Compounds for treating conditions related to PCSK9 activity

Abstract

The present disclosure provides methods of treating hypercholesterolemia and other conditions associated with PCSK9 activity, e.g., atherosclerosis, atherosclerotic cardiovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular and cardiometabolic conditions, by orally administering to a subject an amount of a compound of Formula (I), where A" is selected from a pharma- ceutically acceptable anion, wherein the administered amount is from about 5 mg to about 300 mg of a compound of Formula (I). The present invention also relates to pharmaceutical compositions comprising a compound of Formula (I), including certain salts of the compound of Formula (I), and a permeation enhancer. [Formula 1] TIFF2024532129000025.tif55153

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 234,973 filed on 19 August 2021, U.S. Provisional Patent Application No. 63 / 251,972 filed on 4 October 2021, U.S. Provisional Patent Application No. 63 / 263,095 filed on 27 October 2021, U.S. Provisional Patent Application No. 63 / 311,622 filed on 18 February 2022, and U.S. Provisional Patent Application No. 63 / 371,685 filed on 17 August 2022. The contents of each application are incorporated herein by reference as forming part of this specification.

[0002] This disclosure relates to methods for treating hypercholesterolemia and other conditions related to PCSK9 activity, such as atherosclerosis, atherosclerotic cardiovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular diseases and cardiovascular metabolic states. [Background technology]

[0003] Proprotein-converting saptilisin-kexin 9 (hereinafter referred to as "PCSK9") is a proteinase K-like subtilase, also known as neuronal apoptosis-regulating convertase type I ("NARC-1"), and is identified as the ninth member of the secreted subtilase family. See Seidah et al., 2003 PNAS 100:928-933. PCSK9 belongs to the mammalian proprotein-convertase family of serine proteases and contains an N-terminal signal sequence, prodomain, catalytic domain, and C-terminal domain. See Seidah et al., 2012 Nat. Rev. Drug Discov. 11:367-383. Studies on PCSK9 transcriptional regulation have demonstrated that this regulation is controlled by sterol regulatory element-binding proteins, similar to those found in other genes involved in cholesterol metabolism (Dubuc et al., 2004 Arterioscler.Thromb.Vasc.Biol.24:1454-1459) and Maxwell et al., 2003 J.Lipid Res.44:2109-2119). Statins have been shown to upregulate PCSK9 expression through their cholesterol-lowering effects (see above). In addition, the PCSK9 promoter has been shown to possess two conserved sites involved in cholesterol regulation, sterol regulatory elements, and the Sp1 site (see above).

[0004] While in the endoplasmic reticulum, PCSK9 performs autocleavage between the Gln-152 and Ser-153 residues as its sole catalytic activity. (See Naureckiene et al., 2003 Arch. Biochem. Biophys. 420:55-67; ​​Seidah et al., 2003 Proc. Natl. Acad. Sci. USA 100:928-933.) The prodomain remains firmly associated with the catalytic domain throughout subsequent transport via the trans-Golgi network. Maturation by autocleavage has been demonstrated to be important for PCSK9 secretion and subsequent extracellular function (see Benjannet et al., 2012 J. Biol. Chem. 287:33745-33755). Therefore, several pieces of evidence demonstrate that PCSK9 reduces the amount of hepatic LDLR protein in particular, thereby impairing the liver's ability to remove low-density lipoprotein ("LDL") cholesterol from circulation.

[0005] Adenovirus-mediated overexpression of PCSK9 in mouse liver leads to the accumulation of circulating low-density lipoprotein cholesterol ("LDL-C") due to a dramatic loss of hepatic LDLR protein, without affecting LDLR mRNA levels (Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875; Maxwell & Breslow, 2004 PNAS 101:7100-7105; Park et al., 2004 J. Biol. Chem. 279:50630-50638; and Lalanne et al., 2005 J. Lipid Res. 46:1312-1319). The effect of PCSK9 overexpression on circulating LDL-C levels in mice is entirely dependent on LDLR expression, and furthermore, it indicates that the regulation of LDL-9 by PCSK9 is mediated by the downregulation of LDLR protein. Based on these findings, mice lacking PCSK9, or mice in which PCSK9 mRNA is reduced by antisense oligonucleotide inhibitors, have higher levels of hepatic LDLR protein and a greater capacity to remove circulating LDL-C (Rashid et al., 2005 PNAS 102:5374-5379; and Graham et al., 2007 J. Lipid Res. 48(4):763-767). In addition, siRNA-induced reduction of PCSK9 levels in cultured human hepatocytes also leads to higher LDLR protein levels and increased capacity to take up LDL-C (Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875; and Lalanne et al., 2005 J. Lipid Res. 46:1312-1319). Taken together, these data indicate that PCSK9 action leads to increased LDL-C by reducing LDLR protein levels.

[0006] Several mutations in the PCSK9 gene have been established to be associated with autosomal dominant hypercholesterolemia (ADH), a hereditary metabolic disorder characterized by a marked increase in low-density lipoprotein ("LDL") particles in plasma, which can lead to early circulatory failure. See Abifadel et al., 2003 Nature Genetics 34:154-156; Timms et al., 2004 Hum.Genet. 114:349-353; Leren, 2004 Clin.Genet. 65:419-422. Later research by Abifadel et al. on the S127R mutation reported that patients with this mutation exhibit higher plasma total cholesterol and apoB100 levels, contributing to (1) overproduction of apoB100-containing lipoproteins such as low-density lipoprotein ("LDL"), very low-density lipoprotein ("VLDL"), and intermediate-density lipoprotein ("IDL"), and (2) a decrease associated with the elimination or conversion of these lipoproteins (Ouguerram et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1448-1453).

[0007] Therefore, there is no doubt that PCSK9 plays a role in regulating LDL. PCSK9 expression or upregulation is associated with elevated plasma levels of LDL cholesterol, and corresponding inhibition or deficiency of PCSK9 expression is associated with decreased LDL cholesterol levels. Reduced LDL cholesterol levels associated with sequence mutations in PCSK9 have been found to have a protective effect against coronary heart disease (Cohen, 2006 N.Engl.J.Med.354:1264-1272).

[0008] Clinical trials have shown that a reduction in LDL cholesterol levels is directly associated with a higher rate of coronary events (Law et al., 2003 BMJ 326:1423-1427). Moderate lifetime reductions in plasma LDL cholesterol levels have been found to correlate with a substantial reduction in the incidence of coronary events (Cohen et al., 2006 N.Engl.J.Med. 354:1264-1272). This holds true even for populations with a high prevalence of non-lipid-related cardiovascular risk factors (see above). Therefore, the benefits of managing LDL cholesterol levels are significant.

[0009] Therefore, the identification of compounds and / or drugs effective in treating cardiovascular diseases, including those that antagonize the role of PCSK9 in LDL regulation, is highly desirable. However, since PCSK9 generally circulates in the blood and has the most appropriate binding affinity to cell surface LDL receptors, attempts to utilize this mechanism for treating diseases related to high serum LDL levels have so far focused on the use of large biomolecules such as antibodies. Although either PCSK9-specific siRNA or monoclonal antibody (mAb) therapy can lower LDL-C in patients with hypercholesterolemia, both types of therapies are administered by injection. The therapeutic potential of small peptides or small molecules as drugs targeting PCSK9 is still in its early stages of investigation. For example, Tombling et al., Atherosclerosis 330 (2021) 52-60. In addition, there are few compounds suitable for formulation into dosage forms that utilize the oral administration route for which such compounds can be administered, a route highly desirable for addressing conditions in which regulation of PCSK9 activity can play a role.

[0010] International Publication No. 2019 / 246349 discloses cyclic peptide compounds useful for the treatment of cardiovascular disease and conditions associated with PCSK9 activity. This disclosure advances the latest technology by providing methods for treating hypercholesterolemia and other conditions associated with PCSK9 activity, preferably involving oral administration of identified PCSK9 inhibitors. Novel salt forms of PCSK9 inhibitors are also provided herein. [Prior art documents] [Patent Documents]

[0011] [Patent Document 1] International Publication No. 2019 / 246349 [Non-patent literature]

[0012] [Non-Patent Document 1] Seidah et al.,2003 PNAS 100:928-933 [Non-Patent Document 2] Seidah et al.,2012 Nat. Rev. Drug Discov.11:367-383 [Non-Patent Document 3] Dubuc et al.,2004 Arterioscler.Thromb.Vasc.Biol.24:1454-1459 [Non-Patent Document 4] Maxwell et al.,2003 J.Lipid Res.44:2109-2119 [Non-Patent Document 5] Naureckiene et al.,2003 Arch.Biochem.Biophys.420:55-67 [Non-Patent Document 6] Seidah et al.,2003 Proc.Natl.Acad.Sci.USA100:928-933 [Non-Patent Document 7] Benjannet et al.,2012 J.Biol.Chem.287:33745-33755

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[0013] This disclosure relates to a method for treating hypercholesterolemia and other conditions related to PCSK9 activity, such as atherosclerosis, atherosclerotic cardiovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular diseases and cardiovascular metabolic states, using formula (I): [ka] [In the formula, A - [This is a pharmaceutically acceptable anion.] The present invention provides a method comprising orally administering a compound of formula (I) to a subject who requires administration in a certain amount, wherein the administered amount is approximately 5 mg to approximately 300 mg.

