NO130478B - - Google Patents

Description

Analogy method for the production of

oxadiazole derivatives with hypocholesterolemic

effect.

The present invention relates to an analogue method for the production of new oxadiazole derivatives and pharmaceutically suitable salts thereof, with an effective hypocholesterol effect.

There are many types of anti-arteriosclerosis agents or hypocholesterol agents. However, most known hypocholesterol agents or anti-arteriosclerosis agents are not particularly satisfactory in terms of effectiveness, mechanism of action, toxicity, etc.. For this reason, extensive studies have now been carried out to provide effective hypocholesterol agents or anti-atherosclerosis agents and have succeeded in sensitizing new oxadiazole derivatives defined below.

As far as these new compounds are concerned, it has been established: the compounds have a strong hypocholesterol effect, i.e. are capable of lowering the cholesterol content in the body, they have a relatively low toxicity in mammals, and can therefore be used as a safe and effective medicine for improvement of and/or prevention of atherosclerosis.

The invention has emerged on the basis of these results.

Thus, the main purpose of the present invention is to produce new oxadiazole derivatives which are suitable as safe and effective hypocholesterol agents, anti-atherosclerosis preparations or cholesterol-lowering agents.

According to the present invention, hypocholesterolemically active oxadiazole derivatives with the general formula are thus produced:

where X denotes a group -COOR, where R is benzyl or alkyl with up to 6 carbon atoms or X is an unesterified carboxyl group or a carboxamido group, each of the groups R^ and R is hydrogen, phenyl, cyclohexyl or alkyl with up to. 8 carbon atoms, and R^ is alkyl with 1-15 carbon atoms, benzyl, phenyl or phenyl substituted with lower alkyl, lower alkoxy, halogen, nitro or amino, or a cyclohexylmethyl, pyridyl, furyl or thienyl group, as well as pharmaceutically acceptable salts thereof , and the compounds of formula I are prepared according to the invention by reacting a compound of the formula: where R15 R2 and X have the above meaning with a carboxylic acid of the general formula:

where R has the above meaning, or an acid halide, acid anhydride or ester thereof, after which, if desired, the compounds obtained are converted into pharmaceutically acceptable salts thereof.

The pharmaceutical salts include addition salts with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., and with organic acids such as oxalic acid, maleic acid, malic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, etc.

The acid halide of the compound (III) comprises e.g. corresponding acid chloride, acid bromide etc. Corresponding esters include e.g. alkyl esters (e.g. methyl, ethyl, propyl, butyl esters, etc.), aryl esters (e.g. phenyl, tolyl esters, etc.), etc.

The acid anhydride can be produced by condensation of 2 mol of the compound (III), or be a so-called mixed anhydride produced by condensation of 1 mol of a suitable organic acid (e.g. acetic acid, propionic acid, butyric acid, benzoic acid, caproic acid, capric acid, caprylic acid, myristic acid etc.) and 1 mol of compound (III).

Usually used approx. 1.2 to 1.5 mol of the compound (III) or its derivative per moles of compound (II). The reaction conditions may vary depending on the type of starting compounds or other factors.

When the compound (III) itself or its acid anhydride or ester is used as one of the starting compounds, the reaction is usually carried out without a solvent, while heating to approx. 100°C or higher, preferably 100 to approx. 150°C, but a suitable solvent such as dioxane, toluene, benzene can sometimes be used.

A basic compound can also be used. The basic compound can e.g. be alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), and alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.).

When using an acid halogenide corresponding to compound (III), the reaction is preferably carried out in the presence of an acid acceptor at room temperature or under heating to approx. 150°C or lower.

The acid acceptor can, for example, be organic amines such as pyridine, picoline or triethylamine.

When organic amines are used in larger quantities, it can also be a reaction participant - Other suitable inert solvents such as dioxane, toluene, benzene can also be used. The reaction time is

usually between approx. 30 minutes and several hours.

After completion of the reaction, the relevant compound of general formula (I) can be isolated and purified in the usual way, e.g. by extraction with a suitable solvent (e.g. ethyl acetate, chloroform etc.) followed by evaporation, recrystallization, column chromatography etc.

The compounds with general formula (II) are new compounds and can be prepared according to the following reaction scheme:

(where R 1 , R 2 and X have meanings as previously indicated).

