Note: Descriptions are shown in the official language in which they were submitted.
1~79'737
NOVEL l-SULFONYL-5(6)-SUBSTITUTED-BENZI~ ZOLES
The incidence of viral upper respiratory disease
is immense. It has been estimated that nearly a billion
cases annually appear in the United States alonea Studies
performed in England (Tyrell and Bynoe, 1966) indicated that
74 percent of persons having colds were infected with
rhinoviruses. Because more than 80 strains of rhinoviruses
are already identified, tne development of a practical
rhinovirus vaccine is not feasible, and chemotherapy appears
to be the more desirable approach.
The ability of chemical compounds to suppress the
growt~ of viruses in vitro is readily demonstrated by using
a virus plaque suppression test s:im.ilar to that described by
SiminoEE, Applied Microbiology, 9~1), 66~1961).
Certain antiungal 1-dimethylaminosulfonyl-2--
aminobenzimidazole compounds have been disclosed in U. S.
Patent 3,853,908.
It is the purpose of this invention to provide
novel benzimidazole compounds which inhibit the growth of
viruses, particularly rhinoviruses, polio viruses, Coxsackie
viruses, echo virus, and Mengo virus.
This invention concerns pharmacologically useful
sulEonyl benzimidazole compounds having the general formula
R~ HR (I)
02R
X-4571E -2-
." ~
_ .. __ ..... . .. . ... .. , . . . . . . .. _
~079737
:.
wherein '
R is Cl-C~ alkyl, C5-C7 cycloalkyl, thienyl, phenyl, ~:
or -NR3R~ wherein R3 and R4 are independently
Cl-C3 ~lkyl;
Rl is hydrogen, or Cl-C4 acyl;
OH
R2 is 5 , or R5-C~
R6 7
wherein R5 is CI-C~ alkyl, phenyl, halophenyl, or ;~
C3-C6 cycloalkyl;
R6 is Cl-C7 alkyl; ~:
R7 is C1-C7 alkylidene; and
R2 is at the 5 or 6 position.
Th~ compounds o ormula (I) are prepared by
reacting a tautomeric benæimidazole compound of the general
formula
,:
RG--~C~~~ N~I2 (II)
503R
~.
wherein R and R5 are deined as before, with a C1-C7 alkyl
magnesium halide or Cl-C7 alkyl lithium, followed by
hydrolysis to form the compounds of formula (I) wherei~ ~ ;
OH
R2 is R5-C- , optionally followed by dehydration to form
R6 ',
the compounds of formula (I) wherein R2 is R5-C- , and/or
7 :
X-4571E -3-
., , ~ .
.. . , . , . ~
1~7g73'7
~ollowed by acylation to ohtain the cornpounds of formula (I)
wherein Rl i5 Cl-C4 acyl-
~ preferred group of compounds are the compoundsof formula (I) wherein
R iS Cl-C4 alkyl or -NR3R4 wherein R3 and R4
are independently Cl-C3 a:Lkyl; and
Rl is hydrogen.
An especially preferred group of compounds are
the compounds of formula (I) wherein
R iS Cl-C4 alkyl or -NR3R4 wherein R3 and R4
are independently Cl-C3 alkyl;
Rl is hydrogen; and
R is R -C-
R7
where:in R5 is phenyl ~nd R7 .is defined
~s be.Eore.
Illustrative of such preferred compounds are the ..
following:
l-dimethylaminosulfonyl-2-amino-5(6)-(-hydroxy-
-n-pentylbenzyl)benzimidazole,
l-dimethylaminosulfonyl-2-amino-5(6)-[a-hydroxy-
-(2,4 -dimethyl-3-pentyl)benzyl]benzimidazole,
l-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxy-
-n-hexylbenzyl)benzimidazole,
l-dimethylaminosulfonyl-2-amino-5(6)-(a-hydroxy-
a-se~=butylbenzyl)benzimidazole,
l-dimethylaminosulfonyl-2-amino-5(6)-(a-n-propyl-
idenebenzyl)benzimidazole,
~" :
X-4571E -4-
737
l-dimethylaminosulfonyl-2-amino-5(6)~ n-pentyl-
idenebenzyl)benzimidazole,
l-dimethylaminosulEonyl-2-amino-5(6)-(~-2,4-
dimethyl-3-pentylidenebenzyl)benzimidazole,
l-dimethylaminosulfonyl-2-amino-5(6)-(a-n-hexyl-
idenebenzyl)~enzimidazole,
l-dimethylaminosulfonyl-2-amino-5(6)-~a-_ec-
butylidenebenzyl)benzimidazole,
l-isopropylsulfonyl-2-amino-6-a-isopropylidene-
benzylbenzimidazole,
l-isopropylsulfonyl-2-amino-5(6)-[a-hydroxy-a-
(2,~-dimethyl-3-pentyl)benzyl]benzimidazole, and
l-isopropylsuleonyl-2-amino-5(6)-(a-2,~-dimethyl~
3 pentyliclenebenzyl)berlzlmidazole.
