NO132234B - - Google Patents

Description

The present invention relates to analogous methods for the production of new, therapeutically effective sulfamyl-m-aminobenzoic acids with the general formula: where A is

and R 1 and R 2 are each an alkyl group with 1-8 C atoms, a

cycloalkyl group with 5-6 C atoms or an alkyl group with

1 - h C atoms substituted with a phenyl group, or a phenyl or naphthyl group, the groups R 1 and R 2 as defined above, can further be monohalogen substituted or substituted with an alkyl group, a trifluoromethyl group, a carboxy or caralkyloxy group, an alkylamino group , a hydroxyl group which may be etherified or a sulfonamide group, and where R^ is an alkyl group with 1-8 C atoms or a phenyl group, and where

R^ is an alkyl or alkanoyl group with 1-h C atoms, and where R is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group with 1-8 C atoms, an alkyl group with 1-h C- atoms substituted with a phenyl or methylenedioxyphenyl group, or a furfuryl group, and where R^ is an alkyl group with 1-k C atoms, and where R^, , R^, R^ and R^ can also individually be hydrogen, or salts, cyanomethyl esters, esters with lower aliphatic alkanols or unsubstituted amides thereof.

In particular, R 1 and R 2 can each denote a straight or branched alkyl group, e.g. a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. butyl group, or one of the various isomeric pentyl, hexyl or heptyl groups, a cycloalkyl group, e.g. a cyclopentyl or cyclohexyl group. Illustrative examples of phenyl-substituted C 1 -C 4 -alkyl groups are benzyl, 1- or 2-phenylethyl and the corresponding propyl and butyl groups.

In particular, RJ and R can each denote a straight or branched saturated alkyl group, e.g. a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. butyl group, or one of the various isomeric pentyl, hexyl or heptyl groups, an alkenyl or alkynyl group, e.g. a vinyl, allyl or propargyl group, a cycloalkylr or cycloalkenyl group, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or one of the various isomeric cyclopentenyl or cyclohexenyl groups, or a heterocyclic substituted C 1 - - alkyl group, where the heterocyclic part of the group is a mono- cyclic group containing 5-7 ring atoms and one or two oxygen, sulfur or nitrogen atoms as ring members, e.g. 2-, 3-or ^--pyridyl, 2- or 3-furyl or -thienyl, thiazolyl, imidazolyl and the corresponding hydrogenated ring systems. Illustrative examples of such heterocyclically substituted C 1 -C 4 alkyl groups are furylmethyl and the corresponding ethyl, propyl and butyl groups.

When R denotes an acyl group, it is preferably a lower aliphatic acyl group, e.g. an acetyl or propionyl group.

The salts of the compounds of formula (I) are pharmaceutically acceptable salts and comprise e.g. alkali metal salts, alkaline earth metal salts, the ammonium salt, or amine salts which are formed e.g. from mono-, di- or trialkylamines, or mono-, di- or trialkanolamines or cyclic amines. The esters of the compounds are preferably derived from substituted or unsubstituted lower aliphatic alcohols, aryl or aralkyl alcohols, e.g. methylestrene, cyanomethylestrene, phenylestrene and benzylestrene.

The compounds of formula (I) possess valuable therapeutic properties and, according to animal experiments carried out in connection with the present invention, have a particularly strong effect as diuretics and saluretics, and the ratio between the excretion of sodium ions and potassium ions is very favorable. Furthermore, the compounds are not carbonic anhydrase inhibitors,

and these facts in connection with a favorable therapeutic index and low toxicity make the compounds present here particularly valuable.

The compounds are applicable in the treatment of edema conditions, e.g. cardiac oedema, liver oedema, renal oedema, lung and brain oedema, or oedematous conditions during pregnancy, and in pathological conditions which cause an abnormal retention of electrolytes in the body and in the treatment of hypertension.

The effect of the compounds presented here is surprising

in relation to what is stated in the description of Norwegian patent no. 122,655) as it could not be foreseen that the halogen or trifluoromethyl substituent in a position adjacent to the sulfonamide group could be replaced with the result that compounds with even stronger effects were obtained, since it has been the common belief that such a halogen or halogen-like substituent would be necessary in this type of diuretic.

Data for the effect of a representative selection of the new compounds in comparison with two compounds which are known from the aforementioned Norwegian patent, and with the known diuretic furosemide are indicated in the inventor's article in J. Med. Chem., volume lk, page <1>*32 - 39 (197D .

Illustrative examples of compounds of formula I which have

a particularly strong virion are compounds where A is as defined above, and where R, RJ and Ry are hydrogen, R is a substituted or unsubstituted phenyl group, R is an alkyl group with from 3 to 6 carbon atoms, or a benzyl, furfuryl or thienylmethyl group, R f) is hydrogen, a methyl group or lower aliphatic acyl group, and the methyl esters of these compounds.

The present compounds are effective after oral, enteral or parenteral administration and are preferably prescribed in the form of tablets, pills, dragees or capsules containing the free acid or salts thereof with atoxic bases, or the esters or amides thereof, mixed with carriers and/or aids.

Salts that are soluble in water can be advantageously administered by injection.

The new compounds and their salts should be administered in such doses that the desired effect is achieved without concomitant secondary effects. It has been found that the compounds and their salts are conveniently administered in dosage units containing not less than 0.1 mg and up to 25 mg, preferably from 0.25 to 2.5 mg, calculated as the free acid of formula I.

The method according to the invention is characterized by

an acid with the general formula

where A, R- > and R have the meanings given above, or a salt, an ester or an amide thereof is reduced to convert the nitro group into an amino group,

after which the obtained compound of formula I is, if desired, monoalkylated with a compound of formula R X, where R has the meaning given above for R*4" except for hydrogen, and X is a halogen atom, a hydroxyl-, sulfonyloxy-, alkyl- or arylsulfonyloxy group, or

the resulting compound is reductively alkylated with an aldehyde with the formula R^CHO, where b7 is defined by R^CH0 having the meaning defined for R,

after which the second hydrogen atom in the amino group in the 3-position in the obtained compound of formula I is, if desired, replaced by R^', where R^' has the meaning given above for R^ except for hydrogen, by alkylation with a compound R ^X,

5'

where Pr and X have the meaning stated above, or

that a prepared acid with formula I or a salt, ester or amide thereof as previously defined is converted into one of the other forms in a manner known per se, or

by reductive alkylation with an aldehyde of the formula R oCHO,

8 8

where R is defined by R CH"2 having the meaning defined for R^, or

if desired, an obtained compound of formula I, in which A represents an R pS group, is oxidized to a compound of formula I,

2 2

in which A represents an R SO or R SO 2 group, or

if desired, hydrogen Keres an obtained compound of formula I, in which R or R^ represents an unsaturated alkyl group of the corresponding saturated compound, or-

if desired, an obtained compound of formula I is acylated, in which B.^ represents hydrogen, or

if desired, an obtained compound of formula I is deacylated,

in which R 1 represents an alkanoyl group.

The various steps of the process are standard methods that include reductive alkylation, hydrogenation, esterification, amidation using a reactive derivative of the corresponding carboxylic acid, or hydrolysis, and the reaction conditions may vary according to the starting products and the substituents in the reacting compounds. The compounds are obtained in free form or in the form of their salts, esters or amides, depending on the conditions under which the reaction is carried out.

The starting material with formula IV is prepared according to the following reaction scheme:

in which formulas A and R^ have the meanings given above, and R is lower alkyl, and the compound III is used either as the free carboxylic acid or in the form of a salt or an ester,

in which case the compound IV is also obtained as an ester, which, if desired, can be hydrolyzed. In this case where R 1 is an acyl group, the compounds of formula IV can be obtained by acylation of the corresponding compounds, where R 1 is hydrogen.

If desired, the carboxylic acid group in the compounds of formula IV can be amidated using a reactive derivative of the acid, eg an acid halide.

The starting material with formula II and with formula III, where RJ and R are hydrogen atoms, is described in our Norwegian patent no. 122,655-

The N-substituted sulfamyl derivatives III are prepared by

R6 treats a compound of formula II with an amine RJNH, where R^ is different from hydrogen, and R^ is an alkyl group or hydrogen, preferably under mild conditions, i.e. at low temperature and without an excess of the amine

and usually

in the presence of a base, which does not have the ability to be alkylated,

and which is used as an acceptor for the acid released by the process.

The reaction product of formula III, or an ester or an amide thereof, is treated with a compound of the formula A-H, and A is as defined above, i.e. with an amine, an alcohol,

a thioalcohol, a phenol, a thiophenol, or a sulfinic acid for

to give a compound of formula IV, or the corresponding ester.

In the case where A stands for

A-H is used when reac-

tion in the form of the free amine, in the case where A star

2 2 2

for R -0, R-S or R -O^S, reaction conditions are used in which the ionic form of A is present or where A is an alcoholate, thioalcoholate, phenolate or thiophenolate, or a sulfinate. Water, ethanol, aqueous alcohols, or alcohols of the formula R p -OH, as well as other suitable solvents can, if desired, be used as reaction media in this process, and the reaction temperature depends on the reactants used.

In the case where A stands for

and is identical to the compound of formula II can be transferred in one step to a compound of formula IV using not less than two equivalents of the amine

The compounds of formula IV, where A is R-S, can further be converted into the corresponding sulfinyl or sulfonyl derivatives by oxidation, e.g. with hydrogen peroxide, and the amount of peroxide and the reaction conditions are decisive for the degree of oxidation, after which the compounds of formula I can be obtained as described above.

In an alternative embodiment of the method for the production of the compounds according to the invention, where A stands for R 2 -OS and R 2-OpS, these compounds can also be produced from the corresponding compounds of formula I, where A is R 2-S by oxidation with e.g. hydrogen peroxide. Depending on the amount of hydrogen peroxide and the reaction conditions used, the oxidation results in the sulfinyl or sulfonyl derivatives. Compounds of formula I, where the substituents are unsaturated,

can be hydrogenated or transformed by addition reactions to other compounds of formula I, and further substituents

Ph.D. "

in R and R can be introduced or removed at any reaction step.

The invention also includes that a prepared acid with formula I or a salt, ester or amide thereof as previously defined is converted into one of the other forms in a manner known per se.

The invention will now be described in the following illustrative examples.

Example 1.

3- amino-^- phenoxy- 5- sulfamyl- benzoic acid

A. 3- nitro-^- phenoxy- 5- sulfamyl- benzoic acid

A mixture of >+-chloro-3-nitro-5-sulfa amyl-benzoic acid (1^0 g),

phenol (100 g), sodium bicarbonate (170 g) and water (1000 ml) were heated to 85°C with stirring and held at this temperature for 16 hours. After cooling to k°C, the precipitated sodium salt of 3-nitro-U-phenoxy-5-sulfamyl-benzoic acid was filtered off and washed with ice water. The sodium salt was dissolved in boiling water (3000 ml) and the 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid precipitated by the addition of hydrochloric acid. After cooling, the acid was isolated by suction and dried. The melting point was 255 - 256°C.

B. 3- amino- t+- phenoxy- 5- sulf amyl- benzoic acid

A suspension of 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid (20 g)

in water (100 ml) was adjusted to a pH of 8 by the addition of ln lithium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure after addition of a palladium-on-carbon catalyst (0.6 g of catalyst containing 10$ Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-^f-phenoxy-5-sulfamyl-benzoic acid was precipitated from the filtrate by the addition of ^-n hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol and drying, the melting point was 255-256°C.

Example 2.

3- amino- 5- niethylsulfa amyl-^ f- f enoxy- benzoic acid

A. 5- methylsulfamyl- 3- nitro- 1+- f enoxy- benzoic acid

By replacing β-chloro-3-nitro-5-sulf amyl-benzoic acid with β-chloro-5-methylsulfamyl-3-nitro-benzoic acid (lh-7 g) and following the procedure in example IA, the compound was obtained with a melting point of 219-222°C.

The above starting material is new and was prepared as follows: To a mixture of ln sodium hydroxide (60 ml) and aqueous methylamine (3.^3 g containing 1.2 g of methylamine) was added ^-chloro-5-chlorosulfonyl-3 -nitro-benzoic acid (9.3 g) added in portions with stirring and kept at 0-3°C. The reaction mixture was then allowed to stand until it had reached room temperature, after which the ^-chloro-5-methylsulfamyl-3-nitro-benzoic acid was precipitated by slow acidification with hydrochloric acid. The precipitate was collected by suction and recrystallized from aqueous ethanol. The melting point was 228-229°C.

B. 3-amino-5-methylsulfamyl-^-phenoxy-benzoic acid

By replacing 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid with 5-methylsulfamyl-3-nitro-^-phenoxy-benzoic acid and following the procedure in example IB, the compound was obtained with a melting point of 283°C

Example 3.

