CA1084058A

CA1084058A - 4,5-di-substituted 2-oxazolealkanoic acids, esters and alkali metal salts

Info

Publication number: CA1084058A
Application number: CA256,902A
Authority: CA
Inventors: Toshihiro Kobayakawa; Tsutomu Yamanaka; Kuniki Ikeda; Kunio Ohsuga
Original assignee: Welfide Corp
Current assignee: Welfide Corp
Priority date: 1975-07-25
Filing date: 1976-07-13
Publication date: 1980-08-19
Also published as: DE2632831A1; AT345819B; JPS5217467A; SE7608421L; BE844482A; FR2318869B1; AU1610376A; AR210361A1; ATA538676A; FR2318869A1; GB1501588A; NL7608180A; GR61118B

Abstract

ABSTRACT OF THE DISCLOSURE
This invention relates to novel and therapeutically valuable compounds which are useful as drugs for the treatment of arteriosclerosis with lipid metabolism disorder. They can be administered orally when prepared with a suitable and conventional carrier or adjuvant. The compounds are of the formula:

(I) wherein R represents a phenyl group, a mono- or di-substituted phenyl group (in which the substituents are selected from the group consisting of a halogen atom, a methyl group and a nitro group) or a pyridyl group; R1 represents an ethyl groups each of R2 and R3 represents a hydrogen atom or a methyl group; n represents 0 or 1; and R4 represents a hydrogen atom, an alkyl group having 1 to 2 carbon atoms or an alkali metal atom.
Hypolipidemic action is one of the excellent pharmacological properties possessed by the compounds. The pharmaceutical pre-parations can take any conventional form such as tablets, capsules, granules, powders or injectable solutions.

Description

108405~

1 This invention relates to novel and therapeutically valuable compounds of the formula:

R~/~4 - (CH2)n-COOR (I) N R
wherein R represents a phenyl group, a mono- or di-substituted phenyl group (in which the substituents are selected from the group consisting of a halogen atom, a methyl group and a nitro group) or a pyridyl group; Rl represents an ethyl group; eaçh of R2 and R3 represents a hydrogen atom or a methyl group; n represents 0 or 1; and R4 represents a hydrogen atom, an alkyl group having 1 to 2 carbon atoms or an alkali metal atom.
The compounds of formula (I) can be produced by one of the following methods (a) and (b).
(a) In the case of compounds of formula (I) wherein R represents an alkyl group having 1 to 2 carbon atoms, by dehydrating a compound of the formula:

lCOORl I 4~
R - H - NH - CO - C - (CH ) - COOR (II) wherein R4 represents an alkyl group having 1 to 2 carbon atoms and other symbols are as defined above.
The dehydration is carried out 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-dichlorethane, chloroform, methylene chloride, carbon tetrachloride) at a room temperature or under heating, preferably C, ~
.... .~

i(~84058 1 with phosphorus pentoxide in refluxing 1,2-dichloroethane for a short time in the presence of glass beads or diatomaceous earth as promoter of stirring. In this reaction, all optical isomers of a starting compound of formula (II) and their mixture, namely L-, D- and DL-forms, give one and the same compound of formula (I) due to disappearance of the asymmetric center.
The resulting compound of formula (I), ir desired with or without isolation, may be applied to the following reaction (i.e.method (b)).
(b) In the case of compounds of formula (I) wherein R4 represents a hydrogen atom or an alkali metal atom, by hydrolyzing in the ester part alone of the 2-positional sub-stitutent of a compound of the formula:

R ~ /~ C ~ (CH2)n-COOR4' (III) wherein R, Rl, R , R , R and _ are as defined above.
The hydrolysis is preferably carried out by treating the compound of formula (III) with an alkali hydroxide (e.g., NaOH, KOH) in a solvent such as a lower alcohol (e.g., methanol, ethanol), a lower ketone (e.g., acetone, methyl ethyl ketone), an ether (e.g., dioxane, tetrahydrofuran), water or a mixture thereof at room temperature.
The compounds of formula (I) possess excellent phar-macological property such as hypolipidemic action,as shown, for example, by the following tests, and are useful as drugs for the treatment of arteriosclerosis with lipid metabolism disorder.