The terrn "tautomeric ben~imidazole" reEers to a
benzimidazole reagent which can be substituted at either
nitrogen atom with a hydrogen atom. The benzimidazole
reactant, unsubstituted on nitrogen and bearing a substit-
uent group at the 5 position of the benzene moiety, has a
corresponding tautomeric form wherein the substituent
resides alternatively at the 6 position. The isomer mixture
can be indicated by numbering the alternate positions as
5(6).
The following definitions refer to the various
terms used throughout this disclosure. The term "thienyl"
refers to the thiophene radical attached at the 2 or 3
position.
X-4571E -5-
737
The terrn "Cl-C4 alkyl" refers to the straight and
bran-hed aliphatic radicals o~ one to four carbon atoms
inclllding methyl ethyl propyl isopropyl butyl isobutyl ~ .
sec-butyl and tert-butyl. The term Cl-C4 alkyl includes
within its definition the terms "Cl-C3 alkyl" The term
"Cl-C7 alkyl" refers to the straight and branched aliphatic
radicals of one to seven carbon atoms including methyl,
ethyl, propyl isopropyl butyl isobutyl sec-butyl pentyl
isopentyl hexyl isohexyl heptyl isoheptyl, 2,4-dimethyl-
3-pentyl, t-butyl and neopenty}.
The term "Cl-C4 alkyl carbinol" refers to the
stra.ight and branched aliphatic alcohols of one to four
carbon atoms as exemplified in the term "Cl-C4 alkyl."
The term "C3-C7 cycloalkyl" re.Eers to the sat- ~ ;
urat(3d alicyclic r.ings of three to seven carbon at:om~ such
as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, 1- 2- 3- or 4-methylcyclohexyl and cyclo-
heptyl .
The term "halophenyl" refers to chlorophenyl
or bxomophenyl mono-substituted at any position of the
phenyl ring.
The term "Cl-C4 acyl" refers to the straight and
branc~hed chain aliphatic acyl radicals of one to four carbon
atoms such as formyl, acetyl propionyl butyryl and 2-
methylpropionyl.
The term "Cl-C7 alkylidene" refers to straight ~ :
and branched radicals of one to seven carbon atoms such as
methylene, ethylidene, propyl.idene, isopropylidene butyl-
iden(_ isobutylidene, 3-methyl-2-butylidene 2,4-dimethyl-3-
pentylidene, and n-hexylidene.
X-4571E . -6-
.
~L~79~37
In the above process suitable dehydration agentsare strong acids, such as p-toluenesulfonic acid, sulfuric
acid, trifluoroacetic acid, methanesulfonic acid, or tri-
fluoromethanesulfonic acid. The Cl-C7 alkyl magnesium
halide is an appropriate Grignard reagent followed by
hydrolysis. The Cl-C7 alkyl lithium reagent results in a
product similar to the Grignard reagent. The preferred
solvents for the alkylation process are inert organic
solvents such as tetrahydrofuran; aromatics, such as benzene,
or toluene; and ethers, such as diethyl ether. The pre-
ferred solvents for the dehydration process are aromatics,
such as benzene or toluene; alkanes, such as hexane; and
halocJenated hydrocarbons such as, methylene chloride and
chloroform. The temperature range usually employed is from
about 25C. to the reflux temperature of the solvent.
The starting materials of formula (II) are prepared
as described in Canadian Patent No. 1,063,501, of Paget et
al, granted October 16, 1979.
The product of the reaction is a l-sulfonylbenz-
imidazole compound. The product may be isolated by filter-
ing the reaction mixture and concentrating the filtrate to
induce crystallization. Alternatively, the reaction mixture
can be evaporated to dryness and the residue treated with a
suitable solvent such as acetone or methanol to separate
and remove any insoluble material. The solution containing
the sulfonylbenzimidazole compound is concentrated to crys-
tallize the product or it is evaporated to give a second
residue, which is dissolved in methanol for example. The
sulfonylbenzimidazole compound is recovered from the meth-
anol by crystallization.
