WO1981003172A1 - Novel benzo(1,4)dioxins,methods for their preparation and their use in pharmaceutical compositions - Google Patents
Novel benzo(1,4)dioxins,methods for their preparation and their use in pharmaceutical compositions Download PDFInfo
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- WO1981003172A1 WO1981003172A1 PCT/EP1981/000039 EP8100039W WO8103172A1 WO 1981003172 A1 WO1981003172 A1 WO 1981003172A1 EP 8100039 W EP8100039 W EP 8100039W WO 8103172 A1 WO8103172 A1 WO 8103172A1
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- 0 C*C(C(*1)=CCc2c1cccc2)O Chemical compound C*C(C(*1)=CCc2c1cccc2)O 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
Definitions
- the present invention relates to novel benzo (1,4) dioxins substituted at 2 by an amino-alcohol chain, corresponding to the following general formula:
- X represents hydrogen, alkyl (1-4 C), alkoxy (1-4 C) or CF 3 .
- X is a methoxy group, especially in ortho position.
- the invention further relates to the use of these compounds or of their pharmaceutically acceptable salts in a pharmaceutical composition, particularly because of their interestin ⁇ anti hypertensive properties.
- Another subject of the invention consists of the preparation of these compounds eg starting from a 2-haloformyl benzo (1,4) dioxin. This process may be illustrated as follows:
- Halogen preferably chlorine
- the 2-haloformyl benzo (1, 4) dioxin used as starting material may in itself be prepared according to known methods, for example by treating 2-carbethoxy benzo (1,4) dioxan with N — bromosuccinimide, followed by reacting the 2, 3-dibromo-2-carbethoxy benzo (1,4) -dioxane thus obtained with sodium iodide, and transforming the 2-carbethoxy benzo (1,4) dioxin into 2-haloformyl benzo (1, 4) dioxin by the usual means ( hydrolysis, acidification with HCl and treatment with SOCl 2 ).
- the process according to the invention comprises more precisely (including the pre-steps a and b): a) the addition of eg 2-chloroformyl benzo (1,4) dioxin to an ethereal solution of diazomethane, maintaining the reaction mixture between -2C and -10 oC, and then maintaining it at the ambient temperature, for about 14 hours and the addition of a saturated solution of hydrochloric acid in ether until the diazoketone formed disappears; b) the dissolution in anhydrous ether and the reduction of the 2-chloroacetyl benzo (1, 4) dioxin previously obtained; and as the last step: c) the reaction of 4-phenyl piperazine substituted by X as previously defined with the chloro-alcohol previously obtained in a suitable solvent, eg hexametapol, followed by, if desired, the conversipn of the base thus obtained into a pharmaceutically acceptable salt.
- a suitable solvent eg hexametapol
- the bases obtained are treated with pharmaceutically acceptable acids such as HCl, maleic acid, tartaric acid, fumaric acid, citric acid, etc.
- the hydrochloride for example, is obtained by treating the base with a saturated HCl solution in ether.
- the pharmacological activity of the compounds of the invention is shown in vitro by an interference with the adrenergic receptors ß 1 , ß 2 and ⁇ , and confirmed in vivo by the antihypertensive effects observed after administration of said compounds to spontaneously hypertensive anesthetized rats.
- adrenergic receptors the examination of the antagonism of the positive inotropic effect of isoprenaline on the ß 1 , receptors of the left auricle of a guinea-pig stimulated electrically;
- ß 2 adrenergic receptors the investigation of the antagonism of the bronchodilator effects of isoprenaline on the ß 2 receptors of the tracheal muscle of a guinea-pig; - As to ⁇ adrenergic receptors ,: the study of the interference of the compounds of the invention in the contraction of the isolated "vas deferens" of a rat, caused by cumulative doses of noradrenaline.
- - ⁇ receptors potentiation of 180% of the effects of nor-adrenaline at a dose of 10 -4 M / 1.
