GB1560006A

GB1560006A - Benzoyl furan derivatives process for their preparation and therapeutic applications thereof

Info

Publication number: GB1560006A
Application number: GB3470777A
Authority: GB
Original assignee: Laroche Navarron SA
Current assignee: Laroche Navarron SA
Priority date: 1977-08-18
Filing date: 1977-08-18
Publication date: 1980-01-30
Also published as: FR2400515A1; BE869788A; FR2400515B1

Description

(54) IMPROVEMENTS IN OR RELATING TO BENZOYL FURAN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATIONS THEREOF (71) We, LAROCHE NAVARRON S.A., a French Body Corporate of 20, rue Jean Jaurès, 92800 Puteaux, France, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- This invention relates to new benzoyl furan derivatives, to a process for their preparation and to their therapeutic applications.

B.S.M. 2040 M and U.S. patent 3,188,274 have already disclosed furan derivatives having the formula:

in which R, or R2 represents a p-hydroxy benzoyl radical, the other radical R, or R2 being a hydrogen atom, and R3 represents hydrogen or a lower alkyl radical.

Said compounds are described as being useful for the treatment of diseases of the circulatory system.

The present invention relates to compounds having the following general formula (I):

in which: R, is hydrogen or a straight- or branched-chain C,, alkyl radical; the ketone function is at 2- or 3-position of the furan nucleus; R2 is hydrogen or a straight-chain C14 alkyl radical; m is 0, 1, 2 or 3; R3 is hydrogen or a C14 alkyl radical; and when m is 1 R, may be a hydroxy group; R4 and5, when taken individually, represent independently a hydrogen atom, a straight- or branched-chain Cie alkyl radical, or a C37 cycloalkyl radical or, when taken together with the nitrogen atom to which they are attached, form a 5or 6-membered saturated heterocycle, such as piperidino, morpholino or piperazinyl optionally carrying a C14 alkyl radical on the second nitrogen atom, and their pharmaceutically acceptable acid addition salts.

The acid addition salts may typically be those formed with the hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, formic acid, methane sulfonic acid, acetic acid, maleic acid, fumaric acid, lactic acid, succinic acid, tartaric acid and acidic metal salts such as disodium orthophosphate and monopotassium sulfate.

In addition, the free bases may be in hydrated or anhydrous form.

The compounds of the formula (I) may typically be prepared by reacting a phenol of the formula:

in which R, and R2 have the above-defined meanings, with - either a hydrohalide of a compound of the formula

in which X is a halogen atom, R3 is hydrogen or a C14 alkyl radical and R4 and R5 are as defined above, the reaction being effected in the presence of a base to give a compound of the formula I in which R3 is hydrogen or a C,, alkyl radical; - or glycol epichlorohydrin, in the usual manner, to give the epoxide of the formula:

which is then condensed with an amine of the formula:

to give a compound of formula I in which m = 1 and R3 is a hydroxy group.

A number of phenols of the formula (II) are described in B.S.M. 2040 M.

Generally, the phenols of the formula (II) may be obtained by demethylation, with pyridine hydrochloride or hydrobromic acid in acetic medium, of the methyl ester of the formula:

which, in turn, is obtained according to a Friedel-Crafts reaction by condensing a furoic acid chloride of the formula:

with an anisole of the formula:

The compounds of the formula (VII) have already been disclosed in the literature.

The following Examples illustrate the preparation of compounds of the formula (I).

EXAMPLE 1.

5-Methyl- 2- l4(3-tert-butylamino2-hydroxypropoxy)-3 5-dim ethyl-b enzoyl] furan hydrochloride (a) Preparation of 5-methyl-2-(3,5-dimethyl4-hydroxybenzoyl)furan To a solution of 5-methyl-2-furoyl chloride (1 mole) and 2,5-dimethylanisole (1 mole) in dry methylene chloride (800 ml) is aded portionwise finely powdered aluminum chloride (150 g), while cooling. On completion of the addition, the material is maintained at room temperature for 5 hours. After decomposition of the reaction mixture with a dilute aqueous acid solution, the- organic layer is washed with an alkaline solution and with water, after which it is dried and finally distilled in vacuo. B.p./20 mm = 205"C.

Demethylation is effected by refluxing the above distillate in freshly stripped pyridine hydrochloride (300 g) for 20 minutes. After decomposition of the reaction mixture in water, the resulting finely crystalline material is suction filtered and then recrystallized from alcohol. M.p. = 139"C.

