JP-2026076192-A - A combination of finerenone and an SGLT2 inhibitor for the treatment and/or prevention of cardiovascular and/or renal disease.

Abstract

[Problem] An object of the present invention is to improve the treatment and/or prevention of cardiovascular and renal diseases compared to already known monotherapies. A further object of the present invention is to provide a combination of pharmaceutical active ingredients for treating cardiovascular diseases, particularly cardiac and renal failure, characterized by chronic sodium retention, which reduces patient mortality and/or morbidity. Another object of the present invention is to improve the treatment and/or prevention of cardiovascular and renal diseases by administering a combination comprising finerenone and an SGLT2 inhibitor. [Solution] The present invention relates to pharmaceutical compositions and combinations comprising finerenone or its hydrate, solvate, or pharmaceutically acceptable salt or polymorph thereof, and an SGLT2 inhibitor or its hydrate, solvate, or pharmaceutically acceptable salt or polymorph thereof. The combinations can be used for the treatment and/or prevention of cardiovascular and/or renal diseases in humans and other mammals. [Selection Diagram] None

Inventors

• ペーター・コルクホーフ
• ペーター・ザンドナー
• ラース・ベルファッカー

Assignees

• バイエル アクチェンゲゼルシャフト

Dates

Publication Date

20260511

Application Date

20251226

Priority Date

20200422

Claims (12)

1. A combination comprising 0.25 to 80 mg of finerenone or its hydrate, solvate, or a pharmaceutically acceptable salt, and an SGLT2 inhibitor or its hydrate, solvate, or a pharmaceutically acceptable salt, wherein the SGLT2 inhibitor is selected from the group consisting of ertugliflozin, ipragliflozin, remogliflozin, cergliflozin, sotagliflozin, and tofogliflozin.
2. The combination according to claim 1, which is selected from, or a part of, the group consisting of a fixed combination, a single dosage form, two distinct dosage forms, a combination pack, a parts kit, or an unfixed combination.
3. component: a. One dosage form comprising finerenone or its hydrate, solvate, or a pharmaceutically acceptable salt thereof, b. The combination according to claim 1 or 2, comprising one dosage form comprising an SGLT2 inhibitor or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
4. The combination according to claim 3, wherein components a. and b. are administered separately, sequentially, simultaneously, concurrently, or alternately with a time delay.
5. A combination according to any one of claims 1 to 4, which is a single dosage form.
6. A combination according to any one of claims 1 to 5, for once-daily administration.
7. A pharmaceutical product comprising the combination described in any one of claims 1 to 6.
8. A pharmaceutical agent according to claim 7 for treating and/or preventing a disease.
9. Cardiovascular disorders; • Renal and cardiorenal impairment; Edema, pulmonary edema, cerebral edema, renal edema, and heart failure-related edema; • Cirrhosis of the liver; • NASH (Non-Alcoholic Steatohepatitis); Arterial hypertension, resistant hypertension, pulmonary hypertension, essential hypertension; ·shock; Hypertensive nephropathy, peripheral artery disease (PAD) including claudication and severe limb ischemia, coronary microcirculatory disorders (CMD) including CMD types 1-4, primary and secondary Raynaud's phenomenon, microcirculatory disorders, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic limb ulcers, gangrene, CREST syndrome, erythematous disorders, rheumatic diseases, for promoting wound healing, inflammatory diseases, asthmatic diseases, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α1-antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema and cystic fibrosis (CF); • Lung and cardiopulmonary disorders, central nervous system disorders; Fibrotic disorders and other disease symptoms; ・Sleep apnea; ·obesity; Coronary artery disease (CAD), - Acute kidney injury (AKI), A combination of any one of claims 1 to 6 or the pharmaceutically acceptable
10. Cardiovascular disorders are selected from congestive heart failure, acute heart failure, chronic heart failure, worsening chronic heart failure (WCHF), hospitalization for heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with mildly impaired ejection fraction (HFmrEF), and heart failure with impaired ejection fraction (HFrEF), hypertension, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular arrhythmias, ventricular arrhythmias, atrial fibrillation, atrial flutter, stable angina, unstable angina, myocardial infarction and its complications, aneurysm, adverse vascular remodeling, atherosclerosis, atrial fibrillation, and stroke; - Renal and cardiorenal disorders are selected from chronic kidney disease (CKD), non-diabetic chronic kidney disease (ndCKD), diabetic nephropathy (DKD), hypertensive nephropathy, cardiorenal syndrome, nephrotic syndrome, hepatorenal syndrome, renal hypoperfusion, dialysis-induced hypotension, obstructive urinary tract disease, glomerulopathy, IgA nephropathy, glomerulonephritis, glomerulosclerosis, tubulointerstitial damage, nephropathy, nephritis, Alport syndrome, nephritis, immunological nephropathy, kidney transplant rejection, immune complex-induced nephropathy, toxic substance-induced nephropathy, contrast-induced nephropathy; minimal change glomerulonephritis (lipoid), focal segmental glomerulosclerosis (FSGS), amyloidosis, renal cysts, hypertensive nephrosclerosis, nephrotic syndrome, uremia, anemia, electrolyte abnormalities, bone and carbohydrate metabolism abnormalities, polycystic kidney disease (PCKD), and syndrome of inappropriate ADH secretion (SIADH); The type of shock is selected from cardiogenic shock, septic shock, and anaphylactic shock; - Lung damage and cardiopulmonary damage are accompanied by pulmonary hypertension; • Multiple injuries are selected from ischemia-reperfusion injury, contrast agent administration, cardiopulmonary bypass surgery, shock, and sepsis. The combination or pharmaceutical product according to claim 9.
11. Nephropathy includes primary and congenital kidney diseases; Nephrotic syndrome may be diagnostically characterized by abnormally decreased creatinine and/or fluid excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and/or creatinine, altered urine osmolality or urine volume, increased microalbuminuria, macroalbuminuria, lesions of the glomeruli and arterioles, tubular dilation, hyperphosphatemia, and/or the need for dialysis; Electrolyte abnormalities include hyperkalemia or hyponatremia; Emphysema is smoking-induced emphysema; Other disease symptoms include end-organ damage affecting the brain, kidneys, or heart. The combination or pharmaceutical product according to claim 10.
12. The combination or pharmaceutical product according to claim 9, wherein the disease is selected from chronic kidney disease (CKD), hypertensive nephropathy, diabetic nephropathy (DKD), non-diabetic chronic kidney disease (ndCKD), chronic kidney disease in type 1 diabetes, chronic kidney disease in type 2 diabetes, diabetic retinopathy, diabetic retinopathy in type 1 diabetes, diabetic retinopathy in type 2 diabetes, worsening chronic heart disease (WCHF), heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF).

