FI63394C - ANALOGIFICATION OF CHEMICAL TREATMENT OF CHEMICAL THERAPEUTIC EQUIPMENT - Google Patents

Description

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Patent ·) a register-registered / 44) NihttvUuipwwn and kmjL) uik * taun date. - oR no patent · och registerstyrelsen '' Ainekin uthgd och uti ^ krttm pubUcmd · Ud · · 05 (32) (33) (31) Pyritty «ueikiu * —Bogird priorities 05.06.75

English-England (GB) 2 ^ 22it / 75,

Proven-Styrkt (71) Lilly Industries Limited, Henrietta House, Henrietta Place,

London W.I., England-England (GB) (72) William James Ross, Lightwater, Surrey, John Pomfret Verge,

Henley-on-Thames, Oxon, William Robert Nigel Williamson,

Slough, Buckinghamshire, England-England (GB) (Jb) Oy Kolster Ab (5 * 0 Analogue method for the preparation of chemotherapeutic heteroaryl compounds - Analogifarfarande för framställning av chemoterapeutiskt användbara heteroarylföreningar

The invention relates to an analogous process for the preparation of chemotherapeutically useful heteroaryl compounds of the formula I,

Ar-N-R 1 f 2 (I) CGR ^ wherein Ar represents a heteroaryl ring which is

ΛΤΑ Xa XA-XA

and which may be substituted by C 1-4 alkyl, C 3-8 cycloalkyl or phenyl, the acylamino group -NR 2 COR 2 being attached to the carbon atom of the heteroaryl ring, and in which R 1 is C 1-4 alkyl, C 2-8 alkenyl, -cycloalkyl or R 1 -C 1-6 alkyl, and R 2 is C 1-6 alkyl-C 3-10 cycloalkyl, R 1-6 or C 1-6 alkyl; and R 1 is phenyl which may be substituted by halogen, C 1-6 alkyl or C 1-4 alkoxy provided that: 1 2 (a) when Ar is 1,3,4-thiadiazolyl, R is C 1-4 -alkyl and R is C 1-6 alkyl or C 1-6 cycloalkyl, said 1,3,4-thiadiazolyl group may be unsubstituted or substituted by C 1-6 alkyl, and

Cb] when Ar is phenyl-substituted 1,2,4-oxadiazolyl, neither R1 can be methyl nor benzyl when R is methyl.

Compounds resembling the compounds of this invention have been described in Aiermdn, see, e.g., Bull. Soc. Chim., 1219 (1967) BE Patent 736,854 and GB Patent 1,333,495. However, it should be noted that compounds of this type have previously been shown to have either a completely different use than the compounds of this invention, or have a purely academic interest, in which case no use is shown.

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

The optional substituent on the heteroaryl backbone is preferably C 1-6 alkyl, C 1-6 cycloalkyl or phenyl. Preferred R 1-8 substituents are C 1-6 alkyl, C 1-8 alkenyl, C 3-8 cycloalkyl and benzyl optionally substituted by helogen, C 1-6 alkyl or C 1-6 alkoxy.

2

Preferred R 1 substituents are C 1-6 alkyl, C 1-8 cycloalkyl, benzyl and phenyl optionally substituted with halogen or C 1-6 alkoxy.

The heteroaryl group Ar is preferably substituted by a C 1-6 alkyl group, especially methyl, R is C 1-6 alkyl, especially C 1-8 alkyl, C 1-8 alkenyl or benzyl. And R 6 is C 1-8 alkyl, C 1-8 alkyl. cycloalkyl or benzyl.

The process according to the invention is characterized in that the formula is acylated

An alkyl derivative according to ArNHR 1 (VIII), wherein Ar and R 1 are as defined above.

The acylation of a compound of formula (VIII) may be carried out with an acid halide of formula R CD-X wherein X is chlorine or bromine and R is as defined above in the presence of a proton acceptor such as pyridine or triethylamine in an inert solvent such as benzene. The acylation can also be carried out by heating the alkyl derivative with the appropriate acid anhydride JJR CO) β / in an inert solvent.

3 63394

Those skilled in the art will immediately recognize that other acylating conditions may be used (see, e.g., A.3.Beckwith: "The Chemistry of Amides", 1971; Buehler and Pearson: "Survey of Organic Synthesis", 1970; Sandler and Karo: "Organic Functional Group Preparations ", 1968; Fieser and Fieser:" Reagents for Organic Synthesis ", 1968; etc.).

Derivatives of formula (VIII) may be derived from the corresponding amines of formula ArNI by conventional alkylation or acylation methods.

The amines of formula ArlMh 2 are either known compounds or can be prepared by modifying known synthetic methods.

The compounds of formula (I) have been shown to be useful in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases, including asthma. The compounds have low toxicity.

The compounds or compositions of this invention may be administered orally and rectally, topically, parenterally, for example by injection and continuous intermittent intra-arterial infusion, for example in the form of tablets, lozenges, lozenges, capsules, elixirs, suspensions, aerosols and ointments containing e.g. 10% by weight of active compound in a suitable base, in the form of soft and hard gelatin capsules, suppositories, injections and suspensions (in a physiologically acceptable medium) and sterile packaged powders impregnated with a carrier material for the preparation of injection solutions. For this purpose, the compositions may conveniently be presented in unit dosage form, each dosage unit containing preferably 5 to 500 mg (5.0 to 50 mg for parenteral administration, 5.0 to 50 mg for inhalation and 25 to 500 mg for oral or rectal administration) of formula (I). compound. 0.5 to 300 mg / kg of active ingredient may be administered, preferably 0.5 to 20 mg / kg per day, although it will be appreciated that the physician will determine the amount of compound (s) of formula (I) to be administered, taking into account all relevant circumstances.

