NO144346B - ANALOGUE PROCEDURE FOR THE PREPARATION OF CHEMOTHERAPEUTIC EFFECTIVE HETEROARYL COMPOUNDS - Google Patents

Description

The present invention relates to the preparation of chemotherapeutically active heteroaryl compounds with the formula:

where Ar represents: where R is C^-C^-alkyl, C^-C^g-cycloalkyl or phenyl, and where the acylamino group -NR^COR^ is linked to the carbon atom in the heteroaryl ring, R^ being Cj -C^Q -alkyl, C 2 -C 8 -alkenyl, C 1 -C 10 -cycloalkyl or phenyl-C 1 -g -alkyl where the phenyl group is optionally substituted with C 2 -alkyl, C 1 - alkoxy or halogen, and where R 3 is C 2 -g- alkyl, <C>2_g~alkenyl, C2--] Q~ cycloalkyl, C^_^Q-cycloalkyl-C^_g-alkyl, phenyl optionally substituted with Cj ^- alkoxy or halogen, phenyl-C^g-alkyl or phenyl-C 2-6 -alkenyl; or where R^ and R^ together can form a lactam ring with 5-7 ring atoms, provided that: (a) when Ar is 1,3,4-thiadiazolyl, R 1 is Cj^-alkyl and R 2 is Cj_7~alkyl, C2_2 -alkenyl or C^g-cycloalkyl, then said 1,3,4-thiadiazolyl group cannot be unsubstituted or substituted with a ^-alkyl group, (b) when Ar is 1,3,4-thiadiazolyl substituted with a C^_^ -alkyl group, then R^ cannot be C^_g-alkyl* or C2_6~ alkenyl,

(c) when Ar is 1,3,4-thiadiazolyl substituted with methyl, then

R 2 cannot be methyl, and

(d) when Ar is 1,2,4-oxadiazolyl substituted with phenyl, then

cannot R 1 be methyl or benzyl when R 2 is methyl.

The compounds of formula I are used in chemotherapy

of immediate hypersensitive states. Connections that

similar to those with formula I have previously been described, see e.g. Bull, Soc. Chim. 1219 (1967), Belgian Patent No. 736,854 and British Patent No. 1,333,495. It should, however, be noted that in these references this type of compound has either been assigned a completely different application than that indicated in the present invention, or has not been assigned any application at all.

By the term "Cj _g-alkyl" is understood here a straight or branched alkyl group with 1-6 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-amyk, s-amyl, n -hexyl, 2-ethylbutyl or 4-methylamyl.

Similarly, the term "C^_^-alkyl" means a straight or branched alkyl group of 1-4 carbon atoms, such as methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, t-butyl.

"C 1 -C cycloalkyl" means a saturated ring with 3-10 carbon atoms in the ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and adamantyl. "C 1 -C cycloalkyl-C 1 -C alkyl" means the aforementioned saturated rings attached to a C _g-alkyl pure bridge.

According to the present invention, the compounds of formula I are prepared by

(a) acylates an alkyl derivative of the formula:

where Ar and R are as defined previously; (b) alkylates an acyl derivative of the formula: where Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl and R 2 is as defined previously; (c) reacts a compound of the formula:

where Y is a leaving group and where Ar is as defined

previously, with a salt of the formula:-

where M is a metal from group IA or IIA in the peri-

1 2 odic system, and R and R are as defined previously; or (d) ring-closes a compound of the formula:

where Z is -CO(CH2)nQ, -(CH^^OQ' or cyclopropylcarbonyl, n is a number from 3-5, Q is a leaving group, Q' is a group that activates the adjacent carbonyl group for a nucleophilic attack or -OR 8 , where R 8 is hydrogen or C 1 -alkyl, whereby a compound of formula I is formed where R 1 and R 2 form a lactam ring with from 5-7 atoms.

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

It is obvious that a variety of other acylation conditions can be used (see, for example, "The Chemistry of Amides", 1971 by A.J. Beckwith, "Survey of Organic Synthesis", 1970 by Buehler and Pearson, "Organic Functional Group Preparations ", 1968, by Sandler and Karo, "Reagents for Organic Synthesis", 1968, by Fieser and Fieser, etc.).

Compounds of formula IX can be alkylated by dissolving the amide in a suitable inert anhydrous, polar solvent such as dimethylformamide, whereby an alkali metal salt is formed with an alkali metal hydride, preferably sodium hydride, after which the salt is treated with an alkylating agent of the formula R 1 X 1 where X 1 is a reactive atom, such as a halogen atom or a reactive group, such as an alkyl sulfate group.

