NO149736B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE HETEROCYCLIC SUBSTITUTED 5-SULPHAMOYLBENOS ACID DERIVATIVES - Google Patents

Description

The invention relates to the analogous process for the preparation of therapeutically active heterocyclic substituted 5-sulfamoyl-benzoic acid derivatives of the general formula I

12 3

in which the residues R, R and R are the same or different and mean hydrogen or alkyl with 1-4 carbon atoms, X means one of

4 44

the groups O-R or NHR, in which R means a phenyl optionally substituted with Hal, alkyl with 1-4 C atoms or alkoxy with 1-3 C atoms, and R 6 and R 7 are H or (C1"C3)-alkyl , as well as their pharmaceutically acceptable salts with bases or acids, the method being characterized by

a) 5-halogenesulfonylbenzoic acid derivatives with it

general formula II

wherein R<3>, R4, R^, R7 and X have the indicated meanings and Hal

tyr a halogen atom, is reacted with amines of formula

1 2

where R and R have the indicated meaning., or

b) sulfamoyl compounds of the general formula III

in which the groups R and R, R, R, R andx have the indicated meaning and D means a group convertible into a carboxylic acid, by hydrolysis or mild oxidation reactions are converted into the 3-position heterocyclic substituted 5-sulfamoylbenzoic acids of formula I (R <3>= H), or

c) sulfamoylbenzoic acid derivatives of the general formula

IV

in which the groups R1 to R<3>, R<4>, R<6>, R7 and X have the indicated meanings and L means a leaving group, treated with acids or bases for leaving HL, or d) sulphamoylbenzoic acid derivatives with the general formulas V and VI are reacted with compounds of formula where L, R<1> to R<3>, X has the above meaning and B means a protecting group of the general formula in which R^, R^ and R<10> mean the same or different lower alkyl groups, where R can also mean hydrogen, and/or where two of the substituents R^ and R^ and R1(^ can also be cyclically connected to each other, and where the protective group B is split off by hydrolysis, or e) corresponding to 3- N-pyrrolo compounds with the general formula VIII where R1, R<2>, R<3>, X, R6 and R7 have the indicated meanings are reduced, and that possibly in compounds with formula I, which are obtained according to alternative a) or e), free carboxylic acids of the formula I (R 3=H) are esterified and/or carboxylic acid esters of the general formula I (R 3 ^ H) by hydro lysis or elimination reactions are converted to carboxylic acids (R 3 = H) and/or carboxylic acids of formula I (R 3 = H) by treatment with bases or acids are converted to their pharmaceutically acceptable salts. Preferred compounds of formula I according to the invention are those in which the groups R 1 and R 2 mean hydrogen, or 12 ^ if R means hydrogen, R can also mean lower alkyl; RJ means hydrogen, lower alkyl or optionally substituted benzyl; X means -OR<4>, or NH-R, as R<4> as a phenyl group is of particular importance and the phenyl nucleus can also be single or multiple substituted in all imaginable positions with, for example, the groups Cl, CF^, straight or branched alkyl with 1 - 3 C atoms, or alkoxy with 1 - 2 C atoms. The 5-halogensulfonylbenzoic acid derivatives of formula II required for process alternative a) can be obtained in various ways, e.g. from aminobenzoic acid derivatives with formula IX corresponding to the reaction sequence known according to Meeriwin to that in J.pr./2/152, 251 (1939) resp. German patent 859 461 mentioned way. Halogensulfonylbenzoic acid derivatives are reacted in a known manner: with amines of formula to the final products of formula I. Aminobenzoic acid derivatives of formula IX are obtained in various ways, e.g. from the aminonitrobenzoic acid derivatives of formula X known from the literature according to the reaction scheme by reacting the compounds with carboxylic acid derivatives with compounds XIII in which R<®>, R9 and R<1>^ mean the same or different lower alkyl groups, as R can also mean hydrogen, and/or where two of the substituents R^ and R<9> and R<10> can also be cyclically connected to each other, and where the protecting group B is removed by hydrolysis, or e) corresponding 3-N-pyrrolo compounds with the general formula VIII

1 2 3 6 7

where R , R , R , X, R and R have the indicated meanings, is reduced, and that possibly in compounds of formula I, which are obtained according to alternative a) or e), free carboxylic acids of formula I (R <3> =H) are esterified and/or carboxylic acid esters of the general formula I (R<3> ^ H) by hydrolysis or elimination reactions are converted into carboxylic acids (R 3 = H) and/or carboxylic acids of the formula I (R<3> = H) by treatment with bases or acids are converted into their pharmaceutically acceptable salts.

Preferred compounds of formula I according to

1 2 the invention is those in which the groups R and R mean hydrogen, or if R 1 means hydrogen, R 2 can also mean lower alkyl; RJ -j means hydrogen, lower alkyl or optionally substituted benzyl; X 4 4 4 means -OR , or NH-R , as R^ as a phenyl group is of particular importance and the phenyl nucleus can also be single or multiple substituted in all imaginable positions with, for example, the groups Cl, CF^, straight or branched alkyl with 1 - 3 C- atoms, or alkoxy with 1-2 C atoms. The 5-halogensulfonylbenzoic acid derivatives of formula II required for process alternative a) can be obtained in various ways, e.g. from aminobenzoic acid derivs with formula IX corresponding to the reaction order known according to Meeriwin to that in J.pr./2/152, 251 (1939) resp. German patent 859 461 mentioned way. Halogensulfonylbenzoic acid derivatives are reacted in a known manner: with amines of formula to the final products of formula I. Aminobenzoic acid derivatives of formula IX are obtained in various ways, e.g. from the aminonitrobenzoic acid derivatives of formula X known from the literature according to the reaction scheme by reacting the compounds with carboxylic acid derivatives with compounds XIII

and then reduce the resulting compounds of formula XI to the nitrobenzoic acid esters XII by treatment with boron hydrogen or complex borohydrides in the presence of Lewis acids. The nitro group is then reduced, conveniently by catalytic hydrogenation in the presence of Raney nickel, or according to other common reduction methods.

