a) Field of the Invention
This invention relates to unsymmetrical straight chain alkyl-substituted phenylxanthines which demonstrate potent bronchodilating activity. The compounds are 8-phenylxanthines having a methyl or propyl group at the 1- and 3- positions with the proviso that the 1- and 3-substituents may not be the same and the pharmaceutically acceptable salts of such compounds.
b) State of the Art
Xanthines of various types have been used or proposed as drugs for various indications. For example, theophylline and aminophylline relax the smooth muscle of the bronchial airways and pulmonary blood vessels, thereby acting as pulmonary vasodilators, bronchodilators and smooth muscle relaxants. Like other xanthines these compounds possess the following actions as well: coronary vasodilator, diuretic, cardiac and cerebral stimulant and skeletal muscle stimulant. Dyphylline is another xanthine having activity similar to that of theophylline and aminophylline. Most of these xanthines bear identical alkyl substituents in positions 1 and 3. Nevertheless, a large number of xanthines having different substituents in these positions are known [see, e.g., R.F. Bruns, G.H. Lu, and T. Pugsley, Mol. Pharmacol., 29, 331 (1986); J.W. Daly, W.L. Padgett, and M.T. Shamin, J. Med. Chem , 29, 1305 (1986); J.N. Wells, J.E. Garst, and G.L. Kramer, J. Med. Chem., 24, 954 (1981)] and several have notable pharmacological activity. For example, enprofylline (3-propylxanthine) has bronchodilating and antiasthmatic characteristics [see, e.g., C.G.A. Persson, K.-E.-Andersson and G. Kjellin, Life Sci., 38, 1057 (1986)]and IBMX (3-isobutyl-1-methylxanthine) and related compounds are potent inhibitors of phosphodiesterase [M. Chasin and D.N. Harris, Adv. Cyclic Nucleotide Res., 7, 225 (1976)].
Nevertheless, relatively little prior art exists for 8-phenylxanthines with an unsymmetrical alkyl substitution of the 1 and 3 positions. Bruns et al. [Proc. Natl. Acad. Sci. USA, 80, 2077 (1983)]disclose many 8-arylxanthines. One preferred compound is 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX). The only unsymmetrical alkyl-substituted xanthines which Bruns et al. disclose lack an 8-phenyl substituent.
Many 8-arylxanthines are disclosed in U.S. Pat. No. 4,593,095 to Snyder et al., including the preferred compound PACPX. As with Bruns et al., most of the Snyder et al. compounds are symmetrically substituted. Although one of the preferred compounds of the present invention is generically within Snyder's formula, none is exemplified nor claimed. Indeed, the only exemplified unsymmetrically substituted 1,3-dialkyl-8-phenylxanthine is 1-allyl-3-methyl-8-phenylxanthine [U.S. Pat. No. 4,593,095, column 11; see, also, H.W. Hamilton et al., J. Med. Chem., 28, 1071 (1985)].
Other unsymmetrically substituted 1,3-dialkyl-8-phenylxanthines described in the literature are 1-isoamyl-3-isobutyl-8-phenylxanthine [J.W. Daly et al., J. Med. Chem., 28, 487 (1985)], 3-ethyl-1-methyl-8-phenylxanthine [H.W. Hamilton et al., J. Med. Chem., 30, 91-96 (1987)], and 1-hexyl-3-methyl-8-phenylxanthine [H.G.V. Schub, German Patent 1,091,570 (1960)]. The first two compounds have been studied only in binding assays for affinity for the A.sub.1 and A.sub.2 subtypes of adenosine receptors. For the third compound "drug use" is claimed. The possibility that the therapeutic responses to adenosine receptor antagonists, such as theophylline, may involve such antagonism is uncertain. This uncertainty is based largely on the observation that enprofylline, which is about five-fold more potent than theophylline in man and other species [C.G.A. Perrson, Agents Actions, 13 (Suppl.), 115-129 (1983)], is much less effective than theophylline in diminishing responses to adenosine in all tissues studied, except for the rat hippocampus [B.B. Fridholm and C.G.A. Persson, Eur. J. Pharmacol., 81 673-676 (1982)]. Thus, it is not certain to what extent the two xanthines share common cellular actions or whether adenosine receptor blockade is of significance in the bronchodilator effect that theophylline produces in asthmatic patients [T.W. Rall in "Goodman and Gilman's, The Pharmacological Basis of Therapeutics," 7th Ed., A.G. Gilman, L.S. Goodman, T.W. Rall and F. Murad, eds., MacMillan Publishers, New York 1985, pp. 589-603]. Thus, the potent bronchodilating activity of the compounds of this invention is unexpected and the mechanism by which they produce this pharmacological response remains to be elucidated.
Co-pending application Serial No. 108,990 filed Oct. 1, 1987 (now U.S. Pat. No. 4,783,530) describes various 1,3-alkyl substituted-8-(3,4-or 4-substituted phenyl)xanthines. The 1,3-substituents need not be the same. Among the preferred compounds are: 1-propyl-3-methyl-8-(3-N,N-dimethylaminomethyl-4-hydroxyphenyl)-xanthine and 1-propyl-methyl-8-(4-cyanophenyl-)xanthine.
This invention provides a series of novel 1,3-unsymmetrical straight chain alkyl-substituted 8-phenylxanthines which produce potent bronchodilating activity in a test for reversal of histamine-induced bronchoconstriction, the preferred test for measuring this activity (T.W. Rall, loc. cit.), as well as in a test for prevention of antigen-induced bronchoconstriction in guinea pigs. The compounds also have a decreased tendency to produce unwanted side effects, such as increasing heart rate, decreasing blood pressure and causing emesis, as is seen with prototypic xanthine-type bronchodilators, e.g., theophylline. Binding studies demonstrate that this beneficial bronchodilating action is not correlated with A.sub.1 - or A.sub.2 -adenosine receptor binding.