IL34719A - Aryl pyrazine carboxylic acids - Google Patents

Description

carbosylic acids 2 This invention in carboxylic acids and carboxylic acids and derivatives thereof having the general where and are ortho to each other and is para to either or and phenyl optionally containing one or which may be at any position on the or j X is or where is an alkali or alkaline earth and Y is or with the proviso that and Y cannot both be hydrogen when X is Despite all the research carried on in the development of drugs in the past two knowledge of remains largely criptive and there still has been little a great many new drugs have been Host of these have been steroids of the pregnane while are complex in There is a need in the market for equally effective compounds of simpler It has been found that the pyrazine xylic acids of this invention are effective 3 A preferred aspect of this invention relates to the compounds of formula I where is phenyl or X is dimeth methoxy or and Y is hydroge or with the proviso that and Y cannot both be hydrogen when X is A preferred aspect of this invention relates the compounds of formula I is X is and Y is The compounds of this invention have a useful degree of activity and are effective in the treatment of arthritic and disorders and in like conditions which are responsive to treatment with For these they may be administered or in the form of compositions containing conventional carriers and they may be administered in tablets or the optimum of on the particular compound being used and the type and severity of the condition being Although the optimum quantities of the compounds of this invention to be used in such manner will depend on the compound employed and the type disease condition oral dose levels of preferred compounds in the range of per day in the range of per are useful in control of specific compoimd and the sensitivity of the Comparative dosages may be used in or rectal The compounds of the present invention have further been found to show an and activity and if used of the a the same dosage ranges and conditions as discussed above for activity will Thus the invention also consists in ceutical compositions containing as active ingredient a of formula I arylpyrazine acids of this invention can be prepared by the acid Condensation of with aryl glyoxals results in Hydrolysis of the amide in base followed by diazotization of the group the desired acids A further method of preparation involves condensation of 2 4 with a to form a Upon at elevated tures in a basic the desired acid is formed where X is halo When 5 is condensed with 2 in the same manner as the corresponding are Heating at raised temperatures in the presence of base results in acids which are then diazotized to the pyrazinecarboxylic acids W The acids can be converted to the corresponding esters and amides by conventional The group can also be converted to the desired derivative by conventional acid The preparation of carboxylic acids involves condensation of aryl glyoxals with aminomalondiamide carboxamides are which are then hydrolyzed to the corresponding The acids can be converted to the corresponding esters and amides by conventional The group can also be converted to the desired derivative by conventional The starting materials of this invention are The following are detailed examples which show the preparation of the various compounds described in this They are to be construed as illustrations of said compounds and not as limitations Example I carboxylic acid Example To a solution of aminomaIonamidamidine dihydrochloride in water is added a solution of by the procedure outlined in and in water The resulting solution is kept at by means of an while ammonium hydroxide is with until the pH reaches Additional ammonium hydroxide is added as required to maintain pH during the next 30 The mixture is then stirred overnight at room The precipitate of is collected by and purified by recrystallization from When in the preceding example is replaced by any of the aryl glyoxals of Table I the corresponding pyrazinecarboxamide of Table II below is Table I 9 II butylthio Example A suspension in 1 I is heated reflux for resulting clear solution is adjusted to 3 with centrated hydrochloric acid as a The solid collected by and from aqueous When the of replace in the above the corresponding acids are 10 Example A solution of acid in cold sulfuric acid is treated with a solution of sodium nitrite in cold concentrated sulfuric acid the resulting tion is held at for 4 at room temperature for 4 and then poured onto is stirred overnight at room temperature and The collected is driedand then purified by on from aqueous When the acids of Example are used in place of ic acid in the above the ponding acids of fable below are III acid acid acid acid acid aoid Example A solution of dihydrochloride in aqueous ethanol is treated with sodium acetate and 2 The mixture is heated under reflux for separates as a crystalline solid on It is purified by dissolution in warm 2 N sodium and