3- amino- 5- dimethylsulf amyl- 1*- phenoxy- benzoic acid

A. 5-Dimethylsulfamyl-3-nitro-^-phenoxy-benzoic acid

A mixture of <1>+-chloro-5-dimethylsulfamyl-3-nitrobenzoic acid (3.08 g), phenol (2 g), sodium bicarbonate (3 A g) and water (20 ml) was heated at 90°C for 8 hours . Then water (<*>+0 ml) was added and after cooling the 5-dimethylsulfamyl-3-nitro-^f-phenoxy-benzoic acid was precipitated by acidification with <*>+n hydrochloric acid. After isolation by filtration and several recrystallizations from ethanol, the compound was obtained with a melting point of 22<i>+-226°C.

B. 3-amino-5-dimethylsulfamyl-H-phenoxy-benzoic acid

By following the procedure in Example IB and by replacing 3-nitro-^f-phenoxy-5-sulf amyl-benzoic acid with 5-dimethylsulf amyl-3-nitro-V-phenoxy-benzoic acid, the compound was obtained with a melting point of 211-212 °C.

By replacing ^-chloro-5-dimethylsulfamyl-3-nitro-benzoic acid in Example 3A with 5-n-butylsulfamyl-^-chloro-3-nitro-benzoic acid (3.36 g), 5-n-butylsulfamyl-3 -nitro-1+-phenoxy-benzoic acid obtained with a melting point of 191-192°C.

By replacing 3-nitro-U-phenoxy-5-sulfamyl-benzoic acid in Example IB with 5-n-butylsulfamyl-3-nitro-^-phenoxy-benzoic acid, 3-amino-5-n-butylsulfamyl-^f-phenoxy -benzoic acid obtained as a hemi-hydrate with a melting point of 188-189°C.

The starting materials, ^f-chloro-5-dimethylsulfamyl-3-nitro-benzoic acid and 5-n-butylsulfamyl-V-chloro-3-nitrobenzoic acid, were new and were obtained as described for the starting material under Example 2 by replacing aqueous methylamine with aqueous dimethylamine (3.6 g containing 1.5 g of dimethylamino) respectively n-butylamino (2.2 g) with a melting point of 233-235°C and 196-198°C respectively.

Example h.

3- amino- 1+- anilino- 5- phenylsulfamyl- benzoic acid and sodium salt

A. tf-anilino-3-nitro-5-phenyl sulf amyl-benzoic acid

To a solution of 1f-chloro-3-nitro-5-chlorosulfonyl-benzoic acid (6 g) in ethyl acetate (50 ml) was added aniline (7.5 g) with stirring. The reaction mixture was stirred for an additional 8 hours and filtered. The filtrate was evaporated and the residue dissolved in a mixture of aqueous sodium bicarbonate and diethyl ether. The aqueous layer was separated and the if-anilino-3-nitro-5-phenylsulfamyl-benzoic acid was precipitated by addition of hydrochloric acid. After recrystallization from aqueous ethanol (25% ethanol in water) the melting point was 2<l>f9-250<0>C.

B. 3- amino- U-- anilino- 5- phenylsulf amyl- benzoic acid and sodium salt

A suspension of 1f-anilino-3-nitro-5-phenylsulfamyl-benzoic acid

(2 g) in water (15 ml) was adjusted to pH 8 with 1N sodium hydroxide, and the resulting solution was hydrogenated after addition of Pd (0.15 g) on carbon powder catalyst (10%). After the hydrogen uptake had become negligible, the reaction mixture was heated to 95°C and the catalyst removed by filtration. After cooling, the precipitated sodium salt of 3-amino-if-anilino-5-phenyl-sulfa amyl-benzoic acid was collected by filtration.

1.5 g of the sodium salt of 3-amino-1+-anilino-5-phenylsulfa amyl-benzoic acid was dissolved in hot water (50 ml), hydrochloric acid was added until pH 2 and the mixture was cooled. The precipitated 3-amino-1+-anilino-5-phenylsulfa amylbenzoic acid was collected, recrystallized from aqueous methanol and dried in vacuo at 78°C. The crystalline compound contained 1 mole of water. The melting point was 222-223°C.

Example 5.

3- amino- M-- ( p- methoxy enoxy) - 5- sulf amyl- benzoic acid A. ^ f- ( p- methoxy enoxy) - 3- nitro- 5- sulf amyl- benzoic acid

A mixture of 1f-chloro-3-nitro-5-sulfa amyl-benzoic acid (1h g), p-methoxyphenol (9.3g) and 1n sodium bicarbonate (200ml) was stirred at 90°C for 5 hours. After cooling, the h-(p-methoxyphenoxy)-3-nitro-5-sulfamyl-benzoic acid was precipitated by the addition of hydrochloric acid until the pH was 1 and collected by suction. The crude acid was dissolved in hot methanol (100 mL) and precipitated by addition of water (100 mL) and cooling. After collection and drying in vacuum, the melting point was 229-230°C.

B. 3 - amino- lf - (p- methoxy enoxy) - 5- sulf amyl- benzoic acid

By replacing the 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid in Example IB with (p-methoxyphenoxy)-3-nitro~5-sulfamyl-benzoic acid (7 g), the compound was obtained with a melting point of 260-261° C.

Example 6.

3- amino- 5- sulf amyl- 1*- (m- trifluoromethylphenoxy) - benzoic acid

A. 3-nitro-5-sulfamyl-^f-(m-trifluoromethylphenoxy)-benzoic acid A mixture of <1>f-chloro-3-nitro-5-sulfamyl-benzoic acid (7 g), m-trifluoromethylphenol (20 g) and 1N sodium bicarbonate (100 ml) were stirred at 95°C for 6 hours. The reaction mixture was then acidified by the addition of hydrochloric acid and the excess of trifluoromethylphenol was removed by steam distillation. After cooling, the precipitated 3-nitro-5-sulfamyl-1+-(m-trifluoromethylphenoxy)-benzoic acid was collected by suction and recrystallized several times from methanol-water. The melting point of the pure compound was 205-206°C.

B. 3-amino-5-sulfamyl-i+-(m-trifluoromethylphenoxy)-benzoic acid By replacing 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid in example IB with 3-nitro-5-sulfamyl-lf -(m-trifluoromethylphenoxy)-benzoic acid, the compound was obtained with a melting point of 270°C.

Example 7.

3- amino- lj--( m- chloroph enoxy)- 5- sulf amyl- benzoic acid

A. k -( m- chlorophenoxy)- 3- nitro- 5- sulphamyl- benzoic acid

A mixture of If-chloro-3-nitro-5-sulfamyl-benzoic acid (28 g), m-chlorophenol (26 g), sodium bicarbonate (3k g) and water (200 ml) was stirred at 85°C for 10 hours . After cooling, excess m-chlorophenol was removed by extraction with diethyl ether, and the h-(m-chlorophenoxy)-3-nitro-5-sulfamyl-benzoic acid was precipitated from the aqueous layer by addition of hydrochloric acid. After recrystallization from aqueous methanol, the melting point was 230-232°C.

B. 3 - amino- 1*- (m- chlorophenoxy) - 5- sulph amyl- benzoic acid

A mixture of ammonium chloride (1.2 g), metallic iron powder (11 g), concentrated hydrochloric acid (0.05 ml) and water (30 ml) was heated on a steam bath, ^f-(m-chlorophenoxy)-3-nitro -5-sulfamyl-benzoic acid (3 g) was added with stirring and heating continued for 6 hours. Then 1N sodium hydroxide (50 ml) was added and the reaction mixture was filtered. The filter cake was washed twice with 1N sodium hydroxide (50 ml each time). The combined filtrates were adjusted to a pH of 2.5 by adding Kn hydrochloric acid. After cooling, the precipitated 3-amino-^-(m-chloro-phenoxy)-5-sulfamyl-benzoic acid was collected by suction and recrystallized from aqueous ethanol. The melting point was 239-2if0°C.

Example 8.

3- amino-^ f- me toxy- 5- sulf amyl- benzoic acid

A. h - methoxy- 3- nitro- 5- sulphamyl- benzoic acid

<l>+-chloro-3-nitro-5-sulfamyl-benzoic acid ( 1 h g) was added to a solution of sodium methanolate - prepared from sodium (6.9 g) - in methanol (200 ml). The reaction mixture was refluxed for 5 hours and evaporated in vacuo. The residue was dissolved in water (100 ml) and concentrated hydrochloric acid was added (50 ml). The precipitated 1f-methoxy-3-nitro-5-sulfamyl-benzoic acid was recrystallized from water. The melting point was 200-201°C.

B. 3- amino- 1+- me. toxy-5- sulf amyl- benzoic acid.

1+-Methoxy-3-nitro-5-sulfa amyl-benzoic acid (2.8g) was dissolved in ln sodium bicarbonate solution (12ml), hydrogenated using Pd-on-carbon as catalyst, and 3-amino-1+- The methoxy-5-sulfamyl-benzoic acid was isolated as described in Example IB. After several recrystallizations from water and drying at 78°C

in vacuum the melting point was 210°C during cleavage.

Example 9.

3- amino- i+- anilino- 5- sulf amyl- benzoic acid

A. 1+- anilino-. Vnitro-l7- sulph amyl- benzoic acid

A mixture of 1f-chloro-3-nitro-5-sulfamyl-benzoic acid (8.1 g), aniline (8 h g) and water (h-0 ml) was stirred at 80°C for 2 hours. After addition of 1N hydrochloric acid (50 ml) and cooling, the precipitated i+-anilino-3-nitro-5-sulfamyl-benzoic acid was collected by suction, washed with water and recrystallized from aqueous ethanol. The melting point was 26l-262°C.

B. 3 - amino- lf- anilino- 5- sulf amyl- benzoic acid

A suspension of <!>+-anilino-3-nitro-5-sulfamylbenzoic acid (7 g) in water (80 ml) was adjusted to a pH of 9 by addition of 2n sodium hydroxide or 11tium hydroxide and the resulting solution was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure after the addition of a palladium-on-carbon catalyst (0.3 g of catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration and the 3-amino-^-anilino-5-sulfamyl-benzoic acid was precipitated from the filtrate by the addition of 1-n hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol and drying in vacuum, the melting point was 251°C.

Example 10.

3- amino- 5- sulf amyl-*+ - ( m- toluidino) - benzoic acid

A. 3— nitro- 5- sulf amyl-^ f-( m- toluidino) - benzoic acid

A mixture of )+-chloro-3-nitro-5-sulfamyl-benzoic acid (28 g), m-toluidine (32.2 g) and water (500 ml) was refluxed in

3 hours. After cooling and acidification with 2N hydrochloric acid, the precipitated 3-nitro-5-sulfamyl-U-(m-toluidino)-benzoic acid was collected by suction, washed with water and recrystallized from isopropanol. After drying at 115°C in vacuum, the melting point was 256-259°C'

B. 3- amino- 5- sulf amyl- l)--( m- toluidino)- benzoic acid

By replacing 1+-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with 3-nitro-5-sulfamyl-1*-(m-toluidino)-benzoic acid, the compound was obtained with a melting point of 280-282 °C after recrystallization from ethanol.

Example 11.

3- amino- 5- sulf amyl- M--( p- toluidino) - benzoic acid

A. 3- nitro- 5- sulf amyl- M--( p- toluidino) - benzoic acid

By replacing m-toluidine in example 10A with p-toluidine, the compound was obtained with a melting point of 252-253°C after recrystallization from ethanol and drying.

B. 3-amino-5-sulfamyl-If-(p-toluidino)-benzoic acid

By replacing 1f-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with 3-nitro-5-sulfamyl-1+-(p-toluidino)-benzoic acid, the compound was obtained with a melting point of 2^9-252 °C.

Example 12.

3- amino- 5 - sulf amyl-*+-( o- toluidino) - benzoic acid

A. 3- nitro- 5 - sulf amyl-^ f-( o- toluidino)- benzoic acid

By replacing m-toluidine in Example 10A with o-toluidine, the compound was obtained with a melting point of 251-252°C.

B. 3- amino- 5- sulf amyl-^ f-( o- toluidino) - benzoic acid

By replacing <1>+-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with 3-nitro-5-sulfamyl-1*-(o-toluidino)-benzoic acid, the compound was obtained.

Example 13.

3- amino- 1*-( o- methoxyanilino)- 5- sulfamyl- benzoic acid

A. h -( o- methoxyanilino)- 3- nitro- 1?^ sulfamyl- benzoic acid

By replacing m-toluidine in example 10A with o-anisidine (37 g), the compound was obtained with a melting point of 207-208°C after recrystallization from ethanol and drying in vacuum.

B. 3- amino-^--( o- methoxyanilino)- 5- sulfamyl- benzoic acid

By replacing <1>+-anilino-3-nitro-5-sulfamyl-benzoic acid in example 9B with ^--(o-methoxyanilino)-3--nitro-5-sulfamyl-benzoic acid, the compound was obtained after recrystallization from aqueous ethanol.

Example 1* 4-.

3 - amino- k - - (m- me t o k sy ani li no) - 5- sulf amy 1- b e n z o e s y r e

A. h -( m- methoxyanilino)- 3- nitro- 5- sulphamyl- benzoic acid

By replacing m-toluidine in Example 10A with m-anisidine (37 g) the compound was obtained with a melting point of 253-25°C.

B. 3- amino- h -( m- methoxyanilino)- 5- sulphamyl- benzoic acid

By replacing <*>f-4nilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with h-(methoxyanilino)-3-nitro-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 232-23<! >+<0>C after recrystallization from aqueous methanol.

