PT95017B - PROCESS FOR THE PRODUCTION OF OXIDIAZOLYL-PHENOXYLOCYLISOXAZOLES AND THEIR USE AS ANTI-VIRAL AGENTS - Google Patents

Abstract

A process is described for the production of oxydiazolylphenoxyalkyl isooxazoles and their use as antiviral agents <IMAGE> <IMAGE> in which: Y is an alkylene bridge having 3-9 carbon atoms, R' is lower alkyl or lower hydroxyalkyl having 1-5 carbon atoms, R1 and R2 are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl, and R8 is hydrogen or lower alkyl having 1-5 carbon atoms, provided that when R8 is hydrogen R' is lower hydroxyalkyl, which are useful as antiviral agents, particularly against picornaviruses, including numerous strains of rhinovirus.

Description

The present invention relates to new heterocyclic substituted phenoxyalkylisoxazoles and furans, to processes for their preparation and to compositions and processes for their use as anti-viral agents.

U.S. patent 4,451,476, Dana, issued May 29, 1984, describes compounds with anti-viral activity with the formula (CH „) O-Ar '2'n in which

R is alkyl of 1 to 3 carbon atoms;

n is an integer between 4 and 8; and

Ar is phenyl or phenyl substituted by one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, 1-oxy-lower-alkyl, hydrazinocarbonyl, carbamyl and N, N-di-lower-alkylcarbamyl.

European patent application Publ. No. 137,242, Sterling Drug Inc. published on April 17, 1985, describes compounds with anti-viral activity with the formula

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on what:

R, R ^, R ^, Rg and R ^ are each hydrogen or alkyl of 1 to 3 carbon atoms, optionally substituted by hydroxy, lower alkanoyloxy, lower alkoxy, chlorine, or N = Z, where N = Z is amino, lower alkanoylamino, lower alkylamino, di-lower alkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl; with the proviso that R is different from hydrogen;

Rg is hydrogen, lower alkyl, halogen, nitro, lower alkoxy, lower alkylthio or trifluoromethyl;

X is 0 or a simple link; and n is an integer between 3 and 9 'and its pharmaceutically acceptable acid addition salts.

Published Europeft Patent Application No. 207. ^ 53, Sterling Drug Inc., published on January 7, 1987, describes compounds of formula I, below, where Het is 1,3, ^ - oxadiazol-5-yl and completes compounds where Het is 1,2,4-oxadiazol-5-yl.

The present invention relates to compounds of the formula

s

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JRc where:

Het is selected from among

Nk »N

-R _f

Y is an alkylene bridge of 3-4 carbon atoms;

R 'is lower alkyl 1-5 carbon atoms; or hydroxy lower alkyl of 1-5 carbon atoms;

^R 1 ^{and R} 2 are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl; and

Rg is hydrogen or lower alkyl of 1-5 carbon atoms, provided that when Rg is hydrogen R 'is hydroxy lower alkyl;

or pharmaceutically acceptable acid addition salts of its basic elements.

A preferred class of compounds covered by Formula I are those of formula = 3 =

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CH,

II

The present invention also relates to compositions to fight viruses that correspond to an effective anti-viral amount of a compound of formulas I and II, in a mixture with an appropriate vehicle or diluent and to processes to fight viruses by means of them, including the systemic treatment of viral infections in a mammalian host.

The compounds of Formula I in which Het is a nitrogen-containing heterocyclic group are sufficiently basic to form stable acid addition salts with strong acids and such salts are within the scope of the invention. The nature of the acid addition salt is immaterial, as long as it is derived from an acid whose anion is essentially non-toxic to animal organisms. Examples of suitable acid addition salts include hydrochloride, hydrobromide, sulfate, acid sulfate, maleate, citrate, tartrate, methanesulfate, p-toluenesulfonate, dodecyl sulfate, cyelohexanesulfamate and the like.

When the term halogen is used to define the substituents R ^ and Rg, any of the four common halogens, fluorine, chlorine, bromine or iodine, is contemplated; the terms lower alkyl and lower alkoxy refer to groups having 1-5 carbon atoms and the term lower alkoxy carbonyl to such groups having between two and wed = 4 =

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four carbon atoms.

The compounds of Formula I can be prepared by a process which comprises the reaction of a compound of the formula

Y-Hal

III in which Hal is chlorine, bromine or iodine, with an alkali metal salt of a compound of the formula

The compounds of Formula I can also be prepared by means of an alternative process which comprises the reaction of a compound of the formula

R ’

Hal where Hal 'is bromine or iodine, with a compound of form = 5 =

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mule (R) ₃ Sn-Het

VI where R ”is lower alkyl of 1-6 carbon atoms and Het 'is any of the aromatic type heteroicyclic groups included in the definition of Het in Formula 1} in the presence of a palladium complex catalyst.

The process for preparing compounds of Formula I by reacting intermediates of Formulas III and IV takes place by heating the reagents in an inert solvent, in the presence of an alkali metal base, for example, potassium carbonate or potassium hydroxide at a temperature between about 50 ° C and 15 ° C.

Intermediates of formula III are prepared by reacting an alkali metal derivative of an isoxazole of the formula

CH

VII with a dihalide, Hal-Y'-Hal, where Y 'is an alkylene bridge of 2 to 8 carbon atoms. Said alkali metal derivative is prepared in situ by treating the compound of Formula VII with an organoalkaline metal base under anhydrous conditions. Preferred organoalkaline metal bases are butyllithium and lithium diisopropylamide.

Formula IV intermediates are a = 6 =

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generically known class of substituted heterocyclic phenols, prepared as described below, in the general description and in the specific examples.

In an alternative process comprising the reaction of sets of Formulas V and VI, the process is carried out using approximately equimolar amounts of the reagents in an inert solvent, at a temperature of between about 5θ ° θ ^and 100 ° C, conveniently at the temperature reflux of the solvent. The reaction is completed within a period ranging from ² ^ 5 hours. The palladium complex catalyst, present up to a limit of about 5 mole percent, can any of the known catalysts, which are known to carry out the cross-linking of the organotin compounds with the organic halides / 'cf. Kosugi et al., Bull. Chem. Soc. Japan 59, 677-679 (198627 »for example PdCl ₂ - (PPh ^) ₂ , PdIPPh ^) ^, PdCl ₂ / P (o-tolyl) 3_7 ₂ » PdCl ₂ + 2p (Oet) ₃ and PdCl ₂ (PhCN) ₂ A preferred catalyst is dichlorobis- (triphenylphosphine) -palladium / ~ PdCl ₂ (PPh ₃ ) ₂ _7.

