FR2483232A1 - NOVEL ANTI-RHINOVIRUS AGENTS AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

THE ANTI-RHINOVIRUS MEDICINAL PRODUCTS ACCORDING TO THE INVENTION ARE COMPOUNDS RESPONDING TO THE GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH REPRESENTS A BOND OR A CH2 GROUP; Y IS A BOND OR AN ATOM OF OXYGEN OR SULFUR; X IS AN ATOM OF OXYGEN OR SULFUR; Z AND Z EACH REPRESENT HYDROGEN OR A HALOGEN OR A C-C ALKYL GROUP, C-C OR OH ALCOXY; AND N IS AN INTEGER FROM 4 TO 12; OR ONE OF THEIR ESTERS WITH A PHARMACEUTICALLY ACCEPTABLE SOLUBILIZING ACID OR A DEDIT ESTER SALT.

Description

The present invention relates to ethers and thio-

  biphenyl, benzylphenyl, benzoxyphenyl and benzylthio-

  phenyl substituted or unsubstituted with a, Lu-glycols and hydroxythiols with chain

  straight or branched C4-C12 and their esters with phar-

  maceutically acceptable, which are useful as anti-rhinovirus agents. Some of these compounds are generally described in the prior art as their interest as

  anti-rhinovirus agents is not suggested.

  The anti-rhinovirus compounds of the invention have the general formula Z-Q- - X (Cd12) n-Oa (1) Z 'wherein A represents a single bond or a CH2 group; Y is a bond or an oxygen or sulfur atom; X is an oxygen or sulfur atom; Z and Z 'each represents hydrogen or a halogen or a C1-C4 alkyl, C1-C4 alkoxy or OH group; and n is an integer of 4 to 12. The esters of compounds of formula I with pharmaceutically acceptable solubilizing acids or the salts of these esters are also part of the invention, as well as the

  pharmaceutical compositions containing them and their preprocessing methods

  paration, and their presentation forms. In the aspect of novel products the invention relates to the compounds of formula I and their pharmaceutically acceptable acid esters, with the proviso that when n is 4 and A is a bond, Z is other than Br or CI and Z 'is other than Br, CH3O or isopropyl; when n is 5 and A and Y together form a bond, Z is other than CH30; and when n is 4-7 and A and Y together form a bond, Z is other than OH. Excluded compounds are part of the teaching

  general of the prior art.

  In the compounds of formula I, substituents A and Y are preferably each a bond, or A is CH2 and Y is oxygen. The substituent X is preferably an oxygen atom. The substituents X and Y may be arranged ortho, meta or para to each other on the benzene ring common to both, preferably in meta or para, and more

especially in para.

  The substituents Z and Z 'are each, independently of one another, a hydrogen or halogen atom or a group

  straight or branched chain alkyl or alkoxy or hydroxy group.

  The alkyl groups are illustrated by methyl, ethyl, proFlu, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The same oxygen-linked alkyl groups illustrate the alkoxy groups represented by Z or Z '. The halogen atom can be fluorine, chlorine, bromine or iodine. Z and Z 'can both be in any position of the benzene ring but,

  preferably, they are both hydrogen atoms.

  The linear saturated carbon chain connecting the X group to the hydroxyl group can have a length of 4 to 12 carbon atoms. Compounds having a chain length are preferred

of 6 methylene units.

  The preferred compounds according to the invention are those in which X = O; A and Y together form a bond or a CH20 group; Z and Z 'are both hydrogen atoms; n = 6 and Y is para to X. The esters of the compounds of formula I with pharmaceutically acceptable acids also exhibit anti-rhinovirus activity. Alcohols are often not easily soluble

  in water. Esterification with a pharmaceutically acceptable acid

  table, preferably a polyacid, such as a polycarboxylic acid, a sulfonic acid or sulfurous acid or sulfuric acid

  increases the solubility in water and facilitates the absorption of the compound.

  Particularly desirable esters include monoesters

  polycarboxylic acids and / or the salts of these monoesters: preferably

  sodium salts. Polyhydroxy acid esters or

  halogenated acids are also advantageous.

  These suitable esters include esters of polycarboxylic acids or polyfunctional C 2 -C 12 monocarboxylic acids and having 1 to 5 hydroxyl groups, for example glycolic, citric, maleic, succinic, gallic, fumaric, lactic, glyceric, tartaric and malic acids. and salicylic; and the

  haloalkoxy and / or acyloxy acids, for example

  acetic acid, fluoroacetic acid, trichloroacetic acid, trifluoroacetic acid and 2,4,5-trimethoxybenzoic acid. The esters of these acids and compounds of formula I are prepared by well-known techniques.

  of the man of the art. Some, for example the maleates and

  are suitably prepared by reaction of the compound with

  maleic anhydride or succinic anhydride in pyridine, followed by

  deification and isolation of the mroester.

  The invention also relates to the esters of

  Examples are methanesulphonic acid and the like, and esters, preferably diesters, sulfuric and sulfuric acids. The contemplated equivalents of the foregoing esters include any esters of a compound of Formula I that exhibit improved water solubility relative to alcohol.

from which he derives.

  By way of illustration of the alcohols of the invention, mention may be made of the following compounds: 6- (4-phenylphenoxy) hexane-1-ol, 6- (4-phenylphenylthio) hexane-1-ol, 6- (4 phenoxyphenoxy) hexane-1-ol, 6- (4-phenoxyphenylthio) hexane-1-ol, 6- (4-phenylthiophenoxy) hexane-1-ol, 6- (4-phenylthiophenylthio) hexan-1-ol, 6- (4-phenoxyphenylthio) hexane-1-ol. benzylphenoxy) hexane-1-ol, 6- (4-benzylphenylthio) hexane-1-ol, 6- (4-benzyloxyphenoxy) hexane-1-ol, 6- (4-benzyloxyphenylthio) hexane-1-ol, 6- (4-benzylthiophenoxy) hexane-1-ol and 6 (4-benzylthiophenylthio) hexan-1-ol. The invention also relates to compounds analogous to each of the above, having another straight alkylene chain

  in C4-012 instead of hexamethylene chain, for example 4- (4-

  phenoxyphenoxy) butane-1-ol with 12- (4-phenoxyphenoxy) dodecan-1-ol,

  and the corresponding alcohols in each series above.

  The invention also relates to the isomers of each of the above compounds having X and Y substituents in meta or ortho with respect to one another on the central benzene ring common to both, for example 8- (3-benzoxyphenoxy) octane. 1-ol, 11- (2-phenylthiophenoxy) undecan-1-ol, and the ortho isomers and

  corresponding meta of each of the other compounds above.

