NZ205469A

NZ205469A - Sulfamoylbenzophenone derivatives and pharmaceutical compositions

Info

Publication number: NZ205469A
Application number: NZ205469A
Authority: NZ
Inventors: B Seuring; H Lang; M Hropot; R Muschaweck
Original assignee: Hoechst Ag
Priority date: 1982-09-04
Filing date: 1983-09-02
Publication date: 1986-04-11
Also published as: JPS5973563A; MA19893A1; PT77286A; EP0104483A2; FI833118A0; GR78942B; ES525333A0; NO833157L; EP0104483A3; FI833118A; DK402083A; AU1867883A; KR840006334A; DE3232922A1; DK402083D0; ES8500054A1; ZA836512B; IL69641A0; PT77286B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £05469 205469 Priority Date(s): ;. .9'. .S3. Complete Specification Filed: Class: CQ .K<4fi3.J. 7%J.. 5/ /3SE Publication Date: .. P.O. Journal, No: ./c?5} P? P 1 APR 1986 liiiS N.Z.No. NEW ZEALAND Patents Act, 1953 COMPLETE SPECIFICATION "Sulfamoylbenzophenone derivatives, a process for their preparation, their use and pharmaceutical products based on these compounds." We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany, of D-62 30 Frankfurt/ Main 80. Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - -1- - 2 - 205469 The invention relates to compounds of the formula V z=n ^SO (v) 0 R in which 1 ? 7 R , R and RJ are identical or different and represent hydrogen, halogen, alkyl having 1 to 4 carbon atoms or a I k o >:y having 1 to 4 carbon atoms, it not being possible however 1 2 for R and R both to denote hydrogen, and it being 1 ? possible for R and R together also to denote a bridge comprising 2 to 5 methylene groups or methy I enedioxyv 1 D R denotes alkyl having 1 to 4 carbon atoms, a phenyl protective group, hydrogen or a radical of the formula VI co-y (V I) : R^ \R5 in which R^ and R^ are identical or different and represent hydrogen or alkyl having 1 to 4 carbon atoms or are components of a saturated carbocyclic ring having , . T E * r to 7 members, and Y represents ORin which R demotes < I! - hydrogen, alkyl having 1 to 4 carbon atoms, which*! >\c/"5ffs;ss6^ 2 0 5469 - 3 - optionally be substituted with hydroxyl or alkoxy having 1 to 3 carbon atoms, or denotes aralkyl having 7-9 carbon atoms, or represents a protective group for the carboxyl function which is stable to Lewis acids, and represents 2 hydrogen atoms or a protective group of the formula III R° c-ncT" <iii) R-J in which denotes hydrogen or alkyl-having 1 to 4 carbon atoms and R® and 'r' denote alkyl having 1 to 4 carbon 10 atoms, and their physiologically tolerated salts. Several phenoxyacetic acid derivatives acyLated in the 4-position and having saluretic and/or uricosuric effects have already been described in the literature (cf. 15 G.M. Shutske et al, J. Med. Chem. 2J5_, 36-44 (1 982) and literature cited there). All these compounds have a lipophilic aroyl moiety and they act to produce saluresis in rats either hardly at all or only at relatively high doses. Thus, it was very surprising that compounds according to 20 the invention, of the formula I, which are both phenoxy-. acetic acid derivatives and sulfonamides, exert both a uricosuric and a saluretic effect and that they are superior to the abovementioned compounds in respect of activity and/ or duration of action, as can be demonstrated by experi-2 5 ments on rats. Moreover, benzophenonesulfonamide derivatives having diuretic and saluretic properties have been disclosed in - 4 - 205469 10 15 20 United States Patent No. 3,055,930, but these do not exhibit uricosuric or hypouricemic effects. Compounds of the formula V are preferred in which 1 6% 1 denotes 2 hydrogen atoms, and R -R have the above- mentioned meanings, especially those compounds in vihich Z represents 2 hydrogen atoms, R^and R^ represent hydrogen, halogen and/or methyl, ,10 represents x. 6 c-co-OR with R R" R^ and R"\ representing hydrogen and/or methyl, and representing hydrogen, alkyl having 1 to 4 carbon atoms or benzyl; those compounds being preferred in which Z denotes 2 hydrogen atoms, r'', and denote chlorine, methyl and/or hydrogen, with R^ denotes ^ ~-CO-ORG 4^5 R R R^ and R-* denoting hydrogen and denoting hydrogen or alkyl having 1 to 4 carbon atoms, Of all the compounds of the invention, those are quite particularly preferred in which Z denotes 2 hydrogen atoms, R^ denotes ^ C-CO-OR ^XR5 25 and R? denote chlorine or methyl and 3'^3;936/oj - 5 - 295469 R3 to denote hydrogen, The invention also relates to a process for the preparation of compounds of the formula V which comprises reacting, in a manner known per se by Friedel-Crafts acyl-ation, a carboxylic acid derivative of the formula II Z=N (II) 10 15 20 in which Z represents 2 hydrogen atoms or a protective group of the formula III -.8 R7 I C-N; K" (III) in which denotes hydrogen or alkyl having 1 to 4 carbon atoms and R® and R^ denote alkyl having 1 to 4 carbon atoms, and in which X represents a leaving group, but especially