WO1991010428A1

WO1991010428A1 - Drugs and use thereof

Info

Publication number: WO1991010428A1
Application number: PCT/SE1991/000023
Authority: WO
Inventors: Lars Westfelt
Original assignee: Nobel Chemicals
Priority date: 1990-01-22
Filing date: 1991-01-15
Publication date: 1991-07-25
Also published as: SE9000207D0; AU7221091A; JPH05506642A; CA2074097A1; EP0512024A1; SE9000207L

Abstract

The present invention relates to atenolol-based drugs intended for beta receptor blockade and for treatment of hypertension, and also a method for reducing, with the aid of these drugs, the toxic effect upon drug treatment in order to achieve the desired level of beta receptor blockade or the desired reduction in blood pressure upon drug treatment for hypertension.

Description

Drugs and use thereof

The present invention relates to beta-receptor-blocking drugs which are also effective against hypertension and whose active components include the previously known per se S-(-)-enantiomer of a previously known per se racemic beta-receptor-blocking substance with the generic name (trivial name) atenolol, i.e. (±)-4-(2-hydroxy-3-isopro- pylaminopropoxy)phenylacetamide. According to the invention, replacement of atenolol by the S-(-)- enantio er of atenolol in the drugs reduces their toxic effect.

Beta-receptor-blocking substances (hereinafter called beta blockers) are included in drugs which are used primarily for cardiovascular diseases, such as hyper- tension (high blood pressure), angina pectoris (vascular spasm) and certain arrhythmias, and on one ophthalmic disease (glaucoma) . They exert their pharmacological effect by blocking the beta type of receptors for adrenergic substances, for example adrenaline and nor- adrenaline.

Some of the most commonly known side effects of treatment with beta blockers include reduced resting pulse rate, peripheral cold in the extremities, muscular weakness, tiredness, sleep disturbances, nightmares. In many cases these, like the desired effect, are the consequence of the beta blockade. However, it has been suggested that in some cases other mechanisms are responsible for side effects, for example in the form of an effect on the central nervous system (CNS) or a decrease in the pumping power of the heart.

Most beta blockers, including atenolol, consist of sub¬ stituted 3-aryloxy-2-hydroxypropylamines. A common feature of all these is that they have a chiral centre at carbon atom number 2. All substances containing a chiral centre may exist in two different iso eric forms, so-called enantiomers, which, fully in line with current practice, are referred to as the R-form and S- form respectively.

Hereinafter, as above, again fully in line with current practice, those substances consisting of equal parts of R-form and S-form are called racemic or racemate and those consisting principally of one of these two forms are called homochiral. The generic name (INN) atenolol relates by definition to the racemate.

It is already known that the pharmacological effects of chiral substances may to different extents be associated with their different enantiomers. This is explained by the fact that the human body, like nature as a whole, consists of an extremely complex chiral milieu in which the interaction between the endogenous substances, for example in the form of receptors and enzymes included therein, and the pharmacological substance supplied can take place in a number of different ways. A consequence of this is that the different enantiomers of one and the same chiral compound can give rise to both the same and completely different pharmacological effects, side effects, adverse reactions and toxic effects. However, it has not been possible, at least not as yet, to establish more general rules as to which enantiomer is most effective in each particular case or gives rise to the greatest number of and most serious side effects. It is likewise already known that the S-form of certain specific beta blockers belonging to the group of sub¬ stituted 3-aryloxy-2-hydroxypropylamines exhibits practi- cally all of the desired pharmacological effect of the corresponding racemate.

A small number of studies on the superiority of S- atenolol as a beta blocker compared to the R-form or the racemate have been published. Thus, for example, certain studies have been carried out on the affinity of the two enantiomers of atenolol to receptors in membrane from calf's lung and calf's heart, these studies showing that the S-form has a far greater affinity than the R-form. (Morris, T H, Kaumann, A J: Naunyn-Schmiedeberg's Arch Pharmacol 327. 176 (1984)).

In addition, it has been observed in tests carried out on rats that the S-form of atenolol has a hypotensive effect, while the R-form proved to be inactive. (Pearson, A A, Gaffney, T E, Walle, T, Privitera, P J: J. Pharmacol Exp Ther 25_0, 759 (1989)).

However, it is at present not known which side effects the R-form of atenolol has on animals or man but it is a well-known fact that the R-form of other beta blockers has a depressant effect on the heart. (Scriabine, A (Ed): Pharmacology of Antihypertensive Drugs, Page 317 (Kaplan, HR) Raven Press, NY (1980)).

