(2-pyrimidinylthio)alkanoic acids, esters, amides and hydrazides, as anti-lipemic agents
United States Patent 1 Santilli et al.  
 [451 Apr. 8, 1975 (2-PYRlMlDlNYLTl-ll0)ALKANOIC ACIDS,  
 ESTERS, AMIDES AND HYDRAZIDES, AS ANTl-LlPEMlC AGENTS [75] lnventors: Arthur A. Santilli, Havertown;  
 Anthony C. Scotese, King of Prussia; Rudolph M. Tomarelli, Phoenixville. all of Pa.  
 [73] Assignee: American Home Products Corporation, New York, NY.  
 [22] Filed: Oct. 24, 1973 [211 App]. No.: 409,115  
 Related U.S. Application Data [62] Division of Ser. No. 240,266, March 31, 1972, Pat.  
 N0. 3,8l4,76l.  
  521 U.S. Cl 424/251; 424/250 [5 1] Int. Cl A6lk 27/00 [58] Field of Search 424/251 [56] References Cited UNITED STATES PATENTS 2.347.992 5/1944 DAlelio et al. 260/2565 2,62LI82 l2/l952 Hitchings et al 260/2565 Primary E.\-aminerFrederick E. Waddell Attorney, Agent, or Firm-Richard K. Jackson [57] ABSTRACT (Z-Pyrimidinylthio)alkanoic acid, esters, amides and hydrazides as well as various 4- and 6-substituted derivatives thereof as depicted by the structural formula in warm-blooded 32 Claims, No Drawings (Z-PYRIMIDINYLTHIO)ALKANOIC ACIDS,  
 ESTERS,A&#39;MIDES-AND HYDRAZIDES; AS j;  
  AN&#39;Tl LlPEMl C AGENTS 7 RELATED APPLICATION This application is a division of Ser. No. 240,266 filed Mar. 3l, 1972 now US. Pat. No. 3,814,761.  
 BACKGROUND OF THE INVENTION Anti-lipemic agents in current use include such diverse compounds as ethyl pchlorophenoxyisobutyrate&#39; DESCRIPTION OF THE INVENTION In accordance with this invention, there is provided certain novel anti-lipemic agents presenting the (2- pyrimidinylthio)alkanoic acid, ester, amide and hydrazide structure, methods for their preparation, pharmaceutical compositions for their administration and methods for their administration to reduce the cholesterol and/or triglyceride content of blood serum.  
  The compounds of this invention reduce the concentration of triglycerides in blood serum in normal rats, whereas the concentration of triglycerides and cholesterol are reduced in rats on a hypercholesterolemic diet. Thus, the mechanism of action of the compounds of this invention appears to differ from that of the clofibrate type anticholesterolemic agents, which tend to produce a hypocholesterolemic state in normal and hypercholest erolemic&#39;blood.  
  The (Z-pyrimidinylthio)alkanoic acids, esters, amides and hydrazides of this invention may be depicted by the structural formula:  
 R and R are members independently selected from the group consisting of hydrogen and lower alkyl radicals;  
 R is a member selected from the group consisting of hydrogen, halo and lower alkoxy radicals;  
 Z is a member selected from the group consisting of hydroxy, lower alkoxy, OM and (NH),,-Nl-I radicals,  
 wherein p is or l, and M is an alkali metal cation, an alkaline earth metal cation or the ammonium ion;  
 m is an integer from O to 2;  
 Y is a member selected from the group consisting of an aryl radical of 6 to 10 carbon atoms;  
  wherein wherein R is a hydrogen or lower alkyl radical, R is hydrogen, H N,  
 phenyl, (lower)alkoxyphenyl, or di(lower)alkoxyphenyl, providing that when&#39;R is hydrogen and R is hydrogen, phenyl (lower)alkoxyphenyl or di(lower)alkoxyphenyl, R is halo or lower alkoxy R is a member selected from the group consisting of I a lower alkyl radical, a halo radical, an aryl radical of 6 to 10 carbon atoms and a haloaryl radical of 6 to 10 carbon atoms,  
 R is a member selected from the group consisting of hydrogen, lower alkyl,-lower alkoxy and halo radicals,  
 R is a member selected from the group consisting of hydrogen and lower alkyl radicals, and  
 X is a member selected from the group consisting of (CHR N and N themselves are obtained, for example, by converting 2-thiobarbituric acid to the (4,6-dihydroxy2- pyrimidinylthio)alkanoic acid ester by reaction with an alpha-halo(lower)alkanoic acid ester and subsequently displacing the 4- and 6- positioned hydroxyl groups with chlorine by reaction with an agent such as POCI PCl and the like. Thus,  
  v no HCl ClCHRC0 R Ho Various modifications of the 4,6-halo groups may be accomplished by substitution and displacement reactions. Thus, reactions of the (4,6-dichloro-2- pyrimidinylthio)alkanoic acid esters with primary amines yields the corresponding 4- or 6-amino derivative, reaction with hydrazine affords the 4- or 6- hydrazino derivative which readily converted to a hydrazone by reaction with an aldehyde or a carbonhydrazide by reaction with a carboxylic acid halide. An aryl group is positioned directly on the 4- or 6-position of the pyrimidine nucleus, if desired, by employing 40 4101 I I-sna +C1CHRC02R The anti-lipemic activity of the compounds of this invention was established by orally administering the compounds being tested to each member of a group of young male rats which had been fed a hypercholesterolemic diet for three weeks and grouped, based upon their equal average serum cholesterol concentration determined on 0.01 milliliters of serum separated SCHRCO R from tail blood collected in a capillary tube. The compounds tested were administered orally once or twice a day for three consecutive days. The serum cholesterol was determined on the fourth day and compared to the average of the group of untreated rats. The potency of the test compound is expressed as the percent activity of concomitantly run tests employing Atromid S (clofibrate) as the standard. The test procedure was repeated with normal chow-fed rats to determine the hypolipemic effect in the normal host.  
