Use of SGLT-2 inhibitors for the prevention and / or treatment of kidney diseases in non-human mammals

Abstract

To provide a means for preventing and / or treating one or more kinds of renal diseases in mammals other than humans, for example, carnivores, especially cats or dogs.SOLUTION: The present invention is directed to the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the prophylaxis and / or treatment of one or more kidney diseases in mammals other than humans, for example in carnivores, in particular in cats or dogs.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, in particular to the field of veterinary medicine.The present invention relates to the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs. [Background technology]

[0002] Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in companion animals, particularly carnivores such as cats and dogs, with a prevalence of 1.0-3.0% in cats and 0.5-1.0% in dogs that increases substantially in old age. CKD-related nephron damage is usually irreversible and often progressive. The International Renal Interest Society (IRiS) has classified CKD into different stages based initially on fasting blood creatinine or fasting blood symmetric dimethylarginine (SDMA) concentrations, or (preferably) both, assessed on at least two occasions in hydrated, stable patients. Patients are then divided into the following substages based on proteinuria and blood pressure: 1 - Normal blood creatinine or normal or mildly elevated blood SDMA. Some other renal abnormalities are present (abnormal findings on renal palpation or renal imaging, proteinuria of renal origin, abnormal renal biopsy results, elevated blood creatinine or SDMA concentrations in serially collected samples). Persistently elevated blood SDMA concentrations (>14 μg / dL) can be used to diagnose early CKD. 2- Normal or mildly elevated creatinine, mild renal azotemia (lower end of the range that lies within the reference range for creatinine for many laboratories, but the lack of response to creatinine concentration as a screening test means that patients with creatinine values ​​near the upper reference limits often have excretory insufficiency). Mildly elevated SDMA. Clinical signs are usually mild or absent. 3 - Moderate renal azotemia. Many extrarenal signs may be present, but the extent and severity of these may vary. If no signs are present, the case may be considered early stage 3, but the presence of many or prominent systemic signs may justify classification as late stage 3. 4- Increased risk of systemic clinical signs and the development of urinary toxicity.

[0003] Standard care for treatment usually consists of ACE inhibitors (e.g., enalapril), calcium channel blockers (e.g., diltiazem and amlodipine), and angiotensin receptor blockers (e.g., telmisartan), which target renal hemodynamics. In addition, clinical signs (e.g., vomiting, nausea, weight loss, anorexia) are treated as needed, and a renal diet can be used to manage the disease.

[0004] State-of-the-art therapeutic interventions are based on specific actions on unique pathways for the symptomatic treatment of secondary conditions induced by renal conditions. Beneficial renal effects have been observed in humans with the use of SGLT-2 inhibitors (DAPA-CKD ClinicalTrials.gov number, NCT03036150). However, the direct effects on the kidneys of carnivores such as felines and canines remain unclear. Notable are anatomical, physiological, and pathophysiological differences between species. Initial evidence for these differences is evident in the prevalence of CKD in cats compared with dogs (1.0-3.0% in cats and 0.5-1.0% in dogs) and humans (11-13%, with the majority at stage 3). Furthermore, in contrast to people and dogs, primary glomerulopathy with significant proteinuria is a remarkably rare finding in cats, and the majority of elderly cats with CKD do not have histological evidence of primary glomerular disease. Typical histological features include interstitial inflammation, tubular atrophy, and fibrosis with secondary glomerular sclerosis.In addition, cardiovascular disease (CVD) is a major cause of morbidity and mortality in people, where CKD is considered a promoter of CVD risk and an independent risk factor for CVD events.There is an inverse correlation between graded CVD risk and glomerular filtration rate (GFR), which is independent of age, sex, and other risk factors.This is not true for non-human mammals, such as carnivores, such as dogs and cats, where the etiology of cardiovascular disease (cardiomyopathy, valvular disease) is significantly different from the etiology observed in people (coronary disease).

[0005] Wheeler et al. (Diabetes Ther (2020) 11:2757-2774) review the effects of SGLT-2 inhibitors on the progression of chronic kidney disease in human patients with type 2 diabetes. Dekkers and Gansevoort (Nephrol Dial Transplant (2020) 35: i33-i42) describe the potential application of SGLT-2 inhibitors in non-diabetic kidney disease in humans. EP3508222 discloses a drug or pharmaceutical composition for eliminating senescent cells, comprising an SGLT-2 inhibitor. WO2021 / 092341 discloses sodium-glucose related transporter inhibitors for the treatment of chronic kidney disease, hypertension and heart failure in companion animals. Summary of the Invention

[0006] Despite the disclosures in the literature above, there remains a medical need for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, particularly cats or dogs. The present invention relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use in a method for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs. Corresponding methods for preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, which methods comprise administering one or more SGLT-2 inhibitors to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0007] In one aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more renal diseases are selected from the group consisting of renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulonephritis / tubulointerstitial nephritis (TIN), acute kidney disease, chronic kidney disease.

