IL32647A - Alkoxyalkanoyl-sulfonamides and their preparation - Google Patents

Description

32647/2 en a an i Q » TOR. IS1? ΙΘ-¾ n JKP^KOSI! Alkoxyalkanoyl-sulfonamides and their preparation SPARAMEDICA AG-, C. 30779 This invention relates to substituted sulfanilamides, in particular to N^-(alkoxyalkanoyl) sulfanilamides and to processes for their preparation. The invention also relates to compositions containing said substituted sulfanilamides. This invention relates further to blocked intermediates useful in the production of said substituted sulfanilamides.

This invention accordingly relates to antibacterial substituted sulfanilamides of the general formula wherein R is group, R"1 is hydroge or lowe: alkyl, and A is one of the following- radicals Ila lib S26 7-' lie 2 in which R is lower alk l or lower alkoxy; and p is 0, 1 or 2.

The novel compounds form salts with pharmaceutically acceptabl bases, for example, with alkali metal bases, such as sodium hydroxide and potassium hydroxide.

As used herein, the term "lower alkyl" denotes a hydrocarbon group containing 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl and the like; methyl and ethyl are preferred. The term "alkoxy" denotes an alkyl ether group containing 1-18 carbon atoms, preferably 1-8 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentoxy, octyloxy, decyl-oxy, dodecyloxy, hexadecyloxy, octadecyloxy and the like, preferably methoxy and ethoxy. The term "lower alkoxy" denotes a lower alkyl ether group in which the lower alkyl moiety is as described above, such as methoxy, ethoxy, propoxy, butoxy and the likej methoxy and ethoxy are preferred. The term "halogen" denotes all of the halogens, i.e., bromine, chlorine, fluorine and iodine. The term "alkylene" denotes a hydrocarbon containing 1-18 carbon atoms, preferably 1-8 carbon atoms, such as methylene, ethylene, propylene, trimethyl ne, tetramethylene, decamethylene, and the like. The term "alkanoyl" denotes an aliphatic acyl radical containing 2-9 carbon atoms. The term "alkanoic acid" denotes an aliphatic acid containing 2-9 carbon atoms. The term "ar" denotes aryl of 6-12 carbon atoms, such as phenyl.

Illustrative of the sulfanilamides of formula I of the invention are: -Ethoxyacetyl-N1- (2-pyrimidy1)sulfani1amide; N 1-(2,6-Dimethoxy- -pyrimidyl)-N4-ethoxyacetyl- suifanilamide; N^-Ethoxyacetyl-N1-( -methyl~2-pyrimidyl) sulfanilamide} N1-Ethoxyacotyl-N'L-(2,6-dimethoxy" *-pyrli)iildyl) 32647/2 N -(4,6-Dimethyl-2-pyrimidyI)-N -ethoxyacetyl -sulfanilamide} Ji -i N -Ethoxyacetyl-N - (5~rnethyl-l,3,4-thiadiazol-2-yl) - sulfanilamides 4 1 - \ N -Ethoxyace yl-N -(o-methoxy-J-pyridazlnylJ-sulfanil- amide; N^-Ethoxyacetyl~N1-(2-thlazolyl) sulfanilamide and N^-Ethoxyacetyl-N1-(2-quinoxalinyl) sulfanilamide. fhe invention further 'relates to a process for he preparation of compounds of formula IA, which proceeds via blocked intermediates of the general formula wherein r represents 0 or 1, and E represents a blocking group of the formula 3 wherein R is a tertiary butyl group or an ar-lower alkyl group such as a benzyl group, Illustrative of the sulfanilamides of formula IV ,' •above - are; N^-benzyloxycarbonyl-N1- (2,6-dimethoxy-4- . 4 1 pyrimidyl) sulfanilamide and N -benzyloxycarbonyl-N -ethoxy- acetyl-N1- (2,6-dlmethoxy~4-pyrimidyl) sulfanilamide. 32647/2 The process according to the invention may 'use as a starting material, for example, an unacylated sulfanilamide of the formula wherein A is as defined above.

Exemplary of such known compounds are: sulfaquinoxaline, sulfadiazine, sulfadimethoxine, sulfamerazirte, sulfamethazine, sulfamethizole, sulfamethoxy-pyridazine, sulfathlazole and sulforthomidine .

