Patented Dec. 4, 1951 2,577,231 UNITED STATES PATENT OFFICE 2,577,231 DIAZINE suLFONAMIDES AND METHODs oF PRE PARING THE SAME James W. Clapp, Darien, and Richard O. Robin, Jr., Riverside, Conn., assignors to American Cyanamid Company, New York, N. Y., a corpo ration of Maine No Drawing. Application April 17, 1950, Serial No. 156,484 i4 Claims. (C. 260-250) 2 This invention relates to the preparation of One or more of the following substituents; an new Organic compounds. More particularly, it alkyl group, a halogen radical and the like. relates to diazine sulfonamides and their prep The compounds are, in general, white crystal aration. . line solids having definite melting points and are It is generally recognized that numerous func is reasonably Soluble in Water. tions and actions of the human body are largely The compounds of the present invention are Controlled by a wide variety of enzymes. One of prepared by dissolving a mercaptodiazine in an these numerous enzymes is called carbonic anhy aqueous acid Solution and paSSing chlorine gas drase because it is involved in the netabolism of into Said solution to produce the corresponding carbon dioxide. This enzyme has other func Sulfonyl chloride. This product is then treated tions too, since it can catalyze the conversion With an exceSS of annonia in the form of liquid of carbon dioxide to carbonic acid. The excretion ammonia, or amonium hydroxide to produce the of acid by the kidneys is thought to be due to unsubstituted Sulfonamides and with an alkyl this function of carbonic anhydrase. anine, alkarylamine, arylamine or heterocyclic The excretion of acid by the kidneys is one anine to produce compounds Substituted on the method by which the body normally conserves Sulfonamide group. salt. The maintenance of a constant ratio of salt The reaction time is not too critical but chlo to water in the body is of utmost importance for rine should be added at such a rate that the general health. In some cases, however, excess temperature does not raise excessively and until salt and Water accumulate in the tissues causing an excess is present in the reaction mixture. The a condition which is called edema. It is frequent temperature during the chlorination is preferably ly encountered in a SSociation with congestive maintained within the range of -10° C. to 25° C. heart failure. The excess Salt and water cause When reacting the sulfonyl chloride with am an uncomfortable swelling of the tissues and monia, or the amine a higher temperature may be place an added Strain on the heart. To combat used up to 60° C. or higher. Obviously, the tem this condition. So-called diuretic agents are some perature for the amination should not be higher times used to promote the excretion of the excess than the boiling point of the particular amine salt and water. These agents, for the most part, used. in the past, have been mercury derivatives. Since The amines which may be used in the process these compounds contain mercury, they are not of the present invention may be primary amines Without toxicity on continued use and must be Such as methylamine, ethylamine, propylamine, administered by injection. phenylamine, para-methylphenylamine, benzyl Shortly after sulfanilamide came into wide amine, 2-aminothiazole and the like. Secondary spread use, Mann and Keilin, Nature, 146, 164 amines such as diethylamine, dipropylamine, di (1940), found that it, but none of the other sulfa is butylamine and the like can also be used. drugs, specifically inhibit the enzyme carbonic The compounds of the present invention were anhydrase. Within the past year or two sul found to be effective carbonic anhydrase inhibi fanilamide was experimentally used in several tors and may prove valuable in the relief of cases of congestive heart failure. While the sul edema, associated with congestive heart failure. fanilamide helped to promote the excretion of 40 or in other conditions where inhibition of car excess salt and water, it was not sufficiently ac bonic anhydrase is useful. They are also ac tive to be safely administered in adequate doses. tive, against certain micro-organisms. We have found that diazine sulfonamides show The following examples illustrate the prepara much greater activity than Sulfanilanide in in tion of representative diazine sulfonamides from hibiting carbonic anhydrase. The new coin 45 the corresponding mercaptodiazines. All parts pounds of the present invention may be illus are by Weight unless otherwise indicated. trated by the following general formula: EXAMPLE 1. R / 2-pyrimidinestlfonamide Dz-SON 50 Three parts of 2-mercaptopyrimidine are dis , R Solved in 75 parts of N hydrochloric acid. The in which R and R' are hydrogen, alkyl, alkaryl, solution is stirred in a cooling bath while chlorine aryl or heterocyclic radicals and Dz is a diazine is introduced through a capillary tube until the radical such as pyrimidine, pyrazine and pyrid color of excess dissolved chlorine is pronounced. azine. . The diazine radical may have present 55 About thirty minutes is required. The tempera 2,577,281 3. 