MXPA01007294A - Use of cholesterol-lowering agent - Google Patents

Abstract

The invention concerns the use of particular oral dosages or dosage ranges of the compound (E) -7 -[4 -(4 -fluorophenyl) -6 -isopropyl -2 -[methyl(methylsulfonyl)amino]pyrimidin -5 -yl]-(3R,5S) -3, 5 -dihydr oxyhept -6 -enoic acid or a pharmaceutically acceptable salt thereof, to alter beneficially lipid levels or lipid ratios in a human patient in need thereof, as well as pharmaceutical compositions of said compound or salts adapted for oral administration which comprise such dosages, and methods of preparation thereof.

Description

USE OF AN AGENT THAT REDUCES CHOLESTEROL DESCRIPTION OF THE INVENTION The present invention relates to the use of a Agent that reduces cholesterol, and more particularly to the administration of a particular dose or dosage range of HMG CoA reductase inhibitor, (E) 7- [4- (4-fluorophenyl) -β-isopropyl-2- [ethyl]] (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic and the pharmaceutically acceptable salts thereof, hereinafter referred to as "the Agent", and illustrated (as the salt of calcium) in formula I below. The invention further relates to the range of dosage, starting dose and dosage forms of the Agent. The Agent is described in the Patent Application European, Publication No. 0521471, and in Bioorganic and Medicinal Chemistry, (1997), 5 (2), 437-444 as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) which is an enzyme principal that limits the relationship in cholesterol biosynthesis. The agent is taught as useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. HMG-CoA reductase inhibitors are the most widely prescribed prescription medication for the treatment of hypercholesterolemia. A number of HMG-CoA reductase inhibitors are marketed, mainly lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin and cerivastatin, collectively referred to as "statin". Despite the benefits of statin therapy, less than optimal results may be achieved in patients, due to the level of efficiency and safety achieved at the recommended dosages of currently marketed statins. Consequently, it is important to find dosages of alternative statins that beneficially alter lipid levels to a significantly greater degree than similar dosages of currently used statins and that have a similar or improved safety profile. Surprisingly it has now been found that when dosed orally in patients with hypercholesterolemia at particular dosages or in a particular dosage range the Agent reduces total cholesterol (TC) and cholesterol with low density lipoprotein (LDL-C) to an unexpected degree, and without any significant adverse side effects. When dosed in the same dosages or in the same dosage range, the Agent also modifies other lipoprotein levels (such as by increasing cholesterol levels with low density lipids (HDL-C), reducing triglyceride (TG) levels and by reducing the levels of apolipoprotein B-100 (Apo-B) to an unexpected and beneficial degree, without any significant adverse side effects, increases in the levels of liver enzyme alanine aminotransferase (ALT) s reported for other HMG inhibitors. -CoA reductase Surprisingly it has now been found that when the Agent is dosed in the dosages or dosing ranges discussed herein, clinically significant increases are frequently observed, accordingly, one aspect of the present invention comprises a method for reducing LDL-C levels by 40% or more, and / or reduce total cholesteric levels by 30% or more, and / or reduce the levels of Ig glyceride in 10% or more, and / or reduce apolipoprotein B 100 levels by 30% or more, and / or increase HDL-C levels by 5% more, in a patient in need of them, by administration from 5 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method of treating hypercholesterolemia in a patient in need thereof by administering at 80 mg per day of the Agent. A further aspect of the present invention comprises a method for reducing LDL-C levels by 40 or more in a patient in need thereof by the administration of 5 to 80 mg per day of the Agent. An additional aspect of the present invention comprises a method for reducing LDL-C levels by 45% or more in a patient in need thereof by administration of 10 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for reducing LDL-C levels by 50% or more in a patient in need thereof by the administration of 10 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for reducing LDL-C levels by 55% or more in a patient in need thereof by administration of 20 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for reducing LDL-C levels by 60% or more in a patient in need thereof by the administration of 40 to 80 mg per day of the Agent. A preferred feature of the present invention comprises a method of treatment as described above wherein the LDL-C level of the patient prior to treatment with the Agent, when measured after 12 hours of fasting (water allowed) is 4.1 mmol / liter or more. A further aspect of the present invention comprises a method for reducing total cholesterol levels by 30% or more in a patient in need thereof by administration