DE1936625A1 - Alkoxyalkanoyl sulfonamides - Google Patents

Description

RAN 4440/115

F. Hqffinann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland Alkoxyalkanoyl sulfonamides

The invention relates to substituted sulfanilamides,
in particular N - and / or N - (alkoxyalkanoyl) sulfanilamides and a process for their preparation. The invention also relates to a preparation containing said substituted sulfanilamides. The invention further relates to intermediate products containing protective groups which can be used for the preparation of said substituted sulfanilamides.

The invention accordingly relates to antibacterially active substituted sulfanilamides of the general formula

909884/1801

Ur / 6/26/69

1 2

wherein R and R alkylenej R is hydrogen or lower Alkyl denotes} m and η are 0 or 1, but at least m or η is 1; and A one of the Remnants of the formulas

Ha

Man

-does

Hc

N.

IXd

or

9884/1801,

ÖAD ORIGINAL

4 wherein R is lower alkyl, lower alkoxy or

Represents halogen and ρ = 0, 1 or 2, means

and, if η = 0,.

Salts of the compounds of .Formel I with pharmaceutically acceptable Bases.

The N - (Alkoxyalkanöyl) sulf at Hamide the general

formula

R ²

H-HOCH-CO HH - // XS-SOgNH Α _τττ

2 where R, R and A have the above meaning,

form salts with pharmaceutically acceptable bases, e.g. with bases of alkali metals such as sodium hydroxide and potassium hydroxide.

The term "lower alkyl" denotes as used herein Context a hydrocarbon radical with 1-7 carbon atoms, such as methyl, ethyl, propyl, butyl and the like.} Methyl and ethyl are preferred radicals. The term "alkoxy" refers to an alkyl ether group containing 1-18 carbon atoms contains, preferably 1-8 carbon atoms, e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy, octyloxy * decyloxy, Dodeoyloxy, hexadecyloxy, octadecyloxy and the like are preferred

909884/1801

The remainder are methoxy and ethoxy. With "lower-alkoxy" becomes a lower alkyl ether, in which the lower alkyl part denotes the same as above, such as methoxy, ethoxy, Propoxy, butoxy and the like, methoxy and ethoxy are preferred. The term "halogen" includes bromine, chlorine, fluorine and Iodine. "Alkylene" means a hydrocarbon containing 1-18 carbon atoms, preferably 1-8 carbon atoms, e.g. methylene, ethylene, propylene, trimethylene, tetramethylene, fc decamethylene and the like. The term "alkanoyl" denotes an aliphatic acyl radical having 2-9 carbon atoms. With "alkanecarboxylic acids" the corresponding acids with 2-9 carbon atoms are meant. "Aryl" means aryl with 6-12 carbon atoms, such as phenyl.

Examples of sulfanilamides of the general formula I are:

N -rAethoxyacetyl-N - (2-pyrimidyl) sulfanilamidj t N ¹ - (2,6-dimethoxy-4-pyrimidyl) -N ^2t -ethoxy-

acetylsulfanilamidj

N-ethoxyacetyl-N. (4-methyl-2-pyrimidyl) sulfanilamide; N ¹ -Ae thoxyacetyl-N ¹ - (2,6-dimethoxy-4-pyrimidyl) sulf anilamide;
N ¹ - (4,6-dimethyl-2-pyrimidyl) -N -ethoxyacetyl-

sulfanilamide;

4 1

N-ethoxyacetyl-N - (2-quinoxalinyl) sulfanilamide;

■ 4 1

N-ethoxyacetyl-N - (2-thiazolyl) sulfanilamide;

N ^Jt -Aethoxyacetyl-N ¹ - (5-methyl-1,3,4-thiadiazol-2-yl) sul- 90 9 8 8Λ / 18 0 1

fanilamid;

4 1

N -ethoxyacetyl-N - (6-methoxy-3-pyridaziny]) sulfanilamide.

The invention also relates to protective groups see intermediates of the general formula

B-NH - // \\ - S0 _o NA

^{2 1-1 ^IV

coChorM ^ h

lco

1 2

wherein A, R and R have the above meaning, r = 0 or

^ OC-,

1, and B is a protecting group of the formula R 'where R- ^{5 is} the tertiary butyl group or an aryl-lower alkyl group, such as, for example, the benzyl group.