The compound IX can be particularly advantageously prepared according to the following reaction nucleus:

In the case of reduction of 3-amido- or The 3-imido compounds of formula XII resp. XIV, the same conditions can be used as discussed in the method according to the Norwegian patent 146745. Thereby it is surprising that the reduction also proceeds specifically in the presence of a nitro group.

The compounds of the general formula III used according to process alternative b) are available in different ways.

For example, the compound of formula III, in which D means a -C^OH group, is obtained from carboxylic acid derivatives of formula I by using the reducing agent in excess.

The conversion of the products with the general formula III into final products with the formula I is carried out according to the type of substituent D. If D means a CH2~halogen group, a CH3OCOCH2 or an 0=CH group, the end products are obtained by oxidation. If D means a nitrile group, the amides are formed by the alkaline hydrolysis, which then e.g. by continued hydrolysis can be converted into the free carboxylic acids. By reacting with alcoholic hydrochloric acid, the iminoesters are further obtained from the nitriles, which can be converted to the ester compounds through hydrolysis,

if desired also to the corresponding carboxylic acids.

The sulphamoylbenzoic acid derivatives of formula IV used according to process alternative c) are available in different ways, e.g. from sulfamoylbenzoic acid derivatives of formula XV

by the reduction of the amide group with boron hydrogen or complex borohydrides in the presence of Lewis acids in the manner described in Norwegian patent 146745. In this reduction, it is surprising that the amide group is reduced without the cleavable group L being affected. The cleavable group L is preferably halogen, OH, active ester groups such as o-tosyl, trialkylammonium or pyridinium groups.

The cyclization of the compounds of formula IV during cleavage of HL can be carried out under basic or acidic conditions. If L, for example, means a halogen atom, preferably chlorine or bromine, the cyclization is carried out e.g. by treatment with alkali. In an acidic environment, the cyclization can be carried out in accordance with Ber. 42, 3427 (1907) (Uberblick Chem. Rev. 63, 55, (1963). Thereby the salts of the carboxylic acids with formula I (R 3 = H) are formed. Examples of bases for the cleavage include triethylamine, alkali hydroxides, N,N -dimethylaniline or also alkali acetate.

The compounds produced according to the invention can be obtained according to alternative d) starting from the 3-amino compounds of formula V or VI by reaction with compounds of the formula L-CH2~(C<H>2)2-C<H>2~<L,> with both of the cleavable groups L being cleaved off during the cyclization with the 3-amino group from V resp. VI during cleavage of 2 mol HL and optionally after cleavage of the protecting group B by hydrolysis to compounds of formula I.

Thereby, the compounds V or VI in organic solvents such as acetone, dimethylformamide, ethanol or mixtures of such solvents with an excess of the compounds of formula L-CH2~(CH2)2-CH2-L, suitably heating the reaction mixture under reflux for several hours or days. If L represents bromine or chlorine atoms, it is appropriate to add an alkali iodide in excess to the reaction mixture. In certain cases, turnover is also accelerated by the addition of auxiliary base, e.g. pyridine, triethylamine, NaHCO3 or Na-acetate.

The compounds of formula VIII used according to method alternative e) are obtained from 3-amino-5-sulfamoylbenzoic acid derivatives of formula XVI by reacting them in the usual way with 2,5-dimethoxytetrahydrofurans according to the formulas

where R C and R " 1 have the indicated meanings. The reduction of the pyrrolo compounds VIII formed is preferably carried out by catalytic hydrogenation with the usual catalysts for that purpose.

In accordance with the methods indicated under a) to e), double bonds present in the compounds according to the invention with formula I can optionally be hydrogenated in the usual way, using catalytic hydrogenation. Conversely, double bonds can also be introduced afterwards in elimination reactions, e.g. by cleavage of hydrogen halide from halogenated compounds by hydrogen cleavage from hydroxy compounds and other common cleavage reactions.

If the free carboxylic acids of formula I are first obtained by using corresponding starting compounds, these can be transferred in the usual way to the esters. For this purpose, alcohols with the formula R 3OH or their functional derivatives are used or the esterification is carried out in another way known from the literature. Conversely, first formed carboxylic acid esters of the general formula I can be transferred to corresponding free carboxylic acids. In addition, above all, hydrolysis or, in appropriate cases, hydrogenolysis or other elimination reactions are also mentioned. Thus, for example, the alkyl esters can be cleaved by alkaline hydrolysis, the aralkyl esters, especially the p-nitrobenzyl esters, by hydrolysis or the tert-butyl esters by cleavage of the isobutene by treatment with trifluoroacetic acid.

The free carboxylic acids can be converted into their pharmaceutically acceptable salts by reaction with corresponding bases such as alkali metal, alkaline earth metal or ammonium hydroxides or carbonates. Finally, it is possible to obtain the compounds of formula I according to the invention by releasing the usual protective groups for the hydroxy, amino or mercapto group in the last reaction step, for example acylated hydroxy groups being hydrolysed in the usual way.

Sulfamoylbenzoic acid derivatives of formula I according to the invention as well as their pharmaceutically acceptable salts are highly effective diuretics and saluretics, which can be used as pharmaceuticals in human and veterinary medicine.