Alkylating agents and alkylating conditions which are different from those mentioned above can of course also be used and can easily be determined by experiments.

The compound of formula XI can be prepared by reacting an amide of the formula HNR 1 COR 2 with butyllithium under an inert gas atmosphere such as nitrogen in an inert solvent such as tetrahydrofuran, preferably in the presence of a gelling agent such as tetramethylethylenediamine or diazabicyclooctane. The preparation of the salt preferably takes place at low temperatures, e.g. below -10°C.

Reaction (c) can be achieved by reacting the compounds with formulas X and XI in a suitable inert solvent such as tetrahydrofuran, possibly in the presence of a catalyst such as copper or a copper salt.

The cyclization of the derivative of formula XII can be carried out under basic conditions in the presence of a non-nucleophilic base. Reaction of the cyclopropylcarbonyl derivative gives the lactam of formula I with 5 atoms in the ring.

Derivatives of formula VIII and IX can be derived from the corresponding amines of formula ArNH2 by standard alkylation or acylation. The u-halogenacylamino derivative of formula XII can be prepared by reacting the amine of the formula ArNH2 with a suitable w-halogenacyl halide.

The amines of formula ArNH2 are either known compounds or can be prepared by modification of known synthetic methods.

Compounds of formula I have been shown to be useful in the prophylactic and therapeutic treatment of immediate hypersensitivity disorders, including asthma, and in the alleviation of status asthmaticus. The compound has low toxicity. Compounds or preparations can be administered by oral or rectal means, topically, parenterally, e.g. by injection and by continuous or discontinuous intra-arterial infusion, e.g. in the form of tablets, douches, different types of tablets, powder tablets, elixirs, suspensions, aerosols, ointments, etc., and such preparations can e.g. contain 1-10% by weight of the active compound in a suitable diluent, in soft or hard gelatin capsules, in suppositories, in injection solutions and suspensions in physiologically acceptable media, and in sterile packed powders absorbed on a substrate for the preparation of injection solutions. Advantageously for this purpose, the preparations can be prepared in dosage form, and each dosage unit should preferably contain 5-500 mg (5.0-50 mg for parenteral administration, 5.0-50 mg for inhalation and 25-50 mg for oral or rectal administration) of a compound of formula I or XII. Doses may be 0.5-300 mg/kg body weight/day, preferably 0.5-20 mg/kg body weight of the active ingredient, it being understood that the exact amount of one or more compounds of formula I must be determined by a doctor who takes into account all the circumstances surrounding the condition to be treated, the choice of compound to be used and the method of administration, and the preferred dosage ranges thus do not limit the invention in any way.

The term "dosage unit form" as used herein means a physically discrete unit containing an individual amount of the active ingredient, usually in admixture with a pharmaceutical diluent or otherwise together with a pharmaceutical carrier, and the amount of the active ingredient may be so that one or more units will be necessary for a simple therapeutic treatment, and in connection with divisible units, e.g. in the form of tablets, then at least part of such a unit, e.g. half or 1/4 be what is needed for a simple therapeutic treatment. Preparations will normally consist of at least one compound of formula I mixed with a carrier or diluted with a diluent, or enclosed or encapsulated by a digestible carrier in the form of a capsule, paper or other treatment or in a disposable container such as an ampoule. The carrier or diluent may be solid, semi-solid or liquid and may serve as a solvent, diluent or suspending medium for the therapeutically active compound. Examples of diluents or carriers that can be used in pharmaceutical preparations include lactose, dextrose, sucrose, sortital, mannitol, propylene glycol, liquid paraffin, soft white paraffin, kaolin, fused crushed silicon dioxide, microcrystalline cellulose, calcium silicate, silicon dioxide, polyvinylpyrrolidine, cetostearyl alcohol, starch , modified starch, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of pine aroma, arachis oil, alginates, tragacanth, gelatin, various types of syrups, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol as well as propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In connection with tablets, a lubricant may be incorporated to prevent sticking and/or fixing of the powdered ingredients in different parts of the tablet machine. For such purposes, one can e.g. use aluminium, magnesium or calcium stearates, talc or mineral oil. Preferred pharmaceutical forms are capsules, tablets, suppositories, aerosols, injectable solutions, creams and ointments.

The following examples illustrate the invention.

