US3654275A - Quinoxalinecarboxamide antiinflammatory agents - Google Patents

Abstract

1,2,3,4-TETRAHYDRO - 1 - ACYL-3-OXO-2-QUINOXALINECARBOXAMIDES, A NOVEL CLASS OF HETERCYCLIC COMPOUNDS POSSESSING ANTINFLAMMATORY ACTIVITY.

Description

Patented Apr. 4, 1972 QUINOXALINECARBOXAMIDE ANTIINFLAMMA- TORY AGENTS James M. McManus, Old Lyme, Conn., assignor to Chas.

Pfizer & Co., Inc., New York, N.Y. No Drawing. Filed Oct. 15, 1969, Ser. No. 866,732

Int. Cl. C07d 51/78 US. Cl. 260-250 R 8 Claims ABSTRACT OF THE DISCLOSURE 1,2,3,4-tetrahydro 1 acyl-3-oXo-2-quinoxalinecarboxamides, a novel class of heterocyclic compounds possessing antiinflammatory activity.

BACKGROUND OF THE INVENTION The invention relates to 1,2,3,4-tetrahydro-1-acyl-3- oxo-2-quinoxalinecarboxamides, a novel class of heterocyclic compounds possessing chemotherapeutic activity.

Compounds of the present invention are synthesized via aminolysis of the corresponding 2-carboalkoxyquinoxalines.

SUMMARY OF THE INVENTION The novel antiinflammatory compounds of this invention are quinoxalinecarboxarnides; in particular, they are 1,2,3,4 tetrahydro 7 l acyl-3 oxo-2-quinoxalinecarboxamides of the formula:

and the basic metal salts thereof, \ivherein R and R are each selected from the group consisting of hydrogen, alkyl containing up to 3 carbon atoms, fluorine, chlorine, bro- 'mine, 'alkoxy' and alkylthio each of up to 2 carbon atoms and hydroXy; R and R 'areeach selected from the group 'consistin'gof hydrogen; alkyl containingup to 3 carbon atoms; allc'enyl containing up 04* carbon atoms; cyclo alkyl of from 3 to 6 carbon atoms';-and phenyl andsubstituted phenyl having asub'stitu'erit selected from the group'co'ns'isting of fluorine, chlorine,'bromine,"alkoxy containing up to 2 carbon atoms and alkyl containing up to Jigbo t ms; R is selected from the group consis of alkyl and alkenyl each ofup to 6 carbon atoms; cycloalkyiof from 3 to- 6 carbon atoms;-.pyridyl.,and substituted pyridyl with 1 or Zrnethyl Isubstituents;,-.thiazoly1; and phenyl, benzyl and monoand disubstituted phenyl and benzyl, said substituents being selected from the group consisting of fiuorine, chlorine, bromine, alkyl containing up to,3 carbon atoms, alkoxy an d alkylthio each having upto 2 carbon atoms,hydro xy,,amino, acylamino containing up to 3 .ca'rbon atoms, trifluoromethyl and tri- United States Patent Office Of particular interest are compounds wherein R and R are each hydrogen, R is methyl, R is either hydrogen or alkyl containing up to 3 carbon atoms and R is substituted phenyl with 0 to 2 substituents, said substituents being selected from the group consisting of fluorine, chlorine, bromine, alkyl containing up to 3 carbon atoms, alkoxy and alkylthio each having up to 2 carbon atoms, hydroxy, amino, acylamino containing up to 3 carbon atoms, trifluoromethyl and trifluoromethoxy.

DETAILED DESCRIPTION OF THE INVENTION The quinoxalinecar-boxamides of the instant invention are prepared by several alternate procedures. In the procedure illustrated in Scheme I an appropiately substituted o-phenylenediamine is reacted with a halomalonate ester to yield the quinoxaline ester, I.

preferable to use at least a molar equivalent amount of said reactants and tertiary amine. The reaction is carried out at ambient temperatures, although it may be heated from about 50-80" C. to hasten product formation. Reaction time is not critical, but conversion is usually complete within 2-5 hours, after which the product is isolated. A convenient means of isolation is to cool the reaction mixture, filter the product and remove any coprecipitated tertiary amine hydrogen halide through a water wash. Alternately, the reaction mixture is added to water, which causes the product to precipitate.

