Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1 163637
BACKGROUND OF THE INVENTION
a) Field of the Invention
The invention relates to novel 4-(arylaliphatic)-
isoxazoles, to the preparation thereof and to compositions and
methods for the use thereof as antiviral agents.
b) Description of the Prior Art
J.C. Collins United States Patent 4,093,736, issued
June 6, 1978, discloses diketone derivatives useful as
pesticidal and antiviral agents having the formula
/R
C=o
Ar-Alk-CH
C=O
R
wherein Ar is phenyl or substituted phenyl, Alk is alkylene of
4-10 carbon atoms and R is lower-alkyl.
J.C. Collins and G.D. Diana United States Patent
4,031,246, issued June 21, 1977, discloses diketone derivatives
useful as pesticidal and antiviral agents having the formula
R
C---O
Ar-O-Alk-CH
C;O
R
wherein Ar is phenyl or substituted phenyl, Alk is alkylene of
3-10 carbon atoms and R is lower-alkyl.
D.N. 4583
1 ~63637
The compounds of the above-noted Patents 4,093,736
and 4,031,246 are intermediates in the preparation of the
compounds of the instant invention.
KochetXov et al., Zhur. Obshchei Chem. 30, 3675 (1960)
discloses 4-benzyl-3,5-dimethylisoxazole. No biological
properties are reported.
SUM~IARY OP THE INVE~TIO~
In a composition of matter aspect, the invention relates
to 4-(arylalkyl)isoxazoles and 4-(aryloxyalkyl)isoxazoles, said
isoxazoles having the formula
Ar-Y ~ ¦
R
I
wherein Ar is phenyl substituted by one or two substituents
selected from the group consisting of halogen, lower-alkoxy, nitro
and hydroxy; Y is (CH2)n or O(CH2)n where n is an integer from
1 to 8 and R is lower-alkyl.
In a further ccmposition of matter aspect, the invention
relates to a composition for combatting viruses which comprises
an antivirally effective amount of at least one compound of the
above Formula I in admixture with a suitable carrier or diluent.
In a process aspect, the invention relateR to a process
for preparing a compound of Formula I which comprises reacting
with hydroxyla~ine a diketone of the formula
;
~ 2 -
D.N. 4583
1 1~3637
C . o
Ar-Y-CH
C ~eO
R
II
where Ar, Y and R have the meanings given above.
In a further process aspect, the invention relates to
a method for combatting viruses which comprises contacting the
locus of said viruses with an antivirally effective amount of at
least one compound of Formula I.
D~TAILED D~SCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS
In the compounds of ~ormula I, when the phenyl ring of
~r is substituted by lower-alkoxy, the lower-alkoxy group or
groups preferably have from one to four carbon atoms and when
halogen substituents are present they can be any of the four
common halogens, fluoro, chloro, bromo or iodo. The carbon chain
of R can be straight or branched and preferably has from one to
four carbon atoms.
~he compounds of Formula I are prepared by interacting
a diketone o~ Formula II above with hydroxylamine or an acld-
addition salt thereof. The reaction takes place in an inert
solvent at a temperature between about 50 and 150C. The
nature of the inert solvent is not critical, although preferred
,
; 20 solvents are lower-alkanols, such as methanol or ethanol, acetic
acid and pyridine. Stoichiometrically equivalent amounts of
diketone and hydroxylamine may be used, although a slight excess
of hydroxylamine is generally employed.
'
D~N. 4583
1 ~S3637
The intermediate diketones of Formula II are a known
class of compounds disclosed in U.S. Patents 4,031,246 and
4,093,736.
The structures of the compounds of the invention were
S established by the modes of synthesis, by elementary analysis,
and by infrared and nuclear magnetic resonance spectral deter-
minations.
Biological evaluation of the compounds of the invention
has shown that they possess antiviral activity. They are useful
in combatting viruses present on inanimate surfaces as well as
viral infections in animal organisms. ~he in vitro testing of
the compounds of the invention against herpes simplex virus type 2
has showed that they inhibited viral gro~th at minimum concen-
trations (MIC) ranging from about 1.5 to about 50 micrograms per
milliliter. The MIC values were determined by standard serial
dilution procedures.
The antiviral compositions are formulated by preparing
a dilute solution or suspension in an organic or aqueous-organic
medium, for example ethyl alcohol, acetone, dimethyl sulfoxide,
and the like; and are applied to the locus to be disinfected by
conventional means such as spraying, swabbing or immersing.
