IL32311A - Benzofuran and thianaphthene carboxylic acids,their preparation and pharmaceutical compositions containing them - Google Patents

Benzofuran and thianaphthene carboxylic acids,their preparation and pharmaceutical compositions containing them

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Publication number
IL32311A
IL32311A IL32311A IL3231169A IL32311A IL 32311 A IL32311 A IL 32311A IL 32311 A IL32311 A IL 32311A IL 3231169 A IL3231169 A IL 3231169A IL 32311 A IL32311 A IL 32311A
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carboxylic acid
dihydro
general formula
pharmaceutically acceptable
benzofuran
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IL32311A
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IL32311A0 (en
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Ciba Geigy Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)

Description

32311 2 7Π1Κ o' *3an mnpn **i»i- ni ^man New benzofuran and thianaphthene oarboxylic acids their preparation and pharmaceutical compositions containing them CI3A-GEIGY A.G. c : 30587 The present invention concerns new heterocyclic carboxylic acids, processes for the production thereof, medicaments containing the new compounds and their use.
Heterocyclic earbosylic acids of the general formula ΙΪ wherein R represents an alkyl group, having at most 6 carbon atoms, X represents oxygen or sulphur, Y^ and represent, independently of each other, a hydrogen atom or the methyl group, and 2, and Z represent, independentl of each other, a hydrogen atom atom or a halogen/up to the atomic number 35, or a methyl, ethyl, methoxy or ethoxy group, as well as thei salts with inorganic or organic bases have not been known hitherto.
It has now been found that the new compounds possess valuable pharmacological properties with a high therapeutic index. It has been shown b standard tests cf. E.0. S enger et al., Schweiz, med. Wochensehr. § , 1126 (1959)./, that they exhibit diuretic and saJsretic activity. These properties characterise the new com- pounds as being suitable for the treatment of disturbances caused by insufficient excretion of electrolytes, especially of sodium chloride. Such disturbances are the cause of oedema and hypertension, e.g. the 5-(2-methyl<£en^butyryl) -6-methyl-2 , 3-dihydro-benzofuran-2-carboxylic acid, in a dosage of 5mg/kilo per os in the care of the dog, increases the excretion of sodium and chloride ions to 0.04-0.06 milli equivalent per minute per kilo body weight and the excretion of urine to 0.25 - 0.4 ml/minute per kilo body weight whereas the excretion of potassium ions is increas ed to only 0.005 - 0.008 milli equivalents/minute per kilo body weight .
In the heterocyclic carboxylic adds of the general formula I, occupies the 4- or 6-position and occupies the 6- or 7-position. R represents the methyl, ethyl ¾ propyl, isopropyl, butyl, sec. butyl, ter. butyl, amyl or the hexyl group and and ∑2 represent as alkyl groups the methyl or ethyl group, and as alkoxy groups the methoxy or the ethoxy group.
Compounds of the general formula I are produced, according to the invention, by decomposing a compound of the general formula II, (ID wherein R, X, Y^, Y^* and have the meaning given under formula I, and Am represents the radical of a secondary organic base, with the splitting off of an amine of the general famula III H - Am (III) wherein Am has the meaning given under formula II and optionally, converting the reaction product with an inorganic or organic base into a salt.
As radical of a secondary organic base, Am can be, e.g. the dimethylamino, diethylamino, 1-pyrrolidinyl, piperidino, hexahydro-lH-azepin-l-yl or the morpholino group.
A compound of the general formula II is preferably decomposed by heating in the presence of a weak base in a solvent containing hydroxyl groups. Suitable weak bases, are, e.g. sodium acetate or sodium hydrogen carbonate; they are preferably used in glacial acetic acid or water.
Suitable starting materials of the general formula II are, e. g. such compounds of which the radicals R, X, Y^, Y^, and conform to the groups listed under formula I. These starting materials can be produced, for example, as follows: Starting with car-boxylic acids of the general formula IV, which are starting materials of th≥ second process according to the invention, these compounds are condensed, according to the Friedel-Crafts reaction, with the aid of aluminium chloride in carbon disulphide with carboxylic acid chlorides of the general formula IVa, R - CH - COCl (IVa) wherein R has the meaning given under formula I, to compounds of the general formula IVb, wherein said c formula converted, by means of formaldehyde or paraformaldehyde and a secondary organic base, into the corresponding Mannich derivative of the general formula II.
Compounds of the general formula I are produced, applying a second process according to the invention, by reacting, according to the Friedel-Craf s reaction, a compound of the general formula IV, wherein X, Y , ζ anc* Z ^ave tl:ie meaning given under formula I, with a carboxylic acid halide of the general formula V, or with a carboxylic acid anhydride of the general formula VI, wherein R has the meaning given under formula I, and Q represents a halogen, and, optionally, converting the reaction product with an inorgan ic or organic base into a salt.
As halogen, Q is preferably chlorine or bromine. Suitable catalysts for the reaction according to Friedel-Crafts are, e.g. especially aluminiu chloride and tin(IV) -chloride, also zinc chloride, concentrated sulphuric acid, phosphoric acid, polyphos acid phoric acid or pyrophosphoric ai-ed . The stated acids are prefer entially used where the acylation agent is a carboxylic acid anhydride. The reaction is preferably performed in a solvent. Suitable solvents are, e.g. aliphatic or cycloaliphatic hydrocar bons such as heptane or cyclohexane, nitrohydrocarbons such as nitromethane, nitrocyclohexane or nitrobenzene, or halogen hydrocarbons such as carbon tetrachloride, ethylene chloride, methylene chloride, o-dichlorobenzene and, moreover, carbon disulphide.
