HU211665A9 - Tetrazolyl-(phenoxy and phenoxyalkyl)-piperidinylpyridazines as antiviral agents - Google Patents

Description

BACKGROUND OF THE INVENTION

a) The present invention

The present invention relates to novel tetrazolyl (phenoxy and phenoxyalkyl) -piperidylpyridazine derivatives, pharmaceutical compositions containing them and their use as antiviral agents.

(b) State of the art

European Patent Application Publication No. 0 320 032, published November 17, 1986

discloses compounds of the general formula wherein

R 1 is hydrogen or halogen, C 1-6 alkyl, hydroxy, mercapto, trifluoromethyl, amino, mono- or di (C 1-6 alkyl) amino, cyano; , (C 1-6 alkyl) oxy, aryloxy, aryl (C 1-6 alkyl) oxy, (C 1-6 alkyl) thio, arylthio, (C 1-6) alkyl) sulfinyl, (C 1 -C 6) alkylsulfonyl, arylsulfinyl, arylsulfonyl, (C 1 -C 6) alkoxy) carbonyl, (C 1 -C 6) alkylcarbonyl or aryl;

R ₂ and R ₃ each independently represent hydrogen or C 1-6 alkyl, or R ₂ and R 30 may form a divalent radical of formula -CH = CH-CH = CH-;

Alk is a C 0-6 alkane chain;

G is (i)

-H CH-, wherein m is 2-3; n is 2-3;

R _4, R _{s, R} t are independently hydrogen or 45 halogen atoms, or C 1-6 alkyl, cyano, nitro or amino;

X is O, S, NR _g or a direct bond; wherein R _g is hydrogen or C 1-6 alkyl. ₅₀

These compounds are attributed to antiviral activity.

European Patent Application Publication No. 435,381, issued July 3, 1991

Pyridazine amines of the general formula wherein

R 1 is hydrogen, or C 1 -C 4 alkyl, hydroxy, trifluoromethyl, cyano, C 1 -C 4 alkoxy, (C 1 -C 4 alkyl) thio, (C 1 -C 4 alkyl) sulfinyl -, (C 1-4 alkyl) sulfonyl, (C 1-4 alkyl) oxycarbonyl, (C 1-4 alkyl) carbonyl or aryl;

R ₂ and R ₃ are hydrogen or C 1-4 alkyl;

Alk is C 1 -C 4 alkanediyl;

R 4 and R ₅ represents a hydrogen or halogen atom, or

C 1-4 alkyl; and

Report of the week

rj

groups of the general formula in which

R ₆ is hydrogen, C 1-6 alkyl, hydroxy (C 1-6 alkyl), C 3-6 cycloalkyl, aryl, aryl (C 1-4 alkyl), (C 1-4 alkyl) oxy (C 1 -C 4 alkyl), (C 3 -C 6 cycloalkyl) (C 1 -C 4 alkyl), trifluoromethyl or amino;

each R ₇ is independently hydrogen or C 1-6 alkyl, C 3-6 cycloalkyl, aryl, aryl (C 1-4 alkyl), (C 1-4 alkyl) oxy (1) -C 4 alkyl, C 3 -C 6 cycloalkyl-C 1-4 alkyl, or trifluoromethyl, and each aryl is independently phenyl or phenyl substituted with one or two substituents wherein the substituent (s) is (are) substituted. independently halogen, (C1-C4) alkyl, trifluoromethyl, ((C1-C4) alkyl) oxy, or hydroxy.

These compounds are attributed to antiviral activity.

SUMMARY OF THE INVENTION It has been found that phenoxy or phenoxyalkylpiperidylpyridazines in which the phenoxy group is substituted by a tetrazolyl group or a substituted tetrazolyl group have an antiviral activity.

Accordingly, the present invention relates to .hQ-O— (φΑΑ.

Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein:

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Y is a bond or C 1-6 alkylene;

R 1 is hydrogen or C 1-3 alkyl;

R ₂ is hydrogen, C 1-3 alkyl, or halogen;

R ₃ is hydrogen, C 1-3 alkyl, or halogen;

R ₄ is hydrogen or C 1-3 alkyl.