represents chlorine, with a phenol derivative of the general formula IV (IV) in which R^, and R3 have the abovementioned meanings and ,10 a) denotes alkyl having 1 to 4 carbon atoms, another suitable phenol protective group or hydrogen, -qu 7 b) represents a radical of the formula VI ON -«V -v\Y - 6 - 205469 O \ ^ (VI) / c-r * R ^ R5 in which and have the abovementioned meanings and Y represents 0R^, being defined as above, or represents a protective group for the carboxyl function which is stable to Lei/is acids, to give compounds of the general formula V R3 _ _ 1 0 (V) in which R^, R^, R^, R^ and Z have the abovementioned meanings, (compounds of the formula V in which Z is 2 hydro-1 0 10 gen atoms ond Ru is a radical of the formula VI being identical with compounds of the formula I) 3 n .6 (I) 1 n and converting the latter, when R is alkyl having 1 to 4 carbon atoms or another suitable phenol protective group, 1 n 15 by elimination of the radical R , into the phenols of the formula V in which R^ denotes hydrogen and R^ to R^ and Z have the abovementioned meanings, compounds of the formula V in which Z has the meaning of a p r o t e c t i v e .g ro-ttp^ of the formula III being easily obtained from or converted © 20 into, (! "3,^ Sif\Y '^n\ BB'!986£l 205469 - 7 - compounds having an unprotected sulfonamide group (Z equalling 2 hydrogen atoms), alkylating the phenols of the formula V defined above with an acetic acid derivative of the formula 0 II v1 p \ ^ \ (VII) c x ^ Rf> in which R^, Rand Y have the abovementioned meanings and W has the meaning of a nucleofugic group, such as, for example, bromine, chlorine, iodine, p-1oIuenesuIfonyI or me-thanesulfonyl, to give compounds of the formula V in which R^® represents a radical of the formula VI defined above 1 5 and the radicals R to R , Y and Z have the abovementioned meanings, easily converting the latter, in the case where Z has the meaning of a protective group of the formula III, by alkaline or acid hydrolysis into the compounds of the formula I and optionally mutually interconverting these compounds of the formula I by acid or alkaline hydrolysis, or acid-catalyzed esterification or transesterificat ion reactions respectively, and converting compounds of the formula.I into their physiologically tolerated salts. The preparation of the phenol derivatives of the 1 n formula V (R 1 -hydrogen) is carried out in a manner known per se by reacting the phenol derivatives of the formula IV with carboxylic acid derivatives of the formula II in the manner of a Friedcl-Crafts acylation (cf. Houben-WeyI, Vol.VII/2a, p.15-62, Georg Thieme Verlag, Stuttgart, 1973), . ; "7* aluminum chloride being preferably used as the Fri ede^t-c^'>u 2 0 - - 8 - Crafts catalyst. All solvents customary for Friedel-Crafts acylations can bo used, chlorinated hydrocarbons, such as, for example, methylene chloride or 1,2-dichloroethane being particularly suitable, but carbon disulfide can also be advantageous. The reactions are carried out between -20 and 100°C with 1-4 equivalents of catalyst and, to avoid byproducts, the reactions are advantageously carried out at temperatures below 4 0°C with stoichiometric ainounts of catalyst. In order to convert the phenol ethers of the foi— 1 0 mula V into the phenols V (R =hydrogen), especially for 1 0 R equalling methyl, all customary cleavage reagents for aryl alkyl ethers are suitable, and boron tribromide and aluminum chloridc are particularly preferred, the reaction medium used being, in particular, chlorinated hydrocarbons, such as methylene chloride and 1,2-dichloroethane at temperatures between -20 and +80°C, but preferably between + 20 and -i-50°C. However, the cleavage takes place smoothly in melts of anhydrous pyridinium halides, especially pyridine hydrochloride, at temperatures between 120 and 200°C, especially between 160 and 1 9 0 0 C . In order to avoid side reactions in the subsequent 1 0 alkylation reaction, those phenols V (R =hydrogen) in which the sulfonamide group is protected against alkylation, i.e. in which 7. has the meaning of III, are preferably employed. However, it is also possible quite selectively to alkylate 1 n the OH group of phenols of the formula V (R1-hydrogen) having a free sulfamoyl group by reacting them with a small excess of alkylating agent of the formula VII and a weak ,20Uw -y - 9 - auxiliary base, preferably sodium bicarbonate or potassium carbonate, in a polar aprotic solvent, such as, in particular, acetone, mei,.,'. ethyl ketone, dimethyIformamide, dimethyl acetamide or N-methylpyrrolidone, preferably at temperatures between 0 and 50°C. In the case where the 1 n resulting compounds of the formula V (R-group of the formula VI) must further be converted into the products I, it is possible to carry out, for example, the hydrolysis of esters (R^ having the meaning of alkyl) to give the free phenoxyacetic