The requisite o-phenylenediamines and halomalonate esters are available commercially or may be synthesized by one skilled in the art. For example, C. H. Roeder et al,. J. Org. Chem., 6', 25 (1941), teaches the preparation of N-substituted-o-phenylenediamines and Palmer et al., Org. Syn. Coll., vol. I, 245 (1941), teaches the synthesis of a halomalonate.

Surprisingly, the condensation of the aforesaid o-phenylenediamines with halomalonate esters gives a product resulting from cyclization and an in situ oxidation of 1,2,3,4-tetrahydroquinoxaline to a 3,4-dihydroquinoxaline structure.

Products from the reaction of a o-phenylenediamine unsymmetrically substituted (R =H) in the aromatic moiety and a halomalonate ester give rise to two positional isomers, the separation of which is achieved using thick layer or column chromatography. Structural assignments to the separated isomers are readily carried out through the interpretation of their respective nuclear magnetic resonance spectra.

Reaction product from N-substituted-o-phenylenediamine (R H) and a halomalonate ester, regardless of the substitution in the aromatic portion of the structure, are, almost exclusively, those resulting from alkylation, followed by cyclization and oxidation, on the less hindered, primary amino group.

Reduction of the aforesaid 3,4-dihydroester, I, to II is carried out in a reaction-inert solvent such as ethanol or tetrahydrofuran, using hydrogen gas and a catalytic amount of platinum oxide. Pressures of from 2-50 psi. and temperatures of from 2550 C. may be employed. These pressure and temperature parameters are not critical, and influence only rate of product formation. The reaction product is best isolated by filtration of the spent catalyst, and concentration of the filtrate to dryness.

Acylation of the 1,2,3,4-tetrahydroquinoxaline ester, II, to provide III may be effected by adding an equimolar amount, plus as much as a 10% excess, of the corresponding acrylanhydride to II in a reaction-inert solvent such as tetrahydrofuran or benzene. Reflux temperatures are preferred, although lower temperatures may be used with correspondingly longer reaction times. Removal of the solvent in vacuo leads to the isolation of the crude product, which is further purified by recrystallization from appropriate solvents.

Aminolysis of III to the products of the instant invention, IV, is carried out by heating III with a primary amine, R NH in a suitable solvent such as benzene, toluene, mestitylene or tetraline for such periods of time as to allow for the formation of the desired product, in general 5-10 hours. In instances when R NH is a high boiling amine, the formation of the product, IV, is facilitated by co-distilling the alcohol formed in the reaction with the solvent. Fresh solvent is periodically added to maintain a relatively constant volume.- When R NH is low boiling the reaction is carried out using the. same solvents in a ..sealed bomb or autoclave. Temperatures used in these reactions may ,vary from 200 C. They are not critical, and reflect only on the rate of product formation. Aconvenient means of isolation for the reaction product is to scam I:

l NR 1 N 00 0 co n o c NH CO2 r 0 ix 2 R R2 1' 4 1 comm I RSNHZ 5 -uon comm v r u 1 I 5 v: (R3C0)20 INICONHR 1* l R The first step of Scheme II is a condensation and cyclization of an appropriately substituted o-phenylenediamine and an oxomalonate ester, the products of which are water, an alcohol and I. The reaction is most conveniently carried out by adding an equimolar amount of the oxomalonate to a solution or suspension of the suitable diamine in a reaction-inert solvent such as ethanol. It is preferred that the reaction be heated from about 50-100 C. for a period of 1-5 hours. The reaction product, which is identical in every respect to I prepared via Scheme I, is isolated as a precipitated solid after the reaction mixture is concentrated in volume and cooled.