Examples of compounds of the general formula IV are N -benzyloxycarbonyl-N - (2,6-dimethoxy-4-pyrimidyl) sulfanilamide and N -benzyloxycarbonyl-N -ethoxyacetyl-N - (2,6-dimethoxy-4-pyrimidyl) sulfanilamide.

The compounds of the formulas I and IV can be prepared by methods known per se. You are e.g. from the non-acylated sulfanilamides of the general formula

"909884/18 01 _v -

SO ₂ NH-

where A has the above meaning,
accessible.

Examples of compounds of the formula V are: SuIfachinoxalin, Sulfadiazine, sulfadimethoxine, sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxypyridazine, sulfathiazole and Sulforthomidln.

The sulfanilamides of the general formula I are by Implementation of a sulfanilamide of the general formula

BL NH - // \> SO ₂ NH A VT

or a salt thereof, wherein A has the above meaning and B ^{1 is} hydrogen or a protective group which can be removed by hydrogenolysis or by hydrolysis, with a

or more ^ lower alkoxyalkanecarboxylic acids of the general R ^ r2.

Formulas IIOOCCHOR H and / or HOOCOHORH in which R, R and R are above

90 9 88A / 18 01.

Have meaning, or with a reactive derivative thereof, and, if B ^{1 represents} a protective group, obtained by subsequent hydrogenolytic or hydrolytic removal thereof.

The alkoxyalkanoyl derivatives of formula I can e.g.

S by conversion of an alkoxyalkanecarboxylic acid of the formula HOOCCHOR H

or HOOCCHORH with a sulfanilamide of the formula V. will. This reaction is convenient under normal conditions in the presence of N, N -dicyclohexylcarbodiimide and an organic solvent such as pyridine.

In a further process variant, an alkoxyalkanecarboxylic acid anhydride is used as the acylating agent. For example, the N -alkoxyalkanoyl derivatives of the formula I can be obtained by reacting an alkali metal salt *, preferably the sodium salt, of a sulfanyl amide of the formula V with an alkoxyalkanecarboxylic acid anhydride. Process conditions are not particularly critical, although substantially anhydrous conditions are preferred. While elevated temperatures can be used, it is recommended . normally, the reaction at low temperatures, ie below room temperature (about 20-25 ° C), preferably at temperatures between about 093 and about 15 ^ C to carry out. Furthermore, the reaction is advantageously carried out in the presence of an organic base. Suitable bases are, for example, pyridine, picoline, lutidine, quinoline, trialkylamine,

90 9 8 8Λ / 18 0 1

(e.g. triethylamine) and alkali metal or alkaline earth metal acylates, especially acetates such as sodium acetate. In general, it is recommended that the reactants and the to use organic base in equimolar proportions, but this is not absolutely necessary. The implementation can in the presence of an inert organic solvent, e.g. a ketone such as acetone, or methyl ethyl ketone, a Ethers such as dioxane or tetrahydrofuran, an aromatic hydrocarbon such as benzene, toluene or xylene, one chlorinated hydrocarbon such as chloroform. The use of such a solvent is but not necessary if the organic phase is liquid under the respective reaction conditions. In this case it can excess base can be used as the reaction medium.

4th
The N -alkoxyalkanoylsulfanilamides of the formula I can

can be obtained as by-products of the embodiment described above. In addition, they can arise from the N -alkoxyalkanoylsulfanilamides by isomerization. This isomerization can be readily made at higher temperatures, for example between .Approximately 50 ⁰ C and about 100 ⁰ C or higher und'in presence of an organic base, for example pyridine, and water. For these reasons, lower temperatures and practically anhydrous conditions are preferred when N -alkoxyalkanoyl-

1 4 sulfanilarhide are desired. The N- and N -nPnoalkoxyacylation-

th isomers can easily be identified due to their solubility in

η become; the N 909884/1801

Alkali can be distinguished; the N derivative is insoluble in

BAD ORfGINAL

4th
Alkali, while the N derivative is soluble.

A preferred procedure for the direct preparation of N - (alkoxyalkanoyl) sulfanilamides of the formula I consists in reacting the free sulfanilamide with an alkoxyalkanoic acid anhydride. While the reaction conditions are not particularly critical, but can be applied generally temperatures in the range of about 10 ⁰ C and about 60 ° C, preferably room temperature. In general, equimolecular amounts of the reactants will be used. It is preferred to work under practically anhydrous conditions and in the presence of one of the abovementioned organic solvents.