The sulfanilamides of the general formulas, given above accordingly prepared by a process which comprises acylating a sulfanilamide of the general formula or a salt thereof,, wherein A has the meaning given above and B' represents hydrogen ^ or a blocking group which can be · hydrogenoly sed or hydroly sed, by reacting said sulfanilamide pi .with a lower alkox alkanoic acid of the formula HOOCCHORH as an acylating agent, and subsequently, where B1 represents a blocking group removing said blocking group, whereby said compound of formula I or a salt thereof is obtained..

The (alkoxyalkanoyl) -derivatives of formula I, can thus for example, be obtained by reaction of an alkoxyalkanoic acid with a sulfanilamide of formula V. This reaction is conveniently effected under ambient conditions in the presence of Ν,Ν^-dicyelohexylcarbodiimide and an organic solvent such as pyridine.

As a further procedure for producing the compounds of this invention, an alkoxyalkanoic anhydride may be employed as the acylating agent. By this technique, fcfoe- ^-(alkoxyalkanoyl) -derivatives covered by formula TVare obtained by the reaction of an alkali metal, preferably sodium, salt of the sulfanilamide (V) with an alkoxyalkanoic acid anhydride,, The conditions employed for this reaction are not critical, although substantially anhydrous conditions are preferred. Although elevated temperatures can be employed, the reaction is normally effected at reduced temperatures, i.e., below room temperature (about 20-25°C), with temperatures in the range of from 0°C to about 15°C being preferred. In addition, this reaction is preferably effected in the presence of an organic base as a promoter. Suitable bases include, for example, bases such as pyridine, picoline, lutidine, quinollne, and trialkyl- amines (e.g., triethylamine) and alkali-metal or alkaline- tate. The reactants and organic base are generally employed in equimolar proportions, although this is not essential.

The reaction can be effected in the presence of an inert organic solvent, including ketones, such as acetone or methyl ethyl ketone; ethers such as dioxane or tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene or xylene; chlorinated hydrocarbons such as chloroform; and the like.

The use of such solvents is not necessary, however, when the organic base is liquid under the reaction conditions. , One can employ excess base as the reaction medium.

The N^-(alkoxyalkanoyl) sulfanilamides covered by formula ¾of this invention can be obtained as by-products of the above-described process. In addition, they can be formed by the isomerizatlon of fcfce- N1- (alkoxyalkanoyl) sulfanilamides. This isomerizatlon is readily effected at elevated temperatures, for example, from about 50°C to about 100°C or higher, in the presence of an organic base, e.g., pyridine and water. It is for this reason that, when N^-(alkoxyalkanoyl) sulfanilamides would ■a*»e-4w>-be produced in the manner described above, reduced temperatures and substantially anhydrous conditions aw would be preferred. In this connection, it should be noted that the 1 N - and N -monoalkoxyacylated isomers may be easily distinguished by their solubility in alkali, for the ^-derivative is 4 insoluble whereas the N -derivative is soluble in alkali. 4 A preferred technique for <&&oa i producing the N - (alkoxyalkanoyl) sulfanilamides covered by formula I of this 32647-2 with the free sulfanilamide. The conditions of this reaction are not narrowly critical, although temperatures in the range of from about 10°C to about 60°C are normally employed, with ambient temperatures being preferred. Although not essential, the reactants are normally employed in equimolar amounts. This reaotion Is preferably effected under substantially anhydrous conditions, and in the presence of an inert organic solvent, suoh as those mentioned above.

The in vivo antibacterial activities ,of sulfanilamides of this invention were determined in mice against the following organisms: 1. Escherichia coli 257 2. Klebsiella pneumoniae A 3. Proteus vulgaris 190 4. Pseudomonas aeruginosa B . Salmonella schottmuelleri 6. Salmonella typhosa P 58 a 7. Staphylococcus aureus Smith 8. Streptococcus pyogenes No. 4 For each organism , mice were infected by an intraperitoneal injection containing 100 to 1000 times the minimum lethal dose of the organism per mouse. Treatment groups of 6-10 infected mice each were then treated with the test drug, with different treatment groups having the same infection being treated with the same drug at different dosage levels.

All infected animals, including an untreated control group, were observed for a total of 14 days, and the number of survivors was noted. Cultures were made from the hearts of representative animals to ascertain the presence of the in- fecting organism. The CD^Q in m s as reported herein is based on a count of the animals that died or survived as calculated by the method of Reed and Muench, Am. Jour. Hygiene, 1, 493 (1938) .

Acute toxicity was determined by administering the drug under evaluation to 6 mice. A count of the animals that died as LD in mg/kg as calculated by the method of Reed and Muenc Am. Jour. Hygiene, 2£, 493 (1928).

