DE4001087A1 - USE OF (ALPHA) -AMINOFLUOROKETONES FOR THE TREATMENT OF CARDIOVASCULAR DISORDER AND INCREASED BLOOD PRESSURE - Google Patents

Abstract

Use of ???-aminofluoroketones of US Patent Specification 4518528, especially benzyloxycarbonyl-1- phenylalanylalanylfluoromethylketone, in the production of medicaments having cardiovascular and antihypertensive activity.

Description

The invention relates to the use of α- aminofluoroketones for the treatment of cardiovascular disorders and elevated blood pressure.

US Pat. No. 4,518,528 describes compositions containing α- aminofluoroketones of the formula

wherein R₁ and R₂ independently of one another are hydrogen, alkyl having 1 to 6 carbon atoms, substituted alkyl having 1 to 6 carbon atoms, aryl or alkylaryl, in which the alkyl radical has 1 to 4 carbon atoms, n is an integer from 1 to 4, X represents a terminal peptide protecting group and Y represents an amino acid or a peptide chain containing 2 to 6 amino acids.

Substituted alkyl having 1 to 6 carbon atoms in the meaning R₁ and R₂ is alkyl of 1 to 6 carbon atoms that by hydroxy, amino, guanidino, carboxy or Mercapto groups is substituted.

In the above US patent for the α -aminofluoroketone an irreversible inhibitory effect on serine or cysteine proteases is given, the serine and cysteine proteases cathepsin B, H, C, G, R, elastase, trypsin, plasma kallikrein, glands kallikrein, plasmin , Plasminogen activator and the like. It is noted that the compounds may be useful in the treatment of emphysema, but evidence of cardiovascular effects is nowhere included.

Surprisingly, it has now been found that the α- aminofluoroketones of the formulas I (a) -I (d) described in this US patent have pronounced hypotensive properties. This effect can be seen from results of studies using the spontaneously hypertensive rat model (SH rat) described, for example, by Fozard et al., In J. Cardiovasc. Pharmacol. 9, 328-347 (1987). Accordingly, this effect is achieved by administering an α- amino fluoroketone of formulas I (a) -I (d) in doses of 10 to 50 mg / kg po. In contrast, the compounds do not lower the blood pressure of normotensive rats even at doses up to 60 mg / kg po. Further, as the results of studies using the R. Hof in Brit. J. Pharmacol. 78, 375-394 (1983), α- aminofluoroketones of the formulas I (a) -I (d) enhance and prolong the hypotensive effect of the atrial natriuretic factor (ANF) in the anesthetized rabbit with exposed chest cavity (open chest rabbit).

In terms of their antihypertensive effect are the compounds also indicated for prevention and treatment of cardiovascular Disorders such as heart failure, left ventricular hypertrophy and cerebrovascular seizures such as Stroke.

According to the results of the above investigations, the present invention relates to the use of the α- aminofluoroketones of the formulas I (a) -I (d) for the treatment of cardiovascular disorders and elevated blood pressure. Preferred for these effects are the compounds of the formulas I (a) and I (c), very particularly preferred are those of the formula I (c) wherein Y is a single amino acid which is preferably phenylalanine. Preferably, R₂ is hydrogen and R₁ is methyl. The particularly preferred compound is selected from the α- amino fluoroketones of the formula I (c) and is the benzyloxy-carbonyl-1-phenylalanyl-alanylfluoro-methyl ketone of the formula II

This compound can be either as a recemisches mixture of isomers Z- (L) Phe- (L) Ala-CH₂F and Z- (L) Phe- (D) Ala-CH₂F wherein Z is a Benzyloxycarbonyl group means or occur as pure (L, L) form. The mixture as well as the pure (L, L) form have comparable Effects.

The hypotensive effect occurs slowly and takes a long time The greatest effect will be around 5 hours after administration reached and the effect remains about 24 hours from the time of administration to insist on.

To achieve hypotensive and cardiovascular effects the dose to be administered depends on the compound used of the formulas I (a) -I (d), the living being the connection is administered, the mode of administration and the type and the Severity of the conditions to be treated. In general, be satisfactory results in animals with daily doses of about 10 mg / kg to about 50 mg / kg based on the animal body weight receive. For larger mammals, such as humans, is a daily dose of the order of about 700 mg to about 3.5 g indicated, which expediently in divided doses up to 4 times administered daily.

The compounds of formulas I (a) -I (d) may be any of the customary Way, in particular enteral, preferably orally z. B. in the form of Tablets or capsules or parenterally in the form of injectables  Solutions or suspensions are administered.

The compound of formula II is the preferred compound. It For example, it has been found that this compound is in the above described model of spontaneously hypertonic rat an ED₅₀ of 15 mg / kg. It is therefore indicated that the connection of formula II in larger mammals, for example humans in daily doses of 700 mg to 2.5 g.

Pharmaceutical compositions containing a cardiovascular and can have hypotensive activity, by mixing Compounds of formulas I (a) -I (d) with at least one pharmaceutical Carrier or diluent, for example Methyl hydroxypropyl cellulose, corn starch, lactose, silica gel, Magnesium stearate, etc., can be obtained. Such compositions can be prepared in a manner known per se. unit doses contain, for example, from about 175 mg to about 1.75 g of the Active ingredient.

Example: tablet

A tablet is prepared by mixing the following mentioned ingredients and pressing the mixture on per se known way:

component Weight (mg) Compound of the formula II 250 lactose 58 corn starch 90 methylhydroxypropylcellulose 14 Silica amorphous 3 magnesium stearate  5 Total 420

Claims (4)

1) Use of α- amino fluoroketones of the formulas wherein R₁ and R₂ are independently hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms, aryl or alkylaryl wherein the alkyl radical has 1 to 4 carbon atoms, n is an integer of 1 to 4, X is represents a terminal peptide protecting group and Y represents an amino acid or a peptide chain containing 2 to 6 amino acids for the treatment of cardiovascular disorders and elevated blood pressure. 2) Use of α- aminofluoroketones according to claim 1, characterized in that the α- aminofluoroketone of the formula I (c) is the benzyloxycarbonyl-1-phenylalanylalanylfluoromethylketon of the formula II used. 3) Use of α- amino fluoroketones according to claim 1, characterized in that the a- amino fluorofluoro ketone in daily doses of 700 mg to 3.5 g administered once or in divided doses orally to larger mammals, such as humans. 4) Use of α- amino fluoroketones according to claims 1 and 2 for the preparation of pharmaceutical compositions, characterized in that one uses the active ingredient together with conventional additives such as methyl hydroxypropyl cellulose, corn starch, lactose, silica gel and magnesium stearate.