  The hypolipemic agents of this invention are effectively administrable orally or parenterally. The amount of the active compound needed to reduce the fat content of the blood to the desired level varies with the mode of administration to a certain extent as well as the condition of the individual under treatment with regard to age, fat concentration in the blood and depots, diet, transference factors of the gut and interstitial tissues I SCHRCOZR P0Cl etc.  
 and contributing factors such as the presence of hyperthyroidism, diabetes, cirrhosis of the liver or spleen, pancreatitis, etc.  
 In practice, the compounds are administered to one controlledadministration. The compounds of the invention may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in tablet or capsule form with conventional flavors, diluents, lubricants, disintegrators or binding agents as may be required. They may be administered orally in the form of a solution or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.  
  A suitable tablet formulation is as follows: [4-Chloro-6-( 2,3-xylidino-2-pyrimidinylthio] acetamide .05 mg Microcrystalline Cellulose, N.F. .20 mg Magnesium Stearate. U.S.P. 25.00 mg Lactose, U.S.P. 74.75 mg Total Weight lOO mg A suitable formulation for parenteral administration is as follows:  
 Sodium[4-Chloro-6-( 2.3-.xylidino )-2- pyrimidinylthio] acetate 5 mg. Vehicle: sterile water, containing benzyl alcohol (1 percent) and sodium acetateacetic acid buffer 0.6% 5 ml.  
  The compounds of this invention which exhibit markedly superior anti-lipemic activity when compared to the standard Atromid S in the test procedure, are those compounds of the formula;  
 R is selected from the group consisting of l-l, lower alkyl, halo and lower alkoxy radicals; X is selected from the group consisting of and wherein R and R are independently H or lower alkyl and n is an integer from 0 to 3, providing that when n is 0 and R is lower alkoxy, R is lower alkyl, lower alkoxy or halo; and  
 Z is selected from the group consisting of OH, OM,  
 lower alkoxy and (NH),,NH in which p is an integer from 0 to 1 and M is an alkali metal, alkaline earth metal or ammonium cation.  
  Of these compounds those exhibiting the greatest activity are the [4-chloro-6-arylamino-2-pyrimidinylthio] acetic acid, alkali metal salt, amide, hydrazide and lower alkyl ester in which the aryl group contains from 7 to 12 carbon atoms, and the 6- parachlorophenylamino and 6-parachlorobenzylamino analogues thereof.  
  The compounds embraced by the above structural formula exhibit antihypercholesterolemic activity from 2 to 26 times in excess of that exhibited by Atomid S brand of clofibrate in concomitantly run studies on groups of young male rats which had been previously fed a hypercholesterolemic diet. The antilipemic activity of the compounds of this invention was established by the determination of a quantitative reduction of serum cholesterol concentration determined on the fourth day after oral administration of the active compounds once or twice a day for three days to the rats grouped on the basis of equal average serum cholesterol.  
  The compounds of this invention which exhibit positive antihypercholesterolemic activity to a degree equal to or below that of the standard clofibrate employed in the test procedures (Atromid S) may be represented by the formula:  
 in which A is a member selected from the group consisting of aryl of 6 to 10 carbon atoms and wherein R is H or lower alkyl and R is hydrogen,  
 R is selected from the group consisting of H and lower alkyl;  
 R is selected from the group consisting of H and lower alkyl;  
 R is selected from the group consisting of H, chloro and lower alkoxy radicals, with the proviso that when A is the amino or phenylamino group R is chloro or lower alkoxy; and  
 Z is selected from the group consisting of NHNH lower alkoxy, OH and OM, wherein M is an alkali metal, alkaline earth metal or ammonium cat- The following Examples are presented to illustrate the procedure employed to produce the compounds of this invention and are not to be constructed in themselves as limitations upon the true scope of the subject matter applicants regard as their invention.  
 EXAMPLE 1 (4,6Dichloro-2-pyrimidinylthio )acetic acid, ethyl ester To a Solution of 8.4 g (0.1 mole) of sodium bicarbonate in 500 ml. of water was added with stirring 14.4 g (0.1 mole) of Z-thiobarbituric acid. Ethyl bromoacetate (16.7 g, 0.1 mole) was then added with enough ethanol to make a clear solution. Within one-half hour a precipitate was formed. Stirring was continued for 2 hr. at room temperature. The precipitate amounted to 20.2 g. Recrystallization from ethanol gave the analytical sample mp. 194-197C., of (4,6-Dihydroxy-2- pyrimidinylthio)acetic acid, ethyl ester.  
 Anal. Calcd for C,,H ,N,O S: C. 41.73; H, Found: C. 41.75; H.  