of 10 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for reducing total cholesterol levels by 35% or more in a patient in need thereof by administration of 10 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for reducing total cholesterol levels by 40% or more in a patient in need thereof by the administration of 40 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for treating a hypercholesterolemic patient to bring the patient within the recommended NCEP guidelines (or other recognized regimens) by the administration of 5 to 80 mg per day of the Agent. The recommended NCEP guidelines refer to the LDL-C objective II levels of the Adult Treatment Panel-National Cholesterol Education Program (NCEP-ATP), which are incorporated herein for reference. A summary of these guidelines is given in JAMA, June 16, 1993-Vol 629, No. 23, pages 3015-3023, particularly Figure 1, pages 3018-3019. The NCEP guidelines recommend that patients with clinically evident coronary heart disease (CHD), such as documented atherosclerosis, be titrated at LDL-C concentrations less than or equal to 100 mg / dl. Other recognized guidelines include the guidelines of the European Atherosclerosis Society (EAS), which recommends the aggressive management of lipids in patients with a LDL-C target of 115 mg / dL. Where a patient does not have clinically evident CHD, but has 2 or more risk factors for the disease, the NCEP guidelines recommend that patients be titrated to LDL-C concentrations less than 130 mg / ml. Where a patient does not have clinically evident CHD and one or no risk factor, the goal of the NCEP regimen is less than 160 mg / dL. A further aspect of the present invention comprises a method for treating ipertriglyceridemia by the administration of 5 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for increasing the high density lipid (HDL) levels in a patient in need thereof by the administration of 5 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method for increasing or maintaining the levels of (HDL) while reducing the levels of LDL-C in a patient in need thereof by administering 5 to 80 mg per day of the Agent. Preferred levels of reduction of LDL-C levels, while maintaining or increasing HDL levels, include the percentage reduction levels in LDL-C given in the above methods. A further aspect of the present invention comprises a method for reducing the levels of Apolipoprotein B in a patient in need thereof by the administration of 5 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method of treating mixed hyperlipidemia in a patient in need thereof by administering from 5 to 80 mg per day of the Agent. A further aspect of the present invention comprises a method of treating atherosclerosis in a patient in need thereof by the administration of 5 80 mg per day of the Agent. When herein it is referred to a dosage range of 5 to 80 mg per day, 10 to 80 mg per day, 20 80 mg per day or 40 to 80 mg per day, other particular dosage ranges which are additional independent aspects of the invention include (as appropriate) 80 mg per day, 10 to 60 mg per day, 10 to 40 mg per day, 5 40 mg per day, 5 to 20 mg per day, 10 to 20 mg per day, 20 to mg per day, 20 to 40 mg per day and 40 to 60 mg per day. Accordingly, to avoid doubt, particular independent aspects of the present invention comprise the following: (1) a method for reducing levels of LDL-C in patient in need thereof by (i) 40% or more by administration of 5 to 20 per day of the Agent; (ii) 45% or more by the administration of 10-2 (preferably 10) mg per day of the Agent; (iii) 50% or more by the administration of 10- (preferably 10) mg per day of the Agent; (iv) 55% or more per administration of 20-40 per day of the Agent; (v) 60% or more by the administration of 40-80 mg p day of the Agent; (2) a method for reducing the total cholesterol levels of a patient in need thereof by (i) 30% or more by the administration of 5 to 10 per day of the Agent; (ii) 35% or more per administration of 10 to 20 per day of the Agent; (iii) 40% or more per administration of 20-40 per day of the Agent; or (iv) 45% or more per administration of 40-80 per day of the Agent; (3) a method for increasing HDL-C levels in a patient in need thereof by (i) 5% or more by administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (ii) 8% or more per administration of 5 to 20 m per day of the Agent; or (iii) 10% or more by the administration of 5 to 10 m per day (especially 10 mg per day) of the Agent; (iv) a method for reducing the levels of apolipoprotein B-100 in a patient in need thereof by (i) 30% or more by the administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (ii) 35% or more by the administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (iii) 40% or more per administration of 10 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; (iv) 45% or more per administration of 20 to 80 mg per day of the Agent; or (v) 50% or more by the administration of 40 to 80 mg per day of the Agent; (5) a method for reducing triglyceride levels in a patient in need thereof by (i) 10% or more by the administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; or (ii) 20% or more by the administration of 20 to 40 mg per day of the Agent; Additional independent aspects of the present invention comprise the following: (1) a method for reducing LDL-C levels in a patient in need thereof by 30% or more by the administration of 1 to 5 mg per day, more particularly 2.5 at 5 mg per day, of the Agent; (2) a method for reducing total cholesterol levels in a patient in need thereof by 30% or more by the administration of 2.5 to 5 mg per day of the Agent; (3) a method for increasing HDL-C levels in a patient in need thereof by 5% or more by the administration of 2.5 to 5 mg per day of the Agent; (4) a method for reducing the levels of apolipoprotein B-100 in a patient in need thereof by 30% or more by the administration of 2.5 to 5 mg per day of the Agent; or (5) a method for reducing triglyceride levels in a patient in need thereof by 10% or more by the administration of 2.5 to 5 mg per day of the Agent. Additional aspects of the present invention comprise the following: (1) a method for reducing LDL-C levels by 30% or more and increasing HDL-C levels by 5% (more particularly 8%) or more in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; at HDL-C levels in 5% HDL-levels in 5% (more particularly 8%) or more in a patient need thereof by the administration of 1 to 5 mg per day of the Agent, (2) a method to reduce LDL-C levels by 40% or more and increase HDL-C levels by 5% (more particularly 8%) or more in a patient in need thereof by the administration of 2.5 to 10 mg per day from the people; (3) a method to reduce LDL-C levels by 45% or more and increase HDL-C levels by 5% (more particularly 8%) or more in a patient in need thereof by administering 5 to 20 mg per day of the Agent; (4) a method to reduce LDL-C levels by 50% or more and increase HDL-C levels by 5% (more particularly 8%) or more in a patient in need thereof by administering 10 to 20 mg per day of the Agent; (5) a method to reduce LDL-C levels by 55% or more and increase HDL-C levels by 5% (more particularly 8%) or more in a patient in need thereof by administration, from 20 to 40 mg per day of the Agent; or (6) a method for reducing LDL-C levels by 60% or more and increasing HDL-C levels by 5% (more particularly 8%) or more in a patient in need thereof by the administration of to 80 mg per day of the Agent. Additional aspects of the present invention comprise the following: (1) a method to reduce LDL-C levels by 30% or more and reduce levels of apolipoprotein B-100 by 25% or more by the administration of 1 to 5 mg by Agent's day; (2) a method to reduce LDL-C levels in 45% or more and reduce the levels of apolipoprotein B-100 by 35% or more by the administration of 5 to 20 mg per day (particularly 5 to 10 mg per day) of the Agent; (3) a method to reduce LDL-C levels by 50% or more and reduce levels of apolipoprotein B-100 in 40% or more per administration of 10 to 20 mg per day of the Agent; (4) a method for reducing LDL-C levels by 55% or more and reducing levels of apolipoprotein B-100 by 45% or more by administering 20 to 40 mg per day of the Agent; (5) a method for reducing LDL-C levels by 60% or more and reducing levels of apolipoprotein B-100 by 50% or more by the administration of 40 to 80 mg per day of the Agent; Additional aspects of the present invention comprise the following: (1) a method for reducing LDL-C levels by 30% or more and reducing triglyceride levels by 10% or more by administration of 1 to 5 mg per day of the Agent; (2) a method to reduce LDL-C levels by 45% or more and reduce triglyceride levels by 10% or more by the administration of 5 to 20 mg per day (particularly 5 to 10 mg per day) of the Agent; (3) a method to reduce LDL-C levels in 50% or more and reduce triglyceride levels by 10% or more by administration of 10 to 20 mg per day of the Agent; (4) a method for reducing LDL-C levels by 55% or more and reducing triglyceride levels by 10% (more especially 20%) or more by the administration of 20 to 40 mg per day of the Agent; or (5) a method for reducing LDL-C levels by 60% or more and reducing triglyceride levels by 10% (more especially 20%) or more by the administration of 40 to 80 mg per day of the Agent; Additional aspects of the present invention comprise the following: (1) A method for increasing LDL-C levels in % (particularly 8% and more particularly 10%) or more and reduce the levels of apolipoprotein B-100 by 25% or more in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; or (2) A method to increase LDL-C levels by 5% (particularly 8% and more particularly 10%) or more and reduce triglyceride levels by 10% or more in a patient in need of it by administration. from 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent. Additional aspects of the present invention comprise the following: (1) a method for reducing LDL-C levels by 30% or more, raising HDL-C levels by 5% (more particularly 8%) or more and reducing the triglyceride levels in 10% or more in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; (2) a method to reduce LDL-C levels