The compounds according to the invention are given in doses of

0.5 to 100 mg in capsules, dragees, tablets or solutions with various additives enterally, e.g. orally with a probe or similar or parenterally (injection into the vascular system, e.g. intravenously, or also by intramuscular or subcutaneous injection, etc.). They are suitable for the treatment of edema diseases, e.g. cardiac, renal or hepatic edema and other similar symptoms attributed to disturbances in water and electrolyte balance. The compounds can be used alone or in combination with other salidiuretic substances with also

different mode of action, or with various other drugs alone, alternately or in combination. Above all, mention can be made of Spironolactone, Triamterene, Amiloride and other K<+->retaining compounds alternating with long-acting salidiuretics of the Chlorthalidone type or others together with or separately from the potassium-containing compounds (salts etc.), which are used to replace the K observed in salidiuresis <+->loss.

Example 1

3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

a) 3-N-succinimido-4-phenoxy-5-nitrobenzoic acid methyl ester 105 g 3-amino-4-phenoxy-5-nitrobenzoic acid methyl ester

is mixed with 210 g of succinic anhydride and heated with stirring for 2 hours at 180°C, after which the reaction mixture is stirred into 3 l of water and after some time extracted with methylene chloride. The organic phase is isolated, dried and evaporated. The residue gave, after recrystallization from methanol, the desired compound with a melting point of 152 - 154°C in very good yield. b) 3-(1-pyrrolidinyl)-4-phenoxy-5-nitrobenzoic acid methyl ester.

A solution of 44.4 g of the ester formed under a) in 300 ml of diglyme is reacted under nitrogen gas and stirring at 0°C with 34 g of BF^ etherate and then with a solution of 9.2 g of NaBH^ in 200 ml of diglyme , as the temperature is kept below +15°C. After a further 1 hour, water was added dropwise. After completion of the resulting exothermic reaction, 500 ml of water is added. Thereby, the desired compound is secreted as orange needles with a melting point of 118 - 120°C

in very good profit.

c) 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid methyl ester.

A solution of 30 g of the nitro-benzoic acid methyl ester formed under b) in 500 ml of dioxane was hydrogenated catalytically with the addition of Raney nickel. After completion of hydrogen absorption, the solution was filtered from the catalyst material and evaporated. After recrystallization from methanol, the residue gave the desired compound in the form of colorless crystals with a melting point of 15 3 - 15 6°C in very good yield. d) 3-(1-pyrrolidinyl)-4-phenoxy-5-chlorosulfonyl-benzoic acid methyl ester.

A solution of 24.3 g of the amine ester formed under c) in 150 ml conc. hydrochloric acid is cooled to -5°C and diazotized with a solution of 5.46 g of NaOI^ in 40 ml of water, keeping the temperature below +5 C. After 15 minutes, the light brown diazonium salt solution was introduced into a mixture of 7.8 g of copper ( II) chloride dihydrate, 24 ml conc. hydrochloric acid and 200 ml of a saturated solution of SC^ in glacial acetic acid at 0°C. After the end of gas evolution, stirring is continued for a short time after which the reaction mixture is mixed with water and the precipitated sulphochloride was extracted with methylene chloride. The organic phase was washed twice with water, dried and evaporated. The remaining oil gave, on addition of diisopropyl ether, the desired compound with a melting point of 108 - 112°C in good yield. e) 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester. 25.0 g of the 5-chlorosulfonyl-benzoic acid methyl ester prepared according to d) was added at room temperature in portions with stirring to a mixture of 150 ml of methylene chloride and 75 ml of 25% ammonia, the mixture was then stirred for 1 hour, the organic phase separated, washed with water, dried over sodium sulfate and evaporated. The remaining oil was recrystallized from methanol and gave 5-sulfamoylbenzoic acid ester with melting point 185 - 188°C in very good yield. Saponification of the ester to 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid takes place in the usual way with dilute caustic soda. The acid's melting point 227 - 228°C.

Example 2

3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

a) 3-(1-pyrrolidinyl)-4-phenoxy-5-nitrobenzoic acid.

50 g of 3-(1-pyrrolidinyl)-4-phenoxy-5-nitrobenzoic acid methyl ester (preparation see example 1 step b) is saponified with dilute caustic soda hot. The orange solution was extracted twice with methylene chloride after which the aqueous phase was acidified with concentrated hydrochloric acid. The desired acid was isolated as lyso-

yellow crystals with m.p. 228 - 230°C.

b) 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid.

32.8 g of the nitrobenzoic acid produced under a).

was dissolved in a solution of 8 g of NaOH in 200 ml of water,

cooled to 0°C and mixed with a solution of 90 g of sodium dithionite in 380 ml of water, the temperature being kept below 10°C. The initially red-orange colored solution changed color to light yellow. The solution is then stirred for 1 hour without cooling, then acidified with concentrated hydrochloric acid to pH 1 and evaporated until crystallization begins. The hydrochloride of the desired amino-benzoic acid is obtained as colorless crystals with a melting point of 245 - 247°C.

If the dithionite contains sulfate, you get a corresponding sulfate as colorless crystals with a melting point of 175 - 176°C even before the water solution evaporates.

Both can release amine with a melting point

100 - 103°C is obtained when the water solution is set to pH 4 -

4.5. c) 3-(1-pyrrolidinyl)-4-phenoxy-5-chlorosulfonyl-benzoic acid.

A solution of 8.35 g of the aminobenzoic acid hydrochloride prepared under b) in 25 ml of concentrated hydrochloric acid is diazotized at 0°C with a solution of 1.75 g of sodium nitrite in 15 ml of water, the temperature being kept below 5°C. After 15 minutes in-

the diazonium salt solution is introduced while stirring into a mixture cooled to 0°C of 2 g copper (II) chloride dihydrate, 2 ml conc. hydrochloric acid and 15 ml of a saturated solution of SO 2 in glacial acetic acid.

After the foaming has ended, the mixture is stirred again

30 minutes, then mixed with 150 ml of water and extracted several times with ethyl acetate. The organic phase is washed with water, dried, evaporated and after addition of ether and hexane gave the crystalline sulphochloride with melting point 163 - 165°C.