  To a mixture of 73.6 g of (4,6-dihydroxy-2- pyrimidinylthio)acetic acid, ethyl ester in 500 ml. of phosphorus oxychloride was slowly added 47.7 g of N,N-diethylaniline. After the heat generated by this addition had abated the reaction mixture was heated under reflux for 5 hr. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured onto 2-liters of ice water. The reaction mixture was allowed to stand for 3 days and was filtered. The filter cake was recrystallized from petroleum ether giving 61.0 g of product. Recrystallization a second time from petroleum ether gave an analytical sample; mp. 61-62C.. of the title compound.  
  .02; N. 1 Found: C. 35.95; H. .00; N. l  
 EXAMPLE 2 (4-Amino-6-chloro-2-pyrimidinylthio)acetic acid ethyl ester A mixture of 10.7, g of (4,6-dichloro-2- Anal. Calcd. for  
 -C,.H &#34;N O SCl: C. 38.78; H. 4.07; N, 16.96; Cl, 14.50. Found: C. 38.96; H, 4.09; N, 17.16; Cl. 14.57.  
 EXAMPLE 3 (4-Anilino-6-chloro-Z-pyrimidinylthio)acetic acid ethyl ester A stirred mixture of 8.0 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 2.8 g of aniline and 3.2 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to start precipitation. The crude product was recrystallized from ethanol to afford 6.7 g of product, mp. l09-1l4C.  
 Anal. Calcd for C H N CISO C. 51.93; Found: C. 51.69;  
 EXAMPLE 4 (4-ChIoro-6-(p-chloroanilino) 2-pyrimidinylthio)acetic acid ethyl ester A stirred mixture of 8.0 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 3.8 g of pchloroaniline and 3.2 g of sodium carbonate in ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate until precipitation resulted. Recrystallization of this material from 95% ethanol afforded 3.0 g of product, mp. 109-1l2C.  
 Anal. Calcd for C..H. ,N.,so,c|,; C, 46.9 Found: C. 46.6  
 EXAMPLE 5 [4-Chloro-6-(p-fluoroanilino)-2-pyrimidinylthio]acetic acid ethyl ester A stirred mixture of 10.7 g of (4,6-dichloro 2- pyrimidinylthio)acetic acid ethyl ester, 4.4 g of pfluoroaniline and 4.2 g of sodium carbonate was heated under reflux for 6 hr. and filtered. Water was added to the filtrate to the precipitation point. The precipitate was removed by filtration and recrystallized from 95% ethanol to afford 4.1 g of product; mp. 97-102C.  
 Anal. cam for c,,H, .,N,,CiFso,. c, 49.19  
 1 Found: C. 4  
 EXAMPLE 6 [4-Chloro-6-(d,a,a-trifluoro-m-toluidino)-2- pyrimidinylthio]acetic acid ethyl ester A mixture of 5.2 g of 3-amino benzotrifluoride, 8.5 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 3.4 g of sodium carbonate and 100 ml of ethanol were heated to 135C. for hr. in an autoclave. The reaction mixture was cooled in ice and filtered. Water was added to the filtrate to start precipitation. The solid was collected and recrystallized from 95% ethanol giving 3.3 g of product, mp. ll0 114C.  
  H, 3.34; Found: C, 4  
 EXAMPLE 7 [4-Chloro-6-(2,3-xylidino )-2-pyrimidinylthiolacetic acid ethyl ester A stirred mixture of 2.7 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid, ethyl ester, 1.2 g of 2,3- dimethylaniline and 1.06 g of anhydrous sodium carbonate in ml. of ethanol was heated under reflux for 4 hr. The mixture was filtered and water added to the filtrate until a precipitate appeared. The solid was recrystallized from 95% ethanol to a mp. of 8893C.  
 Anal. Calcd for C H N O ClS: C, 54.62: H, 5.15; N, 11.94. Found: C, 54.80; H, 5.08; N, 12.00.  
 EXAMPLE 8 [4-Chloro-6-(2,4,6-trimethylanilino)-2-pyrimidinylthio]acetic acid ethyl ester A mixture of 5.3 g of (4,6-dich1oro-2- pyrimidinylthio) acetic acid ethyl ester, 2.7 g of 2,4,6- trimethylaniline and 2.1 g of sodium carbonate in 50 ml of ethanol was heated in an autoclave to 200C. for 5 hr. The reaction mixture was filtered and water was added to initiate precipitation. The precipitate was removed by filtration and recrystallized from 95% ethanol to afford 3.2 g of product, mp. 100-103C.  
 Anal. Calcd for c,,H,.,N,ciso,; c. 55.8 Found: C. 55.5  
 EXAMPLE 9 l4-Chloro-6-(p-methoxyanilino)-2-pyrimidiny1thio]acetic acid ethyl ester A stirred mixture of 5.2 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethylester. 2.4g of panisidine and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for i6 hr. The reaction mixture was filtered and the filtrate coo1ed in..ice. A crystalline material was deposited which was purified by recrystallization from ethanol. There was obtained 4.5 g of product, mp. 96-97.5C.  
