CA1181760A - Anti-rhinovirus agents - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Compounds having antirhinovirus activity, and effective in a method for prophylaxis and treatment of a rhinovirus infection, have the formula

Description

~8~'71!~i - ANTl-RIIINOVIRUS AGENTS

FIELD OF INVENTION
_ The present invention relates to substituted and unsubstituted biphenyl, benzylphenyl, benzyloxyphenyl and benzylthiophenyl ethers and thioethers of C4_12 straight-chain a,w-glycols and hydroxythiols, and esters thereof with pharmaceutically acceptable acids, which are use~ul 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 INVENlIO;~
Tne anti-rhinovirus compoùnds of thi â i nvention have the general Formula I
~ ~ 3 ( ~2~n o~

wherein A is a bond or C~12; Y iâ a bondl O or S; X is O or S; Z nd ~' are each H, C1_4 alkyl, Cl_4 alkoxy, OH or halogen; and n ia an integer from 4 to 12. Esters OT compounds of Formula I with solub;li~ing pharma-reutically acceptable acids or salts of said esters are also include~ Wi~hill the scope of thiâ invention, as are pharmaceutical compositions comprisingthem and methods for preparing and using them. In a compos-ition of matter aspect, this invention relates to said compounds of Formula I and eaters thereoT with pharmaceutically acceptable acids, except tha~ when n is ~ ~nd A is a bond, Z is other than Br or ~1 and ~' is other than ~r, CH~O or isopropyl; when n is 5 and A and `, ~oge~hen are 2 bond, ~ is other ~han CH30; and when n is 4-7 and A and `( together are a bond, Z is other tnan ~H.
The ~xcluded compounds are within the ger.eric teach,ngs of the ~rior art.

t -2- ~L~l~3l 76~ M-962 ^ DETAILED DESC~IPTION OF THE INVENTION
In the compounds o~ Formula I, the substituents A and Y pref ra~ly each are a bond or A is a CH2 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 b~n~ene ring common to both, preferably meta or para, and most preFerably in the para orientation.
The substituents Z and 7' each are, independ~ntly of one another, a hydrogen atom, a straight- or branched-chain alkyl or alkoxy group, a hydroxyl group, or a halogen a~om. The alkyl groups are exemplified by methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The same alkyl groups linked to oxyyen exempli~y the alkoxy groups represented by Z or 2'. The halogen atom may be fluorine, ch10-rine, bromine or iodine. Both 2 and Z' may be at any position of the benzene ring but preferably both are hydrogen atoms.
The linear~ saturatod carbon chain linking the group X with the hydroxyl group may range in lPngth from 4 to 12 carbon atoms. Compounds having a chain length of 6 methylene units are preferred.
Preferred compounds according to the present in~Jention are those wherein X - O; A alld Y, collectively, are a bond or CH20; Z and 7' are both a hydrogen atom; n = 6j and Y is para to X.
Esters of the compounds of Formula I with pharmaceutically accept-able acids also show anti~rhinovirus activity. The alcohols are oft~n dif,iculty soluble in wat~r. Esterification with a solubilizing pharma-25 ceutically acceptable acid, preferably a polyfunctional acid such a5 apolycarboxylic acid, a sulfonic acid, or sulfurous or ;ulfuric acids, increases water solubility and facilitakes absorption of the compound.
Particularly desirable such esters include manoesters of polycarboxylic acids and/or the salts of such monoesters, preferably sodium salts.
Also advantageous are esters of polyhydroxylated acids or hdlogenated acids.
Suitable such esters include es~ers of polycarboxylic ac;ds or polyfunctional monocarboxylic acids of 2-12 CarDOn ato~5 and 1-5 hydroxyl ~roups, e.g., glycolic, citric, maleic, succinic, ga11i~ fumaric, lactic, glyceric, tartaric, malic andsalicylic acids; and halo, alkoxy and~or acyloxy acids, e . g ., ch l or caceti c , f l uoroac~t i c , trichloroac2tic, t' ~3~ ~ 962 trifluoroacetic, and 2,4,5-trimethoxybell2Oic acid. Esters of these acids and the compounds of Formula I are preparecl by methods well known to the art. Some, e.g., maleates and succinates are conven-iently prepared by reacting the compound with malPic or succin;c anhydride in pyridine, followed by acitiification and isola~ion 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 fore-going esters ;nclu~e any ester of a compound of Formula I which exhibitsenhanced solubility in water compared to the alcohol from which it was prepared.
Illustrative compounds of this invention are 6-(4-phenylphenoxy)hexan-1-ol, 6-(4-phenylphenylthio)hexan-1-ol, 6-~4-phenoxyphenoxy)hexan-1-ol, 6-t4-phenoxyphenylthio)hexan l-ol, 6 (4-phenylthiophenoxy)hexan-1-ol, 6-~4-phenylthiophenylthio)hexan-1-ol, 6-~4-benzylphenoxy)hexan-1-ol, 6-~4-benzylphenylthio)hexan-1-ol, 6-(4-~enzyloxyphenoxy)hexan-1-ol, 6-(4-benzyloxyphenylthio)hexan-1-ot, 6-(4-benzylthiophenoxy)hexan-1-ol, and 25 . 6-(4^benzylthiophenylthio)hexan-1-ol.
Also included are compounds analo~ous to each of the foregoing having another unbranched alkylene chain of from 4 to 12 carbon atoms in place o~ the hexamethylene chain, e.g., 4-(4-phenoxyphenoxy)butan-1-ol through 12-(4-phenoxyphenoxy)dodecan-1-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-1-ol, 11-(2-phenylthiophenoxy)undecan-1-ol, and the corresponding ortho and meta isomers of each of the other compounds hereinabove.