If you use the aminobenzoic acid sulfate, you get the same sulfochloride in somewhat less yield.

d) 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzo-

acid.

7.6 g of the chlorosulfonyl derivative prepared according to method c) is introduced into 15 ml of liquid ammonia. The ammonia evaporates at room temperature and the residue is absorbed

in a small amount of water. The solution is filtered and adjusted

at pH 1 with conc. hydrochloric acid. Thereby the desired sulphamoylbenzoic acid precipitates as brownish colored crystals, which after recrystallization from methanol/water are isolated as pale yellow crystals with m.p. 2 25°C.

Example 3

3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

a) 3,5-dinitro-4-phenoxy-benzoic acid methyl ester

30 g of 3,5-dinitro-4-phenoxybenzoic acid is formed with 3

ml conc. sulfuric acid in 200 ml of methanol and boil for 3 hours under reflux. After the solvent has been removed, the residue is taken up in ethyl acetate, after which traces of unreacted acid are removed with dilute sodium bicarbonate solution. After drying the ethyl acetate solution, the solvent is driven off, after which re-

the precipitate is recrystallized from ethyl acetate/methanol. The desired ester is obtained with m.p. 171 - 173°C in very good yield.

b) 3,5-diamino-4-phenoxybenzoic acid methyl ester.

25 g of 3,5-dinitro-4-phenoxy-benzoic acid methyl ester

dissolve in 250 ml of ethyl acetate, mix with 10 g of Raney nickel and hydrogenate. When the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the solvent is driven off as the remaining oil crystallizes. The crude product can be reacted further directly or recrystallized from methanol/water, the diamino ester being obtained in good yield in the form of colorless crystals with m.p. 140 - 142°C. Alternatively, the hydrogenation can also be carried out in an autoclave at 50°C and 100 atmospheres. The reaction time then amounts to 3 - 5 hours, depending on the activity of the Raney nickel.

c) 3-succinyl-amino-4-phenoxy-5-amino-benzoic acid methyl ester. 30 g of 3,5-diamino-4-phenoxy-benzoic acid methyl ester is stirred into 300 ml of chloroform or methylene chloride and stirred for 8 hours at room temperature with 12.8 g of succinic anhydride, the desired benzoic acid methyl ester falling out as a colorless precipitate. The separated crystals are isolated, washed with chloroform and recrystallized from methanol. The compound 3-succinylamino-4-phenoxy-5-amino-benzoic acid ethyl ester is obtained as colorless crystals with m.p. 190 - 192°C. d) 3-(1-succinimido)-4-phenoxy-5-amino-benzoic acid methyl ester. 30 g of 3-succinylamino-4-phenoxy-5-amino-benzoic acid methyl ester are introduced into a mixture of 26 0 ml of orthophosphoric acid and 6 0 g of P2°5'°PP, heated for 2 hours at 50°C, then cooled and introduced into 750 ml of water. The precipitated 3-(succinimido)-4-phenoxy-5-amino-benzoic acid methyl ester is obtained. as colorless crystals with m.p. 200 - 201°C in approximately quantitative yield. e) 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid methyl ester.

A solution of 24 g of 3-(1-succinimido)-4-phenoxy-5-amino-benzoic acid methyl ester in 180 ml of diglyme is mixed with 20 g of boron trifluoride etherate and cooled to 10°C. A solution of 5.7 g of NaBH4 in 125 ml of diglyme is added dropwise while cooling to the reaction mixture at such a rate that the temperature does not exceed 15°C. After completion of the addition, the mixture is stirred for a further 1 hour and then carefully mixed with 300 ml of water. The precipitated solid is isolated and recrystallized from methanol. The compound 3-(1-pyrrolidinyl)-4-phenoxy-5-amino-benzoic acid methyl ester is obtained in good yield with m.p. 154 - 156°C. f) 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid.

The reaction sequence indicated in example 1

is repeated. 3-(1-pyrrolidinyl)-4-phenoxy-5-chlorosulfonylbenzoic acid methyl ester is obtained by reaction with saturated ammonia-water solution the desired 3-(1-pyrrolidinyl-(-4-phenoxy-5-sulfa-moylbenzoic acid methyl ester) m.p. 186 - 188°C), which by heating with caustic soda and subsequent acidification can convert to the desired 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

with sm.p. 226 - 228°C.

Example 4

3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

The reaction sequence specified in example 3 is repeated until the formation of 3-succinylamino-4-phenoxy-aminobenzoic acid. Then 10 g of the 3-succinylamino-4-phenoxy-5-aminobenzoic acid ester are stirred for 2 hours at 200°C. After cooling, the reaction mixture is recrystallized from methanol and gives 3-succinimido-4-phenoxy-5-aminobenzoic acid methyl ester with m.p. 199 - 200°C in good yield.

The product formed is converted in the manner described in example 3 to the desired 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid with m.p. 227--228°C.

Example 5

3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

The reaction order specified in example 3 is repeated up to step e). 51 g of 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid methyl ester are heated to boiling for 2 hours in 780 ml of 1-normal caustic soda, forming a clear solution. The product that precipitated after the reaction mixture had cooled and adjusted to pH 4 was dissolved in 60 ml of 2-normal HC1. After a short standstill, the hydrochloride of 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid crystallizes out in large crystals with m.p. 254 - 257°C. Mixture melting point with the product from example 2 (step b): 252 - 254°C.

The hydrochloride of 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid is converted in the manner mentioned in example 2 over the desired 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid with m.p. 225 - 226°C.

