JP2023500685A - Betブロモドメイン阻害物質およびナトリウム依存性グルコース輸送体2阻害物質の組み合わせで主要な心血管有害事象(mace)を処置および/または予防する方法 - Google Patents
Betブロモドメイン阻害物質およびナトリウム依存性グルコース輸送体2阻害物質の組み合わせで主要な心血管有害事象(mace)を処置および/または予防する方法 Download PDFInfo
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- JP2023500685A JP2023500685A JP2022525779A JP2022525779A JP2023500685A JP 2023500685 A JP2023500685 A JP 2023500685A JP 2022525779 A JP2022525779 A JP 2022525779A JP 2022525779 A JP2022525779 A JP 2022525779A JP 2023500685 A JP2023500685 A JP 2023500685A
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- Prior art keywords
- alkyl
- alkoxy
- mace
- hydrogen
- sglt2
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- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000003112 inhibitor Substances 0.000 title claims abstract description 14
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- 230000002411 adverse Effects 0.000 title claims abstract description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title description 2
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- BTCRKOKVYTVOLU-SJSRKZJXSA-N (2s,3r,4r,5s,6r)-2-[4-chloro-3-[[4-(2-cyclopropyloxyethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(OCCOC3CC3)=CC=2)=C1 BTCRKOKVYTVOLU-SJSRKZJXSA-N 0.000 claims description 4
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- WHSOLWOTCHFFBK-ZQGJOIPISA-N Luseogliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S2)O)=C(OC)C=C1C WHSOLWOTCHFFBK-ZQGJOIPISA-N 0.000 claims description 4
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- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 claims description 3
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- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 claims 4
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
Description
R2は、アルコキシ、アルキル、アルケニル、アルキニル、アミド、アミノ、ハロゲン、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、アミノ、ハロゲン、および水素から独立して選択され;
R6は、アミノ、アミド、アルキル、水素、ヒドロキシル、ピペラジニル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そして、R4はHであり、あるいは、WはNであり、そして、pは0である]
またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物を含む。
R2は、アルコキシ、アルキル、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、および水素から独立して選択され;
R6は、アルキル、ヒドロキシル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そして、R4はHであり、あるいは、WはNであり、そして、pは0である]
またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物から選択される。
「場合による」または「場合により」とは、その後に記載される事象または状況が発生してもしなくてもよく、その説明には、その事象または状況が発生する例および発生しない例が含まれることを意味する。例えば、「場合により置換されていてよいアリール」は、以下に定義される「アリール」および「置換アリール」の両方を包含する。当業者には、1つまたはそれ以上の置換基を含むいずれかの基に関して、そのような基は、立体的に実行不可能、合成的に実現不可能、および/または本質的に不安定であるいずれかの置換または置換パターンを導入することを意図しないことが理解されるであろう。
の炭素原子の周りの置換基の配置に応じて、記号「R」または「S」で定義されることがある。本発明は、これらの化合物の種々の立体異性体およびそれらの混合物を包含する。立体異性体には、エナンチオマーおよびジアステレオマーが含まれる。エナンチオマーまたはジアステレオマーの混合物は、命名法において「(±)」と命名されることがあるが、当業者は、構造が暗黙のうちにキラル中心を示し得ることを認識するであろう。
一実施態様において、本発明は、非致死性心筋梗塞、CV系死亡、卒中、およびCVD事象のための入院を含む主要な心血管有害事象(MACE)を処置および/または予防する方法であって、それを必要とする対象に、ナトリウム-グルコース共輸送体2(sodium glucose transport protein 2, SGLT2)阻害物質、および式I:
R2は、アルコキシ、アルキル、アルケニル、アルキニル、アミド、アミノ、ハロゲン、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、アミノ、ハロゲン、および水素から独立して選択され;
R6は、アミノ、アミド、アルキル、水素、ヒドロキシル、ピペラジニル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そして、R4はHであり、あるいは、WはNであり、そして、pは0である]
で示される化合物またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物、の組み合わせを投与することによる方法を提供する。
R2は、アルコキシ、アルキル、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、アミノ、ハロゲン、および水素から独立して選択され;
R6は、アルキル、ヒドロキシル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そして、R4はHであり、あるいは、WはNであり、そしてpは0である]
で示される化合物またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物、を投与することによる方法。
参考文献
Cannon, C. P., Blazing, M. A., Giugliano, R. P., et al. (2015) Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 372(25), 2387-97.
Schwartz, G. G., Olsson, A. G. & Barter, P. J. (2013) Dalcetrapib in patients with an acute coronary syndrome. N Engl J Med, 368(9), 869-70.
Schwartz, G. G., Steg, P. G., Szarek, M., et al. (2018) Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med, 379(22), 2097-107.
Zinman, B., Wanner, C., Lachin, J. M., et al. (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med, 373(22), 2117-28.