This reaction can usually be carried out in a suitable solvent while heating to approx. 70 to 80°C. The solvent can be a mixture of water and a suitable organic solvent (such as methyl alcohol, ethyl alcohol, acetone, etc.).

Compounds of formula (I) have the characteristic strong pharmacological properties mentioned below: 1) Compound (I) has a strong cholesterol level-lowering effect in the living organism, particularly in the liver. 2) The compound effectively reduces the synthesis of cholesterol in the body, especially in the liver, without the production of unwanted steroids (such as desmosterol etc.). 3) They prevent the accumulation of cholesterol in the body, especially in the liver and aorta.

4) They have very low toxicity to mammals.

Due to the above-mentioned characteristic properties, the relevant compounds produced according to the invention can be used as hypocholesterol preparations and/or medicines for improving or preventing atherosclerosis. The compounds are given for this purpose in pure form or in the form of pharmaceutical preparations mixed with suitable and usual carriers and diluents.

The pharmaceutical preparation can take the form of tablets, granules, powders and capsules, and can be given orally or parenterally.

Usual daily doses of compounds of formula I are between approx. 50 mg and 1500 mg per adult patient by oral administration or by injection (e.g. intravenously, intramuscularly, etc.) .

For further elucidation of the invention, reference is made to the examples below where the expression "parts" and "%" are on a weight basis if nothing else is stated, and the ratio between parts and parts by volume corresponds to the ratio between grams and milliliters.

Production of output connections.

In 250 parts by volume of a mixture of ethyl alcohol and water (3:2), 48 parts of 4-(ethoxy-carbonyl-1,1-dimethyl-methoxy)-benzonitrile are dissolved, and 18.2 parts of hydroxyamine hydrochloride and 13.8 parts of anhydrous are added sodium carbonate. The mixture is heated at between 70 and 80°C for 3 hours.

It is then concentrated under reduced pressure. The residue is extracted with ethyl acetate and the ethyl acetate layer is extracted with 150 parts by volume of 10% by weight hydrochloric acid. The acid portion is made alkaline with 10% aqueous sodium hydroxide and the separated oil is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure leaving 20.5 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime melting at 117 to 119°C-

Analysis for C^R^gO^ :

Calculated C 58.63 H 6.8l N 10.62

Found C 58.79 H 6.8l N 10.30

In a similar manner to the above, the following substances are prepared: 4-(1-ethoxycarbonyl-ethoxy)benzamidoxime which melts at 120 to 122°C

4-(1-ethoxycarbonylpentoxy)benzamidoxime melting at 62

to 64°C

4-(1-ethoxycarbonyl-nonyloxy)benzamldoxime melting at 75

to 76°C

4-(ethoxycarbonyl~phenyl-methoxy)benzamidoxime melting at 133

to 13k°C

4-(Ethoxycarbonyl-1-cyclohexyl-methoxy)benzamidoxime melting at 109 to 110°C.

Example 1.

To a solution of 4.2 parts of nicotinic acid chloride in 20 parts by volume of pyridine, 4.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)-benzamidoxime are added and the whole mixture is refluxed for 2.5 hours.

The reaction mixture is concentrated under reduced pressure and the oily residue is dissolved in 200 parts by volume of saturated aqueous sodium bicarbonate solution. The separated oil is extracted with ethyl acetate and the ethyl acetate layer is dried over anhydrous sodium sulfate, concentrated under reduced pressure.

The oily residue is treated with oxalic acid and the crystals are recrystallized from ethyl alcohol. 2.1 parts of 3-/4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7~5-(3~pyridyl)-1,2,4-oxadiazole-oxalate are obtained as colorless needles with a melting point of 129 to 131° C. Dividend: 35.1$.

Analysis for C^H^N^ .iC^O^

Calculated C 60.30 H 5.18 N 10.79

Found C 60.36 H 4.92 N 10.55

Example 2.

To a solution of 2.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 10 parts by volume of pyridine, 2.1 parts of isonicotinic acid chloride are added, and the whole mixture is refluxed for 2.5 hours.

The reaction mixture is poured into 200 parts by volume of ice water and the whole is made alkaline with 10% aqueous sodium hydroxide. The crystals are dissolved in ethyl ether. The solution is treated with oxalic acid and the filtered crystals are recrystallized from methyl alcohol.

