CH647746A5 - BIPHENYL, BENZYLPHENYL, BENZYLOXYPHENYL AND BENZYLTHIOPHENYLETHER AND THIOETHER, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The invention relates to substituted and unsubstituted biphenyl, benzylphenyl, benzyloxyphenyl and benzylthiophenyl ether and thioethers of straight-chain a, a> glycols and hydroxythiols with 4 to 12 carbon atoms and their esters with pharmaceutically acceptable acids, processes for the preparation of these compounds and pharmaceutical preparations for controlling Rhi novirus infections containing these compounds.

The above compounds are useful for controlling rhinovirus infections.

20 Some of these compounds have already been described in general in the literature, but their usefulness as a means of combating rhinovirus infections has not been proposed and recognized.

The compounds according to the invention or the active substances of the pharmaceutical preparations according to the invention have the following general formula:

A - Y

x- (CH2) n-oH 1

wherein A represents a bond or a CH2 group, Y represents a bond, O or S, XO or S, Z and Z 'each represent hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, or halogen atoms and n represents an integer from 4 to 12. Esters of the compounds of formula I with water-solubilizing, pharmaceutically acceptable acids or salts of these esters are also within the scope of this invention. The new compounds of the present invention are the compounds of the above formula I, in which A, Y, X, Z, Z 'and n have the above meanings, and their esters with pharmaceutically acceptable acids, with the proviso that when n is the Number 4 represents and A represents a bond, Z represents no bromine or chlorine atom and Z 'represents no bromine atom and no CH30 group or isopropyl group, and that when n represents the number 5 and A and Y together represent a bond, Z does not represent a CH3 group. The exempted compounds are within the general state of the art.

In the compounds of the formula I, the substituents A and Y each preferably represent a bond or A represents a CH 2 group and Y is an oxygen atom. The substituent X is preferably an oxygen atom. The substituents X and Y can be arranged in the ortho, meta or para position relative to one another on the benzene ring to which both substituents are bonded, the meta or para position being preferred and the para position being particularly preferred.

The substituents Z and Z 'each independently represent a hydrogen atom, a straight-chain or branched-chain alkyl or alkoxy group having 1 to 4 carbon atoms or a halogen atom. Examples of these alkyl groups are the methyl, ethyl, propyl and isopropyl -, n-45 butyl, isobutyl, sec-butyl and the t-butyl group. The same alkyl groups attached to an oxygen atom are examples of the alkoxy groups that Z or Z 'may represent. The halogen atom can be a fluorine, chlorine. Be bromine or iodine. Z and Z 'can both be arranged in any position of the benzene ring, but preferably both Z and Z' represent hydrogen atoms.

The linear, saturated carbon chain that connects the group X to the hydroxyl group can be 4 to 12 carbon atoms long, compounds with a chain length 55 of 6 methylene units are preferred.

Preferred compounds according to the present invention are those in which X is an oxygen atom, A and Y taken together are a bond or a CH20 group, Z and Z 'are each hydrogen atoms and n is the number 6 and 60 and Y is in the para position to X.

Esters of the compounds of formula I with pharmaceutically acceptable acids are also effective against Rhi novirus infections.

The alcohols are often poorly soluble in water. An esterification with a water solubilizing, pharmaceutically acceptable acid, preferably a polyvalent acid, e.g. a polycarboxylic acid, a sulfonic acid, sulfurous acid or sulfuric acid increases the

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Solubility in water and facilitates the absorption of the compound. The particularly desirable esters of this type include monoesters of polycarboxylic acids and / or the salts of such monoesters, preferably the sodium salts. Esters of polyhydroxylated acids or halogenated acids are also advantageous. Such suitable esters include the esters of polycarboxylic acids or polyvalent monocarboxylic acids having 2 to 12 carbon atoms and 1 to 5 hydroxyl groups, e.g. Glycolic acid, citric acid, maleic acid, succinic acid, gallic acid, fumaric acid, lactic acid, glyceric acid, tartaric acid, malic acid and salicylic acids, as well as halogen, alkoxy and / or acyloxy acids, e.g. Chloroacetic acid, fluoroacetic acid, trichloroacetic acid, trifluoroacetic acid and 2,4,5-trimethoxybenzoic acid. Esters of these acids and the compounds of the formula I are usually prepared by known processes. Some esters, e.g. the maleates and the succinates are usually prepared by reacting the compound with maleic or succinic anhydride in pyridine, then acidifying and isolating the monoester.

The esters of the present invention also include the esters of sulfonic acids, e.g. Methanesulfonic acid and the like, as well as esters, preferably diesters, of sulfurous acid and sulfuric acid. Considerable equivalents of the above esters include each ester of a compound of Formula I which has improved water solubility compared to the alcohol from which it was made.

Examples of compounds according to the invention are: 6- (4-phenylphenoxy) hexan-l-ol, 6- (4-phenylphenylthio) hexan-l-ol, 6- (4-phenyoxyphenoxy) hexan-1-ol, 6- (4-phenoxyphenylthio) hexan-l-ol, 6- (4-phenylthiophenoxy) hexan-1-ol, 6- (4-phenylthiophenylthio) hexan-1-ol, 6- (4-benzylphenoxy) hexane 1-ol, 6- (4-benzylphenylthio) hexan-1-ol, 6- (4-benzyloxyphenoxy) hexan-l-ol, 6- (4-benzyloxyphenylthio) hexan-l-ol, 6- (4th -Benzylthiophenoxy) -hexan-1 -ol and 6- (4-benzylthiophenylthio) -hexan-1 -ol.

The compounds according to the invention also include compounds analogous to each of the above compounds which, instead of the hexamethylene chain, have another unbranched alkylene chain having 4 to 12 carbon atoms, e.g. 4- (4-phenoxyphenoxy) butan-l-ol to 12- (4-phenoxyphenoxy) dodecan-l-ol, and the corresponding alcohols in each of the above series.

The invention also encompasses the isomers of each of the above compounds where X and Y are in the meta or ortho position on the central benzene ring to which both are attached, e.g. 8- (3-Benzyloxyphen-oxy) octan-l-ol, 1 l- (2-phenylthiophenoxy) undecan-l-ol and the corresponding ortho and meta isomers of each of the other compounds above.