The N, N -bis (alkoxyalkanoyl) sulfanilamides of the formula I. can be obtained under similar conditions as the monoalkoxyalkanoyl derivatives, with the difference, however, that excess alkoxyalkanecarboxylic anhydride is used. It however, it is advantageous to use the N -alkoxyalkanoyl derivative first

4 as described above and then the N -sub-

to introduce stituents.

The N - (alkoxyalkanoyl) sulfanilamides of the formula

909884/1801

12th
where R, R and A have the above meaning,

can also according to the scheme I shown below Process variant are produced:

Scheme I.

B-NH

SO ₂ NH

(a)

SO ₀ NH-5 A

² IR ²

COCHOR — H

(c)

f
COCHOR * H

VI ¹

VIII

In the formulas V, VI ', VIII and VII, R ¹ , R ² and A have the above meanings, and B represents a protective group, for example that described above. 909884/1801

SAD ORIGINAL

According to reaction scheme I, the sulfanilamide of the formula V is first converted into a compound of the formula Vl ' (Step a) to which carries a protective group on the N -nitrogen atom. This implementation can, for example, under the influence of reagents such as aralkyl haloformates, such as benzyl chloroformate, and tert-Alkylazidoformiaten, such as ter. — ButylazidoformiatiVor go yourself j you can do the usual Use working methods, e.g. in a temperature range of approximately 25 * 0 to 75 ° C and in the presence of a solvent, e.g. acetone, toluene, water, or mixtures of such solvents, work.

The compound of the formula VI 'is conveniently converted into a compound of the formula VIII (step b) by reacting with a reactive derivative of the lower-alkoxyalkanecarboxylic acid, preferably with an anhydride, preferably in the presence of a solvent such as pyridine, and in a Temperature range from approximately 25 ° C to 100 ⁰ C.

In step c, reagents and reaction conditions which remove the protective group B are used. With hydrogenolytic Removal of the latter can be e.g. use .. If desired, you can work in the presence of an inert solvent, such as dimethylformamide. That Reaction product of the formula YII can be

90988 4/1801

methods, e.g. crystal! sation, can be obtained.

The antibacterial effectiveness of the invention Sulphonamides has been tested on mice infected with the following Microorganisms have been infected, determines:

1. Escherichia coil 257

2. Klebsiella pneumoniae A j5. Proteus vulgaris * 190

^ 4. Pseudomonas aeruginosa B

5. Salmonella schottmuelleri

6. Salmonella typLosa P 58 a 7 · Staphylococcus aureus Smith 8. Streptococcus pyogenes No » K

The mice were injected intraperitoneally * containing 100 to 1000 times the minimum Iethalen dose , infected. Groups of 6-10 mice were then treated with the test substance. Different groups with the same Infections were treated with different amounts of the same test substance.

All infected animals, including an untreated control group, were observed over a period of 14 days and the number of surviving animals was determined. The presence of the infecting organism was proven by producing • cultures from the hearts of all animals. The results are given as CD, - ₀ values (mg / kg).

809884 / 1.801 '- '

• ORIGINAL BATHROOM

Calculation according to the method of Reed and Muench, Am. J-our. Hygiene, £ 2, 493 (1938). ■

The acute toxicity was determined by Administration of the test substances to groups of 6 mice each. After 72 hours, the dead and surviving animals became counted. The results are given as LD ^ values (mg / kg). Calculation according to the method of Reed and Muench, Am. Jbur. Hygiene, £ 2, 493 (1938).

The results of these experiments with various Alkoxyalkanoylsul f anil ami dr »n. of formula I are summarized in the following table I:

909884/1801

Table I.