- the compound of example 1 is (weakly) active on ß 1 receptors at a dose of 10 -4 M / 1 and is inactive on the ß 2 and ⁇ receptors.
- the compound of example 2 shows potent anti-hypertensive effects during a period of over 45 minutes at a dose of 2.5 mg / kg (i.v.).
- the compound of example 1 shows anti-hypertensive properties during 20 minutes at a dose of 20 mg / kg
- the oral LD 50 of the compound of example 2 in mice is found to be 120 mg / kg bodyweight.
- the compounds of the invention can be used as anti-hypertensive compounds.
- the preferred daily dose for use in humans is between 50 and 500 mg.
- Preferred compounds of the invention are those compounds of formula I in which X is a substituent in ortho position and preferably represents an alkoxy (1-4 C) group, such as methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy.
- X is a substituent in ortho position and preferably represents an alkoxy (1-4 C) group, such as methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy.
- the methoxy group is the preferred substituent X.
- reaction mixture was allowed to return to the ambient temperature, and the succinimide precipitate was filtered and washed with carbon tetrachloride, whereupon the solvents were driven off.
- the greenish paste obtained was dissolved in a mixture of 400 ml of water, 300 ml of ether and 600 ml of a (1 N) solution of sodium hyposulphite.
- the acid obtained was dissolved in 300 ml of anhydrous benzene, and then treated with 90 g of thionyl chloride maintaining refluxing for about 14 hours. After evaporation of the solvent, 48 g of 2-chloroformyl benzo (1, 4) dioxin were obtained having a melting point of 106-107 ° C.
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Abstract
Benzo(1,4)dioxins of the formula: (FORMULA) and pharmaceutically acceptable acid addition salts thereof, in which X represents hydrogen, alkyl (1-4C), alkoxy (1-4C) or trifluoromethyl, having antihypertensive properties.
Description
NOVEL BENZO( 1,4) DIOXINS, METHODS FOR THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL COMPOSITIQNS. NOVEL BENZO (1.4) DIOXINS, METHODS FOR THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL COMPOSITIQNS.
The present invention relates to novel benzo(1,4) dioxins substituted at 2 by an amino-alcohol chain, corresponding to the following general formula :The present invention relates to novel benzo (1,4) dioxins substituted at 2 by an amino-alcohol chain, corresponding to the following general formula:
The preferred meaning of X is a methoxy group, especially in ortho position.The preferred meaning of X is a methoxy group, especially in ortho position.
The invention further relates to the use of these compounds or of their pharmaceutically acceptable salts in a pharmaceutical composition, particularly because of their interestinσ anti hypertensive properties.
Another subject of the invention consists of the preparation of these compounds e.g. starting from a 2-haloformyl benzo(1,4)dioxin. This process may be illustrated as follows:The invention further relates to the use of these compounds or of their pharmaceutically acceptable salts in a pharmaceutical composition, particularly because of their interestinσ anti hypertensive properties. Another subject of the invention consists of the preparation of these compounds eg starting from a 2-haloformyl benzo (1,4) dioxin. This process may be illustrated as follows:
The 2-haloformyl benzo ( 1 , 4) dioxin used as starting material may in itself be prepared according to known methods, for example by treating 2-carbethoxy benzo(1,4) dioxan with N—bromosuccinimide, followed by reacting the 2, 3-dibromo-2-carbethoxy benzo(1,4)-dioxan thus obtained with sodium iodide, and transforming the 2-carbethoxy benzo(1,4) dioxin into 2-haloformyl benzo(1, 4) dioxin by the usual means (hydrolysis, acidification with HCl and treatment with SOCl2).The 2-haloformyl benzo (1, 4) dioxin used as starting material may in itself be prepared according to known methods, for example by treating 2-carbethoxy benzo (1,4) dioxan with N — bromosuccinimide, followed by reacting the 2, 3-dibromo-2-carbethoxy benzo (1,4) -dioxane thus obtained with sodium iodide, and transforming the 2-carbethoxy benzo (1,4) dioxin into 2-haloformyl benzo (1, 4) dioxin by the usual means ( hydrolysis, acidification with HCl and treatment with SOCl 2 ).