Suitable starting materials of the general formula IV, wherein X represents an oxygen atom, are, e.g. compounds of which the radicals Y^, and conform to the groups listed under formula I. Of these types of compounds, the 2 , 3-dihydrobenzofur f an-2-carboxylic acid [ c^. . Fittig and G. Ebert, Ann. Chem.216 , 116 (1883)] and 2 , 3-dihydro-6-methoxy-benzofuran-2-carboxylic f acid [c . W Will and P. Beck, Chem.Ber. 19,1783 (1886)] are, for example, known. Further compounds of this series, e.g. starting with substituted 2-allyl phenols, can be produced as follows: The substituted 2-allyl phenols are oxidised with peracetic acid to the corresponding 2- (2 , 3-epoxypropyl) -phenols and these are rearranged by heating into the corresponding 2 , 3-dihydro-2~ hydroxymethyl benzofurans, which are oxidised with potassium permanganate to corresponding 2 , 3-dihydrobenzofuran-2-carboxylic acids. For example, the 2 , 3-dihydro-6-chlorobenzofuran-2-carb-oxylic acid is produced by this process, starting the 2-allyl-5-chlorophenyl and by way of the intermediate products 2- (2, 3-epoxypropyl) -5-chlorophenyl and 2 , 3-dihydro-2-hydroxymethyl-6-chloro-benzpfuran. Moreover, compounds of the general formula IV can also be obtained by reducing optionally substituted benzo-furan-2-carboxylic acids, e.g. with sodium amalgam, to obtain corresponding 2 , 3-dihydro-benzofuran-2-carboxylic acids. For example, the 2 , 3-dihydro-6-methylbenzofuran-2-carboxylic acid is produced according to this process, starting with the 6-methylben- f zofuran-2-carboxylic acid [cp. K. von Auwers, Ann. Chem. 408 , 255 (1955).
Starting materials of the general formula II wherein X represents sulphur are produced by an analogous manner by reduction of the corresponding substituent benzo .[ b ] thiophen-2-carboxy- lic acid with sodium amalgam. Some of the benzo[ b ] thiophen-2- carboxylic acids necessary as starting material, are already f known, e.g. the 6-methyl-benzo[ b ] thiophen-2-carboxylic acid (c^.
Y.Matsuki, T.Kanda, Nippon Kagaku Zazshi, 86_, 99 - 102 (B65) and the others can be obtained in an analogous manner, for example by acylating the corresponding substituted benzo[ b ] thiopfen© Also can ¾e obtained GAu-b nhtaing substituted benzo[ b] thiophen-2-carboxylic acids/ by condensation of o-halogen benzene aldehydes to the corresponding substituted 5- (o-halogen-benzyliden^ -rhodanine and boiling these^ with sodium hydroxide and if necessary heating with sodium f , methylate in dimethylene glycol at about 150 - 160° (q M.D.
Castle, R. G. Plevey and Y.C. Tatlow, J. Chem. Soc. 1958, 1225-1277).
Using a third process, according to the invention, compounds of the general formula I are produced by dehalogenating a compound of the general formula VII , wherein R, X, Y^, Y2> and have the meaning defined under formula I , and Q represents a halogen, and, optionally, converting the reaction product with an inor As halogen, Q is preferably chlorine or bromine. Dehalogenat ion can be performed with the aid of metals such as, e.g. copper, magnesium, aluminium, iron, and in particular, by means of zinc $ί dust. Since dehalogenation is, in general, a pronounced exotherm ic reaction, it is advantageously carried out in a solvent. If zinc dust is used as a dehalogenating agent, then suitable solvents are, e.g. lower alkanols, such as methanol or dhanol. Also suitable, apart from metallic dehalogenating agnets, are St non.metallic ones, e.g.jH-kali metal iodides. Examples of these are sodium or potassium iodide, which are likewise preferably used in a solvent. Suitable solvents are, e.g. lower alkanols such as methanol or ethanol, or lower alkanor¾ such as acetone or methylethyl ketone.
As starting materials of the general formula VII, those compounds can, for example, be used, of which the groups Q, R, X, Y^, -^ arid Z2 conform to the groups listed under formula I or VII. Such compounds are obtained, for example, starting with carboxylic acids of the general formula IV, which are starting materials of the second process according to the invention. These carboxylic acids can be acylated in 5-position, e.g. according to the Friedel-Crafts reaction using aluminium chloride in nitrobenzene, with carboxylic acid chlorides of the general formula Vila, CH -Q R - C - COCl (VIIa) Q wherein R has the meaning given under formula I , and Q represents preferably chlorine or bromine.
The new active substances or the pharmaceutically acceptable salts thereof, are preferably administered orally. To form the salts, it is possible to use inorganic or organic bases, such as, e.g. alkali or alkaline-earth metal hydroxides, carbonates or bicarbonates , triethanolamine or chloine. The daily dosages vary between 0.05 - 5 mg/kilo for warm blooded animals. Suitable dosage units such as dragees or tablets, preferably contain 5 - 100 mg of an active substance, according to the invention, i.e. 20 to 907. of a compound of the general formula I. They are produced by combining the active substance, e.g. with solid, pulverent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stear-ate or polyethylene glycols, to form tablets or dragee cores.
The latter are coated, e.g. with concentrated sugar solutions which can also contain/ e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. for distinguishing between varying dosages of active substance. Other suitable dosage units for oral administration are hard gelatine capsules as well as soft, closed capsules made of gelatine and a softener such as glycerin. The hard capsules preferably contain the active substance as a granulate in admixture with lubricants such as talcum or mag- V nesium stearate and, optionally, stabilisers, such as sodium metabisulphite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, whereby stabilisers can likewise be added.
The following prescriptions further illustrate the production of tablets, dragees and capsules: a) 1000 g of 2 , 3-dihydro-5- (2-methylene butyryl)-6-methylbenzofuran-2-carboxylic acid are mixed with 550 g of lactose and 292 g of potato starch. The mixture is moistened with an aqueous solution of 8 g of gelatine and granulated through a sieve. After drying, 60 g of potato starch, 60 g of talcum, 10 g of magnesium stearate and 20 g of colloidal silicon dioxide are mixed in. The mixture is pressed into 10,000 tablets each weighing 200 mg and each containing 100 mg of active substance. Optionally, the tablets can be provided with grooves for a more accurate adjustment of the dosage amoun . b) A granulate is produced from 1000 g of 2 , 3-dihydro-5-(2-methylene butyryl) -6-methylbenzofuran-2-carboxylic acid, 379 g of lactose and the aqueous solution of 6 g of gelatine. After drying, the granulate is mixed with 10 g of colloidal silicon dioxide, 40 g of talcum, 60 g of potato starch and g of magnesium stearate and the mixture pressed into 10,000 dragee cores. These are subsequently coated with a concentrated syrup made from 533.5g.of crystallised saccharose, 20 g of shellac, 75 g of gum arabic, 250 g of talcum, 20 g of colloidal silicon dioxide and 1.5 g of dyestuff, and dried.
