PH26579A - Benzenesulphonamide derivatives - Google Patents

Description

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HOEC!'ST AKTIENGESELLSCHAFT HOE 88/F 335 Dr.v.F./fe

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SA Description 9 6 rr 7 9

Benzenesulphonamide derivatives and processes for their preparation

It is known that the benzenesulphonamide derivative chlorthalidone

Ci H

Qe

HaN-025

HN

0] possesses a strong diuretic and saluretic action.

In the course of the long-standing therapeutic use of the compound as a diuretic and anti-hypertensive, an un- favorable influence on the composition of the serum lipids came to light in addition to other pharmaceutical- caused side effects. It is known that changes of this type in favor of the atherogenic lipids of the LDL fraction increase the risk of atherosclerotic vessel damage.

The invention of diuretics having a favorable effect on the serum lipid composition is described in a recently appearing patent publication (EP 0,288,028). However, in this citation there is no indication of compounds which contain an’ isoindolinone system.

The invention has the object of making available benzene- sulphonamide derivatives having further improved properties.

This has been achieved with benzenesulphonamide derivatives of the formula I

Cl HH . oi JOO

Ng INCOMPLETE DOCUMENT o nN I. HN - * 2 s “0

HO R1

Re

OO

= [ 7 9

Ca. 265 ‘ in which

R' denotes hydrogen or methyl

R? denotes hydrogen or an alkyl radical having 1 - 6 carbon atoms

R’ denotes an alkyl radical having 3 to 5 carbon atoms, and the open-chain tautomeric forms corresponding to I of the formula Ia c

H

R3 2 JO O 02 0 } la)

HO a2 0" "NHR in which R' to R® have the meaning indicated.

Preferred compounds of the formula I are those in which

R! denotes hydrogen, R? denotes methyl, isopropyl or tert.butyl and R® denotes isopropyl or tert .butyl.

The di-tert.butyl derivative 3-[4-chlor-3-(3,5-di-tert.butyl-4-hydroxyphenyl- sulfamoyl)-phenyl ]-3-hydroxy-1-isoindolinone may be particularly preferably mentioned as an outstanding individual compound.

The invention furthermore relates to a process for the preparation of the compounds of the formula I which comprises reacting compounds of the formula II

Cl Cc ~N7 Ne PN

AN °‘< N C ¢ ! f II

Ne” ce Ng” Ne” Ne” No? (] 0

Cc Cc 0

PAS 2 0 Co-X 0 Se”

H R2 with an amine of the formula III

R' - NH, III in which R"'to R® have the meaning indicated.

NN

- 3 = (J)

The compounds I can be in equilibrium with the compounds of the formula Ia by means of tautomerism: I Ia.

Which of the two forms I or Ia of a compound according to the invention is present in the equilibrium to a predo- minant extent depends on the solvent, the temperature and on the substituent R'. The cyclic tautomer form I is preferred.

The compounds of the formula I according to the invention can additionally be present in their possible geometrical isomer forms.

The alkyl radicals of the substituents R? and R’ can be both straight-chain and branched.

The process is advantageously carried out in such a way that, for example, compounds of the formula II, in which

R’ and R’ have the meaning indicated and X is the 0-(C,-

Cs) -acyl radical of a mixed anhydride, are made to react with amines of the formula III. The mixed anhydrides are advantageously generated in situ by a process in which compounds of the formula II, in which X stands for -OM and M denotes hydrogen, are converted using an equivalent of a suitable base, for example an alkali metal hydroxide or alkaline earth metal hydroxide such as KOH, NaOH,

Ca(OH),, an alkali metal carbonate or hydrogen carbonate such as Na,CO,, K,CO,, or using a preferably tertiary amine such as trimethylamine, triethylamine, tripropylamine, tributylamine or dicyclohexylethylamine, into the corres- ponding carboxylic acid salts of the formula IX, in which

X denotes M and M stands for Na, K, Ca or a trialkylam- monium cation, such as [HN(ethyl),)', which are then converted to a mixed anhydride using 1 to 2.5 mols, preferably using 1 to 1.5 mols, of an activated acid derivative.

The activated acid derivative used is advantageously, for example, an alkyl chloroformate, preferably ethyl chloroformate or methyl chloroformate, a carbamoyl

{D - 4 - (J chloride (such as N,N-dimethylcarbamoyl chloride or N,N- diethylcarbamoyl chloride) or the acid chloride or an aliphatic or aromatic sulphonic acid, for example methane, ethane, benzene or p-toluene sulphonyl chloride.

