DE2339714A1 - 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

FARBWEFiKE HOECHST AKTIKNGESELLSCHAi-T 233971 Λ

formerly Master Luciiis & Brüning '' ^

File number: HOE 73 / F 231

Dr. HG / Fk.

Date: August 3, 1973

3-n-Butylamino-U-phenoxy-5- ^su li " ^am ° ylt> ^e nzoic acids and process for their preparation

(Addition to patent application P 23 i4 937 3 (HOE 73 / F 088))

The subject of the main patent is the 3-n-butylamino-4-phenoxy-5 " methoxymethylsulfamic! benzoic acid of the formula I

CH ₅ O-CH ₂ -HNO ₂ S ^^ COOH
as well as their alkali and alkaline earth salts

The main patent also relates to a method of production the compound of formula I and its salts, which is characterized in that one

a) 3-n-Butylamino - ^ - phenoxy-5-sulfamic! benzoic acid of the formula II

H ₂ NO ₂ S ^ v- * COOH

Reacts with formaldehyde in methanol, or / 2

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b) an ester of the general formula III

III

CH ₅ O-CH ₂ -HNo ₂ S

in which R is one or more times in the phenyl radical by alkyl or alkoxy radicals, halogen atoms or nitro groups substituted benzyl radical means hydrogenated in the presence of a palladium catalyst.

In a further embodiment of the invention of the main patent, it has now been found that compounds of the general formula II

1 A * / COOH

R 0-CH ₂ -HNO ₂ S ^^

where R is an optionally branched or monounsaturated alkyl radical with 2-6 carbon atoms or an aralkyl radical with up to 9 carbon atoms, the furfuryl or a 2- 3- or h- pyridylmethyl radical, have valuable diuretic and saluretic properties .

The invention thus relates to compounds of the general formula II in which R is the obi £
a method of making them.

mean formula II, in which R has the above meaning and

The method of production corresponds to the method of the main patent, whereby according to method a) corresponding .Alcohols of the formula R OH instead of methanol and according to

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Procedure b) corresponding starting materials of the formula III are used in which the radical R is analogously in the 5-position instead of the CH "group. Furthermore, the compounds of the formula II according to the invention can be obtained by optionally ^{adding the compound I of the main patent with an alcohol of the formula R 1 OH}
(Procedure c).

Formula R OH may be reacted at elevated temperatures

As alcohols of the general formula R -OH, for example: ethanol, n-propanol, isopropanol, n-butanol, isobutanol, η-amy alcohol, isoamyl alcohol, n-hexanol, allyl alcohol, benzyl alcohol, 2-phenyl ethanol, 2 - And 3-phenylpropanol, and furfuryl alcohol, and the isomeric 2-, 3- or h- pyridylmethyl alcohols.

The reaction according to c) is advantageously carried out in such a way that the 3-n-butylamino - ^ - phenoxy-5-methoxymethylsulfamoylbenzoesäure in the h- to 10-fold amount of an anhydrous alcohol of the general formula R-OH few hours to temperatures heated between 80 and 100C. When the methoxy radical has been replaced by the remainder of the alcohol in question, the mixture is cooled to room temperature and the reaction product, if it has not crystallized out after standing overnight at room temperature, is advantageously deposited by adding petroleum ether crystals in portions.

The details of the invention detailed in the main patent The process also applies to the process of the additional patent, as do the statements about production of the starting material III, again instead of methanol an alcohol of the formula R OH is used.

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Examples;

3-n-Butylamino - ^ - phenoxy-5-ethoxymethylsulfamic! Benzoic acid 200 g 3-n-Butylamino ~ 4 ~ phenoxy-5-sulfamic! Benzoic acid (0.55 mol) 2.0 1 ethanol and 0.2 1 30- percent aqueous formaldehyde solution is refluxed for 5 hours. The mixture is then cooled to room temperature, filtered to remove a slight cloudiness, 1.5 l of water are added to the filtrate and the mixture is left to crystallize overnight at room temperature. The deposited process product is washed thoroughly with water on the suction filter and then dried in vacuo at 40 ° / 0.1 Torr. Yield: 120 p; colorless prisms (52 # d * Th.), Schrnp. 126-12 7 °.