- The obtained dragees each weigh 240 mg and each contain 100 mg of active substance. c) To produce 1000 capsules each containing 100 mg of active substance, 100 g of 2, 3-dihydro-5- (2-methylene butyryl) - 6-methylbenzofuran-2-carboxylic acid are mixed with 9.5 g of talcum and 0.5 g of magnesium stearate and the mixture is put through a sieve (e.g. Sieve IV, Ph. Helv. V). Capsules of size 0 are then uniformly filled from the mixture.
As active substance for the preparation tablet, capsules and dragees can be used the same quantities of the following compounds : a) 2 , 3-dihydro-5- (2-methylene-butyryl) -6-chloro-7-methyl-benzofuran-2-carboxylic acid, b) 2, 3-dihydro-5- (2-methylene-butyryl) -6-fluoro-benzofuran-2-carboxylic acid, c) 2, 3-dihydro-5- (2-methylene-butyryl) -6 , 7-dimethyl-benzofuran-2-carboxylic acid, .methacryloyl d) 2 , 3-dihydro- ¾--aefeky¾ea«-p*oplony¾ -6-methyl-benzofuran-2-carboxylic acid.
The following examples further illustrate the production of the new compounds of the general formula I and of intermediate products no described hitherto, but they in no way represent the only embodiment. The temperatures are given in degrees Centigrade.
Example 1 a) 20.0 g of 2,3-dihydro-5-butyryl-6-methyl- benzofuran-2-carboxylic acid are refluxed, while stirring, with 4.1 g of paraformaldehyde and 8.2 g of dimethylamine hydrochloride in 125 iriL of dioxane for 8 hours . The reaction mixture is then concentrated by evaporation in vacuo. To the obtained crude 2, 3-dihydro-5- (2-dimethylaminomethyl butyryl) -6- hydrochloride methylbenzofuran-2-carboxylic acid/are added 21.0 g ί of anhydrous sodiusj—acetate and 200 ml of glacial acetic acid. The obtained mixture is refluxed for 2 hours, while stirring, and is then concentrated by evaporation in vacuo. The residue is stirred into 100 ml of water, the obtained suspension adjusted to pH 2 with concentrated hydrochloric acid and stirred for one hour at 20°. The organic acid is extracted by being shaken up three times with 150 ml of ether.
The ether solution is dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from cyclohexane and xylene/hexane , whereupon the 2, 3-dihydro-5- (2-methylene butyryl) - 6~methylbenzofuran- 2-carboxylic acid melts at 100-102°.
The 2 , 3-dihydro- 5 -butyryl- 6-methylbenzofuran- 2- carboxylic acid, used as starting material, is produced as follows: b) 35.0 g of 6-methylbenzofuran-2-carboxylic acid f (c . K. von Auwers, Ann.Chem. 408, 255 (1915)] are dissolved in 500 ml of a saturated, aqueous sodium hydrogen carbonate solution, and the solution cooled in an ice bath to 5 . 500.0 g of 5% sodium amalgam are added, the reaction mixture is taken out of the ice bath after 2 hours and is allowed to stand for 24 hours at 20°. The solution is then separated from the mercury, filtered and the filtrate adjusted to pH 1 with concentrated hydrochloric acid. The obtained precipitate is filtered off, washed with 300 ml of water and dried. The obtained 2,3-dihydro- 6-methylbenzofuran-2-carboxylic acid melts at 157° j and, after recrystallisation from methanol/water , i melts at 158° . c) 25.2 g of the carboxylic acid obtained according to b) , are slurried with 135 nil of nitrobenzene and, while stirring and cooling, 69.5 g of aluminium chloride are added in portions within 30 minutes, so that the temperature does not exceed 10°. At the same temperature, 22.3 g of butyryl chloride are added dropwise within 30 minutes. The reaction mixture is then further stirred for 5 hours in the ice bath, allowed to stand for 16 hours at room temperature, heated for a further hour to 40° and then poured on to 500.0 g of ice. 50 ml of concentrated hydrochloric acid are added to the obtained suspension. After the aluminium chloride has decomposed, the reaction mixture is extracted three times with, each time, 150 ml of ether. The ether extract is dried over sodium sulphate and concentrated by evaporation.
The residue is slurried in hexane, shaken up, again separated from the hexane and recrystallised from benzene. The obtained 2 ,3-dihydro-5-butyryl-6-methyl benzofuran-2-carboxylic acid melts at 140-141°.
Example 2 a) Starting with the 2 , 3-dihydro-5-butyryl-7-chloro benzofuran-2-carboxylic acid with parafomialdehyde and dimethylamine hydrochloride is obtained, analogously to example 1 a), the crude 2 , 3-dihydro-5- (2-dimethyl- aminomethyl butyryl) -7-chlorobenzofuran-2-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2,3-dihydro-5- (2-methylene butyryl) -7-chlorobenzofuran-2-carboxylic acid, M.P. 144° (from benzene).
The starting material, the 2 , 3-dihydro-5-butyryl- " 7-chlorobenzofuran-2-carboxylic acid, is produced as follows: fr b) 112.0 g of 2-allyl-6-chlorophenol [c$. D.S.
Tarbell and J.W. Wilson, J.Am.Chem.Soc. 64, 1066 (1942)] are added, while stirring and within 30 minutes, to a carefully cooled mixture of 6.5 g of anhydrous sodium acetate and 160.0 g of 40% peracetic acid.