-4~ 91.'760 M-962 Add;t;onal-compounds of this ;nvent;on include the p-fluoro sub-st;tuted analogue of each of the above free alcohols and esters, e.g., 6-[4-(4-fluorophenyl)phenoxy]hexan-1-ol, 4- E4- (4-fluQrophenoxy)phenoxy]butan-l-Ol, 8-[3-(4-fluorobenzyloxy)phenoxy~octan l-ol and 6-~4-(4-fluorophenyl)phenoxy~-1-hexyl succinate.
Other examples are the ortho-fluoro and meta~fluoro isomers of each of the foreso;ng compounds, and the analogous compoùnds having a chlorine, bromine or ;odine atom in place of the fluorine atom.
Still further spec;~ic illustrations of the compounds of the invention are the monofluoro-substituted compounds having a fluorine atom at an available posit;on on the central benzene ring corresponding to each of the unsubst;tuted alcohols and esters named hereinabove, e.g., 6-(4-phenyl-3-fluorophenoxy~hexan-1-ol, 8-(3-ben~yloxy-4-fluorophenoxy)octan-1-ol, 8-(3-benzyloxy-5-fluorophenoxy)octan-1-ol, 4-(4-phenoxy-2-fluorophenoxy)-1-butyl glycolate, and the central ring mono~luoro-substi~uted compounds otherw;se 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 specif k examples of compounds of this invention.
Other examples of specifi~ compounds of this invention are those corresponding to each of the foregoing monofluoro-substituted alcohols and esters named her~inabova, but having a methyl group rather than thP
fluorine atom as ~he substituent, those having a methoxy group in place of the fluorine atom and those having a hydroxy group in placP Ot the fluorine atom.
Other examples arP compounds wherein both the terminal ~en~ene ring and the central ben~ene ring each bear a single fluor;ne atom thereon, in positions analogous to eaeh of the above monofluoro compounds, e.g., 6-~4-(4-fluorophenyl)-2-fluorophenoxy]hexan-1-ol, and the 2,4'- difluoro-subst;tuted compounds otherwise corresponding to aach of the other 3~ unsubstituted alcohols and esters named hereinabove.

- ~ -5~ M 962 Analogous compounds havin~ 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 fluor;ne 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 w;th various acids, more spec;fically, monoesters with citric, maleic, glycolic, glycer;c, 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 a~ents, reference to "the compounds of Formula I" embraces suitable pharmaceutically acceptable esters thereof.) The rhinovirus subgroup i5 a member of the picornavirus group and csntains over 100 different anti~enic 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 ;n infections w;th these viruses, resulting in syndromes characteristic of the common cold. Rhinoviruses have been classified as serotypes 1 to 89 and subtypes 1A~88,89,90j with at least 20 more types to be added to the classification. ~xperimental studies ;ndicate that nasal mucosal cells are more susceptible to rhino-virus than are the eells of the lower resp;ratory tract. The symptoms of rhinovirus infection have aiso been produced experimentally by drop-ping small amounts of the v;rus on the conjunctiva, ;nd;cating that the eye is another susceptible site of infection. Developed rhinovirus infection is character;zed by hyperemia and edema of the mucous m~mbrane with exudation o~ serous and mucinous fluid. The nasal cavities are narrowed by thickenjng o~ the membrane and engor~ement of the turbinates.
The compounds described here;n have been found to be effective antiviral agents against numerous types of rh;nov;rus, rendering said compounds useful in treating the symptoms of a rhinovirus infection in hosts susceptiblP to said infections, including humans and certa;n - anthropoid apes, such as the chimpanzee. It is known in the art that several test systems can be employed to measure antiviral act;vity against rhinovirus. For example, antirhinovirus activity can be ..... .. .. .. .. .. . . . .. .. . .. . . . . ... ... . .. ... ... . .

