IE43474B1 - Acylated aminothiadiazoles and amino-oxadiazoles - Google Patents

Abstract

Acylamino heteroaryl compounds in which the heteroaryl nucleus is a 5-membered nucleus which contains, as the sole heteroatoms, two nitrogen atoms, and a further heteroatom selected from oxygen and sulphur, methods of making the compounds and pharmaceutical formulations containing the compounds. The compounds have anti-allergy activity.

Description

This invention relates to heterocyclic chemical compounds, more particularly to certain novel 5-membered heteroaryl derivatives substituted by an acylamino group which are useful for tne chemotherapy of immediate hypersensitivity conditions and/or which are useful as intermediates in the preparation of such active compounds. The invention also includes processes for preparing the active compounds of the invention. Furthermore, the invention includes within its scope pharmaceutical compositions containing pharmacologically active compounds and methods of treatment of animals, comprising administering thereto an effective dose of the compound or compounds or of pharmaceutical compositions comprising the active compound or compounds of the invention.

Compounds similar to those of the present invention have been previously described, see, for example, Bull. Soc. Qhein., 1219, (1967)- Belgian Patent No. 736854 and British Patent Specification No. 1,333,495. However, it is to be noted that such prior disclosures of this type of compound have either disclosed a utility quite different from that possessed by the compounds of the invention or have been publications of academic interest only in which no utility whatsoever has been disclosed.

It is an object of the present invention to provide compounds useful in chemotherapy of immediate hypersensitivity conditions.

Accordingly, the present invention provides a novel heteroaryl derivative of the formula: Ar-N-R1 I ? (D CORZ wherein Ar represents a 5-membered heteroaryl nucleus selected from 1,2,4 - oxadiazolyl, 1,3,4 - oxadiazolyl, 1,2,4 thiadiazolyl and 1,3,4 - thiadiazolyl, said heteroaryl nucleus being optionally substituted by formyl, carboxyl, hydroxyl, hydroxyalkyl, C1-4 alkyl, C3_1Q cycloalkyl, C3_g acyloxyalkyl, optionally substituted phenyl or halogen, the acylamino group -NR COR being attached to a carbon atom of the heteroaryl ring, and wherein R1 is alkyl, C3_g alkenyl, C3_g alkynyl, C2_g alkoxyalkyl, C2_g carboxyalkyl,C-^g haloalkyl, C3_4O cyeloalkyl, C3_^Q cycloalkyl-C^_g alkyl,optionally substituted phenyl-C1_g alkyl or optionally substituted phenyl-C3_g alkenyl; and R2 is 03_θ alkyl, Cj_g haloalkyl, C2_g alkenyl, C3_lo cyeloalkyl, C3_1Q cycloalkyl-C^g alkyl, optionally substituted phenyl, optionally substituted phenyl-C^_g alkyl or optionally substituted phenyl-C9 , alkenyl; provided that: 2 (a) when Ar is 1,3,4-thiadiazolyl, R is C^_3 alkyl and R is alkyl, C^_g haloalkyl, C2_3 alkenyl or C3_g cyeloalkyl, said 1,3,4-thiadiazolyl group cannot be unsubstituted or substituted by C^_3 alkyl or halogen; (b) when Ar is 1,3,4-thiadiazolyl substituted by a C. . alkyl 1 ·*·“’ group and R is trichloromethyl, R cannot be C^_g alkyl or C3_6 alkenyl; (c) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, 2 R cannot be methyl or benzyl when R is methyl. (d) when Ar is 1,2,4-thiadiazolyl substituted by halogen and R1 is C^_g alkyl, allyl, Cg_y cyeloalkyl or phenyl-C^_3‘ alkyl R2 cannot be methyl,ethyl or trichloromethyl; (e) when Ar is 1,2,4-thiadiazolyl substituted by isopropyl and R1 is C3_4 alkyl,allyl, C^_g haolalkyl or C2_g alkoxyalkyl R2 cannot be C^_4 alkyl, allyl or C^_g haloalkyl; and (f) when Ar is 1,3,4-thiadiazolyl substituted by methyl and 2 R is allyl, R cannot be dichloromethyl.

The optional substitutent on the heteroaryl nucleus is preferably selected from C^_4 alkyl, 03_θ cyeloalkyl and phenyl. Preferred R substituents are C^_g alkyl, alkenyl, c3_g cyeloalkyl and benzyl optionally substituted by halogen Cx_4 alkyl or C1-4 alkoxy. Preferred R2 substituents are Cl-8 alkyl, C3_g cyeloalkyl, benzyl and phenyl optionally substituted by halogen or 0^_4 alkoxy.

The term C^_g alkyl as used herein means a straight or branched chain alkyl group containing from 1 to 6 carbon atoms such as methyl, ethyl, iso-propyl, n-butyl, s-butyl, Isobutyl, t-butyl, n-amyl, £-amyl, n-hexyl, 2-ethylbutyl or 4-methylamyl.

Similarly the term C1_4 alkyl as used herein means a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, namely methyl, ethyl, Isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, t-butyl. ci_4 hydroxyalkyl and C3_g acyloxyalkyl mean the aforementioned C^_4 alkyl groups substituted with an hydroxy group and acyloxy group respectively. C2-g alkoxyalkyl and C^_g haloalkyl mean the appropriate alkyl group from the aforementioned C^_g alkyl groups substituted with an alkoxy group or one or more halogen atoms, such as methoxyethyl, ethoxyethyl, ethoxybutvl, dibromomethyl, trifluoromethyi, 1chloroethyl, 1,1-dichloroethyl, 1-iodobutyl or pentafluoroethyl.

The term C^ g alkynyl is used herein to indicate an alicyclic hydrocarbon group having from 2 to 6 carbon atoms which contain a -CcC- group. However, it should he noted that the -CsC- group cannot be directly adjacent the nitrogen atom of the acylamino group.

C3-10 cycI°a^1<Y'· means a saturated ring having from 3 to 10 carbon atoms in the ring such as cyclcpropyl, cyclobutyl, cyclopentyl, cyclooctyl, or adamantyl. Cg cycloalkyl-Cj_g alkyl means the aforementioned saturated rings attached to a C^_g alkylene group.

The term optionally substituted phenyl as used herein means a phenyl group unsubstituted or substituted by one or more groups which do not substantially alter the pharmacological activity of the compounds of formula (I), such as halogen, trifluoromethyi, methyl, methoxy, or nitro groups.

Tlie term C^ g carhoxyalkyl as used herein means a g alkyl group substituted by a carboxylic acid group. Examples of such groups are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

Compounds of the invention with these heteroaryl nuclei may ba represented by the structural formulae: (II) -NR^COR2 (III) R NR1COR2 (IV) --N i '-S'XXNR1C0R2 ^•S NR1COR2 (V) (VI) N Λ>α NR1COR2 (VII) 2 where R and R are as previously defined and R is hydrogen or the optional substituent on the heteroaryl nucleus.

Particularly interesting compounds of formula (I) to (VII) are those wherein the heteroaryl group is substituted by a alkyl group, especially methyl, R^ is alkyl, especially C^_6 alkyl, C3__ alkenyl or benzyl and 2 R is Cj g alkyl, Cj_^ cycloalkyl or benzyl.

The present invention also provides a process for preparing compounds - 434/4of formula (I) as defined above Which comprises: (a) reacting an amine of formula: ArNHR1 (VIII) where Ar and R1 are as defined previously, with a reagent 2 which converts the amine hydrogen atom to a R CO - group, (b) reacting an amide of formula: ArNHCOR2 (IX) where Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl and 1,3,42 oxadiazolyl and R is as defined previously, with a reagent which converts the amide hydrogen atom to a R^ group: or (c) reacting a compound of formula: ArY (X) where Y is a good leaving group such as trichloromethyl, tribromomethyl, bromine or chlorine, and where Ar is as defined previously, v/ith a salt of formula: MNR1COR2 (XI) 2 where M is a group IA or IIA metal and R and R are as defined previously.

The acylation of the compound of formula (VIII) may be carried 2 out with an acid halide having the formula R CO-X wherein X is 2 chlorine or bromine and R is as defined above in the presence of a proton acceptor, such as pyridine or triethylamine, in an inert solvent, such as benzene. The acylation may be carried out by heating the alkyl derivative with a suitable acid anhydride, (R CO^O, in an inert solvent.

Those skilled in the art will immediately appreciate that a wide variety of other acylating conditions can be used (See for exanple, The Chanlstry of Amides 1971 by A. J. Beckwith,· Survey of Organic Synthesis, 1970 by Buehler and Pearson; Organic Functional Group Preparations 1968 by Sandler and Karo, Reagents for Organic Synthesis 1968 by Fieser and Fieser, etc.).