Example 15.

3- amino- 1*- ( p- methoxyanilino)- 5- sulf amyl- benzoic acid

A. (p-Methoxyanilino)-3-nitro-5-sulf amyl-benzoic acid

By replacing m-toluidine in example 10A with p-anisidine (37 g), the compound was obtained with a melting point of 2h6°C (decomposition ).

B. 3- amino-^- - (p- methoxyanilino) - 5- sulf amyl- benzoic acid

By replacing <l>*-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with h-(p-methoxyanilino)-3-nitro-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 21<l >f°C.

Example 16.

3- amino- 5- sulf amyl- 1*- ( m- trifluoromethylanilino) - benzoic acid

A. 3-nitro-5-sulf amyl-^--(m-trifluoromethylanilino)-benzoic acid By replacing m-toluidine in example 10A with m-trifluoromethyl-aniline (^9.5 g) and extending the reaction time to 7 hours the compound was obtained after the cooled reaction mixture had been acidified and diluted with ethanol (150 ml). After recrystallization from aqueous ethanol, the melting point was 213-215°C

B. 3- amino- 5- sulf amyl-* f-( m- trifluoromethylanilino) - benzoic acid By replacing <>>+-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with 3-nitro-5 -sulfamyl-^-(m-trifluoromethylanilino)-benzoic acid, the compound was obtained with a melting point of 273-27<1>+°C.

Example 17.

3- amino- M--( 2.^-- dimethylanilino) - 5- sulf amyl- benzoic acid

A. h -( 2, if- dimethylanilino)- 3- nitro- 5- sulphamyl- benzoic acid

By replacing m-toluidine in Example 10A with 2,3-dimethylaniline (36.5 g), the compound was obtained with a melting point of 22+-226°C after recrystallization from ethanol and drying. The compound crystallized with 1 mol of ethanol.

B. 3- amino- 1*- ( 2 , ^- dime tylanilino) - 5- sulf amyl- benzoic acid

By replacing M-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with 3-nitro-5-sulfamyl-!+-(2,V-dimethylanilino)-benzoic acid, the compound was obtained with a melting point of 2 <1>+1-2<1>+1.5°C after recrystallization from ethanol.

Example 18.

3 - amino - ( p - kl or o an i 1 i no) - 5- sulf amy 1 - b e n z o e s y r e

A.. ^-( p- chloroanilino)- 3- nitro- 5- sulfamyl- benzoic acid

By replacing m-toluidine in example 10A with p-chloroaniline (39 g), the compound was obtained with a melting point of 2<1>+1-2<t>f<:>3°c after recrystallization from ethanol and drying in vacuum .

B. 3-amino-If-(p-chloroanilino)-5-sulf amyl-benzoic acid

A mixture of h-(p-chloroanilino)-3-nitro-5-sulfamyl-benzoic acid (7.3 g) > water (50 ml) and concentrated aqueous ammonia (15 ml) was stirred at 25°C and a solution of sodium dithionite (13.5

g) in water (50 ml) was added dropwise. After 1 hour, the pH of the reaction mixture was adjusted to 2.5 and the precipitated reaction product was filtered off. After repeated recrystallizations from aqueous ethanol and after drying for h hours in vacuum, the 3-amino-^f-(p-chloroanilino)-5-sulfa amyl-benzoic acid was obtained with a melting point of 273-271<f>°C

Example 19.

3- amino- h -( p- hydroxyanilino)- 5- sulf amy1- benzo e syr e

A. h —( p- hydroxyanilino)- 3- nitro- 5- sulfamyl- benzoic acid

By replacing m-tuluidine in example 10A with p-aminophenol (2*+.5 g), the compound was obtained with a melting point of 262°C (decomposition) after recrystallization from aqueous ethanol and water.

B. 3- amino- 1!— ( p- hydroxyanilino) - 5- sulf amyl- benzoic acid

. By replacing 3-nitro-U-phenoxy-5-sulfamyl-benzoic acid in Example IB with h-(p-hydroxyanilinino)-3-nitro-5-sulfamyl-benzoic acid (10 g) the compound was obtained with a melting point of 296 °c (decomposition).

Example 20.

3- amino - M-- cyclohexylamino- 5- sulf amyl- benzoic acid

A. ^- cyclo- hexylamino- 3- nitro- 5- sulphamyl- benzoic acid

By replacing m-toluidine in example 10A with cyclohexylamine (30 g), the compound was obtained with a melting point of 185-186°C after recrystallization from aqueous ethanol and drying in vacuum.

B. 3-amino-^-cyclohexylamino-5-sulfamyl-benzoic acid

By replacing 3-nitro-^--phenoxy-5-sulfamyl-benzoic acid in Example IB with 1f-cyclohexylamino-3-nitro-5-sulfamyl-benzoic acid (15 g) the compound was obtained with a melting point of 233° C (cleavage) .

Example 21.

Vamino- 1+- benzylamino- 5- sulfamyl- benzoic acid

A. ^-- benzylamino- 3- nitro- 5- sulf amyl- benzoic acid

A mixture of 1+-chloro-3-nitro-5-sulf amyl-benzoic acid (8, h g), benzylamine (12.8 g) and water (kO ml) was stirred at room temperature for 3 h. After standing for 30 minutes the liquid was decanted, water (100 ml) was added and the 1f-benzylamino-3-nitro-5-sul-familyl-benzoic acid was precipitated by addition of hydrochloric acid. After collection and recrystallization from aqueous methanol, the mp was 188 °C (decomposition).

B. 3- amino-^- benzylamino- 5- sulfamyl- benzoic acid

By replacing 1f-anilino-3-nitro-5-sulfamyl-benzoic acid in example 9B with *f-benzylamino-3-nitro-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 2l8-219°C after recrystallization from aqueous methanol.

Example 22.

3-amino-k-(g-phenylethylamino)-5-sulfamyl-benzoic acid

A. 3-nitro-^--(g-phenylethylamino)-5-sulf amyl-benzoic acid

A mixture of 1f-chloro-3-nitro-5-sulfamyl-benzoic acid (22.5 g), g-phenylethylamine (29 g) and water (200 ml) was refluxed for 2.5 hours. After cooling, the reaction mixture was adjusted to a pH of 9.5 and extracted with diethyl ether. The aqueous layer was then acidified by addition of hydrochloric acid and the precipitated 3-nitro-^-(g-phenylethylamino)-5-sulfa amyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the melting point was 208-208.5°C.

B. 3 - amino- 1!--( g - f phenylethylamino) - 5- sulf amyl- benzoic acid

By replacing <1>+-anilino-3-nitro-5-sulfamyl-benzoic acid-in example-, pel 9B with 3-nitro-^f-(g-phenylethylamino)-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 191+-195°C.

Example 23.

3- amino- 1+-( p- carboxyanilino)- 5- sulf amyl- benzoic acid

A. ^--( p- carbcksyan11±io)- 3- nitro- 5- sulf amyl- benzoic acid.

A suspension of 1f-chloro-3-nitro-5-sulf amyl-benzoic acid (22.<*>+ g)

and p-aminobenzoic acid (10.95 g) in water was adjusted to a pH of

7 by adding sodium bicarbonate.' The resulting solution was refluxed for 10 hours. After surging with

After hydrochloric acid and cooling, the precipitated h-(p-carboxyanilino)-3-nitro-5-sulfamyl-benzoic acid was collected by suction and recrystallized from aqueous ethanol. The melting point was 297°C (decomposition). The compound contained 1 mole of water of crystallization.

B. 3- amino- h -( p- carboxyanilino)- 5- sulfamyl- benzoic acid

By replacing 1f-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with <!>+-(p-carboxyanilino)-3-nitro-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 262°C (cleavage) after drying in vacuum at 115°C.

Example 2h.

3- amino-^ f - ( 2- me toxye tylamino) - 5- sulf amyl- benzoic acid

A. h -( 2- methoxyethylamino)- 3- nitro- 5- sulfamyl- benzoic acid

A mixture of <1>+-chloro-3-nitro-5-sulfamyl-benzoic acid (k, 2 g) 2-methoxyethylamine (5.6 g) and 50% ethanol (10 ml) was heated to 60°C for 1 hour. The ethanol was distilled from under reduced pressure and the ^-(2-methoxyethylamino)-3-nitro-5-sulfamyl-benzoic acid precipitated by addition of hydrochloric acid until pH 2. After recrystallization from water, the melting point was 192-19<i>f °C. The compound crystallized with 1 mole of water.

B. 3-amino- 1+-(2- methoxyethylamino)-5-sulfamyl-benzoic acid ^-(2-methoxyethylamino)-3-nitro-5-sulfamyl-benzoic acid (3.2 g) was dissolved in ln sodium hydroxide (10 ml) and hydrogenated after addition of moist Raney nickel (1 g). After the hydrogen uptake had become negligible, the catalyst was removed by filtration and the 3-amino-^-(2-methoxyethylamino)-5-sulfamyl-benzoic acid precipitated from the filtrate by adding hydrochloric acid until pH 3. After recrystallization from water, the melting point was 209- 211°C.

Example 25.

in.-. 3- amino- 1+- i sopropylamino- 5- sulf amyl- benzoic acid

A. i+-i isopropylamino-3-nitro-5-sulfamyl-benzoic acid Isopropylamine (120 ml) and water (8 ml) were added to ^-chloro-3-nitro-5-sulfamyl-benzoic acid (22.k g) under cooling off. The reaction mixture was then stirred for 5 days at room temperature. After evaporation in vacuo, the residue was triturated with n hydrochloric acid, after which the 1+-isopropylamino-3-nitro-5-sulfamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the acid was obtained with a melting point of 206°C (decomposition).

B. 3- amino-^- i sopropylamino- 5- sulphamyl- benzoic acid

By replacing V-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with <1>+-isopropylamino-3-nitro-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 226°C (decomposition).

Example 26.

3- amino- 1+-( N- methyl- ethanolamino)- 5- sulf amyl- benzoic acid

A. h -( N- methyl- ethanolamino)- 3- nitro- 5- sulphamyl- benzoic acid

A mixture of if-chloro-3-nitro-5-sulfamyl-benzoic acid (1-g), 2-methylamino-ethanol (19 g) and 50% ethanol (30 ml) in water was stirred at 50°C for 2 hours. After addition of water (100 ml), 1N hydrochloric acid was added until pH 2, which causes precipitation of 1+-(N-methyl-ethanolamino)-3-nitro-5-sulfamyl-benzoic acid. After recrystallization from water, the melting point was 125-127°C.

B. 3-Amino(N-methyl-ethanolamino)-5-sulfamyl-benzoic acid 1+-(N-methyl-ethanolamino)-3-nitro-5-sulfamyl-benzoic acid (9 g) was dissolved in water by adjusting pH to 8 using ln sodium hydroxide. Raney nickel catalyst (1 g) was added and the solution hydrogenated until the hydrogen uptake had become negligible. The catalyst was removed by filtration and the 3-amino-h-(N-methyl-ethanolamino)-5-sulfamyl-benzoic acid precipitated from the filtrate by the addition of <*>fn hydrochloric acid until pH 2.5. After recrystallization from water, the melting point was 209-211°C.

Example 27.

3- amino- 4-( 3- dimethylarinopropylamino)- 5- sulphamyl- benzoic acid

A. 4 - ( 3- dimethylaminopropylamino)- 3- nitro- 5- sulphamyl- benzoic acid

To a suspension of 4-chloro-3-nitro-5-sulfamyl-benzoic acid (22.4

g) in water (24 ml) 3-dimethylaminopropylamine (120 ml) was added with cooling. The reaction mixture was then heated to

lOO^C and held at this temperature for 2 hours. After cooling and evaporation in vacuo to dryness, the residue was dissolved in water (80 ml) and adjusted to a pH of 7.5 by adding 4N hydrochloric acid. The precipitated 4-(3-dimethylaminopropylamino)-3-nitro-5-sulfamyl-benzoic acid was collected by suction and recrystallized from water. The melting point was 262°C (decomposition).

B. 3-amino-4-(3-dimethylaminopropylamino)-5-sulfamyl-benzoic acid 4-(3-dimethylaminopropylamino)-3-nitro-5-sulfamyl-benzoic acid (6.92 g) was dissolved in 2N sodium hydroxide (25 ml ), and the reading was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure after adding a palladium-on-carbon catalyst (0.35 g of catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was adjusted to a pH of 8 by the addition of 4N hydrochloric acid. The precipitated 3-amino-4-(3-dimethyl-aminopropylamino)-5-sulfamyl-benzoic acid was collected by suction and recrystallized from water. After drying in vacuum at 115°C for 2 hours, the melting point was 264°C (decomposition).

Example 28.