-6~ ~L~ G~ 962 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 antirh;novirus agents when the test compound is given prior S to, concurrently with, or subsequPnt to virus challenge.
The utility of the compounds described herein as antirhinovirus agents has been demonstrated in a variety of test systems. Fnr example, using G-HeLa cell cultures to which a rhinovirus type 39 challenge of Prom 30 to 100 TCID50 is added concurrently with test compounds at a concentration of 4, 20 or 100 ~g/ml, after which the cell cultures are incubated for 4$ hours, it was found upon microscop;c examination of the cell cultures that compounds of general Formula I markedly inhibit the cytopathic effect of the virus when compared to cell cultures containins vir~s challenge alone. For example, when the compound of Example 1 at 2 concentration of 4 ~g/ml was added to cell cultures togeth~r with a rhinovirus type 39 challenge of 100 TCID50, the cyto~athic 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 ~anner. In neither case was there observable cytotoxicity due to the compounds themselves at the concentration tested, and at con-centrations up to 100 ~g/ml.
The compounds of Examples 1 and 2 were tested for broad-spectrum activity against 25 strains of rhinovirus at concentrations of 10 ~gfml using human embryonic lung cells. The compound of Example 1, 6-(4-phenylphenoxy)hexan-1-ol, was active against 7Z~O OT thP rhinovirus types tested, wh;lc the compound of Example 2, 6-(4-ben~yloxyphenoxy)hexan-1-ol.was active against 36~ of the 25 rhinovirus types tested.
It i5 known that rhinovirus is readily transmitted from one susceptible host to another as commonly occurs, for example, among family members, in classrooms, and ;n military populations. Rhinovirus is shed from the nose, mouth and eyes Gf infected individuals, ;s carried on the sk-in, particularly of the hands and face, and may be released into the environment by handling objects and by coughing, - snee2ing, br ath;ng and speaking. Susceptible individuals may become 3~ exposed to rhinovirus infection by direct physical contact with infected individuals, by handling rhinovirus-contaminated objects, or by breath-ing rhinovirus-bearing air. Interpersonal transmission of rhinovirus infection may b~ 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; ~o en~
vironmental objects, preventing the transfer of viable rhinovirus to uninfected individuals contactin~ the ohjects; or to -the air of enclosed spaces, preventing the inhalation by uninfected individuals of vidble rhinovirus shed by infected ;ndividuals. 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 r;nse, 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, intra-lS nasally, and parenterally, for example~ intramuscularly. Topical admin-istration is preferred. The compounds may be applied topically to the skin or the membranes of the nose, mouth and eye, replication of rnino-virus being blocked at the site of administration and, by means transdermal or transmucosal absorption, systemically.
The compounds are administered preferably in the form of a phar-maceutical preparation to a host susceptible to rh;novirus infection ~ither prior to or after inva~ion 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 treat-ment, for example, an antirhinovirus effectiv~ amount of compound may b~
administered after onset of symptoms or after exposure to rhinovirus for e.g., two weeks.
For prophylactic or therapeut;c tr2atment of rhinovirus infection, any antirhinovirus ~ffect;ve amount of a compound of Formula I may be employed. The amount of compound required to achievP an antirhinovirus - ef~ect will vary depending primarily upon the mode of administration.
for ther~peutic treatment the amount of compound administered will also vary d~pending on the severity of the infection. For oral or parenteral 7~
S~ 9G2 treatment the a~ount of compound administered will vary from about 0.1 mg/kg to 500 mg/kg of body weight of the pa-tient 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 9~ Typically, a unit dose containing from about 0.1 mg to about 1 9 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 composit;ons will typically contain from about 0.001 to SO~ by weight, preferably from 0.01 to 5% by we;ght o~ a compound of Formula I in a liquid or solid carrier. An antirhinoviral effect will, for example, ~e 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 act;ve compound may also be administered by means of a sus-tained release system whereby the compound of Formula I is gradually released at a con~rolled, un;form rate from an inert or bio2rodible carrier by means of diffusion, osmosis, or disintegrat;on of the car-rier, during the treatment period. Controlled release drug deliverysystems may be in the form of a patch or bandage applied to the skin or to the buccal, su~lingual or ;ntranasal 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. Admir,-istration by means of such sustained release dPlivery systems permitsthe t;ssues of the body to be eYposed constantly for a prolonged time period to a therapeutically or prophylatically ~ffective dosage of a compound of Formula I. The unit dosage ~f the compound administered by means of a sustained release system will approximate the amount of an effect;ve daily dosage multiplied by the maximum number of days during which the carrier is to remain on or in the body of the hos~. The susta;ned release carrier may be in the form of a solid or porous matri~
or reservoir and may be formed from one or more natural or synthetic polymers, ; ncl ud;ng modified or unmodif;ed cellulose, starchl gelatin, 3~ collagen, rubber, polyole~ins, polyamides, polyacrylates, polya7conols, polyethers, polyesters, polyurethanes, polysulphones, polysiloxanes and -9~ 962 po1yimides and ~ixtures, laminae, and copolymers thereof The compound of Formula I may be incorporatPd 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 carr;er ;s formed.
The compounds of Formula I together with suitable ph~rmaceutical 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 f~rms 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 ;nert f;llers, 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 Por oral3 topical or parenteral administration. A particularly su;table mode of administration is a liquid formulat;on of the compounds applied directly to the nasal cavi~y, 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, adm;nistered orally, or applied to the membranes of the ora1 cavity and pharynx as a gargle or mouthwash. Liquid formu-lations, including gels and ointments, may take the form cf skin lotions and creams for application to the hands and face. Such lotions and creams may contain emollients, perfumes, or pigments to form cosmetic-ally acceptable moisturizers, astringents, shaving lotions, colognes, cosmetic foundations, and similar preparations. A skin loti3n for uso on the hands comprising a compound of Formula I is especially preferred for prevention of transfer of rhinovirus infection from ;nfected to uninfocted individuals. In general, a topical antiviral composition of this inven~ion will contain from about 0.01 g to about ~ g of a compound of Formula I per 100 ml o~ the composition.

