Mono- or disubstituted 1,2,4,oxadiazoles which are substituted by at least 1-N-substituted carbamoyl group
United States Patent 3991067
1,2,4-Oxadiazoles having as 3- and 5-substituents a hydrogen atom, an aliphatic, cycloaliphatic, araliphatic, aryl or heterocyclic group, or a carbamoyl group of the formula -- CONR1 R2 where R1 & R2 which can be the same or different, are hydrogen atoms or aliphatic, cycloaliphatic, araliphatic or aryl groups or, taken with the N atom, provided that at least one of the 3- or 5-substituents is an N-substituted carbamoyl group. Antimicrobial activity, and particularly antiviral, antiparasitic and antibacterial activity is shown in this group. The corresponding oxadiazolins are also described and are useful intermediates in the preparation of the oxadiazoles.
Inventors:
Gregory, Gordon Ian (Chalfont St. Peter, EN)
Warburton, William Kingston (Pinner, EN)
Seale, Peter William (Pinner, EN)
Application Number:
Publication Date:
11/09/1976
Filing Date:
11/13/1973
Export Citation:
Glaxo Laboratories Limited (Greenford, EN)
Primary Class:
Other Classes:
546/269.1,
546/269.4,
International Classes:
C07D271/06; (IPC1-7): C07D271/06
Field of Search:
260/307G, 260/293.67, 260/268C, 260/247.2A, 260/247.1M, 260/247.5E, 260/295AM
View Patent Images:
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US Patent References:
3720668N/ABreuer260/240A3478049Von Esch et al.260/307
Foreign References:
DL80217July, 1969DL85778November, 1971
Other References:
al.--C.A. 69, 77174s (1968).
Strani et al.--Gazz. Chim. Ital. 93, 482-484 (1963).
Primary Examiner:
Rush, Raymond V.
Attorney, Agent or Firm:
Bacon & Thomas
Parent Case Data:
This application is a continuation-in-part of
application Ser. No. 253,807 of Gregory et al., filed May
16, 1972 now abandoned.
1. A compound selected from the group consisting of 3-adamantylcarbamoyl-1,2,4-oxadiazole, 5-diethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole, 5-α-naphthyl-3-dimethylcarbamoyl-1,2,4-oxadiazole, 5-piperidinocarbonyl-3-p-methoxyphenyl-1,2,4-oxadiazole, 5-piperidinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole, 5-dimethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole, 5-di-n-propylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole and 3-biphenylyl-5-diethylcarbamoyl-1,2,4-oxadiazole.
2. A compound as claimed in claim 1, said compound being 3-adamantylcarbamoyl-1,2,4-oxadiazole.
3. A compound as claimed in claim 1, said compound being 5-diethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.
4. A compound as claimed in claim 1, said compound being 5-α-naphthyl-3-dimethylcarbamoyl-1,2,4-oxadiazole.
5. A compound as claimed in claim 1, said compound being 5-piperidinocarbonyl-3-p-methoxyphenyl-1,2,4-oxadiazole.
6. A compound as claimed in claim 1, said compound being 5-piperidinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole.
7. A compound as claimed in claim 1, said compound being 5-dimethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.
8. A compound as claimed in claim 1, said compound being 5-di-n-propylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole.
9. A compound as claimed in claim 1, said compound being 3-biphenylyl-5-diethylcarbamoyl-1,2,4-oxadiazole.
Description:
This invention relates to new oxadiazole derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same. We have found that interesting physiological activity, particularly antimicrobial activity, including antiviral, antiparasitic and antibacterial activity, is shown by a group of 3 and/or 5-substituted 1,2,4-oxadiazole compounds. In one aspect the invention provides novel 1,2,4-oxadiazole compounds of the general formula ##SPC1##Where R6 represents R, where R represents a hydrogen atom or an aliphatic, cycloaliphatic, araliphatic, aryl o or a carbamoyl group of the formula --CONR1 R2 where R1 and R2, which may be the same or different, represent hydrogen atoms, aliphatic, cycloaliphatic, araliphatic or aryl groups or, together with the intervening N, represent and R7 represents R, where R is as defined above or a carbamoyl group of the formula --CONR3 R4, where R3
and R4 are as defined for R1 and R2 ; provided that at least one of R6 and R7 is an N-substituted carbamoyl group. Thus, for example, R may represent an aryl group which is preferably mono- or bi-cyclic, such as a phenyl, naphthyl or an araliphatic group such as an aralkyl, aralkenyl or aralkynyl group e.g. a benzyl, phenethyl, phenylethynyl or styryl group. R may alternatively represent a heterocyclic group, e.g. a 5- or 6-membered group such as a furyl, thienyl or pyridyl group. Such aryl, araliphatic and heterocyclic groups may carry one or more ring substituents such as lower alkyl, lower alkoxy, lower alkylthio, lowr alkylsulphinyl, lower alkylsulphonyl, amino, acylamino, cyano, thiocyanato or nitro groups or halogen atoms, for example, a tolyl, p-methoxyphenyl, p-nitrophenyl, p-chlorophenyl, p-methylthiostyryl, p-methylsulphinylstyryl or p-methoxystyryl group. The acyl portions of the acylamino may for example be straight or branched lower alkanoyl groups. When an amino ring substituent is present the compounds may form salts e.g. with strong acids such as hydrochloric and sulphuric acid. Where R represents an aliphatic group this may for example be an alkyl, alkenyl or alkynyl group such as a methyl or ethyl group, an allyl group, an ethynyl group or a propargyl group, which may carry heterocyclic groups as substituents e.g. 5- or 6-membered groups such as furyl, thienyl or pyridyl groups which may themselves carry substituents. When R is an aliphatic group it is preferably saturated. Where R is a heterocyclic group or carries a heterocyclic substituent, the hetero atom(s) is preferably S and/or N, and the group is preferably not a nitrofuryl group. Where R is a cycloaliphatic group this may for example be a cycloalkyl group having 3-10 carbon atoms, e.g. a cyclohexyl group. R1, R2, R3 and R4 may, for example, represent aliphatic groups which may be substituted by functional groups such as hydroxy groups, especially lower alkyl groups such as methyl, ethyl, propyl, n-butyl, t-butyl or 2- hydroxyethyl groups, alkenyl groups such as allyl groups or alkynyl groups such
aryl groups especially monocyclic aryl groups such as phenyl groups, which may carry one or more alkyl or aralkyl, aralkenyl or aralkynyl groups especially monocyclic groups such as benzyl groups or cycloaliphatic groups especially monocyclic cycloalkyl groups such as cyclohexyl groups or caged cycloalkyl groups such as adamantyl groups. R1 and R2 or R3 and R4 may together with the intervening N represent a substituted or unsubstituted nitrogen-containing heterocyclic group, which may contain a further hetero atom such as oxygen or nitrogen, e.g. a piperidino, morpholino, pyrrolidin-1-yl, piperazin-1-yl, 4-lower-alkylpiperazin-1-yl or 3-azabicyclo-(3,2,2)-nonan-3-yl group. These heterocyclic groups may be substituted e.g. by the substituents described above for heterocyclic R groups. In general each of the substituents R, R1, R2, R3 and R4 preferably has less than 20 aliphatic groups preferably have up to 6 carbon atoms and alkyl, alkenyl and alkynyl portions of aralkyl, aralkenyl or aralkynyl groups preferably have up to 6 carbon atoms. Heterocyclic groups preferably have 5-10 ring members. Cycloalkyl groups preferably have 3-10, especially 3-7, carbon atoms. It will be understood from the above that preferred compounds in accordance with the invention are generally compounds of the formula I wherein: R6 represents R, where R an alkyl, alkenyl, or alkynyl group containing up to 6 carbon atoms or such a group substituted with a furyl, thienyl, a cycloalkyl group having 3-10 a phenyl, naphthyl, biphenylyl, benzyl, phenethyl, phenylethynyl, styryl, furyl, thienyl or pyridyl group or such a group substituted with one or more lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, amino, lower alkanoyl amino, cyano, thiocyanato or nitro grou or a carbamoyl group of the formula --CONR1 R2, where R1 and R2 which may be the same or different each represents hydrogen, an alkyl, alkenyl, or alkynyl group containing up to 6 carbon atoms or such a group