Example 2

-'l · -phenoxy-5- isopropox ymethylsulfamoylbenzoic acid

195 g of the sodium salt of 3-n ~ butylamino ~ ^z l -phenoxy-5-sulfamic acid (0.50 hol) v / earth with 2.0 l isopropanol and 0.2 l 30 percent. aqueous formaldehyde solution heated under reflux for 5 hours. The reaction solution is then cooled to room temperature, filtered and the J filtrate with stirring at 2.0 1 5 percent. Acetic acid added. The reaction product, which is initially deposited in amorphous form, quickly crystallizes through after being rubbed at room temperature. It is filtered off with suction, washed with water and dried at 30 ° / 0.1 Torr.
Yield: 155 K (71 % of theory). M.p.

Example 3

3-n-Butylamino-4-phenoxy-5 ~ n ~ buto:>: ymothyl5ul · f amoylbensoesgairo 205 6 3-n-Butylamino- ^/ 1-phenoxy-5-methoxymethylsulfamoylbenzoic acid (0.5 mol) are in 1.0 1 n-Butanol heated to 100 ° C. for 2 hours. The clear reaction solution is rubbed with 200 liters of petroleum ether at room temperature until crystallization begins. After standing over night at +10 C a thick crystal paste has formed. It is suctioned off, washed with a little n-butanol / petroleum ether (1: 1) and dried at 30 ° / 0.1 Torr. Yield : 155 g (69 j> d. Th.), M.p. 127-129 °

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example k

3-η-buty! Amino- H -phenoxy-5-benzyloxymethylsulfamic! benzoic acid

205 g of 3-n-butylamino-4-phenoxy-5-methoxymethylsulfamoylbenzoic acid (0.5 mol) are heated to 100 ° C. with 1.0 l of freshly distilled benzyl alcohol for 5 hours. After cooling to room temperature, the reaction solution is initially still clear
but after standing overnight at room temperature to one
Crystal cake solidifies. It is triturated with 0.5 l of benzyl alcohol, filtered off with suction and washed with benzyl alcohol / petroleum ether (1: 1) and
then with pure petroleum ether. It is dried at 60/1 Torr. Yield: I65 g (68 j "theory), mp 158-159 ° C.

The following can be produced in an analogous manner:. ,; ·

benzoic acid

3-n-Butylamino-4-phenoxy-5-Z2- (or 3) -phenylpropyloxymethyl-

j sulfamoyl / benzoic acid

3-n-Butylamino-4-phenoxy-5-furfuryloxymethylsulfamoylbenzoe-

acid

3-n-Butylamino - ^ - phenoxy ^ - (2 ^l -pyridylmethyloxymethylsulf-

"> I amoyl) -benzo β acid

3-n-Butylamino - ^ - phenoxy-5r (3 -pyridylmethyloxymethyl sulf-

j amoyl) benzoic acid

amoyl) benzoic acid 3-n-butylamino-4-phenoxy-5-amyloxymethylsulfamoylbenzoic acid 3-n-butylamino-4-phenoxy-5-isoamyloxymethylsulfamoylbenzoic acid

3-n-Butylamino-i | -phenoxy-5-isohexyloxymethylsulfamoyl-benzene

acid

9 W) 9/1 2 2 1

Claims (2)

Patent claims: . 3-n-Butylamino-4-phenoxy ~ 5-sulfamoylbenzeo acids der Formula II ₀ f- <W ⁽ⁿ⁾ wherein R is an optionally branched or monounsaturated alkyl radical with 2-6 carbon atoms or an aralkyl radical or a heteroaromatic radical with up to 9 carbon atoms the furfuryl or a 2- (3- or ^ -) - pyridyl- - 'me thy Ire st and their alkali and alkaline earth salts means. 2. Process for the preparation of the compounds of the formula II by the process of the main patent, characterized in that that, according to procedure a) instead of methanol, an alcohol of the formula R -OH, in which R is the above "· Has meaning, used, according to procedure b) corresponding Starting materials of the formula III a used, .4 j! £ ~ \ NH-C ₄ H ₉ - (η) - R ¹ O-CH ₂ -HNO ₂ S- ^ ^: ^ ^V COOH III a or according to c) the connection of the main patent Γ \ _O OH ^ O-CH ₂ -HNO ₂ S ^^ COOH ,: x 5 0 9 8 0 9 A J 2 2 1 original inspect ^ 23397U equates to an alcohol of the formula R OH, possibly at elevated levels Tempfe ^ turen implements. Pharmaceutical preparations, characterized by a Content of a compound according to Claim 1, possibly together with common carriers and fillers and, if necessary, in combination with hypotensives or potassium-retaining drugs Process for the production of pharmaceutical preparations according to claim 3, characterized in that compounds according to claim 1 are used in the usual manner. together with the usual carriers and fillers and possibly with ""
brings other pharmaceuticals into a therapeutically suitable application form. 509809/1221