  Other compounds of the invention include the p-fluorosubstituted analogs of each of the above free alcohols and esters, for example: 6- [4- (4-fluorophenyl) phenoxy] hexane-1-ol, 4- [4 (4-fluorophenoxy) phenoxy] butane-1-ol, 8-43- (4-fluorobenzoxy) phenoxy] octan-1-ol, and

  6- [4- (4-fluorophenyl) phenoxy] -1-hexyl succinate.

  Other examples are the ortho-fluoro isomers and

  meta-fluoro of each of the above compounds and the analog compounds

  with chlorine, bromine or iodine in place of

the fluorine atom.

  Other specific examples of the compounds of the inva-

  are the monofluoro-substituted compounds having a fluorine atom at a position available on the central benzene ring corresponding to each of the aforementioned unsubstituted alcohols and esters, for example: 6- (4-phenyl-3-fluorophenoxy) hexane-1 -ol, 8- (3-benzyloxy-4-fluorophenoxy) octan-1-ol, 8- (3-benzyloxy-5-fluorophenoxy) octan-1-ol, 4- (4-phenoxy-2-fluorophenoxy) -l glycolate -butyl, and the monofluoro-substituted compounds at the corresponding central nucleus

  otherwise to each of the other non-substituted alcohols and esters

  above, but substituted at another available position on the central benzene ring. Compounds analogous to the preceding ones having a chlorine, bromine or iodine atom instead of the atom of

  fluorine are still specific examples of the compounds of the invention.

  Other examples of specific compounds of the invention

  are those corresponding to each of the mono alcohols and esters

  above-mentioned fluoro-substituted radicals but having a methyl group instead of the fluorine atom as a substituent, those having a methoxy group instead of the fluorine atom and those having a

  hydroxy group instead of the fluorine atom.

  Other examples are the compounds in which the terminal benzene ring and the central benzene ring each carry a single fluorine atom, in positions similar to

  each of the monofluorocompounds above, for example 6- [4- (4-

  fluorophenyl) -2-fluorophenoxy] hexane-1-ol and the compounds 2,4'-

  difluoro-substituted corresponding otherwise to each of the others

  unsubstituted alcohols and esters mentioned above.

  Other examples of compounds of the invention include analogous compounds having a chlorine, bromine or

  iodine or a hydroxy, alkyl or alkoxy group, as illustrated below.

  above, instead of one or two fluorine atoms in each

  previous difluoro-substituted compounds.

  The invention also relates to the pharmaceutical esters

  of each of the above alcohols with various acids, more particularly monoesters of citric, maleic, glycolic, glyceric, succinic, fumaric, lactic, malic, tartaric and methanesulphonic acids and acid diesters.

sulfurous and sulfuric.

  The compounds of formula I and their suitable esters are of interest as anti-rhinovirus agents (With regard to their use as anti-rhinovirus agents, the term "compounds of formula I" embraces their suitable pharmaceutically acceptable esters.) Rhinovirus group is part of the picornavirus group and contains more than 100 different types of antigains and is known to be responsible for many of the symptoms related to respiratory infections. Lenomderhinovirus indicates the prominent entry into the nasal passages that are observed in infections caused by these viruses, giving rise to

  characteristic syndromes of the current cooling. Rhinos

  viruses were classified into serotypes 1 to 89 and subtypes 1A (88,89,90), with at least 20 other types to be added to the classification. Experimental studies indicate that nasal mucosal cells are more sensitive to rhinovirus than cells in the lower respiratory tract. Symptoms

  of rhinovirus infection have also been experi-

  mentally by drip application of small amounts of the virus on the conjunctiva, indicating that the eye is another site susceptible to infection. The rhinovirus infection developed is characterized by hyperemia and edema of the mucous membrane with exudation of serous and mucinous fluid. The cavities

  nasal passages are narrowed by thickening of the membrane and engorged

turbinates.

  The compounds described herein have been shown to be effective as antiviral agents against many types of rhinoviruses, which makes them useful in treating the symptoms of rhinovirus.

  rhinovirus infection in hosts susceptible to said infections

  including humans, and some anthropoid apes such as chimpanzees. One skilled in the art knows that one can use several

  testing systems to measure antiviral activity against rhino-

  virus. For example, anti-rhinovirus activity can be measured using a plaque assay or a tube assay in which the activity of the compound against the test virus is measured in a cellular system. Using various assay systems, it has been found that the compounds of formula I are effective anti-rhinovirus agents when the test compound is administered before, after, or after

  concurrently with the test virus.

  The utility of the compounds described as anti-

  rhinovirus has been demonstrated in various test systems. For example, using G-Hela cell cultures supplemented with 30 to 100 CID50s of a rhinovirus test virus 39 concurrently with test compounds, at a concentration of 4, 20 or 100 y. After which cell cultures are incubated for 48 hours, it is found on microscopic examination of cell cultures that the compounds of general formula I substantially inhibit the cytopathic effect of the virus, in comparison with cultures of cells containing the test virus alone. For example, when the compound of Example 1 is added at a concentration of 4 μg / ml to cell cultures in conjunction with 100 TCID 50 of virus

  rhinovirus-type 39 test, the cytopathic effect of the virus is entirely

  inhibited, compared to the control. We get the same result

  when the compound of Example 2 is tested in a similar manner.

  In none of the cases was cytotoxicity due to the compounds themselves at the concentration tested, and at concentrations up to

y / ml.

  The broad spectrum activity of the compounds is determined

  examples 1 and 2 against 25 strains of rhinovirus at concentrations

  10 y / ml using embryonic human lung cells. The compound of the example, 6- (4-phenylphenoxy) hexane-1-ol, is active against 72% of the tested types of rhinovirus, while the compound of Example 2, 6- (4-benzoxyphenoxy) hexane-1-ol, is

  active against 36% of the 25 types tested for rhinovirus.

