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JPWO2020014504A5
JPWO2020014504A5 JP2021500714A JP2021500714A JPWO2020014504A5 JP WO2020014504 A5 JPWO2020014504 A5 JP WO2020014504A5 JP 2021500714 A JP2021500714 A JP 2021500714A JP 2021500714 A JP2021500714 A JP 2021500714A JP WO2020014504 A5 JPWO2020014504 A5 JP WO2020014504A5
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ミトコンドリア障害の処置を必要とする患者を処置するための、ｓＧＣ刺激剤またはその薬学的に許容される塩を含む医薬組成物。 A pharmaceutical composition comprising an sGC stimulant or a pharmaceutically acceptable salt thereof for treating a patient in need of treatment for mitochondrial disorders . ミトコンドリア障害が、アルパース病、常染色体優性視神経萎縮症（ＡＤＯＡ）、Ｂａｒｔｈ症候群／ＬＩＣ（致死性小児心筋症）、ベータ酸化欠損、全身性原発性カルニチン欠損症、長鎖脂肪酸輸送欠損症、カルニチンパルミトイルトランスフェラーゼ欠損症、カルニチン／アシルカルニチントランスロカーゼ欠損症、カルニチンパルミトイルトランスフェラーゼＩ（ＣＰＴ Ｉ）欠損症、カルニチンパルミトイルトランスフェラーゼＩＩ（ＣＰＴ ＩＩ）欠損症、極長鎖アシル－ＣｏＡデヒドロゲナーゼ欠損症（ＶＬＣＡＤ）、長鎖アシル－ＣｏＡデヒドロゲナーゼ欠損症（ＬＣＡＤ）、長鎖３－ヒドロキシアシル－ＣｏＡデヒドロゲナーゼ欠損症（ＬＣＨＡＤ）、マルチプルアシル－ＣｏＡデヒドロゲナーゼ欠損症（ＭＡＤ／グルタル酸尿症ＩＩ型）、ミトコンドリア三機能タンパク質欠損症、中鎖アシル－ＣｏＡデヒドロゲナーゼ（ＭＣＡＤ）欠損症、短鎖アシル－ＣｏＡデヒドロゲナーゼ欠損症（ＳＣＡＤ）、グルタル酸尿症ＩＩ型、（ＳＣＨＡＤ）欠損症、短／中鎖３－ヒドロキシアシル－ＣｏＡデヒドロゲナーゼ（Ｓ／ＭＣＨＡＤ）、中鎖３－ケトアシル－ＣｏＡチオラーゼ欠損症、２，４－ジエノイル－ＣｏＡレダクターゼ欠損症、ミトコンドリアエノイルＣｏＡレダクターゼタンパク質関連神経変性症（Ｍｉｔｏｃｈｏｎｄｒｉａｌ Ｅｎｏｙｌ ＣｏＡ Ｒｅｄｕｃｔａｓｅ Ｐｒｏｔｅｉｎ Ａｓｓｏｃｉａｔｅｄ Ｎｅｕｒｏｄｅｇｅｎｅｒａｔｉｏｎ）（ＭＥＰＡＮ）、カルニチン欠損症、クレアチン欠損症候群、コエンザイムＱ１０欠損症、複合体Ｉ、ＩＩ、ＩＩＩ、ＩＶ、Ｖ欠損症、慢性進行性外眼筋麻痺（ＣＰＥＯ）、フリードライヒ運動失調症、カーンズ・セイヤー症候群、白質ジストロフィー、Ｌｅｉｇｈ病または症候群、ＬＨＯＮ、ＬＨＯＮ Ｐｌｕｓ、Ｌｕｆｔ病、ＭＥＬＡＳ（ミトコンドリア筋症、ミトコンドリア脳筋症、乳酸アシドーシス、卒中様症状）、赤色ぼろ線維を伴うミオクローヌスてんかん（ＭＥＲＲＦ）、ミトコンドリア劣性運動失調症候群（ＭＩＲＡＳ）、ミトコンドリア細胞症、ミトコンドリアＤＮＡ枯渇症、ミトコンドリア脳症、ミトコンドリア筋症、多発性ミトコンドリア機能障害症候群、ＭＮＧＩＥ（筋神経胃腸脳症（Ｍｙｏｎｅｕｒｏｇｅｎｉｃ ｇａｓｔｒｏｉｎｔｅｓｔｉｎａｌ ｅｎｃｅｐｈａｌｏｐａｔｈｙ））、ＮＡＲＰ（ニューロパチー、運動失調症、網膜色素変性症、および眼瞼下垂症）、Ｐｅａｒｓｏｎ症候群、ピルビン酸カルボキシラーゼ欠損症、ピルビン酸デヒドロゲナーゼ欠損症またはピルビン酸デヒドロゲナーゼ複合体欠損症（ＰＤＣＤ／ＰＤＨ）、およびＰＯＬＧ変異から選択される、請求項１に記載の医薬組成物。 Mitochondrial disorders include Alpers disease, autosomal dominant optic nerve atrophy (ADOA), Barth syndrome / LIC (fatal childhood cardiomyopathy), beta-oxidation deficiency, systemic primary carnitine deficiency, long-chain fatty acid transport deficiency, carnitine palmitoyl. Transtransferase deficiency, carnitine / acylcarnitine translocase deficiency, carnitine palmitoyl transferase I (CPT I) deficiency, carnitine palmitoyl transferase II (CPT II) deficiency, very long chain acyl-CoA dehydrogenase deficiency (VLCAD), long Chain