Other connections according to the invention include the p-fluoro substituted analogs of each of the above free alcohols and esters, e.g. 6- [4- (4-fluorophenyl) phenoxy] hexan-1-ol, 4- [4- (4-fluorophenoxy) phenoxy] butan-1-ol, 8- [3- (4-fluorobenzyloxy) -phenoxy] octan-1-ol and 6- [4- (4-fluorophenyl) phenoxy] hexyl succinate.

Other examples are the ortho-fluorine and metaFluor isomers of each of the above compounds and the analogue compounds which have a chlorine, bromine or iodine atom in place of the fluorine atom.

Further specific examples of compounds according to the invention are the monofluorosubstituted compounds which contain a fluorine atom at an accessible position on the central benzene ring and correspond to each of the unsubstituted alcohols and esters listed above,

e.g.

6- (4-phenyl-3-fluorophenoxy) hexan-1-ol, 8- (3-benzyloxy-4-fluorophenoxy) octan-l-ol, 8- (3-benzyloxy-5-fluorophenoxy) octane l-ol, 4- (4-phenoxy-2-fluorophenoxy) -l-butyl glycolate,

and the monofluorosubstituted compounds in the central ring, which otherwise correspond to each of the other unsubstituted alcohols and esters above, but which are substituted at another accessible position of the central benzene ring. Further examples of compounds according to the invention are the analogous compounds of the above compounds which have a chlorine, bromine or iodine atom instead of the fluorine atom.

Further examples of specific compounds according to the invention are those compounds which correspond to each of the above monofluorosubstituted alcohols and esters, but which have a methyl group as a substituent instead of a fluorine atom, those which have a methoxy group instead of the fluorine atom and those which have a hydroxyl group instead of the fluorine atom .

Further examples of compounds according to the invention are compounds of the formula I in which both the terminal benzene ring and the central benzene ring each contain a single fluorine atom, in positions which are analogous to those of the above monofluoro compounds, e.g. 6- [4- (4-fluorophenyl) -2-fluorophenoxy] hexan-l-ol and the 2,4'-difluoro-substituted compounds which otherwise correspond to each of the other unsubstituted alcohols and esters above.

Analogous compounds which contain a chlorine, bromine or iodine atom, a hydroxyl group or an alkyl or alkoxy group, as already explained in detail above, instead of one or both fluorine atoms in each of the above difluoro-substituted compounds, further explain the compounds of FIG present invention.

The compounds according to the invention also include the pharmaceutically acceptable esters of each of the above alcohols with various acids, in particular monoesters of citric acid, maleic acid, glycolic acid, glyceric acid, succinic acid, fumaric acid, lactic acid, malic acid, tartaric acid and methanesulfonic acid, and diesters of sulphurous acid and sulfuric acid.

The compounds of the formula I and their pharmaceutically acceptable esters are suitable for preventing the spread of rhinovirus infections and are useful active compounds for combating rhinovirus infections. With regard to their use in pharmaceutical preparations for combating rhinovirus infections, the expression “ the compounds of the formula I, in particular their suitable pharmaceutically acceptable esters.

The rhinovirus subgroup belongs to the picornavirus group and contains over 100 different antigenic species and is known to be responsible for many of the symptoms that accompany respiratory infections. The name rhinovirus indicates that infection with these viruses, which leads to syndromes that are characteristic of the common cold, affects the nose in an exposed manner. The rhinoviruses were classified as sero species 1 to 89 and subspecies 1 A (88, 89.90) with at least 20 other species that can be classified. Experimental studies show that nasal mucosal cells are more susceptible to rhinoviruses than the lower respiratory tract. The symptoms of rhinovirus infections were also ex4

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produced by dripping small amounts of the virus onto the conjunctiva, showing that the eye is another susceptible site of infection. An advanced rhinovirus infection is characterized by hyperemia and edema of the mucous membrane with the exudation of serous and mucinous fluid. The nasal cavities are narrowed by thickening of the membrane and swelling of the nasal conch.

The compounds described herein have been found to be effective antivirals against numerous types of rhinovirus, so that these compounds are useful for treating the symptoms of rhinovirus infection in hosts susceptible to these infections, including humans and certain anthropoid monkeys such as chimpanzees. As is known, various test systems can be used to measure the antiviral activity against rhinovirus. For example, the effectiveness against rhinovirus can be measured using a plaque analysis or a tube test, in which the effectiveness of the compound against a virus attack in a cell system is measured. Using various test systems, it was found that compounds of the formula I are effective agents for combating rhinovirus infections, the test compound being able to be administered before the virus attack, simultaneously with the virus attack or after the virus attack.

The usefulness of the compounds described here as active substances against rhinovirus infections has been shown in various test systems. For example, when using cell cultures G-HeLa, which were infected with rhinovirus 39 from 30 to 100 TCID50 simultaneously with test compounds in a concentration of 4, 20 or 100 ng / ml, after which the cell cultures were incubated for 48 hours, microscopic Examination of the cell cultures found that the compounds of the general formula I markedly inhibited the cytopathic effect of the virus in comparison with cell cultures which only received the virus attack. For example, when the compound of Example 1 was added to cell cultures at a concentration of 4 ng / ml at the same time as rhinovirus 39 of 100 TCID5o, the cytopathic effect of the virus was completely inhibited compared to the control experiment. The same result was obtained when the compound of Example 2 was tested in the same way. In no case was cytotoxicity due to the compounds observed even at the concentrations tested and at concentrations up to 100 ng / ml.

The compounds of Examples 1 and 2 were tested for broad spectrum activity against 25 strains of rhinovirus at concentrations of 10 (ig / ml) using human embryonic lung cells. The compound of Example 1, 6- (4-phenylphenoxy) hexan-l-ol , was effective against 72% of the rhinovirus species tested, while the compound of Example 2, 6- (4-benzyloxy-phenoxy) -hexan-l-ol, was effective against 36% of the 25 rhinovirus species tested.

