NZ196163A - Aromatic ethers and thioethers of glycols and hydroxythiols,pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 96163 -r ' / -- // v 'j 0 Priority Date(s): .77.. ( i M i i i t k Com Co~ Class Publication Data: .... • 54--JUL >1084 P.O. Journal FJo: . • I%-IpP* NEW ZEALAND • «5 .A*.

PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFIC ATI Of [*"2 FEBI981' !£er "ANTI-RHINOVIRUS AGENTS" X/We, RICHARD SON-ME RRELL INC., a corporation organized under the laws of the State of Delaware, United States of America, of Ten Westport Road, Wilton, Connecticut 0689 7, United States of America, hereby declare the invention for which £/ we pray that a patent may be granted to^HK&is, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -■ (followed by page la) ^"^196 1 6 3 ANTI-RHINOVIRUS AGENTS FIELD OF INVENTION The present invention relates to substituted and unsubstituted biphenyl, benzylphenyl, benzyloxyphenyl and benzylthiophenyl ethers and thioethers of straight-chain cr,urglycols and hydroxythiols, and esters thereof with pharmaceutical^ acceptable acids, which are useful as anti-rhinovirus agents.

A few of these compounds are disclosed generically in the prior art, although their utility as anti-rhinovirus agents is not suggested.

SUMMARY OF THE INVENTION The anti-rhinovirus compounds of this invention have the general Formula I I wherein A is a bond or CHg", Y is a bond, 0 or S; X is 0 or S; Z and V are each H, alkyl, alkoxy, OH or halogen; and n is an integer from 4 to 12. Esters of compounds of Formula I with solubilizing pharma-csutically acceptable acids or salts of said esters are also included within the scope of this invention, as are pharmaceutical compositions comprising them and methods for preparing and using them. In a composition of matter aspect, this invention relates to said compounds of Formula I and esters thereof with pharmaceutically acceptable acids, except that when n is 4 and A is a bond, Z is other than Br or CI and Z' is other than Br, CH^O or isopropyl; when n is 5 and A and Y together are a bond, Z is other than CH-jO; and when n is 4-7 and A and Y together are a bond, Z is other than OH. The excluded compounds are within the generic teachings of the prior art. •^1961 6 - DETAILED DESCRIPTION OF THE INVENTION In the compounds of Formula I, the substituents A and Y preferably each are a bond or A is a group and Y is an oxygen atom. The substituent X preferably is an oxygen atom. The substituents X and Y may be disposed ortho, meta or para to one another on the benzene ring common to both, preferably meta or para, and most preferably in the para orientation.

The substituents Z and V each are, independently of one another, a hydrogen atom, a straight- or branched-chain alkyl or alkoxy group, a hydroxyl group, or a halogen atom. The alkyl groups are exemplified by methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The same alkyl groups linked to oxygen exemplify the alkoxy groups represented by Z or Z'. The halogen atom may be fluorine, chlorine, bromine or iodine. Both Z and V may be at any position of the benzene ring but preferably both are hydrogen atoms.

The linear, saturated carbon chain linking the group X with the hydroxyl group may range in length from 4 to 12 carbon atoms. Compounds having a chain length of 6 methylene units are preferred.

Preferred compounds according to the present invention are those wherein X - 0; A and Y, collectively, are a bond or C^O; Z and Z' are both a hydrogen atom; n = 6; and Y is para to X.

Esters of the-compounds of Formula I with pharmaceutically acceptable acids also show anti-rhinovirus activity. The alcohols are often difficulty soluble in water. Esterification with a solubilizing pharnia--ceutically acceptable acid, preferably a polyfunctional acid such as a polycarboxylic acid, a sulfonic acid, or sulfurous or sulfunit: acids, increases water solubility and facilitates absorption of the compound. Particularly desirable such esters include monoesters of polycarboxylic acids and/or the salts of such monoesters, preferably sodium salts.

Also advantageous are esters of polyhydroxylated acids or halogenated acids.

Suitable such esters include esters of polycarboxylic acids or polyfunctional monocarboxylic acids of 2-12 carbon atoms and 1-5 hydroxyl groups, e.g., glycolic, citric, maleic, succinic, gallic, fumaric, lactic, glyceric, tartaric, malic and sal icy! ic acids; and halo, alkoxy and/or acyloxy acids, e.g., chloroacetic, fluoroacetic, trichloroacetic, -3- -M-962- 1 9 6 1 trifluoroacetic, and 2,4,5-trimethoxybenzoic acid. Esters of these acids and the compounds of Formula I are prepared by methods well known to the art. Some, e.g., maleates and succinates are conveniently prepared by reacting the compound with maleic or succinic anhydride in pyridine, followed by acidification and isolation of the monoester.

Also included are esters of sulfonic acids e.g., methanesulfonic acid, and the like, and esters, preferably diesters, of sulfurous and sulfuric acids. Contemplated equivalents of the foregoing esters include any ester of a compound of Formula I which exhibits enhanced solubility in water compared to the alcohol from which it was prepared.

Illustrative compounds of this invention are 6-(4-phenylphenoxy)hexan-l-ol, 6-(4-phenylphenylthio)hexan-l-ol, 6-(4-phenoxyphenoxy)hexan-l-ol, 6-(4-phenoxyphenylthio)hexan-l-ol, 6-(4-phenylthiophenoxy)hexan-l-ol, 6-(4-phenylthiophenylthio)hexan-l-ol, 6-(4-benzylphenoxy)hexan-l-ol, 6-(4-benzylphenylthio)hexan-l-ol, 6-(4-benzyloxyphenoxy)hexan-l-ol, 6-(4-benzyloxyphenylthio)hexan-l-ol, 6-(4-benzylthiophenoxy)hexan-l-ol, and 6-(4-benzylthiophenylthio)hexan-l-ol.

Also included are compounds analogous to each of the foregoing having another unbranched alkylene chain of from 4 to 12 carbon atoms in place of the hexamethylene chain, e.g., 4-(4-phenoxyphenoxy)butan-l-ol through 12-(4-phenoxyphenoxy)dodecan-l-ol, and the corresponding alcohols in each series above.

