NO833857L - NEW BENZODIOX OLDER DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND SIMILAR PHARMACEUTICAL COMPOSITIONS - Google Patents

Abstract

1. Claims (for the Contracting States : BE, CH, LI, DE, FR, GB, IT, LU, NL, SE) Compounds of the general formula I see diagramm : EP0107622,P32,F1 in which R1 represents an alkyl, alkenyl or alkynyl radical that is unsubstituted or substituted by halogen having an atomic number of up to 35, lower alkoxy or by lower alkylthio and has, in total, that is to say including the substituents, a maximum of 12 carbon atoms, or represents a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower cycloalkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, trifluoromethyl, hydroxy, lower alkanoyl, lower alkanoylamino, lower alkoxycarbonylamino and/or by lower alkylsulphonylamino, a monocyclic five-membered hetero ring of aromatic character having two nitrogen atoms or one nitrogen atom and/or one oxygen or sulphur atom in the ring or a six-membered hetero ring of aromatic character having one or two nitrogen atoms in the ring, or a bicyclic radical consisting of the said five- or six-membered hetero rings of aromatic character with a fused benzene ring, alk represents an alkylene, alkenylene or alkylidene radical having a maximum of 5 carbon atoms, n1 represents 0, 1 or 2 and n2 represents 0 or 1, R2 , R3 and R4 each represents, independently of the others, hydrogen, lower alkyl, lower alkoxy or halogen, and A represents the radical -O-R5 wherein R5 represents hydrogen or an alkyl radical having a maximum of 12 carbon atoms that is unsubstituted or is substituted by lower alkoxy or by halogen, 2- or 3-lower alkenyl, 2-lower alkynyl, phenyl-lower alkyl or cinnamyl, in which the phenyl radical may be substituted in the same manner as under R1 , or A represents the radical see diagramm : EP0107622,P33,F1 in which either R6 and R7 each represents, independently of the other, hydrogen or lower alkyl, or R6 and R7 are bonded to one another and, together with the adjacent nitrogen atom, represent optionally lower alkyl-substituted tetra- to hexa-methyleneimino, 4-morpholinyl or 1H-tetrazol-1-yl, salts of compounds of the general formula I in which A represents OR5 wherein R5 represents hydrogen, with bases, and acid addition salts of compounds of the general formula I in which the radical R1 has a basic character, radicals designated "lower" having a maximum of 7 carbon atoms. 1. Claims (for the Contracting State AT) A process for the manufacture of compounds of the formula I see diagramm : EP0107622,P36,F2 in which R1 represents an alkyl, alkenyl or alkynyl radical that is unsubstituted or substituted by halogen having an atomic number of up to 35, lower alkoxy or by lower alkylthio and has, in total, that is to say including the substituents, a maximum of 12 carbon atoms, or represents a phenyl or naphthyl radical that is unsubstituted or substituted by lower alkyl, lower cycloalkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, trifluoromethyl, hydroxy, lower alkanoyl, lower alkanoylamino, lower alkoxycarbonylamino and/or by lower alkylsulphonylamino, a monocyclic five-membered hetero ring of aromatic character having two nitrogen atoms or one nitrogen atom and/or one oxygen or sulphur atom in the ring or a six-membered hetero ring of aromatic character having one or two nitrogen atoms in the ring, or a bicyclic radical consisting of the said five- or six-membered hetero rings of aromatic character with a fused benzene ring, alk represents an alkylene, alkenylene or alkylidene radical having a maximum of 5 carbon atoms, n1 represents 0, 1 or 2 and n2 represents 0 or 1, R2 , R3 and R4 each represents, independently of the others, hydrogen, lower alkyl, lower alkoxy or halogen, and A represents the radical -O-R5 wherein R5 represents hydrogen or an alkyl radical having a maximum of 12 carbon atoms that is unsubstituted or is substituted by lower alkoxy or by halogen, 2- or 3-lower alkenyl, 2-lower alkynyl, phenyl-lower alkyl or cinnamyl, in which the phenyl radical may be substituted in the same manner as under R1 , or A represents the radical see diagramm : EP0107622,P36,F3 in which either R6 and R7 each represents, independently of the other, hydrogen or lower alkyl, or R6 and R7 are bonded to one another and, together with the adjacent nitrogen atom, represent optionally lower alkyl-substituted tetra- to hexa-methyleneimino, 4-morpholinyl or 1H-tetrazol-1-yl, salts of compounds of the general formula I in which A represents OR5 wherein R5 represents hydrogen with bases, and acid addition salts of compounds of the general formula I in which the radical R1 has a basic character, radicals designated "lower" having a maximum of 7 carbon atoms, characterised in that a) a compound of the general formula II see diagramm : EP0107622,P37,F1 in which R1 , alk, n1 , n2 , R2 , R3 and R4 have the meanings given above, or a salt thereof, is reacted with a compound of the general formula III see diagramm : EP0107622,P37,F2 in which Hal represents halogen and A has the meaning given above, or with a salt of such a compound in which A represents OR5 wherein R5 represents hydrogen, or b) in a compound of the general formula IV see diagramm : EP0107622,P37,F3 in which A**b represents carboxy, lower alkoxycarbonyl or acetyl, and R1 , alk, n1 , n2 , R2 , R3 , R4 and A have the meanings given in claim 1, the radical A**b is replaced by hydrogen, or c) for the manufacture of a compound of the general formula I in which A has the meaning given above with the exception of a radical OR5 in which R5 represents hydrogen, and R1 , alk, n2 , R2 , R3 and R4 have the meanings given above and n1 represents 1 or 2, a compound of the general formula V see diagramm : EP0107622,P37,F4 is reacted with a compound of the general formula VI R1 -(alk)n2 -S(O)n1-c -OH or with an anhydride thereof, in which A1 has the meaning given above for A with the exception of a radical OR5 in which R5 represents hydrogen, n1-c represents 1 or 2 and R2 , R3 and R4 , and R1 , alk and n2 have the meanings given above, or d) for the manufacture of a compound in which n2 is 1 or R1 is an aliphatic radical according to the definition and R1 or n2 , as the case may be, alk, n2 , R2 , R3 , R4 and A have the meanings given above, a compound of the general formula VII R1 -(alk)n2-d -Z**d in which Z**d represents a reactively esterified hydroxy group, especially halogen having an atomic number of at least 17, R1 has the meaning given above and n2 represents 1 or, if R2 is an aliphatic radical, may alternatively be 0, or a compound of the general formula VIII see diagramm : EP0107622,P37,F5 in which Z**dd (cation) represents a monovalent anion or the normal equivalent of a polyvalent anion and R1 and n1 have the meanings given above, is reacted with a salt of a compound of the general formula IX see diagramm : EP0107622,P38,F1 in which n1 , R2 , R3 , R4 and A have the meanings given in claim 1, or e) a metal compound, optionally formed in situ, of the general formula Xa or Xb R1 -(alk)n2 -M1 see diagramm : EP0107622,P38,F2 in which M1 represents a monovalent metal ion and M2 represents a divalent metal ion and R, alk and n2 have the meanings given above, is reacted with a compound of the general XIa or XIb see diagramm : EP0107622,P38,F3 see diagramm : EP0107622,P38,F4 in which Hal represents halogen and n1 , R2 , R3 , R4 and A have the meanings given above, or f) for the manufacture of a compound of the general formula I in which A represents OR5 wherein R5 represents hydrogen, and R1 , alk, n1 , n2 , R2 , R3 and R4 have the meanings given above, or a salt of this compound : in a compound of the general formula XIII see diagramm : EP0107622,P38,F5 in which A**f represents a group that can be converted into the carboxy group and R1 , alk, n1 , n2 , R2 , R3 and R4 have the meanings given above, the group A**f is converted into the carboxy group in free or salt form, or g) for the manufacture of a compound of the general formula I in which A has the meaning given above with the exception of a radical OR5 in which R5 represents hydrogen, and R1 , alk, n1 , n2 , R2 and R3 have the meanings given above : in a compound of the general formula XIV see diagramm : EP0107622,P38,F6 in which A**g represents a radical that can be converted into a radical CO-A1 in which A1 has the meaning given above for A with the exception of a radical OR5 in which R5 represents hydrogen, and R1 , alk, n1 , n2 , R2 , R3 and R4 have the meanings given in claim 1, the radical A**g is converted into the radical -CO-A1 , and h) if desired, a compound of the general formula I in which n1 represents 0 or 1 is oxidised to form the corresponding compound in which n1 represents 1 or 2, or i) if desired, a compound of the general formula I in which n1 represents 2 or 1 is reduced to form the corresponding compound in which n1 represents 1 or 0, and/or, if desired, a resulting compound of the general formula I is converted in a different manner known per se into a different compound of the general formula I, and/or a compound of the general formula I obtained in the form of a racemate is separated into the optical antipodes, and/or a resulting compound of the general formula I in which A represents OR5 wherein R5 represents hydrogen is converted into a salt with a base, or such a compound is freed from a resulting salt, or a resulting compound of the general formula I of basic character is converted into an acid addition salt, or such a compound is freed from a resulting salt.

Description

The invention relates to the production of new benzodioxole derivatives.

The new compounds produced according to the invention correspond to the general formula I,

where an unsubstituted or substituted aliphatic, aromatic or heteroaromatic residue, alk means an alkylene, alkenylene or alkylidene residue with at most 5 carbon atoms, n^zero, one or two and n_ zero or one, , R^°9^4regardless of each other means hydrogen, lower alkyl, lower alkoxy or halogen and A the residue -O-R^, in which R,- stands for hydrogen or an unsubstituted or substituted aliphatic or araliphatic hydrocarbon residue, or means the residue

in which Rg and R^ independently of each other stand for

hydrogen or lower alkyl, or linked together and together with the adjacent nitrogen atom of any lower alkyl substituted tetra- to hexa-ethyleneimino, 4-morpholinyl or 1H-tetrazol-1-yl. They can be present as racemates or optical antipodes, or, by equivalent meaning of the variables, also as racemate mixtures. Likewise, the subject of the invention is the method

for the preparation of salts of compounds of the general formula I, where A means OR,- and where R,- means hydrogen, with bases, as well as acid addition salts of compounds of the general formula I, whose residue R^ exhibits basic character. Unless otherwise noted here, lower residues or compounds in the preceding and following shall be understood to be those with no more than 7, preferably no more than 4 carbon atoms.

An aliphatic radical R-^ is in particular an alkyl, alkenyl or alkynyl radical with no more than 12 carbon atoms, preferably lower alkyl, lower alkenyl or lower alkynyl, such as octyl, nonyl, decyl, undecyl, sosecyl, 2,2,4-trimethyl- 1-pentenyl, 1-octynyl or pentyl, isopentyl, hexyl, heptyl, 1-hexenyl or especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butylethenyl, 1-methylethyl, 2-propenyl, 2-butenyl, 2-methyl-2-propenyl, ethynyl or 1-propynyl.

An aromatic residue R is in particular a 1- or 2-naphthyl residue and above all a phenyl residue. A heteroaromatic residue R^

is preferably a bicyclic or especially a monocyclic residue. As a corresponding monocyclic residue, R^ in particular contains two nitrogen atoms or preferably a nitrogen atom and/or an oxygen or sulfur atom, and is, for example, a mono- or di-azacyclic, oxa- or thiacyclic or oxaza- or thiaza-cyclic residue with 5 ring joint, e.g. 1H-pyrrolyl, such as 1H-pyrrol-2-yl or -3-yl, 1H-pyrazolyl, such as 1H-pyrazol-3-yl, -4-yl- or -5-yl, 1H-imidazolyl,

as 1H-imidazol-2-yl, -4-yl or -5-yl, furyl, as 2-

or 3-furyl, thienyl, such as 2- or 3-thienyl, oxazolyl,

as 2-oxazolyl, isoxazolyl, as 3- or 5-isoxazolyl, thiazolyl, as 2- or 4-thiazolyl, or a mono- or diazacyclic residue with 6 ring members, e.g. pyridyl, as 2-

3- or 4-pyridyl, pyridazinyl, such as 3-pyridazinyl, pyrimidinyl, such as 2-, 4- or 5-pyrimidinyl, or 2-pyrazinyl. Corresponding bicyclic residues R^ consist, for example, of a 5-membered heteroring of aromatic character with two nitrogen atoms or with a nitrogen atom and/or an oxygen or sulfur atom as a ring member, and a condensed benzene ring, or of a 6-membered heteroring of aromatic character with two or especially a nitrogen atom as a ring member and a condensed benzene ring. Similarly, bicyclic heteroaryl is e.g. 1H-indolyl, such as 1H-indol-2-yl, -3-yl, -4-yl, -5-yl, or -6-yl, 1H-indazolyl-3-yl, 1H-benzimi-dazolyl, such as 1H -benzimidazol-2-yl, -4-yl, -5-yl or -6-yl, benzofuranyl, such as 2-, 3-, 5- or 6-benzofuranyl,

benzo[bjtienyl, as benzo[b ]thien-2-yl, -3-yl, -5-yl or -6-yl, benzoxazolyl, as 2-, 4-, 5- or 6-benoxazolyl, benzothiazolyl, as 2 -, 4-, 5- or 6-benzothiazolyl, respectively quinolinyl, as 2-, 4-, 5-, or 6-quinolinyl, isoquinolinyl, as 1-, 3-, or 4-isoquinolinyl, quinazolinyl, as 2-, 4- or 6-quinazolinyl, quinoxalinyl, such as 2- or 6-quinoxalinyl, or phthalazinyl, such as 1- or 6-phthalazinyl.

As substituted aliphatic residue, R is, e.g. substituted with halogen such as bromine or especially fluorine or chlorine, by which special mention must be made of the polysubstitution with the same carbon atom, i.e. geminal, and the substitution on a multiple bond, such as e.g. in trichloromethyl, 2,2,2-trichloroethyl or 2-chloroethenyl. Furthermore, an aliphatic residue R^, e.g. also be a substituted with lower alkoxy or lower alkyl thio, such as e.g. with the corresponding residues mentioned further below, and then mean methoxyethyl, ethoxyethyl or methylthio-ethyl. As a substituted aromatic or heteroaromatic residue, R^ is e.g. substituted one or more times, preferably at most 3 times with halogen, such as bromine, iodine or especially fluorine or chlorine, with lower alkyl, such as e.g. ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl or especially methyl, lower cycloalkyl, such as cyclopentyl or especially cyclohexyl, lower alkoxy, lower alkylthio or lower alkyl sulfonyl such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or ethylthio, isopropylthio, butylthio or ethylsulfonyl and branched methoxy respectively. methylthio, respectively methylsulfonyl and/or trifluoromethyl, hydroxy, lower alkanoyl, lower alkanoylamino, lower alkoxycarbonylamino or lower alkylsulfonylamino, such as e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, resp. formamido, acetamido, propionamido, butyramido or isobutyramido, resp. methoxycarbonylamino or ethoxycarbonylamino, respectively methane sulfone amido or ethanesulfonamido, lower alkoxy carbonyl, carbamoyl, mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, such as e.g. methoxy- or ethoxycarbonyl, methyl-, ethyl- or isopropylcarbamoyl, dimethyl- or diethylcarbamoyl, methyl- or ethyl-

sulfamoyl or dimethylsulfamoyl.