3- amino- 4-( B- naphthylamino)- 5- sulfamyl- benzoic acid A. 4-( P- naphthylamino)- 3- nitro- 5- sulfamyl- benzoic acid A mixture of 4-chloro-3-nitro-5-sulfamyl -benzoic acid (28 g), 8-naphthylamine (43.2 g), dry ethanol (250 ml) and dry sodium acetate (8.2 g) were refluxed for 5 hours. The reaction mixture was then evaporated in vacuo and the residue triturated with hot hydrochloric acid (350 ml). The precipitated 4-(B-naphthylamino)-3-nitro-5-sulfomyl-benzoic acid was filtered off and recrystallized from aqueous ethanol. The compound was obtained as a monohydrate and had a melting point of 262°C (dec).

B. 3- amino- 4-( P- naphthylamino)- 5- sulphamyl- benzoic acid

By replacing 4-anilino-3-nitro-5-sulfamyl-benzoic acid in Example 9B with 4-(B-naphthylamino)-3-nitro-5-sulfamyl-benzoic acid, the compound was obtained with a melting point of 245°C.

Example 29.

3- amino- tf- f enylthio- 5- sulf amyl- benzoic acid

A. 3- nltro J+- phenylthio- 5- sulfamyl- benzoic acid

A mixture of 1f-chloro-3-nitro-5-sulfamyl-benzoic acid (28g), thiophenol (10.25ml) and 1N sodium bicarbonate (300ml) was refluxed for 3 hours. After cooling, the precipitated sodium salt of 3-nitro-^-phenylthio-5-sulfamyl-benzoic acid was filtered off. The sodium salt was dissolved in hot water (200 ml) and the 3-nitro-^f-phenylthio-5-sulfamyl-benzoic acid was precipitated by adding •+n hydrochloric acid until the pH was 1. After isolation and recrystallization from aqueous ethanol, the acid obtained with a melting point of 2<i>+5-2^7°C.

B. 3- amino-^- phenylthio- 5- sulfamyl- benzoic acid

A mixture of ammonium chloride (2.U-g), metallic iron powder (2h g), concentrated hydrochloric acid (0.1 ml) and water (60 ml) was heated to 90°C with stirring and 3-nitro-!+-phenylthio The -5-sulfamyl-benzoic acid (10 g) was added in small portions over 2 hours. The reaction mixture was stirred on a steam bath for an additional 2 hours. After adding dilute sodium hydroxide until the pH was 8, the hot reaction mixture was filtered and the filter cake was washed with hot, dilute sodium hydroxide. After adding Kn hydrochloric acid ten! the filtrate until its pH was 2 and cooling, the 3-amino-<1>+-phenylthio-5-sulfamyl-benzoic acid thus precipitated was filtered off and dried at 78°C in vacuum. The melting point was 285°C

Example 3Q.

3- amino- i4— n- butylthio- 5- sulf amyl- benzoic acid e

A. * 4— n- butylthio- 3- Ni tro- 5- sulf amyl- benzoic acid and sodium salt A mixture of 1f-chloro-3-nitro-5-sulfamyl-benzoic acid (28 g), butyl mercaptan (11 ml) and ln sodium bicarbonate (300 ml) was stirred at 90°C for 22 hours. After cooling, the precipitated Na salt of if-n-butylthio-3-nitro-5-sulfamyl-benzoic acid was filtered off. The salt was dissolved in hot water and the acid precipitated by adding <*>fn hydrochloric acid. After cooling, the acid was isolated and recrystallized

lysed from aqueous ethanol. The melting point was 173-17^-°C.

B. 3-amino-^-butylthio-5-sulfamyl-benzoic acid

To a solution of sodium dithionite (1559 g) in aqueous ammonia (13 g NH 2 in 150 ml water) was added ^-n-butylthio-3-nitro-5-sulfamyl-benzoic acid (8.35 g) in portions over the course of 1 hour while stirring. The reaction mixture was then heated on a steam bath for 30 minutes. The hydrochloric acid was added until the pH was 1 and heating was continued for 1 hour. After cooling, the pH was adjusted to 3 by the addition of 2N sodium hydroxide, and isopropanol (25 ml) was added. The precipitated S-amino-n-butylthio-5-sulfamyl-benzoic acid was filtered off and recrystallized from aqueous ethanol. The melting point was 223-22^°C.

Example 31.

3- amino- 5- sulf amyl-^ f-( o- tolylthio) - benzoic acid

A. 3- nitro- 5- sulph amyl-^--( o- tolylthio) - benzoic acid

A mixture of <1>+-chloro-3-nitro-5-sulfamyl-benzoic acid (28 g), O-thiocresol (12.1 g) and 1N sodium bicarbonate (300 ml) was refluxed for 3 hours. After cooling, the precipitated sodium salt of 3-nitro-5-sulfamyl-^-o-tolylthio-benzoic acid was filtered<*>; from and washed with ln sodium bicarbonate solution. Sodium salttc. was dissolved in hot water (250 ml) and the acid was precipitated by the addition of >+n hydrochloric acid (17 ml). After isolation, recrystallization from aqueous ethanol and drying at 115°C and 10 mm Hg for 3 hours, the acid was obtained with a melting point of 165-166°C.

B. 3-amino-5-sulfamyl-^-(o-tolylthio)-benzoic acid

By replacing U-butylthio-3-nitro-5-sulfamyl-benzoic acid in Example 32 B with 3-nitro-5-sulfamyl-^-(o-tolylthio)-benzoic acid (7.7 g), 3-amino -5-sulfamyl-^-(o-tolylthio)-benzoic acid obtained with a melting point of 277°C.

Example 32.

3- amino- 1+- ph enylsulf ony 1- 5- sulf amyl- benzoic acid A. 3- nitro- tf- ph enylsulf onyl- 5- sulf amyl- benzoic acid

A mixture of H-chloro-3-nitro-5-sulfamyl-benzoic acid (2h g),

benzenesulfinic acid (13 g), sodium acetate (16 g) and anhydrous ethanol (65 ml) were stirred at 78°C for 20 hours. After cooling, the precipitated sodium salt of 3-nitro-V-phenylsulfonyl-5-sulfamyl-benzoic acid was collected by suction. The sodium salt was dissolved in aqueous ethanol and the acid precipitated by acidification with hydrochloric acid. After collection by suction and recrystallization from aqueous ethanol, the 3-nitro-[f-phenylsulfonyl-5-sulfamyl-benzoic acid had a melting point of 291°C (decomposition).

B. 3- amino-^- phenylsulfonyl- 5- sulfamyl- benzoic acid

A suspension of 3-nitro-^-phenylsulfonyl-5-sulfamyl-benzoic acid (6 g) in water (300 ml) was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure after addition of Pd-on-carbon catalyst (0.3 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the reaction mixture was neutralized by adding 2N sodium hydroxide and from the resulting suspension the catalyst was removed by filtration. The filtrate was adjusted to a pH of 2.5 by the addition of

<*>fn hydrochloric acid and the precipitated 3-amino-1+-phenylsulfonyl-5-sulf amyl-benzoic acid were collected by suction. After recrystallization from aqueous ethanol, the acid had a melting point of 278°C (decomposition).

Example 3 3.

3- amino- If- n- butylsulf inyl- 5- sulf amyl- benzoic acid

A. h - n- butylsulfinyl- 3- nitro- 5- sulfamyl- benzoic acid

To a solution of 1f-n-butylthio-3-nitro-5-sulfamyl-benzoic acid

(10 g) in acetic acid (150 ml) perhydrol (30 ml 30% hydrogen peroxide in water) was added with stirring. After further stirring for 2 hours at room temperature, the reaction mixture was diluted with water (150 ml) and allowed to stand for 8 hours. The precipitated ^-n-butylsulfinyl-3-nitro-5-sulfamyl-benzoic acid was collected by suction, recrystallized from aqueous ethanol and dried in vacuo. The acid was obtained as a semi-hydrate with a melting point of 165°C (decomposition).

B. 3- amino-^-- n- butylsulf inyl- 5- sulf amyl- benzoic acid

To a solution of sodium dithionite (7.3 g) in water (50 ml) was added concentrated aqueous ammonia (25 ml), after which <*>+-n-butylsulfinyl-3-nitro-5-sulfamyl-benzoic acid ( K g) was added in portions at 25°C with stirring. The reaction mixture was heated on a steam bath for 30 minutes. Kn hydrochloric acid was then added until a pH of 1, while the heating was continued. After the evolution of sulfur dioxide had ceased, the reaction mixture was adjusted to a pH of 2.5 by adding 2N sodium hydroxide and cooled. The precipitated 3-amino-1+-n-butyl-sulfinyl-5-sulf amyl-benzoic acid was collected by suction, recrystallized from aqueous ethanol and dried in vacuo at 115°C. The acid was obtained with a melting point of 237°C (decomposition).

Example 34.

3- amino- 5- sulfamyl-^-( 3, B, B- trifluoroethoxide)- benzoic acid

A. 3- nitro- 5- sulf amyl-)+-( g , 3, 3- trifluoroethoxy) - benzoic acid

To a solution of sodium 3,p,p-trifluoroethanolate in p,B,p-trifluoroethanol (prepared by dissolving 2.1 g of sodium in <1>+5

ml p,g,p-trifluoroethanol) 1+-chloro-3-nitro-5-sulfamyl-benzoic acid C+.2 g) was added and the resulting solution was refluxed for 5 days. After evaporation of the reaction mixture in vacuo, water (50 ml) was added, and the aqueous solution was acidified with n hydrochloric acid. After settling in a clothes cupboard, the sediment was collected by suction. After several recrystallizations from aqueous ethanol, 3-nitro-5-sulfa amyl-1*-(3,p,3-trifluoroethoxy)-benzoic acid was obtained with a melting point of 195-197°C

B. 3-amino-5-sulfamyl-i+-(3iP-3-trifluoroethoxide)-benzoic acid 3-nitro-5-sulfamyl-1f-(3,p,p-trifluoroethoxide)-benzoic acid (2 g)

in water (30 ml) was adjusted to a pH of 9 by addition of lithium hydroxide and the resulting solution was hydrogenated at room temperature and at a hydrogen pressure of 1.1 atmospheres after addition of Pd-on-carbon catalyst (0.2 g of catalyst

which contains 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration and 3-ami-

The no-5-sulfamyl-4-(B,B,B-trifluoroethoxy)-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until a pH of 2.5. After recrystallization from aqueous ethanol and drying, the compound's melting point was 253-254°C.

Example 35.

3- amino- 4-( 4- benzyloxyphenoxy)- 5- sulfamyl- benzoic acid

A. n butyl- 4- chloro- 3- nitro- 5- sulphamyl- benzoate

A mixture of 4-chloro-3-nitro-5-sulfamyl-benzoic acid (10 g), n-butanol (100 ml) and concentrated sulfuric acid (2 ml) was refluxed for 4 hours, during which time 50 ml of oplds The solvent was slowly distilled from. After cooling, the n-butyl 4-chloro-3-nitro-5-sulfamyl-benzoate was isolated by filtration and recrystallized from n-butanol. The compound was obtained with a melting point of 140-141°C..

B. n- butyl 4-( 4- benzyloxyphenoxy)- 3- nitro- 4- sulfamyl benzoate

To a solution of sodium n-butylate in n-butanol (prepared from 0.074 g sodium and 16 ml dry n-butanol) 4-benzyloxy-phenol (0.64 g) and n-butyl 4-chloro-3-nitro- 5-sulfamyl benzoate added. The reaction mixture was refluxed for 4 hours and cooled, after which the precipitated n-butyl 4-(4-benzyloxyphenoxy)-3-nitro-5-sulfamyl-benzoate was isolated and recrystallized from n-butanol. After drying, the compound was obtained with a melting point of 138-144°C.

C. 4-( 4- Benzyloxyphenoxy)- 3- nitro- 5- sulphamyl- benzoic acid

A solution of n-butyl 4-(4-benzyloxyphenoxy)-3-nitro-5-sulfamyl-benzoate (7.3g) in 1N sodium hydroxide (120ml) was heated on a steam bath for h minutes. After cooling and acidification by addition of hydrochloric acid, the precipitated ^-(^-benzyloxy-phenoxy)-3-nitro-5-sulfamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying, the compound was obtained with a melting point of 2<1>+7°C.

D. 3- amino- U— (*+- benzyloxyph enoxy) - 5- sulfamyl- benzoic acid

A suspension of h-(^-benzyloxyphenoxy)-3-nitro-5-sulfamyl-benzoic acid (10 g) in water (250 ml) was adjusted to pH 11 by the addition of 1N sodium hydroxide. The resulting solution was hydrogenated at room temperature and at 1.1 atmospheres of hydrogen pressure after addition of a platinum oxide catalyst (0.kg). After the hydrogen uptake had become negligible, the catalyst was removed by filtration and the 3-amino-^f-(^-benzyloxyphenoxy)-5-sulfamyl-benzoic acid was precipitated by adjusting the filtrate to pH 2.5 by adding <*>+n hydrochloric acid. After recrystallization from aqueous ethanol and drying, the compound was obtained with a melting point of 26°-265°C.

Example 36.

3- amino- 1+- f enoxy- 5- sulf amyl- benzoic acid

A. 3- nitro- U-- f enoxy- 5- sulf amyl- benz oyl chlor id

A mixture of 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid (5 g) and thionyl chloride (50 ml) was heated on a steam bath for 5 hours. After evaporation in vacuo to dryness, the compound was obtained as a crude product, which was used in the following step without further purification.

