DE2625285A1 - HETEROARYL COMPOUNDS, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

50 34-9 - Dr.

Applicant ? LILLY INDUSTRIES LIMITED

Henrietta House, Henrietta Place London ¥ .1, England

Heteroaryl compounds, process for their preparation and pharmaceutical agents containing them

The invention relates to new heterocyclic compounds, in particular new 5-membered heteroaryl derivatives which
are substituted by an acylainino group, suitable for chemotherapy of acute hypersensitivity states and / or as intermediates for the preparation; such active compounds are suitable, as are processes for the preparation of these active compounds and pharmaceuticals containing pharmacologically active compounds
Agents which can be used for the treatment of animals and humans, in which an effective dose of the compound (s) according to the invention or pharmaceutical agents containing them is administered.

609852/1077

Similar compounds are for example already in "Bull. Soc. Chim.", 1219 (1967), in the Belgian patent 736 854- and in British patent specification 1 333 4-95. The connections described therein however, differ from those according to the invention Compounds in terms of their usefulness fundamentally or they are publications by academic interest only, in which no usefulness of any kind is stated.

In the case of the inventive new connections which are used for the Chemotherapy of acute hypersensitivity states (over-hypersensitivity states) are suitable are new Eeteroarylderivate the general lOrnel

(I) Ar-IT-R ¹

COR ²

where mean:

Ar is a 5-membered heteroaryl nucleus or ring, the only heteroatoms containing two nitrogen atoms and a further heteroatom from the group consisting of oxygen and sulfur, the heteroaryl nucleus or ring optionally being replaced by pormyl, carboxyl, hydroxyl, C ^^ - hydroxyalkyl, ^σ ^ _ζμ ~ alkyl, C, _y, Q-Gjc Ioalkyl, C, g-acyloxyalkyl, optionally substituted phenyl or halogen is substituted and

1 2

where the acylamino group -IiR COR on a carbon atom of the heteroaryl ring is bound,

R ¹ C ^ Q-alkyl, G ^ g-alkenyl, C ₂ _ ₆ -alkynyl, alkyl, Coc-carboxyalkyl, C ^, ~ -Ealogenalkyl, Cycloalkyl, C ^ _ ^ Q-Cycloalk7l-C ^ _g-alkyl, optionally substituted phenyl-C._g-alkyl or optionally

809852/107 7 ~ ³ ~

substituted phenyl-C-, - alkenyl and

R ² C _1-8 alkyl ₁ 0 ₁ _ ₆ -halosenalkyl, C ₂ _ ₆ -alkenyl, C _7-1 CT cycloalkyl, C 1-8 cycloalkyl-C 1-6 alkyl, optionally substituted phenyl, optionally substituted phenyl -C., .- alkyl or optionally substituted

1 2

or. R and R together form a lactam ring with 5 to 7 Ring atoms,

with the proviso that

a) when Ar is 1,3,4-thiadiazolyl, RC _1- -, - alkyl and R ^{2 are} C ₁ "-alkyl, C ₁ n-haloalkyl, C _2-7 -alkenyl or C _7-6 -cycloalkyl, 'the 1,3,4 ~ thiadiazole-Ί group cannot be unsubstituted or _{substituted by C 1-} ^ -AIkVl or halogen,

b) if Ar is _{1,3,4-thiadiazolyl substituted by a C 1 Zj} -alkyl group and R is trichloromethyl, R cannot be C ₁ e-alkyl or Cp ^ -alkenyl,

c) when Ar is 1,3, ^ - thiadiazolyl substituted by methyl and R is p-bromophenyl, R cannot be methyl, and

d) if Ar is Λ , 2,4-Cbcadiazolyl substituted by phenyl, R cannot be methyl or benzyl, "if R is methyl.

The substituent of the chin optionally be present on the heteroaryl nucleus or ring is preferably selected from the group C ₁ _ ^ alkyl, O _7, g-cycloalkyl and phenyl. Preferred substituents R are C ₁ _ ₈ alkyl, _g-alkenyl, C, Q Gycloalkyl and benzyl, the given

if substituted by halogen, C ^^ - alkyl or C _1- ^ -AIkOXy. Preferred substituents R ~ are C _1- Q-alkyl, C ^ _g-cycloalkyl, benzyl and phenyl, the given

609852/1077

if substituted by halogen or C, «^ .- alkoxy.

The expression ¹¹ C, -, - alkyl "used here is a straight-chain (unbranched) or branched-chain alkyl group with 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, η-butyl, s-butyl, isobutyl , t-butyl, n-ainyl, s-amyl, n-He: <yl, 2-ethylbutyl or 4-methylamyl. unbranched) or branched-chain alkyl groups with 1 to 4 carbon atoms, in particular methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, t-butyl. The terms "C ^ ^ -Hjdroicyalkjrl ¹¹ and "C ^^ g-acyloxyalkyl" are to be understood as meaning the above-mentioned C ^ _ ^ _- alkyl groups which are represented by a Hydrojcvc ^ ouppe bzv, ^r . an acyloscy group are substituted. The terms' ¹ C _{0 r} - alkoxyalkyl "and ^I! C ^ _g-haloalkyl" used here are to be understood as meaning the abovementioned CL p-alkyl groups which are substituted by an alkoxy group or one or more halogen atoms, such as, for example, 3. Methoxyethyl, Ethoi-cyäthyl, iLtho: ybutyl, dibromomethyl, trifluoromethyl, 1-chloroethyl, 1,1-dichloroethyl, 1-iodobutyl or pentafluoroethyl.

As used herein, "Cp ^ -alkynyl" is an alicyclic hydrocarbon group of 2 to 6 To understand carbon atoms that contains a -C = C group. It should be noted, however, that the -C = C group cannot be directly adjacent to the nitrogen atom of the acylamino group.

Under the term "C ^^ Q-C is a saturated ring with 3 to 10 carbon atoms in the ring, such as cyclopropyl, cyclobutyl,

609852/1077

Cyclooctyl or adamantyl, to be understood. The expression " ^G: 5 ^ Q-Cycloal7 / kl-G ^ __ g-alkyl" is to be understood as meaning the above-mentioned saturated rings which are bonded to a C ^ g -alkylene bridge.

The term "optionally substituted phenyl" used here is to be understood as meaning a phenyl group which is unsubstituted or substituted by one or more groups which do not significantly change the pharmacological effectiveness (activity) of the compounds of the formula I, such as halogen- , Trifluoromethyl, methyl, ilothoxy or nitro groups. As used herein the term "C _0, - carboxy alkyl". Is a 0 _{Λ r} -Alkylgru "OT.e to understand which is substituted by a carboxylic acid group (carboxyl group) Examples of such groups are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl .

It is self-evident to the person skilled in the art that the 5-ring heteroaryl nuclei or rings, which contain nitrogen atoms as the only heteroatoms and a further heteroatom from the group consisting of oxygen and sulfur, the 1,2,4- and 1,3,4- Oxadiazolyl-Rings.y stars and the 1,2, - and 1,3, ^Z : -O? Hiadiazolyl ring systems. The compounds according to the invention with these heteroaryl chains or rings can be represented by the following structural formulas:

N N

V _κ

- NO COR

609852/1077

P N

r j

(V) * ^N

(VI) ¹ SN

1 2
in which R and R have the meanings given above and R is hydrogen or the substituents which may be present on the heteroaryl nucleus or ring.

Particularly advantageous compounds of the formulas I to VII are those in which the heteroaryl group is substituted by a Gy _L , alkyl group, in particular Kethvl, RC ,, - alkyl, in particular G ₁ ^ - alkyl, C ~ _ _I mean - alkenyl or benzyl and RC ^^ - alkyl, C7_g-Cycloallc _t yl or Benayl.

The invention also relates to a method for Preparation of the compounds of the general formula I given above, which is characterized in that one

a) an alkyl derivative of the general formula acylates (VIII) ArHHR ¹

609852/1077

1
wherein Ar and R have the meanings given above,

b) an acyl derivative of the general formula alkylates (IX) ArNHCOR ²

wherein Ar 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-

Oxadiazolyl is and R is as defined above Has,

c) a compound of the general formula

(X) ArY

in which Y is a group which leaves (can be split off) easily, ie trichloromethyl, tribromomethyl, bromine or chlorine and Ar has the meanings given above, is reacted with a salt of the general formula

(XI) MIiR ¹ COR ²

where M is a metal of the size IA or HA of the periodic

1 2 system of elements and R and R have the meanings given above, or

d) a compound of the general formula is cyclized

(XII) ArIiHZ

wherein Ar has the meanings given above and Z is -C0 (CH ₂ ) _n Q, - (CH ₂ ) _n COQ ^I or cyclopropylcarbonyl, where η is an integer from 3 to 5 »Q is an easily leaving (cleavable) group, v / ie halogen, Q ¹ a group which activates the neighboring carbonyl group for a nucleophilic attack, v: ie halogen,

609852/107 7 * -8-

8 "8

Represent chlorine, or -OR, in which R is hydrogen, or Cx] _ _{/ +} -alkyl,

with formation of a compound of the general formula I,

12th
wherein R and R form a lactam ring with 5 to 7 atoms. . ....