[0014] This disclosure also relates to a method for reducing LDL-C in a target that needs to be reduced, wherein formula (I) [wherein A - The present invention provides a method comprising orally administering a compound of formula (I) to a subject in a certain amount, wherein the amount is approximately 5 mg to approximately 300 mg.

[0015] This disclosure relates to a method for treating atherosclerotic cardiovascular disease in subjects requiring such treatment, wherein formula (I) [wherein A - The present invention provides a method comprising orally administering a compound of formula (I) to a subject in a certain amount, wherein the amount administered is approximately 5 mg to approximately 300 mg.

[0016] This disclosure also relates to a method for inhibiting the PCSK9 activity of a target that needs to be inhibited, wherein the method is based on formula (I) [wherein A -The present invention provides a method comprising orally administering a compound of formula (I) to a subject in a certain amount, wherein the amount is approximately 5 mg to approximately 300 mg.

[0017] The present invention also relates to specific salts of the compound of formula (I).

[0018] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), which includes a specific salt of the compound of formula (I), and a permeation enhancer. [Brief explanation of the drawing]

[0019] [Figure 1] The pharmacokinetics of compound 1, the compound of formula (I), after a single dose at various doses ranging from approximately 10 to 300 mg are shown. [Figure 2] This is a summary of plasma pharmacokinetic statistics after administration of a single oral dose of compound 1 ranging from 10 to 300 mg to healthy male participants. [Figure 3] The formulations of the compound of formula (I), as well as known anti-PCSK9 monoclonal antibodies, and their anti-PCSK9 siRNA activity, and the percentage change from baseline LDL-C compared to placebo are shown. [Figure 4] This shows the decrease in plasma levels of free PCSK9 compared to baseline after a single administration of compound 1. [Figure 5] This shows the difference in stability between compound 1, compound 2, and compound 3. [Modes for carrying out the invention]

[0020] This disclosure relates to a method for treating hypercholesterolemia and other conditions related to PCSK9 activity, such as atherosclerosis, atherosclerotic cardiovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular diseases and cardiovascular metabolic states. According to the method of this disclosure, formula (I): [ka] [wherein, A - is a pharmaceutically acceptable anion] The compound of is orally administered to a subject in need of treatment.

[0021] In one embodiment, the present disclosure is a method of treating hypercholesterolemia in a subject in need of treatment, comprising orally administering to the subject a compound of formula (I) [wherein, A - is a pharmaceutically acceptable anion] in an amount that is a compound of formula (I) from about 5 mg to about 300 mg.

[0022] In one embodiment, the present disclosure is a method of reducing LDL-C in a subject in need of reduction, comprising orally administering to the subject a compound of formula (I) [wherein, A - is a pharmaceutically acceptable anion] in an amount that is a compound of formula (I) from about 5 mg to about 300 mg.

[0023] In one embodiment, the present disclosure is a method of treating atherosclerotic cardiovascular disease in a subject in need of treatment, comprising orally administering to the subject a compound of formula (I) [wherein, A - is a pharmaceutically acceptable anion] in an amount that is a compound of formula (I) from about 5 mg to about 300 mg.

[0024] In one embodiment, the present disclosure generally relates to a method of inhibiting PCSK9 activity in a subject in need of inhibition, comprising orally administering to the subject a compound of formula (I) [wherein, A -The present invention relates to a method comprising orally administering a compound of formula (I) to a subject in a certain amount, the amount of which is a pharmaceutically acceptable anion, from about 5 mg to about 300 mg. As used herein, “inhibit” or “antagonize” means providing one or more affected tissues with a compound of formula (I) that counteracts, inhibits, counteracts, neutralizes, or reduces the action of one or more activities or functions of PCSK9 in one or more affected tissues. In some embodiments, the method for inhibiting PCSK9 activity is for the treatment of conditions related to PCSK9 activity as described above, or alternatively, for the treatment of diseases, disorders or conditions that benefit from the effects of a PCSK9 antagonist.

[0025] The following details relating to the compound of formula (I), its pharmaceutically acceptable anion, its amount, the target of treatment, oral administration, oral dosage form, formulation, pharmaceutically acceptable excipients, LDL-C reduction, PCSK9 inhibition, etc., are relevant to all of the methods of this disclosure described above or below.

[0026] Formula (I), also known as "Compound A": [ka] [In the formula, A - [This is a pharmaceutically acceptable anion.] The compounds are used in all of the methods of this disclosure. As used herein, “pharmaceutically acceptable anion” means an anion that is suitable for forming a pharmaceutically acceptable salt.

[0027] The terms “one or more salts” and the phrase “pharmaceutically acceptable salt” as used herein include any of the following: acidic salts formed with inorganic and / or organic acids, basic salts formed with inorganic and / or organic bases, or zwitterionic quaternary ammonium complexes. Salts of the compounds of the present invention can be formed by methods known to those skilled in the art, for example, by reacting the compounds of the present invention with an equivalent amount of acid or base in a medium in which the salt precipitates or in an aqueous medium, followed by freeze-drying.

[0028] The compounds of the present invention contain a positively charged four-coordinate nitrogen atom and can be stabilized by the addition of anions that form a salt, or by the formation of anions in different parts of a molecule that generate a zwitterion; these are sometimes referred to as internal salts. Therefore, the compounds of the present invention can be prepared in the form of a quaternary ammonium salt or a quaternary ammonium zwitterion.

[0029] Accordingly, the presentation of the structures of the compounds of the present invention also includes all other forms of such compounds described above, whether in salt form or zwitterionic form. Thus, one aspect of the present invention is the provision of the compounds of the present invention in pharmaceutically acceptable salt or zwitterionic form. Those skilled in the art will recognize examples in which the compounds of the present invention may form such salts, including cases in which the four-coordinate nitrogen is quaternized and the charged nitrogen form can be stabilized by the bonded anion. The term “pharmaceutically acceptable salt” refers to any salt (including internal salts as salts and zwitterions) that is highly desirable both biologically and otherwise (e.g., non-toxic to the recipient and otherwise non-toxic).

[0030] The formation of pharmaceutically acceptable salts from basic (or acidic) pharmaceutical compounds is generally described, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, DC on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference in their entirety as constituting part of this specification.

[0031] This disclosure envisions all salts of formula (I) that are available as compounds of the salt, including salts that are generally recognized as safe for use in the preparation of pharmaceutical formulations and those that can now be formed within the scope of the art and are later classified as “generally recognized as safe” for use in the preparation of pharmaceutical formulations and referred to herein as “pharmaceutically acceptable salts.”

[0032] Examples of pharmaceutically acceptable acidic salts include acetates including trifluoroacetate, adipines, alginates, ascorbicates, aspartates, benzoates, benzenesulfones, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfons, caprates (also known as decanoates), cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfons, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobroms, and aqueous iodide. Examples of salts include, but are not limited to, hydroxyethanesulfonates, lactates, maleates, methanesulfons, methylsulfates, 2-naphthalenesulfons, nicotinates, nitrates, oxalates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, salicylates, succinates, sulfates, sulfons (as referred to herein), tartrates, thiocyans, toluenesulfons (also known as tosylates), and undecanoates. Therefore, according to this disclosure, the pharmaceutically acceptable anions corresponding to each of these salts are A - It is possible.

[0033] Further examples of pharmaceutically acceptable salts and corresponding pharmaceutically acceptable anions that may be used in this disclosure include, but are not limited to, fluoride anions, chloride anions, bromide anions, iodide anions, acetate anions, and caprate anions. In one embodiment of the present invention, the pharmaceutically acceptable anion is selected from chloride anions, acetate anions, or caprate anions. As used herein, caprate and decanoates are used interchangeably.

[0034] In one embodiment of the present invention, the pharmaceutically acceptable anion is a chloride anion, and the compound of formula (I) is as follows: [ka] That is the case.

[0035] In one embodiment, compound 1 is the amorphous form of the chloride salt of the compound of formula (I). In Figure 5, "API amorphous chloride" refers to compound 1.

[0036] In one embodiment of the present invention, the pharmaceutically acceptable anion is a caprete anion, and the compound of formula (I) is as follows: [ka] This compound is referred to herein as "compound 2". In one embodiment, compound 2 is the amorphous form of the caprinate salt of the compound of formula (I).

[0037] In one embodiment of the present invention, the pharmaceutically acceptable anion is an acetate anion, and the compound of formula (I) is as follows: [ka] This compound is referred to herein as "compound 3". In one embodiment, compound 3 is the amorphous form of the acetate salt of the compound of formula (I).

[0038] In one embodiment, the method of the present invention comprises administering a compound of formula (I), wherein the compound of formula (I) is as follows: [ka] [ka] or [ka] Selected from.

[0039] The preparation of amorphous chloride salts (compound 1) utilizes an acidification step, thereby introducing chloride by supercritical fluid chromatography and the addition of hydrochloric acid to the product after evaporation. Figure 5 demonstrates the risks associated with adding excess HCl to a given batch of compound 1 (referred to as "API amorphous chloride"), as such excess hydrochloric acid, being a strong acid, can lead to increased chemical decomposition of molecules, as observed by the higher impurity levels shown for amorphous chloride salts other than amorphous acetate or amorphous caprate in Figure 5. The stability of amorphous chloride salts varies depending on the process used to synthesize these salts, while amorphous acetate and amorphous caprate demonstrate stability that is not affected by these risks and is independent of the synthetic process used.