 Anal. Calcd for C H N CISO C, 50.92; H. 4.56; N. 11 87 Found: C, 51.16; H 477; N, 1200 EXAMPLE 1O [4-(4-Biphenylylamino)-6-ch1oro-2-pyrimidinylthio]acetic acid ethyl ester A stirred mixture of 5.3 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 3.4 g of 4- aminobiphenyl and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to initiate precipitation. The precipitate was recrystallized from ethanol to give 3.1 g of product, mp. -112C.,  
 Anal. Calcd for C H N CISO C, 58.83;  
  H 10.83 Found: C, 58.72; H,  
 EXAMPLE 1 1 (4-Chloro-6-[4-(p-chlorophenyl)-1-piperaziny11-2- pyrimidinylthio)acetic acid ethyl ester A mixture of 5.3 g of (4.6-dichloro-2- pyrimidinylthio) acetic acid ethyl ester, 3.9 g of N-(p-chlorophenyl)piperazine and 2.1 g of sodium carbonate in ml. of ethanol was warmed on a steam bath for 10 minutes. The reaction mixture was filtered and the filtrate was diluted with water in order to cause precipitation. The precipitate was recrystallized from ethanol to afford 5.3 g of product, mp. l 17-l20C.  
 Anal. Calcd for C,,.H ,,N;SCl O C, 50.59; H, 4.72; N, 13.1 1. Found: C, 50.96; H, 4.99; N, 13.17.  
 EXAMPLE l2 [4-Ch1oro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid A mixture of 21.4 g of (4,6-dich1oro-2- giving 4.3 g of product, mp. 146-l51C.  
 Anal. Calcd for c,,H,,N,c|o,s; C, 51.93; H, 4.36; N, 12.98.  
 Found: C, 51.65; H, 4.31; N, l  
 EXAMPLE 13 [4-Chloro-6-(2,3-xylidino)-2- pyrimidinylthiolacetamide Anal. Calcd for C, H, ,N OCIS: C, 52.09; H, 4.6  
  Found: C. 9;  
 EXAMPLE l4 [4-Chloro-6-(2,3-xylidin0)-2-pyrimidinylthio]acetic acid hydrazide A mixture of 5.0 g of [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio]acetic acid ethyl ester and 5.0 g of hydrazine hydrate (98%) in 40 ml. of ethanol was allowed to stand overnight at room temperature. Water was added to the mixture until a precipitate appeared. This material was recrystallized from ethanol affording 4.8 g of product, mp. l85-l89C.  
 Anal. Calcd for C H N OClS: C, 49.77, H, 4.77; N, 20.73 Found: C, 49.54; H, 5.10; N, 20.74  
 EXAMPLE [4-Chloro-6-(p-chlorobenzylamino)-2-pyrimidinylthiolacetic acid, ethyl ester Anal. Calcd for c,,11,,N.,C1,o,s: C, 4  
 Found: C, 4  
 EXAMPLE 16 l4-Chloro-6-(p-fluorobenzylamino)-2-pyrimidinylthio]acetic acid, ethyl ester A stirred mixture of 3.75 g of p-fluorobenzylamine, 3.18 g of anhydrous sodium carbonate and 8.01 g of (4- ,6-dichloro-2-pyrimidinylthio)acetic acid, ethyl ester in 150 ml of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate until a precipitate was formed. The solid was collected and recrystallized from benzene-petroleum ether giving 3.6 g of product, mp. 70-75C.  
 Anal. Calcd for C -,H N -,ClSO F: C, 50.63; H, 4.25; N, 11.81. Found: C, 0.38; H, 4.26; N, 11.83.  
 EXAMPLE l7 [4-Chloro-6-(3,4-dichlorobenzylamino)-2- pyrimidinylthio]acetic acid, ethyl ester A stirred mixture of 8.0 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 5.3 g of 3,4- dichlorobenzylamine and 3.2 g of sodium carbonate in 200 ml. of ethanol was heated under reflux for 6 hr. The reaction mixture was filtered and water was added to the filtrate to the cloudy point. The mixture was cooled in ice and the resulting precipitate which formed was removed by filtration and recrystallized from aqueous ethanol. The product amounted to 4.8 g, mp. 64-69C.  
 Anal. Calcd for C H N CI SO C, 4  
  4 3 H, Found: C, 44.2  
 EXAMPLE l8 [4-Chloro-6-( 2,4-dimethoxyanilino )-2-pyrimidinylthio]acetic acid A stirred mixture of 10.7 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 6.1 g of 2,4- dimethoxyaniline and 4.24 g. of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and the filtrate taken to dryness in a rotary evaporator. The residue was boiled for 3 minutes with approximately 10 ml. of 30% sodium hydroxide solution and a sufficient quantity of ethanol to obtain a clear solution. The mixture was acidified with concentrated hydrochloric acid solution. An oil was obtained. The supernatant liquid was decanted and the oil was dissolved in 30% aqueous base. Re-acidification with concentrated hydrochloric acid caused a precipitate to deposit. The material was recrystallized from ethanol-petroleum ether giving 3.6 g of product, mp. l30-l34C.  
 Anal. Calcd for C H N CIO,S: C, 47.26: H, l l 7 l H 12.02.  
  3 96; N, Found: C, 4 .0 4.02; N,  
 EXAMPLE l9 [4-Chloro-6-(2,4-dimethylbenzylamino)-2- pyrimidinylthio]acetic acid, ethyl ester Anal. Calcd for C,,H,,,N,,O,CIS: c. 55. 1  
  H, 5.51; N Found: C, .46; H, 5.22; N,  
 I thio)acetic EXAMPLE 20 [4-Chloro-6-(p-chlorophenethylamino)-2-pyrimidiny1- thio]acetic acid, ethyl ester A mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylacid ethyl ester, 6.2 g chlorophenethylamine, and 4.24 g of sodium carbonate in 150 ml. of ethanol was heated under reflux for 15 minutes. The reaction mixture was filtered and the filtrate was cooled in ice. The crystalline product which was deposited was collected and recrystallized from ethanol giving 3.6 g of product, mp. ll08C.  