by 40% or more by raising HDL-C levels by 5% (more particularly 8%) or more and reducing triglyceride levels by 10% or more in a patient in need thereof by the administration of 2.5 to 10 mg per day of the Agent; (3) a method to reduce LDL-C levels by 45% or more, raising HDL-C levels by 5% (more particularly 8%) or more and reducing triglyceride levels by 10% or more in a patient in need thereof by the administration of 5 to 10 mg per day of the Agent; (4) a method to reduce LDL-C levels by 50% or more, raising HDL-C levels by 5% (more particularly 8%) or more and reducing triglyceride levels by 10% or more in a patient in need thereof by the administration of 10 to 20 mg per day of the Agent; (5) a method to reduce LDL-C levels by 55% or more by raising HDL-C levels by 5% (more particularly 8%) or more and reducing triglyceride levels by 10% or more in a patient in need thereof by the administration of 20 to 40 mg per day of the Agent; (6) a method to reduce LDL-C levels by 60% or more, raising HDL-C levels by 5% (more particularly 8%) or more and reducing triglyceride levels by 10% or more in a patient in need thereof by the administration of 40 to 80 mg per day of the Agent; Additional aspects of the present invention comprise the following: (1) A method for increasing HDL-C levels in % (particularly 8% and more particularly 10%) or more, reducing apolipoprotein B-100 levels by 25% or more and reducing triglyceride levels by 10% or more in a patient in need of. same by the administration of 1 to 5 mg per day of the Agent; or (2) A method to increase HDL-C levels by 5% (particularly 8% and more particularly 10%) or more, by reducing levels of apolipoprotein B-100 by 25% or more and by reducing triglyceride levels in 10% or more in a patient in need thereof by the administration of 5 to 80 mg per day (particularly 5 to 40 mg per day, more particularly 10 to 20 mg per day, especially 10 mg per day) of the Agent; Additional aspects of the present invention comprise the following: (1) a method for reducing the LDL-C / HDL-C lipid ratio below 2.2 in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; (2) a method for reducing the LDL-C / HDL-C lipid ratio below 2.0 in a patient in need thereof by the administration of 5 to 10 mg per day of the Agent; (3) a method for reducing the LDL-C / HDL-C lipid ratio below 1.5 in a patient in need thereof by administering 20 to 40 mg per day of the Agent; (4) a method for reducing the LDL-C / HDL-C lipid ratio below 1.2 in a patient in need thereof by administering 80 mg per day of the Agent; (5) a method for reducing the lipid ratio of non-HDL-C / HDL-C down to 2.6 in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; (6) a method for reducing the lipid ratio of non HDL-C / HDL-C down to 2.2 in a patient in need thereof by the administration of 5 to 10 mg per day of the Agent; (7) a method for reducing the lipid ratio of non-HDL-C / HDL-C below 2.0 in a patient in need thereof by the administration of 20 to 40 mg per day of the Agent; (8) a method for reducing the lipid ratio of non-HDL-C / HDL-C below 1.5 in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; (9) a method for reducing the ratio of TC / HDL-C lipids down to 3.6 in a patient in need thereof by the administration of 1 to 5 mg per day of the Agent; (10) a method for reducing the ratio of CT / HDL-C lipids down to 3.3 in a patient in need thereof by the administration of 5 to 10 mg per day of the Agent; (11) a method for reducing the ratio of CT / HDL-C lipids down to 3.0 in a patient in need thereof by the administration of 20 to 40 mg per day of the Agent; or (12) a method for reducing the ratio of CT / HDL-C lipids down to 2.5 in a patient in need thereof by the administration of 80 mg per day of the Agent. A particularly suitable starting dose of the Agent in the methods referred to herein is 5 to 10 mg per day, especially 10 mg per day. After the initiation and / or titration of the Agent, the lipid levels can be analyzed and the dosage adjusted accordingly. A further aspect of the invention is therefore a method as defined above when the Agent is administered at a starting dose of 5 to 10 mg per day, for example a method for reducing LDL-C levels in a patient in need thereof by 40% or more by the administration of 5 or 10 mg per day of the Agent. A further aspect of the present invention comprises a dosage regimen comprising administering an initial dose of 5 or 10 mg per day of the Agent to a patient in need thereof, such as a patient with an LDL-C level of 160. mg / dl or greater without chronic heart disease (CHD) or peripheral vascular disease (PVD) and one or no risk factors, a patient with an LDL-C level of more than 130 mg / dl without CHD or PVD and with 2 or more risk factors, or a patient with an LDL-C level of more than 100 mg / dl with CHD or PVD clinically evident. Another particular group of patients who are treated beneficially with the administration of an initial dose of 5 to 10 mg per day of the Agent includes, for example, those patients whose LDL-C level is >4 mmol / liter and / or whose CT level is> 