Included also are isomers of each of the foregoing compounds having X and Y meta or ortho to one another on the central benzene ring common to both, e.g., 8-(3-benzyloxyphenoxy)octan-l-ol, ll-(2-phenylthiophenoxy)undecan-l-ol, and the corresponding ortho and meta isomers of each of the other compounds hereinabove. -4- -M-962- | C; -C <?. /I. * ^ i! v,; Additional-compounds of this invention include the p-fluoro substituted analogue of each of the above free alcohols and esters, e.g., 6-[4-(4-fluorophenyl)phenoxy]hexan-l-ol, 4-[4-(4-fluorophenoxy)phenoxy]butan-l-ol, 8-[3-(4-fluorobenzyloxy)phenoxy]octan-l-ol and 6-[4-(4-fluorophenyl)phenoxy]-l-hexyl succinate.

Other examples are the ortho-fluoro and meta-fluoro isomers of each of the foregoing compounds, and the analogous compounds having a chlorine, bromine or iodine atom in place of the fluorine atom.

Still further specific illustrations of the compounds of the invention are the monofluoro-substituted compounds having a fluorine atom at an available position on the central benzene ring corresponding to each of the unsubstituted alcohols and esters named hereinabove, e.g., 6-(4-phenyl-3-f1uorophenoxy)hexan-l-ol, 8-(3-benzy1oxy-4-f1uorophenoxy)octan-1-ol, 8-(3-benzyloxy-5-fluorophenoxy)octan-l-ol, 4-(4-phenoxy-2-fluorophenoxy)-1-butyl glycol ate, and the central ring monofluoro-substituted compounds otherwise corresponding to each of the other unsubstituted alcohols and esters hereinabove but substituted at another available position on the central benzene ring. The compounds analogous to the foregoing with a chlorine, bromine or iodine atom in place of the fluorine atom are further specific examples of compounds of this invention.

Other examples of specific compounds of this invention are those corresponding to each of the foregoing monofluoro-substituted alcohols and esters named hereinabove, but having a methyl group rather than the fluorine atom as the substituent, those having a methoxy group in place of the fluorine atom and those having a hydroxy group in place of the fluorine atom.

Other examples are compounds wherein both the terminal benzene ring and the central benzene ring each bear a single fluorine atom thereon, in positions analogous to each of the above monofluoro compounds, e.g., 6-[4-(4-fluorophenyl)-2-fluorophenoxy]hexan-l-ol, and the 2,4'- difluoro-substituted compounds otherwise corresponding to each of the other unsubstituted alcohols and esters named hereinabove. 1 96 1 6 Analogous compounds having a chlorine, bromine or iodine atom, a hydroxy group, or an alkyl or alkoxy group as exemplified hereinabove in place of either or both of the fluorine atoms in each of the foregoing difluoro-substituted compounds further illustrate the compounds of this invention.

Also included are pharmaceutically acceptable esters of each of the above alcohols with various acids, more specifically, monoesters with citric, maleic, glycolic, glyceric, succinic, fumaric, lactic, malic, tartaric and methanesulfonic acids, and diesters with sulfurous and sulfuric acids.

The compounds of Formula I and suitable esters thereof are useful as antirhinovirus agents. (With regard to their use as antirhinovirus agents, reference to "the compounds of Formula I" embraces suitable pharmaceutical^ acceptable esters thereof.) The rhinovirus subgroup is a member of the picornavirus group and contains over 100 different antigenic types and is known to be responsible for many of the symptoms attendant respiratory infections. The name rhinovirus is indicative of the prominent nasal involvement seen in infections with these viruses, resulting in syndromes characteristic of the common cold. Rhinoviruses have been classified as serotypes 1 to 89 and subtypes 1A(88,89,90) with at least 20 more types to be added to the classification. Experimental studies indicate that nasal mucosal cells are more susceptible to rhinovirus than are the cells of the lower respiratory tract. The symptoms of rhinovirus infection have also been produced experimentally by dropping small amounts of the virus on the conjunctiva, indicating that the eye is another susceptible site of infection. Developed rhinovirus infection is characterized by hyperemia and edema of the mucous membrane with exudation of serous and mucinous fluid. The nasal cavities are narrowed by thickening of the membrane and engorgement of the turbinates.

The compounds described herein have been found to be effective antiviral agents against numerous types of rhinovirus, rendering said compounds useful in treating the symptoms of a rhinovirus infection in hosts susceptible to said infections, including humans and certain anthropoid apes, such as the chimpanzee. It is known in the art that several test systems can be employed to measure antiviral activity against rhinovirus. For example, antirhinovirus activity can be -6- -**«-1 96 1 6 3 measured using a plaque assay or tube test wherein the activity of the compound against virus challenge in a cell system is measured. Using a variety of test systems, it was found that compounds of Formula I are effective antirhinovirus agents when the test compound is given prior to, concurrently with, or subsequent to virus challenge.

The utility of the compounds described herein as antirhinovirus agents has been demonstrated in a variety of test systems. For example, using G-HeLa cell cultures to which a rhinovirus type 39 challenge of from 30 to 100 TCIDgQ is added concurrently with test compounds at a concentration of 4, 20 or 100 ng/ml, after which the cell cultures are incubated for 48 hours, it was found upon microscopic examination of the cell cultures that compounds of general Formula I markedly inhibit the cytopathic effect of the virus when compared to cell cultures containing virus challenge alone. For example, when the compound of Example 1 at a concentration of 4 jjg/ml was added to cell cultures together with a rhinovirus type 39 challenge of 100 TCID^, the cytopathic effect of virus was completely inhibited when compared to control. The same result was achieved when the compound of Example 2 was tested in a similar manner. In neither case was there observable cytotoxicity due to the compounds themselves at the concentration tested, and at concentrations up to 100 Mg/ml- The compounds of Examples 1 and 2 were tested for broad-spectrum activity against 25 strains of rhinovirus at concentrations of 10 pg/ml using human embryonic lung cells. The compound of Example 1, 6-(4-phenylphenoxy)hexan-l-ol, was active against 72% of the rhinovirus types tested, while the compound of Example 2, 6-(4-benzyloxyphenoxy)hexan-l-ol was active against 36% of the 25 rhinovirus types tested.