-lo~ 7~ M-962 For liquîd-preparations, the compounds of Formula I can be form-ulated 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 ac;d and isostearic acid; and fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid ~lycerides; with alcohols, such as ethanol, iso-propanol, hexadecyl alcohol, glycerol an~ propylene glycol; with gly-cerol 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 pharmaceutically sui~able surfactant, suspending agent or emulsifying agent.
Peanut oil and sesame oil are particularly useful ;n preparation of formulations for intramuscular injection. Oils can also be employed in the preparation of formulations of the soft gelatin type and supposi-tories. Water, saline, aqueous dextrose and relat~d 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 cellulosP or carboxymethyl cellulose, as wel1 as buffers and preserva-tives. Soaps and synthetic detergents may be employed as surfactants and as vehicles for detergent compositions. Suitab1e soaps inc1ude fatty acid alkali metal, ammonium, and tr;ethanolamine salts. Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetatas;
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 polyoxyethylenepDlyoxypropylen2 ropo1 ymers; and amphoteric detergents, for example, alkyl ~-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, perfum2s, and solvents. Such soap and detergent formulations may be applied to textiles, to environmental surfaces and, preferably, to the skin. A

~ 962 preferred detergent compos;tion is a liquid soap or syn-thetic detergent composition comprising from about 0.01 to about 5 g of a compound of Formula I per lO0 ml of the composition.
Aerosol or spray preparations containing compounds of Formula I may be used as space disinfec~ants or for application to environmental surfaces, to skin, or to mucous membranes. Such composit~ons may con-tain a micronized solid or a solution of a compound of Formula I and may also contain solvents, buffers, surfactants, perfumes, antimicrobial agents, antioxidants and propellants. Such compositions may be applied by means of a propellant under pressure or may be applied by means of a compressible plastic spray bottle, a nebulizer or an atoml~er without the use of a gaseous propeltent. A preferred aerosol or spray compo-sition is a nasal spray.
Pharmaceutical compositions for treatment of rhinovirus infect;on may contain, ;n add;t;on to an antirhinoviral amount of a compound ofFormula I, in an appropriate pharmaceutical carrier, one or more agPnts useful for the treatment of symptoms of rhinovirus infect;on. Agents known in the art to be useful for symptomat;c treatment of rhinovirus infection include antihistamines, decongestants, antipyretics, anal-gesics, antitussives, expectorants, local anesthetics and vitamin C.Examples of suitable antihistam;nes ;nclude t~rfenid;ne, doxylamine,~
chlorphen;ram;ne, brompheniramine, metapyrilene, phenindaminP, phenyl-toloxamine, azatadine, tiprol;dine and dimeth;ndine and the;r pharma-ceutically acceptable acid addition salts. Examples of suitable decon-gestants include ephedrine, levodesoxyephedrine, phenylephrine,xylometazoline, naphthazol;ne, tetrahydrazoline, phenylpropanolamine, cyclopentamine, propylhexedrine, tuaminoheptane and methoxyphenamine and their pharmacPutically acceptab1e acid addition salts. Examples of suitable antitussives include codeine, hydrocodone, ethylmorphine, noscapine, dextromorphan, carbetapen~ane and diphenylhydramine and their pharmaceutically acc~ptable 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, an~ipyrine and aminopyrine. Examples of suitable local -12~ 76~ 1-9~2 anesthetics inc~ude benzocaine, benzyl alcohol and phenol and their pharmaceutically acceptable salts. The amount of each medicament included in the ant;rhinoviral 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 pharmaceu~ical and detergent formulations are set forth hereinbelow.
The compounds sf 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, 1968l p.
316). The reaction is illustrated in the following reaction scheme:

Z ~ A--Y ~ X ~ M ~ ~L~CHzln~OH ~ r II III
In the above reaction sequence, L represents a halogen atom, such as chlorine, bromine or iodine or a sul~onate ester, such as methane-sulfonate or p-toluenesulfonate; M represents a metal salt such as lithium, sodium, po~assium, silver or mercury; and A, X, Y, Z, I' and n are as defined for Formula I.
A phenoxide or thiophenoxide salt, represented by structure II, and conveniently formed in situ by add;tion OT a base such as sodium meth-oxide, potassium carbonate, sodium hydride or potassium hydroxide to the corresponding phenol or thiophenol, 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-oxyg n or carbon-sulfur ether or thioether bond.
The starting phenols ~hich are the precursors of the phenoxide - salt~ are generally commercially available9 or available by entirely conventional synthetic methods well-known in the art. For example, ~G benzyloxyphenols can be prepared by reaction of ben~yl halides with hydroquinones or resorcinols, or with their monoesters, with subsequent hydrolysis.

-13- ~1-962 The benzylphenols are readily prepared by reduction of the corres-ponding hydroxybenzophenones. The latter are prepared, for example, by Friedel-Crafts benzoylation of phenyl acetate, by fries rearrangement of phenyl benzoates, or by oxidation of ben~hydryl alcohols.
Phenoxyphenols may be prepared by the Ullmann react;on of a phen-ox;de and a halophenyl ester~ in the presence of copper salts. See March, "Advanced Organic Chemistry", page 500 (Mc&raw-Hill, New `~ork, 1968). Thiophenoxyphenols are prepared by reacting thiophenoxide salts with halophenyl esters, especially in am;de solvents (ibid., pp. 500-50l).
Phenylphenols 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 conven-tional methods.
The th;ophenols which are the precursors of the thiophenoxide salts II, as well as thiol analogs of the mononuclear phenolic intermediakes mentioned above1 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 hydrolys;s, acidification, extrac-tion and isolation of the thiophenol. This raaction is carried out in substantially the same way as the conversion o, ~-naphthol to ~-thio- `
naphthol reported in Fieser and Fieser, "Reagents for Organic Synthesis, Vol. 2", pages 173-174 (Wiley Interscience, New York, 1969~.
The w-substituted linear alcohols III used in the sequence are also general1y available commercially or by well-known, conventional syn-thetic methods. For example, the ~,w-diol may be converted to the w-haloalcohol using triphenylphospnine and carbon tetrahalide (see C.A., ~3, 13137c (1965) for the preparation of 12;bromododecane-1-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 dimethylsulfoxide, acetonitrile, dimethoxyethane, tetrahydro-furan or toluene.