acids (R ^ equal to H) at the same time as necessary elimination, where appropriate, of the sulfonamide protective group (Z having the meaning of formula III) either using a base or an acid in the presence of water, If the elimination takes place under acid conditions, then a strong mineral acid, such as hydrochloric acid or sulfuric acid, is preferably used. In contrast, if alkaline hydrolysis is carried out, then strong inorganic bases, such as alkali metal or alkaline earth metal bases, such as, for example, lithium, sodium or barium hydroxide, are used, but strong organic bases, such as quaternary ammonium hydroxides, for example tetraethylammonium hydroxide, can be used. Virtually every solvent which is inert to the reac-tants can be used as the solvent, such as, for example, alcohols, preferably methanol, or, if acid hydrolysis is carried out, alkanoic acids, such as, for example, acetic acid. At least one equivalent of water must be added to the reaction mixture per hydrolyzable group, but usually a relatively large excess is used, or water serves as the only solvent, and this is particularly advantageous for alkaline 20^4 „ - 10 - hydrolyses. The reaction temperature can be between 0 and 120°C, and for acid cleavages, the reaction is advantageously carricd out at the reflux temperature of the solvent. The reaction products are most advantageously isolated by 5 adding a non-solvent, such as, for example, water, to the reaction mixture at the boiling point; the product is then usually obtained as crystals on cooling down. Alkaline hydrolyses are generally carried out at temperatures between 0 and 50°C, preferably at room temperature, and, after neu-10 tralization of excess base, the free acids of the formula I (R^ = hydrogen) are precipitated by the addition of further acid, and, where appropriate, sodium chloride, and are filtered off or extracted with a suitable solvent, prefei— ably ethyl acetate, and, where appropriate, recrystallized. 15 In the following text, "room temperature" denotes 20-25°C . The physiologically tolerated salts in this invention comprise the salts of alkali metals and alkaline earth metals and of non-toxic organic bases, for example of etha-20 nolamine, diethanoLamine, trishydrox ym ethyl in ethyla mine, N-methylglucamine or L-arginine. Apart from the compounds described in the practical examples, the compounds of the general formula I which are compiled in the following tables can also be obtained ac-25 cording to the invention. 4i Table 1 - 11 - 20 w H- r <CiVr «:>y3- -(Cii2»2- (Cli) ,• •i CI CI C.1 Cl Cl CI OCH. OCfi. Oil Cl Cl Cl CH3 Cl Cl H Cl Cl cl 0CH3 Cl Cl Cl Cl Cl Cl ch3 cl Cl )V H 11 H 11 11' Cl H II H Cl Cl ;i H CH c:l OCH Cl 11 H 3 (CH 2 2 - (CH_) ,/ Z s> -(CII2V H H ii H H H H H II II R* II ]1 H ]] H II H II IJ H H II H II H II K II H II 13 H II H H H II H • II H. R H II H CH2-ch2--OH ch2--ch2~o-ch3 'L U o 4 o ^ - 12 - The compounds according to the invention, of the formula I, and their physiologically tolerated salts, are diuretics and saluretics having an additional uricosuric component. They can be employed as pharmaceuticals in human and veterinary medicine. For this purpose, they are administered orally, parenterally or intravenously in doses of 1-50 mg/kg of body weight and day. Alone or combined with other substances having hypotensive, vasodilator or diuretic activity, they are suitable both for the treatment of hypei— tension and for the treatment of cardiac, renal or hepatic edema, and other manifestations attributed to disturbances of the electrolyte balance. In this context, the particular importance of the above compounds lies in their double activity as diuretics and uricosurics. It is known that, in many cases during diuretic treatment with known diuretics, there is an increase in the uric acid concentration in the blood of the patient. An increase in the level of uric acid is a serious problem for patients with gout. Moreover, an increased level of uric acid is increasingly being regarded as a risk factor for heart disease. Thus, the diuretic activity associated with excretion of uric acid can be regarded as a major advantage of the compound according to the invention. The compounds can be used alone or combined with other substances having saluretic activity even of a different type. The following may be mentioned in particular: spironolactone, triamterene, arniloride and other K*-retaining compounds. However, other compounds having purely hypotensive activity are also possible as partners in the combination, for example, hydralazine, clonidine, reserpi ne 205469 - 13 - and, in particular, beta-blocking substances, such as, for example, metoprolol or penbutolol. Effective amounts of the compounds according to the invention can be administered to a patient by various routes, for example, orally in the form of capsules or tablets, pa rente