CARAZOLOL HCL

Manufacturing Process

The 4-(2,3-epoxypropoxy)carbazole used as starting material is prepared as follows. A solution of 16.3 g 4-hydroxycarbazole in a mixture of 190 ml dioxan and 98 ml 1 N sodium hydroxide is, after the addition of 66 ml epichlorohydrin, stirred for 2 hours at 40°C to 45°C. The reaction mixture is then diluted with water and shaken out with methylene chloride. The methylene chloride phase is washed with water, dried over anhydrous sodium sulfate and evaporated. There are obtained 16.8 g 4-(2,3- epoxypropoxy)carbazole.A solution of 3.5 g 4-(2,3-epoxypropoxy)carbazole in 50 ml absolute alcohol is mixed with 30 ml isopropylamine and heated for 3 hours under reflux. When the reaction is finished, the reaction mixture is evaporated to dryness. The residue obtained is taken up in methylene chloride and chromatographed over an aluminum oxide column (300 g basic aluminum oxide, activity stage IV; eluent methylene chloride). The eluted fractions are evaporated and the residue is dissolved in methanol and acidified with 2 N ethereal hydrochloric acid.The precipitate obtained is filtered off and recrystallized from methanol. There are obtained 3.1 g (62% of theory) 4-(3-isopropylamino-2-hydroxypropoxy) carbazole hydrochloride; MP 234°C to 235°C.

Therapeutic Function

Beta-adrenergic blocker

Biological Activity

carazolol is a high-affinity, lipophilic, and non-selective ligand of the β-adrenergic receptors [1,2].β-adrenergic receptors have been involved in mediating the physiological responses of the catecholamines, epinephrine and norepinephrine and modulating a myriad of physiological functions, such as relaxation of smooth muscle, chronotropic and inotropic cardiac responses, and lipolysis in adipose tissue. the β-adrenergic receptors exist in nearly all mammalian tissues. until now, three β-adrenergic receptors have been identified, β1-, β2- and β3-adrenergic receptors [3].in cho cells expressing the human β3-adrenoceptor, the ki value of carazolol was 2.0 ± 0.2 and the ic50 was 11.3 ± 1.2 nm. carazolol exhibited an ecs0 of 25 nm and behaved as a full agonist (intrinsic activity = 0.97) towards the murine β3-adrenoceptor. in murine 3t3-f442a-derived adipocytes express the β3-adrenoceptor, carazolol stimulated lipolysis [1]. carazolol bound to cortical β-receptors with a kd value of 0.15 nm. carazolol showed equal displacements constants when binding with calf cerebral cortex (which contained mainly β1 receptors) and calf cerebellum (which contained mainly β2 receptors), indicating that carazolol bound with equal affinity to β1 and β2 receptors [2].

references

[1] méjean a, guillaume j l, strosberg a d. carazolol: a potent, selective β3-adrenoceptor agonist[j]. european journal of pharmacology: molecular pharmacology, 1995, 291(3): 359-366.[2] innis r b, corrêa f m a, snyder s h. carazolol, an extremely potent β-adrenergic blocker: binding to β-receptors in brain membranes [j]. life sciences, 1979, 24(24): 2255-2264.[3] pellegrino s m, lee n h, fraser c m. β-adrenergic receptors[j]. biomembranes: a multi-volume treatise, 1996, 2: 245-279.