 Anal. Calcd for C H N Cl O S: C. 49.75; H, 4.44; N, 10.88. Found: C, 49.81; H, 4.51; N, 10.84.  
 EXAMPLE 21 (4-Chloro-6[(p-chlorobenzyl)methylamino]-2- pyrimidinylthio)acetic acid, ethyl ester Anal. Calcd for c..,|-|,,N,,cl so C, 49.75; Found: C, 49.69;  
 EXAMPLE 22 [4-Chloro-6-( p-chloro-a-methylbenzylamino)-2- pyrimidinylthiolacetic acid A stirred mixture of 2.7 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 1.6 g of p-chloro-a-methylbenzylamine and 1.1 g of sodium carbonate in 120 ml. ethanol was heated under reflux for 2 hr. The reaction mixture was filtered and the filtrate taken to dryness in a rotary evaporator in vacuo. The residual oil was treated with 100 ml. of 30% sodium hydroxide solution containing a few ml. of ethanol. After a few minutes the clear solution was acidified with concentrated hydrochloric acid and the mixture thus formed was extracted with ether (3 X 50 ml.). The ether solution was dried over magnesium sulfate, filtered and filtrate evaporated to dryness. The residue was dissolved in 50 ml. of benzene and petroleum ether was added until the solution became cloudy. On cooling in ice a precipitate was deposited. Recrystallization Anal. Calcd for C H N Cl,O S: C. 46}.  
  94; H, 3.66; N, 11.73. Found: C. 4 09; H, 3.84; N. 11.74.  
 EXAMPLE 23 (4-Chloro-6-[3,4-(methylenedioxy)benzylamino]-2- pyrimidinylthio)acetic acid, ethyl ester A stirred mixture of 5.3 g of (4,6-dichloro-2- pyrimidinylthio)acetic acid ethyl ester, 3.0 g of piperonylamine and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to initiate precipitation. The precipitate was removed by filtration and recrystallized from ethanol to afford 5.3 g of product, mp. 79C.  
 Anal. Calcd for C H N O ClS: C, 50.  
 EXAMPLE 24 [4-Chloro-6-(p-chlorobenzylidenehydrazino)-2- pyrimidinylthio1acetic acid, ethyl ester To a solution of 2.1 g of p-chlorobenzaldehyde in 25 ml. of glacial acetic acid was added a solution of 3.9 g of (4-chloro-6-hydrazino-2-pyrimidinylthio) acetic acid ethyl ester in ml. of glacial acetic acid. The reaction mixture was warmed on a steam bath for a few minutes and then cooled in ice. The resulting precipitate was collected, washed with petroleum ether and recrystallized twice from ethanol affording 3.6 g of product, mp. 162l65C.  
 Anal. Calcd for C H N CI O S: C, 46.76; H, 3.66; N, 14.54. Found: C, 46.48; H, 3.59; N, 14.59.  
 EXAMPLE 25 [4-Chloro-6-[(p-fluorobenzylidene)hydrazino]-2- pyrimidinylthio1acetic acid, ethyl ester To a solution of 5.2 g of (4-chloro-6-hydrazino-2- pyrimidinylthio) acetic acid, ethyl ester in 100 ml. of glacial acetic acid was added 2.5 g of pfluorobenzaldehyde. The reaction mixture was warmed for a few minutes on a steam bath. The resulting precipitate which formed was washed with petroleum ether and recrystallized from ethanol affording 2.7 g of product, mp. l46l49C.  
 Anal. Calcd for C H N O ClFS: C, 48.85  
 Found: C, 48.64;  
 EXAMPLE 26 (4-Chloro-6-hydrazino-2-pyrimidinylthio)acetic acid, ethyl ester, hydrochloride A mixture of 8.01 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 3.18 g of anhydrous sodium carbonate and 1.5 g of 98% hydrazine hydrate in ml. of absolute ethanol was heated with stirring under reflux for 20 minutes. The hot reaction mixture was filtered and the filtrate was cooled in ice. There was obtained 4.9 g of a precipitate. This material was then &#39;15 treated with 20 ml. of concentrated hydrochloric acid solution. The acid solution was diluted with water and the precipitate which resulted was recrystallized from ethanol-petroleum ether affording 4.9 g of product, mp. 208C. decomp.  
 Anal. Calcd for cm mcl ogs 32.11 H 2. H  
  ,4. Found:C.3 l9; ,4.  
 EXAMPLE 27 [4-Chloro-6-(p-chlorobenzylamino )-2-pyrimidinylthio]acetic acid [4-Chloro-6-(p-chlorobenzylamino)-2- pyrimidinylthiolacetic acid ethyl ester (1.4 g) was heated for 5 minutes with 30 ml. of 30% sodium hydroxide solution on a hot plate. The reaction mixture was then cooled and acidified with concentrated hydrochloric acid solution. The resulting precipitate was removed by filtration, washed with water and recrystallized from ethanol to afford 1.0 g of product, mp. 211213C., decomp.  
 Anal. Calcd for C H N CI O S: C,  
 Found:  
 EXAMPLE 28 (4-Chloro-6-(p-chlorobenzylamino)-2-pyrimidinylthio)acetic acid hydrazide A stirred mixture of 1.1 g of (6-chloro-4-pchlorobenzylamino-Z-pyrimidinylthio)acetic acid, ethyl ester, 0.18 g of hydrazine hydrate (98%) and 0.3 g of sodium carbonate in 15 m1. of ethanol was heated under reflux for 3 hr. The reaction mixture was filtered and the filtrate diluted with water until a precipitate appeared. The solid was washed with aqueous (10%) sodium carbonate then recrystallized from ethanol to a mp. of l78-182C.  