su phenyl or phenyl substituted with one or more alkyl or cycloalkyl containing 3-10 a ca or, together with the intervening nitrogen atom, represent a piperidino, morpholino, pyrrolidin-1-yl, piperazin-1-yl, 4-lower-alkylpiperazin-1-yl, or 3-azabicyclo-(3,3,2)-nonan-3-yl group or such a group substituted by one or more lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulphonyl, amino, lower alkanoylamino, cyano, thiocyanato, or nitro grou and R7 represents R, where R is as defined above, or a carbamoyl groups of the formula --CONR3 R4, where R3 and R4 are as defined above for R1 and R2 ; provided that at least one of R6 and R7 is an N-substituted carbamoyl group. Particularly preferred, by virtue of their physiological activity, are those compounds of the general formula I in which R represents an aryl group, especially a bicyclic and/or substituted aryl group, or an araliphatic group, which may also be substituted. The preferred R groups thus possess at least 7 carbon atoms. Preferred examples of substituents which may be present on aryl or araliphatic groups are alkyl (e.g. C1-6 alkyl), alkoxy (e.g. C1-6 alkoxy), alkylsulphinyl or alkylthio (e.g. C1-6 alkyl), thiocyanato or nitro groups, and halogen atoms. Examples of such R groups are a tolyl, α-naphthyl, biphenylyl, p-methoxyphenyl, p-chlorophenyl, p-methylsulphinylstyryl or p-methylthiostyryl group, or a hydrogen atom. Carbamoyl groups of particular interest, especially when an R group as just mentioned is also present, are those in which R1, R2, R3 or R4 represents an adamantyl group, or wherein R1 and R2 or R3 and R4 are both methyl, ethyl or n-propyl groups or, together with the intervening nitrogen atom, a nitrogen-containing heterocyclic group e.g. a piperidino group such as described above. The compounds of formula I may be prepared by any convenient method, in particular by reaction of a compound of the general formula ##SPC2##(where R8 and R9, which may be the same or different, represent R as defined above, a group of the formula --CONR1 R2 or --CONR3 R4 as defined above or a carboxylic acid group or a reactive derivative thereof, provided that at least one of R8 and R9 represents a carboxylic acid group or a reactive derivative thereof) with a nitrogen base of the formula R1 R2 NH or R3 R4 NH (where R1, R2, R3 and R4 are as defined above) or, where a carboxylic acid of formula II is used, with an isocyanate of the formula R1 NCO or R3 NCO. The reactive derivative may be, for example, an ester or an acid halide, e.g. chloride, symmetrical or mixed anhydride or azide. The reactive derivatives are most conveniently the alkyl esters having 1-6 carbon atoms in the alkoxy moiety, e.g. the m araliphatic esters e.g. or aryl esters, e.g. p-nitrophenyl or p-chlorophenyl esters. Where the compound of formula II is base-sensitive, e.g. when R8 or R9 is hydrogen, it is preferred to use an acid azide or halide, e.g. chloride, as reactive derivative. Such acid chlorides or azides may conveniently be prepared from the corresponding esters via the hydrazides. Where the reactive derivative is an ester, this is conveniently reacted with an excess of the nitrogen base either alone or in an inert solvent such as an alcohol, e.g. ethanol or methanol, a cyclic ether such as dioxan, a hydrocarbon solvent, such as toluene or a halogenated hydrocarbon solvent such as chloroform. The reaction is preferably effected at the reflux temperature of the system. Reaction of the acid azide or halide is desirably effected in an inert solvent, e.g. a halogenated hydrocarbon solvent such as chloroform or an ester such as ethyl acetate, at ambient temperature. Where using an acid halide, an acid-binding agent is preferably present, e.g. pyridine, propylene oxide or triethylamine. The amide formation can also be effected by reacting a carboxylic acid of formula II with the nitrogen base in the presence of a water-abstracting agent e.g. a diimide such as dicyclohexylcarbonyldiimide or or alternatively with an isocyanate R1 NCO or R3 NCO giving a product in which R6 and/or R7 represents --CONHR1 or --CONHR3 respectively. The 1,2,4-oxadiazole ring system itself can be synthesised using any convenient method. In particular, the compounds of formula II and certain products of formula I can be prepared from correspondingly substituted amidoximes employing O-acylation and subsequent cyclisation, for example, using acid halides, anhydrides, azides, amides, esters or orthoesters. The acylation may be carried out where necessary in the presence of an acid binding agent such as pyridine, propylene oxide or triethylamine. In one embodiment of this method, an amidoxime of the formula ##STR1## (where R10 represents R as defined above) is reacted with an oxalic acid derivative of the formula HalCOX where Hal represents a halogen atom, especially chlorine, and X a group --CONR3 R4 or an esterified carboxylic acid group, as described in relation to R8 and R9, for example a lower (C1-6) alkoxycarbonyl group, e.g. an ethoxycarbonyl group, to yield either (a) a product of the formula I in which R6 represents R and R7 represents a group of the formula CONR3 R4 or (b) an intermediate of the formula II in which R8 represents R and R9 represents an esterified carboxylic acid group. In another embodiment of the method an amidoxime of the formula III, where R10 represents an esterified carboxylic acid group, is reacted with the derivative of formula HalCOX as defined above to yield an ester of the formula II in which R8 represents an esterified carboxylic acid group and R9 represents an esterified carboxylic acid group or a group of the formula --CONR3 R4. The reaction is advantageously carried out in the presence of an acid binding agent, such as pyridine, propylene oxide or triethylamine. In a further embodiment an amidoxime of the formula III in which R10 represents an esterified carboxylic acid group is reacted with an acid halide of the carboxylic acid RCO2 H where R is as defined above yielding an ester of the formula II where R8 represents an esterified carboxylic acid group and R9 represents R as defined above. The reaction is advantageously carried out in the presence of an acid binding agent, such as pyridine, propylene oxide or triethylamine. Alternatively the amidoxime of formula III where R10 represents R, an esterified carboxylic acid group or a group --CONR1 R2 is reacted with a glyoxylic acid derivative of the formula HCO X where X is as defined above to yield an oxadiazoline of formula ##SPC3##which may be oxidised to give the corresponding oxadiazole of formula II, or where X and/or R10 represents an esterified carboxylic acid group, may be reacted with an amine HNR3 R4 to give an oxadiazoline of formula ##SPC4##where R8 represents R as defined above or a group --CONR1 R2 and R9 represents a group --CONR3 R4 as defined above. Where R10 and X both represent an esterified carboxylic acid group, R8 in the product formed of formula V represents a group CONR1 R2 where R1 and R2 are identical to R3 and R4 in R9. These oxadiazolines (and those wherein R9 represents R) can be oxidised to yield a product of formula I and are themselves of interest as intermediates and accordingly form a further feature of the present invention. Compounds of the formula II (in which R9 represents a hydrogen atom and R8 represents an esterified carboxylic acid group) or compounds of formula I (in which R7 represents a hydrogen atom and R6 represents a group --CONR1 22) may be prepared by reacting an amidoxime of formula III, where R10 represents an esterified carboxyl group or a group --CONR1 R2, with an orthoformate, e.g. triethyl or trimethyl orthoformate in the presence of a Lewis acid such as boron trifluo or with formyl fluoride, conveniently at reduced temperature e.g. -78° to room temperature, in an inert solvent. Alternatively, this reaction may be carried out with a Meerwein reagent (e.g. a dialkyl acetal of dimethylformamide) or the Wilsmeier-Haack reagent (phosphorus oxychloride and dimethylformamide). In general, the preparation of a compound of formula I or formula II, whether substituted or unsubstituted at the 5-position, from an amidoxime of formula