7~7
The 5(6)-isomers are separable by fractional crys-
tallizatiGn or by column chromatography. Usual]y the
6-isomer crystallizes first from a solution of the mixture.
The 2-acylamino sulfonylbenzimidazoles wherein R
is ot:her than hydrogen can be prepared preferably by acyl-
ating the corresponding 2-amino sulfonylbenzimidazole with
the appropriate acid anhydrides. The isomeric 2-acetamido
sulfc,nylbenzimidazoles can be separated by fractional
crystallization from acetone, or preferably, methanol or
ethanol.
The following examples further illustrate the
preparation of the compounds of formula (I). The term "m/e"
used in characterizing the products refers to the mass-to-
char~e ratlo of ions which appear in the mass spectra of the
proflvcts. In g~neral, the values corre.sponcl to molecular
weiyhts of the major peaks.
Example 1
To a solution of 600 ml. of tetrahydrofuran and
21.7 ml. (60 mmole) of methyl magnesium bromide in diethyl
ether, under nitrogen, was added dropwise over 1 hour a
solution of 4.1 g. (12 mmole) of l-dimethylaminosulfonyl-
2-amino-6-benzoylbenzimidazole in 180 ml. of tetrahydro-
furan. The mixture was refluxed for 5 hours, poured into
ice and lN hydrochloric acid, extracted twice with diethyl
ether, washed with saturated sodium chloride, dried, and
filtered to yield 2.9 g., as an amorphous solid, of 1
dimethylaminosulfonyl-2-amino-6-(a-hydroxy-a-methylbenzyl)-
benzimidazole. m/e 360.
~ ~.
X-4571E -8-
:. , .~ ' " ,' . ' :
7~
Y 17 20 4 3
Calcd: C, 56.67; ~1, 5.59; N, 15.54
Found: C, 56.77; H, 5.46; N, 15.27
Example 2
Two grams (5.5 mmole) of l-dimethylaminosulfonyl-
2-amino-6-(a-hydroxy-a-methylbenzyl)benzimidazole in 130 ml.
of chloroform was reacted with 1.3 g. of p-toluenesulfonic
acid. The solution was refluxed with stirring for 6 hours.
The solution was then washed with saturated sodium carbonate,
dried, and filtered to yield 1.7 g. of 1 dimethylamino-
sulfonyl-2-amino-6-(a-methylenebenzyl)benzimidazole, m.p.
201-;~02C.
Analy5is C17ll18N~2~ MW 342
Calccl: C, 59.63; Il, 5.30; N, 16.36
Found: C, 59.67; Il, 5.35; N, 16.07
Example 3
When the procedure of Example 1 was repeated
usinc~ 100 ml. tetrahydrofuran, 22.2 ml. (60 mmole) of ethyl
magnesium bromide (2.7 mmole/ml) in diethyl ether, and 4.1
g. of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimida-
zole, there was obtained 3.2 g., as a foam, of l-dimethyl-
aminosulEonyl-2-amino-6-(a-ethyl-a-hydroxybenzyl)benzimi-
dazole.
High resolution mass spec. Eor C18H22N4O3S
Calcd: 374.14123
Found: 374.141
X-4571E -g-
~9737
ExampLe 4
When the procedure o~ Example 2 was repeated
using 1.2 g. (3.21 mmole) of 1-dirnethylaminosulfonyl~2-
amino-6-(a-ethyl-a-hydroxybenzyl)benzimidazole, 750 mg. of
p-toLuenesulfonic acid, and 100 ml. of chloroform, there was
obtained 388 mg. of 1-dimethylamlnosulfonyl-2-amino-6-
(a-ethylidenebenzyl)benzimidazole, m.p. 200-202C. (dec.)
High resolution mass spec. for C18H20N4O2S
Calcd: 356.13107
Found: 356.131
Example 5
When the procedure of Example 1 was repeated
using 4.1 g. (12 mmole) of l-dlmethyLaminosul~onyl-2-
amino~6-benzoylbenzLmidazole in 1~0 ml. o~ tetrahydroEuran,
100 ml. tetrahydrofuran, ancl 28.6 mL. (60 mrnole) of iso-
propyl magnesium chloride in 100 ml. of te-trahydrofuran,
there was obtained, as a yellow foam, 4.0 g. of l-dimethyl-
aminosulfonyl-2-amino-6-(a-isopropyl-a-hydroxybenzyl)benz-
imidazole, yield 65%.