As in Scheme I, positional isomers are formed. They are separated and identified by aforesaid procedures. Again, as in Scheme I, the condensation of N-substitutedo-phenylenediamines with an oxomalonate ester takes place preferentially on the unsubstituted --NH group.

Conversion of theester, I, to the carboxamide, V, is achieved by heating I with as much as a three fold excess of the aforesaid amine, R NH in a reaction-inert solvent such as dimethylformamide. When R NH is ,a low boiling amine, a sealed bomb or autoclave is employed as the reaction vessel. Aminolysis of I to V is carried out at temperatures of from IOU-200 C., with a preferred temperature of about C. The completion time for the reaction is not critical, longer reaction periods being required when lower temperatures are used. Isolation of ,1 the product, as a precipitate, is achieved by concentration of the reaction mixture in volume, preferably in vacuo,

and cooling. a

Transformation of the 3,4-dihydroquinoxalinecarboxamide, V, to the product of the instant invention, IV, is carried out without isolation of the 1,2,3,4tetrahydrotion-inert solvent such as'tetrahydrofuran, using hydrogen gas and a catalytic amount of platinum oxide. Pressures of from 2-50 p s.i. and temperatures of from 2550 C. are preferred. When the theoretical amount of hydrogen has been absorbed, the spent catalyst is filtered, and the filtrate containing VI is treated with at least an equimolar amount, and preferably a -20% excess, of an acylanhydride, "(-R CO) O-. It is preferred that the reaction be heated from between 50 C. to the reflux temperature. The product precipitates after the reaction mixture is concentrated in vacuo, and cooled.

The final products from Schemes I and II are identical in every respect.

-It is noted that a common characteristic of many antiinflammatory agents is that they contain an acidic hydrogen atom. Each of the 3-carboxamides of the instant invention shares this property and is an effective proton source, with the 'active hydrogen being located at the 3-position.

Pharmaceutically acceptable, basic metal salts of the compoundsof-the present invention are also therapeutic agents, whereinthe cations of said salts include the ammonium, sodium, potassium, calcium, and magnesium ions. The pharmaceutically acceptable salts of the compounds described herein-are prepared by conventional procedures, *as for ex ample, by adding the acid to an aqueous-solution containing an equivalent amount of a pharmaceuticallyacceptable base, i .e., a base containing one of the above cations, followed by concentration of the resultant mixtures to obtain the desired product. The bases may be selected from the hydroxides, oxides and carbonates. Pharmaceutically unacceptable, basic metal salts of the compounds of the present invention, wherein the cations of said salts include barium, strontium, cesium and rubidiumare also prepared by the aforementioned procedure. While said salts are not useful therapeutic agents per se, they are valuable in the purification of the compounds of the present invention and in the preparation of pharmaceutically acceptable salts.

As indicated hereinbefore, the 1,2,3,4-tetrahydro-1- acyl-3-oxo-2-quinoxalinecarboxamides and the pharmaceutically acceptable salts thereof are useful antiinflammatory agents. These compounds are of value in alleviating swelling and inflammation which are symptomatic of rheumatoid arthritis and related disorders which are responsive to treatment with 'antiinfiammatory agents. Either as individual therapeutic agents or as mixtures of therapeutic agents, they .may be administered alone, but are generally-administered with a pharmaceutical carrier selected on the basis of the chosenroute of administration and standard pharmaceutical practice. For example, they may be administeredorally in the form of tablets or capsules containing suchexcipients as starch, milk, sugar or certaintypes of clay, etc. They may be administered orallyin the formof elixirs or oral suspensions with the active ingredients combined with emulsifying and/or suspending agents. They may be injected parenterally, and for this use they, or appropriate derivatives, may be prepared in the form of sterile aqueous solutions. Such aqueoussolution's should be suitably buffered, if necessary, and vshoul d. contain other solutes such as saline or glucose to render them isotonic.