The process according to the invention comprises more precisely (including the pre-steps a and b ) : a) the addition of e.g. 2-chloroformyl benzo(1,4) dioxin to an ethereal solution of diazomethane, maintaining the reaction mixture between -2C and -10 ºC, and then maintaining it at the ambient
temperature, for about 14 hours and the addition of a saturated solution of hydrochloric acid in ether until the diazoketon formed disappears; b) the dissolution in anhydrous ether and the reduction of the 2-chloroacetyl benzo(1, 4) dioxin previously obtained; and as the last step : c) the reaction of 4-phenyl piperazine substituted by X as previously defined with the chloro- alcohol previously obtained in a suitable solvent, e.g. hexametapol, followed by, if desired, the conversipn of the base thus obtained into a pharmaceutically acceptable salt.The process according to the invention comprises more precisely (including the pre-steps a and b): a) the addition of eg 2-chloroformyl benzo (1,4) dioxin to an ethereal solution of diazomethane, maintaining the reaction mixture between -2C and -10 ºC, and then maintaining it at the ambient temperature, for about 14 hours and the addition of a saturated solution of hydrochloric acid in ether until the diazoketone formed disappears; b) the dissolution in anhydrous ether and the reduction of the 2-chloroacetyl benzo (1, 4) dioxin previously obtained; and as the last step: c) the reaction of 4-phenyl piperazine substituted by X as previously defined with the chloro-alcohol previously obtained in a suitable solvent, eg hexametapol, followed by, if desired, the conversipn of the base thus obtained into a pharmaceutically acceptable salt.
In order to obtain the pharmaceutically acceptable salts of these compounds, the bases obtained are treated with pharmaceutically acceptable acids such as HCl, maleic acid, tartaric acid, fumaric acid, citric acid, etc. The hydrochloride , for example, is obtained by treating the base with a saturated HCl solution in ether. The pharmacological activity of the compounds of the invention is shown in vitro by an interference with the adrenergic receptors ß1, ß2 and α, and confirmed in vivo by the antihypertensive effects observed after administration of said compounds to spontaneously hypertensive anaesthetised rats.In order to obtain the pharmaceutically acceptable salts of these compounds, the bases obtained are treated with pharmaceutically acceptable acids such as HCl, maleic acid, tartaric acid, fumaric acid, citric acid, etc. The hydrochloride, for example, is obtained by treating the base with a saturated HCl solution in ether. The pharmacological activity of the compounds of the invention is shown in vitro by an interference with the adrenergic receptors ß 1 , ß 2 and α, and confirmed in vivo by the antihypertensive effects observed after administration of said compounds to spontaneously hypertensive anesthetized rats.
The following experiments have been carried out in vitro.The following experiments have been carried out in vitro.
- As to ß1, adrenergic receptors: the examination of the antagonism of the positive inotropic effect of isoprenaline on the ß1, receptors of the left auricle of a guinea-pig stimulated electrically;- As to ß 1 , adrenergic receptors: the examination of the antagonism of the positive inotropic effect of isoprenaline on the ß 1 , receptors of the left auricle of a guinea-pig stimulated electrically;
- As to ß2 adrenergic receptors: the investigation of the antagonism of the bronchodilator effects of isoprenaline on the ß2 receptors of the tracheal muscle of a guinea-pig;
- As to α adrenergic receptors,: the study of the interference of the compounds of the invention in the contraction of the isolated "vas deferens" of a rat, caused by cumulative doses of nor- adrenaline.- As to ß 2 adrenergic receptors: the investigation of the antagonism of the bronchodilator effects of isoprenaline on the ß 2 receptors of the tracheal muscle of a guinea-pig; - As to α adrenergic receptors ,: the study of the interference of the compounds of the invention in the contraction of the isolated "vas deferens" of a rat, caused by cumulative doses of noradrenaline.