An alkylene, alkenylene or alkylidene residue alk can be linear or branched, and is e.g. 1,1-, respectively 2,2- or 1,2-dimethylethylene, 1-ethylethylene, tetramethylene or 1-propylethylene or 3,3-dimethylpropenylene or 1-methylpropylidene, 2-methylpropylidene, butylidene or 1-ethylpropylidene, but especially a residue with no more than 3 carbon atoms, such as ethylene, propylene, trimethylene or ethenylene, propenylene or 1-methyl-ethenylene or ethylidene, propylidene or 1-methyl-ethylidene and above all methylene.

1*2, R-, and R. are as lower alkyl e.g. ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl and especially methyl, as lower alkoxy, e.g. ethoxy, propoxy, isopropoxy, -butoxy, isobutoxy and especially methoxy, and as halobromine, iodine, special fluorine or above all chlorine.

In the residue A, R is an unsubstituted or substituted aliphatic or araliphatic hydrocarbon residue, e.g. alkyl with no more than 12 carbon atoms, especially lower alkyl, further 2- or 3-lower alkenyl or 2-lower alkynyl, lower alkoxy lower alkyl, halogenated lower alkyl, such as geminal poly-halo lower alkyl, resp. e.g. phenyl lower alkyl or cinnamyl, in which the phenyl radical e.g. may be substituted in the same way as a phenyl radical R]_. R^ is as alkyl e.g. propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neo-pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl and especially methyl or ethyl; R^ is as lower alkenyl e.g. lalyl, 1- or 2-methylallyl, 2-butenyl or 3-butenyl, lower alkynyl, e.g. 2-propynyl, lower alkoxy lower alkyl, especially 2- or 3-lower alkoxy lower alkyl, such as e.g. 2- methoxy-, 2-ethoxy-, 2-isopropoxy- or 2-butoxy-ethyl, 2- or 3-methoxypropyl, 2- or 3- ethoxypropyl, further 3- or 4-methoxybutyl or 3- or 4-ethoxybutyl, and halogenated lower alkyl, especially geminal, i.e. lower alkyl which is polyhalogenated on the same carbon atom as 2,2,2-trifluoro- or 2,2,2-trichloroethyl. R. as phenyl lower alkyl is e.g. benzyl, 2-phenyl-ethyl, 2- or 3-phenylpropyl or 2-, 3- or 4-phenylbutyl.

As lower alkyl Rg and R^ can e.g. those already present as corresponding representatives of the R^ mentioned residues, and as optionally lower alkyl substituted tetra- to hexamethylene-imino means R 5 and R^ together e.g. 2- or 3-methyl-l-pyrrolidinyl, 2,5-, 3,3- or 3,4-dimethyl-l-pyrrolidinyl, 1-piperidinyl, 2-, 3- or 4-methyl-l-piperidinyl, 2 ,6- or 4,4-dimethyl-1-piperidinyl or hexahydro-1H-azepin-1-yl.

Salts of the new compounds are especially salts of compounds of the general formula I, where A means hydroxy and R 5 hydrogen, with bases, above all pharmaceutically usable salts of such compounds with bases. Such salts with bases include, for example, alkali metal or alkaline earth metal salts, such as sodium, potassium, calcium or magnesium salts, further ammonium salts with ammonia or organic amines, such as mono- or di-alkylamines, e.g. methylamine, ethylamine, dimethylamine or diethylamine, or with optionally lower alkylated mono- or di(hydroxyalkyl)amines, or with tri(hydroxyalkyl)amines, e.g. 2-aminoethanol, 2-(diethylamino)-ethanol, 2,2<1->iminodiethanol, N-methyl-2,2'-iminodiethanol or 2,2', 2"-nitrilotri-

ethanol into consideration.

As acid addition salts, especially pharmaceutically acceptable acid addition salts of compounds of the general formula I, in which R-^ exhibits basic character, there are, for example, those with suitable inorganic acids, such as halogen hydrogen acids, e.g. hydrochloric acid or hydrobromic acid, further nitric acid, sulfuric acid or phosphoric acid, or with suitable organic acids, such as carboxylic acid, e.g. Acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methyl-maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, embonic acid , nicotinic acid or isonicotinic acid, or organic sulphonic acids, such as optionally hydroxy-containing, lower alkane sulphonic acids, e.g. methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or ethane-1,2-disulfonic acid, or arylsulfonic acids, e.g. benzenesulfonic acid, 4-methyl-benzenesulfonic acid or naphthalene-2-sulfonic acid or further acidic substances, such as ascorbic acid, in consideration.

The new compounds of the general formula I and their salts have valuable pharmacological properties. They are particularly diuretic and natriuretic in rats in the dose range from 1 to 300 mg/kg per os, and on dogs in doses from 1 to 20 mg/kg per os, as can be determined by collecting urine within 3 hours after delivery (rat), respectively. every hour during 5 hours after delivery (dog), and determination of the urine volumes and the sodium, potassium and chlorine ions. This increases potassium excretion less strongly than sodium excretion. The good tolerability must also be emphasized.

For example, it is increased when delivering 10 mg/kg per os 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid to rats (6 animals per dose) compared with untreated control animals the excretion of sodium ions by 3.6 times, of potassium ions by 1.1 times and of chlorine ions by 2.6 times.'In dogs, e.g. when delivering 20 mg/kg per os 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid (4 animals per dose) the average excretion per minute during the first 5 hours after delivery of the active substance compared to the average excretion per minute during the last hour before the delivery in the case of sodium ions by 13.3 times, in the case of potassium ions by only 1.5 times, in the case of chlorine ions by 10.4 times, and in the case of urine volume by 3, Two times. The increase in potassium ion excretion by the aforementioned carboxylic acid is thus very small in rats as well as in dogs compared to the increase in sodium ion and chlorine ion excretion.

Furthermore, the compounds of the general formula I have uricosuric action, as can be shown e.g. using experiments on Cebus monkeys (Cebus apella). In these experiments, the animals under pentobarbital anesthesia are administered polyfructosan in Ringer's solution intravenously and the test substance is injected

as an aqueous solution in increasing doses intravenously. Before the first test substance administration and after each test substance dose, urine is collected during every 3 10-minute periods and before the first and the last collection period, arterial blood is also taken. Uric acid and polyfructosan "clearance" is calculated from their plasma and urine concentration, and finally the fractional excretion of uric acid (FE) is determined as a coefficient

UK

between uric acid clearance and glomerular filtration rate. Compounds of the general formula I, such as e.g. 5-methyl-6-phenylsulfonyl-1,3-benzodioxo1-2-carboxylic acid shows in this test "effects in the dose range from 1 to 10 mg/kg intravenously. Similarly, compounds of the general formula I and their pharmaceutically acceptable salts can be used as potassium-sparing diuretics with an additional uricosuric effect, e.g. for the treatment of edema and hypertension.

The invention preferably relates to compounds of the general formula I, where R^ is an aliphatic hydrocarbon residue which is unsubstituted or substituted by halogen to atom no. 35, lower alkoxy or lower alkylthio, with a total of

i.e. comprising the substituents, at most 12 carbon atoms, or a mono- or bicyclic aryl residue or equivalent heteroaryl residue with at most 2 nitrogen atoms which is unsubstituted or substituted with lower alkyl, lower cycloalkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, hydroxy, lower alkanoyl , lower alkanoylamino, lower alkoxycarbonylamino and/or lower alkylsulfonylamino, or an oxygen or sulfur atom and optionally a nitrogen atom as a heteroring member, with alk, n-^, n^,

R^ and R^ have the meanings given under formula I, and R5

is hydrogen or an aliphatic or araliphatic hydrocarbon residue with a total of not more than 12 carbon atoms or a residue

in which Rg and R-^ have the meanings given under formula I, which are unsubstituted or substituted with halogen to atom no. 35, hydroxy or lower alkoxy in higher than 1- or -position, as well as salts of such compounds, in which R^ is hydrogen, with bases.

The invention particularly relates to compounds of the general formula I, in which R, means phenyl, thienyl, furyl or ar-benzodiazolyl, which is unsubstituted or highly 3-fold substituted by lower alkyl, lower alkoxy, halogen to atom No. 35, lower alkanoyl and /or lower alkanoylamino, alk means the alkylene, alkylidene or alkenylene with no more than 3 carbon atoms, R2 means lower alkyl or halogen to atom no. 35, R^ means hydrogen, lower alkyl or halogen to atom no. 35, and R^ means hydrogen and n-^, n2 and A have the meaning indicated under formula I, n, in particular, means 2, n2 0, and A OR^, and in which R^ means hydrogen or lower alkyl, as well as the salts of such compounds, in which R5 is hydrogen, with bases.

The invention relates in particular to compounds of the general formula I, in which R-^means phenyl or thienyl which is unsubstituted or at most 3 times substituted by lower alkyl, lower alkoxy, halogen to atom no. 35, lower alkanoyl and/or lower alkanoylamino, alk means the methylene, n-^2,

n20 or 1, R 2 lower alkyl, especially methyl, or halogen, especially fluorine or chlorine, R^hydrogen or lower alkyl, especially methyl,R^hydrogen, and A OR,- and wherein R,_ means hydrogen or lower alkyl, as well as the pharmaceutically acceptable salts of such compounds, in which R 1 is hydrogen, with bases.

The invention relates above all to compounds of the general formula I, in which R^ means phenyl which is unsubstituted or at most 3 times substituted by lower alkyl, lower alkoxy and/or halogen to atom no. 35, alk means methylene, n-, means 2 , n 2 0 or 1, R2lower alkyl, especially methyl, or halogen, especially fluorine or chlorine, R^hydrogen or lower alkyl, especially methyl, R^hydrogen and A = OR^ and wherein R^means hydrogen or lower alkyl, and the phenylsulfonyl residue is attached in the 5- or 6-position, as well as the pharmaceutically acceptable salts of such compounds, in which R 1 is hydrogen, with bases.

The invention primarily relates to compounds of the general formula I, in which R means phenyl which is above all unsubstituted or at most 3 times substituted with lower alkyl, especially methyl, lower alkoxy, especially methoxy and/or halogen, especially chlorine, alk means methylene, n, means 2, n21 or above all 0, R2lower alkyl, especially methyl, or halogen, especially chlorine, R^and R4hydrogen and A OR,- and in which R,, means hydrogen or lower alkyl,

and the phenylsulfonyl residue is attached in the 5- or 6-position, as well as the pharmaceutically acceptable salts of such compounds, in which R5 is hydrogen, with bases, such as the already mentioned 5-methyl-6-phenylsulfonyl-1,3- benzo-dioxole-2-carboxylic acid and its pharmaceutically acceptable salts with bases.

The new compounds with the general formula I and salts of such compounds, in which A is OR^ and in which R,, is hydrogen, or which have a basic character, are prepared according to the invention in a manner known per se, by

a) a compound of the general formula II

where R^, alk, n^,]^, R2/R3 and R^ have the meanings given under formula I, or a salt thereof is reacted with a compound of the general formula III

where Hal means halogen and A has the meaning given under formula I, or a salt of such a compound, where A means OR5 and in which R^ means hydrogen, or

b) in connection with the general formula IV

where A fø means carboxy, lower alkoxycarbonyl or acetyl, and R^, alk, n-^, , R2 1 R3'R4°9A has ^e u>where formula I stated meanings, the residue K° is replaced by hydrogen, or c) for preparation of a compound of the general formula I, in which A has the meaning given under formula I with the exception of a residue OR^, in which R^ is hydrogen, and R^, alk, n£, R3°9R4^ ar ^e meanings indicated under formula I and n^means 1 or 2, a compound of the general formula V is reacted with a compound of the general formula VI, or an anhydride of the same, where A^ has the meaning that is indicated for A under formula I with the exception of a residue 0R5'1 where R1- means hydrogen, n^ means one or two and R2, R-, and R4 respectively. R-^, alk and n 2 have the meanings given under formula I, or d) for the preparation of a compound in which n 2 is one or R^ is a definitional, phaliphatic residue and R-^ respectively n 2 * alk, n 2 , R 2 / R3/R4°9A when the meanings indicated under formula I react with a compound of the general formula VII in which Z represents a reactive, esterified hydroxyl group, especially halogen with an atomic number of at least 17, R^ has the meaning that is indicated under formula I and n2 means a , or if R2 is an aliphatic residue, can also be 0, or a compound of the general formula VIII

dd

in which Z represents a monovalent anion or the normal equivalent of a monovalent anion and R 2 and n 2 have the meanings given under formula I, with a salt of a compound of the general formula IX

in which n-^,]^, R-^ , R^ and A have the meaning indicated under formula I, or, e) an optionally formed in situ metal compound with the general formula Xa or Xa in which means a monovalent respectively . M2 is a divalent metal ion and R, alk and n2 have the meanings given under formula I, is reacted with a compound of the general formula Xla or Xlb, in which Hal means halogen and n^, R2, R3, R^ and A have the meanings which is indicated under formula I, or f) for the preparation of a compound of the general formula I, in which A means OR^ and in which R,, is hydrogen and R-^, alk, n-^, n2, R2 1 R3 and R^ have the meanings given under formula I, or a salt of this compound, is transferred to a compound of the general formula

XIII,

in which A represents a group which can be transferred to a carboxy group and R-^, alk, n-^, n2, R'2, R^ and R^ have the meanings indicated under formula I, the group A^ to the carboxy group in free or salt form, or g) for the preparation of a compound of the general formula I, in which A has the meaning given under formula I with the exception of a residue OR^, in which R^ is hydrogen, and Rj_ , alk, n-^, n2, R2 and R^ have the meanings given under formula I, are transferred in a connection with the general formula XIV

in which A^ means a residue which can be transferred into a residue CO-A.^, in which A^ has the meaning indicated for

A under formula I with the exception of a residue OR^, in which R^ is hydrogen, and R-^alk, n^, n2, R2, R^ and R^ have

the meanings indicated under formula I, the remainder A^

in the rest -CO-A^, and

h) if desired, a compound of the general formula I, in which n-^ means 0 or 1, is oxidized to the corresponding

connection, in which n^ means one or two, or

i) if desired, a compound of the general formula I in which n^ means two or one is reduced to the corresponding compound in which n^ means one or 0, and/or

if desired, an obtained compound of the general formula I is transferred in another manner known per se to another compound of the general formula I, and/or a compound obtained as a racemate of the general formula I is divided into the optical antipodes, and /or an obtained compound of the general formula I, in which A is OR^ and in which R^ is hydrogen, is transferred to a salt with a base or such a compound is liberated from an obtained salt, or an obtained compound of the general formula I

of a basic character is transferred in an acid addition salt, or such a compound is liberated from a salt obtained.

