MXPA96005513A - Tiadiazoles and its use as agentesantipicornavira - Google Patents

Abstract

The present invention relates to a compound of the formula: wherein: Thi is thiadiazolyl or thiadiazolyl substituted with alkoxy, fluoromethyl, trifluoromethyl, 1,1-difluoroethyl, halo, alkyl, cycloalkyl, hydroxyalkyl, or alkoxyalkyl, Y is an alkylene bridge of 3-9átomos carbon; R1 and R2 are independently selected from each other from hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, dialkylaminoalkyl , alkylaminoalkyl, aminoalkyl, difluoromethyl, trifluoromethyl, or cyano; R3 is alkoxycarbonyl, phenyl alkyltetrazolyl or the heterocyclyl is selected from benzoxazolyl, benzothiazolyl, thiadiazolyl, imidazolyl, dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, triazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or substituted phenyl or heterocyclyl or substituted in the substitution is with alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, furyl, thienyl or fluoroalkyl or a pharmaceutically acceptable salt my

Description

TIADIAZOLES AND SÜ USE AS ANTIPICORNAVIRAL AGENTS DESCRIPTION This invention relates to new substituted phenoxyalkyl heterocyclic thiadiazoles, with methods for their preparation and with methods of using them as antipicornaviral agents. It has now been found that the compounds of Formula I are effective antipicornaviral agents. Accordingly, the present invention relates to the compounds of the formula: Formula I wherein: Thi is thiadiazolyl or thiadiazolyl substituted with alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, halo, alkyl, cycloalkyl, hydroxyalkyl, or alkoxyalkyl; Y is an alkylene bridge of 3-9 carbon atoms; R 1 and R 2 are each independently from each other of hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, dialkylaminoalkyl, alkylalkyalkyl, aminoalkyl, difluoromethyl , trifluoromethyl, or cyano; R3 is alkoxycarbonyl, phenyl alkyltetrazolyl, or the heterocyclyl is selected from benzoxazolyl, benzothiazolyl, thiadiazolyl, i idazolyl, dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, triazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or substituted phenyl or substituted heterocyclyl wherein the substitution is with alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, furyl, thienyl and fluoroalkyl; or their pharmaceutically acceptable acid addition salts. The invention also relates to compositions for combating picornaviruses comprising an antipicornavirally effective amount of a compound of Formula I with a suitable carrier or diluent and methods for combating picornaviruses therewith, including the systemic treatment of picornaviral infections in a mammalian host. .

The compounds of Formula I are useful as antipicornaviral agents and are further described in the following. Alkyl and alkoxy mean aliphatic radicals, including branched radicals of 1 to 5 carbon atoms.

Thus, alkyl portion of such radicals include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl and the like. Cycloalkyl means an alicyclic radical having from 3 to 7 carbon atoms as illustrated by cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cycloheptyl and cyclohexyl; and Halo means bromine, chlorine, iodine or fluorine. Heterocyclyl or Het refers to a heterocycle radical based on 5 or 6 carbon members, having one to about four nitrogen atoms and / or one oxygen or sulfur atom, with the proviso that two oxygen atoms and / or or two sulfur atoms are not adjacent in the heterocycle. Examples of these include furyl, oxazolyl, isoisoxazolyl, pyrazyl, i idazolyl, thiazolyl, tetrazolyl, thienyl, pyridyl, oxadiazolyl, thiadiazolyl, triazinyl, pyrimidinyl and the like.

"Heterocycle" refers to the corresponding compounds. The term heterocyclyl includes all known isomeric radicals of the described heterocycles unless otherwise specified, for example thiadiazolyl encompasses 1, 3, 4-thiadiazol-2-yl, 1, 2,4-thiadiazol-5-yl , and 1, 2, 4-thiadiazol-3-yl; thiazolyl embraces 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl and the other known variations of the known hetero heterocyclic radicals. In this way, any isomer of a mentioned heterocycle radical is contemplated. These heterocycle radicals can be attached by means of any nitrogen or carbon, for example, tetrazolyl contemplates 5-tetrazolyl or tetrazolyl linked via any available nitrogen of the tetrazolyl ring; furilo covers furilo bonded through any available carbon, etc. The preparation of such isomers the preparation of such isomers are well known and are within the reach of the skilled technician in medicine or organic chemistry. Certain heterocycles may exist as tautomers., and the compounds as described, while not explicitly describing each tautomeric form is understood to encompass each and all tautomers. For example, pyridinone and its hydroxypyridine tautomer contemplate the same portion. As for the heterocyclic portions of the compounds of the present invention, they may be hydroxy substituted, it is understood that such hydroxy substituted heterocycles are intended to include the corresponding tautomers.

In the use of the terms hydroxyalkyl and alkoxyalkyl, it is understood that the hydroxy and alkoxy groups can occur in any available position of the alkyl. Thus, hydroxyalkyl and alkoxyalkyl include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl, 2-, 3-, 4- and 5-hydroxypentyl and the like; "alkoxy" refers to their corresponding alkylesters. In the use of the term "hydroxyalkoxy", it is understood that the hydroxy group can occur in any available position of alkoxy in part of the C-1 (geminal) position. Thus, the hydroxyalkoxy includes, for example, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, 5-hydroxypentoxy and the like. "Alkylene" refers to a divalent, straight or branched hydrocarbon radical of one to about 5 carbon atoms such as methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1, - (2-methyl) utylene and the like. The alkylene may also contain alkenyl or alkynyl bonds. Halogen refers to the common halogens fluorine, chlorine, bromine and iodine. As used herein, the term "haloalkyl" refers to an alkyl substituted with halo, such as fluoroalkyl, chlorofluoroalkyl, bromochloroalkyl, bromofluoroalkyl, bromoalkyl, iodoalkyl, chloroalkyl, and the like wherein the haloalkyl has one or more of the same or different halogens replaced by a hydrogen. Examples of haloalkyl include chlorodifluoromethyl, 1-chloroethyl, 2,2,2-trichloroethyl, 1,1-dichloroethyl, 2-chloro-1,1,1,2-tetrafluoroethyl, bromoethyl, and the like. As used herein, the term "fluoroalkyl" is a preferred sub-class of haloalkyl and is "" * refers to fluorinated and perfluorinated alkyl, for example Fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 1,1, 2,3-tetrafluorobutyl, and the like. The compounds of Formula I wherein R3 is a nitrogen-containing heterocycle are sufficiently are basic salts to form acid addition salts and are both useful in the free base form and in the form of salts of - addition of acid and both forms are within the scope of the invention. Acid addition salts are, in some cases, a more convenient way to be used and in the practice the use of the salt form, inherently account for the use of the base form. The acids which can be used to prepare acid addition salts preferably include those which produce, when combined with the free base, salts mediately acceptable, that is, salts whose anions are relatively harmless to the animal organism in medicinal doses of the salts, such that the inherent beneficial properties of the free base are not contaminated by side effects attributable to the anions. Examples of the appropriate acid addition salts include hydrochloride, hydrobromide, sulfate, acid sulfate, maleate, citrate, tartrate, methanesulfonate, p-toluenesulfonate, dodecyl sulfate, cyclohexanesulfonate, and the like. However, other salts - Appropriate medicinally acceptable within the scope of the invention, are those derived from other mineral acids and organic acids. The acid addition salts of the basic compounds can be prepared by dissolving the free base in an aqueous alcohol solution containing the appropriate a-acid and isolating the salt by evaporating the solution of the solution, or by the reaction of the free base and an acid in an organic solvent, in which case the salt is directly separated, precipitated with a second organic solvent, or by concentration of the solution or by any of several other known methods. Although the salts medicinally Acceptable basic compounds are preferred, all acid addition salts are within the scope of the present invention. All acid addition salts are useful as sources of the free base form, even if the particular salt per se is desired only as a product Intermediary, for example when the salt is formed only for purification or identification purposes, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange processes. The structures of the compounds of the invention were established by the synthesis mode, by elemental analysis and by infrared, ultraviolet, nuclear magnetic resonance and mass spectroscopy. The course of the reactions and the identity and homogeneity of the products were evaluated by thin layer chromatography (TLC) or gas-liquid chromatography (GLC) or other methods accepted in the art of controlling organic chemistry reactions. As described herein, a non-interacting solvent may be N-methylpyrrolidone (NMP) methylene chloride (CH2C12), tetrahydrofuran (THF), benzene or any other solvent that does not take part in the reaction. In a preferred method, the preparation of the compounds of the invention is carried out in dry solvents under an inert atmosphere. Certain reagents used in the example preparations are specified by the abbreviation: triphenylphosphine (TPP), triethylamine (TEA), diisopropylethylamine (DIPEA), and diethyl azodicarboxylate (DEAD). Ether is ethyl ether unless otherwise specified. The compounds of Formula I can be prepared by several different methods.