63394

The following examples further illustrate the invention.

Example 1 N-Methyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzamide 2- (K-methylamino) -5-methyl-1,3,4-thiadiazole (6 g, 0.046 mol) in pyridine (190 ml) was refluxed for 6 hours with benzoyl chloride (9.7 g> 0.069 mol) and the pyridine was then evaporated under reduced pressure. The residue was treated with water, basified with sodium hydroxide solution and extracted with chloroform. The chloroform was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, filtered and evaporated to give the title compound, which was recrystallized from ethanol.

Example 2 N-2-Nronenyl-N- (5-methyl-1,4,4-tladlazol-2-yl) -benzamide Using the procedure of Example 1, the title compound was prepared from 2- [N- (2-propenyl) -amino] - From 5-methyl-1,3,4-thiadiazole, Prepared by cyclization from 4- (2-propenyl) -thiosemicarbazide.

Example 3 N-Phenylmethyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzeneacetamide (a) N- (3-methyl-1,5,4-thladlazol-2-yl) -benzylamino-2-amino -5-methyl-1,3,4-thiadiazole (23 g, 0.2 mol) and benzaldehyde (29.6 ml, 0.3 mol) were refluxed in ethanol (200 ml) for 1.3 hours. The solution was cooled to room temperature and sodium borohydride (11.33 g »0.3 mol) was added over 3-10 minutes. The mixture was refluxed for 4 hours, further treated with sodium borohydride (3 g) and refluxed overnight. The ethanol was removed by evaporation, the residue was treated with water and extracted with ether. The ether extract was dried over sodium sulfate, filtered and evaporated to leave a solidifying oil. This solid was triturated with ether, filtered, washed with light petroleum (b.p. 40-60 ° C), re-triturated with ether and filtered to give H- (5-methyl-1,3,4-thiadiazol-2-yl) -benzylamine (30.95). g) o to obtain. Its melting point when recrystallized from ether was 140 ° C.

(b) N-Phenylmethyl-H- (5-methyl-1,3,4-thiadiazol-2-yl) -benzeneacetamide N- (5-methyl-1,3,4-thiadiazol-2-yl) benzylamine (15 g> 0.073 mol) in pyridine (200 ml) was refluxed with phenylacetyl chloride for 6 hours. The pyridine was removed under reduced pressure and the residue was treated with water and extracted with ether. The ether solution was dried, filtered and evaporated to dryness, and the residue was recrystallized from ethanol to give the title compound, m.p. 128 ° C.

5 63394

Examples 4-6

The following compounds were prepared by methods similar to those described in Example 3: N- (p-chlorobenzyl) -N- (5-methyl-1,5-4-thladiazol-2-yl) -phenyl.

N-chlorophenylmethyl-1H- (5-methyl-1,3,4-thladiazol-2-yl) -hydrite

Benacetamide N- (p-methylbenzyl) -N- (5-phenyl-1,3,4-methylbenz-2-yl) -cyclopentanecarboxamide

Example 7 N-Hexyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzeneacetate (a) N- (5-methyl-1,3,4-thiadiazol-2-yl) -hexanamidyl 2- amino-5-methyl-1,3,4-thiadiazole (23 g, 0 * 2 moles) in toluene (100 ml) was treated with n-hexanoic anhydride (30 ml) and the mixture was refluxed for 3 hours. The product crystallized on standing at room temperature overnight. · The product was filtered off and recrystallized from ethyl acetate to give N- (5-methyl-1,3,4-thiadlazol-2-yl) -hexanamide, m.p. 203 ° C (20.68 g).

(b) N- (5-methyl-1,3,4-thladiazol-2-yl) -hexyl-N- [N- (5-methyl-1,3,4-thiadiateol-2-yl) -hexanamide (16 g, 0.075 moles) was added to portionwise stirred tetrahydrofuran (THF) (120 mL) containing lithium aluminum hydride (2.9 g, 0.076 moles) at a temperature below 15 ° C. The mixture was stirred and refluxed for 2 hours. The mixture was cooled in ice and treated with THF (29 mL) containing water (2.9 mL) and 2N sodium hydroxide solution (2.9 mL) and water (5.6 mL). 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), m.p. 101-105 ° C.

(c) N-Hexyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -benzenyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) ) -hexylamine (5.96 g, 0.03 mol) in toluene (60 ml) was mixed with triethylamine (4 x 59 ml) and phenylacetyl chloride (4.64 g, 0.03 mol) and refluxed overnight. Additional triethylamine (4.6 mL) and phenylacetyl chloride (4 mL) were added and refluxing was continued for an additional 25 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. The eloroform extract was washed with 2H sodium hydroxide solution and water, dried (NagSO 4), filtered and evaporated to give the title compound as an oil, b.p. 190 ° C / 0.1mm (8.03 g) · This was recrystallized from ethanol to give the title compound as a solid, m.p. 90 ° C.