This gives 1.5 parts of 3-(4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(4-pyridyl)-1,2,4-oxadiazole-oxalate as colorless fine needles with a melting point of 131 to 133°C0 Yield: 50.3$.

Analysis for C-^H-^N.^. ^-C^O^

Calculated C 60.30 H 5.18 N 10.79

Found C 60.09 H 4.97 N 1051

Example 3»

A solution of 2.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 10 parts by volume of isopropionic acid hydride is heated at 140° C. for 2.5 hours and the reaction mixture is poured into 100 parts by volume of water. The entire mixture is made alkaline with 10% aqueous sodium hydroxide and the separated oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is column chromatographed on silica gel and gives 2.1 parts of 3-/4-(ethoxy-carbonyl-1,1-dimethyl-methoxy)phenyl7-5-isopropyl-1,2,4-oxadiazole as a colorless oil. Dividend: 88.9$.

Analysis for C^<-H>^<NgO>^

Calculated: C 64.13 H 6.97 N 8.80

Found C 64.37 H 6.91 N 9.08

NMR spectrum ( (in CDCl^)

2.03(2H, d. J=15 c.p.s. arom. H in 3-phenyl)

3.10 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

Example 4.

A solution of 2.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of benzoyl chloride is heated at 130 to 140°C for 3 hours and the reaction mixture is then poured into 100 parts by volume of ice water. The whole mixture is made alkaline with 10% aqueous sodium hydroxide and the separated oil is extracted with chloroform. The chloroform layer is washed with water, dried and concentrated under reduced pressure. The residue is column chromatographed on silica gel and gives 1.6 parts of 3-/~4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-phenyl-1,2,4-oxadiazole as a colorless oil. Dividend: 51.2$.

Analysis for C26H20<N>2°4

Calculated C 68.17 H 5.79 N 7.95

Found C 67.92 H 5.78 N 7.45

NMR spectrum (*£ ) (in CDCl^)

1.94 (2H, d, J=15 c.p.s., arom. H in 3 phenyl). 2.40 to 2.66 (5H, m. arom. H in 5-phenyl). 3.06 (2H, d,J=15 c.p.s., arom. H in 3-phenyl)„ 5.48 (2H, q, J=12 c.p.s., -O-CH.,- ).

Example 5.

A solution of 2.5 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime and 1.8 parts of furoyl chloride in 5 parts by volume of pyridine is heated at 130 to 140°C for 2.5 hours, and the reaction mixture poured into 100 parts by volume of ice water.

The separated oil is extracted with ethyl acetate and the ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, distilled under reduced pressure to remove the ethyl acetate. The residue is column chromatographed on silica gel and gives 1.2 parts of 3-/4--(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(2-furyl)-1,2,4-oxadiazole as colorless needles of melting point 4l to 43°C. Dividend: 37.3$.

Analysis for CigHi8°5<N>2

Calculated C 63.15 H 5.30 N 8.18

Found C 63.04 H 5.40 N 7.93

Ex emp or 6.

A solution of 1.5 parts of 4-(1-ethoxycarbonyl-ethoxy)-benzamidoxime and 1.6 parts of nicotinic acid chloride in 7 parts by volume of pyridine is refluxed for 3.5 hours. The reaction mixture is poured out

in 75 volumes of ice water and the whole is made alkaline with 10% sodium hydroxide. The separated oil is extracted with chloroform and the chloroform layer is washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove chloroform. The residue is treated by column chromatography on silica gel and gives 0.8 parts of 3-[4-(1-ethoxycarbonyl-ethoxy)phenyl-7-5-(3-pyridyl)-1,2,4-oxadiazole as pink flakes melting at 103 to 105°C. Dividend: 39.7$.

Analysis for C^H^<O>^<N>^

Calculated C 63.71 H 5.05 N 12.38

Found C 64.13 H 5.19 N 12.20

Example 7.

To a solution of 1.3 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine is added 0.9 parts of 4-(t-butyl)benzoyl chloride, and the whole mixture is refluxed in 2.5 hours. The reaction mixture is poured into 50 parts by volume of ice water and the separated oil is extracted with 50 parts by volume of chloroform. The chloroform layer is washed with 10 µg aqueous sodium hydroxide, water, 10 µg hydrochloric acid and water in this order, and dried. The chloroform layer is distilled under reduced pressure and gives a light yellow-brown oil. The oil left behind is column chromatographed over silica gel and gives 1.0 parts of 3-[r*4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7~. 5/J-(t-Butyl)phenyl/-1,2,4-oxadiazole as colorless needles with a melting point of 69 to 70°C. Dividend: 65.0$.