III may be effected in an inert solvent. Alternatively an excess of the reagent may be used, for example when using an orthoformate as reagent. Where acid halides are used, halogenated hydrocarbon solvents such as chloroform are particularly suitable and an acid-binding agent is preferably present, e.g. pyridine, propylene oxide or triethylamine. The reaction with the amidoxime is conveniently effected at an ambient temperature or a moderately elevated temperature, for example the reflux temperature of the system. The oxidation of an oxadiazoline to an oxadiazole is conveniently effected, for example, using manganese dioxide, potassium or sodium permanganate, sodium nitrite, ferric chloride, palladised charcoal and air, chloranil or related quinones. This reaction is conveniently effected in a solvent the nature of which will depend upon the oxidising agent used. Suitable solvents include for example methanol, chloroform and ethyl acetate. The temperature at which the oxidation is carried out will also depend on the oxidising agent used but will generally be between 0° to 100° C. It will be appreciated that for compounds of the formula I in which R represents an aryl or araliphatic group carrying a substituent, it may be preferable first to prepare a compound of formula I having a different substituent by a method as set forth above, which substituent is thereafter converted into the desired substituent. Thus for example, if it is desired that R be an aminophenyl or a cyanophenyl group, it is convenient first to prepare a compound in which R is nitrophenyl, the nitro group being then reduced to an amino group, which latter may then, if desired, be converted to, for example, a cyano group or halogen atom e.g. by a Sandmeyer reaction. Furthermore compounds bearing alkylsulphinyl and alkylsulphonyl groups in the group R may advantageously be prepared from the corresponding alkylthio compounds by oxidation, for example using peracetic acid or aqueo where it is desired to form an alkylsulphinyl group, in general approximately one equivalent of oxidising agent will be used. It should further be noted that the oxidation of such substituents in the group R in a corresponding oxadiazoline ring can yield the oxadiazole product of formula I and this constitutes a variation of the oxidation method described above. As stated above, interesting antiviral activity has been shown in the group of compounds in accordance with the invention, principally against Rhinovirus strains, particularly Rhinovirus Serotype 1 (previously known as M1), and Rhinovirus Serotype 9 (previously known as H9). 3-Adamantylcarbamoyl 1,2,4-oxadiazole has shown noteworthy activity against Influenza A2 and Herpes simplex viruses. The following Table I lists a number of compounds identified with respect to formula I having especially high activity against Rhinovirus, especially the Serotypes 1 and 9.
______________________________________
Rhinovirus
______________________________________
C10 H7 (α)Et2 NCO
1p-MeO-phenylEt2 NCO
1CONMe2 p-Cl-phenyl
1CONMe2 C10 H7 (α)1trans-p-MeS-Me2 NCO
1, 9styrylp-MeO-phenylpiperidinocarbonyl1, 9C10 H7 (α)piperidinocarbonyl1, 9p-MeO-phenylMe2 NCO
1C10 H7 (α)Me2 NCO
1, 9C10 H7 (α)n.Pr2 NCO
9CONMe2 p-tolyl
1trans-p-MeS-Et2 NCO
1, 9styrylBiphenylyl
1, 9trans-p-NCS-styryl
2trans-p-MeS-styryl
pyrrolidinocarbonyl5, 9"
(n-Pr)2 NCO 1B
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The anti-viral compounds may be formulated for administration in conjunction, if desired, with one or more pharmaceutical or veterinary carriers or excipients suitable, for example for oral, topical, rectal, intravaginal or parenteral administration. The pharmaceutical or veterinary composition so formed may include other therapeutically effective compounds, for example antiinflammatory agents such as steroids, e.g. betamethasone-21-phosphate, or antibiotics such as tetracycline. 5-Diethylcarbamoyl-3α-naphthyl-1,2,4-oxadiazole and 3-biphenylyl-5-diethylcarbamoyl-1,2,4-oxadiazole have been found to be particularly suitable for formulation for topical administration. Solid preparations for oral consumption are usually presented in unit dose form and include for instance, tablets, capsules, lozenges, chewing gum and medicated sweets. Each dosage unit preferably contains 0.05 to 4 g of active antiviral material, advantageously 0.1 to 1.0 g. The material may be administered, for example, 1 to 3 times per day but the total daily dose should be in the range 0.1 to 7 g. It will be seen from the forgoing table that the compounds are of particular interest in combatting Rhinovirus infections. Conventional carriers for such preparations may be sugars, starches, sugar alcohols, gelatin, chicle gum, cocoa butter, etc., together with other compounding agents required such as binders, lubricants, stabilisers, coatings, flavourings and colourings. The compositions may also take the form of liquid oral preparations for ingestion such as solutions, suspensions, syrups, elixirs, emulsions, granules for reconstitution before use, etc., which may contain suspending, emulsifying, stabilising and preserving agents and may also contain acceptable sweetening, flavouring or colouring agents. The compounds may be prepared for local application to the mucous membranes of the nose and throat and may take the form of liquid sprays or powder insufflations, nasal drops or ointments, throat paints, gargles or similar preparations. Topical formulations for the treatment of eyes and ears and external applications may be prepared in oily, aqueous or powdered media in the form of conventional ophthalmic preparations and collyria, skin paints, lotions, creams, ointments, dusting powders, medicated dressings, eye drops and lotions, etc. Aerosol forms of the preparations for local application may also be advantageous. Suppositories and pessaries may contain a conventional base e.g. oil of theobroma, polyglycols, glyco-gelatin bases together with surface active agents if required. The injectable preparations may take the form of aqueous or oily solutions, emulsions, suspensions, or solids for reconstitution before use. Suitable vehicles include, for example, sterile, pyrogen-free water, parenterally acceptable oils, oily esters or other non-aqueous media such as propylene glycol if desired containing suspending, dispersing, stabilising, preserving, solubilising, emulsifying or buffering agents. As stated above, antiparasitic activity has also been shown in the group of compounds in accordance with the invention, particularly against Entamoeba histolytica. 5-Diethylcarbamoyl-3-p-methylsulphinylstyryl-1,2,4-oxadiazole and 5-piperidinocarbonyl-3-trans-p-methylsulphinylstyryl- 1,2,4-oxadiazole have been shown to be highly active against this parasite. Other compounds which have shown activity against this parasite are:
5-dimethylcarbamoyl-3-methyl-1,2,4-
5-methylcarbamoyl-3-methyl-1,2,4-
5-diethylcarbamoyl-3-p-methoxyphenyl-1,2,4-
trans-5-diethylcarbamoyl-3-p-methylthiostyryl-1,2,4-
5-pyrrolidinocarbonyl-3-trans-p-methylsulphinylstyryl-1,2,4-
5-n-butylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-
5-methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-
5-di-n-propylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-
5-ethylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-
5-N-ethyl-N-methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-
5-piperidinocarbamoyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole. Activity has also been shown against the Helminth Nematospiroides dubius, particularly by 5-dimethylcarbamoyl-3-phenyl-1,2,4-oxadiazole. Trans-5-diethylcarbamoyl-3-(5-nitrofuryl-2-ylvinyl)-1,2,4-oxadiazole has also shown activity against S. aureus, E. coli, B.C.G. S. typhinurium. It has also been found to be active against M. canis. The compounds may be formulated for antiparasitic and antibacterial administration by the methods described above. When presented in unit dose form, each dosage unit may generally contain 2-500 mg, preferably 2-250 mg, of the active ingredient. The material may be administered at a daily dose of 0.5 to 100 mg/kg, preferably 1-60 mg/kg, and most conveniently 1-20 mg/kg body weight.