Example 1

N- phenylmethyl- N-( 5- methyl- 1, 3, 4- thiadiazol- 2- yl)- benzeneacetamide (a) N-( 5- methyl- 1, 3, 4- thiadiazol- 2- yl)- benzylamine 2 -amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mol) and benzaldehyde (29.6 mL, 0.3 mol) were refluxed in 200 mL of ethanol for 1.5 h. The solution was cooled to room temperature and 11.35 g (0.3 mol) of sodium borohydride was added over 5-10 min. The mixture was refluxed for 4 hours, treated with an additional 5 g of sodium borohydride and refluxed overnight. The ethanol was evaporated, the residue treated with water and then extracted with ether. The ether extract was dried over sodium sulphate, filtered and evaporated to give an oil which solidified. The solid product was treated with ether, filtered, washed with light petroleum (boiling point 40-60°C) and again treated with ether and. filtered, thereby obtaining N-(5-methyl-1,3,4-thiadiazol-2-yl)-benzylamine (30.95 g) which, after recrystallization from ether, had m.p. at 14 0°C.

(b) N-phenylmethyl-N-(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 200 mL pyridine was refluxed with phenylacetyl chloride for 6 hours. The pyridine was removed under reduced pressure and the residue treated with water and extracted with ether. The ether solution was dried, filtered and evaporated to dryness and the residue recrystallized from ethanol to give the above desired compound, m.p. 12 8°C.

Example 2

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

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

23 g (0.2 mol) of 2-amino-5-methyl-1,3,4-thiadiazole in

100 ml of toluene was treated with n-hexanoic anhydride (50 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, whereby 20.68 g of N-(5-methyl-1,3,4-thiadiazol-2-yl)-hexanamide was obtained, m.p.-203°C.

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

16 g (0.075 mol) of N-(5-methyl-1,3,4-thiadiazol-2-yl)-hexanamide was added portionwise to stirred 120 ml of tetrahydrofuran (THF) containing 2.9 g of lithium aluminum hydride (0.076 mol) at a temperature below 15°C. The mixture was stirred and refluxed for 2 hours. The mixture was then cooled with ice and treated with 2.9 ml of water in 29 ml of tetrahydrofuran, after which 2.9 ml of a 2N solution of sodium hydroxide and 5.8 ml of water were added. The mixture was then treated with "Supercel" and filtered. The filtrate was evaporated to the above compound which was recrystallized from 50% aqueous methanol (9.5 g), and it then had a m.p. at 101-105°C. (c) N-hexyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-benzeneacetamide.

N-(5-methyl-1,3,4-thiadiazol-2-yl)-hexylamine (5.98 g, 0.03 mol) in 60 mL of toluene was stirred with 4.59 mL of triethylamine and phenylacetyl chloride (4.64 g, 0.03 mol) and refluxed overnight. An additional 4.6 ml of triethylamine and 4 ml of phenylacetyl chloride were added and refluxing was continued for a further 24 hours. The mixture was evaporated to dryness, treated with water and extracted with chloroform. The chloroform extract was washed with 2N sodium hydroxide solution and with water and then dried over sodium sulfate, filtered and evaporated to give the title product as an oil, bp. 190°C/0.1 mm Hg (8.03 g). The product was recrystallized from ethanol to give the title compound as a solid, m.p. 90°C.

Example 3

The following compound was prepared: N-(5-methyl-1,3,4-thiadiazol-2-yl)-butanamide, m.p. mp 231-233°C. Cream-colored, crystalline solid.

Example 4

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

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

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 LiAlH 4 (0.38 g, 0.01 mol) in 25 ml of dry tetrahydrofuran at 0-5°C under a nitrogen atmosphere. The reaction mixture was stirred and heated under reflux for 2 hours. The cooled solution was then treated dropwise with a solution of 0.38 ml of water in 3.8 ml of tetrahydrofuran, after which 0.38 ml of 2N sodium hydroxide solution and 0.76 ml of water were added and stirred for 1 hour. The mixture was filtered through a cake of supercell and the solution evaporated under reduced pressure to give a solid which was recrystallized from aqueous ethanol to give N-(5-methyl-1,3,4-thiadiazol-2-yl) butylamine as a pale yellow crystal

linsk solid, m.p. 100-102°C.

(b) N-(5-methyl-1,3,4-thiadiazol-2-yl)butylamine (3 g, 0.0175 mol) and 15 ml of isobutyric anhydride were heated on a steam bath for 1 hour. The excess of anhydride was removed under reduced pressure and the residue distilled at 0.3 mm Hg,

and 3.6 g of an oil was obtained (55% yield), boiling point. 132°C which gave the title compound as a white solid, (m.p. 54-57°C) on cooling.

Example 5

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

This compound was prepared in a similar manner to Example 4. It was a colorless oil, bp. 152-154°C at 0.5 mm, n21 1-5108, NMR, IR and UV confirmed the structure. Analysis: C13<H>23<N>3<O>S requires: C 57.99, H 8.55, N 15.61%

found: C 57.81, H 8.67, N 15.76%.