The dosage required to reduce inflammation or swelling in arthritic subjects would be determined by the nature and extent of the symptoms. Generally, small doses will be" administered initially, with a gradual-increase in the dosage until the optimum level is determined; It will generally be found that when the composition is administered orally,p large r quantities of the active ingredient will be required to produce the same level' as produced by a small quantity administered parenterally. In general, from about 0.10 to about 200 mg. of active ingredient per kilogram of body weight,"administered in single or multiple dose units, willefiectively reduce inflammation and swelling.

Particularly effective as antiinfiammatory agents are those carboxamides of Formula IV wherein R and R are hydrogen, R is methyl, R is either hydrogen or alkyl containing up to 3 carbon atoms and R is phenyl with up to 2 substituents selected from the group consisting of fluorine, chlorine, bromine, alkyl containing up to 3 carbon atoms, alkoxy and alkylthio each having up to 2 carbon atoms, hydroxy, amino, acylamino containing up to 3 carbon atoms, trifluoromethyl and trifluoromethoxy. Among these compounds, 1,2,3,4-tetrahydro- 1 acetyl-2',4-difluoro-3-oxo-2-quinoxalinecarboxanilide, 1,2,3,4-tetrahydro 1 acetyl-3-oxo-4-methyl-4'-bromo-2- quinoxalinecarboxanilide and 1,2,3,4 tetrahydro-l-acetyl- 3-oxo-4-ethyl-2-quinoxalinecarboxanilide are preferred.

A standard procedure for detecting and comparing antiinflammatory activity of compounds is the carrageenin rat foot edema test, whereby unanesthetized adult male albino rats of 150-190 g. body weight are each numbered, weighed and marked with ink on the right lateral malleolus. One hour after administration of the drug by gavage, edema is induced by injection of 0.05 ml. of 1% solution of carrageenin into the plantar tissue of the marked paws. Immediately thereafter, the volume of the injected paw is measured. The increase in volume three hours after the injection of carrageenin constitutes the individual response. Compounds are considered active if the difference in response between a control and the drug being tested is significant. Standard compounds are phenylbutazone at 33 mg./kg. and acetylsalicyclic acid at 100 mg./kg., both with oral administration.

The following examples are given to more fully illustrate the instant invention. They are not the only possible embodiments of the invention and are not to be considered as a limitation on the scope thereof. Roman numerals in Examples 1 and II refer to structures in Schemes -I and II, respectively.

EXAMPLE I 3,4-dihydro-3-0xo-2-quinoxalinecarboxylic acid, ethyl ester (1; R R R =-H) 1,2,3,4-tetrahydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (II; R R R =H) A suspension of 2.18 g. (0.01 mole) of I and 500 mg. of platinum oxide in 40 ml. of tetrahydrofuranis shaken in a hydrogen atmosphere at a pressure of 30 psi. for a period of two hours. The resulting reaction mixture is filtered, concentrated to dryness in vacuo, and the residue slurried in water. The solid is filtered, dried and recrystallized from benzene, M.P. 148-149 C.

Analysis.Calcd. for C H N 0 (percent): C, 59.99; H, 5.49; N, 12.72. Found (percent): C, 59.77; H, 5.43; N, 12.75.

1,2,3,4-tetrahydro-1-acetyl-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (III; R R R =H; R =CH To a solution of 14.4 g. (0.065 mole) of n in ml. of tetrahydrofuran is added 7.14g. (0.07 mole) ofacetic anhydride. The reaction mixture is heated to. reflux 40 hours followed by removal of the solvent in vacuo. The residue is recrystallized from ethyl acetate-ether, M.P. 172174 C.

Analysis.Calcd. for C H N Q, (percent): C, 59.53; H, 5.38; N, 10.68. Found (percent): C, 59.28; H, 5.29; N, 10.73.