Example 6
When the procedure of Example 2 was repeated using
1.2 g. (3.~ mmoles) of 1-dimethylaminosul~onyl-2-amino-
6-(a-isopropyl-a-hydroxybenzyl)benzimidazole, 750 mg. of
_-toluenesulfonic acid, and 100 ml. of chloroform, there was
obtained, as a beige solid, 82 mg. of l-dimethylaminosul~
fonyl-2-amino-6-(a-isopropylidenebenzyl)benzimidazole.
X-4571E -10-
. .
1~79-737
Example 7
To a solution of 150 ml. of tetrahydrofuran and
31 ml. (84 mmole) of methyl magnesium bromide in cliethyl
ether, under nitrogen, was added dropwise a solution of
5.0 g. (15 mmole) of 1-isopropylsulfonyl-2-amino-6-benzoyl-
benzimidazole in 200 ml. of tetrahydrofuran. The mixture -
was stirred at 25C. for 1 hour, refluxed for 2 hours,
cooled, poured in-to ice and lN hydrochloric acid, and
extracted with diethyl ether. The 1500 ml. of solution was
concentrated to 800 ml., dried, and concentrated under
vacuum. The product which formed was recrystallized from
diethyl ether/hexane by dissolving the product in diethyl
ether, adding diethyl ether/hexane, and boiling the solution
until turbid. The solution was cooled to 25C., re~ri~erated
at 10C., and filtered to yield 2 ~3. of product. Additional
product was recovered by concentration of the filtrate under
vacuum, yield 2 g. The product was l-isopropylsulfonyl-
2-amino-6-(a-hydroxy-a-methylbenzyl)benzimidazole. m/e 360,
344 base.
Ana y 18 21 3 3
Calcd: C, 60.15; H, 5.89; N, 11.69
Found
(first crop) C, 60.37; ~I, 5.73; ~, 11.46
(second crop) C, 61.30; H, 6.26; N, 10.69
Example 8 ~-
Two grams (5.6 mmole) of 1-isopropylsulfonyl-2-
amino-6-(a-hydroxy-a-methylbenzyl)benzimidazole in 100 ml.
of chloroform was reacted with 1.3 g. of p-toluenesulfonic
acid. The solution was refluxed with stirring for 4 hours.
X-4571E -11-
737
The solution was cooled to 25C., washed twice with saturated
potassium carbonate, washed twice with water, dried over
sodi~m sulfate, concentrated under vacuum, and recrystal~
lized from diethyl ether/hexane to yield 1.1 g., as light
orange crystals, l-isopropylsulfonyl-2-amino-6-(a-methylene-
benzyl)benzimidazole, m.p. 147-148C. m/e 341.
naly is C18 1gN32 MW 341
Calcd: C, 63.32; H, 5.61; N, 12.31
Found: C, 63.58; H, 5.53; N, 12.15
Example 9
When the procedure of Example 7 was repeated using
lS0 ml. of tetrahydrofuran, 31 ml. (84 mmole) oE n-butyl
magnesium bromide, 5.0 y. (L5 mmole) o~ J-i.sopropylsulfonyl-
2-amir)o-6-benzoylbenzimidazole, ancl reeluxlng Eor 20 hours,
there was obtained 5.0 y., as a tan Eoam, of 1-isopropyl-
sulfonyl-2-amino-6-(a-hydroxy-a-n-butylbenzyl)benzimidazole.
Analysis C21H27N3O3S MW 401
Calcd: C, 62.82; H, 6.78; N, 10.47
Found: C, 63.14; H, 6.57; N, 10.17
Example 10
When the procedure of Example 8 was repeated using
1 y. (2.5 mmole) of 1-isopropylsulfonyl-2-amino-6-(a-hydroxy-
a-n-butylbenzyl)benzimidazole, 75 ml. of chloroform, 600 mg.
of _-toluenesulfonic acid, and refluxed for 90 minutes,
there was obtained 790 mg. of 1-isopropylsulfonyl-2-amino-
6-(a-n-butylidenebenzyl)benzimidazole.