The acylation of the compound of formula VIII can, with

2 an acid halide of the formula R CO-X, in which X is chlorine

or "bromine denotes and R has the meanings given above, in the presence of a proton acceptor such as pyridine or triethylamine, in an inert solvent, such as benzene. The acylation can also be carried out in such a way that the alkyl derivative.

2 heated with a suitable acid anhydride of the formula (R CO) pO in an inert solvent. It is readily understood by the person skilled in the art that the most varied of other acylation conditions can be applied to me (cf. eg ₀ AJ Beckwith, "The Chemistry of Amides", 1971, Buehler and Pearson, "Surve7, r of Organic Synthesis", 1970, Sandler and Karo, "Organic Functional Group Prepars.ticns", 1968, Fieser and Fieser, "Reagents for Organic Synthesis", 1968, and the like).

Compounds of Formula IX! can thereby be alkylated, that the amide in a suitable inert, anhydrous ,, polar solvent, such as dimethylformamide, dissolves, with an alkali metal hydride, preferably sodium hydride, making an alkali metal salt of it and then that

1 1 salt treated with an alkylating agent of the formula R X

1
delt, where X is a reactive atom, such as a halogen atom, or a reactive group, such as

an alkyl sulfate group. Others can too

• Alkylating agents and alkylation reaction conditions

609852/1077

than those mentioned above may be applied, the nature of which would be readily apparent to those skilled in the art can be seen.

The compound of formula XI can thereby be prepared that you can get an amide of the formula HITR COE ~ with butyllithium in 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 converts. The preparation of the salt is preferably carried out at deep Temperatures, e.g. at temperatures below -10 0.

The reaction (c) can be effected in the manner that the compounds of the formulas X and XI in one. in addition to inert solvents such as tetrahydrofuran, optionally in the presence of a catalyst such as copper or a salt thereof, reacted with one another.

The cyclization of the derivative of the formula XII can be carried out under basic conditions in the presence of a non-nucleophile Base causes grounding in the reaction of the cyclopropylcarbonyl derivative the lactam of the formula I is obtained, which contains 5 atoms in the ring

The derivatives of the formulas VIII and IX can be derived from the corresponding amines of the formula ArIlHp using customary alkylation, or acylation methods. The to -halogenacylaiuinoderivat of the formula XII can be prepared by reacting the amine of the formula ArMU with a suitable 'co -halog-macylhalogenide. The amines of the formula ArIIH ₂ are either known compounds or compounds which are produced by modifying known synthetic methods who can .on ¹ ".

609852/1077 ~

6AD

A further subject of "the invention" is formed by the Intermediates of the general given above

Formula IX, in which Ar and S have the meanings given above, but with the proviso that (a) Ar is not unsubstituted or substituted by C ._ ^ - alkyl, C, ^^ cycloalkyl or optionally substituted phenyl Thiadiazolyl and R ^{2 are} not C ^^ - alkyl or C, | _ ^ - haloalkyl, and

b) Ar 1,2,4-0xadiazole7 / l not substituted by phenyl

ρ
and R 'is not C 1-6 alkyl; these are new "compounds. The invention also relates to a pharmaceutical agent which is characterized in that it contains at least one heteroaryl derivative of the general formula as active ingredient

(XIII) Ar-KE ¹

I p

COR ^

where mean:

Ar is a 5-gli ^e drigen heteroaryl nucleus or ring that contains as the only heteroatoms two nitrogen atoms and one further hetero atom from the group oxygen and sulfur, wherein the Heteroarlykem or ring is optionally substituted by formyl, carboxyl, Hydro: cyl, CL _b hydroxyalkyl, C ₁ _ _{Z |} _-Haloalkyl, O ^ -alkyl, C, ^ - cycloalkyl, C ₇ c-Acylojiyalkyl, optionally substituted phenyl or halogen is substituted and where the acylamino

Λ 2
group -ITR COR is bonded to a carbon atom of the heteroaryl nucleus or ring,

^G 2-6 ~ ^alkenyl »Cj.g ₂₆

alkyl, C ₂ -C 6 -carboxyalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -cycloalkyl, C 1 -C 4 -cycloalkyl-C 1 -C 4 -alkyl, optionally substituted poly-C 1 -C 6 -alkyl or optionally

609852/1077

substituted phenyl-Cp ^ - alkenyl and

Cycloalkyl, C ₇ , ^ Q-Cycloalkr / 1-CL, - alkyl, optionally substituted phenyl, optionally substituted phenyl-C ₁ , - alkyl or optionally substituted

1 2
or E and B together represent a lactam ring with 5 to 7 atoms,

optionally in combination with a pharmaceutically acceptable carrier or excipient suitable for this purpose contains.

Preferred pharmaceutical agents contain at least one compound of the general formula I.

The compounds of formulas I and XIII are suitable for the prophylactic and therapeutic treatment of acute hypersensitivity disorders (hypersensitivity diseases) including asthma and for relief of the status asthmaticus. The compounds have a low toxicity *

The inventive compounds or pharmaceutical compositions (preparations) may be by the oral and rectal routes, topically, parenterally, eg by injection and by continuous or discontinuous intra-arterial infusion _v for example in the form of tablets, lozenges, sublingual tablets, sachets, cachets, e'n elixir Suspensions, aerosols, ointments, for example those which contain 1 to 10 percent by weight of the active ingredient (the active compound) in a suitable substrate, are soft and hard

- 12 -

609852/1077

Gelatine capsules, suppositories, insect ion solutions and suspensions in physiologically compatible media and in the form of sterile packaged powders which are adsorbed on a carrier material for the preparation of injection solutions. For this purpose, the pharmaceutical agents are expediently in a dosage unit form, each dosage unit preferably 5 to pOO mg (5.0 to 50 mg in the case of parenteral administration, 5.0 to 50 mg in the case of inhalation and 2> to 500 mg mg in the case of oral or rectal administration) of a compound of the formula I or XIlI. Doses of from 0.5 to 300 mg per kg per day, preferably from 0.5 to 20 mg per kg of the active ingredient (the active component) can be administered, although it will of course be understood that the particular amount of the compound (s ) of the formula I or XIII ^r by a physician taking into account all the relevant circumstances including the condition of the patient to be treated, the V. ahl of the compound administered and the Y / ahl the route of administration is set ^ and therefore that no means the present invention * reasonably is limited to the preferred dosage range given above.

The term "dosage unit form" as used herein is to be understood as a physically discrete unit which is a single amount of the active ingredient (the active component) , generally in a mixture with a suitable pharmaceutical diluent or otherwise in combination with a pharmaceutical carrier, contains, wherein the amount of the active ingredient (the active component) is so large that for a single therapeutic Administration usually one or more units are required, or that in the case of under-

- 15 609852/1077

divisible units, such as portioned tablets, at least a fraction, such as half or 1/4, a subdivision unit for a single therapeutic Administration is required.

The pharmaceutical agents (preparations) according to the invention normally consist of at least one compound of the formula I or XIlI, which is optionally mixed with a carrier or diluted by a carrier or in a digestible carrier in l ^? in the form of a capsule, sachet, cachet, paper or other container, or in a removable container such as an ampoule, enclosed or encapsulated. The carrier or diluent can be a solid, semi-solid or liquid material which serves as a carrier, excipient or medium for the therapeutically active substance.

Examples of diluents or carriers which are used in the pharmaceutical agents according to the invention can are lactose, dextrose, sucrose, soibitol, mannitol, propylene glycol, liquid paraffin, white soft Paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silicon dioxide, Polyvinylpyrrolidine, ketostea, acrylic alcohol, starch, modified Starches, acacia gum, calcium phosphate, cocoa butter, ethoxylated esters, theobroma oil, arachis oil, alginates, Tragacanth, gelatine, B.P. syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleylalliohol, as well as propellants such as trichloromonofluoromethane, Dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of 'tablets, a lubricant can be used

609852/1077

be incorporated to the gluing and adhering of the powdery components to the embossing molds and to the die of the tablet-making device to prevent. For this purpose, e.g. aluminum, magnesium or calcium stearate, talc or mineral oil be used.