  It is known that rhinovirus is easily transmitted from one susceptible host to another, as happens, for example - among members of the same family, in classrooms

  and in military populations. The rhinovirus spreads

  shot from the nose, mouth and eyes of infected individuals, it is worn on the skin, especially the skin of the hands and face, and can be released into the environment through the manipulation of objects and coughing, sneezing, breathing and speech. The

  susceptible individuals may be exposed to rhino

  virus through direct physical contact with infected individuals, by

  manipulation of objects contaminated by the rhinivirus or by breathing

  air bearing rhinovirus. Person-to-person transmission of rhinovirus infection may be decreased by application of a compound of formula I to the skin of infected individuals, preventing transfer of viable rhinovirus to other individuals or objects; to the skin of uninfected individuals, preventing the transport of viable rhinoviruses to the mucosa or conjunctiva of these uninfected individuals; surrounding objects, preventing transfer of viable rhinoviruses to uninfected individuals in contact with the objects; or air in closed spaces, preventing inhalation by uninfected individuals of viable rhinovirus spread by infected individuals. For this purpose, the compound may be, for example, in the form of a skin cream, a gel, a lotion or a powder, a detergent composition or a disinfectant for rinsing, or an aerosol or

of a composition to be atomized.

  In the treatment of symptoms of rhinovirus infection, the compounds of formula I may be administered by

  oral, by the local route, for example intranasally, and paren-

  lateral, for example intramuscularly. Local administration is preferred. The compounds can be applied topically to the skin or membranes of the nose, mouth and eyes,

  multiplication of the rhinovirus being blocked at the aministra-

  and generally through transdermal

or transmucosed.

  The compounds are preferably administered in the form of a pharmaceutical preparation to a host susceptible to rhinovirus infection, either before or after the invasion of the patient.

  virus, even until 12 hours after the invasion. For the treatment of

  phylactic, the administration of a medicinal

  the rhinovirus compound for about 1 to 5 days before expected exposure to the virus and about 5 to 10 days after exposure or about 5 to 15 days after exposure to rhinovirus. For the therapeutic treatment, it is possible, for example, to administer a medicinal amount of the compound after the appearance

  symptoms or after exposure to rhinovirus, for example

2 weeks.

  For the prophylactic or therapeutic treatment of rhinovirus infection, any medicinal dose of a compound of formula I may be used. The amount of the compound

  necessary to achieve an anti-rhinovirus effect varies primarily

  according to the mode of administration. For therapeutic treatment

  However, the amount of the compound administered also varies according to the severity of the infection. For oral or parenteral treatment, the amount of the administered compound varies from about 1500 mg / kg body weight of the patient or susceptible host, preferably from about 1 to 100 mg / kg. Preferably, the total amount of the compound administered daily varies from about 100 mg to about

  g. Characteristically, a unit dose containing approximately

  0.1 mg to 1 g of the compound administered 1 to 6 times daily

  will produce the desired effect. For local treatment, apply on

  the mucosa, the conjunctiva or the epidermis a quantity of a

  containing an anti-rhinovirus concentration of the compound

  to cover the area to be treated. These compositions contain

  typically from about 0.001 to 50% by weight, preferably

  from 0.01 to 5% by weight of a compound of formula I in a liquid or solid carrier. For example, an anti-rhinovirus effect will be obtained with 0.1 ml nasal drops containing from 0.1 to 0.5 mg / ml of the

  compound instillationsin each nostril 1 to 8 times daily.

  The active compound can also be administered by means of a delayed release system wherein the compound of formula I is gradually released at a uniformly controlled rate.

  from an inert support or attacked in the body by diffusion

  sion, osmosis or disintegration of the support, during the duration of

  is lying. The controlled release systems of the medicament may be in the form of a tampon or bandage applied to the skin or to the oral, sublingual or intranasal membranes, an ocular implant placed in the cul de sac of the eye or a tablet or capsule.

  gradually disintegrating or a gastrointestinal reservoir admi-

  administered orally. Administration by means of these sustained release systems enables the tissues of the body to be constantly exposed for a prolonged period of time to a dose of a therapeutically or prophylactically effective compound of formula I. The unit dose of the administered medium compound of a sustained release system is close to the product of the daily effective amount by the maximum number of days that the carrier should remain on or in the host organism. The sustained release support may be in the form of a solid or porous matrix or

  a reservoir and can be made of one or more natural polymers.

  synthetic or synthetic, including modified or unmodified

  starch, gelatin, collagen, rubber, poly-

  olefins, polyamides, polyacrylates, polyalcohols, polyethers, polyesters, polyurethanes, polysulfones,

  polysiloxanes and polyimides, and their mixtures,

  and copolymers. The compound of formula I may be incorporated into the sustained release carrier in pure form, or it may be dissolved in a suitable liquid or solid carrier

  whatever, including the polymer of which the support is

maintained ration.

  The compounds of formula 1, together with a suitable pharmaceutical carrier, may be in unit dosage forms such as tablets, capsules, powders and lozenges, in the form of suppositories or coated in a polymer matrix. The powders can be administered orally, locally or by insufflation. In the preparation of solid unit dosage forms, it may be desirable to micronize the compound to be used. In solid unit dosage forms, the compounds may be combined with conventional carriers, for example binders such as gum arabic, corn starch or gelatin, disintegrants, such as corn starch, guar gum, apple starch alginic acid, lubricants, such as stearic acid or magnesium stearate and inert fillers such as

  as lactose, sucrose or corn starch.

  The compounds of formula I can also be

  administered in the form of suspensions or liquid solutions in use

  reading a sterile liquid such as an oil, water, alcohol or

  mixtures thereof, with or without the addition of a pharmaceutical surfactant

  acceptable for a suspending agent or an emulsifying agent

  for oral, local or parenteral administration. A particularly suitable mode of administration is a liquid formulation of the compounds applied directly to the nasal cavity, by

  example in the form of nasal drops or an atomic composition

  ser. The liquid formulations can also be administered directly to the eye as eye drops, administered orally or applied to the membranes of the oral cavity and pharynx in gargles or mouthwashes. Liquid formulations, including gels and ointments, may take the form of skin lotions or creams for application to the hands and face. These lotions and creams may contain emollients, perfumes or pigments to form humectants, astringents, shaving lotions, colognes, cosmetically acceptable foundations, and similar preparations. A lotion

  for the skin to be used on the hands comprising a compound of

  mule I is especially preferred for preventing the transfer of rhinovirus infection from infected individuals to uninfected individuals. In general, a topical antiviral composition according to the invention contains from about 0.01 to 5 g of a

  Formula I per 100 ml of the composition.