Compounds of formula (IX) can be alkylated by dissolving the amide in a suitable inert, anhydrous, polar solvent such as dimethylformamide, forming an alkali metal salt thereof with an alkali metal hydride, preferably sodium hydride, and then treating the salt with an alkylating agent of formula R^X^ where X1 is a reactive atom such as a halogen atom or a reactive group such as an alkyl sulphate group.

Alkylating agents and alkylating reaction conditions other than those specified above can be utilised, the nature of these being readily apparent to those acquainted with the art.

The conpound of formula (XI) wherein M is lithium can be prepared by reacting 1 2 an amide of formula NHR COR with butyl lithium under an inert gas atmosphere such as nitrogen in an inert solvent such as tetrahydrofuran, preferably in the presence of a chelating agent such as tetramethylethylenediamine or diazabicyclooctane. Generation of the salt is preferably accomplished at low temperatures, for example below - 10°C.

Reaction (c) can be accomplished by reacting the compounds of formulae (X) and (XI) together in a suitable inert solvent such as tetrahydrofuran, optionally in the presence of a catalyst such as copper or a salt thereof.

The derivatives of formulae (VIII) and (IX) can be derived from the corresponding amines of formula ArNH2 by standard alkylation or acylation techniques.

The amines of formula ArNH2 are either known compounds or can be prepared by modification of known synthetic methods. - 7 43-17 4 According to one aspect of the present invention there is provided a pharmaceutical formulation comprising a heteroaryl derivative of formula: Ar-N-R2- I 2 CORZ (XIII) vzherein Ar represents a 5-membered heteroaryl nucleus selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl, said heteroaryl nucleus being optionally substituted by formyl, carboxyl, hydroxyl, hydroxyalkyl, alkyl, C3_lo cycloalkyl, C3_g acyloxyalkyl, optionally 1 2 substituted phenyl or halogen, the acylamino group -NR COR being attached to a carbon atom of the heteroaryl nucleus, and wherein R1 is C^_1Q alkyl, C3_g alkenyl, C3_g alkynyl, C2_g alkoxyalkyl, C2_g carboxyalkyl, C^_g haloalkyl, C3_^q cycloalkyl, c3_£_0 cycloalkyl-C^_g alkyl, optionally substituted L5 pheny1-C^_g alkyl or optionally substituted phenyl-C3_g alkenyl; and R is C1-g alkyl, C^g haloalkyl, C2_g alkenyl, C3_1Q cycloalkyl, c3_10 cycloalkyl-C^g alkyl, optionally substituted phenyl, optionally substituted pheny1-C^_g alkyl or optionally substituted phenyl-C2_g alkenyl; associated with a pharmaceutically acceptble carrier therefor. The formulations of the invention conform to the standards of sterility required for pharmaceutical preparations.

Preferred pharmaceutical formulations comprise compounds of formula (I).

Compounds of formulae (I) and (XIII) have been shown to be useful in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases including asthma and in the alleviation of status asthmatlcus. The compounds have low toxicity. - 8 4347« The compounds or formulations of the present invention may be administered by the oral and rectal routes, topically, parenterally, e.g. hy injection and by continuous or discontinuovs intra-arterial infusion, in the form of, for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example, containing from 1 to 107. hy weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injection solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making'injection solutions. Advantageously for this purpose, compositions may be provided in dosage unit form, preferably each dosage t unit containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administration, from 5.0 to 50 mg. in the case of inhalation and from 25 to I 500 mg, in the case of oral or rectal administration) of a compound of formulae (I) or (XXII). Dosages of from 0.5 to 300 mg/kg per day, preferably 0.5 to 20 mg/kg of active Ingredient may he administered although it will, of course, readily be understood that the amount of the compound or compounds of formulae (I) or (XIII) actually to he administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.

In this specification, the expression dosage unit form is used as meaning a physically discrete unit containing an individual quantity ot the active ingredient, generally in admixture with a pharmaceutical diluent I therefor, or otherwise in association with a pharmaceutical carrier, the ί antity of the active ingredient being such that one or more units are cmaily required for a single therapeutic administration or that, in the case severable units such as scored tablets, at least one fraction such as a If or a quarter of a severable unit is required for a single therapeutic ministration.

The formulations of the present invention normally will consist of at ast one compound of formulae (I) or (XIII) mixed with a carrier, or luted by a carrier, or enclosed or encapsulated hy an ingestible carrier the form of a capsule, sachet, cachet, paper or other container or by a sposahle container such as an ampoule. A carrier or diluent may be a solid, mi-solid or liquid material which serves as a venicle, excipient or medium r the active therapeutic substance.

Some examples of the diluents or carriers which aay he employed In the armaceutical compositions of the present Invention are lactose, dextrose, crose, sorhital, mannitol, propylene glycol, liquid paraffin, white Soft raffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium licate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified arches, gum acacia, calcium phosphate, cocoa Sutter, ethoxylated esters, oil theobrona, arachis oil, alginates, tragacanth, gelatin, syrup B.P., methyl llulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and opyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl cohol and propellants such as trichloromonofluoromethane, dichlorodifluorothane and dichlorotetrafluoroethane. In the case of tablets, a lubricant y be Incorporated to prevent sticking and binding of the powdered ingredient^ the dies and on the punch of the tahletting machine. For such purpose ere may be employed for instance aluminium, magnesium or calcium stearates, lc or mineral oil.

Preferred pharmaceutical forms of the present invention are capsules, blets, suppositories, aerosols, injectible solutions, cremes and ointments.

The following Examples will further illustrate the invention.

EXAMPLE 1 Κ-Methyl-N-( 5-me thy1-1,3,4-thiadiazol-2-yl)-benzamide 2-(N-Methyl-amino)-5-methyI-l,3,4-thiadiazole (6g, 0.046 mole) in pyridine (190 ml) was refluxed for 6 hours with benzoyl chloride (9.7g, 0.069 mole) and the pyridine then evaporated off under reduced pressure. The residue was treated with water, made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform was washed with a saturated solution of sodium bicarbonate and a‘ saturated solution of sodium chloride, dried, filtered and evaporated to yield title product which was recrystaliised from ethanol.

EXAMPLE 2 N-2-Propeny1-N-(5-methy1-1,3,4-thladiazol-2-yI)-benzamide.

Using the process of Example 1, the title compound was prepared from 2-[N-(2-propenyl)-amino]-5-methyl-l,3,4-thiadiazole, which had been prepared by cyclisation from 4-(2-propenyl)-thiosemicarbazide.

EXAMPLE 3 N-PhenyImethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-phsnylacetainide.. (a) N-(5-Methyl-1,3,4-thiadiazol-2-yl)-benzylamine. 2-Amino-5-methyl-1,3,4-thiadiazole (23g, 0.2 mole) and benzaldehyde (29.6 ml, 0.3 mole) were refluxed together in ethanol (200 ml) for 1¾ hours. The solution was cooled to room temperature and sodium borohydride (11.35g, 0.3 mole) added over 5 to 10 minutes. The mixture was refluxed for 4 hours, treated with further sodium borohydride (5g) and refluxed overnight.

The ethanol was evaporated off, the residue treated with water and extracted with ether. The ether extract was dried over sodium sulphate, filtered and evaporated to leave an oil which solidified. This solid was triturated with ether, filtered, washed with light petroleum (b.p. 4O-6O°C) and again triturated with ether and filtered to give N-(5-methyl-l,3,4thiadiazol-2-yl)-benzylamine (30.95 g), which on recrystallisation from ether had m.p. 140°C. (b) N-Phenylmethyl-K-(5-Me thyl-1,3,4-thiad iazol-2-yl) -phenyl acetamide, N-(5-Methyl-l,3.,4-thiadiazol-2-yl)-benzylainine (15g, 0.073 mole) in pyridine (200 ral) was refluxed with phenylacetyl chloride for 6 hours.

The pyridine was removed under reduced pressure and the residue treated witi) water and extracted with ether. The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ethanol to give the title compound, m.p. 128°C.

EXAMPLES 4 TO 6 The following compounds were prepared by similar methods to that described in Example 3: H-(j)-Cblorobenzyl)-N-(5-methyl-l,3,4-thiadiazol-2-yl)- benzamide.

K-(o-Chloropheny line thy l)-M-(5-me thyl-1,3,4-thiadiazol-2-yl)-pheny lacetamide.

N- (j)-Me thylbenzyl)-N-(5-pheny1-1,3,4-thiadiazol-2-yl)-cyclopentanecarboxamide.