1,2,3,4 tetrahydro-1-acetyl-2',5'-difiuoro-3-oxo-2-quinoxalinecarboxanilide (IV; R R R =H; R =CH3; 5= 2 e a) A mesityline (65 ml.) solution containing 2.62 g. (0.01 mole) of III and 1.42 g. (0.011 mole) of 2,5-difluoroaniline is heated to the boiling point. The mesitylene which distills off is gradually replaced by fresh solvent. When 110 ml. of mesitylene has been distilled the reaction mixture is cooled, and the solid which precipitates is filtered. The product is dried, and recrystallized from ethyl acetate, M.P. 2092l0 C.

Analysis.-Calcd. for C17H13F2N3O3 (percent): C, 59.13; H, 3.79; N, 12.17. Found (percent): C, 59.21; H, 3.94; N, 11.91.

EXAMPLE II 3,4-dihydro 3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (I; R R R =H) To a suspension of o-phenylenediamine in ethanol is added an equimolar amount of diethyl oxomalonate, and the resulting solution is heated at steam bath temperatures for 1-2 hours. The resulting solution is concentrated in vacuo and cooled. The desired product is filtered, dried and recrystallized from benzene. The product is identical to that synthesized by the procedures outlined in Example I.

To a suspension of I in dimethylformamide is added two molar equivalents of 2,5-difluoroaniline, and the mixture is heated to the reflux temperature for 6 hours. The reaction mixture is concentrated in vacuo, followed by cooling. The resulting product precipitates from solution, and is filtered. Further purification is carried out by recrystallization from ethanol-water.

1,2,3,4-tetrahydro 1-acetyl-2,5-difluoro-3-oxo-2-quinoxalinecarboxanilide (IV; R R R. =H; R =CH R5=2,5-F2C6H3) To a solution of V in tetrahydrofuran is added platinum oxide, and the resulting mixture shaken in a hydrogen atmosphere at an initial pressure of 50 p.s.i. for a period of 3 hours. The catalyst is filtered, and an equimolar amount of acetic anhydride is added to the filtrate. The resulting solution is heated to the reflux temperature for 1 hour, after which the reaction mixture is concentrated under reduced pressure. On cooling, the desired product precipitates from solution. Further purification is carried out by recrystallization from benzene. The product is identical to that synthesized by the conditions outlined in Example I.

EXAMPLE 1H 1,2,3,4-tetrahydro-1-acety1-4'-bromo-3-0xo-2- quinoxalinecarboxanilide A suspension of 2.62 g. (0.01 mole) of 1,2,3,4-tetrahydro-2-oxo-3-carbethoxy-4-acetylquinoxaline and 1.89 g. (0.011 mole) of 4-brornoaniline in 65 ml. of mesitylene is heated to the boiling point, and the mesitylene allowed to distill. After 23 ml. of the solvent is removed (2 hr.) a precipitate starts to form. The reaction mixture is cooled, and the solid is filtered, 3.35 g., M.P. 232243 8 C. The product is further purified by recrystallization from acetonitrile, M.P. 258259 C.

Analysis.--Calcd. for C H BrN O (percent): C, 52.59; H, 3.63; N, 10.82. Found (percent): C, 52.91; H, 3.59; N, 10.85.

EXAMPLE IV The procedure of Example I is repeated, using equivalent amounts of appropriately substituted substrates, to produce the following compounds:

1,2,3,4-tetrahydro-1-acetyl-3-oxo-4'-bromo-4- methyl-2-quinoxalinecarboxanilide A mixture of 1.89 g. (0.011 mole) of p-bromoaniline and 2.76 g. (0.01 mole) of 1,2,3,4-tetrahydro-1-acetyl- 3-oxo-4-methyl-2-quinoxalinecarboxylic acid, ethyl ester in ml. of mesitylene is heated to the boiling point, and the solvent is allowed to distill. Fresh solvent is continually added such that the volume of the reaction mixture remains constant. This process is continued until 250 ml. of solvent has been distilled. The reaction mixture is cooled, and the precipitated solid collected by filtration, dried and recrystallized from benzene.