  For liquid preparations, the compounds of the formula I may be suitably mixed with oils, for example fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and oil. olives; fatty acids such as oleic acid, stearic acid and isostearic acid and fatty acid esters such as oleate

  of ethyl, isopropyl myristate, glycerides of fatty acids and gly-

  cereals of acetylated fatty acids; with alcohols such as ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol;

  with glycerol ketals such as 2,2-dimethyl-1,3-dioxolan-4-

  methanol; with ethers, such as polyethylene glycol of molecular weight 400; with petroleum hydrocarbons such as mineral oil and petroleum jelly; with water; or with their mixtures;

  with or without the addition of a surfactant suspension or emulsifier

  pharmaceutically acceptable.

  Peanut oil and sesame oil are

  particularly interesting in the preparation of compositions for intramuscular injection. It is also possible to use oils

  in the preparation of compositions of the soft gelatin type and

  SITIO. Water, saline, aqueous dextrose and related sugar solutions, and glycols such as polyethylene glycol can be used in the preparation of liquid compositions which may advantageously contain suspending agents such as pectin, carbomers, methylcellulose, hydroxypropylcellulose, and the like. or

  carboxymethylcellulose, as well as buffers and preservatives

  tion. Synthetic soaps and detergents can be used

  as surfactants and as carriers for compositions

  gentes. Suitable soaps include fatty acid salts of alkali metals, ammonium and triethanolamine. Suitable detergents include cationic detergents, for example dimethyldialkylammonium halides, alkylpyridinium halides, and alkylamine acetates; anionic detergents, for example

  alkyl-, aryl- and olefinsulfonates, alkyl-, olefin-, ether- and mono-

  glyceride sulfateset sulphosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polyoxypropylene copolymers; and amphoteric detergents, for example, alkyl 9-aminopropionates and 2-alkylimidazoliniumquaternary salts; and their mixtures. The detergent compositions may be in the form of bread, powder or liquid form and may contain detergency aids, viscosity control agents, antimicrobial agents, preservatives, emollients, dyes, fragrances and the like. solvents. These soaps and detergent compositions can

  be applied to textiles on surrounding surfaces and, preferably,

  to the skin. A preferred detergent composition is a liquid soap or a synthetic detergent composition comprising from about 0.01 to about 5 g of a compound of formula I per 100 ml of the

composition.

  Aerosol or atomizing preparations containing compounds of formula I may be used as space disinfectants or for application to surrounding surfaces, skin or mucous membranes. These compositions may contain a micronized solid or a solution of a compound of formula I and

  may also contain solvents, buffers, tensio-

  active ingredients, fragrances, antimicrobial agents, antioxidants and propellants. These compositions may be applied by means of a propellant under pressure or by means of a compressible plastic bottle for spraying, a nebulizer or an atomizer without the user of a gaseous propellant. A

  The preferred aerosol or spray composition consists of

nasal veration.

  The pharmaceutical compositions for the treatment of rhinovirus infections may contain, in addition to a medicinal dose of a compound of formula 1, in a suitable pharmaceutical carrier, one or more agents of interest for the treatment of the symptoms of rhinovirus infections. Agents known in the art as useful for treating the symptoms of rhinovirus infection include antihistamines,

  decongestants antipyretics, analgesics, anti-inflammatory drugs,

  tussifics, expectorants, local anesthetics and vitamin C.

  Examples of suitable antihistamines include terfenene

  dine, doxylamine, chlorpheniramine, brompheniramine, metapyrilene, phenindamine, phenyltoloxamine, azaphtadine, tiprolidine and dimethindine and their pharmaceutically acceptable acid addition salts. Examples of suitable decongestants include phedrine, levodeoxyephedrine,

  phenylephrine, xylometazoline, naphtazoline, tetrahydrate,

  zoline, phenylpropanolamine, cyclopentamine, propylhexene,

  1, tuaminoheptane and methoxypheniramine, and their pharmaceutically acceptable acid addition salts. Examples of suitable antitussives include codeine, hydrocodone, ethylmorphine, noscapine, dextromorphan, carbetapentane

  and diphinylhydramine and their pharmaceutically acceptable salts.

  Examples of suitable expectorants include guaifenesin,

  terpine hydrate, sodium glycerophosphate, guaiacolol

  potassium sulphonate, ammonium chloride, ipecac, eucalyptus, chloroform and menthol. Examples of analgesic agents

  and appropriate antipyretics include aspirin, salicylic acid and

  cyclic acid, salicylamide, acetanilide, acetophenetidine, acetyl

  minophene, antipyrine and aminopyrine. Examples of anesthetics

  appropriate local antibiotics include benzocaine, benzyl alcohol,

  and phenol and their pharmaceutically acceptable salts.

  The amount of each drug in the antirhinovirus pharmaceutical composition varies depending on the composition of the carrier and the agent

that it incorporates.

  Typical examples of pharmaceutical compositions

  and detergents are indicated below.

  The compounds of formula I are generally prepared by the synthesis of Williamson's ethers (J. March, "Advanced Organic Chemistry Reactions, Mechanisms and Structure", McGraw-Hill Book Company, New York, 1968, page 316). The reaction is illustrated by the following equation: ZAY y) X XM + L (CH 2) n-OH -4 I

{\, M, // / 2

(III)

(II)

- 2483232

  In the above reaction equation, L represents a halogen atom such as chlorine, bromine or iodine or a sulphonic ester residue such as methanesulfonate or p-toluenesulfonate; ) represents a metal cation such as lithium, sodium, potassium, silver or mercury; and A, X, Y, Z, Z 'and n are as defined for formula I.

  A phenolate or thiophenolate is reacted

  formula II and suitably formed in situ by addi-

  of a base such as sodium ethylate, potassium carbonate

  sium, sodium hydride or phenol potassium hydroxide or

  corresponding thiophenol, with an alcohol bearing the eliminated group

  bound on the terminal carbon atom and corresponding to formula III.

  Eliminable group moved, with formation of a link

  ether or thioether, carbon-oxygen or carbon-sulfur.

  The starting phenols which are the phenolate precursors are generally commercially available or can be obtained by quite conventional synthetic techniques well known to those skilled in the art. For example, benzoxyphenols can be prepared by reaction of benzyl halides with hydroquinones or resorcinols or with their monoesters,

with subsequent hydrolysis.

  Benzylphenols are easily prepared by reduction

  corresponding hydroxybenzophenones. These are pre-

  prepared, for example, by Friedel-Crafts benzoylation of phenyl acetate, by Fries rearrangement of phenyl benzoates,

  or by oxidation of benzhydryl alcohols.

