JPH0345055B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention provides anti-rhinovirus (rinovirus)
The present invention relates to biphenyl, benzylphenyl, benzyloxyphenyl of C _4-12 linear α,ω-glycols useful as agents and their esters with pharmaceutically acceptable acids. [Prior Art] Homologs of certain of these compounds have been disclosed in the prior art, for example, in Japanese Patent Publication Nos. 54-46755 and 54-81245. [Problems to be Solved by the Invention] However, regarding compounds similar to some of the compounds of the present invention disclosed in these prior art,
Neither its use nor its effectiveness as an anti-rhinovirus agent has been demonstrated. [Means for Solving the Problems] The anti-rhinovirus compound of the present invention has the general formula I
It is indicated by. where A is a bond, _-CH2- or _-CH2O ,
n is an integer from 4 to 12. Esters of compounds of formula I with solubilizing pharmaceutically acceptable acids selected from polybasic acids such as carboxylic acids, sulfonic acids, sulfurous acids, and sulfuric acids, or salts of such esters, are suitable for use in pharmaceutical preparations containing them. Within the scope of this invention are compositions, methods of manufacture, and methods of use. In compounds of formula I, substituent A is preferably a bond or
It is _CH2O . A and -O(CH ₂ ) _o OH are positioned in the ortho, meta or para position to each other on the benzene nucleus common to both, preferably the meta or para position, and most preferably the para orientation. The linear saturated carbon chain attached to the hydroxy group and O ranges in length from _{C4 to C12} . Compounds with a chain length of 6 methylene units are preferred. In preferred compounds according to the invention, A is a bond or
CH ₂ O; n=6; A and O(CH ₂ ) _o OH are para. Esters of compounds of formula I with pharmaceutically acceptable acids also exhibit anti-rhinoviral activity. Alcohols are often sparingly soluble in water. Esterification with a solubilizing pharmaceutically acceptable acid, preferably a polyfunctional acid such as a polycarboxylic acid, a sulfonic acid, sulfite or sulfuric acid, increases the solubility in water and reduces the absorption of the compound. make it easier. Particularly desirable esters are monoesters of polycarboxylic acids and/or salts of such monoesters, preferably thorium salts. Esters of polyhydroxylated or halogenated acids are also useful. Among the preferred such esters are polycarboxylic acids or _C2-12 polyfunctional monocarboxylic acids with 1 to 5 hydroxyl groups, such as glycolic acid, citric acid, maleic acid, succinic acid, gallic acid. , fumaric acid, lactic acid, glyceric acid,
Included are tartaric acid, malic acid, salicylic acid and esters of halo, alkoxy and/or acyloxy acids such as chloroacetic acid, fluoric acid, trichloroacetic acid, trifluoroacetic acid, and 2,4,5-trimethoxybenzoic acid. Esters of these acids and compounds of formula I are prepared by known methods. Some, such as maleic and succinic esters, are prepared by reacting the compound with maleic or succinic anhydride in pyridine followed by acidification to separate the monoester. Also included are esters of sulfonic acids, such as methanesulfonic acid, and esters of sulfites and sulfates, preferably diesters. Possible equivalents of the esters include all esters of compounds of formula I whose solubility in water is increased compared to the alcohol to which they are derived. The compounds of the present invention are illustrated below. 6-(4-phenylphenoxy)hexane-1
-ol 6-(4-phenoxyphenoxy)hexane-
1-ol 6-(4-benzylphenoxy)hexane-1
-ol 6-(4-benzyloxyphenoxy)hexan-1-ol Also compounds similar to each of the above compounds with another _C4-12 unbranched alkylene chain in place of the hexamethylene chain , for example, from 4-(4-phenoxyphenoxy)butan-1-ol to 12-(4
-phenoxyphenoxy)dodecane-1-ol and the corresponding alcohols of each of the aforementioned series. Furthermore, isomers of each of the above compounds that are meta or ortho to each other on the central benzene ring they both share, such as 8-(3-benzyloxyphenoxy)octan-1-ol, 11-(2-phenyl thiophenoxy)undecane-1-ol and
Ortho and meta isomers corresponding to the other compounds listed above are also included. Also, pharmaceutically acceptable esters of each of the above alcohols with various acids, specifically citric acid, maleic acid, glycolic acid, glyceric acid, succinic acid, fumaric acid, lactic acid, malic acid, tartaric acid and methanesulfonic acid. Also included are monoesters with and diesters with sulfite and sulfuric acid. Compounds of formula I and their suitable esters are:
It is useful as an anti-rhinovirus agent. (For their use as anti-rhinovirus agents, references to "compounds of formula I" also include suitable pharmaceutically acceptable esters of compounds of formula I.) The subgroup of rhinoviruses is the picornaviruses. It is a member of a group that contains more than 100 different antigenic types and is known to cause symptoms associated with respiratory infections. The name rhinovirus refers to the prominent nasal involvement seen in infections with these viruses, which produce a syndrome characteristic of the common cold. The rhinovirus group is serotype 1
-89 and subtype 1A (88, 89, 90), and at least 20 more types have been added to this classification. Experimental nasal mucosal cells have been found to be more susceptible to rhinovirus than lower respiratory tract cells. Furthermore, symptoms of rhinovirus infection can be induced experimentally by instilling a small amount of virus into the conjunctiva, indicating that the eye is another site susceptible to infection.