~ ' ~ M-962 The temperature of the reaction may vary from about 0C to the reflux temperature o, the solver)t, and the reaction time ~ay 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 mag-nesium sulfate, and evaporation of the solvent. Pur;f;cat;on ;s gen-erally effected by distillation or crystallization from a suitable solvent.
l~ sters of compounds of Formula I are formed by conventional methods, such as reaction of the alcohol of Formula I with an acid, an acid hal;de, an anhydride, or other act;vated acyl derivative, often in the presence of an acid acceptor. The product is isolated in a conventional fashion and pur;fied by distillation or crystall;zation from an appro-priate solvent. Salts of monesters of polybas;c acids are prepared by add;tion of base, e.g., NaH, to an ether solution of the ester, followed by filtration of the resultant precipitate.

6-(4-Phenylphenoxy)hexan-1-ol A mixture of 34.0 9 (0.2 mole) of p-phenylphenol (Eastman) and 1C.8 9 (9.2 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-1-ol (MCB) and about 2 9 o~
sodium iodide are added. The mixture is heated to reflux with stirr;ng, 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 (Na2504), and th2 solvent evaporated. The resultant white solid product is recrys-tallized twice from methanol/acetone, to give the desired product, m.p.
103-105C.

EXAMPLE ?
6-(4-Benzyloxyphenoxy)hexan-1-ol A mixture of 106.0 9 (0.53 mole) of p-benzyloxyphenol (Eastman~, 28.6 g (0.53 mole~ sodium methoxide (MCB) and about 2 9 of sodium iodide -15~ ~ M-962 in 600 ml of di~ethylformanlide is stirred ~or 5 mintues, after which 73 9 (0.53 mole) of b-chlorohexan-l-ol (MCB) is added, and the mixture is refluxed with stirring. The methanol formed in the reaction is allowed to distill of~. 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-(ben2yloxyphenoxy)hexane. The filtrate is cooled, where-upon the desired product crystallizes out. The solid product is stirred w;th 1 1iter of acetone at room temperature, the mixture is ~iltered to separate additional insoluble by-product, the acetone boiled off and replaced with methanol, and the methanolic solution cooled to crys-tallize out the desired product, m.p. 94-97C.

6-54-Benzylphenoxy?hexan-1-ol A mixture of 40.0 g (0.217 mole) of p-benzylphenol (Eastman) and 29.7 9 (0.217 mole) of 6-chlorohexan-1-ol (MC3) in 500 ml of dry d;methyl-formamide is stirred and heated to about 100C, after which 33.1 g (0.24 mole) of potassium carbonate ;s added, and the mixture refluxed for 2.5 hours. The mixture is cooled, poured into ice water, and 50 ml of lD%
NaOH is added. The mixture is extracted with ether, the ether extracts washed with watPr and brine, dried (~g2S04), and the ether evaporated.
The resultant oil is redistilled to give the product as a water-white oil fraction distilling at 140-175C, 0.05 mmHg.

12-Chlorododecane-l-ol A mixture of 70.0 g (0.347 mole) of dodècan~-1,12-diol (Aldrich Chemical Company) and 540.0 g (3.~ moles) of carbon tetrachloride in 1 liter of dry acetonitrile is heated to dissolve the diol, cooled to room temperature, flushed with argQn, and 91.5 g (0.350 mole) of triphenyl-phosphine (Aldrich~ is added over 15 minutes. A water bath is used to ~ontrol the heat ~enerated during the addition of triphenylphosphine, and to keep tne reaction mixture near room temperatur~. After the addition is co~plete, the mixture is stirred at room temperature for 1.5 hours, ~L8~GO
-16- ~1-962 then refluxed overnight. The solvent is then dist;lled off under atmos-pheric pressure until the volume i5 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 oil is vacuum distilled. The desired product is obtained as a fraction distilling at 140-150C, 0.02 mmHg.

12-~4-Phenylphenoxy)dodecane-1-ol ~ y the procedure described in Example 2, but using p-phenylphenol in place of p-benzyloxyphenol and using the 12-chlorododecane-1-ol preoared in Example 4 in place of 6-chlorohexan-ol, the solid precip-itate, obtained a~ter ~he reaction mixture i5 diluted with ice-water and treated ~ith base, is isolated, dried, and rPcrystallized twice from butanone to produce the desired product, m.p. 113-114~C.