It is known that rhinovirus is readily transmitted from one susceptible host to another as commonly occurs, for example, among family members, in classrooms, and in military populations. Rhinovirus is shed from the nose, mouth and eyes of infected individuals, is carried on the skin, particularly of the hands and face, and may be released into the environment by handling objects and by coughing, sneezing, breathing and speaking. Susceptible individuals may become exposed to rhinovirus infection by direct physical contact with infected individuals, by handling rhinovirus-contaminated objects, or by breath- 1 96 1 6 -7- -M-96T* 1 ^ ing rhinovirus-bearing air. Interpersonal transmission of rhinovirus infection may be diminished by application of a compound of Formula I to the skin of infected individuals, preventing the transfer of viable rhinovirus to other individuals or to objects; to the skin of uninfected individuals, preventing viable rhinovirus from being carried thereon to the mucosa or the conjunctiva of such uninfected individuals; to environmental objects, preventing the transfer of viable rhinovirus to uninfected individuals contacting the objects; or to the air of enclosed spaces, preventing the inhalation by uninfected individuals of viable rhinovirus shed by infected individuals. For such purposes the compound may be, for example, in the form of a skin cream, gel, lotion or powder, a detergent composition or disinfectant rinse, or an aerosol or spray.

In the treatment of symptoms of rhinovirus infection, the compounds of Formula I can be administered orally, topically, for example, intranasal^, and parenterally, for example, intramuscularly. Topical administration is preferred. The compounds may be applied topically to the skin or the membranes of the nose, mouth and eye, replication of rhinovirus being blocked at the site of administration and, by means of transdermal or transmucosal absorption, systemically.

The compounds are administered preferably in the form of a pharmaceutical preparation to a host susceptible to rhinovirus infection either prior to or after invasion of virus, even as late as 12 hours after invasion. For prophylactic treatment, it is contemplated that an antirhinovirus effective amount of compound be administered for from about 1 to 5 days prior to anticipated exposure to virus and for from about 5 to 10 days subsequent to exposure or for from about 5 to about 15 days subsequent to exposure to rhinovirus. For therapeutic treatment, for example, an antirhinovirus effective amount of compound may be administered after onset of symptoms or after exposure to rhinovirus for e.g., two weeks.

For prophylactic or therapeutic treatment of rhinovirus infection, any antirhinovirus effective amount of a compound of Formula I may be employed. The amount of compound required to achieve an antirhinovirus effect will vary depending primarily upon the mode of administration. For therapeutic treatment the amount of compound administered will also vary depending on the severity of the infection. For oral or parenteral "^196 1 6 treatment the amount of compound administered will vary from about 0.1 mg/kg to 500 mg/kg of body weight of the patient or susceptible host, preferably from about 1 mg/kg to about 100 mg/kg. Preferably, the total amount of compound administered daily will vary from about 100 mg to about 30 g. Typically, a unit dose containing from about 0.1 mg to about 1 g of compound administered from 1 to 6 times daily will achieve the desired effect. For topical treatment an amount sufficient to coat the area to be treated of a composition containing an antirhinovirus effective concentration of compound will be applied to the mucosa, conjunctiva or epidermis. Such compositions will typically contain 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. An antirhinoviral effect will, for example, be attained by 0.1 ml of a nose drop containing from 0.1 to 0.5 mg/ml of compound instilled into each nostril from 1 to 8 times daily.

The active compound may also be administered by means of a sustained release .system whereby the compound of Formula I is gradually released at a controlled, uniform rate from an inert or bioerodible carrier by means of diffusion, osmosis, or disintegration of the carrier, during the treatment period. Controlled release drug delivery systems may be in the form of a patch or bandage applied to the skin or to the buccal, sublingual or intranasal membranes, an ocular insert placed in the cul de sac of the eye, or a gradually eroding tablet or capsule or a gastrointestinal reservoir administered orally. Administration by means of such sustained release delivery systems permits the tissues of the body to be exposed constantly for a prolonged time period to a therapeutically or prophylatically effective dosage of a compound of Formula I. The unit dosage of the compound administered by means of a sustained release system will approximate the amount of an effective daily dosage multiplied by the maximum number of days during which the carrier is to remain on or in the body of the host. The sustained release carrier may be in the form of a solid or porous matrix or reservoir and may be formed from one or more natural or synthetic polymers, including modified or unmodified cellulose, starch, gelatin, collagen, rubber, polyolefins, polyamides, polyaerylates, polyalcohols, polyethers, polyesters, polyurethanes, polysulphones, polysiloxanes and ^196 1 6 polyimides and mixtures, laminae, and copolymers thereof. The compound of Formula I may be incorporated in the sustained release carrier in a pure form or may be dissolved in any suitable liquid or solid vehicle, including the polymer of which the sustained release carrier is formed.

The compounds of Formula I together with suitable pharmaceutical carrier can be in the form of solid unit dosage forms such as tablets, capsules, powders and troches, in the form of a suppository, or embedded in a polymeric matrix. The powders can be administered orally, topically or by insufflation. In the preparation of solid unit dosage forms it may be desirable to micronize the compound to be employed. In solid unit dosage forms the compounds can be combined with conventional carriers, for example, binders, such as acacia, corn starch or gelatin, disintegrating agents, such as 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 may also be administered as liquid suspensions or solutions using a sterile liquid, such as an oil, water, an alcohol, or mixtures thereof, with or without the addition of a pharmaceutically suitable surfactant, suspending agent, or emulsifying agent for oral, topical or parenteral administration. A particularly suitable mode of administration is a liquid formulation of the compounds applied directly to the nasal cavity, for example, in the form of a nose drop or spray. Liquid formulations may also be administered directly to the eye as an eye drop, administered orally, or applied to the membranes of the oral cavity and pharynx as a gargle or mouthwash. Liquid formulations, including gels and ointments, may take the form of skin lotions and creams for application to the handsi and face. Such lotions and creams may contain emollients, perfumes, or pigments to form cosmetically acceptable moisturizers, astringents, shaving lotions, colognes, cosmetic foundations, and similar preparations. A skin lotion for use on the hands comprising a compound of Formula I is especially preferred for prevention of transfer of rhinovirus infection from infected to uninfected individuals. In general, a topical antiviral composition of this invention will contain from about 0.01 g to about 5 g of a compound of Formula I per 100 ml of the composition. *•** 1 96 16 For liquid-preparations, the compounds of Formula I can be formulated suitably with oils, for example, 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; and fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides; with alcohols, such as ethanol, iso-propanol, hexadecyl alcohol, glycerol and propylene glycol; with glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol; with ethers, such as polyethyleneglycol 400; with petroleum hydrocarbons, such as mineral oil and petrolatum; with water; or with mixtures thereof; with or without the addition of a pharmaceutical^ suitable surfactant, suspending agent or emulsifying agent.