Rhinovirus is known to be easily transmitted from one sensitive host to another, as is common among family members, in classrooms, and in military units. Rhinovirus is spread across the nose, mouth, and eyes of infected individuals, is carried on the skin, especially on the hands and face, and can be released into the environment by touching objects and by coughing, sneezing, breathing, and speaking . Sensitive individuals can be exposed to rhinovirus infection by direct physical contact with infected individuals, by touching objects contaminated with rhinovirus, or by inhalation of air containing rhinovirus. Transmission of rhinovirus infection among individuals can be reduced by applying a compound of Formula I to the skin of infected individuals, thereby preventing the transmission of viable rhinovirus to other individuals or to objects; on the skin of uninfected individuals, thereby preventing the transmission of viable rhinovirus on the skin to the mucosa or the conjunctiva of such uninfected individuals; to nearby objects, thereby preventing the transmission of viable rhinovirus to uninfected individuals who touch the objects 15; or to the air from confined spaces, thereby preventing the inhalation of viable rhinovirus released by infected individuals by non-infected individuals. For these purposes, the compound can be in the form of, for example, a skin cream, a gel, a lotion or a powder, a washing or cleaning agent or a disinfectant detergent, an aerosol or spray.

For the treatment of symptoms of rhinovirus infections, the compounds of formula I can be administered orally, topically, e.g. intranasal and parenteral, e.g. intramuscularly. Topical administration is preferred. The compounds can be applied topically to the skin or the membranes of the nose, mouth and eye, systemically blocking a replica of rhinovirus by means of administration and by means of transder-30 maier or transmucosal absorption.

The compounds are preferably administered in the form of a pharmaceutical preparation before or after the virus attack, even 12 hours after the virus attack, to a host susceptible to rhinovirus infections. For prophylactic treatment, an amount of the compound effective against rhinovirus should be administered about 1 to 5 days before the expected virus exposure and about 5 to 10 days after the exposure or about 5 40 to about 15 days after exposure to rhinovirus. For therapeutic treatment, an amount effective against rhinovirus may, for example, after the onset of symptoms or after the individual has been exposed to rhinovirus 45, e.g. administered for a period of 2 weeks.

Any amount of a compound of the formula I which is effective against rhinovirus can be used for the prophylactic or therapeutic treatment of rhinovirus infections. The amount of compound required to have anti-rhinovirus activity varies and depends primarily on the mode of administration. For therapeutic treatment, the amount of the compound to be administered also depends on the severity of the infection. In the case of oral or parenteral treatment 55, the amount of the compound to be administered is about 0.1 to 500 mg / kg body weight of the patient or receptive host, preferably about 1 to about 100 mg / kg body weight. Preferably the total amount of the compound administered daily is from about 100 mg 60 to about 30 g. Typically, the desired effect is achieved by a dosage unit containing about 0.1 mg to about 1 g of the compound administered 1 to 6 times a day. In the case of local treatment, an amount sufficient to coat the area to be treated 65 of a preparation which contains a concentration of the compound which is effective against rhinovirus is applied to the mucosa, the conjunctiva or the epidermis. Such preparations typically contain

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as about 0.001 to 50 wt .-%, preferably 0.01 to 5 wt .-%, a compound of formula I in a liquid or solid carrier. An effect against rhinovirus is achieved, for example, by dropping 0.1 ml of a nasal drop preparation containing 0.1 to 0.5 mg of the compound per ml into each nostril 1 to 8 times a day.

The active compound can also be administered by means of an uninterrupted release system, the compound of formula I being gradually released from an inert or bio-erodible carrier by diffusion, osmosis or decomposition of the carrier during the treatment period at a controlled, uniform rate. Controlled release drug delivery systems can be in the form of adhesive plasters or bandages applied to the skin or on the oral, sublingual or intranasal mucous membranes, in the form of eye pads used in the Douglas area of the eye, or in the form of orally administrable, gradually erodible tablets or capsules or memory preparations for the gastrointestinal tract. Administration with the aid of such continuous delivery systems enables the body tissues to be constantly exposed to a therapeutically or prophylactically effective dose of a compound of the formula I for an extended period of time. The unit dose of the compound administered using a continuous release system is approximately an effective daily dose multiplied by the maximum number of days that the carrier remains on or in the host's body. The continuous release carrier can be in the form of a solid or porous form or a solid or porous storage and can be formed from one or more natural or synthetic polymers, for example modified or unmodified cellulose, starch, gelatin, collagen, rubber, polyolefins , Polamides, polyacrylates, polyalcohols, polyethers, polyesters, polyurethanes, polysulfones, polysiloxanes and polyimides as well as mixtures, »laminates and copolymers thereof. The compound of formula I can be incorporated in pure form in the continuous release vehicle or can be dissolved in a suitable liquid or solid vehicle including the polymer from which the continuous release vehicle is made.

The compounds of formula I can be present together with suitable pharmaceutical carriers in the form of solid unit dosage forms, such as tablets, capsules, powders and lozenges, in the form of suppositories or embedded in a form of polymers. The powders can be administered orally, topically or by blowing. In the manufacture of solid unit dosage forms, it may be desirable to microfine the compound to be used. In solid unit dosage forms, the compounds can be mixed with conventional excipients, e.g. Binders such as acacia, corn starch or gelatin, disintegrants such as e.g. Corn starch, guar gum, potato starch or alginic acid, lubricants such as stearic acid or magnesium stearate, and inert fillers such as lactose, sucrose or corn starch.

The compounds of formula I can also be in the form of liquid suspensions or solutions using a sterile liquid, e.g. an oil, water, an alcohol, or mixtures thereof, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifier for oral, topical or parenteral administration. A particularly suitable mode of administration is a liquid formulation of the compounds which is delivered directly into the nasal cavity, e.g. in the form of a nasal drop preparation or a nasal spray preparation. Liquid formulations can also be applied in the form of eye drops directly to the eye, administered orally or as a gargle or mouthwash on the mucous membranes of the oral cavity and the pharynx. Liquid formulations including gels and ointments can take the form of skin lotions and creams for application to the hands and face. Such lotions and creams can contain plasticizers, paris fums or pigments to form cosmetically acceptable humectants, astringents, aftershaves, colognes, basic cosmetic creams and similar preparations. A skin lotion for use on the hands which contains a compound of formula I is particularly preferred to prevent the transmission of rhinovirus infections from infected to uninfected individuals. In general, an anti-20 viral preparation for topical application according to the present invention contains about 0.01 to about 5 g of a compound of formula I per 100 ml of the preparation.