4 ~heny1thiophenol Following the procedure ~or converting ~-naphthol to ~-thionaphthol, in Fieser and Fieser "Reagents for Organ;c Synthes;sl Volume 2", pages 173-174 (W;ley Interscience, New York, 1969), p-phenylphenol is reacted wi~h dimethylthiocclrbamoyl chlor;de (Aldr;ch Chemical Company) to form biphenylyl dimethylth;ocarbamate. A 10 9 (0.04 mole~ port;on of th~
latter compound is heatPd to 300 320C for 45 minutes in an argon atmos-phere, cooled, and the react;on mixture dissolved ;n ~50 ml of ~thanol.
The ethanol;c solut;on is heated to reflux, treated with 50 ml of aqueous 20% KOH, reflux continued for 1 hour, and the ethanol distilled off and replaced with water. The m;xture ;s cooled, diluted w;th water and extracted with ether. Tne a~ueous layer is then acidiried with concen-~rated HCl, cooled and extracted with ether, the ether layer washed with water, dried, and evaporated to dryness. Recrystalli~ation of the crude product from ethanol gives the pure desired product, m.p. 108-111C.

6-(4-Phenylphenylthi )hexan-1-ol A mixture of 8.2 g (0.044 mole) of p-phenylth;ophenol prepared in Example 6 and 6.9 9 (0.015 mole) of po-~ass;um carbonate in 200 ml OT

6~
-17- ~ M-9b2 dimethylformami~le is stirred for 15 minutes at room temperature under an argon atmosphere. Then 6.8 9 (0.05 mole) of 6-chlorohexan-1-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, driedl and evaporated to dryness.
The resultant crude solid product is vacuum distilled to give a fract;on coming over at 110-180C (0.1 mmHg), m.p. 112-115C. Recrystallization from acetone gives the pure desired product, m.p. 114-115C.

.
2-Chloro-4-be~y~
A mixture of 20.0 g (0.1 mole) o~ p-benzyloxyphenol ~Eastman) in Z50 ml of glacial acetic acid ;s stirred at room temperature until a clear solution is obtained. Then, 14.8 9 (0.11 mole) of sulfuryl chloride, previously filtered through sod;um carbonate, ;s added over the course of 0.5 hour, the m;xture stirred at room temperature for 3 hours, then warmed on a steam bath ~or 1 hour9 and evaporated to dryness under reduced pressure. The resultant crude solid product is recrystallized from ether~hexane to give the pure desired product, m.p. 78-80C.

6-(3-Phenylphenoxx)hexan-l-ol A mixture of 1~.0 g (0.088 mole~ of 3-hydroxybiphenyl, 13.3 9 (0.097 mole) of 6-chlorohexan-1-ol, and 13.8 9 (0.01 mole) of potassium carbonate in 250 ml of dry dimethylformamide is stirred and heated to reflux for 3 hours. The mix~ure is cobled to room temperature, diluted 2~ with water, and extracte~ wi~h 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 bo;ling bPtween 150 and 190C (0.05 mmHg), and solidifying to a soft solid, corresponding to the pure desired product.

, EXAMPLE 13 _ _ _ - Using the procedure of Example 2, the following phenolic compoundsmay be rea~ted with the ;ndicated haloalcohols to produce the compounds shown below (Ph = phenyl):

7~

Phenol Haloalcohol Product M.P. (C) p-Ph-Ph-OH 4-Cl-(CH2)4-OH p-Ph-Ph-O-(CH2)4-OH 110-113 p-Ph-Ph-OH 5-Cl-(CH2)5-OH p-Ph-Ph-O (CH2)5 lOa_1~go p-Ph-Ph-OH 8-Cl (CH2)8-OH p-Ph-Ph-O-(CH2)8-~H 103-106 S p-Ph-Ph~OH 10-Cl-~CH2)1o-OH p-Ph-Ph O (CH2)10 107-108 p-(Ph-CH2-0)-Ph-OH 4-Cl-(CH2~4-OH p-(Ph-CH2-0)-Ph-O-~CH2)4-0~l 97-99 p-(Ph-~l2-0)-Ph-OH 5~Cl-(CH2)5-OH p-(Ph-CH2-0)-Ph-O-(CH2~5-OH 90-~3 By the procedure described in Example 9, 2-chloro-4-ben2yloxy-phenol, prepared in E~ample 8~ is reacted with 6-chlorohexan-1-ol to produce 6-(2-chloro 4-ben~yloxyphenoxy)hexan-1-ol, as 2 light yellow oil, distilling between 185 and 200C (0.02 mmHg~.
By the procedure described in Example 9, 2-chloro-4-phenylphenol (Eastman) is reacted with 6-chlorohexan-1-ol to produce 6-(2-chloro-4~phenylphenoxy3hexan-1-ol, m.p. ~4-65C.