Peanut oil and sesame oil are particularly useful in preparation of formulations for intramuscular injection. Oils can also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols, such as polyethyleneglycol, may be employed in the preparation of liquid formulations which may suitably contain suspending agents, such as pectin, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives. Soaps and synthetic detergents may be employed as surfactants arid as vehicles for detergent compositions. Suitable soaps include fatty acid alkali jnetal, ammonium, and triethanolamine salts. Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides', fatty acid alkanolamides, and polyoxyethylenepolyoxypropylene copolymers; and amphoteric detergents, for example, alkyl p-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof. Detergent compositions may be in bar, powder or liquid form and may incorporate foam builders, viscosity control agents, antimicrobial agents, preservatives, emollients, coloring agents, perfumes, and solvents. Such soap and detergent formulations may be applied to textiles, to environmental surfaces and, preferably, to the skin. A 196 | preferred detergent composition is a liquid soap or 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 spray preparations containing compounds of Formula I may be used as space disinfectants or for application to environmental surfaces, to skin, or to mucous membranes. Such compositions may contain a micronized solid or a solution of a compound of Formula I and may also contain solvents, buffers, surfactants, perfumes, antimicrobial agents, antioxidants and propel 1 ants. Such compositions may be applied by means of a propel!ant under pressure or may be applied by means of a compressible plastic spray bottle, a nebulizer or an atomizer without the use of a gaseous propellent. A preferred aerosol or spray composition is a nasal spray.

Pharmaceutical compositions for treatment of rhinovirus infection may contain, in addition to an antirhinoviral amount of a compound of Formula I, in an appropriate pharmaceutical carrier, one or more agents useful for the treatment of symptoms of rhinovirus infection. Agents known in the art to be useful for symptomatic treatment of rhinovirus infection include antihistamines, decongestants, antipyretics, analgesics, antitussives, expectorants, local anesthetics and vitamin C. Examples of suitable antihistamines include terfenidine, doxylamine,. chlorpheniramine, brompheniramine, metapyrilene, phenindamine, phenyl-toloxamine, azatadine, tiprolidine and dimethindine and their pharmaceutical^ acceptable acid addition salts. Examples of suitable decongestants include ephedrine, levodesoxyephedrine, phenylephrine, xylometazoline, naphthazoline, tetrahydrazoline, phenylpropanolamine, « eye1 opentarnine, propylhexedrine, tuaminoheptane and methoxyphenamine and their pharmaceutical ly acceptable acid addition salts. Examples of suitable antitussives include codeine, hydrocodone, ethylmorphine, noscapine, dextromorphan, carbetapentane and diphenylhydramine and their pharmaceutical ly acceptable salts. Examples of suitable expectorants include guaifenesin, terpin hydrate, sodium glycerophosphate, potassium guaiacolsulfonate, ammonium chloride, ipecac, eucalyptus, chloroform and menthol. Examples of suitable analgesic and antipyretic agents include aspirin, salicylic acid, salicylamide, acetanilide, acetophenetidin, acetaminophen, antipyrine and aminopyrine. Examples of suitable local 196163 anesthetics Include benzocaine, benzyl alcohol and phenol and their pharmaceutically acceptable salts. The amount of each medicament included in the antirhinoviral pharmaceutical composition effective for the symptomatic treatment of rhinovirus infection will vary according to the composition of the carrier and the agent included in it.

Illustrative examples of suitable pharmaceutical and detergent formulations are set forth hereinbelow.

The compounds of Formula I are generally prepared by the Williamson ether synthesis (J. March, "Advanced Organic Chemistry -Reactions, Mechanisms and Structure", McGraw-Hill Book Company, New York, 1968, p. 316). The reaction is illustrated in the following reaction scheme: -0--A X©M©+UlCH2).n*0H II III In the above reaction sequence, L represents a halogen atom, such as chlorine, bromine or iodine or an equivalent reactive leaving group such as a sulfonate ester, eg: methanesulfonate or p-toluenesulfonate; M represents a metal salt such as lithium, sodium, potassium, silver or mercury and A, X, Y, Z, Z* and n are as defined for Formula I.

A phenoxide or thiophenoxide salt, represented by structure II, and conveniently formed in situ by addition of a base such as sodium raeth-oxide, potassium carbonate, sodium hydride or potassium hydroxide to the corresponding phenol or thlophenol, is reacted with an alcohol bearing a leaving group on the terminal carbon atom, and having the structure III. The leaving group is displaced, resulting in the formation of a carbon-oxygen or carbon-sulfur ether or thioether bond.

The starting phenols which are the precursors of the phenoxide salts are generally commercially available, or available by entirely conventional synthetic methods well-known in the art. For example, benzyloxyphenols can be prepared by reaction of benzyl halides with hydroquinones or resorcinols, or with their monoesters, with subsequent hydrolysis. 196 1 6 The benzyl phenols are readily prepared by reduction of the corresponding hydroxybenzophenones. The latter are prepared, for example, by Friedel-Crafts benzoylation of phenyl acetate, by Fries rearrangement of phenyl benzoates, or by oxidation of benzhydryl alcohols.