Preferred compounds of formula I according to the invention are compounds of formula I, or pharmaceutically acceptable acid addition salts thereof, wherein R 1 is hydrogen or C 1-3 alkyl;

R ₂ and R ₃ are each independently hydrogen, fluoro, or C 1-3 alkyl;

m is 0-2.

The invention further relates to antiviral pharmaceutical compositions containing as active ingredient the compounds of formula (I) according to the invention in an effective amount and containing suitable carriers and diluents. The present invention also relates to a method of controlling viruses with pharmaceutical compositions, including systemic treatment of viral infections in mammals.

DETAILED DESCRIPTION OF THE INVENTION together with preferred embodiments

Halogen means fluorine, chlorine, bromine and iodine. C 1-6 alkylene is understood to mean a divalent straight or branched chain containing from 1 to 6 carbon atoms. Examples of such groups include methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene,

1,6-hexylene or 1-methyl-1,4-butylene. The following abbreviations are used in the present invention: diethyl azodicarboxylate DEAD, diisopropylethylamine D1PEA, tetrahydrofuran THF, N-methylpyrrolidine NMP, Ν, Ν-dimethylformamide DMF.

The compounds of formula (I) may be prepared by the following two general procedures. In the following formulas, unless otherwise indicated, R ₁ , R ₂ , R ₃ , R ₄ and Y are as defined above for compounds of formula (I).

Procedure A)

A phenol of the general formula is suitable

The reaction is preferably carried out in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD) in a non-reactive solvent at a temperature of from -50 ° C to 48 ° C, preferably about 0 ° C.

Preparation of intermediates The tetrazolyl phenols of the formula (ΠΙ) are prepared by reacting a suitable R ₂ -R ₃ -4-cyanophenol, which is preferably protected, such as its benzyl ether with sodium azide in a non-reactive solvent such as DMF, preferably in an inert atmosphere at 100-150 ° C for 12-25 hours. The resulting tetrazole, which

It may exist in tautomeric forms - wherein, Bz is a benzyl group - and then with an alkylating agent, such as reaction with an alkyl halide R ₄ X in an inert atmosphere. Alkylation may be carried out on any available nitrogen and the desired isomer may be isolated by conventional means such as fractional crystallization or chromatography. Compounds of formula (III) are obtained by deprotection of a protected phenol such as benzyl ether by reaction with a strong acid such as hydrochloric acid in acetic acid.

The intermediates of formula (IV) may be prepared by reacting 4-hydroxypiperidine or 4- (hydroxyalkyl) piperidine with a

rj

A substituted or unsubstituted halopyridazine of formula A9 wherein X is halogen, preferably chlorine or bromine is reacted in the presence of diisopropylethylamine (DIPEA) in a non-reactive solvent (such as THF, NMP or DMF). (b) at 25-110 ° C, preferably in an inert atmosphere.

The starting materials R ₂ -R ₃ -4-cyanophenol, 4-hydroxypiperidine, 4-hydroxyalkylpiperidine and 3-halo-6-R 1 -pyridazine of formula VI are known compounds and are commercially available. or by methods well known in the art.

Procedure B

The compounds of formula (I) of the present invention may also be prepared by reacting a halopyridazine of formula (VI) with -OYM = 1.

The piperidine derivative of formula Rj is reacted in the presence of (diisopropylethylamine) DIPEA in a non-reactive solvent as described above for the preparation of intermediates of formula (IV).

The intermediate of formula (VII) may be prepared by reacting a phenol of formula (ΠΙ)

The reaction is carried out with 4-hydroxypiperidine or 4- (hydroxyalkyl) piperidine in the presence of DEAD and triphenylphosphine as described above for the preparation of compounds of formula (I).

The compounds of the invention may be used in the form of both the free base and the acid addition salt. These salt forms are within the scope of the present invention. For some applications, acid addition salts are much more suitable, in practice, acid addition salts may be used in greater amounts. The acid addition salts may be formulated with acids which, with the free base, form salts which, at the dosage administered, are not deleterious to the living organism and which do not adversely affect the beneficial properties of the free base. Thus, examples of suitable acid addition salts include: -hydrochloride, -fumarate, -hydrogen sulfate, -methanesulfonate-toluenesulfate or maleate salts.