The invention is further illustrated by the following examples. The preparation of certain novel starting materials is given as a series of Preparations. The products of these Preparations are then used in the Examples. PREPARATION 1 5-Ethoxycarbonyl-3-methyl-1,2,4-oxadiazole To a stirred suspension of acetamidoxime (3.2g.) in ethanol-free chloroform (25 ml.) containing pyridine (10 ml.) was added ethyl oxalyl chloride (8.7 g.) with cooling. The resulting solution was heated under reflux for one hour and then cooled, shaken with 2-N-hydrochloric acid (30 ml), and then water (25 ml.), dried, and evaporated to dryness to give a yellow oil. Distillation under vacuum gave title compound (4.36 g.) b.p. 57°-61° at 0.4 mm. νmax. (CHBr3) 1750 cm.-1 (--CO2 Et). PREPARATION 2 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole A solution of ethoxalyl chloride (24 ml.) in ethanol-free chloroform (25 ml.) was added dropwise with cooling during 30 min. to a suspension of α-naphthylcarbonamidoxime (34.78g.) in ethanol-free chloroform (120 ml.) containing pyridine (30 ml.). The mixture was heated under reflux for 1 hr. and cooled. The solution was washed with 2N-hydrochloric acid and water and then dried. The chloroform solution was evaporated to dryness under reduced pressure leaving a pale yellow solid which was stirred with aqueous methanol to give title compound (31.8 g), m.p. 68°-70°, λmax. (EtOH) 302 nm (ε 8,420). Similarly was prepared PREPARATION 3 3-Biphenylyl-5-ethoxycarbonyl-1,2,4-oxadiazole in 98.6% yield, m.p. 81°-82° (MeOH), λmax. (EtOH) 272 nm (ε 26,400), νmax. (CHBr3) 1750 cm.-1 (CO2 Et). PREPARATION 4 5-Ethoxycarbonyl-3 -trans-p-methylthiostyryl-1,2,4-oxadiazole Ethoxalyl chloride (8.7 g.) in ethanol-free chloroform (50 ml.) was added during 1 hr. to a stirred suspension of p-methylthiocinnamamidoxime (11.6g.) in chloroform (600 ml.) and pyridine (5.15 ml.) at -3°. After 16 hr. at -20° the solution was filtered and refluxed for 1 hr. with azeotropic removal of water. The solution was cooled and washed successively with 2N-hydrochloric acid, sodium hydrogen carbonate solution and water. The solution was dried and evaporated. The residue was crystallised from aqueous acetone (charcoal) to give the title compound (12.7 g.), m.p. 88°-89°, λmax. (EtOH) 237, 326 nm (ε12,400 and 29,500), νmax. (CHBr3)
and 973 cm.-1. PREPARATION 5 5-Ethoxycarbonyl-3-p-methoxyphenyl-1,2,4-oxadiazole Ethoxalyl chloride (11 ml.) in ethanol-free chloroform (5.6 ml.) was added at 0° over a period of 45 min. to a stirred solution of p-methoxybenzamidoxime (13.45g.) in chloroform (73 ml.) containing pyridine (6.5 ml.). Stirring was continued at room temperature for a further 2.5 hr. Chloroform was added and the solution was washed successively with 2N-hydrochloric acid, water, sodium hydrogen carbonate, and water. Evaporation left a residue which was chromatographed on silica (1 kg.) in benzeneethyl acetate (9:1 v/v) to give the oxadiazole as an oil (11.73g.) which slowly crystallised. Recrystallisation from aqueous acetone gave the title compound, m.p. 59°-60°, λmax. (EtOH) 252 nm (ε 21,200). PREPARATION 6 3-trans-p-Chlorostyryl-5-ethoxycarbonyl-1,2,4-oxadiazole p-Chlorocinnamamidoxime (anhydrous, 25.74g.) was dissolved in chloroform (300 ml.) containing pyridine (10.34g.). Ethyl oxalyl chloride (16.5g.) in chloroform (15 ml.) was added dropwise, with stirring. Stirring was continued for 1 hr., then the mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was recrystallised from aqueous ethanol to give title compound (9.76 g.), m.p. 94°-95°. λmax. (EtOH) 228, 285,nm. (ε 12,990, 31,450) νmax. (CHBr3) 975 cm.-1 (trans-CH=CH). PREPARATION 7 3,5-Bis-ethoxycarbonyl-1,2,4-oxadiazole Ethyl oxalyl chloride (10 ml.) was added dropwise, with cooling, to a solution of ethoxycarbonyl-formamidoxime (10g.) in ethanol-free chloroform (100 ml.) containing pyridine (10 ml.). The mixture was heated under reflux for 1 hr., cooled and washed with 2N-hydrochloric acid (50 ml.) and water (50 ml.) and dried. Evaporation gave title compound (6.5 g.), nD21 1.4571. PREPARATION 8 5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (10.0g.) was dissolved in methanol (150 ml.) and hydrazine hydrate (10.0g.) added dropwise with cooling. The mixture was stirred for fifteen minutes and the crystalline precipitate was filtered off, washed with methanol (10 ml.), and dried to give title compound (7.08 g), m.p. 211°-212° (decomp.) λmax. (EtOH) 302 nm (ε 10,100) νmax. (Nujol) 1680 cm.-1 (--CONH--). Similarly were prepared PREPARATION 9 5-Hydrazinocarbonyl-3-methyl-1,2,4-oxadiazole in 54.7% yield, m.p. 150°-151°, νmax. (Nujol) 1672 cm.-1 (--CONH--). PREPARATION 10 trans-5-Hydrazinocarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole in 92.4% yield, m.p. 207° (decomp.) λmax. (EtOH) 238, 326 nm. (ε 15,300, 31,000) νmax. (Nujol) 1670 cm.-1 (--CONH--) τ (d6 DMSO) 7.47 (CH3 S--) 2.73 (doublet, J 16 Hz.) and 2.24 (doublet, J 16 Hz.) -CH=CH- (trans). PREPARATION 11 5-Azidocarbonyl-3-α-naphthyl-1,2,4-oxadiazole 5-Hydrazinocarbonyl-3-α-naphthyl-1,2,4-oxadiazole (6.47g.) was dissolved in acetic acid (125 ml.) and 2N-hydrochloric acid (75 ml.). A solution of sodium nitrite (2.0g) in water (6 ml.) as added at 0° with stirring. After 15 minutes the precipitate was filtered off and dissolved in chloroform. The chloroform solution was washed with water and dried (MgSO4). Evaporation to dryness gave title compound (5.82 g.), m.p. 114° (decomp.), λmax. (EtOH) 300 nm. (ε 8,250), νmax. (CHBr3) 1710 (C=O), 2150 and 2190 cm.-1 (N3). Similarly were prepared PREPARATION 12 trans-5-Azidocarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole in 73.7% yield, m.p. 125° (decomp.) λmax. (EtOH) 237, 325 nm. (ε 12,400, 24,300), λmax. (CHBr3) 1715 (C=O), 2160 and 2202 cm.-1 (N3), τ (d6 -DMSO) values include 2.21 (doublet J 16 Hz) and 2.68 (doublet J 16 Hz, trans CH=CH). PREPARATION 13 5-Azidocarbonyl-3-methyl-1,2,4-oxadiazole in 33.4% yield, m.p. 71°-72°, νmax. (CHBr3) 1710 (C=O), 2150 and 2192 cm.-1 (N3). PREPARATION 14 3-Ethoxycarbonyl-5-p-tolyl-1,2,4-oxadiazole Ethoxycarbonylformamidoxime (46.0g.) was stirred in chloroform (450 ml.) and pyridine (32.5 ml.) and a solution of p-tolyl chloride (54g.) in chloroform (50 ml.) was added during 1 hr. and stirring was continued for a further 1 hr. The solid that separated was filtered off and washed with water to give the O-acylated amidoxime (63.5g., 72%), m.p. 188°-190°. Part of this product (5.0g.) was heated under reflux in xylene (100 ml.) for 4 hr. with azeotro the xylene was then removed under reduced pressure. The residue was recrystallised from aqueous methanol to give the title compound (4.4g.), m.p. 76°-77°, λmax. (EtOH) 263 nm. (ε 19,620) νmax. (CHBr3)