The reaction temperature must not exceed 15-20° during 24 hours. An excess of aqueous, saturated sodium hydrogen carbonate solution is subsequently added The ethereal solution is washed with saturated, aqueous sodium hydrogen carbonate, sodium chloride and iron (II) -sulphate solution, so that the entire excess of peracetic acid is decomposed. (The excess peracetic acid is detected with potassium iodide in water.) The ether solution is then dried over sodium sulphate and 6-chloro-2- (2 , 3-epoxypropyl) -phenol j is heated for minutes to 110° and the reaction mixture distilled under high vacuum. The obtained 2,3-dihydro-2-hydroxyniethyl-7-chlorobenzofuran boils at 101-108°/ 0.02 Torr. c) 15.0 g of 2 , 3-dihydro-2-hydroxymethyl-7- chlorobenzofuran are slurried in 120 ml of 4N sodium hydroxide solution by vigorous shaking, and cooled to 5°. A solution of 72.0 g of potassium permanganate in 1.3 litres of water is added, all at once, to the suspension and the latter, while cooling, is shaken energetically, so that the temperature does not exceed 25°. After the reaction mixture is decolourised, it is filtered off from the manganese dioxide and this is washed with 300 ml of hot water. The cooled solution is adjusted to pH 1 with concentrated hydrochloric acid and then extracted three times with, each time, 500 ml of ether. The ether solution is dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from carbon tetrachloride/ benzene, whereupon the 2 , 3-dihydro-7-chlorobenzofu an~ 2-carboxylic acid melts at 145-146°. d) The carboxylic acid obtained according to c) , is acylated, analogously to example 1 c) , with butyryl chloride to the 2 , 3-dihydro-5-butyryl-7-chlorobenzofuran-2-carboxylic acid, M.P. 161° (from benzene).
Example 3 From 2 , 3-dihyd o- 5-butyrylbenzofuran- 2- carboxylie acid with paraformaldehyde and dimethylamine hydrochloride is obtained, analogously to example 1 a), the crude 2,3-dihydro-5- (2-dimethylaminomethyl butyryl) -benzofuran-2-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2 ,3-dihydro-5- (2-methylene butyryl) -benzofuran-2-carboxylic acid, M.P. 97.5° (from carbon tetrachloride).
The starting material, the 2,3-dihydro-5-butyryl-benzofuran-2-carboxylic acid, M.P. 133° (from acetic acid ethyl ester), is produced, analogously to example 1 c) , from 2 , 3-dihydrobenzofuran-2- f carboxylic acid [c . R. Fittig and G. Ebert, Ann.Chem. 216, 166 (1883) ] and butyryl chloride in the presence of aluminium chloride in nitrobenzene.
Example 4 From 2 , 3-dihydro-5-butyryl- 6-methoxybenzofuran- 2-carboxylic acid with paraformaldehyde and dimethylamine hydrochloride is obtained, analogously to example 1 a), the crude 2 ,3-dihydro-5- (2-dimethyl-aminomethyl butyryl- 6-methoxybenzofuran- 2-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2,3-dihydro- I - (2-methylene butyxyj.) - 6-methoxybenzofuran-2-carboxylic acid, M.P. 124° (from benzene) .
The starting material, the 2 , 3-dihydro-5-butyryl- 6-methoxybenzofuran- 2-carboxylic acid, M.P. 170° (from toluene/acetic acid ethyl ester), is produced, analogously to example 1 c) , from 2 , 3-dihydro- 6- f methoxybenzofuran-2-carboxylic acid [cj . W, Will and P. Beck, Chem.Ber. 19, 1783 (1886) and butyryl chloride in the presence of aluminium chloride in nitrobenzene .
Example 5 From 2 , 3-dihydro-5-butyryl-6-chlorobenzofuran-2- carboxylic acid with paraformaldehyde and dimethylamine- hydrochloride is produced, analogously to example l a), the crude 2 , 3-dihydro-5- (2-dimethylaminomethyl butyryl) - 6-chlorobenzofuran-2-carboxylic acid hydrochloride, which is converted with sodium acetate and glacial acetic acid into the 2 , 3-dihydro-5- (2-methylene butyryl)- 6-chlorobenzofuran-2-carboxylic acid, M.P. 110 (from benzene) . = The starting material, the 2 , 3-dihydro-5-butyryl- 6-chlorobenzofuran-2-carboxylic acid, is produced as follows: Analogously to example 2 b) , the mixture of 2-allyl-3- f chlorophenol and 2-allyl-5-chlorophenol (cjS. W.N.
White, CD. Slater, J.Org.Chem. 26, 3631 (1961)] is converted into the mixture of 2,3-dihydro-2-hydroxymethyl-4-chlorobenzofuran and 2 , 3-dihydro-2-hydroxymethyl- 6-chlorobenzofuran, which distills at 95-115°/0.02 Torr.
The distillate is separated by elution chromatography through silica gel with acetic acid ethyl ester/ benzene (3:100) as the elution agent.
The isolated 2 ,3-dihydro-2-hydroxymethyl-6-chlorobenzofuran is then oxidised, analogously to example 2 c), to the 2 , 3-dihydro- 6-chlorobenzofuran-2-carboxylic acid, M.P. 163° (from benzene), which is acylated, analogously to example 1 c) with butyryl chloride to the 2 ,3-dihydro-5-butyryl-6-chlorobenzofuran- TABLE I - - TABLE II Examp1e 1 .2 g of 2 , 3-dihydro-6-methyl-benzofuran-2-carboxylic acid were mixed with 135 ml of nitrobenzene and 69.5 g of aluminium were chloride As added in portions over a period of 30 minutes with stirring and cooling so that the temperature did not arise above 10° . m At the same temperature 25 g of 2-jethylenebutyryl chloride ere AS, added dropwise to the reaction mixture. The reaction mixture was then stirred for 5 hours in an ice bath and for a further 16 hours at room temperature . The mixture was then poured into 500 g of ice , 50 ml of concentrated hydrochloric acid added and the resulting solution extracted with ether. The ether solution was extracted with sodium hydrogen carbonate . This aqueous solution was acidified to a pH of 1 with hydrochloric acid and then extracted with ether. After evaporating the ether and purifying through a chromatography column 2 , 3-dihydro-5-(2-methylene-butyryl) -6-methyl-benzofuran-2-carboxylic acid was obtained. M.P. 100-104°.