The compounds of Formula I can be prepared by the reaction of the appropriate hydroxy-Y-thiadiazole and appropriate R? -R2-R3-phenol as described in U.S. Patent 5,242,924 incorporated herein by reference. The compounds of Formula I can be prepared by the reaction of the appropriate R1-R2-R3"phenol and the appropriate halo-Y-thiadiazole by the reaction described in U.S. Patent 4,942,241 incorporated herein by reference. Formula I can also be prepared by preparing the thiadiazolyl portion (Thi) in the final stages of the synthesis For the compounds of the formula I, where Thi is 1,4-thiadiazolyl, the compound XYO- [R1-] R2-4-R3-phenyl], wherein X is a functional group displaced by a suitably functionalized 1,2,4-thiadiazole The XYO- [R1-R2-4-R3-phenyl] compounds are prepared from the R-, -R2-4-R3 phenols and hydroxy-YX or halo-YX compounds, by the same methods used to prepare the compounds of formula I described above Typically, X is in the Y-methyl position (is say, the furthest position in the alkylene phenoxy bridge.) Alternatively, X can be placed or on the compound Y-0 [Rj-R2-R3-phenol] just before the reaction with the functionalized thiadiazole. For example, where Y contains an omega-alkene or alkyne, the compound can be reacted with a suitable tin derivative, giving a suitable compound, to give a compound wherein X is for example tributyl. The tin-Y-0 compound [R1-R2-R3-phenyl] is then reacted with halo-1, 2,4-thiadiazole, preferably an iodine-1,2,4-thiadiazole to form a compound of the formula I. Alternatively, 1,2,4-thiadiazole can be made from a functional group attached to Y, typically at the omega position as described above. This method of preparing the 1,2,4 thiadiazoles is well known in the art; see, for example, Katritzky and Rees Comprehensive Heterocyclic Chemistry (1985). For the compounds of formula I where Thi is 1,2,4-thiadiazole; 1, 3, 4-thiadiazole is preferably prepared from a functional group in Y in the final stage. For example, the compound [alkoxycarbonyl] -Y-O- [R1-R2-4 -R3-phenyl] can be reacted to form a carbazide, then an activated sulfur compound, such as Lawesson's reagent P4S-H} or similar, which forms 1, 3, 4-thiadiazole. The preparation of the compound X-Y-0- [R ^ -R ^ -R3-phenyl] where X is a functional group was described in the foregoing. Alternatively, the compound of the fenule I, in which Thi is 1,3,4-thiadiazole, can be prepared by reacting a 1, 3,4-thiadiazole functionalized in a suitable manner, with a compound XYO- [R1-R2-R3- phenyl] when X is a functional group displaced by 1, 3, 4-thiadiazole. The compounds of the formula I in which R3 is phenyl or heterocyclyl can be prepared by reacting a hydroxy-Y-thiadiazole or halo-Y-thiadiazole with an R1-R2-4-functionalized phenol, substituting the functional group with a group phenyl or heterocyclyl, such as pyridyl, furyl and the like, in the final step. For example a borate of Thi-Y-0- [R1-R2-phenyl] can be reacted with a halo pyridine to form a compound of I wherein R3 is pyridyl. Alternatively, certain R3 heterocycles are prepared more easily "in situ" by making the functional group on the phenyl ring in the heterocycle. This method is preferred, with heterocycles having two or more heteroatoms, such as triazolyl, oxadiazolyl, oxazolyl and the like. For example, if R3 is a heterocyclic ring, the heterocyclic ring of the compound of Formula I can be prepared from an appropriate functionalized pyridoxy-Y-thiadiazole R? ~ R2 ~, or the phenyl portion ZO-R1-R2- 4-functionalized in which Z is (Thi) -Y-). In this method, the heterocycle in the phenoxy ring is prepared in the fir.al stage as described in U.S. Patent 5,075,187 incorporated herein by reference. The adequate substitution of the 4-phenoxy position will depend on the heterocycle sought in the final product. For example, where Het 1, 2,4-oxadiazolyl, the compounds are prepared either 4-Z-0-R1-R2-benzonitrile, where z is -Y-thiadiazole, by reaction for example, with hydroxylamine hydrochloride preferably in a non-interacting solvent, preferably an alkanol , for example; methanol, ethanol, n-butanol and the like. The product thus obtained is then reacted with an acid anhydride of the formula (R'CO) 20, where R 'is alkyl, haloalkyl and the like; or by an ortoformate or an ortho-formate ester, if R 'is hydroxy or alkoxy. R 'appears in R3 heterocycle of the final product. The reaction occurs between room temperature and the boiling point of the reaction mixture in a basic solvent, such as pyridine. The product is a compound of formula I, wherein R3 is 5-R'-1,2,4-oxadiazolyl, other compounds are prepared by analogy. The R1-R2-R3-phenols used to prepare the compounds of Formula I are known in the art. Typically, it is prepared by the ur reaction. suitably protected phenol having, in position 4, a functional group such as cyanide, aldehyde, halide, an acid chloride group, as described in U.S. Patent 4,942,241; 4,945,164; 5,051,437; 5,002,960; 5,110,821; 4,936,267; 4,861,971; 4,857,239; 5,242,924; or 4,843,087 incorporated each for reference. To obtain the correspondingly protected, properly protected heterocyclyl phenol which is then deprotected by means well known in the art. Other known phenols can also be used to prepare the compounds of the formula I, for example any of the substituted or unsubstituted 4-phenylphenols, 4-alkoxycarbonylphenols, as described above, can be used. It is expected that any R1-R2-R3-phenol may be reacted with the hydroxy-Y-thiodiazole or to prepare compounds of the formula I. . R 'can be manipulated in any way consistent with the manipulations of the heterocycle side groups, for example replacement of hydroxy with chlorine, cleavage of an ether to a hydroxy, others are contemplated. It will be appreciated that neither the time of elaboration of the heterocyclic substituents or pyridazine nor the order of assembly of the intermediates is crucial for the successful synthesis of the compounds of Formula I.