To form liquid preparations, the compounds of the formula I can conveniently be combined with oils, e.g. fatty oils, 2s such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; with fatty acids such as oleic acid, stearic acid and isostearic acid; and fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides; with alcohols such as ethanol, isopropanol, hexadecyl alcohol-30 hol, glycerin and propylene glycol; with glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol; with ethers such as polyethylene glycol 400; with petroleum hydrocarbons such as mineral oil and petrolatum; with water or with mixtures thereof, with or without the addition of a surface-active agent, suspending agent or emulsifying agent which is compatible with a vehicle.

Peanut oil and sesame oil are particularly useful for making intramuscular injection formulations. Oils can also be used to prepare formulations 40 of the soft gelatin type and suppositories. Water, saline, aqueous dextrose solutions and similar sugar solutions, as well as glycerin and glycols, such as polyethylene glycol, can be used to produce liquid formulations which expediently contain suspending agents, such as pectin, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, and buffer substances and contain preservatives. Soaps and synthetic detergents can be used as surface-active agents and as carriers for detergents and cleaning agents. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents, e.g. Dimethyl-dialkylammonium halides, alkyl-pyridinium halides and alkylamine acetates; anioni-55 see detergents such as e.g. Alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic detergents, e.g. Fatty amine oxides, fatty acid alkanolamides and polyoxyethylene-polyoxypropylene copolymers; and amphoteric detergents such as 60 e.g. Alkyl-ß-aminopropionate and quaternary ammonium salts of 2-alkylimidazoline; as well as mixtures thereof.

Detergents and cleaning agents can be in bar form, powder form or in liquid form and can contain foaming agents, viscosity regulators, antimicrobial agents, preservatives, softening agents, colorants, perfumes and solvents. Such soap and detergent formulations can be used on textiles, on surfaces and preferably on the surface

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Skin to be applied. A preferred detergent and cleaning agent is a liquid soap or a synthetic detergent mixture which contains about 0.01 to about 5 g of a compound of formula I per 100 ml of the composition.

Aerosol or spray preparations which contain compounds of the formula I can be used as room disinfectants or for use on surfaces of the environment, on the skin or on mucous membranes. Such preparations can contain a microfine ground solid or a solution of a compound of formula I and in addition also solvents, buffer substances, surface-active agents, perfumes, antimicrobial agents, antioxidants and propellants. Such preparations can be used under pressure with the aid of a propellant or can be used with the aid of a compressible spray bottle made of plastic, a nebulizer or an atomizer without using a gaseous propellant. A preferred aerosol or spray preparation is a nasal spray.

Pharmaceutical preparations for the treatment of rhinovirus infections can contain, in addition to an amount effective against a rhinovirus, a compound of the formula I in a suitable pharmaceutical carrier one or more agents which are suitable for the treatment of symptoms of rhinovirus infections. Known agents for the symptomatic treatment of rhinovirus infections include antihistamines, anti-congestion agents, antipyretics, analgesics, antitussive agents, expectorants, local anesthetics and vitamin C. Examples of suitable antihistamines include terfenidine, doxylamine, chlorpheniramine, brompheniramine , Metapyrilene, phenindamine, phenyltoloxamine, azatadine, tiprolidine and dimethindine and their pharmaceutically acceptable acid addition salts. Examples of suitable congestion-reducing agents include ephedrine, levodesoxyephedrine, phenylephrine, xylometazoline, naphthazoline, tetrahydrazoline, phenylpropa-s nolamine, cyclopentamine, propylhexedrine, tuaminoheptane and methoxyphenamine and their pharmaceutically acceptable acid addition. Examples of suitable antitussive agents include codeine, hydrocodone, ethylmorphine, noscapine, dextromorphan, carbetapentane io and diphenylhydramine and their pharmaceutically acceptable salts. Examples of suitable expectorants include guaifenesin, terpin hydrate, sodium glycerophosphate, potassium guuaol sulfonate, ammonium chloride, Ipe-cac, eucalyptus, chloroform and menthol. Examples of suitable analgesic and antipyretic agents include aspirin, salicylic acid, salicylamide, acetanilide, aceto-phenetidine, acetaminophen, antipyrin and aminopyrine. Examples of suitable local anesthetics include benzocaine, benzyl alcohol and phenol and their pharmaceutically acceptable salts. The amount of each medicament which is effective for the symptomatic treatment of rhinovirus infections and which is incorporated into the pharmaceutical preparation for combating rhinovirus infections changes depending on the composition of the carrier and agent present therein.

Examples of suitable pharmaceutical preparations and detergents and cleaning agents are listed below.

The compounds of formula I are generally prepared by Williamson's ether synthesis (J. March, "Advanced Organic Chemistry-Reaction, Mechanisms and Structure", McGraw-Hill Book Company, New York, 1968, p. 316). The reaction is explained by the following reaction equation:

0 - A

II

XOM © + L-CCH2lr

.Ott

III

In the above reaction equation, L represents a halogen atom such as e.g. a chlorine, bromine or iodine atom or a sulfonate ester, e.g. represents a methanesulfonate or a p-toluenesulfonate; M + represents a metal salt, e.g. a salt of lithium, sodium, potassium, silver or mercury; and A, X, Y, Z, Z 'and n have the meanings given for formula I.

In this reaction, a phenoxide or thiophene oxide salt represented by structural formula II, which is expediently formed in situ by adding a base, such as sodium methoxide, potassium carbonate, sodium hydride or potassium hydroxide, to the corresponding phenol or thiophenol is reacted with an alcohol which contains a cleavable group at the terminal carbon atom and has the structural formula III, the cleavable group is replaced, which leads to the formation of a carbon-oxygen or carbon-sulfur ether or thioether bond.