In the starting substances with the general formula III, Hal is preferably chlorine or bromine, whereby two different halogen atoms can also be present. The reactions according to method a) are preferably carried out in organic solvents which are inert under the reaction conditions, for example in etheric ones, as well as e.g. dibutyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane, alcoholic, such as e.g. methanol, ethanol, isopropanol, butanol, 2-methoxyethanol or 2-ethoxyethanol, or amide-like, such as e.g. dimethylformamide or N,N,N',N<1>,N",N"-hexamethylphosphoric acid triamide; or in hydrocarbons, such as petroleum ether, cyclohexane, benzene or toluene. Reactions with free compounds of the general formula II and also with free haloacetic acids of the general formula III are preferably carried out in the presence of basic substances. As such, organic or inorganic derivatives of alkali or alkaline earth metals can be used, for example, as organic derivatives, e.g. alkali metal or alkaline earth metal alkoxides, such as sodium or lithium methoxide, -ethoxide, n-butoxide or -tert.-butoxide, or barium methoxide, or as inorganic derivatives, e.g. corresponding hydroxides, such as sodium, potassium or calcium hydroxide, or carbonates, such as e.g. sodium or potassium carbonate. Carbonates in particular can be used in larger, e.g. up to 5 times profit. When using carbonates, additional organic solvents, such as lower alkanones, e.g. acetone or 2-butanone, be considered sufficiently inert.

As salts of compounds of the general formula II and

of dihaloacetic acids which fall under the general formula III and which are optionally used, corresponding alkali or alkaline earth metal salts are suitable, for example. The reaction temperatures are, for example, between room temperature and approx. 150°C and preferably between approx. 70 and 120°C.

A number of starting substances with the general formulas II and

III are known, and can further be prepared analogously to the known compounds. So, for example, starting substances with the general formula II can be prepared by first 1,2-dimethoxybenzene, which can be substituted corresponding to the definition for R2, R^ and R^, condensed with a sulfonic acid of the general formula VI in polyphosphoric acid in heat, f .ex.

at approx. 100-110°C to the corresponding sulfone or is condensed with an acyl halide which is derived from such a sulfonic acid or also a corresponding sulfonic acid according to Friedel-Crafts, e.g. using aluminum chloride in 1,2-dichloroethane at room temperature, likewise to the corresponding sulfone or to the corresponding sulfoxide, and in this both methoxy groups split in a manner known per se, e.g. by heating with pyridine hydrochloride or with 48% hydrobromic acid in acetic acid. If starting substances with formula II are needed, in which alk is a lower alkylidene residue,

but especially a 1-lower alkylidene such as the 1-methylethylidene residue, after the Friedel-Crafts condensation and before the cleavage of the methoxy groups in a sulfone compound, in which alk is methylene or lower alkylidene, one or preferably two lower alkyls may be introduced, respectively . a lower alkyl, esp

methyl, by reaction with a lower alkyl halide, such as methyl iodide, e.g. in a two-phase system of a concentrated aqueous solution of tetrabutyl ammonium hydroxide or bromide and an inert, organic solvent, e.g. methylene chloride. A process that leads directly to dihydroxysulfones of the general formula II and is therefore particularly advantageous is the reaction of sulfinic acids falling under the general formula VI, as sodium salts optionally substituted with 1,2-benzene diols corresponding to the definition for R 3 , R 3 and R^in the presence of potassium hexacyanoferrate-(III) ■ and sodium acetate in water.

Starting substances of the general formula II in which n1s

0, can for example be produced analogously to the method

d) .

For carrying out method b), for example, a starting substance with the general formula IV is heated in which A fø means carboxy and A as well as R^, R^, R3 and R^ have the meanings indicated under formula I, in presence or absence of a catalyst, e.g. copper powder, and/or a solvent or diluent, such as o-dichlorobenzene or 1,2,3,4-tetrahydronaphthalene, until at least the approximately equimolar amount of carbon dioxide is released.

fø Starting substances with the general formula IV, in which A means carboxy and A means OR^ and in which R,, means hydrogen, are prepared, for example, by hydrolysis of corresponding compounds, in which A is OR^ and in which R^ is lower alkyl and lower alkoxy carbonyl or cyano stand as respectively instead of A°, in acidic or alkaline medium, for example by heating with a strong mineral acid in aqueous or aqueous-organic, e.g. aqueous-lower alkanolic medium, resp. with at least twice the molar amount of an alkali metal hydroxide, especially sodium or potassium hydroxide, e.g. in a lower alkanol, such as methanol, ethanol, isopropanol or n-butanol, or in a lower alkanol-

diol or monoalkyl ether thereof, e.g. ethylene

glycol, 2-methoxyethanol or 2-ethoxyethanol, whereby water is optionally added to the mentioned solvents in a volume ratio of solvent to water of approx. 10:1 to 1:2. Furthermore, water or a mixture of water with water-soluble, ethereal solvents, such as dioxane or tetrahydrofuran, can also be used as the reaction medium.

If the hydrolysis takes place in an aqueous mineral acid, the procedural decarboxylation can be carried out in conjunction with this, i.e. in the same medium and work process.

Starting material f is of the general formula IV, in which A*3 means carboxy and A means a residue corresponding to the definition under formula I with the exception of a residue OR^, in which R^ means hydrogen, can be prepared e.g. by partial hydrolysis in an alkaline medium of corresponding compounds with lower alkoxycarbonyl as residue A, the use of approximately equimolar amounts of an alkali metal hydroxide instead of at least the double molar amount. Another possibility for the preparation of such starting substances with the general formula IV consists in the hydrogenolysis of corresponding compounds, in which benzyloxycarbonyl is found instead of A^3.

The desalkoxycarbonylation or deacetylation of corresponding starting substances with the general formula IV, i.e. those in which A fø means lower alkoxycarbonyl or acetyl, and A a definitional residue with the exception of one residue

OR5, in which R,- means hydrogen, takes place, for example, by reaction with the approx. equimolar amount of an alkali metal lower alkoxide in an anhydrous lower alkanol, whereby, if A is a residue OR,-, in which R,- means lower alkyl, preferably the same lower alkanol, e.g. methanol, ethanol, n-butanol, which is selected as a component in the starting ester and the lower alkoxide, as well as the reaction medium. But it is also possible, by using a relatively higher-boiling alkanol that is not identical to the lower alkanol that is present as an ester component, as a reaction medium and distilling off a part of it, at the same time as the conversion according to definition, a transesterification is carried out or also

include a partial transesterification in the purchase, if the ester of the general formula I which is obtained as a reaction product,

should not be directly used as an active substance, but should be hydrolysed to the corresponding acid. Furthermore, as a reaction medium instead of a lower alkanol, e.g. an inert organic solvent is also used, such as benzene or toluene. The definitional turnover is carried out at room temperature or elevated temperature, e.g. at boiling temperatures for the reaction medium used. Optionally, the ester obtained with the general formula I, as already mentioned in connection with the transesterification, can be hydrolyzed in the same process to the corresponding acid, when water is added to the reaction medium.

b The starting substances with the general formula IV, in which A

is lower alkoxycarbonyl or acetyl, as well as the precursors mentioned further above for connection with the general

birth

formula IV with carboxy as the residue A, which contains lower alkoxycarbonyl or cyano as resp. instead of A<*3>, can be prepared analogously to method a) by conversion of

compounds of the general formula II with geminal dihalogen compounds, which differ from those of the general formula III by the presence of lower alkoxycarbonyl, acetyl or cyano, instead of the hydrogen atom located

next to both halogen atoms, in the presence of a base.

According to method c), for example, free sulphonic acids with the general formula VI can be condensed in polyphosphoric acid or pyrophosphoric acid under heating, e.g. at approx. 80

to approx. 120°C, especially at approx. 100 to 110°C with compounds of the general formula V. Furthermore, anhydrides of compounds of the general formula VI, for example their halides, such as chlorides or bromides, further e.g.

their symmetrical anhydrides, are condensed in the presence of common Friedel-Crafts condensing agents, such as aluminum chloride or stannous chloride, further e.g. zinc chloride, further e.g. in concentrated sulfuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoric acid with compounds of the general formula V. The aforementioned acids are preferably used,

when a symmetrical anhydride of a sulfonic acid with the general formula VI is used as starting material. The conversions are carried out using condensing agents, preferably in a solvent. Halogen hydrocarbons, such as 1,2-dichloroethane, carbon tetrachloride, methylene chloride, o-dichlorobenzene, further e.g. aliphatic or cycloaliphatic hydrocarbons, such as heptane or cyclohexane, nitrohydrocarbons, such as nitromethane, nitrocyclohexane or nitrobenzene and, under mild conditions, also carbon sulphur. The reaction temperature is between approx. -20 and +80°C, preferably between approx. 0° and room temperature.

The starting materials with the general formula V can in turn be prepared analogously to method a) from 1,2-benzylene-diol which is optionally substituted corresponding to the definition for R2, R3 and R3, which e.g. 4-methyl-1,2-benzenediol, with dihaloacetic acids or their functional derivatives corresponding to the general formula III. Of the sulfonic or sulfinic acids of the general formula IV and their functional derivatives of compounds of the general formula VI which are required as the second reactant,

are many well-known, and can be manufactured analogously to the well-known ones.

Reactions of compounds with the general formula VII, such as e.g. of optionally substituted alkyl, alkenyl, alkynyl halides or aralkyl, especially benzyl halides, with salts, especially alkali metal salts, e.g. sodium or potassium salts, of compounds with the general formula IX are carried out, for example, in water, aqueous-organic or organic medium, e.g. in a lower alkanol, such as methanol or ethanol, preferably in the heat, i.e. e.g. at approx. 70 to approx. 160°, above all at approx. 80-100°, respectively at the boiling temperature of the medium or in a closed vessel as well

over this one. The salt of the compound of the general formula VII can be formed in situ by the addition of alkali hydroxides or alkali metal salts of weak acids, e.g. of sodium acetate.

The diazonium salts of the general formula VIII are prepared in the usual way from the corresponding primary amines, in which n-j_ is preferably 0 and R 1 is an aromatic residue, e.g.

in aqueous solution by treatment with hydrochloric acid and sodium nitrite, and is reacted under heating and addition of caustic soda with salts of compounds of the general formula IX which are possibly formed in situ. Starting substances with the general formulas VII and VIII are known, respectively. can be produced analogously to the known ones. Starting substances with the general formula IX are obtained, e.g. by reaction of corresponding sulphur-free benzodioxole derivatives with the general formula V with chlorosulfonic acid to corresponding chlorosulfonyl compounds, and per se known reduction to the corresponding sulfinic acids, e.g. with sodium sulphite, respectively to mercaptans, e.g. with zinc dust and concentrated hydrochloric acid in diethyl ether or an ethereal solvent.

In the method according to e), are used as starting materials

with the general formula Xa e.g. butyllithium, phenyllithium or 4-methoxyphenyllithium, etc. e.g. A. Schoenberg et al., Chem. Pray. 66, 237-244 (1933), or equivalent

Grignard compounds, resp. as starting material with the general formula Xb, e.g. diphenylcadmium, bis-(4-chlorophenyl)-cadmium or bis-(4-methoxyphenyl)-cadmium, coll. e.g.

HR Henze et al., J. Chem. Soc. 1957, 1410-1413 or diphenyl mercury, and work is carried out in both cases, e.g.

in absolute diethyl ether or another ethereal solvent. Sulfochlorides of the general formula Xla were already mentioned as precursors for compounds of the general formula IX, as well as the corresponding sulfinic acids

and mercaptans which may be obtained therefrom by reduction. From the first, e.g. sulfinyl chlorides of the general formula Xla with thionyl chloride, resp. from the latter disulphides of the general formula XLb by means of oxidation known per se.

When making a compound with the general formula

In, in which A means the residue OR5 and in which R^ means hydrogen, according to method f), the transformation of a group A into the carboxy group can take place in a manner known per se, especially by hydrolysis in an alkaline or acidic medium, whereby in the first case a salt can also be obtained directly. Starting materials for the hydrolysis are primarily such compounds with the general formula I, in which A is a residue OR^in which R,- means hydrogen, particularly easily hydrolyzable among these compounds, such as e.g. the lower alkyl esters, but also further other functional derivatives of dicarboxylic acids which are desirable as end products, such as e.g. nitriles and imidoesters, especially imidolower alkylesters, of carboxylic acids that fall under the general formula I. The hydrolysis takes place, for example, in lower alkanol or aqueous-lower alkanol alkali hydroxide solutions at room temperature to approx. 100°C, respectively the boiling temperature of the reaction medium. Lower alkyl esters, such as methyl or ethyl esters and other easily cleavable esters of carboxylic acids falling under the general formula I, can be hydrolyzed with water under even milder conditions, e.g. in the presence of potassium or sodium carbonate at room temperature, or if necessary, at slightly elevated temperatures of e.g. 40°C, in aqueous-organic medium, e.g. in a medium that is obtained by adding a reaction mixture that is obtained by the reaction according to a) to a solvent that is miscible with water, such as e.g. 1,2-dimethoxyethane. From the thus first obtained alkali metal salt solutions of dicarboxylic acids which fall under the general formula I, the corresponding pure alkali salt can be obtained directly by evaporation and filtration, resp. evaporation and recrystallization or the carboxylic acid can first be released, and then purified e.g. by oracrystallization and, if desired, again transferred into a salt with a suitable inorganic or organic base. Functional derivatives of dicarboxylic acids that fall under the general formula I can furthermore also in an acidic medium, e.g. by heating in an e.g. 60-70% sulfuric acid diluted with water or in lower alkanol-aqueous hydrochloric acid is transferred to the free carboxylic acid with the general formula I.

The necessary functional derivatives of carboxylic acids,

which fall under the general formula I, are prepared according to one of the aforementioned methods, and other functional derivatives, such as e.g. nitriles, are prepared analogously to these methods.

Starting substances with the general formula XIV correspond to the residue A contained in them, for example carboxylic acids, carboxylic acid halides or anhydrides, especially mixed anhydrides, further activated esters, e.g. cyanomethyl esters, as well as lower alkyl esters, which, optionally in the presence of condensing agents, can be reacted with hydroxy compounds of the general formula XV

or ammonia or amines of the general formula XVI

in which the formulas R^respectively Rg and R-, have the meanings given under formula I, or salts, especially alkali metal or alkaline earth metal salts of the free carboxylic acids, which can be reacted with reactive esters of hydroxy compounds of the general formula XV, which

halides or organic sulfonic acid esters, e.g. lower alkanesulphonic acid or arenesulphonic acid esters, such as methanesulphonic acid or p-toluenesulfonic acid esters, or also with carbamic acid halides which are derived from amines of the general formula XVI whose residues Rg and R^ are different from hydrogen, especially -chlorides, further e.g. imidoesters, particularly imidolower alkyl esters, resp. nitriles which can be hydrolysed to esters, especially lower alkyl esters, resp. to unsubstituted amides. Free carboxylic acids can e.g. also react with diazo lower alkanes to lower alkyl esters or with isocyanates, which are derived from primary amines falling under the general formula XVI, to N-monosubstituted amides.