Neal B., Perkovic V., Mahaffey, K. W., et al. (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med, 377(7), 644-657.
Perkovic, V., Jardine, M. J., Neal, B., et al. (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med, 380(24), 2295-2306.
Guettier, J.M. (2016) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) Meeting. U.S. Food and Drug Administration (FDA).
Rastogi, A., Bhansali, A. (2017) SGLT2 Inhibitors Through the Windows of EMPA-REG and CANVAS Trials: A Review. Diabetes Ther, 8, 1245-1251.
Carbone S., Dixon, D.L. (2019) The CANVAS Program: implications of canaglifozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovasc Diabetol, 18(64), 1-13.
Wiviott, S.D., Raz, M.P., et al. (2019) Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med, 380(4), 347-357.
アパベタロン(RVX-208)は、最近終了した臨床第3相試験(BETonMACE;NCT02586155)において、低HDLコレステロール(男性では40mg/dL未満、女性では45mg/dL未満)、および最近の急性冠症候群(ACS)(7~90日前)を有する2型糖尿病患者のMACEに対する効果について評価した。全患者は、高強度スタチン処置とその他のエビデンスベースの処置を受けた。
BETonMACE臨床試験では、合計N=298人の患者(アパベタロン処置群ではN=150人、プラセボ処置群ではN=148人)に、RVX-208に加えてSGLT2阻害物質(エンパグリフロジン、ダパグリフロジン、またはカナグリフロジン)を指定スタチン療法(アトルバスタチンおよびロスバスタチン)およびその他のガイドラインで定義された処置とともに投与した。無作為化され、最初の事象発生日以前にSGLT2処置を少なくとも1回受けた患者は、事象が確認された日にMACE事象として打ち切った。最初の事象発生日後にSGLT2処置を少なくとも1回受けた患者は、非MACE事象として打ち切り、最終連絡日を打ち切り日とした。試験期間中にSGLT2処置を受けなかったすべての患者については、無作為化日および確定した事象の発生日、または打ち切られた対象についての最後の接触日を用いて、最初の事象までの時間を計算した。
図1~3はそれぞれ、狭義に定義されるMACE(すなわち、心血管系死亡、非致死性心筋梗塞、または卒中として定義される複数の主要エンドポイントの単一複合エンドポイントとして)の累積発生率を、試験群と対照群の2群間で比較しており、以下のように記載する:
i. SGLT2阻害物質およびアパベタロンで処置した患者(試験)、およびSGLT2阻害物質で処置しプラセボを投与された患者(対照)(図1);
ii. SGLT2阻害物質で処置しなかったが、アパベタロンで処置した患者(試験)、およびSGLT2阻害物質で処置しなかったが、プラセボを投与された患者(対照)(図2);および
iii. アパベタロンおよびSGLT2阻害物質で処置した患者(試験)、およびアパベタロンのみで処置した患者(対照)(図3)。
図4~6はそれぞれ、図1~3について上述したのと同じ2群の患者間で、広義に定義されるMACE(すなわち、心血管系死亡、非致死性心筋梗塞、卒中、または心血管疾患(CVD)のための入院として定義される複数の主要エンドポイントの単一複合エンドポイントとして)の累積発生率を比較したものである。
図7~9はそれぞれ、図1~3について上述したのと同じ2群の患者間の非致死的心筋梗塞の累積発生率を比較したものである。
図10~12はそれぞれ、図1~3について上述したのと同じ2群の患者間で心血管系死亡の累積発生率を比較したものである。
図13~15はそれぞれ、図1~3について上述したのと同じ2群の患者間の心血管疾患のための入院の累積発生率を比較したものである。
図16~18はそれぞれ、図1~3について上述したのと同じ2群の患者間で、うっ血性心不全のための入院の累積発生率を比較したものである。
Claims (15)
- 主要な心血管有害事象(MACE)を処置および/または予防する方法であって、それを必要とする患者に、ナトリウム-グルコース共輸送体2(SGLT2)阻害物質、および式I:
R2は、アルコキシ、アルキル、アルケニル、アルキニル、アミド、アミノ、ハロゲン、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、アミノ、ハロゲン、および水素から独立して選択され;
R6は、アミノ、アミド、アルキル、水素、ヒドロキシル、ピペラジニル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そして、R4はHであり、あるいは、WはNであり、そして、pは0である]
で示される化合物またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物を投与することを含む方法。 - MACEの個々の要素のいずれかを処置および/または予防する方法であって、それを必要とする対象に、ナトリウム-グルコース共輸送体2(SGLT2)阻害物質、および式I:
R2は、アルコキシ、アルキル、アルケニル、アルキニル、アミド、アミノ、ハロゲン、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、アミノ、ハロゲン、および水素から独立して選択され;