(b) Preparation of 5-methyl-2- [(2,3-epoxy-prnpyl-oxy) 3,5-dimethyl- benzoyl]furan hydrochloride A mixture of 0.1 mole of the phenol obtained in (a) and 0.3 mole epichlorohydrin with 0.11 mole caustic soda dissolved in 100 ml ethyl alcohol is stirred 24 hours at room temperature. After evaporation of the solvent in vacuo over a water-bath, the residual oil is extracted with ether, washed with water and then distilled in vacuo. B.p./0.01 mm = 2250C.

(c) Preparation of 5-methyl-2-[4-(3-tert-butylamino-2-hydroxy-propoxy)- 3,5- dimethyl-benzoyl]furan hydrochloride 0.62 Mole of the epoxide obtained in (b) and 3 moles tert-butylamine are refluxed for 1.5 hours within absolute alcohol. After evaporation of the solvent in vacuo over a water-bath, the residual oil is solubilized in a minimum amount of dry chloroform saturated with gaseous hydrogen chloride.

The organic solvent is then evaporated in vacuo over a water-bath, and the resulting oily material is recrystallized from alcohol-benzene (2:1) (80 ml). M.p. = 190"C.

EXAMPLE 2.

Preparation of 5-methyl-2- [4-(diethylamino-ethoxy)-3 ,5-dimethyl-benzoyl]furan hydrochloride A mixture of 0.3 mole phenol (prepared as described in Example 1(a)) and 0.3 mole caustic soda with 0.7 mole freshly stripped diethylaminochloroethane is refluxed for 3 hours in 60 ml alcohol.

The reaction mixture is poured over water; the organic phase is extracted with ether, washed with water, dried and distilled in vacuo. B.p./0.03 mm = 210 C.

The resulting viscous brown oil is then solubilized in the minimum amount of anhydrous ether, and the hydrochloride is formed by bubbling dry hydrogen chloride therethrough. The salt is recrystallized from benzene as fine beige crystals, M.p. = 137"C.

The characteristics of the phenol of Example l(a) together with those of other phenols of the formula (II) prepared in an analogous manner are tabulated in Table I below:

Position of Melting R1 the ketone R2 point CH3 2 CH3 1390C H 3 H 1370C H 3 CH3 1460C CH3 CH3 118 C The characteristics of the compounds obtained in Examples 1 and 2, together with those of other compounds of the formula (I) prepared in an analogous manner are summarized in following Table II.

TABLE II

position of the Ex. Rl ketone R2 R3 m R4 R5 M.P.

~ ~ ~ I CH3 2 CH3 OH I H -C ~ CH3 190 C CH3 2 CH3 2 CH3 H O CH C2H5 1373C 1560C 3 CH3 2 CH3 or I X 156 0C CH3 4 CH3 2 CH3 OH 1 H H 1863C NCH3 5 H 3 H H O C2H, C2H5 134C .. ~ 6 H 3 H OH I H - CH3 2120C - CH, 7 H 3 CH3 H O C2H5 C2H5 1420C 8 CH3 3 CH3 H O C2H5 - C2H, 1530C ~ CH3 9 CHs 3 CH3 OH I H ~ CH3 159oC 10 H 2 H H C2Hs C2H5 125 lo H 2 H --H O C,H, C,H, 2250 11 H 2 CH, 2370 180 12 CH3 2 H H 0 13 CH3 2 H H O C2H, C2H5 1430 I ICH, 14 CH3 2 H OH 1 H -C " CH3 \CH, .1802 - CH3 15 H 2 CH3 H O / CaHs C2H5 134 16 CH3 2 CH3 CH3 CH3 17 CH3 2 CH3 CH3 1 CH3 CH3 .1490 The compounds of the formula (I) and their pharmaceutically acceptable acid addition salts possess useful properties which make them therapeutically valuable for the control of cardiovascular diseases and particularly in the treatment of arrhythmias.

The activity of the compounds of the formula I has been investigated according to a conventional method concerning arrhythmia induced in anesthetized dogs by intravenous injection of ouabaine (-- Cosnier D., Grimal J. et Duchene-Marullaz P., 1971 -. Compariason des effets du disopyramide, de la dihydroquinidine et du procainamide sur deux types d'arythmies ventriculaires.

Therapie, XXVI, 97-107. - Luchesi B.R. et Hardman, 1961 - The influence of dichloroisoproterenol (DCI) and related compound upon ouabain and acetyl strophantidin induced cardia arrhythmias. J. Pharmacol. Exp. Ther., 132, 373.).