The reactions of free carboxylic acids with hydroxy compounds of the general formula XV advantageously take place in the presence of an acidic, water-splitting catalyst, such as a protonic acid, e.g. of hydrochloric or hydrobromic, sulphurous, phosphoric or boric acid, benzenesulphonic or toluenesulphonic acid, or a Lewis acid, e.g. of boron trifluoride etherate, in an excess

of the hydroxy compound used and/or in an inert solvent, e.g. in a hydrocarbon of the benzene series,

such as benzene or toluene, a halogenated hydrocarbon such as chloroform, methylene chloride or chlorobenzene, or in an ethereal solvent such as tetrahydrofuran, if necessary under distillation, e.g. axiotropic, removal of water released by the reaction. Furthermore, the turnovers can also be carried out in the presence of other water-binding condensation agents, e.g. carbodiimides which are substituted with hydrocarbon residues,

as N,N'-diethyl-, N,N'-dicyclohexy1- or N-ethyl-N1 -(3-dimethylaminopropyl)-carbodiimide, in inert, organic solvents, e.g. those mentioned above. Halides and mixed anhydrides react, for example, in the presence of acid-binding agents, e.g. organic, especially tertiary nitrogen bases, such as e.g. triethylamine, ethyldiisopropylamine or pyridine, or also inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides or carbonates, such as sodium, potassium or calcium hydroxide, or -carbonate,

in inert, organic solvents, e.g. those mentioned above, and if necessary, during heating. The reactions of reactive esters of carboxylic acids with the general formula I, e.g. the cyanomethyl esters, with hydroxy compounds with

the general formula XV, is carried out, for example, in a solvent which is inert towards the reaction participants, e.g.

in a hydrocarbon such as toluene or xylene, an ethereal solvent, such as tetrahydrofuran or dioxane, or at moderate temperatures also an ester, such as ethyl acetate, in the temperature range from approx. 0°C to approx. 120°C, preferably at room temperature to approx. 60°C. For transesterifications of lower alkyl esters of carboxylic acids of the general formula I, hydroxy compounds of the general formula XV with a boiling point that is clearly above the boiling point of

the esterified, lower alkanol, and the reaction is carried out e.g. in an excess of the hydroxy compound and/or an inert organic solvent which likewise preferably boils well above the lower alkanol, preferably in the presence of a catalyst, e.g. an alkali metal lower alkoxide, such as sodium or potassium methoxide or ethoxide,

in the heat and preferably during distillation of the liberated lower alkanol. The hydrolysis of the imido esters, especially the imido lower alkyl esters, of carboxylic acids with the general formula I takes place, for example, with the aid of aqueous mineral acid, such as hydrochloric acid or sulfuric acid, whereby e.g. the imidoester hydrochloride which is obtained by adding hydrogen chloride to nitrile and reacting with anhydrous hydroxy compounds, with the general formula XV, especially lower alkanols, can, after addition of water, be directly hydrolyzed to the corresponding esters, or e.g. can also be obtained from a mixture of nitrile, hydroxy compounds and sulfuric acid with a suitable water content, without isolation of the imidoester of the corresponding ester of the general formula I which occurs in situ.

The turnover of free carboxylic acids with the general formula

In with compounds of the general formula XVI takes place, for example, in the presence of the above-mentioned water-binding agents and in the inert organic solvents mentioned therein,

but the ammonium salts that are first formed from the free carboxylic acids and the compounds with the general formula XVI can also be formed by heating, possibly in a suitable organic solvent of medium or higher boiling point, such as e.g. xylene, chlorobenzene or 1,2,3,4-tetrahydronaphthalene, and distillative, possibly azeotropic, removal of the water released by the reaction, are transferred to amides of the general formula I.

As reactive, functional derivatives of carboxylic acids of the general formula I for the reaction with compounds of the general formula XVI and as associated condensing agents and solvents come into consideration essentially the same, which were indicated above for the reactions with hydroxy compounds of the general formula XV, with the difference that instead of other, i.e. tertiary, organic bases, it can also use an excess of the compound with the general formula XVI to be used as an acid-binding agent and possibly the only reaction medium. The partial hydrolysis of the corresponding nitriles, which is mentioned as a further possibility for the formation of N-unsubstituted amides, can for example be carried out with the aid of hydrous mineral acids, such as hydrochloric acid or dilute sulfuric acid at room temperature or a moderately elevated temperature.

The free carboxylic acids with the general formula I which are necessary as starting materials for method g) can be prepared in particular according to method a) or b) and their reactive functional derivatives, e.g. from the free carboxylic acids in a manner known per se.

The oxidation according to h) takes place, for example, with the help of hydrogen peroxide in an organic or organic-aqueous solvent which is inert to this, such as possibly water-containing acetic acid, e.g. in the mixture resulting from glacial acetic acid and aqueous hydrogen peroxide solution, at moderately elevated temperatures between approx. 60 and 100°C, especially at approx. 80-90°C, and with more than twice the molar amount of hydrogen peroxide, when a sulfonyl compound is to be obtained as an oxidation product, corresponding to n^= 2. The oxidation of corresponding thio to sulfinyl compounds, corresponding to n^= 0, respectively . 1, is carried out e.g. either according to the above procedure in the temperature range from approx. 20 to 60°C with, if necessary, only an approx. equimolar amount of hydrogen peroxide, or e.g. especially when using alkali metal, especially sodium or potassium periodate, such as sodium metaperiodate in organic-aqueous, e.g. lower alkanol-aqueous, especially ethanolic-aqueous medium in the cold, e.g. at 0°C

to room temperature.

According to procedure i), e.g. compounds of the general formula I, where n^ is 1, are reduced by means of free phenylphosphine in boiling carbon tetrachloride to the corresponding compounds, in which n-^ is 0.

Obtained salt-forming compounds of formula I can on i

and transferred in a known manner to salts, e.g. those with hydroxy as residue A with corresponding bases, such as e.g. alkali metal hydroxides, to salts with bases, or those of a basic nature to their acid addition salts. Preferably, pharmaceutically acceptable salts are prepared.

Obtained salts can be transformed in a manner known per se into the free compounds, e.g. by treatment with an acidic reagent, such as a mineral acid, or with a base, e.g. an alkali metal hydroxide solution, such as caustic soda.

The compounds including their salts can also be obtained in the form of their hydrates, or their crystals can include the solvent used for the crystallization.

According to the close relationship between the new compounds of the general formula I, in which A is hydroxy, in free form and in the form of their salts with bases, as well as of such compounds, whose residue R, exhibits basic character in free form or in form of acid addition salts, shall in the preceding and subsequent terms under the free compounds or their salts be meaningfully and expediently, possibly also mean the corresponding salts or free connections.

The new compounds can, depending on the number of asymmetry centers as well as the choice of starting materials and working methods, be obtained in the form of racemates or racemate mixtures (diastereomer mixtures) or possibly also as pure antipodes.

Obtained racemate mixtures can, due to the physico-chemical differences between the components, be divided in a known manner into the pure racemates, resp. diastereomers, for example by chromatography and/or fractional crystallization. Obtained racemates can be further divided according to known methods into the optical antipodes, for example by recrystallization from an optically active solvent, with the help of microorganisms or by reacting an acidic end product with the general formula I with an optically active base that forms salts with the racemic the acid, respectively reacting a basic end product of the general formula I with an optically active acid, and splitting the salt thus obtained, e.g. because of their different solubilities, in the diastereomers, from which the antipodes can be liberated by the action of suitable agents. Advantageously, the most effective of the two antipodes is isolated.

The invention also applies to those embodiments of the method, according to which the starting point is a compound that is obtained as an intermediate at any step of the method and the missing steps are carried out or a starting substance in the form of a salt and/or racemate, respectively. antipodes are used, or especially formed under the reaction conditions.

By means of the method according to the present invention, such starting materials are preferably used which lead to the compounds indicated at the outset as particularly valuable. New starting materials and methods for their production likewise form an object of the present invention.

The invention further relates to pharmaceutical preparations, which contain the compounds of the general formula I as active substances, as well as the method for their production.

As far as the pharmaceutical preparations are concerned, it matters

about preparations for enteral, such as oral or rectal, as well as for parenteral administration to warm-blooded animals. The dosage of the active substance, which is supplied alone or together with the usual carrier and auxiliary material, depends on the nature of the warm-blooded, its age and the individual condition as well as the method of supply. The daily doses range between 0.15 and 120 mg/kg for mammals, and are for such with approx. 70 kg weight, depending on the individual condition and age, preferably between 10 and 600 mg, especially between 25 and 300 mg. Corresponding oral dosage unit forms, e.g. dragees, tablets or capsules, preferably contain 5 to 150 mg, especially 10 to 100 mg of an active substance produced according to the invention, i.e. a compound of the general formula I or a pharmaceutically acceptable salt of a compound of the general formula I which are capable of forming salts, together with pharmaceutical carriers.

The pharmaceutical preparations are prepared in a manner known per se, e.g. using conventional mixing, granulating, coating, dissolving or lyophilizing methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active substance with solid carriers, an obtained mixture, optionally granulated, and the mixture or the granules, if desired or necessary, are further processed into tablets or dragees

cores after the addition of suitable excipients.

Suitable carriers are especially fillers, such as sugar,

e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders,

such as starch pastes and application of e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starch, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow-regulating and lubricating agents, e.g. silicic acid, lime, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are equipped with suitable, possibly gastric juice-resistant covers, whereby it e.g. concentrated sugar solutions are used, which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide. Lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate, are used. The tablets or dragee coatings may have dyes or pig-

ments, e.g. for identification or for characterizing different doses of active substances.

Further, orally usable pharmaceutical preparations are capsules of gelatin, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The suppositories may contain the active substance in the form of

a granule, e.g. in a mixture with fillers, such as lactose, binders, such as starch, and/or lubricants, such as lime or magnesium stearate, and optionally with stabilizers.

In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as hot oils, paraffin

oil or liquid polyethylene glycols, whereby it also

Stabilizers can be added.

As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, which consist of a combination of the active substance with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which contain a combination of the active substance and a base mass. As base materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or vehicles are used, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally stabilizers.

The new compounds of formula I and the pharmaceutically acceptable salts and such can be used as pharmacologically active compounds, in particular as diuretics with uricosuric additional action, preferably in the form of pharmaceutical preparations in a method for prophylactic and/or therapeutic treatment of animals or humans -bodies, especially for the treatment of edema and/or hypertension.

The following examples illustrate the invention described above. However, they shall not in any way limit its scope. The temperature is indicated in C°.

Example 1.

To a suspension of 10.6 g (40 mmol) of 4-methyl-5-phenylsulfonyl-1,2-benzenediol in 65 ml of cold 1,2-dimethoxyethane, 27.7 g (200 mmol) of anhydrous potassium carbonate is added. With vigorous stirring, a solution of 7.85 g (50 mmol) dichloroacetic acid ethyl ester in 5 ml of 1,2-dimethoxyethane is added dropwise over the course of 30 minutes. The mixture is further stirred at room temperature for 1 hour, and then boiled with stirring and under reflux for 3 hours. It is then cooled to 30°, water is added, stirred for 30 minutes and adjusted to pH 1-2 with hydrochloric acid. In a rotary evaporator, part of the 1,2-dimethoxyethane is removed and the remaining solution is extracted 3 times with ethyl acetate. The combined ethyl acetate solutions are washed with water and then with saturated sodium chloride solution, dried over sodium sulfate, treated with activated charcoal and evaporated. The yellow-green oil obtained is crystallized from ethyl acetate-hexane.

The sand-coloured crystals are dissolved in ethyl acetate and treated again with activated charcoal. The solvent is removed in a rotary evaporator. The remaining yellow oil is crystallized at 0° from methylene chloride, whereby 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid with melting point 169-171° is obtained.

The starting material can be prepared as follows:

a) To a solution of 16.4 g (100 mmol) benzenesulfinic acid sodium salt and 13.6 g (110 mmol) 4-methyl-1,2-benzenediol

in 150 ml of water, a solution of 50 g (152 mmol) of potassium hexacyanoferrate-(III) and 95 g of sodium acetate trihydrate in 200 ml of water is added dropwise under nitrogen at room temperature over the course of 30 minutes. After stirring for 1% hour, the reaction mixture is deacidified and extracted several times with ethyl acetate.

The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is recrystallized from ether-hexane, whereby 4-methyl-5-phenylsulfonyl)-1,2-benzenesiol with m.p. 145-149° is achieved.

Example 2.

A mixture of 20.8 g (100 mmol) 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester, 18.2 g (105 mmol) benzenesulfonic acid sodium salt, 200 g polyphosphoric acid and 85 ml methanesulfonic acid is stirred vigorously at 25°C under nitrogen for 4 days. The reaction mixture is then added under ice-cooling to 500 ml of ice water and extracted 4 times with ether. The combined organic phases are first washed with water and then with a saturated sodium chloride solution, dried over sodium sulfate and

evaporate to dryness. The remaining 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid ethyl ester is purified by column chromatography on silica gel eluting with ethyl acetate-hexane in a 1:1 ratio. The fractions containing uniform substance are combined and evaporated. The yellow, oily residue crystallizes on standing. It is then stirred in 2

hours at 0° with ether, filtered off, washed with cold ether and dried. The ester, which crystallizes in pale yellow needles, melts at 89-90°.

8.6 g (24.7 mmol) of 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid ethyl ester are suspended in 37 ml of methanol. Then, at room temperature, slowly add 37 ml 1-1 sodium hydroxide solution, after which the starting material quickly dissolves. After 1 hour, the reaction mixture is cooled, concentrated hydrochloric acid is added and extracted 3 times with ethyl acetate. The combined organic phases are washed with water and then with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. Add 50 ml of methylene chloride to the remaining yellow oil and stir until crystallization. The filtered off crystals are recrystallized from a little 1,2-dichloroethane, whereby 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid is obtained as white crystals with m.p. 169-171°C.

The 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester used as starting material can be prepared according to one of the two methods described below: a) A solution of 38.7 g (0.3 mol) dichloroacetic acid, 12 g (0.3 mol) sodium hydroxide, 40 ml water and 0.6 g "Aliquat" are stirred under nitrogen and heated to 95°. At this temperature, a solution of 24.8 g (0.2 mol) 4-methyl-1,2-benzenediol (Homopyrocatechol), 100 ml water and 20 g (0.5 mol) sodium hydroxide is added dropwise over the course of 2 hours. which is prepared in advance under nitrogen. It is then stirred for 1h hours at 95 and it is then cooled to room temperature. The reaction mixture is acidified with hydrochloric acid to pH 8, and washed twice with ether. The aqueous phase is then set on

pH 1-2 with concentrated hydrochloric acid and extracted with ether.

The combined ether solutions are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated completely in a rotary evaporator.

b) The crude 5-methyl-1,3-benzodioxole-2-carboxylic acid obtained as a residue in a) is dissolved in 400 ml of anhydrous ethanol and

boiled with 0.5 ml of concentrated hydrochloric acid for 2 hours. The solution is evaporated vigorously and the crude ester obtained is dissolved in ether or methylene chloride. The solution is washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The crude product which remains as a brown oil is distilled under a water jet vacuum, whereby 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester passes over at 105-108°C/5 mbar.

b) To a suspension of 34.6 g (250 mmol) of anhydrous potassium carbonate in 150 ml of dimethylformamide is added a solution of

6.2 g (50 mmol) of 4-methyl-1,2-benzenediol in 20 mol of dimethylformamide. After 5 minutes, a solution of 12 g (55 mmol) of dibromoacetic acid in 25 ml of dimethylformamide is added over 15 minutes and heated for 4 hours at 80°. Water is then added to the reaction mixture, it is acidified and extracted several times with ethyl acetate. The combined extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is esterified as described under a) with ethanol in the presence of slightly concentrated salt

acid.