B. 3- nitro- 1+- f enoxy- 5- sulf amyl- benz amide.

3-nitro-^-phenoxy-5-sulfamyl-benzoyl chloride ( K g) was added in portions to liquid ammonia ( ho ml). Then excess ammonia was distilled off and the residue was triturated with water (50 mL). The precipitated 3-nitro-^-phenoxy-5-sulfamyl-benzamide was isolated by filtration and recrystallized twice from aqueous ethanol. After drying in vacuum, the compound was obtained with a melting point of 255-256°C.

C. 3- amino- If- f enoxy- 5- sulf amyl- benzamide

To a suspension of 3-nitro-^-phenoxy-5-sulfamyl-benzamide (2,<*>f

g) in water (25 ml) was added ln lithium hydroxide (10 ml). The resulting solution was hydrogenated at room temperature and at

1.1 atmospheres of hydrogen pressure after addition of Pd-on-carbon catalyst (0.2 g of catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was then adjusted to pH 7.5 by adding Kn hydrochloric acid. The precipitated S-amino-^-phenoxy-5-sulfamyl-benzamide was isolated and dried in vacuo. The compound was obtained with a melting point of 291-292°C.

D. 3- amino- lf- f enoxy- 5- sulf amyl- benzoic acid

A mixture of 3~amino-1+-phenoxy-5-sulf amyl-benzamide (lg) and

In sodium hydroxide (20 ml) was refluxed for 1 hour. After cooling, the 3-amino-β-phenoxy-5-sulfamyl-benzoic acid was precipitated from the reaction mixture by addition of 3-n hydrochloric acid until pH 2.5. After several recrystallizations from aqueous ethanol and drying, the compound was obtained with a melting point of 252-253 °C

Example 37.

3- amino- 5- acetylsulfa amyl- lf- f enoxy- benzoic acid

A.. 5-Acetylsulfamyl-3-nitro-^f-phenoxy-benzoic acid 3-nitro-^f-phenoxy-5-sulfamyl-benzoic acid (10 g) was dissolved in water (250 ml) by adjusting the pH to 8 at addition of ln lithium hydroxide. Acetic anhydride (12 g) was then added dropwise with stirring, and the pH was kept constant at pH 9 by means of 1N lithium hydroxide using an automatic titrator. After the acetic anhydride had been consumed, the reaction mixture was acidified by - addition of Kn hydrochloric acid. The precipitated 5-acetylsulfamyl-3-nitro-V-phenoxy-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. The compound was obtained with a melting point of 270-271°C.

B. 3- amino- 5- acetylsulfa amyl- M-- phenoxy- benzoic acid

By replacing 3-nitro-^-phenoxy-5-sulfamyl-benzoic acid in example -IB with 5-acetylsulfamyl-3-nitro-^-phenoxy-benzoic acid, the compound was obtained as a monohydrate with a melting point of 290-293°C.

Example 38.

3- n- butylamino-^ f- phenoxy- 5- sulfamyl- benzoic acid and its sodium salt

To a suspension of 3-aminoA-phenoxy-5-sulfamyl-benzoic acid (10 g) in n-butanol (200 ml) was added concentrated sulfuric acid (2 ml)

added while stirring. The reaction mixture was heated under reflux under such conditions that the water formed during the reaction was separated. When the NMR spectrum of a sample of the reaction mixture diluted with n-butanol showed at two doublets of the aromatic protons in the ring bearing the sulfa-myl group that more than 90$ of butyl 3-amino-^f-phenoxy-5-sulfa-mylbenzoate -intermediate that formed was converted to the corresponding 3-n-butylamino-benzoate, which caused a frequency shift to higher range, 2n sodium hydroxide (200 ml) was added and boiling was continued for h-5 minutes. After this saponification, the reaction mixture was neutralized to a pH of 8 by the addition of concentrated hydrochloric acid. After cooling, the sodium precipitated. It was filtered off and recrystallized from water (100 ml). The sodium salt which crystallized with 3 moles of water was then dissolved in boiling water (200 ml). Hydrochloric acid was added until the pH was 2.5 and, after cooling, the precipitated 3-n-butylamino-^-phenoxy-5-sulfamyl-benzoic acid was collected by filtration. After recrystallization from aqueous ethanol and drying, the compound was obtained which was pure with a melting point of 230-231°C.

Example 39.

Ethanolamine salt of 3- n- butylamino- i+- f enoxy- 5- sulf amyl- benzoic acid

3-n-Butylamino-^f-phenoxy-5-sulfamyl-benzoic acid (1.82 g) was dissolved in boiling ethanol (20 ml) and a solution of ethanolamine (0.3 g) in ethanol (15 ml) was added . After cooling, the precipitated ethanolamine salt was collected by filtration and recrystallized from ethanol. The melting point was 19<1>+-195°C.

Example * fQ.

Potassium salt of 3-n-butylamino- tf- f enoxy- 5- sulphamyl- benzoic acid

The ethanolamine salt of 3-n-butylamino-f-phenoxy-5-sulf amyl-benzoic acid (10 g) was dissolved in boiling water (50 ml) and aqueous saturated potassium chloride (5 ml) was added. After cooling, the precipitated potassium salt was collected by filtration and recrystallized from water. The salt was obtained as a hydrate.

Example hl.

Neutral calcium salt of 3-n-butylamino-^-phenoxy-5-sulfamyl-benzoic acid

The ethanolamine salt of 3-n-butylamino-^-phenoxy-5-sulfamyl-benzoic acid (^-.25 g) was dissolved in water (150 ml), an aqueous solution of calcium chloride (2 ml containing h0% CaCl2) was added under agitation. The precipitated calcium salt was collected by suction and dried. The salt contained 355 mol of water of crystallization.

Example h2.

Methyl 3- n- butylamino- i+- f enoxy- 5- sulf amyl- benzoate

A mixture of 3-n-butylamino-1f-phenoxy-5-sulfamyl-benzoic acid (3 g) and methanol (60 ml) was saturated with gaseous hydrochloric acid. The reaction mixture was allowed to warm during saturation. After cooling and standing for 5 hours, the reaction mixture was evaporated in vacuo and the residue was recrystallized from methanol (12 ml), whereby methyl 3-n-butylamino-^f-phenoxy-5-sulf amyl-benzoate was obtained with a melting point of l^t ^C.

Example h3.

Cyanomethyl 3- n- butylamino- lf- f enoxy- 5- sulf amyl- benzoate

A mixture of 3-n-butylamino-1+-phenoxy-5-sulf amyl-benzoic acid (1 g), chloroacetonitrile (0.625 g), triethylamine (0.28 g) and dry acetone (10 ml) was refluxed for 19 hours. After cooling, the formed triethylamine hydrochloride was removed by filtration, and the filtrate was evaporated in vacuo. To the residue, water (20 ml) and ethyl acetate (50 ml) were added and the pH of the aqueous layer was adjusted to pH 7.5. The organic layer was then separated, washed with dilute sodium bicarbonate, dried and evaporated in vacuo. The residue was recrystallized several times from chloroform/petroleum ether to give the cyanomethyl 3-n-butylamino-^-phenoxy-5-sulfamyl benzoate with a melting point of 159-161°C.

Example 1+ 4.

3- butylamino-l+-( 1+- sulf amyl phenoxy)-5- sulfamyl-benzoic acid To the chlorosulfonic acid (5 ml) 3-butylamino-lf-phenoxy-5-sulfa a-myl-benzoic acid (1 g) was added in portions while stirring and by keeping the temperature below !+5°C. The reaction mixture was stirred for 10 minutes and then poured into ice water (10 g ice and 20 ml water). The precipitated 3-butylamino-1)-(1+-chlorosulfonylphenoxy)-5-sulfamyl-benzoic acid was isolated by filtration and without further purification added to aqueous ammonia (10 ml containing 2.5 g of ammonia). Excess ammonia was removed by evaporation, and the resulting solution adjusted to pH 2.5 by addition of hydrochloric acid. The precipitated 3-butylamino-3-(k-sulfamylphenoxy)-5-sulfamyl-benzoic acid was isolated by filtration, recrystallized from aqueous ethanol and dried. The compound obtained had a melting point of 265°C.

Example approx.

3-n-Butylmethylamino-l+-f enooxy-5-sulf amyl-benzoic acid A suspension of 3-n-butylamino-l+-phenoxy-5-sulfamylbenzoic acid (1 g) in aqueous ethanol (20 ml ethanol and 20 ml water) as containing formaldehyde (0.35 g) was hydrogenated at room temperature and at 1.1 atmospheres of hydrogen pressure after addition of Pd-on-carbon powder catalyst (0.1 g of catalyst containing 10$ Pd). When the hydrogen uptake had become negligible, the reaction mixture was heated to 60°C, and the catalyst was filtered off. After adding water (15 ml) to the filtrate and cooling, the precipitated 3-n-butylmethylamino-^-phenoxy-5-sulfamyl-benzoic acid was collected by filtration and recrystallized from aqueous ethanol. After drying in vacuum at 115°C, the compound was obtained with a melting point of 159-162°C,

Example hf> .

3-n-butylamino-^-phenoxy-5-sulf amyl-benzamide

To a solution of 3-butylamino-^-phenoxy-5-sulfamylbenzoe-

acid (1 g) in dry acetone (10 ml) was added triethylamine (0.278

g). Methanesulfonyl chloride (0.315 g) in dry acetone (5 mL) was added to the reaction mixture with stirring. The upheaval was

continued for 1-g- hour at 20°C. The resulting solution of the mixed anhydride was added dropwise to aqueous ammonia (30 mL containing 7 g of ammonia) with stirring. Excess ammonia and acetone were then removed by evaporation under reduced pressure. The pH of the reaction mixture was adjusted to 7.5 using Kn hydrochloric acid, and the precipitated 3-t>utilamino-1+-phenoxy-5-sulfamyl-benzamide was isolated by filtration and recrystallized

cert several times from aqueous ethanol. After drying in vacuum at 115°C, the compound was obtained with a melting point of 223-22lt-°C.

Example 47.

3- benzylamino- 1+- phenylthio- 5- sulf amyl- benzoic acid

A suspension of 3-amino-1+-phenylthio-5-sulf amyl-benzoic acid (^.05

g) in water (100 ml) was adjusted to pH 7.5 by the addition of 1N lithium hydroxide. Benzyl bromide (2.2 g) was added and, with stirring, the pH was maintained at 7.5 by automatic titration with lithium hydroxide. After the base consumption had become negligible, the pH was adjusted to 2.5 by adding dilute hydrochloric acid. The precipitated 3-benzylamino-lf-phenylthio-5-sulf amyl-benzoic acid was collected and recrystallized from ethanol, after which the compound was obtained with a melting point of -221+-225°C.-- ■ -- "~-

3- benzylamino- lf- f enoxy- 5- sulf amyl- benzoic acid

By replacing 3-amino-^-phenylthio-5-sulfamyl-benzoic acid in steps

C in the example above with 3-amino-1+-phenoxy-5-sulfamyl-benzoic acid (3.8 g) 3-benzylamino-^-phenoxy-5-sulfamyl-benzoic acid was obtained after recrystallization from dilute ethanol with a melting point at 261+-265°C.

Example 48.

3- n- butvlamino- M— phenylsulf inyl- 5- sulf amyl- benzoic acid

A. 3..- n- butylamino- lf- phenylthio- 5- sulfamyl- benzoic acid and its

sodium salt

To a suspension of 3-amino-1+-phenylthio-5-sulfamyl-benzoic acid O-O g) in n-butanol (200 ml) was added concentrated sulfuric acid (2 ml) with stirring. The reaction mixture was heated under reflux under such conditions that the water formed during the reaction was separated. When the NMR spectrum of a sample of the reaction mixture diluted with n-butanol showed by the two doublets of the aromatic protons in the ring carrying the sulfamyl group that more than 90$ of butyl 3-amino-<!>+-phenylthio-5- the sulfamyl benzoate intermediate which formed was converted to the corresponding 3-n-butylaminobenzoate, which caused a frequency shift to a higher region, 2N sodium hydroxide (200 ml) was added and boiling was continued for KJ minutes. After this saponification, the reaction mixture was neutralized to pH 8 by the addition of concentrated hydrochloric acid. After cooling, the sodium salt of 3-n-butylamino-V-phenylthio-5-sulfamyl-benzoic acid precipitated. It was filtered off and recrystallized from water (100 ml). The sodium salt which crystallized with 3 mol of water was then dissolved in boiling water (200 ml), in which hydrochloric acid was added until the pH was 2.5?g after cooling the precipitated 3-n-butylamino-^-phenylthio-5-sulfamyl- benzoic acid collected by filtration. After recrystallization from aqueous ethanol and drying, the pure compound was obtained with a melting point of 203-2010°C.