In this way, by the judicious choice of the reactants, the compounds of Formula I can be prepared. Alternatively, where 4-Z-0-R1-R2-benzonitrile with Z as a protecting group, the product is an R1-R2 -R3- (heterocyclic) phenol by deprotection. This phenol is reacted with the thiadiazoalkyl halide or thiadiazolyl alkanol or the halo-Y-X- p hydroxy-Y-X-, in which the thiadiazole is substituted or processed at a later stage in the synthesis of a compound of the Formula I. The hydroxy Y-thiadiazoles used in the invention are known, commercially available or can be prepared by known methods. For example commercially available halo-1,2,4-thiadiazoles can be coupled to an omega-haloalkenyl ester or haloalkylester by standard methods, such as coupling with tin iodide, preferably with subsequent reduction to alkanol by known methods. Alternatively, 1,3,4-thiadiazolylalkyl, 1,3,4-thiazolylalkane halides or the compounds R 1 -R 2 -R 3 -phenoxy-Yl, 3,4-thiadiazole can be prepared by reacting a suitable phenoxy-Y-carbazide with for example, Lawssen reagent, under standard conditions, as described above for the preparation of the compounds of formula I. Carbaziae can be prepared from the reaction of the phenoxyalkyl acid halide or phenoxyalkyl ester with an R '-hydrazide (where R' forms the substitution or a precursor of the substitution for the thiadiazole ring). Simple chemical transformations which are conventional and well known to those skilled in the chemistry art can be used to effect changes in the functional groups in the compounds of the invention. For example, the acylation of the hydroxy- or amino-substituted species to prepare the corresponding esters or amides, respectively; alkylation of phenyl or furyl substituents; the doubling of alkyl ethers or benzyl ethers to produce corresponding alcohols or phenols; and hydrolysis of esters or amides to produce the corresponding acids, alcohols or amides, preparation of anhydrides, acid halides, aldehydes, simple aromatic alkylation, sulfonation of carbazides, formation of chlorine or fluoroalkyls from hydroxyalkyls or keto compounds, displacement of hydroxy by halo in heterocyclic rings and the formation of other heterocycles and the like as desired. For a complete generality of the common reactions used in the chemistry of heterocycles, see for example, Katritzky and Rees Comprehensive Heterocvclic Chemistrv, or Castle Heterocyclic Compounds. or any other comprehensive treatise on the subject.