Antibacterial effectiveness

CD

50 ·

mg / kg

p.o.

link

N -ethoxyacetyl-N (2-pyrimidyl) sulf anilamide

■ N ^ -Ca ^ -Dimethoxy - ^ - ' pyrimi4 * »yl) -N ^ -ethoxy- <o acetylsulfanilamide

S · N ^ -Aethoxyacetyl-N ¹ -Op (4-methyl-2-pyrimidyl) -Op sulfanilamide

** "1 1

· * »N -ethoxyacetyl-N - (2 * 6-

- * dimethoxy-4-pyrimidyl) - ⁰ ^ sulfanilamide

- * N ¹ - (4,6-Dimethyl-2-pyrimidy1) -N ^^ ethoxyapetylsulfanilamide

N -Aethoxyacetyl-N ^ -iS-

ISscherichia cpli

74

240

78

y3
2-yl) sulfanilamide

N ^ -ethoxy-acetyl-N ¹ - (6-Riethoxy-3-pyridazinyl) - sulfanilamide

^{N 1} - ethoxyacetyl N 1 - (2-thiazolyl) sulfanilamide

125

> 500

39

> 1000

Klebsiella pneumoniae A

Proteus Pseudo-Salmonella vulgaris 190 monas aeru- schottmuelleri ; ginosa B

<20 66

<20

20th

159

46

46 500

<20

> 1000

332> 500> 500

500

88

CO CD CT)

Antibacterial efficacy ₀ : mg / kg po

k . ■ η N -ethoxyacetyl-N (2-pyrimidyl) sulfanilamide

N ¹ - (2,6-Dimethoxy-4-pyrimidyl) -N ^ -ethoxyacetylsulfanilamide

§ ■ N ^{2 |} '-iAethoxyaoetyl-N ¹ - (4-

«O methyl-2-pyrimldyl) sulfanil-00 amide

N ³ -Ae thoxyaeetyl-N ¹ - (2,6- * <'dimethoxy-4-pyrimidyl) -JJ sulfanilamide

O Nj- (4,6-dimethyl-2-pyrimldyl) - ~ * N ^ -ethoxyacetylsulfanilamide

acetyl

Salmonella
typhosa P 58 a Staphylococcus
aureus smith Streptococcus
pyogenes' No.4 LD ₁ -Q mg / kg
³ PO 8th 179 ' 27 > 10,000 72 ^ 500 72 > 5,000 15th 121 62 > 10,000 - 141 578 > 500 8th 55 - ■> 5,000 58 ^ -500 > 5,000

1,3,4-thiadiazol-2-yl) sulfanilamide

N ⁴ -Aethoxyacetyl-N ¹ - (6-methoxy-5-pyridazinyl) -sulfanilamide 8 <20-> 5,000

N-ethoxyacetyl-N ¹ - (2-

co

amide 664> 1,000 210> 2,000 cn

cn

This table shows that the compounds of the formula I have considerable antibacterial activity and consequently use in antibacterial agents find körinen. -

The products of the process can be used as remedies, ζ.ΒΓ in the form of pharmaceutical preparations, which they or their salts in a mixture with a pharmaceutical suitable for enteral or parenteral administration, organic or inorganic inert support material, such as e.g. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable ble, polyalkylene glycols ,. Contains petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, coated tablets, suppositories, Capsules; in semi-solid form, e.g. as ointments; or in liquid form, e.g. as solutions, suspensions or Emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, Stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. You can also contain other therapeutically valuable substances.

The compounds of the formula I can also be used for animal feed, directly or enriched in premixes, in the usual way " be added. In such animal feed, the content of sulfanilamides of the formula I is roughly 0.0025

up to 0.05 percent by weight.

809884/1801

In the examples below are the temperatures

H Il

given in degrees Celsius. Parts are parts by weight.

example 1

19. 0 g of ethoxyacetic anhydride v / earth is added over a period of 5 minutes to a stirred suspension of 25 * 0 g of N ¹ - (2-pyrimidyl) sulfanilamide (sulfadiazine) in 25.0 ml of acetone. The reaction mixture is kept at 50 ° for 6 hours with stirring. After cooling to room temperature, the reaction product is filtered off and washed with acetone. It is slurried with 3 η hydrochloric acid, shaken, filtered and the residue is washed with water and recrystallized from 75 # aqueous ethanol. The N-ethoxyacetyl-N - (2-pyrimidyl) sulfanilamide obtained melts at 221-222 °.

Example 2

19 * 0 ethoxyacetic anhydride are used over a period of time of 10 minutes to a stirred mixture of 31 * 0 g N - (2, ö-Dimethoxy - ^ - pyrimidyl) sulfanilamide (sulfadimethoxine) given in 300 ml of acetone. Stir until complete solution * education occurs and leaves overnight. You are now submitting Stir OQO ml of water to the reaction mixture. One leaves Auskrisfcallisierung a period of 2 hours, filtered and

_6A 0

washes the residue with dilute acetone. The reaction product is recrystallized from ethanol; the so obtained

1 4

N - (2,6-Dimethoxy-4-pyrimidyl) -N -athoxyacetylsulfanilamide melts at 189-191 °.