cm.-1 (CO2 Et). PREPARATION 15 5-p-Chlorophenyl-3-ethoxycarbonyl-1,2,4-oxadiazole p-Chlorobenzoyl chloride (9.5g.) in chloroform (20 ml.) was added dropwise to a stirred solution of ethoxycarbonylformamidoxime (7.21g.) in chloroform (60 ml.) and pyridine (18 ml.). After 1 hr. the solid (12.32g.) was filtered off and washed with chloroform. Some of this solid (10.0 g.) was heated under reflux in xylene (250 ml.) for 20 hr., with azeotropic removal of water. The xylene was removed under reduced pressure, and the residue was recrystallised from ethanol to give title compound (8.11 g.), m.p. 93.5°, λmax. (EtOH) 261-262 nm. (ε 2,540), νmax. (CHBr3) 1745 and 1210 cm.-1 (CO2 Et). The following compounds were similarly prepared: PREPARATION 16 3-Ethoxycarbonyl-5-p-nitrophenyl-1,2,4-oxadiazole in 88% yield, m.p. 144°-145°, λmax. (EtOH) 274 nm (ε 21,200) νmax. (CHBr3)1750 and 1218 (CO2 Et), 1536 and 1350 cm.-1 (NO2). PREPARATION 17 3-Ethoxycarbonyl-5-(2-thienyl)-1,2,4-oxadiazole in 43% yield, m.p. 76°, λmax. (EtOH) 263-264, 289 nm, (ε10,960, 16,280), νmax. (CHBr3) 1210 and 1745 cm.-1 (CO2 Et). PREPARATION 18 3-Ethoxycarbonyl-1,2,4-oxadiazole Ethoxycarbonylformamidoxime (39.6g., 300 mmole) was added to triethyl orthoformate (180 ml.) containing boron trifluoride etherate (0.9 ml.), and the solution was heated under reflux for 1 hr., then cooled and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue, dissolved in chloroform was washed with 2N-hydrochloric acid, then with saturated sodium hydrogen carbonate solution and dried (MgSO4). Removal of the solvent left an oil (37.2g.) which partially crystallised. The residual oil was sucked off, leaving the oxadiazole, (33.94g), m.p. 41°-43°, b.p. 80°-90° (bath)/0.6 mm. PREPARATION 19 3-Hydrazidocarbonyl-1,2,4-oxadiazole Hydrazine hydrate (98%, 3.15 ml.) was added at &15° in 3 portions during 20 min. to a stirred solution of 3-ethoxycarbonyl-1,2,4-oxadiazole (5.96 g.) in dry ethanol (29 ml.). The mixture was stirred for 50 min. at 0° and then filtered, to give title compound 5.26 g., m.p. 112° (decomp.) λmax. 242-243 nm (ε 3,950). PREPARATION 20 3-Azidocarbonyl-1,2,4-oxadiazole Sodium nitrite (2.70g.) in water (7.5 ml.) was added, at 0°, with stirring, during 40 min., to a solution of 3-hydrazidocarbonyl-1,2,4-oxadiazole (4.48 g.) in 2N-hydrochloric acid (50 ml.) and glacial acetic acid (20 ml.). After 1 hr., water was added and the product was extracted into chloroform Evaporation of the solvent and removal of residual acetic acid under vacuum gave the azide, (3.17 g), m.p. 89°-90°, λmax. (EtOH) 241 nm (ε 4,580). PREPARATION 21 3-Chlorocarbonyl-1,2,4-oxadiazole Dry hydrogen chloride was passed for 2 hr. through a solution of 3-hydrazidocarbonyl-1,2,4-oxadiazole (11.96g., 93.7 mmole) in dry methanol (630 ml.), then the solution was evaporated to dryness. Dry nitromethane (30 ml.) was added and the evaporation was repeated. The residue was dissolved in nitromethane (200 ml.) and hydrogen chloride was again passed into the solution for 45 min. Chlorine was then passed in for 1 hr., when the evolution of nitrogen ceased. The residual chlorine was removed by the passage of nitrogen, the suspension was filtered, and the filtrate was evaporated to give the crude acid chloride, 10.2 g. Distillation gave title compound b.p. 47-47.5°/2.5 mm. νmax. (CS2) 1785 (COCl), 3130 cm.-1 (CH). PREPARATION 22 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole α-Naphthylcarbonamidoxime (149.5 g.) was suspended in dry ethyl acetate (510 ml.) and propylene oxide (153 ml.). A solution of ethyl oxalyl chloride (97 ml.) in dry ethyl acetate (100 ml.) was added to the stirred suspension at 0° to 5° during 1 hour. The solution was stirred at room temperature for 30 minutes and then heated under reflux for 2 hours. The cooled solution was washed with 2N-sodium carbonate solution and water and dried over sodium sulphate. Removal of the solvent under reduced pressure gave a brown oil (237.9 g.) which was vigorously stirred with methanol-water (7:1, v/v) (131 ml.), and dried to give the ester (193.1 g., 89.7%), m.p. 72°-73°. PREPARATION 23 5-Ethoxycarbonyl-3-p-methoxystyryl-1,2,4-oxadiazole p-Methoxycinnamamidoxime (1.25 g.) was stirred in dry ethyl acetate (20 ml.) and propylene oxide (0.9 ml.) was added. A solution of ethyl oxalyl chloride (0.84 ml.) in ethyl acetate (5 ml.) was added dropwise, with stirring, during 30 minutes at 0°-5°. The suspension was allowed to warm to 18° and was then heated under reflux for 90 minutes. The solution was cooled, washed with 2N-sodium carbonate solution and with water, dried and treated with charcoal. Removal of the solvent and recrystallisation from methanol gave the oxadiazole (1.534 g., 86%), m.p. 115°-116°, λmax. (EtOH) 225.5, 300 (infl.), and 308.5 nm (ε 1 and 26600), νmax. (CHBr3) 820 (C6 H4) 970 (trans-CH=CH), 1752 (C=O), cm.-1. PREPARATION 24 trans-5-Ethoxycarbonyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole trans-5-Nitrofur-2-ylacrylamidoxime (2.0 g.) was suspended in ethanol-free chloroform (40 ml.) containing pyridine (1.6 ml.). Ethoxalyl chloride (2.5 ml.) was added dropwise and the mixture was heated under reflux for 2 hours. After cooling the reaction mixture was poured into water (100 ml.) and extracted with chloroform (100 ml.). The dried (MgSO4) extract was evaporated to dryness and the residue was crystallised from methanol (90 ml.) to give the title compound (2.3 g., 80%), m.p. 138°-139°, νmax. (CHBr3) 1755 (CO2 Et), 1508 and 1350 (NO2), 959 cm.-1 (trans CH=CH). PREPARATION 25 3-Benzyl-5-ethoxycarbonyl-1,2,4-oxadiazole Ethoxalyl chloride (1.75 ml.) in dry ethylacetate (10 ml.) was added at 0°-5° during 10 minutes to a stirred solution of phenylacetamidoxime (1.5 g.) in ethylacetate (10 ml.). After stirring at room temperature for 90 minutes the mixture was heated under reflux for 21/2 hours. The solution was washed with 2N-sodium carbonate and water, dried and evaporated to give a yellow oil which was chromatographed on silica (100 g.). Elution with benzene/ethylacetate (3:1) gave the oxadiazole (2.25 g.) which was subsequently distilled, b.p. 170°-180° at 1.3 mm νmax. (CHBr3) 1750 cm116 1 (ester). EXAMPLE 1 5-Diethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole. 