The results expressed by the usual Parameters of molecular pharmacology in accordance with the criteria used by Van Rossum (Aren. int.Pharmacodyn. 143, 299-330, 1963), are with respect to the compound of example 2;The results expressed by the usual Parameters of molecular pharmacology in accordance with the criteria used by Van Rossum (Aren. Int.Pharmacodyn. 143, 299-330, 1963), are with respect to the compound of example 2;
- ß1 receptors: PA2 - 6,04, PD 2 = 4,84- ß 1 receptors: PA 2 - 6.04, PD 2 = 4.84
- ß2 receptors: inactive,- ß 2 receptors: inactive,
- α receptors: potentiation of 180% of the effects of nor-adrenaline at a dose of 10 -4 M/1. The compound of example 1 is (weakly) active on ß1 receptors at a dose of 10 -4 M/1 and is inactive on the ß2 and α receptors.- α receptors: potentiation of 180% of the effects of nor-adrenaline at a dose of 10 -4 M / 1. The compound of example 1 is (weakly) active on ß 1 receptors at a dose of 10 -4 M / 1 and is inactive on the ß 2 and α receptors.
The in vivo experiments have been carried out with male rats. After anaesthesia with pentobarbital, a catheter was disposed at the level of the Carotid artery to record the arterial pressure and a catheter at the level of a jugular vein to permit injection of the compounds of the invention dissolved in 0.5 ml of PEG 200 (polyethylene glycol). The duration of the injeetion was 1 minute.The in vivo experiments have been carried out with male rats. After anesthesia with pentobarbital, a catheter was disposed at the level of the Carotid artery to record the arterial pressure and a catheter at the level of a jugular vein to permit injection of the compounds of the invention dissolved in 0.5 ml of PEG 200 (polyethylene glycol ). The duration of the injection was 1 minute.
The compound of example 2 shows potent anti-hypertensive effects during a period of over 45 minutes at a dose of 2.5 mg/kg (i.v.).The compound of example 2 shows potent anti-hypertensive effects during a period of over 45 minutes at a dose of 2.5 mg / kg (i.v.).
The compound of example 1 shows anti-hypertensive properties during 20 minutes at a dose of 20 mg/kgThe compound of example 1 shows anti-hypertensive properties during 20 minutes at a dose of 20 mg / kg
(i.v.) .
Particularly, these results show the value of the compound of example 2, which acts in vitro as a very selective antagonist of ß-adrenergic receptors and in vivo possesses a remarkable anti-hypertensive activity.(iv). Particularly, these results show the value of the compound of example 2, which acts in vitro as a very selective antagonist of ß-adrenergic receptors and in vivo possesses a remarkable anti-hypertensive activity.
The oral LD50 of the compound of example 2 in mice is found to be 120 mg/kg bodyweight.The oral LD 50 of the compound of example 2 in mice is found to be 120 mg / kg bodyweight.
Based upon the above mentioned pharmacological results the compounds of the invention can be used as anti-hypertensive compounds.Based upon the above mentioned pharmacological results the compounds of the invention can be used as anti-hypertensive compounds.
Combined with the usual pharmaceutical carriers they may be administered enterally or parenterally at a daily dose of 0.1-50 mg/kg bodyweight. The preferred daily dosis for use in humans is between 50 and 500 mg.Combined with the usual pharmaceutical carriers they may be administered enterally or parenterally at a daily dose of 0.1-50 mg / kg bodyweight. The preferred daily dose for use in humans is between 50 and 500 mg.
Preferred compounds of the invention are those compounds of formula I in which X is a substituent in ortho position and preferably represents an alkoxy (1-4 C) group, such as methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy. The methoxy group is the preferred substituent X.
Preferred compounds of the invention are those compounds of formula I in which X is a substituent in ortho position and preferably represents an alkoxy (1-4 C) group, such as methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy. The methoxy group is the preferred substituent X.