  The phenoxyphenols can be prepared by the Ullmann reaction of a phenolate and a halophenyl ester in the presence of copper salts. See March, "Advanced Organic Chemistry", page 500

  (McCraw-Hlill, New York, 1968). Thiophenoxyphenols are prepared

  res by reaction of thiophenolates with halophenyl esters,

  especially in amide solvents (ibid., pp. 500-501).

  The phenylphenols can be prepared by the reaction

  from Ullmann as indicated by March, op. cit., pp. 507-508.

  Halogenated phenols can also be prepared by reacting a phenol with halogenated agents such as chloride.

  sulfuryl, according to conventional techniques.

  Thiophenols, which are the precursors of thio-

  II phenolates, as well as the thiol analogs of the aforementioned phenol mononuclear intermediates, can be obtained from the corresponding phenols by conversion of phenol to its N, N-dimethylthiocarbamate with dimethylthiocarbamoyl chloride, thermal transposition to N, N-dimethylthiolcarbamate followed by alkaline hydrolysis, acidification, extraction and isolation of thiophenol. This reaction is carried out in substantially the same manner as the conversion of 3-naphthol or thionaphthol indicated by Fieser and Fieser in "Reagents for Organic Synthesis", Vol. 2, pp. 173-174 (Wiley Interscience, New York, 1969). The O-substituted linear alcohols III used in the reaction are also generally commercially available or can be obtained by well-known conventional synthetic methods. For example, α, O-diol can be transformed into

  0-haloalcohol using triphenylphosphine and a tetra-

  carbon halide (see C.A., 63, page 13137c (1965) for the

  preparation of 12-bromododecan-1-ol).

  The Williamson reaction can be carried out with or without a solvent. Suitable solvents for the reaction include lower alcohols such as ethanol and isopropanol, ketones

  such as acetone and butanone and amides such as dimethylformamide

  mide and dimethylacetamide. Other suitable solvents include

  dimethylsulfoxide, acetonitrile, dimethoxyethane, tetra-

hydrofuran and toluene.

  The reaction temperature may vary from about 0 ° C to the reflux temperature of the solvent and the reaction time from about 30 minutes to 80 hours.

  The reaction mixture is suitably treated by extrac-

  product in an organic solvent such as ether, dichloromethane

  methane, chloroform, toluene or the like, brine washing, drying over sodium or magnesium sulphate and evaporation of the solvent. Purification is generally carried out by distillation

  or recrystallization from a suitable solvent.

  The esters of the compounds of formula I are formed by conventional techniques, such as reaction of the alcohol of formula I with an acid, an acid halide, an anhydride or a

  other activated acyl derivative, often in the presence of an acid acceptor.

The product is isolated in a conventional manner and purified by distillation.

  or recrystallization from a suitable solvent. The salts of monoesters of polyacids are prepared by addition of a base, by

  NaH, to an ether solution of the ester, followed by

the resulting precipitate.

  The following examples illustrate the invention without

however, limit its scope.

EXAMPLE 1

  6- (4-phenylphenoxy) hexane-1-ol. A mixture of 34.0 g (0.2 mole) of p-phenylphenol (Eastman Company) and 10.8 g (0.2 mole) of sodium methoxide was heated and stirred in a steam bath for MCB) in 500 ml of anhydrous dimethylformamide, after which 27.3 g (0.2 mol) of 6-chlorohexan-1-ol (MCB) and about 2 g of sodium iodide are added. The mixture is refluxed with stirring and allowed to stand at room temperature. The reaction mixture is distributed between the etheracetone mixture and water and the organic phase is extracted with a base, washed with water and brine, dried over Na 2 SO 4 and the solvent evaporated. The resulting white solid product is recrystallized twice in the mixture

  methanol-acetone to give the desired product; F. 103-105 C.

EXAMPLE 2

  6- (4-BenzoxyphNoxy) hexane-1-ol A mixture of 106.0 g (0.53 mole) of p-benzoxyphenol (Eastman Company), 28.6 g (0.53 mole) of sodium methoxide (MCB) and about 2 g of sodium iodide in 600 ml of dimethylformamide, after which 73 g (0.53 moles) of 6-chlorohexan-1-ol (MCB) are added and the mixture is heated to reflux under reflux.

  stirring. The methanol formed in the reaction is allowed to distill.

  After 2 hours at reflux, the mixture is diluted with ice and water,

  500 ml of 10% potassium hydroxide is added and the

  resulting precipitate and dried. The solid is combined with 1 liter of butanone, heated to reflux and filtered. The residue consists of bis (benzoxyphenoxy) hexane as a by-product. The filtrate is cooled and the desired product crystallizes. The solid product is stirred with 1 liter of acetone at room temperature, the mixture is filtered to separate the additional insoluble by-product, the acetone is boiled off and replaced with methanol,

  and the methanolic solution is cooled to crystallize the

duit sought; F. 94-97 C.

EXAMPLE 3

  6- (4-benzylphénoxy) hexane-l-ol. A mixture of 40.0 g (0.217 mol) of p-benzylphenol (Eastman Company) and 29.7 g is stirred and heated to about 100 ° C.

  (0.217 moles) 6-chlorohexan-1-ol (MCB) in 500 ml of dimethyl

  anhydrous formamide, after which 33.1 g (0.24 mol) of

  potassium bonate and the mixture was refluxed for 2 h 30 min. The mixture is cooled, poured into ice water and 50 ml of 10% NaOH are added. The mixture is extracted with ether, the ether extracts are washed with water and brine, dried over MgSO 4 and the ether evaporated. The resulting oil is redistilled to obtain the product as a clear oil fraction as

  distilling water at 140-175 ° C, at 0.05 mm Hg (0.67 mbar).

EXAMPLE 4

12-chlorododecane-l-ol.

  A mixture of 70.0 g (0.347 mol) of 1,1-dodecane-diol (Snciété Aldrich Chemical Company) and 540.0 g (3.5 mol) of carbon tetrachloride in 1 liter of anhydrous acetonitrile was heated to dissolve the diol, cool to ambient temperature, purge with argon and add 91.5 g (0.350 mol) of

  triphenylphosphine (Aldrich Company) in 15 min. We use a bath-

  to regulate the heat produced during the addition of

  triphenylphosphine, and to maintain the reaction mixture in the

  sinage of the ambient temperature. When the addition is complete, the mixture is stirred at room temperature for 1 h 30 min and then refluxed overnight. The solvent is then distilled off under atmospheric pressure until

  that the volume is reduced to 200 ml, and then under high vacuum.