Analysis for C2Z^28<N>2°4

Calculated C 70.56 H 6.91 N 6.86

Found C 70.67 H 6.79 N 6.42

Example 8.

1.4 parts of 4-nitrobenzoyl chloride are added to a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine, and the whole mixture is refluxed for 2 hours. The reaction mixture is poured into 50 parts by volume of ice water and the separated oil is extracted with 50 parts by volume of chloroform.

The chloroform layer is washed with a 10% aqueous solution of sodium hydroxide, water and 10% hydrochloric acid and water in the specified order, and dried. The chloroform layer is distilled under reduced pressure and yields 1.8 parts of yellow crystals.

The crystals are recrystallized from a mixture of benzene and petroleum gasoline and give 1.1 parts of 3-(4-(ethoxycarbonyl-1,1-dlmethyl-methoxy)phenyl7-5-(4-nitrophenyl)-1,2,4-oxadiazole as yellow needles with a melting point of 91°C. Dividend: 73.5$.

Analysis for C^H^N^Og

Calculated C 60.45 H 4.82 N 10.58

Found C 60.53 H 4.83 N 10.33

Example 9»

1.4 parts of 3-nitrobenzoyl chloride are added to a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine, and the whole mixture is refluxed for 2 hours.

The reaction mixture is poured into 50 parts by volume of ice water

and the whole mixture is extracted with 50 parts by volume of chloroform. The chloroform layer is washed with 10 µg aqueous sodium hydroxide solution, water, 10 µg hydrochloric acid and water in the order indicated, and dried. The chloroform layer is distilled under reduced pressure and leaves behind

1.5 parts pale yellow crystals.

The crystals are recrystallized from a mixture of benzene and petroleum gasoline and give 1.1 parts of 3-(4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl)-5-(3-nitro-phenyl)-1, 2,4-oxadiazole as pale yellow needles with a melting point of 112 to 114°C. Dividend: 73.7$.

Analysis for C^H^N,^

Calculated C 60.45 H 4.82 N 10.58

Found C 60.48 H 4.77 N 10.37

Example 10.

To a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine is added 0.9 parts of 2-chlorobenzoyl chloride, and the whole mixture is heated at 120 to 130°C for 3.5 hours .

The reaction mixture is poured into 50 parts by volume of ice water and the separated oil is extracted with 50 parts by volume of chloroform. The chloroform layer is washed with 10 µg aqueous sodium hydroxide, water, 10 µg hydrochloric acid and water in the order indicated, and dried. The chloroform layer is distilled under reduced pressure and yields 1.7 parts of oil.

The oil is treated by column chromatography on silica gel to give 1.0 parts of 3-(4-(ethoxycarbonyl-1,1-dimethyl-methoxy)-phenyl7-5-(2-chlorophenyl)-1,2,4-oxadiazole as a light tan oil. Dividend: 69.0$.

Analysis for C^H-^^O^Cl

Calculated C 62.09 H 4.95 N 7.24

Found C 61.83 H 4.87 N 6.85

NMR spectrum ("£ ) (in CDCl^)

1.91 (2H, d. J=15 c.p.s., arom. H in 3-phenyl)

2.44 to 2.73 (3H, m, arom. H in 3-phenyl)

3.05 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

5.80 (2H, q. J=12 c.p.s, -O-CHg- )

8.88 (3H, t. J=12 c.p.s. -CH2- CH3)

Example 11.

To a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine is added 0.99 parts of 3-chlorobenzoyl chloride, and the mixture is refluxed for 3 j 5 hours.

The reaction mixture is poured into 50 parts by volume of ice water, and the separated oil is extracted with 50 parts by volume of chloroform.

The chloroform layer is washed with 10% aqueous sodium hydroxide, water and 10% hydrochloric acid and water in the order indicated, and dried. The chloroform layer is distilled under reduced pressure and yields 1.6 parts of brown oil. The oil is treated by column chromatography on silica gel and gives 1.3 parts of (ethoxy-carbonyl-1,1-dimethyl-methoxy)phenyl7-5-(3-chlorophenyl)-1,2,4-oxadiazole. Dividend: $89.6.