In addition, other pharmaceutically acceptable salts derived from other suitable mineral or organic acids may also be present. Acid addition salts of basic compounds can be prepared in a variety of ways, for example by dissolving the free base in an aqueous alcoholic solution, contacting it with the appropriate acid and then isolating the salt by evaporating the solvent; or reacting the free base and the acid in an organic solvent and separating the salt directly by precipitation using a second solvent or by evaporating the solution. While the pharmaceutically acceptable salts of the basic compounds are more preferred, the present invention includes all acid addition salts. All of these acid addition salts can be used as sources of the free base form, even if a particular salt is, of course, only desired as an intermediate product, such as when the salt is formed for purification or identification only, or when the salt is used .

The structures of the compounds of the invention were identified by their synthesis, elemental analysis, infrared, UV, nuclear magnetic resonance and mass spectroscopy methods. The reaction sequence as well as the identity and homogeneity of the product obtained were determined by thin layer chromatography (TLC) or gas-liquid chromatography (GLC).

The invention is illustrated by the following non-limiting examples.

In the Examples, the reactions were carried out under a nitrogen atmosphere and all reagents and solvents used in the processes were anhydrous unless otherwise indicated. All starting materials used in the Examples are commercially available or are prepared by any of the methods known in the art.

Example 7

a) 1.5 ml (10 mmol) of ethyl isonipecotinic acid,

To the reaction mixture containing diisopropylethylamine (3.5 mL, 20 mmol) and N-methylpyrrolidine (5 mL) was added 3-bromo-6-ethylpyridazine (1.67 g, 0.011 mol). After cooling, 100 ml of water were added to the reaction mixture, which was extracted with dichloromethane, washed twice with water and once with brine, and the solvent was removed in vacuo. The resulting oily material was eluted on a short silica gel column with 80% ethyl acetate / 20% hexane and dried under vacuum. The intermediate is taken up in 25 mL of THF and reacted with three times excess lithium aluminum hydride under nitrogen for 1 hour. The reaction mixture was cooled on ice and quenched by dropwise addition of water. The resulting slurry was dried, treated with charcoal and filtered. 6-ethyl-3- (4-hydroxymethyl-1-piperidyl) -pyridazine is obtained. [In the formula (IV), R 1 = -C ₂ H ₅ , Y = -CH ₂ -].

b) A mixture of 325 g of 4-cyanophenol, 346 ml of benzyl chloride and 758 g of potassium carbonate and 1.2 L of NMP was heated at 95 ° C for 1.5 hours with constant stirring. The reaction mixture was cooled to room temperature and poured into cold water (5 L). The resulting white solid was collected, washed with water and hexane, and dried at 70 ° C under vacuum. 570.0 g of 4-benzyloxybenzonitrile are obtained.

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A mixture of the above nitrile (285 g), triethylamine hydrochloride (262.5 g), sodium azide (124 g) and DMF (1.5 l) was heated under reflux under nitrogen for 18 hours. The reaction mixture was cooled to room temperature, poured into 4 liters of cold water and acidified with 3N hydrochloric acid. The resulting solid was collected, washed with water and dried at 60 ° C under vacuum for 48 hours. 337 g of 5- (4-benzyloxyphenyl) tetrazole are obtained.

337 g of a mixed solution of the above tetrazole containing 362 ml of DIPEA and 1 liter of NMP are cooled to 18 ° C and a solution of 200 g of methyl iodide and 170 ml of NMP is added dropwise over 1.5 hours under nitrogen atmosphere. added. After the addition, the reaction mixture was stirred at room temperature for an additional hour, then diluted with water (340 mL) and cooled to 18 ° C. The resulting solid was collected, washed with water, recrystallized from ethanol and dried under vacuum at 50 ° C. 232.3 g of 2-methyl-5- (4-benzyloxyphenyl) -2H-tetrazole are obtained.