[0008] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In one aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more renal diseases are selected from the group consisting of acute kidney disease, chronic kidney disease.

[0009] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In one aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more renal diseases are selected from the group consisting of chronic kidney diseases.

[0010] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0011] In another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives. Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0012] In yet another aspect, the present invention also provides one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the uses disclosed and / or claimed herein, wherein the one or more SGLT-2 inhibitors are (1) Glucopyranosyl-substituted benzene derivatives of formula (1) [ka] (In the formula, R 1 represents cyano, Cl or methyl (most preferably cyano), R 2 represents H, methyl, methoxy or hydroxy (most preferably H), R 3 is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl ter-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, most preferably R 3 is cyclopropyl) or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

[0013] (2) Veragliflozin represented by formula (2): [ka] (3) Dapagliflozin represented by formula (3): [ka]

[0014] (4) Canagliflozin represented by formula (4): [ka]

[0015] (5) Empagliflozin represented by formula (5): [ka]

[0016] (6) Luseogliflozin represented by formula (6): [ka]

[0017] (7) Tofogliflozin represented by formula (7): [ka]

[0018] (8) Ipragliflozin represented by formula (8): [ka] (9) Ertugliflozin represented by formula (9): [ka]

[0019] (10) Atigliflozin represented by formula (10): [ka] (11) Remogliflozin represented by formula (11): [ka]

[0020] (11A) Remogliflozin etabonate represented by formula (11A): [ka]

[0021] (12) Thiophene derivative of formula (12) [ka] (wherein R represents methoxy or trifluoromethoxy) (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13): [ka]

[0022] (14) Spiroketal derivative of formula (14): [ka] (wherein R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl)

[0023] (15) Pyrazole-O-glucoside derivatives of formula (15) [ka] (In the formula, R 1 is C 1-3 -alkoxy, L 1 , L 2 are, independently of one another, H or F, R 6 is H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl

[0024] (16) Sotagliflozin represented by formula (16): [ka]

[0025] (17) Sergliflozin represented by formula (17): [ka]

[0026] (18) Compound represented by formula (18): [ka] (In the formula, R 3is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy -3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, R 3 is most preferably cyclopropyl), or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

[0027] (19) Bexagliflozin represented by formula (19): [ka]

[0028] (20) Janagliflozin represented by formula (20): [ka] (21) Remogliflozin represented by formula (21): [ka] (22) Wanpagliflozin or a pharmaceutically acceptable form thereof.

[0029] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0030] In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the pharmaceutically acceptable form is a crystalline complex of the one or more SGLT-2 inhibitors and one or more amino acids, preferably proline, more preferably L-proline, and most preferably a co-crystal of the one or more SGLT-2 inhibitors, L-proline and water of crystallization.

[0031] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0032] In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the uses as disclosed and / or claimed herein, wherein the non-human mammal, for example a carnivore, in particular a feline or canine patient is in need of such prevention and / or treatment, preferably a carnivore patient in need of such prevention and / or treatment, more preferably a feline or canine patient in need of such prevention and / or treatment, and even more preferably a non-diabetic feline or canine patient in need of such prevention and / or treatment.

[0033] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human animals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof are administered orally, parenterally, intravenously, subcutaneously or intramuscularly, preferably orally.

[0034] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0035] In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the uses disclosed and / or claimed herein, wherein the one or more SGLT-2 inhibitors are administered at a dose of 0.01 mg / kg to 10 mg / kg body weight, preferably at a dose of 0.01 mg / kg to 5 mg / kg body weight, more preferably at a dose of 0.01 mg / kg to 4 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 3 mg / kg body weight, and even more preferably at a dose of 0.01 mg / kg to 5 mg / kg body weight. Preferably, the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof are to be administered at a dose of 0.01 mg / kg to 2 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 1 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.5 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.3 mg / kg body weight, and most preferably at a dose of 0.05 mg / kg body weight (dogs) or 1.0 mg / kg body weight (cats).

[0036] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein such one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof are to be administered once or twice per day.

