DE2924900A1 - Phenoxy-carboxylic acid tetrazolyl-amide derivs - antilipaemics to reduce blood levels of tri-glyceride and cholesterol and anti:atherosclerotic(s) - Google Patents

Abstract

Novel tetrazolylamides of phenoxycarboxylic acids, and their salts with bases are of formula (I): (where R1 and R2 are H or 1-3C alkyl; Hal is halogen; R3 is H or halogen; and X is H or the cation of a physiologically acceptable base). (I) can be prepd. by converting a phenoxycarboxylic acid of formula (II) to a reactive deriv., pref. the acid chloride or anhydride, and reacting this with 5-amino-tetrazol in the presence of a base, and opt. converting the prod. into its salt by reaction with a base, pref. an organic base. (I) can be used as antilipaemic agents to normalise the levels of triglyceride and cholesterol in the blood. (I) can also be used to treat atherosclerosis.

Description

Title: Tetrazolylamides of Phenoxycarboxylic Acid, Process

for their production and containing them new anti-lipemic and antiatherosclerotic drugs B e s c h r e i b u n g I) the new tetrazolylamides of phenoxycarboxylic acids according to the invention Formula I specified in the main claim are characterized, among other things, by a pharmacological Effectiveness on the cholesterol and triglyceride levels of the blood. They're like that e.g. as an anti-lipemic drug to normalize the pathologically disturbed Triglyceride and cholesterol levels in the blood and exceed them iii Activity the active ingredients used so far in this therapeutic area.

I) this improved pharmacological effectiveness of the inventive Tetrazolyl amides of phenoxycarboxylic acids show the following pharmacological results the Triton test (H. Schön and G.

Jerg, Arzneimittel-Forschung 7, 307, 1957), with as representative the net series of compounds is the 4-chlorophenoxyisobutyric acid tetrazolyl (5) amide-3-hydroxymethylpyridinium salt was used. The Triton test was carried out with ß male and female Wistar rats of about 200 g body weight each carried out, and the changes in the C; econtents of serum cholesterol and serum triglycerides versus corresponding Control animals determined. As a comparative substance of the prior art, the particularly effective in reducing cholesterol and triglyceride levels Clofibrate, which is respected in the blood, is used. The results are in the table below listed.

TABLE Compound Dose Change in Change in (mg / kg) Serum Total Serum triglycerol% versus control% versus control 4-chlorophenoxyisobutter acid-tetrazolyl- (5) -amid- 2 - 50.9 - (; 4, 3-hydroxymethylpyridinium salt (according to the invention) Comparative test ethyl 4-chlorophenoxyisobutyrate 250 8, 5 5 -.32.8 Aus the table shows that the Alni (l according to the invention even with a dose of less than one hundredth of the comparative substance clofibrate tested at the same time another significantly superior anti-lipemic and anti-hypercholesterolemic Has effect and that with almost the same toxicity of both substances.

The new compounds of the present invention are surprising not only the strong increase in effectiveness, but also the fact that in addition to the Serum triglycerides also increased total serum cholesterol levels in nearly the same Order of magnitude. Hence, the scope of these new active ingredients is likely compared to the previously common means of combating hyperlipemia and atherosclerosis can be expanded considerably.

The tetrazolylamides according to the invention can be prepared by methods known per se. In a particularly simple method of preparation, phenoxycarboxylic acids of the general formula II what in the substituents have the meanings given in the claim, after introducing a customary reactive group instead of the carboxyl group, for. 1 », after conversion into an acid chloride or acid anhydride, reacted in a manner known per se with 5-aminotetrazole in the presence of an organic or inorganic lyase as the acid acceptor. For salt formation, the tetrazolylamides obtained can then be suspended in an organic solvent, for example in acetone, and reacted with a suitable organic nitrogen base with heating until a clear solution has formed.

After the reaction mixture has cooled down, the base addition compounds can precipitated and isolated with ether or petroleum ether in the usual way.

To l 1 elaboration of the forms of application of the anti-lipemic and Antiaetherosclerotic drugs can use the new active ingredients along with usual ones Aids can be pressed into tablets and processed into dragées. Also in gelatin capsules When filled, they can be administered orally or, if appropriate, intravenously in an aqueous solution injected or infused Example 1 10.3 g of 5-aminotetrazole hydrate CH3N5eH20 C103.2 are dissolved in 100 ml of dimethylformamide and after adding 13> 8 ml of triethylamine C6H15M [101.19] with stirring with a solution of 23.3 g of 2- (4-chlorophenoxy) -2-methylpropionic acid chloride C19H10Cl2O2 E233, added to 100 ml of dimethylformamide.