6-(2-H~droxy-5-phenylpheno~y)hexan-1-ol and p e ~ a~
A mixture of 55.9 9 ~0.3 mole) oF 4-phenylpyrocatechol (E~stman~
and 52.8 9 tO.38 mole) of potassium carbonate in 500 ml of dry dimeth~l-formamide is stirred at room temperature. 45.1 9 ~0.33 mole) of 6-chlorohexan-1-ol is added, the reaction flask ;s flushed with nitrogen and stirred at room temperature ~or 48 hours, then heated to reflux for 5 hours. The reaction mixture is cooled, diluted with water, acidified 2~ with lN HCl, and extract~d with e~her. The ether layer is washed with ~ater, dried and evaporated to dryness. Th~ semi-solid residue is vacuum distilled in an evaporative still. Fractions coming over at 1~0-170C, 180-200C and 220-240C (O.l mmHg) are collected. The 180-200C frac-tion is recrystallized from acetone/hexane to give the 2,4-subst;tuted product. The ~20-240C fraction is recrystalli_ed from acetone/hexane to giYe the diether, m.p. 80-82C. Additional 2,4-substituted product - is obtained from the residue of d;stillat;on of the 1SO-170C -fraction.
The mother liquors of the earlier crystallizations are combined and vacuum distille~, and fractions coming over at 160-16sQC, 170-}90C and ~18~
-l9- M-962 210-220C (0.1-~.05 ~mHg) are obtained. The 160-165 fraction is crys-tallized from acetone/hexane, comb;ned with the aforementioned distil-lation residue, and recrystallized, to give pure 2,4-product, m.p.
122-123C. The mother liquor from the crystallization is evaporated to dryness and redistilled, and a fraction ta~en at 160-165C (0.05 mmHg?
corresponding to the pure 2,5-product.

6-~4-Benzyloxyphenox ~
A m;xture of 25 9 (0.08 mole) of 6-(4-benzyloxyphenoxy3hexan-1-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, drie~ and evaporated, to ~;ve the desired product, m.p. 80-82C.

Bis-4-(4-phenylpheno~y2_1-buty! sulfite By the procedure of Example 13, using 4-(4-phenylphenoxy)butan-1-ol and an excess of thionyl chlor;de, the desired ester is obtained, m.p.
138-139C.

-6-(4-PhenvlDheno~v~ hexvl succinate ~monoester) A mixture of :L0 g (0.037 mole) of 6-(4-phenylphenoxy)hexan-1-ol, prPpared in Example 1, and 10 g of suceinic 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 ac;di-fied with HCl. The resultant precipitate is collPcted, washed, dried and recrystallized from butanone, to give the pure monoester, m.p.
113^115C.

._ ,, _,, ,, . ,, . _ ., . ~ _ , , _ , . _ ., _~ _ ,.. . .. . _ _ _ __. , , . ,. .. , , _ . . . _ .. . .

, -20~ 7~a ~l-962 EXA~PLE 16 Solution .
6-(4-Phenylphenoxy)hexan-1-ol 0.85 9 Alcohol 78.9 ml Isopropyl Myristate 5.0 g Polyethylene Glycol 400 ~Av. M.W. 400) 10.0 9 Purif;ed Water suffic;ent to make 100 ml Combine the alcohol, isopropyl myristate and polyethylene glycol 400 and dissolve the drug substance therein. Add sufficien~ purified water to give 100 ml.

. . _ _ .
. Tablet For 15 000 ?. __ 6-(4-Ben~yloxyphenoxy~hexan-1-ol - 75 Lactose 1.216 kg Corn Starch 0.3 kg Mix the active ingred;ent, 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 5tarch suff;cient to make 1.725 kg Compress on a suit,able tablet machine to a weight of 0.115 g/tablet.

Soft &elatin Capsule 6-(4-Phenylphenoxy)hexan-1-ol 0.25 kg ~5 Polysorbate 80 (Polyoxyethylene (20) sorbitan mono-sleate) 0.25 ky Corn Oil suTficient to make 25.0 kg Mix and f;ll into 50,000 soft gelatin capsules.

k Tr~de Mark ,~

-21- ~-962 EXA~PLE 19 I~l Injections A. Oil Type: .
6-(4-Phenylphenoxy)hexan-1-ol 25 mg Butylated hydroxyanisole 0.01% w/v Butylated hydroxyto1uene 0.01% w/v Peanut Oil or Sesame Oil sufficient to m~ke 1.0 ml B. Suspension Type:
6-(4-Pher,ylphenoxy)hexan-l-ol 25 m~
Sodium Carboxymethylcellulose 0.5~ w/v Sodium Bisulfite 0.0~% w/v ~ater for injection, sufficient to make1.0 m1 Powder 6~(4-Phenylphenoxy)hexan-1-ol 1% w/w Silicon dioxide, anhydrous 0.5% w/w Corn starch, lactose, fine powder - eachg with the ~otal suffiGient to make 50 k~

Nasal Dr ~ or S~y 6-(4-Phenylphenoxy)hexan-l-ol 0.10 9 Ethyl oleate ?0 0 g . ' Butylated hydroxyanisole 4.0 mg Poloxamer 235 (Poly(oxypropylene)poly~oxyethylene) copolymer sur~actant,. Av. M.W. 46,000)25.D g - Benzyl alcohol 4.7 ml Sorensen Buffer (A 50~50 mixture of sodium biphosphate solution and sodium phosphate solution rendered isoton;c by addition of sodium chloride~ sufficient to make 500.0 ml * Trade Mark . .

... ...... . . .

