DE2314937A1 - 3-Butylamino-4-phenoxy-5-sulphamoyl-benzoic acids - as diuretic and saluretic agents - Google Patents

Abstract

Cpds. (I):- (where R' is 1-6C alkyl opt. branched and opt. contng. one unsatd. bond; or an aralkyl group contng. up to 9C or 2-, 3- or 4- pyridylmethyl) may be prepd. either by reacting 3-butylamino-4-phenoxy-5-sulphamoyl benzoic acid (II) with R'OH and HCHO; or hydrogenating a (I)-benzyl ester, or reacting (I; R' = Me) with R'OH to give (I; R' = 2-6C alkyl). Thus (I; R' = Me) is prepd. by refluxing (II), HCHO and MeOH.

Description

3-n-Butylamino-4-phenoxy-5-methoxymethylsulfamoylbenzoic acid and process for its preparation The invention relates to 3-n-butylamino-4-phenoxy-5-methoxymethylsulfamoylbenzoic acid of the formula I as well as their alkali and alkaline earth salts.

The invention also relates to a process for the preparation of the compound of the formula I and its salts, which is characterized in that a) 3-n-butylamino-4-phenoxy-5-sulfamoylbenzoic acid of the formula II reacts with formaldehyde in methanol, or b) an ester of the general formula III where R is a benzyl radical optionally substituted one or more times in the phenyl radical by alkyl or alkoxy radicals, halogen atoms or nitlo groups, hydrogenated in the presence of a palladium catalyst.

The implementation according to the process mentioned under a) is carried out in the manner carried out that the compound 11 with a large excess of methanol and 1.5 refluxing heated to 4 molar equivalents of formaldehyde. The condensation takes place relatively slow and ends after about 8 hours. The response is running ahead, too if an excess of formaldehyde is used, practically no formation of by-products.

The Pormaldchyd is advantageous in the form of the commercially available one Formalin, an aqueous 37 percent formaldehyde solution containing 8-10% methanol, a. But you can also work completely water-free and the corresponding amount Introduce gaseous formaldehyde into methanol. The amount of methanol is chosen so that a clear reaction solution is obtained at reflux temperature. That corresponds to the 10 to 20 times the amount of methanol, based on the compound ii.

For work-up, the reaction product can be taken directly from the reaction solution Separate them in crystalline form by adding water. However, it is advantageous to steam them Reaction solution initially completely absorbs excess formaldehyde in a vacuum and to remove water and then recrystallize the residue from methanol. Even Mitromethane is suitable for recrystallizing the pre-process product. Furthermore can it is made from ethyl acetate, in which it is easily soluble at room temperature, by portions Add crystalline petroleum ether, ethanol and homologues are for recrystallization of I not suitable, since in these solvents the methoxy group versus the alkoxy group of the affected battery is replaced.

Instead of the free carboxylic acid of the formula II, its alkali and alkaline earth salts can be used in the reaction. When using these salts the reaction proceeds much more quickly and is refluxed after about 2 hours completed. Otherwise, those specified for the implementation of the free carboxylic acid are available Reaction conditions are accepted.

If one wants to isolate the alkali metal or alkaline earth metal salts of I as such, the reaction solution is evaporated completely in vacuo and the crystallized Residue from water. After dom drying. in a vacuum the salts are at room temperature stable and storable.

If you want to isolate I in the form of the free acid: 30 you add the if necessary, filtered to the reaction solution at room temperature with about twice the amount 5- to 10-pros. Acetic acid. The process product separates immediately in crystalline form and is advantageously air-dried after vacuuming and washing with water and then recrystallized from methanol.

In the implementation according to the process mentioned under b), one sets advantageous the unsubstituted benzyl ester of the general formula III, because it is most easily accessible and can be split hydrogenolytically sufficiently quickly leaves.

Particularly substituted benzyl esters are p-nitrobenzyl, p-chlorobenzyl or 2,3, and / or 4-methylbenzyl ester in question.

The solvent used in the hydrogenation is advantageously methanol. Acetate, dioxane and tetrahydrofuran are also examples of solvents suitable. The palladium catalyst is advantageously in the form of freshly prepared Palladium black, in an amount of 2 to 5 ß based on the ester of the general Formula III, used. It is preferred to hydrogenate in the shaking duck in a stirred autoclave at a hydrogen pressure of 0.2 to 0.5 atm. Depending on the equipment and batch size the hydrogenation is complete in 1-4 hours.

After the catalyst has been separated off, the solution is evaporated and crystallized the residue is advantageously converted from methanol. The yields are over 80% of the Theory.

The 3-n-butylamino-4-phonoxy-5-methoxymethylsulfamoylbenzoic acid benzyl ester of the formula IIIa, which can be used as starting material, can be represented, for example, according to the reaction scheme below.

The compound IIIa can also be prepared, for example, by esterifying compound II with benzyl alcohol and then the benzyl ester Reacts with methanol / formaldehyde.

The new process products have valuable diuretic and saluretic Properties with very low toxicity and are more comparable to known diuretics Structure superior.

