IL30442A

IL30442A - Substituted benzofuran carboxylic acids and process for their production

Info

Publication number: IL30442A
Application number: IL30442A
Authority: IL
Original assignee: Ciba Geigy Ag
Priority date: 1967-07-28
Filing date: 1968-07-26
Publication date: 1972-01-27
Also published as: CH484094A; FI49416C; AT283346B; IE32222B1; AT285595B; FI49415B; FI49416B; YU178368A; SE364270B; YU32705B; IE32222L; PL69796B1; BR6800997D0; AT280272B; CS153467B2; IL30442A0; SU393827A3; CS153468B2; GT197640170A; BG15387A3

Description

pn"7 T'ynni a'TsrrsD New substituted benzofuran carboxylic acids and process for their production CI3A-G-EIGY C. 28701 The present Invention concerns new heterocyclic carboxyllc acids, as well as processes for the production thereof, and medicaments which contain the new compounds.

Heterocyclic carboxylic acids of the general formula Ii wherein Q represents a chlorine ©r bromine atom, R represents an alfcyl group having at most 4 carbon atoms, Y represents a hydrogen atom or a methyl group, and 2^ and Z2 re res n independently of each other a hydrogen atom, an alfcyl or alkoxy group having at most 4 carbon atoms, or a fluorine, chlorine or bromine atom as well as their pharmaceutically acceptable salts with bases, have not been known hitherto.

It has now been found that the new compounds of formula I above have valuable pharmacological properties. They have diuretic and saluretic activity. These properties characterize these compounds as suitable for the treatment of disturbances which are due to insufficient excretion of electrolytes, particularly of sodium chloride. Such disturbances are the cause of oedema and hypertension. These new substances increase considerably the excretion of urine and of sodium and chlorine ions in the dog and in the rabbit.

In the heterocyclic carboxylic acids of general formula I, R, Z-j^ and , as low alkyl groups, represent e.g. the methyl, ethyl, propyl, isopropyl, butyl or the tert. butyl group.

Z^ and ∑2 as low alkoxy groups represent e.g. the methoxy, ethoxy, propoxy, isopropoxy, butoxy or the sec. butoxy group.

Compounds of the general formula I are produced according to the invention by adding halogen to a compound of the general formula II wherein R, Y, Z-^ and ∑ have the meanings given in formula I.

This addition of halogen is carried out e.g. by adding the equimolar amount of chlorine or bromine to the stirred solution of the compound of the general formula II in an appropriate solvent, such as e.g. glacial acetic acid, nitrobenzene or a halogenated hydrocarbon.

The starting material of the general formula II can be produced by reacting, according to Friedel-Crafts , a compound of the general formula III . wherein Y, and have the meanings given in formula I, with a carboxylic acid halide of the general formula IV or with a carboxylic acid anhydride of the general formula V CH9 R - C - C ° (V) wherein R has the meaning given in formula I , and Q represents a halogen atom.

Ill Starting materials of the general formula ~X are describe in the literature, e,g. benzofuran-2-carboxylic acid [cf. R.

Fittig et al., Ann. Chem. 216 , 162 (1883)], 6-methyl-benzo-furan-2-carboxylic acid [cf. K. von Auwers, Ann. Chem. 408 , 255 (1915)] and 4 , 6-dimethyl-benzofuran-2-carboxylic acid (cf. F.M. Dean et al, J. Chem. Soc . 1953 , 1250). These compound can be acylated in the 5-position, e.g. according to Friedel- As halogen, Q is preferably chlorine or bromine. Suitable catalysts for the reaction according to Friedel-Crafts are, e.g.: in particular aluminium chloride and stannic chloride, also zinc chloride, concentrated sulphuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoric acid. The acids mentioned are used, preferably, when a carboxylic acid anhydride is the acylating agent. The reaction is preferably performed in a solvent. As such can be used, e.g. aliphatic or cyclo-aliphatic hydrocarbons such as heptane or cyclohexane, nitrated hydrocarbons such as nitromethane , nitrocyclohexane or nitrobenzene, or halogenated hydrocarbons such as carbon tetrachloride, ethylene chloride, methylene chloride, o-dichlorobenzene and, also, carbon disulphide.

Advantageously the starting materials of the general formula II can also be produced by reacting according to Friedel-Crafts a compound of the general formula III with a carboxylic acid chloride of the general formula VI wherein R has the meaning given in formula I .