Example 6 N-butyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)cyclopropanecarboxamide.

N-(5-methyl-1,3,4-thiadiazol-2-yl)butylamine (1.7 g, 0.01 mol) in 20 mL of benzene was treated with 1.53 mL of triethylamine and 1.15 g of cyclopropanecarboxylic acid chloride. The mixture was refluxed for 20 hours. The solution was then evaporated to dryness and the residue treated with ether and then filtered. The solution was washed with water, dried and treated with charcoal, then filtered and evaporated, after which the residue was recrystallized from petroleum ether (40-60°C) to give N-butyl-N-(5-methyl-1,3,4 -thiadiazol-2-yl)cyclopropanecarboxamide as a white crystalline solid.

Sm.p. 82-84°C.

Example 7

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

This compound was prepared in a similar manner to Example 6. It was a colorless oil with a boiling point. 162-16 4°C at 0.4 mm Hg. The NMR, IR and UV spectra confirmed the structure.

Analysis: <C>13<H>21<N>3<O>S requires: C 58.4, H 7.9, N 15.7%

found: C 58.5, H 7.6, N 15.9 I.

Example 8

N-(1-methylethyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide. (a) N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-methylethylamine. 2-Amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mol) in IPA (700 mL) and 100 mL of acetone was treated with 20 g of sodium borohydride in portions with stirring and cooling. The reaction mixture was then stirred and heated to reflux for 3 hours. The solution was then poured into 3 liters of water and extracted with 3 liters of ether. The ether solution was dried, filtered and evaporated to give the title compound as a cream solid, m.p. 145°C. (b) N-(5-methyl-1,3,4-thiadiazol-2-yl)-1-methylethylamine (5 g, 0.032 mol) in 100 mL of pyridine was treated with 4.1 mL of benzoyl chloride. The reaction mixture was stirred and heated

to boil under reflux for 5i hours. The pyridine was removed under reduced pressure and the residue treated with water and extracted with ether. The ether solution was dried, filtered and evaporated to dryness, and the residue recrystallized from ether/-

petroleum ether (40-60°C), whereby the title compound was obtained as pale yellow crystals, m.p. 82.5-83.5°C.

The following compounds were prepared in the same manner.

Examples 9 and 10

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

This was a pale ocher 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°C.

Example 11

(a) 5-chloro-3-methyl-1,2,4-thiadiazole

A suspension of acetamidine hydrochloride (47.0 g, 0.5 mol) and trichloromethanesulfenyl chloride (83.0 g, 0.45 mol) in 500 mL of dichloromethane was placed in a three-necked flask equipped with a stirrer, dropping funnel, and thermometer. While cooling in an acetone bath and stirring, a solution of sodium hydroxide (100 g, 250 mol) in 150 ml of water was slowly added while keeping the temperature below -8°C by means of a cold bath. After approx. half of the solution had been added, further addition gave a color change from red via orange to yellow. After the last addition (about 5 hours), the precipitated sodium chloride was filtered off and washed with CH 2 Cl 2 . The organic phase was separated from the water, the latter being shaken 3 times with 30 ml of CH 2 Cl 2 . The combined CH2Cl2 solutions were washed with water until a neutral reaction was obtained, and it was then dried over magnesium sulfate. The solvent was evaporated and a red liquid was obtained. This was distilled in vacuo to give 5-chloro-3-methyl-1,2,4-thiadiazole as a colorless liquid. Yield 27 g (45%), boiling point. 25°C/3.5 mm Hg.

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

5-chloro-3-methyl-1,2,4-thiadiazole (27 g, 0.20 mol) was dissolved in 200 ml of ethanol bg while cooling in an ice bath, an ethanolic solution of butylamine (44 g, 0.60 mol) was added ). This was stirred at room temperature overnight and evaporated to a smaller volume. When ether was added, a white precipitate of butylamine hydrochloride was obtained and this was filtered off. The yellow filtrate was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness to give a yellow oil which was distilled under vacuum to give 5-butylamino-3-methyl-1,2,4-thiadiazole as a pale yellow liquid. Yield 29.9 g, (87.2%), boiling point. 101-102°C/0.14 mm Hg.

