Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
  • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
  • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/423—Oxazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics

Definitions

• the present invention relates to a blood LDL cholesterol lowering agent.
• Non-Patent Documents 1 to 3 set management targets for blood LDL-C according to the risk of developing coronary artery disease.
• statins HMG-CoA reductase inhibitors
• statins HMG-CoA reductase inhibitors
• Non-patent Document 4 Non-patent Document 4, 5
• the options for drug therapy aimed at lowering blood LDL-C are limited, and new therapeutic agents are considered useful in order to adequately manage blood LDL-C.
• Patent Document 1 contains the following formula (1):
• 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 4b are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, 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 alkylthio group, or R 3a and R 3b or R 4a and R 4b combine to represent an alkylenedioxy group; represents an oxygen atom, a sulfur atom, or NR 5 (R 5 represents a hydrogen atom, a C 1-4 alkyl group, a C
• Japan Arteriosclerosis Society (ed.): Arteriosclerosis disease prevention guidelines 2017 edition. Japan Arteriosclerosis 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 dyslipidaemias: Lipid modification to reduce cardiovascular risk.
• An object of the present invention is to provide a new blood LDL-C lowering agent, as well as a preventive and/or therapeutic agent for diseases that can be expected to have a therapeutic effect by lowering blood LDL-C.
• the present invention provides the following [1] to [28].
• the blood LDL cholesterol lowering agent according to [1] which is administered to patients whose blood LDL cholesterol is not sufficiently lowered by statins or whose administration of statins is restricted.
• [4](R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, its salts, or their salts A prophylactic and/or therapeutic agent for hyper-LDL cholesterolemia, which contains a solvate as an active ingredient.
• the present invention provides a new drug useful for the prevention and/or treatment of diseases for which therapeutic effects can be expected by lowering blood LDL-C.
• it is possible to provide a new blood LDL-C lowering agent to patients whose blood LDL-C is not sufficiently lowered by statins or to whom statin administration is limited, and to reduce blood LDL-C. It becomes possible to provide new preventive and/or therapeutic options to patients with diseases for which a therapeutic effect can be expected due to the reduction.
• FIG. 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.
• FIG. 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 fasting blood lasosterol 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. Shows percentage change from baseline.
• the compound A can be produced, for example, according to the method described in International Publication No. 2005/023777 pamphlet. It can also be formulated according to methods described in literature. Furthermore, a preparation containing Compound A has been approved in Japan as a hyperlipidemia therapeutic agent "Palmodia (registered trademark) tablets", and the “Palmodia tablets” can also be used.
• Palmodia registered trademark
• a salt or solvate of Compound A can also be used.
• Salts and solvates can be produced by conventional methods.
• the salt of Compound A is not particularly limited as long as it is pharmaceutically acceptable, but examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts. , organic base salts such as trialkylamine salts; mineral acid salts such as hydrochlorides and sulfates; and organic acid salts such as acetates.
• Examples of the solvate of Compound A or its salt include hydrates, alcoholates (eg, ethanolates), and the like.
• Compound A was shown to reduce the LDL-C concentration in the blood, and also to reduce both cholesterol synthesis and absorption markers. From this, Compound A is considered to have the effect of lowering blood LDL-C by suppressing the synthesis of LDL-C in the body and the absorption of cholesterol from meals. Therefore, Compound A, a salt thereof, or a solvate thereof can be an active ingredient of a blood LDL-C lowering agent. In addition, Compound A, its salts, or solvates thereof can be used to prevent and/or treat diseases for which a therapeutic effect can be expected by lowering blood LDL-C through lowering blood LDL-C concentration. Useful.
• blood LDL-C lowering agent refers to, for example, a drug for diseases that can be expected to have a therapeutic effect by lowering blood LDL-C. It refers to Specifically, it refers to a drug for diseases that can be expected to have a therapeutic effect by lowering blood LDL-C by inhibiting LDL-C synthesis and cholesterol absorption in living organisms.
• the mode of lowering LDL-C is not particularly limited, and includes, for example, inhibition of LDL-C synthesis, inhibition of cholesterol absorption, promotion of cholesterol excretion, and the like.
• disorders for which therapeutic effects can be expected by lowering blood LDL-C include, for example, hypercholesterolemia, familial hypercholesterolemia (homozygote), familial hypercholesterolemia ( heterozygotes), etc.
• hypercholesterolemia is preferred, and hypercholesterolemia is more preferred.
• Patients with these diseases include patients for whom existing LDL-C lowering drugs are insufficiently effective, for example, patients whose blood LDL-C is not sufficiently lowered by statins. Also included are patients who are not suitable for treatment with existing LDL-C lowering drugs, such as patients for whom statin administration is restricted.
• a patient whose blood LDL-C is not sufficiently lowered by statins is a patient whose blood LDL-C is not sufficiently lowered even under statin administration.