The process is illustrated in more detail in the following examples.The process is illustrated in more detail in the following examples.
Preparation starting product 2-chloroformyl benzo(1,4) dioxinPreparation starting product 2-chloroformyl benzo (1,4) dioxin
A reactor containing 300 ml of anhydrous carbon tetrachloride, 62.4 g (0.3 M) of 2-carbethoxy benzo(1,4) dioxan, 120 g (0.66 M) of N-bromosuccinimide and 2.0 g of benzoyl peroxide was caused to reflux for 6 to 7 hours.A reactor containing 300 ml of anhydrous carbon tetrachloride, 62.4 g (0.3 M) of 2-carbethoxy benzo (1,4) dioxane, 120 g (0.66 M) of N-bromosuccinimide and 2.0 g of benzoyl peroxide was caused to reflux for 6 to 7 hours.
When the reaction was terminated, the reaction mixture was allowed to return to the ambient temperature, and the succinimide precipitate was filtered and washed with carbon tetrachloride, whereupon the solvents were driven off.When the reaction was terminated, the reaction mixture was allowed to return to the ambient temperature, and the succinimide precipitate was filtered and washed with carbon tetrachloride, whereupon the solvents were driven off.
In thxs manner 100 g of 2,3-dibromo 2-carbethoxy benzo(1,4) dioxan were obtained having a melting point of 88 °C.In thxs manner 100 g of 2,3-dibromo 2-carbethoxy benzo (1,4) dioxane were obtained having a melting point of 88 ° C.
The crude product thus obtained was dissolved in 600 ml of anhydrous acetone and treated withThe crude product thus obtained was dissolved in 600 ml of anhydrous acetone and treated with
180 g of anhydrous sodium iodide, while the reaction mixture was maintained at ambient temperature, while stirring, for about one and a half hours.180 g of anhydrous sodium iodide, while the reaction mixture was maintained at ambient temperature, while stirring, for about one and a half hours.
After evaporation of the acetone, the greenish paste obtained was dissolved in a mixture of 400 ml of water, 300 ml of ether and 600 ml of a (1 N) solution of sodium hyposulphite.After evaporation of the acetone, the greenish paste obtained was dissolved in a mixture of 400 ml of water, 300 ml of ether and 600 ml of a (1 N) solution of sodium hyposulphite.
After Separation, purification and drying of the organic phase and after elimination of the ether by evaporation and recrystallization in pentane,After separation, purification and drying of the organic phase and after elimination of the ether by evaporation and recrystallization in pentane,
58 g of 2-carbethoxy benzo(1, 4) dioxin were obtained having a melting point of 39-40 °C.58 g of 2-carbethoxy benzo (1, 4) dioxin were obtained having a melting point of 39-40 ° C.
The ester was then treated at 95 C with an 8% sodium hydroxide solution and subsequently with concentrated hydrochloric acid. After filtration, washing with water and petroleum ether, drying in
vacuo and recrystallization in benzene, 45 g of 2-carboxy benzo(1, 4) dioxin acid were obtained having a melting point of 176 °C.The ester was then treated at 95 C with an 8% sodium hydroxide solution and subsequently with concentrated hydrochloric acid. After filtration, washing with water and petroleum ether, drying in vacuo and recrystallization in benzene, 45 g of 2-carboxy benzo (1, 4) dioxin acid were obtained having a melting point of 176 ° C.
In order to obtain the acid Chloride used as starting material in the present synthesis, the acid obtained was dissolved in 300 ml of anhydrous benzene, and then treated with 90 g of thionyl chloride maintaining refluxing for about 14 hours. After evaporation of the solvent, 48 g of 2-chloroformyl benzo(1, 4) dioxin were obtained having a melting point of 106-107 °C.In order to obtain the acid Chloride used as starting material in the present synthesis, the acid obtained was dissolved in 300 ml of anhydrous benzene, and then treated with 90 g of thionyl chloride maintaining refluxing for about 14 hours. After evaporation of the solvent, 48 g of 2-chloroformyl benzo (1, 4) dioxin were obtained having a melting point of 106-107 ° C.