5 mmol / l and / or whose HDL-C level is < 1 mmol / liter and / or whose TG level is > 2 mmol / liter. An initial dose of 5 to 10 mg per Agent unexpectedly has a superior efficiency and safety profile comparable to the best, compared to initial doses of other statins, and is therefore particularly advantageous. Carrying out the methods of the invention, Agent will be administered to a patient in the form of a pharmaceutical composition. A further aspect of the invention is therefore a pharmaceutical composition comprising 5 to 80 mg of the Agent together with a pharmaceutically acceptable diluent excipient. Particular pharmaceutical compositions which are themselves independent additional aspec of the invention comprise, for example, 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of the Agent ju with a pharmaceutically acceptable diluent carrier. Pharmaceutical compositions will be in the form of a conventional dosage unit, for example tablet capsules. Accordingly, a further aspect of the invention comprises a tablet or capsule containing Agent in the amounts given above. The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Preferably the Agent is administered as a single dosage once daily. It will be appreciated that for each treatment method referred to above, a further aspect of the invention comprises the use of the Agent in the amount specified for the manufacture of a medicament for use in the treatment methods. Preferably the Agent is calcium salt of bis [(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2 [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) - 3,5-dihydroxyhept-6-enoic]. Where a dose of (or a pharmaceutical composition comprising) 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of the Agent is referred to herein, this includes a dose (or pharmaceutical composition comprising) of 5.2 mg, 10.4 mg, 20.8 mg, 41.6 mg and 83.2 mg respectively of the calcium sa of formula 1. Such doses (or compositions) are calculated to provide the equivalent of 5 mg, 10 mg, 2 mg, 40 mg and 80 mg respectively of the libr acid form when dosed. Pharmaceutical Compositions The following Example illustrates, but is not intended to limit, pharmaceutical dosage forms that are suitable for use in the invention as defined herein: Capsule mg Agent 5.0 Lactose 42.5 Corn starch 20.0 Microcrystalline cellulose 32.0 Pregelatinized starch 3.3 Synthetic hydrotalchite 1.1 Magnesium stearate 1.1 Capsules containing 1, 2.5 or 10 mg of the Agent can be obtained similarly using more or less lactose as appropriate to maintain a total filling weight of 105 mg. Such preferred formulations are those in which the Agent is the calcium salt of bis [(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5] il] - (3R, 5S) -3,5-dihydroxyhept-6-enoic]. To illustrate the invention, a randomized study was carried out in parallel groups of dose response with the calcium salt of bis [(E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [] acid. methyl (methylsulfonyl) amino] -pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic acid] (hereinafter referred to as ZD4522) and atorvastatin (ATORV) in subjects with primary hypercholesterolemia. Main Objectives The main objective of this test was to estimate the dose response relationship between the dose of ZD4522 and the percentage of reduction of LDL-C from the value of the baseline with respect to a placebo. Secondary Objectives. Secondary objectives of this test include: estimating the effect of doses of 10 and 80 mg of atorvastatin on LDL-C levels; to estimate the effects of ZD4522 and atorvastatin on levels of HDL-C, TG, TC, apolipoprotein A-1, apolipoprotein Lp (a), apolipoprotein B-100 and LDL-C (by indirect method); to evaluate the pharmacokinetics of the oral doses of 1,2,5,5,10,20, and 40 mg ZD4522 (formulations in capsules) during a treatment period of 6 weeks; and to assess the tolerability and safety of ZD4522 compared to placebo. Test Design After a 6-week diet insertion, subjects were randomly placed in doses of atorvastatin (10 or 80 mg), supplied with open incorporation, or for placebo or a six-dose ZD4522 (supplied blindly). The analysis of the blind portion of the test directed to the primary objective. The open atorvastatin groups were included to obtain additional data on the initial and high doses of an agent that reduces the cholesterol tested in this patient population.