EXAMPLE VI The procedure of Example V is repeated, using equivalent amounts of appropriately substituted substrates, to produce the following compounds: I

1,2,3,4-tetrahydro-1-propiony1-3-oxo-4-ethyl-6-methoxy- 2-quinoxalinecarboxanilide Q 1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-ethyl-7-methoxy-2- quinoxalinecarboxanilide 1,2,3,4-tetrahydro-1-isobutyryl-3-oXo-4-ethyl-8methoxy quinoxalinecarboxanilide t 1,2,3,4-tetrahydro-1-formyl-3-oxo-4-ethyl-5-methoxy 2-quinoxalinecarboxanilide 1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-ethyl-6-methoxy- 2-quinoxalinecarboxanilide 1,2,3,4-tetrahydro-1-acetyl-3-oxo-4-ethyl-8 methoxy- 2-quinoxalinecarboxanilide I v v EXAMPLE VII The following products are prepared by the procedure of Example VI, by substituting the appropriate starting materials:

0 1,2,3,4-tetrahydro-1-propionyl-3-oxo 4',7 dichloro-6-- methyl2-quinoxalinecarboxanilide r 1,2,3,4-tetrahydrol propionyl-3'-oxo 4' chloro-7- methyl-2-quinoxalinecarboxanilidev l H 1,2,3,4-tetrahydro-1-propionyl-3-oxo-4'-chloro-5-ethyl- 2-quinoxalinecarboxanilide 1,2,3, i-tetrahy dro-l=propionyl-3-oxo 4-chloro-G-ethyllent amounts of appropriately substituted substrates, to

2-quinoxalinecarboxanilide. Y produce the following compounds: l,2,3,4-tetra hyd:ro-1 propionyl-3-oxo-4'-chl0ro-8-methyl- 2 quinoxali necarboxanilide 1,2,3,4-tetrahydro-1-propionyl-3-oxo-4'-chloro-7-npropyl-2-quinoxalinecarboxanilide EXAMPLE VIII The procedure of Example VI is-repeated, using equivalent amounts of v approximately substituted starting mao H "1 d th r11 d 1's terla s, to pro uce e o owmg compoun s. C1 I R1 R2 R4 R5 G-methyl Hydrogen Methyl r. Ethyl. 7-methyl do. n-Hexyl. 2O fiethylm 7-methyl Cyclohexyl.

(i-n propy Hydrogen- Cyelopropyl. 5-methyl 7-methyl Methyl Methallyl. 8-methyl Hydrogen n-Propyl. 2,2dimethyl-3- butenyl.

6-Cl fgCH S-Cl CH3 8-Cl CH S-F (Z-2H5, 6 F z s EXAMPLE XI S-Br 5 n-C H- 1,2,3,4-tetrahydro-1-acetyl-3-oxo-quinoxaline-2-[N-(6- 5-OCH '1' n-C H- methyl-Z-pyridyl)]carboxamide 5-OCH .3, CH 5.00 11 A mixture of 1.19 g. (0.011 mole) of 2-amino-6-meth- H CH yl-pyridine and 2.62 g. (0.01 mole) of 1,2,3,4-tetrahydro- H t p 6 1 1 1-acetyl-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester in H i-C H 65 ml. of mesitylene is heated to the boiling point. Fifty H 11 milliliters of the solvent is allowed to slowly distill from A the reaction mixture and is replaced by 50 ml. of fresh I H EXAMPLE IX- solvent. This process is repeated until 265 ml. of mesityli f ene has been distilled. The resulting solution is cooled, P o P V i eqmva' and the solid which precipitates is filtered and dried, 2.0 lent amounts ofappropnately substituted substrates, to g My. 212.50 C. The purified product is obtained by recrystallization from ethanol, M.P. 230 C. dec.