In this test, the compounds of the formula I, administered by the intravenous route, at a dosage of 5 mg/kg, have a antiarrhythmic activity which is higher than the activity of quinidine.

The investigation of the toxicity has not revealed a high toxicity of the compounds.

Thus, the present invention includes also within its scope therapeutic compositions arising, as active ingredient, a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, typically in combination with a pharmaceutically acceptable excipient.

Said compositions may . be formulated, typically, as tablets, capsules or injectable ampoules. The compositions may typically contain from 1 wt% to 60 wt G active ingredient, depending on the route of administration.

The compositions formulated for the oral route may be compositions with gastric or enteric disintegration.

The dosages administrable to humans, expressed as active ingredient, may vary from 0.5 mg/kg to 20 mg/kg for the oral route, and from 0.2 mg/kg to 5 mgkg for the'intravenous route.

WHAT WE CLAIM IS: 1. A compound having the following general formula (I):

in which: R, is hydrogen or a straight- or branched-chain C14 alkyl radical; the ketone function is at 2- or 3-position of the furan nucleus; R2 is hydrogen or a straight-chain C14 alkyl radical; m is 0, 1, 2 or 3; R3 is hydrogen, a C14 alkyl radical; and when m is 1 R3 may be a hydroxy group; R4 and R5, when taken individually, represent independently a hydrogen atom, a straight- or branched-chain C16 alkyl radical, or a C37 cycloalkyl radical or, when taken together with the nitrogen atom to which they are attached, form a 5or 6-membered saturated heterocycle, such as piperidino, morpholino or piperazinyl optionally carrying a C14 alkyl radical on the second nitrogen atom, or a pharmaceutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1 in which R3 is selected from hydrogen and a hydroxy group.

3. A process for the preparation of a compound of the formula I as defined in claim 1 in which R3 is hydrogen or a C14 alkyl radical, comprising reacting a phenol of the formula:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. The compounds of the formula (I) and their pharmaceutically acceptable acid addition salts possess useful properties which make them therapeutically valuable for the control of cardiovascular diseases and particularly in the treatment of arrhythmias. The activity of the compounds of the formula I has been investigated according to a conventional method concerning arrhythmia induced in anesthetized dogs by intravenous injection of ouabaine (-- Cosnier D., Grimal J. et Duchene-Marullaz P., 1971 -. Compariason des effets du disopyramide, de la dihydroquinidine et du procainamide sur deux types d'arythmies ventriculaires. Therapie, XXVI, 97-107. - Luchesi B.R. et Hardman, 1961 - The influence of dichloroisoproterenol (DCI) and related compound upon ouabain and acetyl strophantidin induced cardia arrhythmias. J. Pharmacol. Exp. Ther., 132, 373.). In this test, the compounds of the formula I, administered by the intravenous route, at a dosage of 5 mg/kg, have a antiarrhythmic activity which is higher than the activity of quinidine. The investigation of the toxicity has not revealed a high toxicity of the compounds. Thus, the present invention includes also within its scope therapeutic compositions arising, as active ingredient, a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, typically in combination with a pharmaceutically acceptable excipient. Said compositions may . be formulated, typically, as tablets, capsules or injectable ampoules. The compositions may typically contain from 1 wt% to 60 wt G active ingredient, depending on the route of administration. The compositions formulated for the oral route may be compositions with gastric or enteric disintegration. The dosages administrable to humans, expressed as active ingredient, may vary from 0.5 mg/kg to 20 mg/kg for the oral route, and from 0.2 mg/kg to 5 mgkg for the'intravenous route. WHAT WE CLAIM IS:

1. A compound having the following general formula (I):

in which R, and R2 are as defined in claim 1, with a hydrohalide of a compound of the formula

in which X is a halogen atom, R3 is hydrogen or a C14 alkyl radical and R4 and R5 are as defined in claim 1, the reaction being effected in the presence of a base.

4. Process for the preparation of compounds of the formula I as defined in claim I in which R3 is a hydroxy group, comprising reacting a phenol of the formula:

in which R1 and R2 are as defined in claim 1, with epichlorohydrin, to give the epoxide of the formula:

which is then condensed with an amine of the formula:

5. A therapeutic composition comprising a compound of the formula I as claimed in claim 1 or a pharmaceutically acceptable acid addition salt. thereof, together with a pharmaceutically acceptable excipient.

6. A compound as claimed in claim 1, substantially as described in any one of the Examples.