Example 6

3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid

To a solution of 38.7 g of 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester in 500 ml of water is added at 20°C 35.2 g of boron trifluoride etherate and then 10 g of sodium borohydride. The reaction mixture is stirred for 2 hours at 75°C, then cooled and first carefully mixed with 200 ml of water. When gas evolution has ceased, 2 1 water is added and the precipitated crystals are isolated, washed with water and dried. 24.4 g of 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzene alcohol with m.p. 155°C.

Oxidation with dilute alkaline permanganate solution gives 3-(1-pyrrolidinyl)-4-phenoxy-5-sulfamoylbenzoic acid with m.p. 277°C.

Example 7

3.5 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-

in benzyl alcohol is suspended in 50 ml of water and 1 g of sodium hydroxy is added. Add 8 g of nickel peroxide in portions while stirring to the resulting solution and stir c. 3 hours at 60°C. It is then filtered and the filtrate is acidified to pH 3 - 4. 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid precipitates and is recrystallized from CH3OH/H20. Yield 65%.

Analogously, according to this method, the following active substances can be prepared from corresponding benzyl alcohols: 4-phenoxy-3-(3<1->methyl-1-pyrrolidinyl)-5-sulfamoylbenzoic acid, m.p. 207°C,

4-(4'-methylphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid, m.p. 23 3 - 235°C,

4-(4<1->methylphenoxy)-3-(3<1->methyl-1-pyrrolidinyl)-5-sulfamoylbenzoic acid, m.p. 220 - 221°C,

4-(3<1->methoxyphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid, m.p. 218°C,

4-(4'-fluorophenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid, m.p. 250 - 252°C.

Example 8

4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid.

a) 3.43 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzonitrile with m.p. 198 - 200°C dissolve in 4-n NaOH and

boiled for several hours under reflux. After the completion of the reactions (thin-layer chromatography control), 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is precipitated by acidification with conc. HCl to pH 3 - 4 and recrystallization from CH3OH/H2O. Sm.p.

226 - 227°C. Yield 80%.

b) In an analogous manner, 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid amide is saponified with m.p. 249 - 251°C.

Example 9

4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid

a) 3.43 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-benzamide (m.p. 249 - 251°C) are dissolved in conc. hydrochloric acid and

boil under reflux. The reaction is followed by thin-layer chromatography. After the end of the reaction, the pH is adjusted to 3 - 4 with lye. The precipitated 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is recrystallized from CH^OH/H^O. SM.p. 226 - 227°C. Yield 63%. b) 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzonitrile is hydrolysed in an analogous manner.

Example 10

4-(4'-methylphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid

4-(4<1->methylphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoyl-benzonitrile is converted analogously to example 8 to the corresponding benzoic acid.

Recrystallization from methanol. Sm.p. 234 - 237°C.

Example 11

4-phenoxy-3-(3<1->methyl-1-pyrrolidinyl)-5-sulfamoylbenzoic acid

4-phenoxy-3-(3'-methyl-1-pyrrolidinyl)-5-sulfamoyl-benzonitrile is converted analogously to example 8 into corresponding acids.

Recrystallization from methanol/H2O. Sm.p. 206 - 208°C.

Example 12

4-(4'-methylphenoxy)-3-(3'-methyl-1-pyrrolidinyl)-5-sulfamoylbenzoic acid 4-(4<1->methylphenoxy)-3-(3'-methyl-1-pyrrolidinyl)-5 -sulfamoylbenzonitrile is converted analogously to example 8 to the corresponding acid.

Recrystallization from CH3OH/H2O. Sm.p. 220 - 221°C.

Example 13

4-(4'-fluorophenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid

4-(4'-fluorophenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzamide is converted analogously to example 9 to the corresponding acid.

Recrystallization from CH3OH/H20. Sm.p. 250 - 252°C.

Example 14

4-(4<1->methoxyphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid

4-(4<1->methoxyphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzamide is converted analogously to example 9 to the corresponding acid.

Recrystallization from CH3OH/H20. Sm.p. 228 - 229°C.

Example 15

4-(4<1->chlorophenoxy)-3-(3<1->methyl-1-pyrrolidinyl)-5-sulfamoylbenzoic acid

4-(4'-chlorophenoxy)-3-(3'-methyl-1-pyrrolidinyl)-5-sulfamoylbenzonitrile is converted analogously to example 8 to the corresponding acid.

Recrystallization from acetonitrile. Sm.p. 257 - 258°C.

Example 16

4-(3-Methoxyphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid

4-(3'-Methoxyphenoxy)-3-(1-pyrrolidinyl)-5-sulfamoylbenzonitrile is converted analogously to example 8 to the corresponding acid.

Recrystallization from CH3OH/H20. Sm.p. 218°C.

Example 17

4- f enoxy- 3 - ( 1- pyrrolidinyl) - 5- sulfamoy^ benzaldehvd

0.01 mol of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzene alcohol is added to a suspension of 0.025 mol of pyridine chlorochromate (PCC) in 200 ml of methylene chloride. The mixture is stirred for 2 - 3 hours until the reactions according to thin layer chromatography have ended, the CH2Cl2 solution is filtered and evaporated. On recrystallization from CH3OH/H20, yellow crystals with m.p. 164 - 166°C. The aldehyde is suspended in dilute NaOH and, by addition of NiC^, oxidized to the corresponding benzoic acid 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid.

Example 18

3- N- pyrrolidino- 4- phenoxy- 5- sulfamoylbenzoic acid

a) 3-N-(2-chlorobutyrylamino)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester. 24 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester and 7.5 ml of pyridine in 100 ml of abs. dioxane and 21.2 g w-chlorobutyric acid chloride in 100 ml abs. acetone is set during approx. 2 hours slowly and as evenly as possible drop by drop to 100 ml boiling abs. dioxane. After 1 hour of continued stirring, the solution is evaporated. The remaining oil is taken up in a small amount of acetone and dropped into ice water with vigorous stirring. The 3-N-(co-chlorobutyrylamine)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester precipitates and is recrystallized from methanol. Sm.p. 151 - 153°C. b) 3-N-(w-chlorobutylamino)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester 12 g of 3-N-(w-chlorobutyrylamino)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester are suspended in 150 ml diglyme. Then add 7 ml of BF^-etherate. A solution of 2.2 g of NaBH in 150 ml of diglyme is slowly added dropwise at room temperature. After a few minutes of stirring, the product is carefully precipitated with water.