Analysis.--Calcd. for C17H16N403 (percent): C, 62.95; H, 4.97; N, 17.28. Found (percent): C, 62.92; H, 5.02;

produce the following compounds;

g l p u I I N, 16.17.

. RB 1 v p 1 EXAMPLE XII The procedure of Example V is repeated, using equivalent amounts of the appropriately substituted substrates, to provide the following compounds:

., b 3 I I 0 R3 H 4-SOH: NE-R5 The procedure of Example H is repeated, usiugec uiva- EXAMPLE XIII The procedure of Example XII is repeated, using equivalent amounts of aniline in place of said heterocyclic amine, to produce the following compounds:

EXAMPLE XIV The procedure of Example I is repeated, using equivalent amounts of the appropriately substituted substrates, to produce the following compounds:

EXAMPLE XV Sodium salt of l,2,3,4-tetrahydro-l-propionyl- 3-oxo-2-quinoxalinecarboxanilide To a methanol solution of 1,2,3,4-tetrahydro-1-propionyl-3-oxo-2-quinoxalinecarboxanilide is slowly added one equivalent of sodium hydroxide dissolved in a minimum amount of the same solvent. The resulting turbid 7 solution is concentrated in vacuo, and the residue induced to solidifying by trituration with ether.

EXAMPLE XVI tivity and were found to be active at the indicated dose level:

What is claimed is 1. A compound selected from those of the formula:

and the basic metal salts thereof, wherein:

R and R are each selected from the group consisting of hydrogen, alkyl containing up to'3 carbon atoms, fluorine, chlorine, bromine, alkoxy and alkylthio each of up to 2 carbon atoms and hydroxy; I R and R are each selected from the group consisting of hydrogen; alkyl containing up to 3 carbon atoms; alkenyl containing up to 4 carbon atoms; cycloalkyl of from 3 to 6 carbon atoms; and phenyl and substituted phenyl having a substituent selected from the group consisting of fluorine chlorine, bromine, alkoxy containing up to 2 carbonatoms and alkyl containing up to 3 carbon atoms; R is selected from the group consisting of alkyl and alkenyl each of up to 6 carbon atoms; cycloalkyl of from 3 to 6 carbon atoms; pyridyl and substituted pyridyl with 1 or 2 methyl substituents; thiazolyl; and phenyl, benzyl, and monoand disubstituted phenyl and benzyl, said substitutents being selected from the group consisting of fluorine, chlorine, bromine, alkyl containing up to 3 carbon atoms, alkoxy and alkylthio each having upto 2 carbon atoms, hydroxy, amino, acylamino'containing up to 3 carbon atoms, trifluoromethyl and trifluoromethoxyl. 1 2. The compound of claim 1 wherein R and R are hydrogen, R is alkyl containing up to 4 carbon atoms and R is hydrogen. 7 7 a c 3. The compound of claim 1 wherein R and R are hydrogen R is methyl and R is alkyl containing up to 4 carbon atoms.

4. The compound of claim 1 wherein R is hydrogen, R is alkoxy of up to 2 carbon atoms, R is ethyl and R is phenyl.

13 5. The compound of claim 1 wherein R is alkyl containing up to 4 carbon atoms, R is ethyl, R is hydrogen and R is 4-chloropheny1.

6. The compound of claim 1 wherein R is 7-chloro,

R is methyl, R is alkyl containing up to 3 carbon atoms 5 and R is 4'-methoxyphenyl.

7. 1,2,3,4-tetrahydro-1-acetyl-2,4'-difluoro 3 oX0-2- quinoxalinecarboxanilide.

8. 1,2,3,4-tetrahydro-1-acetyl-4' bromo 3 oxo- 4- methyl-2-quinoxalinecarboxanilide.

14 References Cited UNITED STATES PATENTS 3,479,348 11/1969 Yamamoto et al. 260-250 R NICHOLAS S. RIZZO, Primary Examiner US. Cl. X.R. 424250