The reaction is advantageously carried out in an an- hydrous polar organic solvent, for example in acetone, methyl ethyl ketone, an alkyl (C,-C4)-alkanocate such as methyl acetate or ethyl acetate, an alkanoic acid amine, for example dimethylformamide, dimethylacetamide, in dimethyl sulphoxide, in acetonitrile, in a lower aliphat- ic alcohol, for example in methanol, ethanol or iso- propanol, preferably in a cyclic or open-chain ether or polyether, such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether. The duration of the reaction for a 0.1 molar batch is 1 minute to 5 hours, the mixture preferably being stirred over a period of 5 to 60 minutes. The reaction can be carried out in a temperature range from -50°C to 100°C, advantageously working between -30°C and +30°C, preferably between -10°C and +15°C.

Although the mixed anhydrides can be isolated, for example, by evaporating the solvent at temperatures between -5°C and +10°C and extracting with a suitable solvent, such as ethyl acetate, from the residue, a procedure is advantageously used in which the isolation of the mixed anhydride is avoided and the amine of the formula III is added to the reaction mixture. The amine can be added both undiluted and in the form of a solution where, as the solvent, that of the reaction mixture or one of the solvents indicated therefor and aqueous solutions of the amine or of ammonia can advantageously be used. In this case, relative to the compound of the formula II, at least 1 mol, but frequently advantageously a clear molar excess of amine (10-fold and more) is used.

The reaction is carried out in a temperature range between -30°C and +100°C, preferably between +5°C and +40°C. The reaction time is between 10 minutes and 5

CO be - 5 = (_ days, it being possible to follow the progress of the reaction by thin layer chromatography, advantageously on silica gel.

The acid chlorides of the formula II, in which X stands for chlorine, which can be prepared from compounds of the formula II, with X having the meaning of OH, using COCl1,, oxalylchloride, POCl1,, SOCl,, PCl, or PCl, are in principle reacted as the mixed anhydrides in the manner described above.

A likewise advantageous variant of procedure a) consists in the reaction of the carboxylic acids of the formula

II, with X having the meaning of OH, with 1 mol of carbonyldiimidazole, the activated carboxylic acid imidazolide of the formula II with X=1-imidazolyl being formed in an inert polar solvent under the mild reaction conditions indicated, which carboxylic acid imidazolide can then be converted into the compounds of the formula

I according to the invention using an amine of the formula III under analogous conditions as for the mixed acid anhydride described above.

A further advantageous variant of process variant a) consists in the reaction of compounds of the formula II, in which R' to R® have the meaning indicated and X denotes a lower alkoxy group having 1 to 6 carbon atoms in the alkyl moiety, preferably methoxy and ethoxy, or a phenyl- oxy radical optionally substituted by F, Cl or Br, with an amine of the formula III. The reaction is advantage- ously carried out in water or a polar organic solvent which is inert to amines, for example in a lower alkanoic acid amide, such as dimethyl formamide, dimethylacetamide, dimethyl sulphoxide, in a cyclic or open chain ether or polyether, such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, but preferably in a lower alcohol, such as methanol, ethanol, propanol, isopropanol or in a pure undiluted amine of the formula III without the use of a solvent. The reaction is preferably carried out in

(> . - 6 - (L 8 temperature range from 10 to 60°C, particularly preferably at 15 to 30°C. The end of the reaction is advantageously determined by thin layer chromatography on silica gel. Depending on the reaction temperature and amino component used, the duration of the reaction is usually between 1 hour and 14 days, for example between 5 and 72 hours at room temperature. The carboxylic acid esters of the formula II and the amines of the formula

III are preferably reacted in a molar ratio of 1:1 to 1:3, where, however, the amine can also be used in an up to 10-fold molar excess. The compound of the formula II, in which R' to R? have the abovementioned meaning and X stands for -0-(C,-C¢)~alkyl, is obtained by protonic catalysis in a manner known per se, for example in the presence of an organic or inorganic acid chloride, by the action of a lower alkanol having 1 to 6 carbon atoms, preferably methanol, ethanol, propanol, isopropanol and butanol.

In an identical manner, the corresponding activated esters of the formula II with X=CN, N, or -0-CH,CN can likewise be made to react with an amine of the formula

III.

A further advantageous variant of procedure a) consists in the reaction of compounds of the formula II, in which

R? and R® have the meaning indicated and X denotes a 1- benzotriazolyloxy radical, with an amine of the formula

III. These activated carboxylic acid 1-benzotriazolyloxy esters are obtained in a manner known per se by reaction of the carboxylic acids of the formula II, with X having the meaning of OH, with l1-hydroxybenzotriazole in the presence of dicyclohexylcarbodiimide, advantageously working between 0°C and 60°C in a polar organic solvent, such as in dimethyl formamide or dimethylacetamide.

The carboxylic acids of the formula II, with X having the meaning of OH, are obtained by reaction of the sulpho- chloride of the formula IV which is known from the

- - 7 - (/ literature with an aniline derivative of the formula V © R3 NH2 1 .NEt3 in 0LO ’ Cl ee, Rd 11 c1025 0 COC mo R2 2.HC! (x=OH)

Iv v in which R? and R’® have the meaning indicated, in the presence of a suitable inorganic or organic base.