 Anal. Calcd for C H N OCl- S: C,  
  43.58; H, 3. Found: C. 43.76; H, 3.  
 EXAMPLE 29 2-(4,6-Dichloro-2-pyrimidinylthio)propionic acid, ethyl ester Anal. Calcd for C,.H,,N,O S: C,  
  44.25; H. 4.95; N, 11.47. Found: c. 4.24; 11.5.19; 34.  
  A mixture of 12.8 g of 2-(4,6-dihydroxy-2- pyrimidinylthio)propionic acid ethyl ester and 7.8 g of diethylaniline in 100 ml. of phosphorus oxychloride was heated under reflux for 6 hr. The excess phosphorus oxychloride was removed in a rotary evaporatory and the residue was poured onto a mixture of ice and water. The mixture was extracted with ether (3 X 150 ml.) and the ether phase was washed with water (100 ml.), 10% sodium bicarbonate (100 ml.) and again with water. The washed ether phase was dried over magnesium sulfate, filtered and taken to dryness. The title compound as a residual oil (8.2 g) was used without further purification in the following Example.  
 EXAMPLE 3O 2-[4-Chloro-6-(p-chlorobenzylamino )-2- pyrimidinylthio]propionic acid A stirred mixture of 5.6 g of 2-(4,6-dichloro-2- pyrimidinylthio) propionic acid ethyl ester, 2.9 g of pchlorobenzylamine and 2.1 g of anhydrous sodium carbonate in 50 ml. of ethanol were heated under reflux for 6 hr. The reaction mixture was filtered and taken to dryness on a rotary evaporator. The residue was dissolved in ether and filtered free of insoluble material.  
 The ether was removed on a rotary evaporator and the residue was treated with approximately 10 ml. of 30% sodium hydroxide solution to which was added enough ethanol until a clear solution was obtained. The reaction mixture was heated on a steam bath for a few minutes then acidified with concentrated hydrochloric acid solution. The precipitate which was formed was recystallized from ethanol affording 5.0 g of product, mp. 133l36C.  
 Anal. Calcd for C H N O Cl S: C, 46.94; H, 3.66; N, 11.73. Found: C, 46.79; H. 3.80; N. 11.70.  
 EXAMPLE 31 (4-Chloro-6-phenyl-2-pyrimidinylthio)acetic acid, ethyl ester To a stirred solution of 8.4 g of sodium bicarbonate in 450 ml. of water and ml. of ethanol was added 20.4 g of 6-phenyl-2-thiouracil. The mixture was heated on a hot plate until a clear solution was obtained then 16.7 g of ethyl bromoacetate was added. A precipitate was deposited which was removed by filtration and washed with water. The dried product amounted to 28.1 g, mp. 214218C. decomp. The analytical sample of (4-hydroxy-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester was obtained by recrystallization from dimethyl formamide, mp. 217-2l9C.  
 Anal. Calcd for C H N O S: C. 57. 4.86; 05; 9.79.  
  2; H N. Found: C, 58.04; H. 5. N.  
  A solution of 18.0 g of (4-hydroxy-6-phenyl2- pyrimidinylthio)acetic acid ethyl ester in 200 m1. of phosphorus oxychloride was heated under reflux for 17 hr. The excess phosphorus oxychloride was removed in a rotary evaporator. The residual oil crystallized on standing. Recrystallization from petroleum ether afforded 8.7 g of the title compound, mp. 82-84C.  
 Anal. Calcd for C H CIN O S: C. 54.46; H. 4.24; N. 9.07;  
  S. 10.38; Cl. 11.48. Found: C. 54.17; H. 4.27; N. 9.39; 8. 10.41; Cl. 11.76.  
 ide and the solution was diluted to 200 ml. The reaction mixturewas allowed to stand at room temperature for 1.5 hr. cooled in ice and acidified with concentrated hydrochloric acid; The resulting precipitate was recrystallized from aqueous ethanol affording 1.4 g of product, mp. 157-159C.  
 Anal. Calcd for C. ,1-1. N,o.s; C. 56.52; H, 4.38; N 10.14; 5, 11.58. Found: C. 56.69; H. 4.77; N 10.35; 5. 11.76.  
 EXAMPLE 33 [4-( p-Chlorobenzylamino )-2-pyrimidinylthio acetic acid, ethyl ester A stirred mixture of 32.1 g of (4-hydroxy-2- pyrimidinylthio)acetic acid, ethyl ester and 22.4 g of N,N-diethylaniline in 400 ml. of phosphorus oxychloride were heated under reflux for 5 hr. The phosphorus oxychloride was removed in a rotary evaporator in vacuo. The residue was poured onto ice and the mixture was extracted with 1 liter of ether. The ether solution was dried over MgSO. and then filtered. The filtrate was taken to dryness in a rotary evaporator yielding 22.9 g of (4-chloro-2-pyrimidinylthio)ace tic acid, ethyl ester (an oil). This material was used directly in the next step without purification.  