4. ture is held below 10° C. and preferably below 5° overnight. 100 parts of water are added, and the C. The precipitated solid is filtered and Washed mixture is stirred and acidified. The precipitated With a little ice-cold water. oil crystallizes on chilling and rubbing. It is The crude damp 2-pyrimidinesulfonyl chloride filtered, then resuspended in cold dilute acid, is added gradually to a large excess (about 350 stirred well, refiltered, and dried. It can be puri parts) of liquid ammonia. After about thirty fied by solution in ether, treatment with acti minutes, the excess ammonia, is allowed to eva wated charcoal, filtration, and removal of the porate and the residue is extracted with a Small Solvent. The pure compound is a White, Waxy, amount of diluate ammonium bydroxide. The crystalline solid, melting point 25.5-26 C. The extract is treated with activated charcoal, fil product is insoluble in water but soluble in most tered, and the filtrate made slightly acid, with organic solvents. chilling. If no precipitate forms, the Solution is EXAMPLE 6 concentrated. The product is filtered and dried. The product is recrystallized from a minimum 4,6-dimethyl-2-pyrimidinesulfon-p-toluide amount of water. The pure compound is a white 4,6-dimethyl-2-pyrimidinesulfonyl chloride is crystalline solid, melting point 180.5°-18 C., prepared and purified by the method previously With bubbling. described. Four parts of the Sulfonyl chloride EXAMPLE 2 are added gradually to 50 parts of p-toluidine in 5-chloro-2-pyrimidinesulfonamide 50 parts of dry pyridine, with stirring in a cool 2. ing bath. The Solid dissolves, and the mixture 5-chloro-2-mercaptopyrimidine is converted to is allowed to stand four hours. It is diluted. With the sulfonyl chloride by the method of Example water and acidified. A solid crystallizes On rub , Four parts of the mercapto compound is sus bing and chilling. It is filtered and washed pended in 100 parts of 1 N hydrochloric acid, and thoroughly with water. It is dissolved in dilute chlorine is introduced for about seventy-five min Sodium hydroxide, and the Solution is filtered lutes. The crude damp sulfonyl chloride is con and acidified. The precipitate is filtered and re verted to the sulfonamide with liquid ammonia. crystalized from a large Volume Of carbon-tetra by the method described above. The product is chloride. The pure compound is a White Crystal recrystallized from water. The pure compound line solid, melting point 180.5°-18°C. is a white crystalline solid, melting point about 3) 135°-40° C. EXAMPLE 7 EXAMPLE 3 4,6-dimethyl-2-pyrimidinesulfonbenaylamide 4,6-dimethyl-2-pyrimidinesulfonamide 4,6-dimethyl-2-pyrimidinesulfonyl chloride is 4,6-dimethyl - 2 - mercaptopyrimidine is con prepared as described in Example 1. Five parts verted to the sulfonyl chloride by the method of of Crude damp Sulfonyl chloride are added grad Example 1. 2.5 parts of the mercapto compound ually to 50 parts of benzylamine. The mixture are used, dissolved in 25 parts of 1 N hydrochloric was stirred for some time, then diluted with Water acid, and chlorine is passed in for about thirty and acidified. The precipitated solid is filtered minutes. The product can be purified by dis 40 and washed, then redissolved in dilute sodium solving in ether, drying the solution and remov hydroxide, and filtered. The filtrate is acidified ing the solvent in vacuo. The pure compound is and the product is filtered and recrystallized from a white crystalline solid, melting point 41-42 water. The pure compound is a white crystalline C. The crude damp Sulfonyl chloride is con solid, melting point 130.5-131 C. verted to the Sulfonanide in liquid annonia by EXAMPLE 8 the method desscribed above. It is recrystallized from water. The pure product is a White crystal N-(2-thidaolyl)-4,6-dimethyl-2-pyrimidines line solid, melting point 200-200.5 C., with bub Sulfonamide bling. Yield, 46% theory, based on mercapto 4,6-dimethyl-2-pyrimidinesulfonyl chloride is compound. prepared and purified as previously described. EXAMPLE 4 50 Four parts of the sulfonyl chloride are added gradually to a mixture of 40 parts of 2-amino 4,6-dimethyl-2-pyrimidinesulfon-n-progylamide thiazole and 50 parts of dry pyridine, with stirring 4,6-dimethyl-2-pyrimidinesulfonyl chloride is in a cooling bath. Continued stirring slowly gives prepared and purified as described in Example 3. complete solution. The pyridine is removed in Four parts of the Sulfonyl chloride are added 55 vacuo and the residue is diluted. With Water and gradually to 50 parts of dry n-propylamine with acidified. A brown solid slowly precipitates. On Stirring in a cooling bath. The mixture Was chilling, and is filtered and washed, then redis stirred an additional brief period, and the excess solved in dilute sodium hydroxide. The solution anine allowed to evaporate. The residue is is treated with activated charcoal, filtered, and stirred with water and acidified. The solid