acidification of the filtrate to pH When the following substituted 2 phenones of Table IV below are used in the above example in place of 2 the corresponding of Table V below are Table IV 2 2 5 acetophenone 2 2 2 5 2 acetophenone t butylaootophonone 12 4 4 5 may be replaced in the above example by with the substituted 2 of Table IV gives the corresponding Example acid is heated in an autoclave with 4 N sodium hydroxide at for 24 The solution is diluted with water heated to and acidified to pH The precipitated acid is collected by filtration and recrystallized from aqueous When the or of Example are used in place of in the above the corresponding pyrazinecarboxylic acids or pyrazinecarboxylic are The latter may be converted to the corresponding acids by the method of Example The products obtained are listed in Table VI Table VI acid acid acid 4 acid 5 aoid 14 acid acid acid acid acid lic acid acid acid acid Example II acid Example in water is treated with aqueous sodium 50 mixture is stirred for 45 minutes at room in is and the mixture is warmed for hours on the steam crystalline cipitate of and is collected by washed with water and and compound is purified by on from 1 When the aryl glyoxals of Example 2 are used in place of in the 3 preceding the corresponding 4 pyrazinecarboxamides are 5 Example 6 acid 7 8 amide hydroxide 9 and ethanol are heated in a steel 0 bomb at for 16 After water 1 is and the ethanol removed by 2 evaporation in The alkaline aqueous reaction 3 mixture is then heated to filtered hot by 4 and the filtrate acidified to pH 4 with 5 concentrated hydrochloric The precipitate of 6 acid 7 is collected after and recrystallized from 8 9 When the 0 amides of Example are used in place of 1 in the above 2 the corresponding 3 carboxylic acids of Table VII below are 4 Table VII 5 acid 6 acid 7 acid 8 acid 9 acid lphen 3 pyrazineearboxylic aoid Pre aration of When the pyrazine is refluxed with absolute methanol and sulfuric the methyl ester is prepared When the methanol is replaced by other appropriate alcohols such as 15 16 or the corresponding ester is A representative list of the esters 18 thus prepared is shown 19 20 Methyl 21 Methyl ate 25 Methyl 26 27 Methyl 28 30 Ethyl 16 Preparation of Derivatives acid sodium g in anhydrous methanol and methyl iodide are heated together under reflux for several Methanol is removed by evaporation and the residue is treated with rater The mixture is rendered alkaline with sodium hydroxide to ensure dissolution of unaltered starting and then is extracted with ether x 25 The combined ethereal extracts are dried over anhydrous magnesium and evaporated in to give phen The ester is hydrolyzed with alcoholic potassium hydroxide to give pyrazinecarbox lic The procedure outlined in the preceding example may be applied to the preparation of other alkoxy carboxylic acids by substituting the appropriate hydroxy carboxylic acid for and the appropriate alkyl halide for methyl 1acid Ethyl carboxylate acid is treated with phosphorus oxychloride So the finely pulverized phosphorus pentachloride is added in small Once the evolution of hydrogen chloride has the mixture is warmed on the for 1 Excess phosphorus oxychloride is removed by tion in and the residual syrup is poured onto cracked ice 50 The mixture is extracted with chloroform 50 the combined extracts washed with dried over anhydrous sodium and evaporated to give ethyl Ethyl carboxylate To a solution of sodium g in absolute is added ethyl carboxylate 1 The solution is refluxed for 2 After neutralization by passing dry gas and 3 the resultant solution is evaporated 4 to dryness under reduced The residue is taken 5 up in water and extracted with The ethereal 6 layer is washed with dried over and 7 Recrystallization of the residue from aqueous acetone gives ethyl 10 11 carboxylic acid 12 The ethoxy ester is hydrolyzed with 13 alcoholic potassium hydroxide to give I pyrazine carboxylic The procedure outlined in the preceding 17 example may be to the preparation of other 18 alkoxy carboxylic acids by substituting the appropriate 19 hydroxy carboxylic acid representative 20 list of the products is 21 aoid 22 23 acid 24 acid 25 acid 3 acid aoid aoid 29 acid 30 acid 31 acid 32 aoid 20 of Derivatives acid is treated with acetic anhydride a catalytic amount of concentrated sulfuric acid The is the s with frequent for 30 and then is taken to dryness in vacuo to give When carboxylic acid is replaced in the example by any of the carboaylic acids of this the responding is A sentative list o these produces is shown acid acid 21 acid aci acid acid When acetic is replaced in the example by propionic butyric valeric benzoic hydride or phenylacetic the corresponding acid is of Amides pyrazine is for 1 hoar methanol concentrated hydroxide Methanol is added hot solutio which is then treated with and chilled is collected by and ized from aqueous When pyrazlne of the above procedure is replaced by any of the esters of this the corresponding carboxamide is carboxylic acid is added gradually