Example 1 2-methanol α[4-(3-trifluoromethyl phenyl)piperazinyl-1] methyl benzod, 4) dioxin.Example 1 2-methanol α [4- (3-trifluoromethyl phenyl) piperazinyl-1] methyl benzod, 4) dioxin.
In a reactor containing a solution of diazomethane, that has previously been prepared from 28 g of N-nitroso-methylurea, 38 g of potassiumhydroxide, 64 ml of water and 280 ml of ether at a temperature of between -20 and -10 °C, a solution of 16.0 g (0.081 M) of 2-chloroformyl benzo (1,4) dioxin in 350 ml of ether was added drop by drop. When the addition was terminated, stirring at that temperature was allowed to continue for 30 minutes and then for 14 hours at ambient temperature. The diazoketone formed was then displaced by the rapid addition of a saturated HCl solution in ether. The ethereal phase was then washed with a saturated solution of sodium bicarbonate and subsequently with water. After drying on sodium sulphate and evaporation of the ether the product was dissolved in 40 ml of benzene/petroleumether (1/4) and the solution obtained was filtered. After evaporation of the solvents and washing the crystals with 75 ml of petroleum ether-ether (1/2), 13.5 g of 2-chloroacetyl benzo ( 1 , 4) dioxin were obtained having a melting point: 91-92 °C.
In the second stage 10.50 g (0.050 M) of the chloroketone previously obtained were dissolved in 400 ml of anhydrous ether. While the solution was maintained at a temperature lower than 20 ºC, lithiumaluminiumhydride were added to the reaction mixture until the reduction was terminated (end of reaction checked by chromatography on a thin layer). After hydrolysis with a minimum of water, drying on magnesium sulphate and filtration, the ether was evaporated under reduced pressure yielding 10.5 g of 2-methanol α-chloromethyl benzo (1,4) dioxin obtained in the form of a slightly yellow oil.In a reactor containing a solution of diazomethane, that has previously been prepared from 28 g of N-nitroso-methylurea, 38 g of potassium hydroxide, 64 ml of water and 280 ml of ether at a temperature of between -20 and -10 ° C , a solution of 16.0 g (0.081 M) of 2-chloroformyl benzo (1,4) dioxin in 350 ml of ether was added drop by drop. When the addition was terminated, stirring at that temperature was allowed to continue for 30 minutes and then for 14 hours at ambient temperature. The diazoketone formed was then displaced by the rapid addition of a saturated HCl solution in ether. The ethereal phase was then washed with a saturated solution of sodium bicarbonate and subsequently with water. After drying on sodium sulphate and evaporation of the ether the product was dissolved in 40 ml of benzene / petroleumether (1/4) and the solution obtained was filtered. After evaporation of the solvents and washing the crystals with 75 ml of petroleum ether-ether (1/2), 13.5 g of 2-chloroacetyl benzo (1, 4) dioxin were obtained having a melting point: 91-92 ° C. In the second stage 10.50 g (0.050 M) of the chloroketone previously obtained were dissolved in 400 ml of anhydrous ether. While the solution was maintained at a temperature lower than 20 ºC, lithium aluminum hydride were added to the reaction mixture until the reduction was terminated (end of reaction checked by chromatography on a thin layer). After hydrolysis with a minimum of water, drying on magnesium sulphate and filtration, the ether was evaporated under reduced pressure yielding 10.5 g of 2-methanol α-chloromethyl benzo (1,4) dioxin obtained in the form of a slightly yellow oil.
