US3818072A - Alkyl substituted-benzoylacetates antilipemic agents - Google Patents

Abstract

Disclosed are novel compounds of the formula

WHEREIN R1 is lower alkyl of from one to four carbon atoms and R2 is a straight or branched chain alkyl of from eight to 14 carbon atoms which may be substituted on any position of the ring. The novel compounds are useful in the treatment of hyperlipemic states characterized by elevated blood lipid levels.

Description

[lite States Patent [191 Grisar et a1.

[ June 18, 1974 [75] Inventors: Johann M. Grisar, Cincinnati, Ohio;

Willhelmus Janssens, Aarschot,

Belgium [73] Assignee: Richardson-Merrell Inc., New York,

[22] Filed: Dec. 1, 1971 [21] Appl. No.: 203,868

[52] US. Cl. 260/476 R, 424/308 [51] Int. Cl C070 69/76 [58] Field of Search 260/476 R [56] References Cited UNITED STATES PATENTS 2,848,459 8/1958 Pribyl et al. 260/3402 3,155,649 11/1964 Krapcho et al. i. 260/476 R FOREIGN PATENTS OR APPLICATIONS 798,941 5/1936 France Primary Examiner-Lorraine A. Weinberger Assistant ExaminerPatrick J. Hagan Attorney, Agent, or Firm-L. Ruth I-Iattan; Eugene O. Retter; George W. Rauchfuss, Jr.

[ ABSTRACT Disclosed are novel compounds of the formula wherein R is lower alkyl of from one to four carbon atoms' and R is a straight or branched chain alkyl of from eight to 14 carbon atoms which may be substituted on any position of the ring. The novel compounds are useful in the treatment of hyperlipemic states characterized by elevated blood lipid levels.

6 Claims, N0 Drawings ALKYL SUBSTlTUTED-BENZOYLACETATES ANTILIPEMIC AGENTS This invention relates to novel compounds having utility as antilipemic agents. More particularly, this invention relates to novel compounds useful to produce a reduction of plasma cholesterol and triglyceride levels.

The need to lower the blood level cholesterol and triglycerides without undesirable side effects has heretofore been recognized. The buildup and deposition of such lipoidal material in the intima of blood vessels, particularly the arterial system, characterizes the most common form of arterial disease, atherosclerosis. The fatty deposits in the vessel walls are high in cholesterol and its esters. Heretofore, compounds useful in reducing the concentration of plasma lipids have been characterized by the occurrence of hepatomegaly. It is, therefore, an object of this invention to provide novel compounds useful to produce a reduction in the concentration of plasma lipids characterized by a lesser degree of hepatomegaly occurrence.

The foregoing objects and others which are apparent from the following description are accomplished by providing novel alkylbenzoylacetic esters represented by the formula o @PJ-Cllrfi-Olh R2 wherein R, is a lower alkyl radical of from one to four carbon atoms and R is a straight or branched chain alkyl radical of from eight to 14 carbon atoms which may be substituted on any position of the ring. These novel compounds reduce the concentration of plasma lipids when administered to a patient in a plasma lipid lowering effective amount.

As examples of the novel compounds of this invention there may be mentioned, for example, ethyl p-octylbenzoylacetate, methyl p-decylbenzoylacetate, ethyl p-n-dodecylbenzoylacetate, methyl p-n-dodecylbenzoylacetate, n-butyl propyl m-nonylbenzoylacetate, butyl o-undecylbenzoylacetate, ethyl p-tridecylbenzoylacetate and the like. Especially preferred compounds of this invention are those compounds of the above formula wherein R, is methyl or ethyl and R is dodecyl.

