CA1163637A - Antiviral 4-(arylaliphatic)isoxazoles - Google Patents
Antiviral 4-(arylaliphatic)isoxazolesInfo
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- CA1163637A CA1163637A CA000376636A CA376636A CA1163637A CA 1163637 A CA1163637 A CA 1163637A CA 000376636 A CA000376636 A CA 000376636A CA 376636 A CA376636 A CA 376636A CA 1163637 A CA1163637 A CA 1163637A
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- chloro
- hexyl
- heptanedione
- isoxazole
- diethyl
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Abstract
ABSTRACT OF THE DISCLOSURE
4-(Arylaliphatic)isoxazoles, having antiviral activity, are prepared by reacting with hydroxylamine a diketone of the formula Ar-Y-CH(CO-R)2, wherein Ar is substituted phenyl, Y is (CH2)n or O(CH2)n, and R is lower-alkyl.
4-(Arylaliphatic)isoxazoles, having antiviral activity, are prepared by reacting with hydroxylamine a diketone of the formula Ar-Y-CH(CO-R)2, wherein Ar is substituted phenyl, Y is (CH2)n or O(CH2)n, and R is lower-alkyl.
Description
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 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~ :
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 -
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 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~ :
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 -
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula (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) - or -O-(CH2) -;
R is lower alkyl; and n is an integer of from 1 to 8;
which process comprises reacting a compound of the formula in which Ar, Y and R are as defined above, with hydroxylamine or an acid addi-tion salt thereof.
Y is -(CH2) - or -O-(CH2) -;
R is lower alkyl; and n is an integer of from 1 to 8;
which process comprises reacting a compound of the formula in which Ar, Y and R are as defined above, with hydroxylamine or an acid addi-tion salt thereof.
2. A compound of formula I as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1 wherein Ar is 2-chloro-4-methoxyphe-nyl.
4. A compound of the formula in which R and Y are as defined in claim 1, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
5. A process for the preparation of 3,5-diethyl-4-[(4-methoxyphenyl3methyl]isoxazole, which comprises reacting 4-(4-methoxyphenylmethyl)-3,5-heptanedione with hydroxylamine hydrochloride.
6. 3,5-Diethyl-4-[(4-methoxyphenyl)methyl]isoxazole whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.
7. A process for the preparation of 3,5-diethyl-4-[6-(4-methoxy-2-nitrophenoxy)hexyl]isoxazolewhich comprises reacting4-[6-(4-methoxy-2-nitrophenoxy)hexyl]-3,5-heptaned with hydroxylamine hydrochloride.
8. 3,5-Diethyl-4-[6-(4-methoxy-2-nitrophenoxy)hexyl]--isoxazole whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
9. A process for the preparation of 3,5-diethyl-4-16-(4-bromophenoxy)hexyl]isoxazole which comprises reacting 4-[6-(4-bromophenoxy)hexyl]-3,5-heptanedione with hydroxylamine hydrochloride.
10. 3,5-Diethyl-4-[6-(4-bromophenoxy)hexyl]isoxazole whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
11. A process for the preparation of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethylisoxazole which comprises reacting4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione with hydroxylamine hydrochloride.
12. 4-[6-(2-Chloro-4-methoxyphenoxy)hexyl]-3,5-diethyll-isoxazole whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
13. A process for the preparation of 4-[(2-chloro-4-methoxy-phenyl)methyl]-3,5-diethylisoxazole which comprises reacting 4-[(2-chloro-4-methoxyphenyl)methyl]-3,5-heptanedione with hydroxylamine hydrochloride.
14. 4-[(2-Chloro-4-methoxyphenyl)methyl]-3,5-diethyl-isoxazole whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
15. A process for the preparation of 4-[4-(2-chloro-4-methoxyphenoxy)butyl]-3,5-diethylisoxazole which comprises reacting4-[4-(2-chloro-4-methoxyphenoxy)butyl]-3,5-heptanedione with hydroxylamine hydrochloride.
16. 4-[4-(2-Chloro-4-methoxyphenoxy)butyl]-3,5-diethylisoxazole whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.
17. A process for the preparation of 3,5-diethyl-4-[(4-methylphenyl)methyl]isoxazole which comprises reacting 4-[(4-methylphenyl)methyl]-3,5-heptanedione with hydroxylamine hydrochloride.
18. 3,5-Diethyl-4-[(4-methylphenyl)methyl]isoxazole whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000376636A CA1163637A (en) | 1981-04-30 | 1981-04-30 | Antiviral 4-(arylaliphatic)isoxazoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000376636A CA1163637A (en) | 1981-04-30 | 1981-04-30 | Antiviral 4-(arylaliphatic)isoxazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1163637A true CA1163637A (en) | 1984-03-13 |
Family
ID=4119867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000376636A Expired CA1163637A (en) | 1981-04-30 | 1981-04-30 | Antiviral 4-(arylaliphatic)isoxazoles |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1163637A (en) |
-
1981
- 1981-04-30 CA CA000376636A patent/CA1163637A/en not_active Expired
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