Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to the optical isomers of (benzodioxane-1,4 yl-2) -2 ⁇ -2 imidazoline, their preparation and their therapeutic application.
• Dl (benzodioxane-1,4-yl-2 -) - 2 ⁇ -2 imidazoline is easily obtained by the usual methods of preparation of imidazolines, starting from benzodioxane-1,4-carboxylic-2 acid or one of its functional derivatives. Its formula is as follows:
• the isomers of the compound according to the present invention can be used in the form of salts, in particular salts with an optically active and pharmaceutically acceptable acid which will make it possible to stabilize the isomer by avoiding its racemization.
• salts in particular salts with an optically active and pharmaceutically acceptable acid which will make it possible to stabilize the isomer by avoiding its racemization.
• tartrates Among the interesting salts, mention should be made in particular of tartrates.
• the expression “isomer d” or “isomer I” will be understood to denote not only the pure isomer but also its mixture with less than 50%, preferably less than 10%, of the other isomer since it is quite difficult to obtain pure isomers.
• the optical isomers d or 1 of this compound can be prepared by salification of the racemic compound with optically active tartaric acid, separation of the corresponding tartrate by fractional crystallization and, where appropriate, release of the optically active base with a strong base. The following example illustrates this operation.
• the bases are released from the tartrates by the calculated amount of 2N sodium hydroxide in the presence of ether.
• the bases thus obtained can be salified with pharmaceutically acceptable acids such as hydrochloric acid.
• the hydrochlorides are obtained from a solution of the bases in ethyl ether by addition of hydrochloric ether.
• the salts are stable in the crystallized state or in solution.
• optical purity of the base samples could only be determined by C 13 NMR.
• the product in the form of salt or base, gives an unusable melting endotherm for measuring optical purity.
• Bypass reagents do not provide a single derivative. Under these conditions, the assay cannot be carried out using DSC ("differential scanning calorimetry", differential scanning calorimetry), CPV (vapor phase chromatography) or HPLC (high pressure liquid phase chromatography).
• DSC differential scanning calorimetry
• CPV vapor phase chromatography
• HPLC high pressure liquid phase chromatography
• the bases d and l have a composition, expressed in enantiomeric excess, greater than or equal to 0.9.
• the isomers according to the invention have been subjected to pharmacological tests.
• the 1 and d isomers reverse the effects of adrenaline.
• the d isomer displaces the adrenaline dose response curve by 3.6 logarithmic units, while the l isomer l by 1 logarithmic unit.
• the dose-action curve of adrenaline is shifted by 0.3 logarithmic units for the derivative while the l is inactive.
• a pure ⁇ 1 agonist (Lefevre et al., Eur. J. pharmacolo. 43, 85 (1977)
• the derivative l is inactive at a dose of 1 mg / kg and it is necessary to reach a very high of 10 mg / kg to obtain a displacement of the curve.
• the derivative d displaces the dosing curve of cirazoline by 5 logarithmic units at a dose of 1 mg / kg. This displacement appears maximum because the higher doses do not have no larger effects.
• the derivative l In the presence of derivative l, it is necessary to increase the doses of clonidine to obtain the same inhibition as in the absence of derivative l. In addition, if the derivative is administered when the effects of, clonidine are established, it reverses them.
• the derivative l behaves like piperoxane or yohimbine but is more active.
• the derivative d even at the dose of 1 mg / kg IV, does not increase the tachycardia of the cardio-accelerating nerve of the dog, but blocks the inhibitory effects of clonidine on the tachycardizing effects of stimulation of the nerve.
• the Ki isomers are respectively: I: 680 nM with respect to 3 H prazosin, 18 nM against 3 H rauwolscine; d: 54 nM vis-à-vis 3 H prazosin and 300 nM vis-à-vis rauwolscine. All of these experiments show that the l isomer has a selective activity for the ⁇ 2 adrenoceptors while the d isomer is more selective for the adrenoceptors.
• the d-isomer was found to be a potent antagonist, being 3.5 times more active than the dl mixture and much more potent than piperoxane. (about 10 to 100 times).
• the isomer I is a weak antagonist in this experiment.
• derivative I would be an antagonist of the peripheral 2 adrenoceptors, whereas derivative d is more active on the central ⁇ adrenoceptors responsible for sleep.
• the l isomer can be used therapeutically for the treatment of depression, asthma, orthostatic hypotension and possibly diabetes and obesity.
• the d isomer can be used in the treatment of hypertension and as a psychotropic drug.
• the advantage of the present invention comes from the demonstration of the specificity of action of the l isomer, since there is now a product acting only on the ⁇ 2 receptors.
• the l or the d. (benzodioxane-1,4 yl-2) -2 ⁇ -2 imidazoline or their pharmaceutically acceptable salts can be administered orally or parentetally at a daily dose of 5 to 100 mg.
• the compositions for oral administration can be in the form of tablets, capsules, or dragees, for example containing from 5 to 25 mg of active substance and the usual compatible pharmaceutical excipients such as lactose, starch, talc and stearates .
• the parenteral compositions can comprise aqueous or saline solutions of the active substance, preferably in the form of a salt such as the hydrochloride and at a unit dose ranging from 5 to 20 mg.
• capsules can be used containing 10 mg of hydrochloride of 1. (benzodioxane-1,4 yl-2) - 2 ⁇ -2 imidazoline and 40 mg of talc.

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• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1982
  • 1982-05-19 FR FR8208810A patent/FR2527208B1/fr not_active Expired
• 1983
  • 1983-05-18 WO PCT/FR1983/000096 patent/WO1983004025A1/fr not_active Application Discontinuation
  • 1983-05-18 JP JP50163883A patent/JPS59500862A/ja active Pending
  • 1983-05-18 EP EP19830901386 patent/EP0108766A1/de not_active Withdrawn

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