CA1085860A - Acylamino derivatives - Google Patents

Abstract

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

~L~85~

This invention relates to heterocyclic chemical compounds, more particularly to certain novel 5-membered heteroaryl deriva-tives substituted by an acylamino group which are useful for the 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. Fur-thermore, the invention includes within its scope pharmaceutical composi-tions containing pharmacologically actlve compounds and methods of treatment of animals, including humans, comprising administer-ing 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. Chim., 1219, (1967); Belgian Patent No. 736854 and U.K. Patent No.
1,333,495. However, it is to be noted that such prior disclo- ;
sures 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 com-pounds useful in the chemotherapy of immediate hypersensitivity conditions.
Accordingly, the present invention provides a novel hetero-aryl derivative of the formula:

Ar-N- Rl COR (I) wherein Ar represents a 5-membered heteroaryl nucleus selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl and

- 2 - ~

1~135~

1,3,4-thiadiazolyl, said heteroaryl nucleus being optionally substituted by Cl 4 alkyl, C3 10 cycloalkyl, or phenyl, the acylamino group -NRlCOR2 being attached to a carbon atom of the heteroaryl ring, and wherein Rl is Cl 10 alkyl, C2 6 alkenyl, r C3 10 cycloalkyl, or phenyl-Cl 6 alkyl optionally substituted with halo, alkyl or alkoxy; and R2 is Cl 8 alkyl, C3 10 cyclo-alkyl, phenyl optionally substituted with halo or alkyl, or phenyl Cl 6 alkyl, pro~ided that:
(a) when Ar is 1,3,4-thiadiazolyl, Rl is Cl 3 alkyl and R2 is Cl 7 alkyl, or C3 6 cycloalkyl, said 1,3,4-thiadiazolyl group cannot be unsubstituted. or substituted by C1 3 alkyl;
(b) when Ar is 1,3,4-thiadiazolyl substituted by methyl and is p-bromophenyl, R cannot be methyl;
(c) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, cannot be methyl or benzyl when R2 is methyl; and (d) when Ar is 1,2,4-thiadiaæolyl substituted by isopropyl and Rl is Cl 4 alkyl, R2 cannot be Cl 4 alkyl.
The optional substituent on the heteroaryl nucleus is pre-ferably selected from C1 ~ alkyl, C3 8 cycloalkyl and phenyl.
Preferred R1 substituents are Cl 8 alkyl, C3 6 alkenyl, C3 8 cycloalkyl and benzyl optionally substituted by halogen, Cl 4 alkyl or Cl 4 alkoxy. Preferred R2 substituents are Cl 8 alkyl, C3 8 cycloalkyl, benzyl and phenyl optionally substituted by halogen or Cl 4 alkoxy.
The term "Cl 6 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, 1 butyl, t-butyl, n-amyl, s~amyl, n-hexyl, 2-ethylbutyl or 4-methylamyl.
Similarly the term "Cl 4 alkyl" as used herein means a 30 straight or branched chain alkyl group containing from 1 to 4 carbon atoms, namely methyl, ethyl, 1sopropyl, n-propyl, n-butyl, ~51~6~

l butyl, s-butyl, t-butyl. "Cl 4 hydroxyalkyl" and "C3 6 acyl-oxyalkyl" means the aforementioned Cl 4 alkyl groups substituted with an hydroxy group and acyloxy group respectively. "C2 6 alkoxyalkyl" and "Cl 6 haloalkyl" mean the aforementioned Cl 6 alkyl groups substituted with an alkoxy group or one or more halogen atoms, such as methoxyethyl, ethoxyethyl, ethoxybutyl, dibromomethyl, trifluoromethyl, l-chloroethyl, l,l-dichloroethyl, l-iodobutyl or pentafluoroethyl.
The term "C2 6 alkynyl" is used herein to indicate an ali-cyclic hydrocarbon group having from 2 to 6 carbon atoms whichcontain a -C=C group. ~owever, it should be noted that the -C C- group cannot be directly adjacent the nitrogen atom of the acylamino group.
''C3 10 cycloalkyl" means a saturated ring having from 3 to 10 carbon atoms in the ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, or adamantyl. "C3 10 cycloalkyl-Cl 6 alkyl" means the aforementioned saturated rings attached to a Cl 6 alkylene bridge.
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, tri-fluoromethyl, methyl, methoxy, or nitro groups.
The term "C2 6 carboxyalkyl" as used herein means a Cl 5 alkyl group substituted by a carboxylic acid group. Examples of such groups are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.
Those skilled in the art will appreciate that the 5-membered heteroaryl nuclei containing as sole heteroatoms two nitrogen atoms and a further heteroatom selected from oxygen and sulphur ~ _ 4 _ ~5~6~
,~
comprise the 1,2,4- and 1,3,4-oxadiazolyl, and the 1,2,4- and 1,3,4-thiadiazolyl ring systems.
Compounds of the invention with these heteroaryl nuclei may be represented by the structural formulae:

N N
R ~ ~ RlCOR2 (II) O
!

- 4a -~ j ~

~35~;1~3 1 .