Phenoxyphenols may be prepared by the Ullmann reaction of a phenoxide and a halophenyl ester, in the presence of copper salts. See March, "Advanced Organic Chemistry", page 500 (McGraw-Hill, New York, 1968). Thiophenoxyphenols are prepared by reacting thiophenoxide salts with halophenyl esters, especially in amide solvents (ibid., pp. 500-501).

Phenyl phenols may be prepared by the Ullmann reaction, as shown in March, op. cit.. pp. 507-508.

Halogenated phenols may also be prepared by reaction of a phenol with halogenating agents, such as sulfuryl chloride, according to conventional methods.

The thiophenols which are the precursors of the thiophenoxide salts II, as well as thiol analogs of the mononuclear phenolic intermediates mentioned above, may be obtained from the corresponding phenols by converting the phenol to its N,N-dimethylthiocarbamate with dimethyl-thiocarbamoyl chloride, thermally rearranging it to the N,N-dimethyl-thiolcarbamate, followed by alkaline hydrolysis, acidification, extraction and isolation of the thiophenol. This reaction is carried out in substantially the same way as the conversion of p-naphthol to p-thio-naphthol reported in Fieser and Fieser, "Reagents for Organic Synthesis, Vol. 2", pages 173-174 (Wiley Interscience, New York, 1969).

The ursubstituted linear alcohols III used in the sequence are also generally available commercially or by well-known, conventional synthetic methods. For example, the a.urdiol may be converted to the urhaloalcohol using triphenylphosphine and carbon tetrahalide (see C.A., 63, 13137c (1965) for the preparation of 12-bromododecane-l-ol).

The Williamson reaction may be carried out with or without solvents. 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, tetrahydro-furan or toluene. *** 1 96 1 6 The temperature of the reaction may vary from about 0°C to the reflux temperature of the solvent, and the reaction time may vary from about 0.5 hour to 80 hours.

The reaction is conveniently worked up by extraction of the product into an organic solvent, such as ether, dichloromethane, chloroform, toluene, or the like, washing with brine, drying over sodium or magnesium sulfate, and evaporation of the solvent. Purification is generally effected by distillation or crystallization from a suitable solvent.

Esters of compounds of Formula I are formed by conventional methods, such as reaction of the alcohol of Formula I with an acid, an acid halide, an anhydride, or other activated acyl derivative, often in the presence of an acid acceptor. The product is isolated in a conventional fashion and purified by distillation or crystallization from an appropriate solvent. Salts of monesters of polybasic acids are prepared by addition of base, e.g., NaH, to an ether solution of the ester, followed by filtration of the resultant precipitate.

EXAMPLE 1 6-(4-Phenylphenoxy)hexan-l-ol A mixture of 34.0 g (0.2 mole) of p-phenylphenol (Eastman) and 10.8 g (0.2 mole) of sodium methoxide (MCB) in 500 ml of dry dimethyl-formamide is heated and stirred on a steam bath for 0.5 hour, after which 27.3 g (0.2 mole) of 6-chlorohexan-l-ol (MCB) and about 2 g of sodium iodide are added. 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, and the organic phase is extracted with base, washed with water and brine, dried (Na2S0^), and the solvent evaporated. The resultant white solid product is recrys-tallized twice from methanol/acetone, to give the desired product, m.p. 103-105°C.

EXAMPLE 2 6-(4-Benzyloxyphenoxy)hexan-l-ol A mixture of 106.0 g (0.53 mole) of p-benzyloxyphenol (Eastman), 28.6 g (0.53 mole) sodium methoxide (MCB) and about 2 g of sodium iodide ~196 1 6 3 in 600 ml of dimethylformamide is stirred for 5 mintues, after which 73 g (0.53 mole) of 6-chlorohexan-l-ol (MCB) is added, and the mixture is refluxed with stirring. The methanol formed in the reaction is allowed to distill off. After 2 hours reflux, the mixture is diluted with ice and water, 500 ml of 10% potassium hydroxide is added, and the resultant precipitate collected and dried. The solid is combined with 1 liter of butanone, refluxed and filtered. The residue consists of by-product bis-(benzyloxyphenoxy)hexane. The filtrate is cooled, whereupon the desired product crystallizes out. The solid product is stirred with 1 liter of acetone at room temperature, the mixture is filtered to separate additional insoluble by-product, the acetone boiled off and replaced with methanol, and the methanolic solution cooled to crystallize out the desired product, m.p. 94-97°C.

EXAMPLE 3 6-(4-Benzylphenoxy)hexan-l-ol A mixture of 40.0 g (0.217 mole) of p-benzylphenol (Eastman) and 29.7 g (0.217 mole) of 6-chlorohexan-l-ol (MCB) in 500 ml of dry dimethyl-formamide is stirred and heated to about 100°C, after which 33.1 g (0.24 mole) of potassium carbonate is added, and the mixture refluxed for 2.5 hours. The mixture is cooled, poured into ice-water, and 50 ml of 10% NaOH is added. The mixture is extracted with ether, the ether extracts washed with water and brine, dried (Mg2$0^), and the ether evaporated. The resultant oil is redistilled to give the product as a water-white oil fraction distilling at 140-175°C, 0.05 mmHg.

EXAMPLE 4 12-Chlorododecane-l-ol A mixture of 70.0 g (0.347 mole) of dodecane-l,12-diol (Aldrich Chemical Company) and 540.0 g (3.5 moles) of carbon tetrachloride in 1 liter of dry acetonitrile is heated to dissolve the diol, cooled to room temperature, flushed with argon, and 91.5 g (0.350 mole) of triphenyl-phosphine (Aldrich) is added over 15 minutes. A water bath is used to control 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, 1 96 1 6 then refluxed overnight. The solvent is then distilled off under atmospheric pressure until the volume is reduced to 200 ml, and then under high vacuum. The oily residue is extracted with hexane, the combined hexane extracts evaporated to dryness, and the resultant light yellow 5 oil is vacuum distilled. The desired product is obtained as a fraction distilling at 140-150°C, 0.02 mmHg.