The novel compounds of this invention, which can exist in both the keto and enol tautomeric forms, are prepared by condensing an RQSUbStitUted benzoyl halide with an ester of acetoacetic acid followed by alkaline hydrolysis of the resulting aroylacetoacetate. The compounds may also be prepared by condensing the desired R -substituted benzoic acid ester with an ester of acetic acid, employing abasic substance, such as sodium ethoxide. as a catalyst. The reaction is generally completed within a period of up to about 48 hours.

ln the hereinbefore mentioned, reaction schemes the starting materials are generally known materials or can be prepared by well known routes. For example, commercially available, alkyl substituted benzenes are re-. acted with acetyl chloride in a Friedel Craft synthesis according to A. Zaki and H. Fahim (J. Chem. Soc. (1942) l 307) to produce alkyl substituted phenyl methyl ketone which can be oxidized to the corresponding alkyl substituted-benzoic acid by sodium brop-tetradecylbenzoylacetate,'

mite in an analogous manner to the method of Johnson, Gutsche and Offenhauer (J. Am. Chem. Soc. 68 (1946) 1648). Reaction of the substituted benzoic acid with excess thionyl chloride or with an alcohol results in the formation of the substituted benzoyl halide and substituted benzoylester reactants, respectively.

In the process according to this invention the reaction may be carried out in the presence of a suitable solvent, such as, for example, an aromatic hydrocarbon, such as benzene, toluene, xylene and the like; an halogenated aromatic hydrocarbon such as chlorobenzene and the like. As examples of suitable basic catalysts there may be mentioned, for example, sodium methoxide, sodium ethoxide, sodium hydride, sodium carbonate and the like.

The compounds of this invention may also be prepared by a Friedel-Crafts acylation of an appropriately R -substituted benzene derivative with carb-(lower )alkoxyacetyl chloride in a solvent such as 1,l,2,2- tetrachloroethane, 1,2-dichloroethane, carbon tetrachloride and the like in the presence of a catalyst such as aluminum chloride or zinc chloride.

The R -substituted benzene derivatives are commercially available as described hereinabove and the carb-(lower)-alkoxyacetyl chloride compounds may be prepared from'dialkyl malonates by the method of P. Freon and F. Tatibou'et Compt. Rend. 244, 2399 (1957).

Additionally, the compounds of this invention may be prepared by treating R -substituted-phenyl methyl ketones with magnesium methyl carbonate in dimethylformamide and reacting the resulting chelate with a lower aliphatic alcohol in the presence of hydrogen chloride.

The compounds of the instant invention have utility as antilipemic agents. The compounds of the present invention can beadministered to a patient to lower the plasma cholesterol and triglyceride levels. With the use of the compounds of this invention toreduce plasma lipids there is a much lesser occurrence to reduce hepatomegaly than there is with the heretofore known antilipemic agent, 2-(p-chlorophenoxy)-2- methylpropionic acid ethyl ester, known as clofibrate. The dosage unit administered can be any plasma lipid lowering effective amount. A typical dosage range varies from about 500 mg to about 3 g in single or multiple doses per day taken orally. The active compounds of this invention can be administered in any of the suitable conventional modes for administering such antilipemic materials. i i

The following examples, in which the parts and percentages are on a weight basis unless otherwise specified, areillustrative of the invention.

EXAMPLE 1' over magnesium sulfate, concentrated in vacuo and the residue wasrecrystallized from methanol to give an isomer of the title compound, M.P. 5860C., which was 1 subsequently recrystallized from methanol containing a catalytic amount of triethylamine to give the lower melting isomer of the named product, M.P. 495lC.

EXAMPLE 2 PREPARATION OF ETHYL Z-p-DODECYLBEN- ZOYLACETATE A mixture of 195 grams (1.5 moles) of ethyl acetoacetate and 34.5 grams sodium in 3 liters of benzene is refluxed for 20 hours and the mixture cooled. 484 grams (1.7 moles) of p-dodecylbenzoyl chloride is added over a two hour period and then refluxed for 6 hours, cooled by the addition of ice and shaken. The benzene layer is separated,- washed with sodium bicarbonate solution and dried. The benzene is distilled off and the residue gives about 294 grams of ethyl Z-p-dodecylbenzoylacetoacetate. 90 grams (.25 mole) of this material is added to a solution of 32 grams ammonium chloride in 150 ml water at 40C. and kept at this temperature for minutes and cooled rapidly. The solution is extracted with 200 ml of ether and the extracts dried. After distilling the ether, the residue is distilled in vacuo to give ethyl Z-p-dodecylbenzoylacetate.