Analogously to Example 19 2 , 3-dihydro-6-methyl-benzofuran-2- methacryloyl carboxylic acid was acylated to produce 2 , 3-dihydro-5- 2-methy1-Άθ£1ϋ-) -6-methyl-benzofuran-2-carboxylic acid, H.P. 100-102°, with nitrobenzene , aluminium chloride and me hylaerylie acid anhydride (c#f. Brotherton, J.Smith, Jr. and J .W . Lynn, J.Org. Chem. 26, 1283- , 1961) Example 21 a) 8.7 g of 2 , 3-dihydro-5- (2-bromo-2-bromomethyl- tyryl) - 6-methyl-benzofuran-2-carboxylic acid were refluxed for 10 minutes with 20 g of potassium iodide in 100 ml of ethanol and cooled. After cooling the mixture was mixed with excess aqueous sodium thio sulphate solution, then acidified with hydrochloric acid and extracted with ether. The ether solution was evaporated under vacuum and the residue was purified by column chromatography. 2 , 3-Dihydro-5- (2-methylene-butyryl) -6-methyl - benzofuran- 2- carboxylic acid, M.P. 100-102° was obtained. analogously to example 19 b) The starting material was prepared/as follows : ,2 g of 2 , 3-dihydro-6-methyl-benzofuran-2-carboxylic acid in 125 /YJj ml of nitrobenzene was acylated to 2 , 3-dihydro-5- (2-bromo-2- CM.P.1570 from cyclobexane/ethvl-ace ate) bromomethyl-butyryl) - 6-methyl-benzofuran-2-carboxylic acid/with 59 g of 2-Bromo-2-bromomethyl-butyryl chloride in the presence of 69.5 g of aluminium chloride.
Example 22 g of 2 , 3-Dihydro-5- (2-bromo-2-bromomethyl-butyryl) -6-methyl-benzofuran-2-carboxylic acid was boiled under reflux for 1 hour with 3 g of zinc dust in 100 ml of ethanol and the resulting solution filtered and concentrated. The 2 ,3-dihydro-5- (2-methylene-butyryl) -6-methyl-benzofuran-2-carboxylic acid obtained, M.P. 100-102°, was purified by column chromatography. Analogously, 2,3-dihydro-5- (2-bromo-2-bromomethyl-valeroyl) -6-methyl-benzofuran-2-carboxylic acid, M.P. 179° (from benzene) was prepared similarly 2 , 3-dihydro-5- (2-bromo-2-bromomethyl-hexanoyl) -6-methyl-benzofuran-2-carboxylic acid, M.P. 146°, from benzene .
Example 23 g of 2 , 3-dihydro-5-butyryl-6-methyl-benzofuran-2-carboxylic acid was boiled under reflux for 8 hours with 4.1 g hydrochloride of paraformaldehyde and 12.5 g of morpholine in 125 ml of dioxane. The reaction mixture was then concentrated in vacuo and to the raw 2 , 3-dihydro-5- (2-morpholino-methyl- hydrochloride butyryl) -6-methyl-benzofuran-2-carboxylic acid/obtained 21 g of water free sodium acetate and 200 ml of glacial acetic acid was added. The resulting mixture was boiled under reflux and with stirring for 2 hours" and evaporated in vacuo. The residue was stirred with 100 ml of water. The resulting suspension was acidified with concentrated hydrochloride to a pH of 2 and stirred for 1 hour at 20°. The organic acid was extracted by shaking 3 times with 150 ml of ether. The ether solution was dried over sodium sulphate and evaporated in vacuo. The residue was recrystallised from cyclohexane and xylene-hexane to give 2,3-dihydro-5- (2-methylene-butyryl) -6-methyl-benzofuran-2-carboxylie acid melting at 100-102°. 27 - - Example 24 g of 2 , 3-dihydro-5-butyryl-6-methyl-benzofuran-2- W6X*6 carboxylic acid wa-e- boiled under reflux with stirring for 8 hours with 4.1 g of paraformaldehyde and 12 g of piperidine-hydrochloride ekie^ky^f-i-ebe in 125 ml of dioxane. The reaction mixture was then concentrated in vacuo and to the raw 2 , 3-dihydro-5- (2-piperidino-methyl-butyryl) -6-methy1-benzofuran-carboxylic hydrochloride acid 21 g of water free sodium acetate and 200 ml of glacial were acetic acid u&e added. The resulting mixture was boiled under reflux with stirring for 2 hours and evaporated in vacuo. The residue was stirred with 100 ml of water. The resulting suspension was acidified with concentrated hydrochloride to a pH of 2 and stirred for 1 hour at 20° . The organic acid was extracted by shaking 3 times with 150 ml of ether. The ether solution was dried over sodium sulphate and evaporated in vacuo. The residue was recrystallised from cyclohexane and xylene-hexane to give 2 , 3-dihydro-5- (2-methylene-but yryl) -6-methyl-benzofuran-2-carboxylic acid melting at 100-102° .
Example 25 a) An amount, of 22.2 g of 2 , 3-dihydro-5-valeryl- 6, 7- dimethylbenzofuran-2-carboxylic acid' is refluxed with 4.1 g of paraformaldehyde and 8.2 g of dimeth lamine hydrochloride i 125 ml of dioxane'for 8 hours while stirring is maintained. The reaction mixture is then concentrated in vacuo. To the obtained crude 2,3-dihydro- 5- (2-dimethylaminomethyl-valeryl) - 6, 7-dimethyl- benzofuran-2-carboxylic acid hydrochloride are added 21 g of anhydrous sodium acetate and 200 ml of glacial acetic acid. The obtained mixture is refluxed, with stirring, for 2 hours, and is then concentrated in vacuo.