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

Cyclohexanecarboxylic acid chloride (9.92 g, 0.068 mol). was slowly added to a solution of 5-methylamino-3-methyl-1,2,4-thiadiazole (7.0 g, 0.054 mol) in dry benzene containing triethylamine (6.87 g, 0.068 mol) and the mixture was heated with refluxing for 1J rime, cooled and washed with 2N hydrochloric acid, then with a saturated solution of sodium bicarbonate and then water, dried over magnesium sulfate, filtered and evaporated to a yellow oil which crystallized on standing. This was recrystallized twice from petroleum ether (60-80°C) and white crystals of N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-methyl-cyclohexanecarboxamide were obtained. Yield 8.23 g (63.8%), m.p. 96°C.

Examples 12-21

The following examples were produced in a similar manner

manner as indicated in example 11.

N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-butyl-2-methylpropanamide (bp. 115-117°C/0.1 mm Hg).

Analysis: O^H^N^S 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, O 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-thiadiazol-5-yl)-N-butylphenylcarboxamide.

(m.p. 77°C).

N-(3-cyclobutyl-1,2,4-thiadiazol-5-yl)-N-octylcyclooctanecarboxamide.

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

(m.p. 86°C).

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

(m.p. 61°C).

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

N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-n-butyl-n-hexanamide (bop. 1 30-135°C/0.15 mm Hg, purified by column chromatography)

Analysis: <C>14<H>25<N>3<O>S requires: C 59.33, H 8.89, N 14.83, 0 5.65,

S 11.31%

found: C 59.39, H 8.82, N 15.19, 0 5.87, N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-2-propenylphenylacetamide (cf. at 70°C).

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

Example 22

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

(a) 5- butylamino- 3- methyl- 1, 2, 4- oxadiazole

3-Methyl-5-trichloromethyl-1,2,4-oxadiazole (43 g, 0.21 mol) was added to n-butylamine (46.75 g, 0.63 mol) and stirred at room temperature overnight. Excess amine was removed under vacuum and the residue distilled (oil bath, 110°C/0.5 mm Hg). Recrystallization from petroleum ether 60-80°C gave the title compound as white plates, 26 g, m.p. 62-65°C.

(b) 5-butylamino-3-methyl-1,2,4-oxadiazole (4.2 g, 0.03 mol) and butyric anhydride (4.75 g, 0.033 mol) were refluxed in 30 mL of toluene for 3 hours. After removal of toluene under vacuum, the residue was refluxed in methanol (60 mL) with a few drops of triethylamine for 1 hour. The methanol was evaporated under vacuum and the residue taken up in carbon tetrachloride, washed twice with 2N HCl and twice with a saturated solution of sodium bicarbonate and then dried over magnesium sulfate. The product was purified by column chromatography (silica gel 120 g), eluted with petroleum ether, 40-60°C, with increasing solvent polarity to 10% ether/petroleum ether. The fractions were combined and distilled in a Kugelrohr air bath at 119°C/3.3 mm Hg. Analysis: C^H N302 requires: C 58.64, H 8.50, N 18.65, O 14.20%

Found: C 58.78, H 8.30, N 18.40, O 14.18%

Example lines 23 - 29

The following oxadiazoles were prepared using the procedure of Example 22.

N-ethyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide (bp. 92°C/3.0 mm Hg).

Analysis: CgH15N3C>2 requires: C54.80, H 7.66, N 21.30, 0 16.22%

found: C 54.68, H 7.46, N 21.14, 0 16.33%

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

n20 1 .47-48, in liquid.

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

Analysis: C^H^^C^ requires: C 58.65, H 8.50, N 18.66, 0 14.20%

found: C 58.49, H 8.22, N 18.40, 0 14.18%

N- n- butyl- N-( 3- methyl- 1, 2, 4- oxadiazol- 5- yl) hexanamide Analysis: <C>13<H>23<N>3<0>2 requires: c 61.63 , H 9.15, N 16.58, 0 12.63%

found: C 61.89, H 9.39, N 16.33, 0 12.65%

N-ethyl-N-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide (m.p. 48°C).

N-butyl-N-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide (boiling point 140°C/7 mm Hg, air bath temperature). Analysis: C16<H>21N3°2 requires: c 66.88, H 7.37, N 14.62, 0 11.14%

found: C 67.07, H 7.38, N 14.38, 0 11.06%

N- ethyl- N-(3- phenyl- 1, 2, 4- oxadiazol- 5- yl)- n- butanamide

(m.p. 74°C).

Example 3 0

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

5-n-hexylamino-3-methyl-1,2,4-oxadiazole (4.6 g, 0.025 mol) was dissolved in 25 mL of acetic anhydride and refluxed for 3 hours and then evaporated to dryness in vacuo. The residue was dissolved in 50 ml of chloroform and washed twice with 2N HCl and twice with a saturated solution of NaHCO 3 and then dried over MgSO 4 . (bop. 113-114°C/1.0 mm Hg). Analysis: O^H^N^ requires: C 58.64, H 8.50, N 18.65, 0 14.20%

found: C 58.66, H 8.76, N 18.57, O 14.48%

Example 31

The following compound was prepared using the procedure of Example 30.