Formula V intermediates are prepared by reacting an alkali metal salt of a phenol of the formula

with a compound of formula III, in a process analogous to = 7 =

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of the reaction of III with IV.

The Formula VI organotin reagent is prepared by known processes, which comprise the reaction of a tri-lower alkyl halide of tin with unsubstituted aromatic heterocycle, in the presence of a strong base such as butylithium under anhydrous conditions. The trialkyl tin portion enters the most active position on the heterocyclic ring; however, the trialkyl tin portion may be directed to other positions on the heterocyclic ring by using the appropriate halo substituted halo substituted heterocycle.

Some compounds according to the invention can be prepared by constructing the Het ring from intermediates with a cyano or starch group on the phenyl ring, as follows.

the present invention relates to compounds of the formulas

= 8 =

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XIII where R 'is lower alkyl or hydroxy alkyl of 1-5 carbon atoms, Rg is hydrogen or lower of 1-5 carbon atoms and Y, R _x and R ₂ meanings provided above.

The compounds of Formula XI can be prepared by reacting an amide of formula XIV 2 ^N - ° followed by reaction of the resulting product with hydroxylamine in acetic acid solution (below) with a compound of formula (CHq) x lower alkyl. (OCH ₃ ) ₂ -Rg,

The Formula XIV amides are in turn prepared by acid hydrolysis of the corresponding nitrile

R »

Y-0

XlVa

R.

R,

CN ‘0 = 9 =

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The compounds of Formula XII can be prepared by reacting a nitrile of formula IX, or its derivative of imino chloride, with hydroxylamino, followed by reaction of the resulting product with an anhydride of the formula (RgCO3).

Alternatively, the compounds of Formulas XI and XII can be prepared by reacting a horn of one of the formulas:

XV

XVI with a 1-nitroalkane (ROHgNOg) and phenylisocyanate or with an alkanocarboxaldehyde oxime (R'CHsN0H) and N-halosuccinamide, where halo is bromo or chloro. The intermediates of formulas XV and XVI are, in turn, prepared using the processes described above and as illustrated

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in Example 5 »below.

The Formula XIII compounds are prepared by reacting a Formula III compound with a Formula IV compound where Het is 1,3,4-oxadiazol-2-yl or 5-lower alkyl-1,3,4 oxadiazole -2-yl. These latter Formula IV phenolic compounds are prepared as described in U.S. Patent 4,218.4 · 5θ 'issued on August 9, 1980.

Alternatively, compounds of Formula XIII can be prepared by cyclizing the compounds of formula

Q

CNHNHCRg

XVII

II put hexamethyldisilazane in the presence of tetrabutylammonium trifluoride, according to the process of Rigo et al., Synthetic Communications 16, 1665-9 (1986). The intermediate acylhydrazines of Formula XVII are also part of the invention and are prepared from the corresponding carboxylic acids.

COOH

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through conventional amide formation. The XVIII acid is conveniently prepared by hydrolysis of the nitrile from

Formula XlVa.

The compounds of Formula XIII where R * is lower alkyl of 1-5 carbon atoms, can also be prepared from the compounds of Formula I, where Het is 1H-tetrazol-5-yl, by reaction with a halide of alkanoic acid, R ^ CO-Hal is chlorine or bromine, or an alkanoic acid anhydride, (RgCOj ^ O ·

The structures of the compounds of the invention were established by the forms of synthesis, by elemental analysis and by infrared spectrography and nuclear magnetic resonance.

The following examples will better illustrate the invention.

Example 1

3-Methyl-5- (5- ^ ~ 4- (1,3 _t 4-oxadiazol-2-yl) -phenoxy7-pentyl-isoxazole / "li; R ^ and R ^ = H, Het = 2- (1,3 , 4-oxadiazolyl

A mixture of 23.6 g of 4- (1,3, ^ - oxadiazolyl) phenol (U.S. Pat. 4,218,458, Example XIX), 35 g of

5- (5_bromopentyl) -3-methylisoxazole and 40 g of ground potassium carbonate in 1.5 liters of acetonitrile under nitrogen, was heated to reflux. A catalytic amount of sodium iodide was added and reflux was continued for 4 hours. The reaction mixture was filtered and concentrated to a solid residue. The latter was dissolved in ethyl acetate and the solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from triethylamine to give 18.5 g of 3-netyl-512

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-5- (5 - / ”4- (1,3,4-oxadiazol-2-yl) phenoxy / -pentyl) isoxazole, on white needles, m.p., 84-86 ° C,

It is also envisaged that 4- (1,2,4-oxadiazol-5-ϋ) -phenol can be reacted with 5- (5-bromopentyl) -3-methylisoxazole, according to the procedure of Example 1, to give 5- (5- / ~ 4- (1,2,4-oxadiazol-5-yl) phenoxy-pentyl) -3-methylisoxazole / 11; e = H, Het = 1,2,4-oxadiazol-5-yl) 7 ~ Example 2

a) 3,5-Uimethyl-4 - / ’’ 5- (3-methylisoxazol-5 "yl) pentyloxy / -benzamide /" XIV; Y = (CHg) ^, R '= CH ^, and

R ₂ = 3.5- (CH ₃ ) ₂ _7.

A solution of 6.3 g of 5- / 5- ^(2, 6-dimethyl-4-cyanophenoxy) pentil7-3-methylisoxazole / XIVa;

Y s (CH ₂ ) ₅ , R = CH ₃ , R _x and R ₂ = 2,6- (CH ₃ ) ₂ ; mp 50-51 ° C. 7 'in 15 ml of sulfuric acid at 97 ° C was stirred at room temperature for 1.5 hours. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from isopropyl acetate-hexane and used directly in the next reaction.

b) 5 "(5 / ^-2, 6-dimethyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) -fenoxilpentil) -3-methylisoxazole / XI ~; Y = (CH ,,) ^, and R ₂ = 2,6- (CH ₃ ) ₂ , R _g =

A suspension of 2.7 g of the product of part (a) in 15 ml of dimethyl acetal was heated to reflux under nitrogen for two hours. The reaction mixture was concentrated in vacuo and then treated with 0.7 g of hydroxylamine hydrochloride, 2.0 ml of 5N hydroxy solution = 13 =

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of sodium and 7 »5 ml of 70% aqueous acetic acid. The resulting mixture was stirred for 30 minutes and then 4.5 ml of water were added. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to intermittent filtration (silica gel $ 1: 1 hexane / ethyl acetate) and chromatography (MPLC, silica gel 60; 1: 1 hexane / ethyl acetate) to give 2.4 g (80 fo) 5- (5 - / * 2,6-dimethyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenoxy 7pentyl) -3-methylisoxazole, mp 54-56 ° C when crystallized at from isopropyl acetate / hexane.