After recrystallization from methanol, the product has a m.p. at 125°C. c) 3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid 3-N-(co-chlorobutylamino)-4-phenoxy-5-sulfamoylbenzoic acid methyl ester is suspended in 1-normal NaOH and heated on a steam bath until a clear solution is formed. From the cold solution, 3-N-pyrrolidine-4-phenoxy-5-sulfamoylbenzoic acid is precipitated with 1-normal HCl.

Example 19

4- phenoxy- 3 ( 1- pyrrolidinyl)- 5- sulfamoylbenzoic acid

a) 10 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester are heated for several days under reflux together with 1,4-dibromobutane and 10 g of NaJ in an acetone/DMF mixture. The reaction is followed by thin-layer chromatography. After completion of the reaction, the mixture is evaporated to dryness, the excess of dibromobutane is extracted with ether, the residue is decanted and saponified with 1-normal NaOH. From the clear solution, 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is precipitated with 2-normal HCl. b) 10 g of 3-amino-4-phenoxy-5-NjN-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester are heated for 5 hours under reflux together with 25 g of 1,4-dibromobutane in DMF. It is then evaporated to dryness, the excess of dibromobutane is extracted with ether, decanted and the remaining red oil is taken up with a small amount of methanol. On standing, the 4-phenoxy-3-(1-pyrrolidinyl)-5-N,N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester crystallizes. This is saponified with caustic soda and 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is precipitated with HCl.

Example 20

4-anilino-3 (1-pyrrolidinyl)-5-sulfamoylbenzoic acid

12.8 g of 3-amino-4-anilino-5-sulfamoylbenzoic acid methyl ester are suspended in glacial acetic acid and boiled under reflux. 5.6 ml of 2,5-dimethoxytetrahydrofuran dissolved in a little glacial acetic acid is then added dropwise. After a reaction time of around 0.5 hours, the mixture is stirred in ice water and the precipitated product is separated.

4-anilino-3-N-pyrrolo-5-sulfamoylbenzoic acid ethyl ester is dissolved as crude product in methanol and hydrogenated for 16 hours at 100°C and 100 atmospheres in the presence of Pd/charcoal (~1 g). It is then filtered and the filtrate is evaporated. The residue is taken up with 2-normal NaOH and heated to a clear solution. When 2-n HCl is added to pH 4, 4-anilino-3-(1-pyrrolidin-yl)-5-sulfamoylbenzoic acid is precipitated.

To purify the product, this is dissolved in a little acetone, an excess of saturated ethereal HCl solution is added and the mixture is stirred into a double amount of ether. The hydrochloride of 4-anilino-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid precipitates. It is separated, washed with acetone, dissolved in 2-n NaOH and adjusted with 2-n HCl to pH 4. The precipitated 4-anilino-3-(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is recrystallized from CH^OH/H20. Yellow crystals with m.p. 214 - 216°C.

Example 21

4- phenoxy- 3 ( 1- pyrrolidinyl)- 5- sulfamoylbenzoic acid

a) 3-N-pyrrolo-4-phenoxy-5-sulfamoylbenzoic acid

8 g of 3-amino-4-phenoxy-5-sulfamoylbenzoic acid methyl ester are heated under reflux with 5 g of 2,5-dimethoxytetrahydrofuran in 100 ml of glacial acetic acid. After 1.5-2 hours, stir the mixture into ice water. The thus precipitated crude product is heated on a steam bath with 1-normal NaOH until a clear solution is formed. On acidification with 2-normal HCl, 3-N-pyrrolo-4-phenoxy-5-sulfamoyl-benzoic acid precipitates. It can be recrystallized from methanol or glacial acetic acid/water.

White-grey crystals with m.p. 214°C.

b) 8.8 g of 3-N-pyrrolo-4-phenoxy-5-sulfamoylbenzoic acid methyl ester (crude product) is dissolved in glacial acetic acid and hydrogenated with 1 g of Pd charcoal at normal pressure. The reaction is finished after approx.

30 hours. If the hydrogenation is carried out in an autoclave at

40 - 50°C and 100 atmospheres, the reaction is finished already after

5 hours.

The solution is filtered and evaporated and the solid residue is saponified with 1-normal NaOH on a steam bath. The clear solution is cooled and acidified with 2-normal HCl. The precipitated 4-phenoxy-3(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is recrystallized from methanol/water. Sm.p. 226 - 227°C.

Example 22

4-phenoxy-3-(1-pyrrolidinyl)-5-dimethylsulfamoyl-benzoic acid

7.2 g (0.02 mol) of 4-phenoxy-3-(1-<p>yrrolidinyl)-5-sulfamoylbenzoic acid are dissolved in 100 ml of n NaOH and mixed with 10 ml of dimethyl sulphate. The mixture is stirred well at room temperature. After approx. After 30 minutes, a white mushy substance falls out.

It is sucked off and heated with 2 n NaOH on a steam bath. After a clear solution has formed, it is allowed to cool and 4-phenoxy-3-(1-pyrrolidinyl)-5-dimethyl-sulfamoyl-benzoic acid is precipitated with 2 n HCl. The substance can be recrystallized from methanol/water. Yellow fibers of sm.p. 214-215°C.