Description

This invention relates to a combination of finerenone or its hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof, and an SGLT2 inhibitor, its hydrate, solvate, pharmaceutically acceptable salt, or polymorph thereof, for the treatment and/or prevention of cardiovascular and/or renal diseases. In particular, these diseases may be characterized by chronic sodium retention. The fluid content of the human body is subject to various physiological control mechanisms, the goal of which is to maintain a constant volume (volume homeostasis). In this process, both the volume filling of the vascular system and the volume-osmolality of the plasma are continuously recorded by appropriate sensors (baroreceptors and osmoreceptors). The information these sensors supply to relevant centers in the brain regulates drinking behavior and controls fluid excretion via the kidneys through fluid and neural signals. The steroid hormone aldosterone plays a crucial role in maintaining fluid and electrolyte homeostasis by promoting sodium retention and potassium secretion in the epithelium of distal nephrons, thereby maintaining a constant extracellular volume and contributing to blood pressure regulation. In addition, aldosterone exhibits direct effects on the structure and function of the cardiovascular system, although the underlying mechanisms are not yet fully understood (R.E. Booth, J.P. Johnson, J.D. Stockand, Adv. Physiol. Educ. 26(1), 8–20 (2002)). (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, a compound of formula (I), is finerenone. It is a mineralocorticoid receptor antagonist (MR antagonist). Its synthesis, pharmacological properties, and pharmaceutical formulations/dosage forms are described in detail in International Publication No. 2008/104306. International Publication No. 2008/104306 states that the MR IC50 of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (racemic mixture, Example 4) is 23 nM, and the IC50 of ent-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide ((-)-enantiomer, Example 5; "finerenone") is 16 nM (see International Publication No. 2008/104306, Section B.1, "Evaluation of Pharmacological Activity"). Further methods for producing finerenone are described in International Publication No. 2016/016287. MR antagonists (e.g., the steroid compounds spironolactone, canrenone/canrenoate, and eplerenone, as well as more recent nonsteroidal MR antagonists, e.g., MT-3995, CS-3150, AZD9977, KBP-5074, LY2623091, PF-03882845, and finerenone) counteract aldosterone-mediated sodium retention in the kidneys (natriuretic effect). Thus, MR antagonists result in increased sodium excretion, which is a proven therapeutic concept for patients with hypertension and/or heart failure and/or renal failure. However, MR antagonists can only exert their natriuretic effect in the renal segment where aldosterone also exerts its physiological effects via MR. These are particularly the late distal tubule and collecting duct portions, which are only partially involved in sodium reabsorption, while the majority of sodium secretion and reabsorption occurs in the proximal tubule portion. Absolutely speaking, aldosterone affects only about 2% of total sodium reabsorption via MR in the distal tubules and renal renal tubules, thereby limiting the natriuretic effect of MR antagonists. While the use of MR antagonists is already part of the guideline-compliant pharmacological treatment for patients with chronic heart failure, the natriuretic effect of MR antagonists is limited. Sodium-glucose cotransporter-2 (SGLT2) is expressed in the proximal tubules and reabsorbs approximately 97% of filtered glucose. SGLT2 inhibitors block the reabsorption of both glucose and sodium, thus acting on glucosuria and natriuresis, resulting in antihyperglycemia, diuresis, blood pressure reduction, weight loss, and increased insulin sensitivity. This is an outcome benefit among diabetic patients with chronic heart failure (CHF) and chronic kidney disease (CKD). Interestingly, SGLT2 inhibition has recently been demonstrated to exert cardiovascular and renal benefits not mediated through changes in blood glucose, namely, reduced morbidity and mortality in both diabetic and non-diabetic patients. While the precise and beneficial mechanisms of action of SGLT2 inhibition, particularly in non-diabetic CHF and/or CKD, are not fully understood, one key component of these benefits is natriuretic activity, as pathological hyperreabsorption of sodium in the early proximal tubules is primarily mediated by increased SGLT2 activity in diabetic kidneys [Vallon V.]. [The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255-70]. This increased reabsorption reduces sodium delivery to the macula densa, which, via tubuloglomerular feedback, causes afferent arteriole dilat