Example 3.

Analogous to example 1, a mixture is boiled under reflux

of 27.1 g (196 mmol) potassium carbonate, 12.5 g (39.16 mmol) 4-chloro-5-(2-chlorophenylsulfonyl)-1,2-benzenediol and 6.76 g (43.08 mmol) dichloroacetic acid ethyl ester in 200 ml of 1,2-dimethoxyethane for 15 hours. The solid material that has deposited on the wall is scraped off, and a further 27.1 g (196 mmol) of potassium carbonate and 6.76 g (43.08 mmol) of dichloroacetic acid ethyl ester are added, and it is further boiled under reflux for 8 hours. The reaction mixture is poured onto ice/water, acidified and extracted with ethyl acetate. 5-Chloro-6-(2-chlorophenyl-sulfonyl)-1,3-benzodioxole-2-carboxylic acid, which remains as a brown oil after evaporation, is crystallized from acetonitrile and recrystallized once more from there, whereupon it is obtained as white crystals with m.p. 226-227°.

The necessary 4-chloro-5-(2-chlorophenylsulfonyl)-1,2-benzenediol is prepared as follows: a) To a solution of 28.8 g (163 mmol) of 2-chlorobenzenesulfinic acid, (obtained by reduction of 2- chlorobenzenesulfonyl chloride with sodium sulphite) in 163 ml of 1 N sodium hydroxide solution, 24.6 g (170 mmol) of 4-chloro-1,2-benzenediol are added while stirring and under nitrogen. A solution of 82 g (240 mmol) of potassium hexacyanoferrate-(III) and 150 g of sodium acetate trihydrate in 300 ml of water is added dropwise at room temperature over the course of 40 minutes. The solution became cloudy and an oil formed, which crystallized after 2 hours of stirring. The reaction mixture is extracted 3 times with ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution, dried and evaporated.

The raw, brown crystals are dissolved in warm isopropanol and treated with activated charcoal. The solution is filtered, evaporated to 200 ml, dropped into 800 ml of ice-cold water and stirred for 2 hours under ice-cooling. The white suspension is suctioned off, the residue on the filter is washed with water and dried, whereby 4-chloro-5-(2-chlorophenylsulfonyl)-1,2-benzenediol is obtained as white crystals with m.p. 226-229°C.

Example 4.

A suspension of 12.0 g (43.1 mmol) of 4-methyl-5-(4-methylphenyl-sulfonyl)-1,2-benzenediol and 30 g (216 mmol) of freshly annealed potassium carbonate in 200 ml of dry 1,2 -dimethoxyethane is stirred for 5 minutes under nitrogen with a stirrer at high stirring speed. The temperature thereby rises to 75°. Then add in drops under moderate stirring, (propeller stirrer) during 1

hour, a solution of 6.77 g (43.1 mmol) of dichloroacetic acid ethyl ester in 50 ml of dry 1,2-dimethoxyethane and the mixture is then refluxed for 15 hours. It is then poured onto a mixture of ice and water, and adjusted to pH 1-2 with concentrated hydrochloric acid. Part of the 1,2-dimethoxyethane is evaporated in a rotary evaporator and the remaining solution is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in a rotary evaporator. The black oil obtained is dissolved in ethanol, 0.5 g of p-toluenesulfonic acid is added and refluxed in a vessel equipped with a Soxhlet apparatus, which is filled with a molecular sieve.

The ethanolic solution is then completely evaporated and chromatographed on silica gel (solvent ethyl acetate/hexane in the ratio 1:1). The uniform fractions containing the desired substance are combined and evaporated. 5-Methyl-6-(4-methylphenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester is then obtained as a yellow oil, which can be directly hydrolyzed.

A solution of 10 g of 4-methyl-5-(4-methylphenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester in 30 ml of methanol is cooled to 5°. Under nitrogen and with stirring, 41.3 ml of sodium hydroxide solution are added, whereby the temperature rises to 30°. The mixture is cooled to 20° and stirred at room temperature

for another 30 minutes. Then ice water is added to it, filtered,

the filtrate is adjusted to pH 1-2 with concentrated hydrochloric acid and extracted 3 times with ethyl acetate. The combined ethyl acetate phases are washed with water and with a saturated sodium chloride solution, dried over sodium sulfate and evaporated completely. The residue is crystallized from acetonitrile. The crystallisate is then stirred with cold ether, then filtered off and dried. The thus obtained 5-methyl-6-(4-methylphenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid melts at 162-165°.

The necessary 4-methyl-5-(4-methylphenylsulfonyl)-1,2-benzenediol is prepared as follows: a) Under nitrogen, a mixture of 500 g of polyphosphoric acid and 47.6 g (250 mmol) of p-toluenesulfonic acid monohydrate is heated

to 10° and 41.9 g (275 mmol) of 1,2-dimethoxy-4-methylbenzene (4-methyl-veratrol) are then added. The reddish suspension is stirred for 30 minutes at 105°, cooled to 80°, 1500 ml of water are added and cooled to room temperature. The reaction mixture is extracted with ethyl acetate. The organic phase is washed with water, dried, treated with activated carbon and evaporated. The solid substance obtained is recrystallized from toluene, but can also be reacted directly further. 1,2-Dimethoxy-4-methyl-5-(4-methylphenylsulfonyl)-benzene is obtained from toluene as white crystals with m.p. 133-134.5°.

b) 326 g of anhydrous pyridine hydrochloride are heated to 180°. While stirring, 33 g (113 mmol) of 1,2-dimethoxy-4-methyl-5-(phenylsulfonyl)-benzene are quickly added. The reaction mixture is heated for a further 15 minutes at 190° and stirred at this temperature for 1 hour. The hot reaction mixture is poured onto an ice-water mixture and extracted 3 times with ether. The ether fractions are combined, washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in the rotary evaporator. Dark brown crystals are then obtained, which are crystallized from ether-hexane. In this way, 1,2-dimethoxy-4-methyl-5-(phenylsulfonyl)-benzene is obtained with m.p. 162-163° as sand colored crystals. These are used

further without further purification.

Example 5.

Analogous to example 4, using 25.0 g (83.7 mmol) of 4-(4-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol, 13.2 (83.7 mmol) dichloroacetic acid ethyl ester, 57 g (418 mmol) potassium carbonate, 220 ml of 1,2-dimethoxyethane and subsequent saponification with caustic soda in methanol the desired 5-(4-chlorophenyl-sulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid as white crystals with m.p. 169-171°C from 1,2-dichloroethane.

The required 4-(4-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol is prepared as follows: a) To a solution of 35.0 g (198.2 mmol) 4-chlorobenzenesulfinic acid (obtained by reduction of 4-chlorobenzenesulfonyl chloride

with sodium sulphite) in 198.2 ml of aqueous 1-1 sodium hydroxide solution, added with stirring and under nitrogen 27.9

g (224.6 mmol) 4-methyl-1,2-benzenediol. At room temperature, a solution of 109 g (330.3 mml) of potassium hexacyanoferrate-(III) and 198.2 g of sodium acetate trihydrate in 400 ml of water is added dropwise over the course of 40 minutes. After stirring for 1h hours, the reaction mixture is acidified and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated.

The solid residue is recrystallized from 1,2-dichloroethane. The 4-(4-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol thus obtained melts at 184-186°.

Example 6.

Analogously to example 4, 25.0 g (72.2 mmol) of 4-(4-cyclohexylphenylsulfonyl)-5-methyl-1,2-benzenediol is obtained by condensation with 11.3 g (72.7 mmol) of dichloroacetic acid ethyl ester and 50 g (361 mmol) of potassium carbonate in 190 ml of 1,2-dimethoxyethane and subsequent saponification with caustic soda in methanol 5-(4-cyclohexylphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid as white crystals with m.p. 159-161.5° from ethyl acetate/hexane.

4-(4-cyclohexyl phenyl sulfonyl)-5-methyl-1,2-benzenediol, which is used as starting material, is obtained from 28.2 g (226.7 mmol) of 4-methyl-1,2-benzenediol and 44.9 g (200 mmol) 4-cyclohexyl benzenesulfinic acid (obtained by reduction of the corresponding sulfonyl chloride with sodium sulfite (by oxidative condensation analogously to example 5a).

Example 7.

A suspension of 34.6 g (250 mmol) of freshly annealed potassium carbonate in 150 ml of dimethylformamide is stirred first with a high-speed stirrer for 5 minutes and then with a normal stirrer. A solution of 16.07 g (50 mmol) of 4-(3-acetamido phenyl sulfonyl)-5-methyl-1,2-benzenediol in 50 ml of dimethylformamide is then added. After 5 minutes, a solution of 11.98 g (55 mmol) of dibromoacetic acid in 25 ml of dimethylformamide is added over 15 minutes and this reaction mixture is heated to 80° for 4 hours. Water is then added, acidified with hydrochloric acid and suctioned off. The filtrate is extracted several times with ethyl acetate. The solid substance is dissolved in the combined organic phase and the solution is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated at 60° until crystallization begins. 5-(3-acetamido phenyl sulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is recrystallized from ethyl acetate, m.p. 186-188°.

The necessary 4-(3-acetamido phenyl sulfonyl)-5-methyl-1,2-benzenediol is obtained analogously to example 3a from 29.7 g (150 mmol) of 3-acetamido benzene sulfinic acid and 21.1 g (170 mmol ) 4-methyl-1,2-benzenediol by oxidative coupling, m.p. 220-222° from isopropanol/water.

Example 8.

Analogously to example 4, 19.0 g (67.3 mmol) of 4-(4-fluorophenylsulfonyl)-5-methyl-1,2-benzenediol is obtained by condensation with 10.6 g (67.3 mmol) dichloroacetic acid ethyl ester and 46 ,5

g (336.5 mmol) potassium carbonate in 200 ml 1,2-dimethoxyethane and subsequent saponification with caustic soda in methanol the desired 5-(4-fluorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid as white crystals with m.p. 157-158.5° from 1,2-dichloroethane.

The required 4-(4-fluorophenylsulfonyl)-5-methyl-1,2-benzenediol is obtained by oxidative condensation of 31.6 g (197 mmol) of p-fluorobenzenesulfinic acid (prepared either by reduction of the corresponding sulfonyl chloride with sodium sulfite or by Friedel-Craft reaction between fluorobenzene and sulfur carbon) with 38.7 g (213 mmol) of 4-methyl-1,2-benzenediol analogous to example 5a), as yellow crystals with m.p. 175-177°

from acetonitrile.

Example 9.

A suspension of 72.8 g (526 mmol) of freshly annealed potassium carbonate in 300 mL of 1,2-dimethoxyethane is stirred under nitrogen for 10 minutes with a high-speed stirrer and then, with normal stirring, 37.0 g (105.3 mmol ) 4-(3-acetamido-4-methoxy phenyl sulfonyl)-5-methyl-1,2-benzenediol, 16.5 g (105.3 mmol) dichloroacetic acid ethyl ester and 3 g tetrabutylammonium bromide. The mixture is refluxed, 300 ml of acetone is added, further refluxed for 3 hours, a further 60 g of potassium carbonate and 16.5 g dichloroacetic acid ethyl ester are added and refluxed for a further 9 hours. The reaction mixture is poured onto water and acidified with hydrochloric acid to pH 1-2. One of the solvent is evaporated under vacuum and the remaining water phase is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in a rotary evaporator. The residue is recrystallized 4 times from acetonitrile, whereby 5-(3-acetamido-4-methoxyphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained as white crystals with m.p. 230°, (sinters at 150°).

The necessary 4-(3-acetamido-4-methoxyphenylsulfonyl)-5-methyl-1,2-benzenediol is obtained analogously to example 5a) from 34.4

g (150 mmol) 3-acetamido-4-methoxybenzenesulfinic acid and 211

g (170 mmol) 4-methyl-1,2-benzenediol as crystals with m.p. 230-232° (from isopropanol).

Example 10.

Analogous to example 4, 30.0 g (111 mmol) of 4-methyl-5-(2-thienylsulfonyl)-1,2-benzenediol, 17.4 g (111 mmol) dichloroacetic acid ethyl ester and 76.7 g (555 ml) of potassium carbonate in 300 ml of 1,2-dimethoxyethane under reflux. After 18 hours, the reaction mixture is poured into water, stirred at room temperature for 1 hour, and then adjusted using hydrochloric acid to pH 1-2. One of the 1,2-dimethoxyethane is distilled off under vacuum and the remaining mixture is extracted with ethyl acetate.

The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in a rotary evaporator. The dark red oil obtained is chromatographed on silica gel. As eluent, a mixture of chloroform-methanol-concentrated ammonia in the ratio 40-10-1 is used until elution of the starting diol, and then the analogous mixture in the ratio 12-5-1. The uniform fractions are combined and evaporated almost completely. The remainder is added to ice/water and adjusted to pH 1-2 with concentrated hydrochloric acid. The acidic solution is extracted with ethyl acetate. The combined organic phases are washed, dried and evaporated. The residue is boiled in diisopropyl ether and decanted from the precipitated, black sludge. The clear solution is strongly evaporated, and the crystallized substance is suctioned off. The crystals are recrystallized from 1,2-dichloroethane, whereby 5-methyl-6-(2-thienylsulfonyl)-1,3-benzodioxole-2-carboxylic acid is obtained

as white crystals with m.p. 162.5-164.5°.

a) 4-methyl-5-(2-thienyl sulfonyl)-1,2-benzenediol, which is used as starting material, is obtained analogously to example 5a) from 90

g (600 mmol) of 2-thiophenesulfinic acid (obtained by reduction of 2-thiophenesulfonyl chloride with sodium sulfite) and 84.5 g (681 mmol) of 4-methyl-1,2-benzenediol as yellowish crystals with m.p. 161-163.5° (from ethyl acetate).

Example 11.

Analogous to example 4, 21.3 g (64 mmol) of 4-(2,5-dichloro-phenylsulfonyl)-5-methyl-1,2-benzenediol are boiled, 10.0 g (64 mmol)

dichloroacetic acid ethyl ester and 44.2 g (320 mmol) of potassium carbonate in 160 ml of 1,2-dimethoxyethane under reflux. After 18 hours, the reaction mixture is filtered and the solid filter material is washed twice with 1,2-dimethoxyethane. To the combined organic solutions, 44 g of fresh potassium carbonate and 10 g of dichloroacetic acid ethyl ester are added, stirred for 5 minutes with a high speed stirrer and further boiled under normal stirring for 17 hours. The preparation takes place analogously to example 10. After careful drying, 5-(2,5-dichlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained as white crystals with m.p. 155-157° (from diisopropyl ether) .

a) 4-(2,5-dichlorobenzenesulfonyl)-5-methyl-1,2-benzenediol obtained from 40 g (189.5 mmol) of 2,5-dichlorobenzenesulfinic acid

(produced by reduction of 2,5-dichlorobenzene sulfochloride

with sodium sulphite) and 26.7 g (215 mmol) of 4-methyl-1,2-benzene-diol analogously to example 5a) as sand-coloured crystals with m.p. 209.5-212° (from acetonitrile).