The phenols used as starting material, which are the precursors of the phenoxide salts, are in general

Commercially available or can be obtained by conventional synthetic methods, which are well known. For example, benzyloxyphenols can be prepared by reacting benzyl halides with hydroquinones or resorcinols or with their monoesters and subsequent hydrolysis.

55 The benzylphenols are easily produced by reducing the corresponding hydroxybenzophenones. The latter are produced, for example, by benzoylation of phenyl acetate according to Friedel-Crafts, by Fries' rearrangement of phenyl benzoates or by oxidation of benzyl 60-alcohols.

Phenoxyphenols can be prepared by reacting a phenoxide with a halophenyl ester according to Ullmann in the presence of copper salts, cf. March, "Advanced Organic Chemistry," p. 500 (McGraw-Hill, New 65 York, 1968). Thiophenoxyphenols are prepared by reacting thiophene oxide salts with halophenyl esters, especially in amides as solvents (loc. Cit., Pp. 500-501).

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Phenylphenols can be prepared by the above-mentioned Ullmann reaction as described by March, op. Cit., Pp. 507-508.

Halogenated phenols can also be obtained by reacting a phenol with a halogenating agent, e.g. Sulfuryl chloride, can be prepared by conventional methods.

The thiophenols, which are the precursors of the thiophene oxide salts II, and the abovementioned thiol analogs of the mononuclear phenolic intermediates can be obtained from the corresponding phenols by converting the phenol into its N, N-dimethylthiocarbamate with dimethylthio-carbamoyl chloride, the thermal rearrangement of which N, N-dimethylthiol carbamate, subsequent alkaline hydrolysis, acidification, extraction and isolation of the thiophene are obtained. This reaction is carried out in essentially the same way as the conversion of β-naphthol into β-thionaphthol, as described in Fieser and Fieser, "Reagents for Organic Synthesis", Vol. 2, pp. 173-174 (Wiley Interscience , New York, 1969).

The © -substituted linear alcohols III which are used in the reaction are also generally commercially available or can be obtained by known conventional synthesis methods. For example, the a, œ-diol can be converted to the co-haloalcohol using triphenylphosphine and a tetrahalocarbon (cf. Chemical Abstracts, Vol. 63 (1965), section 13137c for the preparation of 12-bromododecan-l-ol).

The Williamson reaction can be carried out with or without a solvent. Suitable solvents for this reaction include lower alcohols, e.g. Ethanol and isopropanol, ketones such as e.g. Acetone and butanone, or amides such as e.g. Dimethylfomamide and dimethylacetamide. Other suitable solvents include Dimethyl sulfoxide, acetonitrile, dimethoxyethane, tetra-hydrofuran or toluene.

The temperature of the reaction can be changed from about 0 ° C to the reflux temperature of the solvent, and the reaction time is about 0.5 to 80 hours.

The reaction product is conveniently extracted by extracting the product into an organic solvent, e.g. Worked up ether, dichloromethane, chloroform, toluene or the like, washing with saline, drying over sodium or magnesium sulfate and evaporation of the solvent. Purification is generally accomplished by distillation or crystallization from a suitable solvent.

Esters of the compounds of formula I are made by conventional methods, e.g. Reaction of the alcohol of formula I with an acid, an acid halide, or an acid anhydride, often in the presence of an acid acceptor. The product is isolated in the usual way and purified by distillation or crystallization from a suitable solvent. Salts of the monoesters of polybasic acids are obtained by adding a base, e.g. NaH, to an ether solution of the ester and subsequent filtration of the precipitate obtained.

Example 1 6- (4-phenylphenoxy) hexan-1 ol

A mixture of 34.0 g (0.2 mol) of p-phenylphenol (Eastman) and 10.8 g (0.2 mol) of sodium methoxide (MCB) in 500 ml of dry dimethylformamide was heated on a steam bath with stirring for 0.5 hours whereupon 27.3 g (0.2 mol) of 6-chlorohexan-l-ol (MCB) and about 2 g of sodium iodide were added. The mixture was heated under reflux with stirring and then cooled to room temperature. The reaction mixture was then partitioned between ether / acetone and water, and the organic phase was extracted with a base, washed with water and brine, dried over sodium sulfate and freed from the solvent by evaporation. The white solid product obtained was recrystallized twice from methanol / acetone, the desired product having a melting point of 103 to 105 ° C.

Example 2 6- (4-Benzyloxyphenoxy) hexan-l-ol A mixture of 106.0 g (0.53 mol) of p-benzyloxyphenol (Eastman), 28.6 g (0.53 mol) of sodium methoxide (MCB) and About 2 g of sodium iodide in 600 ml of dimethylformamide was stirred for 5 minutes, then 73 g (0.53 mol) of 6-chlorohexan-l-ol (MCB) were added and the mixture was then heated under reflux with stirring. The methanol formed during the reaction is distilled off. After refluxing for 3 hours, the mixture was diluted with ice and water, 500 ml of a 10% potassium hydroxide solution was added, and the resulting precipitate was collected and dried. The solid was combined with 11 butanone, heated to reflux and filtered. The residue consisted of the secondary product bis- (benzyloxy-phenoxy) -hexane. The filtrate was cooled, whereupon the desired product crystallized. The solid product was stirred with 11 acetone at room temperature, then the mixture was filtered to separate further insoluble by-product, the acetone was boiled and replaced with methanol, and the methanolic solution was cooled to crystallize the desired product with a melting point of 94 to 97 ° C .

Example 3 6- (4-Benzylphenoxy) hexan-1-ol A mixture of 40.0 g (0.217 mol) of p-benzylphenol (Eastman) and 29.7 g (0.217 mol) of 6-chlorohexan-1-ol (MCB ) in 500 ml of dry dimethylformamide was heated to about 100 ° C. with stirring, whereupon 33.1 g (0.24 mol) of potassium carbonate were added and the mixture was heated under reflux for 2.5 hours. The mixture was cooled, poured into ice water, and 50 ml of a 10% sodium hydroxide solution was added. The mixture was extracted with ether, the ether extracts were washed with water and brine and dried over magnesium sulfate, and the ether was evaporated. The oil obtained was recrystallized to obtain the product as a water-white oil which distilled in vacuo at 0.067 mbar and 140 to 175 ° C.

