• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:WO1981003172A1
    申请号:PCT/EP1981/000039
    申请日:1981-05-04
    公开日:1981-11-12
    发明作者:G Coudert；L Lalloz；G Guillaumet；V Loppinet
    申请人:Cerm Cent Europ Rech Mauvernay；G Coudert；L Lalloz；G Guillaumet；V Loppinet；
    IPC主号:C07D319-00
    专利说明:
    [0001] NOVEL BENZO( 1,4) DIOXINS, METHODS FOR THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL COMPOSITIQNS.
    [0002] The present invention relates to novel benzo(1,4) dioxins substituted at 2 by an amino-alcohol chain, corresponding to the following general formula :
    [0003]
    and pharmaceutically acceptable salts thereof, in which X represents hydrogen, alkyl (1-4 C) , alkoxy (1-4 C) or CF3.
    [0004] The preferred meaning of X is a methoxy group, especially in ortho position.
    [0005] 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:
    [0006]
    (Ha1 is halogen, preferably chlorine)
    [0007]
    [0008] 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).
    [0009] 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.
    [0010] 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.
    [0011] The following experiments have been carried out in vitro.
    [0012] - 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;
    [0013] - 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.
    [0014] 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;
    [0015] - ß1 receptors: PA2 - 6,04, PD 2 = 4,84
    [0016] - ß2 receptors: inactive,
    [0017] - 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.
    [0018] 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.
    [0019] 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.).
    [0020] The compound of example 1 shows anti-hypertensive properties during 20 minutes at a dose of 20 mg/kg
    [0021] (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.
    [0022] The oral LD50 of the compound of example 2 in mice is found to be 120 mg/kg bodyweight.
    [0023] Based upon the above mentioned pharmacological results the compounds of the invention can be used as anti-hypertensive compounds.
    [0024] 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.
    [0025] 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.
    [0026] The process is illustrated in more detail in the following examples.
    [0027] Preparation starting product 2-chloroformyl benzo(1,4) dioxin
    [0028] 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.
    [0029] 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.
    [0030] In thxs manner 100 g of 2,3-dibromo 2-carbethoxy benzo(1,4) dioxan were obtained having a melting point of 88 °C.
    [0031] The crude product thus obtained was dissolved in 600 ml of anhydrous acetone and treated with
    [0032] 180 g of anhydrous sodium iodide, while the reaction mixture was maintained at ambient temperature, while stirring, for about one and a half hours.
    [0033] 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.
    [0034] After Separation, purification and drying of the organic phase and after elimination of the ether by evaporation and recrystallization in pentane,
    [0035] 58 g of 2-carbethoxy benzo(1, 4) dioxin were obtained having a melting point of 39-40 °C.
    [0036] 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.
    [0037] 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.
    [0038] Example 1 2-methanol α[4-(3-trifluoromethyl phenyl)piperazinyl-1] methyl benzod, 4) dioxin.
    [0039] 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.
    [0040] 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 analysis
    [0041] C % H % N % found 62.62 5.18 6.85 theoretical 62.13 5.21 6.90
    [0042] Example 2 2-methanol α[4(2-methoxyphenyl)piperazinyl-1]methyl benzo(1,4)dioxin
    [0043] 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:
    [0044] C % H % N % found 68.01 6.63 7.58 theoretical 68.54 6.57 7.61
    [0045] In a corresponding manner is prepared: 2-methanol α [4-phenyl piperazinyl-1]methyl benzo (1,4)dioxin.
    权利要求:
    Claims
    1. Benzo(1, 4) dioxin derivatives of the formula:
    and pharmaceutically acceptable acid addition salts thereof, in which
    X represents hydrogen, alkyl (1-4 C) , alkoxy (1-4 C) or trifluoro-methyl.
    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:
    in which Hal represents halogen, preferably chlorine, is reacted with a compound of the formula:
    or an acid addition salt thereof, in which X has the aforesaid meanings, after which the compound thus obtained may be converted into a pharmaceutically acceptable acid addition salt.
    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.
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    同族专利:
    公开号 | 公开日
    IE810992L|1981-11-07|
    ES502003D0||
    FR2482101A1|1981-11-13|
    ES502003A0|1982-03-01|
    EP0039646A1|1981-11-11|
    ZA8102948B|1982-05-26|
    DK417481A|1982-01-08|
    JPS57500510A|1982-03-25|
    FR2482101B1|1983-05-27|
    ES8202811A1|1982-03-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR3579M|1963-02-13||Ici Ltd|Nouveau médicament a base de dérivés de 1,4-benzodioxanne.|
    US3928358A|1973-05-21|1975-12-23|Boehringer Sohn Ingelheim|Piperazine derivatives|WO1998025617A1|1996-12-13|1998-06-18|Merck & Co., Inc.|Substituted aryl piperazines as modulators of chemokine receptor activity|US3910930A|1973-01-04|1975-10-07|Janssen Pharmaceutica Nv|1-{55 1-{8 2--2-hydroxyethyl{9 -4-piperidyl{56 -2-benzimidazolinones|JPH02138181A|1988-11-08|1990-05-28|Ist Luso Farmaco Italia Spa|2,2-disubstituted-2,3-dihydro-1,4-benzodioxine derivative having blood pressure decreasing activity|
    法律状态:
    1981-10-19| WWE| Wipo information: entry into national phase|Ref document number: 813264 Country of ref document: FI |
    1981-11-12| AK| Designated states|Designated state(s): AU DK FI HU JP US |
    优先权:
    申请号 | 申请日 | 专利标题
    FR8010223A|FR2482101B1|1980-05-07|1980-05-07||
    FR8010223||1980-05-07||AU70767/81A| AU7076781A|1980-05-07|1981-05-04|Novel benzodioxins, methods for their preparation and their use in pharmaceutical compositions|
    DK417481A| DK417481A|1980-05-07|1981-09-21|Hidtil ukendte benzodioxiner fremgangsmaader til deres fremstilling og anvendelse i farmaceutiske midler|
    FI813264A| FI813264L|1980-05-07|1981-10-19|Nya bensodioxiner foerfaranden foer framstaellning av dem och anvaengning av dem i farmaceutiska kompositioner|
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