[0040] This disclosure also relates to a method for inhibiting the PCSK9 activity of a target that needs to be inhibited, wherein the method is based on formula (I) [wherein A - The present invention provides a method comprising orally administering a compound of formula (I) to a subject in a certain amount, wherein the amount is approximately 5 mg to approximately 300 mg.

[0041] The compound of formula (I) is a PCSK9-specific antagonist or inhibitor because it possesses properties that antagonize PCSK9 function. The compound of formula (I), as well as the method for preparing the compound, is disclosed in International Publication No. 2019 / 246349, and the entire disclosure is incorporated herein by reference as constituting part of this specification.

[0042] The compound of formula (I) is presented using conventional stereochemical notation for some of the chiral carbon centers. Therefore, the solid black "wedge" bonds represent bonds protruding from the plane of the representation, while the dashed "wedge" bonds represent bonds that are fabricated into the plane of the representation. As in conventional notation, flat solid lines represent all spatial configurations of the depicted bonds. Thus, especially where stereochemical notation is not provided, such representations are intended to indicate all stereochemical and spatial orientations of the structural features.

[0043] The compound of formula (I) is stable. As used herein, “stable” means a compound that can be prepared and isolated, and whose structure and properties are maintained, or which can remain essentially unchanged for a sufficient period of time, enabling the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0044] The compound of formula (I) is bioavailable, and in particular, orally bioavailable. As used herein, “bioavailable” refers to the ability of the compound of formula (I) to be absorbed and utilized by the body. As used herein, “orally bioavailable” means that the compound of formula (I) can be absorbed and utilized by the body when taken orally.

[0045] As used herein, the terms “to treat” or “to cure” mean the inhibition or mitigation of a disease, condition, or disorder in an object experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder. For example, inhibition of a disease, condition, or disorder means preventing further development of the disease, condition, or disorder, or the state and / or symptoms. Furthermore, mitigation of a disease, condition, or disorder means reversal of the pathology and / or symptoms, such as a reduction in the severity of the disease.

[0046] When used herein, “prevent,” “preventing,” or “prevention” includes the prevention of at least one symptom associated with or caused by a disease, condition, or disorder being prevented.

[0047] As used herein, “Subject” means an animal, preferably a mammal, and in particular humans, or non-humans including but not limited to livestock such as cattle, horses, sheep, pigs, goats, rabbits, cats, and dogs, and other mammals in need of treatment. In some embodiments, the subject is a human.

[0048] As used herein, the terms “administer” and its variation (e.g., “administering”) with respect to the compound of formula (I) mean to provide the compound to a subject in need of treatment. As used herein, “orally” and its variation (e.g., “oral”) mean administration by mouth, i.e., administration of the compound of formula (I) by mouth.

[0049] Administering a compound of formula (I) to a subject includes both self-administration and administration to the subject by another person. The subject may need or may desire treatment for an existing disease or medical condition, or may need or may desire prophylactic treatment to prevent or reduce the risk of developing a disease or medical condition. As used herein, a subject “needing” treatment for an existing condition or prophylactic treatment includes both a determination of need by a healthcare professional and a patient’s request for such treatment.

[0050] Unless otherwise specified, or as is clear from the context, the term “about” as used herein shall be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.

[0051] In one embodiment, the amount administered to the subject is approximately 5 mg to approximately 300 mg of the compound of formula (I). Natural numbers and half-integers between 5 and 300 mg are included in the present invention. In one embodiment, the amount administered is approximately 10 mg to approximately 300 mg of the compound of formula (I). In one embodiment, the amount administered is approximately 10 mg or approximately 20 mg of the compound of formula (I). In one embodiment, the amount administered is approximately 5 mg, approximately 6 mg, approximately 10 mg, approximately 12 mg, approximately 15 mg, approximately 18 mg, approximately 20 mg, approximately 24 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, or approximately 100 mg of the compound of formula (I). In one embodiment, the amount administered is approximately 10 mg, approximately 12 mg, approximately 15 mg, approximately 18 mg, approximately 20 mg, approximately 24 mg, approximately 25 mg, or approximately 30 mg of the compound of formula (I). In one embodiment, the administered dose is approximately 10 mg, approximately 10.5 mg, approximately 11 mg, approximately 11.5 mg, approximately 12 mg, approximately 12.5 mg, approximately 13 mg, approximately 13.5 mg, approximately 14 mg, approximately 14.5 mg, approximately 15 mg, approximately 15.5 mg, approximately 16 mg, approximately 16.5 mg, approximately 17 mg, approximately 17.5 mg, approximately 18 mg, approximately 18.5 mg, approximately 19 mg, approximately 19.5 mg, approximately The compound is of formula (I) in amounts of 20 mg, approximately 20.5 mg, approximately 21 mg, approximately 21.5 mg, approximately 22 mg, approximately 22.5 mg, approximately 23 mg, approximately 23.5 mg, approximately 24 mg, approximately 24.5 mg, approximately 25 mg, approximately 25.5 mg, approximately 26 mg, approximately 26.5 mg, approximately 27 mg, approximately 27.5 mg, approximately 28 mg, approximately 28.5 mg, approximately 29 mg, approximately 29.5 mg, or approximately 30 mg. In one embodiment, the administered amount is a daily dose of approximately 5 mg to approximately 300 mg.In one embodiment, the administered doses are approximately 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, and 20 mg. The daily dose of the compound of formula (I) is approximately 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, or 30 mg. In one embodiment, the amount administered is approximately 5 mg, 6 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, or 30 mg of the compound of formula (I). In one embodiment, the administered dose is a daily dose of approximately 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, or 30 mg of the compound of formula (I).

[0052] In one embodiment, the amount of formula (I) administered to the subject is approximately 10 mg to approximately 30 mg of the compound of formula (I). In another embodiment, the amount administered to the subject is approximately 12 mg to approximately 27 mg of the compound of formula (I). In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 25 mg of the compound of formula (I). In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 20 mg of the compound of formula (I). In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 20 mg of the compound of formula (I).

[0053] In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 30 mg of compound 1. In another embodiment, the amount administered to the subject is approximately 12 mg to approximately 27 mg of compound 1. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 25 mg of compound 1. In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 20 mg of compound 1. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 20 mg of compound 1. In one embodiment, the amounts are approximately 10 mg, approximately 10.5 mg, approximately 11 mg, approximately 11.5 mg, approximately 12 mg, approximately 12.5 mg, approximately 13 mg, approximately 13.5 mg, approximately 14 mg, approximately 14.5 mg, approximately 15 mg, approximately 15.5 mg, approximately 16 mg, approximately 16.5 mg, approximately 17 mg, approximately 17.5 mg, approximately 18 mg, approximately 18.5 mg, approximately 19 mg, approximately 19.5 mg of compound 1. The daily doses are approximately 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, or 30 mg. In one embodiment, the daily doses are approximately 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, or 22 mg of compound 1. In yet another embodiment, the dose administered to the subject requiring administration is approximately 15 mg, 17.5 mg, 18 mg, 20 mg, or 22 mg of compound 1.

[0054] In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 30 mg of compound 2. In another embodiment, the amount administered to the subject is approximately 12 mg to approximately 27 mg of compound 2. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 25 mg of compound 2. In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 20 mg of compound 2. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 20 mg of compound 2. In one embodiment, the amounts are approximately 10 mg, approximately 10.5 mg, approximately 11 mg, approximately 11.5 mg, approximately 12 mg, approximately 12.5 mg, approximately 13 mg, approximately 13.5 mg, approximately 14 mg, approximately 14.5 mg, approximately 15 mg, approximately 15.5 mg, approximately 16 mg, approximately 16.5 mg, approximately 17 mg, approximately 17.5 mg, approximately 18 mg, approximately 18.5 mg, approximately 19 mg, approximately 19.5 mg of compound 2. The daily doses are approximately 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, or 30 mg. In one embodiment, the daily doses are approximately 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, or 22 mg of compound 2. In yet another embodiment, the dose administered to the subject requiring administration is approximately 15 mg, 17.5 mg, 18 mg, 20 mg, or 22 mg of compound 2.

[0055] In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 30 mg of compound 3. In another embodiment, the amount administered to the subject is approximately 12 mg to approximately 27 mg of compound 3. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 25 mg of compound 3. In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 20 mg of compound 3. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 20 mg of compound 3. In one embodiment, the amounts are approximately 10 mg, approximately 10.5 mg, approximately 11 mg, approximately 11.5 mg, approximately 12 mg, approximately 12.5 mg, approximately 13 mg, approximately 13.5 mg, approximately 14 mg, approximately 14.5 mg, approximately 15 mg, approximately 15.5 mg, approximately 16 mg, approximately 16.5 mg, approximately 17 mg, approximately 17.5 mg, approximately 18 mg, approximately 18.5 mg, approximately 19 mg, approximately 19.5 mg of compound 3. The daily doses are approximately 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg, 25 mg, 25.5 mg, 26 mg, 26.5 mg, 27 mg, 27.5 mg, 28 mg, 28.5 mg, 29 mg, 29.5 mg, or 30 mg. In one embodiment, the daily doses are approximately 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, or 22 mg of compound 3. In yet another embodiment, the dose administered to the subject requiring administration is approximately 15 mg, 17.5 mg, 18 mg, 20 mg, or 22 mg of compound 3.