acyl-CoA dehydrogenase deficiency (LCAD), long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD), multiple acyl-CoA dehydrogenase deficiency (MAD / glutaric aciduria type II), mitochondrial trifunctional protein deficiency , Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase deficiency (SCAD), glutaric aciduria type II, (SCHAD) deficiency, short / medium-chain 3-hydroxyacyl-CoA dehydrogenase ( S / MCHAD), medium chain 3-ketoacyl-CoA thiolase deficiency, 2,4-dienoyl-CoA reductase deficiency, mitochondrial enoyl CoA reductase protein-related neurodegenerative disease (Mitochondrial Enoyl CoA Reductase Protein Association) Carnitine deficiency, creatin deficiency syndrome, coenzyme Q10 deficiency, complex I, II, III, IV, V deficiency, chronic progressive external eye muscle palsy (CPEO), Friedrich ataxia, Kerns Sayer syndrome, white quality Dystrophy, Leig's disease or syndrome, LHON, LHON Plus, Luft's disease, MELAS (mitochondrial myopathy, mitochondrial encephalomyopathy, lactic acidosis, stroke-like symptoms), myokronus epilepsy with red rag fibers (MERRF), mitochondrial recessive ataxia syndrome (MIRAS), mitochondrial cytosis, mitochondrial DNA depletion, mitochondrial encephalopathy, mitochondrial myopathy, multiple mitochondrial dysfunction syndrome, MNGIE (Myoneurogenic gastrointestinal encephalopathy), NARP (neuropathy) -, Ataxia, retinitis pigmentosa, and ptosis), Pearson syndrome, pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency or pyruvate dehydrogenase complex deficiency (PDCD / PDH), and POLG mutations The pharmaceutical composition according to claim 1. 患者が、ＡＬＳ、デュシェンヌ筋ジストロフィー、慢性疲労症候群、心筋症、サルコペニア、悪液質、運動失調障害、加齢および老化、鎌状赤血球症、アルツハイマー病、パーキンソン病、ハンチントン病、がん、多発性硬化症、海馬硬化／てんかん、てんかん、緑内障、Ｈａｒｄｉｎｇ症候群、糖尿病（ｄｉａｂｅｔｅｓ）（１型およびＩＩ型）、糖尿病（ｄｉａｂｅｔｅｓ ｍｅｌｌｉｔｕｓ）および難聴（ＤＡＤ）、認知症、双極性障害、統合失調症、不安障害、心血管疾患、ガラクトシアリドーシス、片頭痛、卒中、神経障害性疼痛、一過性脳虚血発作（ｔｒａｎｓｉｅｎｔ ｓｃｈｅｍｉｃ ａｔｔａｃｋ）、冠動脈疾患、線維筋痛症、網膜色素変性症、Ｃ型肝炎、原発性胆汁性肝硬変症（ｐｒｉｍａｒｙ ｂｉｌｉａｒｙ ｃｉｒｒｏｈｏｓｉｓ）、またはＸ連鎖性副腎白質ジストロフィーを有する、請求項１に記載の医薬組成物。 