EXAMPLE 7 M-n-Haxyl-N- (5-methyl-l, 3, 4-thiadiazol-2-yl) -phenylacetamide. (a) N-(5-Me thyl-1,3,4- thiadiazol-2-yl)-hexana'inide. 2-Amino-5-methyl-l,3,4-thiadiazole (23g, 0.2 mole) in toluene (100 ml) was treated with .n-hexanoic anhydride (50 ml) and the mixture was refluxed for 3 hours. The product crystallised on standing at room temperature overnight. The product was filtered off and recrystallised from ethyl acetate to give N-(5-methyl-l,3,4-thiadiazol-2-yl)-hexanamide, m.p. 203°C (2O.68g). (b) N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexylamine. N-(5-Methyl~l,3,4-thiadiazol-2-yl)-hexanamide (16g, 0.075 mole) was added portionwise to stirred tetrahydrofuran (THF) (120 ml) containing lithium aluminium hydride (2.9g, 0.076 mole) at a temperature below 15°C.

The mixture was stirred and refluxed for 2 hours. The mixture was cooled in ice and treated with water (2.9 ml) in THF (29 ml) followed by a 2N solution of sodium hydroxide (2.9 ml) and water (5.8 ml). The mixture was then treated with Supercel (Registered Trade Mark) and filtered. The filtrate was evaporated to give the title product vihich was recrystallised frcm 50% from the aqueous methanol (9.59) m.p. 101-105°C. (c) N-n-Hexyl-N-(5-3fethyl-l·» 3,4-thladiazol-2-yl)-phenylacetamlde N-(5-Mcthyl-l,3,4-thiadiazol-2-yl)-hexylamine (5.98g, 0.03 mole) in toluene (60 ml) was stirred together with triethyiamine (4.59 ml) and phenylacetyl chloride (4.64g, 0.03 mole) and refluxed overnight. Further triethyiamine (4.6 ml) and phenylacetyl chloride (4 ml) were added and refluxing was continued for a further 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform.

The chloroform extract was washed with 2N sodium hydroxide solution and with water, and was dried (Na2S04), filtered and evaporated to yield the title product as an oil, b.p. 190°C/0.1 mm (8.03g), This was recrystallised from ethanol to give the title compound as a solid, m.p. 90°C.

EXAMPLE 8 N-(5-methyl-l,3,4-thladiazol-2-yl·)-2-me thylpropanamide. 2-Amino-5-methyl-l,3,4-thiadiazole (15 g, 0.13 mole) was treated with isobutyric anhydride (70 ml). The reaction mixture was stirred and heated to reflux in an oil bath at 18O-2OO°C for 1¾ hours. The excess anhydride was distilled off under reduced pressure and the solid residue was recrystallised from ethyl acetate to give N-(5-methyl-l,3,4-thiadiazole-2-yl)· 2-methylpropanamide as golden needles.

EXAMPLES 9 AND 10 The following compounds were similarly prepared: N-(5-Methyl-l,3,4-thiadiazol-2-yl)butanamide. (m.p. 231-233°C).

Cream crystalline solid.

N-(5-methyl-1,3,4-thiadiazol-2-yl)heptanamide.

Cream crystalline solid. 3 4 7 4 EXAMPLE 11 N-(5-methyl-l,3,4-thiadiazolyl-2-yl) butylamine.

N-(5-methyl-l,3,4-thiadiazol-2-yl)butanamide (1.85g, 0.01 mole) was added in small portions to a stirred suspension of LiAlH^ (O.38g, Q.01 mole) in dry THF (25 ml) at 0-5°C. under a nitrogen atmosphere. The reaction mixture was stirred and heated to reflux for 2 hours. The cooled solution was then treated dropwise with a solution of water (0.38 mol) in THF (3.8 ml) followed by 2N sodium hydroxide solution (0.38 ml) followed by water (0.76 ml) and stirred for % hour. The mixture was filtered through a pad of supercel and the solution evaporated under reduced pressure to give a solid which was recrystallised from aqueous ethanol to give N-(5-methyl-l,3,4-thiadiazol-2-yl) butylamine as a pale yellow crystalline solid, m.p. 100-102°C.

N-n-Butyl-N-(5-methy1-1,3,4-thiadiazol-2-yl)-2-methylpropanamide W-(5-methy1-1,3,4-thiadiazol-2-yl)butylamine (3 g, 0.0175 mole) and isobutyric anhydride (15 ml were heated together on the steam bath for 1¾ hours. The excess isobutyric anhydride was removed under reduced pressure and the residue distilled at 0.3 mm to give an oil (3.6 g, 55%) b.p. 132°C which gave the title compound as a white solid (m.p. 54 57°C) on cooling. _ 14 EXAMPLES 12 AND 13 N-n-Hexyl-N- (5-methyl-l, 3,4-thiadiazol-2-yl) -2-methylprcpanamlde This W3S a colourless oil b.p. 152-154°C. at 0.5 mn. I.jIOS NMR, IR and UV supported the structure.

Analysis: C13H23N3OS Requires: C 57.99; H 8.55; N 15.617.

Pound: C 57.81; H 8.67; N 15.767.

N-nrifeptyl-M-(5-methyl-l,3,4-thiadiazol-2-yl)-2-methylprppanamide EXAMPLE 14 M-n-Butyl-N-(5-methyl-l,3,4-thiadiazol-2-yl) cyclqprcpane carboxamide N-(5-methyl-l,3,4-thiadiazol-2-yl)butylamine (1.7 g, 0.01 mole) in benzene (20 ml) was treated with triethylamine (1.53 ml) and cyclopropane carboxylic acid chloride (1.15 g). The reaction mixture was heated to reflux for 20 hours. The solution was then evaporated to dryness and the residue treated with ether and filtered. The solution was washed with water, dried and charcoaled, filtered and evaporated end the residue recrystallised from petrol ether (40-60°C.) to give N-n-bufcyl-M-(5-methyll, 3,4-thiadiazol-2-yl)cyclopropane carboxamide as a white crystalline solid, m. p. 82-84°C.

EXAMPLE 15 The following compound was similarly prepared.

N-n-Butyl-N- (5-nethyl-l, 3,4-thi adiazol-2-yi|qyclcpentane-catbcoeaflii(3e.

This was a colourless oil b.p. 162-164°C. at 0.4 mm. NMR, XR and UV supported the structure.

Analysis: Cj^H^jNjOS Requires: C 58.4; H 7.9; N 15.77, Pound: C 58.5; H 7.6; N 15.97.

EXAMPLE 16 N-(5-inethyl-l,3,4-thiadi.a?.oi.-2-yI-)~l-n,ethylethylainin.e 2-Amino-5-methyl-l,3,4-thiadiazolc (23 g, 0.2 mole) in IPA (700 ml) and acetone (100 ml) was treated with sodium borohydride (20 g) in portions with stirring and cooling. The reaction mixture was then stirred and heated to reflux for 3¾ hours. The solution was then poured into water (3 L) and extracted with ether (x 3). The ethereal solution was dried, filtered and evaporated to give the title compound as a cream solid, m.p. 14S°G.

EXAMPLE 17 Ν-Ο-πιαίΙιγΙ-Ι,Β,Α-ίΙιϊΒάϊΒζοΙ-Ζ-γΌογοΙοΙίΒχγΐΗπιΙηΒ, White crystalline solid (from ethyl acetate) m.p. 192-194°C. This was prepared by the route described in Example IS.

EXAMPLE 18 H-(l-methylethyl)-N-(5-metbyl-l,3,4-thiadiazol-2-yl)benzamlde N-(5-methyl-l,3,4-thiadiazol-2-yl)-l-methylethylamine (5 g, 0.032 mole) in pyridine (100 ml) was treated with benzoyl chloride (4.1 ml). The reaction mixture was stirred and heated to reflux for 5¾ hours. The pyridine was removed under reduced pressure and the residue treated with water and extracted with ether (x 3). The ethereal solution was dried, filtered and evaporated to dryness and the residue recrystallised from ether/petrol ether (40-60°C.). to give the title compound as a pale yellow crystalline solid m.p. 82.5-83.5°C. 4347/( The following compounds were similarly prepared.

EXAMPLES 19 AND 20 H-(l-Mcthylethyl)-N-(5-methyl-l ,3,4-thiadiazo].-2-yl)phen.yl acetamide.

This was a buff crystalline solid. m.p. 83-85°C.

N-Cyclohexyl-N-(5-methyl-l,3,4--thiadiazol-2-yl)cyclopropane carboxamide.

This was a yellow crystalline solid m.p. 76.5-78.5°C.