  A stirred mixture of 10.0 g of (4-chloro-2- pyrimidinylthio)acetic acid, ethyl ester, 6.0 g of pchlorobenzylamine and 4.5 g of sodium carbonate in 150 ml. of ethanol was heated under reflux for 5 hr.  
  The reaction mixture was filtered and water was added to the filtrate to induce crystallization. After cooling in ice the precipitate was collected on a filter. Recrystallization from benzene-petroleum ether afforded 5.5 g of product, mp. 175l78C.  
 [4-(p-Chlorobenzyl)methylamino-2-pyrimidinylthio1acetic, acid ethyl ester A mixture of 9.2 g of (4-chloro-2-pyrimidinylthio)acetic acid ethyl ester, 6.2 g of N-methyl-pchlorobenzylamine and 4.2 g of sodium carbonate in ml. of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and the filtrate taken to dryness in a rotary evaporator in vacuo. The residual oil was dissolved in about 50 ml. of benzene and petroleum ether was added until the solution became cloudy. On cooling the mixture in ice a precipitate was formed. The precipitate .was removed by filtration and recrystallized from ethanol to afford 3.8 g of product, mp. 5861C.  
 Anal. Calcd for C H N O SCI: C. 54.62; Found: C, 54.72;  
 EXAMPLE 35 (4,6-Dich1oro-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester To a solution of 4.0 g (0.0475 mole) of sodium bicarbonate in 40 ml of water was added with stirring 7.5 g (0.0475 mole) of 5-methyl-2-thiobarbituric acid. Ethyl bromoacetate (7.9 g, 0.0475 mole) was then added and 40 ml of ethanol to make a clear solution. After onehalf hour a precipitate was formed. Stirring was continued for one-half hour at room temperature. The precipitate was collected and recrystallized from ethanol to give 6.3 g of (4,6-dihydroxy-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester mp. 21 1-214C.  
 Anal. Calcd for C H, N O.S: C, 44.25: H. 4.95; N, 11.47. Found: C. 44.53; H, 5.01; N. 11.31.  
  To a mixture of 25.3 g of (4,6-dihydroxy-5-methyl-2- pyrimidinylthio)acetic acid, ethyl ester in 200 ml of phosphorus oxychloride was slowly added 15.3 g of N,N-diethylaniline. The reaction mixture was heated under reflux for 5 hr. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured onto 2-liters of ice water. The precipitate was collected and dried. A 5.0 g portion of this solid was recrystallized from petroleum ether to afford 1.7 g of product, mp. 66-70C.  
 Anal. Calcd for C,,H,.,Cl N O S: C, 38.44; H. 3.58; N. 9.96. Found: 38.78; H. 3.59; N, 10.02.  
 EXAMPLE 36 [4-Chloro-6-(p-chlorobenzylamino)-5-methy1-2- pyrimidinylthio]acetic acid, ethyl ester A stirred mixture of 4.2 g of p-chlorobenzylamine, 3.18 g of sodium carbonate and 8.4 g of (4,6-dichloro- 5-methyI-Z-pyrimidinylthio)acetic acid, ethyl ester in 100 ml of ethanol was heated under reflux for 4 hr. The reaction mixture was filtered and water was added to the filtrate to start precipitation. The collected solid was recrystallized from benzene-petroleum ether to give 3.6 g of product, mp. 114-l 17C.  
 Anal. Calcd for CuJ&#39;lnClgNaOgS: C, 49.75; H 4.44, N, 10.88 Found: C, 49.88; H, 4.41, N, 10.88  
 EXAMPLE 37 (4-Chloro-6-[p-chlorobenzyl)methylamino]-5-methyl- 2-pyrimidinylthio)acetic acid, ethyl ester A stirred mixture of 4.65 g of N-methyl-pchlorobenzylamine, 3.18 g of sodium carbonate and 8.4 g of (4,6-dichloro--methyl-2-pyrimidinylthio)acetic acid, ethyl ester in 100 ml of ethanol was heated under reflux for 5 hr. The reaction mixture was filtered and water was added to the filtrate to the precipitation point. The precipitate was removed by filtration and recrystallized from benzene-petroleum ether to afford 4.1 g of product, mp. l03-l07C.  
 Anal. Calcd for C H N CI O S: C, 51.00; H, 4 78; N, 10.50. Found: C, 51.26; H, 4 76; N, 10.35.  
 EXAMPLE 38 [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid, sodium salt, hemihydrate Anal. Calcd for C, H, N;,O ClSNa.l/2H O:  
  C, 47.39; H, 3.98; N, 11.84. Found: C, 47.64; H, 3.79; N, 11.52.  
 What is claimed is:  
  1. A process for treating hyperlipemia in a warmblooded animal which comprises administering to said animal, orally or parenterally, an effective amount of a composition containing as the essential active ingredient at least one compound of the formula:  
 in which R, R R R and R are members independently selected from the group consisting of hydrogen and lower alkyl radicals;  
 R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl of 6 to 10 carbon atoms, haloaryl of 6 to 10 carbon atoms, halo, and trifluoromethyl radicals;  
 R is selected from the group consisting of hydrogen,  
 lower alkyl, halo and lower alkoxy radicals;  
 R and R when taken together, represent the dioxymethylene group;  
 Z is a member selected from the group consisting of -OH, OM, lower alkoxy, (Nl-l) NH in which p is an integer from 0 to l, inclusive and M is an alkali metal, alkaline earth metal or ammonium cation; and  
 n is an integer from 0 to 3, inclusive.  