Example 3

A mixture of 26.4 g of N ¹ - (4-methyl-2-pyrimidyl) -

^ sulfanilamide (sulfamerazine), 30.0-.ml acetone and 19.0 g ethoxyacetic anhydride is refluxed for 2 hours with stirring. The reaction mixture is then in a. Ice bath

chilled. The product is filtered off and from 75 $ ~ igem

4 recrystallized ethanol. The N-ethoxyacetyl-N - (4-methyl-2-pyrimidyl) sulfanilamide melts at 213-217 °.

Example 4

"33 * 2 g of the sodium salt of N ^ (2,6-dimethoxy-4-

pyrimidyl) sulfanilamide (sulfadimethoxin) in 100 ml of water and add 50 ml of acetone. Is now added over a period of 30 minutes (the pH of the solution is maintained at 7-8 by the addition of lO ^^ sodium hydroxide solution) 77 4 $ ^ hydride in toluene dropwise to Benzylehloroformiat. So that the temperature remains below 35 ° during the addition of the reagent, it is cooled »After the addition, nooh. 'Stirred for 2 hours. A surplus (10 ml) of 10%

900884/1801

BAD ORfGfNAL

Sodium hydroxide is added to make the mixture strongly alkaline close. Man'verdünnt with 100 ml of water, filtered the Residue from and acidify the filtrate by adding 10 ml Acetic acid with stirring to a pH of 5. It educates an initially ummi-like precipitate, which however solidified by stirring the mixture. It is filtered off and washed first with water, then with ether.

It is recrystallized from ethanol; the so obtained

N -Benzyloxycarbonyl-N - (2,6-dimethoxy-4-pyrimidyl) sulfanil-

amide melts at 173-175 °.

Example 5

20 g ethoxyacetic anhydride are over a time

space of 5 minutes to a solution of 20 g of N -benzyloxycarbonyl-N - (2,6-dimethoxy-4-pyrimidyl) sulfanilarnide in 4o rnl given to dry pyridine. The reaction mixture is heated on a steam bath and kept at one temperature for 10 minutes of over 80 °. It is then cooled to room temperature and then poured into 400 ml of ice-cold water while stirring * The supernatant liquid is poured off and 100 ml of ethanol are added to the gummy precipitate. By stirring the mixture results in a fine-grained precipitate which

H. is recrystallized from acetonitrile. The N benzyloxycarbonyl-N -ethoxyacetyl-N - (2, o-dimethoxy - ^ - pyrimidyl) sulfanilamide thus obtained melts at 168-170 °.

809884/1801

BATH ORIGINAL Example 6

"4 1

A solution of 12.2 g of N -benzyloxycarbonyl-N -ethoxy

acetyl-N - (2,6-dirnethoxy-4-pyrimidyl) sulfanilamide in N, N-Dimethylformamide is placed in a Parr bomb that contains 2 g Contains 10 ^ palladium on activated carbon. The initial hydrogen pressure should be 3.38 atm. After complete hydrogenolysis, the catalyst is filtered off and the Dimethylformamide is distilled off in vacuo at 0.1 mm Hg on a water bath at 50-55 °. The crystalline residue is slurried in 50 ml of dry ether, filtered and washed the residue with dry ether. The resulting N ethoxyacetyl-N - (2,6-dimethoxy-4-pyrimidyl) sulfanilamide melts at 168-170 °.

Example 7

19 g Aethoxyessigsäureanhydrid added to a stirred suspension of 27.8 g over a period of 5 minutes N ^'f - (4,6-dimethyl-2-pyrimidyl) sulfanilamide (SuIfamethazin) in 300 ml of acetone. The reaction mixture is refluxed with stirring for 2 hours. It is then cooled to room temperature and diluted with 900 ml of water to induce crystallization. The precipitate formed is filtered off and crystallized twice from 100 ml

1 4

Ethanol and receives N - (4,6-dimethyl-2-pyrimldyl) -N -ethoxy-

acetylsulfanilamide with a melting point of 158-159 °.

