JP-7855670-B2 - PCSK9 antagonist compounds

JP7855670B2JP 7855670 B2JP7855670 B2JP 7855670B2JP-7855670-B2

Inventors

ウッド，ハロルド・ビー
ブランカ，ダニーラ
ウー，チェンウェイ
ション，ユーシェン
ハー，スクヒ・ニコール
リュー，ジアン
ボガ，ショーバナ・バーブ
ジョサイアン，ヒューバート・ビー
タッカー，トーマス・ジョセフ
ケレケス，アンジェラ・ドーン
トン，リン
ウォルジ，アッバース・エム
ネアー，アニルクマール・ジー
ディン，ファー－シャン
ビアンキ，エリザベッタ

Assignees

メルク・シャープ・アンド・ドーム・エルエルシー

Dates

Publication Date: 20260508
Application Date: 20241217
Priority Date: 20180621

Claims (17)

A combination agent comprising a compound of formula I and an additional active agent, Here, the additional active agent is an antihypertensive agent or an anti-atherosclerotic agent. And here, the compound of formula I is either a compound having the following structure, or a pharmaceutically acceptable salt thereof: [In the formula, X is H, F, Cl, or Br; R1 is selected from the following: (a) - H; or (b) - (CH 2 ) z - R 14A , where z is 1 - 6 and R 14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time, but independently 2 to 4 ; and R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); and (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aiii)-N + ( CH3 ) 3 ; or (aiii) formula: (This is the part) and; R2 is selected from the following: (a) -H; and (b) -( CH2 ) z -R14A , where z is from 1 to 6 and R14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time, but independently 2 to 4 ; and R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); and (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aii)-N + ( CH3 ) 2R14ca (wherein R14ca is -CH3 or -( CH2 ) 1-4 - OCH3 ); (aiii) Formula: The part of; or the (aiv) expression: The part is selected from (where y 14Cb and y 14Cc are between 1 and 4); or R 1 and R 2 are combined into the formula: The part may be formed, in the formula: G1 , RG1a , and RG1b are defined as follows: (a) G1 is formula: The linker portion is the part in the formula where n q1 is 1 to 6, and m q1 is 0, 1, or 2, and together the values of n q1 and m q1 are selected so that the length of the linker portion they define does not exceed 8 carbon atoms and/or oxygen atoms in total, including the carbon atoms in the chain that form the carbonyl portion; R G1a is selected from: (i) -H; and (ii) alkyl groups with up to four carbon atoms; And R G1b is: (i) Formula: The part of; and (ii) formula: (b) G 1 is selected from the following parts; or (b) G 1 is formula: The linker portion is defined in the formula, where n q2 is 0, 1, or 2, and m q2 is 1 to 6, and together the values of n q2 and m q2 are selected so that the length of the linker portion they define does not exceed 8 carbon atoms and/or oxygen atoms in total, including the carbon atoms in the chain that form the carbonyl portion; R G1a is: (i) Formula: The part of; and (ii) formula: The portion is selected from; and R G1b is: (i) -H; and (ii) alkyl with up to 4 carbon atoms is selected; R 8 is -CH 3 or formula: This is the part where R 8a is either -H or a linear, branched, or cyclic alkyl group of up to four carbon atoms; A is: (a) Formula: The part; (b) -CH₂ - ( CH₂ ) y -CH₂ - (where y is between 1 and 6); (c) Formula: The part of the formula (where A b1 is: (i) Formula: This is the part where x is between 1 and 6; or (ii) equation: This is the part where y is between 1 and 5 in the formula; (d) Equation: -CH₂- ( CH₂ ) m -O-( CH₂ ) n- part (where m is from 1 to 5 and n is 0 or from 1 to 4) Selected from; B is: (a) combination; (b) - (CH 2 ) 1-2 ; or (c) formula: This is the part; D is: (a) Formula: The part of the formula (wherein E is -CH2- or -( CH2 ) 2-4 -O-, and A and B are as defined above); (b) Formula: The part of the formula (wherein A and B are as defined above); (c) Formula: (d) the part of the formula (wherein n a is 1, 2 or 3, ma a is 2, 3 or 4, n a + ma a is ≥ 3, and A and B are as defined above); or formula (d): This is the part (wherein R 34b is -H or a linear, branched, or cyclic alkyl group of up to four carbon atoms, and A and B are as defined above). The aforementioned combination agent.
The combination agent according to claim 1, wherein the compound of formula I is a compound having the structure of formula IIE, or a pharmaceutically acceptable salt thereof; [In the formula, R1 is selected from the following: (a) - H; or (b) - (CH 2 ) z - R 14A , where z is 1 - 6 and R 14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time but independently 2 to 4; and R14B is : -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); and (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aii)-N + ( CH3 ) 3 ; and R2 is selected from the following: (a) - H; and (b) - (CH 2 ) z - R 14A , where z is from 1 to 6 and R 14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time, but independently 2 to 4 ; and R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); and (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aii)-N + ( CH3 ) 2 R14ca (wherein R14ca is -CH3 or -( CH2 ) 1-4 - OCH3 ); A is selected from the following: (a) -CH₂ - ( CH₂ ) y -CH₂ - (where y is between 1 and 6); (b) Formula: The part of the formula (where A b1 is: (i) Formula: This is the part where x is between 1 and 6; or (ii) equation: This is the part where y is between 1 and 5 in the formula; (c) Equation: the part of -CH₂- ( CH₂ ) m -O-( CH₂ ) n- (where m is from 1 to 5 and n is 0 or from 1 to 4); The aforementioned combination agent.