Example 12.

To a fine-grained suspension of 50.9 g (385 mmol) of freshly annealed potassium carbonate in 180 ml of dry dimethylformamide, 23 g (77 mmol) of 4-(2-chlorophenylsulfonyl)-5-methyl-1,2-benzene- diol and, over 15 minutes, a solution of 8.50 g (39 mmol) of dibromoacetic acid in 80 ml of dimethylformamide is added dropwise. The mixture is then stirred for 15 hours at 80°.

The reaction mixture is then poured onto ice and adjusted to pH

1-2 with concentrated hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried with sodium sulphate and evaporated. The brown oil obtained is stirred with 150 ml of ethyl acetate at 0° until crystallization. The thus obtained crude 5-(2-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is recrystallized twice from acetonitrile, after which it is obtained as sand-colored crystals with m.p. 211-213.5°.

a) The 4-(2-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol is obtained from 26.5 g (150 mmol) of 2-chlorobenzenesulfonic acid and 21.1 g (170

mmol) 4-methyl-1,2-benzenediol analogous to example 5a) as white crystals, m.p. 225-229° from ethyl acetate.

Example 13.

Analogous to example 12, 5-(3-acetamido-4-chlorophenyl-sulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained by condensation of 22.0 g (61.8 mmol) 4-(3 -acetamido-4-chlorophenyl-sulfonyl)-5-methyl-1,2-benzenediol with 16.25 g (74.18 mmol) of dibromoacetic acid and 42.7 g (309 mmol) of potassium carbonate in 225 ml of dimethylformamide, m.p. 198-200°.

The work-up also takes place analogously to example 12. The dark red oil that is obtained as crude product is, however, chromatographed over a silica gel funnel (chloroform-methanol-concentrated ammonia 40:10:1).

The uniform fractions are extracted with ethyl acetate, and

the substance that remains after evaporation of the extract,

recrystallized from acetonitrile, whereby the end product is obtained as sand-colored crystals with m.p. 198-200° (sinters from 120°) .

4-(3-acetamido-4-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol, which is used as starting material, is prepared as follows: a) 66 g (297.8 mmol) 4-chloro-3-nitro-benzenesulfinic acid (produced by reduction of 4-chloro-3-nitro-benzenesulfonyl chloride

with sodium sulphite), is condensed with 41.95 g (337.9 mmol) of 4-methyl-1,2-benzenediol analogously to example 4, whereby 4-(4-chloro-3-nitrophenylsulfonyl)-5-methyl-1 ,2-benzenediol as crystals with m.p. 196-197° (from ethyl acetate/hexane).

b) 47.5 g (138.2 mmol) of the product obtained according to

a), is catalytically hydrogenated with hydrogen in the presence of Raney nickel to 4-(3-amino-(4-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol. The latter crystallizes from 1,2-dichloroethane as sand-colored crystals with mp 191-193° c) 40 g (112.42 mmol) of the amine obtained according to b) is acetylated with 11.48 g (112.42 mmol) of acetic anhydride in 240

ml of glacial acetic acid to the desired 4-(3-acetamido-4-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol, which is obtained from acetonitrile as white crystals with m.p. 224-226.5°.

Example 14.

21.0 g (70.3 mmol) of 4-chloro-5-(4-methylphenylsulfonyl)-1,2-benzenediol and 48.6 g (about 350 mmol) of anhydrous, powdered potassium carbonate are suspended at room temperature under inert gas for 160 ml of dimethylformamide. A solution of 16.8 is then added dropwise at room temperature over 15 minutes

g (77.4 mmol) of dibromoacetic acid in 80 ml of dimethylformamide with stirring. The reaction mixture is then heated with stirring for 15 hours to 95°. For work-up, the reaction mixture is poured onto an ice-water mixture and acidified with concentrated salt

acid to pH 2. The crude product is extracted with ethyl acetate and the solvent is evaporated. The remaining crude acid is dissolved in 100 ml of methanol and 0.5 ml of concentrated hydrochloric acid is added. After 5 hours of rest at room temperature, crystallization starts. The crystal suspension is cooled in an ice bath for 18 hours, then the crystals are filtered off and washed with ice-cold methanol. They are then suspended in 60 ml of methanol and 35 ml of 2-N caustic soda is added at room temperature, whereby dissolution occurs. After standing for 1 hour, the solution is poured onto an ice/water mixture and acidified with 6-n hydrochloric acid. 5-chloro-6-(4-methylphenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid precipitates and is extracted with ethyl acetate. The evaporation residue of the extract is recrystallized from acetonitrile and the above substance is obtained as sand-coloured crystals with m.p. 181-183.5°.

The aromatic starting material is prepared as follows:

a) Analogous to example 5a), p-toluenesulfinic acid is condensed oxidatively with 4-chloro-1,2-benzenediol. Upon recrystallization

from 1,2-dichloroethane, 4-chloro-(4-methylphenylsulfonyl)-1,2-benzenediol is obtained as colorless crystals with m.p. 162-164°.

Example 15.

42.6 g (approx. 0.13 mol) 4-bromo-5-(phenylsulfonyl)-1,2-benzenediol and 90.0 g (approx. 0.65 mol) anhydrous, powdered potassium carbonate are stirred in 300 ml of dimethylformamide under inert gas protection. At room temperature, half of a solution of 57.0 g (approx. 0.26 mol) of dibromoacetic acid in 100 ml of dimethylformamide is added. The reaction mixture is stirred for 8 hours at 95°,

then the rest of the dibromoacetic acid solution is added and the mixture is stirred for 8 hours at 95°. The dime-tylph ormamide is then distilled off under reduced pressure, the residue is dissolved in water, the solution is adjusted to pH 1-2 with concentrated hydrochloric acid,

and extracted with ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate and evaporated. The rest

dissolve in 150 ml of methanol and add 0.3 ml of concentrated hydrochloric acid. After standing overnight at room temperature, the solution is evaporated and the residue is chromatographed on a column of silica gel with the eluent mixture ethyl acetate/hexane 1:1. The uniform fractions are combined and evaporated. This evaporation residue is added to 50 ml of 2-n caustic soda and stirred with a magnetic stirrer at room temperature, until a solution is obtained. This is adjusted to pH 1-2 with concentrated hydrochloric acid, and the precipitated acid is extracted repeatedly with ethyl acetate. The combined ethyl acetate solutions are washed with water, dried with sodium sulfate, filtered and evaporated, whereupon the 5-bromo-6-(phenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid precipitates as a white crystalline crust. After recrystallization from ethyl acetate/hexane, the above-mentioned substance is obtained as colorless crystals with m.p. 219-222° (decomposition).

The aromatic starting material is obtained in the following way.

a) 48.0 g of 4-bromo-1,2-benzenediol (cf. W. Rosenmund, Ber. 62, 1262 etc. (1923)) is condensed oxidatively with 33.4 g

benzenesulfinic acid sodium salt analogous to example 5a). After crystallization from 1,2-dichloroethane, 4-bromo-5-(phenylsulfonyl)-1,2-benzenediol is obtained as colorless crystals with m.p. 166-168°.

Example 16.

25.0 g (approx. 85 mmol) of 4-(4-methoxyphenylsulfonyl)-5-methyl-1,2-benzenediol are reacted in 200 ml of dimethylformamide using 60 g of potassium carbonate with 20.4 g (93.5 mmol) of dibromoacetic acid in 100 ml of dimethylformamide completely analogously to example 14. The crude acid obtained is dissolved in ethyl acetate and a solution of 5.8 g of hexanoic acid sodium salt in methanol is added.

The crystals thus precipitated are filtered off and dried. The sodium salt of 5-(4-methoxyphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is thus obtained as colorless crystals, which melt above 220° (decomposition).

The aromatic starting material is obtained in the following way:

a) 27.5 g 4-methoxybenzenesulfinic acid (obtained, for example, by reducing 4-methoxybenzenesulfonyl chloride with sodium sulfite)

is condensed oxidatively with 30.7 g of 4-methyl-1,2-benzenediol analogously to the method described in example 5a) and is obtained after crystallization from 1,2-dichloroethane 4-(4-methoxyphenyl-sulfonyl)-5-methyl- l , 2-benzenediol as colorless crystals with m.p. 145-147.5°.

Example 17.

15.0 g (0.05 mol) 4-(2,4-difluorobenzenesulfonyl)-5-methyl-1,2-benzenediol and 34.6 g (0.25 mol) potassium carbonate are suspended under nitrogen protection in 100 ml of dimethylformamide at room temperature. During 10 minutes, a solution of 11.9 g (approx. 0.055 mol) of dibromoacetic acid in 30 ml of dimethylformamide is added dropwise and the reaction mixture is then heated with stirring for 5.5 hours at 90°. The reaction mixture is poured into 1500 ml of water and adjusted to pH 1-2 with concentrated hydrochloric acid. The crude acid is extracted with ethyl acetate,

the ethyl acetate solution is washed with water, dried over sodium sulfate, filtered and evaporated. To the evaporation residue, add 50 ml 1-1 sodium hydroxide solution and the solution thus obtained is evaporated in a rotary evaporator, until the sodium salt begins to

crystallize. By adding isopropanol and heating to reflux, a solution is again obtained, which is added to activated carbon and filtered. The sodium salt of 5-(2,4-difluorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid separates from the filtrate on cooling in colorless needles. After filtering and drying, the salt melts above 200°, after sintering from 160°.

The starting material is produced as follows:

a) In the Meerwein reaction starting from 2,4-difluoroaniline, 2,4-difluorobenzenesulfonyl chloride is obtained with boiling point 87°/mbar. b) By reducing 2,4-difluorobenzenesulfonyl chloride with sodium sulphite, 2,4-difluorobenzenesulfinic acid is obtained. c) Analogous to example 5a) is obtained by oxidative condensation of 23.5 g of 2,4-difluorobenzenesulfinic acid with 18.5 g of 4-methyl-1,2-benzenediol after recrystallization from 1,2-dichloroethane 4-(2,4- difluorobenzenesulfonyl)-5-methyl-1,2-benzenediol with m.p. 158-162°.

Example 18.

Analogous to example 1, 18.3 g of 4-(3-chloro-4-fluoro-phenylsulfonyl)-5-methyl-1,2-benzenediol are reacted in the presence of 39.9 g of potassium carbonate with 10.0 g of dichloroacetic acid ethyl ester in 150

ml of dimethoxyethane. After analogous work-up and recrystallization from acetonitrile, 5-(3-chloro-4-fluorogenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained as colorless crystals with m.p. 188.5-190.5°.

The aromatic starting material is prepared as follows:

a) The 3-chloro-4-fluorobenzenesulfochloride used in example 18b with boiling point 90-95°/5 mbar is obtained according to methods known in the literature, thus e.g. by Meerwein reaction from 3-chloro-4-fluoroaniline. b) By reducing 3-chloro-4-fluorobenzenesulfochloride with sodium sulphite, 3-chloro-4-fluorobenzenesulfinic acid is obtained with

a m.p. 6 6-68°.

c) Analogously to example 5a), the 4-(3-chloro-4-fluorophenylsulfonyl)-5 used in example 18 above is obtained by oxidative condensation of 3-chloro-4-fluorobenzenesulfinic acid with 4-methyl-1,2-benzenediol -methyl-1,2-benzenediol with a melting point of 166-167.5° as colorless crystals.

Example 19.

Analogous to example 17, 14 g (42.8 mmol) of 5-(4-chloro-2,5-dimethylphenylsulfonyl)-4-methyl-1,2-benzenediol and 10.3 g of dibromoacetic acid are reacted in the presence of 29.6 g of potassium carbonate in 150 ml of dimethylformamide and it is obtained after working up, salt formation with caustic soda and recrystallization from isopropanol/water 5-(4-chloro-2,5-dimethylphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid sodium salt as colorless crystals with m.p. above 180°, (splitting).

The starting material 5-(4-chloro-2,5-dimethylphenyl-sulfonyl)-4-methyl-1,2-benzenediol is obtained by oxidative condensation of 4-chloro-2,5-dimethylbenzenesulfonic acid (in turn obtained by reduction of 4-chloro-2,5-dimethylbenzenesulfochloride with sodium sulphite) with 4-methyl-1,2-benzenediol analogous to example 5a) and crystallization from ethyl acetate as yellowish crystals with m.p. 193-196° (sintering from 143°).

Example 20.

31.2 g (0.1 mol) 5-(4-chloro-2,5-dimethylphenylsulfonyl)-4-methyl-1,2-benzenediol and 55 g (0.4 mol) potassium carbonate are suspended under inert gas in 150 ml dimethylformamide. At room temperature, 17.3 g (0.11 mol) dichloroacetic acid ethyl ester are added and the mixture is then heated for 10 hours to 80°. For processing, the dimethylformamide is distilled off in a vacuum and the residue is dissolved in water. The solution is acidified with concentrated hydrochloric acid to pH 1-2, and the precipitated, crude acid is extracted several times with ethyl acetate. The combined ethyl acetate solution is evaporated and the residue is dissolved in the heat in the equivalent amount of 2-n caustic soda. On cooling, the sodium salt of 5-(4-chloro-2,5-dimethylphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is separated. After cooling, it is filtered off and recrystallized from isopropanol as in example 19.

Example 21.

Analogous to example 17, 25 g (71.7 mmol) of 4-(2,4-dichloro-5-methylphenylsulfonyl)-5-methyl-1,2-benzenediol are reacted with 17.14 g (78.7 mmol) of dibromoacetic acid in the presence of 49.5 g of potassium carbonate in 250 ml of dimethylformamide. After work-up, salt formation and recrystallization, analogously to example 17, the sodium salt of 5-(2,4-dichloro-5-methylphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained as colorless crystals with m.p. 200° (decomposition).

a) The 4-(2,4-dichloro-5-methylphenylsulfonyl)-5-methyl-1,2-benzenediol used above is obtained by oxidative condensation

from 2,4-dichloro-5-methyl-benzenesulfinic acid (from 2,4-dichloro-5-methyl-benzenesulfochloride by reduction with sodium sulphite) with 4-methyl-1,2-benzenediol analogously to example 5a), m.p. 203.5-206° (dec., from acetonitrile).

Example 22.

Analogous to example 15, 60.0 g of 4-(4-bromophenylsulfonyl)-5-methyl-1,2-benzenediol are reacted in the presence of 120 g of potassium carbonate in 300 ml of dimethylformamide with a solution of 76.2 g of dibromoacetic acid in 100 ml dimethylformamide. After work-up and chromatographic purification analogous to example 15 and crystallization from 1,2-dichloroethane, 5-(4-bromophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is obtained as sand-colored crystals with m.p. 170-172.5°.

a) The 4-(4-bromophenylsulfonyl)-5-methyl-1,2-benzenediol that was used in the above example is obtained by oxidative

condensation of 76.0 g p-bromobenzenesulfinic acid (from p-bromobenzenesulfochloride by reduction with sodium sulfite) with 53.0

g 4-methyl-1,2-benzenediol analogous to example 5a) as colorless crystals with m.p. 190-191.5° (from chloroform).