63394

Example 8 N- (5-Methyl-1,5,4-triflatol-2-yl) -2-methylpropanamide 2-Amino-5-methyl-1,3,4-thiadiazole (15 g, 0.13 mol) was treated with isobutyric anhydride ( 70 ml). The reaction mixture was stirred and heated at reflux in an oil bath at 180-200 ° C for 1.5 hours. 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 as golden needles.

Examples 9 and 10

In a similar manner the following compounds were prepared: F- (5-methyl-1,3,4-tladiazol-2-yl) butanamide (m.p. 231-233 ° C), Cream-colored crystalline solid * W- (5-methyl-1,4- thladiazol-2-yl) heptanamide Creamy crystalline solid.

Example 11 N- (5-Methyl-1,3,4-trifluoro-2-yl) -butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -butanamide (1.85 g, 0, 01 mol) was added in small portions to a stirred suspension of lithium aluminum hydride (0.38 g, 0.01 mol) in dry THF (25 ml) at 0-5 ° C under a nitrogen atmosphere. The reaction mixture was stirred and heated at reflux for 2 hours. The cooled solution was treated dropwise with water (0.38 ml) in THFtssä (3 »8 mL), followed by the addition of 2N sodium hydroxide solution (0.38 ml) and water (0.76 mL) and stirred for half an hour ·

The mixture was filtered through a pad of Supercel and the solution evaporated under reduced pressure to a solid which was recrystallized from aqueous ethanol to give N- (5-methyl-1,3,4-thiadiazol-2-yl) butylamine as a pale yellow crystalline solid, m.p. 100-102 ° C.

Example 12

In a similar manner, the following compound was prepared.

N- (5-methyl-1,3,4-thiadiazol-2-yl) heptylamine Example 13 g-Butyl-N- [5-methyl-1,3,4-thiadlazol-2-yl) -2-methylnronanamide N- (5-methyl 1,3,4-thiadiazol-2-yl) butylamine (3 g, 0.0175 mol) and isobutyl anhydride (15 ml) were heated together on a steam bath for 1.5 hours. Excess isobutyric anhydride was removed under reduced pressure and Residual B was distilled at 0.3 mm to give an oil (3.6 g, 55 *), b.p. 132 ° C, which on cooling afforded the title compound as a white solid (m.p. 54-57 ° C).

In a similar manner, the following compounds were prepared.

7 f: 7, 7 Q A

Examples 14 and 15 H-Hexyl-N- (5-methyl-1,3,4-thladazol-2-yl) -2-methylnropane This was a colorless oil, b.p. 152-154 ° C / 0.5 mm. V.21 1.5108 HMR, IB and UV confirmed the structure.

Analysis: C ^ Hg H 08 requires: C 57.99 »H 8.55» H 15.6l £ found: C 57.81 »H 8.67» N $ 15.76 N-heptyl-N- (5- methyl-1,3,4-thladazol-2-yl) -2-methylpropylamide Example 16 N-butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) cyclopropanecarboxylic acid (5-Methyl-1,3,4-thiadiazol-2-yl) butylamine (1.7 g, 0.01 mol) in benzene (20 ml) was treated with triethylamine (1.53 ml) and cyclopropanecarboxylic acid chloride (1.15 ml). g) · The reaction mixture was heated at reflux 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 charcoal, filtered and evaporated and the residue recrystallized from petroleum ether (40-60 ° C). To obtain H-butyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) -8-cyclopropanecarboxamide as a white crystalline solid, m.p. 82-84 ° C.

Example 17

In a similar manner, the following compound was prepared.

E-butyl-N- (5-methyl-1,3,4-thladiazol-2-yl) cyclopentanecarboxamide This was a colorless oil, b.p. 162-164 ° C / 0.4 mm. EMR, IR and UV confirmed the structure.

Analysis: C 18 H 19 N 2 O requires: C 58.4 »E 7.9» N 15.7 # found: C 58.5 »H 7.6; E 15.9 #

Example 18 N- (5-Methyl-1,5,4-methyl-2-yl) -1-methylethylamine 2-Amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mol) in IPA (700 ml) and acetone (100 ml) were treated with sodium borohydride (20 g) in portions with stirring and cooling. The reaction mixture was then stirred and refluxed for 3.5 hours. The solution was poured into water (3 L) and extracted with ether (x 3). The ether solution was dried, filtered and evaporated to give the title compound as a cream solid, m.p. 145 ° C.

Example 19 H- (5-Methyl-1,3,4-thiadiazol-2-yl) cyclohexylamine White crystalline solid (from ethyl acetate), m.p. 192-194 ° C. This was prepared as described in Example 18.

8

Example 20 6 3 3 9 4 N- (1-methylethyl) -N- (5-methyl-1,5,4-thladazol-2-yl) benzamide N- (5-methyl-1,3,4-thiadiateol-2-yl) 1-Methylethylamine (5 g, 0.052 mol) in pyridine (100 ml) was treated with benzoyl chloride (4.1 ml). The beak mixture was stirred and heated at reflux for 5.5 hours. The pyridine was removed under reduced pressure and the residue was treated with water and extracted with ether (x 5). The ether solution was dried, filtered and evaporated to dryness, and the residue was recrystallized from a mixture of ether and petroleum ether (40-60 ° C) to give the title compound as a pale crystalline solid, m.p. 82.5-83.5 ° C.