  The oily residue is extracted with hexane, the combined hexane extracts are evaporated to dryness and the yellow oil is distilled off in vacuo.

  resulting light. The desired product is obtained in the form of a fraction.

  distilling at 140-150 ° C at 0.02 mm Hg (0.27 mbar).

EXAMPLE 5

  12- (4-phénylphlnoxy) dodecane-l-ol. By the procedure described in Example 2, but

  using p-phenylphenol instead of p-benzoxyphenol and using

  12-chlorododecan-1-ol prepared in Example 4 instead of

  6-chlorohexan-1-ol, the solid precipitate obtained after dilution is isolated.

  of the reaction mixture with ice water and treatment with a base, dried and recrystallized twice in butanone to

  obtain the desired product; F. 113-114 C.

EXAMPLE 6

  4-phénylthiophénol. Following the procedure for conversion of Pnaphtol to P-thionaphthol of Fieser and Fieser "Reagents for Organic Synthesis, Volume 2", pp. 173-174 (Wiley Interscience, New York,

  1969), p-phenylphenol is reacted with dimethyl chloride.

  thiocarbamoyl (Aldrich Chemical Company) to form biphenylyl dimethylthiocarbamate. A 10 g (0.04 mole) portion of this latter compound is heated at 300 ° C. for 45 min in an argon atmosphere, cooled and the reaction mixture is dissolved in 250 ml of ethanol. The ethanolic solution is refluxed, treated with 50 ml of 20% KOH, refluxing is continued for 1 h and the ethanol is distilled off and replaced with water. The mixture is cooled, diluted with water and extracted with ether. The aqueous layer is then acidified with concentrated HCl, cooled and extracted with ether, the ether layer is washed with water, dried and evaporated to dryness. Recrystallization of the crude product in ethanol gives the product

sought pure; F. 108-111 C.

EXAMPLE 7

6- (4-phenylenylthio) hexane-1-ol.

  Stirred for 15 minutes at room temperature,

  under argon atmosphere a mixture of 8.2 g (0.044 mol) of p-phenyl-

  thiophenol prepared in Example 6 and 6.9 g (0.015 mol) of potassium carbonate in 200 ml of dimethylformamide. 6.8 g (0.05 mol) of 6-chlorohexan-1-ol are then added, the mixture is refluxed with stirring for 2 hours, cooled, diluted with water and extracted with ethereal mixture. acetone. The combined organic extracts are washed with water, dried and evaporated to dryness. We distill

  under vacuum the resulting crude solid product to obtain a fraction of

  passing to 110-180 ° C at 0.1 mm Hg (1.3 mbar), m.p. 112-115 ° C. Recrystallization from acetone gives the desired pure product;

F. 114-115 ° C.

EXAMPLE 8

  2-chloro-4-benzoxyphénol. A mixture of 0 g (0.1 mole of p-benzoxyphenol (Eastman Company) in 250 ml of glacial acetic acid is stirred at room temperature until a solution is obtained.

  clear. 14.8 g (0.11 mol) of sulphuryl chloride are then added.

  ryle previously filtered on sodium carbonate, in 30 min, on -

  The mixture is stirred at room temperature for 3 hours, then warmed on a water bath for 1 hour and evaporated to dryness under reduced pressure. The resulting crude solid product is recrystallized from the etherhexane mixture to give the pure desired product;

Mp 78-80C.

EXAMPLE 9

  6- (3-phenylphenoxy) hexane-l-ol. A mixture of 15.0 g (0.088 mol) of 3-hydroxybiphenyl, 13.3 g, is heated and refluxed for 3 hours.

  (0.097 mole) 6-chlorohexan-1-ol and 13.8 g (0.01 mole) of carbon.

  potassium nate in 250 ml of anhydrous dimethylformamide. The mixture is cooled to room temperature, diluted with water

  and extracted with ether, the ethereal extracts are dried and

  pore under reduced pressure to obtain a light yellow oil. We

  distil the crude product under vacuum to obtain a boiling fraction

  between 150 and 190 ° C at 0.05 mm Hg (0.67 mbar) and solidifies

  relying on a soft solid corresponding to the desired pure product.

EXAMPLE 10

  Using the procedure of Example 2,

  can react the following phenolic compounds with the halogenated

  genoalcohols indicated to produce the compounds indicated below (Pa = phenyl): Phenol p-Ph-Ph-OH p-Ph-Ph-OH p-Ph-Pn-OH p-Ph-Ph-OH p- (Ph- CH 2 -O) p -OH p- (Ph-C-12-O) -Ph-OH Haloalcohol 4-Cl- (CH 2) 4-OH

-C1- (CH2) 5-OH

8-CI- (CH2) 8-OH

  -C1- (CH2) 10oOH 4-Cl- (CH2) 4-OH -Cl- (CH2) 5-OH Product p-Ph-Ph-O- (CH2) 4-OH pPh-Ph-O- (CH2) 5-OH p-Ph-Ph-O- (CH2) 8-OH p-Ph-Ph-O- (CH2) O-OH p- (Ph-CH2-O) Ph-O- (CH2) 4-OH p .- (P h -Cl 2 -O) -Ph-O- (CH 2) 5 -OH F. (oC) -113

108-109

103-106

107-108

97-99 -93 m o o0 1.> 4 The r%,

EXAMPLE 11

  By the procedure described in Example 9, the 2-chloro-4-benzophenol prepared in Example 8 is reacted with

  6-chlorohexane-1-ol to produce 6- (2-chloro-4-benzoxyphenoxy) -

  hexane-1-ol, in the form of a light yellow oil distilling between

  and 200 C at 0.02 mm Hg (0.27 mbar).

  By the operating method described in Example 9,

  react 2-chloro-4-phenylphenol (Eastman Company) with 6-chloro

  hexane-1-ol to produce 6- (2-chloro-4-phenylphenoxy) hexane-1-ol,

F. 64-65 C.

EXAMPLE 12

  6- (2-hydroxy-5-phenylphenoxy) hexane-1-ol and

  6- (2-hydroxy-4-phenylphenoxy) hexan-1-ol.

  A mixture of 55.9 g (0.3 mole) of 4phenylpyrocatechol (Eastman Company) and 52.8 g is stirred at ambient temperature.