Example 23.

39.6 g (approx. 0.105 mol) of 4-[(2-tert.butyl-6-benzothiazolyl)-sulfonyl]-5-methyl-1,2-benzenediol and 72.3 g (0.523 mol) of potassium carbonate are stirred under inert gas protection at room temperature in 300 ml dimethylformamide. Half of a solution of 45.6 g (0.209 mol) of dibromoacetic acid in 100 ml of dimethylformamide is added dropwise over the course of 20 minutes. The reaction mixture is then stirred for 21 hours at 100°, and during this time the remainder of the dibromoacetic acid solution is added in small portions. For processing, the dimethylformamide is distilled off in a rotary evaporator under a water jet vacuum. The residue is dissolved in water and adjusted to pH 1-2 with concentrated hydrochloric acid. The precipitated acid is extracted 3 times with ethyl acetate. The combined ethyl acetate solutions are washed once with water, dried over sodium sulphate, filtered and evaporated. The residue is dissolved in 500 ml of ethanol, and the solution is allowed to stand

10 days at room temperature after adding 0.5 ml of concentrated hydrochloric acid. The ethyl ester of 5-methyl-6.[(2-tert.-butyl-6-benzothiazolyl)-sulfonyl]1,3-benzodioxole-2-carboxylic acid precipitates under this as colorless crystals. The crystal suspension is cooled to 0° and the crystals are filtered off. 90 ml are added to the crystals which are still moist from ethanol

2-n caustic soda and the mixture is stirred for 2 hours at room temperature whereby a solution is formed. This is acidified with concentrated hydrochloric acid and the precipitated acid is extracted 3 times with ethyl acetate. The ethyl acetate solutions are washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to dryness. The residue is recrystallized from ethyl acetate, whereby 5-methyl-6-[(2-tert.butyl-6-benzothiazolyl)-sulfonyl] 1,3-benzodioxole-2-carboxylic acid is obtained as colorless crystals, with m.p. 247° (decomposition), after sintering from 203°.

The starting material is produced as follows:

The starting material was prepared as follows:

a) 2-tert.-butyl-6-benzothiazole sulfochloride is obtained by means of the known Meerwein reaction, starting from 6-amino-2-tert.-butyl-benzothiazole. b) By reduction of 2-tert.-butyl-6-benzothiazole sulfochloride, 2-tert.-butyl-benzothiazole-2-sulfinic acid is obtained, which melts

above 150°.

c) 4-methyl-5-[(2-tert.butyl-6-benzothiazolyl)-sulfonylj-1,2-benzenesiol is obtained analogously to example 5a) and subsequent chromatography with a m.p. of 185° (cleavage).

Example 24.

Analogous to example 15, corresponding amounts of 4-chloro-5-phenylsulfonyl-1,2-benzenediol and dibromoacetic acid are reacted in dimethylformamide in the presence of potassium carbonate. After work-up, purification and recrystallization, analogous to example 15, 5-chloro-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid is obtained with m.p. 183-185°.

a) The 4-chloro-5-phenylsulfonyl-1,2-benzenediol used in the above example is obtained by reacting benzenesulfinic acid

with 4-chloro-1,2-benzenesiol analogously to example 5a), m.p. 161-165°.

Example 25.

Analogous to example 15, by reaction of corresponding amounts of 4-chloro-5-(4-chlorophenylsulfony1)-1,2-benzenediol and dibromoacetic acid in dimethylformamide in the presence of potassium carbonate and analogous work-up, purification and recrystallization 5-chloro-6-(4 -chlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid, m.p. 194-196°.

a) The 4-chloro-5-(4-chlorophenylsulfonyl)-1,2-benzenediol used in the above example is obtained by reacting 4-chlorobenzenesulfinic acid and 4-chloro-1,2-benzenediol analogously to example 5a), m.p. 165-176°.

Example 26.

20.1 g of 4-(4-acetylphenylsulfonyl)-5-methyl-1,2-benzenediol and 28.3 g of dibromoacetic acid are reacted in 130 ml of dimethylformamide in the presence of 45 g of potassium carbonate analogously to example 14. After analogous work-up and purification, obtain 5-(4-acetyl-phenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid,

m.p. 107-110°.

The aromatic starting material is prepared as follows:

a) By reducing 4-acetylbenzenesulfonyl chloride with sodium sulphite, 4-acetylbenzenesulfinic acid is obtained. b) By oxidative condensation of 4-acetylbenzenesulfinic acid with 4-methyl-1,2-benzenediol, 4-(4-acetylphenylsulfonyl)-5-methyl-1,2-benzenediol is obtained with m.p. 184-188°.

Example 27.

10.0 g (0.0359 mol) of 4-phenylsulfonyl-5-ethyl-1,2-benzenediol and 31.5 g (0.288 mol) of potassium carbonate are added to 100 ml of dimethylformamide at room temperature under inert gas protection and 9.0 g (0.413 mol) of dibromoacetic acid. The reaction mixture is kept under stirring for 14 hours at an internal temperature of approx. 80°. The dimethylformamide is then distilled off on a rotary evaporator under a water jet vacuum, and the residue is taken up in water. The solution is adjusted to pH 1-2 with concentrated hydrochloric acid, the crude acid is extracted with ethyl acetate, the extract is dried with sodium sulfate, filtered and evaporated to dryness on a rotary evaporator. The residue is dissolved in 100 ml of absolute ethanol, 0.2 ml of concentrated hydrochloric acid is added and the solution is refluxed for 2 hours. It is evaporated to dryness, the residue is taken up in ethyl acetate and washed

in a separatory funnel once with saturated sodium bicarbonate solution and twice with water. The ethyl acetate phase is dried over sodium sulphate, filtered and evaporated. 20 ml of 2-n sodium hydroxide is added to the residue and heated on a hot water bath until a yellowish solution is formed. It is cooled, adjusted to pH 1-2 with concentrated hydrochloric acid, and the purified 5-phenylsulfonyl-6-ethyl-1,3-benzodioxole-2-carboxylic acid is extracted with ethyl acetate. The extract solution is dried over sodium sulfate and filtered. 50 ml of toluene is added and the ethyl acetate is evaporated on a rotary evaporator. The acid precipitates in the form of colorless crystals, m.p. 143-145°. a) The 4-phenylsulfonyl-5-ethyl-1,2-benzenediol used in the above example is obtained by oxidative coupling of benzenesulfinic acid with 4-ethyl-1,2-benzenediol analogously to example la), m.p. 180-182°.

Example 28.

27.5 g (0.097 mol) 4-(2-methyl-phenylsulfonyl)-5-methyl-1,2-benzenediol, 62.1 g (0.45 mol) potassium carbonate and 32.7 g (0.145 mol) dibromoacetic acid ( 97%-ig) is reacted in 300 ml of dimethylformamide under an inert gas atmosphere analogously to example 27. After work-up, purification over the ethyl ester and saponification, completely analogously to example 27, colorless crystals with m.p. 178-180° (on toluene) 5-(2-methylphenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid.

The 4-(2-methylphenylsulfonyl)-5-methyl-1,2-benzenediol used above is prepared as follows: a) 33.2 (0.108 mol) 1,2-dimethoxy-4-(2-methylphenylsulfonyl)-5-methylbenzene and 70 g (0.6 mol) of pyridine hydrochloride are heated in a bath at 200° for 2.5 hours together to a melt. The mixture is poured onto ice and 20 ml of concentrated hydrochloric acid is added and it is then extracted with ethyl acetate. The extract solution is washed twice with water, dried with sodium sulphate, filtered and evaporated on a rotary evaporator. When a volume of approx. 100 ml, the product begins to crystallize. It is cooled for half an hour in an ice bath, filtered off and the obtained beige crystals of 4-(2-methylphenylsulfonyl)-5-methyl-1,2-benzenediol are dried, m.p. 221-223°.

The starting material used in example 28a) is obtained in the following way: b) 50 g of phosphorus pentoxide is poured over 400 ml of methanesulfonic acid and stirred at 60° until a clear solution has formed.

30.4 g (0.2 mol) of 1,2-dimethoxy-4-methylbenzene are then added

and 43 g (0.2 mol) of 2-methylbenzenesulfonic acid (80%) and the internal temperature is increased for 30 minutes to 80°. The mixture is poured into 4 liters of ice water and extracted with ethyl acetate. The extract solution is washed twice with water, dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The remaining oil crystallizes stretched. It is extracted with diethyl ether and filtered off. Colorless crystals of 1,2-dimethoxy-4-(2-methylphenylsulfonyl)-5-methylbenzene are thus obtained, m.p. 126-128°.

Example 29.

24.5 g (0.088 mol) 4-(3-methylphenylsulfonyl)-1,2-benzenediol, 60.7 g (0.44 mol) potassium carbonate and 29.6 g (0.132 mol) dibromoacetic acid (97%) are reacted in 300 ml of dimethylformamide analogously to example 27. After work-up, purification over the ethyl ester and saponification analogously to example 27, colorless crystals of 5-(3-methyl-phenylsulfonyl)-6-methyl-1,3-benzenedioxole are obtained from toluene/ethyl acetate 2-carboxylic acid,

m.p. 155-157°. a) The 4-(3-methylphenylsulfonyl)-1,2-benzenediol used above is prepared analogously to example 28a) by ether cleavage of 1,2-dimethoxy-4-(3-methylphenylsulfonyl)-5-methyl-benzene using pyridine -hydrochloride. Temp. 172-174°,

(from toluene/ethyl acetate).

b) The above 1,2-dimethoxy-4-(3-methylphenylsulfonyl)-5-methylbenzene is obtained by reacting 3-methylbenzenesulfonic acid with 1,2-dimethoxy-4-methylbenzene analogously to example 28b), m.p. 135-140° (from ether).

Example 30.

13.1 g (0.0438 mol) 4-(3-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol, 30.0 g (0.217 mol) potassium carbonate and 14.7 g (0.065 mol) dibromoacetic acid (97% -ig) is stirred in 150 ml of dimethylformamide for 5 hours under an inert gas atmosphere at an internal temperature of 80°. After working up, purification over the ethyl ester and saponification analogously to example 27, colorless crystals of 5-(3-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid are obtained, m.p. 172-174°, (from toluene/ethyl acetate). a) The 4-(3-chlorophenylsulfonyl)-5-methyl-1,2-benzenediol used above is obtained analogously to example 28a) by ether cleavage from 1,2-dimethoxy-4-(3-chlorophenylsulfonyl)-5-methyl-benzene , m.p. 185-187°, (from toluene/ethyl acetate). b) The 1,2-dimethoxy-4-(3-chlorophenylsulfonyl)-5-methylbenzene used in example 30 a) is obtained analogously to example 28b)

by condensation of 3-chlorobenzenesulfonic acid with 1,2-dimethoxy-4-methylbenzene in phosphorus pentoxide/methanesulfonic acid by heating for 1 hour to 80°, m.p. 151-152° (from toluene).

Example 31.

9.2 g (0.029 mol) 4-chloro-5-(3-chlorophenylsulfonyl)-1,2-benzenediol, 18.0 g (0.13 mol) potassium carbonate and 9.5 g (0.042 mol) dibromoacetic acid ( 97% strength) is reacted in 70 ml of dimethylformamide analogously to example 27. After work-up and esterification analogously to example 27, the crude ester is chromatographed

with the solvent mixture hexane/ethyl acetate (9:1) over 200 g of silica gel, the uniform fractions are combined, evaporated and then saponified with 2-n sodium hydroxide. After liberation and isolation of 5-chloro-6-(3-chlorophenylsulfonyl)-1,3-benzerioxole-2-carboxylic acid, this is recrystallized from toluene/ethyl acetate, m.p. 182-184°. 4,5-dichloro-6-(3-chlorophenylsulfonyl)-1,3-benzenedioxole-2-carboxylic acid, 5-bromo-6-(3-chlorophenylsulfonyl)-1,3-benzenedioxole-2 -carboxylic acid, m.p. 189-192, and 5-chloro-6-(3-methyl-phenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid.

The 4-chloro-5-(3-chlorophenylsulfonyl)-1,2-benzenediol used above can be prepared in the following ways: a) By oxidative coupling of 3-chlorobenzenesulfinic acid with 4-chloro-1,2-benzenediol analogously to example 3a) , is obtained after crystallization from toluene/ethyl acetate 4-chloro-5-(3-chlorophenylsulfonyl)-1,2-benzenediol with m.p. 192-194°. b) By ether cleavage of 1,2-dimethoxy-4-chloro-5-(3-chlorophenyl-sulfonyl)-benzene using pyridine hydrochloride analogous to example 28a) 4-chloro-5-(3-chlorophenyl) is also obtained -sulfonyl)-1,2-benzenediol. c) The 1,2-dimethoxy-4-chloro-5-(3-chlorophenylsulfonyl)-benzene used in example 31 b) is obtained by reacting 3-chloro-benzenesulfonic acid with 1,2-dimethoxy-4-chlorobenzene analogous to example 28b), m.p. 154-156°.

Example 32.

19.7 g (0.065 mol) 4-chloro-5-(4-fluorophenylsulfonyl)-1,2-benzenediol, 40.1 g (0.29 mol) potassium carbonate and 23.6 g

(0.108 mol) of dibromoacetic acid (97% strength) is stirred in 160 ml of dimethylformamide for 24 hours under an inert gas atmosphere at 80°. The dimethylformamide is evaporated on a rotary evaporator under water jet vacuum and the residue is taken up in water. pH is set

of 1-2 using concentrated hydrochloric acid, then extract with ethyl acetate. The extract solution is evaporated and the residue is dissolved in 250 ml of absolute ethanol. After adding 0.2

ml of concentrated hydrochloric acid, it is boiled for 2 hours at reflux and then evaporated to dryness. The resinous residue is chromatographed with a solvent mixture of chloroform/hexane/ethyl acetate (1:1:1) over 400 g of silica gel. The uniform fractions are collected and evaporated. The thus obtained ethyl ester of 5-chloro-6-(4-fluorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid is added to 100 ml of 2-n sodium hydroxide and stirred for 1 hour at 80°. The yellow solution thus obtained is added to activated charcoal in heat and filtered. On cooling, the sodium salt of 5-chloro-6-(4-fluorophenylsulfonyl)-1,3-benzenedioxole-2-carboxylic acid crystallizes in fine, colorless leaves, m.p. 216-220°, (decomposition).

a) The 4-chloro-5-(4-fluorophenylsulfonyl)-1,2-benzenediol used above is obtained analogously to example 3a) by oxidative

coupling of 4-chloro-1,2-benzenediol with 4-fluorobenzenesulfinic acid, m.p. 180-182°, (from ethyl acetate/toluene).

Example 33.