Example 3

a) 3,5-Dimet11-4 - / ^ 3- (3-methylisoxazol-5-yl-propyloxy-benzamide / “XIV; Y = (CH ₂ ) ₃ , R '= CH ^; R _x e

Rg = 3,5- (CH-j) 2 7 was prepared from 6 g of

5 - / ”3 - /” 2,6-dimethyl-4-cyanophenoxy) propyl7-3-methylsoxazole / XlVaj Y = (CHg) ^, R = CH ^, and Rg = 2,6- (CH ₃ ) ₂

mp 46-48 ° C when recrystallized from methanol 7 according to the procedure of Example 2, part (a) and a yield of 65% was obtained as a colorless solid, mp 16-63 ° C when re-crystallized from methanol.

b) 5- (3- / ~ 2,6-Dimethyl-4- (3-methyl-1,2,4-oxadiazol-5-5-yl) -phenoxy / propyl) -3-methylisoxazole / “XI; Y = (CH ₂ ) ₃ , R »= CH, R _x and R ₂ = 2,6- (CH ₃ ) ₂ ,

Πθ »CH ₃ 7 was prepared from 6 g of the product from part (a), 30 g of dimethylacetamide, dimethylacetal and 1.75 S of hydroxylamine hydrochloride according to the procedure of Example 1, part (b) and was obtained (1.7 g) as a colorless solid, mp 55.5-56.5 ° C when = 14 62.561

Case 3707-S JR recrystallized from isopropyl acetate-hexane.

ç

It is also contemplated that, according to the previous procedures, 5- / ^_ 5- (2,6-dimethyl-4-cyanophenoxy) pentyl) -3-hydroxymethylisoxazole (yellow-brown solid, mp 63-64 ° C from diethyl ether) can be converted to 3 »5-dimethyl-4 - /” 5- (3-hydroxymethylisoxazol-5-yl) p®nyloxy7benzamide / ”XIV; Y = (CH „) is

CM CM tíw <5

R '= H0CH ₂ , R ^ and R ₂ = 3,5- (CH ₃ ) ₂ _7 β the latter converted to 5- (5- / 2,6-dimethyl-4- (3-methyl-1,2) , 4-oxadiazol-5-yl) phenoxy 7 P ⁽ enyl) -3-hydroxymethylisoxazole / -XI; Y = (CH ₂ ) ₅ . R '= H2O ₂ , R _x and R ₂ - 2,6- (01 ^) ₂ , R _g = CH _3- 7.

nitrile intermediate was prepared from 2,6-dimethyl-4-cyanophenol and 5- (5-®loropentyl) -5-hydroxymethylisoxazole, the latter prepared, in turn, through the reaction of l-bromo-4-chlorobutane with 3-hydroxymethyl-5-methylisoxazole in the presence of n-butylthio. The 3-hydroxymethyl45-methylisoxazole (e.g. 77-SO ° C., 0.5 mm) was in turn prepared by reducing methyl 5-methylxisoxazole-3-carhoxylate with lithium aluminum hydride.

Similarly, £ £ 5 - / “5- (2,6-dichloro-4-cyanophenoxy) pentyl7-3-methylisoxazole (mp 59-6o ° C) can be converted to 5- (5- / ^- 2 , 6-dichloro-4- (3-methyl-1,2,4-oxadiazol-5-yl) phenoxy 7Ρ ^εη ^ χΐ) -3-methyl-

Example 4

a) 5- (3-Chloropropyl) -3-®tilisoxazole

A mixture of 11.56 g of 1-nitropropane, 15 g of 1-chloro-4-pentine / ~ HC = C (CH ₂ ) ₃ C1 /, 37 g of phenylisocyanate and 4 ml of triethylamine in 3θθ ml of toluene, it was stirred at room temperature for 3 days.

= 15 =

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The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was chromatographed (silica gel, eluted with hexane and 20% ethyl acetate in hexane) to give 12 g of 5- (2-chloro-propyl) -3-ethylisoxazole as a yellow oil.

b) 5- / 3- (2,6-Dimethyl-4-cyanophenoxy) propyl / -3-ethylisoxazole / XlVa; Y = R »= ^C 2 ^H 5» ^R l and R ₂ = 2,6- (CH ₃ ) ₂ J.

To a mixture of 7 »θ ^ S of 4-cyano-2.69dimethylphenol, 3» 57 g of potassium hydroxide and 10.6 g of potassium iodide in 200 ml of acetonitrile, 12 g of 5- (2 -chloro-propyl) -3-®tilisoxazole and the mixture was heated to reflux for about 16 hours. The reaction mixture was concentrated in vacuo and the residue due between ethyl acetate and water. The ethyl acetate layer was washed with aqueous sodium hydroxide (10%) until the excess starting phenol was removed and the solution was contracted to give 10 g of 5 - / * 3- (2,6-dimethyl- ^ -cyanophenoxy) propyl / -3-ethylisoxazole as a yellow oil. A sample of the latter was obtained in a crystalline form, m.p. 5θ-51 ° Ο by crystallization from methanol at -50 ° C.

c) 3,5-bimethyl-4- / ~ 3- (3- © tilisoxazol-5-yl) propyloxybenzamide [XIV]; Y - (CH ₂ ) ₃ , R '= C ^, and

R ₂ = 3,5- (CH ₃ ) ₂ / was prepared from the product of part (b) (10 g) by the process of Example 2, part (a) and was obtained (8.7 g) in the form of a solid, mp 132-13 ° C, when washed with ethyl acetate.

d) 5- (3 - / ”2,6-Dimethyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) -phenoxy / propyl) -3-ethylisoxazole /” XI; Y = = 16 =

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was prepared from 4.15 g of the product of part (c), 20.5 g of dimethylacetamide, dimethyl acetal and 1.2 g of hydroxylamine hydrochloride according to the procedure of

Example 1, part (b) and was obtained (2, 1g) as a colorless solid, m.p. 40-40 ° C, when recrystallized from isopropyl acetate / hexane.