Patients have ALS, Duchenne muscular dystrophy, chronic fatigue syndrome, myocardial disease, sarcopenia, malaise, ataxia, aging and aging, sickle erythema, Alzheimer's disease, Parkinson's disease, Huntington's disease, cancer, multiple sclerosis Disease, Kaiba sclerosis / epilepsy, epilepsy, glaucoma, Harding syndrome, diabetes (types 1 and II), diabetes (diabetes mellitus) and hearing loss (DAD), dementia, bipolar disorder, schizophrenia, anxiety disorder , Cardiovascular disease, galactosialidosis, migraine, stroke, neuropathy pain, transient cerebral attack, coronary artery disease, fibromyalgia, retinal pigment degeneration, hepatitis C, primary The pharmaceutical composition according to claim 1, which has primary diabetic sickness, or X-linked adrenal leukodystrophy. 単独療法として投与される、請求項１から３のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, which is administered as a monotherapy. 治療的有効量の１つまたは複数のさらなる治療剤と組み合わせて投与される、請求項１から４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, which is administered in combination with a therapeutically effective amount of one or more additional therapeutic agents. さらなる治療剤がＡＣＥ阻害薬である、請求項５に記載の方法。 The method of claim 5, wherein the further therapeutic agent is an ACE inhibitor . さらなる治療剤が、エナラプリル、カプトプリル、ペリンドプリル、またはリシノプリルから選択される、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the further therapeutic agent is selected from enalapril, captopril, perindopril, or lisinopril . さらなる治療剤が、ＮＯ経路を上方制御することが知られている化合物である、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the further therapeutic agent is a compound known to upregulate the NO pathway. さらなる治療剤が、一酸化窒素、ＮＯドナー、アルギニン、シトルリン、ｓＧＣ刺激剤、ｓＧＣ活性剤およびＰＤＥ５阻害剤からなる群から選択される、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the further therapeutic agent is selected from the group consisting of nitric oxide, NO donors, arginine, citrulline, sGC stimulants, sGC activators and PDE5 inhibitors. ｓＧＣ刺激剤が、リオシグアト、ネリシグアト、ベリシグアト、ＢＡＹ－４１－２２７２、ＢＡＹ ４１－８５４３およびエトリシグアトからなる群から選択される、請求項１から９のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9 , wherein the sGC stimulant is selected from the group consisting of Riociguat, Nerisiguat, Verisiguat, BAY-41-2272, BAY 41-8543 and Etriciguat. 請求項１から９のいずれか一項に記載の医薬組成物であって、ｓＧＣ刺激剤は式Ａで示される化合物である：
Figure 2020014504000001
 （式中、
各Ｙは、独立して、Ｎ、ＮＪ ｃ 、ＣＨ、またはＣＪ ｃ から選択され；
各Ｘは、Ｎ、ＮＪ ｃ 、ＣＨ、またはＣＪ ｃ のいずれかであり；
ＸおよびＹの最大３事例は、同時にＮまたはＮＪ ｃ であり；
Ｊ ｃ は、ハロ、ＣＮ、または任意選択で１から３つのハロで置換されているＣ １～３ アルキルであり；
各Ｊ Ｂ は、ハロまたはＣ １～４ アルキルから独立して選択され；
ｎは、０、１、２、または３であり；
Ｒ １０ は、任意選択で、ハロ、－Ｃ（Ｏ）Ｒ ｂ２ 、フェニル、および５もしくは６員のヘテロアリールから独立して選択される１、２、もしくは３つの基と置換されているＣ １～４ アルキルであり、フェニルおよび５もしくは６員のヘテロアリールは、任意選択で１、２、もしくは３つのハロまたはＣ １～４ アルキルと置換されており、ヘテロアリールは、Ｎ、Ｏ、およびＳから独立して選択される１、２、もしくは３つのヘテロ原子を含み；