1 For example, the compounds of formula (I) listed below have the following pharmacological properties:
A: ethyl-4-p-chlorophenyl-5-ethoxy-2-oxazoleacetate B: 4-p-chlorophenyl-5-ethoxy-2-oxazoleacetic acid C: ethyl 4-(3,4-dichlorophenyl)-5-ethoxy-2-oxazoleacetate D: ethyl-4-p-bromophenyl-5-ethoxy-2-oxazoleacetate E: 4-m-chlorophenyl-5-ethoxy-2-oxazoleacetic acid F: 4-p-chlorophenyl-5-ethoxy-a-methyl-2-oxazoleacetic acid The tests were carried out by the following methods:

Hypolipidemic Action (i) Male rats with normal serum lipid (Table 1) Table 1 shows the change in serum lipid levels observed after the 5 days consecutive administration of the test com-pound to Sprague-Dawley strain male rats weighing 200-300 g.
Each test group was composed of more than 5 rats. The test compound was orally given by a gastric tube. Serum cholesterol and triglyceride level were measured by the standard methods using an autoanalyzer (Technicon Inc.). The levels in the 20 control (placebo) group were considered as 100~ and the reduction (%) in the test group was calculated.

(ii) Dietary hyperlipidemia in male mice (Table 2) dd-Strain male mice weighing 20-25 g. were used. Each group was composed of 8 mice. Animals were fed with CA-l food (Japan Clea Co., Tokyo) containing 1% of cholesterol, 0.2% of cholic acid and 5~O of olive oil, and the serum cholesterol level was measured by the use of an autoanalyzer after 5 days administration of the test compound. The levels in the test group was compared with that in the control group given the same diet.

iO84058 1 (iii) Triton hyperlipidemia in male mice (Table 3) Each group was composed of eight dd-strain male mice weighing 20-25 g. Immediately after intraperitoneal adminis-tration of the test compound to the animals, Triton WR-1339 was intravenously given. Eighteen hours after Triton administration, the serum cholesterol level was measured and compared with that of the control group treated in the same way.

Acute Toxicity 10 The test compound was orally administered to groups ID
' each of ~ male mice. The LD50 was calculated from the lethal ~" ~ Se~
rate (50%) within two days after administration of the test compound. The results are shown in Table 4.

Compound Dose Lowering Rate Lowering Rate (mg/kg/day) (%) of Serum ~%) of Serum Cholesterol Level Triglyceride Lev~

- . .
.
Clofibrate 25 14 15 (for comparison) 100 20 33 iO84058 . .
Dose Lowering Rate t%) of Compound (mg/kg/day) Serum Cholesterol Level Clofibrate 50 0 ..... 100 DoseLowering Rate (%) of Compound (mg/kg/day) Serum Cholesterol Level D 100 25 I~
l E 100 21 Clofibrate 100 10 ._ Compound LD50 (mg/kg) per os (mouse) - ... _ Clofibrate 1500 - iO84058 1 In view of the tests including those mentioned above, the compounds (I) of the present invention can be administered safely as drugs for the treatment of arteriosclerosis with lipid metabolism disorder, in the form of a pharmaceutical preparation with a suitable and conventional carrier or adjuvant, administered orally, without harm to the patient.
The oral daily dose of compound (I) for human adults usually ranges from 500 to 1500 milligrams, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the response to the medication.
The pharmaceutical preparations can take any conventional form such as tablets, capsules, granules, powders or injectable solutions.