Advanced rhinovirus infections are characterized by hyperemia and edema of the mucous membranes, along with exudation of serous fluid and mucus. The nostrils are narrowed by thickening of the membranes and hyperemia of the nasal turbinates. The compounds described herein have been found to be effective antivirals against a number of rhinoviruses and are useful in treating the symptoms of infection in hosts susceptible to rhinoviruses, including humans and great apes such as chimpanzees. This makes the above compounds useful. It is known that several test methods can be used to measure antiviral activity against rhinovirus. For example, anti-rhinovirus activity is
The activity of a compound against a viral challenge in a cell line is measured using a plaque assay or a test tube test. Using a variety of test systems, compounds of Formula I have been found to be effective anti-rhinoviral agents when the test compound is administered before, simultaneously with, or after viral challenge. The utility of the compounds described herein as anti-rhinoviral agents has been demonstrated in a number of test systems.
For example, using a G-Hela (HeLa) cell culture, rhinovirus type 39 challenge at 30-100 TCID ₅₀ was added simultaneously with the test compound at a concentration of 4, 20 or 100 μg/ml, followed by cell culture for 48 hours. By microscopic observation of cell cultures, it was found that the compound of general formula I significantly inhibits the cytopathological effects of the virus compared to a cell culture medium containing only the virus. For example, the compound of Example 1 at a concentration of 4 μg/ml,
When cells are cultured with 100TCID ₅₀ rhinovirus type 39 challenge, the cytopathological effects of the virus are completely inhibited compared to the control. Similar results are achieved when the compound of Example 2 is tested in the same manner. In both cases, no cell toxicity was observed due to the compound itself at the tested concentrations and at concentrations up to 100 μg/ml. The compounds of Examples 1 and 2 were used to inhibit rhinovirus 25 at a concentration of 10 μg/ml using human fetal lung cells.
A wide range of activity was tested against bacterial strains. Example 1
The compound of Example 2, 6-(4-phenylphenoxy)hexan-1-ol, was active against 72% of the rhinovirus types tested, whereas the compound of Example 2, 6-(4-benzylphenoxy)hexan-1-ol, was active against 72% of the rhinovirus types tested. Enoxy)hexane-1-ol was used to treat 36 of the 25 rhinovirus types tested.
%. Rhinoviruses are known to be easily passed from an infected host to others, as is often the case, for example, within families, in classrooms, and among military personnel. Rhinoviruses are released from an infected person's nose, mouth, and eyes, are carried to the skin, especially on the hands and face, and are spread by handling objects, coughing, sneezing, breathing, and speaking. Susceptible individuals become exposed to rhinovirus infection through direct physical contact with an infected person, handling rhinovirus-contaminated materials, or breathing rhinovirus-containing air. Transfer between people infected with rhinovirus can be achieved by applying a compound of Formula I to the skin of an infected person to prevent the transfer of viable rhinovirus to other people or objects; to prevent viable rhinovirus from being carried and attached to the mucous membranes or conjunctiva of uninfected people by applying it to the skin of people who are not infected, and by applying it to surrounding objects.
To prevent the transfer of viable rhinovirus to uninfected people who touch the object, or by applying it to the air in a closed space to prevent viable rhinovirus released from an infected person from being transmitted to uninfected people. reduced by preventing inhalation.
For such purposes compounds can be used, for example, in skin creams, gels, lotions and powders, cleansers,
Can be made into a disinfectant rinse, aerosol or spray. In the treatment of rhinovirus infections, compounds of formula I can be administered orally, topically, e.g. intranasally,
and parenterally, eg, intramuscularly. Preferably, it is applied locally. The compounds are applied topically to the skin and membranes of the nose and eyes so that rhinovirus replication is inhibited at the site of application and systemically by absorption across the skin and mucous membranes. The compound is shown to be effective against rhinovirus-susceptible hosts.