Furthermore, it will be appreciated that obtaining the desired product by some reactions will be facilitated by blocking or making certain non-reactive functional groups. This practice is well recognized in the art, see for example, Theodora Greene, Protective Groups in Organic Synthesis (1991). In this way, when the reaction conditions are such that they can cause undesirable reactions with other parts of the molecule, the skilled artisan will appreciate the need to protect these reactive regions of the molecule and act accordingly. The starting materials used to prepare the compounds of Formula I are commercially available, known in the art or prepared by known methods. Many of the preparations of the initial materials herein are incorporated for reference in the patent literature. Exemplary Description As used in the present R- ^, R2, R3, R4, X, Y and Het have the same meanings in the description of intermediary species as the compounds of formula I. For the purpose of naming the substituents in Formula I, in phenyl ring, of any compound of formula I must be numbered; Thus, when a compound of formula I has substitution on the phenyl ring, it refers to this numbering system without considering how the compound is actually called. For example, if a compound is prepared and the designation R- ^ R2 = 3, 5-dimethyl, this means without considering whether 3,5-dimethyl or 2,6-dimethyl appears in the name of the compound. For the purpose of naming the substituents in formula I, the 1, 3, 4-thiadiazole rings described herein must be numbered without considering the substituent that appears in position 2 of 1, 3, 4-thiadiazo, to avoid c alcruier confusion in part of the reader, who is not very familiar in the technique of chemical nomenclature. Thus; N-N CHjCO - ~~ - ' it is represented as 2-acetyl-l, 3,4-thiadiazol-5-yl and it is represented as 1, 3, 4, -thiadiazol-5-yl, although the accepted nomenclature rules may cause the radical to be named differently. Example 1 A. 4- [4 (4-Cyano-2,6-dimethyl) phenoxy] butyric acid To a solution of 5 g (34 mmol) of 4-cyano-2,6-dimethylphenol in 120 ml of N-methyl pyrrolidinone 5.86 g (42 mmol) of potassium carbonate, 0.85 g (3 mmol) of potassium iodide and 4.8 ml (34 mmol) of ethyl 4-bromobutyrate are added, and the resulting mixture is heated at 60 ° C for 24 h. The reaction mixture is cooled, diluted with water, filtered, and a white solid residue is washed with water to yield 5.9 g (quantitative yield) of 4- [(4-cyano-2,6-dimetii) phenoxy] but - ethyl acetate. The above ester was stirred at room temperature with 120 p-ethanoi / water (4: 1) containing 820 mg (34 mmoles) of LiOH, the ethanol was removed in vacuo, and the aqueous layer was washed with water. The aqueous layer is acidified, a white solid is filtered and dried to yield 6.93 g (88%) of 4- [(4-cyano-2,6-dimethyl) phenoxybutyric acid. B. N- [- [(4-cyano-2,6-dimethyl) phenoxy] butyryl] t-butyl carbazate To a solution of 4- [(4-cyano-2,6-dimethyl) phenoxy] butyric acid (654 mg, 2.81 mmol) in 15 ml of methylene chloride are added 1.2 ml of thionyl chloride (16.86 mmol) and the mixture is refluxed for 3 h. The mixture is concentrated in vacuo, a pale yellow residual oil in 20 mL of THF is mixed with 409 mg (3.09 mmol) of t-butyl carbazate and a few drops of triethylamine and then the mixture is refluxed for 1.5 h. The reaction mixture is cooled, concentrated in vacuo, diluted with water and extracted with methylene chloride (x3). The combined organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield 899 mg (92%) of N-f4-, (4-cyano-2,6-dimethyl) phenoxy] butyryl. ] t-butyl carbazate. C. N- [4- [(4-Cyano-2,6-dimethyl) phenoxy] butyryl] hydrazine To a mixture of 6.73 g (19.4 mmol) of [- [4- [(4-cyano-2,6-dimethyl) phenoxy] butyroyl] t-butyl carbazate and 25 ml of trifluoroacetic acid in 100 ml of methylene chloride were added. allow to stir at 0 ° C for 1 h, and then concentrate in vacuo to dryness. The residue is diluted with water, washed with ether, and the aqueous layer is made basic (pH 9) with sodium hydroxide. The white solid is filtered, washed with water and dried in vacuo to yield 3.65 g (76.2%) of N-f4 - [(4-cyano-2,6-dimethyl) phenoxy] butyryl] hydrazine. D. N-acetyl-N '- [4- [(4-cyano-2,6-dimethyl) phenoxy] -butyryl] hydrazine To a solution of 4- [(4-cyano-2,6-dimethyl)] phenoxy] butyric (3.9 g, 16.74 mmoles) in 120 ml of methylene chloride are added 6 ml of thionyl chloride and the resulting mixture is refluxed for 3 h, cooled, and concentrated to yield a yellow oil. To the yellow oil are added 120 ml of THF, 1.22 g (16.74 mmoles) of acetyl hydrazine, and 5 drops of triethylamine, and the mixture is refluxed for 3 h. The mixture is cooled, a white solid is filtered, washed with water and dried in vacuo to yield 3.5 g (42%) of N-acetyl-N- [4- (4-cyano-2,6-dimethyl) phenoxy] ] butyryl] hydrazine. E. 2-methyl-5- [3- (4-cyano-2,6-dimethylphenoxy) propyl] -1,3,4-thiadiazole To a solution of 2.79 g (6.92 mmoles) of agent Esson in 150 ml of TKF 1.57 g (5,443 -rmcles) of N-acetyl-N1 - [4- [. -cyano-2, 6-dimethyl) fenoxibunirii. hydrazine and the mixture is refluxed for 3 h and then heated at 60 ° C overnight. The reaction mixture is concentrated in vacuo, the residue is purified by flash column chromatography of silica (60% ethyl acetate / hexane) to yield 700 mg of a yellow oil which is further purified by recrystallization from ethyl acetate. hexane followed by flash chromatography (hexane / ethyl acetate) to yield 750 mg (48%) of 2-methyl-5- [3- (3-cyano-2,6-dimethylphenoxpropyl] -1,3,4-thiadiazole. 2-methyl-5- [3- (4-aminohydroximinomethyl-2,6-dimethylphenoxy) propyl] -1,3,4-thiadiazole To a solution of 2-methyl-5- [3- (4-cyano-2, 6-dimethylphenoxy) propyl] -1,3,4-thiadiazole (0.69 g, 2.4 mmol) in 75 mL of ethanol were added 1.65 g (12 mmol) of potassium carbonate and C.34 g (12 mmol) of hydrochloride of hydroxylamine and the mixture is stirred at 50 ° C. for 14 h.The mixture is filtered, the residue is washed with hot ethanol several times and the filtrate is concentrated in vacuo to yield 0.98 g of 2-methyl-5- [3- (4-aminohydroximinomethyl-2,6-di) methylphenoxy) -propyl] -1,3,4-thiadiazolo. p.f. 79-80 ° C. G. 2-methyl-5- [3- [4- (5-methyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1,3,4-thiadiazole (Y = 1, 3 -propylene, R-j_ = R2 = 3, 5-dimetiic, Thi = 2-methyl-l, 3,4-thiadiazole-5-ii, R ^ = 5-methyl-1, 2, 4- oxadiazolyl) To a solution of 2-methyl-5- [3- (4-aminohydroximinomethyl-2,6-dimethylphenoxy) propyl-1, 3,4-thiadiazole (980 mg) in 10 ml of pyridine and 0.3 ml (4.2 ml) mmoles) of acetyl chloride, and the resulting mixture is refluxed for 1 h, cooled, and diluted with water. The mixture is extracted with ethyl acetate (x4), the organic layer is washed with an aqueous HCl solution, and brine, and dried over sodium sulfate. The organic layer is concentrated in vacuo and a yellow oil residue is purified by MPLC (75% ethyl acetate in hexane) to yield 342 mg (42%) of 2-ethyl-5- [3- [4- (5 -methyl-l, 2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1, 3,4-thiadiazole, as a white crystalline solid, mp 83-84 ° C (from ether / pentane). Example 2 A. N-propionyl-N '- Í4 - [(4-cyano-2,6-dimethyl) phenoxy] -butyryl] hydrazine To a solution of N- [4- [(4-cyano-2, 6- dimethyl) phenoxy] butyryl] hydrazine (2.3 g, 9.31 mmol prepared according to the method of example 1) in THF were added 0.81 ml ^ 9.31 mmol) of propionyl chloride and 1 ml of triethylamine and the resulting mixture was stirred at room temperature. room temperature for 2 h. The mixture is concentrated in vacuo, the white solid product is triturated with water, filtered, washed with ether, and dried to yield 2569 g Si%, of N-propionyl-N 1 - [4- [(4-cyano-2,6-dimethyl) phenoxy] butyryl] -hydrazine. B. 2-ethyl-5- [3- (4-cyano-2,6-dimethylphenoxy) propyl] -1,4,4-thiadiazole To a suspension of 2.58 g (8.51 mmol) of N-propionyl-N '- [4- [(4-Cyano-2,6-dimethyl) phenoxy] butyryl] hydrazine in 200 ml of dry THF is added 3.44 g (8.51 mmol) of Lawesson's reagent and the mixture is refluxed for 20 h. The reaction mixture is concentrated in vacuo, and the residual yellow oil is purified by flash chromatography on short silica column (hexane / ethylene acetate, 2: 1) and CLAP (hexane / ethyl acetate, 1: 1) to produce 2.09 g (82%) of 2-ethyl-5- [3- (4-cyano-2,6-dimethylphenoxpropyl] -1.3.4-thiadiazole C. 2-ethyl-5- [3- (4-aminohydroximinomethyl-2, 6-dimethylphenoxy) propyl] -1, 3, 4-thiadiazole To a solution of 2-ethyl-5- [3- (4-cyano-2,6-dimethylphenoxy) ropil] -1, 3, 4-thiadiazole (1.6 g, 5.32 mmol) in ethanol were added 3.67 g (26.58 mmol) of potassium carbonate and 1.85 g (26.58 mmol) of hydroxylamine hydrochloride, and the mixture was stirred at room temperature for 1.5 days, the mixture was filtered and the filtrate was filtered. Concentrate ip vacuo to yield 1.12 g of 2-ethyl-5-3- (4-aminohydroxymecr.cr.eti1-2.6-dimethylphenoxy) propyl] -1,3,4-thiadiazoi, mp 158-160 ° C.