A mixture of 214.2 g of the methyl tetrazole derivative obtained above, 140 ml of concentrated hydrochloric acid and 1.08 L of glacial acetic acid is refluxed for 19 hours. Most of the acetic acid was evaporated under reduced pressure at 60 ° C and the resulting slurry was diluted with 1.5 L of cold water. The solid thus obtained is collected, washed with water and then dried. Recrystallization from ethanol. The product was dried at 60 ° C for 20 hours. 104.3 g of 2-methyl-5- (4-hydroxyphenyl) -2H-tetrazole are obtained. [In the formula (III), R ₂ = R ₃ = H, R ₄ = -CH ₃ ].

c) Dissolve 1.57 g (6.0 mmol) triphenylphosphine (TPP), 6.6 g (3.07 mmol) 6-ethyl-3- (4-hydroxymethyl) in 20 ml of anhydrous dichloromethane at room temperature. lpiperidyl) -pyridazine (R) in the compound of formula (IV) = -C ₂ H ₅ , Y = -CH ₂ ], and 0.53 g (3.01 mmol) of 2-methyl-5- (4-hydroxyphenyl) -2H-tetrazole [R ₂ = R ₃ = H, R ₄ = -CH ₃ ], and the resulting solution is cooled with ice in an atmosphere of nitrogen. Diethyl azodicarboxylate (DEAD) (0.9 mL, 6 mmol) was dissolved in dichloromethane (5 mL) and added dropwise to the stirred solution obtained above over 10 min. After the reaction, 50 ml of water were added to the reaction mixture, and the aqueous layer was extracted twice with dichloromethane. The organic layer was washed with 10% sodium hydroxide solution, followed by 1N sodium chloride solution and then dried over magnesium sulfate. The solution was concentrated in vacuo and the residue acidified with methanesulfonic acid (100 mL). The yellow solution was washed three times with diethyl ether. The aqueous solution was treated with activated carbon and filtered. The filtrate was made basic with 35% w / w sodium hydroxide. The precipitate was collected, washed with water and then recrystallized from dichloromethane and then methanol. A compound of formula I is obtained wherein R 1 = C ₂ H ₅ , R ₂ = R ₃ =

H, R ₄ = -CH ₃ , Y = -CH ₂ - Yield: 42%, mp 159-160 ° C.

EXAMPLE 2 Ethyl isonipecotinic acid ethyl ester (5 mmol), NMP (5 mL) and diisopropylethylamine (DIPEA) (20 mL) were treated with 6-methyl-3-chloropyridazine (55 mmol) and the resulting mixture was refluxed for 6 hours. using a boil. The product was isolated as described in Example 1a. 3- (4-Carboethoxy-1-piperidyl) -6-methylpyridazine is obtained. Yield 44%. 18.8 mmol of this compound are reduced with a solution of 56.6 mmol of Dili AL and 100 mL of THF, which contains Rochelle's salt as the extinguishing agent. 3- (4-Hydroxymethyl-1-piperidyl) -6-methylpyridazine is obtained [in the formula (IV): R 1 = -CH ₃ , Y = -CH ₂ -] which is used without purification in the final step.

The product (5 mmol) prepared in Example 1b is reacted with 4.5 mmol of 3- (4-hydroxymethyl-1-piperidyl) -6-methylpyridazine according to the procedure described in Example le). Recrystallization from ethyl acetate was carried out at -70 ° C. The compound of formula I is obtained wherein R 1 = R 4 = -CH ₃ , R ₂ = R ₃ = Η, Y = -CH ₂ -. Yield 12%, m.p. 180-185 ° C.

Example 3

9.6 mmol of 6- (n-propyl) -3-chloropyridazine and

4-Hydroxy-piperidine (19.2 mmol) was dissolved in NMP (2 mL) and DIPEA (2 mL) was added dropwise. After the addition, the reaction mixture was refluxed for 18 hours. The product was washed on a column filled with Kieselguhr with dichloromethane containing 5% methanol. After evaporation of the solvents, 6- (n-propyl) -3- (4-hydroxy-1-piperidyl) pyridazine is obtained, wherein R 1 = n-propyl, Y = valence bond in formula IV. Yield: 68%.

4.5 mmol of the intermediate obtained above and 5 mmol of tetrazole prepared according to Example 1b) are refluxed for 40 minutes with an equimolar amount of DEAD and TPP. Recrystallization from ethyl acetate gives the compound of formula I wherein R 1 = η-propyl, R ₂ = R ₃ = H, R ₄ = -CH ₃ , Y = valence bond. Yield 71.9%, m.p. 138-140 ° C.