Example 5

a) Ethyl 3.5-dimethyl-4- (3-ethynylpropoxy) benzoate

A suspension of 6.42 g of ethyl 3,5-dimethyl-4-hydroxybenzoate, 5.5 g of potassium iodide,

3.7 g of 1-chloro-4-pentine and 2.3 g of powdered potassium hydroxide in 650 ml of acetonitrile, was heated to reflux under nitrogen for 16 hours. The mixture was filtered, concentrated in vacuo and subjected to intermittent filtration (silica gel, 4: 1 hexane / ethyl acetate) to give 7.4 g of ethyl

3,5-dimethyl-4- (3-ethynylpropoxy) benzoate as a yellow oil.

b) Acid 3 «5-Diffl € ^! tyl-4- (3-ethynylpropoxy) benzoic

The ethyl ester of part (a) (7.4 g) was hydrolyzed, first with 0.9 g of lithium hydroxide, 25 ml of methanol and 10 ml of water, stirred at room temperature for 3 days and then with 50 ml 10% sodium hydroxide in 100 ml of ethanol, heated to reflux for 2 hours. The product was isolated by acidification, extraction; ether and concentration to give 4.7 g of 3,5-dimethyl-4- (3-ethynylpropoxy) benzoic acid, m.p. 129-13 ° C.

c) 3.5-Dimethyl-4- (3-e tinylpropoxy) benzamide

To a solution of 4.7 g of 3,5-dimethyl-4- (3-ethynylpropoxy) benzoic acid in 100 ml of tetra17 =

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d) 5 - / ^ 3,5-Dimethyl-4- (3-ethynylpropoxy) phenyl7-3-methyl-1,2,4-oxadiazole / XV; Y = (CHg) ^, R ^ and Rg = = 3.5 (CH ^) g, Rg = ^was P ^re Stopped from

4.7 g of 3,5-dimethyl-4- (3-®thinylpropoxy) benzamide, 31 ml of dimethylacetal dimethylacetamide and 1.7 g of hydroxylamine hydrochloride according to the procedure of Example 2, part (b) obtained (4.8 g) as a viscous oil used directly in the next reaction. A sample, when crystallized from isopropyl acetate / hexane, had mp 38-40 ° C,

e) 5- (3- / 2 _> 6-Dimethyl-4- (3-methyl-1,2,4-oxadiazol-. 5-yl) phenoxypropyl) -3- (n-propyl) isoxazole Y = = (CHg ), R '= CH ^ CHg, eR ₂ = 2,6- (CH ₃ ) g, ^R 8 ^{= CH} 3-7 ·

To a solution of 4.4 g of the product from part (d), 1.7 g of 1-nitrobutane and 12 drops of triethylamine in 4 ml of dry toluene, was added a solution of 3.7 ml of phenylisocyanate in 5 ml of dry toluene, drop by drop, over a period of 2 hours. The reaction mixture was stirred at room temperature for five days, under nitrogen, then filtered, concentrated and chromatographed (MPLC, silica gel, 3ϊ1 hexane / ethyl acetate). A first fraction produced 1.2 g of the starting material in part (d) and a second fraction 3.0 g of the pro _s 18 =

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desired product which was recrystallized from isopropyl acetate / hexane at -50 ° C, to give 2.5 g of 5- ^ 3- / 2,6-dimethyl-4- (3-methyl-1,2,4 -oxadiazol-5-yl) phenoxy / propoxy ^ · -3- (n-propyl) isoxazole, mp 35-37 ° C.

Example 6

5- 5- / ~ 2,6-Pimethyl-4- (5-methyl-1,2,4-oxadiazo1-3-yl) -phenoxy / pentyl-3-methylisoxazole XII; Y - (CHg) ^,

R '= CHg, R _x and R ₂ = 2,6- (CH ₃ ) ₂ , R _g = CH ₃ J7.

A suspension of 7.0 S 5- / ~ 5- (2,6-dimethyl-4-cyanophenoxy) pentyl7-3-methylisoxazole, 1.8 g of hydroxylamine hydrochloride and 3.5 g of sodium acetate trihydrate in 4-0 ml of 95% ethanol it was heated to reflux under nitrogen for two days. The reaction mixture was filtered, concentrated in vacuo and the residue, in 5θ ml of acetic anhydride, was heated to reflux for 3 hours. The reaction mixture was poured over ice / 10% sodium hydroxide and extracted with ether. The ether extracts were washed with water and dried saturated sodium bicarbonate (K ₂ CO ₃ ), concentrated and subjected to intermittent filtration (silica gel 60, 3 hexane / ethyl acetate) followed by chromatography (MPLC, silica gel 60, 3 : 1 hexane / ethyl acetate). The resulting product was crystallized from isopropyl acetate / hexane to give 2.7 g of 5- {5 - ^ * 2,6-dimethyl-4- (5-methyl-1,2,4-oxadiazole-3 -yl) phenoxy-pentyl ^ -3-methylisoxazole, mp 45-6 ° C.

Similarly, it is contemplated that 5 - / ”5- (2,6-dimethyl-4-cyanophenoxy) pentyl / -3-hydroxymethylisoxazole or 5- / ~ 5- (2,6-dichloro-4-cyanof enoxy) pentyl / -3-methylisoxazole can be converted, respectively, to 5- (5 - / ^, 6-dimethyl-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy / pentyl ) -3-hydroxymethylisoxazole / “XII; Y = (CH ^) ^, = 19 =

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R '- H2O ₂ , and R ₂ = 2,6- (CH ₃ ) ₂ , R _g = or 5 - / ”2,6-dichloro-4- (5-methyl-1,2,4-oxadiazole- 3-yl) phenoxy / -pentyl -3-methylisoxazole / * XII; Y = (CHg) ^, R '- CH ^, ^R i ® ^R 2 ^{= 2} » ⁶ “ ^C1 2' ^R 8 ^{= CH} 3 J '

Example 7

5- 3- / ~ 2,6-Dimethyl-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy / propyl-3-methylisoxazole / “XII; Y = (CHg) ^,

R · = CH ^, R _x and R ₂ = 2,6- (CH ₃ ) ₂ , R _g = CH ^ J was prepared from 6 g of imino chloride derived by reaction of 5 - / ”3- ( 2,6-dimethyl-4-cyanophenoxy) propyl / -3-methylisoxazole with ethanolic hydrogen chloride, 1.49 g of hydroxylamine hydrochloride and 100 ml of acetic anhydride according to the procedure of Example 6, f4 g) was obtained under the form of a colorless solid, mp * 80-82 ° C, when recrystallized from methanol.