N-(3-methyl-1,2,4-oxadiazol-5-yl)-N-2-propenylacetamide (bp. 82°C/1.5 mm Hg, air bath temperature).

Analysis: CgH^N^ requires: C 53.02, H 6.12, N 23.19, O 17.66%

found: C 52.78, H 5.90, N 23.03, O 17.69%

Example 32

N-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(4-methylphenyl)methylamino-cyclopropanecarboxamide

Cyclopropanecarboxylic acid chloride (3.45 g, 0.033 mol) was added dropwise to a solution of 5-(4-methylphenyl)-methylamino-3-methyl-1,2,4-oxadiazole (6.1 g, 0.03 mol) and triethylamine (3.45 g, 0.033 mol) in dry benzene while keeping the temperature below 10°C. After the addition was finished, the temperature was allowed to rise to room temperature, after which the mixture was boiled under reflux overnight. After cooling, the mixture was washed twice with 2N HCl and twice with a saturated solution of sodium bicarbonate and then dried over magnesium sulfate and then decolorized with charcoal. The product was purified by column chromatography on 110 g of silica gel and eluted with petroleum ether, 40-60°C, with increasing 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 33-44

The following oxadiazoles were prepared using the procedure of Example 32.

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

(m.p. 74°C)

N-n-butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropane-carboxamide, (n^<6> 1.4882).

N- hexyl- N-(3- methyl- 1, 2, 4- oxadiazol- 5- yl) cyclopentane-carboxamide

(boiling point 121°C/1.4 mm Hg (air bath temperature).

Analysis: C15H25N302 requires: C 64.48, H 9.02, N 15.04, O 11.52%

found: C 64.76, H 8.86, N 14.82, O 11.52%

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

(boiling point 157°C/1.5 mm Hg, air bath temperature).

Analysis: ci6H27N3°2 requires: c 65.49, H 9.27, N 14.32, O 10.9%

found: C 65.58, H 9.05, N 14.19, O 10.95%

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

(boiling point 126°C/0.2 mm Hg, air bath temperature).

Analysis: C16H21N302 requires: C 66.87, H 7.36, N 14.62, O 11.13%

found: C 66.85, H 7.35, N 14.58, 0 11.27%

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

(boiling point 120°C/10 mm Hg air bath temperature)

N-(3-methyl-1,2,4-oxadiazol-5-yl)-N-phenylmethylcyclohexanecarboxamide, (m.p. 73°C).

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

(m.p. 75°C).

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

(bop. 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-oxadiazol-5-yl)-2-methylpropanamide, (boiling point 118°C at 0.2 mm Hg, air bath temperature). N-(4-methylphenyl)methyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclopropanecarboxamide, (m.p. 50°C).

Example 4 5

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

Isobutyric anhydride (7.9 g, 0.05 mol) was added to isopropylamino-3-methyl-1,2,4-oxadiazole and kept at 100°C overnight. On cooling, 60 ml of methanol and a few drops of triethylamine were added and the mixture was refluxed for 1 hour. After removal of the methanol in vacuo, the residue was dissolved in ether and washed twice with a saturated solution of NaHCO 3 (bp. 90°C/1.3 mm Hg), Kugelrohr air bath temperature.

♦

Example 4 6

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

(a) 1-Acetyl-4-allyl-semicarbazide

Allyl isocyanate (25 g, 0.30 mol) was slowly added to a boiling solution of acethydrazide (22.2 g, 0.30 mol) in 300 mL of dry benzene. The mixture was heated for 1 hour and two layers formed. The benzene was evaporated and the residue treated with ether to give the title compound as a white solid, m.p. 71-74°C.

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

1-Acetyl-4-n-propyl-semicarbazide (35 g, 0.22 mol) prepared by the procedure of (a) above was refluxed with POCl₂ (150 mL) for 2 hours, until no HCl was evolved. The excess P0Cl3 was withdrawn using a water pump, and the mixture poured into 200 ml of ice water and neutralized with 50% NaOH to pH 7. A red oil was extracted with dichloromethane (2 x 180 ml), dried, filtered and evaporated to an oil which was distilled in a Vigreux column to the title compound which was a pink liquid 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-propyl-cyclobutane-carboxamide

5-Methyl-2-n-propylamino-1,3,4-oxadiazole (6 g, 0.04 mol) prepared as described under (b) above was refluxed with cyclobutanecarboxylic acid chloride (5.5 g, 0.05 mol) in 25 mL of benzene in the presence of triethylamine (4.72 g, 0.05 mol) for 2 hours. The mixture was filtered and the filtrate washed with dilute hydrochloric acid, with a saturated solution of NaHCO^ and water, dried over magnesium sulfate, filtered, after which the solvent was evaporated and a red-brown liquid was obtained which was distilled twice in a Vigreux column and obtained the title compound as a pale pink liquid (bp. 110-111°C/0.27 mm Hg).