The reaction is preferably carried out with aluminium chloride in nitrobenzene and yields a compound of the general formula VII wherein R, Y, and have the meaning given under formula I. These 5-alkanoyl compounds are then reacted with formaldehyde or paraformaldehyde and a secondary organic base to give the corresponding Mannich derivatives of the general formula VIII wherein R, Y, Z-^ and ^ have the meaning given under formula I and Am represents the radical of a secondary organic base.

Suitable organic bases are, e.g. dimethylamine , diethylamine , pyrrolidine, piperidine, morpholine or hexahydro-lH-azepin .

The Mannich derivatives of the general formula VIII can be decomposed in a simple manner by heating it in a solvent containing hydroxyl groups and in the presence of a weak base to yield a compound of the general formula II . Examples of weak bases are sodium acetate or sodium hydrogen carbonate; they are preferably used in water or low fatty acids.

According to a second process, the compounds of the general formula I can be obtained by reacting a compound of the general formula III according to Friedel-Crafts with carboxylic acid chlorides of the general formula IX R - 1 (IX) wherein R has the meaning given in formula I and Q is chlorine or bromine.

The new active substances or pharmaceutically acceptable salts thereof are preferably administered orally. Inorganic or organic bases such as alkali or alkaline earth hydroxides, carbonates or bicarbonates , triethanolamine or choline can be used for the salt formation. The daily dosages vary between 50 and 1,000 mg for adult patients. Suitable dosage units such as dragees (sugar coated tablets), tablets, preferably contain 25-500 mg of an active substance according to the invention, i.e. 20-80% of a compound of the general formula I. They are produced by combining the active substance with, e.g. solid, pulverulent 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 stearate 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. to distinguish between varying dosages of active substance.

Other suitable dosage units are hard gelatine capsules as well as soft closed capsules made from gelatine and a softener, such as glycerine. The hard gelatine capsules preferably contain the active substance as a granulate, e.g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilisers such as sodium metabisulphite or ascorbic acid. In soft gelatine capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilisers can also be added.

The following prescriptions further illustrate the production of tablets and dragees : a) 1,000 g of 5- (2-bromo-2-bromomethyl-butyryl) - 6-methyl-benzofuran-2-carboxylic acid are mixed with 500 g of lactose and 270 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 and the mixture is pressed into 10,000 tablets each weighing 20 mg and containing 100 mg of active substance. If desired, the tablets can be grooved for better adaptation of the dosage. b) A granulate is produced from 1,000 g of 5- (2-bromo-2-bromomethyl-butyryl) 6-methyl-benzofuran-2-carboxylic acid , 345 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, 40 g of potato starch and 5 g of magnesium stearate and the mixture is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup consisting of 533 g 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 dragees obtained each weigh 240 mg and contain 100 mg of active substance.

The following examples further illustrate the production of the new compounds of general formula I and of hitherto undescribed intermediate products, but these are by no means the sole methods of producing same. The temperatures are given in degrees Centigrade.

Example 1 a) A solution of 0.65 g of bromine in 1 ml of chloroform is added dropwise at room temperature to a stirred solution of 1.0 g of 5- (2-methylen butyryl) -6-methyl-benzofuran-2-carboxyl acid. This addition takes 5 minutes and the reaction mixture is left to stand for 20 minutes. The chloroform is then evaporated under reduced pressure and the residue is recrysta-llised from ethyl acetate. Thus 5- (2-bromo-2-bromomethyl-butyryl) -6-methyl-benzofuran-2-carboxylic acid is obtained, which melts with decomposition at 193-195° .

The 5- (2-methyle¾^butyryl) -6-methy1 benzofuran-2-carboxylic acid used as starting material is obtained as follows : b) 5.5 g of 6-methyl-benzofuran-2-carboxylic acid [cf.

