FR2555179A1 - New 1-Ä2-carbethoxy-4-(furyl- or benzofurylcarboxamido)phenoxyÜ-3-amino-2-propanols: their preparations and their applications in therapeutics - Google Patents

Abstract

New compounds of formula: Diuretic and b1-blocking properties. Treatment of hypertension (high blood pressure).

Description

Novel [2-carbethoxy-furyl- or 4-benzofuryl-4-carboxamido-phenoxy] -3-amino-2-propanols: their preparations and their applications in therapy.

 The present invention relates to novel composts having original pharmacological properties and which consist of derivatives of p-furylcarboxamido (and p-benzofurylcarboxamido) o-carbethoxyphenoxyaminopropanol corresponding to the general formula (I) and their non-toxic acid addition salts. The derivatives in question have an original and surprising pharmacological profile, insofar as they are endowed with diuretic properties with a high degree of activity, associated with interesting anti-blocking properties, good selectivity and low toxicity.

 The present invention also relates to the process for the preparation of said products and their applications in therapeutics. It also relates to new intermediate compounds for the synthesis of said products.

The new compounds according to the invention belong to the group consisting of the products of general formula (I) and their non-toxic acid addition salts.

In formula (I)
the carboxamide function can be located on the vertices 2 or 3 of the furan cycle,
R represents an alkyl radical of 1 to 5 carbon atoms, linear or branched, advantageously the ethyl radical,
R 1 represents an alkyl radical of 1 to 5 carbon atoms, linear or branched advantageously the tert-butyl or isopropyl radicals,

<tb> - <SEP> the
<tb><SEP> R3 <SEP> 4
<tb> represents
or a furan ring in which R 2, R 3 and R 9, which are bound together on the vertices 2, 3 4 or 5 of the furan, represent, simultaneously or separately, a hydrogen atom, or a linear or branched alkyl radical of 1 at 5 carbon atoms, preferably the methyl radical,
or a benzofuran ring in which R2, R3 and R4 attached to the vertices 2, 3, 4, 5, 6 or 7 of the benzofuran represent, simultaneously or separately, a hydrogen atom, a linear or branched alkyl radical of 1 to 5 carbon atoms, a halogen, an alkoxy group, advantageously the BeO group, a thioalkoxy group, preferably the MeS group.

The compounds according to the invention are synthesized by the action of a base e NE 2 (R 1 being defined as above) on a compound of formula (II), without a solvent or in a usual organic solvent such as alcohols, at a temperature of between 200C and 1500C.

In the formula (II) R, R2, R3, R4 and defined as above.

are
In general, the compounds of formula (II) can be obtained by reacting a phenol of formula (III) with an epihalohydrin, especially epichlorohydrin, in the presence of a catalyst or a metalating agent. As a catalyst, mention will be made more particularly of benzyltrimethylammonium chloride (BTMA), at a temperature of 110 to 130 ° C., and as metalating agent, mention will be made of sodium hydroxide, potassium hydroxide, an alcoholate, sodium hydride and the like. In the case of metalations, the reaction may be carried out in an alcoholic solvent, hydroalcoholic, or in DMF (dimethylformamide) at a temperature between 200C and 150 C.

sont définis comme ci-dessus.In formula (III), R, R2, R3, R4 and

are defined as above.

Another mode of preparation of the compounds of general formula (II) consists in treating an olefin of structure (IV) with a peracid, in particular metachloroperbenzoic acid or peracetic acid, or hydrogen peroxide, in a usual organic solvent as chloroform or methylene chloride, at a temperature between 20 and 700 C.

sont définis comme ci-dessus. In the formula (IV) R, R2, R3, R4 and

are defined as above.

In general, the compounds of formula (IV) are prepared by reaction of a phenol of formula (III) with bromide or allyl chloride, in a solvent such as alcohols or
DMF, in the presence of a basic agent, alcoholates, sodium hydride, or sodium or potassium carbonate, at a temperature between 20 and 800 ° C.

The compounds of formula III can be obtained either by esterification of the acid of general formula (v) in a sulfuric medium, or by action of the corresponding furoic acid or benzofuroic acid chloride on a 4-amino-2-carbalkoxyphenol, in the presence of a base such as triethylamine, in a solvent such as acetone or toluene.

ont la même signification que ci-dessus.In the formula (V) R2, R3, R4 and

have the same meaning as above.