~O 1NR1COR2 SIII) I' R~NJ~2~RICOR2 (IV) R15111RICOR2 (V) R~ _ -N
~ ~ S l NRlcoR (~

R ~ N ~ ~ NR COR

wh re R and R are as previously defined and R is hydrogen or the optional substituent on the heteroaryl nucleus.
l P~rt cularly interesting compounds of fornwla (I) to (VII) are those ¦ wherein the heteroaryl group is substituted by ~ Cl 4 alkyl group, espncially ~.cthyl, Rl is Cl 6 alkyl, especially C~ 6 alkyl~ C3 5 alker.yl or ber.zyl arid ~ is 53 6 alkyl, C3 6 cycloalkyL or benzyl-The presellt invention also provides a process for preparing compounds ~35~

of formula (I) as defined above which comprises:
(a) acylating an alkyl derivative of formula:

ArNHR (VIII) where Ar and Rl are as defined previously;
(b) alkylating an acyl derivative of formula:

ArNHCOR (IX) where Ar is 1,2,~-thiadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxa-diazolyl and R2 is as defined previously: or (c) reacting a compound of formula:

ArY (X) where Y is a good leaving group such as trichloromethyl, tri-bromomethyl, bromine or chlorine, and where Ar is as defined previously, with a salt of formula:

~ NRlCOR2 (XI) where M is a group IA or IIA metal and Rl and R are as defined previously.
The acylation of the compound of formula (VIII) may be carried out with an acid halide having the formula ~2CO-X wherein X is chlorine or bromine and R2 is de~ined above in the presence of a proton acceptor, such as pyridine or triethylamine, in an inert solvent, such as benzene. The acylation may also be carried out by heating the alkyl derivative with a suitable acid anhydride, (R2CO)20, 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 example, "The Chemistry of Amides" 1971 by A.J. beckwith; "Survey or 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 ~`

~8~8~

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 RlXl where Xl 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 compound of formula (XI) can be prepared by reacting an amide of formula HN~lCOR2 with butyl lithium under an inert gas atmosphere such as nitrogen in an inert solvent such as tetra-hydrofuran, preferably in the presence of a chelating agent such as tetramethylethylenediamine or diazabicyclooctane. Generation of the salt is preferably acccmplished at low temperatures, for example below -10C.
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 cyclisation of the derivative of formula (XII) can be accomplished under basic conditions in the presence of a non-nucleophilic base. Reaction of the cyclopropylcarbonyl deriva-tive yields the lactam of formula (I) containing 5 atoms in the ring.
; The derivatives of formulae (VIII) and (IX) can be derived from the corresponding amines of formula ArNH2 by standard alkyla-tion or acylation techniques. The ~-haloacylamino derivative of formula (XII) may be obtained by reaction of the amine of formula ArNH2 with an appropriate w-haloacyl halide.
The amines of formula ArNH2 are either known compounds or can be prepared by modification of known synthetic methods.
The intermediates of formula (IX) except when 5~16~

(a) Ar is 1,2,4-thiadiazolyl unsubstituted or substituted by Cl 4 alkyl, C3 10 cycloalkyl or optionally substituted phenyl and R is Cl_4 alkyl or Cl 4 haloalkyl;
(b) Ar is 1,2,4-oxadiazolyl substituted by phenyl and R2 is C1 8 alkyl, are novel and are provided in a further aspect of the invention.
According to one aspect of the present invention there is provided a pharmaceutical formulation comprising a heteroaryl derivative of formula:

Ar-~-Rl coR2 (XIII) wherein Ar represents a 5-membered heteroaryl nucleus containing as the sole heteroatoms 2 nitrogen atoms and a further heteroatom : selected from oxygen or sulphur, said heteroaryl nucleus being ;
optionally substituted by formyl, carboxyl, hydroxyl, Cl 4 hydroxyalkyl, Cl 4 haloalkyl, Cl 4 alkyl, C3 10 cycloalkyl, C3 6 acyloxyalkyl, optionally substituted phenyl or halogen, the acyl-amino group -NRlCOR2 being attached to a carbon atoms of the -heteroaryl nucleus, and wherein Rl is Cl 10 alkyl, C2 6 alkenyl, C3 6 alkynyl, C2 6 alkoxyalkyl, C2 6 carboxyalkyl, Cl 6 haloalkyl, C3_10 cycloalkyl, C3_10 cycloalkyl-Cl_6 alkyl, optionally sub-stituted phenyl-Cl 6 alkyl or optionally substituted phenyl-C2 6 alkenyl; and R2 is Cl 8 alkyl, Cl 6 haloalkyl, C2 6 alkenyl, C3 10 cycloalkyl, C3 10 cycloalkyl-Cl 6 alkyl, optionally substituted phenyl, optionally substituted phenyl-Cl 6 alkyl or optionally substituted phenyl-C2 6 alkenyl; or R1 and R2 together form a lactam ring having 5 to 7 ring atoms; associated with a pharma-ceutically acceptable carrier therefor.
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 asthmaticus. The compounds have low toxicity.
The eompounds or formulations of the present invention may be administered by the oral and rectal routes, topically, paren-terally, e.gO by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspen-sions, aerosols, ointments, for example, containing from 1 to 10by 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 paekaged powders adsorbed onto a support material for making injection solutions. Advantageously for this purpose, composi-tions may be provided in dosage unit form, preferably each dosage 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 500 mg. in the case of oral or reetal administration) of a compound of formulae (I) or (XIII). Dosages of from 0.5 to 300 mg/kg per day, preferably 0.5 to 20 mg/kg of active ingredient may be administered although it will, of eourse, readily be understood that the amount of the compound or compounds of formulae (I) or (XIII) actually to be administered will be determined by a physician, in the light of all the relevant eir-eumstanees ineluding the condition to be treated, the ehoiee of compound to be administered and the choice of route of administra-tion and therefore the above preferred dosage range is not intend-ed 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 individ-ual quantity of the active ingredient, generally in admixture g _ ~8S~

with a pharmaceutlcal diluent therefor, or otherwise in associa-tion with a pharmaceutical carrier, the quantity of the active ingredient being such that one or more units are noramlly re-quired for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction such a~ a half or a quarter of a severable unit is required for a single therapeutic administration.
The formulations of the present invention normally will consist of at least one compound of formulae (I) or (XIII) mixed with a carrier, or diluted by a carrier, or enclosed or encapsu-lated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active therapeutic substance.
Some examples of the diluents or carriers which may be employed in the pharmaceutical compositions of the present inven-tion are lactose, dextrose, sucrose, sorbitol, mannitol, pro-pylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium sili-cate, silica, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup ~.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxy-benzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorote-trafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purposes there y~ - 10 -may be employed for instance aluminium, magnesium or calcium stearates, talc or mlneral oil.
Preferred pharmaceutical forms of the present invention are capsules, tablets, suppositories, aerosols, injectible solutions, creams and ointments.
The following Examples will further illustrate the inven-tion.