909 88 4/18 01

BATH ORIGINAL

Example 8

To a mixture of 27 g of N - ^ - methyl-l ^^ - thiadiazol-2-yl) sulfanilamide (Sulfamethizole) in 200 ml of acetone are added to 19 g of ethoxyacetic anhydride. The reaction mixture is stirred 2 hours. It occurs first, then complete solution formation Crystallization. Cool in an ice bath and filter the precipitation. After recrystallization from 600 ml of acetonitrile melts the N-ethoxyacetyl-N - (5-methyl-1,3 »^ - thiadiazol-2-yl) sulfanilamide at 200-201 °.

Example 9

To a stirred suspension of 28 g of N - (6-methoxy-3-pyridazinyl) sulfanilamide (Sulfamethoxypyridazine) in 200 ml of acetone are added to 19 g of ethoxyacetic anhydride. One stirs 3 hours, a clear solution resulting. 400 ml of dry ether are added and the mixture is stirred for a further hour. The resulting Precipitate is filtered off and recrystallized from acetonitrile. The N-ethoxyacetyl-N - Come thoxy-3-pyridazinyl) sulfanilamide melts at 153-155 °.

Example IQ

To a stirred suspension of 24.3 g of N - (2-thiazolyl) sulfanilamide (sulfathiazole) in 300 ml of acetone is added a period of 10 minutes 19> 9 g ethoxyacetic anhydride.

The reaction mixture is stirred for 5 hours, then the resulting one Filtered off precipitate and washed with acetone. After recrystallization from 1,800 ml of acetonitrile, the Melting point of N-ethoxyacetyl-N - (2-thiazolyl) sulfanilamide 216-218 °. -

Example 11

A mixture of 3 g of sulfachinoxaline, > 0 ml of acetone and 2.05 g of ethoxyacetic anhydride is kept under reflux for 3 hours with stirring. It is then cooled to room temperature and the precipitate formed is filtered off. After recrystallization from acetonitrile, the melting point of the N-ethoxyacetyl-N - (2-quinoxalinyl) sulfanilamide obtained is 195-197 °.

Example 12

Pharmaceutical forms of use can be composed as follows:

A) capsule

₍ Total weight
909884 / ItOt per capsule 50 mg U r
M -Aefchoxyaeetyl-N - (2-pyrimidyl) sul-
fanilamid 125 mg Lactose 30 rag Cornstarch 5 mg Talk 210 mg

BATH ORIGINAL

capsule

N -ethoxyacetyl-N - (2,6-dimethoxy-4-pyrimidyl) -sulfanilamide

Lactose

Cornstarch talc

per capsule

50 mg 125 mg 30 mg 5 mg total weight 210 mg

tablet

N-ethoxyacetyl-N - (2-pyrimidyl) sulfanilamide} 2% excess

Dicalcium Phosphate Dihydrate Corn Starch FD and C Yellow No.

fully hydrogenated vegetable oil (containing 100 ^ triglycerides)

Calcium stearate

per tablet mg 255 mg 230 mg 70 mg 2 mg 25th mg 3

Total weight 5Ö5 mg

D) premix for animals

N -ethoxyacetyl-N - (2-pyrimidyl) -sulfanilamide

Corn flour

partially hydrogenated coconut oil (containing a. mixture of mono-, Di- and triglycerides)

Total weight gram / kilo

125 g 831 g

kk g 1000 grams

909884/1801

by ml 1, 0 mg 1 mg

E) Parenteral solution

N -ethoxyacetyl-N - (2-pyrimidyl) -sulfanilamide

Disodium salt of ethylenediaminetetraacetic acid (EDTA)

Sodium hydroxide ad pH 10

Water (for injections) q.s. ad 1.0 ml

F) Veterinary drinking water solution

per ml

N ".- Aethoxyacetyl-N - (2-pyrimidyl) -

sulfanilamide 50 mg

EDTA disodium salt 0.1 mg

Sodium bisulfite 1.0 mg

Sodium hydroxide q.s. ad pH 10

Distilled water q.s. ad 1 ml

909884/1001

Claims (1)