D. 2-ethyl-5- [3- [4- (5-difluoromethyl-1, 2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1,3,4-thiadiazole (Y = 1,3-propylene, R -, = R2 = 3,5-dimethyl, Thi = 2-ethyl-l, 3,4-thiadiazol, R3 = 5-difluoromethyl-1,2,4-oxadiazol-3-yl ) To a solution of 2-ethyl-5- [3-aminohydroximinomethyl-2,6-dimethylphenoxy) propyl] -1,3,4-thiadiazole (800 mg, 2.4 mmol) in N-methyl-pyrrolidinone (3 ml) was add 1.44 ml (14.46 mmoles) of ethyl difluoroacetate, and the resulting mixture is heated at 95 ° C for 4 h, cooled, and diluted with water. The mixture is extracted with ethyl acetate (x4), the organic layer is washed with water, and brine, and dried over sodium sulfate. The organic layer is concentrated in vacuo and the residue is purified by CLAP (25% -40% ethyl acetate in hexane) to yield 500 mg (55%) of 2-ethyl-5- [3- [4- (5 -difluorophenyl-1,2,4,4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1,3,4-thiadiazole, as a white crystalline solid, mp 83-84 ° C (from methylene chloride and hexane). Example 3 A. To a solution of ethyl succinium chloride (25 g) at 0 ° C in 300 ml of CH2Cl2 are added 13.2 g of propionylhydrazine in a mixture of 100 ml of CH2C12 and 27.4 ml of diisopropyl alcohol, added in drops. The mixture is stirred at room temperature for 2 h. The mixture is quenched with water, extracted with ethylene chloride, and the organic layer is dried and concentrated in vacuo. The above solid is recrystallized from EtOAc / hexane (5: 1) to yield N-propionyl-N '- (ethyl) succinyl hydrazide. B. 28.1 g of the product of example 3A is dissolved in 2 1 of THF. 89.8 g of P4S-LQ are added and the mixture is refluxed for 2 h. During cooling, 800 ml of 5% sodium carbonate solution and 1 1 of ether is added and the mixture is filtered. The filtrate is separated and the aqueous layer is extracted with 750 ml of Et20. The organic layer is dried over MgSO4 and concentrated in vacuo to yield 22.7 g (53%) of ethyl 3- (5-ethyl-l, 3,4-thiadiazol-2-yl) propionate. C. 112 ml of lH LAH (in ether) is cooled to -20 ° C under nitrogen. An equimolar amount (24 g) of the propionate prepared by the 3B method is added dropwise as a suspension (in ether) and stirred for 15 minutes. The reaction is stopped with water and a base. For the preparation of 3- (5-ethyl-l, 3,4-thiadiazol-2-yl) propanol (13.46 g) is obtained in 78% yield, the product is vacuum distilled (0.1 mm Hg) to 130- 140 ° C before the next stage. D. 9.7 g of 2,6-dimethyl-4- (5-difluoromethyl-1,2,4-oxadiazol-3-yl) phenol described in United States Patent Application 07 / 969,287 allowed, incorporated herein by reference Reference, and 15.7 g of triphenylfoe and 6.9 g of propanol are extracted in 80 ml of THF. The mixture is cooled to < 5 ° C. 10.4 g of DEAL in 80 ml of THF is added dropwise under nitrogen and the mixture is stirred for 1 hour. The solution is drained in hexane and stirred until a gummy solid is formed. The mixture is filtered to remove solids. The solution is concentrated in vacuo to a pale yellow solid. The unpurified material is purified by column chromatography, yielding a compound of the formula I, 2-ethyl-5- [5- [4- (5-difluoromethyl-1,2,4-oxadiazol-3-yl) - 2,6-dimethylphenoxy] propyl] -1,3,4-thiadiazole (Y = 1, 3-propylene, R -, - -. R2 = 3,5-dimethyl, Thi = 2-ethyl-1, 3,4-thiadiazol-5-yl, R 3 = 5- 10 difluoromethyl-l, 2,4-oxadiazol-3-yl), mp. 84 ° C. Example 4 A. N- [4- [(4-cyano-2,6-dimethyl) phenoxy] butyroyl] -methyl carbazate To a solution of 4- [(4-cyano-2, 6- 15 dimethyl) phenoxy] ] butyric (247 mg, 1.06 mmol) in 15 ml of methylene chloride are added 0.4 ml (5.48 mmol) of "*" thionyl chloride and the mixture is refluxed at reflux for 3 h. The mixture is concentrated in vacuo, and the oil residue is mixed in 20 ml of THF with 104 mg (1.16 mmol) of 2C methyl carbazate and 3 drops of triethylamine, and then the mixture is refluxed for 2 h. The reaction mixture is cooled, concentrated in vacuo, diluted with water, and a white solid product is filtered and dried to yield 275 g of N- [4-. (4-c ar.c-2, c-d rr, et? L, fer.cxi "butyroyl 'carbazate of methyl p.f. 154-155 ° C.