- lOa -. .

5~6~) -Methyl-N-(5-meth~l-1,3,4-thiadiazol-2-yl)-benzanlide 2~(N-Methyl-amino)-5-methyl-1,3,4-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 and a saturated solution of sodium chloride, dried, filtered and evaporated to yield the title product which was recrystallised from ethanol.
, . ':

N-2-Propenyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-benzamide.
Using the process of Example 1, the title compound was prepared from 2-~N-(2-propenyl)-amino]-5-methyl-1,3,4-thiadiazole, which had been prepared by cyclisation from 4-(2-propenyl)-thiosemicarbazide.
' :.

N-Phenylmethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-ben~eneacetamide.
(a) N-(5-Methyl~ ~4-thiadiazol-2~yl)~benzylamine.
2-Amino-5-methyl-1,3,4-thiadiaæole (23g, 0.2 mole) and benzaldehyde (29.6 ml, 0.3 mole) were refluxed together in ethanol (200 ml) for 1~ 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 40-60 C) and again triturated with ether and filtered to give N-(5-me~hyl-1,3,4-thiadiazol-2-yl)-benzylamine (30.95 g)~ which on recrystallisation from ether had m.p. 140 C

~ ~r~

~85~
1 ~ (b) N-Phenylmetllyl-~-(S-Methyl-l~3,4-tllladiazo]-2-Yl)-benzene acetami(le.
~-~5-Methyl-1~3,4-thiadiazol-2-yl)-benzylamine (15g, 0.073 mole) ir~
pyridine (200 ml) was refluxed with phenylacetyl chloride for 6 hours.
The pyridine was removed under reduced pressure and the residue treated ~ith water and extracted with ether. The ethereal solution was dried, filtered and evaporated to dryness and the residue recrys~allised Erom ethanol to give the title compound, m.p. 128 C.

EX~MPLFS 4 T0 6 The following compounds were prepared by similar methods to that , described in Example 3:
-Chlorobenzyl)-N-(5-methyl-1,3,4-thiadiazol-~-yl)- benzamide.
. _ .
N-o-Chlorophenylmethyl-N-(5~methyl-1,3,4-thiadiazol-2-yl)-benzeneacetamide.
~ ~ . _ _ N~(p-Methylbenz.yl)-N-(5-phenyl-1,3,4-thiadiazol-2-yl)-cyclopentanecarboxamide.
_ : . ' N-Hexyl-N-(5-methyl-1,3~4-thiadiazol-2-yl)-b~
(a) N-(5-Methyl-1,3,4-thiadiazol-2-yl)-hexa~amide.
2-Amino~5-methyl-1~3,4~thiadia~ole (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-1,3,4-thiadiazol-2-yl)-hexanamide, m.p. 203C (20.68g). -(b~ N-(5-Methyl-193,4-thiadiazol-2-yl)-hexylamine.
N-(5-Methyl-1,3,4-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~ and Eiltered. The filtrate *Trad~ ~

ll)P,~B60 1 was evaporated to give the title producL which ~LIS recryst~llised S.om 50~/O
aqueous methanol (9.5 g) m.p. 101-105 C.
(c~ N-He~ N-(5-methyl-l~4-thiadiaz~l-2-yl benzeneacetamide.
N-(5~Methyl~l,3,4-thiadiazol-2-yl)-hexylamine (5.9~3g, 0.03 rnole) in toluene (60 ml) was sti-rred together with triethylamine (4.59 ml) and phenylacetyl chloride (4.64g, 0.03 mole) and refluxed overnight. Further triethylamine (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 dr;ed (Na2S04), filtered and evaporated to yield the title product as an oil, b.p. 190 C/0.1 ~ (8.03g). This was recrystallised from ethanol to give the title compound as a solid, m.p. 90 C.
. .

' ~

2-Amino-5-methyl-1,3,4-thiadiazole (15 g, 0.13 mole) was treated with _ butyric anhydride (70 ml). The reaction mixture was stirred and heated to reflux in an oil bath at 180-200 C for 1~ hours. The excess anhydride was distilled off under reduced pressure and the solid residue was recrystallised from ethyl acetate to give N-(5 methyl-1,3,4~-thiadiazole-2-yl)-2-methylpropanamide as golden needles.
:
EXAMPLES 9 ~ND 10 The following compounds were similarly prepared:
N-(5-Methyl-1,3,4-thiadiazol-2-yl)butanamide. (m~ 231-233 C).
; Cream crystalline solid.
~, N-(5-methyl-1~3,4-thiadiazol-2-yl)heptanamide.
Cream crystalline solid.

iO858~;0 1 EXAIn'lE 11 N-(5-metllyl-1,3,4-thiadiazol~2-~l)butylamine.
N-(5-methyl-1~3~4 thiadiazol-2-yl)butanamide (1~85g, 0.01 mole) was added in small portions to a stirred suspension of LiAlH4 (0.38 g, 0.01 mole) in dry THF (25 ml) at 0-5C. under a nitrogen atmosphereO The reaction mix.ure was stirred and heated to reflux for 2 hours. The cooled solution was then treated dropwise with a solution of water (0.38 ml) in THF (3.8 ml) followed by 2N sodium hydroxide solution (0.38 ml) followed Dy water (0.76 ml) and st-rred for ~ hour. The mixture was filtered through a pad of "Supercel"* and the solution evaporated under reduced pressure to give a soIid which was recrystallised from aqueous ethanol to give N-(5-methyl-1,3,4-thiadiaæol-2-yl)butylami~e as a pale yellow crystalline solid. m.p.
100-102C.

The following compound was similarly prepared.
N-t5-¢et~yl-~ 4-thiadiazol-2-yl)heptylamine.
. ., .