EXAMPLE 21 (a) 5-Chloro-3-methvl-1,2,4-thiadiazole A suspension of acetamidine hydrochloride (47.0 g, 0.50 mol) and trichlorcmethanesulfenyl chloride (83.0 g, 0.45 mol) in 500 ml dichloromethane was placed in a three-necked flask fitted with a stirrer, dropping funnel and thermometer. Cooling in an acetone bath and stirring, a solution of sodium hydroxide (100 g, 2.50 mol) in 150 ml water was added slowly, keeping the temperature below -8°C. by means of a cold plate. After about half of the solution had been added, upon further addition the colour changed from red through orange to yellow. After final addition (about five hours) the precipitated NaCl was filtered off and washed with Cf^C^. The organic phase was separated from water, the latter being shaken 3 times with CH^Clj (30 ml). The combined CH^Cl^ solutions were washed with water until it became neutral and then dried over magnesium sulphate. The solvent was evaporated off to yield a red liquid. The liquid was distilled tinder vacuum to give 5-chloro3-methyi-l,2,4-thiadiazole as a colourless liquid. Yield 27 g(45%), b.p. 25°C/3.5 mm Hg. 4S474 (b) 5-Butylamino~3-methyl-l,2,4-thiadiasole -Chloro-3-methyl-l,2,4-thiadiazole (27 g, 0.20 mol) was dissolved in 200 ml ethanol and, under cooling in an ice bath, added to an ethanolic solution of butylamine (44 g, 0.60 mol), stirred at room temperature overnight and evaporated to small hulk. Upon addition of ether a white precipitate of butylamine hydrochloride formed which was filtered off. The yellow filtrate was washed with water, dried over magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which was distilled under vacuum to give 5-butylamino-3-methyl-l,2,4-thiadiazole as a pale yellow liquid. Yield 29.9 g, (87.2%), b.p. 101-102°C/0.14 mmHg. ' (c) N-CS-Methyl-l^^-thladiazol-S-vlj-N-methylcyclohexane carboxamide Cyclohexane carboxylic acid chloride (9,92 g, 0,068 mol) was added slowly to a solution of 5-methylamino-3-methyl-l,2,4-thiadiazole (7.0 g, 0.054 mol) in dry benzene containing triethylamine (6.87 g, 0.068 mol) and the mixture heated under reflux for 1¾ hours, cooled and washed with 2N hydrochloric acid, saturated solution sodium hydrogen carbonate and water; dried over magnesium sulphate, filtered and evaporated down to yield yellow oil which crystallised upon standing. This was recrystallised twice from petroleum ether 6O-8O°C. to yield off-white crystals of N- (3-methyl-l,2,4-thiadiazol5-yl)-N-methylcyclohexane carboxamide. Yield 8.23 g, (63,8%), m.p. 96°C.

EXAMPLES 22 TO 31 The following compounds were prepared by similar methods to that described in Example 21» M-(3-Methyl-l,2,4-thiadiazol-5-yl)-M-a-butyl-2-methylpropanaiiiide (b.p. 115-117°C /0.1 mmHg).

Analysis; C11H19N3OS Requires; C 54.74; H 7.93; N 17.41; 0 6.63; S 13.28% Found; C 54.64; H 7.97; N 17.37; 0 6.48; S 13.36% IS N-(3-Meihyl-l,2,4-thiadiazol-5-yl)-IHl-butylcyclopropane carboxamide, (m.p. 43°C).

N-(3-Mcthyl-l,2,4-thjadiazol-5-yl)-N-a-butylbenzaniide. (m.p. 77°C).

N“(3-Cyclobutyl-1,2,4-thiadiazol-5-yl)-N-a-octylcyclooctane carboxamide.

' N-(3-Methyl-1,2,4-thiadiazol-5-yl)-N-methyIpheny1 acetamide (m.p. 86°C).

N-(3-Methyl-l,2,4-thiadiazol-5-yl)-N-2-propenyl acetamide (m.p. 61°C).

N-(3-Methy1-1,2,4-thiadiazol-5-yl)-N-methyl-2-methyl pEopaaamlde. (m.p. 54°C) N-(3-Metliyl-l,2,4-thiadlazol-5-yl)-N-fl-butyl-n-hexanamide (b.p. 13O-135°C/ 0,15 mmHg> purified by column chromatography).

Analysis: C14H25N3OS Requires: C 59.33; H 8.89; N 14.83; 0 5,65; S 11.317. found: C 59.39; H 8.82; N 15.19; 0 5.877.

N-(3-Methyl-l,2,4-thladiazol-5-yl)-N-2-propenyIpheny! acetamide (m p, 70°C).

N-(3-Methyl-1,2,4-thiadiazol.-5-yl)-N-2-propenylcyclopropane carboxamide. (m.p. 76°C).

EXAMPLE 32 3-Phenyl-5-trichlorome tliyl-1,2,4-oxadiazole Trichloroacetic anhydride (154.5 g, 0,5 mole) was added to a stirred solution of henzamidoximc (34.0 g, 0.25 mole) in dry trichloroacetic acid (160 g,) in an oil bath at e>60°C, The reaction mixture was heated at 120°C. for 20 minutes and on cooling was poured into ice/water (400 ml.).

The organic layer was separated, washed with water and taken up in carbon tetrachloride (500 ml) and neutralised hy washing with a saturated solution of NaHCOj. After drying over MgSO^ and evaporating off the carbon tetrachloride, the product was distilled, (b.p. 118°C/0.07 mmHg).

EXAMPLE 33 3-Methyl-5-trichloromethyl-l,2,4-oxadiazole was similarly prepared.

EXAMPLE 34 -a-ButylaminD-3-:rogthyl-l, 2,4-cxadlazole. 3-Methyl-5-trichloromethyl-1,2,4-oxadiazole (43 g,’ 0.21 mole)was added to n-butylamine (46.75 g, 0.63 mole) and stirred at room temperature overnight. Excess amine was removed under vacuum and the residue distilled (oil bath I10°C/0.5 mm Hg). Recrystallisation from petroleum ether 60-80°C gave the title compound as white plates 26 g, m.p. 62-65°C.

EXAMPLE 35 N-n-Buty1-N-(3-methy1-1,2,4-oxadiazol-5-yl)n-butanamide.

-Butylamino-3-methyl-l,2,4-oxadiazole (4.2g, 0.03 mole) and butyric anhydride (4.75g, 0.033 mole) were refluxed in toluene (30 ml) for 3 hours. After removing the toluene under vacuum, the residue was refluxed in methanol (60 ml) with a few drops of triethyiamine for 1 hour. The methanol was evaporated under vacuum and residue taken up in Cl^Cl^, washed twice with - 20 43474 2N HCl and twice with a saturated solution of NaHCO^ and dried over MgSO^. The product was purified by column chromatography (silica gel 120 g) eluted with petroleum ether 40-60°C, increasing solvent polarity to 10% ether/ petroleum ether. Fractions were combined and distilled in a Kugelrohr airbath at 119°C/3.3 mmHg.

Analysis: Requires: C 58.64; H 8.50; N 18.65; 0 14.207.

Found: C 58.78; H 8.30; N 18.40; 0 14.187.

EXAMPLES 36 to 42 • The following oxadiazoles were prepared using the method described in Example 35.

N-Ethyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-2-methylpropanamide (b.p. 92°C/3.0 mmHg).

Analysis: C9H15N3°2 Re9uires: £ 54.80; H 7.66; N 21.30; 0 16.227.

Found: C 54.68; H 7.46; N 21.14; 0 16.337.

N-n-Butyl-N-(3-niethyl-l,2,4-oxadiazol-5-yl)acetamide 1.4748, of liquid.

N-n-Butyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-2-methy lpropanamide (b.p. (airbath temperature) 98°C/1.5 mm.Hg).

Analysis: C11H19N3°2 Reuires’ £ 58.65; H 8.50; N 18.66; 0 14.207.

Found: C 58.49; H 8.22; N 18.40; 0 14.187.

N-n-Butyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)hexanamide Analysis: C13H23N3°2 Requires: C 61.63; H 9.15; N 16,58; 0 12.637.

Found: C 61.89; H 9.39; N 16.33} 0 12.657.

N-Ethyl-N-(3-Phenyl-l,2,4-oxadiazol-5-yl)-2-methylpropanamide (m.p. 48°C).

N-n-Butyl-N- (3-phenyl-l, 2,4-oxadiazol-5-yl) -2-sethylpropanamide (b.p· 140°C/7 mmHg airbath temperature).

Analysis: Ο^θΗ^^Ν^Ο^Requires: £ 66,88; £ 7.37} N 14.62; 0 11,147.