Analysis C21H25N32S MW 383
Calcd: C, 65.77; H, 6.S7; N, 10.96
Found: C, 65.49; H, 6.31; N, 10.78
X-457lE -12-
1~7~737
~xample ll
When the procedure of Example 7 was repeated
using 40 ml. (85 mmole) of isopropyl magnesium bromide,
5.0 g. (15 mmole) of l-isopropylsulfonyl~2-amino-6-benzoyl-
benzimidazole and 200 ml. of tetrahydrofuran, there was
obta.ned, as a yellow foam, 5.0 g. of l isopropylsulfonyl-
2-amino-6-(a-hydroxy-a-isopropylbenzyl)benæimidazole.
m/e 399.
Example 12
When the procedure of E'xample 7 was repeated
usin~l ~1 ml. (2.7 mmole in diethyl ether) Oe ethyl macJnesium
bromide, 5 g. (15 mmoles) of L-isopropylsulonyl-2-amino-6-
benzoylbenzimidazole, and 150 ml. of -tetrahydrofuran, there
was obtained, as a beige foam, 4.6 g. of l-isopropylsulfonyl-
2-amino-6-(a-hydroxy-a-ethylbenzyl)benzimidazole. m/e 373,
343.
Example 13
When the procedure of Example 8 was repeated
using 890 mg. (2.4 mmole) of l-lsopropylsulEonyl-2-amino-6-
(c~-hydroxy-a-ethylbenzyl)benzimidazole, 50 ml. of chloro-
form, and 600 mg. of p-tc~luenesulfonic acid, there was
obta~ned, as an amorphous foam, 630 mg. of 1-isopropyl-
sulfonyl-2-amino-6-(-ethylidenebenzyl)benzimidazole.
X-4571E -13-
.
: : -
.
~l~79'737 :
19 21N32S MW 355
Calcd: C, 64.20; H, 5.96; N, 11.82
Found: C, 63.93; H, 6.04; N, 11.64
Example 14
When the procedure of Example 1 was repeated using
30 ml. (60 mmole) of n-propyl magnesium bromide in 100 ml.
of tetrahydrofuran, and 4.1 g. (5 mmole) of l-dimethylamino-
sulfonyl-2-amino-6-benzoylbenzimidazole in 150 ml. of tetra-
hydrofuran, there was obtained, as a tan foam, 3.5 g. of
10 1-dimethylaminosulfonyl-2-amino-6-(~-hydroxy-a-n-propyl-
benzyl)benzimidazole. m/e 388.
Example 15
When the procec]ure o~ Example 1 was repeated using
80 ml. oE tetrahydrofuran, Ll.l ml. oE n-butyl ma~lne~ium
bromicle, and 2.05 g. of 1-dimethylarninosulfonyl-2-amino-6-
benzoylbenzimidazole in 90 ml. of tetrahydrofuran, there was
obtained, as a white foam, 1.7 g. of l-dimethylaminosulfonyl-
2-amino-6-(~-hydroxy-a-n-butylbenzyl)benzimidazole. m/e 402.
~xample 16
When the procedure of Example 2 was repeated using :
402 mg. of 1-dimethylaminosulfonyl-2-amino 6-(~-hydroxy-a-
n-butylbenzyl)benzimidazole in 20 ml. of chloroform, 234 mg.
of p-toluenesulfonic acid, and 100 ml. of chloroform, there ~ ?
was obtained 302 mg. of 1-dimethylaminosul~onyl-2-amino-6-
(a-n-butylidenebenzyl)benzimidazole. m/e 384.
X-4571E -14-
,
f ~C~79737
~ he compounds of formula (I) exhibit a broad spec-
trum of antiviral activity. Not only are they especially
effective in inhibi~ing the growth of echo virus, Mengo,
Coxsackie, (A9, A21,B5), polio (types I, II, III) or rhino-
virus (25 strains) but they also inhibit various types of
influenza viruses including influenza strains such as Ann
Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and
; Taylor C (types A,B). The ability of compounds coming
within the scope of formula (I) above to suppress the growth
of different viruses in vitro is readily demonstrated by
, .
using a plaque suppression test similar to that described by
Siminoff, Applied Microbiology, 9(1), 66-72 ~1961). The
~pecific tests are described in detail hereinbelow. The
compounds of formula ~I) were tested by the following methods.
