SYNTHESIS OF NEW PROPRANOLOL DERIVATIVES AS POSSIBLE PRODRUGS

Abstract

Propranolol is a nonselective-adrenergic blocker used in the treatment of hypertension, cardiac arrhythmias, and angina pectoris. A significant problem in propranolol therapy is that it undergoes extensive presystemic metabolism after oral administration leading to reduced bioavailability. In this paper, two new propranolol derivatives have been designed, synthesized and characterized. These compounds were formed by acylation of propranolol followed by nucleophilic substitution reaction of acylated propranolol, these derivatives were analyzed for IR, CHN, melting points, and evaluated for their lipophilic properties compared with propranolol. The lower partition coefficient of these two derivatives revealed that the prodrug approach may be an effective means of avoiding first-pass metabolism.

Headnote

ABSTRACT

Propranolol is a nonselective-adrenergic blocker used in the treatment of hypertension, cardiac arrhythmias, and angina pectoris. A significant problem in propranolol therapy is that it undergoes extensive presystemic metabolism after oral administration leading to reduced bioavailability. In this study, two new propranolol derivatives have been designed, synthesized and characterized. These compounds were formed by acylation of propranolol followed by nucleophilic substitution reaction of acylated propranolol, these derivatives were analyzed for IR, CHN, melting points, and evaluated for their lipophilic properties compared with propranolol. The lower partition coefficient of these two derivatives revealed that the prodrug approach may be an effective means of avoiding first- pass metabolism.

Keywords: propranolol; prodrugs; bioavailability; first- pass metabolism.

(ProQuest: ... denotes formula omitted.)

INTRODUCTION

Propranolol; 1- [(1-Methylethyl)amino]-3-(1- naphthalenyloxy)-2-propanol (compound 1 figure1), is the first generation ?-blocker.1

It is prototypical and non selective beta-blocker, so it has a moderate affinity for beta 1 and beta 2 receptors. It is representative of ?-adrenolytic drug, which is in clinical use in the management of diseases frequently associated with lipid metabolism disorders, i.e. coronary heart disease, cardiac arrhythmias or hypertension, furthermore, propranolol penetrates well into the central nervous system, it has found use in the treating anxiety and alcohol withdrawal syndrome.2 Propranolol has a high lipophilicity (partition coefficient - 20.2), propranolol is extensively metabolized by the liver.3

Despite of its complete absorption, propranolol has a variable bioavailability due to extensive first-pass metabolism, in addition to decreasing the percentage of dose reaching its intended site of action.4 While first-pass metabolism can be avoided by selecting alternative routes of administration (i.v., transdermal, rectal etc.), oral administration is generally the preferred route. Rational approaches for bypassing first-pass metabolism which could be applied to drug candidates.

There are a number of examples (figure 1) of the prodrug approach to reduce first-pass metabolism and thereby increase oral bioavailability; pivaloyloxyethyl ester of methyldopa exhibited a 2.3 fold higher systemic availability of methyldopa following an oral dose compared to an equivalent oral dose of last one due to decreased first-pass metabolism5, different derivatives of L-dopa; such as diacetyl ester, benzyl ester and dipeptides are effectively provided protection against metabolism occurred in the GIT and/or the liver; resulting in better bioavailability of the drug.6 The oral bioavailability of Etilefrine(R) (?-[(ethylamino)-methyl] -3'- hydroxybenzyl alcohol) is 0.5, even though it is completely absorbed, due to gut wall metabolism. To avoid this effect, the 3'-hydroxy group was masked by the formation of the 3'-acetate prodrug.7

The value of liver intrinsic elimination clearance, liver permeation clearance and permeability- surface, all increase with the increase lipophilicity of cationic drug.8

A series of ester prodrugs of propranolol was synthesized by incorporating substituents (O-acetyl-, O-butyryl-, O- isovaleryl- and O-cyclopropanoyl-) into the ?-hydroxy function of propranolol with the aim of protecting the drug against first-pass metabolism following oral administration, the overall in-vitro and in-vivo results showed that these prodrugs having higher chemical and enzymatic stability in buffers and plasma, but susceptible to hydrolysis in the liver homogenate, to be the most promising prodrugs for improving oral bioavailability of propranolol.9,10 Garceau et al.11 have shown that following oral administration of propranolol hemisuccinate (figure 1) in dogs, plasma propranolol levels were 8 times higher than after an equivalent dose of propranolol. Thus, the prodrugs effectively protect the drug from first- pass elimination by the liver.

In the view of these observations new propranolol derivatives have been designed, synthesized and characterized to be evaluated for their lipophilic properties compared with propranolol.

CHEMISTRY

Steps of preparation of the two compounds are represented in scheme 1. Acylation of propranolol with 4- nitophenylchloroformate resulted in the synthesis of compound I. Reaction of aminobenzothiazole and cysteine amino acid with compound I (nucleophilic substitution reaction) results in synthesis of compound II and III, respectively.

