USE OF ANTHENOTRIAZOLODIAZEPINE TO INCREASE THE LEVELS OF APOLIPOPROTEIN A-I
DESCRIPTION OF THE INVENTION
The present invention is based on the finding of new physiological properties of the compound 9-methyl-4-phenyl-6H-thieno [3,2-f] -s-triazolo [4, 3-a] [1,4] diazepine, hereinafter referred to as compound C. Compound C and its preparation are described in US Patent No. 4,155,913. This patent also describes analogues of compound C and contains data showing the anticonvulsant and muscle relaxant activity of one of these analogues. It has now been found that compound C is active in increasing plasma apolipoprotein A-I (apo A-I). Apo A-I is one of the main protein constituents of plasma high density lipoproteins (HDL). It is known that low plasma levels of HDL are associated with a lower incidence of coronary artery diseases (LINEAR OR BRANCHED CHAIN). The same applies both to low plasma levels of apo A-I and to high levels of apolipoprctein 3 (apo B); J of Biol. REF: 26937 Chem. 264: 6488-6494, 1989; Mayo Clin. Proc. 61: 313-320, 1986; New England J. of Medicine 325: 373-381, 1991; Am. J. Cardiol. 69: 1015-1021, 1992; Am. College Cardiol. 19: 792-802, 1992. In one aspect, the present invention relates to the use of compound C for the manufacture of medicaments for the treatment and prevention of diseases that are caused by low plasmatic concentrations of apo A-I. Examples of such diseases are the aforementioned CADs, mainly myocardial infarction and atherosclerosis. In a further aspect, the present invention relates to drugs that increase plasma levels of apo AI, which contain compound C as an active ingredient, as well as a process for the manufacture of such drugs, wherein the process comprises giving the compound C and if desired to another or other therapeutically valuable substances, a galenic administration form. In another aspect, the present invention relates to a method for increasing the plasma concentration of apo AI in mammals, particularly humans, which comprises administering an effective amount of compound C. The activity of compound C on plasma levels of apo AI It can be demonstrated by standard methods. For example, male hamsters were fed a diet enriched in coconut. We used 10 control animals and 5 animals treated with the drug. Compound C was administered with the feed at a daily dose of 30 mg / kg for 10 days. The experiment was carried out in the manner described in J. Lipid Res. 36: 1565-1585, 1995. For each of the plasma parameters of apo AI, apo B and triglycerides, the average concentrations in g / 1 or mg / dl, both on day 1 and on day 10 of the trial, were the following:
Plasma parameter Control Compound C day 1 day 10 day 1 day 10 apo AI (g / 1) 1.00 ± 0.08 0.97 ± 0.09 0.91 + 0.08 1.30 ± 0.15 apo B (g / 1) 0.79 ± 0.09 120 ± 0.19 * 0.84 ± 0.11 1.20 ± 0.35 triglycerides (mg / dl) 312 ± 46 288 ± 34 ** 197 ± 23 307 ± 19 **
* significantly different (p <0.05, paired t test) compared to day 1 ** not significantly different compared to day 1 The results show that the administration of compound C results in an increased level of apo AI in the control group, without significantly affecting the levels of apo B and triglycerides. The administration of compound C did not induce any overt adverse effects. The animals remained healthy, conscious, continued to eat and grow at normal levels and showed no signs of sedation. Compound C can be used as an active ingredient in pharmaceutical preparations. The pharmaceutical preparations are administered orally, for example in the form of tablets, coated tablets, dragees, hard gelatine capsules and soft gelatin capsules, solutions, emulsions or suspensions. The active ingredient can be mixed with pharmaceutically inert, organic or inorganic carriers, for the purpose of manufacturing such preparations. Lactose, corn starch, talc, stearic acid can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes or fats; however, depending on the nature of the active ingredient, vehicles are normally not required in the case of soft gelatine capsules. Suitable vehicles for the manufacture of oral solutions are, for example, water, sucrose, invert sugar and glucose. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, pH regulators, coating agents or antioxidants. They may also contain other therapeutically valuable substances. As mentioned above, compound C can be used in the control or prevention of diseases such as atherosclerosis and CAD, particularly myocardial infarction. The dose can vary within wide limits and, of course, will be adjusted to the individual requirements of each particular case. In general, a daily dose of about 10 mg to about 1 g, preferably about 100 to about 500 mg, would suffice. The daily dose can be taken in one, two or three individual doses, for example, with food. A single dose form contains from about 10 to 500 mg of compound C. A hard gelatin capsule contains, for example, 30, 60, 125, 250 or 500 mg of compound C and finely crystalline lactose up to a weight of 580. at 590 mg. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as an antecedent, what is contained in the following is claimed as property.