Analysis for C^H^I^O^Cl

Calculated C 62.09 H 4.95 N 7.24 Cl 9.17

NMR spectrum ("*£) (in CDCl^)

1.78 to 2.00 (2H, m.arom. H in 5-phenyl)

1.96 (2H, d. J=15 c.p.s., arom. H in 3-phenyl)

2.48 to 2.58 (1H, m. arom. H in 5-phenyl)

2.68 (1H, s. arom. H in 5-phenyl)

3.07 (2H, d, J=15 c.p.s., arom., H in 3-phenyl)

8.88 (3H, t. J-12 c.p.s., -CH2- CH3 )

Example 12.

To a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine is added 0.99 parts of 4-cbrbenzoyl chloride, and the whole mixture is refluxed for 2 hours. The reaction mixture is poured into 50 parts by volume of ice water and the separated crystals are extracted with chloroform. The chloroform layer is washed with 10 µg aqueous sodium hydroxide, water, 10 µg hydrochloric acid and water again in the order indicated, and dried. The chloroform layer is distilled under reduced pressure and gives 1.8 parts of bright red crystals. The crystals are recrystallized from petroleum ether and give 0.9 parts of 3-(4-chlorophenyl)-1,2,4- oxadiazole as bright red needles; down m.p. 93 to 9^° C. Yield: 62.0$..

Analysis for C^T^NgO^C!

Calculated C 62.09 H 4.95 N 7.24 Cl 9.17

Found C 62.35 H 4.93 N 7.24 Cl 9.16

Example 13»

To a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine is added 0.96 parts of 2-methoxybenzoyl chloride, and the whole mixture is refluxed for 3.5 hours. The reaction mixture is poured into 50 parts by volume of ice water and the entire mixture is extracted with 100 parts by volume of chloroform. The chloroform layer is washed with 10 µg aqueous sodium hydroxide, water and 10 µg hydrochloric acid and water in the order indicated, and dried. The chloroform layer is distilled under reduced pressure and yields 1.7 parts of colorless oil. The oil is column chromatographed on silica gel and gives 1.0 parts of 3-/~4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(2-methoxy-phenyl)-1,2,4-oxadiazole as colorless plates with melting point 79

to 80°C. Dividend: 69.0$.

Analysis for C2iH22<N>2°4

Calculated C 65.95 H 5.80 N 7.33

Found C 65.67 H 5.78 N 6.84

Example 14.

To a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy) benzamidoxime in 5 parts by volume of pyridine is added 0.96 parts of 4-methoxybenzoyl chloride, and the mixture is refluxed for 3 hours. The reaction mixture is poured into 50 parts by volume of ice water and the separated oil is extracted with 10 parts by volume of chloroform. The chloroform layer is washed with 10 µg aqueous sodium hydroxide, water, 10 µg hydrochloric acid and water in the order indicated and dried. The chloroform layer is distilled off under reduced pressure and yields 1.5 parts of colorless crystals. The crystals are recrystallized from methyl alcohol to give 0.9 parts of k-(ethoxycarbonyl-1,1-dimethyl-methoxy)-phenyl7-5-(4-methoxyphenyl)-1,2,4-oxadiazole as colorless needles, m.p. 83 to 85° C. Dividend: $62.6.

Analysis for C21H22<N>2°4

Calculated C 65.95, H 5.80 N 7.33

Found C 66.04 H 5.89 N 7.05

Example 15.

To a solution of 1.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 5 parts by volume of pyridine is added 0.91 parts of 4-aminobenzoyl chloride, and the whole mixture is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure. 10 parts by volume of 10% aqueous sodium hydroxide are added to the residue and the mixture is extracted with 50 parts by volume of chloroform.

The chloroform layer is washed with water, dried and evaporated to dryness. This procedure yields a brown oil.

The oil is treated by column chromatography on silica gel and gives 1.3 parts of 3-(4-(ethoxy-carbonyl-1-1,1-dimethyl-methoxy)-phenyl7-5-(4-aminophenyl)-1,2,4-oxadiazole as light brown short needles with a melting point of 109 to 111°C. Yield: 92.4

Analysis for c2oH21<N>3°4

Calculated C 65.38 H 5.76 N 11.44

Found C 65.02 H 5.65 N 11.71

Example 16.