B. 2-Oxo-5- [3- (4-cyano-2,6-dimethylphenoxy) propyl] -2,3-dihydro-1,3,4-thiadiazole To a solution of 1.72 g (5.65 mmol) of N - [4 - [(4-cyano-2,6-dimethyl) phenoxy] butyroyl] carbazate in 100 ml of THF is added 2.22 g (5.50 mmol) of the Lawesson reagent and the mixture is refluxed overnight. The reaction mixture is concentrated in vacuo, and the yellow oil residue is purified by CLAP (hexane / ethyl acetate, 1: 1) to yield 0.406 g (24.5%) of 2-oxo-5- [3- (4 -cyano-2, 6-dimethylphenoxy) propyl] -1.3.4-thiadiazol-3H-2-one. C. 2-oxo-5- [3- (4-aminohydroximinomethyl-2,6-dimethyl-phenoxy) propyl] -1,3,4-thiadiazole-3H-2-one To a solution of 2-oxo-5- [3- (4-cyano-2,6-dimethylphenoxy) propyl] -2,3-dihydro-1,3,4-thiadiazole (801 mg, 2.77 mmol) in 75 ml of ethanol is added 963 mg (13.86 mmol) of hydroxylamine hydrochloride and 191. 3 mg (13.86 mmol) of potassium carbonate and the mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is concentrated in vacuo to yield 826 mg (93% of 2-OXO-5- [3- (4-aminohydroximinomethyl-2,6-dimethylphenoxy) propyl] -1,2-dihydro-1.3. 4-thiadiazole B. 2-oxc-S- [3- [4- (5-difluoromethyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1, 2- ? ihydro-l, 3, 4-thiadiazoi (Thi = 2-hydroxy-l, 3,4-thiadiazol-5-yl, R1 = R = 3,5-dimethyl, Y = l, 3-propylene, R3 = 5 -difluoromethyl-1,2,4-oxadiazol-3-yl) To a solution of 2-oxo-5- [3- (4-aminohydroximinomethyl-2,6-dimethyl-phenoxy) propyl] -1,2-dihydro 1, 3,4-thiadiazole (700 mg, 2.17 mmol) in N-methyl-pyrrolidinone (3 mL) is added 1.3 mL (13.02 mmol) of ethyl difluoroacetate, and the resulting mixture is heated at 90 ° C overnight The mixture is cooled, diluted with water, and extracted with methylene chloride (x4), the organic layer is washed with brine, dried over sodium sulfate, the organic layer is concentrated in vacuo and the residue is brown. It is purified by CLAP (25% -35% e-acetate) tyl in hexane) to yield 637 mg (67%) of 2-oxo-5- [3- [4- (5-difluoromethyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxypropyl] -1, 2 - dihydro-1,3,4-thiadiazole. p.f. 110-111 ° C (recrystallization from methylene chloride / hexane) Example 5 The following compounds of the invention were prepared according to the methods described in the foregoing: wherein Y is 1,3-propylene, R1, R2 = 3, 5-dimethyl, R3 = 5-R5-l, 2,4-oxadiazol-3-yl; Thi = 2-R4-l, 3,4-thiadiazolyl The following compounds of formula 1b were made; R? Formula 1b Example 6 A. 3-Methyl-5-tributyltin-1, 2,4-thiadiazole To a cooled solution (-95 ° C, under liquid nitrogen and hexapc, of 3-methyti-β-bromo-1, 2, 4- tiadiazci -9.4 g 52.5 tp-noles) in 200 ml of THF are added 61.8 mlm. 105 ms) of 1.7 N-butyllithium is added in droplets at -90 ° C. The resulting pink solution is stirred for an additional 15 minutes and then 17.8 g (55 mmol) of tributyltin chloride is added dropwise at -90 ° C. The cold solution is allowed to warm to 50 ° C and then stopped with ammonium chloride solution. The reaction mixture is extracted with ether, the organic layer is dried over sodium sulfate and concentrated in vacuo to yield 3-methyl-5-tributyltin-1,2,4-thiadiazole. "B. ß- (3-Methyl-1,2,4-thiadiazol-5-yl) ethyl acrylate 0 To a solution of 3-methyl-5-tributyltin-1,2,4-thiadiazole (49 mmol) in 160 mL of xylene is added 11 g (49 mmol) of ethyl ß- (iodo) acrylate followed by Pd (PPh3) 4 (2.2 g, 2.45 mmol) The mixture is heated at 120 ° C for 18 h, cooled and saturated aqueous KF solution is added The mixture is filtered (filter paper), the residue is washed with ethyl acetate, and the aqueous layer is extracted with ethyl acetate (3x) The combined organic layer is dried over sulfate The residue is purified by silica chromatography (10 cm column, methylene chloride / acetone 15/1 ai / 0) and recro-tomography (10 cm silica column)., ethyl acetate / hexane 1/5) to yield 2 g (21%) of ethyl ß- (3-methyl-1,2,4-thiadiazol-5-yl) acrylate, with a white solid recrystallization from ethyl acetate / hexane). 5 Then the acrylate is reduced to alcohol with LAH and the saturated alkyl is prepared with palladium in carbon and hydrogen. C. 3-methyl-5- [3- [4- (5-difluoromethyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1,2,4-thiadiazole (I , Thi = 3-methyl-l, 2,4-thiadiazol-5-yl, Y = 1, 3-propylene, R1 --- R2 = methyl, R3 = 5-difluoromethyl-1, 2-4-oxadiazole-3 -il) To a mixture of 5- (3-hydroxypropyl) -3-methyl-1, 2,4-thiadiazole (242 mg, 1.53 mmol), 4- (5-difluoromethyl-1,2,4-oxadiazole-3) -yl) -2,6-dimethylphenol described in U.S. Patent Application 07 / 869,287, allowed, incorporated herein by reference (400 mg, 1.67 mmol) and DEAD (290 mg, 1.67 mmol) are dissolved in 16 ml of THF. To the above solution, triphenylphosphine (438 mg, 1.67 mmol) is added at 0 ° C and the mixture is allowed to warm to 20 ° C overnight. The solvent-e is removed in vacuo, a solution of aqueous sodium bicarbonate is added and the mixture is extracted with methylene chloride (7x). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (10 cm column, ethyl acetate / hexane 1/6 to 1/4) followed by recrystallization from ethyl acetate / hexane to yield 471 mg (81%) of the 3-methyl-5- [3- [4- (5-difluoromethyl-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxypropyl-1,2,4-thiadiazole. as a white crystalline solid, m.p. 62-64 ° C.

D. 3-methyl-5- [3- [4- (5-methyl-l, 2,4-oxadiazol-3-yl) -2,6-dimethylphenoxypropyl] propyl] -1,2,4-thiadiazole (I , Thi = 3-methyl-l, 2,4-thiadiazol-5-yl, Y = 1, 3-propylene, R1 = R2 = methyl, R3 = 5-methyl-l, 2,4-oxadiazol-3-yl ) To a mixture of 5- (3-hydroxypropyl) -3-methyl-1,2,4-thiadiazole (66 mg, 0.42 mmol), 4- (5-methyl-1,2,4-oxadiazol-3-yl) ) -2,6-dimethylphenol (94 mg, 0.46 mmol), and DEAD (80 mg 0.46 mmol) is dissolved in 5 ml of THF. To the above solution is added triphenylphosphine (120 mg, 0.46 mmol) at 0 ° C and the mixture is allowed to warm to 20 ° C overnight. The solvent is removed in vacuo, a solution of aqueous sodium bicarbonate is added and the mixture is extracted with methylene chloride (3x). The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (20 cm column, ethyl acetate / hexane, 1/6 to 1/4) followed by recrystallization from ethyl acetate / hexane to yield 88 mg (61%). of 3-methyl-5- [3-14- (5-methyl-l.2.4-oxadiazol-3-yl) -2,6-dimethylphenoxy] propyl] -1.2.4-thiadiazole, as a white crystalline solid, mp 67-71 ° C. EXAMPLE 7 As other examples, the phenols described only so far generally can be reacted with any known thiadiazolylalcanol, thiadiazolylalkyl halide or any of those described herein, using the methods previously described herein to provide a compound of the formula I. It is contemplated that any phenol described in the allowable application 07 / 869,287, incorporated herein by reference, was made to a thiadiazole of the formula I, using the methods described in the foregoing. For the convenience of the reader, the same naming conventions described herein for the compounds of - the formula I are adhered to and a reference of literature describing the known phenol.

Example 8 It is contemplated that 4-hydroxy-3,5-dimethylbenzonitrile can be reacted with hydroxylamine hydrochloride using the conditions of Example 2C, and the resulting product can then be reacted with ethyl chloroformate and acetone. By working-up a compound is provided wherein Y = 1,3-propylene, yielding a phenol, where R ± and R2 = 3, 5-dimethyl, R3 = 5-hydroxy-l, 2,4-oxadiazole-3. ilo. This phenol can be reacted with any of the preceding thiadiazolyl alkanols to form the compounds of the formula I. B. The compound described above, can be reacted with phosphorus oxychloride-pyridine (on a base trap) by refluxing (about 4 hours) a 5-chloro-1,2,4-oxadiazol-3-yl is obtained of the formula I.