Example 23

4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid methyl ester

36.2 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyolbenzoic acid are dissolved in 200 ml of methanol and 7 ml of concentrated H2SO4 and heated for 4-6 hours under reflux. On cooling, the ester crystallizes. Recrystallization from methanol, m.p. 191°C.

Example 2 4

4-(4<1->methylanilino)-3-pyrrolidinyl)-5-sulfamoyl-benzoic acid

3-amino-4-(4'-methylanilino)-5-sulfamoyl-benzoic acid methyl ester is reacted with 2,5-dimethoxy-tetrahydrofuran and then the precipitated crude product is saponified with 2 n NaOH. After acidification with 2 n HCl to pH 3-4, 4-(4-'-methylaninilino)-3-N-pyrrolo-5-sulfamoyl-benzoic acid of m.p. 226-228°C.

(From CH3OH/H20) .

This is dissolved in acetic acid and hydrogenated for 16 hours at 100°C and 150 atmospheres in the presence of rhodium/charcoal. The filtrate is evaporated, the residue is taken up with a little acetone (absolute) and ethereal HCl is added. On further ether addition, the hydrochloride of 4-(4<1->methylanilino)-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid precipitates. It is separated, washed with a little acetone/etheric HCl and then dissolved in 2 n NaHl. On acidification to pH 3-4, 4-(4'-methylanilino)-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid precipitates. Recrystallization from CH2OH/H2O gives yellow crystals of melting point 188-191°C.

Example 25

4-chloro-5-N-pyrrolidinylmethyleneaminosulfonylbenzoic acid

To a solution of 58.9 g (0.25 mol) 4-chloro-5-sulfamoylbenzoic acid in 24 0 ml (2.5 mol) N-formylpyrrolidine is added dropwise at -10 to 0°C 69 ml (0.75 mol) P0C13- The solution is then allowed to come to room temperature, stirred for several hours, diluted with N-formylpyrrolidine and poured onto ice. After extraction, the precipitate is suspended in water, and the suspension is adjusted to pH 6. After longer stirring at room temperature, undissolved is extracted, and the free acid is precipitated by acidifying the filtrate to pH 1 - 2.

4-chloro-5-N-pyrrolidinylmethyleneaminosulphonylbenzoic acid is obtained from m.p. 250 - 252°C.

4-Chloro-3-nitro-5-N-pyrrolidinylmethyleneaminosulfonyl-benzoic acid

To 90 ml of 20% oleum, 63 ml of fuming nitric acid are dripped under ice-cooling, then 57 g (0.18 mol) of 4-chloro-5-N-pyrrolidinylmethylaminosulphonyl-benzoic acid are introduced.

After 6-7 hours of stirring at 80°C, it is cooled to room temperature, the solution is introduced into ice, and the precipitate is washed neutrally with water. 4-chloro-3-nitro-5-N-pyrrolidinylmethyl-enamino-sulfonyl-benzoic acid is obtained in crystals of m.p. 275°C.

40 g (0.11 mol) of 4-chloro-3-nitro-5-N-pyrrolidinyl-methyleneaminosulfonyl-benzoic acid are stirred in a solution of 200 ml of thionyl chloride containing 5 drops of DMF for 45 minutes under reflux. After removal of excess thionyl chloride in vacuo, the solid acid chloride is suspended in 300 ml of methanol. The suspension is boiled for half an hour at reflux, and then cooled. The precipitate is filtered, washed with cold methanol and

Example 23

4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid methyl ester

36.2 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyolbenzoic acid are dissolved in 200 ml of methanol and 7 ml of concentrated H2SO4 and heated for 4-6 hours under reflux. On cooling, the ester crystallizes. Recrystallization from methanol, m.p. 191°C.

Example 2 4

4-(4'-Methylanilino)-3-pyrrolidinyl)-5-sulfamoylbenzoic acid

3-amino-4-(4'-methylanilino)-5-sulfamoyl-benzoic acid methyl ester is reacted with 2,5-dimethoxy-tetrahydrofuran and then the precipitated crude product is saponified with 2 n NaOH. After acidification with 2 n HCl to pH 3-4, 4-(4-'-methylaninilino)-3-N-pyrrolo-5-sulfamoyl-benzoic acid of m.p. 226-228°C.

(From CH3OH/H20) .

This is dissolved in acetic acid and hydrogenated for 16 hours at 100°C and 150 atmospheres in the presence of rhodium/charcoal. The filtrate is evaporated, the residue is taken up with a little acetone (absolute) and ethereal HCl is added. Upon further addition of ether, the hydrochloride of 4-(4'-methylanilino)-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid precipitates. It is separated, washed with a little acetone/etheric HCl and then dissolved in 2 n NaHl. On acidification to pH 3-4, 4-(4'-methylanilino)-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid precipitates. Recrystallization from CH2OH/H20 gives yellow crystals of melting point 188-191°C.

Example 25

4-Chloro-5-N-pyrrolidinyImethyleneaminosulfonyl-benzoic acid

To a solution of 58.9 g (0.25 mol) of 4-chloro-5-sulfamoylbenzoic acid in 24 0 ml (2.5 mol) of N-formylpyrrolidine is added dropwise at -10 to 0°C ) P0C13- The solution is then allowed to come to room temperature, stirred for several hours, diluted with N-formylpyrrolidine and poured onto ice. After extraction, the precipitate is suspended in water, and the suspension is adjusted to pH 6. After longer stirring at room temperature, undissolved is extracted, and the free acid is precipitated by acidifying the filtrate to pH 1 - 2.

4-chloro-5-N-pyrrolidinylmethyleneaminosulphonylbenzoic acid is obtained from m.p. 250 - 252°C.