The residue is mixed by stirring with 100 ml of water; the obtained suspension is adjusted with concentrated hydrochloric acid to pH 2, and stirred for one hour at °. The organic acid is extracted by the suspension being shaken out three times with 150 ml of ether. The ether solution is dried over sodium sulphate, and concentrated by evaporation. The residue is recrystallised from to give heptane, jh piViffljjifw . the 2, 3-dihydro-5- (2-methylene-valeryl) - ing o 6, 7-dimethylbenzofuran-2-carboxylic acid melt/ at. 82 .
The starting material is produced as follows: b) 45 g of 2 , 3-dimethylphenol and 50 g of malic acid are ground to powder, and well mixed together; to the mixture are added 100 ml of concentrated sulphuric acid, and the whole slowly heated, with stirring, so that the reaction temperature after 30 minutes is 130°. The solution is maintained for a further 30 minutes at this temperature; it is then poured on to 1 kg of ice, and the formed suspension stirred for 30 minutes. The precipitated crystals are filtered off under suction, and recrystallised from ethanol. In this manner is obtained 7 , 8- dimethyl- coumarm, M.P. 128-130 yield 36.3 g. c) An amount of 34.8 g of the coumarin obtained according to b) is dissolved in 60 ml of chloroform. To this solution is added dropwise a solution of 32.5 g of bromine in 20 ml of chloroform, with stirring and occasional cooling with ice, so that the reaction temperature is 20-25°. The mixture is stirred for a further 20 minutes at room temperature, and the chloroform is subsequently completely evaporated off in vacuo.
The residue is added portionwise to a mixture of 90 g of potassium hydroxide with 300 ml of ethanol, the reaction temperature being maintained by ice cooling between 30 and 40°. The mixture is subsequently stirred for 30 minutes at 40° and for 30-minutes at 80°; it is then poured on to 2 litres of ice water. The aqueous alkaline solution is washed twice with 400 ml of ether each time, and the pH-value adjusted to 2-3 with cone, hydrochloric acid. The obtained suspension is stirred for half an hour at room temperature. The precipitated crystals are filtered off under suction, and recrystallised from ethanol. In this manner is obtained 6, 7-dimethylbenzofuran-2-carboxylic acid, M.P. 237-239°. d) An amount of 35 g of the acid obtained according to c) is dissolved in 500 ml of a saturated aqueous sodium hydrogen carbonate solution, and the solution cooled in an ice bath to 5°. To the solution are added 500 g of 5% sodium amalgam, the reaction mixture is removed after 2 hours from the ice bath, and is allowed to stand for 24 hours at 20°. The solution is subsequently separated from from the mercury, filtered, and the filtrate adjusted with concentrated hydrochloric acid to pH = 1. The formed precipitate is filtered off, washed with 300 ml of water, and dried. The obtained 2, 3-dihydro- 6, 7-dimethylbenzofuran-2-carboxylic acid melts at 182° (from ethanol) . e) To 27.2 g of the carboxylic acid obtained accordin to d) are added 135 ml of nitrobenzene; to the mixture are added portionwise in the course of 30 minutes, with stirring and cooling, 69.5 g of aluminium chloride, so that the temperature does not exceed 10°. At the same temperature are added dropwise, within 30 minutes, 25.3 g of valeryl chloride. The reaction mixture is then further stirred for 5 hours in an ice bath; it is afterwards allowed to stand for 16 hours at room temperature, heated for a further hour to 40°, and then poured on to 500 g of ice. To the obtained suspension are added 50 ml of concentrated hydrochloric acid. After the aluminium chloride complex has decomposed, the reaction mixture is extracted three times with 150 ml of ether each time. The ether extract is dried over sodium sulphate, and concentrated by evaporation. The residue is suspended in fi hexane, shaken up, separated from the hexane, and recryatallised from ethyl acetato/hexane, The obtained 2,3->dihydro-5-valeryl-6,7-dimethylbenzo: ran-2-carboxylie acid melts at 128-129°.
EXAMPLE 26 Analogously to Example 19 the following end products •were obtained; a) From 19.2 g of 2,3-dihydro-6,7-dimethyl-bensofxiran-2-carboxylic acid and 23 g of 2-raethyl-aerylic acid anhydride; the 2,3-dihydro-»5«-(2-methyl--acrylyl)-6-iaethyl-benzofuran-2-carboxylic acid, M.P. 118°C (from toluene-heptane). b) From 17.8 g of ,3-dihydro-6-aiethyl-benaofuran-2-carboxylic acid and 15.2 g of 2-methylene-laovaleryi chloride [see V.P. Gol'mov OA £, 269 c (19630)1, the 2,3-dihydro-5-(2-sethylene-3-methyl-butyryl)-6-methyl-benzofuran-2-carboxylie acid M.P. 115-116°C (from ethyl acetate). c) From 19«2 g of 2,3~dihydro-6,7-dimethyl-ben30furan-2-earboxyllc acid and 14.0 g of 2-methylene-butyryl chloride the ,3-dihydro-5~( -methylene-butyryl)-6,7-dimethyl-benaofran-2-carboxylic acid, M.P. 102-104°C (from carbon tetrachloride). d) From 19.7 g of 2,3-dihydro-6-chloro-benzofuran-2~ carboxylic acid and 14.0 g of 2-methylene-butyryl chloride the 2,3-dihydro-5-(2-methylene-butyryl)-6-chloro-benzofuran-2-earboxylic acid, M.P. 11O°0 (from bensese).
EXA PI 127 a) Analogously to Example 19» 2,5-dihydro-5-(2-methylene-butyryl)-6-chloro-7-methyl-benzofuran-2-carboxylic acid, M.P. 152-153° is obtained from 21.0 g of 2,3-dihydro-6-chloro*7- - - methyl-benzofuran-2-carboxylic acid and 17.0 g of raethylene-butyryl chloride.