ｑは、０または１であり；
Ｒ １１ は、Ｈ、ハロ、－ＮＲ ａ２ Ｒ ｂ２ 、Ｃ １～４ アルキル、５から６員のヘテロアリール、またはＣ ３～６ シクロアルキルであり、Ｃ １～４ アルキル、５から６員のヘテロアリール、およびＣ ３～６ シクロアルキルは、各々任意選択で、独立してハロから選択される１、２、もしくは３つの基と置換されており、ヘテロアリールは、Ｎ、Ｏ、およびＳから独立して選択される１、２、もしくは３つのヘテロ原子を含み；
Ｒ ａ２ は、水素またはＣ １～４ アルキルであり；ならびに
Ｒ ｂ２ は、水素またはＣ １～４ アルキルである）。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the sGC stimulant is a compound represented by the formula A:
Figure 2020014504000001
 (During the ceremony
Each Y is independently selected from N, NJ c , CH, or CJ c ;
Each X is either N, NJ c , CH, or CJ c ;
Up to 3 cases of X and Y are N or NJ c at the same time;
J c is a halo, CN, or C 1-3 alkyl optionally substituted with 1 to 3 halos ;
Each JB is selected independently of halo or C 1-4 alkyl ;
n is 0, 1, 2, or 3;
R 10 is optionally substituted with 1, 2, or 3 groups independently selected from halo, -C (O) R b2 , phenyl, and 5 or 6 membered heteroaryls. ~ 4 Alkyl, phenyl and 5 or 6 membered heteroaryls are optionally substituted with 1, 2, or 3 halos or C 1-4 alkyls, and heteroaryls are N, O, and S. Contains 1, 2, or 3 heteroatoms independently selected from;
q is 0 or 1;
R 11 is H, halo, -NR a2 R b2 , C 1-4 alkyl, 5-6 member heteroaryl, or C 3-6 cycloalkyl, C 1-4 alkyl, 5-6 member hetero. Aryl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 groups independently selected from halo, and heteroaryl is independent of N, O, and S. Containing 1, 2, or 3 heteroatoms selected in
R a2 is hydrogen or C 1-4 alkyl; and
R b2 is hydrogen or C 1-4 alkyl) . 請求項１１に記載の医薬組成物であって、ｓＧＣ刺激剤は式Ｂで示される化合物である：
Figure 2020014504000002
 （式中、
Ｙは、ＮまたはＣＨであり；
各Ｊ Ｂ は、ハロまたはＣ １～４ アルキルから独立して選択され；
ｎは、０、１、２、または３であり；
Ｒ １１ は、Ｈ、ハロ、－ＮＲ ａ２ Ｒ ｂ２ 、Ｃ １～４ アルキル、５から６員のヘテロアリール、またはＣ ３～６ シクロアルキルであり、Ｃ １～４ アルキル、５から６員のヘテロアリール、およびＣ ３～６ シクロアルキルは、各々任意選択で、独立してハロから選択される１、２、もしくは３つの基と置換されており；
Ｒ ａ２ は、水素またはＣ １～４ アルキルであり；ならびに
Ｒ ｂ２ は、水素またはＣ １～４ アルキルである）。 The pharmaceutical composition according to claim 11, wherein the sGC stimulant is a compound represented by the formula B:
Figure 2020014504000002
 (During the ceremony
Y is N or CH;
Each JB is selected independently of halo or C 1-4 alkyl ;
n is 0, 1, 2, or 3;
R 11 is H, halo, -NR a2 R b2 , C 1-4 alkyl, 5-6 member heteroaryl, or C 3-6 cycloalkyl, C 1-4 alkyl, 5-6 member hetero. Aryl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 groups independently selected from halos;