Example 4 (Reference example) 12-chlorododecan-1-ol A mixture of 70.0 g (0.347 mol) of dodecane-1, 12-diol (Aldrich Chemical Company) and 540.0 g (3.5 mol) of carbon tetrachloride in 11 dry acetonitrile was heated to dissolve the diol, cooled to room temperature, purged with argon, and 91.5 g (0.350 mol) of triphenylphosphine (Aldrich) was added over 15 minutes. A water bath was used to regulate the heat generated during the addition of triphenylphosphine and to keep the reaction mixture at about room temperature. After the addition was complete, the mixture was stirred for a further 1.5 hours at room temperature and then refluxed overnight. Then the solvent was distilled off under normal pressure until the volume was reduced to 200 ml. The remaining solvent was then distilled off under high vacuum. The oily residue obtained was extracted with hexane ex8

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55

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647 746

tracted, the combined hexane extracts were evaporated to dryness, and the light yellow oil obtained was distilled in vacuo. The desired product was obtained as a fraction which distilled at 0.027 mbar at 140 to 150 ° C.

Example 5 12- (4-Phenylphenoxy) -dodecan-1 -ol The procedure of Example 2 was repeated, except that instead of the p-benzyloxyphenol used there, p-phenylphenol and instead of the 6-chlorohexan-l-ol used in that example 4-prepared 12-chlorododecan-l-ol was used, the solid precipitate obtained after diluting the reaction mixture with ice-water and treatment with a base was isolated, dried and recrystallized twice from butanone to give the desired product with a melting point to get from 113 to 114 ° C.

Example 6 (Reference Example) 4-Phenylthiophenol According to the method used by Fieser and Fieser in “Reagents for Organic Synthesis”, Vol. 2, pp. 173-174 (Wiley Interscience, New York, 1969) for the conversion of β-naphthol to β- Thio-naphthol described procedure, p-phenylphenol was reacted with dimethylthiocarbamoyl chloride (Aldrich Chemical Company) to form biphenylyl-dimethylthiocarbamate. An amount of 10 g (0.04 mol) of the latter compound was heated at 300 to 320 ° C for 45 minutes in an argon atmosphere and then cooled, after which the reaction mixture was dissolved in 250 ml of ethanol. The ethanolic solution was heated to reflux, treated with 50 ml of a 20% aqueous KOH solution and refluxed for another 1 hour, after which the ethanol was distilled off and replaced by water. The mixture was cooled, diluted with water and extracted with ether. The aqueous layer was then acidified with concentrated hydrochloric acid, cooled and extracted with ether, the ether layer was washed with water, dried and evaporated to dryness. The pure desired product with a melting point of 108 to 111 ° C. was obtained by recrystallization of the crude product from ethanol.

atmosphere stirred. Then 6.8 g (0.05 mol) of 6-chlorohexan-l-ol were added, whereupon the mixture was heated under reflux with stirring for 2 hours, cooled, diluted with water and extracted with ether / acetone. The combined organic extracts were washed with water, dried and evaporated to dryness. The crude solid product obtained was distilled in vacuo to give a fraction with a melting point of 112 to 115 ° C which transited at 110 to 180 ° C. (0.133 mbar). The pure desired product with a melting point of Get 114 to 115 ° C.

Example 8 (Reference example) i5 2-chloro-4-benzyloxyphenol

A mixture of 20.0 g (0.1 mol) of p-benzyloxyphenol (Eastman) in 250 ml of glacial acetic acid was stirred at room temperature until a clear solution was obtained. 14.8 g (0.11 20 mol) of sulfuryl chloride, which had previously been filtered through sodium carbonate, were then added over the course of 0.5 hours. The mixture was then stirred at room temperature for 3 hours, then heated on a steam bath for 1 hour and finally evaporated to dryness under reduced pressure. The crude solid product obtained was recrystallized from ether / hexane to obtain the pure desired product having a melting point of 78 to 80 ° C.

Example 9

30 6- (3-phenylphenoxy) hexan-1-ol

A mixture of 15.0 g (0.088 mol) of 3-hydroxybiphenyl, 13.3 g (0.097 mol) of 6-chlorohexan-l-ol and 13.8 g (0.01 mol) of potassium carbonate in 250 ml of dry dimethylformamide was used for 3 hours heated under reflux with stirring. The mixture was then cooled to room temperature, diluted with water and extracted with ether. The Etherex tracts were dried and evaporated under reduced pressure to give a light yellow oil. The crude product was distilled in vacuo to give a fraction boiling between 150 and 190 ° C. at 0.067 mbar, which was solidified to a soft solid and corresponded to the pure desired product.

Example 7 6- (4-phenylphenylthio) -hexan-1-ol A mixture of 8.2 g (0.044 mol) of p-phenylthiophenol, which had been prepared according to Example 6, and 6.9 g (0.015 mol) of potassium carbonate in 200 ml of dimethylformamide was treated for 15 minutes at room temperature under an argon45 example 10

Using the procedure of Example 2, the following phenolic compounds were obtained with the specified halogen alcohols to form the compounds listed below, where pH = phenyl:

Phenol halogen alcohol product Mp (° C)

p-Ph-Ph-OH 4-Cl- (CH2) 4-0H p-Ph-Ph-0- (CH2) 4-0H 110-113 °

p-Ph-Ph-OH 5-Cl- (CH2) 5-OH p-Ph-Ph-0- (CH2) s-0H 108-109 °

p-Ph-Ph-OH 8-Cl- (CH2) 8-OH p-Ph-Ph-0- (CH2) 8-0H 103-106 °

p-Ph-Ph-OH 10-C1- (CH2) 10-OH p-Ph-Ph-0- (CH2) lfl-0H 107-108 °

p- (Ph-CH2-0) -Ph-0H 4-Cl- (CH2) 4-OH p- (Ph-CH2-0) -Ph-0- (CH2) 4-0H 97-99 °

p- (Ph-CH2-0) -Ph-0H 5-Cl- (CH2) 5-OH p- (Ph-CH2-0) -Ph-0- (CH2) 5-0H 90-93 °

Following the procedure of Example 9, the 2-chloro-4-benzyloxyphenol prepared in Example 8 was treated with 6-chloro-hexan-l-ol to form 6- (2-chloro-4-benzyloxyphen-oxy) -hexan-l- ol reacted, which was a light yellow oil distilling at 0.0267 mbar between 185 and 200 ° C.

ipiel 11

Following the procedure of Example 9, 2-chloro-4-65 phenylphenol (Eastman) was reacted with 6-chlorohexan-l-ol to form 6- (2-chloro-4-phenylphenoxy) -hexan-l-ol, the one Melting point of 64 to 65 ° C had.

