DE2632831A1 - 4,5-DISUBSTITUTED 2-OXAZOLE ALKANIC ACIDS, ESTERS AND ALKALINE SALTS OF THESE ACIDS, PROCESS FOR PREPARING THESE COMPOUNDS, AND DRUGS CONTAINING THESE COMPOUNDS - Google Patents

Description

8 MUNICH

MAXIMILIANSTRASSE

July 21, 1976. P 10 660-60

Yoshitomi Pharmaceuticals Industries, Ltd. No. 55, Hiranomachi 3-chome, Higashi-ku, Osaka, Japan

4,5-disubstituted 2-oxazole alkanoic acids, esters and alkali salts these acids, processes for the preparation of these compounds and medicaments containing these compounds

The invention relates to a new and therapeutically valuable compound represented by the formula

(D

λ- C- (CH 1) _ -COOR

in which R is a phenyl group, a mono- or disubstituted phenyl group in which the substituents have been selected from a group comprising halogen atoms, a methyl group and a nitro group, or a pyridyl group and R ₁ an alkyl group having 1 or 2 carbon atoms and R ₂ and R _{3 represent} a hydrogen atom or a methyl group,

in which η is an integer of 0 or 1, and R _{4 is} a hydrogen atom, an alkyl group with 1 or 2

609886/1173

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ORIGINAL INSPECTED

Represents carbon atoms or an alkali metal atom.

The compounds represented by the formula (I) can be prepared by the following processes (a) and (b).

According to process (a), those compounds of the formula (I) in which R. is an alkyl group having 1 or 2 carbon atoms represents, by dehydrating a compound of the formula

COOR ₁ R ₁

I 'I
K-CH-NH-CO-C- (CH ₂ ) -COOR * (II)

• ^E 3

in the R. ' an alkyl group having 1 to 2 carbon atoms or other of the symbols defined above.

Dehydration is accomplished by treating the compound of formula (II) with a strong dehydrating agent such as Phosphorus pentoxide, in an inert solvent (e.g. benzene, toluene, ligroin, 1,2-dichloroethane, chloroform, methylene chloride, Carbon tetrachloride) at room temperature or with heating, preferably in the presence of phosphorus pentoxide in refluxing 1,2-dichloroethane, within a short time in the presence of glass beads or diatomaceous earth as a stirring intensifier carried out. In this reaction, all the optical isomers of the starting compound according to the formula (II) and their Mixtures, namely the L-, D- and DL-form, one and the same compound of the formula (I), which leads to the disappearance of the Center of asymmetry is due. The compound of the formula (I) obtained can, if desired, after or without isolation - are used to carry out the following reaction (e.g. method (b)).

According to process (b), compounds of the formula (I) in which R- represents a hydrogen atom or an alkali metal atom, by hydrolysis only of the * ester residue of the self

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Substituents in the 2-position of the compound of formula

C- (CH,) -COOR4 (III)

ι. ²ⁿ /

E ₃

in which R, R ₁ , R ₂ , R ₃ , R ₄ . ¹ and η have the meaning given above.

The hydrolysis is preferably effected by treating the compound of formula (III) with an alkali hydroxide (e.g. NaOH and KOH) in a solvent such as a lower alcohol (e.g. methanol and ethanol), a lower ketone (e.g. acetone and methyl ethyl ketone), an ether (e.g. dioxane and tetrahydrofuran) , Water or mixtures thereof at room temperature.

The compounds of formula (I) have excellent pharmacological properties Properties such as hypolipemic effectiveness thypolipidemic action "), which can be demonstrated, for example, by the following described Experiments is shown. They are also used as drugs for the treatment of arteriosclerosis with lipid metabolism disorder ("lipid metabolism disorder") useful.

For example, the compounds of formula (I) listed below have the pharmacological properties given below:

A: ethyl 4-p-chlorophenyl-5-ethoxy-2-oxazole acetate

B: 4-p-chlorophenyl-5-ethoxy-2-oxazole acetic acid

C: ethyl 4- (3,4-dichlorophenyl) -5-ethoxy-2-oxazole acetate

^: D: ethyl 4-p-bromophenyl-5-ethoxy-2-oxazole acetate

E: .4-m-Chlorophenyl-5-ethoxy-2-oxazole acetic acid

F: 4-p-chlorophenyl- ⁱ 5-ethoxy- _o £ -methyl-2-oxazole acetic acid.

The experiments were carried out according to the following procedures:

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(I) Hypolipemic Efficacy

Male rats were treated with normal serum lipoid (Table 1). Table 1 shows the change in Serum lipoid levels observed in male Sprague-Dawley breed rats weighing 200 to 300 g after they were administered the test compound for 5 consecutive days. Each experimental group consisted of more than 5 rats. The test compound was administered orally through a gastric tube. The serum cholesterol and the Triglyceride levels were measured according to standard methods using an autoanalyzer (Technicon ine.). the Levels in the control (placebo) group were set at 100% and the reduction in% for the test group is calculated.