Biological Evaluation The biological evaluation of the representative compounds of the formula I has shown that they possess antipicornaviral activity. They are useful in inhibiting the replication of picornaviruses in vitro and are mainly active against picornaviruses, including enteroviruses, echoviruses and coxsackie viruses, especially rhinoviruses. In vitro testing of the representative compounds of the invention against picornaviruses showed that viral replication was inhibited at minimum inhibitory concentrations (MIC) in the range of 0.05 to 7.4 micrograms per ml (μg / ml). MIC values were determined by a 50% infectious dose assay in automated tissue culture (TCID-50). The monolayer HeLa cells in plaques in groups of 9 £ groups were infected with-a piccmavirue dilution, which had empirically shown to produce 80% to 100% cytopathic effect (CPE) in 3 days in the absence of the drug. The compound to be tested is serially diluted by cycles of 10, 2 times and added to the infected cells. After an incubation of 3 days at 33 ° C and 2.5 carbon dioxide, the cells are fixed with a 5% solution of glutaraldehyde, followed by staining with a solution ai G.25% gentian violet in water. Then the plates are rinsed, they are dried and the amount of staining that remains in the well (a measurement of the intact cells / is quantified with an optical density reader.) The MIC is determined to be the concentration of the compound, which protected 50% of the cells CPE-induced CPE in relation to an untreated picornavirus control In the above test procedures, representative compounds of formula I were tested against some of the serotypes of a panel of 10 human rhinovirus serotypes (HRV). , HRV-3, -4, -5, -9, -16, -18, -38, -66, -75 and -67, (noted in the table as panel B) and the CIM value, expressed in a micromolar concentration, for each rhinovirus serotype was determined for each picornavirus, then the CIM5Q and CIMQQ values, which are the same concentrations of the compound required to inhibit 50% and 80%, respectively of the serotypes tested, were determined. find that they present activ antipicornavirality against one or more of these serotypes. The following Table gives the test results for representative compounds of the invention. The panel of the picornaviruses used in the test appear before the CI-Q and CIM- ~ number and the number of serotypes which the compound was tested against (N) is indicated after the CXMgn and CIM? P.

* Active against 4 serotypes The 3d example was also tested against 101 human rhinoviruses; la, Ib, and 3-100 (except HRV 74) using the protocol described in the above. The CIM? G and CIM80 for the 3d example were 0.04 μ, and 0.19 μ, respectively. Preliminary data indicate that the 3d example provides excellent in vitro and in vivo protection against the ccxsackie B3 virus. Using the prctccclc described above, the 3d example gives a CIK50 of. 1 g, my go-, vitro.

Preliminary data indicate that PD50 (the protective dose to prevent death in 50% of a population of infected mice) is of a range that makes the example useful in preventing coxsackie virus infection in mammals, avoiding death due to to the infection. The preliminary bioavailability data obtained in dog, suggests that the availability for the 3d example is very good. Its solubility is 1.1 mg / ml in the simulated gastric fluid and 0.63 mg / ml in simulated intestinal fluid. Formulations The compounds of the formula I can be formulated into compositions, including sustained release compositions together with one or more physiologically acceptable, non-toxic carriers, adjuvants or vehicles, which are collectively referred to herein as carriers, in any conventional form, using the techniques of formulation conventions for preparing compositions for the treatment of infection or for prophylactic use, using formulations well known to the skillful pharmaceutical chemist, for parenteral injection c for oral or nasal administration, in solid or liquid form, for topical administration, or the like.

The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitonially, locally (powders, ointments or drops) or as an aerosol, for example as a nasal spray or oral Compositions suitable for parenteral injection may consist of sterile, physiologically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable non-aqueous and aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (polypropylene glycol, polyethylene glycol, glycerol, polyalkylene glycols and the like), their suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting, misusing and dispersing agents. The prevention of the action of the microorganisms can be ensured by various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid and the like. It is also advantageous to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents that retard absorption, for example aluminum monostearate and gelatin. Solid dosage forms for oral administration include capsules, tablets, pills, powders, dragees and granules, which can be slowly dissolved in the mouth, for washing the mouth and ducts associated with a solution of the active ingredient. In such solid dose forms, the active compound is mixed with at least one usual, inert excipient (carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or diluents, eg, starches, lactose, sucrose, glucose, mannitol and salicylic acid, (b) binders, such as carboxymethylcellulose, algis, polyvinylpyrrolidone gelatin, sucrose and acacia gum (c) humectants, such as glycerol, (d) disintegrating agents, such as agar-agar , calcium carbo, potato starch or tapioca, alginic acid, certain complex silicates and sodium carbo, íe? retarders of the solution, such as paraffin, (f) absorption accelerators, e.g., quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents, such as example, caulin and bentonite, and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also consist of buffering agents. Certain solid dosage forms may be delivered through the inhalation of a powder manually or by means of a device, such as a SPIN-HALER used to deliver disodium cromoglycolate (INTAL). When this latter device is used, the powder may be encapsulated. When using a liquid composition, the drug can be delivered through a nebulizer, an aerosol vehicle or by means of any device, which can divide the composition into discrete portions, for example, a medicine dropper or an atomizer. Solid compositions of a similar type can also be formulated for use in soft and hard gelatin capsules, used excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and bodies and castles, such as enteric coatings and others well known in the art. They may contain opacifying agents and may also be of such composition that they release the active compound or compound in a certain part of the intestinal tract in a delayed manner. The active compounds may also be in microencapsule form, if appropriate, with one or more of the excipients mentioned in the foregoing. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Also solid formulations can be prepared as a base for liquid formulations. In addition to the active compounds, the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as eg ethyl alcohol, isopropyl alcohol, ethyl carbonate. , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylethylene glycol, dimethylformamide, oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and oil of safflower, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or a mixture of these and similar substances. In addition to such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavors and perfumes. The suspension, in addition to the active compounds may contain suspending agents, for example ethoxylated isostearyl alcohols, polyethylene sorbitol, polyethylene glycols of varying molecular weights and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum tragacanth, or mixtures of these substances and the like. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid to the Ordinary temperatures, but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active compound. Compositions for administration as aerosols are prepared by dissolving a compound of Formula I in water or a suitable solvent, for example an alcohol ether, or other inert solvent and mixing with a volatile propellant and placing in a pressurized container having a metering valve for Release the material in a useful drop size. The liquefied propellant employed is usually one which has a boiling point below the ambient temperature at atmospheric pressure. For use in intended compositions for producing aerosols for medical use, the liquefied propellant must not be toxic. Among the suitable liquefied propellants which may be employed are lower alkanes containing up to 5 carbon atoms, such as butane and pentane, or an alkyl chloride, such as methyl, ethyl or propyl chloride. Other suitable propellants • liquefied are fluorinated and fluorinated alkanes such as those which are sold under the trademarks "Freon" and "Genetron". The mixtures of the propellants mentioned in the above can be used suitably. Preferred liquefied propellants are propellants without chlorine, for example 134a (tetrafluoroethane) and 227c (heptafluoropropane) which can be used as described in the above. Typically, one uses a cosolvent, such as an ether, alcohol or glycol in such aerosol formulations.

The specifications for dosage unit forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the inherent limitations in the art of forming such compounds as an active material for use in humans and animals, as described in detail in this specification, these being the characteristics of the present invention. Examples of suitable dosage unit forms according to this invention are capsules adapted for ingestion or, aerosols with measured discharges, multiple segregated from any of the foregoing and other forms as described herein. The compounds of the invention are useful for the prophylaxis and treatment of suspicious picornaviral etiological infections such as aseptic meningitis, upper respiratory tract infection, enterovirus infections, coxsackie viruses, enteroviruses and the like. An effective but non-toxic amount of the compound is used in the treatment. The dose of the compound used in the treatment depends on the route of administration, for example intranasal, intrabronchial and the potency of the particular compound. Lae dosage forms for topical administration include ointments, powders, aerosols and inhalants. The active component is mixed under sterile conditions with a physiologically acceptable carrier and any of the preservatives, buffers or propellants as may be required. Ophthalmic formulations, ointments for eyes, powders and solutions are also contemplated. It will be appreciated that the starting point for dose determination both for the prophylaxis and treatment of picornaviral infection is based on a plasma level of the compound at levels of almost the minimum inhibitory concentration determined for a compound in the laboratory. For example, a MIC of 1 μg / ml would give a desired initial plasma concentration of 0.1 mg / dl and a dose for an average 70 kg mammal of almost 5 mg. It is specifically contemplated that the dosage range may be 0.1-1000 mg. The actual dose levels of the active ingredient in the compositions can be varied to obtain the amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. Therefore, the dose level selected depends on the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors and is easily determined by those skilled in the art.