The compound I according to the invention and raw salts are valuable therapeutics especially for the treatment of high blood pressure as well as cardiac, renal and other Edema. They are preferably administered orally, but can also be used parenterally will.

The therapeutic preparations are therefore mainly tablets, Dragees and capsules in question. The therapeutic unit dose of- Active ingredient in these preparations is generally between 0.1 and 10 mg.

These preparations may contain the usual fillers and carriers and can also contain other active ingredients. For the treatment of high blood pressure you can, for example, with hypotensives such as reserpine, clonidine, t-methyldopa, Guanethidine or hydralazine can be combined.

In certain cases, potassium-retaining drugs such as Amiloride, triamterene and spironolactone. can be added.

Examples 3-n-Butylamino-4-phenoxy-5-methoxymethylaulfamoyl-benzoic acid Example 1 200 g of 3-n-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid (0.55 mol) 2.0 1 methanol and 0.2 1 30 percent. aqueous formaldehyde solution are heated to smell. A clear solution has formed after about an hour. After another seven hours At reflux, the starting material has disappeared.

(Control by thin layer chromatography on silica gel in the Mobile phase dioxane / water / ethyl acetate / benzene / 18: 2: 4: 5 /.

The starting material has Rf = 0.60, the end product Rf = 0.66).

The reaction solution is evaporated in vacuo and the crystalline The residue was recrystallized from 1.5 l of methanol. After washing with methanol this becomes End product dried to constant weight at 600/1 Torr.

Yield: 128 g of colorless prisms (57% of theory), melting point 155-156 ° C below Decomposition.

Elemental analysis: C19H24N2O6S (408.5) Calc .: G 55.8 H 5.9 N 6.85 S 7.8 Ilethoxyl 7.6 Gef .: "55.8" 5.7 "6.9" 8.0 "7.4 is obtained from the mother liquor by concentrating to half a further 56 g of pale yellowish prisms from the decomposition P. 152-154 ° C and therefrom by recrystallization from 0.3 l of methanol a further 30 g of pure Process product from Scbmp 155-156 ° C and decomp.

Example 2 195 g of the sodium salt of 3-n-butylamino-4 "phenoxy-5-sulfamoylbenzoic acid (0.50 mol) with 3.0 1 of methanol and 0.2 1 of 30 percent. aqueous formaldehyde solution 2 Refluxed for hours. The following appears in the from of a slight cloudiness filtered off. After it has been cooled to room temperature, the filtrate is placed in advance with stirring with 0.3 1 5 percent. Acetic acid. The end product separates out immediately in crystalline form. After standing briefly at room temperature, it is filtered off with suction, washed with water and dried at 50 ° in vacuo.

Yield: 160 g of colorless crystals (79% of theory). Decomp. P.

150-152 ° purification of the crude product by recrystallization from nitromethane.

Final yield: 135 g (67% of theory), decomposition P. 157-158 ° The sodium salt the 3-n-butylamino-4-phenoxy-5-methoxymethylsulfamoylbenzoic acid is obtained, by not acidifying the filtered reaction solution, but in a vacuum to dryness evaporates. The residue is recrystallized from water 'at a temperature does not exceed 600. It is dried at 600/1 Torr until the weight is constant.

Yield: 157 g of colorless Prismon (74% of theory) which has the compound no sharp melting point or decomposition P.

and is uniform according to thin-layer chromatography.

Other alkali and alkaline earth salts can also be used analogously to this specification of the process product are produced.

Example 3 50 g of 3-n-butylaumino-4-phenoxy-5-methoxymethylsulfamoyl Benzoic acid benzyl ester (0.1 mol) are dissolved in 1.0 1 of methanol and after addition from freshly prepared palladium black hydrated in the shaking duck. After 2 hours and a hydrogen uptake of 2.5 1, the hydrogenation comes to a standstill Of the The cold analyzer is separated off, the solution is evaporated in vacuo and the residue is removed recrystallized from methanol.

Yield: 34.5 g of colorless prisms (85% of theory). Decomposition P. 15 @ The product of the process is identical in terms of thin-layer chromatography and IR spectroscopy to that according to Example 1 obtained compound.

Claims (4)

Claims <3-n-Butylamino-4-phenoxy - $ - methoxymethylsulfamoylbenzoic acid de formula I and their alkali and alkaline earth salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that either a) 3-n-butylamino-4-phenoxy-5-sulfamoylbenzoic acid of the formula II reacts with formaldehyde in methanol, or b) an ester of the general formula III where R is a benzyl radical optionally substituted one or more times in the phenyl radical by alkyl or alkoxy radicals, halogen atoms or nitro groups, hydrogenated in the presence of a palladium catalyst. 3. Pharmaceutical preparations, characterized by a content on a compound according to claim 1, optionally together with customary carriers and fillers and possibly in combination with hypotensives or potassium-retaining drugs. 4. Process for the production of pharmaceutical preparations according to Claim 3, characterized in that one compounds according to claim 1 in the usual Way, if necessary together with customary carriers and fillers and if necessary with other pharmaceuticals brings into a therapeutically suitable application form.