In a similar manner, the following compounds were prepared.

Examples 21.1a 22 N- (1-methylethyl) -N- (5-methyl-1,3,4-thiadiazol-2-yl) benzeneacetamide This was a brown-yellow crystalline solid, m.p. 83-85 ° C. N-cyclohexyl-N- (5-methyl-1,3,4-thiadiazol-2-yl) cyclopropanecarboxamide____ This was a yellow crystalline solid, m.p. 76.5-78.5 ° 0.

Example 23 (a) 5-Chloro-5-methyl-1,2,4-tladlazole

A suspension of acetamidine hydrochloride (47.0 g, 0.50 mol) and trichloromethanesulfonyl chloride (83.0 g, 0.45 mol) in 500 mL of dichloromethane was placed in a 3-necked flask equipped with a stirrer, dropping funnel and thermometer. With cooling in an acetone bath and stirring, a solution of sodium hydroxide (100 g, 2.50 mol) in 150 ml of water was slowly added to the mixture, keeping the temperature below -8 ° C by means of a cold plate. After about half of the solution had been added, the color of the mixture changed from red to orange through the addition of the solution. At the end of the addition (about five hours), the precipitated sodium chloride was removed by filtration and washed with CH 2 Cl 2. The organic phase was separated from water, the water was extracted three times with CH 2 Cl 2 (30 mL). The combined CH 2 Cl 2 solutions were washed with water until neutral and then dried over magnesium sulfate.

The solvent was removed by evaporation to give a red liquid. The liquid was distilled under reduced pressure to obtain 5-chloro-3-methyl-1,2,4-thiadiazel as a colorless liquid. Yield 27 g (47, b.p. 25 ° C / 3.5 mm Hg.

(b) β-Butylamino-4-methyl-1,2,4-thiadlazole 5-Chloro-3-methyl-1,2,4-thiadiazole (27 g, 0.20 mol) was dissolved in 200 any ethanol and added with ice-bath cooling with butylamine ( 44 g, 0.60 mol) of ethanol solution, stirred at room temperature overnight and 9 63394 evaporated to a small volume. Upon addition of ether, a white precipitate formed which was butylamine hydrochloride, which was removed by filtration. The yellow filtrate was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to a yellow oil which was distilled under reduced pressure to give 5-butylamino-3-methyl-1,2,4-thiadiazole as a pale yellow liquid. Yield 29.9 g, (87.2 56), b.p. 101-102 ° C / 0.14 am Hg.

(c) N- (5-methyl-1,2,4-thiadiazol-5-yl) -1T-methylcyclohexanecarboxylic acid

Cyclohexanecarboxylic acid chloride (9.92 g, 0.068 mol) was added slowly to a solution of 5-methylamino-1,2,4-thiadiazole (7.0 g, 0.054 mol) in dry benzene containing triethylamine (6.87 g, 0.068 mol) and a mixture of heated at reflux for 1.5 hours, cooled and washed with 2N hydrochloric acid, saturated sodium hydrogen carbonate solution and water, dried over magnesium sulphate, filtered and evaporated to a yellow oil which crystallized on standing. This was recrystallized twice from petroleum ether (60-80 ° C) to give off-white crystals which were N- (3-methyl, 1,2,4-thiadiazol-5-yl) -N-methyl-cyclohexanecarboxamide. Yield 8.23 S »(63 * 8%), m.p. 96 ° C.

Examples 24 to 33

The following compounds were prepared by the method described in Example 23. N- (3-methyl-1,2,4-thladazol-5-yl) -1H-butyl-2-methylpronanamide (b.p. 115-117 ° C / 0.1 mmHg).

Analyzes C 19 H 19 N 2 OS requires: C 54-74; H $ 7.93 N $ 17.41 $ 0 6.63 $ S 13.28 # found: C $ 54.64 H $ 7.97 N $ 17.37 0 $ 6.48 S 13.36 * N- (3-methyl-1, 2,4-Thiadiazol-5-yl) -N-butylcyclopropanecarboxamide (m.p. 43 ° C).

N-3-methyl-1,2,4-thladazol-5-yl) -K-butylphenylcarboxamide (m.p. 77 ° C) N- (3-cyclobutyl-1,2,4-thiadiazol-5-yl) -N-octylcyclo -octane-carboxamide-N- (3-methyl-1,2α-thladiazol-5-yl) -N-methylphenylacetamide (m.p. 86 ° C).

N- (3-methyl-1,2,4-thiadlatol-5-yl) -N-2-nitropenylacetamide (m.p. 6 ° C).

N- (N-methyl-1,2,4-thladiazol-5-yl) -γ-methyl-2-methylpropanamide (m.p. 54 ° C).

N-methyl-1,2,4-thlazol-5-yl) -N-n-butyl-n-hexanamide (b.p. 130-135 ° C / 0.15 mm Hg, purified by column chromatography).

10 63394

Analysis requires C 59.33} H 8.89} N 14.83; 0.5.65} S 11.31 £ found * C 59.39} H 8.82; K 15.19} O $ 5.87 N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-2-pronepylphenylacetamide (m.p. 70 ° C).

H- (3-methyl-1,2,4-thiadiazol-5-yl) -N-2-propenylcyclopropanecarbox- (m.p. 76 ° C).