Example 4

Using 2,6-dimethyl-4-cyanophenol starting material 2-methyl-5- (3,5-dimethyl-4-hydroxyphenyl) -2H-tetrazole [ ₂ = R ₃ = R ₄ = -CH ₃ ].

4.5 mmol of 6-methyl-3- (4-hydroxy-1-piperidinyl) -pyridazine [R (= methyl, Y = -CH ₂ -] in formula IV), 1.14 g of DEAD, 6 , 8 mmol TPP and 5 mmol 2-methyl-5- (3,5-dimethyl-4-hydroxyphenyl) -2-H-tetrazole [R ₂ = R ₂ = R ₃ = R ₄ = -CH ₃ ] is reacted as described in Example le). Recrystallization is carried out from ethyl acetate. The compound of formula (I) is obtained wherein R 1 - R ₂ - R ₃ = R ₄ = -CH ₃ , Y = -CH ₂ -. Melting point: 183-184 ° C.

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Example 5

Following the procedure of Example 3, 81 mmol of 6-methyl-3-bromopyridazine, 16 mL of DIPEA and 163 mmol of 4-hydroxypiperidine were heated at 120 ° C for 16 hours. 6-Methyl-3- (4-hydroxy-1-piperidyl) -pyridazine is obtained. [In the formula (IV) R) = CH ₃ , Y = valence bond]. Yield: 24%.

6.8 mmol of the above intermediate and

7.4 mmol of 2-methyl-5- (4-hydroxy-3,5-dimethylphenyl) -2H-tetrazole [R ₂ = R ₃ =! <, = -CH ₃ ] in equimolar amounts of DEAD-. and TPP according to the procedure described in Example le). Recrystallization from methanol. The compound of formula (I) is obtained wherein R 1 = R ₂ = R ₃ = R ₄ = - CH ₃ , Y = valence bond. Yield: 74%. Melting point: 188-189 ° C.

Example 6

2.1 mmol of 6-methyl-3- (4-hydroxy-1-piperidinyl) -pyridazine (R) = -CH ₃ , Y = valence bond prepared according to the procedure described above 9.8. mmol of the above described 2-methyl-5- (4-hydroxyphenyl) -2H-tetrazole [R ₂ = R ₃ = H, R ₄ -CH _{3 in} the formula (III)] according to the procedure of Example le) acting on TPP and DEAD. Recrystallization from ethanol. The compound of formula (I) is obtained wherein R 1 = R ₄ = -CH ₃ , R ₂ = R ₃ = H, Y = valence bond. Yield: 67.6%. Melting point: 157-158 ° C.

Example 7

a) 16.5 g (0.1 mol) of ethyl 4-pyridylacetic acid,

8.4 ml (0.1 mol) of 12N hydrochloric acid solution and 2.5 g of platinum oxide are dissolved in absolute ethanol and hydrogenated in a Parr shake flask at 272 kPa (40 psi). After 1 hour, the reaction mixture was filtered and concentrated in vacuo. 27.79 g of ethyl 4-piperidylacetic acid are obtained.

b) The sample obtained in step a) is dissolved in 100 ml of dichloromethane and 13.8 ml (0.12 mol) of benzyl chloride are added under a nitrogen atmosphere. Triethylamine (16.7 mL, 0.12 mol) was added dropwise to the reaction mixture under ice-cooling. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The organic phase is washed with water, then with alkali and then with saturated brine. The organic phase is then concentrated in vacuo. An oily substance is obtained from which crystals are precipitated.

14.61 g of N-benzyl-4-piperidylacetic acid ethyl ester are obtained. Yield: 56%.

c) 14.40 g (0.055 mol) of the compound obtained above is taken up in 100 ml of anhydrous THF under a nitrogen atmosphere. Lithium aluminum hydride (2.3 g, 0.06 mol) was added slowly, and the reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water / diethyl ether. The reaction mixture was basified with sodium hydroxide and the organic phase was dried over magnesium sulfate and then concentrated in vacuo. N-benzyl-4- (2-hydroxyethyl) piperidine was obtained in quantitative yield.