E.YAMPLr 13 N ~uty~N-_5-methvl-1?3,4-thiadiazol-2-yl)-2-methylpropanamide.
N-(5-methyl-1~3~4-thiadia2O1-2-yl)butylamine (3 g, 0.0175 male) and isobutyric anhydride (15 ml) were heated together on the steam bath for 1~ 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. 132C. which gave the title compound as a white solid (m.p.
54-57C.) on cooling.

The following compounds were similarly prepared.
. .~
*Trademark :
, . .

~ - 14 -~
~1 ., ".: I . ........ , .

~ 358~

l EX~ME'Il~S 14 AND 15 N-He~ N-(5-mcth~yl~l~3,4 ~
This ~as a colourless oil b.p~ 152-154C. at 005 mm. ~21 1.5108 N~g IR and UV supported the structureO
~nalysis: C13H23N30S requires: C 57,99; H 8.55, N 15.61%
found: C 57.81; H 8.67; N 15.76%

. N-Hepty-l--N-~5-methyl-l~3~4~thiadiazol-2 yl~ y~eropana~ e.

X~PL~ 16 -B-U~ l~N-(~-~L~ c!~ L~lopropane carl~oxamide N-(5-methyl-1~3~4-thiadia~ol-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 ; 15 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 and the residue recrystallised from petrol ether (40-60C.) to give N-butyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)cyclopropane car-boxamide as a white crystalline solid~
m.p. 82-84 C. -. .
EXAMPLE 17_ The following compound was similarly prepared.
~ N ~ eth 1-1 3 4-thiadia~ol-2-yl)cyclopentatle carboxamide ., ~L
This was a colourless oil b.p. L62-164 C. at 0.4 mmO NMR~ IP~
and UV supported the structure.
Analysis: C13H21N30S requires: C 58.4; H 7.9; N 15.7%
found: C 58.5; H 7.6; N 15.9%
' ' l~B586~

l XAMPI~ 18 N-(5-metn~yl~l 3 4-thiadiazol-2-yl)~l-methyle~larninc 2-Ami~o-5~meth)rl-1~394-thiadiazole (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 3~ 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 solidO m,p.
145C.

EX~MPLE 19 N-(5-methyl-1,3,4-thiadiazol-2-yl)cyclohexylamine.
15White crystalline solid (from ethyl acetate) m.p 192-194 C. This was prepared by the route described in Example 18.

N-(l-me~y~ethyl~-N-(5-methyl-1,3~4-thiadiazol-2-yl)benzamide N-(5-methyl-1,3,4-thiadiazol~2-yl)-1-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 5~ 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-~0Co) to give the title compound as a pale yellow crystalline solid ~:: m.p. 82.~-83.5C.

', '' .

~ 5~

l The folJowirlg cotnpoullds were simi~lrly prepared.

EXAMPL~S 21 hND 22 N~ Meth ~ thy])-N--(5-rn~thyl 1,3,4-thladiazol-2-yl)benzene acetamide.
~his was a buff crystalline solid. m.p. 83-85 C

N-Cyclohexyl-N-(5-methyl-1,3,4-thiadiazol_2-yl)cyclopropane carboxamide.
This was a yellow crystalline solid m p. 76 5--78.5 C.
~ ' .

3XAMPLg 23 (a) ~
A suspension of acetamidine hydrochloride (h7.0 g, 0.50 mol) and ~ trichloromethanesulfenyl chloride (83.0 g, 0.45 mol) in 500 ml dichloromethane ; was placed in a three-necked flask fitted with a stirrer~ dropping runnel and thermometer. Cooling ln 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 -8C~ 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 CH2C12. The organic phase was separated from water~ the latter being shaken 3 times with CH2G12 (30 ml).
~ The combined CH2C12 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 under vacuum to give 5-chloro-

3-methyl-1~2,4-thiadiazole as a colourless liquid. Yield 27 g(45%)~ b.p.
25C/3 5 mm ~Ig 17 ~
''' ' ,~

l (b) 5 Bul:ylamil~o~3-meth~ 2~4-thiadiaxole 5-Ch~orn-3 methyl-1~2,4 thiadiaxole (27 g, 0.20 mol) was d;ssolved 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 overnlght and evaporated to small bulk. Upon addition of ether a white precipitate of butylamine hydrochloride formed which was filtered off. The yellow filtrate was washcd with water~ dried o-~er magnesium sulphate~ filtered and evaporated to dryness to yield a yellow oil which was distilled under vacuum to give 5-butylamino~3-methyl-1,2,4-thiadiazole as a pale yellow liquid. Yield 29.9 g, (87.2%), b.p. 101-102 C/0014 mmHg.

(c) N-(3-M~ LJ~____iad Cyclohexane carboxylic acid chloride (9.92 g, ODO68 mol) was added slowly to a solution of 5-methylamino-3-methyl-192,4-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 1~ 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 petro~ um ether 60-80C. to yield off-white crystals of N-(3-methyl-1,2,4-thiadiaxol-5-yl)-N-methylcyclohexane carboxamide. Yield 8.23 g, ~63.8%), m.p. 96C.

The following compounds were prepared by similar methods to that described in Example 23.

N- Methyl-1~2~4_ hiadiaxol-5~ N-butyl-2-me ~ l~panamide (b.p. 115-117C
/o.l mmHg).
Analysis:CllH15N30S requires: C 54.74; H 7r93; N 17~41; 0 6.63;
S. 13.28%
found: C 54.649 H 7~97; N 17~37; 0 6.48;
S 13.36%

~5 1 _(3 ~ethyl 1,22ll-th~ oL-5 y~ N ~ y~(]~E--o~ e ~ar~ox~lrlllde-(m.p. 43 C).

N-(3-Methyl-1 2 4-thiadlazol-5-yl)-N-butylphenyl carboxamide. (m.p 77 C) N-(3-Cyclobutyl-1,2~4-thiadiazol-5-yl)-N-octylcyclooctane carboxamide.
.
N-(3-Methyl-1,2,4-thiadiazol-5-yl?-N-methyl h_ yl acetamlde (m.p~ 86 C).

