Drug for lowering blood LDL cholesterol

Abstract

Provided is a novel preventive or therapeutic agent that is useful in the prevention and / or treatment of disease that is expected to respond to treatment for lowering blood LDL-C.　The present invention relates to a drug for preventing and / or treating disease that is expected to respond to treatment for lowering blood LDL-C. This drug contains the therapeutically effective dose of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid or a salt or a solvate thereof.

Description

Blood LDL cholesterol lowering agent

[0001] The present invention relates to a blood LDL cholesterol-lowering agent.

[0002] Many epidemiological studies have shown that the incidence and mortality of coronary artery disease increase with an increase in blood LDL cholesterol (LDL-C). Furthermore, in recent years, a series of reports have shown that actively lowering blood LDL-C can suppress the onset of cardiovascular events in patients at risk of developing coronary artery disease, making blood LDL-C lowering therapy clinically important. Against this background, clinical practice guidelines in various countries set blood LDL-C management targets according to the risk of developing coronary artery disease (Non-Patent Documents 1 to 3).

[0003] While managing blood LDL-C levels is primarily based on lifestyle modification, including diet and exercise therapy, pharmacological therapy is required for patients in whom lifestyle modification alone is insufficient. While HMG-CoA reductase inhibitors (hereinafter referred to as statins) are recommended as the first-line drug for pharmacological therapy, many patients are unable to achieve their blood LDL-C target levels with statins alone, and these patients require the addition of other therapeutic agents, such as ezetimibe or PCSK9 inhibitors (Non-Patent Documents 1-3). Furthermore, a certain number of patients are unable to continue statin administration due to side effects such as muscle-related or liver damage, and these patients also require other therapeutic agents, such as ezetimibe or PCSK9 inhibitors (Non-Patent Documents 4 and 5). However, pharmacological therapy options aimed at lowering blood LDL-C levels are limited, and new therapeutic agents may be useful for adequately managing blood LDL-C levels.

[0004] On the other hand, Patent Document 1 discloses the following formula (1):

[0005]

[0006] (In the formula, R 1 and R 2 are the same or different and represent a hydrogen atom, a methyl group, or an ethyl group; R 3a , R 3b , R 4a and R 4bare the same or different and are a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, C 1-4 Alkyl group, trifluoromethyl group, C 1-4 Alkoxy group, C 1-4 Alkylcarbonyloxy group, di-C 1-4 Alkylamino group, C 1-4 Alkylsulfonyloxy group, C 1-4 Alkylsulfonyl group, C 1-4 alkylsulfinyl group, or C 1-4 represents an alkylthio group, or R 3a and R 3b Or R 4a and R 4b are bonded to form an alkylenedioxy group; X is an oxygen atom, a sulfur atom, or N—R 5 (R 5 is a hydrogen atom, C 1-4 Alkyl group, C 1-4 Alkylsulfonyl group, C 1-4 represents an alkyloxycarbonyl group; Y represents an oxygen atom, S(O) l It has been disclosed that compounds represented by the following formula (I) (I represents a group (I represents a number from 0 to 2), a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or an NH group; Z represents CH or N; n represents a number from 1 to 6; and m represents a number from 2 to 6), their salts, or solvates thereof have a selective PPARα activation effect and are useful as prophylactic and / or therapeutic agents for diabetes, diabetic complications (diabetic nephropathy, etc.), inflammation, heart disease, etc., which are not accompanied by weight gain or obesity in mammals including humans. However, there is no description or suggestion as to what effect these compounds have on blood LDL-C.

[0007] International Publication No. 2005 / 023777

[0008] Japan Atherosclerosis Society (ed.): Atherosclerotic Disease Prevention Guidelines 2017 Edition. Japan Atherosclerosis Society, 2017. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA / ACC / AACVPR / AAPA / ABC / ACPM / ADA / AGS / APhA / ASPC / NLA / PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology / American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Jun 18;139(25):e1082-e1143. Authors / Task Force Members 2019 ESC / EAS guidelines for the management of dyslipidemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis 2019 Nov;290:140-205. Rodrigo Alonso1, Ada Cuevas1, Alberto Cafferata. Diagnosis and Management of Statin Intolerance. J Atheroscler Thromb, 2019; 26: 207-215. Working Group for the Development of Statin Intolerance Guidelines: Koji Kajinami, Kazuhisa Tsukamoto, Shinji Koba et al. 2018 Statin Intolerance Guidelines

[0009] An object of the present invention is to provide a novel blood LDL-C lowering agent, as well as to provide a preventive and / or therapeutic agent for diseases that can be expected to have therapeutic effects by lowering blood LDL-C.