is 6 acidified. The product is filtered, washed, and filtered, redissolved in dilute Sodium hydroxide dried, then recrystallized from ethanol. The pure and reprecipitated by acidification. The product compound is a nearly white, crystalline solid, is filtered and recrystallized from carbon tetra melting point 161-163. C., with decomposition. chloride. The pure compound is a white crystal line solid, melting point 111-111.5° C. 65 EXAMPLE 9 EXAMPLE 5 2-pyrazinesulfonamide 2-mercaptopyrazine is converted to the Sulfonyl ,6-dimethyl-2-pyrimidinesulfondi-n-butylamide chloride by the method of Example 1. Two parts 4,6-dimethyl-2-pyrimidinesulfonyl chloride is 0. of the mercapto compound are used, dissolved in prepared and purified as described in Example 1. 50 parts of N hydrochloric acid, and chloride Four parts of the sulfonyl chloride are added is introduced for about fifty-five minutes. The gradually to 50 parts of di-n-butylamine with crude oily sulfonyl chloride is converted to the stirring in a cooling bath. The mixture was sulfonamide by the method above, with the use stirred about two hours and allowed to stand 5 of liquid ammonia. The product is recrystal 2,577,281 5 6 lized from ethyl acetate. The pure compound is said 4,6-dimethyl-2-pyrimidineSulfon-n-propyl a white crystalline solid, melting point 166° amide therefron. 66.5° C. 12. A method of preparing 2-pyrazineSulfon We clain: amide which comprises dissolving 2-mercapto 1. Compounds of the group consisting of those pyrazine in aqueous hydrochloric acid Solution, having the general formula: passing chlorine into said Solution, mixing the reaction product thus obtained With liquid am monia, and recovering Said 2-pyrazineSulfonamide in which Dz, is a pyrimidine radical. therefrom. 2. 2-pyrimidinesulfonamide. IO 13. Compounds of the group consisting of those 3. 4,6-dimethyl-2-pyrimidinesulfonamide. having the general formula: 4. 4,6-dimethyl - 2 - pyrimidineSulfonbenzyl R amide. 5. 4,6 - dimethyl-2-pyrimidinesulfon-n-propyl DZ-S o,NY amide. R 6. 2-pyrazineSulfonamide. in Which R and R' are members of the group con 7. A method of preparing conpounds having sisting of hydrogen, lower alkyl, monocyclic aryl, the general formula: monocyclic lower aralkyl and thiazolyl radicals and DZ is a monocyclic aromatic diazine having 20 in which DZ is a pyrimidine radical which con tWO nitrogen and four carbon atom radicals, con prises dissolving a mercaptopyrimidine in an sisting of those having nitrogens in the 1,3-posi aqueous acid solution, passing chlorine into said tions and those having nitrogen in the 1,4-posi Solution, mixing the resulting product with a tions. member of the group consisting of liquid annonia, 14. A method of preparing compounds having and annonium hydroxide and recovering the 25 the general formula: pyrimidinesulfonamide therefrom. R 8. A method of preparing 2-pyrimidinesulfon amide Which comprises dissolving 2-mercaptO Yp pyrimidine in aqueous hydrochloric acid solution, passing chlorine into said Solution, mixing the 30 in which R and R' are members of the group con resulting product With liquid annonia and re sisting of hydrogen, lower alkyl, monocyclic aryl, covering said 2-pyrimidine-Sulfonanide there monocyclic lower aralkyl and thiazolyl radicals from and DZ, is a monocyclic aromatic diazine having 9. A method of preparing 4,6-dimethyl-2-py two nitrogen and four carbon atom radicals, rinidineSulfonamide which comprises dissolving 35 consisting of those having nitrogens in the 1,3- 4,6-dinnethyl-2-mercaptopyrinidine in an aqueous positions and those having nitrogens in the 1,4- hydrochloric acid solution, passing chlorine into positions which comprises reacting said diazine said Solution, mixing the resulting product with having a mercapto group with chlorine in the liquid amonnia, and recovering said 4,6-dimeth presence of an aqueous acid Solution and subse yl-2-pyrimidinesulfonamide therefrom. 40 quently with a member of the group consisting of 10. A method of preparing 4,6-dimethyl-2-py annonia, a lower alkylamine, a nonocyclic aryl rimidinesulfonbenzylamide which comprises dis amine, a monocyclic lower aralkylamine and a Solving 4,6-dimethyl-2-mercaptopyrimidine in thiazolylamine. aqueous hydrochloric acid Solution, passing chlo AMIES. W. CAPP. rine into said Solution, treating the reaction prod 45 RICHARD O. ROBLIN, JR. luct thus obtained With benzylamine and recov ering Said 4,6-dimethyl-2-pyrimidineSulfonben REFERENCES CATE Zylamide therefrom. The following references are of record in the 11. A method of preparing 4,6-dimethyl-2-py file of this patent: rinidinesulfon-n-propylamide which comprises 50 Johnson et al.: Chen. Rev., 13, 198-199 (1933). dissolving 4,6-dimethyl-2-mercaptopyrimidine in Northey: The Sulfonamides and Allied Com aqueous hydrochloric acid solution, passing chlo pounds, Monograph Series, No. 106, page 484, rine into said Solution, mixing the resulting reac Eld Publishing Corp., New York, N. Y. tion product With n-propylamine and recovering (1948).