N-(3-Methyl-_,2,4-tlliadiazol-5-yl)-N-2-propenyl acetamide (m.p. 61 C).

N-(3-Methyl-1,2,4-thiadiazol-5-yl)-N-methyl-2-methylpropanamide. (m.g. 54 C).
. ..
.

4 hi azol-5-yl)-N n--butyl-n-hexanamide ~bop~ 130-135 C/
0.15 mm.Hg, purified by column chromatography).
-; Analysis:Cl~H25N30S requires: C 59.33j H 8.89; N 14.83; 0 5,65;
S 11.31%
found: C 59.39; H 8.82; N 15.19; 0 5.87%
' .:

~ N-(3-Methyl-1,2,4-thiadiazol-5-yl)-N-2-propenylphenyl acetamide (m p. 70 C).
.
':
N-(3-Methyl-1,2,4-thiadiazol-5-yl)-N-2 propenylcyclopropane carboxamide.
~- 30 (m.p. 76 C).

fi~ ~
1 EX~IPLE 34 ., 3-Phen 1-5-trichlorometh 1-1 2 4-oxadiAzole . Y _ _ Y_~ 2 __ .
Trichloroacetic anhydride (154.5 g, 0.5 mole) was added to a stirred solution of benzamidoxime (34.0 g, 0025 mole) in dry trichloroacetic acid (160 g,) in an oil bath at rv60C. The reaction mixture was heated at 120C. 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 ~etrachloride (500 ml) and neutralised by washing with a saturated solution of NaHC03. Af~er drying over MgS04 and evaporating off the carbon tetra-chloride, the product was distilled. (b.p. 118C/0.07 mmHg). `
. ' .

3-Methyl-5-trichloromethyl-1,2~4-oxadiazole was similarly prepared.

EX.4MPLE 36 . .

5-Butylam3r ~ oxadiazole 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 over-night. Excess amine was removed under vacuum and the residue distllled ~oil bath 110 C/0.5 mm Hg). Recrystallisation from petroleum ether 60-80C gave the title compound as white plates 26 g, m.p~ 62-65C.
. . . I ~. r ~

r~ N-n-Butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl~n-butanamide.
~
5-Butylamino-3-methyl-1,2,4-oxadiazole (4 2g, 0.03 mole) and butyr;c 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 triethylamine for 1 hour. The methanol was evapo a ed under vacuum and the residue taken ~p in CX2Cl2, washed twice with ~1:
~ - 20 -L~i ~ q~ ,~

~N HCl and twice with a saturated ~olution of NaHCO3 and dried over MgSO4. The product was purified by column chromatography (silica gel 120 g) eluted with petroleum ether 40-60C, increasing solvent polarity to 10% ether/petroleum ether. Fractions were combined and distilled in a "Kugelrohr"* airbath at 119C/3.3 mmHg.
Analysis: CllH19N3O2 requires: C 58.64; H 8.50; N 18 65; O 14 20%
found: C 58.78; H 8.30; _ 18.40; _ 14.18%

The following oxadiazoles were prepared using the method described in Example 37.

N-Ethyl-N-(3-methyl-1,2,4~oxadiazol-5-yl)-2-methylpropanamide (b.p. 92 C/3.0 mmHg).
Analysis: CgH15N3O2 requires: C 54.80; _ 7.66; _ 21.30; _ 16.22%

found: C 54.68; H 7.46; N 21.14; O 16.33%

N-n-Butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)acetamide ~.
- ~20 1.4748, of liquid.

N-Butyl-N-(3-methyl-1,2,4-oxaaiazol-5-yl)-2-methylpropanamide , (b.p. (airbath temperature) 98C/1.5 mm.Hg).

Analysis: CllHlgN3O2 requires: C 58.65; H 8.50; N 18.66; O 14.20%
found: C 58.49; H 8.22; _ 18.40; _ 14.18%

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

:~
Analysis: C13H23N3O2 requires: C 61.63; H 9.15; N 16.58; _ 12.63%
found: C 61.89; H 9.39; N 16.33; O 12.65%

N-Ethyl-N-(3-Phenyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide .
(m.p. 48C ).

*Trademark ~L1318~
N-Butyl-N-(3-phenyl-1,2,4-oxadiazol-5-yl)-2~methylpropanamide (b.p. 140C/7 mm.Hg airbath temperature).
Analysis: C16H21N3O2 requires: C 66.88; H 7.37; N 14.62; O 11.14%
found: _ 67.07; H 7.38; N 14.38; O 11.06~_ _ N-Ethyl-N-(3-phenyl-1,2,4-oxadiazol-5-yl)-n-butanamide .
(m.p. 74C.).

N-n-Hexyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)acetamide _ 5-_-Hexylamino-3-methyl-1,2,4-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 CHC13 (50 ml) and washed twice with 2N HCl and twice with a saturated solution o~ NaHCO3 and dried over MgSO4. (b.p.
113-114C/l.0 mmHg.).
Analysis: CllHlgN3O2 requires: C 58.64; H 8.50; N 18.65; O 14.20%
found: C 58.66; H 8.76; _ 18.57; 14.48%

The following oxadiazole was similarly prepared using the process of Example 45.

N-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-2-propenylacetamide (b.p. 82C/1.5 mm.Hg airbath temperature).
Analysis: C8HllN3O2 requires: C 53.02; H 6.12; N 23.19; O 17.66%
found: C 52.78; H 5.90; N 23.03; O 17.69%

. .
N-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-(4-methylphenyl)methylamino 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-1,2,4-oxadiazole (6.1 g, 0.03 mole) and triethylamine (3.45 y, 0.033 mole) in dry benzene keeping the temperature below 10C. After the addition the temperature was 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 ~gSO4 and charcoaled.
The product was purified by column chromatography - silica gel (110 g) eluting with petroleum ether 40-60C. increasing polarity to 10% ether in petroleum ether. The title compound was re-crystallised from petroleum ether 60-80C. as white needles.
m.p. 49.5-50.5C.