Preferred forms of the pharmaceutical agents according to the invention are capsules, tablets, suppositories, aerosols, injectable solutions, creams and ointments.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

6 0 9852/1077

example 1

6 g (0.046 mol) of 2- (N-methylamino) -5-methyl-1,3, ^/ l -thiadiazole in 190 ml of pyridine were refluxed with 9.7 g (0.069 mol) of benzotrichloride for 6 hours and then the pyridine was evaporated under reduced pressure. The residue was treated with water, made alkaline with a sodium hydroxide solution and extracted with chloroform. The chloroform was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried, filtered and evaporated to give the title compound, which was recrystallized from ethanol.

Example 2

N-2-propenyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) benzamide _ · _

The title compound was prepared from 2- [N- (2-propenyl) amino] using the procedure described in Example 1 -5-methyl-1,3,4 ~ thiadiazole, das was produced by cyclizing 4- (2-propenyl) thiosemicarbazide.

Example 3

N-phenylmethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) benz-

(a) N ₌ £ 3> -Methy_l ₌ 1 _X 3i ^ ithiadiazol ^ yl) benzylamine 23 g (0.2 mol) of 2-amino-5-methyl-1,3,4-thiadiazole

-16 6 0 9852/1077 ^:

and 29.6 ml (0.3 mol) of benzaldehyde were refluxed together in 200 ml of ethanol for 1 1/2 hours heated. The solution was cooled to room temperature and over a period of 5 to 10 minutes 11.35 g (0 »3 mol) of sodium borohydride were added. The mixture was refluxed for 4 hours, treated with additional 5 S sodium borohydride and refluxed overnight. The ethanol was evaporated, the residue was washed with water and extracted with ether. The ether extract was dried over sodium sulfate, filtered and evaporated to leave an oil which solidified. This solid was triturated with ether, filtered, washed with petroleum ether (boiling point 40 to 60 ° C.) and again triturated with ether and filtered, 30.95 g of N- (5-methyl-1,3,4-thiadiazol-2-yl) Benzylamine received, had a melting point of 140 ° C after recrystallization from ether.

(b) N-phenylmethyl-N- (5-methyl-1,3,4-thiadiazole-2-

15 grams (0.073 moles) of N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzylamine in 200 ml of pyridine were refluxed with phenylacetyl chloride for 6 hours. That Pyridine was removed under reduced pressure and the residue was treated with water and with Ether extracted. The ethereal solution was dried, filtered and evaporated to dryness and the residue was recrystallized from ethanol to give the title compound, mp 128 ° C.

Examples 4 to 6

Following procedures similar to that described in Example 3

- 17 -609852/1077

Procedures were similar, the following Vex 'bonds were made manufactured:

N- (p-Chlorobenzyl) -N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzamide

N- o- (Chlorophenylmethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) benzene acetamide

N- (p-Methylbenzyl) ~ N- (5-phenyl-1,3,4-thiadiazol-2-yl) cyclopentane-carboxamide.

Example 7

N-hexyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) benzene acetamide

23 g (0.2 mole) of 2-amino-5-methyl-1,3,4-thiadiazole in 100 ml of toluene were mixed with 50 ml of η-hexanoic anhydride and the mixture was refluxed for 3 hours. The product crystallized when left to stand at room temperature overnight. The product was filtered off and off Recrystallized ethyl acetate, 20.68 g of N- (5-methyl-1,3,4-thiadiazol-2-yl) hexanamide, Mp 203 ° C.

(b) N-O ^

16 g (0.075 mol) of N- (5-methyl-1,3,4-thiadiazol-2-yl) hexanamide were added in portions to 120 ml of stirred tetrahydrofuran (THF) containing 2.9 g (0.076 mol) of lithium aluminum hydride, at a temperature below 15 ⁰ C added. The mixture was stirred and refluxed for 2 hours. The mixture

- 18 -

609852/1077

v; was cooled in ice and mixed with 2.9 ml of water in 29 ml THF, then with 2.9 ml of a 2N sodium hydroxide solution and 5? 8 ml of water treated. The mixture was then Treated with "Supercel" and filtered. The filtrate was evaporated to give the title compound. which was recrystallized from 50% aqueous methanol (9.5 g), mp 101-105 ° C

(c) N ~ hexyl-K- (5-methyl-1,3,4-thiadiazol-2-yl) benzene acetamide _

5.98 grams (0.03 moles) of N- (5-methyl-1,3,4-thiadiazol-2-yl) -hexylamine in 60 ml of toluene were together with 4.59 ml Triethylamine and 4.6A g (0.03 mol) phenylacetyl chloride stirred and refluxed overnight. There were another 4.6 ml of triethylamine and 4 ml Phenylacetyl chloride was added and boiling under the flow of water was continued for an additional 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. Of the Chloroform extract was washed with a 2N sodium hydroxide solution and with water and dried over Ua ^ SO ^, filtered and evaporated to give 8.03 g of the title compound as an oil, b.p. 190 ° C / 0.1 mm. This was recrystallized from ethanol and the title compound was obtained in the form a solid, m.p. 90 ° C.

Example 8

15 grams (0.13 moles) of 2-amino-5-methyl-1,3,4-thiadiazole were treated with 70 ml of isobutyric anhydride. The reaction mixture was allowed to last 1 1/2 hours

_ 19 609852/1077

stirred and heated in an oil bath at 180 to 200 ⁰ C under reflux · The excess anhydride was distilled off under reduced pressure and the solid residue was recrystallized from ethyl acetate to give N- (5-methyl-1,3,4 thiadiazol-2 ~ -yl) -2-methylpropanamide in the form of golden needles.

Examples 9 and 10

The following connections were made in a corresponding manner:

Mp 231-233 ° C, off-white crystalline solid

off-white crystalline solid.

Example 11

1.85 g (0.01 mol) of N- (5-methyl-1,3,4-thiadiazol-2-yl) butanamide were in small portions to a stirred suspension of 0.38 g (0.01 mol) LiAlH ^ in 25 ml added dry THF at 0-5 ° C under a nitrogen atmosphere. The reaction mixture was 2 Stirred and refluxed for hours. A solution of 0.38 was then added to the cooled solution ml of water in 3.8 ml of THF, then 0.38 ml of a 2N sodium hydroxide solution and finally 0.76 ml of water added dropwise and stirred for 1/2 hour. The mixture was filtered through a Su'percel pad and the

- 20 609852/1077

Solution was evaporated under reduced pressure to give a solid which was recrystallized from aqueous ethanol to give ET- (5-methyl-1,3,4-thiadiazol-2-yl) butylamine as a pale yellow crystalline solid, F. 100 to 102 ⁰ C, was obtained.

Example 12

The following was prepared in a similar manner: N- (5-methyl-1,3,4-thiadiazol-2-yl) heptylamine

Example 13

N-butyl-N- (5-methyl-1,3,4 ~ thiadiazol-2-yl) -2-methyl-

3 g (0.0175 mol) of N- (5-methyl-1,3,4-thiadiazol-2-yl) -butylamine and 1'5 ml of isobutyric anhydride were slowly heated on a steam bath for 1 1/2 hours. The excess isobutyric anhydride was removed under reduced pressure and the residue was at a. Pressure of 0.3 nim distilled to give 3.6 g (55%) of an oil, bp. 132 ⁰ C, which is the title compound as a white solid, mp 54 to 57 ° C, gave on cooling.

The compounds given below were prepared in a similar manner.

Examples 14 and 15

_ 21 _ 609852/1077

groganaraid

It was a colorless oil having a boiling point from 152 to 154 ^O C at 0.5 mm, Tj ₂₁ = 1.5108; the NMR, IR and UV spectra confirmed the structure.

Analysis for 0> j, H ₂ , N, 0S:

calc .: C 57.99 H 8.55 N 15.61 found: 57.81 8.67 15.76%.

N-heptyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -2 ~ methyl-

Example 16

N-butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) cyclopro-

1.7 g (0.01 mole) F- (5-methyl-1,3 _J 4-thiadiazol-2-yl) butylamine in 20 ml benzene and 1.15 ml of triethylamine S cyclopropane carboxylic acid chloride was treated with 1.53. The reaction mixture was refluxed for 20 hours. The solution was then evaporated to dryness - and the residue was treated with ether and filtered. The solution was washed with water, dried and treated with activated charcoal, filtered and evaporated and the residue was recrystallized from petroleum ether (bp. 40 to 60 ⁰ C) to give N-butyl-N- (5-methyl-1,3, 4-thiadiazol-2-yl) cyclopropane-carboxamide in the form of a white crystalline solid, P. 82 to 84 ° C.

- 22 -

609852/1077

Example 17

The connection given below was established in a corresponding manner:

N-Butyl-N- (5-methyl-1,3,4 ~ thiadiazol-2-yl) cyclopentane-carboxamide_ _

It was a colorless oil having a boiling point of from 162 to 164- ⁰ C at 0.4 mm; the NMR, IR and UV spectra confirmed the structure. Analysis for C ₁₅ H ₂₁ N ₃ OS:

calc .: C 58.4- H 7.9 N 15.7 found: 58.5 7.6 15.9 %.