[0010] In order to achieve the above-mentioned object, the present inventors have conducted extensive research and have completely unexpectedly found that the compound disclosed as Example 85 in the above-mentioned Patent Document 1, namely, (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (hereinafter, sometimes referred to as "Compound A" or "pemafibrate"), reduces blood LDL-C levels and is useful for the prevention and / or treatment of diseases for which a reduction in blood LDL-C levels can be expected to have a therapeutic effect, and have thus completed the present invention.

[0011] That is, the present invention provides the following [1] to

[28] . [1] A blood LDL cholesterol-lowering agent comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient. [2] The blood LDL cholesterol-lowering agent according to [1], for administration to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or to patients for whom statin administration is restricted. [3] An agent for preventing and / or treating hypercholesterolemia comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient. [4] A preventive and / or therapeutic agent for hyper-LDL cholesterolemia, comprising (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient. [5] The preventive and / or therapeutic agent according to [3] or [4], for administration to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or patients for whom statin administration is restricted. [6] A pharmaceutical composition for preventing and / or treating hypercholesterolemia, comprising a therapeutically effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof. [7] A pharmaceutical composition for preventing and / or treating hyper LDL cholesterolemia, comprising a therapeutically effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof. [8] The pharmaceutical composition according to [6] or [7], for administration to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or to patients for whom statin administration is restricted. [9] A method for lowering blood LDL cholesterol, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[10] The method according to [9], wherein the compound is administered to a patient in whom blood LDL cholesterol is not sufficiently reduced by statins or to a patient in whom statin administration is restricted.

[11] A method for preventing and / or treating hypercholesterolemia, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[12] A method for preventing and / or treating hyper LDL cholesterolemia, comprising administering an effective amount of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof to a patient in need thereof.

[13] The method for preventing and / or treating the compound according to

[11] or

[12] , wherein the compound is administered to a patient in whom blood LDL cholesterol is not sufficiently reduced by statins or to a patient in whom statin administration is restricted.

[14] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for lowering blood LDL cholesterol.

[15] The use according to

[14] , wherein the compound is administered to patients in whom blood LDL cholesterol is not sufficiently lowered by statins or patients for whom statin administration is restricted.

[16] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for preventing and / or treating hypercholesterolemia.

[17] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for preventing and / or treating hyper-LDL cholesterol.

[18] The use according to

[16] or

[17] , wherein the compound is administered to a patient in whom blood LDL cholesterol is not sufficiently reduced by statins or to a patient for whom statin administration is restricted.

[19] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of a blood LDL cholesterol-lowering agent.

[20] The use according to

[19] , which is a blood LDL cholesterol-lowering agent for administration to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or patients for whom statin administration is restricted.

[21] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for the manufacture of a pharmaceutical composition for preventing and / or treating hypercholesterolemia.

[22] Use of (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for producing a pharmaceutical composition for preventing and / or treating hyper-LDL cholesterol.

[23] The use according to

[21] or

[22] , which is a pharmaceutical composition for administration to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or patients for whom statin administration is restricted.

[24] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in lowering blood LDL cholesterol.

[25] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof according to

[24] , which is administered to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or patients for whom statin administration is restricted.

[26] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of hypercholesterolemia.

[27] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof for use in the prevention and / or treatment of hyper-LDL cholesterol.

[28] (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof according to

[26] or

[27] , which is administered to patients in whom blood LDL cholesterol is not sufficiently reduced by statins or patients for whom statin administration is restricted.

[0012] The present invention provides a new drug useful for the prevention and / or treatment of diseases for which a reduction in blood LDL-C is expected to have a therapeutic effect. According to the present invention, it is possible to provide a new blood LDL-C-lowering agent for patients for whom a statin does not sufficiently reduce blood LDL-C or for patients for whom statin administration is restricted, and also to provide a new option for prevention and / or treatment for patients with diseases for which a reduction in blood LDL-C is expected to have a therapeutic effect.

[0013] Figure 1 shows the rate of change in fasting blood LDL-C concentration when Compound A (0.4 mg per day) was administered to patients with non-alcoholic fatty liver disease. Figure 2 shows the rate of change in fasting blood LDL-C concentration when Compound A (0.4 mg per day) was administered to patients with non-alcoholic fatty liver disease. Figure 3 shows the rate of change from baseline in fasting blood lathosterol concentration, blood sitosterol concentration, and blood campesterol concentration when Compound A (0.4 mg per day) was administered to patients with non-alcoholic fatty liver disease.