It is preferable to administer it in the form of a preparation before or after the virus has invaded (even 12 hours after the virus has invaded). For prophylactic treatment, an effective amount of an anti-rhinovirus compound is administered for about 1 to 5 days before expected exposure to the virus and for about 5 to 10 days to about 5 to 15 days after exposure. be done. Therapeutic treatment includes, for example, administering an anti-rhinovirus effective amount of the compound after symptoms have begun or after exposure to rhinovirus, for example, for two weeks. Preventive or therapeutic treatments for rhinovirus infections include:
Any anti-rhinovirus effective amount of a compound of Formula I is used. The amount of compound necessary to achieve anti-rhinoviral efficacy will vary primarily depending on the method of administration. In therapeutic treatment, the amount of compound administered will also vary depending on the severity of the infection. For oral or parenteral treatment, the amount of compound administered is about 0.1 to 500 mg per kg of body weight of the patient or susceptible host;
Preferably from about 1 to about 100 mg/kg. The total daily dosage of the compound is desirably from about 100 mg to about 30 g. Typically, by administering unit doses from 1 to 6 times daily, containing from about 0.1 mg to about 1 g of the compound.
The desired effect will be achieved. For topical treatment, a composition containing an effective anti-rhinovirus concentration of the compound is applied to the mucus, conjunctiva, or epidermis in an amount sufficient to coat the area to be treated. Such compositions typically contain about 0.001 to 50%, preferably 0.01 to 5%, by weight of a compound of Formula I in a liquid or solid carrier. For example, the anti-rhinovirus effect is as follows: 0.1 ml of nasal spray containing 0.1-0.5 mg of the compound per ml instilled into each nostril.
This is achieved by instillation of 1 to 8 times daily. The active compound is added to a sustained release system in which the compound of formula I is gradually released from an inert or biodegradable carrier at a controlled and uniform rate during the treatment period, either by diffusion, osmosis or by decomposition of the carrier. It is administered even if it is distorted. Systems for delivering controlled-release drugs include patches or bandages applied to the skin or buccal, sublingual, or intranasal membranes, ophthalmic inserts placed in the cul-de-sac of the eye, or gradual It may be in the form of a tablet or capsule that is broken down, or a gastrointestinal container that is administered orally. When dosed in a system that distributes the drug by such sustained release, human tissues are treated with formula I
can be constantly exposed to therapeutically or prophylactically effective dosages of the compound over an extended period of time. A unit dosage of a compound administered by a sustained release system will be approximately equal to the daily effective dosage times the maximum number of days that the carrier should be in the host's body. The sustained release carrier may be in the form of a solid or porous matrix or container and may be formed from one or more natural or synthetic polymers, including modified or unmodified cellulose, Included are powders, gelatin, collagen, rubbers, polyolefins, polyamides, polyacrylates, polyalcohols, polyethers, polyesters, polyurethanes, polysulfones, polysiloxanes and polyimides, and mixtures, laminates and copolymers thereof. A compound of Formula I can be placed in a sustained release carrier in pure form or dissolved in a suitable liquid or solid excipient, including polymers to form a sustained release carrier. I can do it. The compounds of Formula I, together with a suitable pharmaceutical carrier, may be in the form of solid unit dosage forms such as tablets, capsules, powders, and troches, or suppositories, or embedded within a polymeric matrix. The powder can be taken orally;
It can be applied topically or by insufflation. For the preparation of solid unit dosage forms, it is desirable to micronize the compound used. In solid unit dosage forms, the compound may be present in the customary carriers, binders such as gum arabic, corn starch or gelatin, and disintegrants such as corn starch, guar gum, japonica starch or alginic acid, and stearin. It is combined with a lubricant such as acid or magnesium stearate and an inert filler such as lactose, sucrose or corn starch. The compounds of formula I can be administered orally, topically or parenterally in oils, water, alcohols or the like, with or without the addition of pharmaceutically suitable surfactants, suspending agents or emulsifying agents. It can also be administered as a suspension or solution using sterile liquid, such as a mixture. A particularly suitable mode of administration is a liquid formulation of the compound applied directly to the nasal passages, for example in the form of intranasal drops or spray. The liquid formulation may be applied directly to the eye as eye drops, or orally, or applied to the membranes of the oral cavity or pharynx as a gargle or mouthwash. Liquid formulations, including gels and ointments, can take the form of skin lotions and creams that are applied to the hands and face. Such lotions and creams may contain emollients, fragrances, or pigments, cosmetically acceptable humectants, astringents,
It can form shaving lotions, cologne waters, cosmetic foundations and similar products. Hand skin lotions containing compounds of formula I are particularly preferred for preventing the transfer of rhinovirus from infected to non-infected individuals. usually,
The topical anti-rhinovirus compositions of the present invention contain from about 0.01 to about 5 g of a compound of Formula I per 100 ml of composition. For liquid formulations, the compounds of the formula are suitably formulated with the substances listed below, with or without the addition of pharmaceutically suitable surfactants, suspending agents or emulsifying agents. For example, oils such as fixed oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil; fatty acids such as oleic acid, stearic acid and isostearic acid; ethyl oleate;
Fatty acid esters such as isopropyl myristate and fatty acid glycerides and acetylated fatty acid glycerides; ethanol, isopropanol,
Alcohols such as hexadecyl alcohol, glycerol, propylene glycol; glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol; ethers such as polyethylene glycol 400; petroleum carbonizations such as mineral oil and petroleum hydrogen; water; or mixtures thereof. Peanut oil and sesame oil are particularly useful in preparing intramuscular injection formulations. The oil is in the form of soft gelatin.