Example 54 5-Phenyl-5-trichloromethyl-1,2,4-oxadiazole

Trichloroacetic anhydride (154.5 g> 0.5 mol) was added to a stirred solution of Bente-amidochemical (34.0 g, 0.25 mol) in dry trichloroacetic acid (160 g) in an oil bath at about 60 ° C. The reaction mixture was heated at 120 ° C for 20 minutes and after cooling was poured into a mixture of ice and water (400 ml). The organic layer was separated, washed with water and taken up in carbon tetrachloride (500 mL) and neutralized by washing with saturated NaHCO 3 solution. The product was distilled after drying over magnesium sulphate and evaporation of carbon tetrachloride (b.p. 118 ° C / 0.07 mmHg).

Example 55

Similarly, 3-methyl-5-trichloromethyl-1,2,4-oxadiazole was prepared.

Example 36 5-Butylamino-5-methyl-1,2,4-oxadlazole 3-Methyl-5-trichloromethyl-1,2,4-oxadiazole (43 g, 0.21 mol) was added to n-butylamine (46.73 g, 0 , 63 moles) and stirred at room temperature overnight. Excess amine was removed under reduced pressure and the residue was distilled (oil bath 110 ° / 0.5 mm Hg). Recrystallization from petroleum ether (50-80 ° C) afforded the title compound as white plates, 26 g, m.p.

62-65 ° C.

Example Rn-Butyl-1H- (N-methyl-1,2,4-octadibol-5-yl) -n-butanamide-5-butylamino-3-methyl-1,2,4-oxadiazole (4.2 g, 0, 03 moles) and butyric anhydride (4.73 g, 0.033 moles) were refluxed in toluene (30 mL) for 3 hours. After removal of toluene in vacuo, the residue was refluxed for 1 hour in methanol (60 mL) containing a few drops of triethylamine. The methanol was evaporated under reduced pressure and the residue was taken up in CH 2 Cl 2, washed twice with 2N hydrochloric acid and twice with saturated sodium bicarbonate solution and dried over magnesium sulfate. The product was shaken by column chromatography (silica gel 120 g), eluting with petroleum ether (40-60 ° C), increasing the polarity of the solvent so that it finally contained 10 # of ether per petroleum ether. Fractions were combined and distilled in a Kugelrohr air bath at 119 ° C / 3.3 amH & U 63394

Analysis: C H 8.50; N 18.65; 0 14.20 # found: C 58.78; E 8.50; N 18.40; 0 $ 14.18

Examples 58 to 44

The following okeatethiols were prepared using the procedure described in Example 57.

N-ethyl-U- (5-methyl-1,2,4-oxadlat-8-5-yl) -2-methylpropionic acid (b.p. 92 ° C / 5.0 mm Hg).

Analysis: C 18 H 12 O 2 requires: C, 54.80; H 7.66; K 21.50; 0 16.22 # found: C 54.68; H 7.46; K 21.14; 0 16.55 $ N-n-butyl-N- (5-methyl-1,2,4-oxadiazol-5-yl) acetamethyl 7 \ 20 1.4748, with liquid.

N-butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methylpropanamide (b.p. (air bath temperature) 98 ° C / 1.5 mm Hg).

Analysis: Requires: C 58.65; H 8.50; N 18.66; 0 14.20 56 found: C 58.49; H 8.22; K 18.40; E-n-butyl-N- [3- (methyl-1,2,4-oxadiazol-5-yl) hexapamyl]

Analysis: C 12 H 18 N 2 O 2 requires: C, 61.65; H 9.15; K 16.58; 0 12.65 # found: C 61.89; H 9.39; N 16.53; N-Ethyl-N- (5-phenyl-1,2,4-oxadlazol-5-yl) -2-methylpropanamide (m.p. 48 ° C).

N-butyl-N- (3-phepyl-1,2,4-octadata-5-yl) -2-methylpropanamide (b.p. 140 ° C / 7 mm Hg, air bath temperature).

Analysis: Requires: C 66.88; H 7.37; N 14.62; 0 £ 11.14 Found: C, 67.07; H 7.38; N 14.38; N-ethyl-N- (5-enylphenyl-1,2,4-oxadlatol-5-yl) -n-butanamide (m.p. 74 ° C).

Example AS

N-Hexyl-N- (3-methyl-1,2,4-oxadlatol-5-yl) acetamide 5-n-Hexylamino-3-methyl-1,2,4-oxadiateol (4.6 g, 0.025 mol) was dissolved in acetic anhydride. (25 ml), refluxed for 3 hours and then evaporated to dryness under reduced pressure. The residue was taken up in CHCl 3 (50 mL) and washed twice with 2N hydrochloric acid and twice with saturated sodium bicarbonate solution and dried over magnesium sulfate (b.p. 113-114 ° C / 1.0 mm Hg).

Analysis: C 12 H 12 N 2 O 2 requires: C, 58.64; H 8.50; H 18.65; Found: C, 58.66; H 8.76; N 18.57; 0 14.48

Example 46

The following oxadiazole was also prepared using the method of Example 45.

12 63394 N- (3-methyl-1,2,4-oxadiazol-5-yl) -H-2-propenylacetate (b.p. 82 ° C / 1.5 Hg, evening bath temperature).