R 1 is: (a) - (CH 2 ) z - R 14A , where z is 1 - 6 and R 14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time but independently 2 to 4; and R14B is : -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); and (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aii)-N + ( CH3 ) 3 ; and R 2 is: (a) - (CH 2 ) z - R 14A , where z is from 1 to 6 and R 14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time, but independently 2 to 4 ; and R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); or (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aii)-N + ( CH3 ) 2 R14ca (wherein R14ca is -CH3 or -( CH2 ) 1-4 - OCH3 ); A is: (a) -CH₂ - ( CH₂ ) y -CH₂ - (where y is between 1 and 6); The combination agent according to claim 2.
R 1 is: (a) - (CH 2 ) z - R 14A , where z is 1 - 6 and R 14A is: (i) - H; R 2 is: (a) - (CH 2 ) z - R 14A , where z is from 1 to 6 and R 14A is: (i) - H; (ii)-NH 2 ; (iii)-N + H 3 ; (iv)-N + (H 3 C) 3 ; (v)-NH-C(O)-[( CH2 ) 2 -O-] 2- ( CH2 ) 2R14B (wherein R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vi)-NH-C(O)-[( CH2 ) y12 -O-] 2- ( CH2 ) y13R14B (wherein y12 and y13 are not both 2 at the same time, but independently 2 to 4 ; and R14B is: -NH2 ;-N + H3 ;-N( CH3 ) 2 ; or-N + ( CH3 ) 3 ); (vii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is -O-( CH2 ) 3-4 -N + ( CH3 ) 3 ); or (viiii)-NH-C(O)-( CH2 ) y R14C (wherein y is 1 to 6 and R14C is: (ai)-O-(CH 2 ) 2 -N + (CH 3 ) 3 ; (aii)-N + ( CH3 ) 2 R14ca (wherein R14ca is -CH3 or -( CH2 ) 1-4 - OCH3 ); A is: (a) -CH₂ - ( CH₂ ) y -CH₂ - (where y is between 1 and 6); The combination agent according to claim 3.
The combination agent according to claim 1, wherein the compound of formula I is selected from the following: Here, A- is a pharmaceutically acceptable anion.
A combination of any of claims 1 to 5, wherein the additional active agent is a lipid-lowering agent, a cholesterol absorption inhibitor, an HMG-CoA reductase inhibitor, niacin in immediate-release or controlled-release form; a niacin receptor agonist or niacin receptor partial agonist, a PPARα agonist, or a bile acid metal ion chelating agent.
A combination of any of claims 1 to 6, wherein the additional active agent is selected from simvastatin, lovastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, cerivastatin, and pitavastatin.
A combination of any two claims, wherein the additional active agent is rosuvastatin.
A combination formulation according to any one of claims 1 to 8, wherein the compound of formula I and an additional active agent constitute a single drug formulation.
A combination formulation according to any one of claims 1 to 8, wherein the compound of formula I and the additional active agent are separate drug formulations.
A combination agent comprising a compound of formula I with the following structure, Here, A- is a pharmaceutically acceptable anion. The aforementioned combination agent comprises an additional active agent, wherein the additional active agent is an antihypertensive agent or an anti-atherosclerotic agent. Combination agent.
The compound of formula I is as follows: The combination agent according to claim 11.
The combination agent according to claim 11 or 12, wherein the additional active agent is a lipid-lowering agent, a cholesterol absorption inhibitor, an HMG-CoA reductase inhibitor, niacin in immediate-release or controlled-release form, a niacin receptor agonist or niacin receptor partial agonist, a PPARα agonist, or a bile acid metal ion chelating agent.
A combination of any one of claims 11 to 13, wherein the additional active agent is selected from simvastatin, lovastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin, cerivastatin, and pitavastatin.
A combination of any two claims 11 to 14, wherein the additional active agent is rosuvastatin.
A combination formulation of any one of claims 11 to 15, wherein the compound of formula I and an additional active agent constitute a single drug formulation.
A combination formulation according to any one of claims 11 to 15, wherein the compound of formula I and an additional active agent are separate drug formulations.