Example 8

a) 3,5-dimethyl-4- (3-ethynylpropoxy) benzonitrile

A mixture of 40 g of 3,5-dimethyl-4-hydroxybenzonitrile, 3θ »77 g of l-chloro-4-pentino,

74.63 g of potassium carbonate and 130 ml of N-methylpyrrolidone, was heated with stirring to 100 ° C and stirring was continued at 100 ° C for 4 hours. The mixture was cooled to room temperature and 800 ml of water was added. This mixture was extracted with 400 ml of ethyl acetate and the extract was washed with 2N sodium hydroxide and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting black oil, dissolved in ethyl acetate, was passed through a florisyl pad to remove the color and the filtrate was concentrated in vacuo. 0 residue • Ó / M90

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it was recrystallized from methyl alcohol to provide 34.64 g (6o, 2 of 3, 5-dxmethyl-4- (3-ethynxl-propoxy) benzonitrile, m.p., 48-49 ° C.

b) 3- / 3 '5-Di ^methyl-4- (3-etinilpropoxi) phenyl / "5-methyl-1,2,4-oxadiazole.

A mixture of 25 g of benzonitrile from part (a), 16.6 g of hydroxylamine hydrochloride, 32.64 g of sodium acetate trihydrate, 200 ml of ethyl alcohol and 40 ml of water, was refluxed for 5 hours and cooled at room temperature, ethyl alcohol was removed by vacuum distillation and the residue, after standing overnight at room temperature, was suspended in 200 ml of acetic anhydride and the mixture was refluxed for 2 hours and allowed to cool to at room temperature, sodium hydroxide (2N) was added slowly with stirring and cooling through an ice bath, during which time heat and gas were turned. The mixture was extracted with ether and the extract was washed successively with diluted solution of sodium hydroxide, diluted sodium bicarbonate solution and saturated saline. The extract was dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil. A solution of oil in ethyl acetate was passed through a column of florisil to remove the color and concentrated in vacuo. The residue was subjected to chromatography (MPLC, silica gel, 15:85 ethyl acetate / hexane) to give 17 , 8 g (56 µ) of 3 - / “3,5-dimethyl-4- (3-ethynylpropoxy) phenyl7-5-methyl-1,2,4-oxadiazole in the form of a white solid, mp, 4l, 5-43, 0 ° C.

c) 5- / 3- / ~ * 2,6-Pimethyl-4- (5-methyl-1,2,4-oxadiazol-3-yl) -phenoxy / propyl] -3-ethylisoxazole / '“' X. YL; Y = «(CH ₂ ) ₃ , R '= CH ₃ CH ₂ , and R ₂ = 2,6- (CH ₃ ) ₂ ,

R ₈ - 0H ₃ J.

=

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Case 4707 - S JR

ÁM90

A mixture of 3 »99 g of N-chlorosuccinimide, 2 drops of pyridine and 75 ml of N-methylpyrrolidone, was stirred at room temperature until clear and 2.19 g of propionaldehyde oxime was added over 10 minutes. was continued for a long time at room temperature and a portion was added

2.7 S of the 1,2,4-oxadiazole of part (b) in 25 ml of N-methylpyrrolidinone. The mixture was heated to 90 ° C, 4.2 ml of triethylamine was added over 3 hours and stirring and heating was continued for 1 hour.

The mixture was cooled to room temperature, suspended in water and extracted with methylene chloride. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to chromatography (MPLC, silica gel, 35 J: 65 ethyl acetate / hexane) to give 1.86 g (55 of 5- £ 3- / 2,6-dimethyl-4- (5-methyl) -1,2,4-oxadiazol-3-yl) -phenoxy / propyl-3 — ethylisoxazole as a white solid mp 85-86 ° C, after recrystallization from methyl alcohol.

Example 9

5- {3- / 2,6-Dimethyl-4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxypropyl-3-propylisoxazole / “XII; Y = (CH ₂ ) ₃ , R '= CH ₃ CH ₂ CH ₂ , R _T and R ₂ = 2,6- (CH ₃ ) ₂ , Rg = CH ₃

Following a procedure similar to that of Example 8 (c), but replacing with 2.6 g of butyraldehyde oxime to propionaldehyde oxime and using 3.99 g of N-chlorosuccinimide, 2 drops of pyridine, 50 ml of N-methylpyrrolidinone, 2.7 g of 1,2,4-oxadiazole from part (b) of Example 8 and 4.2 ml of triethylamine, obtained 22

62,561

Case 4707-S JR

after chromatography (MPLC, silica gel, 30 · 7θ ethyl acetate / hexane), 2.06 g (58 fo) of the title compound as white needles, mp 69.0-70 »0 ° C., when recrystallized from methyl alcohol,

/

Example 10

a) 3,5-Dichloro-4-hydroxybenzoic acid hydrazide

A mixture of 10.0 g of methyl 3 »5-dichloro-4-hydroxybenzoate and 15 ml of hydrazine hydrate, was heated in a steam bath for 3 hours. The excess hydrazine was removed in vacuo and the residue recrystallized from 2-propanol water (80:20) to give 9 g of the hydrazide, used directly in the next reaction.

b) 2,6-Dichloro-4- (1,3,4-oxadiazol-2-yl) phenol ^ IV; = 2, -Cl, R ₂ = 6-C1, Het = ^1,3,4 - ^oxadiazol -2-yl /.

A mixture of 8.9 g of ^3,5-d i acid hydrazide ° chloro-4-hydroxybenzoic acid and 5θθ ml of triethyl orthoformate was stirred and heated at reflux for 4 hours, 0 solvent was removed in vacuo to yield the product (9.8 g) as a yellow solid, used directly in the next reaction.

c) 5- f 5 - / ”2,6-Dichloro-4- (1,3» 4-oxadiazol-2-yl) phenoxy / “-pentyl} -3-methylisoxazole /“ II; R ₁ and R ₂ = Cl, Het el, 3 »4-oxadiazol-2-yl_7 was prepared from 8.5 g of 2,6-dichloro-4- (1,3,4-oxadiazol-2-yl) ) phenol and 20 g of 5 "(5-bromopentyl) -3-methylisoxazole according to the procedure of Example 1 and was obtained in a yield of 34 fo (4.8 g), mp 73-74 ° C, when recrystallized at from triethylamine.