Founds £ 67.07; H 7.38; N 14.38; 0 11.067. ' N-Ethyl-N-(3-phenyl~1.2,4-oxadiazol-5-yl)-n-butanamide (m.p. 74°C.).

EXAMPLE 43 N-n-Hexyl-N-(3-methyl-lj 2,4-oxadiazol-5-yl)acetamide. -n-Hexylainino-3-methyl-l,2,4-oxadiazole (4.6 g, 0.025 mole) was dissolved in acetic anhydride (25 ml) and refluxed for 3 hours and then evaporated down to dryness under vacuum. The residue was taken up in CHCl^ (50 ml) and washed twice with 2N HCl and twice with a saturated solution of MaHCOj and dried over MgSO^. (b.p. 113-ll4°C/1.0 mmHg.).

Analysis! C11H19N3®2 ^e9u^ress £ 58.64; H 8.50; N 18.65; 0 14.207.

Founds C 58.66; H 8.76; N 18.57; 0 14.487.

EXAMPLE 44 The following oxadiazole was similarly prepared using the process of Example 43.

N-(3-Methyl-l.2,4-oxadiazol-5-yl)-N-2-propenylacetaniide (h.p. 82°C/1.5 mm.Hg airbath temperature).

Analysis: CgHjjN^ Requires: £ 53.02; H 6.12; N 23.19; 0 17.667.

Found: £ 52.78; H 5.90; N 23.03 ; 0 17.697.

EXAMPLE 45 N-(3-Methyl-l,2,4-oxadiazol-5-yl)-H-(4-methylphenyl)methyl cyclopropane carboxamide Cyclopropane carboxylic acid chloride (3.45 g, 0.033 mole) was added dropwise to a solution of 5“(4-methylphenyl)methylamino-3-methyl-l,2,4-oxadiazPl.e (ύ.Ι g, 0.03 mete) and triethylamine (1.45 g, 0,033 mole) in dry henyeue keeping the temperature below 10°C. After Lhe addition the temperately v.-as allowed to reach room temperature and then refluxed overnight. On cooling the reaction mixture was washed twice with 2N HCl and twice with a saturated solution of NaHCO3 and dried over MgSO^ and charcoaled. The product was purified by column chromatography silica gel (110 g) eluting with petroleum ether 40-60°C. increasing polarity to 10% ether in petroleum ether. The title compound was recrystallised from petroleum ether 6O-8O°C. as white needles, m.p. 49.5-50.5°C.

EXAMPLES 46 - 57 The following further oxadiazoles were prepared using the process of Example 45.

N-Methyl-N-(3-methyl-l,2,4-oxadiazol“5-yl)benzamide (m.p. 74°C.).

N-n-Butyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)cyclopropane carboxamide (Tip6 1.4882).

N-n-Hexyl-N- (3-methyl-l, 2,4-axadiazol-5-yl) cyclopentane carboxamide (b.p. 121°C/1.4 mmHg(airbath temperature), Analysis: C15H25N3°2 Pe9ulres! £ 64.48; H 9.02; N 15.04; 0 11.52% Found: C 64.76; H 8.86; N 14.82; 011.52% N-n-Hexyl-N-(3^nethyl-l,2,4-oxadiazol-5.-yl)cyclohexane carboxamide (b.p. 157°C/1.5 mmHg airbath temperature).

Analysis: C16H27N3°2 Requires: C 65.49; H 9.27; N 14.32; 0 10.9% Found: C 65.58; H 9,05; N 14.19; 0 10.95% N-n-Hexyl-N- (3-methy 1-1,2,4-oxadiazol-5-yl) benzamide (b.p. 126°C/0.2 mmHg airbath temperature).

Analysis: C16H21N3°2 Requires: C 66.87; H 7.36; N 14.62; 0 11.13% Found: C 66.85; H 7.35; N 14,58; 0 11.27% 3474 N-CS-Methyl-l^.A-oxadiazol-S-yD-N-Z-propenylcyclopropane carboxamide (b.p. 120°C/10 mmHg airbath temperature).

N-(3-Me thy 1-1,2,4-oxadiazol-5-yl )-N-pheny line thylcyclohexane carhoxamide (m.p. 73°C).

H- ( 3-Methy 1-1,2,4-oxadiazol-5-yl )-N-phenylinethylbenzamide ,(m.p. 75°C).

N-(3-Methyl-l,2,4-oxadiazol-5-yl)-N-phenylmethyl-2-methylpropanamide (b.p.’ 127°C/3.OO mmHg).

N- (4-Me thoxyphenyl)me thyl-N-(3-methyl-1,2,4-oxadiazol-5-yl·)cyclohexane carboxamide. (m.p. 70°C).

N-(4-Methoxyphenyl)methyl-N- (3-me thy 1-1,2,4-oxadiazol-5-yl )-2-me thylprcpansnri.de (b.p. 118°C at 0.2 mmHg airbath temperature). Ν-(4-ΜΒί1ιν1ρ1κ3ην1)πΐ6ί1ΐ7ΐ-Ν-(3-πΐ6ίΙιγ1-1.2,4-οχ3άΐ3ζο1-5-γΙ)Ενο1ορΓθρ8ηΒ carboxamide (m.p. 50°C), EXAMPLE 58 N-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-isopropy1-2-methylprcpanamide iSoButyric anhydride (7.9 g, 0.05 mole) was added to isopropylamino-3methyl-l,2,4-oxadiazole and heated at 100°C.overnight. On cooling, methanol (60 ml) and a few drops of triethylamine were added and refluxed for 1 hour. After removal of the methanol under vacuum, the residue was taken up in ether and washed twice with a saturated solution of NaHCOy (b.p. 90°C/1.3 mmHg. Kugelrohr airbath temperature).

EXAMPLE 59 N-(5-Methyl-1,3,4-oxadiazol-2-yl)-N-n-propyl cyclobutane carboxamide -------------------- ι----------—.....................-...... (a) I-Acetyi-4-allyl-.

Allyl isocyanate (25 g, 0.30 mol) was added slowly to a boiling solution 5 of acethydrazide (22.2 g, 0.30 mol) in dry benzene (300 ml). The. mixture was heated for 1 hour whereupon 2 layers formed. The benzene was then evaporated off and the residue triturated with ether to yield the title compound as a white solid, (m.p. 71-74°C). (b) 5-Methyl-2-n-propylamino-1,3,4-oxadiazole l-Acetyl-4-n-propyl semicarbazide (35 g, 0.22 mol) prepared by method (a) above, was refluxed with POC13 (150 ml) for 2 hours, until no more HCl was evolved. Excess POC13 was taken off by a water pump and the mixture poured into 200 ml. iced water and neutralized with 50% NaOH to pH 7. Red oil was extracted with dichloromethane (2 x 180 ml), dried, filtered and evaporated down to yield an oil which was distilled in a vigreux flask to yield the title compound as a pink liquid which crystallised upon standing to a solid, (m.p. 46.5-47.5°C.). (c) N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-n-propyl cyclobutane carboxamide 5-Methyl-2-n-propylamino 1,3,4-oxadiazole (6 g, 0.04 mol) prepared as in (b) above, was refluxed with cyclobutanecarboxylic acid chloride (5.5 g, 0,05 mol) in benzene (25 ml) in the presence of triethylamine (4.72 g, 0.05 ) mol) for 2 hours. The mixture was filtered and the filtrate washed with dilute HCl, saturated solution of NaHC03 and water; dried over magnesium sulphate, filtered, solvent evaporated off to yield a reddish brown liquid which was distilled twice in a vigreux flask to yield the title compound as a slightly pink liquid (b.p. 11O-111°C/O,27 mm Hg).

EXAMPLES 60 to 67 Using the procedure described in Example 59 the following further oxadiazoles were prepared; - 25 N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-n-propyl 2-methylpropanamide (b.p.85-87°C/ 0.4 mm Hg).

N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-n-propyl cyclohexane carboxamide (b.p. 120-121°C/0,2 mm Hg).

N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-n-propyl cyclopentane carboxamide (b.p, 110-112°C/0.01 mm Hg).

N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-2-propenyl-2~methylpropanamide (b.p. 93°C/0.18 mm Hg).

N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-2-propenylcyclcpentana carbcotand.de (b.p. 114-116°C/0.12 mm Hg).

N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-tt-hexyl-n-hexatiamide (b.p. 116°C/O.l mm Hg). · ' N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-n-butyl-2-methylpropanamide (b.p. 82-84°C/O.l mm Hg).

N-(5-Methyl-l,3,4-oxadiazol-2-yl)-N-n-butylacetamide (b.p. 82-84°C/O.l mm Hg).