[0037] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more SGLT-2 inhibitors is velagliflozin, which is to be administered as the sole SGLT-2 inhibitor, preferably orally, more preferably once or twice per day, at a dose of 0.01 mg / kg to 1 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.5 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.3 mg / kg body weight, and most preferably at a dose of 0.05 mg / kg body weight (dogs) or 1.0 mg / kg body weight (cats).

[0038] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the uses disclosed and / or claimed herein, wherein velagliflozin is the sole SGLT-2 inhibitor to be orally administered at a dose of 0.01 mg / kg to 1.0 mg / kg body weight once daily, preferably at a dose of 0.05 mg / kg body weight (dogs) or 1.0 mg / kg body weight (cats) once daily.

[0039] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention. In yet another aspect, the present invention also relates to one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for the uses disclosed and / or claimed herein, wherein the one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof are to be administered before, after or simultaneously with the administration of one or more other active pharmaceutical ingredients, preferably selected from the group consisting of another SGLT-2 inhibitor or a pharmaceutically acceptable form thereof, one or more ACE inhibitors, such as benazepril, ramipril or enalapril; one or more calcium channel blockers, such as diltiazem or amlodipine; one or more angiotensin receptor blockers, such as telmisartan; one or more calcium channel sensitizers and / or positive inotropes, such as pimobendan and / or digitalis alkaloids; and / or one or more phosphate binders, such as chitosan.

[0040] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0041] In yet another aspect, the present invention also provides one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for the uses disclosed and / or claimed herein, wherein the prophylactic and / or therapeutic effect is measured in one or more of the following clinical and / or biochemical parameters: - improved renal efficiency, characterized by a reduction in proteinuria and a reduction and / or stabilization of serum SDMA and / or serum creatinine; - increased hepatic ketone body production, characterized by increased plasma levels of 3-hydroxybutyric acid and / or the corresponding acylcarnitine, i.e., hydroxybutyrylcarnitine, and increased plasma levels of one or more branched-chain amino acids (e.g., valine, leucine, and isoleucine); - Improved blood pressure; - Improved hydration status; - delaying the onset of renal failure, preferably by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer, or delaying and / or halting the progression of one or more renal diseases, in particular chronic kidney disease, and / or improving the classification stage of one or more renal diseases, in particular CKD (e.g. improving from phase 3 to phase 2); - increased survival time of non-human mammalian patients, preferably at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more, and / or lower kidney-related mortality and / or morbidity; - Improved clinical signs, e.g., reduction in polydipsia, polyuria, vomiting and / or lethargy; - Higher quality of life or a pharmaceutically acceptable form thereof, characterized in that:

[0042] Corresponding methods of preventing and / or treating one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, comprising administering one or more SGLT-2 inhibitors as disclosed and / or claimed herein to such non-human mammals, preferably carnivores, in particular cats or dogs, as well as corresponding uses of one or more SGLT-2 inhibitors as disclosed and / or claimed herein for the preparation of medicaments for the prevention and / or treatment of one or more kidney diseases in non-human mammals, such as carnivores, in particular cats or dogs, are also intended to be encompassed by the present invention.

[0043] The present invention further relates to pharmaceutical compositions comprising one or more SGLT-2 inhibitors as disclosed and / or claimed herein or pharmaceutically acceptable forms thereof for the uses / methods as disclosed and / or claimed herein.

[0044] The advantages of the present invention include one or more of the following: - improved renal efficiency, characterized by a reduction in proteinuria and a reduction and / or stabilization of serum SDMA and / or serum creatinine; - increased hepatic ketone body production, characterized by increased plasma levels of 3-hydroxybutyric acid and / or the corresponding acylcarnitine, i.e., hydroxybutyrylcarnitine, and increased plasma levels of one or more branched-chain amino acids (e.g., valine, leucine, and isoleucine); - Improved blood pressure; - Improved hydration status; - delaying the onset of renal failure, preferably by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer, or delaying and / or halting the progression of one or more renal diseases, in particular chronic kidney disease, and / or improving the classification stage of one or more renal diseases, in particular CKD (e.g. improving from phase 3 to phase 2); - increased survival time of non-human mammalian patients, preferably at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more, and / or lower kidney-related mortality and / or morbidity; - Improved clinical signs, e.g., reduction in polydipsia, polyuria, vomiting and / or lethargy; - Higher quality of life. DETAILED DESCRIPTION OF THE INVENTION