In the thxrd stage, 3.80 g (19 mM) of the chloro-alcohol previously obtained and 10 g (45 mM) of 4(3-trifluoromethylphenyl)-piperazine were dissolved in 50 ml of hexametapol and the solution was maintained while stirring at 85 ºC for 40 hours In this manner 4.2 g of the title product was obtained with melting point: 140 ºC and elemental analysisIn the thxrd stage, 3.80 g (19 mM) of the chloro-alcohol previously obtained and 10 g (45 mM) of 4 (3-trifluoromethylphenyl) -piperazine were dissolved in 50 ml of hexametapol and the solution was maintained while stirring at 85 ºC for 40 hours In this manner 4.2 g of the title product was obtained with melting point: 140 ºC and elemental analysis
C % H % N % found 62.62 5.18 6.85 theoretical 62.13 5.21 6.90C% H% N% found 62.62 5.18 6.85 theoretical 62.13 5.21 6.90
Example 2 2-methanol α[4(2-methoxyphenyl)piperazinyl-1]methyl benzo(1,4)dioxinExample 2 2-methanol α [4 (2-methoxyphenyl) piperazinyl-1] methyl benzo (1,4) dioxin
2-Methanol α-chloromethyl benzo (1 , 4) dioxin was prepared as indicated in Example 1.- 5.25 g (25 mM) of this chloroalcohol and 12.2 g (62.5 mM) of 4(2-methoxyphenyl)piperazine were dissolved in 15 ml of tetrahydrofuran and 30 ml of hexametapol, after which the solution was maintained at 85 ºC for 30 hours while stirring.
In this manner 5 g of the title product was obtained. Melting point 102 ºC; elemental analysis:2-Methanol α-chloromethyl benzo (1, 4) dioxin was prepared as indicated in Example 1.- 5.25 g (25 mM) of this chloroalcohol and 12.2 g (62.5 mM) of 4 (2-methoxyphenyl) piperazines were dissolved in 15 ml of tetrahydrofuran and 30 ml of hexametapol, after which the solution was maintained at 85 ºC for 30 hours while stirring. In this manner 5 g of the title product was obtained. Melting point 102 ° C; elemental analysis:
C % H % N % found 68.01 6.63 7.58 theoretical 68.54 6.57 7.61C% H% N% found 68.01 6.63 7.58 theoretical 68.54 6.57 7.61
In a corresponding manner is prepared: 2-methanol α [4-phenyl piperazinyl-1]methyl benzo (1,4)dioxin.
In a corresponding manner is prepared: 2-methanol α [4-phenyl piperazinyl-1] methyl benzo (1,4) dioxin.
Claims
1. Benzo(1, 4) dioxin derivatives of the formula:1. Benzo (1, 4) dioxin derivatives of the formula:
X represents hydrogen, alkyl (1-4 C) , alkoxy (1-4 C) or trifluoro-methyl.X represents hydrogen, alkyl (1-4 C), alkoxy (1-4 C) or trifluoromethyl.
2. The compound of claim 1, in which X represents a methoxy group in ortho position.2. The compound of claim 1, in which X represents a methoxy group in ortho position.
3. Process for the preparation of a compound of the general formula defined in claim 1, characterised in that a compound of the formula:3. Process for the preparation of a compound of the general formula defined in claim 1, characterized in that a compound of the formula:
4. Use of the compounds according to claim 1 or 2 as antihypertensive agents.4. Use of the compounds according to claim 1 or 2 as antihypertensive agents.