Examples 47-54

Using the procedure from Example 46, the following oxadiazoles were prepared: N-(5-methyl-1,3,4-oxadiazol-2-yl)-N-n-propyl-2-methylpropanamide, (bp. 85-87°C/0 .4 mm Hg).

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

N-(5-methyl-1,3,4-oxadiazol-2-yl)-N-n-propyl-cyclopentane-carboxamide (bp. 110-112°C/0.01 mm Hg).

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

N-(5-methyl-1,3,4-oxadiazol-2-yl)-N-2-propenyl-2-cyclopentanecarboxamide (bp. 114-116°C/0.12 mm Hg).

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

N-(5-methyl-1,3,4-oxadiazol-2-yl)-N-n-butyl-2-methylpropanamide (bp. 82-84°C/0.1 mm Hg).

N-(5-methyl-1,3,4-oxadiazol-2-yl)-N-n-butylacetamide (bp. 82-84°C/0.1 mm Hg).

Example 55

The following 1,2,4-oxadiazole was prepared by the same procedure as in example 22 (b)

N-n-hexyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide, (bop. 90°C/1.1 mm Hg).

Analysis: C13H23N3°2 requires: c 61.63, H 9.15, N 16.58, 0 12.63%

found: C 61.47, H 8.98, N 16.84, 0 12.70%

Examples 56-58

Using the method described in example 32, the following oxadiazoles were prepared: N-methyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclohexanecarboxamide

Analysis: C^H^N^ requires: C 59.17, H 7.67, N 18.82, 0 14.33%

found: C 59.05, H 7.59, N 18.41, 0 14.73% N-(3-methyl-1,2,4-oxadiazol-5-yl)-N-2-propenylheptanamide (bop. 104°C/1.5 mm Hg).

Analysis: C^ 2U2^ 3°2 requires: C 62.12, H 8.42, N 16.71, 0 12.73%

found: C 62.16, H 8.20, N 16.54, O 12.63%

N-(3-methyl-1,2,4-oxadiazol-5-yl)-N-n-butyl-2-ethylbutanamide (bp. 71°C/0.055 mm Hg).

Analysis: C-|3<H>23<N>3°2 requires: c 61.63, H 9.15, N 16.59, 0 12.63%

found: C 61.46, H 8.90, N 16.57,0 12.47%

Example 59

N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-phenylmethyl-n-hexanamide (m.p. 72°C) was prepared by the method indicated in example 11.

Examples 60-62

The following 1,2,4-thiadiazoles were prepared by the same method as described in example 11: N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-hexylacetamide (m.p. 38°C ). N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-hexylphenylacetamide (m.p. 57°C). N-(3-methyl-1,2,4-thiadiazol-5-yl)-N-phenylmethylphenylacetamide, (m.p. 134°C).

Examples 63-71

The following 1,2,4-oxadiazoles were prepared by the same method as described in example 32: N-butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-phenylcarboxamide Analysis: c-i4< H>i2<N>3°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- N-(3- methyl- 1, 2, 4- oxadiazol- 5- yl)- 4- chlorophenylcarboxamide

Analysis: C^H^ClN^ requires: C 57.24 H 5.49 Cl 12.07 N 14.30

O 10.89

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- methoxyphenyl-carboxamide, (bop. 105°C/0.015 mm Hg)

Analysis: C15H19N303 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

N-butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclohexane-carboxamide, (bop. 70°C/0.01 mm Hg).

Analysis: c-i4H23N3°2 requires: C 63.37, H 8.74, N 15.84

found: C 63.54, H 8.55, N 15.60

N-butyl-N-(3-methyl-1,2,4-oxadiazol-5-yl)-cyclobutane-carboxamide, (bop. 67°C/0.02 mm Hg).