Formulation Examples The following is an example of formulations when a com-pound of the invention is administered for pharmaceutical purposes:
(a) 200 mg Tablets are prepared from the following compositions:
Compound (I) 200.0 mg Lactose 35,5 Starch 30.0 Microcrystalline Cellulose 10.0 Talc 3.5 Magnesium Stearate 1.0 Total 280.0 mg (b) 200 mg Capsules are prepared from the following compositions:

iO84058 1 Compound (I) 200.0 mg Lactose 46.0 Talc 2.0 Magnesium Stearate 2.0 Total 250.0 mg The present invention will be better understood from the following examples, which are merely intended to be illustrative and not limitative of the present invention.

c~/~ro A suspension of 92 g. of ethyl N-(p-chlorophenyl--ethoxycarbonylbenzyl)malonamate 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 6,50 ml. of 1,2-dichloroethane. The mixture is heated under reflllx with stirring for 30 minutes. The reaction mixture is ! cooled and made alkaline with a saturated aqueous sodium bicarbonate solution, and the diatomaceous earth is filtered off.
The filtrate is allowed to separate into an aqueous layer and an 20 organic layer in a separatory funnel. The aqueous layer is extracted with a small amount of ethyl acetate. rrhe 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-oxazoleacetate melting at 45.5-47.5C.

; A solution of 2.5 g. of potassium hydroxide in 18 ml. of 80% methanol is added dropwise with stirring at room temperature to a solution of 9.5 g. of ethyl 4-p-chlorophenyl-5-ethoxy-2-1 oxazoleacetate (produced ~y the procedure of Example 1) in 14 ml.
of methanol. The mixture is stirred at room temperature for about

2 hours, and the methanol is distilled off in vacuo. The residue is diluted with water and extracted with ether. The aqueous layer is cooled with ice and adjusted to pH 3.5 with hydrochloric acid. The resulting crystals are collected by filtration, dried and recrystallized from ethanol to give 5.5 g.
of 4-p-chlorophenyl-5-ethoxy-2-oxazoleacetic acid as white needle~ melting at 122.5-124C.

A solution of 17 g. of ethyl N-lp-chloro-a-ethoxy-carbonylbenzyl)-2,2-dimethylmalonamate in 50 ml. of 1,2-dichloro-ethane 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 I reaction mixture is treated in an identical manner as described in Example 1. The resulting residue ~14.5 g.) is dissolved in 15 ml. of methanol, and to the solution is added dropwise with stirring at room temperature a solution of 4 g. of potassium hydroxide in 40 ml. of 70~ methanol. The mixture is stirred at room temperature for about 2 hours, and the solvent is distilled off in vacuo. The crystallized residue is collected by fil-tration, dried and recrystallized from a mixture of 2-propanol and isopropyl ether to give 9 g. of potassium 4-p-chlorophenyl-5-ethoxy-a,a-dimethyl-2-oxazoleacetate melting at 202-204 C.

EXAMPLES 4 to 18 Using the procedure set forth in the above examples, but substituting equivalent amount of the appropriate starting 30 materials, the following compounds are also produced:

` iO8~058 ~O IR 4 R~ /~ C - (CH2) n-COOR

. _ _ .
1 2 3 4 melting point Exampl R R R R n R (C ) _ 4 m-ni trophenyl ethy 1 H H O ethyl 59 -61 11~ 5 p-chlorophenyl ethyl H H 1 ethyl 52-55 6 3,4-dichlorophen~ 1 ethy H H O ethyl 73-74.5 7 p-bromophenyl ethyl H H O ethyl 42-51 8 phenyl ethyl H H O H 120 -122 9 p-chlorophenyl ethyl H H 1 H 109-111.5

3,4-dichlorophen ,lethyl H H H 145-146.5 _ 11 3,4-dlchlorophen ,lethyl H H 1 H 132-134 12 p-bromophenyl ethyl H H H 128-130 _ __ _ 13 p-bromophenyl ethyl H H 1 H 116-119 14 ;n-chlorophenyl ethyl H H C H 118-121 p-tolyl ethyl H H C H 111-113 16 p-tolyl ethyl H H 1 H 106-109 , _ 17 p-chlorophenyl ethyl Hmethy H 109-111 18 3-pyridyl ethyl H H ] H 175-177.5 _ 9 _

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of producing compounds of the general formula (I):

(I) wherein R represents a phenyl group, a mono- or di-substituted phenyl group (in which the substituents are selected from the group consisting of a halogen atom, a methyl group and a nitro group) or a pyridyl group; R1 represents an ethyl group; each of R2 and R3 is a hydrogen atom or a methyl group; n represents 0 or 1; and R4 represents a hydrogen atom, an alkyl group having 1 to 2 carbon atoms or an alkali metal atom; which comprises:
(a) when R4 represents an alkyl group having 1 to 2 carbon atoms, dehydrating a compound of the formula:

