IL21194A - Preparation of pyrazinoylguanidines and pyrazinamidoguanidines and novel 4h-pyrazino(2,3-d)(1,3)oxazine compounds - Google Patents

Description

invention relates to processes for the preparation of and to novel compounds which are intermediates in these The invention consists in processes for the preparation of and guanidines of the general formula in which R is lower lower lower or R is lower or dialicylamino or A is amino or the group 5 in which R is alkyl or phenyl and Bis a R or 2 in which is a straight or branched chain lower alkyl of 1 to 5 carbon particularly methyl but also ethyl through phenyl either stit or having one or more lower alkyl or lower alkoxy aralkyl especially the phenyl radical being unsubstituted or substituted with lower alkyl or lower is h dro en lower alk l of 1 to 5 carbon atoms either which the groups may be linked with the to which they are attached to form an azacycloalky especially phenyl either unsubstituted or substituted with lower alkyl or lower or is an aryl grou especially phenyl either unsubstituted or substituted with lower alkyl or lower an group having the structure wherein is lower alkyl especially especially the phenyl radicals being unsubstituted or substituted with lower alkyl or lower an or aralkylldeneamino is lower alkyl or substituted lower alkyl of 1 to 5 carbon n wherein an optionally or acid of the formula is reacted with a carboxylic acid anhydride of the formula to the corresponding of the formula 0 the latter is reacted with a guanidine or with an guanidine of the formulae or to produce corresponding guanidine or of the formulae or V if the group of the latter is converted by hydrolysis into the amino grou 4 In the above formulae R R and have the same meaning as in formula The invention also consists in the of II above which are intermediates for the preparation of the compounds of X These reactions chemically represented as Compound I Compound The designation in this specification and claims includes iodine and fluorine for ΐΰ The compounds V and VI possess diuretic and natriuretic properties useful in the treatment of other diseases known to be responelve to this The compounds II are useful intermediates in the preparation of compounds V and Examples illustrate typical procedures for the conversion of the novel compounds II into useful diuretic compounds V or The methods of this invention are particularly useful for preparing which have a substituent attached to the pyrazine as shown in compounds III and since these products are difficultly accessible by other These methods also useful if one desires to introduce an acyl substituent in the guanidine moiety an acyl group represented by in compounds V or The reaction of the aoil with carboxylic acid anhydride is preferably carried out at a temperature within the range of about and most conveniently at the reflux temperature of the reaction The reaction is usually complete in from one to four An excess of the organic acid anhydride is The amount varies from four to about ten moles anhydride per of the The product crystallizes from tho reaction e and can recovered by Typical of the anhydrides which can be used are acetic propionic butyric and acid anhydrides such as phenylacetic Compounds of where represents hydrogen are obtained by utilizing a of acid and acetic in the proportions of about by reacts with a guanidine or an to form the corresponding or the These products will be recognized as the coapounds of this invention having an acyl radical attached to the in the This reaction takes place in an anhydrous solvent in an inert atmosphere under basic Details of the actual reaction conditions for the preparation of these compounds are provided in Examples 13 through a typical the guanidine or salt the added to sodium prepared in situ by adding sodium to boiling The sodium salt which precipitates then is filtered The which is having a carbon group in can be prepared from the corresponding by heating on a steam bath with sodium hydroxide solution to form the sodium salt of the The salt is dissolved in hot water and acidified with hydrochloric acid to form the corresponding The preparation of the various esters and is described in Belgium Patent issued on April the disclosure of which is incorporated herein by The preparation of the pyra2inoic acids of formula I in which is an aralkylsulfonyl or a dialkylamino group has been described in Israel Patent Specification The invention is illustrated by way of Example only by the following Step Preparation of A solution of in 50 of acetic anhydride for 45 The solution then and the product which separatee is recrystallized from acetic anhydride to obtain of Analysis calculated EXAMPLE 3 A mixture of acid from 2 and 100 of acetic anhydride is and heated at reflux for one mixture is cooled to and the solid collected to obtain 37 of Analysis calculated for 4 A solution of acid in acetic anhydride is heated 2 hours on the eteam and then The product Analysis calculated for EXAMPLE 5 A solution of acid in acetic anhydride heated 5 hours on the steam cooled and the precipitated from acetone to obtain of Analysis calculated for EXAMPLE 6 A solution of acid in acetic anhydride is heated 5 hours on the steam Volatile materials are distilled in vacuo and the residue is reerystallized from benzene to give of Analysis calculated for EXAMPLE 7 EXAMPLE Preparation of acid A mixture of lp and sodium hydroxide solution is stirred and heated on a steam bath for 30 aainutes whereupon a clear solution is The solution is chilled and the odium salt of 3 acid which precipitates is on a salt then is dissolved in boiling water and the solution is filtered and acidified with conoentrated hydrochloric The mixture is and the precipitated product is washed with insufficientOCRQuality

Claims (1)

1. HAVING HOW particularly described and ascertained the nature of our said invention and in what the same is to be we declare that what we claim A process for the preparation of guanidines and of the general formula in which is lower lower lower or is lower or 5 dialkylamino or A is amino or the group in which alkyl or phenyl and B is a group 2 in which is a straight or branched chain lower alkyl of 1 to 5 carbon particularly methyl but also ethyl through aryl especially phenyl either uted or having one or more lower alkyl or lower alkoxy aralkyl especially phenyl radical being unsubstituted or substituted with lower alkyl or lower 3 is lower alkyl of 1 to 5 carbon atoms either unsub in which the groups may be linked with the to which they are attached to form an azacycloalkyl especially phenyl either uneubatituted or substituted with lower alkyl lower alkoxyj or is an aryl group especially phenyl either unsubstituted or substituted with lower alkyl or lower an group having the structure wherein is lower alkyl especially especially the phenyl radicals being unsubstituted or substituted with lower alkyl or lower an alkylidenamino or is lower alkyl or substituted lower alkyl of 1 to 5 carbon atoms M ii i I i T wherein an optionally or acid of the formula ie reacted with a carboxylic acid anhydride of the formula of the formula 0 the latter is reacted with a guaaldiae or with an aminoguanidine of the to produce the corresponding guanldine or of the formulae or if the group of the latter is converted by hydrolysis into the amino in which formulae R and have the same meaning as in formula A process according to Claim wherein the oarboxylic acid anhydride is acetic A process according to Claim 1 or wherein the reaction between the acid of formula I in Claim 1 and the acid anhydride carried out at a temperature of about 70 to A process according to any of Claims 1 to wherein acid is reacted with acetic anhydride to produce and the latter is converted to the corre ndin razino luanidne or uanidine A process according to any of Claims 1 to wherein acid in which R is a group or where Z is lower alkyl or alkyl is reacted with acetic anhydride to produce one and the latter is converted to the corresponding pyrazinoylguanidine of of formula X in Claim A process according to any of Claime 1 to wherein acid is reacted with acetic anhydride to produce and the latter is converted to the corresponding pyrazinoylguanidine of of formula in Claim Processes for the preparation of guanidine and pyrazinamidoguanidines of the general formula X in Claim substantially as described herein with to Examples 13 to and pyrazinamidoguanidines of the general formula X in Claim when prepared by the processes according to any of Claims 1 to of the formula wwhheerreeiinn RR iiss lloowweerr lloowweerr lloowweerr lloowweerr acetamino and is or lower 1 of the formula II in Claim substantially as described herein with reference to Examples 1 to Dated this 19th day of April For the Applicants insufficientOCRQuality