  2. The process of claim 1 in which said essential active ingredient is a [4-chloro-6-arylamino-2- pyrimidinylthio]acetic acid, alkali metal salt, hydrazide and lower alkyl ester in which the aryl group contains from 7 to 12 carbon atoms, and the 6- parachlorophenylamino and -parachlorobenzylamino analogues thereof.  
  3. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(p-chlorobenzylamino)- 2-pyrimidinylthio1acetic acid, ethyl ester.  
  4. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(p-methoxyanilino)-2- pyrimidinylthio]acetic acid, ethyl ester.  
  5. The process of claim 1 in which said essential active ingredient is (4-chloro-6-(p-chloroanilino)-2- pyrimidinylthio)acetic acid, ethyl ester.  
  6. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio]acetic acid, ethyl ester.  
  7. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,4,6-trimethylanilino)- 2-pyrimidinylthio]acetic acid, ethyl ester.  
  8. The process of claim 1 in which said essential active ingredient is [4-(4-biphenylylamino)-6-chloro-2- pyrimidinylthio]acetic acid, ethyl ester.  
  9. The process of claim 1 in which said essential active ingredient is [4-chloro-6-( pchlorophenethylamino)-2-pyrimidinylthiolacetic acid, ethyl ester.  
  10. The process of claim 1 in which said essential active ingredient is (4-chloro-6-[ P&#39; chlorobenzyl)methylaminol-2-pyrimidinylthio)acetic acid, ethyl ester.  
 &#39; tive 11. The process of claim 1 in which said essential active ingredient is [4-chloro-6-( 3 ,4-  
 dichlorobenzylamino)-2-pyrimidinylthiolacetic ethyl ester.  
 acid,  
 tive ingredient is (4-anilino-6-chloro-Z-pyrimidinylthio)acetic acid, ethyl ester.  
  27. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(p-fluoroanilino)-2- 12. The process of claim 1 in which said essential ac- 5 py diny t l acid. ethyl ester ingredient is [4-(p-chlorobenzylamino-Z- pyrimidinylthio1acetic acid, ethyl ester.  
  13. The process of claim 1 in which said essential active ingredient is [4-(p-chlorobenzyl)methylamino-2- pyrimidinylthio1-acetic acid, ethyl ester.  
  14. The process of claim 1 in which said essential active ingredient is [4-chloro6-(p-fluorobenzylamino-2- pyrimidinylthio]acetic acid, ethyl ester.  
  15. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(p-chlorobenzylamino)- 5-methyl-2-pyrimidinylthiolacetic acid, ethyl ester.  
  16. The process of claim 1 in which said essential active ingredient is [4-chloro-6-( p-chloroamethylbenzylamino)-2-pyrimidinylthio]acetic acid.  
  17 The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,3-xylidino )-2- pyrimidinylthiolacetic acid.  
  18. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,4-dimethoxyanilino)- 2-pyrimidinylthio1acetic acid.  
  19. The process of claim 1 in which said essential active ingredient is [4-chloro 6-(p-chlorobenzylamino)- 2-pyrimidinylthio1acetic acid.  
  20. The process of claim 1 in which said essential active ingredient is 2-[4-chloro-6-(pchlorobenzylamino)-2-pyrimidinylthio]propionic acid.  
  21. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthio1acetic acid, sodium salt, hemihydrate.  
  22. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,3-xylidino)-2- pyrim-idinylthio]acetamide.  
  23. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,3-xylidino)-2- pyrimidinylthiolacetic acid hydrazide.  
  24. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(a,a,a-trifluoro-mtoluidino)-2-pyrimidinylthio]acetic acid, ethyl ester.  
  25. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(2,4- dimethylbenzylamino)-2-pyrimidinylthio]acetic acid, ethyl ester.  
 26. The process of claim 1 in which said essential ac- 28. The process of claim 1 in which said essential active ingredient is (4-chloro-6-[ 3 ,4- (methylenedioxy)benzylamino]-2-pyrimidinylthio)acetic acid, ethyl ester.  
  29. The process of claim 1 in which said essential active ingredient is (4-chloro-6-[pchlorobenzyl)methylamino]-5-methyl-2-pyrimidinylthio)acetic acid, ethyl ester.  
  30. The process of claim 1 in which said essential active ingredient is [4-chloro-6-(p-chlorobenzylamino 2-pyrimidinylthio1acetic acid, hydrazide.  
  31. A composition in dosage form for use in the treatment of hyperlipemia comprising as the essential active ingredient, at least one compound of the formula:  
  5 R 0 N ll in which R, R R R and R are members independently selected from the group consisting of hydrogen and lower alkyl radicals;  
  R is selected from the group consisting of hydrogen,  
 lower alkyl, halo and lower alkoxy radicals;  
 R and R when taken together, represent the dioxymethylene group;  
 Z is a member selected from the group consisting of -Ol-l, OM, lower alkoxy, (Nl-l),,-NH in which p is an integer from 0 to l, inclusive and M is an alkali metal, alkaline earth metal or ammonium cation; and  
  i is an integer from 0 to 3, inclusive, in an amount of from 0.05 to 25 milligrams per dose, and a pharmaceutical adjuvant.  
  32. The composition of claim 31 in which said essential active ingredient is [4-chloro-6(2,3-xylidino)-2- pyrimidinylthio1acetic acid, lower alkyl ester, hydrazide, alkali metal salt, alkaline earth metal salt or ammonium salt.