 The acid addition salts of the compounds of Formula (I) can be obtained by reacting one of these compounds with a mineral or organic acid according to a customary method. Among the acids that can be used for this purpose, we will mention more particularly hydrochloric acid, hydrobromic acid, acetic acid, succinic acid, malonic acid, maleic acid, fumaric acid, oxalic acid, cinnamic acid, citric acid, ascorbic acid, lactic acid, p-toluenesulfonic acid, methanesulfonic acid, glutamic acid, etc. .

 The new compounds according to the invention possess remarkable pharmacological properties. Indeed, in therapeutics, they can be used for the treatment of hypertension, both as diuretics having a more interesting action intensity and pharmacological profile than thiazides, and as selective and low-toxic anti-blocking agents. a blocking action intensity equivalent to that of propranolol.

 In human therapy, the compounds of formula (i) and their acid addition salts can be administered, in particular, orally. It is then recommended to use capsules or tablets containing from 50 to 300 mg of active ingredient in lasso ciation with physiologically acceptable excipients. The compounds according to the invention have the advantage of making the treatment easier and compared to the combinations (ss-blockers-diuretics) used in the treatment of hypertension, the compounds of formula I have the advantage of pharmacokinetics unique.

Other examples of possible indications include angina, arrhythmia, and migraines.

 Other features of the invention will appear better on reading some non-limiting examples given by way of illustration.

 The exemplified compounds are collected in the following single table.

Example 1
Carbethoxy-2 (2-furyl carboxamido) -4-epoxy-2,3-propane
Formula II carboxamido in 2 R = C2H5
furan ring R2 = R3 = R4 = H
In a flask with stirring is heated 7 g of carbethoxy-2 (furyl-2-carboxamido) -4-phenol in 30 ml of epichlorohydrin. At 110 ° C., 0.7 g of benzyltrimethylammonium chloride is introduced into the reaction mixture, which is then heated for half an hour at 120 ° C. and 100 ml of water are cooled to 500 ° C.

Once the mixture is well stirred, the organic phase is separated by decantation and the aqueous phase extracted with 2 times 50 ml of methylene chloride. The organic phases are combined and dried, and then concentrated in vacuo. The resulting residue crystallized from ethyl ether to give 3 g of 2-carbethoxy-2-furyl carboxamido-2,3-epoxypropane in the form of crystals melting at 950C.

Example 2
Carbethoxy-2 (2-methyl-3-furyl carboxamido) -4-epoxy-2,3-propane
Formula II carboxamido in 3 R = C2H5
furan cycle R =}% in 2 R2 = R3 = H
According to the procedure of Example 1, 25 g of carbethoxy-2 (2-methyl-3-furylcarboxamido) -4-phenol provide 30 g of carbethoxy-2 (2-methyl-3-furylcarboxamido) -4-epoxy-2,3-propane in the form of an oil used as is for the future.

Example 3 [Carbethoxy-2 (2-furyl-carboxamido) -4-phenoxy] -1-terbutylamino-3-propanol
Formula I carboxamido in 2 R = C2H5
furan cycle R4 =

8 g of the epoxide obtained in Example 1 in 50 ml of terbutylamine are heated under reflux for 8 hours in a flask. The reaction solution is then concentrated in vacuo and the pasty residue obtained is taken up in a mixture of ethyl acetate (150 ml), water (150 ml) and acetic acid (5 ml). It is stirred until clear. It is verified that the aqueous solution has an acidic pH otherwise the organic phase is extracted again with a dilute solution of acetic acid (5%). The aqueous phases are neutralized with aqueous ammonia and extracted with methylene chloride (3 × 50 ml). The organic solution thus obtained is dried and the organic solution thus obtained is evaporated off under vacuum. The crude solid obtained is washed with ether to give 5 g of 2-carboxy-2 (2-furyl-carboxamido) -phenoxy-1-terbutylamino-3-propanol. 2 as yellow-white crystals melting at 108 C.
Example 4 [Carbethoxy-2 (2-methyl-3-furylcarboxmaido) -4-phenoxy] -1-terbutylamino-3-propanol
Formula I Carboxamido in 3 R = C2H5
furan cycle R3 = R2 = H
R4 CH3 in 2

 According to the procedure of Example 3 but starting from 19 g of the epoxide prepared in Example 2, 3.5 g of carbethoxy-2 (2-methyl-3-furylcarboxamido) -4-phenoxy] -1 are obtained. terbutylamino-3-propanol in the form of brown crystals crystallized in pentane and melting at 89-90 C.