[0056] In one embodiment, the method of the present invention comprises administering an oral dosage form containing a certain amount of the compound of formula (I). In a further embodiment, the method comprises administering a single oral dosage form containing a certain amount of the compound of formula (I). In a further embodiment, the method comprises administering a single oral dosage form containing a certain amount of the compound of formula (I) once daily.

[0057] In one embodiment, a certain amount is a therapeutically effective or prophylactically effective amount of the compound of formula (I). As used herein, “therapeutically effective” or “prophylactically effective” with respect to a certain amount refers to the amount required in the intended dose to achieve the desired therapeutic and / or prophylactic effect over a desired period of time. The desired effect may be, for example, relief, remission, reduction, or cessation of at least one symptom associated with the treatment condition. For example, in the treatment of hypercholesterolemia, a reduction in LDL-C is the desired effect. As those skilled in the art will understand, the amount may vary according to a variety of factors, including but not limited to the disease state, the age, sex, and weight of the individual, and the ability of the PCSK9 antagonist to induce the desired effect in the individual. The response has been demonstrated by in vitro assays, in vivo non-human animal studies, and / or may be further supported by clinical trials.

[0058] In one embodiment, oral administration includes administering a single oral dosage form containing a certain amount of the compound of formula (I). In one embodiment, oral administration includes administering one or more oral dosage forms, each containing a certain amount of the compound of formula (I) or a portion thereof. In one embodiment, oral administration includes administering a single oral dosage form containing a certain amount of the compound of formula (I) once daily. In one embodiment, oral administration includes administering one or more oral dosage forms, each containing a certain amount of the compound of formula (I) or a portion thereof, once daily. In one embodiment, oral administration includes administering a single oral dosage form containing a certain amount of the compound of formula (I) two or more times a day, for example, two, three, or four times a day. In one embodiment, oral administration includes administering one or more oral dosage forms, each containing a certain amount of the compound of formula (I) or a portion thereof, two or more times a day, for example, two, three, or four times a day. The oral dosage forms may be administered with or without fasting, i.e., with or without food. In one embodiment of the present invention, the subject requiring treatment is fasted for approximately 30 minutes before administration of the compound of formula (I).

[0059] In one embodiment, the single oral dosage form is administered once daily for at least 14 days. In one embodiment, the single oral dosage form is administered once daily for 14 days. In one embodiment, the single oral dosage form is administered once daily for as long as the subject requires treatment.

[0060] As used herein, “oral dosage form” refers to a pharmaceutical preparation comprising the compound of formula (I) and at least one pharmaceutically acceptable excipient suitable for oral administration of the subject. As used herein, the terms “oral dosage form” and “pharmaceutical composition” are intended to encompass both a particular combination of components in a particular amount and any products arising directly or indirectly from such a combination of components in a particular amount. An oral dosage form may contain a total amount of the compound of formula (I), for example, about 5 mg to about 300 mg, which may or may not be a daily dose. An oral dosage form may contain a portion of a daily dose of the compound of formula (I).

[0061] The oral dosage forms according to this disclosure may be solid, semi-solid, or liquid. Such oral dosage forms include, but are not limited to, powders, dispersible granules, minitablets and beads (for example, which may be used for tableting, encapsulation, or direct administration), pills, tablets, coated tablets, sugar-coated tablets, hard and soft capsules including gelatin capsules, medicinal drops, fast-dissolving tablets, aqueous solutions, alcoholic or oily solutions, gels, syrups, emulsions, or suspensions. The oral dosage forms according to this disclosure may further include one or more coatings that modify release properties, such as coatings that provide delayed release or formulations having sustained-release properties. Formulations intended to be converted to a suspension or solution immediately before use are also included in this disclosure, and examples include, but are not limited to, lyophilized formulations and liquid formulations absorbed into a solid absorbent medium. In one embodiment, the oral dosage form is a liquid-filled capsule, such as a hard gelatin capsule filled with a compound of formula (I) combining Labrasol® and propylene glycol in a ratio of, for example, 2:1. In one embodiment, the oral dosage form is a hard gelatin capsule filled with a compound of formula (I), for example, Labrasol® and propylene glycol in a ratio of, for example, 2:1, and encapsulated in an enteric-coated capsule, such as HPMC Vcaps® enteric-coated capsules (Capsugel®, Lonza). In one embodiment, the oral dosage form is a suspension of a compound of formula (I), for example, OraBlend SF and propylene glycol in a ratio of, for example, 2:1. In one embodiment, the oral dosage form is a dry-filled enteric-coated capsule, such as dry-filled HPMC Vcaps® enteric-coated capsules. In one embodiment, the oral dosage form is a tablet. In one embodiment, the oral dosage form is a tablet. In a further embodiment, the oral dosage form is a film-coated tablet.

[0062] As will be understood by those skilled in the art, pharmaceutically acceptable excipients are any components that adapt a composition to a particular route of administration or that assist in the processing of a drug into a dosage form without exerting an effective pharmaceutically acceptable effect themselves. Generally, a composition comprises two or more pharmaceutically acceptable excipients, one or more of which are selected based on the form of the oral dosage form. Examples of methods for producing pharmaceutically acceptable excipients and the oral dosage forms described above can be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

[0063] Suitable pharmaceutically acceptable excipients for use in this disclosure include carriers (e.g., lactose, starch, starch derivatives, talc, stearic acid or salts thereof for pills, tablets, sugar-coated tablets and hard gelatin capsules; fats, waxes, semi-solid and liquid polyols, natural oils or hydrogenated oils for soft gelatin capsules; solutions (emulsions or syrups), fillers, disintegrants, binders, lubricants, pressurizing agents, wetting agents, stabilizers, emulsifiers, absorption enhancers, penetration enhancers, permeation enhancers, dispersants, preservatives, sweeteners, colorants, flavorings, fragrances, thickeners, diluents, buffers, solvents, solubilizers, agents for achieving depot effects, and agents for altering osmotic pressure. Examples of excipients include, but are not limited to, salts of, water for coatings and / or antioxidants, physiologically acceptable sodium chloride solutions, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, and vegetable oils. Certain one or more pharmaceutically acceptable excipients and one or more amounts thereof are selected for use in oral dosage forms such that the oral dosage form can provide therapeutic serum levels effective over an acceptable period in the subjects to whom the oral dosage form is administered, and that the oral dosage form provides a desired amount of the compound of formula (I) in an acceptable amount of oral dosage form such that the oral dosage form maintains biological activity during storage within an acceptable temperature range over an acceptable period.

[0064] In one embodiment, the pharmaceutical composition of the present invention contains a diluent selected from polyethylene glycol (of various molecular weights greater than 3000), crystalline cellulose, mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, or a combination thereof. In one embodiment, the pharmaceutical composition of the present invention contains a diluent selected from macrogol (PEG4000), crystalline cellulose, mannitol, lactose, or a combination thereof. In a further embodiment, the diluent is selected from macrogol (PEG4000), crystalline cellulose, or lactose. In one embodiment, the pharmaceutical composition of the present invention contains a disintegrant selected from croscarmellose sodium, crospovidone, or sodium starch glycolate. In a further embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the pharmaceutical composition of the present invention contains a lubricant selected from silicon dioxide, starch, talc, magnesium stearate, or tricalcium phosphate. In a further embodiment, the lubricant is selected from silicon dioxide or tricalcium phosphate. In one embodiment, the pharmaceutical composition of the present invention contains a lubricant selected from magnesium stearate or sodium stearyl fumarate or both. In one embodiment, the pharmaceutical composition of the present invention contains a solubilizer selected from propylene glycol, polysorbate 80, sorbitol, cremohol EL, castor oil, corn oil, cottonseed oil, sunflower oil, sesame oil, soybean oil, peppermint oil, olive oil, migliol, glycerin, or a combination thereof. In a further embodiment, the solubilizer is propylene glycol.

[0065] In one embodiment, the oral dosage form further comprises a permeabiliser. As used herein, “permeabiliser” refers to a pharmaceutically acceptable excipient that improves the absorption of an effective drug from the gastrointestinal tract, such as a compound of formula (I). Permeabilisers facilitate the absorption of cell-impermeable compounds by promoting size-limited passage through tight junctions between intestinal epithelial cells. (DJDrucker, Advances in oral peptide therapeutics, Nat Rev Drug Discov, 19, pp 277-289 (2020)). Suitable permeabilisers include, but are not limited to, sodium caprate, Labrasol®, sodium salcaprozate (SNAC), and combinations thereof. Labrasol® is also known as caprylcaproylmacrogol-8 glyceride and is manufactured by Gattefosse, Saint Priest, Lyon, France. In one embodiment, the oral dosage form comprises Labrasol®. In one embodiment, the oral dosage form comprises sodium caprate. When available in oral dosage form, the amount of permeabilis enhancer may be up to 1800 mg, up to approximately 720 mg, up to approximately 540 mg, up to approximately 360 mg, in the range of approximately 90 mg to approximately 360 mg, in the range of approximately 180 to approximately 360 mg, or 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form contains a permeabilis enhancer in an amount of up to approximately 360 mg, in the range of approximately 90 mg to approximately 360 mg, in the range of approximately 180 to approximately 360 mg, or 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form of the present invention contains a permeabilis enhancer in an amount of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form of the present invention contains a permeabilis enhancer in an amount of 180 mg or 360 mg.