4-Chloro-3-nitro-5-N-pyrrolidinylmethyleneaminosulfonyl-benzoic acid

To 90 ml of 20% oleum, 63 ml of fuming nitric acid are dripped under ice-cooling, then 57 g (0.18 mol) of 4-chloro-5-N-pyrrolidinylmethylaminosulphonyl-benzoic acid are introduced.

After 6-7 hours of stirring at 80°C, it is cooled to room temperature, the solution is introduced into ice, and the precipitate is washed neutrally with water. 4-chloro-3-nitro-5-N-pyrrolidinylmethyl-enamino-sulfonyl-benzoic acid is obtained in crystals of m.p. 275°C.

40 g (0.11 mol) of 4-chloro-3-nitro-5-N-pyrrolidinyl-methyleneaminosulfonyl-benzoic acid are stirred in a solution of 200 ml of thionyl chloride containing 5 drops of DMF for 45 minutes under reflux. After removal of excess thionyl chloride in vacuo, the solid acid chloride is suspended in 300 ml of methanol. The suspension is boiled for half an hour at reflux, and then cooled. The precipitate is filtered, washed with cold methanol and

recrystallized from DMF/methanol.

4-chloro-3-nitro-5-N-pyrrolidinylmethyleneamino-sulfonyl-benzoic acid methyl ester is obtained, crystals of m.p. 158°C.

3-nitro-4-phenoxy-5-N-pyrroidinyimethyleneaminosulfonylbenzoic acid methyl ester

A solution of 37.6 g (0.1 mol) 4-chloro-3-nitro-5-N-pyrrolidinylmethyleneaminosulfonyl-benzoic acid methyl ester and 15.8 g (0.12 mol) potassium phenolate in 200 ml DMF is stirred for 2 hours at 80° C. After cooling, the solution is poured into ice water and then stirred for half an hour. The precipitate is filtered off, dried and recrystallized from DMF/methanol.

One obtains 3-nitro-4-phenoxy-5-N-pyrrolidinyl-methylene-aminosulfonyl-benzoic acid methyl ester of m.p. 213 - 215°C.

3-amino-4-phenoxy-5-N-pyrrolidinylmethylaminosulfonylbenzoic acid methyl ester 30 g (0.07 mol) 3-nitro-4-phenoxy-5-N-pyrrolidinyl methyleneaminosulfonylbenzoic acid methyl ester is hydrogenated in DMF with Raney nickel at 50°C and 50 atu H2 for 8 hours. After filtering the catalyst, the filtrate is evaporated in a vacuum and the residue is mixed with methanol.

3-amino-4-phenoxy-S-N-pyrrolidinylmethylene-amino-sulfonyl-benzoic acid methyl ester is obtained, crystals of m.p. 208 - 209°C.

3-N-succinimido-4-phenoxy-5-N-pyrrolidinyimethylene-amino-sulfonyl- benzoic acid methyl ester

22.2 g (0.055 mol) of 3-amino-4-phenoxy-5-N-pyrrolidinyl-methylaminosulfonyl-benzoic acid methyl ester are mixed with 17 g (0.17 mol) of succinic anhydride and heated for 1% hour at 108°C. The still warm melt is dissolved in a little DMF and the imide is precipitated from excess methanol. Recrystallization from DMF/methanol gives 3-N-succinimide-4-phenoxy-5-N-pyrrolidinyl-methyleneamino-sulfonyl-benzoic acid methyl ester of m.p. 276 - 277°C.

Claims (1)

Analogous process for the preparation of therapeutically active heterocyclic substituted 5-sulfamoylbenzoic acid derivatives of the general formula I in which the residues R , R and R are the same or different and mean hydrogen or alkyl with 1-4 carbon atoms, X means one of the groups o-R<4> or NHR<4>, in which R<4> means an optionally with Hal, alkyl- with 1-4 C atoms or alkoxy with 1-3 C atoms substituted phenyl, and R fi and R 7 are H or ^ ci~ C2^~ alkyl, as well as their pharmaceutically acceptable salts with bases or acids, characterized in that a ) 5-halogenesulfonylbenzoic acid derivatives with it general formula II in which R<3>, R<4>, R^, R7 and X have the indicated meanings and Hal means a halogen atom, is reacted with amines of formula where R 1 and R 2 have the stated meaning, or b) sulfamoyl compounds of the general formula III in which the groups R1 and R<2>, R<4>, R<6>, R7 and X have the indicated meaning, and D means a group convertible into a carboxylic acid, by hydrolysis or mild oxidation reactions are converted into the heterocyclic ones in the 3-position the substituted 5-sulfamoylbenzoic acids of formula I (R <3>= H), or c) sulfamoylbenzoic acid derivatives of the general formula IV in which the groups R1 to R<3>, R<4>, R<6>, R7 and X have the indicated meanings and L means a leaving group, treated with acids or bases for leaving HL, or d) sulphamoylbenzoic acid derivatives with the general formulas V and VI reacted with compounds of formula wherein L, R 1 to R 3, X have the above meaning and B means a protecting group with the general formula Q Q IQ in which R , R and R mean the same or different lower alkyl groups, with R 8 also o can mean hydrogen, and/or where two of the substituents R Q and R Q and R 2.0 can also be cyclically connected to each other, and where the protecting group B is split off by hydrolysis, or e) corresponding 3-N-pyrrolo compounds with the gen- or formula VIII 1 2 3 6 7 where R , R , R , X, R and R have the indicated meanings, is reduced and that, where appropriate, in compounds of formula I, which are obtained according to alternatives a) to e), free carboxylic acids of formula I (R^H) are esterified and/or carboxylic acid esters of formula I (R<3> ^ H) by hydrolysis or elimination reactions are converted into carboxylic acids (R<3>=H) and/or carboxylic acids of formula I (R 3=H) by treatment with bases or acids are converted to its pharmaceutically acceptable salts.