The results of these tests on the sulfanilamide derivatives of this invention are summarized in Table I.

TABLE I Escherichia Klebsiella Prot Compound coli 257 pneumoniae A vulg N^-Ethoxyacetyl-N1-(2-pyrimidyl) sulfan¬ < 20 < ilamide 74 N1-(2,5-Dimethpxy- -pyrimidinyl ) -N^-ethoxy-acetylsulfanilamide 240 72 4 1 N -Ethoxyace yl-N - (4~methy1-2-pyrimidyl )- < 20 < sulfanilamide 78 N1 -Ethoxyacetyl N1 (2,6-dimothoxy *l pyrimidyl-)-sulfanllamlde - N1-(4,6-Dimethyl-2-pyrimidyl) -N^-ethoxy-acetylsulfanilamide 125 160 Ni-Ethoxyacetyl-N1-(5-methyl-l,3»4-thiadiazol- 2-yl) sulfanilamide >500 >500 5 4 1 N -Ethoxyacetyl-N - (6-methoxy-3^pyridazinyl ) — sulfanilamide 39 39 < N^-Ethoxyacetyl-N1- (2-thiazolyl)sulfanil- . amide 1°00 >10 ANTIBACTERIAL ACTIVITY CD, mg/kg p.o. 22: Samonella Staphylococ Compound typhosa P 58 a aureus Smit N -Ethoxyacetyl-N* - ( 2- 8 179 pyrimidyl )sulfanilamide N1- (2 , 6-Dimethoxy-4-pyrimidyl ) - 72 .500 N4-ethoxyacetylsulfanilaraide N4-Ethoxyacetyl-N*- (4-methyl- 2-pyrimidyl )sulfanilamide 15 121 N4 Ethoxyaoo yl-N^ y -dimethoxy- 4-pyrimidy 1 ) oulfctnilamido Ii- V Hj4 N4"- ( ,6-Dimethy 1-2-pyrimidyl )- N4-ethoxyacetylsulfanilamide 8 55 N4-E hoxyacetyl-N4- ( 5-methyl-l , 3, 4- fehiadiazol-2-yl) sulfanilamide 58 . 00 N4-Ethoxyacetyl-N-- (6-methoxy- 3-pyrldazinyl ) sulfanilamide 8 <20 N -Ethoxyaoetyl-N - { 2-thiazolyl)- sulfanilamide 664 >1, 000 As is readily. apparent, the compounds of Formula I of this invention exhibit substantial antibacterial activity, and are therefore useful as antibacterial agents.

The compounds of Formula I can be used as medicaments, for example, in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical organic or inorganic carrier material suited for enteral or parenteral application, such as, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, and the like. The pharmaceutical preparations can be in solid form, for example, tablets, dragees, suppositories, capsules, or in liquid form, for example, as solutions, parenteral solutions, suspensions or emulsions.

They may be sterilized and may contain additives, such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

The compounds of formula I can also be formulated into animal feedstuffs either directly or by first formulating an animal feedstuff premix in a conventional manner. I¾ the final animal feedstuff the amount of sulfanilamide is conveniently from 0.0025$ to 0.05$ by weight.

The following non-limiting examples further illustrate the invention. All parts are by weight and all temperatures are in degrees Centigrade, unless otherwise mentioned.

Example 1 N -Ethoxyacetyl-N - ( 2-pyrlmidyl ) sulfanilamide I9.O g of Ethoxyacetlc anhydride were added over a 5-minute period to a stirred suspension containing 25.0 g of 2-pyrimidyl) sulfanilamide (sulfadiazine) in 25.0 ml of O acetone The mixture was stirred and warmed at 50 for o hours. After cooling to room temperature, the product was filtered and washed with acetone. After triturating and shaking with 3N hydrochloric acid, filtering and washing with water, the product was crystallized from 75 percent aqueous ethanol to yield N4-ethoxyacetyl-N3-(2-pyrimidyl)sulfanilamide having a melting point of 221-222°.

Example 2 M1- (2,6-dimethoxy- -pyrimidyl ) -N -ethoxyacetylsul ani lamlde 19.0 g of Ethoxyacetic anhydride were added over a 10-minute period to a stirred mixture containing 31·0 g of N1-- (2 , 6-dimethoxy-4-pyrimidyl ) sulfanilamide ( sulfadimethoxine } and 300 ml of acetone. Stirring was continued until solution was complete. The reaction mixture was allowed to stand overnight. Thereafter, with stirring 600 ml of water were added. The product was allowed to crystallize over a period of 2 hours before it was filtered, and washed on the filter with dilute having a melting point of 189-I9I0.