rally in the form of sterile solutions or suspensions and, in some cases, also intravenously as sterile so lut i ons . The free acids, which are themselves active,can be formulated and administered in the form of their pharmaceutical^ tolerated salts for reasons of stability, readier crysta 11izabiIity, readier solubility etc. For oral administration, the active compounds of the invent ion can be mixed with a diluent or ingestible vehicle, or be enclosed in gelatin capsules or compressed to form tablets. For oral therapeutic administration, the active compounds can be incorporated in a vehicle and used in the form of tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers, chewing gum etc. These products should contain at least 0.5% of active substance, however, depending on the particular form, the content can vary between 4 and 70% of the weight of the unit. The amount of active compound in products of these types is calculated so that a suitable dose can be readied. Preferred mixtures and products contain 10 and 300 mi I Iigrams■ of the active compound per unit oral dose. The tablets, pills, capsules, pastilles etc. can additionally contain the following constituents: binders, such as inicrocrystalline cellulose, gum tragacanth or 205469 - 14 - gelatine, vehicles, such as starch or lactose, disinteg-rants, such as alginic acid, corn starch etc., lubricants, such os magnesium stearate or colloidal silicon dioxide, sweeteners, such as sucrose or saccharin, or an aromatic agent, such as peppermint, methyl salicylate or orange aroma. In the case of a unit dose in the form of capsules, these can contain, in addition to the substances mentioned, a liquid vehicle, for example an oil. Tablets or coated tablets can, for example, also be provided with sugar, shellac or other enteric coatings. A syrup can contain, in addition to the active compound, sucrose as a sweetener and certain preservatives, colorants and flavorings. The materials used for the production of the mixtures should be pharmaceutical^ pure and non-toxic in the amounts added. For parenteral therapeutic administration, the active compounds according to the invention can be incorporated in a solution or suspension. Products of these types should contain at least 0.1% of the active compound, but the content can vary between 0.5 and 30% by weight. The products contain an amount of active compound such that a suitable unit dose can be obtained. The mixtures and products according to the invention preferably contain between 10 and 500 mg of active substance per unit parenteral dose. The solutions and suspensions can contain the following components: a sterile diluent, such as water for injection, saline, non-volatile oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial agents, such as benzyl alcohol; antioxidants, 205469 - 15 - such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting the tonicity, such as sodium chloride or dextrose. 5 The parenteral products can be filled into vials, disposable syringes or multi-dose bottles made of glass or plastic. The following examples illustrate the invention. Example 1: ?/3-dichloro-4-(4-chloro-3-sulfamoylbenroyl)phenoxyacetic 10 acid a) 4~mcthoxy-5'-sulfamoyl-2,3,4'-trichlorobenzophenone 635 g (2.5 mo I) of 4-chloro-3-sulfamoylbenzoyl chloride are added in portions, with stirring, at -100C to a suspension of 610 g (4.6 mol) of aluminum chloride. The 15 mixture is stirred at -10 to -5°C for about 30 mins and then a solution of 35 4 g (2.0 mol) of 2,3-dichloroanisole in 0.6 liters of methylene chloride is added dropwise. The resulting mixture is stirred at room temperature until the evolution of HCl is finished (2-5 days), then 20 it is poured into a mixture of about 6 kg of ice and 1.5 Liters of concentrated hydrochloric acid, the precipitated solid is filtered off with suction, thoroughly washed with water, sodium bicarbonate solution and water again, dried and recrystallized from acetone, ethanol or a mixture of 25 dimethylformamide and water. Colorless crystals of melting point 219-221°C. b) 4-hydroxy-5'-suLfamoyl-2,3,4'-trichlorobenzophenone 25 ml (0.26 mol) of boron tribromide are added drop-wise, at -20 C, to a stirred suspension of 21 g (0.053 mol) 2 0 5469 - 16 - of 4-inethoxy-3'-sulfamoyl-2,3,4,-trichlorobenzophenone in about 400 ml of toluene- After stirring at room temperature for 5 days, the red-brown mixture is poured into about 0.7 liters of ice-cold saturated sodium bicarbonate solution, 5 with vigorous stirring, and the beige-co I ored solid is removed by filtration with suction, was lied with dilute hydrochloric acid and water and dried in a vacuum dessicator over phosphorus pentoxide. Crea in- colored powder of melting point 214-218°C (decomposition). 