Example 18

23 g (0.2 mol) of 2-amino-5-methyl-1,3,4-thiadiazole in 700 ml of IPA and 100 ml of acetone were treated with 20 g of sodium borohydride in portions with stirring and cooling. The reaction mixture was then stirred and refluxed for 31/2 hours. The solution was then poured into 3 l of water and extracted three times with ether. The ethereal solution was dried, filtered and evaporated to give the title compound as a cream-colored solid, mp 14-5 ⁰ C was obtained.

Example 19

It was a white crystalline solid, mp 194- 192 to ⁰ C (from ethyl acetate), the

- 23 - 609852/1077

according to the procedure given in Example 18 vmrde

Example 20

N- (1-methylethyl) -N- (5-methyl-i, 3,4-thiadiazol-2-yl) -benzamide

5 g (0.032 mol) of N- (5-methyl-1,3,4-thiadiazol-2-yl) -1-methylethylamine in 100 ml of pyridine were mixed with 4.1 ml
Benzoyl chloride treated. The reaction mixture was stirred and refluxed for 5 1/2 hours. The pyridine was taken under reduced pressure
removed and the residue was treated with water and extracted three times with ether. The ethereal solution was dried, filtered and evaporated to dryness and the residue was recrystallized from ether / Petroiäther (Kp. 40 to 6O ⁰ C) to give
the title compound as a pale yellow crystalline solid, m.p. 82.5 to 83.5 ⁰ C, obtained.

In a corresponding manner the following compounds were made manufactured:

Examples 21 and 22

1T_ (1-methylethyl) -N- (5-methyl-1,3,4-thiadiazol-2-yl) -

It was a leathery yellow crystalline solid, F. 83 to 85 ⁰ C.

N-Cyclohexyl-li- (5-methy1-1,3,4-thiadiazol-2-yl) cyclo-

Ε £ 2ϊ§2; ζ2§ϊ! ^: ^ 25 ££ ΐ ^

It was a yellow crystalline

-24 609852/1077

Solid, Fo 76.5 to 78.5 ⁰ C.

Example 25

(a) §r2 ^ i2izlr5

A suspension of 47.0 g _(Q? 50 Hol) acetamidine hydrochloride and 83.0 g _(0? 45 Hol) Trichlormethansul-fonylchlorid in 500 ml Diciilormethan was in a flask equipped with a stirrer, a dropping funnel and a thermometer, three-necked flask A solution of 100 g (2.50 mol) of sodium hydroxide in 150 ml of water was slowly added while cooling in an acetone bath and with stirring, keeping the temperature below -8 C by means of a cold plate. After about half of the solution had been added, a color change from red through orange to yellow occurred on further addition. After the addition was complete (after about 5 hours) the precipitated NaCl was filtered off and washed with CHoClo. The organic phase was separated from the water, the latter was shaken _{three times with 30 ml of CH 2} Cl _2. The combined CH ₂ Cl ₂ solutions were washed with water until neutral and then dried over magnesium sulfate. The solvent was evaporated and a red liquid was obtained. The liquid was distilled under vacuum and 27 g (45 %) of 5-chloro-3-methyl-1,2,4-thiadiazole were obtained in the form of a colorless liquid, boiling point 25 ° C./3.5 mmHg.

(b) 5z

27 grams (0.20 moles) of 5-chloro-3-methyl-1,2,4-thiadiazole were dissolved in 200 ml of ethanol and with cooling in

609852/1077

added to an ice bath to an ethanolic solution of 44 g (0.60 mol) of butylamine, overnight at room temperature stirred and concentrated to a small volume. After the addition of ether, a white one fell Butylamine hydrochloride precipitate, which was filtered off. The yellow filtrate was washed with water washed, dried over magnesium sulfate, filtered and evaporated to dryness to give a yellow oil which was distilled in vacuo; included 29.9 g (87.2%) of 5-butylamino-3-methyl-1,2,4-thiadiazole were obtained in the form of a pale yellow liquid, b.p. 101 to 10 2 ° C / O, 14 mmHgo

(c) N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-methylcyclohjsxane-carboxamide _

9.92 g (0.068 mol) of cyclohexanecarboxylic acid chloride was slowly added to a solution of 7 * 0 g (0.054 mol) of 5-methylamino-3-methyl-1,2,4-thiadiazole in dry benzene containing 6.87 g (0.068 Mol) triethylamine was added and the mixture was refluxed for 1 1/2 hours, cooled, vxia washed with 2N hydrochloric acid, a saturated sodium hydrogen carbonate solution and water,.; dried over magnesium sulfate, filtered and concentrated to give a yellow oil which crystallized on standing. This xtfurde twice from petroleum ether (bp. 60 to 80 ⁰ C) recrystallized to give 8.23 g (63.8%) white crystals of N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-methylcyclohexane-carboxamide, Fo 96 ⁰ C.

Examples 24 to 33

Using procedures similar to that in Example

- 26 609852/1077

■ were similar to those described, were the following compounds manufactured:

N- (3-methyl-1,2,4-thiadiazol-5-yl) -li-butyl-2-methyl ~

Bp. II5 to 11? ° C / 0.1 mtnHg
Analysis for C ^ ILjqNzOS:

Calcd .: C 5 ^, 7 ^ H 7.93 N 17.4-1 O 6.63 S 13.28 found: 54.64-7.97 17.3? 6.48 15.36%

N -. (3_Hethyl-1,2,4-thiadiazol-5-yl) -N-butylcycloprppanecarboxamide _ __

F. 43 ⁰ C

H ~ (3-methyl- _{1,2 i} 4-thiadiazol-5-yl) -1) f-butylphenylcarboxamide ^ ^

F. 77 ⁰ C
N- (3-cyclobutyl-1,2 _i 4-thiadiazol-5-yl) -N-octylcyclo «

H- (3-methyl-1 _i 2,4-thiadiazol-5-yl) -N -niethylphenyl

acetamiä_ _ _ _ _ _ "" _,,.

F ₃ 86 ° 0

-1,2,4-thiadiazol-5-yl) -N-2- propenylacetamide

F. 61 ⁰ G

F- (3-methyl-1,2,4-thiadiazol-5-yl) -N -niethyl-2-methyl £ rop_anamid

F » ⁰

H- (3-methyl-1,2,4-thiadiazol-5-yl) -IT- n -butyl-n-hexane amide

Bp. 130 to 135 ° C / O, 15 mmHg _t purified by column chromatography.

- 27-609852 / 1077

Analysis for

calc .: C 59.33 H 8.89 Π 14.83 0 5.65 S 11.31 found : 59.39 8 ₅ 82 15.19 5.87%

N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-2-propenyl-phenyl-acetamide

M.p. 70 ° C

N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-2-propenylcyclogropane-carboxamide _ _ __

F. 76 ⁰ C
Example 34

154.5 S (0.5 Hol) trichloroacetic anhydride was added to a stirred solution of 34.0 g (0.25 mole) benzamidoxime in 160 g dry trichloroacetic acid in an oil bath at about 60 ° C. The reaction mixture was ^{heated to 120 °} C. for 20 minutes and poured into 400 ml of ice / water to cool. The organic layer was separated, washed with water and taken up in 500 ml of carbon tetrachloride and neutralized by washing with a saturated NaHCO ^ solution. After drying over MgSO ^ and after evaporation of the carbon tetrachloride, the product was distilled, boiling point 118 ° C./0.07 mmHg.

Example 35

3-Methyl-5-trichloromethyl-1,2,4-oxadiazole was prepared in a similar manner.

-28 -

609852/1077

Example 36

43 g (0.21 mol) of 3-methyl-5-trichloromethyl-1,2,4-oxadiazole were added to 46.75 g (0.63 mol) of n-butylamine, and the mixture was stirred at room temperature over times The excess amine was removed in vacuo and the residue was distilled (oil bath 110 ° C./0.5 mmLTg). Recrystallization from petroleum ether (boiling point 60 to 80 ° C.) gave 26 g of the title compound in the form of white Plate, F. 62 to 65 ⁰ C.