Example 3 N -Ethoxyacetyl-!^1- (4-methyl-2-pyrimidyl ) sulfanilamide A mixture containing 26.4 g of N1- (4-methyl-2-pyrimidyl ) sulfanilamide ( sulfamerazine ) , 300 ml of acetone and I9.O g of ethoxyacetic anhydride was stirred and refluxed for 2 hours. The mixture was cooled in ice. The product was filtered and recrystallized from 75 percent ethanol to yield N -ethoxy-acetyl- i-(4-methyl-2-pyrimidyl) sulfanilamide having a melting point of 213- 15° .

Example 4 N -Benzyloxycarbony 1-N1- ( 2 , 6-dimethoxy-4- yrimidyl ) sulfanilamide 33.2 g of the sodium salt of N1- ( 2 , 6-dimethoxy-4- pyrimidyl ) sulfanilamide (sulfadimethoxine ) were dissolved in 100 ml of water and 50 ml of acetone were added. 24- 3 g of 77 · percent benzyl chloroformate in toluene were added drop- wise over a 30-minute period, while the pH was maintained at 7 to 8 by the addition of 10 percent aqueous sodium hydroxide as needed. The reaction mixture was cooled during the addition so as to maintain the temperature below 35°* and stirred for 2 hours. Excess ( 10 ml) 10 percent sodium hydroxide was then added to make the mixture ston l alkaline. After dilution acidified to H 5 by addition of 10 ml of acetic acid with stirring. The initially gummy precipitate which solidified on agitation was filtered and washed on the filter with water and then with ether to yield N -benzyloxycarbonyl-N1- (2 , 6-dimethoxy-^-pyrimidyl)sulfanilamide which upon recrystallizat-ion from ethanol had a melting point of 173-175° · Example N4-Benzyloxycarbonyl-Ni-ethoxyacetyl-N1- (2 , 6-dimethoxy-4- pyriinidyl)sulfanilamide g of ethoxyacetic anhydride were added over a -minute period to a solution containing 20 g of N4-benzyloxy-carbonyl-N*-( 2 , 6-dimethoxy- -pyrimidyl ) sulfanilamide in 40 ml of dry pyridine. The mixture was heated on a steam bath and n O maintained above oO for 10 minutes. After being cooled to room temperature, the mixture was poured into kO ml of ice-cold water with stirring. Thereafter, the supernatant liquid was removed by decantation and 100 ml of ethanol were added to the gummy precipitate. On trituration, a finely divided solid was obtained which was crystallized from aceto-^ nitrile to yield I^-benzyloxycarbonyl-N^-ethoxyacetyl-N1- ( 2 ,6-dimethoxy-4-pyrimidyl ) sulfanilamide having a melting point of 168-170° .

Example 6' ^ - (^ .S-Dlmethyl- -pyrlmldyD-^-ethoxyaGetylsulfanllamlde 19 g of ethoxyacetic anhydride were added to a stirred suspension containing 27 .8 g of N''- (4 , 6-dimethyl-2-pyrimidyl.)-sulfanilamide (sulfamethazine) in 300 ml of aoetone over a "5-roinute period. The mixture was stirred and re luxed for 2 hours, cooled to room temperature, and diluted with 900 ml of water to induce crystallization. The , mixture was filtered and twice recrystallized from two 100 ml portions of ethanol. to yield - ( ,6-dimethyl-2-pyrimidyl)-N4-ethoxyacetylsulfanil- amide having a melting point of 158-159°,, 7 Example $ N -Ethoxyacetyl-N - ( 5-methyl°l,3 ,4-thiadiazol-2-yl ) sulfanilamide . 19 g of ethoxyacetic anhydride were added to a mixture containing 27 g of Na-(5-methyl-l,3,4-thiadiazol-2-yl )sulfanil-amide ( sulfamethizole ) in 200 ml of acetone. The reaction mixture was stirred for 2 hours. Complete solution was obtained before the product began to crystallize. The mixture was cooled in ice and was filtered. The residue was recrystallized from 600 ml of acetonitrile to yield ^-ethoxyacetyl-N1- (5-methyl-lj3*^-thiadiazol-2-yl)sulfanilamide having a melting point of 200-201°. 8 Example $ N4-Ethoxyacetyl"NA-(6-methoxy-3-pyrldazlnyl) sulfanilamide 19 S of ethoxyacetic anhydride were added to a stirred suspension containing 28 g of Na-(6-methoxy-3-pyridazinyl) sulfanilamide (sulfamethoxy-pyridazine ) in 200 ml of acetone. The mixture was stirred for 3 hours and a clear solution was obtained. 400 ml of dry ether were added and the mixture was allowed to crystallize with stirring for an hour. and filtered. The residue was recrystallized from acetonitrile to yield 9 Example ίθ- N4-Ethoxyacety1-N1- (2-thlazoly1 ) sulfanilamlde I9.9 g of ethoxyacetic anhydride were added to a stirred suspension containing 2 .3 g of Na-(2-thiazolyl) sulfanilamide (sulfathiazole ) in 300 ml of acetone over a period of minutes. The mixture was stirred for three hours, filtered and washed with acetone. The residue was recrystallized from 1800 ml of acetonitrile to yield N -ethoxyacetyl-N4- (2-thia-zolyl) sulfanilamide having a melting point of 2l6-2l8°.