Claims 1. Process for the preparation of substituted SuI-fanilamides the general formula H- -ROCHCO 1 2
wherein R and R are alkylene, R is hydrogen or lower alkyl; m and Ti = O or 1, but at least m or n = 1; and A is one of the radicals of the formulas Ha lib Ilß Hd or 4th
wherein R is lower alkyl, lower alkoxy or Represents halogen, and ρ = 0, 1 or 2, means, and, if η = 0, vcn salts of the compounds of formula I with pharmaceutically acceptable bases, characterized in that one '
Sulphanilamide of the general formula -NH- / \ y- SO ₂ NH-A vi wherein A has the above meaning and B 'is hydrogen or a protective group which is by hydrogenolysis or
Hydrolysis can be removed means
or a salt thereof, with one or more lower-alkoxy ^r2 ι alkanecarboxylic acids of the general formulas HOOCOHOR H and / or HOOCCHORH, in which R, R and R have the above meanings, or with w a reactive derivative thereof, and, if B 'represents a protective group, this hydrogenolytically or removed hydrolytically. 2 »Method according to claim 1, characterized in that that an alkali metal salt of a sulfanilamide of the general Formula VI with a lower alkoxyalkanecarboxylic acid anhydride implements. 3> · Method according to claim 2, characterized in that that the reaction is carried out at low temperatures. 4. The method according to claim 2 and 3 »characterized in that that the reaction is carried out in the presence of an organic base. 5. The method according to claim 1, characterized in that that you have a free sulfonamide of the general formula / with ■ alkati
a lower alkoxy ^ arboxylic acid anhydride. 6. The method according to claims 1-5 »characterized in that Β 'represents a protective group which is hydrogenolytically or can be removed hydrolytically. 7. The method according to claim. 6, characterized in that -2 -7. that B ^{1 represents} the radical of the formula R-OCO-, in which R "^ is aryl-lower-alkyl or tertiary-lower alkyl. 8. The method according to claim J, characterized in that B 'means benzyl or tert-butyl'. 9. Process according to claims 1-8, characterized in that that a lower alkoxyacetic acid is used as the lower alkoxyalkanecarboxylic acid. 909884/1801 10. The method according to claims 1-9, characterized in that m = 0 and n = 1. 11. ' Method according to claims 1-5 »characterized in that that m = 1 and n '= 0. 12. The method according to claims 1-11, characterized in that that R and / or R is alkylene with 1 to 8 carbon atoms represent. 13. The method according to claims 1-12, characterized in that p
indicates that R is hydrogen. 14. The method according to claims I-I3, characterized in that that R denotes methoxy or ethoxy. 15. The method according to claims 1-5 * thereby indicates that the compound of the general formula IN- 1 '"Ethoxyacetyl-N - (2 ~ pyrimidyl) sulf on Hamid or a salt thereof with a pharmaceutically acceptable base. 16. The method according to claims 1-5, characterized in that that the compound of the general formula I N - (2,6-dimethoxy-4-pyrimidyl) -N -ethoxyacetylsulfanilamide or a salt thereof with a pharmaceutically acceptable base represents. 909884/1801 BAD ORlGiNAL 17 · Process according to claims 1-5 * characterized in that that the compound of the general formula I N -Aethoxyacetyl-N - (4-methyl-2-pyrimidyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base represents. 18. The method according to claims 1-9 »characterized in that that the compound of the general formula I N -Aethoxyacetyl-N - (2,6-dimethoxy-4-pyrimidyl) sulfanilaniia, represents. 19. The method according to claims 1-5, characterized in that that the compound of general formula I IT "- (4,6-Dimethyl-2 ^ pyrimidyl) -N -ethoxyacetylsulfanilamide or a salt thereof with a pharmaceutically acceptable one base 20. The method according to claims 1-5, characterized in that that the compound of general formula I N - ethoxyacetyl-N - (2-Ghinc4inyl) sulfanilainid or a salt thereof with a pharmaceutically acceptable base ;. 