EXAMPLE 63 The following 1,2,4-oxadiazole was prepared using a similar method to that described in Example 35. ' N-n-Hexyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-2-methyl propanamide (b.p. 90°C/l.l mmHg).

Analysis! C13H23N3°2 ^e4uiress £61.63; H 9.15; N 16.58; 0 12.637.

Founds C 61.47; H 8.98; N 16.84; 0 12.707. 2643474 EXAMPLES 69 tai 71 Similarly, using the process generally described in Example 45 , the following further oxadiazoles were prepared; N-methyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-cyclohexane carboxamide Analysis! C11H17N3°2 Re<iuirefS £ 59.17; H 7.67; N 18.82; 0 14.33% Found: C 59.05; H 7.59; N 18.41; 0 14.737.

N-(3-methyl-l,2,4-oxadiazol-5-yl)-N-2 propenyl heptanamide 10 (b.p. 104°C/1.5 mm Hg).

Analysis: C13H21N3°2 Re8uires: £ β2.12; H 8.42; N 16.71; 0 12.737.

Found: C 62.16; H 8.20; N 16.54; 0 12.637.

N-(3-methyl-1.2,4-oxadiazol-5-yl)-N-a-tiutyl2-ethyl butanamide (b.p. 71°C/0.055 mm Hg).

Analysis: C13H23N3°2 Re9uiress £ 61.63; H 9.15; N 16.59; 0 12.637.

Found: C 61.46; H 8.90; N 16.57; 0 12.477.

EXAMPLE 72 2o N-(3-methyl-l,2,4-thiadiazol-5-yl)N-phenylmethyl-n-hexanamide (m.p. 72°C) was prepared using the procedure outlined in Example 21. 347 4 ΕΧΑΜΓΙ !‘S 73 TQ 75 The following further 1,?t4~:hi.tdl.trol··» were ptnpaietl hy «ΙΐιιΐΜ» «ιμΙΙιοΙ* to that used in Example 21.

M-(3-Methyl-l, 2,4-thiadiazol-5-yl)-H-n-hsxyl acetamide (m.p. 38°C.).

I'i-(3-Hethyl-l,2>4-thiadia7.o1.-ii-yl)-yi-n~hexyl phenyl acetamide (m.p. 57°C.).

N-(3-Methyl-l,2,4-thiadiazol-5-yl)-H-tl-bengyl ghenylacetamide (m.p. 134°C.).

EXAMPLES 76 TO 84 The following further 1,2,4-oxadiazoles were prepared by similar methods to that used in Example 47: bt-n-Butyl-N- (3-itBthyl-l, 2,4-axadiazol-5-yl) -phenyl carboxamide.

Analysis: 8ΐ4Ηΐ2Ν3θ2 ^a<lu^res! £ 64,84; H 6.61; N 16.21; 0 12.34 Found: C 65.09; H 6.35; N·15.99; 0 12.07 - ae K-n-Butyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-4-chlorabenzamide.

Analysis: C^H 6C1N 02 Requires: C 57.24; H 5.49; Cl 12.07; N 14.30 ι ‘0 10.89 Found: C 57.45; H 5.63; Cl 12.07; N 14.14 011.17 N-n-Butyl-N- (3-methyl-l, 2,4-oxadiazol-5-yl) -4-roethoxybenzamide. (b.p. 105°C/0.015 mm Hg) Analysis: C15H19N3°3 S.eHuireS! £ 62.27; H 6.62; N 14.52; 0 16.59 Found: C 61.99; H 6.47; N 14.42; 0 16.74 N-n-Butyl-N- (3-methy 1-1,2,4-oxadiazol-5-yl) -cyclohexane carboxamide. (b.p. 70°C/0.01 mm Hg) Analysis: ^14^23^3^2 Requires: C 63.37; H 8.74; N 15.84 Found: C 63.54; H 8.55; N 15.60 N-n-Butyl-N-(3-methy1-1,2,4-cxadiazol-5-yl)-cvclobutane carboxamide. (b.p. 67°C/0.02 inn Hg) Analysis: ^12ΐ9^3θ2 ®e<lu^res: £ 60.74; jl 8.07; N 17.71; 0 13.49 Found: C 60.44; jj 7.88; N 17.54; 0 13.21 N-(3-Mcthyl-l,2,4-oxadiazol-5-yl)-H-propyl 2-methyl propanamide, (b.p. 62°C/0.15 mm Hg) Analysis: Ε1ΟΗ17Ν3θ2 Requires: C 56.85; jj 8.11; N 19.89 Found: C 56.93; jj 8.14; H 19.64 N-n-Butyl-N-(3-n-butyl-1,2,4-oxadlazol-5-yl)-cyclopropane carboxamide.

Analysis: C14H23N3°2 Se9uires; £ 63·37) £ 8.74; jj 15,84; 0 12.06 Found: C 63.19; jj 8.51; jj 15.58; 0 11.82 N-n-Butyl-N-(3-ethyl-l,2,4-axadiazol-5-yl)-cyclopropane carboxamide. (b.p. 65°C/0.01 mm Hg) Analysis: C12H19N3°’ fce9uiTesi £ 6Ο·74; jj 8.07; N 17.71; 0 13.49 Found: C 60.50; £ 7.78; N 17.43; 0 13.19 N-n-Butyl-N- (3-cyclohexyl-l, 2,4-oxadiaz<51-5-yl) -cyclcprooane carboxamide.

Analysis: C16H25N3°2 Requires: C 65.95; jj 8.65; N 14.42; 0 10.98 Found: C 66.15; H 8.83; N 14.51; 0 10.86 EXAMPLES S5 TO 87 Similarly, by methods similar to that used in Example 58, the following further oxadiazoles were prepared: (b.p. 65°C/0.02 ιικ Hg) Analysis: C12H21M3°2 60.22; H 8.85; N 17.56; 0 13.37 Found: C 59.96; H 8.68; N 17.36; 0 13.22 N-n-rButyl-N- (3-n-bufcyl-l, 2,4-oxadiazol-5-yl) 2-methyl propanamide. (b.p. 64°C/0.05 mm Hg) Analysis: C14H25N3°2 ®e8uiresi £ 62.89; H 9.42; N 15.72; 0 11.97 Found: C 62.65; H 9.20; H 15.46; 0 11.72 N-n-Butyl-H-(3-cyclohexyl-l,2,4-oxadiazol-5-yl)-2-nEthylpropanamide. (b.p. 92°C/0.02 mm Hg) Analysis: ^16^27^3θ2 &eclu^resi £ 65.49; H 9.28; £ 14.32; 0 10.91 Found: C 65.26; H 9.09; N 14.07; 0 11.05 The following Examples 88 to 95 illustrate pharmaceutical formulations containing the active compound N-n-hexyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)cyclopentane carboxamide.

EXAMPLE S8 Soft gelatin capsules were prepared using the following ingredients: Quantity (mg/capsule) Active compound 30 Butylated hydroxyanisole B.P. 0.02 Fractionated Coconut Oil B.P.C. 70 100.02 The above ingredients were mixed and filled into soft gelatin capsules, the main shell components of which were gelatin and glycerine.

EXAMPLE 89 The procedure of Example 88 was repeated except that an identical quantity of propyl jpllate was used in place of the butylated hydroxyanisole as antioxidant.

EXAMPLE 90 Hard gelatin capsules were prepared using the following ingredients: Quantity(fflg/capsule) Active compound 23 Silicon dioxide (fumed) 23 Lactose 48 Butylated hydroxyanisole B.P. 0,02 The butylated hydroxyanisole was dissolved in the active ingredient and the solution so formed adsorbed onto the silicon dioxide (fumed). The lactose was then added and the whole mixed. Finally, the mixture was filled into hard gelatin capsules. EXAMPLE 91 An ointment was made up from the following ingredients: Active compound 1,57. by weight Butylated hydroxyanisole B.P, 0,027, by weight White soft paraffin q.s. 1007.

The hydroxyanisole was dissolved in the melted paraffin and the active compound then added in, and the mixture allowed to cool. - 31 . 4S474 EXAMPLE'92 ' A topical cream containing 1.07. of the compound is prepared as follows: Active compound grams, 1.0 Cetomacrogol 1000 3.0 Cetostearyl alcohol 11.5 Liquid Paraffin 9.0 Butylated hydroxyanisole B.P. 0.02 Distilled water to 100.0 _The compound was mixed with the hydroxyanisole and suspended in the liquid paraffin. The cetostearyl alcohol was added and the mixture heated to 70°C. with stirring. The cetomacrogol 1000 was dissolved in 60 g. of water heated to 70°C. The cetostearyl alcohol and liquid paraffin active compound mixture were then poured into the aqueous cetomacrogol 1000 solution with stirring and the stirring continued until the cream was cold. The cream was then made up to weight with water and passed through a stainless steel colloid mill set at a gap of 15/1000 inch.