[0066] When available in oral dosage form, amounts of sodium caprate are used in amounts of up to approximately 360 mg, in the range of approximately 90 mg to approximately 360 mg, in the range of approximately 180 to approximately 360 mg, or in amounts of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form of the present invention contains sodium caprate as a permeabilis enhancer in amounts of 90 mg, 180 mg, or 360 mg. In one embodiment, 180 mg of sodium caprate is used in the oral dosage form. In one embodiment, 360 mg of sodium caprate is used in the oral dosage form.

[0067] In one embodiment of the present invention, a dry-filled capsule or tablet may be used to administer a compound of formula (I) to a subject in need of administration. The pharmaceutical composition of the present invention may include a permeation enhancer. In one embodiment, the amount of the permeation enhancer, such as sodium caprate, may range from 1% to 75% by weight. As used herein, wt% refers to the weight percentage of the component relative to the total weight of the pharmaceutical composition. In another embodiment, the amount of the permeation enhancer in the pharmaceutical composition is about 18% to about 65% by weight. For tablets, the amount of the permeation enhancer, such as sodium caprate, may range from about 22% to about 65% by weight. Oral dosage forms may be manufactured by standard methods including wet granulation and dry granulation.

[0068] [Table 1]

[0069] In one embodiment, the present invention is represented by formula (I): [ka] [In the formula, A - [This is a pharmaceutically acceptable anion.] The pharmaceutical composition comprises a compound and a permeation enhancer. In a further embodiment, the permeation enhancer is sodium caprate. In another embodiment, the pharmaceutical composition further comprises a diluent. In a further embodiment, the composition comprises two or more diluents, the two or more diluents comprising a combination of crystalline cellulose, macrogol (PEG4000), and lactose.

[0070] In one embodiment of the present invention, the pharmaceutical composition comprises a) 1% to 7% by weight of a compound of formula (I) relative to the total weight of the pharmaceutical composition, b) about 1% to 75% by weight of a permeation accelerator relative to the total weight of the pharmaceutical composition, c) at least one diluent, and may also comprise d) a lubricant and / or a lubricant. In one embodiment, about 18% to 74% by weight of a permeation accelerator relative to the total weight of the pharmaceutical composition is present in the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition comprises a) about 1% to 7% by weight of a compound of formula (I) relative to the total weight of the pharmaceutical composition, b) about 22% to 67% by weight of a permeation accelerator selected from sodium caprate or Labrasol®, relative to the total weight of the pharmaceutical composition, c) at least one diluent or solubilizer selected from PEG4000, crystalline cellulose, propylene glycol, and lactose, and may also comprise d) a lubricant and e) a lubricant.

[0071] In one embodiment of the present invention, the pharmaceutical composition comprises a) a compound of formula (I) in an amount of about 2% to 6% by weight relative to the total weight of the pharmaceutical composition; b) a permeation enhancer, which is sodium caprate, in an amount of about 18% to 74% by weight relative to the total weight of the pharmaceutical composition; c) at least one diluent selected from PEG4000, crystalline cellulose, or lactose; d) a lubricant, which is silicon dioxide, in an amount of 0% to about 3% by weight relative to the total weight of the pharmaceutical composition; e) a lubricant, which is magnesium stearate, in an amount of 0% to about 2% by weight relative to the total weight of the pharmaceutical composition; and may also comprise f) at least one disintegrant.

[0072] In one embodiment, the subject has a history of treatment for hypercholesterolemia with one or more statins, which have been discontinued or not discontinued. In other words, the subject treated with the compound of formula (I) is currently being treated with statin therapy or has been treated with it in the past. In one embodiment, the subject is statin-naive. In other words, the subject has never been treated with statin therapy. In one embodiment, the subject is being treated with statin therapy concurrently, but the treatment goals are being achieved or not achieved.

[0073] In one embodiment, one or more additional pharmacologically effective agents may be administered in combination with the compound of formula I. As used herein, “one or more additional pharmacologically effective agents” is intended to mean one or more pharmaceutically effective agents that are effective in the body, including prodrugs that, unlike the compound of formula I, are converted to a pharmacologically effective form after administration, and also include free acids, free bases, and pharmaceutically acceptable salts of the additional pharmacologically effective agents. Generally, one or more any suitable additional pharmacologically effective agents, including but not limited to antihypertensive agents, lipid-modifying compounds and other lipid-anti-atherosclerotic agents, antidiabetic agents and / or anti-obesity agents, may be used in some way in combination with the compound of formula I in a single oral dosage form (a fixed-dose compound) or administered to the subject in one or more separate dosage formulations. This may enable simultaneous or sequential administration (simultaneous administration of separate effective agents) of the compound of formula (I) and one or more additional pharmacologically effective agents.

[0074] Examples of additional pharmacologically effective drugs that may be used include angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, seronapril, cilazapril, delapril, enalapril, enalapril, hosinopril, imidapril, lisinopril, movertipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), and angiotensin II receptor antagonists (e.g., losartan, i.e., COZAAR®, valsartan, candesartan, olmesartan, termesa Any of these drugs used in combination with hydrochlorothiazides such as rutan and HYZAAR®), neutral endopeptidase inhibitors (e.g., thiophan and phosphoramidone), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of dipeptides and tripeptides (U.S. Patent No. 5,116,835), amino acids and derivatives (U.S. Patents No. 5,095,119 and 5,104,869), amino acid chains linked by non-peptide bonds (U.S. Patent No. 5,114,937), dipeptide derivatives) The renin body and tripeptide derivatives, peptidylaminodiol and peptidyl beta-aminoacylaminodiol carbamates, as well as small molecule renin inhibitors (diol sulfonamide and sulfinyl), N-morpholino derivatives, N-heterocyclic alcohols and pyrroleimidazolone, pepstatin derivatives and fluoro and chloro derivatives of staton-containing peptides, Enalcrain, RO42-5892, A65317, CP80794, ES1005, ES8891, SQ34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2 (Carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamide hemifmalate) SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verapalmil, diltiazem, garopamil, niridipine, nimodipine, nicardipine),Potassium channel activators (e.g., nicorandil, pinacidil, chromalim, minoxidil, aprilcarim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympathomimetic blockers, beta-adrenergic blockers (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartrate), alpha-adrenergic blockers (e.g., doxazosin, prazotin, or alpha-methyldopa), central alpha-adrenergic agonists, peripheral vasodilators (e.g., hydrazine), lactone prodrug forms These are marketed as ZOCOR® and MEVACOR®, and after administration, they function as inhibitors, such as lipid-lowering agents like simvastatin and lovastatin, which are HMG-CoA reductase inhibitors, atorvastatin (especially the calcium salt sold under LIPITOR®), rosuvastatin (especially the calcium salt sold under CRESTOR®), pravastatin (especially the sodium salt sold under PRAVACHOL®), and fluvastatin (especially the one sold under LESCOL®). Pharmacologically acceptable salts of dihydroxy ring-opening acid HMG-CoA reductase inhibitors such as sodium salts, crivastatin and pitavastatin, and cholesterol absorption inhibitors such as ezetimibe (ZETIA®) and ezetimibe used in combination with any other lipid-lowering agent such as the above HMG-CoA reductase inhibitors, particularly ezetimibe used in combination with simvastatin (VYTORIN®) or atorvastatin calcium, immediate-release or controlled-release forms, and / or niacin, acipimox and avian used in combination with HMG-CoA reductase inhibitors. (i) PPARγ agonists such as niacin receptor agonists such as cifran, and niacin receptor partial agonists, metabolic modifiers including insulin and insulin mimetic (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, linagliptin, vildagliptin), (i) PPARγ agonists such as glitazone (e.g., pioglitazone, AMG131, MBX2044, mitoglitazone, robeglitazone, IDR-105, rosiglitazone and paraglitazone),Furthermore, (1) PPAR alpha / gamma dual agonists (e.g., ZYH2, ZYH1, GFT505, tiglitazar, mulaglitazar, alleglitazar, soderglitazar and nabeglitazar), (2) PPAR alpha agonists such as fenofibrate derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPAR γ modifiers (SPPARγMs), (e.g., International Publication Nos. 02 / 060388, 02 / 08188, 2004 / 019869, 2004 / (i) Other PPAR ligands including PPARγ partial agonists (as disclosed in Nos. 020409, 2004 / 020408 and 2004 / 066963), (ii) metformin and its pharmaceutically acceptable salts, particularly biguanides such as metformin hydrochloride, and sustained-release formulations thereof such as Glumetza®, Fortamet® and GlucophageXR®, and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814), insulin Or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro and their respective inhaled formulations), leptin and leptin derivatives and leptin agonists, amylin and amylin analogs (e.g., pramulintide), sulfonylurea and nonsulfonylurea insulin secretagogues (e.g., tolbutamide, glibride, glipizide, glimepiride, mitiglinide, meglitinide, nateglinide and repaglinide), α-glucosidase inhibitors (e.g., acarbose, voglibose) Incretin mimes such as GLP-1, GLP-1 analogs, GLP-1 derivatives and GLP-1 mimes, GLP-1 receptor agonists (e.g., including their intranasal, intradermal and once-weekly formulations, including dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131 and BIM-51077), bile acid chelating agents (e.g., cholestirand, colestimide,(Coreseveram hydrochloride, colestipol, cholestylamine and dialkylaminoalkyl derivatives of cross-linked dextran), acyl-CoA: cholesterol acyltransferase inhibitors (e.g., abasimib), anti-obesity compounds, drugs intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors, glucokinase activators (GKAs) (e.g., AZD6370), type I 11β-hydroxysteroid dehydrogenase inhibitors (e.g., those disclosed in U.S. Patent No. 6,730,690 and LY-2523199), CETP inhibitors (e.g., anacetrapib, torcetrapib and evacetrapib), fructose 1,6-Bisphosphatases (e.g., those disclosed in U.S. Patents 6,054,587, 6,110,903, 6,284,748, 6,399,782 and 6,489,476), inhibitors of acetyl-CoA carboxylase-1 or 2 (ACC1 or ACC2), AMP-activated protein kinase (AMPK) activators, other agonists of G protein-bound receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821) and (iii) GPR-40 (e.g., TAK875), SSTR3 antagonists (e.g., those disclosed in International Publication No. 2009 / 001836), neuromedin U receptor agonists (e.g., neuromedin S (NMS)) However, not limited to those disclosed in International Publication No. 2009 / 042053), SCD modifiers, GPR-105 antagonists (e.g., those disclosed in International Publication No. 2009 / 000087), SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin, canagliflozin, BI-10773, ertugliflozin, remogliflozin, TS-071, tofogliflozin, ipragliflozin and LX-4211), acyl coenzyme A inhibitors: diacylglycerolacyltransferases 1 and 2 (DGAT-1 and DGAT-2), fatty acid synthase inhibitors, acyl coenzyme A inhibitors: monoacylglycerolacyltransferases 1 and 2 (MGAT-1 and MGAT-2),Examples of drugs beneficial for the treatment of the above-mentioned conditions or disorders include TGR5 receptor agonists (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR), ileal bile acid transporter inhibitors, PACAP, PACAP mimetic and PACAP receptor 3 agonists, PPAR agonists, protein tyrosine phosphatase-1B (PTP-1B) inhibitors, IL-1b antibodies (e.g., XOMA052 and canakinumab), bromocriptine methylate and its rapid-release formulations, and bempedoic acid, as well as other drugs beneficial for the treatment of the above-mentioned conditions or disorders, including, where chemically possible, free acids, free bases, and pharmaceutically acceptable salt forms of the additional pharmacologically effective drugs mentioned above.