  (0.38 moles) of potassium carbonate in 500 ml of dimethylformate

  anhydrous mide. 45.1 g (0.33 mol of 6-chlorohexan-1-ol,

  the reaction flask is purged with nitrogen and stirred at room temperature.

  room temperature for 48 h, then heated at reflux for 5 h. The reaction mixture was cooled, diluted with water, acidified with 1N HCl and extracted with ether. The ether layer is washed with water, dried and evaporated to dryness. The semi-solid residue is distilled under vacuum in a distillation column. The fractions passing at 150-1700C, 180-200 ° C. and 220 ° -240 ° C. are collected at 0.1 mm Hg (1.3 mbar). The 180-200 ° C fraction is recrystallized from acetone-hexane to give the 2,4-substituted product. The fraction passing 220-240 ° C is recrystallized from acetone-hexane to give the diether; F. 80-82 C. 2.4-Substituted product is obtained from the distillation residue of the fraction at 150 ° -170 ° C. The mother liquors of the preceding recrystallizations are combined and distilled under vacuum and fractions are obtained. to 160-165 ° C, 170-190 ° C and 210-220 ° C at 0.1-0.05 mm Hg (1.3-0.67 mbar). The fraction passing through 160-165 ° C. is recrystallized from acetone-hexane, combined with the above-mentioned distillation residue and recrystallized to give the pure product 2.4; F. 122-123 C. The mother liquor of recrystallization is evaporated to dryness and redistilled and obtained

  a fraction passing at 160-165 ° C. at 0.05 mm Hg (0.67 mbar) corresponding to

spawning to the product 2.5 pure.

EXAMPLE 13

  6- (4-Benzoxyphenoxy) -1-hexyl methanesulfonate.

  A mixture of 25 g (0.08 mole) of 6- (4-

  benzoxyphenoxy) hexane-1-O4 prepared in Example 2, in 250 ml of pyridine with 28.6 g (0.25 moles) of methanesulionyl chloride (Eastman Company) and stirred at room temperature for 3 h. The reaction mixture is distributed between the water and the ether, the ether extracts are washed, dried and evaporated to obtain the product.

research; F. 80-82 C.

EXAMPLE 14

  Bis-4- (4-phenylphenoxy) -1-butyl sulfite.

  By the procedure of Example 13, we obtain

  the desired ester; F. 138-139 C using 4- (4-phenylphenoxy) -

  butan-1-ol and an excess of thionyl chloride.

EXAMPLE 15

  6- (4-phenylphenoxy) -1-hexyl hemisuccinate.

  A mixture of 10 g (0.037 mole) of 6- (4-phenylphenoxy) hexane-1-ol prepared at room temperature is refluxed with stirring for 3 hours.

  Example 1 and 10 g of succinic anhydride in 250 ml of pyridine.

  The pyridine is removed under vacuum in a water bath, the residue is inverted

  in water and acidified with HC1. The resulting precipitate is collected

  so much, it is washed, dried and recrystallized in butanone

  to obtain the pure monoester; Mp 113-115C.

EXAMPLE 16

  6- (4-Phenylphenoxy) hexane-1-ol solution 0.85 g alcohol 78.9 ml isopropyl myristate 5.0 g polyethylene glycol average molecular weight 400 10.0 g

(PEG 400)

Purified water q.s. 100 ml

  Combine alcohol, isopropyl myristate and polyethylene

  400 and dissolve the drug. Add enough water

purified to make 100 ml.

EXAMPLE 17

  Tablets For 15,000 tablets 6- (4-benzoxyphlenoxy) hexane-1-ol 75 g lactose 1.216 kg corn starch 0.3 kg Mix uniformly the active ingredient, lactose and corn starch. Granulate with 10% starch paste. Dry up to a

  moisture content of about 2.5%. Sieve with 1.68 mm sieve.

  Add and mix the following ingredients: Magnesium stearate 0.015 kg Corn starch q.s. 1.725 kg Press the mixture into a tablet machine suitable for

weight of 0.115 g per tablet.

EXAMPLE 18

Soft gelatin capsules.

  6- (4-phenylphenoxh) hexane-1-ol 0.25 kg polyoxyethylene (20) sorbitan monooleate "Polysorbate 80" 0.25 kg Corn oil q.s. 25.0 kg Mix and fill with the mixture 50 000 soft gelatin capsules

EXAMPLE 19

Injection mixture i.m.

  A. Oil blend: 6- (4-phenylphenoxy) hexane-1-ol 25 mg butylated hydroxyanisole 0.01% w / w butylated hydroxytoluene 0.01% w / v peanut oil or sesame oil qosop. 1.0 ml B. Suspension type mixture: 6- (4-phenylphenoxy) hexane-1-ol sodium carboxymethylcellulose sodium bisulfite water for injection mg 0.5% w / v 0.02% w / v q.s. 1.0 ml O

EXAMPLE 20

  Powder. 6- (4-phenylphenoxy) hexane-1-ol silicon dioxide, anhydrous, corn starch, lactose, each in fine powder,

total qa.s.p.

EXAMPLE 21

Drops or nebulisate for the nose.

  6- (4-phenylphenoxy) hexane-1-ol ethyl oleate hydroxyanisole butyl

  polyoxypropylene-polyoxy-type surfactant

  ethylene, molar weight 46,000, "Poloxamer 235" benzyl alcohol Sorensen's buffer (50/50 mixture of solutions of sodium bisphosphate and sodium phosphate made isotonic by addition of chloride of

sodium) q.s.

EXAMPLE 22

Drops or nebulisate for the nose.

  6: (4-Phenylphenoxy) hexane-1-ol isostearic acid "Poloxamer 215" (average molecular weight 42,000)

NaOH q.s.

  benzyl alcohol mannitol powder

demineralized water q.s.

EXAMPLE 23

Hand lotion.

  6- (4-phenylphenoxy) hexane-1-ol isostearic acid stearic acid "Poloxamer 235" propylene glycol

demineralized water q.s.

  1% by weight 0.5% by weight kg 0.10 g, 0 g 4.0 mg, 0 g 4.7 ml 500.0 ml 0.125 g, 0 g 12.5 g pH 7.6 4, 7 ml 500 ml 0.15 g, 0 g 8.0 g, 0 g, 0 g, 0 ml

EXAMPLE 24

Liquid soap.

  6- (4-phenylphenoxy) hexane-1-ol green soap tincture

EXAMPLE 25

Liquid detergent.

6- (4-phenylphenoxy) hexane-1-ol

  35% solution of 1-carboxymethyl hydroxide

  4,5-dihydro-l- (2-hydroxyethyl) -2-nonyl-lH-imi-

  dazolium, sodium salt, and 5% NaCl, pH 8.9-9.1 ("Miranol SM Concentrate" from Miranol Chem Co., Irvington, NJ) polyoxyethylene glycol monolauryl ethers having an average of 4 oxyethylene groups ( "Laureth-4")

demineralized water a. s ..