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (30.9 g.) was heated under reflux in an excess of diethylamine (35.6g.) for 1.5 hr. The mixture was cooled and evaporated under reduced pressure to give a solid which was recrystallised from methanol yielding title compound (29.3 g.), m.p. 101.5°-102.5°, λmax. (EtOH) 302 nm. (ε 9,700), νmax. (CHBr3) 1662 cm.-1 (CONEt2). EXAMPLE 2 trans-5-Diethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole trans-5-Ethoxycarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole (600 mg.) was heated to reflux for 30 min. in an ethanolic solution of dimethylamine (10 ml.). The reaction mixture was evaporated to dryness and the solid residue was recrystallised from methanol (8 ml.) to give title compound (544 mg.), m.p. 119°-120°, λmax. (EtOH) 238, 315 (inflection), 327 nm. (ε 15,800; 26,000, 30,950) νmax. (CHBr3) 1668 (--CONMe2) and 978 cm.-1 (trans CH=CH). EXAMPLE 3 trans-5-Diethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole trans-5-Ethoxycarbonyl-3-p-methylthiostyryl-1,2,4-oxadiazole (13.3g.) was heated under reflux with a mixture of diethylamine (80 ml.) and methanol (20 ml.) for 1 hr. The cooled reaction mixture was evaporated and the residue was recrystallised from aqueous methanol to give the title amide (11.5 g.), m.p. 78°-79°, λmax.(EtOH) 237, 311 (inflection), 326 nm (ε 16,100; 23,000, 32,000) νmax. (CHBr3) 1663 (CONEt2) and 972 cm.-1 (trans CH=CH). EXAMPLE 4 5-Dimethylcarbamoyl-3-α-naphthyl-1,2,4-oxadiazole 5-Ethoxycarbonyl-3-α-naphthyl-1,2,4-oxadiazole (618 mg.) was dissolved in an ethanolic solution of dimethylamine (10 ml., 33% v/v). After 1 hr. The solution was evaporated leaving a residue that was recrystallised from methanol (3.5 ml.) to give title compound (424 mg.,) m.p. 109°-110°, λmax. (EtOH) 302.5 nm (ε 9,400) νmax. (CHBr3) 1660 cm.-1 (CONMe2). EXAMPLE 5 3-Adamant-1-ylcarbamoyl-1,2,4-oxadiazole. 3-Azidocarbonyl-1,2,4-oxadiazole (350 mg.) was added to a solution of 1-aminoadamantane (378 mg.) in chloroform (15 ml.) and the mixture was stirred for 24 hr. The chloroform solution was evaporated to dryness under reduced pressure and the residue was recrystallised from aqueous methanol to give title compound (167 mg.), m.p. 141°-142°, νmax. (EtOH) 230 nm (ε 3,910), λmax. (Nujol) 3392 (--NH--) 1692 and 1515 cm.-1 (CONH). Further examples provided in Table II were prepared by the following general methods: Method A The appropriate 3- or 5-alkoxycarbonyl-1,2,4-oxadiazole was treated with an excess of the primary or secondary amine (1-10 equivs.) at a suitable temperature, between room temperature and the boiling point. Excess amine was removed under reduced pressure and the product was recrystallised. Method B Similar to Method A except that a solvent such as ethanol or methanol was used as diluent. Method C The appropriate 3- or 5-azidocarbonyl-1,2,4-oxadiazole was treated with the primary or secondary amine (1-2 equivs.) at room temperature in a suitable solvent (e.g. chloroform) and the product isolated by evaporation and recrystallisation. Method D Similar to Method C except that the 3- aor 5-chlorocarbonyl-1,2,4-oxadiazole was used to acylate the amine. Examples 6-40 and 52-60 refer to the formula ##SPC5## Examples 41-51 refer to the formula ##SPC6##
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MeOH 79- 244
MeOH 114---
N(C2 H5)2A
petrol45- --
71(40- 4660°)9
EtOH/89- --
79petrol90(40-60°)10 CH3
MeOH/35- --
70(MeOH)petrol37(60-80°)11 Ph
MeOH/110---
72petrol112(80-100°)12 Ph
638513 CH3
benzene99- --
10114 Ph##STR2##
EtOH 138- 140231
18,0001650
6015 Ph##STR3##
EtOH 66- 67.5235
17,0001660
4716 Ph##STR4##
Et2 O81- 83224
18,3001655
4917 Ph##STR5##
EtOH 82- 83235
15,3001658
8218##STR6##
N(C2 H5)2A
EtOH 62- 63256.519,3601643
3519##STR7####STR8##
MeOH/ H2 O78- 79258
19,6601656
4320##STR9##
N(CH3)2B (EtOH)EtOH 123- 124256
19,6001665
8121 αC10 H7##STR10## A
MeOH/ H2 O107- 108302.510,2601655
5522 αC10 H7N(CH3)2B
MeOH 109-302.59,3701660
11023 αC10 H7N(C3 H7)2A
MeOH 41.5-302.510,3501658
524324 αC10 H7N(CH3)PhC
MeOH 88- 293
408925 αC10 H7N(C4 H9)2C
7826 (C2 H5)2 NCON(C2 H5)2A
MeOH 55- 235 inf.6,0301660
555627##STR11##
N(C 2 H5)2A
MeOH 81- 82275.528,1001660
7228##STR12####STR13## C
EtOH 130- 131(238 (32716,800) 30,600)1700
71.529 αC10 H7##STR14## C
MeOH/ H2 O64- 65302
8130##STR15##
MeOH 105- 106(237 (32617,300) 30,500)1692
5731##STR16##
N(C2 H5)2A
MeOH 73- 74(221 (227 (28518,700) 16,100) 31,9001660
8732##STR17##
MeOH 115- 116(220 (227.518,900) 15,400)1660 8033 CH3##STR18## C
6534 αC10 H7##STR19## C
MeOH 120- 121302
5935##STR20##
NHC(CH3)3A
MeOH 113- 114(235.5 (32516,800)
30,400)1702
6736##STR21##
N(C2 H5)2A
MeOH 84- 85(226 (246 (32238,900) 25,500) 15,3001665
6737 αC10 H7N(CH2 CH2 OH)2B
MeOH 118-301.59,3001662
6611938 αC10 H7##STR22## B
MeOH 119- 120302.5
7539 αC10 H7NHCH2 CHB
EtOH 105-302.5
10640 PhCH2
N(C2 H5)2A
10041 (CH3)2 NCH3
48(MeOH)42 CH3 NH
MeOH/109---
74(MeOH)petrol110(40-60°)43 (CH3)2 NPh
CHCl3 /80- --
78petrol8160-80°44 (C2 H5)2 NPh
6845##STR23##
156- 157271.511,3001710
77, 9746 (CH3)2 N##STR24## B (MeOH)MeOH/ H2 O97- 99260
28,2001650
6547 (CH3)2 NαC10 H7B
MeOH/109-239) 312)27,600 17001652
70(MeOH)H2 O11048 (CH3)2 N##STR25## B (MeOH)MeOH/ H2 O113- 114287
17,5001650
7249 (C2 H5)2 N##STR26## B (CHCl3)MeOH/ H2 O119- 120274
19,4001645
3550 (CH3)2 N##STR27## B (MeOH)MeOH 58- 59262
30,9001660
5851##STR28##
MeOH/ H 2 O128- 129--
7352##STR29####STR30## B
aqueous methanol117- 118237.5 32717,000 30,0001650
8753 "##STR31## B
ethanol137- 139237 326.515,900 30,6001660
9354 "##STR32## B
methanol122- 123236.5 326.516,300 30,0001660
9355 "##STR33## B
acetoneCa. 45236.5 32716,500 29,9001660
ethanol200-235
16,8001708
29,20057 "
aqueous123-236
17,5001704
87methanol124 326
28,90058 "
N(CH3)C2 H5B
methanol74- 236
15,6001665
30,00059 "
N[C3 H7(n) ]2B
methanol58- 237
32,00060 "
NHC4 H9 (n)B
aqueous110-236 32617,200 29,2001700
96methanol111