[0075] In one embodiment, additional pharmacologically effective agents include statins, ezetimibe, bempedoic acid, any other cholesterol-lowering agent considered to be standard treatment, or any combination thereof.

[0076] In one embodiment, the method of the present disclosure further includes the step of administering a statin. Thus, the compound of formula (I) is administered co-administered with at least one statin. The compound of formula (I) may be administered simultaneously or separately with a statin. This co-administration may include co-administration of the compound of formula (I) and the statin in the same oral dosage form, co-administration in separate dosage forms, and separate administration. That is, the compound of formula (I) and the statin may be formulated together in the same oral dosage form and administered simultaneously. Alternatively, the compound of formula (I) and the statin may be administered co-administered, and both may be in separate formulations. In another alternative, the compound of formula (I) may be administered immediately after the administration of the statin, or vice versa. In some embodiments of separate administration protocols, the compound of formula (I) and the statin may be administered with a difference of minutes, hours, or days.

[0077] In one embodiment, the LDL-C level of a subject after treatment with the compound of formula (I) is reduced from the baseline level of LDL cholesterol before treatment with the compound of formula (I). In one embodiment, the LDL-C level of a subject after treatment with the compound of formula (I) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, more than 50%, at least 60%, more than 60%, at least 65%, more than 65%, at least 70%, more than 70%, at least 75%, more than 75%, at least 80%, more than 80%, at least 85%, more than 85%, or at least 90% from the baseline level of LDL-C before treatment with the compound of formula (I). In one embodiment, the LDL-C level of a subject after treatment with the compound of formula (I) is reduced by more than 50% from the baseline level of LDL-C before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by more than 60% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by more than 65% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by more than 70% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level is reduced by more than 50% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level is reduced by more than 60% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level decreases by more than 65% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). In another embodiment, the subject's LDL-C level decreases by more than 70% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). Both the baseline and post-treatment levels of LDL-C can be determined by standard clinical tests used to measure blood cholesterol.

[0078] In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by at least 50% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by at least 60% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by at least 65% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level after treatment with the compound of formula (I) is reduced by at least 70% from the baseline LDL-C level before treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level is reduced by at least more than 50% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). In one embodiment, the subject's LDL-C level decreases by at least 60% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). In another embodiment, the subject's LDL-C level decreases by at least 65% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). In yet another embodiment, the subject's LDL-C level decreases by at least 70% from the baseline LDL-C level 14 days after treatment with the compound of formula (I). Both the baseline and post-treatment levels of LDL-C can be determined by standard clinical tests used to measure blood cholesterol.

[0079] In one embodiment, the present invention relates to a method for reducing apolipoprotein B (ApoB) levels in a subject requiring treatment, comprising orally administering a certain amount of a compound of formula (I) to the subject. In some embodiments, after treatment with the compound of formula (I), the apolipoprotein B (ApoB) levels of the subject requiring treatment are reduced from the baseline level of ApoB prior to treatment with the compound of formula (I). In one embodiment, the ApoB level of the subject after treatment with the compound of formula (I) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, more than 50%, at least 60%, more than 60%, at least 65%, more than 65%, at least 70%, more than 70%, at least 75%, more than 75%, at least 80%, more than 80%, at least 85%, more than 85%, or at least 90% from the baseline level of ApoB prior to treatment with the compound of formula (I).

[0080] In one embodiment, the non-high-density lipoprotein cholesterol (non-HDL-C) level of a subject after treatment with the compound of formula (I) is reduced from the baseline level of non-HDL-C before treatment with the compound of formula (I). In one embodiment, the non-HDL-C level of a subject after treatment with the compound of formula (I) is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 50%, at least 60%, at least 60%, at least 65%, at least 65%, at least 70%, at least 70%, at least 75%, at least 75%, at least 80%, at least 85%, at least 85%, or at least 90% from the baseline level of non-HDL-C before treatment with the compound of formula (I).

[0081] One or more inhibitory or antagonistic effects on PCSK9-related functional properties can be readily determined according to methodologies known in the art (see, for example, Barak & Webb, 1981 J. Cell Biol. 90:595-604; Stephan & Yurachek, 1993 J. Lipid Res. 34:325330; and McNamara et al., 2006 Clinica Chimica Acta 369:158-167) and the methods described herein. The inhibitory or antagonistic effect results in a reduction of PCSK9 activity compared to the activity observed in the absence of the antagonist, or compared to the activity observed, for example, in the presence of an unrelated specificity control antagonist. Preferably, the compound of formula (I) antagonizes functional PCSK9 to a point where the measured parameters, including but not limited to the activities disclosed herein, are reduced by at least 10%, and more preferably, antagonizes functional PCSK9 to a point where the measured parameters are reduced by at least 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, and 95%.

[0082] The compound of formula (I) is highly effective in lowering LDL cholesterol and is generally well-tolerated after single and multiple oral doses in healthy volunteers. Following a single dose of the compound of formula (I), levels of free PCSK9 protein, which contributes to high LDL cholesterol, are reduced by more than 90% from baseline. After 14 days of once-daily oral administration, the compound of formula (I) reduces blood LDL cholesterol by approximately 65% ​​from baseline levels in participants already receiving moderate to high-intensity statin basal therapy. These participants were already taking statins to control their cholesterol levels. The compound of formula (I) may be a highly effective treatment for patients suffering from high cholesterol.

[0083] These examples are provided for further illustrative purposes only and are not intended to limit the scope of this disclosure.

[0084] [Examples] [Example 1] Preparation of Compound 1 (amorphous chloride salt) [ka]

[0085] 0.5 L of acetonitrile (MeCN), followed by compound 4 (294.7 g, 206 mmol), was added to a 50 L cylindrical reactor at room temperature (the method for synthesizing compound 4, the starting material, is described in International Publication No. 2019 / 246349; see Example 1). An additional 2.4 L of MeCN was used to rinse all the solids and place them at the bottom of the reactor. Compound 5 (5-carboxy-N,N,N-trimethylpentane-1-aminium chloride, 47.5 g, 227 mmol) was added. An additional 2.0 L of MeCN was used to rinse all the solids and place them at the bottom of the reactor. N,N-diisopropylethylamine (iPr2NEt, 216 mL, 1236 mmol) was added, and the liquid was rinsed with 0.5 L of MeCN and placed at the bottom of the reactor. 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU, 94g, 247mmol) was added to the reactor, and all solids were rinsed with 0.5L of MeCN and placed at the bottom of the reactor. After 3 hours at room temperature, isopropyl acetate (iPrOAc, 17.7L) was added dropwise over 1 hour. The slurry was filtered, and the wet cake was washed three times with 2.9L of iPrOAc. The solids were dried under vacuum using N2 sweep to obtain 337g of crude product.