1.82 parts of 3-aminobenzoyl chloride are added to a solution of 2.0 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime in 10 parts by volume of pyridine, and the whole mixture is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure and 20 parts by volume of 10% aqueous sodium hydroxide are added to the residue. The entire mixture is extracted with 50 parts by volume of chloroform and the chloroform layer is washed with water and dried. The chloroform layer is distilled under reduced pressure and gives a brown oil. This oil is treated by column chromatography on silica gel and gives 1.3 parts of 3-(4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(3-aminophenyl)-1,2,4-oxadiazole as a light brown oil. Dividend: $54.4>„

Analysis for C^H^N^

Calculated C 65.38 li 5.76 N 11.44

Found C 65.4l H 5.91 N 11.03

NMR spectrum (~£) (in CDCl )

1.96 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

2.39 to 2.86 (2H, m. arom. H in 5-phenyl)

2.50 (JH, a. arom. H in 5-phenyl)

3, Ok to 3,26'(1H, m. arom. H in 5-phenyl)

3.07 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

5.77 (2H, q. J=12 c.p.s. -O-CH2-)

8.88 (3H, t. J = 12 e.p.s. -CH2- CH3)

Example 17.

A solution of 1.3 parts of 4-{ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime and 1.7 parts of 2-thienoyl chloride in a mixture of 2 parts by volume of triethylamine and 10 parts by volume of dioxane is heated at 120 to 130°C for 4 hours and the reaction mixture is dissolved in 100 parts by volume of ice water.

The separated oil is extracted with ethyl acetate and the organic layer is washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure. The residue is treated by column chromatography on silica gel and gives 1.5 parts of 3-(4-ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(2-thienyl)-1,2,4-oxadiazole as colorless needles with melting point 89 to 91°C. Dividend: 85.7$.

Analysis for cigHig<N>2°4<S>

Calculated C 60.33 H 5.06 N 7.82

Found C 60.4l H 5.23 N 7.53

Example 18.

A solution of 1.3 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime and 1.9 parts of phenylacetyl chloride in a mixture of 2 parts by volume of triethylamine and 10 parts by volume of dioxane is heated at 120 to 130°C for 4 hours and the reaction mixture poured into 100 parts by volume of ice water.

The separated oil is extracted with ethyl acetate and the organic layer is washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is column chromatographed on silica gel and gives 1.6 parts of 3"/"^-(ethoxy-carbonyl-1,1-dimethyl-methoxy)phenyl7-5-benzyl-1,2,4-oxadiazole as a pale yellow oil. Dividend: 89.5$.

Analysis for <C>21H22<N>2°4

Calculated C 68.83 H 6.05 N 7.65

Found C 68.79 H 6.22 N 7.6l

NMR spectrum ( X.) U CDC1 ) .

2.02 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

2.67 (5H, s. arom. H in benzyl)

3.10 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

8.80 (3H, t. J=12 c.p. So -CH 2 -CH 2 ).

Example 19.

A solution of 1.3 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime and 2.0 parts of cyclohexylacetyl chloride in a mixture of 2 parts by volume of triethylamine and 10 parts by volume of dioxane is heated at 130 to 140°C for 5 hours and the reaction mixture poured into 100 parts by volume of ice water.

The separated oil is extracted with . ethyl acetate and the organic layer are washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure.

The residue is treated by column chromatography on silica gel to give 1.6 parts of 3-[4-(ethoxycarbonyl-1,1-dimethyl-methoxy)-phenyl]-5-(cyclohexyl-methyl)-1,2,4-oxadiazole as a light yellow-brown oil. Dividend: 88.0$.

Analysis for C2iH28<N>2°4

Calculated C 67.72 H 7.58 N 7.52

Found C 67.45 H 7.56 N 7.32

NMR spectrum ("£) (in CDCl^).

2.02 (2H, d. J=15 c.poS. arom. H in 3-phenyl)

3.09 (2H, do J=15 c.p.s. arom. H in 3-phenyl)

5.76 (2H, q. J=12 c.p.s. -O-CH 2 -CH 3 ).

Example 20.