d) 5.98 g (0.025 mol) of the alcohol obtained in the above step were taken up in 25 ml of 0 'C dichloromethane. To the solution was added 0.025 mol of triphenylphosphine, 0.025 mol of 2-methyl-5- (hydroxyphenyl) -2H-tetrazole under nitrogen, and a solution of 0.025 mol of DEAD and 25 ml of dichloromethane was added dropwise. After the addition was complete, the reaction mixture was concentrated in vacuo and the residue was recrystallized from ethanol.

intermediate.

e) 3.91 g (9.64 mmol) of the intermediate obtained in the above step, 7 ml (35 mmol) of 5 molar ammonium formate and a catalytic amount of palladium-on-carbon

The talcator was dissolved in methanol (50 mL) and the reaction mixture was refluxed for 1.5 hours. The reaction mixture was evaporated and the residue was crystallized from methanol. 1.63 g of debenzylated product are obtained. In the formula (VII), R ₁ = -CH ₃ , R ₂ = R ₃ = H, Y = -CH ₂ CH ₂ -.

f) 1.34 g (4.66 mmol) of the product obtained in the above step is mixed with 0.77 g (6 mmol) of 6-methyl-3-chloropyridazine and a minimal amount of NMP under a nitrogen atmosphere. The reaction mixture was heated to 120 ° C and a small amount of diisopropylethylamine was added. The reaction mixture was refluxed for 8 hours, then dissolved in dichloromethane and extracted with 2N sodium hydroxide solution, water and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The solid was recrystallized from methanol. 0.92 g of a compound of formula I is obtained wherein R 1 = R ₄ = -CH ₃ , R ₂ = R ₃ = H, Y = -CH ₂ CH ₂ -. 132133 ° C. Yield: 52%.

Example 8

The procedure of Example 7d) is followed; 3.95 g of N-benzyl-4- (2-hydroxyethyl) piperidine and 3.45 g of the 2-methyl-5- (3,5-dimethyl-4-hydroxyphenyl) -2H-tetrazole described above are condensed. In the presence of TPP and DEAD. The resulting product is debenzylated as described in Example 7e and the debenzylated product is reacted with 6-methyl-3-chloropyridazine as described in Example 7f. A compound of formula I is obtained wherein R 1 = R ₂ = R ₃ = R ₄ = -CH ₃ ; Y = -CH ₂ CH ₂ - Melting point: 176-177 ° C.

Biological assays of the compounds of formula (I) according to the invention show that these compounds possess antiviral activity. These are the compounds

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are active in the inhibition of viral replication in vitro and are primarily active against picomaviruses including enteroviruses, echoviruses and coxsakie viruses, and in particular against many strains of rhinoviruses. In vitro assays of the compounds of the invention against picomaviruses indicate that inhibition of viral replication occurs at a minimum concentration of inhibitor (MIC) of 0.01-5 pg / ml.

MIC values were determined by a standard plaque reduction assay in the following 10 ways: monolayer HeLa (Ohio) was infected with virus at a concentration of approximately 80 monolayers in the control assay (drug not present). Serial dilutions of the test compound are mixed in the topsheet of the agar medium and, in some cases, during the adsorption period. The MIC value is the concentration at which the test compound reduces the number of plaques by 50%. 20

In the standard assay, the compounds were tested in 15 human rhinovirus (HRV) serotypes, i.e., HRV-2, -1A, -1B, -6, -14, -21, -22, -15, -25, -30, -50,

Against -67, -89, -86 and -41. MIC values are determined for each rhinovirus serotype and the potency of the compound is _{expressed as} MIC ₅₀ and MIC _g0 . These values correspond to the concentration of compounds at which 50% and 80% of the serotypes tested are inhibited. 30

The test results are given in the table below. The MIC ₈₀ values are the number of serotypes (N).