-~`2- ~8~7~ C2 fX~lPLE 22 Nasal Dro~ 5e~Y
6-(4-Phenylphenoxy)hexan-1-ol 0.125 9 Isostearic acid 5.0 g Pol~xamer 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 9 Deionized water sufficient to make 500 ml Hand Lotion 6-(4-Phenylphenoxy)hexan-1-ol 0.15 9 Isostearic acid 10.0 g Steari~ acid 8.0 g *Poloxamer 235 5. n g Propylene glycol 10.0 9 Deionized water sufficient to make 100.0 ml Liquid Soap _ .
6-(4-Phenylphenoxy)hexan-1-ol . 0.3 9 Green soap tincture, NF 100 ml Liquid Detergent 6-(4-Phenylphenoxy)hexan-1-ol 0.025 g Miranol SM Concentrate ~ (Miranol Chem. Co., Irvington, N.~.) (3~% 1-Carboxymethyl-4,5-dihydro-1-(2-hydroxyethyl)-2-nonyl-lH-imidazolium . hydroxide, sodium salt, 5% NaCl, pH 8.9-9.l~ 25.0 ,9 Laureth-4 (Monolauryl ethers of polyoxyethylene glycols containing an average of 4 oxyethylene groups) ? ~ g Deionized water sufficient to make , 100 mt s * Trade Mark -.
., .

Claims (22)

1. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
   
   l. A process for preparing a compound of the formula wherein A is a bond or CH2; Y is a bond, O or S; X is O or S;
   Z and Z' are each H, C1-4 alkyl, C1-4 alkoxy, OH or halogen;
   and n is an integer from 6 to 12; with the proviso that when n is 6 or 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; which comprises the step of either (a) reacting a compound of the formula wherein A, X, Y, Z and Z' are as defined hereinabove; with a compound of the formula L-(CH2)n-OH
   
   wherein n is as defined hereinabove; and L is Cl, Br I or an equivalent reactive leaving group, said reaction being effected in the presence of base; or (b) reacting an alcohol of the formula wherein A; X, Y, Z, Z' and n are as defined hereinabove with an appropriate acid, acid chloride, acid anhydride or other activated acyl derivative to form an ester thereof with a solubilizing pharmaceutically acceptable acid; or (c) reacting an ester as prepared in step (b) with a base to produce a salt of said ester.
2. 2. The process according to claim 1 wherein X is oxy-gen.
3. 3. The process according to claim 1 wherein A and Y
   collectively are a bond or CH2O.
4. 4. The process according to claim 1, wherein Z and Z' are each H.
5. 5. The process according to claim 1, wherein X and Y
   are para to one another on the benzene ring to which both are joined.
6. 6. The process according to claim 1, wherein A and Y
   collectively are a bond or CH2O; X is O; and Z and Z' are each H.
7. 7. The process according to claim 1, wherein n is 6.
8. 8. The process according to claim 1, wherein p-phenyl-phenol is reacted with a compound of the formula L-(CH2)6-OH
   wherein L is defined in claim 1 and the compound thus prepared is 6-(4-phenylphenoxy)hexan-l-ol.
9. 9. The process according to claim 1, wherein p-benzyl-oxyphenol is reacted with a compound of the formula L-(CH2)6-OH
   and the compound thus prepared is 6-(4-benzyloxyphenoxy)hexan-l-ol.
10. 10. The process according to claim 1, wherein 6-(4-phenylphenoxy)hexan-l-ol is esterified by reaction with suc-cinic acid, succinyl chloride or succinic anhydride and the compound thus prepared is 6-(4-phenylphenoxy)-1-hexyl suc-cinate (monoester).
11. 11. The process according to claim 1, wherein 6-(4-benzyloxyphenoxy)hexan-l-ol is esterified by reaction with methanesulfonic acid or the acid chloride or the acid anhy-dride thereof and the compound thus prepared is 6-(4-benzyl-oxyphenoxy)-l-hexyl methanesulfonate.
12. 12. A compound of the formula wherein A is a bond or CH2; Y is a bond, O or S; X is O or S;
    Z and Z' are each H, C1-4 alkyl, C1-4 alkoxy, OH or halogen;
    and n is an integer from 6 to 12; with the proviso that when n is 6 or 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, when prepared by the process of claim 1.
13. 13. A compound as defined in claim 12, wherein X is oxy-gen, when prepared by the process of claim 2.
14. 14. A compound as defined in claim 12, wherein A and Y
    collectively are a bond or CH2O, when prepared by the process of claim 3.
15. 15. A compound as defined in claim 12, wherein Z and Z' are each H, when prepared by the process of claim 4.
16. 16. A compound as defined in claim 12, wherein X and Y are para to one another on the benzene ring to which both are joined, when prepared by the process of claim 5.
17. 17. A compound as defined in claim 12, wherein A and Y
    collectively are a bond or CH2O; X is O; and Z and Z' are each H, when prepared by the process of claim 6.
18. 18. A compound as defined in claim 12, wherein n is 6, when prepared by the process of claim 7.
19. 19. A compound as defined in claim 12, wherein the compound is 6-(4-phenylphenoxy)hexan-1-ol, when prepared by the process of claim 8.
20. 20. A compound as defined in claim 12, wherein the compound is 6-(4-benzyloxyphenoxy)hexan-1-ol, when prepared by the process of claim 9.
21. 21. A compound as defined in claim 12, wherein the compound is 6-(4-phenylphenoxy)-1-hexyl succinate (monoester), when prepared by the process of claim 10.
22. 22. A compound as defined in claim 12, wherein the com-pound is 6-(4-benzyloxyphenoxy)-1-hexyl methanesulfonate, when prepared by the process of claim 11.