The following further oxadiazoles were prepared using the process of Example 47.

N-Methyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide (m.p. 74 C.).

N-n-Butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane carbox-amide ~ (~26 1.4882)-- N-Hexyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopentane carboxamide (b.p. 121C/1.4 mmHg (airbath temperature).
Analysis: C15H25N3O2 requires: C 64.48; _ 9-02; N 15-04; _ 11-52~
20 found: _ 64.76; 8.86; N 14.82; _ 11.52%

N-Hexyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexane carboxamide (b.p. 157C/1.5 mmHg airbath temperature).

Analysis: C16H27N3O2 requires: C 65.49; H 9.27; N 14.32; _ 10.9%
found: C 65.58; H 9.05; N 14.19; O 10.95%_ N-Hexyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide _. .
(b.p. 126C/0.2 mmHg airbath temperature).
Analysis: C16H21N3O2 requires: _ 66.87; _ 7-36; N 14-62; _ 11-13%
found: C 66.85; _ 7.35; N 14.58; _ 11.27%

N-(3-Methyl-1,2,4-oxadiazol-5-yl)-N'-?.-propenylcyclopropane carboxamide (b.p. 120C/10 mmHg airbath temperature).

N-(3-Methyl-1~2~4-oxadiazol-5-yl)-N-phenylmethylcyclohexane carboxamide (m.p. 73C).

N-(3-Methyl-1,2,4'-oxadiazol-5-yl)-W-phenylmethylbenzamide (m.p. 75C).

N-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-phenylmethyl-2-methy'lpro-panamide (b.p. 127C/3.00 mmHg).

N-(4-Methoxyphenyl)methyl-N-(3-methyl-1,2,4-oxadiazol-5-yl')-cyclohexane carboxamide.

;
(m.p. 70C.

N-(4-Methoxyphenyl)methyl-N-(3-methyl--1,2,4-oxadiazol'-5-yl)-2-methylpropanamide _ (b.p. 118C at 0.2 mmHg airbath temperature).

N-(4-Methylphenyl)methyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropane carboxamide (m p 50C) EXAMæLE 60 N-(3-Methyl-1,2,4-oxadiazol-5-yl)-N-isopropylamino-2-methyl-propanamide isoButyric anhydride (7.9 g, 0.05 mole) was added to iso_ propylamino-3-methyl-1,2,4-oxadiazole and heated at 100C. over- ~' night. On cooling, methanol (60 ml) and a few drops of triethyl-amine were added and refluxed for 1 hour. After r~moval of the methanol under vacuum, the residue was taken up in ether and washed twice with a saturated solution of NaHCO3. (b.p. 90C/1.3 mmHg. "Kugelrohr"* airbath temperature).

*Trademark 35~

N-(5-Methyl-1,3,4-oxadiazol-2-yl)-N-n-propyl cyclobutane carboxamide (a) l-Acetyl-4-ailyl-semicarbazide Allyl isocyanate (25 g, 0.30 mol) was added slowly to a boiling solution 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. 71-74C~.
(b) S-Methyl-2-n-propylamino-1,3,4-oxadiazole .;
. . . .. . . .. . . __ , . .. --- ----- ---- -- --- - --IO 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 L5 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-1,3,4-oxadiazol-2-yl)-N-n-propyl cyclobutane carboxamide , __.
5-Methyl-2-n-propylamino 1,3,4-oxadiazole (6 g, 0.04 mol~ prepared as ~ZO in (b) abo~e~ was refluxed with cyclobutanecarboxylic acid chloride (5.5 g~
0005 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, a saturated solution of NaHC03 and water; dried over magnesium sulphate, filtered~and the solvent evaporated off to yield a reddish brown li~uid ¦ which was distilled twice in a vigreux flask to yield the title compound as a slightly pink liquid (b.p. 110-111C/0.27 mm Hg)~

EXAMPLES 62 to 6a Using the procedure described in Example 61 the following further oxadiazoles were prepared:

~'~i ' .
~,~.

~85~

1 N (5-Methyl-193~4-oxadiazol~2-yl)-N~~I proE)yl 2-~1ethylpropa~ Lide (blp~85 87 0.4 ~n ~-lg).

N-(5-Methyl-1~354-oxadiaæol 2-yl)-N-n-propyl cyclohex~ne carboxamlde (b.p.
120-121 C/0~2 n~m Hg).

N-(S-Methyl-1~374-oxadiazol-2-yl)-N-n-propyl cyclopentane carboxamide (b.p, ` 110-112 C/0,01 mm Hg)o N-(5~Methyl-1~394-oxadiaæol-2-yl)-N-2-propenyl-2-methylpropanamide ;~ (b.p. 93C/0.18 mm Hg).
.~', ('~
N-(5-Methyl-1~3,4-oxadiaæol-2 yl)-N-2-propenyl-2-cyclopentane carboxamide . (bopo 114-116 C/0.12 mm Hg).
``i 15 .
N-(5-Methyl-1j3J4-oxadiazol-2-yl)-N-n-hexyl-n-hexanamide (bop~ 116 C/0,1 ~m Hg).
~'' . ' , N (5-Methyl 1,3,4-Gxadiazol-2-yl)~N-n-butyl-2-methylpropanamide (b~p~
~0 82-84 C/0.1 mm Hg).

N-(5-Methyl-1~3j4-oxadiazol-2-yl)-N-n-butylacetamide (b.p. 82-84C/0,1 ~n Hg).

