4,5-DI-SUBSTITUTED 2-OXAZOLEALKANOIC ACIDS, ESTERS AND ALKALI METAL SALTS

SELS DE METAUX ALCALINS, ESTERS ET ACIDES 4,5-DI-A SUBSTITUANT-2-OXAZOLEALCANOIQUES

English 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:
<IMG> (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.

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):
<IMG> (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:
<IMG> (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
<IMG> (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.
11

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.
12

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.
13

Description

108405~
1 This invention relates to novel and therapeutically
valuable compounds of the formula:
R10 R2
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)
R3
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 R2
R ~ /~ C ~ (CH2)n-COOR4' (III)
N R3
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.

1084058
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.
TABLE 1
Compound Dose Lowering Rate Lowering Rate
(mg/kg/day) (%) of Serum ~%) of Serum
Cholesterol Level Triglyceride Lev~
A 25 30 19
100 33 40
D 100 26 52
F 100 41 26
- . .
.
Clofibrate 25 14 15
(for comparison) 100 20 33
4 --

iO84058
1 TABLE 2
. .
Dose Lowering Rate t%) of
Compound (mg/kg/day) Serum Cholesterol Level
100 26
100 27
E 100 35
Clofibrate 50 0
..... 100
TABLE 3
DoseLowering Rate (%) of
Compound (mg/kg/day) Serum Cholesterol Level
A 100 10
B 100 17
C 100 44
D 100 25 I~
l E 100 21
Clofibrate 100 10
TABLE 4
._
Compound LD50 (mg/kg) per os (mouse)
A 1500
- ... _
Clofibrate 1500
-- 5

- 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:
-- 6 --

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.
EXAMPLE 1
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.
EXAMPLE 2
; 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-

84058
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.
EXAMPLE 3
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:
-- 8 --

` iO8~058
R O 2
~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 _