= 23 =

62,561

Case 4707-S JR

It is further contemplated that by replacing 5-15-bi'omopentyl) -3-methylisoxazole in the previous process with an equivalent molar amount of 5 "(5-doropentyl) -3-hydroxymethylisoxazole, 5- ^ 5- /" 2,6-dichloro-4- (1,3,4-oxadiazol-2-yl) -phenoxy / pentyl-3-hydroxymethylisoxazole / “XIII; R 'β HOCH ^, R ^ and R ^ = 2,6-Cl ₂ , Y = (CH ₂ ) ₅ ^ 7. 5- (5-chlorophenyl-3-hydroxymethylisoxazole was prepared by reacting 1-bromo-4-chlorobutane with 3-hydroxymethyl-5-methylisoxazole in the presence of n-butylthio. 3-hydroxy-methyl-5-methylisoxazole (eg 77-80 ° C, 0.5 mm) was in turn prepared by reducing methyl 5-methylisoxazol-3-carboxylate with lithium aluminum hydride.

Example 11

a) 3,5-Dichloro-4- / ~ 5- (3-methylisoxazol-5-yl) -pentyloxybenzoigo acid / “XVIII; R '= CH ^, Y = (CH ^, P ^ and R ₂ = 3,5-Cl ₂ _7

A mixture of 6.11 f of 5- / ~ 5- (2,6-dichloro-4-cyanophenoxy) pentyl7 "3-methylisoxazole (mp 59-6 ° C), 75 ml of 35% sodium hydroxide and 75 ml of ethanol, was stirred on a steam bath for a few hours.

The reaction mixture, when allowed to stand, separated into a lower transparent layer and an upper yellow layer. The latter was separated, diluted with cold water and acidified with hydrochloric acid. The resulting solid was collected and recrystallized from acetonitrile to give 5.24 g of 3,5-dichloro-4- / ~ 5- / 3-methylisoxazol-5-yl) -pentyloxy-benzoic acid, mp 67-69 ° C.

b) N-Acetyl-N * - ^ 3,5-dichloro-4 - / “5- (3-methylisoxazol-5-yl) -pentyloxy / benzoyl L hydrazine

I — b— ll.l. .......................... Τι ·, ». ,, .. · .— ιιιι ^“ XVIII; R '= CH ₃ , Υ = (CH ^, and R ₂ = 3,5-Cl ₂ , = 24 =

62,561

Case 4707-S JR

r ₈ = oh ₃ .7.

A solution of 5> 19 g of the product of part (a) and 2.59 g of carbonyldiimidazole in 50. ml of tetrahydrofuran (THR) in a nitrogen atmosphere, was heated to reflux until the gas emission ceased. The mixture was cooled and 1.1β g of acetylhydrazine was added.

The resulting mixture was heated to reflux for 5-6 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate and filtered through a plug of silica gel. A colorless solid (1.24 g) of N-acetyl-N'- £ 3,5-dichloro-4 - / '5 “(3-πιβϋϋ3θΧαζο1-5-1ΐ) pentyloxy / benzoyl ^ f hydrazine, mp (polymorphic) 118 ° and 134 ° C, when recrystallized from isopropyl acetate.

^c ) 5- £ 5 - / ”2,6-Dichloro-4- (5-methyl-1,3,4-oxadiazol-2-yl) -phenoxy / pentyl-3-methylisoxazole ^“ XIII; R '= CH ^, Y = (CHg) ^, R ₁ and R _g = 2,6-C1 ₂ , Rg = ch ₃ J.

A mixture of 0.94 g of the product from part (b), 1 ml of hexamethyldisilazane, 0.5 ml of tetrabutylammonium fluoride and 10 ml of chlorobenzene, was heated to 125 ° C under nitrogen, with stirring. A catalytic amount of imidazole as the silylating catalyst was then added. After an hour, an additional 0.5 ml of hexamethyldililazane and a catalytic amount of tetrabutylammonium fluoride were added and the reaction mixture was heated at 125 ° C for three days. The mixture was then cooled and filtered through a plug of silica gel and eluted with ethyl acetate. The product isolated from the filtrate was recrystallized from isopropyl hexane acetate to give 0.53 g of 5- ^ 5 - / * 2,6-dichloro-4- (5-methyl-1,2,4-oxadiazole- £ 5-yl) phenoxy-pentyl -3-methylisoxazole, solid = 25 =

62,561

Case 4707-S JR

light brown, mp 71-72 ° C.

It also contemplates that by substituting 5- / ~ 2- (2,6-dichloro-4-cyanophenoxy) pentyl / -3-methylisoxazole in part (a) with an equivalent molar amount of 5- / ~ 5- (2.6 -dimethyl-4-cyanophenoxy) pentyl7-3-hydroxymethylisoxazole, 3,5-dimethyl-4 - / '' 5- / ~ 3hydroxymethylisoxazol-5 "-yl) p®nyloxy7benzoic acid /“ XVIII;

R '= HOEHg, Y = (CHg) ^, R ₁ and R ₂ = 3,5- (CH ₃ ) ₂ J, N-acetyl-N' - (3,5-dimethyl-4 - / “5- ( 3-hydroxy trimethoxazol-5-yl) pentyloxy / benzoyl hydrazine (XVITj R * = H2O ₂ , Y ~ = (CH ₂ ) ₅ , and R ₂ = 3,5- (CH ₃ ) ₂ , R _g = CH ₃ J and 5- £ - | 5 - / “2,6-dimethyl-4- (5-methyl-1,3,4-oxadiazol-2-yl) phenoxy / pentyl $ -3-hydroxymethylisoxazole / ~ XIII; R '= HOCHg, Y = = (CH ₂ ) ₅ , R _x and R ₂ - 2,6- (CH ₃ ) ₂ , Rg = CH ₃ J. The intermediate 5- / ~ 5- (2,6-dimethyl-4- cyanophenoxy) pentyl 7-isoxazole (brownish yellow solid, mp 63-64 ° C from diethyl ether) was prepared from 2,6-dimethyl-A-cyanophenol and 5- (5-chloropentyl) -3-hydroxymethylisoxazole.

Example 12

a) Ethyl 3,5 "dimethyl --- i - / 3" (3-methylisoxazol-5-yl) -propyloxy / henzoate.

.............................-.....—, r »-.......... ...........