Test Methods
African green monkey kidney cells (BSC-l) or ~ela
cells (5-3) were grown in 25 cc. Falcon flasks at 37C. in
medium 199 with 5 percent inactivated fetal bovine serum
(FBS), penicillin (150 units 1 ml.) and streptomycin (150
mcg./ml.). When confluent monolayers were formed, the
supernatant growth medium was removed and 0.3 ml. of an
appropriate dilution of virus (echo, Mengo, Coxsackie, polio
or rhinovirus) was added to each flask. Af~er absorption
for on~ hour at room temperature, the virus infected cell
~- sheet was overlaid with a medium comprising one part of 1
percent Ionagar No. 2 and one part double strength medium
.- 199 with FBS, penicillin, and streptomycin which contains
; drug at concentrations of 100, 50, 25, 12, 6, 3 and 0 micro-
:.
:
X-457lE -15-
1~7~737
grams per milliliter (mcg./ml.). The flask containing no
drug served as the control for the test. The stock solu-
tions o~ sul~onylbenzimidazole compounds were made up in
dimet:hylsulfoxide dilution at a concentration of 10~ mcg./ml.
The ilasks were incubated for 72 hours at 37C. for polio,
Coxsackie, echo, and Mengo virus and 120 hours at 32C. for
rhinovirus. Plaques were seen in those areas where the
virus infected and reproduced in the cel.ls. A solution of ~:
10 percent formalin and 2 percent sodium acetate was added
to each flask to inactivate the vi.rus and fix the cell sheet
to the surface of the flask. The virus plaques, irrespective
of size, were counted after staining the surrounding cell
areaC with crystal violet. The plaque count was compared to
the control count at each drug concentrAtion. The activity
Oe the tcst compound was expre5sed as percentacJe plaque
reduction, or percent inhibition. Alternatively, the drug
concentration which inhibits plaque formation by 50 percent
can be used as a measure of activity. The 50 percent inhibi-
tion is indicated by the symbol I50.
Test results are expressed in terms of Polio virus
type I inhibition because the virus is easy to grow and
consistent test results are obtained. However, the activity
of the compounds of formula (I) was conEirmed against other
virus cultures such as Coxsackie (A9, A21, BS), echo virus
(strains 1-4), Mengo, rhinovirus (25 strainsl and Polio
(type I, II, III). Test results for various sulfonylbenz-
imidazole compounds are summarized in Table I below where
column 1 give the Example number from the previous chemical
X-~571E -16- !~
~L~7~737
-;sa~n:,lcs, column ~ ~JiVCS thc '; ~6) -position of the corre-
spondiny benzimidazole product, and columns 3-10 indicate
the percentage virus plaque reduction at drug dilutions from
0.75-100 micrograms per milliliter (mcg./ml.).
X-4571E -17-
.
~ ~737 ~
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X-4571E -18-
, ' ~
~C379737
The sulfonylbenzlmidazole compounds of formula (I)
were tested as pure compounds and as isomer mixtures. Both
isomers inhibit virus growth, the 6-isomer generall~ being
more active than the 5-isomer.
Compounds of formula (I) are able to suppress the
growth of several viruses when added to a medium in which
the virus is growing. The compounds of formula (I) can
therefore be used in aqueous solution, preferably with a
surfactant, to decontaminate surfaces on which polio,
Coxsackie, rhinovirus or other viruses are present, such
surfaces including hospital glassware and hospital working
surEaces and similar areas in the preparation of food.
Furthermore, the compounds of formula (I) can be
orally admlnistered to warm-blooded mammals includincJ hùmans
.in doses of 1 to 300 m~./k~. Oe mammalian body weiyht. The
administration can be repeated periodically as needed. In
accordance with general practice, the antiviral compound can
be administered every four to six hours.
Preferably, the compounds to be employed in
accordance with the present invention are employed in
combination with one or more adjuvants suited to the par-
ticular route of administration. Thus, in the case of oral
administration, the compound is mod.iEied with pharmaceutical
diluents or carriers such as lactose, sucrose, starch
powder, cellulose, talc, magnesium stearate, magnesium
oxide, calcium sulfate, acacia powder, gelatin, sodium
alginate, sodium benzoate and stearic acid. Such compo-
sitions can be formulated as tablets or enclosed in capsules
for convenient administration. In addition, the compounds
can be administered parenterally.
X-4571E -19-
~979~37 : ~:
The compounds can also be mixed with a liquid and ~
administered as nose drops or intranasal spray. ~ :
j X-4571E -20- ~ ,
' ~ "
!... . . . ~ . : . ~
,: ~ . ,, . ~