R a2 is hydrogen or C 1-4 alkyl; and
R b2 is hydrogen or C 1-4 alkyl) . 請求項１１に記載の医薬組成物であって、ｓＧＣ刺激剤は式Ｃで示される化合物である：
Figure 2020014504000003
 （式中、
各Ｊ Ｂ は、ハロまたはＣ １～４ アルキルから独立して選択され；
ｎは、０、１、２、または３であり；
Ｒ １１ は、Ｈ、ハロ、－ＮＲ ａ２ Ｒ ｂ２ 、Ｃ １～４ アルキル、５から６員のヘテロアリール、またはＣ ３～６ シクロアルキルであり、Ｃ １～４ アルキル、５から６員のヘテロアリール、およびＣ ３～６ シクロアルキルは、各々任意選択で、独立してハロから選択される１、２、もしくは３つの基と置換されており；
Ｒ ａ２ は、水素またはＣ １～４ アルキルであり；
Ｒ ｂ２ は、水素またはＣ １～４ アルキルである）。 The pharmaceutical composition according to claim 11, wherein the sGC stimulant is a compound represented by the formula C :
Figure 2020014504000003
 (During the ceremony
Each JB is selected independently of halo or C 1-4 alkyl ;
n is 0, 1, 2, or 3;
R 11 is H, halo, -NR a2 R b2 , C 1-4 alkyl, 5-6 member heteroaryl, or C 3-6 cycloalkyl, C 1-4 alkyl, 5-6 member hetero. Aryl and C 3-6 cycloalkyl are each optionally substituted with 1, 2, or 3 groups independently selected from halos;
R a2 is hydrogen or C 1-4 alkyl;
R b2 is hydrogen or C 1-4 alkyl) . 請求項１３に記載の医薬組成物であって、Ｒ １１ は、任意選択で１、２、または３つのハロと置換されているＣ １～４ アルキルである、前記医薬組成物。 13. The pharmaceutical composition according to claim 13, wherein R 11 is C 1-4 alkyl optionally substituted with 1, 2, or 3 halos . 請求項１～９のいずれか一項に記載の医薬組成物であって、ｓＧＣ刺激剤またはその薬学的に許容される塩は以下のうちの１つである、前記医薬組成物：
Figure 2020014504000004
Figure 2020014504000005
Figure 2020014504000006
Figure 2020014504000007
 The pharmaceutical composition according to any one of claims 1 to 9, wherein the sGC stimulant or a pharmaceutically acceptable salt thereof is one of the following.
Figure 2020014504000004
Figure 2020014504000005
Figure 2020014504000006
Figure 2020014504000007
 請求項１５に記載の医薬組成物であって、ｓＧＣ刺激剤またはその薬学的に許容される塩は以下のうちの１つである、前記医薬組成物：
Figure 2020014504000008
Figure 2020014504000009
Figure 2020014504000010
 The pharmaceutical composition according to claim 15, wherein the sGC stimulant or a pharmaceutically acceptable salt thereof is one of the following.
Figure 2020014504000008
Figure 2020014504000009
Figure 2020014504000010
 請求項１５に記載の医薬組成物であって、ｓＧＣ刺激剤が以下の化合物である、前記医薬組成物：
Figure 2020014504000011
 The pharmaceutical composition according to claim 15, wherein the sGC stimulant is the following compound :
Figure 2020014504000011
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