18.1 g (0.05 mol) 4-chloro-5-(4-bromophenylsulfonyl)-1,2-benzenediol, 31.0 g (0.244 mol) potassium carbonate and 18.4 g (0.083 mol) dibromoacetic acid (97% -ig) is reacted in 120 ml of dimethylformamide analogously to example 37. After work-up, purification over the ethyl ester and saponification completely analogously to example 27, 5.8 g of 5-chloro-6-(4-bromophenylsulfonyl)-1,3-benzenedioxole-2- carboxylic acid, m.p. 193-196° (from toluene). a) The 4-chloro-5-(4-bromophenylsulfonyl)-1,2-benzenediol used above is obtained by oxidative coupling of 4-bromobenzenesulfonic acid with 4-chloro-1,2-benzenediol analogously to example 3a), m.p. 183-187°.

Example 34.

12.3 g (0.037 mol) of 5-phenylsulfinyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ester are heated with 20 ml of 2-n sodium hydroxide for half an hour to 60-70°. It cools, set on

pH 1-2 with 2-n hydrochloric acid and extracted with ethyl acetate. The extract solution is washed with water, dried over sodium sulphate, filtered and evaporated. The crystalline residue of 10 g is dissolved hot with 300 ml of ethyl acetate and 50 ml of acetone, activated carbon is added and filtered. The filtrate is evaporated on a rotary evaporator to 100 ml. Thereby precipitated beige-colored crystals of 5-phenylsulfinyl-6-methyl-1,3-benzodioxole-2-carboxylic acid, m.p. from 170° (cleavage).

The ethyl ester used above is prepared as follows: a) 20.8 g (0.1 mol) 5-methyl-1,3-benzodioxo-2-carboxylic acid ester (Example 2b) and 19.2 g (0.125 mol) phenylsulfine -acid chloride is dissolved in 200 ml of 1,2-dichloroethane and cooled with an ice bath to 5°. At 5-10° add while stirring during approx. 15 minutes 13.3 g (0.1 mol) aluminum chloride. It is stirred further for 1 hour in an ice bath and then poured into ice water. The emulsion thus obtained is diluted with 200 ml of dichloroethane and filtered over a layer of a filter aid (e.g. Hyflo). The filtrate is fed to a separatory funnel and the layers are separated. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A light brown, honey-like product, the 5-phenylsulfinyl-6-methyl-1,3-benzo-dioxole-2-carboxylic acid ester, is obtained.

Example 35.

24.4 g (0.065 mol) of 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzo-dioxole-2-carboxylic acid, (obtained according to example 25) are added to 250 ml of absolute ethanol and 0.2 ml of concentrated hydrochloric acid and boiled for half an hour at reflux. 100 ml of ethanol is distilled off and from the remaining solution crystallized

are seen on cooling coarse, colorless crystals of 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester m.p. 122-123°.

Example 36.

Dissolve 3.88 g (0.0069 mol) of 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzo-dioxole-2-carboxylic acid ester in 20 ml of dimethylformamide and add 0.71 g (0.012 mol) at room temperature guani-din. The mixture is stirred at room temperature for 2 hours, and then poured into 200 ml of water. After half an hour of stirring, a crystal suspension forms. This is filtered, washed with water and the raw product is dried in a vacuum drying cabinet at 30-40°. The crude product is then digested with 25 ml of ethyl acetate, whereby partial dissolution and recrystallization occur. It is cooled for half an hour in an ice bath, filtered, dried

and it is obtained, as beige crystals 5-chloro-6-(4-chlorophenyl-sulfonyl)-1,3-benzodioxole-2-carboxylic acid-guanidine, m.p.

from 215° (cleavage).

Example 37.

4.03 mol of 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid ethyl ester is dissolved in 50 ml of dichloromethane at room temperature. With vigorous stirring, 50 ml of a concentrated aqueous ammonia solution is added and stirring is continued for 18 hours. From the emulsion formed initially, a thick crystal suspension was formed. By adding 6-n hydrochloric acid, adjust the pH to 2-3 at room temperature, filter and then wash with water. After drying, colorless crystals of the 5-chloro-6-(4-chlorophenylsulfonyl)-1,2-benzodioxole-2-carboxylic acid amide are obtained, m.p. 240-242°.

Example 38.

34.8 g (0.1 mol) 5-phenylfulsonyl-6-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester (from example 2) is dissolved in 350

ml of absolute dioxane and treated in a pressure autoclave with approx. 20 g of ammonia gas. The reaction mixture is heated in the autoclave for 10 hours at 80°, the pressure is relieved and the solution is evaporated under reduced pressure to dryness. The residue is recrystallized from 120 ml of ethanol and colorless crystals of 5-phenylsulfonyl-6-methyl-1,3-benzodioxole-2-carboxylic acid are obtained, m.p. 138-141°.

Example 39.

Tablets containing 50 mg of 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid can, for example, be prepared with the following composition:

Manufacturing.

The active substance is mixed with milk sugar, part of the wheat starch and with colloidal silicic acid and the mixture is stirred through a sieve. A further part of the wheat starch is pre-pasted with 5 times the amount of water in a water bath and this powder mixture is crushed with this paste, until a slightly plastic mass is obtained. The mass is driven through a sieve with approx. 3 mm mesh size, is dried and the dry granulate is again passed through a sieve. The rest of the wheat starch, talc and magnesium stearate are then added. The resulting mixture is pressed into tablets of 250 mg with a break section.

Example 40.

To prepare 1000 capsules, each containing 50 mg of active substance, 50.0 g of 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid is mixed with 223.0 g of lactose, the mixture is evenly moistened with an aqueous solution of 2.0 g gelatin and it is granulated through a suitable sieve (e.g. sieve III according to Ph. Heiv. V.). The granulate is mixed with 10.0 g of dried corn starch and 15.0 g of talc, and it is filled evenly into 1000 hair gel tin capsules of size 1.

Instead of 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid, in examples 39 and 40 another compound with the general formula I or a pharmaceutically acceptable salt of a compound with the general formula can also be used In which is capable of salt formation, e.g. one of the compounds described in examples 3 to 38 or a pharmaceutically acceptable salt thereof.

Claims (15)

1. Process for the preparation of compounds of the formula I where R 1 means an unsubstituted or substituted aliphatic, aromatic or heteroaromatic residue, alk an alkylene, alkenylene or alkylidene residue with no more than 5 carbon atoms, n^ 0, one or 2, and n 2 0 or one, R^' R3°9 R4 independently of each other means hydrogen, lower alkyl, lower alkoxy or halogen, and A the residue -O-R^ , where R<- stands for hydrogen or an unsubstituted or substituted aliphatic or araliphatic hydrocarbon residue, or means the residue Rg -N <R>7 where Rg and R^ independently of each other stand for hydrogen or lower alkyl, or connected to each other and together with a nearby nitrogen atom stand for optionally lower alkyl-substituted tetra- to hexa-methyleneimino, 4-morpholinyl or 1H-tetrazole -l-yl, salts of compounds of the general formula I, in which A means OR^ and where R, means hydrogen, with a base, as well as acid addition salts of compounds of the general formula I, whose residue R^ exhibits basic character, characterized by that a) a compound of the general formula II where R^ , alk, n^ , n^ , R2 , R3°9 R4 ^are ^e the meanings given above, or a salt thereof is reacted with a compound with the general formula III where Hal means halogen and A has the meaning given above, or a salt of such a compound, in which A means OR^ and where R 5 means hydrogen, orb) in a compound of the general formula IV where A fø means carboxy, lower alkoxycarbonyl or acetyl, and R^ , alk, n-^ , n,,, R2 , R^' R4°9 A ^ar ^e meanings stated above, the residue A° is replaced by hydrogen , or c) for the preparation of a compound of the general formula I, where A has the meaning given above with the exception of a residue OR^ , where R^ means hydrogen, and R^ , alk, n2 , R2 , R^ and R^ have the meanings given above and n^ means one or two, a compound of the general formula V reacted with a compound of the general formula VI, or an anhydride of the same, where A^ has the meaning given above for A with the exception of a residue OR^, where R^ means hydrogen, n^ means one or 2, and Rj, R^ and R^ respectively. R-1, alk and n2 have the meanings indicated above, or d) for the preparation of a compound, where n2 is one or is a defined aliphatic residue and R^ respectively. n2 , alk, n2 , R2 , R^ , R^ and A have the meanings given above, a compound of the general formula VII where Z means a reactive esterified hydroxy group, especially halogen with an atomic number of at least 17, R^ has the above-mentioned meaning and n2 means 1, or if R2 is an aliphatic residue, can also be 0, or a compound of the general formula VIII dd where Z means a monovalent anion or the normal equivalent of a polyvalent anion and R] _ and n^ have the meanings given above, is reacted with a salt of a compound of the general formula IX where n^ , , R^- in R 4 and A have the meanings indicated above, or e) a metal compound which is possibly formed in situ with the general formula Xa or Xb where means a single-valued or M2 a divalent metal ion and R, alk and n2 have the meanings given above, react with a compound of the general formula Xla or Xlb, where Hal means halogen and n^ , R2 , R^ , R^ and A have the meanings indicated above, or f) for the preparation of a compound with the general formula I, where A means OR,- and where Rc means hydrogen and R^ , alk, n^ , n^ , R2 , R3 and R^ have the meanings indicated above, or a salt of this compound, in a compound with the general formula XIII where A^ means a group which can be transferred to a carboxy group and R^ alk, n^ n,,, R^, R^ and R4 have the above meanings, the group A is transferred to the carboxy group in free or salted form, or g) for the preparation of a compound of the general formula I, where A has the meaning given above with the exception of a residue OR,-, where R^ means hydrogen, and R^ , alk, n^ , n^ , R 2 and R ^ has the meanings given above, in a connection with the general formula XIV where A^ means a residue that can be transferred to a residue CO-A^ , where A^ has the above meaning with the exception of a residue ORj -, where R^ means hydrogen, and R^ , alk, n^ , n2 , R2 , R^ and R^ have the above-mentioned meanings, the residue A^ is transferred to the residue -CO-A-^ , and h) if desired, a compound of the general formula I, where means 0 or one, is oxidized to the corresponding compound, where n^ means one or two, or, i) if desired, a compound of the general formula I where n^ means two or one is reduced to the corresponding compound, where n^ means one or zero, and/or if desired, an obtained compound of the general formula I is transferred in another manner known per se to another compound of the general formula I, and/or a compound of the general formula I obtained as a racemate is cleaved in the optical antipodes, and/or an obtained compound of the general formula I, where A means OR^ and wherein R,, means hydrogen, is transferred to a salt with a base or such a compound is liberated from a obtained salt, or an obtained compound of the general formula I of a basic character is transferred to an acid addition salt or such a compound is liberated from a salt obtained. 2. Process according to claim 1, characterized in that compounds of formula I, where R 1 is an aliphatic hydrocarbon residue with a total, i.e. including the substituents, of no more than 12 carbon atoms, which are unsubstituted or substituted with halogen to atom no. 35, lower alkoxy or lower alkylthio, or a mono- or bi-cyclic aryl residue or corresponding heteroaryl residue with at most 2 nitrogen atoms, which is unsubstituted or substituted with lower alkyl, lower cycloalkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, trifluoromethyl, hydroxy, lower alkanoyl, lower alkanoylamino. lower alkoxycarbonylamino and/or lower alkylsulfonylamino, or is an oxygen or sulfur atom and optionally is a nitrogen atom as a heteroring member, alk, n1 , n2 , R2 , R^ and R^ have the meanings given in claim 1, and R^ is hydrogen or an aliphatic or araliphatic hydrocarbon residue with a total of not more than 12 carbon atoms or a residue where Rg and R- have the meanings given in claim 1, which are unsubstituted or substituted with halogen to atom no. 35, hydroxy or lower alkoxy in higher than 1- or the a-position, as well as salts of such compounds, in which R^ is hydrogen, with bases are prepared. 3. Method according to claim 1, characterized in that compounds are produced with for mel I, where R^ is phenyl, thienyl, furyl or ar-benzothiazolyl which is unsubstituted or at most three times substituted with lower alkyl, lower alkoxy, halogen to atom no. 35, lower alkanoyl and/or lower alkanoylamino, alk means alkylene, alkylidene or alkenylene with no more than 3 carbon atoms, R^ means lower alkyl or halogen to atom no. 35, R^ means hydrogen, lower alkyl or halogen to atom No. 35, and R^ means hydrogen and n^, n 2 and A have the meanings given in claim 1, as well as the salts of such compounds, where R^ is hydrogen, with bases. 4. Method according to claim 1, characterized in that compounds of formula I are prepared where R-^ is phenyl or thienyl which is unsubstituted or at most three times substituted with lower alkyl, lower alkoxy, halogen to atom no. 35, lower alkanoyl and/ or lower alkanoylamino, alk means methylene, n^ is two, n~ is zero or 1, R^ is lower alkyl or halogen, R^ is hydrogen or lower alkyl, R^ is hydrogen, and A OR,- and where R, - is hydrogen or lower alkyl, as well as the pharmaceutically acceptable salts of such compounds, where R 1 - is hydrogen, with bases. 5. Process according to claim 1, characterized in that compounds of formula I are prepared, where R 1 is phenyl which is unsubstituted or at most three times substituted with lower alkyl, lower alkoxy and/or halogen to atom no. 35, alk is methylene, n^ is two, n^ is zero or one, R2 is lower alkyl or halogen, R^ is hydrogen or lower alkyl, R4 is hydrogen and A is OR,, and where R,- is hydrogen or lower alkyl, and the phenylsulfonyl residue is bonded in the 5- or 6-position, as well as the pharmaceutically acceptable salts of such compounds, where R 1 is hydrogen, with bases. 6. Process according to claim 1, characterized in that compounds of formula I are prepared where R^ is phenyl which is unsubstituted or at most three times substituted with methyl, methoxy and/or chlorine, alk is methylene, n^ is two, n_ is zero or one, R 2 is methyl or chlorine, R 2 and R 4 are hydrogen and A is OR 2 , and where R 2 is hydrogen or lower alkyl, and the phenylsulfonyl residue is attached in the 5- or 6-position, as well as the pharmaceutically acceptable salts of such compounds, wherein R 5 is hydrogen, with bases. 7. Method according to claim 1, characterized in that 5-methyl-6-phenylsulfonyl-1,3-benzodioxole-2-carboxylic acid and its pharmaceutically acceptable salts with bases are produced. 8. The method according to claim 1, characterized in that 5-chloro-6-(2-chlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid and its pharmaceutically acceptable salts with bases are produced. 9. Method according to claim 1, characterized in that 5-(2-chlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid is prepared and their pharmaceutically acceptable salts with bases. 10. Process according to claim 1, characterized in that 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzodioxo-2-carboxylic acid and its pharmaceutically acceptable salts with bases are produced. 11. The method according to claim 1, characterized in that 5-(3-chlorophenyl-sulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid and its pharmaceutically acceptable salts with bases are produced. 12. Method according to claim 1, characterized in that 5-chloro-6-(3-chlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid and its pharmaceutically acceptable salts with bases are produced. 13. Method according to claim 1, characterized in that 5-chloro-6-(4-chlorophenylsulfonyl)-1,3-benzodioxole-2-carboxylic acid is produced. 14. Pharmaceutical preparations containing a compound produced according to one of claims 1-9. 15. Pharmaceutical preparations containing a compound prepared according to claims 10-12.