5. Pharmaceutical composition containing a compound according to claim 1 or 2 as the active component, in admixture with one or more of the usual pharmaceutical carriers. 5. Pharmaceutical composition containing a compound according to claim 1 or 2 as the active component, in admixture with one or more of the usual pharmaceutical carriers.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU70767/81A AU7076781A (en) | 1980-05-07 | 1981-05-04 | Novel benzo (1,4) dioxins, methods for their preparation and their use in pharmaceutical compositions |
| DK417481A DK417481A (en) | 1980-05-07 | 1981-09-21 | PRESENT UNKNOWN BENZO (1,4) DIOXINES PROCEDURES FOR THEIR PREPARATION AND USE IN PHARMACEUTICAL AGENTS |
| FI813264A FI813264L (en) | 1980-05-07 | 1981-10-19 | NYA BENSO (1,4) DIOXINER FOERFARANDEN FOER FRAMSTAELLNING AV DEM OCH ANVAENGNING AV DEM I PHARMACEUTICAL COMPOSER |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8010223 | 1980-05-07 | ||
| FR8010223A FR2482101A1 (en) | 1980-05-07 | 1980-05-07 | 2-METHANOL A-AMINOMETHYL BENZO (1,4) DIOXINS, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION |
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| WO1981003172A1 true WO1981003172A1 (en) | 1981-11-12 |
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| PCT/EP1981/000039 WO1981003172A1 (en) | 1980-05-07 | 1981-05-04 | Novel benzo(1,4)dioxins,methods for their preparation and their use in pharmaceutical compositions |
Country Status (8)
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| EP (1) | EP0039646A1 (en) |
| JP (1) | JPS57500510A (en) |
| DK (1) | DK417481A (en) |
| ES (1) | ES8202811A1 (en) |
| FR (1) | FR2482101A1 (en) |
| IE (1) | IE810992L (en) |
| WO (1) | WO1981003172A1 (en) |
| ZA (1) | ZA812948B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998025617A1 (en) * | 1996-12-13 | 1998-06-18 | Merck & Co., Inc. | Substituted aryl piperazines as modulators of chemokine receptor activity |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02138181A (en) * | 1988-11-08 | 1990-05-28 | Ist Luso Farmaco Italia Spa | 2,2-di-substituted 2,3-dihydro- 1,4-benzodioxine derivative having antihypertensive activity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3579M (en) * | 1963-02-13 | 1965-10-04 | Ici Ltd | New drug based on 1,4-benzodioxane derivatives. |
| US3928358A (en) * | 1973-05-21 | 1975-12-23 | Boehringer Sohn Ingelheim | Piperazine derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910930A (en) * | 1973-01-04 | 1975-10-07 | Janssen Pharmaceutica Nv | 1-{55 1-{8 2-(1,4-Benzodioxan-2-yl)-2-hydroxyethyl{9 -4-piperidyl{56 -2-benzimidazolinones |
-
1980
- 1980-05-07 FR FR8010223A patent/FR2482101A1/en active Granted
-
1981
- 1981-05-04 WO PCT/EP1981/000039 patent/WO1981003172A1/en active Application Filing
- 1981-05-04 JP JP56501462A patent/JPS57500510A/ja active Pending
- 1981-05-04 ZA ZA00812948A patent/ZA812948B/en unknown
- 1981-05-06 IE IE810992A patent/IE810992L/en unknown
- 1981-05-06 EP EP81400710A patent/EP0039646A1/en not_active Withdrawn
- 1981-05-07 ES ES502003A patent/ES8202811A1/en not_active Expired
- 1981-09-21 DK DK417481A patent/DK417481A/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR3579M (en) * | 1963-02-13 | 1965-10-04 | Ici Ltd | New drug based on 1,4-benzodioxane derivatives. |
| US3928358A (en) * | 1973-05-21 | 1975-12-23 | Boehringer Sohn Ingelheim | Piperazine derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998025617A1 (en) * | 1996-12-13 | 1998-06-18 | Merck & Co., Inc. | Substituted aryl piperazines as modulators of chemokine receptor activity |
Also Published As
| Publication number | Publication date |
|---|---|
| ES502003A0 (en) | 1982-03-01 |
| EP0039646A1 (en) | 1981-11-11 |
| ZA812948B (en) | 1982-05-26 |
| JPS57500510A (en) | 1982-03-25 |
| FR2482101A1 (en) | 1981-11-13 |
| IE810992L (en) | 1981-11-07 |
| ES8202811A1 (en) | 1982-03-01 |
| FR2482101B1 (en) | 1983-05-27 |
| DK417481A (en) | 1982-01-08 |
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