It can also be used in the preparation of suppository formulations. Glycerols such as water, saline, aqueous dextrose and related sugar solutions and polyethylene glycols, pectins, carbomers, methylcellulose,
Suspending agents such as hydroxypropyl cellulose, carboxymethyl cellulose, and optionally buffering agents and preservatives may be included in the preparation of liquid formulations. Soaps and synthetic detergents are used as surfactants and as vehicles for cleaning compositions. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids. Suitable detergents include cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkyl amine acetates, such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates. Anionic detergents such as aliphatic amine oxides, fatty acid alkanolamides and
Nonionic detergents such as polyoxyethylene polyoxypropylene copolymers, and alkyl β
- Amphoteric detergents such as aminopropionates and 2-alkylimidazoline quaternary ammonium salts,
and mixtures thereof. The cleaning composition may be in bar, powder or liquid form and may contain foaming agents, viscosity modifiers, antimicrobial agents, preservatives, softeners, colorants, fragrances and solvents. Such soaps and cleaning formulations are applied to textiles, surrounding surfaces and preferably to the skin. Preferred cleaning compositions are liquid soaps or synthetic detergents containing from about 0.01 to about 5 grams of a compound of formula per 100 ml of composition. Aerosol or spray preparations containing compounds of formula are used as disinfectants of spaces or applied to surrounding surfaces, skin or mucous membranes. The composition may contain a finely divided solid or liquid of the compound of formula and also include a solvent, buffer,
Contains surfactants, fragrances, antimicrobials, antioxidants and propellants. The composition is used with a pressurized propellant or without the use of a gas propellant in a compressible plastic spray bottle, atomizer or atomizer. A preferred aerosol or spray composition is a nasal spray. Pharmaceutical compositions for the treatment of rhinovirus infections contain, in addition to an anti-rhinovirus amount of a compound of the formula, one or more agents useful for treating the symptoms of rhinovirus infections in a suitable pharmaceutical carrier. You may do so. Agents known in the art to be effective in treating the symptoms of rhinovirus infection include antihistamines, decongestants, laxatives, analgesics, antitussives, expectorants, local anesthetics, and vitamin C. Examples of suitable antihistamines include terfenidine, doxylamine,
Included are chlorpheniramine, brompheniramine, metapyrylene, phenyndamine, phenyltoloxamine, azatadine, typrolidine, dimethindine, and pharmaceutically acceptable acid addition salts thereof. Preferred examples of decongestants include efuedrine, levodesoxyephedrine, phenylephrine, xylometazoline, naphthazoline, tetrahydrazoline, phenylpropanolamine, cyclopentamine, propylhexedrine,
Includes tuaminoheptane, methoxyphenamine and pharmaceutically acceptable acid addition salts thereof.
Examples of suitable antitussive agents include codeine, hydrocodone, ethylmorphine, noscapine, dextromorphan, carbetapentane, diphenylhydramine, and pharmaceutically acceptable salts thereof. Good examples of expectorants include guaifuenesin,
Terpine hydrate, sodium glycerophosphate, potassium guaiacol sulfonate, ammonium chloride,
Contains root root, eucalyptus oil, chloroform and menthol. Preferred examples of analgesics and laxatives include aspirin, salicylic acid, salicylamide, acetanilide, acetophenetidine, acetaminophene, antipyrine and aminopyrine. Good examples of local anesthetics include benzocaine, benzyl alcohol, phenols, and pharmaceutically acceptable salts thereof. The amount of each drug included in an anti-rhinovirus composition effective for treating the symptoms of rhinovirus infection will vary depending on the composition of the carrier and the drug contained therein. Examples of preferred pharmaceutical formulations and cleaning formulations are discussed below. Compounds of formula are generally prepared by Williamson ether synthesis. (J. March, “Advanced Organic Chemistry Reactions, Mechanisms and Structures”, McGraw-Hill Publishers,
New York, 1968, P316). The reaction is shown in the reaction diagram below. In the above reaction system, L represents a halogen such as chlorine, bromine, or iodine, or a sulfonate ester such as methanesulfonate or p-toluenesulfonate, and M ⁺ represents a metal salt such as lithium, sodium, potassium, silver, or mercury. where A and n are the same as defined in formula. The phenoxide salt of the formula is conveniently obtained in situ by addition of a base such as sodium methoxide, potassium carbonate, sodium hydride or potassium hydroxide to the corresponding phenol, with a leaving group on the terminal carbon atom. React with an alcohol of the formula. This leaving group is removed and the carbon-
Generates oxygen or carbon-sulfur ether bonds. The starting phenols, which are precursors to the phenoxide salts, are generally commercially available and obtained by fairly conventional synthetic methods well known in the art.