EXAMPLE 93 Suppositories containing 25 and 50 mg. of the compound were prepared as follows: Active compound 2.5 g, Henkel base 97.5 g.

The active compound was mixed with the Henkel base which had been previously melted using the minimum amount of heat possible. The mixture was then poured into suppository moulds of a nominal capacity of g. or 2 g. as desired, to produce suppositories each containing 25 mg. or 50 mg. of the active compound. 434 74ΕΧΛΜΡΙ.Ε 94 An aerosol was prepared containing the following itigr, ilienta: Quantity per ml.

Active compound 10.00 Propylene glycol 10.00 Dichloro te trafluoroethane (Propellant 114) 550.00 Dichlorodifluoromethane (Propellant 12) 830.00 The active compound was mixed with the propylene glycol and the mix added to the propellant 114, the mixture cooled to -15 to -20°C. and transferred to a filling device. At the same time a mixture of propellants 114 and 12, previously cooled to -15 to -20°C. was fed into a second filling device. A metered amount of propellant from the second filling device was introduced into a stainless steel container, followed by the required amount of material from the first filling device. The valve units were then fitted and sealed to the container. These valve units were equipped with a metering device so that approximately 0.15 mg. of the active compound is released by a single actuation of the valve.

EXAMPLE 95 Tablets were prepared using the following components: Active compound 10.00 mg. Microcrystalline Cellulose 250.00 mg. Sodium Carboxymethyl Starch 25.00 mg. Magnesium Stearate 3.00 mg. Butylated Hydroxyanisole B.P. 0.002 mg The hydroxyanisole was dissolved in the active compound, the solution adsorbed onto the microcrystalline cellulose. This was mixed with the sodium carboxymethyl starch and then the magnesium stearate was mixed in , Finally, the mixture was compressed to form tablets. - 33.

In the foregoing Examples 88 to 95, the liquid active compound used may, in accordance with the invention, be replaced wholly or in part by other liquid active compounds of formula I or XIII. If the active compound is a solid, appropriate modification will of course have to he made.

Claims (40)

1. CLAIMS:1. A process for preparing a heteroaryl compound of the formula: Ar-N-R 1 I 2 (I) COR wherein Ar represents a 5-maribered heteroaryl nucleus selected fran 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4thiadiazolyl, said heteroaryl nucleus being optionally substituted by formyl, carboxyl, hydroxyl, C^_ 4 hydroxyalkyl, Cj_ 4 alkyl, C 3 _-£ Q cycloalkyl, Cj_ 6 acyloxyalkyl, optionally substituted phenyl or halogen, 1 2 the acylamino group -NR COR being attached to a carbon atom of the heteroaryl ring, and wherein R 1 is alkyl, C 3 _ g alkenyl, C 3 _ g alkynyl, C 2 _ g alkoxyalkyl, C 3 _ g carboxyalkyl, C^_ g haloalkyl, C 3 _^ Q cycloalkyl, C 3 _ 1Q cycloalkyl-C^g alkyl, optionally substituted phenyl2 Cj_ g alkyl or optionally substituted pheny1-Cj_ g alkenyl; and R is C-£_g alkyl, C^_ g haloalkyl, C 2 _galkenyl, C 3 _j Q cycloalkyl, C 3 _^ o cycloalky1-C^_ g alkyl, optionally substituted phenyl, optionally substituted phenyl-Cj_ g alkyl or optionally substituted phenyl-C2_g alkenyl; provided that: 1 2 (a) when Ar is 1,3,4-thiadiazolyl, R is C^_ 3 alkyl and R is alkyl, haloalkyl, C 2 _ 3 alkenyl or C 3 _ g cycloalkyl, said 1,3,4-thiadiazolyl group cannot be unsubstituted or substituted ty Cj_ 3 alkyl or halogen; (b) when Ar is 1,3,4-thiadiazolyl substituted by a C-^_ 4 alkyl 2. 1 group and R is trichlorcmethyl, R cannot be C^_g alkyl or C 3 _galkenyl; (c) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, R 1 cannot be methyl or benzyl when R is methyl; (d) when Ar is 1,2,4-thiadiazolyl substituted ty halogen, and 1 2 R is alkyl, allyl, C g _^ cycloalkyl or phenyl-C^_ g alkyl, R cannot be methyl, ethyl or trichlorcmethyl; (e) when Ar is 1,2,4-thiadiazolyl substituted hy isopropyl and R 1 is - 35 474 C^ 4 alkyl allyl, haloalkyl or alkoxyalkyl, R cannot be Cj_ 4 alkyl, allyl or haloalkyl j and (£) when Ar is 1,3,4-thiadiazolyl substituted by methyl and R 1 is 2 allyl, R cannot be dichlorcniethyl, which process canprises: (a) reacting an amine of formula: ArNHR 1 (VHX) where Ar and R 1 are as defined previously, with a reagent which oonverts 2 the amine hydrogen atom to a R CO group; (b) reacting an amide of formula: AlNHCOR 2 (IX) where Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl or l,3,4-oxacliazolyl and 2 R is as defined previously, with a reagent which converts the amide hydroger atcm to Regroup; (c) reacting a conpound. of formula: ArY (X) where Y is a leaving group and where Ar is as defined previously, with a salt of formula: MNR-'-COR 2 (XI) 1 2 where M is a group IA or IIA metal and R and R are as defined previously.

2. A process according to claim 1, wherein the heteroaryl nucleus Ar is optionally substituted by a group selected from C^_ 4 alkyl, cycloalkyl and phenyl; R 1 is C^g alkyl, C 3 _ g alkenyl, C 3 _ g cycloalkyl or benzyl optionally substituted by halogen, C^_ 4 alkyl or C^_ 4 alkojy and R is C^_ g alkyl, C g _ g cycloalkyl, benzyl or phenyl optionally substituted by halogen or C^_ d alkojy.

3. A process according to Claim 1, wherein the heteroaryl nucleus Ar is substituted by a C^_ 4 alkyl group; R 1 is C^gHlkyl, C g _ g alkenyl or 2 benzyl and R is C 3 _ g alkyl, C 3 _ g cycloalkyl or benzyl.

4. A process according to Claim 1, 2 or 3, wherein the heteroaryl nucleus is a 1,2,4-oxadiazolyl system.

5. , A carpound of formula (I) whenever prepared by a process according to any one of Claims 1 to 4.

6. A heteroaryl compound of the formula: Ar-N-R 1 1 2 COR Z (I) wherein Ar represents a 5-nenbered heteroaryl nucleus selected frcm 1.2.4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4thiadiazolyl, said heteroaryl nucleus being optionally substituted by formyl, carboxyl, hydroxyl, C.j_ 4 hydroxyalkyl, 0 χ _ 4 alkyl, C 3 _ 1Q cyeloalkyl, C 3 _ g acyloxyalkyl, optionally substituted phenyl or halogen, the acylamino group -NR 1 C0R 2 being attached to a carbon atan of the heteroaryl ring, and wherein R 1 is Cj_ 30 alkyl, C 3 _ g alkenyl, C 3 _ g alkynyl, C 2 _g alkojyalkyl, C 2 _ g cafboxyaUyl, Cj_ g haloalkyl, C 3 _ lo cyeloalkyl, C 3 _ 1Q cycloalkyl-C^g alkyl, optionally substituted pheny 1-C^g alkyl or optionally substituted phenyl~C 3 _ g 2 alkenyl; and R is C^_ g alkyl, C^g haloalkyl, C 2 _ g alkenyl, C g _ i0 cyeloalkyl, C 3 _ lo cycloalkyl-C^g alkyl, optionally substituted phenyl, optionally substituted pheny 1-C^_ g allyl or optionally substituted phenyl-C 2 _ g alkenyl; provided that: 1 2 (a) when Ar is 1,3,4-thiadazolyl, R is C^_ 3 alkyl and R is alkyl, C 1 _ g haloalkyl, C 2 _ 3 alkenyl or C 3 _ g cycloalkyl,said 1.3.4- thiadiazolyl group cannot be unsubstituted or substituted by Cj_ 3 alkyl or halogen; (b) when Ar is 1,3,4-thiadiazolyl substituted by a C^__ 4 alkyl group and r 2 is trichloroiethyl, R 1 cannot be C^_ g alkyl or C^_ g alkenyl; (o) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, R 1 2 cannot be methyl or benzyl when R is methyl; - 37 43474 (d) when Ar is 1,2,4-thiadiazolyl substituted by halogen, and 1 2 R is C^_ g alkyl, allyl, C g _ 7 cycloalkyl or phenyl-C^ alkyl, R cannot be methyl, ethyl or trichloramethyl; (e) vixen Ar is 1,2,4-thiadiazolyl substituted by isopropyl and R^ is alkyl, allyl, C^_ g haloalkyl or C 2 _ g alkoxyalkyl, R cannot be C^_ 4 alkyl, allyl or Cj_ g haloalkyl; and (f) when Ar is 1,3,4-thiadiazolyl substituted by methyl and 1 2 R is allyl, R cannot he dichlorcmethyl.