Description

Cross-reference of related applications: This application claims priority to U.S. Patent Application No. 62/687,913, filed on 21 June 2018, which is incorporated herein by reference in its entirety. The identification of compounds and/or agents effective in treating cardiovascular diseases is highly desirable. In clinical trials, a reduction in LDL cholesterol levels has been directly associated with the incidence of coronary events; Law et al., 2003 BMJ 326:1423-14 27. A moderate lifetime reduction in plasma LDL cholesterol levels was found to correlate with a substantial reduction in the incidence of coronary events; Cohen et al., 2006 N. E. ngl. J. Med. 354:1264-1272. This was true even in populations with a high prevalence of non-lipid-related cardiovascular risk factors; see above. Therefore, the benefits of managing LDL cholesterol levels are significant. Proprotein convertase subtilisin-kexin type 9 (hereinafter referred to as "PCSK9") PCSK9, also known as neuronal apoptosis-modulating convertase ("NARC-1"), is a proteinase K-like subtilase 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. 11:3 See 67-383. As seen in other genes involved in cholesterol metabolism, studies of PCSK9 transcriptional regulation suggest that this is a sterol regulatory element-binding protein (" It has been demonstrated that it is controlled by SREBP; Maxwell et al., 2003 J. Lipid Res. 44:2109-2119, this is typical for other genes involved in lipoprotein metabolism; Dubuc et al., 2004 Arterioscler . Thromb. Vasc. Biol. 24:1454-1459. Statins have been shown to upregulate PCSK9 expression in a manner attributable to their cholesterol-lowering effect; see above. Furthermore, the PCSK9 promoter has been shown to have two conserved sites involved in cholesterol regulation: a sterol-regulating element and an Sp1 site; see above. While present within the endoplasmic reticulum, PCSK9 performs autocleavage between Gln-152 and Ser-153 as its sole catalytic activity; Naureck iene et al., 2003 Arch. Biochem. Biophys. 420:55-6 7; Seidah et al., 2003 Proc. Natl. Acad. Sci. U. S. A. See 100:928-933. During subsequent trafficking through the trans-Golgi network, the prodomain remains tightly associated with the catalytic domain. Maturation via autocleavage has been demonstrated to be important for PCSK9 secretion and subsequent extracellular function (Benjannet et al., 2012 J. Biol. Chem. 287:337). See 45-33755). Therefore, several pieces of evidence demonstrate that PCSK9 reduces the amount of hepatic LDLR protein in particular, and thus impairs the liver's ability to remove LDL cholesterol from circulation. Adenovirus-mediated overexpression of PCSK9 in mouse liver leads to a dramatic loss of hepatic LDLR protein, resulting in accumulation of circulating LDL-C, but without affecting LDLR mRNA levels; Benjannet et al., 2004 J. Biol. Chem. 279. :48865-48875; Maxwell & Breslow, 2004 PNAS 1 01:7100-7105; Park et al., 2004 J. Biol. Chem. 279: 50630–50638; and Lalanne et al., 2005 J. Lipid Res 46:1312-1319. PC for elevated circulating LDL-C levels in mice. The effect of SK9 overexpression is entirely dependent on LDLR expression, and this is also related to PCSK9. This suggests that the regulation of LDL-C is mediated through the downregulation of LDLR protein. Consistent with these findings, mice lacking PCSK9, or mice in which PCSK9 mRNA has been reduced by antisense oligonucleotide inhibitors, have higher levels of hepatic LDLR protein and a superior ability to clear circulating LDL-C; R Ashid et al., 2005 PNAS 102:5374-5379; and Graham Et., 2007 J. Lipid Res. 48(4):763-767. In addition, reducing PCSK9 levels in cultured human hepatocytes by siRNA also results in higher LDLR protein levels and improved LDL-C uptake ability; Ben jannet et al., 2004 J. Biol. Chem. 279:48865-48875 ; and Lalanne et al., 2005 J. Lipid Res. 46:1312-13 19. These data, taken together, suggest that PCSK9's action leads to an increase in LDL-C by lowering LDLR protein levels. Many mutations in the PCSK9 gene also cause autosomal dominant hypercholesterolemia (" ADH is definitively linked to low-density lipoprotein (L) in the plasma. DL) A hereditary metabolic disorder characterized by a significant increase in particles, which can lead to premature cardiovascular failure; Abifadel et al., 2003 Nature Genetics 3 4:154-156; Timms et al., 2004 Hum. Genet. 114:349- See 353; Leren, 2004 Clin. Genet. 65:419-422. Subsequent studies on the S127R mutation described by Abifadell et al. have reported that patients carrying such mutations exhibit higher plasma total cholesterol and apoB100 due to (1) overproduction of apoB100-containing lipoproteins, such as low-density lipoprotein ("LDL"), very low-de