(II) Dietary hyperlipidemia ("dietary hyperlipidemia") in male mice (see Table 2)

Male dd breed mice weighing 20 to 25 g were used. Each group consisted of 8 mice. the Animals were fed a CA-1 diet (Japan Clea Co., Tokyo) fed that contained 1% cholesterol, 0.2% cholic acid and 5% olive oil. After 5 days of administration of the test compound the serum cholesterol level was measured using an autoanalyzer. The mirror in the test group was compared with that of the control group given the same diet.

(III) Triton hyperlipemia in male mice (see

i ■ Table 3) ^

Each group consisted of 8 male dd breed mice weighing 20 to 25 g. Immediately after the intraperitoneal Administration of the test compound to the animals was administered intravenously with Triton WR-1339. 18 hours after After Triton administration, the serum cholesterol level was measured and that of the control group treated in the same way compared.

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acute toxicity

The test compound was orally administered to groups of 10 male mice each. The LD _5Q value was determined after the lethal dose (50%) within 7 days after the administration of the
Trial connection calculated. The results are given in the table.

Table 1

link dose
(mg / kg / day) Humiliation
value (%) des
Serum cholesterol
rin mirror Degradation value
(%) of serum trigly
cerid mirror A. 25th
100 U) U)
U) O 19th
40 D. 100 26th 52

100

41

Clofibrate
(for comparison)

25 100

14 20

26th

15 33

T a b e .1 1 e 2 link dose
(mg / kg / day) Depression value (%) des
Serum cholesterol level A. 25th
100 9
26th B. 100 27 E. 100 35 Clofibrate 50
100 0
16

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link dose
(mg / kg / day) Depression value (%) des
Serum cholesterol level A. 25th
100 5
10 B. 100 17th C. 100 44 D. 100 25th E. 100 21 Clofibrate 100 10

Table 4

link ^LD 50 (mg / kg); orally; mouse A. 1500 Clofibrate 1500

In view of the experiments including those mentioned above, the compounds (I) according to the present Invention can be reliably administered as a medicament for the treatment of arteriosclerosis with lipid metabolism disorder, so in the form of a pharmaceutical preparation with a suitable and customary carrier or auxiliary in the case of oral Administration without harm to the patient.

The daily dose of the compound (I) to be administered orally in adult humans usually varies from 500 to 1500 mg. But it can also depend on the age, on the body weight and / or on the severity of the illness to be treated as well as on the reaction to the medical

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- 7 treatment vary.

The pharmaceutical preparations can be in any conventional form. So it can be tablets, capsules, granules, Trade powder or injectable solutions.

Formulation examples

Formulation examples are given below when a compound according to the invention is used for pharmaceutical purposes is supplied:

(a) 200 mg tablets were made using the following compounds:

Connection (I) 200.0 mg lactose 35.5 mg strength 30.0 mg microcrystalline cellulose 10.0 mg Talk 3.5 mg Magnesium stearate 1.0 mg all in all 280.0 mg

(b) 200 mg capsules were made from the following compounds:

Compound (I) 200.0 mg

Lactose 46.0 mg

Talc 2.0 mg

Magnesium stearate 2.0 mg

a total of 250.0 mg

The present invention will be better understood from the following examples, which are only intended to illustrate the to explain the present invention. They are not to be regarded as a limitation.

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example 1

A suspension of 92 g of ethyl N- (p-chloro- ^ - ■ henzyl) - malonamate. (Iiälonamate -. Ester of the monoamide of. Malonic acid) - in 220 ml of 1,2-dichloroethane is added with stirring and heating under reflux to a suspension of 120 g of phosphorus pentoxide and 66 g of diatomaceous earth in 650 ml of 1,2-dichloroethane. The mixture is stirred under reflux for 30 minutes. The reaction mixture is cooled and made alkaline with a saturated aqueous sodium bicarbonate solution. The diatomaceous earth is filtered off. In a separatory funnel, the filtrate is separated into an aqueous layer and an organic layer. The aqueous layer is extracted with a small amount of ethyl acetate. The extract and the organic layer are combined, and the combined solution is washed with water, dried and concentrated. The residue is recrystallized from a mixture of hexane and ethanol to give 45 g of ethyl-4-p-chlorophenyl-5-ethoxy-2-oxazolacetat a melting point 45.5 to 47.5 C ⁰ to be delivered.

Example 2

A solution of 2.5 g of potassium hydroxide in 18 ml of 80 percent methanol is added dropwise with stirring and at room temperature to a solution of 9.5 g of ethyl 4-p-chlorophenyl-5-ethoxy-2-oxazole acetate (prepared according to the procedure of Example 1) added in 14 ml of methanol. The mixture will be at Stirred at room temperature for about 2 hours. The methanol is distilled off under reduced pressure. The residue will diluted with water and extracted with ether. The aqueous layer is cooled with ice and made up with hydrochloric acid pH adjusted to 3.5. The resulting crystals are collected by filtration, dried and recrystallized from ethanol, around 5.5 g of 4-p-chlorophenyl-5-ethoxy-2-oxazole acetic acid in the form of white needles with a melting point of 122.5 to 124 ° C.