Example 5 [Carbethoxy-2-benzophenyl-2-benzamido-4-phenoxy] -3-propene
Formula IV R = and Carboxamido in 2

R2 = R3 = R4 = H
3
10 cm 3 of allyl bromide are added dropwise, at 60 ° C., to a mixture of 24.5 g (0.075 mol) of 2-carbethoxy-2- (4-benzobenzylbenzamido) phenol and 12 g of potassium carbonate in 75 ml of dimethylformamide.

 After the end of the addition, the reaction medium is heated for 3 hours at 70 ° C.

 Allowed to cool, diluted with water. The precipitate obtained is drained, washed with water and then taken up in chloroform, and the chloroform phase is washed with dilute sodium hydroxide and then with water, and dried.

After evaporation, 26.1 g of 2- (2-carbethoxy-2- (benzofur-2-benzamido) -phenoxy] propene, melting at 1120 ° C., are obtained.

Example 6 [Carbethoxy-2-benzophido-2-benzamido-4-phenoxy] -1-epoxy-2,3-propane
Formula II
R = C2H5

Carboxamido in 2 R2 = R3 = R4 4H
The solution of 26.1 g (0.07 mol) of [2-carbethoxy-2- (benzofur-2-benzamido) -4-phenoxy] propane in 200 ml of methylene chloride is treated with 21.5 g of metachloroacetic acid. perbenzoic
After refluxing for 5 h, the cooled solution is washed with dilute NaOH, then with water, and dried.

 After evaporation; the residue is taken up in ether, to give 17 g of [2-carbethoxy-2-benzophurylbenzamido-4-phenoxy] -1-epoxy-2,3-propane, melting at 105 ° C.

cycle benzofuranne
9 g de [carbéthoxy-2 (benzofuryl-2 benzamido)-4 phénoxy]-1 époxy-2,3 propane Sont traités par 30 ml de terbutylamine dans 100 il d'éthanol, au reflux pendant 1 h, puis à température ambiante pendant 2 jours.Example 7 [Carbethoxy-2 (2-benzoburyl-benzamido) -4-phenoxy] -1-terbntylamino-3-propanol and hydrochloride
Formula IR = And R2 = R3 = R4 = H

benzofuran cycle
9 g of [carbethoxy-2 (2-benzophuryl-benzamido) -4-phenoxy] -1-epoxy-2,3-propane are treated with 30 ml of terbutylamine in 100 μl of ethanol, at reflux for 1 h, then at room temperature for 2 days.

 The solvents are evaporated and the residue is taken up in an acetic acid-water mixture. The solution obtained is washed with ether; then alkalinized with ammonia and extracted with chloroform.

 After evaporation of the chloroform, the residue obtained is crystallized from an isopropyl ether-acetone mixture. There is thus obtained 6 g of [2-carbethoxy-2- (2-benzobenzylbenzamido) phenoxy] -2-terbutylamino-2-propanol melting at 1120 C.

Preparation of the hydrochloride
6 g of [carbethoxy-2 (2-benzoburyl-benzamido) -4-phenoxy] -1-terbutylamino-3-propanol-2 are dissolved in 100 ml of acetone and the resulting solution is acidified to pH 2 with hydrochloric ether.

 The precipitate obtained is recrystallized from acetonitrile to give 5.4 g of [2-carbethoxy-2- (2-benzobenzylbenzamido) phenoxy] -1-tert-butylamino-3-propanol, in the form of crystals melting at 171 ° C. -173 C.

Example 8 [Carbethoxy-2 (2-benzofuryl-benzamido) -4-phenoxy] -1-isopropylamino-3
Propanol-2 and hydrochloride.

cycle benzofuranne
Suivant le mode opératoire décrit à l'exemple précé- dent mais à partir de 8 g de l'époxyde préparé à l'exemple 6, 30 ml d'isopropylamine et 100 mi d'éthanol, on obtient après cristallisa- tion dans l'éther 5 g de (carbéthoxy-2 (benzofuryl-2 benzamido)-4 phénoxy]-1 isopropylamino-3 propanol-2, fondant à 111 C.Formula IR = And R2 = R3 R3 R4 H

benzofuran cycle
According to the procedure described in the preceding example but starting from 8 g of the epoxide prepared in Example 6, 30 ml of isopropylamine and 100 ml of ethanol are obtained after crystallization in ether 5 g of 2-carbethoxy-2- (2-benzobenzylbenzamido) -phenoxy] -3-isopropylamino-2-propanol, melting at 111 ° C.