EXPERIMENTAL

All solvents and reagents were of analytical grade and were used as received from the commercial supplier (BDH-England, Merck-Germany, Riedal-Dehaen-Germany and Fluka-chemicals USA). Propranolol was purchased from SDI Company, Iraq. The synthesis steps of the derivatives (compound II and III) are as presented:

The synthesis of 1-(isopropylamino)-3-(naphthalene- 4-yloxy) propan-2-yl (4-nitrophenyl) carbonate (Compound I): Propranolol (5mmol) was first dissolved in DMF (50ml) with conc. HCl (5mmol). The solution was cooled to 0°C and then a calculated amount of pyridine (6mmol) and 4-nitrophenylchloroformate (5mmol) were added while stirring the mixture for 3hr at 0°C. The cold water was then added, and the isolated precipitate (compound I -scheme 1) was washed twice with cold water. Recrystallized from water and ethanol (1:1).

The synthesis of 1-(isopropylamino)-3-(naphthalen-4- yloxy)propan-2-yl benzothiazol-2-yl carbamate (Compound II) and 2-amino-3-(((( 1-isopropylamino)- 3-(naphthalene-1-yloxy) propan-2-yl) oxy) carbonyl) thio) propanoic acid (Compound III): Compound I (2mmol) was dissolved in 15ml of DMSO & pyridine(1:1) and 2-aminobenzothiazole (2mmol) was then added, after stirring at room temperature. For 48 hr, the compound II was precipitated by cold water and recrystallized from diethyl ether. The same procedure was repeated with 2mmoles of cysteine to prepare compound III, as shown in scheme 1. The percentage yield, physical data and melting points are presented in table 1.

The IR data of these 3 compounds

Compound I: The characteristic IR bands (KBr disc): 1780 (C=O) carbonate, 1520 & 1342 (N=O), 1190(C-O), 1020 (C- O-C), 870 ((C-N) nitoaromatic) and 842 ((C-H) p- disubstituted aromatic) cm-1.

Compound II: The characteristic IR bands (KBr disc): 1734 (-O-CO-NH-), 796 and 771 ((C-H) o-disubstituted aromatic) cm-1.

Compound III: The characteristic IR bands (KBr disc): 3401 and 3455 (-NH2), 2851- 3055 (-OH of COOH group), 1732 (C=O), 643 (C-S) cm-1.

Standard Curve preparation

A series of different concentrations of chloroform solutions for propranolol and its derivatives (compound II and III) prepared from their stock solutions.12 The absorbance of these solutions was obtained using UV spectrophotometer at λ240 nm and then plotting these absorbance versus their corresponding concentrations, the standard curve (calibration curve) constructed for these compounds as illustrated in figure 2, 3 and 4.

Partition Coefficient Estimation

Partition coefficient of propranolol and compounds II and III were estimated by taking 10 ml of 0.03mg/ml of chloroform solution of each these compounds and mixed with an equal volume of distilled water in a separatory funnel, then shake well for 30min, left for 10min to complete separation of the two layers. Next step is collecting and measuring the absorbance of the chloroform layers at λ 240 nm.13 By interpretation of the absorbance obtained by standard curve, we got the corresponding concentration of these compounds in organic layer and then by subtracting the concentration in organic layer from the original concentration we can get the concentration remained in the aqueous layer.

The partition coefficient P values calculated by the following equation:

...

All the values recorded in table 2.

RESULTS AND DISCUSSION

All the synthesized compounds (I-III) were purified by successive recrystallization. The purified compounds were determined on the basis of their FTIR and CHN data.

The IR spectra of, the compound I showed the presence of (C=O) stretching band at 1780 cm-1 for the carbonate group, and (N=O) stretching frequencies at 1520 & 1342 cm-1 corresponding to aromatic nitro compounds, for the compound II was the appearance of 1734 cm-1 stretching band of (-O-CO-NH-) for urethane group, and 796 & 771 cm-1 bending for (C-H) o-disubstituted aromatic compound. While the IR bands of compound III were 3455 & 3401 cm-1 stretching of primary amine, 3055-2851 cm-1 stretching of OH of the carboxylic acid group, and a characteristic band at 1732 cm-1 that is observed from the overlap of the C=O of the thiocarbonate and carboxyl groups. CHN analysis was run to prove their own empirical formula and the observed percents of elements were acceptable with those calculated (Table 3).

The compounds II and III are more polar than propranolol (lower partition coefficient) suggesting that compounds maybe an effective means of bypassing the first-pass metabolism. However, two possible mechanisms are (1) reduced uptake due to the hydrophilic nature of these two compounds and (2) avoidance of first-pass glucuronidation of the ?- hydroxyl group which is blocked. The former possibility follows from the fact that compound II and III are more polar therefore likely to be poorly transport through the hepatocyte membrane. Reduced uptake into the hepatocyte would lead to reduced hepatic extraction and minimal metabolism, since the enzymes involved are intracellular. Avoidance of first- pass glucuronidation is also considered as a possibility in light of the observation that the AUC of propranolol glucuronide after an oral dose of propranolol was seven times higher than after an intravenous dose.11 Since the site of glucuronide formation is blocked, the hydrolysis would have to occur prior to glucuronidation. This additional requirement may lead to reduced first- pass elimination.

CONCLUSION

The synthesis of the final target compounds (compounds II and III) was effectively accomplished by following the stated procedures as previously described. The results obtained from this study indicated that the approach tailored for the synthesis of the designed derivatives was successful, since the conformity of synthesized compounds was achieved according to the data shown by the physical and chemical analysis including (TLC, melting point, FT-IR and Elemental analysis (CHN)). Further biological evaluation of synthesized compounds may lead to the development of novel prodrug of propanolol.

References

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