21. The method according to claims 1-5 *, characterized in that that the compound of the general formula ϊ N-ethoxyacetyl-K »(2-thlazQlyl} sulfanilamide or a salt of which represents with a pharmaceutically acceptable base, 9Q9884 / 18Ö1 22i Process according to claims 1-5, characterized in that the compound of the general formula IN ^il -Aethoxyacetyl-N ¹ - (5-methyl-1,3 ^ -fchiadiazol-2-yl) sulfanilamide or a salt thereof with a pharmaceutically represents compatible base. . 23. The method according to claims 1-5 »characterized in that that the compound of the general formula I N -Aethoxyacetyl-N - (6-methoxy-3-pyi '* idazinyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base. 909884/1801 - 31 - 193662a 24. Process for the production of preparations with antibacterial properties, characterized in that there is a substituted sulfanilamide of the general formula H- -ROCHCO 12th
wherein R and R are alkylene, R is hydrogen or lower alkyl; m and n = 0 or 1, but at least m or n = 1; and A is one of the radicals of the formulas Ila (R ⁴ ), Man Jl lic Hd or Hey 909 88 4 / "t 801 4 where R is lower alkyl, lower alkoxy or halogen and ρ = 0 * 1 or 2, or salt thereof with a pharmaceutically acceptable base as active ingredient for therapeutic administration; suitable, non-toxic, inert solid and liquid carriers and / or excipients that are usual in such preparations mixed. 25 · Antibacterial preparations, characterized by a content of a substituted sulfonataid of the general formula 1 2
wherein R and R are alkylene, R is hydrogen or lower alkyl; m and n == 0 or 1, but at least m or n = 1, j and A is one of the radicals of the formulas 909884/1801 BAD OBlGtNAi. (R ⁴ J Ha Man Ii i Jl ⁴ Hc Hd or -in ⁴ ), Hey where R is lower alkyl, lower alkoxy or halogen, and ρ = 0, 1 or 2,
or a salt thereof with a pharmaceutically acceptable base, 26. Compounds of the general formula - R * H- 3CK ROCKCO- 909884/1801 1 2 wherein R and .R alkylene, = R .hydrogen or lower ■ alkyl mean-; m and n =? 0 or 1, but at least m or n = 1; and A is one of the radicals of the formulas Ha (R ⁴ ), Man Uc Hd or (R ⁴ ) Hey where R is lower alkyl, lower alkoxy or halogen, and ρ = O, 1 or 2, and, if η is - O, Salts of the compounds of the formula I with pharmaceutically acceptable bases. 27. Compounds according to claim 26, wherein m = O and η 1 is. 909884/1001 BATH ORIGINAL 28. Compounds according to claim 26, wherein m = 1 and η = and salts thereof with pharmaceutically acceptable bases. 29. Compounds according to claims 26-28, wherein R and / or R represent alkylene with 1-8 carbon atoms, and Salts thereof with pharmaceutically acceptable bases. 30. Compounds according to claims 26-29, wherein R ^{2 is} hydrogen, and salts thereof with pharmaceutically acceptable bases. 31 · Compounds according to claims 26-30, wherein R Represents methoxy or ethoxy, and salts thereof with pharmaceutical compatible bases. 32. N-ethoxyacetyl-N ¹ - (2-pyrimidyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base. 33. N ¹ - (2,6-dimethoxy-4-pyrimidyl) -W-ethoxyaeetylsulfanilamide or a salt thereof with a pharmaceutically acceptable base. 34. N -ethoxyacetyl-N - (4-methyl-2-pyrimidyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable one Base" 35 »N -Aethoxyacetyl-N ¹ - (2,6-dimethoxy-4-pyriinidyl) -sul f anilamid aa ' e 90988A / 18Ö1 36. N ¹ - (4,6-dimethyl-2-pyrimidyl) -N -ethoxyacetylsulfanilamide or a salt thereof with a pharmaceutically acceptable base. xa 37. N -ethoxyacetyl-N - (2-quinoilinyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base. 38. N-ethoxyacetyl-N ¹ - (2-thiazolyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base. 39. N ^ -Aethoxyacetyl-N ¹ - (5-methyl-1,3,4-thiadiazol-2-yl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base. 40. N -ethoxyacetyl- N - (6-methoxy-3-pyridazinyl) sulfanilamide or a salt thereof with a pharmaceutically acceptable base. V- ■ ' 41. Compounds of the general formula B-NH. 1 2 wherein R is alkylene, R is hydrogen or lower alkyl 909884/1801 mean, r = 0 or 1 1st, mid. B a protective cap of the formula RiPC-, whereT? In- <ir ^ i & ie ^ teirt. ^ Äi ^ ylgrwppe: ofer represents an aryl-lower ^ 3 ± y! Group, tiedeuiret and A one of the. Best of the formulas ρ = Q, X Mter 2 Ha ;. wasin A # the rest r ä ö - ^ i ¹ - (2,6-ö4 BATH sulfanilamide. . MMe r ^ r = 1. . ίί T