Bases used advantageously are alkali metal carbonates or 5 hydrogen carbonates, or organic bases, such as triethyl- amine, pyridine or dimethylaminopyridine. The reaction is advantageously carried out in a polar protic or aprotic solvent, for example in methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, dimethoxy- ethane, dimethyl sulphoxide, dimethyl formamide or dimeth- ylacetamide, in a preferred temperature range between 20° and 80°C. The preferred work-up after the reaction is carried out by partially or completely evaporating the solvent under reduced pressure and subsequently adding hydrochloric acid or sulphuric acid, which leads to precipitation of the carboxylic acid.

According to the invention, for example, in addition to the benzenesulphonamides described in the exemplary embodiments, the following compounds of the structure I can also be prepared: 3-[4-chloro-3-(3,5-diisopropyl-4-hydroxyphenyl-sulfa- moyl)-phenyl)-3-hydroxy-1l-isoindolinone, 3-[4-chloro-3-(3-tert.butyl-5-methyl-4-hydroxyphenyl- sul famoyl ) -phenyl ]-3-hydroxy-1-isoindolinone.

The process products are useful pharmaceuticals and are distinguished by a large number of very favorable thera- peutically utilizable properties, in particular by the combination of their very good diuretic and saluretic actions with pronounced anti-atherosclerotic properties.

C

-8-

Lv This is therefore in particular of considerable thera- peutic interest since the saluretics commercially available up to now either do not decrease or even increase those lipid components (VLDL and LDL fractions) of the blood which are held responsible for inducing or advancing atherosclerosis so that, in particular in the last case, active compounds of this type possess a certain atherogeneric potential.

Even today, because of their numerous favorable proper- ties and their relatively good tolerability, diuretics still belong to the basis therapeutics in the treatment of high blood pressure. Since high blood pressure in old Ld age to a substantial extent is a consequence and initiator of atherosclerotic vessel changes, which in turn increase the high blood pressure, saluretic active a compounds, with a reduction of the atherosclerotic risk ! by lowering, in particular, the atherogeneric LDL frac- : tion of the cholesterol in the blood, are of particular fi therapeutic significance.

It was surprising that the compounds of the formula I, which differ from chlorthalidone by the introduction of a substituted phenyl radical on the sulphonamide group, possess an wrt ton Bower ing the serum level of the athero- generic lipid fractions in addition to the diuretic and I saluretic action. Such a profile of action signifies a therapeutic advance in the treatment of hypertonia of old people. 0

From numerous publications in recent years, it emerges that the formation of atherosclerotic plaques proceed injuries to the vessel endothelium. Endothelial injuries of this type can be caused by fatty acid peroxides, 80 that a reduction of the atherogenic risk is inevitably connected with a reduction in these lipid peroxides, which are essentially transported in the LDL fraction.

The compounds according to the invention are able to suppress the formation of malondialdehyde, which is a

CO

- 9 -

CL measure of lipid peroxidation. The antioxidative active component can be traced back to the hydroxyphenylamino substituent on the sulphonyl group of the compounds I.

The compounds according to the invention do not only reduce the advance of atherosclerosis by reducing the '/ atherogenic cholesterol fraction and by reducing the ¥ increased blood pressure, but moreover act preventatively E against a renewal of the atherosclerotic plagues through the destruction of the lipid peroxides. .

The compounds I according to the invention show a salur- etic action comparable to that of hydrochlorothiozide and chlorthalidone in animal experiments (rat). Moreover, the compounds 1 are distinguished by a long-lasting duration of action. The compounds I according to the invention are therefore also suitable for the treatment of hypertonic states where, as generally customary today, they are optionally combined with another antihypertonic.

The compounds I are used in doses of at least 0.5 mg/kg and day, preferably 1 mg/kg and day to at most 10 mg/kg/- | \ day, preferably up to 5 mg/kg/day, based on an adult human of about 75 kg body weight.

Suitable therapeutic preparations of the new compounds are, above all, tablets, coated tablets, capsules and suppositories and also ampoules for parenteral adminis- tration (i.v., s.c. and i.m.). The therapeutic unit dose is between 0.5 and 500 mg, preferably between 10 and 300 mg per tablet.

In addition to the customary fillers and excipients, these preparations may additionally contain an antihyper- tensive, especially in the treatment of high blood pressure, such as, for example, reserpine, hydralazine, “guanethidine, a-methyldopa, clonidine, a g-sympatholytic ’ active compound, such as propanolol, or an ACE inhibitor, such as captopril, enalapril or ramipril.