Example 37

N-n -Butyl-N- (3-methyl-1,2,4-oxadis.zol-5-yl) -n -butanamide

4.2 g (0.03 col) of 5-butylamino-3-methyl-1,2,4-oxadiazole and 4.75 g ("0.033 mol) of butyric anhydride were refluxed in 30 ml of toluene for 3 hours After removing the toluene in vacuo, the residue was refluxed in 60 ml of methanol with a few drops of triethylamine for 1 hour, the methanol was evaporated in vacuo and the residue was taken up in CHoClo, twice with 2N HCl and twice with saturated NaHCO3 , washed solution over MgSO (40 Kp. ⁰ to 60 C) to thereby obtain the solution polarity to 10% ether / -Petroläther was increased _2-dried. the product was purified by column chromatography (120 g silica gel) with Petroiäther page. Fractions were combined and distilled in a Kugelrohr air bath at 119 ° C / 3.3 mmHg.

- 29 * 609852/1077

Analysis for C ^ H ^ gN ^ O ..,:

Calcd .: C 58.64- H 8.50 N 18.65 O 14-, 2O found: 58.78 8.30 18.40 14-, 18%.

Examples 38 to 44-

Using the procedure described in Example 37 " the following oxadiazoles were produced:

N-ethyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methyl-

Bp 92 ° C / 3.0 o

Analysis for CnH ^ ₁₁ N ^ Og:

calc .: C 54.80 H 7.66 IT 21.30 O 16.22 found: 54.68 7.46 21.14 16.33%.

i £ l £ z? B £ 2iliizi5-2ethyl-1 ^ 2 _Α 4-οχ8αΐΕζο1 ~ _: 5-2.1) acetamid V 2Ω ⁼ ^ * ^ + ^{8 of the} liquid.

N-butyl-N- (5-ffiethyl-1,2,4-oxadiazol-5 ~ yl) -2-methyl-

p_rop_anamid, ___,

Kp. (Air bath temperature) 98 ° C / 1.5 mffillg. Analysis for C ^^ K ^ gN ^ Og:

calc .: C 58.65 H 8.50 K 18.66 O 14.20 found: 58.49 8.22 18.40 14.18%.

Analysis for C ^, Ho ₇ N ^ Og:

Calcd .: C 61.63 H 9.15 N 16.58 O 12.63 found: 61.89 9.39 16.33 12.65%.

- 30 609852/1077

groganamid
48 ° C.

N-Butyl-II- (3-phenyl-1,2,4-oxadiazol-5-yl) -2-diethyl propanamide _ _

Bp. 140 ° C / 7 imnHg air bath temperature. Analysis for C ^ gHp ^ lLjO-:

calc .: C 66.88 H 7.37 N 14.62 0 11 found: 67.07 7.38 14.38 11.06%.

M.p. 74 ^° C

Example 4 5

4.6 g (0.025 mole) of 5-n-hexylamino-3-metnyl-1 _f 2,4-oxadiazol ^^ nirden dissolved in 25 ml of acetic anhydride and refluxed for 5 hours under ₅ then evaporated to dryness. The residue was dissolved in 50 ml of CHOl? taken up and washed twice with 2N HCl and twice with a saturated HaHCO ^ solution and _{dried over MgSO 4} , boiling point 113 to 114 ° _{C./1 9} 0 mmHg. Analysis for C ^ H

calc .: C 58.64 H 8.50 Ή 18.65 0 14.20 found: 58.66 8.76 18.57 14.48%.

Example 46

Using the Ver The following oxadiazole was produced:

-31 " 609852/1077

N- (3-methyl-1,2,4-oxadiazol-5-yl) -IT ~ 2-propenylacetate amid _ _

Bp. 82 ° C / 1.5 mmHg air bath temperature. Analysis for CqILj ^ EUO ₂ :

calc .: C 53.02 H 6.12 N 23.19 0 17.66 found: 52.78 5.90 23.03 17.69%

example

N- (3-methyl-1,2,4-oxadiazol-5-yl) -Ii- (4-methyl / 1-phenyl) -meth ^ laminoc ^ cloprojan-carboxamide '

3 »4-5 S (0.033 mol) of cyclopropanecarboxylic acid chloride was added to a solution of 6.1 g (0.03 mol) of 5- (4-methylphenyl) methylamino-3-methyl-1,2,4-oxadiazole and 3,4 -5 g (0.033 mol) of triethylamine in dry benzene were added dropwise, the temperature being kept below 10 ° C. After the addition was complete, the temperature was allowed to reach room temperature and then refluxed overnight. After cooling, the reaction mixture was washed twice with 2N HCl and twice with a saturated NaHCO, solution, dried over MgSOn and treated with activated charcoal. The product was purified by column chromatography (110 g silica gel), where (kp. 40 to 60 ⁰ C) with petroleum ether was eluted by increasing the polarity to 10% ether in petroleum ether. The title compound was recrystallized from petroleum ether (bp. 60 to 80 ⁰ C) to give white needles received, F. 49.5 "to 5O, 5 ° C.

Examples 48 to 59

Using that described in Example 47

-32 609852/1077

The method indicated below wide ren oxadiazoles were prepared:

N-n-Butyl-i! - (3-methyl-1,2,4-oxadiazol-5-yl) cyclo-

ψ = 1.4882.

-1,2,4-oxadiazol-5-yl) cyclopentanecarboxamide _._ _

Bp. 121 ° C / 1.4 mmHg (air bath temperature! Analysis for C ^ c ^ 2 ^c F ⁷ P2 ''

calc .: C 64.48 H 9.02 Έ 15.04 0 11.52 found: 64.76 8.86 14.82 11.52%.

K-Hexyl-IT- (3-ynethyl-1,2,4-oxadiazol-5-yl) cyclohexanes arboxamid _

Bp. 157 ° C / 1.5 mmHgC air bath temperature X Analysis for € ^^ 2 ^ x02:

calc .: C 65.49 H 9.27 Ή 14.32 0 10.9 found: 65.58 9.05 14.19 10.95%.

N-hexyl-ΪΓ- (3-methy_l-1 _i 2 _i 4-oxadiasol- _: 5-yl) benzamide

Bp. 126 ° C / 0.2 mmHg (air bath temperature). Analysis for C ^ g ^^ MVOp:

calc .: C 66.87 H 7.36 IT 14.62 0 11.13 found: 66.85 7.35 14.58 11.27%.

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-2-propenylcyclo-

grogan-carboxamide _

Bp. 120 ° C / 10 mmHg (air bath temperature).

- 33 -

609852/1077

N- (3-Methy1-1,2,4-oxadiazol-5-yl) -N-phenylmethyl-

73 ° C.

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-phenylniethylbenzamide _.

F. 75 ⁰ C

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-phenylmethyl-2 methy_lp_roj> anamid _ _

Bp 127 ° C / 3.00 mmHg.

N- (4-methoxyphenyl) methyl-N- (3-diethyl-1,2,4-oxadiazol-5-yl) -cycloiiexane-carboxamide

M.p. 70 ° C.

-1,2,4-oxadi -) - 2-meth2; l2roganamid_

Bp. 118 ° C at 0.2 ramHg (air bath temperature) N- (4-methylphenyl) methyl- N- (3-met] 3yl-1,2,4-oxadiazole

Example 60

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N -isopropylamino-2

7 »9 g (0.05 mol) of isobutyric anhydride became Isopropylamino-3-diethyl-1,2,4-oxadiazole added and heated to 100 ° C overnight. After cooling, 60 ml of methanol and a few drops of triethylamine were added added and refluxed for 1 hour. After removing the methanol under vacuum

-34 _ 609852/1077

the residue was taken up in ether and washed twice with a saturated NaHCO, solution, bp. 90 ° C / 1.3 mmllg, Kugelrohr air bath temperature.

Example 61

N- (5-methyl-1,3 »^ - oxadiazol-2-yl) -N-n-propylcyclo-

(a) 1-Acetyl-4-alljlsemicarbazide

25 g (0.30 mol) of allyl isocyanate slowly added a boiling solution of 22.2 g (0.30 mol) of acet-,: hydrazide in 300 ml of dry benzene was added. The mixture was heated for 1 hour during which two. Layers formed. The benzene was then evaporated and the residue was triturated (treated) with ether, whereby the title compound was obtained as a white solid, mp 71-74 ° C.

(b) 5-MethyJL-2-n- £ rop £ lamino-1l ^ j,

35 g (0.22 mol) of 1-acetyl-4-n-propylsemicarbazide, prepared according to the procedure given in section (a) above, was refluxed with 150 ml of POCl _{5 for} 2 hours until no HCl more was developed. The excess POCl was removed by means of a water pump and the mixture was poured into 200 ml of ice water and neutralized to pH 7 with 50% NaOH. A red oil was extracted with 2 180 ml of dichloromethane, this was dried, filtered and evaporated to dryness to give an oil which was distilled in a Vigreux flask to give the title compound as a pink liquid which at the Let stand to a solid

609852/1077

crystallized, m.p. 46.5 to 4-7.5 ° C

(c) N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl-C2clobutane-earboxamid_

6 g (0.04 mol) of 5-methyl-2-n-propylainino-1,3,4-oxadiazole, which had been prepared as indicated in section (b) above were treated with 5 »5 S (0.05 mol) Cyclobutanecarboxylic acid chloride in 25 ml of benzene in the presence of 4.72 g (0.05 mol) of triethylamine heated under reflux for 2 hours. The mix was filtered and the filtrate was washed with dilute HCl, a saturated NaHCO, solution and water, dried over magnesium sulphate, filtered, the solvent was evaporated and one obtained reddish-brown liquid that has been distilled twice in a Vigreux flask to give the title compound received in the form of a pale pink liquid, boiling point 110 to 111 ° C / 0.27 mmHg.