(II) wherein R4' represents an alkyl group having 1 to 2 carbon atoms and other symbols are as defined above;

(b) when R4 represents a hydrogen atom or an alkali metal atom, hydrolyzing in the ester part alone of the 2-position substituent of a compound of the formula:

Claim 1 continued (III) wherein R, R1, R2, R3, R4 and n are as defined above.
2. A method of producing compounds of the formula (I) of claim 1 when R4 represents an alkyl group having 1 to 2 carbon atoms comprising the method in sub-paragraph (a) of claim 1.
3. A method of producing compounds of the formula (I) of claim 1 when R4 represents a hydrogen atom or an alkali metal atom comprising the method in sub-paragraph (b) of claim 1.
4. A method as claimed in claim 1 for producing ethyl 4-p-chlorophenyl-5-ethoxy-2-oxazoleacetate, which comprises de-hydrating ethyl N-(p-chloro-.alpha.-ethoxycarbonylbenzyl)malonamate.
5. A method as claimed in claim 1 for producing 4-p-chlorophenyl-5-ethoxy-2-oxazoleacetic acid, which comprises hydrolyzing ethyl 4-p-chlorophenyl-5-ethoxy-2-oxazoleacetate.
6. A method as claimed in claim 1 for producing ethyl 4-(3,4-dichlorophenyl)-5-ethoxy-2-oxazoleacetate, which comprises dehydrating ethyl N-(3,4-dichloro-.alpha.-ethoxycarbonylbenzyl)-malonamate.
7. A method as claimed in claim 1 for producing ethyl 4-p-bromophenyl-5-ethoxy-2-oxazoleacetate, which comprises de-hydrating ethyl N-(p-bromo-.alpha.-ethoxycarbonylbenzyl)malonamate.
8. A method as claimed in claim 1 for producing 4-m-chlorophenyl-5-ethoxy-2-oxazoleacetic acid, which comprises hydrolyzing ethyl 4-m-chlorophenyl-5-ethoxy-2-oxazoleacetate.
9. A method as claimed in claim 1 for producing 4-p-chlorophenyl-5-ethoxy-.alpha.-methyl-2-oxazoleacetic acid, which comprises hydrolyzing ethyl 4-p-chlorophenyl-5-ethoxy-.alpha.-methyl-2-oxazoleacetate.
10. A member selected from the group consisting of com-pounds of the formula (I) as defined in claim 1, whenever produced by the method of claim 1 or an obvious chemical equivalent.
11. A compound of the formula (I) as defined in claim 1 wherein R4 represents an alkyl group having 1 to 2 carbon atoms whenever produced by the method as claimed in claim 2 or an obvious chemical equivalent.
12. A compound of the formula (I) as defined in claim 1 wherein R4 represents a hydrogen atom or an alkali metal atom whenever produced by the method as claimed in claim 3 or an obvious chemical equivalent.
13. Ethyl 4-p-chlorophenyl-5-ethoxy-2-oxazoleacetate, whenever produced by the method of claim 4 or an obvious chemical equivalent.
14. 4-p-Chlorophenyl-5-ethoxy-2-oxazoleacetic acid, when-ever produced by the method of claim 5 or an obvious chemical equivalent.
15. Ethyl 4-(3,4-dichlorophenyl)-5-ethoxy-2-oxazoleacetate, whenever produced by the method of claim 6 or an obvious chemical equivalent.
16. Ethyl 4-p-bromophenyl-5-ethoxy-2-oxazoleacetate, when-ever produced by the method of claim 7 or an obvious chemical equivalent.
17. 4-m-Chlorophenyl-5-ethoxy-2-oxazoleacetic acid, when-ever produced by the method of claim 8 or an obvious chemical equivalent.
18. 4-p-Chlorophenyl-5-ethoxy-.alpha.-methyl-2-oxazoleacetic acid, whenever produced by the method of claim 9 or an obvious chemical equivalent.