The formulation of a pharmaceutical dosage form, including the determination of the appropriate ingredients to be employed in the formulation and determination of the appropriate concentrations of the active ingredient to be used, to achieve optimal bioavailability and the longest duration in blood plasma and similar, it is within the knowledge of the skilled technician, who normally considers dose-response relationships in vivo, when developing a pharmaceutical composition for therapeutic use. In addition, it will be appreciated that the appropriate dose to achieve optimal therapy results is a matter well within the knowledge of the skilled technician who normally considers the dose-response relationship when developing a regimen for therapeutic use. For example, the skilled artisan can consider the minimum inhibitory concentrations in vitro as a guide for the effective plasma levels of the drug. However, this and other methods are all within the scope of the skillful technician's practice when developing a pharmaceutical product. It will be understood that the specific dose level for any particular patient will depend on a variety of factors, including body weight, general health, sex, diet, time and day of administration, absorption and excretion rates, combination with other drugs and severity of the disease that is treated and is easily determined by the doctor with skill. When administered before infection, ie prophylactically, it is preferred that the administration be within approximately 0 to 48 hours before the infection of the host animal with the pathogenic picornavirus.

When administered therapeutically to inhibit an infection, it is preferred that the administration be about 1 day or two days after infection with the pathogenic virus. The dose unit administered will depend on the picornavirus for which the treatment or prophylaxis is desired, the type of animal involved, its age, health, weight, extent of infection, type of concurrent treatment, if any, frequency of treatment and the nature of the desired effect. The compound of the invention also finds utility in preventing the spread of picornaviral infection. The compounds can be used in aerosol sprayers applied to contaminated surfaces to disposable products, such as tissues and the like used by an infected person. In addition, the compounds can be used to impregnate household products such as fabrics, other paper products, disposable swabs and the like to avoid disseminating. of infection by inactivation of picornavirus. Because the compounds of the invention are capable of suppressing the growth of picornaviruses when added to a medium in which the picorr.avirus is growing, it is specifically contemplated that the compounds of the invention can be used in disinfectant solutions, by example in aqueous solution with a surfactant to decontaminate the surface on which the polio virus, Coxsackie virus and / or other picornaviruses are present are present, such surfaces include, but are not limited to, hospital glassware, work surface of the hospital, tables of restaurants, surfaces of work of the service of foods, baths of bath and any other that is expected that can carry picornavirus. Hand contact of the nasal mucus may be the most important mode of rhinovirus transmission. The sterilization of the hands of people who come into contact with people infected with rhinovirus prevents the spread of the disease. It is contemplated that a compound of the invention incorporated in a hand-washing or hand-washing process or product inhibits rhinovirus production and decreases the likelihood of the disease.

Claims (19)

1. CLAIMS 1. A compound of the formula; Formula I characterized in that: Thi is thiadiazolyl or thiadiazolyl substituted with alkoxy, fluoromethyl, difluorpethyl, trifluoromethyl, 1,1-difluoroethyl, halo, alkyl, cycloalkyl, hydroxyalkyl, or alkoxyalkyl; Y is an alkylene bridge of 3-9 carbon atoms; R1 and R2 are independently selected from hydrogen, halo, alkyl, alkenyl, amino, alkylthio, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkoxy, nitro, carboxy, alkoxycarbonyl, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, difluoromethyl, trifluoromethyl, or cyano; R3 is alkoxycarbonyl, phenyl alkyltetrazolyl, or the heterocyclyl is selected from benzoxazolyl, benzothiazolyl, thiadiazolyl, imidazolyl, dihydroimidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, furyl, triazolyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or substituted phenyl or substituted heterocyclyl wherein the substitution is alkyl, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, furyl, thienyl or fluoroalkyl or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1, characterized in that Y is a linear hydrocarbon chain three to approximately five carbons.
3. 3. The compound according to claim 2, characterized in that R3 is substituted or unsubstituted oxadiazolyl or tretrazolyl.
4. The compound according to claim 3, characterized in that R3 is selected from the group consisting of 5-difluoromethyl-1,2,4-oxadiazolyl, 5-fluoromethyl-1,2,4-oxadiazolyl, 5-trifluoromethyl-1 , 2,4-oxadiazolyl, and 2-methyl-5-tetrazolyl.
5. 5. The compound according to claim 4, characterized in that R1 and R2 are in the 3 and 5 position and R1 and R2 are each independently hydrogen, methyl, chloro, fluoro or cyano.
6. 6. The compound according to claim 5, characterized in that R- ^ and R2 represent 3,5-dimethyl.
7. 7. The compound according to claim 6, characterized in that R3 is 5-difluoromethyl-1,2,4-oxadiazolyl; R- ^ and R2 are 3,5-dimethyl, Y is 1,3-propylene and Thi is 1,3,4-thiadiazolyl substituted with ethyl or methoxymethyl.
8. 8. The pharmaceutical composition characterized in that it contains as an active ingredient an antipycholactomically effective amount of a compound according to claim 1.
9. 9. The pharmaceutical composition characterized in that it contains as an active ingredient an antipicinically effective amount of a compound according to the claim 3.
10. The pharmaceutical composition characterized in that it contains as an active ingredient an antipycholactomically effective amount of a compound according to claim 5.
11. 11. The pharmaceutical composition characterized in that it contains as an active ingredient an antipicinically effective amount of a compound in accordance with 7.
12. The method for preventing or treating picornaviral infection in a mammalian host characterized in that it comprises administering an antipicornavirally affective amount of a compound according to claim
13. 13. The method for preventing or treating picornaviral infection in a mammalian host characterized in that it comprises administering an effective antipicomaviral amount of a compound according to claim 3.
14. 14. The method for preventing or treating picornaviral infection in a mammalian host. characterized in that it comprises administering an antipicornaviral effective amount of a compound according to claim 5.
15. 15. The method for preventing or treating picornaviral infection in a mammalian host characterized in that it comprises administering an antipicornavirally effective amount of a compound according to claim 7.
16. The method for combating picornaviruses characterized in that it comprises contacting the site of the virus according to claim 1.
17. 17. The method for combating picornaviruses characterized in that it comprises contacting the virus site in accordance with the claim ation 3 53
18. 18. The method for combating picornaviruses characterized in that it comprises contacting the site of the virus according to claim 5.
19. 19. The method for combating picornaviruses characterized in that it comprises contacting the site of the virus according to claim 7.