A solution of 1.3 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime and 2.0 parts of octanoyl chloride in a mixture of 2 parts by volume of triethylamine. and 10 parts by volume of dioxane are heated at 120 to 130°C for 5 hours and the reaction mixture is poured into 100 parts by volume of ice water. The separated oil is extracted with ethyl acetate and the organic layer is washed with water. dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue is column chromatographed on silica gel to give 1.7 parts of 3-[4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl-7-5-heptyl-1,2,4-oxadiazole as a pale yellow oil. Dividend: 93.0$.

Analysis for Cg ^H^NpO^

Calculated C 67.35 H 8.08 N 7.48

Found C 67.36 H 8.46 N 7.20

NMR spectrum (<*>£) (in CDCl^).

2.03 (2H, d. J=15 c.p. So arom. H in 3-phenyl) 3.09 ( 2H, d. J=15 c.p.s. arom. H in 3-phenyl) 5.77 (2H, q. J =12 c.p.s. -O-CH2-CH3).

8.66 to 9.12 (16H, m. -CH2-CH^, - (CHg^- CH^ )

Example 21.

A solution of 1.3 parts of 4-(ethoxycarbonyl-1,1-dimethyl-methoxy)benzamidoxime and 2.7 parts of palmitic anhydride in 10 parts by volume of dioxane is heated at 130 to 140°C for 5 hours and the reaction mixture is poured into 100 parts by volume of ice water. The separated oil is extracted with ethyl acetate and the organic layer is washed with 10% aqueous sodium hydroxide and then water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue is treated by column chromatography on silica gel to give 1.5 parts of 3-^"*4-(ethoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-*5-pentadecyl-1,2,4-oxadiazole as colorless needles of m.p. 35 to 37° C. Yield: $73.3.

Analysis for C^<H>^<gNgO>^

Calculated C 71.57 H 9.53 N 5.76

Found C 71.56 H 9.86 N 5.69

Example 22.

A solution of 2.0 parts of 4-(1-ethoxycarbonyl-1-phenyl-methoxy)benzamidoxime and 1.3 parts of nicotinyl chloride hydrochloride in a mixture of 2 parts by volume of triethylamine and 10 parts by volume of dioxane is heated at 120 to 130°C for 2 hours and the reaction mixture is poured into 100 parts by volume of ice water.

The separated oil is extracted with ethyl acetate and the organic layer is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue is column chromatographed on silica gel to give 1.7 parts of 3-/"k-(1-ethoxycarbonyl-1-phenyl-methoxy)phenyl7~5-(3-pyridyl)-1,2,4-oxadiazole as colorless needles of m.p. 89 to 91°C0 in yield 66.6fo0

Analysis for Cg^H-^<N>^<O>^

Calculated C.68.81 H 4.77 N 10.47

Found C 68.47 H 4.65 N 10.18

Example 23.

A solution of 3.0 parts of 4-(1-ethoxycarbonyl-nonyl-oxy)benzamidoxime and 1.7 parts of nicotinyl chloride hydrochloride in a mixture of 2 parts by volume of triethylamine and 10 parts by volume of dioxane is heated at 120 to 130°C for 2 hours, and the reaction mixture is poured into 100 parts by volume of ice water. The separated oil is extracted with ethyl acetate and the organic layer is washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue is column chromatographed on silica gel to give 1.6 parts of 3""/""^~(1-ethoxycarbonyl-nonyloxy)-phenyl7-5-(3-Pyridyl)-1,2,4-oxadiazole as a light tan oil. Dividend: 42.9$.

Analysis for Cg^H^<N>^<O>^

Calculated C 68.63 H 7.14 N 9.6l

Found C 68.30 H 7.01 N 9.30

NMR spectrum ) (in CDCl^)

0.60 (lH,d0 J=3 c.p.s. aroma, H in 5-pyridyl)

1.20 (lH, q. J=9 c.p.s., J=3 c.p.s. arom. H in 5 pyridyl) 1.58 (lH, Se. J=9 c.p.s. arom., H in 5-Pyridyl)

1.93 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

2.54 (lH, q. J=15 c.p.s., J=9 c.p.s. arom. H in 5-pyridyl) 3.01 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

8.64 to 9.22 (18 H, m. -O-CHg-CH^, -(CHgjgCH^)

Example number 24.