[0014] The (R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid (Compound A) used in the present invention has the following chemical formula (A):

[0015]

[0016] The compound A can be produced, for example, according to the method described in the pamphlet of International Publication No. 2005 / 023777 or the like. It can also be formulated according to the method described in the literature. Furthermore, a preparation containing compound A has been approved in Japan as a hyperlipidemia treatment agent "Palmodia (registered trademark) Tablets," and these "Palmodia Tablets" can also be used.

[0017] In one embodiment of the present invention, a salt or solvate of Compound A can also be used. Salts and solvates can be prepared by conventional methods. The salt of Compound A is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic base salts such as ammonium salt and trialkylamine salt; mineral acid salts such as hydrochloride and sulfate; and organic acid salts such as acetate. Solvates of Compound A or its salts include hydrates, alcoholates (e.g., ethanolates), and the like.

[0018] As shown in the Examples below, Compound A was shown to lower blood LDL-C levels and also to lower both cholesterol synthesis and absorption markers. From these results, Compound A is considered to have the effect of lowering blood LDL-C levels by inhibiting the synthesis of LDL-C in the body and the absorption of cholesterol from food. Therefore, Compound A, its salts, or solvates thereof can be the active ingredient of blood LDL-C-lowering agents. Furthermore, Compound A, its salts, or solvates thereof are useful for the prevention and / or treatment of diseases for which a reduction in blood LDL-C levels is expected to have a therapeutic effect, via a reduction in blood LDL-C levels.

[0019] Unless otherwise specified, in this specification, the term "blood LDL-C lowering agent" refers to, for example, a drug for treating a disease or the like for which a therapeutic effect can be expected by lowering blood LDL-C through its application. Specifically, it refers to, for example, a drug for treating a disease or the like for which a therapeutic effect can be expected by lowering blood LDL-C through inhibition of LDL-C synthesis or cholesterol absorption in the body. The manner in which LDL-C is lowered is not particularly limited, and examples include suppression of LDL-C synthesis, inhibition of cholesterol absorption, and promotion of cholesterol excretion.

[0020] As used herein, "diseases for which a therapeutic effect can be expected from a reduction in blood LDL-C levels" include, for example, hypercholesterolemia, familial hypercholesterolemia (homozygous), familial hypercholesterolemia (heterozygous), and the like. Of these, in the present invention, hypercholesterolemia is preferred, and hyper LDL-cholesterolemia is more preferred. Patients with these diseases include those for whom existing LDL-C-lowering drugs do not provide sufficient relief, for example, patients in whom blood LDL-C levels are not sufficiently reduced by statins. Patients for whom treatment with existing LDL-C-lowering drugs is not suitable, for example, patients for whom statin administration is restricted. Here, "patients for whom statin administration is restricted" refers to patients for whom statin administration is not sufficiently achieved, even with statin administration. Furthermore, "patients for whom statin administration is restricted" refers to patients for whom statin administration is restricted due to contraindications such as muscle-related side effects or liver damage. In the present invention, there are no particular limitations on the subjects for administration, but from the viewpoint of providing a new option for drug therapy aimed at lowering blood LDL-C, the subject is preferably a patient in whom blood LDL cholesterol is not sufficiently lowered by statins or a patient for whom statin administration is restricted.

[0021] In the present invention, Compound A, a salt thereof, or a solvate thereof can be used alone because it itself reduces blood LDL-C levels, but in one embodiment of the present invention, from the viewpoint of lowering blood LDL-C, Compound A, a salt thereof, or a solvate thereof may be used in combination with other LDL-C-lowering drugs intended to lower blood LDL-C levels. Examples of such drugs include anion exchange resins, statins, small intestinal cholesterol transporter inhibitors, and PCSK9 inhibitors.

[0022] Examples of anion exchange resins include cholestyramine and colestimide. Examples of cholestyramine include Questran (registered trademark) powder 44.4% and the like, which are available commercially. Examples of colestimide include Cholevain (registered trademark) tablets 500 mg and the like, which are available commercially. Examples of statins include pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, salts thereof, or solvates thereof.

[0023] Examples of small intestinal cholesterol transporter inhibitors include ezetimibe. As ezetimibe, for example, Zetia (registered trademark) tablets 10 mg and the like are available as commercially available drugs. As PCSK9 inhibitors, for example, human anti-PCSK-9 monoclonal antibody preparations and the like are included. As human anti-PCSK-9 monoclonal antibody preparations, for example, Repatha (registered trademark) subcutaneous injection 140 mg pen and the like are available as commercially available drugs.