.
EX~MPLE 70 The following 1,2,4-oxadiaæole was prepared uslng a similar method to that described in Example 37.
.' .' (b.p~ 90C/l.l mll~g).
Analysis: C13H23N302 requires: C 61.63; H 9.15; N 16.58; 0 12.63%
¦ folmd: C 61047; H 8.98; N 16.84; 0 12.70%

~ ~ 26 -1 EY.AMPIr',_7]-3 Similarly, using the process generally described in Example 47, the following further oxadiazoles were prepared:

~ oxamide . ~,., AnaLysis: C111ll7N302 requires: C 59.17; H 7.67, N 18082; 0 14.33%
found: C 59.05; H 7~59; N 18.41; 0 14.73%

-5=y~-N-2 p o~ e~ de (b.p. 104C/1 5 mm Hg).
Analysis: C13H2lN302 requires: C 62.12; H 8042; N 16.71; 0 12.73%
found: C 62.16; H 8.20; N 16054; 0 12.63%

~2 4-o ~_.
(b.p. 71C/OrO55 mm Hg).
alysis: C13H23N302 requires: C 61.63; H 9.15; N 16.59; 0 12.63%
found: C 61.46; H ~;90; N 16.57; 0 12.47%
., .

N-(3-methyl-1,294-thiadiazol-5-yl)N-phenylmethyl-n-hexana~ide (m.p. 72C) was prepared using the procedure outlined in Example 23.
~,~ . , 1a~8~6~
1 IYAMPIFS /5 ro 77.
The follol7ing further 1,2,4-thiadiazoles were prep~red by similar method ; to that us~d in Example 23:
.

N-(3~Methyl-1,2,4-thiadiazol-5-yl)-N hexyl_acetarnide (m p 38 C ) _ ,.

~ N-(3~Methyl~1?2~4 thiadiazol~5-yl)-N-lexYl phenyl acetamide (m,p. 57 C.).
~~ . . .
N-(3-Methyl-1?2,4-thiadia201-5-yl)-N~phenylmethyl phenyl acetamide (m.p. 134 C
. ' .
The following further 1,2,4-oxadiazoles were prepared by similar methods to that used in Example 47:
"'. .

~ N-Butyl-N~3-methyl-1,2,4-oxadiazol-5-yl)-phenyl carboxamide.
:'' i Analysis: C14H12N302 requires: C 64.84; H 6.61; N 16.21; 0 12.34 l found: C 65.09; H 6.35; N 15.99; 0 12.07 , , N-Butyl-N-(3-methyl-1,2,4-oxadiaæol-5-yl)-4-chlorophenyl carboxam;de.
20Analysis: C14H16ClN302 requires: C 57.24; H 5.49; Cl 12.07; N 14.30 0 10.89 found: C 57.45; H 5.63; Cl 12.07; N 14.14 ; ` 0 11.17 25N-Butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-4-methoxyphenyl carboxamide.
.
(b.p. 105 C/0.015 mm Hg) Analysis: C15HlgN303 requires: C 62.27; H 6.62; N 14.52; 0 16.59 found: C 61.99; H 6.47; N 14.42; 0 16.74 ~ ~35~361~
1. I~-Butyl-N~(3~llle~ l22,4-o~cad:ia~,ol-5-yl)-cyclollexclne carboxnmide.
~ .....
(b.p. 70 C/0.01 mm tlg~
Analysis: C1411A3N302 req~lires: C 63.37; H 8.74; N 1$.84 found: C 63.54; H 8.55; N ]5 60 N-Butyl-N-(3 methyl-1,2,4-oxadiazol-5-yl?-cyclobutane carboxarnide.
(b.p. 67 C/0.02 mm Hg) Analysis: C12H19N302 requires: C 60.74; H 8.07; N 17.71; 0 13.49 found: C 60.44; H 7.88; N 17.54; 0 13.21 N-(3-Methyl-1,2,4-oxadiazol-S- ~ -N-propyl 2-methyl propanamide.
(b.p. 62 C/0.15 mm Hg) Analysis: CloH17N302 requires: C 56.85; H 8.11; N 19.89 found: C 56.93; H 8.14; N 19.64 N-Butyl-N-(3-butyl-l,2,4-oxadiazol-5-yl)-cyclopropane carboxcmide.
Analysis: C14H23N302 requires: C 63.37; H 8.74; N.15.84; 0 12.06 found: C 63.19; H 8.51; N 15.58; 0 11.82 N-Butyl-N-(3-ethyl-1,2,4 oxadiazol-5-yl)-cyclopropane carboxamide.
(b,p. 65 C/0.01 mm Hg) Analysis: C12HlgN302 requires: C 60.74; H 8.07; N 17.71; 0 13.49 found: C 60.50; H 7.78; N 17.43; 0 13.19 '.' N-Butyl~N-(3-cyclohexyl-1,2,4-oxadiazol-5-yl)-cyclopropane carboxamide.
Analysis: C16H25N302 requiresO C 65.95; H 8.65; N 14.42; 0 10.98 found: C 66.15; H 8.83; N 14.51; 0 10.86 ~L0~51360 _X~MPLES 8-i 10 ~') Similarly, I)y methods sil~l;lar to that used in E~ample 6~, the followillg further oxadiazoles were prepared:
. =~=~

(b.p. 65 C/0.02 mm Hg) Analysis: C12H~lN302 requires:C 60.22; H 8.85; N 17.56; 0 13.37 found: C 59.96; H 8.68, N 17.36; 0 13.22 .
~ 10 N-Butyl-N-(3-buty1-1,2,4-oxadiazol-5-yl)2-methyl propanamide.
,; .
(b.p. 64 C/0.05 mm Hg) Analysis: C14H25N302 requires: C 62.89; H 9.42; N 15.72j 0 11.97 found: C 62.65; H 9.20; N 15.46; 0 11 72 N-Butyl-N-(3-cyclohexy]-1,2,4-oxadiazol-5-yl)-2-methy~~opanamide (b.p. 92 C/0.02 mm Hg) Analysis: C16H27N302 requires: C 65.49; H 9.28; N 14.32; 0 10.91 found: ~ 65.26; H 9 09; N 14.07; 0 11.05 The following Examples 90 to 97 illustrate pharmaceutical formulations containing the active compound N-n-hexyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopentane carboxamide.