For example, benzyloxyphenol can be obtained by reacting benzyl halide with hydroquinone or resorcinol, or by reacting these monoesters, followed by hydrolysis. Benzylphenols are easily prepared by reduction of the corresponding hydroxybenzophenones. The latter can be obtained, for example, by Friedel-Crafts benzoylation of phenyl acetate, by the Fries rearrangement of phenyl benzoate or by oxidation of benzhydryl alcohol. Phenoxyphenols are produced by the Ullmann reaction of phenoxides and halophenyl esters in the presence of copper salts. See March, Advanced Organ Chemistry, p. 500 (McGraw-Hill, New York, 1968). Thiophenoxyphenols are prepared by reacting thiophenoxide salts with halophenyl esters, especially in amide solvents (ibid., pages 500-501). Phenylphenol is described in March, supra, 507~
Produced by the Ullmann reaction shown on page 508. The ω-substituted straight chain alcohol used in the reaction scheme is generally commercially available or obtained by known conventional synthetic methods. For example, α, ω−
The diol is converted to an ω-haloalcohol using triphenylphosphine and carbon tetrahalide (for the preparation of 12-bromododecan-1-ol, see Chemical Abstracts, Vol. 63,
13137c (1965)). Williamson reactions are carried out with or without solvent. Suitable solvents for the reaction include lower alcohols such as ethanol and isopropanol, ketones such as acetone and butanone, or amides such as dimethylformamide and dimethylacetamide. Other suitable solvents include dimethyl sulfoxide, acetonitrile, dimethoxyethane, tetrahydrofuran or toluene. The reaction temperature ranges from about 0° C. to the reflux temperature of the solvent, and the reaction time ranges from about 0.5 hours to 80 hours. The reaction can be worked up by extracting the product into ether, dichloromethane, chloroform, toluene, or other organic solvent, washing with brine, drying over sodium sulfate or magnesium sulfate, and evaporating the solvent. It's convenient. Purification is usually carried out by distillation or crystallization from a suitable solvent. Esters of compounds of formula can be prepared by conventional methods such as reacting an alcohol of formula with an acid, acid halide, acid anhydride or other activated acyl derivative, often in the presence of an acid acceptor. manufactured by The products are separated in a conventional manner;
Purified by distillation or crystallization from a suitable solvent. Salts of monoesters of polybasic acids can be prepared using bases such as
It is obtained by adding NaH to an ethereal solution of the ester and then filtering the formed precipitate. Example 1 6-(4-phenylphenoxy)hexane-1
-all p-phenylphenol (Eastman)
A mixture of 34.0 g (0.2 mol) of sodium methoxide (MCB) and 10.8 g (0.2 mol) of sodium methoxide (MCB) in 500 ml of dry dimethylformamide was heated on a steam bath and stirred for 0.5 h, then 6-chlorohexane-1 −
Add 27.3 g (0.2 mol) of all (MCB) and about 2 g of sodium iodide. The mixture is heated to reflux with stirring and then allowed to cool to room temperature. The reaction mixture is partitioned between ether/acetone and water, the organic phase is extracted with base, washed with water and brine,
Dry with Na ₂ SO ₄ and evaporate the solvent. The white solid product produced is recrystallized twice from methanol/acetone to obtain the desired product with a melting point of 103-105°C. Example 2 6-(4-Benzyloxyphenoxy)hexan-1-ol p-benzyloxyphenol (Eastman) 106.0 g (0.53 mol), sodium methoxide (MCB) 28.6 g (0.53 mol) and iodide After stirring a mixture of about 2 g of sodium in 600 ml of dimethylformamide for 5 minutes, 73 g (0.53 mol) of 6-chlorohexan-1-ol (MCB) are added and the mixture is then refluxed with stirring. Methanol produced in the reaction is distilled off. After refluxing for 2 hours, the mixture is diluted with ice and water, 500 ml of 10% potassium hydroxide is added, and the precipitate formed is collected and dried. Combine the solid with 1 part of butanone, reflux and filter. The residue consists of bis-(benzyloxyphenoxy)hexane by-product. Upon cooling the filtrate, the desired product crystallizes out. The solid product is stirred with acetone 1 at room temperature, the mixture is filtered to separate additional insoluble byproducts, the acetone is removed at the boil and replaced with methanol, and the methanol solution is then cooled to a melting point of 94~ Crystallize the desired product at 97°C. Example 3 6-(4-benzylphenoxy)hexane-1
-ol p-benzylphenol (Eastman)
40.0g (0.217mol) and 6-chlorohexane-1-
A mixture of 29.7 g (0.217 mol) of all (MCB) in 500 ml of dry dimethylformamide was stirred to approx.