647 746

10th

Example 12

6- (2-hydroxy-5-phenylphenoxy) hexan-1-ol and 6- (2-hydroxy-4-phenylphenoxy) hexan-1-ol A mixture of 55.9 g (0.3 mol) 4- Phenylpyrocatechol (Eastman) and 52.8 g (0.38 mol) of potassium carbonate in 500 ml of dry dimethylformamide were stirred at room temperature, then 45.1 g (0.33 mol) of 6-chlorohexan-l-ol were added, followed by the reaction flask flushed with nitrogen and the mixture was stirred for 48 hours at room temperature and then refluxed for 5 hours. The reaction mixture was then cooled, diluted with water, acidified with 1N HCl and extracted with ether. The ether layer was washed with water, dried and evaporated to dryness. The semi-solid residue was distilled in vacuo in an evaporator. The fractions which passed at 150 to 170 ° C, at 180 to 200 ° C and at 220 to 240 ° C (0.133 mbar) were collected. The fraction passed at 180 to 200 ° C was recrystallized from acetone / hexane, whereby the 2,4-substituted product was obtained. The fraction passed over at 220 to 240 ° C. was recrystallized from acetone / hexane, the diether having a melting point of 80 to 82 ° C. being obtained. Additional 2,4-substituted product was obtained from the distillation residue of the fraction passing at 150 to 170 ° C. The mother liquors from the previous crystallizations were combined and distilled in vacuo to give the fractions passing at 160 to 165 ° C, at 170 to 190 ° C and at 210 to 220 ° C (0.133 to 0.067 mbar). The fraction passed at 160 to 165 ° C was recrystallized from acetone / hexane, combined with the aforementioned distillation residue and recrystallized, whereby pure 2,4-product with a melting point of 122 to 123 ° C was obtained. The mother liquor from the crystallization was evaporated to dryness and distilled again, a fraction passing at 160 to 165 ° C. (0.067 mbar) corresponding to the pure 2.5 product being collected.

Example 13

6- (4-Benzyloxyphenoxy) -1-hexyl methanesulfonate A mixture of 25 g (0.08 mol) of 6- (4-benzyloxyphen-oxy) hexan-l-ol, prepared according to Example 2, in 250 ml of pyridine was combined with 28.6 g (0.25 mol) of methanesulfonyl chloride (Eastman) and stirred for 3 hours at room temperature. The reaction mixture was partitioned between water and ether, whereupon the ether extracts were washed, dried and evaporated to give the desired product with a melting point of 80 to 82 ° C.

Example 14 Bis-4- (4-phenylphenoxy) -l-butyl-sulfite Following the procedure of Example 13, 4- (4-phenylphenoxy) -butan-l-ol and an excess of thionyl chloride were used to obtain the desired ester with egg -, Nem melting point of 138 to 139 ° C obtained.

Example 15

6- (4-phenylphenoxy) -1-hexyl-succinate (monoester) A mixture of 10 g (0.037 mol) of 6- (4-phenylphenoxy) -hexan-l-ol, prepared according to Example 1, and 10 g of succinic anhydride in 250 ml of pyridine was refluxed with stirring for 3 hours. Then the pyridine was removed in vacuo on a steam bath and the residue poured into water and acidified with hydrochloric acid. The precipitate obtained was collected, washed, dried and recrystallized from butanone, the pure monoester having a melting point of 113 to 115 ° C. being obtained.

Example 16

solution

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

0.85 g

alcohol

78.9 ml

Isopropyl myristate

5.0 g

Polyethylene glycol 400

(average molecular weight 400)

10.0 g of purified water

100 ml

Alcohol, isopropyl myristate and polyethylene glycol 400 15 are combined and the active ingredient is dissolved in it.

Sufficient purified water is then added to give a total volume of 100 ml.

20 tablets

Example 17

6- (4-benzyloxyphenoxy) hexan-l-ol

Lactose

Corn starch for 15,000 75 g 1.216 kg 0.3 kg

The active ingredient, lactose and corn starch are mixed evenly. Then it is granulated with 10% starch paste. It is then dried to a moisture content of about 2.5% and passed through a sieve with a light

30 th mesh size of 1.68 mm sieved. Then the following ingredients are added and mixed in: Magnesium stearate 0.015 kg

Corn starch to 1.724 kg

35 The mixture is compressed into tablets with a weight of 0.115 g / tablet on a suitable tablet machine.

Example 18

40 soft gelatin capsules 6- (4-phenylphenoxy) hexan-l-ol 0.25 kg

Polyoxyethylene (20) sorbitan monooleate (polysorbate 80) 0.25 kg

Corn oil to 25.0 kg

45

The ingredients are mixed and filled into 50,000 soft gelatin capsules.