Analysis: <C>12<H>19<N>3°2 requires: C 60.74, H 8.07, N 17.71.0 13.49

found: C 60.44, H 7.88, N 17.54, O 13.21

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

(bop. 62°C/0.15 mm Hg)

Analysis: C, QE^?N302 requires: C 56.85, H 8.11, N 19.89

found: C 56.93, H 8.14, N 19.64

N-butyl-N-(3-buty1-1,2,4-oxadiazol-5-yl)- cyclopropane-carboxamide

Analysis: C14<H>23<N>3°2 requires: c 63.37, H 8.74, N 15.84.0 12.06

found: C 63.19, H 8.51, N 15.58, O 11.82

N-butyl-N-(3-ethyl-1,2,4-oxadiazol-5-yl)-cyclopropane-carboxamide, (boiling point 65°C/0.01 mm Hg)

Analysis: <c>i2<H>-|9<N>3°2 requires: c 60.74, H 8.07, N 17.71, O 13.49

found: C 60.50, H 7.78, N 17.43, 0 13.19

N- butyl- N-( 3- cyclohexyl- 1, 2, 4- oxadiazol- 5- yl)- cyclopropane-carboxamide

Analysis: •C16H25N302 requires: c 65.95, H 8.65, N 14.42, O 10.98

found: C 66.15, H 8.83, N 14.51, O 10.86

Examples 72-74

Using the methods described in example 45, the following oxadiazoles were prepared: N-butyl-N-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-methylpropanamide

(bop. 65°C/0.02 mm Hg)

Analysis: C-|2H21<N>3°2 requires: c 60 .22 , H 8.85, N 17.56, O 13.37

found: C 59.96, H 8.68, N 17.36, O 13.22

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

(bop. 64°C/0.05 mm Hg)

Analysis: <C>i4<H>25<N>3°2 requires: C 62.89, H 9.42, N 15.72, O 11.97

found: C 62.65, H 9.20, N 15.46, O 11.72

N- butyl- N- ( 3- cyclohexyl- 1, 2, 4- oxadiazol- 5- yl)- 2- methylpropanamide, (bop. 92°C/0.02 mm Hg)

Analysis: <C>16<H>2?<N>3<0>2 requires: C 65.49, H 9.28, N 14.32, 0 10.91

found: C 65.26, H 9.09, N 14.07, O 11.05

Claims (1)

Analogous method for the preparation of chemotherapeutically active heteroaryl compounds with the formula: where Ar represents: where R is C^-C^-alkyl, C^-C^Q-cycloalkyl or phenyl, and where the acylamino group -NR^COR<2> is linked to the carbon atom in the heteroaryl ring, R being -Cj Q-alkyl, C2~ C 6 -alkenyl, C 3~C-| Q-cycloalkyl or phenyl-C^_g-alkyl where the phenyl group is optionally substituted with Cj^-alkyl, C^_3~ alkoxy or halogen, and where R<2> is C^_g-alkyl, C2_g-alkenyl, C3_i0~ cycloalkyl , C^_^Q-cycloalkyl-C 1-6 -alkyl, phenyl optionally substituted with C 1-6 - alkoxy or halogen, phenyl-C, ,-12 alkyl or phenyl-C 2-6 -alkenyl; or where R and R together can form a lactam ring with 5-7 ring atoms, provided that: (a) when Ar is 1,3,4-thiadiazolyl, R 1 is C^^-alkyl and R 2 is C^_^- alkyl, C2-3-alkenyl or C-1g-cycloalkyl, then said 1,3,4-thiadiazolyl group cannot be unsubstituted or substituted with a -3-alkyl group, (b) when Ar is 1,3,4-thiadiazolyl substituted with a C^_^-alkyl group, then cannot be C^g-alkyl or c2-6-alkenyl, (c) when Ar is 1,3,4-thiadiazolyl substituted with methyl, then 2 cannot R be methyl, and (d) when Ar is 1,2,4-oxadiazolyl substituted with phenyl, then 1 2 when R is methyl, R cannot be methyl or benzyl; characterized by: (a) acylating an alkyl derivative with the formula: where Ar and R 1 are as defined previously; (b) alkylates an acyl derivative of the formula: where Ar is 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl and R 2 is as defined previously; (c) reacts with a compound of the formula:• where Y is a leaving group and where Ar is as defined previously, with a salt of the formula: where M is a metal from group IA or IIA in the periodic table, and R 1 and R 2 are as defined previously; or (d) ring-closes a compound of the formula: where Z is -CO(CH2)nQ, -(CH2)nCOQ' or cyclopropylcarbonyl, n is a number from 3-5, Q is a leaving group, Q' is a group that activates the adjacent carbonyl group for a nucleophilic attack or - OR 8 , where R 8 is hydrogen or C 1 -alkyl, whereby a compound of formula I is formed where R 1 and R 2 form a lactam ring with from 5-7 atoms.