10 A product of almost identical quality is obtained by heating, for about 3 hours, a mixture of the same starting material with 2.5 parts by weight of anhydrous pyridine hydrochloride at 180°C under nitrogen and then introducing the still liquid melt into a mixture of ice and hydrochloric 15 acid, and washing and drying the resulting beige-colored solid. c■* Methyl 2,3-dichloro-4-(4-chloro-5-sulfamoylbenzoyl)phen-oxyacetatc A mixture of 58 g (0.152 inol) of 4-hydroxy~3'-sul-20 fairtoyl-2,3/.4'-trichlorobenzoph&none, 21 g (0.152 mol) of ground potassium carbonate and 2.2 g (0.015 rnol) of sodium iodide is dissolved or suspended in about 1.2 liters of degassed methyl ethyl ketone^ 29 g (0.195 mol) of methyl bro-moacfctate is very slowly added dropwise at room temperature, 25 then the mixture is stirred until reaction is complete (checked by thin-layer chromatography, 2-6 days),filtered, the filtercake is thoroughly washed with warm acetone, the filtrate is evaporated to dryness in a rotary evaporator, the residue is digested with water until crystallization, 2 0 5469 - 17 - the solid is removed, boiled with a little methanol, and after cooling down the solid is filtered off with suction and dried under high vacuum. White to cream-coIored powder of.melting point 191-194°C. After recrystallization from methanol/acetone: colorless crystals of melting point 203-206°C. d) 2/3-dichloro-4~(4-chloro-*3-sulfamoylbenzoyl)phcnoxy-acetic acid 31.6 ci (70 mmol) of methyl 2 ,3-d i c h I o ro-4-(4-c h I o ro-3-suIfamoylbenzoy I)phenoxyacetate (1c) are suspended in about 700 ml of methanol. 1 liter of 0.15 N aqueous lithium hydroxide solution is added dropwise, with stirring, at 0°C with in. 1 hour. The mixture is stirred overnight at a temperature between 0 and 1 0 0 C , then 1.5 kg of ice and 0.5 liters of saturated brine are added to the clear solution, the pH is adjusted to 3 by dropwise addition of 2 N hydrochloric acid (about 70 ml), the voluminous pale precipitate is removed by centrifugation, end the centrifu-gate is washed once with water and recrystallized from a mixture of acetic acid and water with the addition of active charcoal and the product is dried over phosphorus pentoxide at 80°C and under 150 Torr. Colorless plates of melting point 184~6°C . Example 2 : 5-c hIoro-2-methyL-4~(4-chloro-5-sulfamoylbenzoyl)phenoxy~ acctic acid The compound is prepared in analogy to the reaction sequence described in Example 1, but with 5-ch I oro-2-methyI anisole as the starting material. The intermediate products 2 0 54 6 9 - 18 - and the final product have the following melting points: a) Z^'-dichloro^-methoxy-S-methyl-S'-sulfamoylbenzophe-none, melting point 172-173°C. b) 2,4,-dichloro-4-hydroxy-5-rnethyl-3l~sulfamoylbenzophe-5 none, melting point 230~234°C. c) methyl 5-chLoro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetiitc, melting point 1 65-1 69°C. d) 5-chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)phenoxy-acetic acid, melting point 2 42-246°C. 10 Example 3: 3-chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)phenoxy- acetic acid The compound is prepared in analogy to the reaction sequence described in Example 1, but with 3--chloro-2-methyl 15 anisole as the starting material. The intermediate products and the final product have the following melting points: a) 2,41 -dichIoro-4-methoxy-3-methy1-3'-suIfamoyIbenzophe-none, melting point 222-224°C. b) 2,4,-dichloro-4-*hydroxy-3-methyl-3,-sulfamoylbenzophe-20 none, melting point 220-224°C. c) methyl 3~chloro-2-methyl-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacctate, melting point 192-196°C. d) 3-c hIoro-2-rnethy 1-4 - (4 -chloro-3-sulfamoylbenzoyl)phenoxy-acetic acid, melting point 182-4°C. 2 5 Example 4 : The compound is prepared in analogy to the reaction sequence described in Example 1 , but with 2- c h I o ro-3-m et hy 1. anisole as the starting material. The intermediate products and the final product have the following melting points: -19- 205469 a) 3/4'-dich Loro-A-niethoxy-2-methyL--3,-suLfamo>'Lben2ophe-nonc, melting point 186-188°C. b) 3r4,-dichloro-4-hydroxy-2-methyl-3'-sulfamoyLben2ophe--none, melting point 194-197°C. c) methyl 2-ch I oro-3-methy 1-4-(4-ch I oro-3-su I famoy lb enzoy I)-phenoxyacetate, melting point 152-154°C. d) 2-chloro-3-methyl-4- (4-chloro-3-sulfamoylbenzoyl)phenoxy-acetic acid, melting point 178-180°C. Example 5: Ethyl 2/3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)phenoxy-acetate a) The compound is prepared in analogy to the procedure described in Example 1 Section 1c, but using ethyl chloroacetate in place of methyl bromoacetato, and the product is purified by column chromatography on silica gel with Cl^C^-ethyl acetate as the eluting agent and recrystallized from ethanol/water. Colorless crystals of melting point 146-1 48°C . b) 150 ml of ethanol, 0.2 g of strongly acid ion exchange resin (Dowex 50 W) and 50 ml of toluene are added to 4.4 g (10 mmol) of 2i,3-dichloro-4-(4-chloro-3-sulfamoyl~ benzoyUphenoxyacetic acid (Example 1) and the mixture is stirred under reflux with a water separator until separation of water is complete (about 4 h). The ion exchanger is removed by filtration, the filtrate is evaporated in vacuo and the residue is recrystallized from a mixture of ethanol, acetone and water. Colorless crystals of melting point 145-148°C. 205469 - 20 - Example 6: Tert.