Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~8~'71!~i
-1- M 962
- 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-
3 -962
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.
EXAMPLE 1
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.
EXAMPLE 3
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.
EXAMPLE 4
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.
EXAMPLE 5
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.
EXAMPLE 6
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.
EXAMPLE 7
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.
EXAMPLE 8
.
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.
EXAMPLE 9
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~
-18- M-962
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
EXAMPLE 11
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.
EXAMPLE 12
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.
EXAMPLE 13
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.
EXAMPLE 14
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.
EXAMPLE 15
-
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.
EXAMPLE 17
. . _ _ .
. 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.
EXAMPLE 18
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
EXAMPLE 20
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~
EXAMPLE 21
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
EXAMPLE 23
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
- EXAMPLE 24
Liquid Soap _ .
6-(4-Phenylphenoxy)hexan-1-ol . 0.3 9
Green soap tincture, NF 100 ml
EXAMPLE 25
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 -.
., .