Table 35

Example number mic _{5 (} , (rhinovirus) mic ₈₀ (rhinovirus) N First 13.166 .2815 15 Second 13.337 0.141 15 Third 15.697 1.823 13 4th 20.137 1,482 15 5th 0.92 1.8 2 6th 0.27 0.52 2 7th 6.64107 0.04 15 8th 16.813 0.66 15

The antiviral compositions of the invention may be prepared in the form of a dilute solution or suspension in pharmaceutically acceptable aqueous, organic or aqueous / organic media for parenteral administration by topical, intravenous or intramuscular injection, or for intranasal or ophthalmic use; or for oral administration with conventional pharmaceutical excipients in the form of tablets, capsules or aqueous suspensions. 60

Claims (30)

The compound of formula (I): or a pharmaceutically acceptable acid addition salt thereof, wherein Y is a bond or C 1-6 alkylene; R 1 is hydrogen or C 1-3 alkyl; R ₂ and R ₃ are each independently hydrogen, C 1-3 alkyl or halo; R ₄ is hydrogen or C 1-3 alkyl. Compounds of formula (I) according to claim 1, wherein R ₂ and R ₃ are independently hydrogen or methyl. Compounds of formula I according to claim 2, wherein R ₂ and R ₃ are each hydrogen or methyl. Compounds of formula I according to claim 3, wherein Y is a bond or methylene or ethylene. Compounds of formula (I) according to claim 4, wherein R 1 is methyl. Compounds of formula I according to claim 5, wherein R 1 is methyl. Compounds of formula I according to claim 5, wherein R ₂ and R ₃ are each hydrogen. Compounds of formula I according to claim 7, wherein R 1 is ethyl. The serine compound of claim 8, wherein Y is a methylene group. Compounds of formula (I) according to claim 7, wherein R 1 is n-propyl. Compounds of formula I according to claim 10, wherein Y is a bond. 12. Pharmaceutical formulations against picomaviruses, characterized in that they contain an effective amount of a pharmaceutical carrier and Comprising a compound of formula A9 or a pharmaceutically acceptable acid addition salt thereof, wherein: Y is a bond or C 1-6 alkylene; R 1 is hydrogen or C 1-3 alkyl; R ₂ and R ₃ are each independently hydrogen, C 1-3 alkyl, or halogen; R ₄ is hydrogen or C 1-3 alkyl. 13. A composition according to claim 12, which comprises as an active ingredient a compound of formula (I) wherein R ₂ and R ₃ are each hydrogen or methyl. 14. A composition according to claim 13, which comprises as an active ingredient a compound of formula (I) wherein R4 is methyl. 15. A composition according to claim 14, which comprises as an active ingredient a compound of formula (I) wherein R 1 is selected from the group consisting of swept. 16. A composition according to claim 12, which comprises as an active ingredient a compound of formula I wherein Y is a bond, ethylene or methyl. 17. A composition according to claim 16 comprising as active ingredient a compound of formula (I) wherein R 1 is methyl. 18. A composition according to claim 16 comprising as active ingredient a compound of formula (I) wherein R 1 is ethyl and Y is methylene. 19. A composition according to claim 16, which comprises as an active ingredient a compound of formula (I) wherein R 1 is n-propyl and Y is a bond. 20. A method of controlling picomaviral infections comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein: Y is a bond or C 1-6 alkylene; R 1 is hydrogen or C 1-3 alkyl; · R. and R ₃ is independently hydrogen, C 1-3 alkyl, or halogen; R ₄ is hydrogen or C 1-3 alkyl. 21. The method of claim 20, wherein the compound of formula I wherein R ₄ is methyl. 22. A process according to claim 21 wherein Y is a bond, ethylene or methylene. 23. The method of claim 22, characterized in that (I) compound is added, wherein R ₂ and R ₃ are identical and are methyl or hydrogen. 24. The method of claim 23, wherein the compound of formula I wherein R 1 is methyl. 25. The method of claim 23, characterized in that (I) compound was added, a hydrogen atom R is ethyl, Y is methylene and R ₂ and R ₃ represents wherein. 26. The method of claim 23, characterized in that (I) compound is added, wherein R is n-propyl, Y is a bond and R ₂ and R ₃ is hydrogen. 27. A method of controlling a picornavirus infection, comprising administering to a patient in need thereof a composition according to claim 12. 28. A method of controlling a picornavirus infection, comprising administering to a patient in need thereof a composition according to claim 17. 29. A method of controlling a picornavirus infection, comprising administering to a patient in need thereof a composition according to claim 18. 30. A method of controlling a picornaviral infection, comprising administering to a patient in need thereof a composition according to claim 19.