1 to
11*- The compounds formula I_f <I_D) in claim 1°

3* having the

AP 0 0 0 1 8 8

R (I,) vherein R, R_x, X, Y, Z, n and p have definitions given in claim 1°
12·- A process for producing a compound of general formula I according to any of claims 1 to 11*

CH.

/ (Z)--Ar ^P \

CH,

- 46 0.

(I) vherein Ar is an aromatic mono- or bicyclic hydroxylated radical selected from the group consisting of

- phenyl derivatives having the formula vherein X is a hydroxy free,- esterified by a carboxylic or sulphonic organic acid, by phosphoric acid, or by sulphuric acid,

I I y.

or etherified by a lover alkyl or alkenyl radical

Z is a substituent selected from the group consisting of hydrogen, halogens, hydroxy a lover alkoxy, an acyloxy, a phenyl lover alkyl, a lover alkyl, a lover alkyl substituted by a [(lover alkyl) oxycarbonyl L, a (lover alkyl) substituted by a hydroxy carbonyl, a moiety CH(CH₂)_B CH, vherein m in an integer of from 1 to 4, a moiety CHOH-(CH,)'-CH, vherein m' is an integer of from 1 to 4, a carboxamido group optionally substituted by one or tvo lover alkyl radicals, a phenyl and a phenoxy and the naphtalenic derivatives selected from the group consisting of the naphtyl derivatives of the formula vherein A is a free hydroxy or an esterified or etherified hydroxy

Z is defined as above-given and p is an integer of from 1 to 3 »

- 47 and those of formula vherein A, Z and p are defined as above-given

Ar' is an aromtic mono- or bicyclic radical selected from the group consisting of

- the benzenic derivatives of formula vherein 7 is a hydrogen, a halogen, a (lover alkylene)dioxy, a hydroxy, a lover alkoxy, an acyloxy derivated from in organic carboxylic acid, a lover alkyl, a lover alkyl substituted by a (lover alkyl) carbonyle, an oxo alkyl chain of the formula CO(CH₂)_B CHj vherein m is an integer of from 1 to 4, or an hydroxy alkyl chain of the formula CHOH-(CH₂)_b,-CH₃ vherein m' is an integer of from 1 to 4.

- the naphtalenic derivatives selected from the group consisting of naphtyl derivatives of formula

AP 0 0 0 1 8 8 vherein 7 is defined as above-given and n is an integer of from 1 to 4 „ V

- 48 - and the naphtalenic derivatives of formula vherein Y and n are defined as above-given

R is a hydrogen, a hydroxy, the oxygene of a keto group or a love; alkyl radical

R_x is a hydrogen or a lover alkyl radical vhich comprises the steps consisting of

- condensing a phenolic derivative of the formula II

Ar - X (II) '^-(Z)_p vherein Ar, X, Z are defined as given in claim 1° vith an aryl aceto nitrile of the formula III

OCB₂ CN

Ar' (III) (T)„ vherein Ar', Y and n have the definitions given in claim 1° in the presence of an acidic catalyst to produce a diarylethanone of the formula IV (IV) »* vherein Ζ, Y, Ar, Ar', n and p the definitions given in claim 1* and X is a free hydroxyl group reducing the latter by means of an alkali metal mixed hycride in the presence of a aetalic catalyst or by reaction vith a lover alkyl chloroformate and reduction of the intermediate so-produced compound by means of an alkali metal borohydride to obtain a compound of formula I according to claim 1*
13*- A process for producing a compound of formula I according to any of claims 1 to 11° vhich comprises the steps of condensing a phenol of formula II_A <Π_Α) vherein Ζ, X and p have the definitions given in claim 1° vith a phenoxy acetonitrile of the formula III_A (Hix)

CO

GO o

o o

a.

vherein Y and n have the definitions given in claim 1* in the presence of an acidic catalyst, to produce the ethanone of generale formula IV_A vherein Z, T, n and p have the definitions given in claim 1° and Z is a free hyroxyl

- reducing the latter into a compound of general formula I_A by means of an alkali metal mixed hydride in the presence of a metallic catalyst or by reaction vith a lover alkyl chloroformate then reduction of the thus-formed intermediate compound vith an alkali metal borohydride vhich may be alkylated by means of an alkylating reagent in basic medium or acylated by means of functional derivative of a carboxylic, sulphonic, sulphuric or phosphoric acid.
14*- A process for producing a compound of formula I according to any of claims 1 to 11* vhich comprises the steps of