7. A heteroaryl compound of formula (I) as claimed in Claim 6, wherein the heteroaryl nucleus Ar is optionally substituted hy a group selected from Cj_ 4 alkyl, C g _ g cycloalkyl and phenyl; R 1 is C^_ g alkyl, C g _ g alkenyl, C g _ g cycloalkyl or benzyl opstionally substituted by halogen, C^_ 4 alkyl or Cj_ 4 alkoxy and R is Cj_ g alkyl, C g _ g cycloalkyl, benzyl or phenyl opstionally substituted by halogen or alkoxy. “38

8. A hetercaryl compound of formula (I) as claimed in Claim 6, wherein the heteroaryl nucleus Ar is substituted by a C^ alkyl group; R 7 is alkvl, C, . alkenyl or benzyl and R' is C, . alkvl, C, , cvcloalkvl or benzyl. ’ 3-3 · J n-o i-o J

9. A hcteroaryl compound of formula (f) as claimed in claim 6, 7 or 8, 5 wherein the heteroaryl nucleus Ar is a 1,2,4-oxadiazolyl system.

10. N-n-llexy 1-N-(5-methy 1-1,3,4-thiadiazol-2-yl)-2-methylpropanamide.

11. N-n-Butyl-N-(5-methy1-1,3,4-thiadiazol-2-yl)-cyclopentane carboxamide.

12. N-(3-Methyl-l,2,4-thiadiazol-5-yl)-N-methyl pbenylacetamide.

13. N-(3-Methyl-l, 2,4-thiadiazol-5-yl)-N-methyl-2-me thylpropanami.de.

14. N-(3-Metliyl-l,2,4-thiadiazol-5-yl)-N-2-propenylcyclopropane carboxamide.

15. N-n-Buty1-N-(3-methy1-1,2,4-oxadiazol-5-yl)-n-butanamide.

16. N-Ethyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-2-methylpropanamide.

17. N-n-Buty1-N-(3-methy1-1,2,4-oxadiazol-5-y1)-2-methylpropanamide. 15 lg. N-lt-Butyl-N-(3-methyl-l,2,4-oxadiazol-5-yl)-hexanamide.

18. 19. N-Ethy1-N-(3-pheny1-1,2,4-oxadiazol-5-y1)-2-methylpropanamide.

19. 20. N-n-Buty1-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropane carboxamide.

20. 21. N-n-Hexy1-N-(3-methy1-1,2,4-oxadiazol-5-yl)-cyclopentane carboxamide.

21. 22. N-(3-Methyl-l,2,4-oxadiazol-5-yl)-N-2-propenylcyclopropane carboxamide.

22. 23. N-(3-Mcthy]-l, 2,4-oxadiazol-5-yl)-N-phenylmethy 1·· 2-methylpropanamide

23. 24. N-(5-Methyl-1,3,4-oxadiazol-2-yl)-N-2-propenyl· cyclopentane, carboxamide.

24. 25. N-(5-Methyi-l,3,4-oxadiazol-2-yl)-N-n-butyl-2-methylpropanamide.

25. 26. N-n-Butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-benzamide.

26. 27. N-n-Butyl-N-(3-methy1-1,2,4-oxadiazol-5-yl)-cyclohexane carboxamide. 2©. N-(3-Methyl-l,2,4-oxadiazol-5-yl)-N-propyl 2-methylpropanamide.

27. 29. N-*tt-Butyl-N-(3-ethyl-l,2,4-oxadiazol-5-yl)-cyclopropane carboxamide.

28. 30. N-n-Butyl-N-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide,

29. 31. N-n-Butyl-N-(3-cyclohexyl-l,2,4-oxadiazol-5-yl)-2-methylpropanamide.

30. 32. A pharmaceutical formulation comprising a heteroaryl derivative of formula: Ar-N-R 1 1 2 COR (XIII) wherein Ar represents a 5-mentoered heteroaryl nucleus selected from 1,2,4axadiazolyl, 1,3,4-axadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl, said heteroaryl nucleus being optionally substituted by formyl carboxyl, hydroxyl, hydroxyalkyl, C.^ alkyl, eycloalkyl, C g _ 6 acyloxyalkyl, optionally substituted phenyl or halogen, the acylamino group 1 2 -NR COR being attached to a carbon atom of the heteroaryl nucleus, and wherein R 1 is ΰ χ _ 10 alkyl, C^g alkenyl, C 3 _ g alkynyl, C 2 _ g alkoxyalkyl, C 2 _g carboxyalkyl, C^g haloalkyl, C 3 _ 1Q eycloalkyl, C 3 _ 1Q cyclQalkyl-C 3 _g alkyl, optionally substituted phenyl-C^_g alkyl or optionally substituted phenyl-C^g alkenyl; and R is Cj_ g alkyl, Cj_g haloalkyl, C 2 _g alkenyl, C 3 _ 1Q eycloalkyl, cycloalkyl-C-^g alkyl, optionally substituted phenyl, optionally substituted pheny1-C^_g alkyl or optionally substituted phenyl-C 2 _g alkenyl; associated with a pharmaceutically acceptable carrier therefor.

31. 33. A pharmaceutical formulation according to Claim 32 in the form of a tablet, capsule, ointment, cream, suspension, suppository, injection solution, aerosol or anpoule.

32. 34. A pharmaceutical formulation according to claim 32 or 33, wherein the compound of formula (XIII) is a compound as claimed in any one of claims 6 to 31.

33. 35. A method of preparing a pharmaceutical formulation which comprises admixing a heteroaryl conpound of formula (XIII): - 41 • 43474 Ar-N-R 1 1 2 CQIC «tin wherein Ar represents a 5-mgrrbered heteroaryl nucleus selected fran 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and 1,3,4thiadiazolyl, said heteroaryl nucleus being optionally substituted 5 by formyl, carboxyl, hydroxyl, hydroxyalkyl, C.^ alkyl, C 3 _ 1Q cycloalkyl, Cg_ g acyloxyalkyl, optionally substituted phenyl or halogen, 1 2 the acylamino group -NR COR being attached to a carbon atan of the heteroaryl nucleus, and wherein R 1 is alkyl, C 3 _ g alkenyl, C 3 _ g alkynyl, C 2 _ g alkoxyalkyl, C 2 _ g carboxyalkyl, haloalkyl, C 3 _ 1Q 3 cycloalkyl, C 3 _^ Q cycloalkyl-C^_ g alkyl, optionally substituted phenyl2 C^g alkyl or optionally substituted phenyl-C^g alkenyl; and R is C-^g alkyl, C 1-g haloalkyl, C 2 _ g alkenyl, C 3 _ 1Q cycloalkyl, C 3 _ 1Q cycloalkyl-C^g alkyl, optionally substituted phenyl, optionally substituted phenyl-C^_ g alkyl or optionally, substituted phenyl-C 2 _ g alkenyl; i with a pharmaceutically acceptable carrier therefor.

34. 36. A process according to Claim 1 for preparing a compound of formula (I) substantially as hereinbefore described with reference to any one of the foregoing Examples.

35. 37. A canpound of formula (I) as claimed in Claim 7 substantially as hereinbefore described with reference to any one of the foregoing Examples.

36. 38. A cojnpound of formula (I) whenever prepared by the process of Claim 36.

37. 39. A pharmaceutical formulation comprising a compound according to Claim 37 or 38 in admixture with a pharmaceutically acceptable carrier therefor. - 42 43474 w'

38. 40. A method of making a pharmaceutical formulation carprising admixing a compound according to Claim 37 or 38 with a pharmaceutically acceptable carrier.

39. 41. A pharmaceutical formulation including a compound of formula (I) 5 as claimed in Claim 6 substantially as hereinbefore described in anyone of Exanples 88 to 95.

40. 42. A method of making a pharmaceutical formulation including a conpound of formula (I) as claimed in Claim 6 substantially as hereinbefore described in any one of Exanples 88 to 95.