Alternatively, the compounds can be formulated as ointments or
creams by incorporating them in conventional ointment or cream
bases, such as alkylpolyether alcohols, cetyl alcohol, stearyl
alcohol and the like; as jellies by incorporating them in
conventional jelly bases such as glycerin and tragacanth; or as
aerosol sprays or foams. The antivirally effective component of
the composition is present in a concentration of between about
D.N. 4583
1 163637~
0.7 part per million and about 5 percent by weight, depending
upon the chemical species used, the object to be treated and the
type of formulation employed. For disinfection of inanimate
surfaces with aqueous or aqueous-organic solutions, concentrations
in the lower part of the range are effective. For topical appli-
cation in medical or veterinary use in the form of ointment,
cream, jelly or aerosol, concentrations in the upper part of the
range are preferred.
The following examples will further illustrate the
invention.
Example 1
4-~6-(2 Chloro-4-methoxyphenoxy)hexvl~-3,5-diethylisoxazole
[I; Ar is 2-Cl-4-CH30C6H3' Y is (CH2)6~ 2 5
A mixture of 18.5 g. (0.050 mole) of 4-[6-(2-chloro-4-
methoxyphenoxy)hexyl]-3,5-heptanedione, 3.82 g. (0.055 mole) of
hydroxylamine hydrochloride and 150 ml. of pyridine was stirred
on a steam bath for one hour and allowed to stand at room
temperature for two days. The reaction mixture was concentrated
in vacuo, and the semi-solid residue was partitioned between
methylene dichloride and water. The methylene dichloride extract
was washed with water and dried over anhydrous magnesium sulfate.
The methylene dichloride was removed ~n vacuo and the residual
product was chromatographed on 360 g. of silica. The chromato-
gram was eluted with a 3:1 mixture of n-hexane and ethyl acetate,
five one liter fractions being collected. The material in the
first fraction, shown to be a homogeneous product by thin layer
chromatography, was isolated by removal of the solvent to give
D N. 4583
1 1~3637
10.1 g. ~55%) of 4-~6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-
diethylisoxazole as a yellow oil.
Anal. Calcd. for C28H28ClN03: C, 65.65; H, 7.71 ~, 3.83.
Found: C, 65.63; H, 7.78; N, 3.80.
4-[6-(2-Chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-
isoxazole when tested in vitro against herpes simplex virus type 2
showed antiviral activity at a minimal inhibitory concentration
(MIC) of 6 micrograms per milliliter (~g~ml).
Example 2
a) 4-~(4-Methylphenvl)methvl3-3 5-heptanedione.
To a suspension of 2.78 g. (0.35 mole) of lithium
hydride in 250 ml. of dimethylformamide was added dropwise over
a period of 30 min. a solution of 44.6 g. (0.35 mole~ of 3,5-
heptanedione in 50 ml. of dimethylformamide. Thereafter, 42.5 g.
~0.3 mole) of ~-chloro-p-xylene was added all at once, and the
reaction mixture was stirred at 70-75C. for 22 hrs. The mixture
was then poured ~to a solution of 100 ml. of concentrated hydro-
chloric acid in one liter of water. The product wa~ extracted
with methylene dichloride and the extracts washed with water and
dried over anhydrous magnesium sulfate. The solution was
concentrated in vacuo an~ the residue distilled twice, at
90-106C. (0.03 mm.) and 103-105C. (0.03 mm.) to give 41.8 g.
of 4-~(4-methylphenyl)methyl]-3,5-heptanedione.
b) 3 5-Diethyl-4-C(4-methvlphenvl)methyl]isoxazole [I; Ar is
4-CH3C6H4, Y is CH2, R is C2H5].
A mixture of 41.8 q. of 4-[(4-methylphenyl)methyl]-
3,5-heptanedione from part (a) above, 12.5 g. of hydroxylamine
hydrochloride and 100 ml. of pyridine was stirred at reflux
-- 6 --
D.N. 4583
1 ~3637
temperature for three hours and then all~wed to stand at room
temperature for two days~ The reaction mixture was concentrated
in vacuo, and the residue was partitioned between dilute aqueous
hydrochloric acid and methylene dichloride. The latter solution
S was washed with water, dried over anhydrous magnesium sulfate and
concentrated in vacuo. The product was distilled at 101-103~C.
(0.2 mm.) to give 8.1 g. of 3,5-diethyl-4-[(4-m~thylphenyl)-
methyl]isoxazole MIC = 1.5 ~g/ml (herpes 2).
Anal. Calcd. for C15HlgN0: C, 78.56; H, 8.35; N, 6.11.
Found: C, 78.67; H, 8.44; N, 5.98.