- bloking the phenolic function of a hydroxy acetophenone of formula V

CO CH, vherein Ar, Z and p are defined as given in claim 1* and Z i a free hydroxyl uing an easily-split reagent submitting the so-blocked phenol of formula VI

OB (Z)_p - Ar (VI)

CO CH,

- 51 vherein B is a leaving group

Z and p have the definitions given in claim 1°

- submitting the latter of the action of a brominating agent to produce an e-bromoketone of formula VII (Z)_F (VII) vherein Z, Ar, B and p have the meaning given in claim 1*

- condensing this derivative vith a phenolic derivative of formula

OH

Ar' (T).

vherein Ar', Y and n are defined as indicated in claim 1° to produce a phenoxy ethanone of formula VIII

COCHj 0 Ar' - (Y)„ (Z)_F - Ar (VIII) vherein the definitions of the substituents Y, Z, Ar, n and p remain the same that in claim 1° and X is a hydroxy group blocked by an easily-split radical

- submitting the compound of formula VIII to hydrogenolysis in the presence of a metallic-catalyst or to an acidolysis, to make free the hydroxy group and produce a phenoxy ethanone of formula IX

8 8 L 0 0 0 dV *»

- 52 CO CBj 0 (2)_ρ - Ar

Ar' - (Y).

(Π)

OB vherein Z, Y, Ar, Ar', n and p have the sam meanings than in claim 1 0

- treating the latter vith a reducing agent to produce the hydroxylated derivative thereof of formula X (Z)_p - Ar

CBOB - CBjO ^Ar' - (Y)_BOB (X) in vhich Z, Y, n, p, Ar and Ar' are defined as indicated in claim

1· and X is a free hydroxyl
15*- A process for producing a compound of general formula I according to claims 1 to 3* vhich comprises the steps of

- blocking the free hydroxyl of a hydroxy acetophenone of formula V_A

ΧΛ (V*)

CO CB, vith an easily-split blocking reagent

- submitting this blocked phenolic derivative to the action of a brominating agent to produce the corresponding α-bromo ketone

- condensing this bromoketone vith a phenol of formula »*

- 53 OB e

vherein Y and n are defined as given in claim 1* to obtain a phenoxy ethanone of formula VI_A vherein the meaning of the substituents Z, Y, p and n are the same than in claim 1* and X is a blocked hydroxyl

- submitting this compound to hydrogenation in the presence of a metallic catalyst or to acidolysis, to make free the hydroxyl function and obtain a phenoxy ethanone of formula VII_A vherein X is a hydroxy and Z, Y, p and n are defined as given in claim 1°

- reducing the compound of formula VII_A by means of a reducing agent to produce the corresponding alkanol of formula VIII_A

OH vherein Z, and X is a

Y, n and p are defined as given in claim 1° free hydroxyl
16*- A process for producing a compound of formula I according to any of claims 1 to 3* vherein R is a lover alkyl radical vhich comprises the steps of submitting a phenoxy ethanone of formula VIII »· a;

vherein Ζ, Y, Ar, Ar', p and n have the definitions given in claim 1* and X is a blocked hydroxy group to the action of a triaryl alkyl phosphonium bromide under the conditions of the Vittig's reaction to produced an ethylenic derivative of formula VI

R

I (Z)_ - Ar - C - · CH - 0 - Ar' - (Y)_a (VI) \

X vherein Ζ, Y, Ar, Ar', n and p are defined as given in claim 1*

X is a blocked hydroxy group and R is a lover alkyl radical

- submitting this compound to hydrogenolysis in the presence of a metallic catalyst to produce the α-alkylated derivative of formula I **

- 55 R

I (Z), - AR - CH - CH₂ - 0 - AR' - (Y)„ (I) vherein z, y, ar, ar', n and p are defined as given in claim 1* x is a free hydroxy group vhich may, vhen desired, be alkylated or acylated under the conditions previously defined
17*- A process for producing a compound of formula i vherein r is a lover alkyl radical, according to any of claims 1 to 3* vhich comprises the steps of reacting a phenoxy ethanone of formula VI_A vherein y, z, n nd p have the definitions given in claim 1° and x is a blocked phenolic group vith a triaryl (lover alkyl) phosphonium bromide under the conditions of the vittig's reaction to produce an ethylenic derivative of formula IX_x

AP 0 0 0 1 8 8 vherein z, y, n and p have the definitions given in claim 1’

R is a lover alkyl radical and X is blocked-phenolic group and submitting this latter to hydrogenolysis in the presence of a metallic catalyst to produce an α-alkyl ethoxy derivative of formula Ι_λ