-butyl 2,3-dichloro-4-(4-chloro-3-sulfamoylbenzoyl)-phenoxyacetate The compound is prepared in analogy to the proce-5 dure described in Example 1 Section 1c, but tert.-butyl bromoacetate is used in place of in ethyl bromoacetate, and the product is purified by column chromatography on silica gel with Cl^C^-ethyl acetate (20:1 to 3:1) as the elut-ing agent, recrystallized from isopropanol/water and dried. 10 Pale yellow crystals of melting point 145-147°C. Example 7 Methyl 2/3-dichloro-4-(4-chLoro~3-sutfarnoylbenzoyL)phenoxy-acetate The compound is identical with the intermediate 15 product described in Example 1 Section 1c and can be prepared as described there or obtained in the following manner: 4.4 g (10 rnmol) of 2 ,3-d i c h I o ro-4- (4-c h lo r o-3-s u l-fanioyLbenzoyDplienoxyacetic acid (obtained in accordance 20 with Example 1 or Example 16) are dissolved in 200 ml of anhydrous methanol and, after the addition of 1 ml of concentrated sulfuric acid, the mixture is allowed to stand at room temperature for about 1 day. The precipitated solid is filtered off with suction and dried in vacuo. 25 Colorless crystals of melting point 208-210°C. Example 8: 2,3-dimethyl"4-(4-chloro-3-sulfamoylbenzoyl)phenoxyacetic acid 40 g (0.3 mol) of aluminum chloride are suspended 2054 6 - 21 - in 300 ml of methylene chloride and 25.4 g (0.1 mol) of 4-chIoro-3-suLfamoy I benzoy I chloride are stirred in, with exclusion of moisture, at the temperature of an ice bath. The mixture is stirred for 45 minutes and then 18 g (0.1 5 no I) of 2,3-dimethylphenoxyacetic acid are added in portions, with stirring, at 0°C. Stirring is continued at room temperature, the mixture gradually becoming viscous. After standing for several days, a mixture of ice, water and hydrochloric acid is added, the aqueous phase is ex-10 tracted several times by shaking with ethyl acetate, the organic phases are dried, evaporated in a rotary evaporator and the resinous residue is recrystallized, initially from isopropanol and then from aqueous acetic acid, with the addition of active charcoal each time. Colorless crystals 15 of melting point 186-190°C. Example 9: Methyl 2,3-dimethyl-4-(4-chloro-3-sulfarnoylbenzoyl)phenoxy-acetate 4.0 g (10 mmol) of 2 ,3 - d i m e t h y 1-4-(4 - c h lo r o-3-su l~ 20 famoylbenzoyUphenoxyacetic acid (Example 9) are dissolved in a just sufficient amount of boiling methanol and heating is continued for 15 mi n. . The colorless crystals obtained after slow cooling down and scratching are collected and the solvent is removed in vacuo, melting point 157~162°C. 25 Example 10: 3-methyl~4 - (4 - c h I o r o-3 - s u I f a in o y I b e n z o y I) p h e n o x y a c e t i c acid The compound is prepared in analogy to Example 9, but with 3-methylphenoxyacetic acid as the starting material. Colorless crystals of melting point 208~211(>C. - 22 - 205469 Example 11 : 2-methyL-4-(4-chloro-5-sulfamoylbenzoy[)pheno>,yacetic acid This compound is prepared in analogy to the route described in Example 9 , but with 2-methylphenoxyacetic acid as the starting material. Colorless crystals of melting point 1 98-2 00°C. Example 12: 2,6-dimethyl-4-(4-chloro-siilfamoylbenzoyl>phenoxyacetic acid The compound is prepared in analogy to Example 9, but with 2,6-dimethylphenoxyacetic acid as the starting material. Colorless crystals of meLting point 237-240°C. Example 13: 2"chloro-4-(4-chloro-3-sulfamoylbenzoyl)phenoxyaceti c acid The compound is prepared in analogy to Example 9, but 2-chlorophenoxyacetic acid is used as the starting material in place of 2,3-dimethylphenoxyacetic acid, and the components are stirred in 1,2-dichloroethane at about 50°C for about 3 days. The crude product is purified by several consecutive recrysta I Iizations from water/acetone and iso-propanol/toluene. White crystals of melting point 163-167°C. Example 14: ?-,?>-riichloro-4-(4-chloro-5-sulfamoylbenzoyl)phenoxyacetic acid. a) 4-methoxy~3 '-dimethylaminoinethylenearninosulfonyl-2,3,4'-tri chlorobenzophenone 19.7 g (50 mmol) of 4-methoxy-3'-suIfamoy1-2,3,4'-tri chlorobenzophenone are suspended in 200 ml of methylene 205469 - 23 - chloride, and 20 ml of dimethylformamide dimethyl acetal are added at room temperature with exclusion of moisture. On stirring, solution rapidly takes place and this is left to stand overnight. Evaporation to dryness and recrystal-5 lization of the residue from isopropanol/dimethyl formamide provides coarse pale-yellow crystals of melting point 200-2 02 °C. b) 4-hydroxy~3'~dimethylaminomethylenearninosulfonyl~2,3,4'-t rich lorobenzophenone 10 45 g (0.1 mol) of 4-methoxy-3'-dimethylaminomethyl- eneaminosulfonyl-2,3,4'-trichLorobenzophenone (stage a) are suspended in 250 ml of dry 1,2-dichloroethane and stirred under a nitrogen atmosphere. 