EXAMPLE 5 12-(4-Phenylphenoxy)dodecane-l-ol By the procedure described in Example 2, but using p-phenylphenol 10 in place of p-benzyloxyphenol and using the 12-chlorododecane-l-ol prepared in Example 4 in place of 6-chlorohexan-ol, the solid precipitate, obtained after the reaction mixture is diluted with ice-water and treated with base, is isolated, dried, and recrystallized twice from butanone to produce the desired product, m.p. 113-114°C.

EXAMPLE 6 4-Phenylthiophenol Following the procedure for converting p-naphthol to p-thionaphthol, in Fieser and Fieser "Reagents for Organic Synthesis, Volume 2", pages 173-174 (Wiley Interscience, New York, 1969), p-phenylphenol is reacted 20 with dimethylthiocarbamoyl chloride (Aldrich Chemical Company) to form biphenylyl dimethylthiocarbamate. A 10 g (0.04 mole) portion of the latter compound is heated to 300-320°C for 45 minutes in an argon atmosphere, cooled, and the reaction mixture dissolved in 250 ml of ethanol. The ethanolic solution is heated to reflux, treated with 50 ml of aqueous 25 20% K0H, reflux continued for 1 hour, and the ethanol 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 HC1, cooled and extracted with ether, the ether layer washed with water, dried, and evaporated to dryness. Recrystallization of the crude 30 product from ethanol gives the pure desired product, m.p. 108-111°C.

EXAMPLE 7 6-(4-Phenylphenylthio)hexan-l-ol A mixture of 8.2 g (0.044 mole) of p-phenylthiophenol prepared in Example 6 and 6.9 g (0.015 mole) of potassium carbonate in 200 ml of dimethylformamide is stirred for 15 minutes at room temperature under an argon atmosphere. Then 6.8 g (0.05 mole) of 6-chlorohexan-l-ol is added, the mixture heated to reflux with stirring for 2 hours, cooled, diluted with water, and extracted with ether/acetone. The combined organic extracts are washed with water, dried, and evaporated to dryness. The resultant crude solid product is vacuum distilled to give a fraction coming over at 110-180°C (0.1 mmHg), m.p. 112-115°C. Recrystallization from acetone gives the pure desired product, m.p. 114-115°C.

EXAMPLE 8 2—Chioro-4-benzyloxyphenol A.mixture of 20.0 g (0.1 mole) of p-benzyloxyphenol (Eastman) in 250 ml of glacial acetic acid is stirred at room temperature until a clear solution is obtained. Then, 14.8 g (0.11 mole) of sulfuryl chloride, previously filtered through sodium carbonate, is added over the course of 0.5 hour, the mixture stirred at room temperature for 3 hours, then warmed on a steam bath for 1 hour, and evaporated to dryness under reduced pressure. The resultant crude solid product is recrystallized from ether/bexane to give the pure desired product, m.p. 78-80°C.

EXAMPLE 9 6-(3-Phenylphenoxy)hexan-l-ol A mixture of 15.0 g (0.088 mole) of 3-hydroxybiphenyl, 13.3 g (0.097 mole) of 6-chlorohexan-l-ol, and 13.8 g (0.01 mole) of potassium carbonate in 250 ml of dry dimethylformamide is stirred and heated to reflux for 3 hours. The mixture is cobled to room temperature, diluted with water, and extracted with ether, the ether extracts dried and evaporated under reduced pressure to give a light yellow oil. The crude product is vacuum distilled to give a fraction boiling between 150 and 190°C (0.05 mmHg), and solidifying to a soft solid, corresponding to the pure desired product.

EXAMPLE 10 Using the procedure of Example 2, the following phenolic compounds may be reacted with the indicated haloalcohols to produce the compounds shown below (Ph = phenyl): 196 1 6 Phenol * Haloalcohol Product M. P.

(°C) p-Ph-Ph-OH 4-Cl-(CH2)4-0H p-Ph-Ph-0-(CH2)4-0H 110- ■113° p-Ph-Ph-OH -Cl-(CH2)5-0H p-Ph-Ph-0-(CH2)5-0H o CO 1 ■109° p-Ph-Ph-OH 8-Cl-(CH2)8-0H p-Ph-Ph-0-(CH2)8-0H 103- ■106° p-Ph-Ph-OH io-ci-(ch2)10-oh p-Ph-Ph-0-(CH2)1(J-0H 107- ■108° p-(Ph-CH2-0)-Ph-0H 4-Cl-(CH2)4-0H p-(Ph-CH2-0)-Ph-0-(CH2)4- •0H 97- •99° p-(Ph-CH2-0)-Ph-0H -Cl-(CH2)5-0H p-(Ph-CH2-0)-Ph-0-(CH2)5- ■OH 90- ■93° EXAMPLE 11 By the procedure described in Example 9, 2-chloro-4-benzyloxyphenol , prepared in Example 8, is reacted with 6-chlorohexan-l-ol to produce 6-(2-chloro-4-benzyloxyphenoxy)hexan-l-ol, as a light yellow oil, distilling between 185 and 200°C (0.02 mmHg).

By the procedure described in Example 9, 2-chloro-4-phenylphenol (Eastman) is reacted with 6-chlorohexan-l-ol to produce 6-(2-chloro-4-phenylphenoxy)hexan-l-ol, m.p. 64-65°C.

EXAMPLE 12 6-(2-Hydroxy-5-phenylphenoxy)hexan-l-ol and 6-(2-hydroxy-4-phenylphenoxy)hexan-l-ol A mixture of 55.9 g (0.3 mole) of 4-phenylpyrocatechol (Eastman) and 52.8 g'(0.38 mole) of potassium carbonate in 500 ml of dry dimethyl-formamide is stirred at room temperature. 45.1 g (0.33 mole) of 6-chlorohexan-l-ol is added, the reaction flask is flushed with nitrogen and stirred at room temperature for 48 hours, then heated to reflux for 5 hours. The reaction mixture is cooled, diluted with water, acidified with IN HCli and extracted with ether. The ether layer is washed with water, dried and evaporated to dryness. The semi-solid residue is vacuum distilled in an evaporative still. Fractions coming over at 150-170°C, 180-200°C and 220-240°C (0.1 mmHg) are collected. The 180-200°C fraction is recrystallized from acetone/hexane to give the 2,4-substituted product. The 220-240°C fraction is recrystallized from acetone/hexane to give the diether, m.p. 80-82°C. Additional 2,4-substituted product is obtained from the residue of distillation of the 150-170°C fraction. The mother liquors of the earlier crystallizations are combined and vacuum distilled, and fractions coming over at 160-165°C, 170-190°C and 210-220°C (0.1-0.05 mmHg) are obtained. The 160-165° fraction is crystallized from acetone/hexane, combined with the aforementioned distillation residue, and recrystallized, to give pure 2,4-product, m.p. 122-123°C. The mother liquor from the crystallization is evaporated to dryness and redistilled, and a fraction taken at 160-165°C (0.05 mmHg) corresponding to the pure 2,5-product.