Examples 62 to 69

Using the procedure described in Example 61, the following additional ones were identified Oxadiazole manufactured:

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl-2-

Bp. 85 to 87 ° C / 0.4 mmHg.

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N- n -propylcyclo

Bp. 120 to 121 ° C / 0.2 mmHg.

- 36 609852/1077

gentane carboxamide

Bp. 110 to 112 ° C / 0.12 mmHg.

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-2-propenyl-2

Bp 93 ° C / O.18 mmHg.

N- (5-methyl-1,3,4-oxadiasol-2-yl) -N-2-propenyl-2

Bp 114 to 116 ° C / O, 12 mmHg.

IT- (5-methyl-1,3,4-oxadiazol-2-yl) M "-n-hexyl-n-hexanamide

Bp 116 ° C / O, 1 mmHg.

N- (5-methyl-1,3, ^ - oxadiazol-2-yl) -N-n-buty3r2-methyl groganamid

Bp. 82 to 84 ° C / 0.1 mmHg.

Bp. 82 to 84 ° C / 0.1 mmHg.

Example 70

Using a procedure similar to that described in Example 37, the following was carried out specified 1,2,4-oxadiazole produced:

N-n-hexyl-N- (3-methyl-1,2,4 ~ oxadiazol-5-yl) -2-

Bp. 90 ° C / 1.1 mmHg.

Analysis for 0 ^^ 2, ^, 02:

calc .: C 61.63 H 9.15 N 16.58 0 12.63 found: 61.47 8.98 16.84 12.70%.

-37 -609852/1077

Examples 71 "to 73

Using the procedure as generally described in Example 4-7 ", the following were made specified other oxadiazoles produced:

N-methyl-N- (3-methyl-1,2,4-oxadiazol - 5-yl) cyclohexane

Analysis for

calc .: G 59.17 H 7.67 N 18.82 O 14.33 found: 59.05 7.59 18.41 14.73 %.

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-2-propenylhegtanamide

Bp. 104 ° C / 1.5 mmHg.

Analysis for C ^ iL ^ lM ^:

calc .: C 62.12 H 8.42 N 16.71 0 12.73 found: 62.16 8.20 16.54 12.63%.

E "- (3-methyl-1,2,4-oxadiazol-5-yl) -N-n-butyl-2-ethyl butanamide

Bp. 71 ° C / O, O55 mmHg.

Analysis for (Lj ^ H ^ IM ^:

calc .: G 61.63 H 9.15 N 16.59 0 12.63 found: 61.46 8.90 16.57 12.47%.

Example 74

N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-phenylmethyl-n-hexanamide

This compound, m.p. 72 ° G, - was made using the procedure given in Example 23.

609852/1077

_38 _.

Examples 75 to 77

Using procedures similar to that described in "Example", the following were set forth other 1,2,4 - thiadiazoles produced:

F. 38 ⁰ C

N- (3-methyl-1,2,4-thiadiazol-5-yl) -Ii-hexylphenyl acetate

F. 57 ⁰ G

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

Examples 78 to 86

Using procedures similar to that described in Example, the following were set forth other 1,2,4-oxadiazoles produced: N-butyl-N- (3-niethyl-1,2,4-oxadiazol-5-yl) phenyl-

Analysis for

calc .: C 64.84 H 6.61 N 16.21 O 12.34 found: 65.09 6.35 15.99 12.07%.

R-Butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -4-chlorjhenyl-carboxamide

Analysis for O

calc _. : C 57.24 H 5.49 Cl 12.07 N 14.30 O 10.89 Found: 57.4-5 5.63 12.07 1 ^, 14 11.17%.

- 39 609852/1077

N-Butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -4-methoxyphenyl-carboxamide _ _ _ _ _ _ _ _

B.p. 105 ° C / 0.15 mmHg

Analysis for C ^, -H ^ qN, O,:

calc .: C 62.27 H 6.62 N 14.52 0 16.59 found: 61.99 6.47 14.42 16.74%.

N-Butyl-K- (3-ynethyl ~ 1,2,4-oxadiazol-5-yl) cyclohexanecarboxamide_ _ _ _

Bp 70 ° C / 0.01 mmHg

Analysis for C ^ H ₂₇ IUO ₂ :

calc .: C 63.37 H 8.74 Ν 15.84 found: 63.54 8.55 15.60%.

N-butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclobutane

carboxamide ______ _ __ _

Bp 67 ° C / 0.02 mmHg

Analysis for

calc .: C 60.74 H 8.07 N 17.71 0 13.49 found: 60.44 7.88 17.54 13.21%.

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-propyl-2-methylgroganamide _ _ _ _ _ _ _ _ _ _

Bp 62 ° C / 0.15 mmHg

Analysis for C ^ qH ^, JÜM ^:

calc .: C 56.85 H 8.11 N 19.89 found: 56.93 8.14 19.64%.

K-butyl-N- (3-butyl-1,2,4-oxadiaz ol-5-yl) cy c3opropan-

Analysis for

calc .: C 63.37 H 8.74 N 15.84 0 12.06 found: 63.19 8.51 15.58 11.82%.

- 40 -609852/1077

-1,2,4- oxadiazol-5-yl) cyclopropan-

Bp 65 ° C / 0.01 mmHg

Analysis for C ^ ₂ Hzjo ^ zC ^:

Calcd .: C 60.74- H 8.07 B "17.71 0 13.4-9 found: 60.50 7.78 17.4-3 13.19%.

N-Butyl-N-O-cyclohexyl-i, 2,4-oxadiazol-5-yl) cyclo-

Analysis for C ^ gHgcN ^ Og. ·

calc .: 0 65.95 H 8.65 N 14-, 42 0 10.98 found: 66.15 8.83 14.51 10.86%.

Examples 87 to 89

Using procedures similar to that described in Example, the following were made specified other oxadiazoles produced:

N-butyl-K- (3-ethyl-1,2,4-oxadiazol-5-yl) -2-methylp_ro £ anaide

Bp 65 ° C / 0.02 mmHg

Analysis for Cz ₁₂ H ₂ ^ NxOg:

calc .: 0 60.22 H 8.85 N 17.56 0 13.37 found: 59.96 8.68 17.36 13.22%.

N-butyl-IT- (3-butyl-1,2,4-oxadiazol-5-yl) -2-methylp_rop_§namide

Bp 64 ° C / 0.05 mmHg
Analysis for

calc .: C 62.89 H 9.42 Ή 15.72 0 11.97 found: 62.65 9.20 15.46 11.72%.

-41 -

609852/1077

N-Butyl-N- (3-cyclohexyl-1,2,4-oxadiazol-5-yl) -2-methylpropanoid

Bp 92 ° C / 0.02 mraHg

Analysis for ^ ΐβ ^ οηΝ, Ορ:

Calcd .: C 65.9 H 9.28 N 14.32 O 10.91 found: 65.26 9.09 14.07 11.05%.

Examples 90 to 97 given below illustrate pharmaceutical preparations (agents) that as the active ingredient the active compound F-n-hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclopentane-carboxaraid contain.

Example 90

Soft gelatin capsules were made using the components listed below:

g ( mg / capsule )

active compound (active ingredient) 30 butylated hydroxyahisole BP 0.02 fractionated coconut oil B.PvC. 70

100.02

The above components were mixed together and filled into soft gelatin capsules, whose main shell components were gelatin and glycerin.

Example 9 ^

The procedure of Example 90 was repeated, wherein

- 42 609852/1077

this time instead of the butylated hydroxyanisole as Antioxidant an identical amount of propyl gallate was used.

Example 92

Using the components listed below hard gelatin capsules were made:

Amount (mg / capsule)

active compound (drug) 23

Silica (fumed) 23

Lactose 48 butylated hydroxyanisole B.P. 0.02

The butylated hydroxyanisole was dissolved in the active compound (drug) and thus obtained Solution was adsorbed on the silica (fumed). Then the lactose was added and that Everything was mixed. Finally the mixture was filled into hard gelatin capsules.