Heat to 100℃, then 33.1g (0.24mol) of potassium carbonate
is added and the mixture is refluxed for 2.5 hours. Cool the mixture, pour into ice water and add 50 ml of 10% NaOH.
The mixture is extracted with ether, the ether extract is washed with water and brine, dried over Mg ₂ SO ₄ and the ether is evaporated. The resulting oil is redistilled to give a concentration of 140 to 175
The product is obtained as a water-white oil fraction distilled at 0.05 mmHg. Reference example 1 12-chlordodecane-1-ol Dodecane-1,12-diol (Aldrich
Chemical Company) 70.0g (0.347mol),
A mixture of 540.0 g (3.5 moles) of carbon tetrachloride in 1 part dry acetonitrile is heated to dissolve the diol, cooled to room temperature, flushed with argon,
Triphenylphosphine (Aldrich) 91.5g
(0.350 mol) is added over 15 minutes. A water bath is used to suppress the heat generated during the addition of triphenylphosphine and to keep the reaction mixture near room temperature. After the addition is complete, the mixture is stirred at room temperature for 1.5 hours and refluxed overnight. Then the capacity is 200ml
The solvent is distilled off under atmospheric pressure until the volume is reduced to . The oily residue is extracted with hexane, the combined hexane extracts are evaporated to dryness, and the resulting pale yellow oil is vacuum distilled. The desired product is obtained as a fraction at 140-150°C and 0.02 mmHg. Example 4 12-(4-phenylphenoxy)dotecan-1
-ol 12 produced in Reference Example 1 using p-phenylphenol instead of p-benzyloxyphenol and replacing 6-chlorohexane-1-ol.
The reaction mixture was diluted with ice water and the solid precipitate obtained after treatment with base was separated and dried, and then this was combined with butanone by the procedure described in Example 2 using -chlordodecane-1-ol. Recrystallization twice from 100 to obtain the desired product with a melting point of 113-114°C. Example 5 6-(3-phenylphenoxy)hexane-1
-ol 3-hydroxybiphenyl 15g (0.088mol), 6
- stirring a mixture of 13.3 g (0.097 mol) of chlorhexan-1-ol and 13.8 g (0.01 mol) of potassium carbonate in 250 ml of dry dimethylformamide;
Heat to reflux for 3 hours. Cool the mixture to room temperature,
Dilute with water and extract with ether, dry the ether extract and evaporate under reduced pressure to give a pale yellow oil. The crude product was vacuum distilled to 150-190℃ (0.05mmHg)
A boiling fraction is obtained and solidified to a soft solid corresponding to the pure desired product. Example 6 Using the procedure of Example 2, the following phenolic compounds can be reacted with the indicated haloalcohols to produce the compounds shown below (where Ph is phenyl).

[Table] Example 7 6-(4-benzyloxyphenoxy)-1-hexylmethanesulfonate 25 g (0.08 mol) of 6-(4-benzyloxyphenoxy)hexan-1-ol produced in Example 2. ) in 250 ml of pyridine is combined with 28.6 g (0.25 mol) of methanesulfonyl chloride (Eastman) and stirred for 3 hours at room temperature. The reaction mixture is partitioned between water and ether, the ether extract is washed, dried and evaporated to give the desired product with a melting point of 80-82°C. Example 8 Bis-4-(4-phenylphenoxy)-1-butylsulfite 4-(4-phenylphenoxy)butan-1-ol and thionyl chloride were prepared by the procedure of Example 13. Melting point 138-139℃ using excess amount of
The desired ester is obtained. Example 9 6-(4-Phenylphenoxy)hexylsuccinate (monoester) 10 g (0.037 mol) of 6-(4-phenylphenoxy)hexan-1-ol prepared in Example 1
and 10 g of succinic anhydride in 250 ml of pyridine is refluxed with stirring for about 3 hours. The pyridine is removed under vacuum on a steam bath and the residue is poured into water and acidified with hydrochloric acid. The generated precipitate was collected, washed with water, dried, and recrystallized from butanone to determine the melting point.
Obtain pure monoester at 113-115 °C. Pharmacological Effects G-Hea cells infected with the previously described rhinovirus strain 39 were cultured with the six compounds at various concentrations to examine inhibition of rhinovirus replication. The results are shown in Table 1.