EXAMPLE 13 6-(4-Benzyloxyphenoxy)-l-hexyl methanesulfonate A mixture of 25 g (0.08 mole) of 6-(4-benzyloxyphenoxy)hexan-l-ol, prepared in Example 2, in 250 ml of pyridine is combined with 28.6 g (0.25 mole) of methanesulfonyl chloride (Eastman) and stirred at room temperature for 3 hours. The reaction mixture is partitioned between water and ether, the ether extracts are washed, dried and evaporated, to give the desired product, m.p. 80-82°C.

EXAMPLE 14 Bis-4-(4-phenylphenoxy)-l-buty1 sulfite By the procedure of Example 13, using 4-(4-phenylphenoxy)butan-l-ol and an excess of thionyl chloride, the desired ester is obtained, m.p. 138-139°C. - >•- EXAMPLE 15 6-(4-Phenylphenoxy)r-l-hexyl succinate (monoester) A mixture of 10 g (0.037 mole) of 6-(4-phenylphenoxy)hexan-l-ol, prepared in Example 1, and 10 g of succinic anhydride in 250 ml of pyridine is refluxed with stirring for 3 hours. The pyridine is removed under vacuum on a steam bath, the residue poured into water and acidified with HC1. The resultant precipitate is collected, washed, dried and recrystallized from butanone, to give the pure monoester, m.p. 113-115°C.

EXAMPLE 16 Solution 6-(4-Phenylphenoxy)hexan-l-ol 0.85 g Alcohol 78.9 ml Isopropyl Myristate 5.0 g Polyethylene Glycol 400 (Av. M.W. 400) 10.0 g Purified Water sufficient to make 100 ml Combine the alcohol, isopropyl myristate and polyethylene glycol 400 and dissolve the drug substance therein. Add sufficient purified water to give 100 ml.

EXAMPLE 17 Tablet For 15,000 6-(4-Benzyloxyphenoxy)hexan-l-ol 75 g Lactose 1.216 kg Corn Starch 0.3 kg Mix the active ingredient, the lactose and corn starch uniformly. Granulate with 10% starch paste. Dry to a moisture content of about 2.5%. Screen through a No. 12 mesh screen. Add and mix the following: Magnesium Stearate 0.015 kg Corn Starch sufficient to make 1.725 kg Compress on a suitable tablet machine to a weight of 0.115 g/tablet.

EXAMPLE 18 Soft Gelatin Capsule 6-(4-Phenylphenoxy)hexan-l-ol 0.25 kg Polysorbate 80 ( Polyoxyethylene (20) sorbitan mono-oleate) 0.25 kg Corn Oil sufficient to make 25.0 kg Mix and fill into 50,000 soft gelatin capsules. -21- ^M'90fr EXAMPLE 19 19 IM Injections A. Oil Type: 6-(4-Phenylphenoxy)hexan-l-ol 25 mg Butylated hydroxyanisole 0.01% w/v Butylated hydroxytoluene 0.01% w/v Peanut Oil or Sesame Oil sufficient to make 1.0 ml B. Suspension Type: 6-(4-Phenylphenoxy)hexan-l-ol 25 mg Sodium Carboxymethylcellulose 0.5% w/v Sodium Bisulfite 0.02% w/v Water for injection, sufficient to make 1.0 ml EXAMPLE 20 Powder 6-(4-Phenylphenoxy)hexan-l-ol 1% w/w Silicon dioxide, anhydrous 0.5% w/w Corn starch, lactose, fine powder - each, with the total sufficient to make 50 kg EXAMPLE 21 Nasal Drop or Spray 6-(4-Phenylphenoxy)hexan-l-ol 0.10 g Ethyl oleate 20.0 g Butylated hydroxyanisole 4.0 mg Poloxamer 235 (Poly(oxypropylene)poly(oxyethylene) copolymer surfactant, Av. M.W. 46,000) 25.0 g Benzyl alcohol 4.7 ml Sorensen Buffer (A 50/50 mixture of sodium biphosphate solution and sodium phosphate solution rendered isotonic by addition of sodium 30 chloride) sufficient to make 500.0 ml

Claims (32)

-22- 96 1 6 EXAMPLE 22 Nasal Drop or Spray 6-(4-Phenylphenoxy)hexan~l-ol 0.125 g Isostearic acid 5.0 g 5 Poloxamer 215 (Av. M.W. 42,000) 12.5 g NaOH sufficient to achieve ph 7.6 Benzyl alcohol 4.7 'ml Mannitol powder 25.35 g Deionized water sufficient to make 500 ml 10 EXAMPLE 23 Hand Lotion 6-(4-Phenylphenoxy)hexan-l-ol 0.15 g Isostearic acid 10.0 g Stearic acid 8.0 g 15 Poloxamer 235 5.0 g Propylene glycol 10.0 g Deionized water sufficient to make 100.0 ml EXAMPLE 24 Liquid Soap 20 6-(4-Phenylphenoxy)hexan-l-ol 0.3 g Green soap tincture, NF 100 ml EXAMPLE 25 Liquid Detergent 6-(4-Phenylphenoxy)hexan-l-ol 0.025 g 25 Miranol SM Concentrate ® (Miranol Chem. Co., Irvington, N.J.) (35% 1-Carboxymethyl-4,5-dihydro-l-(2-hydroxyethyl)-2-nonyl-lH-imidazolium hydroxide, sodium salt, 5% NaCl, pH 8.9-9.1) 25.0 g 30 Laureth-4 (Monolauryl ethers of polyoxyethylene glycols containing an average of 4 oxyethylene groups) 2.0 g Deionized water sufficient to make - 100 ml -23- CLAIM IS: .