Example 93

An ointment was prepared using the following components:

active compound (active ingredient) 1.5% by weight butylated hydroxyanisole BP 0.02% by weight white soft paraffin ad 100 %

-43 609852/1077

The hydroxyanisole was in the molten paraffin dissolved tmd the active compound (the drug) has been then added and the mixture allowed to cool.

Example 94-

A topical cream containing 1.0 % of the active compound (ingredient) was prepared as follows:

Amount in g

active compound (drug) 1.0

Cetomacrogol 1000 3.0

Cetostearyl alcohol 11.5

liquid paraffin 9.0

butylated hydroxyanisole B.P. 0.02

distilled water ad 100.0

The active compound was mixed with the hydroxyanisole and suspended in the liquid paraffin. The cetostearyl alcohol was added and the mixture was heated with stirring to 70 ⁰ C. The cetomacrogol 1000 was dissolved in 60 g of water heated to 70 ⁰ C wor-.the was dissolved. The cetostearyl alcohol and the liquid paraffin / active compound mixture were then poured into the Cetomacrogol 1000 aqueous solution with stirring, and stirring was continued until the cream was cold. The cream was then brought to the desired weight with water and passed through a stainless steel colloid mill with a gap set at 0.381 mm (15 mils).

- 44 609852/1077

Example 95

As indicated below, suppositories were made the 25 mg and 50 mg of the active compound (of the active ingredient) contained:

active compound (ingredient) 2.5 g Ilenkel base 97? 5 6

The active compound (the active ingredient) was made with the handle base, previously using a possible a small amount of heat had been melted. The mixture was then put into suppository forms with a nominal capacity of 1 g or 2 g, as desired, poured, preserving suppositories each containing 25 mg or 50 mg of the active ' ven compound (of the active ingredient) contained.

Example 96

An aerosol was produced which contained the following components:

Amount per ml

active compound (drug) 10.00 mg propylene glycol 10.00 mg

Dichlorotetrafluoroethane
(Propellant 114) 550.00 mg

Dichlorodifluoromethane
(Propellant 12) 830.00 mg

The active compound (drug) was mixed with the propylene glycol and the mixture became the Propellant 114 was added, the mixture was adjusted to -I5

609852/1077

Cooled to -20 ⁰ C and transferred to a filling device. At the same time, a mixture of the propellant 114 and the Propellant 12, which had previously been cooled to -15 to -20 ⁰ C, poured into a second filling device. A metered amount of the propellant from the second filling device was introduced into a stainless steel container, after which the required amount of material was introduced from the first filling device. Then the valve units were inserted and the container was sealed. These valve units were provided with a metering device so that about 0.15 mg of the active compound (the active ingredient) was released (dispensed) with a single actuation of the valve.

Example 97

Tablets were made using the components listed below:

active compound (ingredient) 10.00 mg

microcrystalline cellulose 250.00 mg

IT aJbr ium carboxy methyl 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 drug) and the resulting solution was adsorbed on the microcrystalline cellulose. This was mixed with the sodium carboxymethyl starch and then the magnesium stearate was mixed in. Eventually the mixture turned into tablets

_ 46 609852/1077

pressed.

In the above-described examples 90 to, the liquid active compound (the active ingredient) used according to the invention can be completely or partially replaced by one or more other liquid active compounds (active ingredients) of the formula (I) or (XIII) given above. Of course, if the active compound (ingredient) is a solid, appropriate modification must be made.

Pat ent test 609852/1077

Claims (34)