EXAMPLE 3 METHYL 2-(p-DECYLBENZOYL)ACET ATE A solution of 174 g of magnesium methyl carbonate in 400 ml of dimethylformamide was heated and stirred at 120C. under a carbon dioxide atmosphere while 65 g of 4-decylacetophenone was added. The reaction mixture was stirred and heated for 4 hours under a nitrogen atmosphere, cooled and mixed with 4 liters of ether. The precipitated solid was filtered, dissolved in 400 ml of methanolic hydrogen chloride, cooled to -C., filtered, washed with water and recrystallized from methanol to give the desired product, M.P. 54S6C., A max 257, E,' 509.

EXAMPLE 4 METHYL 2-(p-TRIDECYLBENZOYL)ACETATE Following the procedure of Example 3, only substituting for 4-decylacet0phenone 37.8 g of 4- tridecylacetophenone and using 87 g of magnesium methyl carbonate and 200 ml of dimethylformamide, the desired product was obtained, M.P. 45-47C., A Max 257, E a, 4S5.

EXAMPLE 5 In a manner identical to that described in Example 2 but substituting the appropriate molar equivalent of octylbenzoyl chloride, nonylbenzoyl chloride, and tetradecylbenzoyl chloride for dodecylbenzoyl chloride and methyl acetoacetate for the ethyl ester, the following three compounds are prepared:

\ methyl octylbenzoylacetate,

methyl nonylbenzoylacetate, and methyl tetradecylbenzoylacetate.

Intermediate Preparation CARBOMETHOXY ACETYLCHLORIDE A mixture of 198 g of dimethyl malonate and 980 ml of methanol was stirred and treated with a solution of 84 g of potassium hydroxide in 980 ml of methanol. The reaction mixture was stirred 5 hours, allowed to stand overnight and filtered. The filtrate was concentrated to 300 ml and filtered to give 195 g of potassium carbomethoxyacetate,

A mixture of 156 g of potassium carbomethoxyacetate and 400 ml of ether was stirred and treated in a dropwise manner, with 165 g of thionyl chloride. The mixture was refluxed 2 hours, filtered, the filtrate was concentrated and the residue distilled to give the desired product. B.P. 72-74C.

EXAMPLE 6 The usefulness of the compounds of this invention is demonstrated in the hereinafter described tests con ducted in normal rats. Male Wistar rats were treated for 10 days with a diet containing 0.3 percent of the compound of Example 1 in Purina Lab Chow. Similarly, a second group of such rats were treated for 10 days with a diet containing 0.4 percent of clofibrate, a known antilipemic agent, in Purina Lab Chow. At the end of the test period, blood was obtained from each animal by cardiac puncture and plasma cholesterol and triglyceride levels were analyzed. The livers were excised, weighed and the weights were expressed as grams of liver per grams of body weight. All values were compared with the values obtained for untreated control rats run concurrently. The results are set forth in the following table.

7; Reduction of Plasma Lipids Dose Chulcs- Trigly- '7: Increase Compound Mg/KgJDuy terol cerides of Liver Wt.

Example I 327 53 84 2O Clofibratc 41 l 4] 78 49 We claim:

1. A compound of the formula 0 9 @imrao... R2

6. A compound of claim 1 wherein R is tridecyl.

Claims (5)

1. 2. A compound of claim 1 wherein R2 is dodecyl.
2. 3. A compound of claim 2 wherein R1 is methyl.
3. 4. A compound of claim 2 wherein R1 is ethyl.
4. 5. A compound of claim 1 wherein R2 is decyl.
5. 6. A compound of claim 1 wherein R2 is tridecyl.