Test Plan. A total of 10 visits were made to each clinic. Three of these took place during the period of placebo-controlled diet insertion (weeks -6, -2 and -1), five during the treatment phase (weeks 0 = randomization visit, weeks + l, + 2, +4 and +6) and two continuation visits (weeks +8 and +10). The Number of Subjects. The main endpoint on which the sample size is based is the percentage of baseline reduction in LDL-C values (LDL cholesterol). A sample size of 9 in each group will have 90% power to detect a difference in the middle of 25% between 2 groups, assuming that the common standard deviation is 15% using a group of 2 t tests with a level of significance of two sides of 0.05. This has been increased to 12 subjects per group to adjust for multiple comparisons of groups against placebo while retaining a power of at least 90% (based on simulations). This sample size also leads to an estimate of the dose response curve for the percent decline in LDL-C with a confidence band width of less than 10% for the majority of the dose range. Inclusion criteria. For inclusion in the diet insertion period, subjects had to meet all of the following criteria: (1) LDL cholesterol fasting (> 4.14 but < 6.21 mmol / L); (2) fasting levels of triglycerides (< 3.39 mmol / L); (3) male subjects, from 18 to 70 years of age. Female subjects 50 to 70 years of age; (4) absence of menstruation for more than two years and of hormone that stimulates follicles (FSH), luteinisante hormone (LH) and estradiol within the post-menopausal range (using local laboratory ranges); (5) Body mass index < 30 kg / m2. For inclusion in the randomized treatment phase of the test, subjects had to meet all of the following criteria: (6) LDL cholesterol fasting > 4.14 mmol / L but < 5.69 mmol / L of measurements taken in weeks -2 and -1 before randomization, with the lowest value within 15% of the highest value; (7) TG fast < 3.39 mmol / L in weeks -6, -2 and -1, before randomization; (8) a Food Register Evaluation Score (FRR) < 15 in weeks -2 and -1, before randomization, to demonstrate compliance with the diet of Stage -1 of the American Heart Association. Exclusion Criteria Any of the following was considered as a criterion for the exclusion of the test: (1) Subjects who use drugs that reduce cholesterol (this therapy may have been discontinued at least 4 weeks before the beginning of the insertion period of the The subjects who take probucol must have discontinued 12 months before inclusion in this study). (2) History of serious reactions or hypersensitivity to other inhibitors of HMG-CoA reductase. (3) Subjects with active arterial disease such as unstable angina, myocardial infarction, transient ischemic attack (TIA), cerebrovascular accident (CVA) or coronary artery bypass graft (CABG) within 6 months or angioplasty within 3 months of entry to the study. (4) History of malignancy except in subjects whose only malignancy has been squamous cell carcinomas of the skin. Female subjects who have a history of cervical dysplasia unless 3 consecutive normal cervical smears have been recorded before entry. (5) Uncontrolled hypertension (diastolic blood pressure = 95 mm Hg). Subjects who are taking thiazide diuretics and beta-blockers will not be excluded on the condition that they remain at a stable dose starting 3 months before the start of the study and through the study. (6) Diabetes mellitus and / or other metabolic endocrine diseases known to be associated with alterations in plasma lipid levels (uncontrolled hypothyroidism defined as a TSH> 1.5 times in ULN at week -6, subjects with nephrotic syndrome). (7) Known homozygous familial hypercholesterolemia or known type III hyperlipoproteinaemia (familial dysbetalipoproteinemia). (8) use of medications with detailed concomitants as follows: MEDICATIONS REJECTED Anti-Seizure Drugs Cimetidine Cisapride Systemic Steroids Triamcinolone Acetonide Triamcinolone Diacetate Betamethasone Sodium Phosphate Betamethasone Acetate Hydrocortisone Hydrocortizone Acetate Hydrocortizone Sodium Phosphate. Sodium Hydrocortisone Succinate. Cortisone Acetate Dexamethasone Dexamethasone Acetate Dexamethasone Sodium.

Antiarrhythmics Digoxin Anticoagulant Warfarin Antihistamine Astemizole Terfenadine Systemic steroids Prednisolone Phosphate Methylprednisolone (9) History of alcohol and / or drug abuse. (10) Subjects with active liver disease or liver dysfunction as defined by elevations in liver enzymes (ALT, AST,? GT, ALP) or bilirubin > = 1.5 times ULN at any time before randomization in Visit 4. (11) Subjects with serum creatinine > 180 μmol / L before randomization. (12) Participation in another study less than 3 months before enrollment in the period of diet insertion. (13) CK in serum > 3 times ULN in weeks -6 and -1 (Visit 1 and 3). (14) Clinically significant ophthalmic abnormalities, which will allow simple refractive errors. (15) Subjects who have received randomized medication can not re-enter this study. (16) Subjects who have serious or unstable medical or psychological conditions that, in the opinion of the researcher, would compromise the subject's safety or successful participation in the study. (17) Subjects who are receiving hormone replacement therapy (HRT). (18) Subjects receiving digoxin and / or coumarin anticoagulants. Test Methods Summary Subjects were asked to take the study drug once daily, not less than 3 hours after the evening meal. At visits 1, 2, 3, 4, 6, 7, 8, 9 and 10 the test subjects were reported to the clinic after fasting for 12 hours (water allowed) and blood was drawn to determine fasting lipids. Subjects provided a urine sample, and blood samples for clinical biochemical and haematological evaluation. Where the clinical biochemical and lipid measurements were calibrated at the same visit, only one sample was