[0086] The crude product was purified using supercritical fluid chromatography (stationary phase: DIACEL DCpak P4VP [30 × 250 mm, 5 μm]; mobile phase: 45% modifier (0.25% NH4OH and 5% H2O in MeOH) and 55% CO2). The fraction containing the product was concentrated using rotary evaporation. The residue after evaporation was dissolved in water (3.2 L), and 0.1 M aqueous HCl solution (1389 mL, 139 mmol) was added at room temperature (the pH at the end of the addition was measured to 6 using pH paper). The resulting solution was filtered through a 0.22 μm line filter, and the filtrate was freeze-dried to obtain 238 g of compound 1 (amorphous chloride salt).

[0087] [Example 2] Preparation of frozen compound 2 (amorphous caprine) Porous anion exchange resin AG MP-1M (6g, 100-200 mesh, chloride form) was packed into a 60mL funnel. The packed resin was washed five times with a mixture of acetonitrile and water (1:1). The resin was washed twice with 200mL of 1M NaOH, followed by 10mL of water. The resin was transferred to a glass column and washed three times with 10mL of water. The resin was then washed twice with 10mL of EtOH, followed by five washes with 9mL of 1M caprylic acid EtOH solution, followed by three washes with 9mL of EtOH. Compound 1 (0.3g) was dissolved in 6mL of MeCN / water (1:1) and added to the resin-packed column. The filtrate was collected in a 20mL vial. The column was washed three times with a solution of MeCN and water (1:1) and the filtrate was collected in a 20mL vial. The fractions containing the caprine salt of compound 2 were combined and concentrated, and MeCN was removed. The desired amorphous compound 2 (0.29 g) was then isolated by lyophilization.

[0088] [Example 3] Preparation of freeze-dried compound 3 (amorphous acetate) Porous anion exchange resin AG MP-1M (6g, 100-200 mesh, chloride form) was packed into a 60mL funnel. The packed resin was washed five times with 9mL of acetonitrile / water mixture (1:1 ratio). The resin was washed twice with 200mL of 1M NaOH, followed by 50mL of 1M AcOH in water. The resin was transferred to a 100mL round-bottom flask containing a solution of compound 1 (chloride salt, 0.3g) in 6mL of acetonitrile and water (1:1 ratio). An additional 18mL of MeCN / water (1:1 ratio) was added. The mixture was allowed to mature at room temperature for 30 minutes, and the resulting mixture was transferred to a 60mL funnel. The filtrate was collected, the resin was washed three times with 10mL of MeCN / water (1 / 1 ratio), and the filtrate was collected in a 20mL vial. The fractions containing compound 3 were combined and concentrated, and MeCN was removed. Next, the desired amorphous compound 3 (0.304 g) was isolated by freeze-drying the solution.

[0089] [Example 4] Preparation of tablets containing the compound of formula (I) Sodium caprate (1.5 kg) and macrogol (499.9 g) were placed in a 10 L high-shear granulator. The two components were dry-mixed in a high-shear grator for 1 minute at an impeller speed of 183 rpm. Water was added during continuous mixing in the high-shear granulator until the appropriate degree of granulation was achieved. The wet powder was ground in a 2.0 mm screen-size cone mill, then transferred to a fluidized bed dryer, and dried at an inlet temperature of 70°C until the desired loss of moisture (less than 3.00%) was reached. The dry powder was ground in a 1.0 mm screen-size cone mill. The dry powder (1.275 kg) was then mixed in a 10 L diffusion blender with compound 1 (26.96 g), lactose (150.4 g), and silicon dioxide (22.58 g) at 920 rpm. The mixture was then ground in a 0.8 mm screen-size cone mill. Next, the mixed blend was mixed with magnesium stearate (22.58 g) in a 10 L diffusion blender at 460 rpm. Finally, the lubricated powder was compressed into tablets using a rotary tablet press to a target weight of 564.9 mg.

[0090] [Example 5] Manufacturing process for dried-filled capsules Crystalline cellulose (179.7 g), sodium caprate (661 g), compound 1 (41 g), and silicon dioxide (8.996 g) were mixed at 375 rpm using a 10 L diffusion blender. Magnesium stearate (4.498 g) was then added to the blender and mixed for 250 rpm. The blend was then granulated by roller compression using a roll pressure of 21 bar, a 2.0 mm coarse screen, and a 1 mm fine screen. The roller-compressed powder (761.9 g) was mixed with magnesium stearate (3.8 g) at 250 rpm using a 5 L diffusion blender. Finally, the lubricated powder was manually sealed to a target filling weight of 490 mg.

[0091] [Example 6] Liquid-filled capsule manufacturing process A solution of Labrasol® ALF (caprylocaproyl macrogol-8 glyceride, 100 mL) and propylene glycol (50 mL) was prepared as a solvent in a 250 mL bottle using a stirring plate. Compound 1 (0.7747 g) was dissolved in the solvent (49.7 mL) in a 125 mL bottle for 5 minutes using a stirring plate, followed by sonication for 15 minutes. The final solution was filled into rigid gelatin capsules to a target weight of 548 mg. The rigid gelatin capsules were then manually sealed with a 50% ethanol aqueous solution and inspected for leaks. The final rigid gelatin capsules were encapsulated in enteric-coated capsules that were manually sealed with a 90% ethanol aqueous solution. The 50% ethanol aqueous solution was prepared by mixing 10.4 mL of ethanol (96%) and 9.6 mL of water in a 30 mL bottle for 15 minutes using a stirring plate. A 90% ethanol aqueous solution was prepared by mixing 18.8 mL of ethanol (96%) and 1.2 mL of water in a 30 mL bottle using a stirring plate for 15 minutes.

[0092] test Compound 1: Chemically stable and resistant to gastrointestinal (GI) degradation: [ka] The amorphous chloride salt of the compound of formula (I) showed binding affinity to human PCSK9 at picomolar concentrations. GI absorption of compound 1 was improved by co-administration with a permeabilis enhancer (Labrasol, sodium caprate) in rats and non-human primates. Pre-symptomatic Good Laboratory Practice (GLP) toxicity studies in rats and non-human primates support clinical development, and these studies were conducted using both subcutaneous administration (to achieve high forward exposure to compound 1) and oral / arm administration (to assess topical / GI tolerability). No adverse events were observed in these GLP toxicity studies, including up to the highest dose administered.

[0093] Safety testing The pharmacokinetics, pharmacodynamics (decrease in free PCSK9 from baseline), and safety and tolerability of a single dose of compound (I) were investigated in normal, healthy male volunteers aged 18–50 years. The objective of this study was to evaluate the safety and tolerability of a single dose of compound 1 (approximately 10 mg to 300 mg) and the pharmacokinetics (PK) of compound 1. Furthermore, this study investigated the effects of permeabilis enhancers on PK, the effects of food on PK, and the effects of various capsule formulations on PK. The pharmacodynamic endpoint measured in this study was target engagement (percentage change in free PCSK9). For each panel in this study, participants were randomized to receive either compound 1 or placebo (PBO) in a 9:3 randomization scheme (n=9 compound 1:n=3 PBO). The baseline characteristics of the participants in this study are shown in Table 2.

[0094] [Table 2]

[0095] Compound 1, an amorphous chloride salt of the compound of formula (I), was administered as a single dose in liquid-filled rigid gelatin capsules. The capsules contained various potencies of Compound 1, or no Compound 1 (placebo), and a mixture of Labrasol®, a liquid permeability enhancer, and propylene glycol in a 2:1 ratio, with varying amounts of Labrasol® up to 1800 mg. The capsules were encapsulated in enteric-coated capsules (HPMC Vcaps®, Enteric, Capsugel®, Lonza).

[0096] This study also evaluated a 40 mg / mL suspension of Compound 1 containing OraBlend SF and propylene glycol in a 2:1 ratio, administered via syringe / PO administration, and dry-filled enteric-coated capsules (HPMC Vcaps® Enteric, Capsugel®, Lonza) containing Compound 1 and sodium caprate at various potencies up to 1800 mg. The minimum dose of Compound 1 administered in this study was 10 mg, and the maximum dose administered was 300 mg. Compound 1 was well-tolerated at doses up to 300 mg, and there were no deaths, serious adverse events, or clinically significant trends in clinical safety tests, vital signs, or ECG for the purpose of the study treatment. No deaths or severe adverse events (SAEs) occurred in this study. Of the 60 total participants, 6 discontinued the study. Three of these were due to adverse events (maculopapular rash, concussion / trauma-related wounds, and low back pain), two due to protocol violations, and one due to occupational conflict. Adverse events (AEs) related to compound 1, as reported by the principal investigator of this study, included abdominal discomfort, diarrhea, dyspepsia, headache, and maculopapular rash. All treatment-related AEs were mild to moderate, with the exception of one participant who experienced severe low back pain unrelated to the administration of the drug.