B. 3- n- butylamino-^- phenylsulfinyl- 5- sulfamyl- benzoic acid

To a suspension of 3-n-butylamino-^-phenylthio-5-sulfamyl-benzoic acid (0.5 g) in acetic acid (5 ml) was added with stirring perhydrol (2.5 ml 30$ hydrogen peroxide in water). The reaction mixture was stirred for a further 2K hours at 30°C, after which the 3-n-butylamino-1+-phenylsulfinyl-5-sulf amyl-benzoic acid was collected by suction and washed with aqueous acetic acid. After recrystallization from aqueous ethanol, the compound was obtained with a melting point of 203-20^°C (decomposition).

Example 49.

lf- anilino- 3- benzylamino- 5- sulfamyl- benzoic acid

A. Ethyl ^- anilino-^- benzylamino- 5- sulfamyl- benzoate

A mixture of 3-amino-<1>+-anilino-5-sulfamyl-benzoic acid (2 g), benzyl bromide (3 g) and ethanol (50 ml 99.9$) was refluxed for 8 hours. After cooling, the ethyl β-anilino-3-benzylamino-5-sulfamyl benzoate crystallized and was collected by suction. After recrystallization from ethanol, the melting point was 160-161°C.

B. ^-anilino-3-benzylamino-5-sulfamyl-benzoic acid

A solution of ethyl <1>+-anilino-3-benzylamino-5-sulfamyl-benzoate (1 g) in 1N sodium hydroxide (15 ml) was heated on a steam bath for 1 hour. After cooling, the ^-anilino-3-benzylamino-5-sulfamyl-benzoic acid was precipitated by the addition of acetic acid, collected and recrystallized from 60% ethanol in water. The melting point was 2<l>f8-2<l>+9°C.

Example 50.

tf-anilino-3-benzylamino-5-phenylsulfamyl-benzoic acid

A. Ethyl i+- anilino- 3- benzylamino- 5- phenylsulfamyl- benzoate

By replacing in example 52A 3-amino-!+-anilino-5-sulfamyl-benzoic acid (2 g) with 3-amino-1-anilino-5-phenylsulfamyl-benzoic acid C^,^ g) and increasing the amount of benzyl bromide to 3 .9 g of ethyl h-anilino-3-benzylamino-5-phenyl-sulfamyl-benzoate was obtained with a melting point of 166-167°C.

B. 1f-anilino-3-benzylamino-5-phenylsulfamyl-benzoic acid

A solution of ethyl >+-anilino-3-benzylamino-5-phenylsulfamyl-benzoate (3 g) in 1N sodium hydroxide (30 ml) was heated at

steam bath for 1 hour. The 1f-anilino-3-benzylamino-5-phenylsulfamyl-benzoic acid was precipitated by addition of 1f hydrochloric acid until pH 2 and recrystallized from acetone-water and 80% ethanol in water. The melting point was 2<l>+3°C.

Example 51.

3-Benzylamino-^-phenylsulfinyl-5-sulfamyl-benzoic acid To a suspension of 3-benzylamino-^-phenylthio-5-sulfamyl-benzoic acid (0.8 g) in acetic acid (20 ml) was added perhydrol (1.5 ml 30% hydrogen peroxide in water) while stirring. The reaction mixture was stirred for a further 75 hours at room temperature, after which the 3-benzylamino-V-phenylsulfinyl-5-sulfamyl-benzoic acid was collected by filtration and washed with acetic acid. After recrystallization from aqueous methanol and drying, the acid had a melting point of 231+°C.

Example 5 2.

3- benzylamino- lf- n- butylsulfinyl- 5- sulf amyl- benzoic acid A mixture of 3-amino-1+-n-butylsulfinyl-5- sulf amyl-benzoic acid (2 g), benzyl bromide (3.5 g) and dry ethanol (20 mL) was refluxed for 16 h. The reaction mixture was evaporated in vacuo. The residue containing the ethyl S-benzylamino-n-butylsulfinyl-5-sulfamyl-benzoate was saponified by adding 1N sodium hydroxide (30 ml) and standing for 16 hours at room temperature. After extraction with diethyl ether, the aqueous layer was adjusted to a pH of 7A by addition of hydrochloric acid and the sodium salt of 3-benzylamino-<1>+-n-butylsulfinyl-5-sulfamyl-benzoic acid was precipitated by addition of sodium chloride (5 g). The sodium salt was isolated and recrystallized from a small amount of water. The salt was dissolved in aqueous ethanol (25% ethanol in water) and the 3-benzylamino-<!>+-n-butylsulfinyl-5-sulfamyl-benzoic acid was precipitated by the addition of hydrochloric acid until a pH of 3. After recrystallization tion from aqueous ethanol and drying in vacuo, the compound was obtained as a monohydrate with a melting point of 182°C (decomposition).

Example 53.

3-( 3,^- methylenedioxybenzylamino)-^- phenoxy- 5- sulfamyl-benzoic acid

To a suspension of 3-amino-<1>+-phenoxy-5-sulfamyl-benzoic acid (1.5^ g) in acetic acid (30 ml) was added piperonal (0.75 g)• After the addition of platinum oxide (25 mg ) and a catalytic amount of p-toluenesulfonic acid, the reaction mixture was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure, until the hydrogen uptake had become negligible. The reaction mixture was then filtered by suction. The filter cake was suspended in water (100 ml) and the pH was adjusted to 8.5 by the addition of lithium hydroxide. After the catalyst was removed from the resulting solution, the 3-(3,^-methylenedioxybenzylamino)-k-phenoxy-5-sulfamyl-benzoic acid was precipitated from the filtrate by the addition of hydrochloric acid until the pH was 3. After recrystallization from methanol, the melting point was 229-230°C.

Example 54.

3- n- hexylamino- l+- f enoxy- 5- sulf amyl- benzoic acid and its sodium salt

A. n- hexyl 3- n- hexylamino- l+- f enoxy- 5- sulf amyl- benzoate

A mixture of 3-amino-^-phenoxy-5-sulf amyl-benzoic acid (k, 62 g) 1-bromo-n-hexane (5 g), methanesulfonic acid (0.05 ml) and n-hexanol (<1 >+0 ml was refluxed for 60 hours. After cooling, the precipitated n-hexyl 3-n-hexylamino-1+-phenoxy-5-sulfa amyl benzoate was collected and recrystallized from hexanol. Melting point was 137-138°C

B. 3- n- hexylamino- l+- f enoxy- 5- sulf amyl- benzoic acid and its

sodium salt

n-Hexyl 3-n-hexylamino-^-phenoxy-5-sulfamyl-benzoate (2 g) was dissolved in 1N sodium hydroxide (30 ml) and heated on a steam bath for 1 hour. The reaction mixture was then adjusted to a pH of 8 by the addition of <1>+n hydrochloric acid. After cooling, the sodium salt of 3-n-hexylamino-^-phenoxy-5-sulfamyl-benzoic acid was collected by suction and dried. The sodium salt was dissolved in hot water (100 ml) and the acid was precipitated by the addition of hydrochloric acid until the pH was 2.5. After cooling, the acid was collected and recrystallized from aqueous ethanol. The melting point was 221-223°C.

Example <5>. 0.

3- allylamino- >-+- f enoxy- 5- sulph amyl- benzoic acid

A. Ethyl 3- allylamino- 1+- phenoxy- 5- sulf amyl- benzoate

A mixture of 3-amino-1+-phenoxy-5-sulfa amyl-benzoic acid (3.08 g), allyl bromide (7.25 g) and dry ethanol was refluxed for 2 hours. After cooling, the precipitated ethyl 3-allylamino-^-phenoxy-5-sulfamyl-benzoate was filtered off and recrystallized from ethanol. The melting point of the ester was 153-15+ °C.

B. 3- Allylamino- lf- f enoxy- 5- sulf amyl- benzoic acid

Ethyl 3-allylamino-1f-phenoxy-5-sulfamyl-benzoate (1g) was dissolved in 1N sodium hydroxide (15ml) and allowed to stand at room temperature for 2<*>+ hours. Then water (5 ml) was added and the pH was adjusted to 3 by adding 1N hydrochloric acid. The precipitated 3-allylamino-^-phenoxy-5-sulfamyl-benzoic acid was collected and dried. The melting point was 223-225°C.

Example 56.

K - f enoxy- 3- propargylamino- 5- sulphamyl- benzoic acid

A. Ethyl h - f enoxy- 3- propargylamino- 5- sulphamyl- benzoate

By replacing the allyl bromide in example 55A with propargyl bromide (h, 8 g) and extending the reaction time to h8 hours, ethyl β-phenoxy-3-propargylamino-5-sulfamyl-benzoate was obtained with a melting point of 189-190°C.

B. 1+- phenoxy- 3- propargylamino- 5- sulfamyl- benzoic acid

By replacing ethyl 3-allylamino-^-phenoxy-5-sulfamyl-benzoate in Example J5B with ethyl 1+-phenoxy-3-propargylamino-5-sulfamyl-benzoate and by recrystallizing from dilute ethanol, h-phenoxy-3- propargylamino-5-sulfamyl-benzoic acid obtained with a melting point of 222-223°C.

Example 57.

h - phenoxy- 3- n- propylamino- 5- sulphamyl- benzoic acid A. Ethyl- lf- f enoxy- 3- n- propylamino- 5- sulphamyl- benzoate

A solution of ethyl 3-allylamino-1+-phenoxy-5-sulfamyl-benzoate (1.65 g) in ethanol (150 ml) was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure after addition of a palladium-on-carbon catalyst (0.6 g catalyst containing 10$ Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was recrystallized twice from aqueous ethanol, resulting in ethyl 1f-phenoxy-3-n-propylamino-5-sulfamyl-benzoate with a melting point of 150-151°C.

B. h - f enoxy- 3- n- propylamino- 5- sulphamyl- benzoic acid

Ethyl Lt-phenoxy-3-n-propylamino-5-sulfamyl-benzoate (1 g) was dissolved in 1N sodium hydroxide (15 ml) and heated on a steam bath for 1 hour. After cooling, the 1f-phenoxy-3-n-propylamino-5-sulfamyl-benzoic acid was precipitated by the addition of hydrochloric acid until the pH was 2.5. The melting point was 223-22<l>+°C.

Example 58.

3- e tylamino- i+- f enoxy- 5- sulph amyl- benzo oe acid

A mixture of 3-amino-l-phenoxy-5-sulfamyl-benzoic acid (3.08 g), ethyl iodide (20 ml) and ethanol (20 ml) was refluxed for 6 days. After cooling, the reaction mixture was evaporated to dryness and the residue was washed with a little ethanol followed by diethyl ether. The ethyl 3-ethylamino-[f-phenoxy-5-sulfamyl-benzoate which is obtained was dissolved in 1N sodium hydroxide (35 ml) and heated on a steam bath for 30 minutes. After cooling, the reaction mixture was adjusted to pH 2.5 by adding hydrochloric acid, and the precipitated 3-ethylamino-1+-phenoxy-5-sulfamyl-benzoic acid was isolated by filtration. After recrystallization from ethanol and drying in vacuum at 115°C, the compound was obtained with a melting point of 236-237°C.

Example 59.

3-n-pentylamino-M--phenoxy-5-sulf amyl-benzoic acid

A. n- pentyl 3- n- pentylamino- i+- f enoxy- 5- sulf amyl- benzoate

A mixture of 3-amino-l-phenoxy-5-sulfamyl-benzoic acid (6 g), n-pentanol (60 ml) and concentrated sulfuric acid (0.5 ml) was refluxed for 2 hours. After cooling, the precipitated n-pentyl 3-n-pentylamino-1+-phenoxy-5-sulfamyl-benzoate was isolated by filtration and recrystallized from n-pentanol. After drying in vacuum, the compound was obtained with a melting point of 138-139°C.

B. 3- n- pentylamino- 1+- f enoxy- 5- sulf amyl- benzoic acid

A mixture of n-pentyl 3-n-pentylamino-1f-phenoxy-5-sulfamyl-benzoate (K,J g) and 1N sodium hydroxide (70 ml) was heated on a steam bath for 1 hour. After cooling, the reaction mixture was adjusted to a pH of 2.5 by adding Kn hydrochloric acid. The precipitated 3-n-pentylamino-1f-phenoxy-5-sulfamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying in vacuum, the compound was obtained with a melting point of 223-22l+°C.

Example 60.

3- benzylamino- U--(^- benzyloxyphenoxy) - 5- sulf amyl- benzoic acid

A. Ethyl 3- benzylamino- i+- (*+- benzyloxyphenoxy) - 5- sulf amyl-benzoate

A mixture of 3-amino-3-C+-benzyloxyphenoxy)-5-sulfamyl-benzoic acid (K g), benzyl bromide (3.1 g) and ethanol (60 ml) was refluxed for K hours. After cooling, the precipitated ethyl 3-benzylamino-Li-(i+-benzyloxyphenoxy)-5-sulfa amyl-benzoate was isolated by filtration and recrystallized from ethanol. The compound was obtained with a melting point of 166°C.

B. 3- benzylamino- lf-( lf- benzyloxyphenoxy) - 5- sulfamyl- benzoic acid

A solution of ethyl 3-benzylamino-^-(if-benzyloxyphenoxy)-5-sulfamyl-benzoate (2 g) in 1N sodium hydroxide (KJ ml) was allowed to stand at room temperature for <!>+0 hours. The reaction mixture was then adjusted to pH 2.5 by the addition of hydrochloric acid. The precipitated 3-benzylamino-^-(1+-benzyloxyphenoxy)-5-sulfamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol.-After drying, the compound was obtained with a melting point of 2^-9-2 51 °C .