54.2 g (0.4 mol) of aluminum chloride are added in portions, the temperature rising to 15 about 35°C and the mixture becoming virtually homogeneous. Stirring is continued at 40-50°C until starting material is no longer detectable in a thin-layer chromatogram (about 5 hours). The mixture, which has by this time become resinous, is stirred with external cooling while ice-water is 20 rapidly added and stirring is continued until a crystalline solid separates out. This is filtered off with suction, washed with water to neutrality, dried and recrystallized from methanol with the addition of active charcoal. Grey-yellow crystals of melting point 196-198°C. 2 5 c) Methyl 2,3-dichloro-4-(4--chloro-3-dim'ethylaminomethylene-annnosulfonylbenzoyOphcnoxy acetate 4.3 g (10 mmol) of 4-hydroxy-31-dimethy I aminomethy~ IeneaminosuIfony 1-2,3,41 -1richIorobenzophenone (stage b), 1.7 g (12 mmol) of finely ground potassium carbonate, 0.75 g 205469 - 2 4 - of sodium iodide, 20 ml of drydimethylformamide and 1.8 g (13 mmol) of methyl bromoacetate are mixed in this order and vigorously stirred at room temperature until reaction is complete, checking by thin-layer chromatography, (about 5 4 hours). For working up, the mixture is poured into ice-cold dilute hydrochloric acid, the pale yellow solid is filtered off with suction and crystallized from methanol/ ethyl acetate. Colorless crystals of melting point 13 0-132°C. 10 d) 2,3-di ch loro-4 - (4 - c hloro-3-sulfamoylbenzoyl)ph e no x y acetic acid 44.5 g (0.09 mol) of methyl 2,3-dichIoro-4-(4-c h I o r o-3 - dimethylaminomethyloneaminosulfonylben?. oyUphenoxy-acetate (stage c) in a mixture of 150 ml of acetic acid.. 15 450 ml of water and 4 5 ml of concentrated hydrochloric acid are stirred under reflux for 3 hours, a clear colorless solution being produced. On allowing slowly to cool down, a finely crystalline precipitate is produced which is filtered off with suction and recrystallized, if necessary 20 with the addition of active charcoal, from acetic acid/ water. Colorless crystals of melting point 186-18G°C. Example 15: 2-C2 ,3-di ch loro-4 - (4-chloro~3-su Ifamoylben 7. oy I) ] phenoxy propionic acid 25 The compound is prepared in analogy to the reaction sequence described in Example 15, but with ethyl 2~bromo~ propionate as the alkylating agent in stage c) (at 50°C). The intermediate product and the final product have the following melting points: </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 205469 - 25 - c) ethyl 2-[2,3-dichloro-4~(4~chloro-3-dimethylaminomethy-Lene aminos u IfonylbenzoyDDphenoxypropionate, melting point 141-143°C. d) 2 - C2 , 3-dich loro-4 - (4 -chloro-3-sulfam oylbenzoyL)3ph e no xy~ propionic acid, melting point about 145°C (obstinately retains residual solvent). Example 16: 2-C2,3-di ch 1 oro-4- (4-chloro-3-sulfamoy I b e n z o y I) ] p h e n o x y-2 -methylpropionic acid The compound is prepared in analogy to the reaction sequence described in Example 15, but with ethyl 2-bromo-2-methylpropionote as the alkylating'agent in stage c) at a reaction temperature of about 60°C and a reaction time of about 20 hours. The intermediate product (after purification by column chromatography) and the final product have the following melting points: c) ethyl 2 - C2 ,3- d i cli loro-4 - (4-chloro-3-dimetliylatTiinomethyl-eneominosulfonylbenzoyl)Dphenoxy-2-methylpropionate, melting point 112-114°C. d) 2~[2,3-dichloro-4-(4-chloro-3~sulfainoylbenzoyl)Hphenoxy-2-methylpropionic acid, melting point 219-220°C . tfr: .J* what^'we claim IS: - 26 - 206489 A compound of the formula V z =n (V) i n u h i c h , R^ and R^ are identical or different and represent hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, it not being possible however 1 2 for R and R both to denote hydrogen, and it being 1 7 possible for R and Rc together also to denote a bridge ,10 comprising 2 to 5 methylene groups or methy I enedioxy, denotes alkyl having 1 to 4 carbon atoms, hydrogen or a radical of the formula VI 2 FEB1986' III * co-y (VI) in which R^ and R^ are identical or different and represent hydrogen or alkyl having 1 to 4 carbon atoms or are components of a saturated carbocyclic ring having 3 to 7 members, and Y represents 0R^, in which R^ denotes hydrogen, alkyl having 1 to 4 carbon atoms, which can optionally be substituted with hydroxyl or alkoxy having 1 to 3 carbon atoms, or denotes aralkyl having 7-9 carbon atoms, and represents 2 hydrogen atoms or a protective group of the 205169 - 27 - formula III \f /r8 >-«Xr9 in which r'' denotes hydrogen or alkyL having 1 to 4 carbon atoms and R® and R^ denote alkyl having 1 to 4 carbon atoms.