• To a mixture of 10.05 g of ethyl 3,5-dimethyl-4-hydroxybenzoate and 8.0 g of 5- (3-chloropropyl) -3-methylisoxazole in 550 ml of dry acetonitrile, 4.87 g of potassium hydroxide and 12.9 g of potassium iodide. The reaction mixture was stirred at reflux overnight and then filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer concentrated to a yellow oil. The latter was crystallized from ethyl acetate / hexane (ls4) at -50 ° C to give 14 g of product, 12 dos = 26 =

62,561

Case 4707-S JR

which were used directly in the next hydrolysis reaction. An ester sample was purified by chromatography on silica to give a pure compound, m.p. 49-5θ ° θ ·

b) 3,5-dimethyl-4- / ~ 3- / ~ 3-methylisoxazol-5-yl) propyloxy / benzoic acid / "XVIII; R ’=

Y s (CH ₂ ) ^, and R ₂ = 3.5- (CH ^) ₂ J was prepared by hydrolysis of 12 g of the crude product of part (a) with 120 ml of 10% sodium hydroxide in 120 ml of ethanol, stirred at reflux for two hours. The reaction mixture was acidified and the product isolated to give 9 g of 3,5-dimethyl-4 - / ”3- (3-methylisoxazol-5-yl) -propyloxy / benzoic acid, mp 156-157 ° ^, when recrystallized from isopropyl acetate-hexane (lily).

c) N-Acetyl-N «- {3,5-dimethyl-4 - /“ 3- (3-methylisoxazol-5-yl) -propyloxybenzoyl hydrazine / “XVII; R »= CH ₃ , Y = (CH ₂ ) ₃ , ^{and R} 2 = 3.5- (CH ₃ ) ₂ , Rg = CH ₃ 7 was prepared from 8.3 g of the product from part (h) of according to the procedure of Example 11, part (h) and it was obtained (10.2 g) as a colorless solid, mp 144-142 ° C. When recrystallized from ethyl acetate-hexane (lil).

d) 5- f 3-7 "2 _> 6-Dimethyl-4- (5-methyl-1,3,4-oxadiazol-2yl) -phenoxy7propyl-3-methylisoxazole /"XIII; R »= CH ₃ , Y = (CH ₂ ) ₃ » and Rg = 2,6- (CH ₃ ) ₂ , Rg = CH ₃ J was prepared from 10 g of the product of part (c) according to procedure of Example 11, part (c) and was obtained (0.6 g after chromatography on silica) as a colorless solid, mp, 99-100 ° C, when recrystallized from isopropyl acetate.

= 27 =

62,561

Case 4707-S JR

g * g-SP ^l0 ...... 1 ?.

3-Methyl-5- $ 7 - / ** 4- (5-methyl-1,3,4-oxadiazol-2-yl) phenoxy / -heptyl isoxazole / 'XIII; R «= CH ₃ , Y = (0¾), and R _g = H, R _g =

A 1.3 g mixture of 5- (7 - / ”4- (1h-tetrazol-5-yl) -phenoxy / heptyl) -3-methylisoxazole (US Patent 4,857,539, Example 48 (&} J 50 mg of hydroquinone and ml of acetic anhydride under nitrogen, was stirred and heated to reflux for one hour, allowed to stand at room temperature overnight, treated with cold water and stirred for about three hours. the resulting brown solid was recrystallized from methyl alcohol to give 1.09 S (θΐ $) of the title compound, mp 93-95 ° θ.

Example l4

5- £ 5- / ~ 2,6-Pimethyl-4- (5-methyl-1,3,4-oxadiazol-2-yl) -phenoxy7-pentyl -3-methylisoxazole

.................................................. ................................... ........... .... ..... ..... II / “XIII; R · = CH ^, Y = (CH ^, ^s x ^{and R} 2 = 2,6- (0¾) ^

Βθ = oh ₃ _7.

A mixture of 2.39 g of 5- É5- / ^"2, 6-dimethyl-4- (tetrazol-5-ϋ) phenoxy / tihsoxazol pentyl -3 me / 'US Patent 4857539, Example 49 ( a) J, 100 mg of hydroquinone and 20 ml of acetic anhydride under nitrogen, was stirred and heated to reflux for one hour, allowed to stand at room temperature overnight and poured into 150 ml of cold water with stirring. The aqueous mixture was extracted with ethyl acetate and the extract was washed with water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried only = 28 ss

62,561

Case 4707-S JR

IJ

on magnesium sulphate and concentrated in vacuo to give, when crystallized from isopropyl acetate, 1.2 g (48%) of the title compound, m.p.

The biological evaluation of the compounds of Formulas I and II demonstrated that they have an antiviral activity. They are useful for inhibiting virus replication in vitro and are mainly active against picornaviruses, including enteroviruses poliovirus and coxsackie virus, and especially numerous rhinovirus strains. In in vitro tests of the compounds of the invention against picornavirus, viral replication was found to be inhibited at minimal MIC inhibitory concentrations ranging from 0.01 to about 5 micrograms per milliliter.

MIC values were determined using a standard plaque reduction assay as follows: HeLa cells (Wisconsin) in monolayers were infected at a virus concentration to provide approximately 80 plaques per monolayer in the control virus (no medication present). The compound to be tested was serially diluted and included in the cover agar medium and, in some cases, also during the adsorption period. The MIC was determined to be the concentration of the compound that reduced the number of plaques by 5θ% relative to the untreated control virus.

In normal test procedures, compounds were tested by comparison with a panel of fifteen human rhinovirus (HRV) serotypes; namely HRV-2, -ΙΑ, -ÍB, -6, -14, -21, -15, -25, -30, -50,

-67, -89, -86 and -4l. The MIC value for each of the rhinovirus serotypes was determined and the efficacy of each of the compounds was determined in terms of MlCgg and MlCgg values, which are the concentration of values to inhibit 5θ $ ⁶ 80 respectively, the serotypes tested.

= 29 =

62,561

Case 4707-S JR

Z *

The following Table provides the results of the tests carried out with the compounds of the invention. For some of the compounds, the values ΜΙΟ ^ θ and ΜΙΟβθ are based on the assay of less than 15 rhinovirus serotypes. In these cases the number of serotypes viruses (N) is indicated in parentheses after the value ΜΙΟθθ.