R »» vherein Z, 7, n and p have the definitions given in claim 1”

X is a hydroxy and R is a lover alkyl radical vhich may vhen desired, be alkylated or acylated under the above-defined conditions.
18*- A process for producing a compound of formula I according to any of the claims 1 to 3*, vhich comprises the steps of reacting a substituted aryl aldehyde of formula X (Z)_ - Ar - CHO (X) vherein Z and p are defined as given in claim 1* and X is a blocked phenolic group vith a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Vittlg's reaction to produce an ethylenic compound of the formula XII (7)„ - Ar' - 0 - CH - CH - Ar - Z (XII)

X^ vherein Z, Ar, Ar', X, Ί, n and p have the definitions given in claim 1’

- hydrogenating the latter by means of hydrogen in the presence of a metallic catalyst into a compound of formula I (Y)„ - Ar' - 0 - CH₂ CH₂ - Ar - (Z)_p (I) »»

- 57 vherein the substituents Z, Ar, Ar', 7, n, p and X have the definitions given in claim 1®
19*- A process for producing a compound of formula I according to claims 1 to 3* vherein a substituted benzaldehyde of formula X_A

CHO vherein Z and p have the definitions given in claim 1* and X is a blocked phenol is reacted vith a triaryl (phenoxy methyl) phosphonium salt under the conditions of the Vitting's reaction to produce an ethylenic derivative of formula XI_A

CH - CH OH vherein Z, 7, n and p have the definitions given in claim 1* and X is a blocked phenolic group vhich is further hydrogenated into a compound of formula I_A by means of hydrogen in the presence of a metallic catalyst.

AP 0 0 0 1 8 8
20*- A process for producing a compound of formula I according to claims 1 to 3’ vhich comprises the steps of blocking the reactive functions of a hydroxy aryl alkanol of formula XIII (Z)_P

Ar \

CH

CHOH (XIII)

X .Γ- *

- 58 vherein Z, Ar, R and R_x have the definitions given in claim 1° and X is a free hydroxyl by means of an easily-split reagent, then reacting the thusblocked derivative vith a phenolic derivative of formula XIV

OB

Ar' (XIV) vherein Y, n and Ar' have the definitions given in claim 1* to produce an aryloxy ethyl arylidenic derivative of formula XV

R R,

I I (Z)_B - Ar - CB - CB - 0 - Ar' - (Υ). (XV)

X vherein Z, Y, Ar, Ar', n and p have the definitions given in claim 1°

R and R_x, the same or different each other, are a hydrogen or a lover alkyl radical and X is a blocked phenolic group and make free the hydroxy function by means of an alkaline agent to produce a compound of formula I
21*- A process for producing a compound of formula I accordint to any of claims 1 to 3· vhich comprises the steps of blocking the reacting functions of a (hydroxy phenyl) ethanol of formula XII_x (Z)_p

CB - CBOH (XII_A) vherein Z and p are defined as given in claim 1* X is a hydroxy s

- 59 R and R_: are a hydrogen or a lover alkyl by means of a reagent vhich is easily split, contacting the thusblocked derivative vith a phenol of formula XIII_A

HO vherein Y and n have the definitions given in claim 1° to produce a phenylethoxy phenyle of formula XIV_A vherein Ζ, Y, n and p have the definitions given in claim 1°

R and R_x are hydrogen or a lover alkyl and X is a blocked phenolic group and making free the hydroxyl function by means of an alkaline agent, to produce a compound of formula I_A
22*- As intermediate compounds, the ethylenic derivatives of formula

AP 0 0 0 1 8 8

R

C-CH vherein Y, Ζ, X, R, n and p have the definitions given in claim 1®
23*- As intermediate compounds, the ethylenic derivatives of formula *» vherein Z, Y, X, n ana p are defined as given in claim 1’
24·- The pharmaceutical composition vhich containg as active ingredient at least one compound of formula I

CH, - CH, - 0 (Z)_p - Ar^ ^Ar'-(Y)_n (I)

X vherein Z, Ar, Ar', Y, X, n and p have the definitions given in claim 1’ according to any of claims 1 to 11® in admixture or conjunction vith an inert, non-toxic, pharmaceutically-acceptable carrier or vehicle.
25*_ A pharmaceutical composition according to claim 24° vherein the carrier or vehicle is one of those vhich are appropriate for the administration through parenteral, digestive, rectal, permucous or percutaneous vays.
26*- A pharmaceutical composition according to any of claims 24 and 25’ vherein the content of active ingredient ranges from 1 to 200 mg per unit dosage.