Exanple 3
a) 4-(4-MethoxyPhenylmethyl?-3,5-heptanedione was pxepared from
62.5 g. of p-methoxybenzyl chloride and the lithium salt fro~
57.5 g. of 3,5-heptanedione according to the procedure of
Example 2, part (a), and was obtained in the form of a pale
yellow liquid, b.p. 138-139C. (0.03 mm.); yield 80.0 g.
b) ~ [I; Ar is
4-CH30C6H4, Y is CH2, R is C2H5] was prepared from 41.1 g. of
4-(4~methoxyphenylmethyl)-3,5-heptanedione and 12.0 g. of
hydroxylamine hydrochloride in 100 ml. of pyridine acco~ng to
the procedure of Example 2, part (b), and wa~ obtained in the
form of a colorless oil, b.p. 145-146C. (0.1 mm.), MIC =
25 ~g/ml (herpes 2).
Anal~ Calcd. for C15HlgN02: C, 73.44; H, 7.81 N, 5-71-
Found: C, 73.43; H, 7.67; N, 5.55.
xample 4
a) 4-~2-Chloro-4-methoxYphenyl)meth~1]-3,5-heptanedione was
prepared from 48.9 g. of 2-chloro-4-methoxybenzyl bromide and
1163637 D.N. 4583
the lithium salt from 32 g. of 3,5-heptanedione according to the
procedure of Example 2, part (a), and was obtained in the form
of a yellow oil, b.p. 143-144C. (0.03 mm.~; yield 51.1 g.
b~ 4-~(2-Chloro-4-methoxvPhenyl)methYl]-3,5-diethYlisoxazole
~I; Ar is 2-Cl-4-CH3OC6H3, Y is CH2, R is C2H5] was prepared from
30.9 g. of 4-~(2-chloro-4-methoxyphenyl)methyl]-3,5-heptanedione
and 7.96 g. of hydroxylamine hydrochloride in 65 ml. of pyridine
according to the procedure of Example 2, part (b), and was
obtained in the form of a pale yellow oil, b.p. 144-147C.
(0.08 mm.); yield 21.6 g.; MIC = 12 ~g/ml ~herpes 2).
Anal Calcd. for C H ClN~ :
15 18 2
C, 64.39 H, 6.48 ~, 5.01; Cl, 12.67.
Found: C, 64.67; H, 6~51; N, 4.99; Cl, 12.40.
Example 5
3,5-Diethyl-4-[6-(4-methoxy-2-nitrophenoxy)hexYl]isoxazole
tI; Ar is 2-O2N-4-CH30C6H3, Y is O(CH2)6, R is C2H5] was prepared
from 10.0 g. of 4-~6-(4-methoxy-2-nitrophenoxy)hexyl~-3,5-
heptanedione and 2~0 g. of hydroxylamine hydrochloride in 40 ml.
of pyridine according to the procedure of Example 2, part (b),
and was obtained in the form of a yellow oil, b.p. 200-205C.
(0.02 mm.) yield 7.5 g., MIC . 3 ~g/ml lherpes 2).
Anal. Calcd for C20H28N205: C, 63.81, H, 7.50; N, 7.44.
Found: C, 63.81; H, 7.50, N, 7.24.
Example 6
4-[6-~4-Bromophenoxy)hex~1]-3 5-diethYlisoxazole [I; Ar is
6 4 2)6' R is C2H5] was prepared from 10 0
4-[6-(4-bromophenoxy)hexyl]-3,5-heptanedione and 2.0 g. of
hydroxylamine hydrochloride in 40 ml. of pyridine according to
D.N. 4583
1 1~3637
the procedure of Example 2, part (b), and was obtained in the
form of a pale yellow oil, b.p. 190-195C. (0.001 mm.); yield
7.3 g. MIC = 12 ~g/ml (herpes 2).
Anal. Calcd. for ClgH26BrNO2:
C, 60.00 H, 6.89; ~, 3.68; Br, 21.01.
Found: C, 60.19; H, 6.77; N, 3.65; Br, 21.21.
Example 7
4-~4-(2-Chloro-4-methoxvPhenoxy)butyl]-3~5-diethYlisoxazole
CI; Ar is 2-C1-4~CH30C6~3, Y is O~CH2)4, R is C2H5] was prepared
from 16.2 g. of 4-[4-(2-chloro-4-methoxyphenoxy)butyl]-3,5-
heptanedione and 3.3 g. of hydroxylamine hydrochloride in 65 ml.
of pyridine according to the procedure of Example 2, part (~),
and was obtained in the form of a yellow oil, b.p. 180-190C.
(0.1 mm.); yield 9.3 g.; MIC = 6 ~g/ml (herpes 2).
Anal- Calcd- for C18H24C1~3- C, 63-99; H~ 7-16; Cl, 10-49-
Found: C, 63.~5 H, 7.18; Cl, 10.36.