[0097] Compound 1 (the amorphous chloride salt of compound (I)) showed a dose-dependent increase in plasma exposure and a mean maximum decrease of over 90% in free plasma PCSK9 levels from baseline at all tested dose levels. See Figure 2 and Table 3 below.

[0098] The pharmacokinetic results are shown in Figure 1. This study also demonstrated that the permeabilis enhancer improved absorption, as evidenced by the increase in Cmax and AUC0-24 (see Figure 2). The PKs of compound 1 in the presence of the permeabilis enhancer Labrasol® and sodium caprate are similar (as shown in Figure 2). This study also demonstrated that food consumed 30 minutes prior to administration resulted in lower plasma exposure compared to a fasted state, and food consumed 30 minutes after administration had only a minimal effect on plasma exposure (see Figure 2).

[0099] As shown in Figure 4, administration of compound 1 is associated with a decrease in plasma levels of free PCSK9 protein, which contributes to elevated LDL cholesterol levels exceeding 90% compared to baseline levels.

[0100] [Table 3]

[0101] LDL cholesterol reduction test The effectiveness of compound 1 in achieving a target of over 50% reduction in LDL-C was evaluated using a multi-dose study in male and female participants aged 18–65 years who were receiving statin-based therapy to control their blood cholesterol. Participants' baseline mean LDL-C was approximately 87 mg / dL, and 85% of participants were receiving moderate or high-intensity statins. Either placebo or compound 1 was administered once daily in the morning for 14 days after an overnight fast. After the once-daily dose, participants were provided with a standard takeaway meal to consume within 30 minutes. In addition to vital signs, ECG, and standard safety monitoring, including clinical safety tests, plasma lipids (total cholesterol, LDL-C, HDL-C, and TG) were measured. LDL-C was monitored as part of the safety laboratory.

[0102] The starting dose of 20 mg of compound 1 and 360 mg of sodium caprate was associated with a mean reduction of approximately 62% in plasma LDL-C. 10 mg of compound 1 and 360 mg of sodium caprate was the next dose tested. This dose was associated with a mean reduction of approximately 64% in LDL-C. A third dose level was also 10 mg of compound 1, but the formulation contained 180 mg of sodium caprate. The 10 mg of compound 1 and 180 mg of sodium caprate dose was associated with a mean reduction of approximately 60% in LDL-C. The pharmacokinetic (PK) from this dose was similar to that of the 10 mg of compound 1 and 360 mg of sodium caprate dose, which supported the similarity in LDL-C reduction. All formulations containing either sodium caprylate alone (placebo) or both sodium caprate and compound 1 were in the form of dry-filled enteric-coated capsules (HPMC Vcaps®, Enteric, Capsugel®, Lonza).

[0103] Serum LDL cholesterol levels were measured before administration and on days 3, 7, 14, 15, and 21 after administration using standard clinical laboratory procedures. The results of this study are shown in Figure 3. As shown in Figure 3, the maximum reduction in LDL cholesterol observed at doses of 10 mg and 20 mg corresponds to the range of LDL-C reduction observed with the anti-PCSK9 monoclonal antibodies Repatha and Praluent. This has been reported in phase III cardiovascular trials and phase III lipid trials of the anti-PCSK9 siRNA Inclisiran. See Repatha cardiovascular outcomes trial FOURIER reporting 59% reduction in LDL-C, N Engl J Med 2017 May 4, 376(18):1713-1722; Praluent cardiovascular outcomes trial ODYSSEY reporting 59% reduction in LDL-C, N Engl J Med 2018, 379:2097-2107; and Inclisiran phase 3 lipid trials reporting 49-52% reduction in LDL-C, N Engl J Med 2020, 382:1507-1519. In contrast, placebo-treated participants showed a reduction of less than 5% in LDL-C from baseline.

[0104] Hard gelatin capsules containing 5 mg of compound 1 and 180 mg of sodium caprate were administered to male and female participants taking statins to control cholesterol in separate studies. No percentage reduction in LDL-C was observed in the studies reported above (less than 50% reduction from baseline).

Claims

1. In the manufacture of pharmaceuticals for methods of treating hypercholesterolemia in subjects requiring treatment, Compound 2 below: 【Chemistry 1】 The use of the method comprises orally administering a therapeutically effective amount of compound 2 in an oral dosage form further comprising sodium caprate to the subject. The therapeutically effective dose of compound 2 to be administered is 5 mg to 300 mg.

2. The use according to claim 1, wherein the therapeutically effective dose of compound 2 administered is 10 mg to 30 mg.

3. The use according to claim 1 or 2, wherein the therapeutically effective dose of compound 2 administered is 10 mg, 12.5 mg, 15 mg, 17.5 mg, 18 mg, or 20 mg.

4. The use according to claim 1 or 2, wherein the therapeutically effective dose of compound 2 administered is 10 mg or 20 mg.

5. The use according to claim 1 or 2, wherein the oral dosage form contains 180 mg of sodium caprate.

6. The use according to claim 1 or 2, wherein compound 2 is administered in a single oral dosage form once daily for at least 14 days.

7. The use according to claim 1 or 2, wherein the subject is currently being treated with statin therapy or has been treated with statin therapy in the past.

8. The use according to claim 1 or 2, wherein the level of LDL cholesterol in the subject after treatment is lower than the baseline level of LDL cholesterol before treatment.

9. The use according to claim 8, wherein the level of LDL cholesterol in the subject after treatment is reduced by more than 50% from the baseline level of LDL cholesterol before treatment.

10. The use according to claim 1 or 2, wherein the subject is a human.

11. In the manufacture of pharmaceuticals for methods of lowering LDL-C in subjects who need to have their LDL-C levels reduced, Compound 2 below: 【Transformation 5】 The use of the method comprises orally administering a therapeutically effective amount of compound 2 in an oral dosage form further comprising sodium caprate to the subject. The therapeutically effective dose of compound 2 is 5 mg to 300 mg.

12. In the manufacture of pharmaceuticals for methods of treating atherosclerotic cardiovascular disease in subjects requiring treatment, Compound 2 below: 【Transformation 6】 The use of the method comprises orally administering a therapeutically effective amount of compound 2 in an oral dosage form further comprising sodium caprate to the subject. The therapeutically effective dose of compound 2 is 5 mg to 300 mg.

13. Compound 2 in the manufacture of a pharmaceutical for a method of inhibiting PCSK9 activity in a target requiring treatment: 【Transformation 5】 The use of the method comprises orally administering a therapeutically effective amount of compound 2 in an oral dosage form further comprising sodium caprate to the subject. The therapeutically effective dose of compound 2 is 5 mg to 300 mg.

14. The use according to claim 1 or 2, wherein the subject requiring administration fasts for approximately 30 minutes before administration of compound 2.

15. Compound 2 below: 【Transformation 8】 A pharmaceutical composition comprising a compound and sodium caprate for treating a condition related to PCSK9 activity, wherein the condition is selected from hypercholesterolemia, atherosclerosis, atherosclerotic cardiovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular diseases and cardiovascular metabolic states.

16. The pharmaceutical composition according to claim 15, further comprising a diluent selected from polyethylene glycol, crystalline cellulose, mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, or a combination thereof.

17. The pharmaceutical composition according to claim 16, wherein the diluent is selected from crystalline cellulose, lactose, or macrogol (PEG 4000).

18. The pharmaceutical composition according to claim 15 or 16, wherein the pharmaceutical composition is in the form of a tablet.

19. The pharmaceutical composition according to claim 15 or 16, wherein the pharmaceutical composition is in the form of a capsule.

20. The aforementioned pharmaceutical composition a) Compound 2 in an amount of 1% to 7% by weight relative to the total weight of the pharmaceutical composition, b) Sodium caprate in an amount of 1% to 75% by weight relative to the total weight of the pharmaceutical composition, c) At least one diluent and Includes, d) Lubricants and / or lubricants The pharmaceutical composition according to claim 15, which may also contain the following:

21. The aforementioned pharmaceutical composition a) Compound 2 in an amount of 2% to 6% by weight relative to the total weight of the pharmaceutical composition, b) 18% to 74% by weight of sodium caprate relative to the total weight of the pharmaceutical composition, c) At least one diluent selected from PEG4000, crystalline cellulose, and lactose, d) A lubricant which is silicon dioxide, in an amount of 0% to 3% by weight relative to the total weight of the pharmaceutical composition, e) A lubricant, which is magnesium stearate, in an amount of 0% to 2% by weight relative to the total weight of the pharmaceutical composition. Includes, f) At least one type of disintegrant The pharmaceutical composition according to claim 15, which may also contain the following:

22. The use according to any one of claims 11 to 13, wherein the subject is a human.

23. The use according to claim 1 or any one of claims 11 to 13, wherein the therapeutically effective amount corresponds to 20 mg of compound 2 in its free form.

24. The pharmaceutical composition according to claim 15 or 16, comprising an amount of compound 2 equivalent to 20 mg in its free form.

25. The pharmaceutical composition according to claim 15 or 16, comprising 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, or 24.5 mg of compound 2.

26. The pharmaceutical composition according to claim 15 or 16 for use in the treatment of hypercholesterolemia.

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