• a patient for whom statin administration is restricted refers to a patient for whom statin administration is restricted due to contraindications such as muscle-related side effects or liver damage.
• the recipients there are no particular restrictions on the recipients, but from the viewpoint of providing a new option for drug therapy aimed at lowering blood LDL-C, it is preferably patients whose blood LDL-cholesterol has not been sufficiently lowered by statins or Patients for whom statin administration is restricted.
• Compound A, a salt thereof, or a solvate thereof can be used as a single agent because it itself reduces the LDL-C concentration in the blood.
• Compound A, a salt thereof, or a solvate thereof may be used in combination with other LDL-C lowering drugs aimed at lowering blood LDL-C.
• LDL-C lowering drugs include anion exchange resins, statins, small intestinal cholesterol transporter inhibitors, PCSK9 inhibitors, and the like.
• anion exchange resin examples include cholestyramine and colestimide.
• cholestyramine for example, Questran (registered trademark) powder 44.4% is available as a commercially available drug.
• colestimide for example, Colevine (registered trademark) tablets 500 mg are available as a commercially available drug.
• statins include pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, salts thereof, or solvates thereof.
• small intestinal cholesterol transporter inhibitors examples include ezetimibe and the like.
• ezetimibe for example, Zetia (registered trademark) tablets 10 mg are available as a commercially available drug.
• PCSK9 inhibitors include human anti-PCSK-9 monoclonal antibody preparations.
• a human anti-PCSK-9 monoclonal antibody preparation for example, Repatha (registered trademark) subcutaneous injection 140 mg pen is available as a commercially available drug.
• Compound A, a salt thereof, or a solvate thereof when used as a medicine, it can be prepared into tablets, capsules, or granules using other pharmaceutically acceptable carriers as necessary. , a powder, a lotion, an ointment, an injection, a suppository, and the like. These formulations can be manufactured by known methods.
• Pharmaceutically acceptable carriers include excipients, disintegrants, binders, lubricants, plasticizers, flow agents, diluents, solubilizers, suspending agents, isotonic agents, and pH adjusters. Examples include agents, buffers, stabilizers, coating agents, coloring agents, flavoring agents, and deodorants.
• Compound A, a salt thereof, or a solvate thereof may be administered orally or parenterally, but oral administration is preferred.
• the therapeutically effective amount and frequency of administration of Compound A, its salt, or solvate thereof will vary depending on the patient's weight, age, sex, symptoms, etc., but can be determined as appropriate by those skilled in the art.
• 0.05 to 0.8 mg of Compound A can be administered per day in 1 to 3 divided doses, preferably 0.1 to 0.4 mg per day in one or three doses. The dose is divided into two doses, more preferably 0.2 to 0.4 mg per day, administered once or twice.
• Example 1 Examination of the effect of compound A on blood LDL-C.
• Compound A was administered at a dose of 0.4 mg per day (compound A 0.2 mg tablet twice a day) for patients with non-alcoholic fatty liver disease (NAFLD).
• NAFLD non-alcoholic fatty liver disease
• the effect on blood LDL-C when administered orally for 12 weeks was compared with placebo administration (60 cases).
• Figure 1 shows the rate of change (%) in blood LDL-C concentration from baseline at 12 weeks after the start of administration
• Figure 2 shows the rate of change (%) for each initial blood LDL-C level. show.
• Figure 3 shows the percentage change from baseline in blood lasosterol concentration (%), the percentage change from baseline in blood sitosterol concentration, and the baseline blood campesterol concentration at 8 weeks after the start of administration. Indicates the percentage change from the line.
• Figure 1 shows that both the overall population, including patients taking existing LDL-C-lowering drugs, and patients not taking existing LDL-C-lowering drugs, received Compound A compared to placebo. It was revealed that the fasting blood LDL-C concentration decreased. Furthermore, from FIG. 2, it was revealed that the lowering effect of Compound A on LDL-C was greater as the blood LDL-C concentration before administration was higher. From FIG. 3, it was revealed that the administration of Compound A lowered the fasting blood lasosterol concentration, which is a cholesterol synthesis marker, compared to the administration of a placebo. Furthermore, it was revealed that administration of Compound A lowered the fasting blood sitosterol concentration and blood campesterol concentration, which are cholesterol absorption markers, compared to the administration of a placebo.
• the present invention was completed based on the discovery for the first time that Compound A has a clear lowering effect on blood LDL-C concentration in the fasting state. It is useful as a medicine for preventing and/or treating diseases for which therapeutic effects are expected.

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• 2023
  • 2023-07-14 EP EP23839693.1A patent/EP4556006A4/en active Pending
  • 2023-07-14 WO PCT/JP2023/025980 patent/WO2024014524A1/ja not_active Ceased
  • 2023-07-14 CN CN202380054016.8A patent/CN119546300A/zh active Pending
  • 2023-07-14 US US18/880,136 patent/US20260014122A1/en active Pending
  • 2023-07-14 KR KR1020247043248A patent/KR20250034041A/ko active Pending
  • 2023-07-14 JP JP2024533757A patent/JPWO2024014524A1/ja active Pending
  • 2023-07-14 TW TW112126331A patent/TW202408500A/zh unknown
• 2025
  • 2025-01-13 JO JOJO/P/2025/0007A patent/JOP20250007A1/ar unknown

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