R6は、アミノ、アミド、アルキル、水素、ヒドロキシル、ピペラジニル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そしてR4はHであり、あういは、WはNであり、そしてpは0である]
で示される化合物またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物を投与することを含む方法。 - 式Iで示される化合物が、式1a:
R2は、アルコキシ、アルキル、および水素から選択され;
R5およびR7はそれぞれ、アルキル、アルコキシ、および水素から独立して選択され;
R6は、アルキル、ヒドロキシル、およびアルコキシから選択され;
WはCおよびNから選択され、ここで、WがNである場合、pは0または1であり、そして、WがCである場合、pは1であり;そして
W-(R4)pにおいて、WはCであり、pは1であり、そして、R4はHであり、あるいは、WはNであり、そして、pは0である]
で示される化合物またはその立体異性体、互変異性体、薬学的に許容できる塩、またはその水和物から選択される、請求項1または2に記載の方法。 - 式IまたはIaで示される化合物が、2-(4-(2-ヒドロキシエトキシ)-3,5-ジメチルフェニル)-5,7-ジメトキシキナゾリン-4(3H)-オン(RVX-208またはRVX000222)またはその薬学的に許容できる塩である、請求項1~3のいずれか一項に記載の方法。
- 1日用量として2-(4-(2-ヒドロキシエトキシ)-3,5-ジメチルフェニル)-5,7-ジメトキシキナゾリン-4(3H)-オン200mgまたは対応量のその薬学的に許容できる塩を、それを必要とする対象に投与する、請求項1~4のいずれか一項に記載の方法。
- それを必要とする対象に、2-(4-(2-ヒドロキシエトキシ)-3,5-ジメチルフェニル)-5,7-ジメトキシキナゾリン-4(3H)-オン100mgまたは対応量のその薬学的に許容できる塩を1日に2回投与する、請求項5に記載の方法。
- SGLT2阻害物質が、エンパグリフロジン、カナグリフロジン、レモグリフロジン、イプラグリフロジン、HM41322、およびダパグリフロジンから選択される、請求項1~6のいずれか一項に記載の方法。
- SGLT2阻害物質が、ベキサグリフロジン、エルツグリフロジン、ソタグリフロジン、ルセオグリフロジン、およびトホグリフロジンから選択される、請求項1~6のいずれか一項に記載の方法。
- 該対象がヒトである、請求項1~8のいずれか一項に記載の方法。
- 該対象が、2型糖尿病および低HDLコレステロール(男性では40mg/dL未満、女性では45mg/dL未満)および最近の急性冠症候群(ACS)(7~90日前)を有するヒトである、請求項1~9のいずれか一項に記載の方法。
- 該対象がスタチン療法を受けている、請求項1~10のいずれか一項に記載の方法。
- MACEが、非致死性心筋梗塞、心血管系死亡、卒中、および心血管疾患事象のための入院から選択される、請求項1~11のいずれか一項に記載の方法。
- 心血管疾患事象がうっ血性心不全である、請求項12に記載の方法。
- 心血管疾患事象のための入院がうっ血性心不全のための入院である、請求項12に記載の方法。
- MACEが、非致死性心筋梗塞、心血管系死亡、および卒中から選択される、請求項1~11のいずれか一項に記載の方法。
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US20230398137A1 (en) * | 2020-10-30 | 2023-12-14 | Resverlogix Corp. | Methods for lowering hba1c level with a combination of a bet bromodomain inhibitor and a sodium dependent glucose transport 2 inhibitor |
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AMERICAN JOURNAL OF CARDIOVASCULAR DRUGS, vol. 19, JPN6023049714, February 2019 (2019-02-01), pages 249 - 257, ISSN: 0005212280 * |
CARDIOVASCULAR THERAPEUTICS, vol. 35, JPN6023049713, 2017, pages 12265, ISSN: 0005212279 * |
DIABETES CARE, vol. 42, JPN6023049715, February 2019 (2019-02-01), pages 318 - 326, ISSN: 0005212281 * |
DIABETOLOGIA, vol. 61, JPN6023049717, 2018, pages 2108 - 2117, ISSN: 0005212282 * |
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EP4054584A4 (en) | 2023-11-08 |
BR112022008223A2 (pt) | 2022-09-06 |
MX2022005029A (es) | 2022-07-12 |
TW202131924A (zh) | 2021-09-01 |
IL292696A (en) | 2022-07-01 |
WO2021090061A1 (en) | 2021-05-14 |
CN114650824A (zh) | 2022-06-21 |
US20220370452A1 (en) | 2022-11-24 |
KR20220098757A (ko) | 2022-07-12 |
AU2020377539A1 (en) | 2022-05-19 |
EP4054584A1 (en) | 2022-09-14 |
JP7502811B2 (ja) | 2024-06-19 |
CA3160147A1 (en) | 2021-05-14 |
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