[0024] In one embodiment of the present invention, when Compound A, its salt, or a solvate thereof is used as a medicine, it can be made into dosage forms such as tablets, capsules, granules, powders, lotions, ointments, injections, suppositories, etc., using other pharmaceutically acceptable carriers as necessary. These preparations can be produced by known methods. Examples of pharmaceutically acceptable carriers include excipients, disintegrants, binders, lubricants, plasticizers, fluidizing agents, diluents, solubilizing agents, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, coating agents, colorants, flavoring agents, and odor-correcting agents.

[0025] In one aspect of the present invention, Compound A, a salt thereof, or a solvate thereof can be administered orally or parenterally, with oral administration being preferred. The therapeutically effective amount and frequency of administration of Compound A, a salt thereof, or a solvate thereof vary depending on the patient's weight, age, sex, symptoms, etc., but can be appropriately determined by one skilled in the art. For example, for a typical adult, Compound A can be administered at a dose of 0.05 to 0.8 mg per day in one to three divided doses, preferably 0.1 to 0.4 mg per day in one or two divided doses, and more preferably 0.2 to 0.4 mg per day in one or two divided doses.

[0026] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0027] Example 1: Study of the effect of Compound A on blood LDL-C The effect of Compound A on blood LDL-C when orally administered to patients with non-alcoholic fatty liver disease (NAFLD) at a dose of 0.4 mg per day (0.2 mg tablet of Compound A administered twice daily in the fasting state, 58 cases) for 12 weeks was compared with that of placebo administration (60 cases).

[0028] FIG. 1 shows the change (%) from baseline in blood LDL-C concentration 12 weeks after the start of administration, and FIG. 2 shows the change (%) for each initial blood LDL-C value.

[0029] Figure 3 shows the percentage change from baseline in blood lathosterol concentration, the percentage change from baseline in blood sitosterol concentration, and the percentage change from baseline in blood campesterol concentration at 8 weeks after the start of administration.

[0030]

[0039] Figure 1 clearly shows that administration of Compound A reduced fasting blood LDL-C levels compared to placebo in both the overall population, including patients taking existing LDL-C-lowering drugs, and in patients not taking existing LDL-C-lowering drugs. Figure 2 also clearly shows that the LDL-C-lowering effect of Compound A is greater the higher the blood LDL-C level before administration. Figure 3 clearly shows that administration of Compound A reduced fasting blood lathosterol levels, a cholesterol synthesis marker, compared to placebo. It also clearly shows that administration of Compound A reduced fasting blood sitosterol levels and blood campesterol levels, which are cholesterol absorption markers, compared to placebo.

[0031] The present invention was completed based on the first finding that Compound A has a clear effect of lowering blood LDL-C levels in fasting state, and is useful as a pharmaceutical for preventing and / or treating diseases for which a reduction in blood LDL-C levels is expected to have a therapeutic effect.

Claims

1. A blood LDL cholesterol lowering agent comprising (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient, for administration to patients in whom blood LDL cholesterol reduction by statins is insufficient or in patients for whom statin administration is restricted.

2. A prophylactic and / or therapeutic agent for hypercholesterolemia, comprising (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof as an active ingredient, for administration to patients in whom statin-induced reduction of blood LDL cholesterol is insufficient or in whom statin administration is restricted.

3. (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof is an active ingredient, and is a prophylactic and / or therapeutic agent for patients in whom statin-induced reduction of blood LDL cholesterol is insufficient or in whom statin administration is restricted, for use in patients.

4. Use of (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof, for the production of a blood LDL cholesterol lowering agent for administration to patients in whom blood LDL cholesterol reduction by statins is insufficient or in patients for whom statin administration is restricted.

5. Use of (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof, for manufacturing a pharmaceutical composition for preventing and / or treating hypercholesterolemia, for administration to patients in whom the reduction of blood LDL cholesterol by statins is insufficient or in patients for whom statin administration is restricted.

6. Use of (R)-2-[3-[[N-(benzoxazole-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, a salt thereof, or a solvate thereof, for the manufacture of a pharmaceutical composition for preventing and / or treating hyper-LDL cholesterolemia, for administration to patients in whom the reduction of blood LDL cholesterol by statins is insufficient or in patients for whom statin administration is restricted.