Example 19

so injection solutions IM

A. Oil-based: 6- (4-phenylphenoxy) hexane-1-ol butylated hydroxyanisole butylated hydroxytoluene

55 peanut oil or sesame oil

B. Suspension:

6- (4-phenylphenoxy) -hexan-l-ol sodium carboxymethyl cellulose 6o sodium bisulfite water for injection

Example 20

powder

65 6- (4-phenylphenoxy) -hexan-l-ol anhydrous silicon dioxide corn starch, lactose, each finely powdered, in total

25 mg

0.01% (w / v) 0.01% (w / v)

1.0 ml

25 mg 0.5% (w / v) 0.02% (w / v)

1.0 ml

1% by weight 0.5% by weight

50 kg

11

647 746

Example 21 Nose drops or nasal spray

6- (4-phenylphenoxy) hexan-l-ol 0.10 g ethyl oleate 20.0 g butylated hydroxyanisole 4.0 mg poly (oxypropylene) poly (oxyethylene) copolymer, avg. Molecular weight 46,000 (Poloxamer 235) 25.0 g benzyl alcohol 4.7 ml Sörensen buffer mixture (mixture of 50 parts of sodium biphosphate solution and 50 parts of sodium phosphate solution,

made isotonic by adding sodium chloride) to 5ÔÔ, Ô ml

Example 22

Nasal drops or nasal spray

6- (4-phenylphenoxy) hexan-ol 0.125 g

Isostearic acid 5.0 g poly (oxypropylene) poly (oxyethylene) copolymer, average Molecular weight

42,000 (Poloxamer 215) 12.5 g

NaOH sufficient to adjust pH 7.6

Benzyl alcohol 4.7 ml

Mannitol pulverizes 25.35 g of deionized water to 500 ml

Example 23

Hand lotion

6- (4-phenylphenoxy) -hexan-1 -ol isostearic acid s stearic acid poly (oxypropylene) poly (oxyethylene) mixed polymer, average Molecular weight 46,000

Propylene glycol in deionized water

Example 24

Liquid soap

6- (4-phenylphenoxy) -hexan-ol-i5 green soap tincture, NF

Example 25 Liquid washing and cleaning agent 6- (4-phenylphenoxy) hexan-l-ol 20 Miranol-SM-concentrate® (35% l-carboxymethyl-4,5-dihydro-l- (2-hydroxyethyl) -2- nonyl-1 H-imidazolium hydroxide-antrium salt, 5% NaCl, pH 8.9-9.1) monolauryl ether of polyoxyethylene glycols 25 with average 4 oxyethylene groups (Laureth-4)

deionized water

0.15 g 10.0 g 8.0 g

5.0 g 10.0 g 100.0 ml

0.3 g 100 ml

0.025 g

25.0 g

2.0 g 100 ml

40

45

55

60

S

Claims (19)

647746 PATENT CLAIMS 1. Biphenyl, benzylphenyl, benzyloxyphenyl and benzylthiophenyl ether and thioether of the general formula I Â Y X- (CH-) -OH J. cn wherein A represents a formation or a CH2 group, Y represents a bond, O or S, XO or S, Z and Z 'each represent hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, Alkoxy groups having 1 to 4 carbon atoms, or halogen atoms and n represents an integer from 4 to 12, with the proviso that when n is 4 and A represents a bond, Z is not a bromine or chlorine atom and Z 'is not a bromine atom , means no CH30 group and no isopropyl group; or that when n is 5 and A and Y together represent a bond, Z does not represent a CH30 group; as well as the esters of the compounds of formula I with a water-solubilizing, pharmaceutically acceptable acid and the salts of these esters. 2. A compound according to claim 1, wherein X of the formula represents an oxygen atom. 3. A compound according to claim 1, wherein A and Y of the formula together represent a bond or the CH20 group. 4. A compound according to claim 1, wherein Z and Z 'each represent hydrogen atoms. 5. A compound according to claim 1, wherein X and Y are para to the benzene ring to which both are attached 15 to each other. 6. A compound according to claim 1, wherein A and Y together represent a bond or the CH20 group, X represents an oxygen atom and Z and Z 'each represent hydrogen atoms. 7. A compound according to claim 1, wherein n is of formula 6. 8. 6- (4-phenylphenoxy) hexan-l-ol as a compound according to claim 1. 9. 6- (4-Benzyloxyphenoxy) hexan-l-ol as a compound 25 according to claim 1. 10. 6- (4-phenylphenoxy) -l-hexyl succinate as a compound according to claim 1. 11.6- (4-Benzyloxyphenoxy) -l-hexyl methanesulfonate as a compound according to claim 1. 30 12. A process for the preparation of the compounds of formula I according to claim 1, characterized in that a compound of general formula o wherein A, X, Y, Z and Z 'have the meanings given in claim 1, in the presence of a base with a compound of the general formula L- (CH2) n-OH implements, wherein n has the meaning given in claim 1 and L represents a chlorine, bromine or iodine atom or a reactive, cleavable group. 13. A process for the preparation of the esters of the compounds of the formula I according to claim 1, characterized in that X- * R O that the alcohols obtained according to the process of claim 12 are reacted to form an ester with a water-solubilizing, pharmaceutically acceptable acid with a suitable acid or an acid chloride or acid anhydride, and optionally the ester thus obtained is formed with a corresponding salt with a base implements. so 14. Pharmaceutical preparation for combating rhinovirus infections, containing a compound of general formula I. x-CCH2) n-0H wherein A represents a bond or a CH2 group; Y represents a bond, O or S, XO or S, Z and Z 'each represent hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, or halogen atoms and n represents an integer from 4 to 12, or an ester of such a compound with a water-solubilizing, pharmaceutically acceptable acid or a salt of this ester, and a carrier. 15. Preparation according to claim 14, characterized in that the active ingredient is a compound according to one of claims 2 to 11. 3rd 647 746 16. Preparation according to claim 14 in the form of nasal drops or nasal spray. 17. Preparation according to claim 14, characterized in that it contains the active ingredient in a concentration of 0.01 to 5 wt .-% in a liquid carrier. 18. Preparation according to claim 14 in the form of a skin lotion, a skin cream, a skin gel or a skin ointment. 19. Preparation according to claim 18, characterized in that it contains the active ingredient in an amount of 0.01 to 5 g per 100 ml of the preparation. 20. Preparation according to claim 14, characterized in that it is effective in the carrier one or more Contains agents for the symptomatic treatment of rhinovirus infections selected from antihistamine, congestion-reducing, antipyretic, analgesic, antitussive, expectorant and local anesthetic agents. 21. A preparation according to claim 14 in the form of a detergent or cleaning agent, wherein the pharmaceutically acceptable carrier is a detergent. 22. Preparation according to claim 21 in liquid form, io 23. Preparation according to claim 21, characterized in that it contains the active ingredient in an amount of 0.01 to 5 g per 100 ml of the preparation.