Analysis * requires * C 53.02; H 6.12; N 23.19; 0 £ 17.66 found »C 52.78; E 5.90; N 23.03; 0 £ 17.69

Example 47 N- (3-methyl-1,2,4-oxadiazol-5-yl) -N- (4-methylphenylmethyl) -cyclopropanecarboxamide

Cyclopropanecarboxylic acid chloride (3.45 g, 0.033 mol) was added dropwise 5 - [(4-methylphenyl) methyl] n-β-methyl-1,2,4-octadiazole (6.1 g, 0.03 mol) and triethylamine (3.43 g, 0.033 moles) in dry benzene, keeping the temperature below 10 ° C. After the addition, the temperature was allowed to rise to room temperature and the mixture was then refluxed overnight. After cooling, the reaction mixture was washed twice with 2N hydrochloric acid and twice with saturated sodium bicarbonate solution, dried over magnesium sulfate and treated with charcoal. The product was purified by column chromatography (silica gel, 110 g) eluting with petroleum ether (40-60 ° C) increasing the polarity to 10% ether in petroleum ether. The title compound was recrystallized from petroleum ether (60-80 ° C) as white needles, m.p. 49.5 - 50.5 ° C.

Examples 48 to 59

The following other okeadiazoles were prepared using the method of Example 47.

N-methyl-N- (3-acetyl-1,2,4-ochadiazol-5-yl) benzoic acid (m.p. 74 ° C).

N-n-butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclopropanecarboxamide (H-6 1,4882).

N-hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclopentanecarboxamide (b.p. 121 ° C / 1.4 mm Hg, air bath temperature).

Analysis * C 12 H 19 N 2 O 3 requires * C 64.48; H 9.02; H 15.04; 0 11.52 36 found * C 64.76; H 8.86; N 14.82; 11.52 μl N-hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclohexanecarboxamide (b.p. 157 ° C / 1.5 am Hg, air bath temperature).

Analysis * C ^ H ^ ^ Og requires * C 65.49; H 9.27; N 14.32; 0 10.9 # found * C 65.58; H 9.05; N 14.19; 0. 10.95 # N-Hexyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -b- (b.p. 126 ° C / 0.2 mm Hg, air bath temperature).

13 6 3 3 9 4

Analysis: requires: C 66.87} H 7.56 * N 14.62 * 0 11.13 # found: C 66.85 * H 7.55 * N 14.58 * 0 $ 11.27 N- (3 -methyl-1,2,4-oxadiazol-5-yl) -phenyl-2-propenylcyclopropane-cyclohexyl.H 2 H__________________ (b.p. 120 ° C / 10 nun Eg, air bath temperature).

N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-phenylmethylcyclohexanecarboxane] -1 (m.p. 75 ° C).

E- (3-methyl-1,2,4-ocbadiatobQ-5-yl) -H-phenylmethylbenzamide (m.p. 75 ° C).

N- (5-methyl-1,2,4-oxadiazol-5-yl) -N-phenylmethyl-2-phenylpropanamide (b.p. 127 ° C / 3.00 mm Hg).

N- (4-methoxyphenyl) methyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclohexanecarboxamide_______________________________________ (m.p. 70 ° C).

N- (4-methoxyphenyl) methyl-N- (3-methyl-1,2,4-oxadiateol-5-yl) -2-methyl] methylate (b.p. 118 ° C / 0.2 mm Hg, air bath temperature) .

N- (4-methylphenyl) methyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) cyclopronanecarboxamide (m.p. 50 ° C).

Example 60 N- (3-Methyl-1,2,4-oxadiazol-5-yl) -N-isopropylamino-2-methyl-p-propyl-1H-1H

Isobutyl anhydride (7.9 g, 0.05 mol) was added to isopropylamino-3-methyl-1,2,4-oxadiazole and heated at 100 overnight. After cooling, methanol (60 ml) and a few drops of triethylamine were added and the mixture was refluxed for one hour. After removal of the methanol in vacuo, the residue was taken up in ether and washed twice with saturated sodium hydrogen carbonate solution (b.p. 90 ° C / l, 3 mm Hg, Kugelrohr air bath temperature).

Example 61 N- (5-Methyl-1,3,4-oxadiazol-2-3ryl) -N-n-propyl-cyclobutanecarboxamide (a) 1-acetyl-4-allyl-enecarbazide

Allyl isocyanate (25 g, 0.30 mol) was added slowly to a boiling solution of acetic hydrazide (22.2 g, 0.30 mol) in dry benzene (300 mL). The mixture was heated for one hour during which time two 14 6 3 394 layers formed. The benzene was removed by evaporation and the residue was triturated with ether to give the title compound as a white solid (mp * 71-74 ° C).

(b) 5-methyl-2-n-propylamino-1,3,4-oxadiazole

The 1-acetyl-4-n-propyl semicarbazide (35 St 0.22 mol) prepared according to method (a) described above was refluxed with FOCl 3 (150 ml) for 2 hours until no more hydrogen chloride was evolved. Excess POCl 2 was removed with a water pump and the mixture was poured into 200 any ice-water and neutralized with $ 50 sodium hydroxide to pH 7. * The red oil was extracted into dichloromethane (2 x 180 mL), dried, filtered and evaporated to a distilled oil , which crystallized on standing to a solid (m.p. 46.5-47 → 5 ° C).