1. A pharmaceutical composition which comprises an antirhinovirus effective amount of a compound of the formula x-tch2)n-0h wherein A is a bond or CH2; Y is a bond, 0 or S; X is 0 or S; Z and V are each H, alkyl, alkoxy, OH or halogen; and n is an integer from 4 to 12; or an ester thereof with a soliiailizing pharmaceutically acceptable acid or a salt of said ester; and a pharmaceuticany acceptable carrier, m

2. A composition of Claim 1» wherein A and Y collectively are a bond or CH20; X is 0; and Z and Z1 are each H. »

3. A composition of Claim wherein the compound is 6-(4-phenylphenoxy)hexan-l-ol.

4. A composition of Claim l, wherein the compound is 6-(4-benzyloxyphenoxy)hexan-l-ol.

5. The composition of Claim 1, wherein the compound is 6-(4-phenyl phenoxy)-l-hexyl succinate.

The composition of Claim '1* wherein the compound is 6-(4-benzyloxyphenoxy)-l-hexyl methanesulfonate.

7. A composition of Claim l, which is in the form of a nasal drop or spray.

8. The composition of Claim 7„ wherein the compound is present \\ in a concentration of from 0.01 to 5% by weight in a liquid carrier.

9. A composition of Claim which is in the form of a skin lotion, cream, gel or ointment.

10- A composition of Claim wherein the compound is present in an amount of from 0.01 to 5 grams per 100 ml of the com position. 0 < 1 / u I -24-

11. A composition of Claim 1, which is in unit dosage form.

12. A composition of Claim 1, which has included in the carrier one or more agents effective for symptomatic treatment of rhinovirus infection selected from antihistamine, decongestant, antipyretic, analgesic, antitussive, expectorant and local anesthetic agents.

A detergent composition which comprises an antirhinovirus effective amount of a compound of the formula O X-(CH2)n-0H wherein A is a bond or CH2; Y is a bond, 0 or S; X isO or S; Z and Z' are each H, C^_4 alkyl, C^_4 alkoxy, OH or halogen; and n is an integer from 4 to 12; or an ester thereof with a solubilizing pharmaceutically acceptable acid or a salt of said ester; and a detergent carrier.

14. A composition of Claim 13, which is in liquid form.

.15. A composition of Claim 14? wherein the compound is present in an amount of from 0.01 to 5 grams per 100 ml of the com position.

16. A compound of the formula o X-(CH2)n-°H wherin A is a bond or CH2; Y is a bond, 0 or S; X is 0 or S; Z and Z' are each H, C^4 alkyl, C^4 alkoxy, OH or halogen; and n is an integer from 4 to 12; with the proviso that when n is 4 and A is a bond, Z is -25- other than Br or CI and Z' is other than Br, CH^O or isopropyl; when n is 5 and A and Y together are a bond, Z is other than CH^O; and when n Is 4-7 and A and Y together are a bond, Z is other than OH; or an ester thereof with a solubilizing pharmaceutically acceptable acid or a salt of said ester.

17. A compound of Claim ,16,wherein X is oxygen.

18. A compound of Claim 16, wherein A and Y collectively are a bond or Q^O.

I9* A compound of Claim 16, wherein Z and Z' are each H.

20., A compound of Claim *6, wherein X and Y are para to one another on the benzene ring to which both are joined.

21. A compound of Claim 16, wherein A and Y collectively are a bond or CHgO; X is 0; and Z and Z' are each. H.

22. A compound of Claim 16, wherein n is 6.

23. A compound of Claim 16>, wherein the compound is 6-(4-phenylphenoxy)hexan-l-ol.

24. A compound of Claim 16, wherein the compound is 6-(4-benzyloxyphenoxy)hexan-l-ol.

25. A compound of Claim 16 ^ wherein the compound is 6-(4-pheny1phenoxy)-l-hexyl succinate.

26. A compound of Claim 16,, wherein the compound is 6-(4-benzyloxyphenoxy)-l-hexyl methanesulfonate. -26-

27.. A process for preparing a compound of the formula O X-CCH2ln-0H wherein A is a bond or CH2; Y is a bond, 0 or S; X is 0 or S; Z and V are each H, C^4 alkyl, alkoxy, OH or halogen; and n is an integer from 4 to 12; 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, CH^O, or isopropyl; when n is 5 and AY together are a bond, Z is other than CH^O; and when n is 4-7 and AY together are a bond, Z is other than OH; or an ester thereof with a solubilizing pharmaceutical^ acceptable acid or a salt of said ester; which comprises the step of (a) reacting a compound of the formula O wherein A, X, Y, Z and Z1 are as defined hereinabove; with a compound of the formula L"(CH2)n'0H wherein n is as defined hereinabove; and L is CI, Br, I or an equivalent reactive leaving group; said reaction being effected in the presence of base; and, optionally, (b) reacting the alcohol produced in step (a) with the appropriate acid, acid chloride, acid anhydride or other activated acyl derivative to form an ester thereof with a solubilizing pharmaceutical^ acceptable acid; and, optionally, (c) reacting the ester produced in step (b) with base to produce the salt thereof. 1961,63 -27-

28. A composition as claimed in any one of claims 1 to 12 substantially as hereinbefore described with reference to any example thereof.

29* - A composition as claimed in any one of claims - J. P. & 1 .r ^ to ^ substantially as hereinbefore described with M( reference to any example thereof.

30. a compound as claimed in any one of claims 16 to 26 substantially as hereinbefore described with reference to any example thereof.

31. A process as claimed in claim 27 when performed substantially as hereinbefore described.

32. The product as defined in claim 16 of the process as claimed in claim 27 or 31. ^. .TED THIS ^ ' DAY OF 19 <3U- A. J. PARK & SON PER AGENTS FOR THE APPLICANTS