2(4-n-Hexadecyl amino or oxy phenyl) 5 ethoxy oxazoleacetic acid

Details 2(4-n-Hexadecyl amino or oxy phenyl) 5 ethoxy oxazoleacetic acid 2(4-n-Hexadecyl amino or oxy phenyl) 5 ethoxy oxazoleacetic acid

1981-07-28

1982-12-21

Daus, Donald G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

424272, C07D26342, A61K 3142

Patent

active

043650660

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD AND DISCLOSURE OF THE INVENTION

This invention relates to novel and therapeutically valuable oxazoleacetic acid derivatives of the formula ##STR2## and salts thereof, wherein: R is a higher alkyl group having 10 to 20 carbon atoms (e.g. decyl, dodecyl, tetradecyl, hexadecyl or octadecyl), a higher alkenyl group (e.g. decenyl, dodecenyl, tetradecenyl, hexadecenyl or octadecenyl), a benzyl group or a halogen(fluorine, chlorine, bromine or iodine)-substituted benzyl group; X is O, S or NH; R.sup.2 is a lower alkyl group (e.g. methyl, ethyl, propyl or butyl), a phenyl group or a halogen-substituted phenyl group; and R.sup.3 is a hydrogen atom or a lower alkyl group.
Examples of the salts of compounds of the formula (I) are inorganic salts, e.g. sodium salts, magnesium salts, calcium salts, aluminum salts, ammonium salts; amine salts, e.g. dimethyl amine salts; trimethyl amine salts; or amino acid salts, e.g. arginine salts, lysine salts.
The compounds of the formula (I) can be prepared according to one of the following methods (1) to (3):


METHOD (1)

In the case of compounds of formula (I) wherein R.sup.3 is a lower alkyl group, by dehydrating for ring-closure a compound of the formula ##STR3## wherein R.sup.1, X and R.sup.2 are as defined above and R.sup.4 is a lower alkyl group.
The reaction is carried out by treating the compound of formula (II) with a dehydrating agent such as phosphorus pentoxide, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, tosyl chloride or concentrated sulfuric acid, at room temperature or under heating, optionally in a solvent such as benzene, toluene, chloroform or 1,2-dichloroethane. In the case of compounds of formula (II) wherein X is NH, the compound is preferably protected with an amino-protecting group (e.g. formyl, trifluoroacetyl, tosyl, benzyloxycarbonyl or phthalyl), and then subjected to dehydration for ring closure and to removal of the protecting group.
The starting compounds of formula (II) can be prepared in a conventional manner from aspartic acid which may have L-, D- or DL-configuration.


METHOD (2)

In the case of compounds of formula (I) wherein R.sup.3 is a hydrogen atom, by hydrolyzing a compound of formula (I) wherein R.sup.3 is a lower alkyl group.
The hydrolysis may be carried out with an acid or an alkali, preferably with a diluted alkali solution (e.g. sodium hydroxide or potassium hydroxide) in water, a water-soluble organic solvent (e.g. methanol, ethanol, acetone, dioxan or tetrahydrofuran) or a mixture thereof.


METHOD (3)

In the case of compounds of formula (I) wherein R.sup.3 is a lower alkyl group, by reacting a compound of formula (I) wherein R.sup.3 is a hydrogen atom (a carboxylic acid) or a functional derivative thereof [e.g. an acid chloride, an acid anhydride, an acid azide, or a reactive ester (e.g. p-nitrophenyl ester or N-hydroxysuccinimide ester)] with a lower alkanol.
The oxazoleacetic acid derivatives and salts thereof of this invention possess an excellent hypolipidemic activity and very low toxicity, as shown by the following experiments, and are useful as drugs for the treatment of atherosclerosis with lipid metabolism disorder or intermediates therefor.


EXPERIMENTS

(1) Test Compounds acid
(2) Test methods and results:
(i) Male Sprague-Dowley rats were used. Each group was composed of 8 animals. Rats were fed a diet containing 1% of cholesterol. The test compound was orally administered to the animal by feeding with the diet to which the compound was blended in a ratio of 0.1% (W/W) for 5 days. Cholesterol and triglyceride in the serum were determined by the standard methods using an autoanalyzer (Technicon Inc.). The levels in the control group were considered as 100% and the reduction rate in the test group was calculated. The results are shown in Table 1.


TABLE 1 ______________________________________ Test Reduction Rate (%) Compound Cholesterol Triglyceride ______________________________________ A 21 35 B 31 28 C 31 37 D 37 42 E 22 23 __________________

REFERENCES:
patent: 4012412 (1977-03-01), Yamanaka et al.
patent: 4053478 (1977-10-01), Yamanaka et al.
patent: 4175130 (1979-11-01), Yamanaka et al.
88:89653c, Yamanaka et al., Chemical Abstracts.
86:89792f, Yamanaka et al., Chemical Abstracts.

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