  0.3 g ml 0.025 g, 0 g 2.0 g ml It is understood that the invention is not limited

  to the preferred embodiments described above as illus-

  tration and that those skilled in the art can make various modifications

  and various changes without departing from the framework and

took the invention.

Claims (20)

  1 - New drugs used especially for the   treatment or prevention of rhinovirus infections,   in that they comprise as active ingredient at least one compound of the general formula ZiA-y- - X- (CH2) nOH Z- T ".Z't - [ "7 / ----   wherein A represents a bond or a CH2 group; Y is a bond or an oxygen or sulfur atom; X is an oxygen or sulfur atom; Z and Z 'each represents hydrogen or a halogen or a C1-C4 alkyl, C1-C4 alkoxy or OH group; and n is an integer of 4 to 12; or one of their esters with a solubilizing acid   pharmaceutically acceptable salt or a salt thereof.   2 - Drug according to claim 1, characterized   rised in rised in the other, in that what X is oxygen.   3 - Drug according to claim 1, characterized   what A and Y together form a connection or a CH20 group,   4 - Drug according to claim 1, characterized   that Z and Z 'are each hydrogen.   Medicinal product according to claim 1, characterized in that X and Y are in the para position with respect to   on the benzene ring to which both are linked.   Drug according to claim 5, characterized in that A and Y together form a bond or a CH 0 group,   X is oxygen and Z and Z 'are each hydrogen.   7 - Drug according to claim 6, characterized in that n is equal to 6.   8 - Drug according to claim 1, characterized   in that the active ingredient is 6- (4-phenylphenoxy) hexane-1-ol.   9 - Medicament according to claim 1, characterized   in that the active ingredient is 6- (4-benzyl-phenoxy) hexane-1-ol.   Medicinal product according to claim 1, characterized   in that the active ingredient is 6- (4-phenylphenoxy) succinate   l-hexyl. 11 - Drug according to claim 1, characterized in that the active ingredient is 6- (4-benzyloxyphenoxy) -hexyl methanesulfonate. 12 - Pharmaceutical composition, characterized in that it contains as active ingredient at least one drug according to   any of claims 1 to 11l associated with a support or   non-toxic pharmaceutically acceptable vehicle,   13 - Composition according to claim 12, characterized   ridiculous in that it is presented in the form of lotion, cream,   gel or ointment containing an amount of active ingredient of about   0.01 to 5 g / 100 g for topical, intranasal application, or on the skin.   14 - Composition according to claim 12, characterized   because it is presented in the form of drops or pul-   is effective for the nose and contains the active ingredient at a concentration of 0.01 to 5% by weight associated with a vehicle liquid.   Composition according to Claim 12, characterized   in that it comprises in the carrier one or more effective agents for the symptomatic treatment of rhinovirus infections, selected from antihistamines, decongestants, antipyretics, analgesics, antitussives, expectorants and local anesthetics.   16 - An antiviral detergent composition, characterized in that it comprises an amount effective against the rhinovirus of a compound of the general formula -) ti) X (CH 2 O) n H 'z' in which A represents a bond or a CH 2 group ; Y is a bond or an oxygen or sulfur atom; X is an oxygen or sulfur atom; Z and Z 'each represents hydrogen or a halogen or a C1-C4 alkyl, C1-C4 alkoxy or OH group; and n is an integer of 4 to 12; or an ester thereof with a pharmaceutically acceptable solubilizing acid or a salt thereof, and a carrier of detergent. 17 - Detergent composition according to claim 16,   characterized in that it is in liquid form.   18 - Detergent composition according to claim 16, characterized in that the compound is present in an amount of about   0.01 to 5 g per 100 ml of the composition.   19 - Non-substituted ethers and thioethers of biphenyl, benzylphenyl, benzoxyphenyl and benzylthiophenyl, substituted or unsubstituted by a-v-glycol and hydroxythiol, characterized in that they correspond to the general formula <X- (CH2) -OR   Z 'wherein A represents a bond or a CH2 group; Y is a bond or an oxygen or sulfur atom; X is an oxygen or sulfur atom; Z and Z 'each represent hydrogen or a halogen or a C1-C5 alkyl, C1-C4 alkoxy or OH group; and n is an integer of 4 to 12; with the following additional conditions: when n is 4 and A is a bond, Z is other than Br or Cl and Z is other than Br, CH 3 0 or isopropyl; when n is equal to and A and Y together form a bond, Z is other than CH30; and when n is 4-7 and A and Y together form a bond, Z is   other than OH; and their esters with solubilizing acids pharma-   and the salts of said esters.   20 - Compounds according to claim 19, characterized in that X is oxygen.   21 - Compounds according to claim 19, characterized   in that A and Y form a bond or a CH 2 O group.   22 - Compounds according to claim 19, characterized   in that Z and Z 'are each hydrogen.   23 - Compounds according to claim 19, characterized in that X and Y are in the para position with respect to each other on the benzene ring to which both are bonded. 24 - Compounds according to claim 19, characterized in that A and Y together form a bond or a CH20 group,   X is oxygen and Z and Z 'are each hydrogen.   Compounds according to claim 19, characterized in that it is 1-hexyl. is equal to 6.   26 - Compound according to claim 19, characterized   consists of 6- (4-phenylphenoxy) hexan-1-ol.   27 - Compound according to claim 19, characterized   consists of 6- (4-benzoxyphenoxy) heen-1-ol.   28 - Compound according to claim 19, characterized   consists of 6- (4-phenylphenoxy) -1-hexyl succinate.   29 - Compound according to claim 19, characterized   consists of 6- (4-benzyloxyphenoxy) methanesulphonate   - Process for the preparation of compounds according to claim 19, characterized in that it comprises the following steps: (a) reacting a compound of general formula Z --- (- "- A- Y- (tX-   Z 'wherein A, X, Y, Z and Z' are as defined above, with a compound of the general formula L- (CH2) n-OH wherein n is as defined above and L is the chlorine, bromine or iodine or an equivalent reactive eliminable group, in the presence of a base; and, optionally, (b) the alcohol produced in step (a) is reacted with the appropriate acid, acid chloride, acid anhydride or other derivative   activated acylate to form an ester with a solubilizing acid   ecologically acceptable; and, optionally, (c) reacting the ester produced in step (b) with a base to produce its salt.