The toxicity of beta blockers has generally been regarded as being a direct consequence of and therefore as being in proportion to their beta-blocking effects. Surpris- ingly, we have now been able to establish that a certain amount of atenolol (i.e. the racemate) exhibits the same toxicity as the same amount of its S-form in acute tests on rats, i.e. the R-form has been found to be as toxic as the S-form. Therefore, we have now proposed that in future, instead of the racemate, the homochiral S-form of atenolol should be used for achieving an effect on the cardiovascular system, it being possible for the drug dosage to be reduced by about half. Such a change should mean that the toxic effects on the body are reduced by half.

The present invention thus concerns new drugs which contain homochiral S-atenolol as the pharmacologically active component, alone or in combination with other components, but which otherwise are made up of auxiliaries commonly used for drugs and are produced in a conventional manner. The invention also concerns the use of these drugs, only about half as much being employ¬ ed as when the racemate is used.

The advantage of the present invention therefore lies in the fact that, in using a drug containing homochiral S- atenolol, only about half as great a dose needs to be used in order to obtain the same degree of beta blockade and/or blood pressure reduction as with a certain dose of racemic atenolol. In this way the toxic effects and the stress imposed on the body by the drug are reduced by about half, which is of great importance, since beta blockers are used in long-term therapy. The number of subjects taking 50-100 mg of racemic atenolol on a daily basis is probably of the order of magnitude of 10 mil¬ lion, in other words an extremely large number of people. Each one of these people consumes during their period of illness (if the latter is assumed to be about 20 years) approximately 1/4 kg of the R-form of atenolol, whose side effects have not been investigated but whose acute toxicity we have found, as mentioned, to be just as high as that of the S-form and which, regardless of side effects or toxicity, imposes a strain on the detoxifying functions of the body. It is therefore maintained that the present invention constitutes a significant possibility of improved treatment. The invention is defined in the subsequent patent claims and is illustrated by the study described below and thus includes, as emerged from the above, on the one hand a drug and on the other hand a method for reducing the toxic burden on the human body in drug treatment with beta-receptor-blocking agents and in drug treatment of hypertension.

Toxicity study

A study was carried out on rats, in which the acute toxic effect of intravenously administered S-atenolol was compared with the corresponding effect of racemic atenolol.

Scope and plan of study

-10 CD rats per dose level and substance (racemate or S-form), - 5 dose levels.

- counting number of deaths.

Results of study

Within the 95 % confidence interval, the LD₅₀ for S- atenolol was found to be 97-116 mg/kg, and for racemic atenolol 84-100 mg/kg, which means that in this test S- atenolol is as toxic as or possibly slightly less toxic than the racemate and thus, indirectly, also less toxic than the R-form.

Claims

PATENT CLAIMS

1. Drugs intended as beta-receptor-blocking agents and for treating hypertension, comprising 4-(2-hydroxy-3- isopropylaminopropoxy)phenylacetamide as active comp¬ onent, characterised in that the said active component consists for the most part of S-(-)-4-(2-hydroxy-3- isopropylaminopropoxy)phenylacetamide.

2. Drugs according to Claim 1, characterised in that the weight ratio between incorporated S-(-)-4-(2-hydroxy-

3-isopropylaminopropoxy)phenylacetamide and R-(+)-4-(2- hydroxy-3-isopropylaminopropoxy)phenylacetamide is greater than 90:10.

3. Drugs according to Claim 1, characterised in that the said weight ratio is greater than 99:1.

4. Drugs according to Claim 1, characterised in that the only incorporated active component consists of 4-(2- hydroxy-3-isopropylaminopropoxy)phenylacetamide, and in that they otherwise consist of auxiliary substances, which are conventional for medicines and drugs, and any impurities accepted in this context.

5. Method for reducing the toxic effect upon drug treatment with 4-(2-hydroxy-3-isopropylaminopropoxy)- phenylacetamide in order to obtain beta receptor blockade or as a drug for treating hypertension, characterised in that the active component used is S-(-)-4-(2-hydroxy-3- isopropylaminopropoxy)phenylacetamide, and then only in about half as great an amount as when the racemate of the same compound (atenolol) is employed.

6. Method according to Claim 5, characterised in that the weight ratio between S-(-)-4-(2-hydroxy-3-isopropyl- aminopropoxy)phenylacetamide and likewise incorporated R- (+) -4-(2-hydroxy-3-isopropylaminopropoxy)phenyl- acetamide is kept greater than 90:10.

7. Method according to Claim 5, characterised in that the weight ratio between incorporated S-(-)-4-(2-hydroxy- 3-isopropylaminopropoxy)phenylacetamide and likewise incorporated R-(+)-4-(2-hydroxy-3-isopropylaminopropoxy)- phenylacetamide is kept greater than 99:1.