K. von Auwers et al . , Ann. Chem. 408255 (1915)] are suspended in 20 ml of nitrobenzene and the suspension is cooled to 0° . 12.0 g of pulverised aluminium chloride are added in portions to this suspension so that the temperature of the reaction mix ture does not rise above 10°. 4.0 g of butyryl chloride are then added all at once. The mixture is then heated to room temperature while stirring. Stirring is continued for 24 hours at this temperature and then it is poured onto 100 g of ice in 20 ml of concentrated hydrochloric acid. The hydrochloric acid suspension is extracted twice with 100 ml of acetic acid ethyl ester each time, the acetic acid ethyl ester solution is washed with 50 ml of water and extracted twice with 50 ml of concentrated sodium hydrogen carbonate solution each time. The pH of the sodium hydrogen carbonate solution ia adjusted to 3 with concentrated hydrochloric acid, the mixture is stirred for 30 minutes and the precipitated crude produet is filtered off, dried in vacuo o at 60 and recrystallised from benzene, -Butyi^l-6Hflethyl-ben-5ofuran-2-carboaylic acid, K.P. 154-156° is obtained. c) 2.3 g of 5-butyryl-6-methyl-benzofuran-2-carboxylic acid are slurried with 0.5 g of paraformaldehyde and 1 g of diaethylamine hydrochloride in 2© ml of dioxan and the suspension is refluxed for 5 hours while stirring. The reaction mixture is cooled, the precipitate formed is filtered off, washed well with ether and recrystallised from ethanol/ether* The pur© 5-(2*dimeth laminomethyl-butyryl)-6-methyl-benzofuran-2-earfeox ie acid hydrochloride melts at 187-188°. This is then heated in the presence of sodium acetate in glacial acetio acid to yield 5-(2-aetaylene-butyryl)-6-methyl-benzo-furan-2-carbox lic acid, M.P. 1 3-1 4°.

Analogously to this example the following compounds have been produced.

Sxample 2 -(2-bromo-2-bromomethyl-butyr 1)-6-ethoxy-bensofuran-2-carboxylic acid, M.P. 74-176° deeomp. from starting from 5-(2-methylei butyryl)-6-ethoxy-beneofuran*2-carboxylic acid, M.P. 142-144°.

Example -(2-bromo-2-bromomethyl-propionyl)-6-methyl-benzofuran 2-carboxylic acid, M.P. 210-211° decomp. from ethyl acetate, starting from 5-(2-methylei^pr©pi©nyl)-6-methyl-benzof^ran-2-carboxylie acid, Μ·Ρ. 85-186°.

Example 4 3 , 6-dimethyl-5- (2-bromo-2-bromomethyl-butyr 1) -benzofuran-2-carboxylic acid, M.P. 193-194° decomp. from benzene, starting from 3 , 6-dime hy1-5- (2-methyle¾^butyryl) -benzofuran-2-carboxylic acid', M.P. 152-154°; Example 5 4-chloro-5- (2-bromo-2-bromomethyl-butyryl) -benzofuran-2-carboxylic acid, M.P. 193-194° decomp. from benzene, starting from 4-chloro-5- (2-methyle -butyryl) -benzofuran-2-carboxylic acid, M.P.156-158° ; Example 6 - (2-bromo-2-bromomethyl-valeroyl) -6-methyl-benzofuran-2-carboxylic acid, M.P. 205-206° decomp. from ethyl acetate, starting from 5- (2-methylen-valeroyl) -6-methyl-benzofuran-2-carboxylic acid, M.P. 160-162°.

Example 7 a) A stream of gaseous chlorine is blown at room temperature into a stirred solution of 1.1 g of 5- (2-methylen¾butyryl) -6-ethyl-benzofuran-2-carboxylic acid in 20 ml of chloroform.

The introduction of chlorine is interrupted when a persisting yellow colouring in and above the solution is attained. The reaction mixture is then stirred for 15 minutes. After this, the chloroform is removed in vacuo and the residue is recrystallized from benzene-hexane . Thus 5- (2-chloro-2-chloro-methyl-butyryl) -6-ethyl-benzofuran-2-carboxylic acid, melting at 158-159° is obtained.

The 5- (2-methylen^-butyryl-6-ethyl-benzofuran-2-carboxylic b) A mixture of 50.0 g of m-ethylphenol , 55.0 g of malic acid and 100 ml of concentrated sulfuric acid are slowly heated to 130° while stirring. Stirring is continued for 20 minutes when this temperature is reached. The reaction mixture is then poured onto 2 kg of crushed ice and extracted with 500 ml of ether. The ether extract is washed with 200 ml of saturated aqueous sodium bicarbonate solution, washed over magnesium sulfate and evaporated. The residue consists of crude 7-ethyl-coumarin^, which is used without purification. c) 30.4 g of this 7-ethyl-coumarin^ are dissolved in 40 ml of chloroform and a solution of 29 g of bromine in 20 ml of chloroform are added dropwise thereto. The reaction mixture is stirred and the temperature is kept at 20-25° by immersing the reaction vessel from time to time into an ice bath. Stirring is continued at room temperature after all the bromine is added. The chloroform is then removed under reduced pressure at 50° and the residue is added in portions to a solution of 80 g potassium hydroxide in 160 ml of ethanol which was preheated to 30° and is kept between 30 and 40° by cooling the reaction vessel .