{

Co - 10 ~-

CO

In addition, therapeutic combination preparations with potassium-retaining compounds, such as aldosterone antagonists, for example spironolactone or pseudo= aldosterone antagonists, such aes triamterine or amilor- ide, are of interest. Furthermore, potassium substitu- tion in various use forms, for example coated tablets, tablets, effervescent tablets, syrups etc. is possible.

Combinations of the compounds according to the invention with an active antihyperuricemic and/or uricosemic agent which avoids strong increases in blood uric acid either by an inhibition of xanthine oxidase or by increasing the renal uric acid excretion may likewise be of therapeutic interest.

In the following example, melting point and decomposition points are not corrected.

Example 1: 3-[4-chloro-3-(3,5-di-tert.butyl-4-hydroxyphenyl-sulfa- moyl )-phenyl]-3-hydroxy-1-isoindolinone a) 4'-chloro-3'-(3,5-di-tert.butyl-4-hydroxyphenyl- sul famoyl ) -benzophenone-2-carboxylic acid

A mixture of 8.6 g of 4-amino-2,6-di-tert.butyl-phenol, 80 ml of ethyl acetate and 6 ml of triethylamine are added to a solution of 14.3 g of 4'-chloro-3’'-chlorosul- phonylbenzophenone-2-carboxylic acid in 70 ml of ethyl acetate. After the exothermic reaction has subsidided, the mixture is warmed to 55°C for two hours, 300 ml of water are then added at room temperature and the aqueous phase is adjusted to pH 1 using 2 N hydrochloric acid.

The organic phase is separated off and washed once with water. After drying over magnesium sulphate, the solvent is distilled off and the viscous residue is made to crystallize by addition of 50 ml of isopropanol and 250

. ml of N-hexane. After allowing to stand for several days, the crystals are filtered off and dissolved and allowed to crystallize several times from isopropanol /N- hexane.

Colorless to pinkish colored crystals, m.p. 150°-152°C. b) 3-[{4-chloro-(3,5-di-tert.butyl-4-hydroxyphenyl- sul famoyl)-phenyl ]-3-hydroxy-1-isoindolinone

A solution of 3.3 g of dicyclohexyl carbodiimide in 50 ml of anhydrous dimethylformamide is added dropwise with the exclusion of moisture and with magnetic stirring at room temperature to a solution of 8.7 g of 4'-chloro-3'-(3,5- di-tert.butyl-4-hydroxyphenyl-sulfamoyl)-benzophenone-2- carboxylic acid and 2.38 g of l-hydroxybenzotriazole in 50 ml of anhydrous dimethylformamide. After the weakly exothermic reaction has subsided, the reaction is stirred for 3 hours at room temperature and the mixture is filtered off from the dicyclohexyl urea precipitate.

After adding dropwise to a 25% strength aqueous ammonia solution, the mixture is subsequently stirred for 30 min. at room temperature, adjusted to pH 1-2 with 2 N HCl and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, the solvent is distilled off, the amorphous residue is made to crystallise under 50 ml of warm diisopropyl ether and the product is purified by column chromatography on 150 g of silica gel (0.063- 0.200) using ethyl acetate/toluene = 1:3 to 1:1.

Colorless crystals, b.p. 145°C-148°C (dec.). t.

Claims (1)

Cl HOE 88/F 335 Patent claims

1. A compound of the formula I c H R3 H 0 or OH y, oz NX HO p2 RrR1 0 in which R! denotes hydrogen R?’ denotes hydrogen or an alkyl radical having 1 - 6 carbon atoms R® denotes an alkyl radical having 3 to 5 carbon atoms, and the open-chain tautomeric forms corresponding to I of the formula Ia ct H R3 ©) O . Oz ° lo) , in which R! to R’ have the meaning indicated. (2- A compound I as claimed in claim 1, wherein R' denotes hydrogen, R? denotes methyl, isopropyl or tert.- butyl and R® denotes isopropyl or tert.butyl. Gr A compound as claimed in claim 1, which is 3-[4- chloro-3-(3,5-di-tert.butyl-4-hydroxyphenylsulfamoyl)- phenyl ]-3-hydroxy-l1l-isoindolinone. a! A process for the preparation of a compound of the formula 7 as claimed in claim 1 0] H H TOO Oo ’ wo 92 oN 2» in which R2 R R' denotes hydrogen

’ R? denotes hydrogen or an alkyl radical having 1 - 6 carbon atoms R® denotes an alkyl radical having 3 to 5 carbon atoms, and the open-chain tautomeric forms corresponding to I of the formula Ia cl H R3 OL Oz o Jo) HO RZ 0" ‘NHR in which R' to R® have the meaning indicated, which comprises reacting compounds of the formula II Cl Cc N “ZN J CX 3 H c c c c RL ZC N ¢ J ! ! i i c Cc c SNS 02 5 0 dl Co-X H k2 with an amine of the formula III R' - NH, 111 in which R! to R’ have the meaning indicated and option- ally converting into the salt. “