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

The 5-methyl-2-N-propylamino-1,3,4-okeadiazole (6 g, 0.04 mol) prepared according to method (b) was refluxed with cyclobutanecarboxylic acid chloride (5.5 St 0.05 mol) in benzene (25 ml) in the presence of triethylamine (4.72 g, 0.05 mol) for 2 hours. The mixture was filtered and the filtrate was washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, dried over magnesium sulphate, filtered, the solvent removed by evaporation to give a reddish brown liquid which was distilled twice in a Vigreux flask to give the title compound as a weak compound. 0.27 mm Hg).

Examples 62-69 Using the procedure described in Example 61, the following other oxadiazolite N- (5-methyl-1,3,4-oxadiazol-2-yl) -Hn-propyl-2-methylpropanamide (b.p. 85-87 ° C / 0.4) was prepared. mm Hg).

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propylcyclohexanecarboxamide (b.p. 120-121 ° C / 0.2 mm Hg).

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-n-propyl cyclopentanecarboxamide di_________________ (b.p. 110-112 ° C / 0.01 mm Hg).

N- (5-methyl-1,3,4-oxadiazol-2-yl) -N-2-propenyl-2-methylpropanamide (b.p. 93 ° C / 0.18 mm Hg).

15 6 3 3 9 4 N- (5-methyl-1,3,4-okeadiazol-2-yl) -N-2-propenyl-2-cyclopentanecarbolamine (b.p. 114-116 ° C / 0 , 12 nun Hg).

N- (5-methyl-1,3,4-octadol-2-yl) -N-n-hexyl-n-hexanamide (b.p. 116 ° C / 0.1 mm Hg).

? - (5-methyl-1,3,4-ocbadlatol-2-yl) -W-n-butyl-2-methyl-N, N-Yl (b.p. 82-84 ° C / 0.1 mm Hg).

N- (5-methyl-1,3,4-octadol-2-yl) -N-n-butylacetane (b.p. 82-84 ° C / 0.1 ng Hg).

Example 70

The following 1,2,4-oxadiazole was prepared by the method described in Example 37.

N-n-hexyl-H- (3-methyl-1,2,4-oxadiazol-5-yl) -2-methylnronanamide (b.p. 90 ° C / 1.1 mg Hg).

Analysis: C 12 H 18 N 2 O 2 requires: C, 61.63; H 9.15; H 16.58; 0 12.63 # found: C 61.47; H 8.98; N 16.84; 0 12.70

Examples 71-7¾

In a similar manner, using the procedure generally described in Example 47, the following other oxadiazoles were prepared: N-methyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -ecyclohexylcarbamamide

Analysis: requires: C 59 * 17 »H 7.67; N 18.82; Found: C, 59.05; H 7.59; E 18.41; 14.73 * N- (3-methyl-1,2,4-oxadiazol-5-yl) -N-2-propenylhentanamide (b.p. 104 ° C / 1.5 mm Hg).

Analysis: c 13 H 21 N 3 O 2 requires c 62.12; H 8.42; N 16.71; Found: C, 62.16; H 8.20; H 16.54; 12.63 1 H- (3-methyl-1,2,4-oxadlazol-5-yl) -E-n-butyl-2-ethylbimethyl (b.p. 71 ° C / 0.055 mm Hg).

Analysis: C 18 H 18 N 2 O 2 requires: C, 61.63; H 9.15; H 16.59; 0 12.63 1 »found: C 61.46; H 8.90; N 16.57; 0 12.47 #

Example 74 N- (3-Methyl-1,2,4-triflatol-5-yl) -N-phenylmethyl-n-hexBanamide (m.p. 72 DEG C.) was prepared using the procedure described in Example 23. Examples 75-77

The following other 1,2,4-thiadiazoles were prepared using the same methods as in Example 23: N- (3-methyl-1,2,4-thiadiazol-5-yl) -N-hexylacetamide (m.p. 38 ° C).

16 63394 H- (3-methyl-1,2,4-thladlazol-5-yl) -H-hexylphenyl>> »+ - fl» <λ i (ep. 57 ° C).

3-methyl-L. 2.A-Thladrazol-5-yl enylmethylphenylacetamide (m.p. 134 ° C).

Examples 78-86

The following other 1,2,4-oxadiazoles were prepared using the same procedures as in Example 47: N-butyl-N- (3-methyl-1,2,4-oxadlatol-5-yl) -phenylcarboxamide Analysis: C 14 H 12 N 3 O 2 requires : C 64.84 * H 6.61} N 16.21; 0 12.34 Found: C 65.09} H 6.35; N 15.99; O 12.07 N-butyl-H- (3-methyl-1,2,4-oxadiazol-5-yl) -4-chlorophenylcarboxamide

Analysis: C H 5.49; Cl 12.07l H 14.30; O 1 (189 found: C 57.45? H 5.63; Cl 12.07; N 14.14 * O 11.17 N-butyl-N- (3-methyl-1,2,4-oxadiazol-5 -yl) -4-methoxyphenylcarboxamide (b.p. 105 ° C / 0.015 mm Hg).

Analysis: δ ^ Η ^ Ν ^ Ο ^ requires: C 62.27 * H, 6.62; N 14.52; O 16.59 Found: C 61.99 * H 6.47 * N 14.42; O 16.74 H-butyl-N- (3-methyl-1,2,4-okeadiazol-5-yl) -cyclohexanecarbokeamide (b.p. 70 ° C / 0.01 mm Hg).