The starting material is produced as follows: b) 30 g of 2-methyl-3-chloro-phenol (see F. Ullmann and L. Panchaud, A.252» 108 (1906)), 28.6 g of malic acid and 57 ml of concentrated sulfuric acid are heated to 90-100° while stirring, until evolution of carbon dioxide -has ceasef. The reaction mixture is then poured onto ice and the crude product extracted with ether, The ether solution is concentrated by evaporation and the residue reerystallized from ethanol. 7-Chloro-8-methyl-c°umarin, M.P, 143°C is thus obtained. c) 17.2 g of the prepared according to (b) were suspended in 35 ml of chloroform. Tb this suspension is added dropwise a solution of 4.7 ml of bromine in 10 ml of chloroform with continuous stirring at 25°C during 20 minutes. The reaction mixture is stirred or another 30 minutes and evaporated in vacuo. The oily residue obtained is added dropwise under continuous stirring to a solution of 39*5 g' of potassium hydroxide in 120 ml of ethanol so that the temperature rises to 40°C. Stirring is subsequently continued at 25° for 30 minutes and at 80° for further 30 minutes. The suspension is then poured onto ice. The solution thus obtained is brought toja pH of 7 with 4N sulfuric acid, washed with ether and treated th concentrated hydrochloric the solution is acidic to acid until/congo red. The precipitated cr^de carboxylic acid is extracted with ether, the ether solution38 dried over sodium sulfate and concentrated by evaporation. The residue is crystallized from a mixture of cyclohexane-ethylacetate to, yield 6-chloro-7-methyl^ben.5ofuran-2-carboxylic acid, M.P, 225°C. 32311 3* d) Analogously to Example 1(b) 41.5 g of the carboxylic acid obtained according to (c) is reduced with 500 g of sodium amalgam of 5$, to yield 39.6 g of 2,3-dihydro-6-chloro-7-methyl-benzofuran-2-carboxylic acid, M.P. 133°C (from cyclohexane-ethyl acetate).
EXAMPLE 28 a) Analogously to Example 21 (a), 2 ,3-dihydro-5-(2-methylene-3-methyl-butyryl)-6-metnyl-benzofuran-2-carboxylic acid, M.P. 115-116°C (from ethyl acetate) is obtained from .0 g of crude 2,3-dihydro-5-(2-bromo-2-bromomethyl)-3-methyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid and 10 g of potassium iodide in 50 ml of ethanol.
The starting material is produced as follows: b) Analogously to Example 19, 4.0 g of 2 ,3-dihydro-6-methyl-benzofuran-2-carboxylic acid in 20 ml of nitrobenzene were acylated with 10 g of 2-bromo-2-bromomethyl-3-methyl-butyryl chloride in the presence of 14 g of aluminium chloride. The 2,3-dihydro-5-(2-bromo-2-bromo_ae hyl-3-methyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid thus formed was further worked up as the crude product. a) Analogously to Example 21 (a), 2,3~dihydro-5-(2-methylene-butyryl)-6-chloro-7-methyl-benzofuran-2-carboxylic acid, M.P. 152-1 3°C is obtained from 5.2 g of crude 2,3-dihydro-5-(2-bromo-2-bromometh l-butyryD-6-chloro-7-me hyl-benzofuran-2-carboxylic acid and 10 of potassium iodide in 50 ml of ethanol. - m - The starting material is produced as follows: b) Analogously to Example 19, 4.5 g of 2,3-dihydro-6-chloro-7-methyl-ben2ofuran-2«carboxylic acid i 20 ml of nitrobenzene is acylated in the presence of 14 g of aluminium chloride ith 8 of 2-bromo-2-bromomethyl~butyryl chloride. The 2,3-di-hydro-5-(2-bromo^2-broraomethyl-butyryl)-6-cnloro-7~methyl-benso-furan-2-carboxylic acid thus obtained is used as the crude product.
EXAMPLE 30 a) Analogously to Bxample 22, 2t3-dihydro-5-(2-methylene-propionyl)~6r7-diiaethyl-benzofuran-2-Garboxylic acid, M.P. 118°C (from toluene-heptane ) is prepared from 11.0 g of crude 2¾:3-dihydro-5-(2-¾romo-2-bromomethyl-propioiiyl)-6,7-dimethyl-benzo- furan-2-carbosylic acid and 3 g of zinc powder in 100 ml of ethanol.
The starting material is produced as follows; b) Analogously to Example 19» 8·0 g o 2,3-dihydro-6,7-dimethyl«benzofuran-2-carboxylic acid in 40 ml of nitrobenzene is acylated in the presence of 30 g of aluminium chloride with 16 g of 2-bromo~2-bromomethyl-propionyl chloride. The 2,3-dihydro-5-(2-brorao-2-bro-a©methyl-propioayl)-6,7-dimethyl-benso-furan-2-carhoxylic acid is used as the crude produc · EXAMPLE 31 a) Analogously to Example 21 (a), 2,3-dihydro*5-(2-*methylene-butyryl)-6,7-dimethyl-benzofuran-2-.carboxylic acid, M.P. 102-104° (from carbon tetrachloride) is prepared from 5»0 g of crude 2,3-dihydro-5-(2-bromo-2-bromomethyl-butyryl)-6,7~dimethyl-*-benzo-furan-2-carboxylic acid and 10 g of potassium iodide in 50 ml of *r MI - The starting material is produced as follows: b) Analogously to Example 19, 4.9 g of 2,3-dihydro-6,7-dimethyl-benaofuran-2-carboxylic acid in 20 ml of nitrobenzene are acylated in the presence of 15 g of aluminium chloride with 8 g of 2-bromo-2-bromomethyl=butyryl chloride. The 2,3~dihydro-5-(2-brorao-2-bromomethyl-butyryl)-6,7-dimethyl benzofuran-2-carboylie acid is used a3 the crude product.
EXAMPLE 32 a) Analogously to Example 22, 2,3-dihydro-5-(2-methylene-butyryl)-6-chloro-benzofuran-2-carboxylic acid, M.P. 110°C (from benzene) is obtained from 5.3 g of crude ,3-dihydro-5- (2-bromo-2-bromomethyl-butyryl)-β-chloro-benzofuran-2«carbox lie acid and 1.6 g of sine dust in 50 ml of ethanol.