taken. At visits 4, 6, 7 and 8, pharmacokinetic samples were collected. Weight, blood pressure and heart rate were measured and recorded in all visits. Visits 1 and 10 were made in ECG. The analytical laboratory used is certified for standardization of lipid analysis as specified by the standardization program of the centers for the control and prevention of diseases and the National Heart, Lung and Blood Institute. Analysis (a) Lipids The concentrations of the following lipids LDL-C, HDL-C, TG, TC, apo AI, apo A-II, Lp (a), apo B, LDL-C (by the Friedewald equation) were determined. and the ß-quantification method). (b) Biochemistry The concentrations of the following, AST, ALT, CK1? GT, ALP and total bilirubin, sodium, potassium, calcium, chloride, phosphate, bicarbonate creatinine, fasting blood and serum tyrosine (T4) were determined. and hormone that stimulates thyroid (TSH). Unless they were surgically sterilized, the female subjects had post-menopausal status confirmed by the measurement of FSH, LH and estradiol at visit 1. Hematology. Complete blood counts were performed and included the following; count of heritrocytes, hemoglobin, hematocrit, leukocyte cell count, platelets red cell distribution width differential percentage of leukocyte count (including percentage of unstained large cells) mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration. He performed a coagulation screen on visits 1 and 10 only. Urine analysis. At visits .1, 3, 4, 5, 6, 7, 8, 9 and 10, urinalysis was performed on 10 ml of urine samples at half the flow and tested at the clinic for the following using labstix. dipstix: pH, glucose, blood, ketones, protein and bilirubin. Results 1. Study Branch Percentage of Average LDL-reduction in Week 6 (Friede ald method) Placebo 8 ZD4522 1 mg 36 ZD4522 2.5 mg 43 ZD4522 5 mg 45 ZD4522 10 g 52 ZD4522 20 mg 59 ZD4522 40 g 63 Atorvastatin 10 mg 44 Atorvastatin 80 mg 59 2. Study Branch Lipid parameters (% mean change from base line in week 6) TC TG [DL-C Apo-B Placebo -5.3 - -1.7 +2.8 -2.8 ZD4522 1 mg -25.3 -16.9 + 8.8 -28.8 ZD4522 2.5 mg -30.8 -12.3 + 8.8 -34.6 ZD4522 5 mg -32.9 -34.8 + 13.2 -37.6 ZD4522 10 g -36.7. -12.0 + 13.7 -42.3 ZD4522 20 mg -41.9 -26.2 + 9.2 -48.9 ZD4522 40 mg -46.1 -25.5 + 9.4 -54.6 Atorvastatin 10 mg -32.0 -13.6 + 6.8 -36.4 Atorvastatin 80 mg -46.1 -30.7 -3.2 -50.2 Note: In 2, a positive value indicates a percentage of average increase in level of lipid parameters and a negative value indicates a percentage of average reduction for level of lipid parameter. 3. Branch of Study Lipid Relations (Mean value in week 6) no HDL-C / HDL-C TC / HDL-C LDL- -C / HDL-C Placebo 4.3 5.3 3.8 ZD4522 1 mg 2.5 3.5 2.2 ZD4522 2.5 mg 2.5 3.5 2.1 ZD4522 5 mg 2.2 3.2 1.9 ZD4522 10 mg 2.2 3.2 1.8 ZD4522 20 g 1.8 2.8 1.4 ZD4522 40 mg 1.5 2.5 1.3 Atorvastatin 10 mg 2.5 3.5 2.1 Atorvastatin 80 mg 2.1 3.1 1.7 4. The effects in each study branch on the percentage of total cholesterol change from the BASE LINE is given in Figure 1. The dosage started at the BASE LINE after an initial 6-week diet insertion period, according to with the previous clinical protocol. The dosage was stopped 6 weeks after the BASE LINE.

. The effects in each study branch on the percentage of LDL cholesterol (calculation of the Friedewald equation) percentage change from the BASE LINE are given in Figure 2. The dosage started in the BASE LINE after a period of insertion Initial diet of 6 weeks, according to the previous clinical protocol. The dosage was stopped at 6 weeks after the BASE LINE. 6. The effects on each branch of study on the percentage of change of HDL cholesterol from the BASE LINE are given in Figure 3. The dose started in the BASE LINE after an initial dietary insertion period of 6 weeks, according to the previous clinical protocol. The dosage was stopped at six weeks after the BASE LINE. 7. The effects on each branch of study on the percent change of apolipoprotein B-l00 from the BASE LINE is given in Figure 4. Dosing started at the BASE LINE after an initial dietary insertion period of 6. weeks, according to the previous clinical protocol. The dosage was stopped 6 weeks after the BASE LINE. 8. Effects on each branch of study on the percentage of triglyceride exchange from the baseline are given in Figure 5. Dosing started at the BASE LINE after an initial dietary insertion period of 6 weeks in accordance with the previous clinical protocol. The dosage was stopped 6 weeks after the BASE LINE.

It will be appreciated that alternative or additional tests of shorter or longer duration can be carried out with the agent to demonstrate the present invention, such as other randomized double-blind tests, optionally controlled with placebo with selected dose of agent and selected dose of statins commercially available (eg, atorvastatin, pravastatin, simvastatin) as comparators in subjects with hypercholesterolemia with or without a history of CHD or PVD or with risk factors for them, measuring changes in LDL-C and other lipids or lipoprotein fractions and the safety of the agent with respect to, for example, serum transaminase levels.