to a refluxing solution of thionyl chloride in benzene When the addition is refluxing is continued for 30 The mixture is allowed to and to it is added a solution of diethylamine in benzene The mixture is stirred warmed briefly on the and carboxamide is and purified by recrystallization from aqueous When acid of the above procedure is replaced by any of the carboxylic acids of this the corresponding is When the diethylamine of the above example is replaced by other appropriate primary or secondary 23 amines as dipropylamin the corresponding amide 1B A representative list of amides prepared is shown Preparation of gaits pyra To a solution of of sodium hydroxide in 15 of water is mole of lic acid in 10 of f e mixture is stirred and heated for hours and orated in vacuo to obtain sodium hydroxy When one equivalen potassium lithium sodium carbonate or hydroxide are in plaee of eodium hydroxide the corresponding salt is When the carboxylic acid of the above procedure replaced by any of the carboxylic acid compounds of this corresponding salt is When two equivalents of the above bases are used in the above the corresponding salt is The following representative examples trate the interconversion or introduction of functional groups which can be accomplished at various stages of the preparation of the final Methyl late A mixture of methyl water and concentrated sulfuric acid is cooled to and a solution of sodium nitrite in a minimum of water is added When the presence of free nitrous acid is detected the addition is stopped and the diazotization mixture is allowed to warm to room then heated on a until there is no more nitrogen The mixture is extracted well with the combined chloroform layer concentrated to a methanol added plus trated sulfuric the mixture heated gently for several the mixture concentrated in vacuo to remove most of the the residue partitioned between sodium bicarbonate the chloroform layer filtered and concentrated to a Chromatography of the residue on a silica gel column using an ether system as eluant yields methyl 25 A mixture of in dloxane 200 reacted hydrogen at room temperature in the presence of She mixture is the cake washed well with the filtrate evaporated in the residue chromatographed on a silica gel column using a methylene chloride system as eluant to yield methyl By the same procedure the compounds listed in the various tables or mere nitro in the phenyl ring are converted into the corresponding phenyl Methyl thiopheny e A mixture of methyl pyrasineearboxylate in a solution with at room temperature ove one the mixture extracted well with the dried ethe extracts chromatographed on a silica gel an ether system eluant yielding methyl carbox 26 lic an of in is added a solution sodium in a of and the mixture is stirred a until precipitation of sodium is is removed b the vents removed in and the taken up in form and combined organic extracts are filtered and Purification of the acid effected via recrystalliza or chromatography of its insufficientOCRQuality

Claims (1)

1. CLAIMS Arylpyrazine of the formula where ortho to each other and para to either or and is phenyl optionally containing one or R which may at any position is alk or X is alkoxy earth metal or e is alkali or and is hydrogen or with the that and Y cannot be hydrogen when Compounds according to Claim being acid derivatives of the where and have the same meaning as in Claim Compounds according Claim being acid derivatives of the 28 X and the same g in Claim Compounds of formula Claim substantially as described herein with reference Pharmaceutical compositions which comprise as an ingredient a compound according to any of Claims 1 to A process for the preparation o compounds according to Claim of the formula where and Ar have the same meaning as in Claim which comprises condensing with an aryl the formed and the A process the preparation of compounds according to the formula given in Claim comprises condensing with a followed by heating at increased temperatures in a basic A process for the preparation of compounds of the formula given in Claim which comprises condensing with a heating the formed at an elevated temperature in a basic and A process for the preparation of compounds according to Claim of the formula where and Ar have the same meaning as in Claim which comprises condensing an aryl glyoxal with hollowed by process according to any one of Claims 9 to 11 2 being applied to the preparation of henyl A process according to Claim being applied to the preparation of carbox lic A process for preparing arylpyrazine compounds according to Claim which comprises reacting compound of formula 30 with a reactive inorganic acid followed by ment wit a of the formula where and Y are as defined in A process or preparing arylpyragine compounds according to which reacting a compound of the where and X are as defined in with an acid for the preparation of of formula I in Claim substantially as described herein with reference to the For the Applicants COM insufficientOCRQuality