The starting material is produced as follows; b) Analogously to Example 19, 4.0 g of 2,3-dihydro-6-chloro-benzofuran-2-corboxylic acid in 20 ml of nitrobensene L^ are acylated in the presence of 14 g of aluminium chloride with 8 g of 2~bromo-2-bromomethyl-butyryl chloride. The 2,3- ihydro-5-(2-bromo-2-bromomethyl-butyryl)-6-chloro-benzofuran-2-carboxylic acid obtained is worked up as the crude product.

Claims (23)

What we claim is:
1. Heterocyclic carboxylic acids having the general formula I wherein R represents an alkyl group having maximally 6 carbon atoms, X represents an oxygen or sulphur atom, and Y2 represent, independently of each other, a hydrogen atom or the methyl group, Z-j_ and ∑2 represent, independently of each other, a hydrogen atom or a halogen atom up to the atomic number 35, or a methyl, ethyl, methoxy or ethoxy group, and their pharmaceutically acceptable salts with bases .
2. Heterocyclic carboxylic acids having the general formula I as illustrated in claim 1, wherein R has the meaning given in claim 1, X represents an oxygen atom, Y^ and Y2 represents hydrogen atoms, and represents a hydrogen atom, while ∑2 represents the methyl group or a chlorine or fluorine atom in the 6-position or and ∑2 simultaneously represent methyl groups in the 6- and 7 positions respectively, and their pharmaceutically acceptable salts with bases.
3. 2 , 3 ~Dihyd.ro-5- (2-methylene-butyry 1) -6-methyl-benzofuran- 2-carboxylic acid.
4. Pharmaceutically acceptable salts of 2 , 3-dihydro-5- (2-me hylene -butyryl) - 6-methyl-benzofuran-2-carboxylie acid with bases .
5. 2 , 3-Dihydro-5- (2-methylene-butyryl) -b-chloro-benzofuran-2 carboxylic acid.
6. Pharmaceutically acceptable salts of 2 , 3-dihydro-5- (2-methylene-butyryl) -6-chloro-benzofuran-2- carboxylic acid wi h bases .
7. 2 , 3-Dihydro-5- (2-methylene-3-methyl-butyr.yl) -6-methyl-benzofuran-2-carboxylic acid.
8. Pharmaceutically acceptable salts of 2 , 3-dihydro-5- (2-methylene-3 -methyl-butyryl) -6-methyl-benzofuran-2-carboxylic acid with bases .
9. 2 , 3 -Dihydro-5- (2-methylene-butyryl) -6-fluoro-benzofuran-2 carboxylic acid.
10. Pharmaceutically acceptable salts of 2 , 3-dihydro-5- (2-methylene-but yryl) -6-fluoro-benzofuran-2-carboxylic acid with bases . 38 - -
11. 2 , 3-Dihydro-5- (2-methylene-butyryl) -6 , 7-dimethyl-benzo- furan-2-carboxylic acid.
12. Pharmaceutically acceptable salts of 2 ,3-dihydro-5- (2-methylene-butyryl) -6 , 7-dimethyl-benzofuran-2-carboxylic acid with bases .
13. 2 , 3-Dihydro-5- (2-methylene-propionyl)-6-methyl-benzofuran-2-carboxylic acid.
14. Pharmaceutically acceptable salts of 2 , 3-dihydro-5- (2-methylene-propionyl) -6-methyl-benzofur n-2-carboxylic acid with bases .
15. Process for the production of' heterocyclic carboxylic acids having the general formula I as defined in claim 1 and pharmaceutically acceptable salts thereof with bases, which comprises decomposing the corresponding compound having the general formula II wherein Am represents the radical of a secondary organic base, so as to split off an amine having the general formula III H - Am (III) and, when required, converting a heterocyclic carboxylic acid having the general formula I thus obtained into a pharmaceutically acceptable salt thereof with a base.
16. Process as claimed in claim 15 wherein Am represents the dimethylamino , diethylamino , 1-pyrroiidinyl , piperidino, hexahydro-lH-azepin-l-yl or morpholino radical.
17. Process for the production of heterocyclic carboxylic acids having the general formula I as defined in claim 1, and pharmaceutically acceptable salts thereof with bases, which comprises reacting the corresponding compound having the general formula IV with a carboxylic acid halide having the general formula V CH0 0 If 2 I! R - C - C - Q (V) wherein R has the meaning given in claim 1 for formula I and Q represents a halogen atom, or with a carboxylic acid anhydride having the general formula p ~ f VI GB etc. wherein R has the meaning given in claim 1 for formula I? according to the Friedel-Crafts method and, when required, converting a heterocyclic carboxylic acid having the general formula I thus obtained into a pharmaceutically acceptable salt thereof with a base.
18. Process for the production of heterocyclic carboxylic acids having the general formula I as defined in claim 1, and pharmaceutically acceptable salts thereof with bases which comprises dehalogenating the corresponding compound having the general formula VII wherein and Q2 represents halogen atoms and, when required, converting a heterocyclic carboxylic acid having the general formula I thus obtained into a pharmaceutically acceptable salt thereof with a base.
19. Process for the production of heterocyclic carboxylic acids having the general formula I as defined in claim 1, and pharmaceutically acceptable salts thereof with bases, substantially as hereinbefore described with reference to any one of Examples 1 to 5.
20. Process for the production of heterocyclic carboxylic acids having the general formula I as defined in claim 1, and pharmaceutically acceptable salts thereof with bases, substantially as hereinbefore described with reference to any one of Examples 6 to 24.
21. A heterocyclic carboxylic acid having the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with a base, whenever prepared by a process as claimed in any one of claims 1 to 19.
22. A heterocyclic carboxylic acid having the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with a base, whenever prepared by a process as claimed in claim 20.
23. A pharmaceutical composition comprising a heterocyclic carboxylic acid having the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with a base, together with a pharmaceutically acceptable diluent or carrier therefor. 19.5.69 JMS GSG ml
IL32311A 1968-05-30 1969-05-29 Benzofuran and thianaphthene carboxylic acids,their preparation and pharmaceutical compositions containing them IL32311A (en)

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