Example 61.

3- benzylamino- l+-( I+- hydroxyphenoxy) - 5- sulphamyl- benzoic acid A suspension of S-benzylamino-^-(^-benzyloxyphenoxy)-5- sulphamyl-benzoic acid (0.5 g) in water (5 ml) was adjusted to a pH of 11 by addition of ln sodium hydroxide. The resulting solution was hydrogenated at room temperature and 1.1 atmospheres of hydrogen pressure after addition of Pd-on-carbon powder catalyst (0.025 g of catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and from the filtrate the 3-benzylamino-lf-(lf-hydroxyphenoxy)-5-sulfa amyl-benzoic acid was precipitated by the addition of hydrochloric acid until a pH of 2. After isolation by filtration and recrystallization from aqueous ethanol, the compound was obtained with a melting point of 276-277°C (decomposition).

Example 6 2.

3- furfurylamino- U-- ph enooxy- 5- sulf amyl- benzoic acid and its sodium salt

A. Sodium salt of 3- amino- 1+- f enoxy- 5- sulf amyl- benzoic acid

A suspension of 3-amino-<>>+-phenoxy-5-sulfamyl-benzoic acid (10 g) in water (25 ml) was adjusted to a pH of 8 by addition of 1N sodium hydroxide at 80°C. After cooling, the precipitated sodium salt was collected by suction and dried in vacuum at 115°C.

B. Sodium salt of 3-furfurylamino-1+-phenoxy-5-sulf amyl-benzoic acid

A mixture of the sodium salt of 3-amino-^-phenoxy-5-sulfamyl-benzoic acid (5 g), furfural (2.2 g) and methanol (75 ml) was refluxed for 5 hours. The reaction mixture was then cooled to 0°C and sodium borohydride, NaBH 2 , (2.2 g) was added in portions over 1 hour while stirring and maintaining the temperature at 0-5°C. After standing for 16 hours, the solvent was distilled off in vacuo, and the residue dissolved in water (<1>+5 ml). The solution was adjusted to a pH of 7.5 by adding hydrochloric acid and cooled. The precipitated sodium salt of 3-furfurylamino-β-phenoxy-5-sulfa amyl-benzoic acid was collected by suction, recrystallized from water and dried. C. 3-furfurylamino- lf- f enoxy- 5- sulf amyl- benzoic acid The sodium salt of 3-furfurylamino-<>>+-phenoxy-5-sulfamyl-benzoic acid (1 g) was dissolved in water (50 ml) at 50° C and acetic acid (mml) were added dropwise with stirring. After cooling, the precipitated acid was collected by suction and recrystallized from aqueous ethanol. The melting point was 219-220°C.

Example 63.

3 , lf-dibenzylamino-5-sulfamyl-benzoic acid and its sodium salt A suspension of 3-amino~<1>+-benzylamino-5-sulfamyl-benzoic acid

(1 g) in water (20 ml) was adjusted to a pH of 7.5 by the addition of 1N sodium hydroxide. To the solution was added benzyl bromide (0.5^+ g) and, with stirring, the pH was maintained at 7.5 at

automatic titration with sodium hydroxide. After the base consumption had become negligible, the precipitated sodium salt of 3,^-dibenzylamino-5-sulfamyl-benzoic acid was collected by suction and washed with a little water. The sodium salt was dissolved in aqueous ethanol (62 ml containing 25% ethanol) and the acid was precipitated by the addition of acetic acid (2 ml). The acid was collected by suction and dried. The melting point was 205°C.

Example 64.

3- Benzylamino-M-(B-phenylethylamino)-5-sulfamyl-benzoic acid A mixture of 3-amino-<l>+-(B-phenylethylamino)-5-sulfamyl-benzoic acid (3.35 g), benzyl bromide (5.3 g) and anhydrous ethanol (30 ml) were refluxed for K8 hours. After cooling, the precipitated ethyl ester was collected by suction, recrystallized from ethanol and saponified by heating in 1N sodium hydroxide (30 ml) for 1 hour. The 3-benzylamino-<I>+-(8-phenylethylamino)-5-sulfamyl-benzoic acid was precipitated at room temperature by the addition of ^+n hydrochloric acid until the pH was 2.5- After recrystallization from aqueous ethanol, the compound was obtained with a melting point at 203°C.

Example 65.

3- Benzylamino-1+-isopropylamino-5-sulfamyl-benzoic acid A mixture of 3-amino-1+-isopropylamino-5-sulfamyl-benzoic acid (2.62 g), benzyl bromide ( K, 28 g) and anhydrous ethanol ( 25 ml) was refluxed for 2K hours. The reaction mixture was evaporated in vacuo, 1N sodium hydroxide (30 mL) was added and the mixture heated on a steam bath for 1 hour. After cooling down

and extraction with diethyl ether, the aqueous layer was adjusted to a pH of 3 by addition of Kn hydrochloric acid. The precipitated 3-benzylamino-3-isopropylamino-5-sulfamyl-benzoic acid was collected by suction and recrystallized from aqueous ethanol. The melting point was 233-<2>3^°C.

Example 66.

Ethyl 3- benzylamino- 5- sulfamyl- lf-( m- trifluoromethylphenoxy-benzoate

A mixture of 3-amino-5-sulfamyl-1-(m-trifluoromethyl-phenoxy)-benzoic acid (1.82 g), benzyl bromide (2 g) and anhydrous ethanol (15 ml) was refluxed for 7 hours. The solution was cooled and the precipitated ethyl 3-benzylamino-5-sulfamyl-U-(m-trifluoromethylphenoxy)-benzoate was collected by suction. After recrystallization from ethanol, the melting point was 166-168°C.

Ethyl 3- benzylamino- Lh-( p- methoxyanilino)- 5- sulf amyl- benzoate

By replacing 3-amino-5-sulfa amyl-1f-(m-trifluoromethylphenoxy)-benzoic acid with 3-amino-1+-(p-methoxyanilino)-5-sulfa amyl-benzoic acid (1.69 g) and extending the heating time to 20 hours, the compound was obtained with a melting point of 1<1>+5°C.

Ethyl 3 - benzylamino- 1* - (m- me toxy anilino) - 5- sulf amyl- benzoate

By replacing 3-amino-5-sulfa amyl-^f-(m-trifluoromethylphenoxy)-benzoic acid with 3-amino-^-(m-methoxyanilino)-5-sulfamyl-benzoic acid (1.69 g) and extending the heating time to 20 hours, the compound was obtained with a melting point of 1<1>+9-152°C.

Ethyl 3- benzylamino- I+-( p- methoxyphenoxy)- 5- sulfamyl- benzoate

By replacing 3-amino-5-sulfamyl-^-(m-trifluoromethylphenoxy)-benzoic acid with 3-amino->+-(p-methoxy enoxy-5-sulfa amyl-benzoic acid (1.69 g) the compound was obtained as a precipitate during the heating time After collection by suction and recrystallization from acetone, the compound had a melting point of 189-190°C.

Ethyl 3- benzylamino-)+- cyclohexylamino- 5- sulf amyl- benzoate

By replacing 3-amino-5-sulfamyl-1+-(m-trifluoromethylphenoxy)-benzoic acid with 3-amino-1+-cyclohexylamino-5-sulfamyl-benzoic acid (1.5 g) and adding water (13 ml) to the cooled reaction mixture, the compound was obtained with a melting point of 176-177°C.

Ethyl 3-benzylamino-5-sulfamyl-^-(m-trifluoromethylanilino)-benzoate

By replacing 3-amino-5-sulfamyl-^-(m-trifluoromethylphenoxy)-benzoic acid with 3-amino-5-sulfamyl-4-(m-trifluoromethylanilino)-benzoic acid (1.8 g) and increasing the amount of ethanol to 50 ml, the compound was obtained with a melting point of 189-190°C.

ate y_l 3^benzylamino-4-(B- naphthylamino)- 5- sulf amyl- benzoate Vod to replace 3-amino-o-sulf c.myl-4-(m-trifluoro::,. ty If :: iocyl)-benzoic acid with 3-amino-4-(B-naphthylamino)-5-sultamyl-benzoic acid (1.8 g) and increasing the amount of ethanol to 25 ml, the compound was obtained with a melting point of 199-201UC.

Example 67.

Ethyl 3-benzylamino-5-sulfamyl-4-(m-toluidino)-benzoate

A mixture of 3-amino-5-sulfamyl-4-(m-toluidino)-benzoic acid (1.5 g), benzyl bromide (2.5 g) and anhydrous ethanol (50 ml) was heated under reflux for 10 hours. The resulting solution was cooled and the precipitated ethyl 3-benzylamino-5-sulfamyl-4-(m-toluidino)-benzoate collected by suction. After recrystallization from ethanol, the compound had a melting point of 169-170°C.

Ethyl 3- benzylamino- 5- sulphamyl- 4-( p-toluidino)- benzoate

By replacing 3-amino-o-sulfamyl-4-(m-toluidino)-benzoic acid with 3-amino-5-sulfamyl-4-(p-toluidino)-benzoic acid, the compound was obtained with a melting point of 159-160°C .

Ethyl 3- benzylamino- 4-( p- chloroanilino)- 5- sulfamyl- benzoate

By replacing 3-amino-o-sulfamyl-4-(m-toluidino)-benzoic acid with 3-amino-4-(p-chloroanilino)-5-sulfamyl-benzoic acid (2 g) the compound was obtained with a melting point of 187 °C.

Ethyl 3- benzylamino- 4-( 2, 4- dimethylanilino)- 5- sulfamyl- benzoate By replacing 3-amino-5-sulfamyl-4-(m-toluidino)-benzoic acid. with 3-amino-4-(2,4-dimethylanilino)-5-sulfamyl-benzoic acid (2 g) the compound was obtained with a melting point of 167-168°C.

Example 68.

Ethyl 3-benzylamino-4-n-butylthio-5-sulfamyl benzoate

A mixture of 3-amino-4-n-butylthio-5-sulfamyl-benzoic acid (1.5 g), benzyl bromide (2.1 g) and anhydrous ethanol (20 ml) was refluxed for 24 hours. After the first 7 hours of refluxing, benzyl bromide (0.7 g) was added. After cooling, the precipitated ethyl 3-benzylamino-4-n-butylthio-5-sulfamyl-benzoate was collected and recrystallized from ethanol, after which the compound was obtained with a melting point of 151-157°C.

Ethyl 3- benzylamino- 4-( p- carboxyanilino)- 5- sulf amyl- benzoate By replacing 3-amino-4-n-butylthio-5-sulfamyl-benzoic acid with 3-amino-4-(p- carboxyanilino)- 5-sulfamyl-benzoic acid (1.7 g) the compound was obtained with a melting point of 161°C.

Example 69.

Ethyl 3- benzvlamino- 5- sulfamyl- 4-( 3, B, P- trifluoroethoxy)- benzoate A compound of 3-amino-5-sulfamyl-4-(3,3,3-trifluoroethoxy)-benzoic acid (0.6 g), benzyl bromide (1.2 g) and dry ethanol (8 ml) were refluxed for 5 h. After cooling, the precipitated ethyl 3-benzylamino-5-sulfamyl-4-(3,3,3-trifluoroethoxy)-benzoate was collected by suction and recrystallized from dry ethanol. After drying, the compound had a melting point of 163-165°C.

Example 70.

^-substituted 3-benzylamino-5-sulfamyl-benzoic acids by saponification of the corresponding ethyl esters

General procedure;

The corresponding ethyl ester (2 g) prepared as in Examples 71 to 75 was dissolved in 1N sodium hydroxide (30 ml) and heated on a steam bath for 1 hour. After cooling, the acid was precipitated by adding hydrochloric acid until the pH was 2.5, collected by suction, recrystallized from aqueous ethanol and dried at 115°C in vacuum.

The following acids were obtained: 3-benzylamino-5-sulfamyl-1+-(m-toluidino)-benzoic acid with a melting point of 226-227°C

3-Benzylamino-5-sulfamyl-^-(p-toluidino)-benzoic acid with a melting point of 217-218°C

3-benzylamino-^-(p-methoxyanilino)-5-sulf amyl-benzoic acid with a melting point of 207-208°C

3-benzylamino-5-sulfamyl-^-(m-trifluoromethylanilino)-benzoic acid with a melting point of 227-228°C after recrystallization from isopropanol.

3-benzylamino-lf-(p-chloroanilino)-5-sulfamyl-benzoic acid with a melting point of 2<l>+5-2<1>+6°C

3-Benzylamino-LH-(2,1+-dimethylanilino)-5-sulfamyl-benzoic acid with a melting point of 2<1>+5-2<1>+6°C.