[Table] Xanol succinate formulation example solution 6-(4-phenylphenoxy)hexane-1-
All 0.85g Alcohol 78.9ml Isopropyl myristate 5.0g Polyethylene glycol 400 (average molecular weight 400)
10.0g pure water Combine enough alcohol, isopropyl myristate and polyethylene glycol 400 to make 100ml and dissolve the drug substance therein. Add enough pure water to make 100ml. For 15,000 tablets : 75g of 6-(4-benzyloxyphenoxy)hexan-1-ol, 1.216Kg of lactose, 0.3Kg of cornstarch. Mix the active ingredient, lactose and cornstarch uniformly. Granulate with 10% starch paste. Dry until the moisture content is approximately 2.5%. Sieve through a No. 12 mesh sieve. Next, the following are added and mixed and compressed using a suitable tablet making machine to a weight of 0.115 g/tablet. Magnesium stearate 0.015Kg Sufficient amount of corn starch Quantity to make 1.725Kg Soft gelatin capsule 6-(4-Phenylphenoxy)hexane-1-
All 0.25Kg Polysorbate 80 (polyoxyethylene (20) sorbitan mono-oleate) 0.25Kg Sufficient amount of corn oil Amount to make 25.0Kg Mix in 50000 soft gelatin capsules,
Fill. Intramuscular injection A Oily type: 6-(4-phenylphenoxy)hexane-1-
All 25mg Butylated Hydroxyanisole
0.01% weight/volume butylated hydroxytoluene
0.01% weight/volume Sufficient amount of peanut oil or sesame oil Amount to make 1.0ml B Suspension type: 6-(4-phenylphenoxy)hexane-1-
All 25mg Sodium Carboxymethyl Cellulose
0.5% weight/volume Sodium bisulfite 0.02% weight/volume Sufficient water for injection Powder to make 1 ml Agent 6-(4-Phenylphenoxy)hexane-1-
All 1%wt/wt Anhydrous silicon dioxide 0.5wt/wt Corn starch, lactose fine powder, total amount
Nasal drops or spray 6-(4-phenylphenoxy)hexane-1- in an amount sufficient to make up to 50 kg.
All 0.10g Ethyl oleate 20.0g Butyretated hydroxyanisole 4.0mg Poloxamer 235 (poly(oxypropylene) poly(oxyethylene) copolymer surfactant, average molecular weight 46000) 25.0g Benzyl alcohol 4.7ml Enough to make the right amount amount of Sorensen buffer (a solution of sodium biphosphate and sodium phosphate made isotonic by the addition of sodium chloride)
50/50 mixture) Amount to make 500.0ml Nasal injection solution or spray 6-(4-Phenylphenoxy)hexane-1-
All 0.125 g Isostearic acid 5.0 g Poloxamer 215 (average molecular weight 42000) 12.5 g NaOH Enough to bring the pH to 7.6 Benzyl alcohol 4.7 ml Manitol powder 25.35 g Deionized water Enough to make 500 ml Hand Lotion 6-( 4-phenylphenoxy)hexane-1-
All 0.15g Isostearic acid 10.0g Stearic acid 8.0g Poloxamer 235 5.0g Propylene glycol 10.0g Deionized water Enough liquid soap to make 100.0ml Liquid soap 6-(4-phenylphenoxy)hexane-1-
All 0.3g soft soap tincture, NF 100ml liquid cleaning agent 6-(4-phenylphenoxy)hexane-1-
All 0.025g Milanol SM Concentrate
(Miranol SM Concentrate) [Miranol Chemical Company, Irvington, New Jersey] (35% 1-carboxymethyl-4,
5-dihydro-1-(2-hydroxyethyl)-2
-nonyl-1H-imidazolium hydroxide,
Sodium salt, 5% NaCl, pH 8.9-9.1) 25.0 g Laureth-4 (monolauryl ether of polyoxyethylene glycol containing an average of 4 oxyethylene groups) 2.0 g deionized water to 100 ml Enough amount to do.

Claims (1)

[Claims] 1 formula [In the formula, A is a bond, -CH ₂ - or -CH ₂ O-,
n is an integer from 4 to 12] or their esters with a pharmaceutically acceptable solubilizing acid selected from polyfunctional acids such as polycarboxylic acids, sulfonic acids, sulfurous acid, and sulfuric acid, or the above. An anti-rhinoviral agent comprising an anti-rhinoviral effective amount of a salt of an ester. 2. The anti-rhinovirus agent of claim 1, comprising an anti-rhinovirus effective amount of the above compound and a pharmaceutically acceptable carrier. 3 formulas [In the formula, A is a bond, -CH ₂ - or -CH ₂ O-,
n is an integer from 4 to 12] or their esters with a pharmaceutically acceptable solubilizing acid selected from polyfunctional acids such as polycarboxylic acids, sulfonic acids, sulfurous acids, and sulfuric acids; containing an anti-rhinovirus effective amount of a salt, applied to or administered to an environmental surface that is in contact with a host or patient, to inhibit the spread of rhinovirus infection to a host susceptible to and exposed to rhinovirus infection; An anti-rhinovirus agent according to claim 1 for preventing or treating patients suffering from symptoms of rhinovirus infection. 4. The anti-rhinovirus agent according to claim 3, wherein A is a bond or CH ₂ O. 5 Claim 3 in which A and -O(CH ₂ )nOH are mutually para in the benzene ring bonded to them.