After 1 hour of stirring at room temperature, the precipitated triethylamine hydrochloride is suctioned off and the solution evaporated in vacuo until crystallization. The firm one The residue is then stirred with 100 ml of water, filtered off with suction and in vacuo at 70.degree getroclcnet. After recrystallization from acetone-petroleum ether, yield: 25.3 g = 90 % of th. 2- (4-Chlorophenoxy) -2-methyl-propionic acid tetrazolyl- (5) -amide C11H12ClN5O2 [281.7] Melting point 219-221 ° C (Z), Rf value: 0.27 on ready-made silica gel TLC plate 60 from Merck in the mobile phase chloroform / methanol / aqueous ammonia 12.5 (ióig 70: 25: 5 (v / v / v) with chamber saturation and spray reagent: bromothymol blue Elemental analysis: C. H N calculated 46.90 4.29 24.68 found 46.88 4.26 24.70 According to this procedure are also produced: 2- (4-chlorophenoxy) -propionic acid-tetrazolyl- (53-amide C1oHloClN502 [267.7] Melting point: 235-236 OC (Z) 4-chlorophenoxy-acetic acid tetrazolyl- (5) -amide CgH8ClN502 [253.6] Melting point: 242-244 OC (Z) 2- (4-chlorophenoxy) -valeric acid tetrazolyl- (5) -amide C12H14C1N502 [295.7] Melting point: 206-209 OC (Z) 2- (4-fluorophenoxy) -2-methyl-propionic acid tetrazolyl- (5) -amide C11H12FN5O2 [265.2] Melting point: 185-187 ° C (Z) Salt formation: 2- (4-chlorophenoxy) -2-methyl-propionic acid-tetrazolyl- (5) -amide is suspended in acetone and after adding the equivalent amount of 3-hydroxymethylpyridine heated to 60 ° C. until a clear solution has occurred. After cooling to room temperature petroleum ether is added to the solution until it starts to become cloudy. The substance then slowly crystallizes from yield:> 90% CO.Th 2- (4-chlorophenoxy) -2-methyl-propionic acid-tetrazolyl- (5) -amid-3-hydroxymethylpyridinium-salk C17H19ClN6O3 [390.8] Melting range: 122 - 178 OC, According to the appropriate The following procedure is obtained: 2- (4-chlorophenoxy) -2-methyl-propionic acid-tetrazolyl- (5) -amide-pyridoxinium salt C19H23ClN6O5 [450.6] Melting point: 125-128 ° C 2- (4-Chlorophenoxy) -2-methyl-propionic acid-tetrazolyl- (5) -amide-dimethylammonium ethanol salt C15H23ClN603 [370.8] Melting point: 122-125 oC Example 2 21.4 g of 2- (4-chlorophenoxy) -2-methyl-propionic acid C10H11ClO3 [214.6] are dissolved in 200 ml of dimethylformamide and, after adding 13.8 ml of triethylamine C6H15N [101.19] were cooled to 0 ° C. with stirring. The solution becomes 9.6. ml of ethyl chloroformate C3H5ClO2 [108.5] are added and after 15 minutes with 10.3 5-aminotetrazole hydrate CH3N5 # H2O 2103, in 70 ml of dimethylformamide mixed.

After 1 hour of stirring at room temperature, the precipitated triethylamine hydrochloride is suctioned off and the solution concentrated in vacuo until crystallization. The firm one The residue is stirred with 100 ml of water, filtered off with suction and dried at 70 ° C. in vacuo. Recrystallization from acetone petroleum ether gives 19.7 g = 70% of theory. 2- (4-Chlorophenoxy) -2-methyl-propionic acid-tetrazolyl- (5) -am CllHl2ClN502 [281.7] Melting point: 219-221 oC (Z).

Example 3 10.3 g of 5-aminotetrazole hydrate CH3N5 # H2O [103.1] and 4.0 g sodium hydroxide is dissolved in 250 ml water. While stirring vigorously, a Solution of 23.3 g of 2- (4-chlorophenoxy) -2-methyl-propionic acid chloride in 125 ml of toluene added dropwise. D suspension is 2 hours at room temperature and 1 hour at 60 ° C weitergerü The solid residue is filtered off with suction, washed with water and in vacuo dried at 70. Recrystallization from acetone-petroleum ether. Yield: 22.5 g x 80% 2- (4-chlorophenoxy) -2-methyl-propionic acid tetrazolyl- (5) -amide C11H12ClN5O2 [281 Melting point: 219-221 ° C (Z).

Example 4 24.9 g of 2- (2,4-dichlorophenoxy) -2-methyl-propionic acid C10H10C1203 [249.0] are dissolved in 200 ml of dimethylformamide and after adding 13.8 ml of triethylamine C6H15N [101.19] cooled to 0 oC with stirring. The solution is made with 9.6 nil ethyl chloroformate C3H5ClO2 [108.5] was added and after 15 minutes with 10.3 g of 5-aminotetrazole hydrate CH3N5 # H2O [103.1] mixed in 70 ml of dimethylformamide. After stirring for 1 hour at The precipitated Tritith3rlaminhydrochlorid is sucked off and the room temperature The solution was concentrated in vacuo to the point of crystallization. The solid residue is with 100 ml of water are stirred up, filtered off with suction and dried at 70 ° C. in vacuo. After recrystallization from acetone petroleum ether are obtained 18.9 g = 61% of theory 2- (2,4-dichlorophenoxy) -2-methyl-propionic acid-tetrazolyl- (5) -amide C11H11Cl2N5O2 [316.1] Melting point: 180-182 ° C (Z).

Claims (2)

Claims 1. Tetrazolylamides of phenoxycarboxylic acids and their salts with bases of the following general formula where R1 and R2 denote a hydrogen atom or an alkyl group having 1-3 carbon atoms, Hal denotes a halogen atom, RQ denotes a hydrogen or a halogen atom and X denotes a hydrogen atom or the cation of a physiologically permissible base. 2. Process for the preparation of the new tetrazolylamides of phenoxycarboxylic acids according to claim 1, characterized in that a phenoxycarboxylic acid of the formula is used by introducing a reactive group, preferably converted into an acid chloride or anhydride and allowing this to react with 5-aminotetrazole in the presence of an organic or inorganic base, whereupon the reaction product is optionally converted into the salt by reaction with a 13ase, preferably with an organic base , 3, medicaments with anti-lipemic and antiatherosclerotic action, characterized by a content of a compound according to claim 1 as an active ingredient in addition to those for the oral or intravenous use of suitable excipients.