Analysis: C ^ H 2 N 2 O 2 ****** 1 c 63.37 * H 8.74 * N 15.84 found: C 63.54; H 8.55 * H 15.60 K-Butyl-N- (3-methyl-1,2,4-oxadiazol-5-yl) -cyclobutanecarbox-8-amldl ________ (b.p. 67 ° C / 0.02 mm Hg) .

Analysis: C 12 H 12 N 2 O 2 requires: C 60.74 »H 8.07; H 17.71} O 13.49 Found: C 60.44 »H 7.88; N 17.54 * 0 13.21 N- (5-methyl-1,2,4-oxadiazol-5-yl) -N-propyl-2-methylpronanamide (b.p. 62 ° C / 0.15 mm Hg).

Analysis requires C H 8.11; H 19.89 Found: C 56.93 »H 8.14; H 19.64 N-Butyl-N- (3-butyl-1,2,4-oxadiateol-5-yl) -cyclopropanecarboxamide

Analysis: C ^ Hg ^ Og requires: C 63.37 * H 8.74} H 15.84 * 0 12.06 Found: C 63.19 * E 8.51 * N 15.59 * 0 11.82 17 63394 N-butyl-N- (3-ethyl-1,2,4-olC-6-adrazol-5-yl) -cyclopropanecanicarboxane (b.p. 65 ° C / 0.01 sun Hg).

Analysis: Requires: C 60.74; H 8.07; N 17.71; 0 13.49 Found: C 60.50; H 7.78; N 17.43; 13,19 N-butyl-N- (3-cyclohexyl-1,2,4-oxadiazol-5-yl) 'cyclopropanecarboxanide

Analysis: O 2 requires: C 65.95; H 8.65; K 14.42; Found: C, 66.15; H 8.83; N 14.51; 0 10.86

Examples 87 to 89

In a similar manner to methods similar to Example 60, the following other oxadiazoles were prepared: N-butyl-N- (3-ethyl-1,2,4-octadiazol-5-yl) -> 2-methyluropanamide (b.p. 65 ° C / 0 ° C); 02 mm Hg).

Analysis: C 12 H 9 O 2 O requires: C, 60.22; H 8.85; N 17.56; 0 13.37 Found: C 59.96; H 8.68; N 17.36; 13,22 K-Butyl-N- (5-butyl-1,2,4-oxadlatol-5-yl) -2-methylmethanamide (b.p. 64 ° C / 0.05 mm Hg).

Analysis: C 18 H 28 N 2 O 3 requires: C, 62.89; H 9.42; N 15.72; 0 11.97 Found: C 62.65; H 9.20; N 15.46; 11.72 H-Butyl-N- (3-cyclohexyl-1,2,4'-oxadiazol-5-yl) -2-methylpropanamide (b.p. 92 ° C / 0.02 mm Hg).

Analysis: C 12 H 9 O 2 O requires: C, 65.49; H 9.28; H 14.32; Found: C, 65.26; H 9.09; N 14.07; : 0 11.05

Claims (4)

18 63394 1. R may be methyl and not benzyl when R is methyl; characterized in that an alkyl derivative of the formula ArNHR1 (VIII) in which Ar and are as defined above is acylated. 19 63394 An analogous process for the preparation of chemotherapeutically useful heteroaryl compounds of the formula I, Ar-N-R1 I 2 I CORz in which Ar denotes a heteroaryl ring which is NN R — Π-NN, -, NR TT N ΛοΛ Xa Λ · λ “Χλ and which may be substituted by C 1-6 alkyl, C 3-6 cycloalkyl or phenyl, the acylamino group -NR 2 OOR 2 being attached to the carbon atom of the heteroaryl ring, and wherein R 1 is C 1-4 alkyl, 3 C 1 -C 8 alkenyl, C 3-8 cycloalkyl or R 3 -C 8 alkyl, and R is C 1-8 alkyl, C 3-10 cycloalkyl R 3 or R 3 -C 1-8 alkyl; and R 3 is phenyl which may be substituted by halogen, C 1-4 alkyl or C 1-4 alkoxy provided that: (a) when Ar is 1,3,4-thiadiazolyl, R 1 is C 1-4 alkyl and Process according to Claim 1, characterized in that the heteroaryl ring Ar is optionally substituted by C 1-6 alkyl, R 1 is C 1-6 alkenyl, C 1-6 cycloalkyl or optionally by halogen, C 1-6 alkyl or Benzyl substituted with C 1-6 alkoxy, and R 6 is C 1-6 alkyl, C 3-8 cycloalkyl, benzyl or phenyl optionally substituted by halogen or C 1-6 alkoxy. 2. R is C 1-7 alkyl or C 3-8 cycloalkyl, said 1,3,4-thiadiazolyl group may be unsubstituted or substituted by C 1-3 alkyl, and (b) when Ar is phenyl substituted 1,2,4-oxadiazolyl , no Process according to Claim 1, characterized in that the heteroaryl ring Ar is substituted by a C 1-6 alkyl group; R is C 1-6 alkyl, C 3-8 alkenyl or benzyl and R is C 3-6 cycloalkyl or benzyl. Process according to Claim 1, 2 or 3, characterized in that the heteroaryl ring is α, 1, 1,2,4-oxadiazolyl. 63394 20