1. Field of the Invention:
The invention relates to pharmaceutically efficacious, antiarrhythmic and diuretic pteridine derivatives.
2. Description of the Background:
In 1944 Lippschitz and Hadidian (W. L. Lippschitz, Z. Hadidian, J. Pharmacol. Exp. Ther. Vol. 81, pp. 84-94 (1944); E. Mutschler & H. Knauf Publ., 30 Jahre Triamteren, Wissenschaftsverlag Koln, 1984, pp. 11-18) formulated a hypothesis about the relationship between the chemical structure and diuretic efficacy of nitrogen-containing compounds which is that the structural element ##STR2## should be present in compounds as a prerequisite for diuretic activity. Even though non-supportable with facts, still this hypothesis resulted in the development of a number of diuretically efficacious structures including compounds of the purine, pyrimidine, triazine, uracil, pteridine, and other heterocycle classes. Of particular note is 2,4,7-triamino-6-phenylpteridine (U.S. Pat. No. 3,081,230), which has proven to be an excellent potassium sparing drug (Triamterene). Weinstock & Wiebelhaus have researched the relationship between chemical structure and diuretic action of approximately 500 pteridine derivatives (cf. K. Fellinger, Therapie mit Triamteren, Georg Thieme Verlag 1967, pp. 2-21). However, the correlations which have been made have not remained unrefuted. (Cf. E. Wolf in E. Mutschler & H. Knauf, 30 Jahre Triamteren, loc., cit., pp. 11-18). Thus, G. H. Mudge finds in Goodman-Gilman "The Pharmacological Basis of Therapeutics," 5th Ed., McMillan Publishing Co., Inc., p. 838, with respect to Triamterene: "It is a pteridine compound, related chemically to folic acid. The diuretic activity of closely related homologues of Triamterene has been examined, but no specific structural requirements have been established."
At variance with the hypothesis developed by Weinstock & Wiebelhaus, it has been found that derivatives of Triamterene, in which the para-position of the 6-phenyl ring is etherified with a hydrophilic group, have a diuretic and anti-potassium uretic activity (GB Pat. No. 1,597,881; DE-A 34 07 695). U.S. Pat. No. 4,621,085 (or DE-A 34 12 765) shows cardioactive, in particular, antiarrhythmic properties for pharmaceutical drugs which contain Triamterene derivatives as the active substance, whose 6 phenyl group is substituted lipophilically in the paraposition. Fluorine, chlorine branched or cyclic alkyl having 3 to 6 carbon atoms, benzyl, trifluoromethyl or nitro-substituents in particular are suitable lipophilic substituents.
The previous ideas concerning the correlation between structure and action are seriously questioned by the Triamterene derivatives which have more recently been discovered and reported in the patent literature. Apparently the relationships contributing to the desired pharmaceutical properties are quite complex so that the relevant finding in the DE-A 34 07 697 is still valid; "A number of parameters go into the profile of an active substance such as efficacy, acute and chronic toxicity, compatibility with other active substances, pharmacokinetics and dynamics, metabolism, physical and chemical parameters such as stability, solubility, accessibility, and the like. However, the state of the art is such that it does not offer any criteria regarding what direction to look for further development of existing structures in order to achieve improved properties. In particular, there is a need for compounds that can be administered orally, whereby, however, no fewer demands were to be made on the other pharmacological properties than those of prior art. It was found surprisingly that derivatives of para-benzyltriamterene come very close to these requirements or even surpass them.
A need therefore continues to exist for pharmaceutically efficacious compounds which exhibit antiarrhythmic and diuretic properties.