The reaction mixture is eventually stirred 30 minutes at room temperature and 30 minutes at 80° and then poured into 1 1. of ice water. The aqueous alkaline solution is washed twice with 300 ml of ether and then acidified to pH 2-3 with concentrated hydrochloric acid. A precipitate forms, which is filtered off and recrystallised from ethanol. After drying in vacuo, the 6-ethyl-i»-bu yi!tyt-benzofuran-2-carboxyl-c acid melts at - ° ■ 13- 30442/2 d) The product of step c) is reacted with butyric acid chloride in the presence of aluminium chloride analogously to Example lb) to produce 6-ethyl-5-butyryl-benzofuran-2-carboxylic acid Μ·Ρ. 152-153° (from carbon-tetrachloride) . reacted acid, paraformaldehyde and dimethylamino-hydrochlorlde are to give 3H5Vbe$. analogously to the method described in Example lc -½«¾o-the crude 5-£5-(dimetl¾rlaminomethyl)-6-ethyl-butyryl7-ben2ofuran-2-carboxylic acid hydrochloride, which is converted with sodium acetate in glacial acetic acid into the 5- (2-methylene-butyryl)-6-ethyl-benzofuran-2-carboxylic acid which melts at 121-122° when recrystallised from benzene.

Claims

3044*. Isr. 4-2660 A WHAT WE CLAIM IS:

1. Heterocyclic carboxylic acids having the formula 1 wherein Q represents a chlorine or bromine atom, R represents an alkyl group having at most 4 carbon atoms Y represents a hydrogen atom or methyl group, and and ∑2 represent, independently of each other, a hydrogen atom, an alkyl or alkoxy group having at most 4 carbon atoms, or a fluorine, chlorine or bromine atom as well as their pharmaceutically acceptable salts with bases .

2. 5- (2-Bromo-2-bromomethyl-butyryl) -benzofuran-2- carboxylic acid.

3. 5- (2-Bromo-2-bromomethyl-butyryl) -6-methyl-benzofuran-2 carboxylic acid V'

4. 3, 6-Dimethyl-5- (2-bromo-2-bromomethyl-butyryl) -benzofuran- 2 -carboxylic acid 1

5. 5-(2-Bromo-2-bromomethyl-valeroyl) -6-methyl-benzofuran- 2-carboxylic acid.

6. The pharmaceutically acceptable salts of a compound as claimed in any one of claims 2 to 5 with bases.

7. Process for the production of heterocyclic carboxylic acids having the formula I as defined in claim 1 and their pharmaceutically acceptable salts with bases, which comprises reacting, according to the Friedel- Crafts method, the corresponding compound having the formula III wherein Υ,Ζ^ and ∑2 have the meanings given in claim 1 with a carboxylic acid chloride having the formula IX 30442/2 wherein R and Q have the meanings given in claim 1 and, when required, converting a heterocyclic carboxyl acid having the formula I thus obtained into a pharmaceutically acceptable salt thereof with a base.

8. Process for the production of heterocyclic carboxylic acids having the formula I as defined in claim 1 and their pharmaceutically acceptable salts with bases which comprises chlorinating or brominating the corresponding compound having the formula II wherein R,Y,Z-^ and have the meanings given in claim 1 and, when required, converting a heterocyclic carboxylic acid having the formula I thus obtained into a pharmaceutically acceptable salt thereof with a base.

9. Process as claimed in claim 7 or 8 substantially as hereinbefore described with reference to any one of the accompanying Examples 30442/2

10. Heterocyclic carboxylic acids having the formula I as defined in claim 1 substantially as hereinbefore described with reference to any one of the accompanying Examples.

11. Heterocyclic carboxylic acids having the formula I as defined in claim 1 and their pharmaceutically acceptable salts with bases whenever prepared by a process as claimed in any one of claims 7 to 9.

12. A pharmaceutical composition comprising a heterocycl carboxylic acid as claimed in claim 1 or a 6θ pharmaceutically acceptable salt thereof with a base, together with a pharmaceutically acceptable diluent or carrier therefor.