Example Ϊ N4-Ethoxyacetyl-N1-(2-quinoxallnyl) sulfanilamide A mixture containing 3 g of sulfaquinoxaline, 30 ml of acetone and 2.0 g of ethoxyacetic anhydride was refluxed with stirring for 3 hours. Thereafter, it was cooled to room temperature and filtered. The residue was recrystallized from acetonitrile to yield N4 -ethoxyacetyl-N1- (2-quinoxalinyl ) sulfanilamide having a melting point of 19 -197°.

The following Example shows how the antibacterial compounds of this invention may be formulated for administration; 11 Example 3t Capsule Formulation Per Capsule N4-Ethoxyacetyl-N1- ( 2-pyrlmidyl)sulfanilamide 0 mg Lactose 125 mg Corn Starch 30 mg Talc 5 m¾ Total Weight 210 mg B) Capsule Formulation Per Capsule 4 N" -Ethoxyacetyl-N1 - ( 2 , 6-dimethoxy-4-pyrimidyl)- sulfanilamide 50 mg Lactose 125 mg Corn Starch 30 mg Talc 5 m Total Weight 210 mg C) Tablet Formulation Per Tablet J^-Et oxyacetyl-N1- ( 2-pyrimidyl ) sulfanilamide ( 2 percent excess) 2 mg Dicalcium Phosphate Dihydrate 230 mg Corn Starch 70 mg FD and C Yellow No. - Aluminum Lake 25 percent 2 mg Fully hydrogenated domestic vegetable oil having 100 percent triglycerides 25 mg Calcium Stearate 3 mg D) 20 Percent Premix for Animal Use Prams/Kilo N -Ethoxyacetyl-N¾ - ( 2-pyrimidyl) sulfanilamide 125 g Corn Germ Meal 831 g Partially hydrogenated coconut oil comprising a mixture of mono-, di- and triglycerides 44 g Total Weight 1000 g E ) Parenteral Formulation Per ml N -Ethoxyacetyl-N1-- ( 2-pyrimidyl) sulfanilamide 1 .0 mg Disodium Edetate 0.1 mg Sodium Hydroxide ad pH 10 Water for Injection q.s. ad 1 .0 ml F) Veterinary Drinking Water Solution 5 percent w/v Per ml N4-Ethoxyacetyl-N1- ( 2-pyrimidyl) sulfanilamide 50 mg Sodium Edetate 0.1 mg Sodium Bisulfite 1 .0 mg Sodium Hydroxide q.s. ad pH 10 Distilled Water q.s. ad 1 ml

Claims (30)

32647/*

1. Substituted sulfanilamides of the general formula herein B is a lower alkylene group, E is hydrogen or lower alkyl, and A is one of the following radicals in which R is lower alkyl or lower alkoxy; and p is 0, 1 or 2} and salts with pharmaceutically acceptable bases.

2. » Sulfanilamides and salts thereof as claimed in Claim 1, wherein E represents ethylene.

3. · Sulfanilamides and salts thereof as claimed in Claim 1 or 2, wherein R1 represents hydrogen.

4. Sulfanilamides and salts thereof as claimed in any 2 of Claims 1 to 3» wherein represents a raethoxy or ethoxy group. ■32647-3

5. N -.ethoxyacetyl-N -(2-pyrimidyl)sulfonamide or a salt thereof with a pharmaceutically acceptable base.

6. N^-ethoxyacetyl-N^-i2, 6-dimethoxy-4-pyrimidyl)sulfanilamide or a salt thereof with a pharmaceutically acceptable base.