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Example 3

A solution of 17 g of ethyl N- (p-chloro - ^ '- ethoxy carbonylbenzyl) -2,2-dimethylmalonamate. _{in 50 ml} /, 2-dichloroethane is added with stirring and heating under reflux to a suspension of 22 g of phosphorus pentoxide and 12 g of diatomaceous earth in 120 ml of 1,2-dichloroethane. The reaction mixture is treated in the same manner as that described in Example 1. The residue obtained (14.5 g) is dissolved in 15 ml of methanol. A solution of 4 g of potassium hydroxide in 40 ml of 70 percent methanol is added dropwise to this solution with stirring and at room temperature. The mixture is stirred at room temperature for 2 hours and the solvent is distilled off under reduced pressure. The crystallized residue is collected by filtration, dried and recrystallized from a mixture of 2-propanol and isopropyl ether to give 9 g of potassium 4-p-chlorophenyl-5-ethoxy- _u ^ ', _I /' - dimethyl-2-oxazole acetate Melting point of 202 to 204 ⁰ C to deliver.

Examples 4 to 18

Using the procedure outlined in the previous examples, but substituting equivalent amounts Using the appropriate starting materials, the following compounds were also made:

- COOR4

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- ίο -

at
game R. ^R 1 ^R 2 R ₃ η 1 ^R 4 Enamel
point ( ⁰ C) 4th m-nitrophenyl ethyl H H 0 ethyl 59-61 5 p-chlorophenyl ethyl H H 1 ethyl 52-55 6th 3,4-dichloro
phenyl ethyl H H 0 ethyl 73-74.5 7th p-bromophenyl ethyl H H 0 ethyl 42-51 8th Phenyl ethyl H H 0 H 120-122 9 p-chlorophenyl ethyl H H 1 H 109-111.5 10 3,4-dichloro
phenyl ethyl H H 0 H 145-146.5 11 3,4-dichloro
phenyl ethyl H H 1 H 132-134 12th p-bromophenyl ethyl H H 0 ' H 128-130 13th p-bromophenyl ethyl H H 1 H 116-119 14th m-chlorophenyl ethyl H H 0 H 118-121 15th p-tolyl ethyl H H 0 H 111-113 16 p-tolyl ethyl H H 1 H 106-109 17th p-chlorophenyl ethyl H Methyl 0 H 109-111 18th 3-pyridyl ethyl H H H 175-177.5

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Claims (9)

- 11 claims 1 j Chemical compound identified by the formula \ - C- (CH ₂ ) _n -COOR ₄ in which R is a phenyl group, a mono- or disubstituted phenyl group in which the substituents have been selected from a group comprising halogen atoms, a methyl group and a nitro group, or a pyridyl group and R ₁ an alkyl group with 1 or 2 carbon atoms and Rp and R- , represent a hydrogen atom or a methyl group, in which η is an integer of 0 or 1 and R _{4 is} a hydrogen atom, an alkyl group having 1 or 2 carbon atoms or an alkali metal atom. 2. Ethyl 4-p-chlorophenyl-5-ethoxy-2-oxazole acetate. 3. 4-p-Chlorophenyl-5-ethoxy-2-oxazole acetic acid. 4. Ethyl 4- (3,4-dichlorophenyl) -5-ethoxy-2-oxazole acetate. 5. Ethyl 4-p-bromophenyl-5-ethoxy-2-oxazole acetate. 6. 4-m-Chlorophenyl-5-ethoxy-2-oxazole acetic acid. 7. 4-p-Chlorophenyl-5-ethoxy-C1-methyl-2-oxazole acetic acid. 8. A method for the preparation of the compounds according to any one of claims 1 to 7, characterized in that one Compound of formula 609886/1 173 _E - f )) - C - (CH ₀ ) - COOR X _n // I. ^ a 4 ■ k ' in which R is a phenyl group, a mono- or disubstituted phenyl group in which the substituents have been selected from a group comprising halogen atoms, a methyl group and a nitro group, or a pyridyl group and R ₁ an alkyl group having 1 or 2 carbon atoms and R ₀ and R -, represent an atom of water or a methyl group, ' in which η is an integer of 0 or 1 and R _{4 is} a hydrogen atom, an alkyl group with 1 or 2 carbon atoms or an alkali metal atom, (a) when R. is an alkyl group with 1 or 2 carbon atoms represents, by dehydrating a compound of the formula COOR R
ι 1 i2 R-CH- KH - CO -C - (CH ₂ ) _n - COCI ^ in which R _{4 represents} an alkyl group having 1 or 2 carbon atoms or other of the symbols defined above, produces or (b) when R _{4 represents} a hydrogen atom or an alkali metal atom, by hydrolysis only the ester radical of the substituent in the 2-position of the compound d Fl the formula ^R 1 ° \ in which R, R ₁ , R ₃ , R ₃ and R ₄ and η have the meaning given above. 609886/1 173 9. Medicament containing at least one compound according to one of claims 1 to 7 and customary pharmacological compatible carriers and / or diluents. 609886/1173 _1mq ppcted ORIGINAL INSPECTED