To notifier ; Lilly Industries Limited 0 R 9 r, 7 Q r: Henrietta House, Henrietta Placed L J ZO ο London W.1 / England Claims JK Process for the preparation of a heteroaryl compound the general formula (I) Ar-KE ^{1 1} p . coir where mean: Ar is a 5-membered heteroaryl nucleus or ring which contains zv / ei'nitrogen atoms as the only heteroatoms and a further heteroatom from the group consisting of oxygen and sulfur, the heteroaryl nucleus or ring optionally being replaced by IPormyl, carboxyl, hydroxyl, C ₁ ^ -Hydroxyalkyl, C ₁ ^ -AIlCyI, C ^ Q -cycloalkyl, C-, g-acyloxyallcyl, optionally substituted phenyl or halogen is substituted and where the Ί 2
Acylamino group -KR COR is bound to a carbon atom of the heteroaryl ring, E ¹ C _1-10 -AlCyI, C ^ g-alkenyl, C ₂ _ ₅ -alkynyl, C ₂ __ ₆ -alkoxyalkyl, Cp _ ^ - carboxyalkyl, C ₁ _g-haloalkyl, C _7-10 -cycloalkyl, C ^ _{- 1} Q-CyClOaIk; ¹ '1-C ₁ _g-alkyl, optionally substituted phenyl-C ₁ _g-alkyl or optionally substituted phenyl-Cp_g-alkenyl and. EC ^ _{1 D} -alkyl, C _x, - haloalkyl, C _0, - alkenyl, C, _ΛΓί - cycloalkyl, C ₇ _ ₁₀ cycloalkyl-C ₁ _ ₆ -alk7 / l, optionally substituted phenyl, optionally substituted phenyl-C 1, - alkyl or optionally substituted phenyl-C ₂ _g-alkenyl 1 · '2
or E and E together form a lactam ring with 5 to 7 single atoms, 609852/1077 _ ₂ - with the proviso. that then " a) when Ar is 1,3 ₅ 4-thiadiazolyl, RC _{x ,?} 2
and _{R x} , "-alkyl, C _x ," -haloalkyl, C ₀ , -alkenyl or C 1-4 cycloalkyl, the 1,3,4-thiadiazole / l group not unsubstituted or by C _x , 1-4 alkyl or Halogen can be substituted, b) if Ar is substituted by a C _x , _b -alkyl group 1 i3i ^ ~ '^ h.ia.diRzo1zr1 and R is trichloromethyl, E cannot be C _X | _g-alkyl or C ₀ , - alkenyl, c) when Ar is 1,3,4-thiadiazolyl substituted by meth.yl 1 2 and R is p-bromophenyl, R cannot be methyl d) if Ar is 1,2,4-0xadiazol7 / l substituted by phenyl i P means that R cannot be methyl or benzyl if R ~ represents methyl, characterized in that one a) acylated an alkyl derivative of the general formula (VIII) ArKHR ¹ wherein Ar and R have the meanings given above, b) an acyl derivative of the general formula is alkylated (IX) ArMCOR ² wherein Ar 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl or 1,3,4- Is oxadiazolyl and R has the meanings given above, c) a compound of the general formula (X) * ArY 609852/1077 " ³ " wherein Y is a leaving (removable) group and Ar has the meanings given above, is reacted with a salt of the general formula (XI) '■ - MKR ¹ COR ² wherein M is a Group IA or HA metal of the Periodic 1 2 iVystems means the elements and E and R the above have given meanings, or d) a compound of the general formula is cyclized (XII) - ArMEZ where Ar has the meanings given above and Z is -CO (OH ₂ J _n Q, - (CH ₂ ) _n COQ 'or cyclopropylcarbonyl, where η is an integer from 3 to 5 »Q is a leaving (removable) group and Q' a group that the neighboring carbonyl group for nucleophilic attack O O activated, or -OR, in which R is hydrogen or C ^] _ j, -alkyl, with formation of a compound of the general formula I in which R and R form a lactam ring with 5 to 7 atoms * 2. The method according to claim 1, ■ characterized in that a compound of the general formula I given in claim 1 is prepared, wherein the Heteroarjrlkern or ring Ar is optionally substituted by a representative from group G , alkyl, C- , "-Cycloalkyl • j I— f, 9 — O and phenyl, RC ^ _ ₈ -alkyl, C ^ g-alkenyl, C, Λ-cycloalkyl or benzyl, which is optionally substituted by halo- p gen, C ^ | _ ^ - alkyl or C ^ _ ^ - alkoxy, and R C ^^ g Cycloalkyl, benzyl or phenyl, which is optionally substituted by halogen or C * ^ .- alkoxy, mean. 609852/1077 3. The method according to claim 1, characterized in that the heteroaryl nucleus or. ^r . -ring Ar through a CL ^ - Alkyl group is substituted, RC ^ _g-alkyl, C ₇ _c-alkenyl or benzyl and RC ^ _- g-alkyl, C ^ ^ cycloalkyl or benzyl "mean. 4. The method according to one of the · claims 1 "to 3» characterized in that characterized in that the heteroaryl nucleus or ring is a that of the 1,2,4-oxadiazolyl system ^ is. 5. Compound characterized by the general formula (IX) ArKHCOH ² wherein Ar is a 1,2,4-thiadiazoyl, optionally substituted phenyl or halogen optionally substituted by formyl, carboxyl, hydroxyl, C ^^ - alkyl, C ^ _ _{10 ~ cycloalkyl, C ^ _g-acyloxyalkyl} , 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl nucleus bz #. -ring loading 2
and R have the meanings given in claims 1 to 3, with the proviso that then, (a) if Ar is unsubstituted or _{substituted by G ^^ - alkyl, C 7} .Q-cycloalkyl or optionally substituted phenyl 2 ated 1,2,4-thiadiazolyl means, R is not C 1-4 _z . or G can represent _x , ^ -haloalkyl, and (b) when Ar is 1,2,4-oxadiazolyl substituted by phenyl, R not G ^ _Q -Alk7, ^r can be l.
ι — ο 609852/1077 - 5 - 6. heteroaryl compound, characterized by the general formula (I) Ar-NR ^{1 1} ο coir where "mean: Ar is a 5-membered heteroaryl nucleus or ring, the the only heteroatoms are two nitrogen atoms and one another heteroatom from the group oxygen uiid Containing sulfur, wherein the heteroaryl nucleus or ring is optionally substituted by formyl, carboxyl, H7 / dro>: yl, C ₁ ^ -Hydroxylaklyl, C ₁ _ ₄ ~ alkyl, C ^ _{1 Q} -CycIoalkyl, C, g-acyloxyalkyl, optionally substituted phenyl or halogen and wherein the acylanino 1-2
group -NR COR on em carbon atom of the hetero- aryl ring is built,
RC ^ Q-alkyl, C ₂ _g-Alken7 / 1, C ₂ _g-alkynyl, C ₂ _galkyl, C2_g-carboxyalkyl, C ^^ - haloalkyl, 0, ^ ₀ -cycloalkyl, C, _ ^ Q -cycloalkyl-C ^^ - alkyl, optionally substituted phenyl-C ^ g-alkyl or optionally substituted phenyl-C2 ^ -alkenyl and R ² is C _1-8 -A ^ yI, C _1-6 haloalkyl, C ₂ _ ₆ alkenyl, C _3-10 cycloalkyl, C ₇ __ ₁ Q-cycloalkyl-C ₁ _g alkyl, optionally substituted phenyl, optionally substituted phenyl-C ^ _ ^ - alkyl or optionally substituted phenyl-C ₂ _g-alkenyl, 1 p
or R and R together form a lactam ring with 5 to 7 ring atoms, with the proviso that then, 609852/1077 a) if Ar is 1,3,4 ~ thiadiazolyl, R 0, _Λ , -alkyl and EC ₁ "-alkyl, C ^^ - haloalkyl, C ₂ , -alkenyl or C, - are cycloalkyl, the 1, not unsubstituted 3,4-thiadiazolyl, or by C ₁ _ - alkyl or halogen may be substituted, b) if Ar is _{1,3,4-thiadiazolyl substituted by a C x} , ^, - alkyl group and R is trichloromethyl, R ¹ cannot represent C _x , - alkyl or Cp _- , - alkenyl, c) when Ar is 1,3,4-thiadiazolyl substituted by methyl and R is p-bromophenyl, R cannot be methyl, and d) when Ar is 1,2,4-oxadiazolyi substituted by phenyl, R cannot be methyl or benzyl when R ^{2 is} methyl. 7. A compound according to claim 6, characterized in that in the general formula I the heteroaryl nucleus or ring Ar is optionally substituted by a representative from the group C ₁ -Z, -alkyl, C-, g-cycloalkyl and phenyl, R ¹ C ^ "alkyl, C _x , - alkenyl, G ₇ " cycloalkyl or Benz7 / "lj <3- ^{as is} optionally substituted by Ha- 2 logenC ^, .- alkyl or C _x, ,, - alkoxy, and R G _{n R} alkyl, C ^ o-cycloalkyl, benzyl or phenyl, which is optionally substituted by halogen or C ₁ _ _L alkoxy radical. 8. A compound according to claim 6, characterized in that in the general formula I the heteroaryl nucleus bz'v. -ring Ar is substituted by a C _{1- /} , -alkyl group, RC _1-6 -AIlCyI, C _- , - alkenyl or benzyl and R ^G 5_ß-alkyl, C -, __ g-cycloalkyl or benzyl. 9. A compound according to any one of claims 6 to 8, characterized in that it is the heteroaryl nucleus or -ring Ar around one of the 1,2,4-oxadiazole system acts. 6 09852/1077 10. N-hexyl-n- (5-methyl-1,3, ^ - thiadiazol-2-1) ~ 2-yneth; / l propanamide. -1,3, ^ - thiadiazol-2-yl) -cyclopentane-carboxamide. 12. IT -. (3-Methyl-1,2,4-thiadiazol-5-yl) - N -methylph-n7iacetamide. 13. Έ- (3-Methy1-1,2,4-thiadiazol-5-yl) -N-methyl-2-methylpropane arid. 14-. N- (3-methyl-1,2,4-thiadiazol-5-yl) -1 · T -2-propenylc; 7clo propane carboxamide. 15. H-n-Butyl-N-O-methyl-i, 2,4-oxadiazol (5-yl) -n- "butanamide. 16., N-ethyl-H- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methyl- propanamide. 17. N -Butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methylpropaniaide. 18. N -Butyl-H- (3-methyl-1,2,4-oxadiazol-5-yl) -hexanamide 19. N-Ethyl-H- (3-phenyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide. 20. N-n -Butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -cyclopropanecar "boxaniid. 21. F-Hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -cyclopentanecarboxanide. 609852/1077 "8" -SV- 22. N- (3-Hethyl-1,2,4-oxadiazol-5-yl) -N-2-propenylcyclo propane-carboxamide. 23. N- (3-methyl-1,2,4-oxadiazol-5-yl) -F-2-methylpropananide. 24. N- (5-diethyl-1,3,4-oxadiaz o 1-2-7 / 1) -! T-2-propenyl-2-cyclopeni: arLcarboxamide. 25. N- (5-methyl-1,3,4-oxadiazol-2-yl) -F-n -but7l-2-methylpropanamide. 26. N-Butyl-N- (3-methyl-1,2,4-oxadiazole-5-7l) -phenylcarboxaraid. 27. N -Butyl-H- (3-methyl-1,2,4-oxadiazol-5-yl) -cyclohexanecarboxamide. 28. N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-propyl-2-methylpropanamide. 29. N-Biityl-lf- (3-ethyl-1,2,4-oxadiazol-5-yl) -cyclopropanecarboxamide. 30. ir -Butyl-N- (3-ethyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide. 31. H-Butyl-K- (3-cyclohexyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide. 609852/1077 32 · Pharmaceutical agent, characterized in that There is at least one Heterοary! connection of the general formula (XIII) 'Ar-HR ¹ COR ² where "mean: Ar a ^ -glleärlgeiL heteroaryl nucleus "or ring, which contains as the only heteroatoms zv / ei nitrogen atoms and a further heteroatom from the group oxygen and sulfur, the heteroaryl nucleus or ring optionally by sbrmyl, carboxyl, H7 / droxyl, C. . ^ - Hydroxyalkyl, C ^ -haloalkyl, C ,, ^ -alkyl, C _3-10 -cycloalkyl, C _3-6 -ACyIoxyalkyl, optionally substituted phenyl or halogen is substituted and the 1 2
Acylamino group -ITR CuR is bonded to a carbon atom of the heteroaryl nucleus or ring, R ¹ is C _1-10 -AIk ₇ I, C ₂ _ ₆ alkenyl, C _3-6 -AIkIn ₇ I, C ₂ _ ₆ alkoxyalkyl, C _2-6 carboxyalkyl, C _1-6 haloalkyl, C _{3 -10} -Cycloalkyl, C ^ Q -cycloalkyl-C ^ g-alkyl, optionally substituted phenyl-C ^ g-alkyl or optionally substituted phenyl-C _2-6 -alkenyl and R ² is C _1-8 alkyl, C _1-6 -HaIOgOiIaIl ^ l, C ₂ _ ₆ alkenyl, C _3-10 cycloalkyl, C _3-i0 cycloalkyl-C _1-6 alkyl, ■ if gegebenen- substituted phenyl, optionally substituted phenyl- _6- alkyl or optionally substituted phenyl-C _2-6 -alkenyl or R and R together form a lactam ring with 5 to 7 ring atoms, possibly in combination with a suitable Contains pharmaceutically acceptable carrier or excipient . · 609852/1077 - 10 - 33 · Pharmaceutical agent according to claim 33, characterized in characterized in that there is at least one compound according to one of claims 6 as the compound of formula XIII to 31 contains. 34. Pharmaceutical agent according to claim 33 or 34-, characterized in that it is in the form of a tablet, a capsule, an ointment, a cream, a suspension, a suppository, an injection solution, an aerosol or an ampoule. 609852/1077