MIC MIC _en 50 (Rinovirus) mic _8o (n) (Rhinovirus) Example No. (Polio 2) : 1 0.05 2.56 (l) 2 (b) 0.053 0.42 (6) 3 (b) 0.026 0.12 (15) 4 (d) 0.042 0.15 (15) 5 (e) 0.036 0.06 (7) 6 0.018 0.10 (5) 7 0.012 0.069 (13) 8 (c) 0.017 0.05 (6) 9 0.025 0.04 (6) 10 (c) 2.24 0.25 0.91 11 (c) o, i4 0.46 (15) 12 (d) 0.054 0.35 (6) 13 2.3 3.2 (2) l4 0.34 0.67 (2)

The following table compares the MIC values for the compound of Example 10 (c) and the methylated derivatives of Example 11 (c) for 15 rhinovirus serotypes s = 30 =

62,561

Case 4707-S JR

Serotype

Example 11 (c)

Example 10 (c)

IA 1.45 0.44 1B 0.53 0.14 2 0.41 0.016 6 7.06 0.46 14 2.02 0.19 15 1.92 0.42 21 0.24 0.0092 22 0.45 0.018 25 2.42 0.7 30 0.10 0.031 41 2.76 99 * 50 0.091 o, o4i 67 0.64 0.1 86 1.28 o, 57 89 0.28 0.01

Inactive at the tested dosage level

The previous data shows that, except in the case of serotype 41, the compound of Example 11 (c) is substantially more effective than the compound of Example io (c),

Antiviral compositions are formulated for use by preparing a diluted solution or suspension in a pharmaceutically acceptable aqueous, organic or aqueous-organic medium for topical or parenteral administration by intravenous or intramuscular injection, or for intranasal or ophthalmic application; or are = 31 =

62,561

Case 4707-S JR prepared in the form of tablets, capsules, or aqueous suspension with conventional excipients for oral administration.

Claims (7)

1? - Process for the production of oxyzolyl-phenoxyalkylisoxazoles and their use as anti-viral agents comprising the formula in which: Y is an alkylene bridge of 3-9 carbon atoms; R 'is lower alkyl or hydroxy-lower alkyl of 1-5 carbon atoms; R4 and Rg are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that when Rg is hydrogen R 'is hydroxy-alkyl32 = 62,561 Case 4707-S JR '6 an: 99 -bottom; or respective pharmaceutically acceptable acid addition salts which comprise the reaction of a compound of the formula with a compound of the formula (CHg) ₂ NC (0CHg) ₂ -Rg, followed by reaction of the resulting product with hydroxylamine in a solution of acetic acid to produce a compound. 2 + - Process for the production of oxyzolyl-phenoxyalkylisoxazoles and their use as anti-viral agents, according to claim 1, characterized in that it comprises the compound R ·· -: - * Il N in which Y is an alkylene bridge of 3-9 carbon atoms; R 'is lower alkyl or hydroxy-lower alkyl of 1-5 carbon atoms; = 33 = 62,561 Case 4707-S JR R ^ and R ^ are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, alkoxycarbonyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that when Rg is hydrogen R 'is hydroxy-lower alkyl; or their pharmaceutically acceptable acid addition salts, which comprises the reaction of a compound of the formula or its derivative of imino chloride with hydroxylamine, followed by the reaction of the resulting product with an anhydride of the formula (RgCOjgO to produce a compound of the formula. 3 * - Process for the production of zolyl-phenoxy-alkylisoxazole oxidation and its use as anti-viral agents, according to claim 1, characterized in that it also comprises the compound of the formula = 34 62,561 Case 4707-S JR Het is selected from among which; ^X K where ' Y is an alkylene point of 3-9 carbon atoms; R 'is lower alkyl or hydroxy-lower-alkyl of 1-5 carbon atoms; R 2 and R 2 are hydrogen, halogen, lower alkyl, lower alkoxy nitro, lower alkoxycarbonyl or trifluoromethyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that when Rg is hydrogen R 'is hydroxy-lower alkyl; or their pharmaceutically acceptable acid addition salts, which comprises the reaction of a compound of the formula = 35 = 2,561 Case 4707-S JR with a compound of the formula ROH ^ NO ^, and phenyl isocyanate. 4 - Process for the production of oxiduazolyl-phenoxyalkylisoxazoles and their use as anti-viral agents, according to claim 1, characterized in that it also comprises the compound of the formula in which Het is selected from among Y is an alkylene bridge of 3-9 carbon atoms 5 R * is lower alkyl or hydroxy-lower alkyl of 1-5 carbon atoms; = 36 = 62,561 Case 4707-S JR íj. ÂCO1990 tÍÂ L R4 and Rg are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that Rg is hydrogen R 'is hydroxy-lower alkyl; or its pharmaceutically acceptable acid addition salts, which comprises reacting a compound of the formula or with a compound of the formula R 'CH = NOH and N-halosuccinamide in which the halo is bromine or chlorine. 5- - Process for the production of oxyzolyl-phenoxyalkylisoxazoles and their use as anti-viral agents, according to claim 1, characterized = 37 = 62,561 Case 4707-S JR tj sfl-990 do because it also comprises the compound of the formula in which: Y is an alkylene bridge of 3-9 carbon atoms; R · is lower alkylene or hydroxy-lower alkyl of 1-5 carbon atoms; R4 and Rg are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that when Rg: is hydrogen R * is hydroxy-lower alkyl; or their pharmaceutically acceptable acid addition salts, which comprises the reaction of a compound of the formula R · -Y-Hal with a compound of the formula = 38 = 62,561 Case 4707-S JR where Hal is chlorine, bromine or iodine. 6 - Process for the production of oxyzolyl-phenoxyalkylisoxazoles and their use as anti-viral agents, according to claim 1, characterized in that it also comprises the compound of the formula in which Y is an alkylene bridge of 3-9 carbon atoms; R * is lower alkyl or hydroxy-lower alkyl of 1-5 carbon atoms; R4 and Rg are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that when = 39 = 62,561 Case 4707-S JR Rg is hydrogen R 'is hydroxy-lower alkyl; or its pharmaceutically acceptable acid addition salts, which comprises reacting a compound of the formula with hexamethyldisilazane in the presence of tetrabutylammonium trifluoride, 7 ^is - Process for the production of oxidiazolil-fenoxialquilisoxazolas and their use as antiviral agents according to claim 1, characterized in that it also comprises the compound; of the mule form in which Y is an alkylene bridge of 3-9 carbon atoms; R 'is lower alkyl of 1-5 carbon atoms; = 40 = 62,561 Case 4707-S JR R ₂ and R ₂ are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl; and Rg is hydrogen or lower alkyl of 1-5 carbon atoms, with the proviso that when Rg is hydrogen R 'is hydroxy-lower alkyl} or its pharmaceutically acceptable acid addition salts, which comprises the reaction of a compound of the formula R- Het where: Y is an alkylene bridge of 3-9 carbon atoms; Z is N $ R is lower alkyl of 1-5 carbon atoms; R4 and Rg are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, lower alkoxycarbonyl or trifluoromethyl 5 and Het 'is 1H-tetrazol-5-ϋο with an alkaneic acid chloride of the formula RgCO-Hal is chloride or bromine, or an alkaneic acid anhydride of the formula (RgC0) 20.