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EXAMPLE 61 5-Diethylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole. Peracetic acid (1 ml., comml. ca. 40%) was extracted with methylene chloride (5 ml.) and a portion (3.5 ml.) of this extract was added dropwise at room temperature to a stirred solution of 5-diethylcarbamoyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole (1.00g) in methylene chloride (50 ml.) during 70 minutes. The solution was shaken with saturated sodium hydrogen carbonate solution (20 ml), and then water (20 ml), and dried Removal of the solvent reduced pressure gave an off-white solid which was stirred with petroleum (50 ml, b.p. 40°-60°), filtered off and dried under vacuum to give title compound (1.00 g.), m.p. 101.5°-102°, λmax. (EtOH) 288.5 nm (ε 32,000), νmax. (CHBr3) 1650 (CONEt2) and 970 cm.-1 (trans CH=CH), τ (CDCl3) values include 2.19, 2.82 (quartet J 16.5 Hz, trans CH=CH) and 7.25 (SOMe). EXAMPLE 62 5-Diethylcarbamoyl-3-trans-p-methylsulphonylstyryl-1,2,4-oxadiazole Peracetic acid (3 ml. comml. ca. 40%) was extracted with methylene chloride (15 ml) and a portion (9.0 ml) of this extract was added dropwise at room temperature to a stirred solution of 5-diethylcarbamoyl-3-trans-p-methylthiostyryl-1,2,4-oxadiazole (0.961g.) in methylene chloride (50 ml.) during 100 minutes. The solution was shaken with saturated sodium hydrogen carbonate solution (30 ml), and then water (20 ml), and dried Removal of the solvent under reduced pressure gave title compound (1.01 g.), m.p. 123°-124°, λmax. (EtOH) 284.5nm (ε34,900), νmax. (CHBr3) 1650 (CONEt2) and 952 cm.-1 (trans CH=CH), τ (CDCl3) values include 2.17, 2.77 (quartet J 16.5, Hz, trans CH=CH) and 6.90 (SO2 Me). EXAMPLE 63 5-Dimethylcarbamoyl-3-p-methylsulphinylstyryl-1,2,4-oxadiazole 5-Dimethylcarbamoyl-3-p-methylthiostyryl-1,2,4-oxadiazole (700 mg.) was dissolved in methylene chloride (40 ml.). A solution of ca. 40% peracetic acid in methylene chloride (6.7% w/v; 2.8 ml.) was added dropwise the reaction was followed by thin-layer chromatography. The solvent was removed under reduced pressure and the residual solid was stirred with light petroleum (b.p. 40°-60°), leaving the sulphoxide (670 mg., 90.7%), m.p. 136°-137°. A sample recrystallised from toluene had m.p. 137°-138°, λmax. (EtOH) 226, 288.5, and 305 nm, (ε1, and 21500) νmax. (CHBr3) 317 (C6 H4). 972 (trans-CH=CH), 1043 (S ? 0), 1660 cm-1 (CON&). EXAMPLE 64 5-Diethylcarbamoyl-3-p-methoxystyryl-1,2,4-oxadiazole 5-Ethoxycarbonyl-3-p-methoxystyryl-1,2,4-oxadiazole (1.25 g.) was suspended in dry methanol (5 ml.) and diethylamine (7.25 ml.) was added. The mixture was heated under reflux for 1 hour, when a solution was obtained. The solvent was removed under reduced pressure and the residual oil was dissolved in methanol and treated with charcoal. Evaporation of the filtrate left an oil, which was recrystallised from aqueous methanol to give the amide (1.199 g., 87.4%), m.p. 69°-70°, λmax. (EtOH) 225.5 300 (infl.) and 308 nm. (ε1 and 25000), εmax. (CHBr3) 820 (C6 H4), 970 (trans-CH=CH), 1650 (CO.N&), EXAMPLE 65 trans-5-Diethylcarbamoyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole trans-5-Ethoxycarbonyl-3-(5-nitrofur-2-ylvinyl)-1,2,4-oxadiazole (332 mg.) was heated under reflux with diethylamine (5 ml.) for 30 min. to give a deep red solution. Evaporat recrystallisation from methanol (3 ml.) gave trans-5-diethylcarbamoyl-3-(5-nitrofur-2-ylvinyl)1,2,4-oxadiazole (208 mg., 57%), m.p. 118°-119°, λmax. (EtOH) 240 and 349 nm. (ε18,600 and 19,900), νmax. (CHBr3) 1665 (CONEt2),
(NO2) and 960 cm.-1 (trans CH=CH). EXAMPLE 66 The following compounds were prepared as described in Example 63. 3-trans-p-methylsulphinylstyryl-5-pyrrolidinocarbonyl-1,2,4-oxadiazole 74% yield, m.p. 162°-163° (from toluene-light petroleum b.p. 80°-100°), λmax (EtOH) 289.5 and 305 nm (ε31,900 and 21,400), νmax. (CHBr3) 812 (p-C6 H4), 970 (trans-CH=CH), 1041 (S?O), 1655 cm-1 (CON&). 3-trans-p-methylsulphinylstyryl-5-piperidinocarbonyl-1,2,4-oxadiazole 73% yield, m.p. 95°-96° (from toluene-light petroleum, b.p. 80°-100°), λmax. (EtOH) 288.5 nm (ε21,200), νmax. (CHBr3) 812 (p-C6 H4), 9701 (trans-CH=CH), 1041 (S?O), 1660 cm-1 (CON&). 5-Methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole 76% yield, m.p. 193°-194° (from toluene-ethanol), λmax. (EtOH) 288.5 nm (ε 31,600), νmax. (Nujol) 818 (p-C6 H4), 969 (trans-CH=CH), 1030 (S?O), 1680 cm-1 (CONH). 5-Ethylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole 73% yield, m.p. 147°-148° (from toluene-ethanol), λmax. (EtOH) 288 nm (ε 32,800), νmax. (CHBr3) 811 (p-C6 H4), 970 (trans-CH=CH), 1040 (S?O), 1648 cm-1 (CONH). 5n-Butylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazole 83% yield, m.p. 130°-131° (from toluene-light petroleum, b.p. 80°-100°), λmax (EtOH) 288.5 nm (ε 32,300), νmax. (CHBr3) 812 (p-C6 H4), 970 (trans-(CH=CH), 1040 (S?O), 1624 cm-1 (CONH). 5-N-Ethyl-N-methylcarbamoyl-3-trans-p-methylsulphinylstyryl-1,2,4-oxadiazol 86.5% yield, m.p. 109° (from toluene), λmax. (EtOH) 288.5 nm (ε 34,500) νmax. (CHBr3) 820 (p-C6 H4), 978 (trans-CH=CH), 1050 (S?O), 1670 cm-1 (CON&). 3-trans-p-Methylsulphinylstyryl-5-di-n-propylcarbamoyl-1,2,4-oxadiazole. 66% yield, liquid (from aqueous methanol), λmax. (EtOH) 289 nm (ε 28,200), νmax. (CHBr3) 818 (p-C6 H4), 977 (trans-CH=CH), 1050 (S?O), 1670 cm-1 (CON&). EXAMPLE 67 5-Diethylcarbamoyl-3-trans-p-thiocyanatostyryl-1,2,4-oxadiazole 3-trans-p-Aminostyryl-5-diethylcarbamoyl-1,2,4-oxadiazole (1.42 g) was dissolved in glacial acetic acid (30 ml) and 2N-sulphuric acid (10 ml). The solution was stirred, and sodium nitrite (400 mg) in water (10 ml) was slowly added at &5°. The diazonium solution was added dropwise at 0° to a stirred aqueous solution of cuprous thiocyanate (1.5 g) and potassium thiocyanate (15 g). The mixture was allowed to warm to room temperature and the pH was adjusted to 7 (NaHCO3). The solid that separated was extracted into chloroform. The filtered chloroform solution was washed with sodium hydrogen carbonate solution and with water, dried (Na2 SO4) and evaporated, leaving an oil, which slowly crystallised. The crystals were washed with a little methanol, giving the thiocyanate compound (700 mg, 43%), m.p. 97°, λmax. (EtOH) 291.5 nm (ν 29,000), 223 nm (ε 15,400) νmax. (CHBr3) 1662