3-Benzylamino-^f-(p-carboxyanilino)-5-sulfamyl-benzoic acid prepared from ethyl 3-benzylamino-U-(p-carbethoxyanilino)-5-sulfamyl-benzoic acid and precipitated at a pH of 1.5 , with a melting point higher than 300°C and containing 1/2 mol of water of crystallisation

3-Benzylamino-5-sulfamyl-<1>+-(o-tolylthio)-benzoic acid with a melting point of 227-228°C.

3-Benzylamino-^-(p-methoxyphenoxy)-5-sulfamyl-benzoic acid with a melting point of 230-232°C.

3-Benzylamino-5-sulfamyl-1-(m-trifluoromethylphenoxy)-benzoic acid with a melting point of 220-222°C.

3-benzylamino-^-(B-naphthylamino)-5-sulfamyl-benzoic acid with et

melting point of 26i-263°C.

3-benzylamino-4-cyclohexylamino-5-sulfamyl-benzoic acid with a melting point of 249-250°C.

3-benzylamino-<1>+-n-butylthio-5-sulfamyl-benzoic acid with a melting point of 210-211°C.

3-Benzylamino-5-sulfamyl-1+-(6,B,(3-trifluoroethoxy)-benzoic acid with a melting point of 230-232°C.

Example 71.

*+- anilino- 3- butylamino- 5- sulf amyl- benzoic acid

A mixture of 3-amino-1+-anilino-5-sulf amyl-benzoic acid (k g), n-butanol (50 ml) and concentrated H 2 SO 4 (0.k ml) was refluxed with a water separator for 5 days. The resulting solution of butyl 1f-anilino-3-butylamino-5-sulfamyl-benzoate was saponified by adding 2N sodium hydroxide and refluxing for kj minutes. After neutralization with hydrochloric acid, the reaction mixture was evaporated in vacuo. The residue was dissolved in hot water (50 ml) and the ^-anilino-3-butylamino-5-sulfamyl-benzoic acid was precipitated by addition of hydrochloric acid to pH 3. The crude acid was dissolved in diethyl ether

(50 mL) and undissolved impurities were filtered off. The ethereal solution was evaporated to dryness and the residue was recrystallized from acetone-water and aqueous ethanol, after which the compound was obtained with a melting point of 230-231°C.

Example 7' 2.

3- benzylamino-^-butylamino- 5- sulfamyl- benzoic acid

A. *+- butylamino- 3- nitro- 5- sulf amyl- benzoic acid

A mixture of 1f-chloro-3-nitro-5-sulfamyl-benzoic acid (8.kg), n-butylamine (8.7g) and water (25ml) was stirred at 90°C in In-time. After cooling, the pH was adjusted to 2, and the precipitated k-butylamino-3nitro-5-sulfamyl-benzoic acid was collected by filtration. After several recrystallizations from aqueous methanol, the melting point was 192.5°C.

B. 3-amino-k-butylamino-5-sulfamy1-benzoic acid e

A suspension of M-butylamino-3-nitro-5-sulfamyl-benzoic acid (8.6

g) in water (175 ml) was adjusted to pH 9.5 by addition of 2N sodium hydroxide. The resulting solution was hydrogenated

after addition of Pd (0.5 g) on carbon catalyst (10%). After the hydrogen uptake had become negligible, the catalyst was removed by filtration and the 3-amino-i+-butylamino-5-sulfamyl-benzoic acid was precipitated from the filtrate by the addition of hydrochloric acid until pH 3. After recrystallization from aqueous methanol, the melting point was 211-211 .5°C.

C. 3- benzylamino-^-butylamino- 5- sulphamyl- benzoic acid

A suspension of 3-amino-<!>+-butylamino-5-sulfamyl-benzoic acid (6.5 g) in water (30 ml) was adjusted to pH 7.5 by the addition of 1N sodium hydroxide. Benzyl bromide (3.87 g) was added and, with stirring, the pH was maintained at 7.5 by automatic titration with 1N sodium hydroxide. After the base consumption had become negligible, the pH was adjusted to 3 by adding dilute hydrochloric acid. The precipitated 3-benzylamino-1f-butylamino-5-sulfa amyl-benzoic acid was collected and recrystallized several times from aqueous methanol, after which the compound was obtained with a melting point of 198.5-199°C.

Example 7 3.

5- acetylsulfamyl- 3- benzylamino- M-- phenoxy- benzoic acid A mixture of 3-amino-5-acetylsulfamyl-^-phenoxy-benzoic acid

(1 g), benzaldehyde (0.3 g) and acetic acid (ho ml) were heated on a steam bath for 2 hours. After cooling to room temperature, platinum oxide catalyst (0.035 mg) was added and the reaction mixture hydrogenated at room temperature and at 1.1 atmospheres of hydrogen pressure. After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. After several recrystallizations of the residue from aqueous ethanol and after drying in vacuum at 76 C, the compound was obtained with a melting point of 2<l>+1<I>+-3°C. The compound crystallized as a hemi-hydrate.

Example 74. ■

3- benzylamino- 1+- f enoxy- 5- sulf amyl- benzoic acid

A mixture of 5-acetylsulfa amyl-3-benzylamino-<1>+-phenoxy-benzoic acid (1 g), ethanol (20 ml) and hydrochloric acid (5 ml) was refluxed for 2-J hours. Then 2N sodium hydroxide (15 ml) was added and the reaction mixture was heated on a steam bath for 30 minutes. After cooling, the pH was adjusted to 2.5 by adding hydrochloric acid and the precipitated 3-benzylamino-1+-phenoxy-5-sulfamyl- benzoic acid was isolated by filtration. After recrystallization from aqueous ethanol and drying, the compound was obtained with a melting point of 26l+-265°C.

Example 75.

3- benzylamino- 5- methylsulfamyl- lf- f enoxy- benzoic acid

A. Ethyl 3- benzylamino- 5- niethylsulfamyl- lf-phenoxy- benzoate

A mixture of 3-amino-5-methylsulfamyl-<1>+-phenoxy-benzoic acid (1

g), benzyl bromide (1.25 g) and dry ethanol (15 ml) were refluxed for 9 h. After 3 hours and after 6 hours it was more

benzyl bromide (0.6 g) added. After cooling, the precipitated ethyl 3-benzylamino-5-methylsulfamyl-4-phenoxybenzoate was collected by suction, recrystallized from ethanol and dried in vacuum. The melting point of the compound was 162.5°C.

B. 3- benzylamino- 5- methylsulfamyl- lf- f enoxy- benzoic acid

Ethyl 3-benzylamino-5-methylsulfamyl-1f-phenoxybenzoate (0.5 g) was dissolved in 1N sodium hydroxide (8 ml) and heated on a steam bath for 1 hour. After cooling, 3-benzylamino-5-methylsulfamyl-V-phenoxy-benzoic acid was precipitated by the addition of <*>+n hydrochloric acid until a pH of 2.5. The precipitate was collected by suction and recrystallized from aqueous ethanol. After drying in vacuum, the melting point of the compound was 231-233°C.

Example 76.

3- benzylamino- 5- dimethylsulfamyl-^-- phenoxy- benzoic acid

A. Ethyl 3- benzylamino- 5- dimethylsulfamyl- lf- f enoxy- benzoate

A mixture of 3-amino-5-dimethylsulfamyl-3-benzoic acid (1.68 g), benzyl bromide (2 g) and ethanol (15 ml) was refluxed for 5 hours. After cooling, the precipitated ethyl 3-benzylamino-5-dimethylsulfamyl-^-phenoxybenzoate was isolated and recrystallized from ethanol. After drying in vacuum, the compound was obtained with a melting point of 15°-155°C.

B. 3- benzylamino- 5- dimethylsulfamyl- 1+- f enoxy- benzoic acid

Ethyl 3-benzylamino-5-dimethylsulfamyl-U-phenoxybenzoate (1 g) was heated on a steam bath with 1N sodium hydroxide (15 ml) for 6 hours. From the resulting solution, the 3-benzylamino-5-dimethylsulfamyl-^-phenoxy-benzoic acid was precipitated by addition of hydrochloric acid until a pH of 2.5. After isolation and recrystallization from aqueous ethanol, the compound was obtained with a melting point of 205-206°C.

Ethyl 3-benzylamino-5-n-butylsulfamyl-^-phenoxy-benzoate

By substituting in step A in front of the 3-amino-5-dimethylsulfamyl-^f-phenoxy-benzoic acid with 3-amino-5-butylsulfamyl-1+-phenoxy-benzoic acid (1.8 g), the compound was obtained with a melting point of m-9-Hf9.5°C.

3- benzylamino- 5- n- butylsulfamyl- V- phenoxy- benzoic acid By substituting in step B in front of ethyl 3-benzylamino-5-dimethylsulfamyl-^-phenoxy-benzoate with ethyl 3-benzylamino-5-n-butylsulfamyl-^- phenoxybenzoate and after recrystallization from ethanol the compound was obtained with a melting point of 212°C.

Example 77.

3-butylamino-5-n-butylsulfamyl-^-phenoxy-benzoic acid 3-amino-5-n-butylsulfamyl-<1>+-phenoxy-benzoic acid was used instead of 3-aminoA-phenoxy-5-sulfamyl-benzoic acid in example at After the saponification, the organic solvents were removed from the reaction mixture by azeotropic distillation. The aqueous solution obtained was adjusted to pH 2.5 by adding hydrochloric acid. The precipitated 3-n-butylamino-5-n-butylsulfamyl-1f-phenoxy-benzoic acid was isolated by filtration and recrystallized several times from aqueous ethanol. After drying in vacuum at 115°C, the compound had a melting point of

Example 78.

* 4— anilino- 3- benzylamino- 5- phenylsulf amyl- benzoic acid

A. Ethyl if-anilino-^-benzylamino-^-phenylsulfamyl-benzoate

By replacing 3-amino-5-sulfamyl-^-(m-trifluoromethylphenoxy)-benzoic acid in Example 71 with S-amino-^-anilino-J-phenylsulfamyl-benzoic acid (1.8 g) the compound was obtained with a melting point of 165°C.

B. anilino-3-benzylamino-5-phenylsulfamyl-benzoic acid

Ethyl 1f-anilino-3-benzylamino-5-phenylsulfamyl-benzoate (3g) was dissolved in 1N sodium hydroxide (35ml) and the solution was heated on a steam bath for 1 hour. After cooling, the reaction mixture was adjusted to a pH of 2.5 by adding <*>+n hydrochloric acid. The precipitated ^-anilino-3-benzylamino-5-phenylsulfamyl-benzoic acid was collected by suction and recrystallized from

acetone/water. The compound was obtained with a melting point of

2<l>+3°C.

Claims (1)

Analogous process for the preparation of therapeutically active sulfamyl-m-aminobenzoic acids of the general formula I where A is or and R 1 and R 2 are each an alkyl group with 1-8 C atoms, a cycloalkyl group with 5-6 C atoms or an alkyl group with 1-k C atoms substituted with a phenyl group, or a phenyl- 1 2 or naphthyl group, the groups R and R as defined above may further be monohalogen-substituted or substituted with an alkyl group, a trifluoromethyl group, a carboxy or caralkyloxy group, an alkylamino group, a hydroxyl group which may be etherified or a sulfonamide group, and where R^ is an alkyl group with 1-8 C atoms or a phenyl group, and where R^ is an alkyl or alkanoyl group with 1-h C atoms, and where R^ is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group with 1-8 C atoms, an alkyl group with 1 - k C atoms substituted by a phenyl or methylenedioxyphenyl group, or a furfuryl group, and where R^ is an alkyl group with 1 - k C atoms, and where R 1 , R 3 , R h , R *? and R can also individually be hydrogen, or salts, cyanomethyl esters, esters with lower aliphatic alkanols or unsubstituted amides thereof, characterized in that an acid with the general formula where A, R-3 and R have the meanings indicated above, or a salt , an ester or an amide thereof is reduced to convert the nitro group into an amino group, after which the obtained compound of formula I is, if desired, monoalkylated with a compound of formula R X, where R has the above meaning for R h except for hydrogen, and X is a halogen atom, a hydroxyl, sulfonyloxy, alkyl or arylsulfonyloxy group , or the compound obtained is reductively alkylated with an aldehyde of the formula R^CHO, where b<7> is defined by R^CH0 having the letter 2 for R defined meaning, after which the second hydrogen atom in the amino group in the 3-position in the obtained compound of formula I, if desired, is replaced by R^ , where R y has the meaning given above for R^ except for hydrogen, by alkylation with a compound B. y tX , < i where R^ and X have the meaning indicated above, or that a prepared acid with formula I or its salt, ester or amide as previously defined is converted into one of the other forms in a manner known per se, or by reductive alkylation with an aldehyde of the formula R oCH0,where Q O ff ( R is defined by R CH2 having that for R? defined meaning, or if desired, an obtained compound of formula I, in which A represents an R 2S group, is oxidized to a compound of formula I, ? 2 in which A means an R SO - or R SO 2 ~ group, or if desired, an obtained compound of formula I, in which R or R^ represents an unsaturated alkyl group, is hydrogenated to the corresponding saturated compound, or if desired, an obtained compound of formula I is acylated, i wherein R means hydrogen, or if desired, a compound of formula I obtained, in which R represents an alkanoyl group, is deacylated.