Formula I

Claims (21)

1. CLAIMS 1. The use of the acid compound (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) -3 , 5-dihydroxyhept-6-enoic or a pharmaceutically acceptable salt thereof, for the manufacture of an oral dosage form comprising 5 to 80 mg of the compound for use to reduce LDL-C levels by 40% or more, and / or reduce total cholesterol levels by 30% or more, and / or reduce triglyceride levels by 10% or more, and / or reduce levels of apolipoprotein B-100 by 30% or more and / or increase levels of HDL-C at 5% or more in a human patient in need thereof, where the compound is administered from 5 to 80 mg per day.
2. 2. The use of the compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the oral dosage manufacture comprising from 5 to 10 mg of the compound for use to reduce the levels of LDL-C 40% or more , and / or reduce total cholesterol levels by 30% or more, and / or reduce triglyceride levels by 10% or more, and / or reduce apolipoprotein B-100 levels by 30% or more, and / or increasing HDL-C levels by 5% or more in a human patient in need thereof, wherein the compound is administered from 5 to 10 mg per day.
3. 3. The use of the compound or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of an oral dosage form characterized in that it comprises from 5 to 10 mg of the compound for use to lower LDL-C levels by 45% or more in a human patient in need of it.
4. 4. The use of the compound or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of an oral dosage form characterized in that it comprises 5 to 10 mg of the compound for use to reduce the total cholesterol levels by 35% or more in a human patient in need of it.
5. 5. The use of the compound or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of an oral dosage form characterized in that it comprises 5 to 10 mg of the compound for use to reduce triglyceride levels by 10% or more in a human patient in need of it.
6. 6. The use of the compound or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of an oral dosage form characterized in that it comprises 5 to 10 mg of the compound for use to reduce apolipoprotein levels of B-100 in 35% or more in a human patient in need of it. The use of the compound or a pharmaceutically acceptable salt thereof according to claim 2, for the manufacture of an oral dosage form characterized in that it comprises from 5 to 10 mg of the compound for use to increase the levels of HDL-C in 8% or more in a human patient in need of it. The use according to any one of claims 1 to 7, characterized in that the oral dosage form is administered as a single dose, once daily. 9. A pharmaceutical composition adapted for oral administration comprising 5 to 80 mg of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (ethylsulfonyl) amino] pyrimidin-5-acid. il] - (3R, 5S) -3,5-dihydroxyhept-6-enoic or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. 10. A pharmaceutical composition adapted for oral administration comprising from 5 to 10 mg of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-acid. il] - (3R, 5S) -3,5-dihydroxyhept-6-enoic or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier. 11. A pharmaceutical composition according to claim 9 or 10, characterized in that it comprises 5.2 to 10.4 mg of the calcium salt of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2-acid. [ethyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic, together with a pharmaceutically acceptable diluent or carrier. A method for preparing a pharmaceutical composition according to claim 9, 10 or 11, characterized in that it comprises mixing the compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier diluent. 13. A method to reduce LDL-C levels by 40% or more, and / or reduce total cholesterol levels by 30% or more, and / or reduce triglyceride levels by 10% or more, and / or reduce apolipoprotein B-100 levels by 30% or more, and / or increase HDL-C levels by 5% or more, in a human patient in need thereof, by oral administration of 5 to 80 mg per day of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-acid enoic or a pharmaceutically acceptable salt thereof. 14. A method according to claim 13, characterized in that 5- (10 mg) per day of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [ethyl (methylsulfonyl)] is administered per day. amino] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic or a pharmaceutically acceptable salt thereof. 15. A method according to claim 14, characterized in that it is a method for reducing LDL-C levels by 45% or more. 16. A method in accordance with the claim 14, characterized in that it is a method for reducing total cholesterol levels by 35% or more 1
7. 7. A method according to claim 14, characterized in that it is a method for reducing triglyceride levels by 10% or more. 1
8. 8. A method according to claim 14, characterized in that it is a method for reducing apolipoprotein B-100 levels by 35% or more. 1
9. 9. A method according to claim 14, characterized in that which is a method for increasing HDL-C levels by 10% or more. 20. A method for reducing the LDL-C / HDL-C lipid ratio below 2.0 in a patient in need thereof by the administration of 5 to 10 mg per day of (E) -7- [4- (4 -fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic or a pharmaceutically acceptable salt thereof. 21. A dosing regimen comprising the administration of a dose of 5 to 10 mg per day of (E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] acid ] pyrimidin-5-yl] - (3R, 5S) -3,5-dihydroxyhept-6-enoic or a pharmaceutically acceptable salt thereof to a patient having (i) an LDL-C level of 160 mg / dl or elderly without chronic heart disease or peripheral vascular disease and one or no risk factor for said disease; (ii) a level of LDL-C of more than 130 mg / dl without chronic heart disease or peripheral vascular disease and two or more risk factors for said disease; or (iii) an LDL-C level of more than 100 mg / dl with clinically evident chronic heart disease or peripheral vascular disease.