7. N^-ethoxyacetyl-N1-(4-methyl-2-pyrimidyl)sulfanilamide or a salt thereof with a pharmaceutically acceptable base.

8. ^-ethoxyacetyl-N^-C , 6-dimethyl-pyrimidyl-sulfanil-amide or a salt thereof with a pharmaceutically acceptable base.

9. N 4-ethoxyacetyl-N1(/2-quinoxalinyl\)sulfanilamide or a salt thereof with a pharmaceutically acceptable base.

10. N^-eth0xyacetyl-N1-(2-thiazolyl)sulfonamide or a salt thereof with a^pharmaceutically acceptable base.

11. N 4. -ethoxyacetyl-N1-(/5-methyl-l, 3,4-thiadiazol-2-yl)x sulfanilamide or a salt thereof with a pharmaceutically acceptable base. - r,

12. 1 . N^-ethoxyacetyl-N^-(6-methoxy-3-pyridazinyl)sulfanilamide or a salt thereof with a pharmaceutically acceptable base.

13. Substituted sulfanilamides according to Claim 1, substantially as described herein with reference to the Examples

14. A process for the production of sulfanilamides of the general formula I in Claim 1 and of salts with pharmaceutically acceptable bases, wherein a sulfanilamide of the en r l' f r or salt thereof, is reacted with a lower alkoxyalkanoio acid of the formula HOOCCHORH, in which formula© R, B1, and A have the same meaning as in Claim 1 and B represents hydrogen, •2 9 * or a blocking group P/O-C- wherein io a tertiary butyl group or an ar-lower alkyl group and which can be hydrogenolysed or hydrolysed, or with a reactive derivative of the aforesaid alkoxyalkanole acid, as an aeylating agen , and subsequently, where B* represents a blocking group, the blocking group is removed, and any B^-alkoxy-alkanoyl sulfanilamide/ is isomerised at an elevated temperature in the presence of an organic base and water to for® a compound of formula I·

15. A process according to Claim 14, wherein a compound of formula ¥1 in which B' is hydrogen and having the formula is reacted with an alkoxy&lkanoic acid.

16. A process according to Claim 15, wherein the reaction ie effected at ambient conditions in the presence of il,K^-dicyclohexyl earbodiiaide and of an organic solvent e.g. pyridine,

17. A process according to Claim 14, wherei an alkali metal salt of the sulfanilamide of the general formula 11 is acylated with a lower alkoxyalkanoic anhydride.

18. A process according to Claim 17, wherein the acylation is carried out at reduced temperatures, i.e. below room temperature.

19. Λ process according to Claim 17 or 18, wherein the acylation is carried out in the presence of an organic baoee

20. A process according Claim 19, wherein, where the organic base used is not liquid under the reaction conditions, the reaction ia effected in an organ c solvent medium.

21. A process according to Claim.14, wherein a Sulfanilamide of the general formula V in Claim 15 is reacted with a lower alkoxyalkanoic anhydride.

22. A process according to Claim 21, wherein the r action is effected under substantially anhydrous condition arid in the presence of an organic solvent.

23. A process according to Claim 200r wherein the organic solvent medium is a ketone, an ether, an aromatic hydrocarbon or a chlorinated hydrocarbon.

24. A process according to Claims 14 to-^23, wherein a lower alkoxyalkanoic acid of the formula H00CCH0RH or a reactive derivative thereof in which R represents an alkylene group having from 1 to 8 carbon atoms are used.

25. A process according to Claim 14 to 23, wherein a lower alkoxyalkanoic acid of the formula H00C0H0RK or a reactive' derivative thereof in which R^" represents hydrogen are used.

26. A process according to Claims 24 and 25, wherein the lower alkoxyalkanoic acid or reactive derivative thereof is a lower' alkdy acetic acid or a lower alkoxy acetic acid anhydride.

27. A process according to Claim 24 or 25, wherein a compound of formula0 VI in Claim 14 is used in which the sub- ί •32647-3

28. Processes for the manufacture of substituted sulfa-'."., nilamides of formula I in. Claim 1 substantially as described herein with reference to Examples 1 to 3 and 7 to 11.

29. · Sulfanilamides of formula I in Claim 1, when prepared by the processes according to any of Claims 14 to 28.

30. Compositions having antibacterial activity, containing as an active ingredient a sulfanilamide or a salt thereof as defined in any of Claims 1 to 13.