2. A compound as claimed in claim 1 of the formula I ,3 n (I) O R in which R^ , R^, R'', R/f, R"* and R^ have the meanings de-fined in claim 1.
3. A compound of the formula V as claimed in claim 1, wherein Z denotes 2 hydrogen atoms, R , R and R represent 1 0 hydrogen,, halogen and/or methyl and R represents .CO-OR5 C r \ 5 . R Rb with R ^ and R ^ representing hydrogen and/or methyl and R ^ representing hydrogen, alkyl having 1-4 carbon atoms or benzyl.
4. A compound of the formula V as claimed in claim 1, wherein Z denotes 2 hydrogen atoms, R^ , R^ and R^ denote chlorine, methyl and/or hydrogen, and 5169 - 28 - 20. R*'® denotes , with and R"* CO-OR \ / being hydrogen and R° 'being hydrogen or alkyl having 1-4 carbon atoms.
5. A compound of the formula V as claimed in claim 1, wherein Z denotes 2 hydrogen atoms, R^denotes c , • -C-CO-OR /\5 R R 1 ? R1 and R denote chlorine or methyl and to denote hydrogen.
6. A compound of the formula V as claimed in claim 1, 12 3 wherein Z denotes 2 hydrogen atoms and R, R and R have 1 n the meanings indicated in claim 1 and R denotes hydrogen,
7. A process for the preparation of a compound of the formula V as claimed in claim 1, which comprises reacting, in a manner known per se by Friedel-Crafts acylation, a carboxylic acid derivative of the formula II Cl 0 <">. in which Z has the meaning defined in claim 1 and X represents a leaving group, with a phenol derivative of the formula IV (iv) in which R1 . . . j . -f; ' v - 29 - on |"W 1/ 12 t R, R and RJ have the meanings defined in claim 1 and R^O a) denotes alkyl having 1 to A carbon atoms, b) denotes another suitable phenol protective group or c) denotes hydrogen or d) represents a radical of the formula VI 0 1 \ (VI) Y 4' \ 5 R R in which and Rhave the meanings defined in claim 1 and Y represents 0 R ^ , R ^ being defined as in claim 1 , or represents a protective group for the carboxyl function which is stable to Lewis acids, to give a compound of the formula V ,3 CI. (V) in which R^ , R^, R3, R10 and Z have the abovementioned meanings, (compounds of the formula V in which Z denotes 2 hydrogen atoms and R^® denotes a radical of the formula VI being identical to compounds of the formula I) and converting the latter, when R^ is alkyl having 1 to 4 carbon atoms or another suitable phenol protective group, by elimination of the radical R^, into the phenols of the formula V, in which r1° denotes hydrogen and R*' to R3 and Z have the above-mentioned meanings, it being possible for a compound of the .. formula V, in which Z has the meaning of a protective group of the formula III, to be obtained from or converted into, - 30 - 205-469 in a manner known per se, a compound having an unprotected sulfonamide group (Z being 2 hydrogen atoms), alkylating the phenol of the formula V defined above with an acetic acid derivative of the formula VII 9 (VII) in which R^, and Y have the abovementioned meanings and W has the meaning of a nucleofugic group, to give 1 n a compound of the formula V, in which R u represents a radical of the formula VI defined above and the radicals 1 5 R to R , Y and Z have the abovementioned meanings, and converting the latter, in the case where Z has the meaning of the protective group of the formula III, by alkaline or acid hydrolysis into the compound of the formula I and optionally mutually interconverting these compounds of the formula I by acid or alkaline hydrolysis, or acid-cat aLyzed esterification or transesterification reactions respectively, and converting a compound of the formula V, where appropriate into its physiologically toLerated saLts.
8. A compound as claimed in one of claims 2 to 5 for use as a medicament.
9. An agent containing a compound as claimed in one of claims 2 to 5. a
10. A compound according to claim 1 substantially! as herein described and exemplified. ' V HOECHST AKTIENGESELLSCHAFT. By Their Attorneys HENRY H^^Ip^IMITEpL^ </div>