Anti-rhinovirus agent. 6. The anti-rhinovirus agent according to claim 4, wherein n is 6. 7. The anti-rhinovirus agent according to claim 2 or 3, wherein the compound is 6-(4-phenylphenoxy)hexan-1-ol. 8. The anti-rhinovirus agent according to claim 2 or 3, wherein the compound is 6-(4-benzyloxyphenoxy)hexan-1-ol. 9 The compound is 6-(4-phenylphenoxy)-1
- The anti-rhinovirus agent according to claim 2 or 3, which is hexyl succinate. 10. The anti-rhinovirus agent according to claim 2 or 3, wherein the compound is 6-(4-benzyloxyphenoxy)-1-hexylmethanesulfonate. 11. The anti-rhinovirus agent of claim 3, wherein the compound is administered systemically to a patient suffering from rhinovirus infection in an amount of about 0.1 mg/Kg to about 1500 mg/Kg per patient body weight. 12. The anti-rhinovirus agent of claim 3, wherein the compound is administered intranasally. 13. The anti-rhinovirus agent of claim 3, wherein the compound is administered locally. 14 The compound is about 0.01g to about 5g per 100g of the composition
4. The anti-rhinoviral agent of claim 3, wherein the composition is applied to the skin of a host. 15. The anti-rhinovirus agent according to claim 2, which is in the form of nasal drops or spray. 16. The anti-rhinovirus agent of claim 15, wherein the compound is present in the liquid carrier at a concentration of 0.01 to 5%. 17. The anti-rhinovirus agent according to claim 2, which is in the form of a skin lotion, cream, gel or ointment. 18 Compound is about 0.01 to about 5g per 100ml of composition
18. The anti-rhinoviral agent of claim 17 present in an amount of . 19. The anti-rhinovirus agent of claim 2 in unit dosage form. 20 A patent claim containing in a carrier one or more agents effective in treating the symptoms of rhinovirus infection selected from antihistamines, decongestants, antipyretics, analgesics, antitussives, expectorants, and local anesthetics. An anti-rhinovirus agent according to item 2 of the scope. 21 formula [In the formula, A is a bond, -CH ₂ - or -CH ₂ O-,
n is an integer from 4 to 12] or polyfunctional acids such as polycarboxylic acids, pharmaceutically acceptable solubilizing acids selected from sulfonic acids, sulfurous acid, and sulfuric acids and their esters or salts of the above esters. A detergent composition comprising an anti-rhinovirus effective amount of and a detergent carrier. 22. The composition of claim 21 in liquid form. 23 The compound is about 0.01 g to about 100 ml of the composition.
22. The composition of claim 21, present in an amount of 5g. 24 formula [In the formula, A is a bond, -CH ₂ - or -CH ₂ O-,
n is an integer from 4 to 12] or polyfunctional acids such as polycarboxylic acids, pharmaceutically acceptable solubilizing acids selected from sulfonic acids, sulfurous acid and sulfuric acid and esters thereof, or esters thereof; salt. 25. The compound of claim 24, wherein A is a bond or _CH2O . 26 Claim 24, in which A and O(CH ₂ ) _o -OH are mutually para in the benzene ring bonded together.
compound of term. 27. The compound of claim 24, wherein n is 6. 28 The compound is 6-(4-phenylphenoxy)
Claim 2 which is hexan-1-ol
Compound of item 4. 29. The compound of claim 24, wherein the compound is 6-(4-benzyloxyphenoxy)hexan-1-ol. 30 The compound is 6-(4-phenylphenoxy)-
25. The compound of claim 24 which is 1-hexyl succinate. 31 6-(4-benzyloxyphenoxy)-1
-hexyl methanesulfonate. 32 (a) formula [wherein A is a bond _-CH2- or _-CH2O- ] is a compound of the formula L-( _CH2 ) _o -OH [wherein n is an integer from 4 to 12; and L
is Cl, Br, I or an equivalently reactive leaving group] in the presence of a base, and if necessary (b) reacting the alcohol produced in step (a) with Pharmaceutically acceptable solubilization selected from polyfunctional acids such as polycarboxylic acids, sulfonic acids, sulfites, and sulfuric acids by reaction with appropriate acids, acid chlorides, acid anhydrides, or other activated acyl derivatives. a formula consisting of forming an ester with an acid and, if necessary, (c) reacting the ester prepared in step (b) with a base to form its salt; A process for preparing compounds of the formula (A and n are as defined above), their esters with the pharmaceutically acceptable solubilizing acids described above, or salts of the esters described above.