Preparation of the hydrochloride
5 g of [carbethoxy-2 (2-benzoburyl-benzamido) -4-phenoxy] -1-isopropylamino-3-propanol are dissolved in 100 ml of acetone, and the solution obtained is acidified with hydrochloric ether. up to pH 2. There is thus obtained 4.5 g of [2-carbethoxy-2- (2-benzobenzylbenzamide) phenoxy] -1-isopropylamino-3-propanol-2 as crystals melting at 192-194 C.

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Claims (6)

 h represents an alkyl radical of 1 to 5 carbon atoms, linear or branched, advantageously the tertiary radicals;  R represents an alkyl radical of 9 to 5 carbon atoms, linear or branched, advantageously the ethyl radical,  the carboxamide function can be located on the vertices 2 or 3 of the furan cycle,  in which

 1. New compounds characterized in that they respond to the formula MeO, a thioalkoxy group, preferably the MaS group, or consist of the non-toxic acid addition salts of these compounds.  or a benzofuran ring in which R2, R3 and R4, attached to the vertices 2, 3, 4, 5, 6 or 7 of benzofuran, represent, simultaneously or separately, a hydrogen atom, a linear or branched alkyl radical; from 1 to 5 carbon atoms, a halogen, an alkoxy group, advantageously the group  or a furan ring in which R2, R3 and R4, directly attached to the vertices 2, 3, 4 of the furan 5, represent, simultaneously or separately, a hydrogen atom, or a linear or branched alkyl radical of 1 a. 5 carbon atoms, preferably the methyl radical, <tb> represents <tb> <SEP> R <tb> <SEP> - <SEP> the <SEP> cycle <SEP> j <SEP> 3 <tb> butyl <SEP> or <SEP> isopropyl, 2. New compounds according to claim 1, characterized in that they are chosen from those in which - R represents an ethyl radical, - R1 represents a tert-butyl or isopropyl radical,

 a halogen atom, or a methoxy or methylthio group, and their non-toxic acid addition salts.  benzofuran, represent simultaneously or separately  R4, fixed on the vertices 2, 3, 4, 5, 6 or 7 of the cycle  a benzofuran ring where the radicals R2, R3 and  hydrogen atom or a methyl radical;  cycle, represent simultaneously or separately, a  directly attached to vertices 2, 3, 4 or 5 of the  a furan ring in which R2, R3 and R4> <tb> represents <tb> <SEP> h <SEP> R4 <tb> <SEP> R3 <SEP> R4 <tb> - <SEP> the 3. New compounds according to claim 1 or 2, characterized in that they are selected from the following: - [carbethoxy-2 (furyl-2-carboxamido) -4-phenoxy] -1-terbutylamino-3  2-propanol Formula I carboxamido in 2 R = C2H5  furan cycle R = R3 = R2 = H

 2-carboxy-2 (2-methyl-3-furylcarboxamido) -4-phenoxy] -1-tertbutyl  3-amino-propanol-2 Formula I carboxamido in 3 R = C2H5  furan cycle R3 = R2 = H  R4 = CH3 in 2

 2- [2-carbethoxy-2-benzofur-2-benzamido] -phenoxy-1-terbutylamino-3  propanol-2 and hydrochloride Formula I R = And

 R1 - NH2 on a compound of formula  R2 3 R3 = R4 H benzofuran ring 4. Process for the preparation of the compounds according to any one of Claims 1 to 3, characterized in that a base is reacted.

Formula I R = And  propanol-2 and hydrochloride R2 = R3 = R4: H benzofuran - carbethoxy-2 (2-benzofuryl-benzamido) -4-phenoxy-1-isopropylamino-3 ring  being as defined in any one of claims 1 to 3, without a solvent or in a conventional organic solvent, such as an alcohol, at 20 - 150 C.

R1, R2 to R4 and 5. New compounds useful as intermediates for the synthesis according to claim 4 of the compounds according to any one of claims 1 to 3, characterized in that they correspond to the formula

 in which R, R2; R3; R4 and

 being as defined in any one of claims 1 to 3. 5. New medicaments characterized in that they contain at least one compound according to any one of claims 1 to 3. 6. New medicaments useful as diuretics and p-blockers, characterized in that they contain at least one compound according to any one of claims i h 3.