(--CON&), 972 (trans-CH=CH), 814 (p-C6 H4), 2180 cm-1 (SCN). The starting material for the above transformation was prepared from p-nitrocinnamamidoxime by the following sequence 5-Ethoxycarbonyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole. p-Nitrocinnamamidoxime (17.06 g) was stirred in ethyl acetate (1 l) containing propylene oxide (8.8 ml, 9.63 g). Ethyl oxalyl chloride (16.9 ml, 13.6 g) was added dropwise during 45 min. The solution was refluxed for 1.5 hr, cooled, and washed with 2N-sodium carbonate, then with water, dried (Na2 SO4), and treated with charcoal. The filtered solution was evaporated under reduced pressure and the residue was recrystallised from toluene to give the ester (14.02 59%), m.p. 145°, λmax. (EtOH) 308.5nm (ε 22,800), λinfl. 228 nm (ε 11,800), νmax. (CHBr3) 1525 and 1348 (NO2), 1753 (CO2 Et), 835 (p-C6 H4), 972 cm-1 (trans-CH=CH). 5-Diethylcarbamoyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole 5-Ethoxycarbamoyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole (13.0 g) was refluxed in diethylamine (102 ml, 72.4 g) dissolved in methanol (520 ml) and ethanol (200 ml) for 1.5 hr. The solution was treated with charcoal, filtered, and evaporated. The residue was recrystallised from aqueous methanol to give the amide (11.7 g, 82.5%), m.p. 118°, λmax. (EtOH) 305.5 nm (ε 26,100), λinfl. 234.5 nm (ε 12,700) νmax. (CHBr3) 1529 and 1349 (NO2), 1666 (--CON&), 838 (p-C6 H4), 974 cm-1 (trans-CH=CH). 3-trans-p-Aminostyryl-5-diethylcarbamoyl-1,2,4-oxadiazole 5-Diethylcarbamoyl-3-trans-p-nitrostyryl-1,2,4-oxadiazole (11.2 g) was dissolved in acetone (250 ml) and acid titanous chloride solution (15% W/V; 260 ml) was added to the stirred solution during 1 hr. The pH was adjusted to 7 and the solid that separated was filtered off and dissolved in acetone. The acetone solution was filtered and evaporated, leaving the crude amine (10.7 g,&100%), m.p. 174°-180°, νmax. (Nujol)
(bonded NH2), 1645 (--CON&), 812 (p-C6 H4, 962 cm-1 (trans-CH=CH), τ (Me2 SO d6) 4.36 (NH2). EXAMPLE 68
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3-α-naphthyl-5-diethylcarbamoyl-1,2,4-oxadiazole
Gum Acacia
Magnesium stearate
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The active ingredient was taken up in sufficient water to form a granulating fluid and the pH value adjusted to about 5.0 with the aid of citric acid. The gum acacia was dissolved in the same solution and this solution was used to granulate the lactose. The granules were passed through a 20 mesh (B.S.) sieve, dried, lubricated with the magnesium stearate and compressed. EXAMPLE 69 Tablet Tablets were prepared as described in Example 51 using half quantities of excipients and 250 mg. per tablet of 3-p-methylthiostyryl-5-diethylcarbamoyl-1,2,4-oxadiazole as active ingredient. EXAMPLE 70
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Hard gelatin capsules
3-α-naphthyl-5-diethylcarbamoyl-
1,2,4-oxadiazole
Magnesium stearate
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The active ingredient and the lactose were blended together homogeneously. The magnesium stearate was also blended in to provide good flow properties and the powder distributed into hard gelatin capsules so that each contained 250 mg. of the active ingredient. EXAMPLE 71
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Eye Drops (Oily)
3α-naphthyl-5-diethylcarbamoyl-
1,2,4-oxadiazole
Castor oil
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The active ingredient was reduced to a fine state by sub-division to a particle size of less than 10μ. The castor oil was sterilised by heating in a hot air oven at 160° C. The active ingredient was sterilised and dispersed in the sterile castor oil to yield a homogeneous mixture. EXAMPLE 72
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Eye Drops (aqueous)
5-diethyl carbamoyl-3-biphenylyl-
1,2,4-oxadiazole
Sodium chloride
Phenyl ethanol
Benzalknoium chloride
Water (for injection)
Methyl cellulose
a sufficient amount
to yield a final
product with a
viscosity of not
less than 3000
centistokes.
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The methyl cellulose, sodium chloride, phenyl ethanol and benzalkonium chloride were dissolved in the water and sterilised by heating in a sealed container in an autoclave. The sterile micro-fine (particle size &10μ) active ingredient was then suspended in the sterile vehicle. EXAMPLE 73
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Eye Ointment
3α-naphthyl-5-diethylcarbamoyl-
1,2,4-oxadiazole
Neomycin sulphate
Liquid paraffin
Soft paraffin
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The paraffins were mixed, melted and strained, and were then sterilised by heating in a hot air oven at 160° C. The sterile micro-fine (particle size &10μ) active ingredient and neomycin sulphate were then suspended and homogeneously dispersed in the paraffin. EXAMPLE 74
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Nasal Spray
3α-naphthyl-5-diethylcarbamoyl-
1,2,4-oxadiazole
Methyl cellulose
Sodium chloride
Nipa 82121
Distilled water
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The Nipa 82121, which is a mixture of the methyl, ethyl, propyl and butyl esters of para hydroxy benzoic acid, was dissolved in hot water, and the solution cooled to room temperature. The methyl cellulose, glycerin and sodium chloride were then dissolved in the Nipa 82121. The solution was clarified by filtration and the micro-fine active ingredient (particle size &10μ) suspended in it. EXAMPLE 75
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5-Diethylcarbamoyl-3-trans-p-methylsulphinylstyryl-
1,2,4,-oxadiazole
Polyethylene Glycol 6000
Magnesium Stearate
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The active ingredient is ground to a powder having a particle size between 1 and 10 microns. It is then granulated with the aid of a chloroform solution of the polyethylene glycol by passing it through a No. 12 mesh British standard sieve, and dried in vacuo. The dried granulate is passed through a No. 16 mesh British standard sieve. The granulate is then blended with the magnesium stearate which acts as a lubricant and compressed on 8 mm punches, preferably having a breakline. Each tablet weighs 260 mg. These tablets may if desired be film-coated in conventional manner.
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