Example 8
4-L?- (2-Chloro-4-methoxyphenoxy)heptyl]-3,5-diethylisoxazole
[I; Ar is 2-Cl-4-CH3OC6H3, Y is o(C~2)7, R is C2H5] was prepared
from 19.2 g. of 4-~7-(2-chloro-4-methoxyphenoxy)heptyl]-3,5-
heptanedione, S g. of hydroxylamine hydrochloride and S.0 g. of
triethylamine in 100 ml. of absolute ethanol. The reaction
mixture was stirred at reflux for 24 hrs., then concentrated in
vacuo and partitioned between water and methylene dichloride.
The material o~tained from the methylene dichloride extracts was
chromatographed on silica and eluted with a 4:1 mixture of
hexane and ethyl acetate. The resulting product was distilled
twice in vacuo to give 5.2 g. of 4-[7-~2-chloro-4-methoxyphenoxy)-
_ g _
D.N. 4583
1 1~3637
heptyl]-3,5-diethylisoxazole, pale yellow oil, b.p. 180-190C.
(0.01 mm.), MIC = >25 ~g/ml ~herpes 2).
Anal. Calcd. for C21H30ClN03: C, 66.39; H, 7.96; ~, 3-69-
Found: C, 66.83; H, 8.02; N, 3.27.
Example 9
a~ 4-~(4-H~droxyphenYl)methyl]-3 5-heptanedione was prepared
by hydrogenolysis, in ethanol solution in the presence of loX
palladium-on-carbon catalyst, of 17.0 g. of 4-C(4-benzyloxy-
phenyl)methyl]-3,5-heptanedione, m.p. 4~-54C., in turn prepared
iO from 4-ben~yloxybenzyl chloride and the lithium salt of
3,5-heptanedione. The product thus obtained was recrystallized
from methanol to give 4.6 g. of 4-C(4-hydroxyphenyl)methyl3-3,5-
heptanedione, m.p. 95-96C.
b) 3 5-Diethyl-4-[(4-hYdroxyphenyl)methyl]isoxazole [I; Ar is
lS 4-HOC6H4, Y is CH2, R is C2H5] can be prepared by reacting
4-~(4-hydroxyphenyl)methyl~-3,5-heptanedione with hydroxylamine
hydrochloride in pyridine according to the procedure of Examples
1 or 2.
It is further contemplated that the following
compounds:
4-[6-~4-hydroxyphenyl)hexyl]-3,5-heptanedione
4-~6-(3,4-dihydroxyphenyl)hexyl]-3,5-heptanedione
4-~6-(4-hydroxyphenoxy)hexyl]-3,5-heptanedione
4-[6-(2-fluorophenoxy)hexyl]-3,5-heptanedione
4-~6-(3-iodophenoxy)hexyl]-3,5 heptanedione
3-[8-(2-chloro-4-methoxyphenoxy)octyl]-2,4-pentanedione
and 4-[6-~2-chloro-4-methoxyphenoxy)hexyl]-2,2,6,6-tetra-
methyl-3,5-heptanedione
can be reacted with hydroxylamine in accordance with the
procedures described above to give, respectively:
- 10 _
D.N. 4583
1 1~363~-
3,5-diethyl-4-[6-(4-hydroxyphenyl)hexyl]isoxazole
[I; Ar is 4-HOC6H4, Y is (CH2)6, X is C2H5]
3,5-diethyl-4-[6-(3,4-dihydroxyphenyl)hexyl]isoxazole
' )2C6~3~ Y is (CH2)6, R is C2H5]
3,5-diethyl-4-~6-(4-hydroxyphenoxy)hexyl]isoxazole
[I; Ar is 4-HOC6H4, Y is O(CH2)6, R is C2H5]
3,5-diethyl-4-~6-(2-fluorophenoxy)hexyl]isoxazole
[I; Ar is 2-FC6H4, Y is O~CH2)6, R is C2H5]
3,5-diethyl-4-~6-(3-iodophenoxy)hexyl]isoxazole
~I; Ar is 3-IC6H4, Y is O(CH2)6, R i5 C2H5]
4-t8-(2-chloro-4-methoxyphenoxy)octyl]-3,5-
dimethylisoxazole [I Ar is 2-Cl-4-CH30C6H3, Y is O(CH2)8,
R is CH3~
and 4-~6-~2-chloro-4-methoxyphenoxy)hexyl]-3,5-di-
tertiary-butylisoxazole [I; Ar is 2-Cl-4-CH30C6H3, Y is
O(CH2)6, R is C(CH3)3].
TLJ/BE
8.28.79 - 11 -