A solution of 3.0 parts of 4-(1-ethoxycarbonyl-1-cyclohexyl-methoxy)benzamidoxime and 2.0 parts of nicotinoyl chloride hydrochloride in a mixture of 2 parts by volume of triethylamine and 20 parts by volume

dioxane is heated at 120 to 130°C for 2 hours.

The reaction mixture is poured into 200 parts by volume of ice water. The separated oil is extracted with ethyl acetate and the organic layer is washed with water, dried over anhydrous sodium sulphate and distilled under reduced pressure. The residue is column chromatographed on silica gel to give 1.0 parts of 3-/~4-(1-ethoxycarbonyl-1-cyclohexyl-methoxy)-phenyl7-5-(3-pyridyl)-1,2,4-oxadiazole as colorless needles of m.p. 105 to 107°C. Dividend: 24.2$.

Analysis for C^H^N,^

Calculated C 67.79 H 6.18 N 10.31

Found C 67.46 H 6.08 N 10.42

Example 25.

A solution of 3.0 parts of 4-(1-ethoxycarbonyl-pentyl-oxy)benzamidoxime and 2.7 parts of nicotinyl chloride hydrochloride in 15 parts by volume of pyridine is heated at 130 to 140°C for 2 hours, and the reaction mixture is poured into 150 parts by volume of ice water . The separated oil is extracted with chloroform and the organic layer is washed with water, dried over anhydrous sodium sulphate and distilled under reduced pressure. The residue is column chromatographed on silica gel and gives 2.7 parts of 3-/"4-(1-ethoxy-carbonyl-pentyloxy)phenyl7-5-(3-pyridyl)-1,2,4-oxadiazole as a light brown oil. Yield: 69 .5$.

Analysis for c2i<H>23<N>3°4

Calculated C 66.12 H 6.08 N 11.02

Found C 65, iK H 6.20 N 10.85

NMR spectrum ( ) (in CDCl^)

0.6o (lH, d. J=3 c.p.s. arom. H in 5-pyridyl)

1.19 (lH, q. J=9 c.p.s., J=3 c.p.s. arom. H in 5-pyridyl) 1.58 (lH. Se. J=15 c.p.s., J=3 c.p.s arom. H in 5-pyridyl)

1.93 (1H, d. J=15 c.p.s. arom. H in 3-phenyl)

2.54 (lH, q. J=15 c.p.So J=9 c.p.s. arom. H in 5-pyridyl) 3.02 (2H, d. J=15 c.p.s. arom. H in 3-phenyl)

5.78 (2H, q. J=12 c.p.s. -O-CHg-CH^)

7.90 to 9.20 (12H, m. -O-CHg-CH^, -(CH2)^- CB^)

In a similar manner to the examples above, the following compounds were prepared: 3-(5-(benzyloxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(3-pyridyl)-1,2,4-oxadiazole with melting point 72 5il 73 °C.

3~/5-(Carbamoyl-1,1-dimethyl-methoxy)phenyl7-5~(3-pyridyl)-1,2,4-oxadiazole with melting point 174 to 175°C.

3-(5-(butoxycarbonyl-1,1-dimethyl-methoxy)phenyl7-5-(3-pyridyl)-1,2,4-oxadiazole, melting point 82 to 84°C.

3-(5-(Carboxy-1,1-dimethyl-methoxy)phenyl?-5-(3-pyridyl)-1,2,4-oxadiazole with melting point 195 to 197°C.

Claims (1)

Analogous method for the preparation of hypocholesterolemically active oxadiazole derivatives with the general formula: where X denotes a group -COOR where R is benzyl or alkyl of up to 6 carbon atoms or X is an unesterified carboxyl group or a carboxamido group, each of the groups R-^ and R,, is hydrogen, phenyl, cyclohexyl or alkyl of up to 8 carbon atoms, and R^ is alkyl with 1-15 carbon atoms, benzyl, phenyl or phenyl substituents with lower alkyl, lower alkoxy, halogen, nitro or amino, or a cyclohexylmethyl, pyridyl, furyl or thienyl group, as well as pharmaceutically acceptable salts thereof, characterized in that a compound with the general formula: where R , Rp and X have the meaning given above, is reacted with a carboxylic acid with the general formula: where has the meaning given above, or an acid halide, acid anhydride or ester thereof, after which, if desired, the compounds obtained are converted to pharmaceutically acceptable salts thereof.