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 .

ilD8513~;0 ... The above ingredierlts were mixecl and filled i.nto soft gelatin Cap5~ S, the main shel.l c(,l.lpoeellts of which were gelatln and glycerlne, ,, ~ The procedure of Example 90 was repeated except that an identi.cal .~ quantity of propyl gallate was used in place of the butylated hydroxyanisole . as antioxi.dant, :'~

EX~MPLE 92 llard gelatin capsules were prepared using the following ingredients:
Quantity(mg/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 wa.s filled into hard gelatin capsules.
. .
~; EXAMP~E 93 ~n ointment was made up from the following ingredients: .
Active compound 1.5% by weight Butylated hydroxyanisole B.P. 0.02% by weight White soft paraffin q.s. 100%
The hyclroxyanisole was dissolved in the melted paraffin and the active compound then added in, and the mixture allowed to cool.

~ 1 EX~MehE 94 ~5~
A topical cream containing 1~0% of the compound is prepared as follo-7s:
grams - Active compound 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 sl~spended 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 Cetomacrogol 1000" was dissolved in 60 g. of l compound mixture were then poured into the aqueous "Cetamacrogol lO00" solution ; lS with stirring and the stirring continued un~il 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 lS/1000 inch.
.

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 wi~h the Henkel base which had been previolIsly melted using the minimum amount of heat possible. The mixture was then poured into suppository moulds of a nominal capacity of l g. or 2 g. as desired, to produce suppositories each containing 25 mg.
or 50 mg. of the active compound.
. . :
i *Trademark for polyethylene glycol 1000 monocetyl ether. A descriptionof this material may be found in ~artindale's Extra Pharmacopo~, 27th Edition (1977), The Pharmaceutical Press, London, England, page 322.

I '"'~,`1 1 ~

1 EXAMPI.E 96 An aerosol was prepared ccntaining th~ following ingrrdients:
Quantlty_per ml.
Active compound 10.00 mg.
Propylene glycol lO.00 mg ; Dichlorote~rafluoroethane ("Propellant 114"*)550.00 mg.
Dichlorodifluoro ethane ("Propellant 12"*~830.00 mg.
Il . ~:
~ ll The actLve compound was mixed with the propylene glycol and the mix ; added to the "Propellant 114", the mixture cooled to -15 to -20C. 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 ~illing 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 ~he 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.
, ~

.
Tablets were prepared using the following components:
Active compound lO.00 mg.
Microcrystalline Cellulose250.00 mg.
; Sodium Carboxymethyl Starch25.00 mg.
25 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 .
I Finally, the mixture was compressed to form tablets.
*Trademark .
**Trademark ; ~!~

1i)85~360 ,~ ].I~ thc ~oregoin~ L:xamlJles 90 to 97~ the liquid active compound . . used may, i.n accordance with the invention, ~e re~ ced wholly or in par~ by .~ other liquid activ~ cornpourlds of formula I or XIII. If tlle active compound is a solid, appropriate ~nodification will of course have to be made.

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a heteroaryl compound of the formula:

(I) 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 sub-stituted by C1-4 alkyl, C3-10 cycloalkyl, or phenyl, the acylamino group -NR1COR2 being attached to a carbon atom of the heteroaryl ring, and wherein R1 is C1-l0 alkyl, C2-6 alkenyl, C3-10 cyclo-alkyl, or phenyl-C1-6 alkyl optionally substituted with halo, alkyl or alkoxy; and R2 is C1-8 alkyl,C3-10 cycloalkyl, phenyl optionally substituted with halo or alkyl, or phenyl C1-6 alkyl, provided that:
(a) when Ar is 1,3,4-thiadiazolyl, R1 is C1-3 alkyl and R2 is C1-7 alkyl, or C3-6 cycloalkyl, said 1,3,4-thiadiazolyl group cannot be unsubstituted or substituted by C1-3 alkyl;
(b) when Ar is 1,3,4-thiadiazolyl substituted by methyl and R1 is p-bromophenyl, R2 cannot be methyl;
(c) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, R1 cannot be methyl or benzyl when R2 is methyl; and (d) when Ar is 1,2,4-thiadiazolyl substituted by isopropyl and R1 is C1-4 alkyl, R2 cannot be C1-4 alkyl; which process comprises:
(a) acylating an alkyl derivative of formula:
ArNHR1 (VIII) where Ar and R1 are as defined previously;
(b) alkylating an acyl derivative of formula:
ArNHCOR (IX) where Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadi-azolyl and R2 is as defined previously; or (c) reacting a compound of formula:
ArY (X) where Y is a leaving group and where Ar is as defined previously, with a salt of formula:
MNR1COR2 (XI) where M is a group IA or IIA metal and R1 and R2 are as defined previously.

2. A process according to claim 1, wherein the heteroaryl nucleus Ar is optionally substituted by a group selected from C1-4 alkyl, C3-8 cycloalkyl and phenyl; R1 is C1-8 alkyl, C3-6 alkenyl, C3-8 cycloalkyl, or benzyl optionally substituted by halogen, C1-4 alkyl or C1-4 alkoxy; and R2 is C1-8 alkyl, C3-8 cycloalkyl, benzyl, or phenyl optionally substituted by halogen or C1-4 alkoxy.

3. A process according to claim 1, wherein the heteroaryl nucleus Ar is substituted by a C1-4 alkyl group; R1 is C1-6 alkyl, C3-5 alkenyl or benzyl and R2 is C3-6 alkyl, C3-6 cycloalkyl or benzyl.

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

5. A heteroaryl compound of formula I as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

6. A heteroaryl compound of formula I as defined in claim 5, wherein the heteroaryl nucleus is a 1,2,4-oxadiazolyl system, whenever prepared by a process according to claim 4 or an obvious chemical equivalent thereof.