[0045] Before embodiments of the present invention are described in further detail, it should be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All given ranges and values ​​may vary by 1-5% unless otherwise indicated or known to those of ordinary skill in the art; therefore, the term "about" is typically omitted from the description and claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods, devices, and materials are described herein. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the substances, excipients, carriers, and methodology as reported in the publications that may be used in connection with the present invention. Nothing herein should be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0046] In the course of the present invention, the terms "carnivore" and "non-human primarily carnivorous mammal" are used interchangeably. In a preferred embodiment, the carnivore is a non-human primarily carnivorous mammal, more preferably a canine, in particular a dog, and / or a feline, in particular a cat. In another preferred embodiment, the "non-human mammal" is selected from the group consisting of cattle, canines, goats, horses, felines, lagomorphs, sheep, pigs, and rodents. More preferably, it is selected from the group consisting of cows, cows, dogs, goats, horses, ponies, donkeys, cats, sheep, pigs, rabbits, rats, and mice. Even more preferably, it is selected from the group consisting of canines and / or felines. Most preferably, it is selected from the group consisting of dogs and / or cats.

[0047] Mammals are a class of vertebrates characterized by the presence of mammary glands in females, while both males and females have sweat glands, hair, three middle ear bones used for hearing, and neocortical regions in the brain. Within this class, placentals are preferred and characterized by the use of the placenta during pregnancy. Mammals can be further divided based on their feeding behavior. Some mammals feed on prey animals. This includes a carnivorous diet (and insectivorous diet). Other mammals, called herbivores, eat plants. Omnivores eat both prey and plants. Carnivorous mammals have simple digestive tracts because the proteins, lipids, and minerals found in meat require little specialized digestive support. Plants, on the other hand, contain complex polysaccharides, such as cellulose. Therefore, the digestive tracts of herbivores accommodate bacteria that ferment these substances, making them digestible. The present invention is specifically designed for carnivores, primarily non-human carnivorous mammals. Such mammals include in particular all feliforms, such as domestic or big cats, and most caniforms, such as dogs, wolves, and foxes. Due to the economic importance of companion animals in modern life, the present invention is particularly designed for dogs and / or cats.

[0048] In the course of the present invention, the term "renal dysplasia" refers to a rare renal malformation in which the kidney(s) are present but their development is abnormal, resulting in malformations of the histological structure of the kidney. In the course of this invention, the term "glomerulopathy" refers to the development of glomerulonephritis with or without accompanying conditions. In the course of this invention, the term "polycystic kidney disease" refers to an inherited disorder in which fluid-filled sacs develop within the kidney tissue. In the course of this invention, the term "amyloidosis" refers to a group of diseases in which abnormal proteins known as amyloid fibrils accumulate in (kidney) tissues. In the course of this invention, the term "acute kidney disease" refers to the sudden onset of renal failure or damage.

[0049] In the course of this invention, the terms "tubulonephritis" and "tubulointerstitial nephritis (TIN)" are used interchangeably to refer to a common cause of acute kidney injury (AKI) that can lead to chronic kidney disease (CKD). TIN is associated with immune-mediated infiltration of the renal interstitium by inflammatory cells, which can progress to fibrosis. In the context of this invention, the term "chronic kidney disease (CKD)" refers to a pathophysiological process in which the remaining renal function is insufficient to maintain the glomerular filtration rate at a physiological level. CKD can also be defined as a complex clinical syndrome, based on abnormal kidney structure and function, characterized by weight loss, bad breath, poor hair quality, proteinuria, hypertension, azotemia, polyuria, polydipsia, vomiting, and anemia. It is a mostly chronic condition with progressive nephron damage and is initiated by different factors, including diabetes, ischemic stroke, toxic invasion, some viral infections, and cardiac conditions that result in hypertension.

[0050] SGLT-2 inhibitors for use according to the present invention include, but are not limited to, glucopyranosyl-substituted benzene derivatives, such as those described in WO01 / 27128, WO03 / 099836, WO2005 / 092877, WO2006 / 034489, WO2006 / 064033, WO2006 / 117359, WO2006 / 117360, WO2007 / 025 943, WO2007 / 028814, WO2007 / 031548, WO2007 / 093610, WO2007 / 128749, WO2008 / 049923, WO2008 / 055870, WO2008 / 055940, WO2009 / 022020 or WO2009 / 022008.

[0051] Furthermore, the one or more SGLT-2 inhibitors for use according to the present invention may be selected from the group consisting of the following compounds or pharmaceutically acceptable forms thereof: (1) Glucopyranosyl-substituted benzene derivatives of formula (1) [ka] (In the formula, R1 represents cyano, Cl or methyl (most preferably cyano); R 2 represents H, methyl, methoxy or hydroxy (most preferably H), R 3 is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy -3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, most preferably R 3 is cyclopropyl) or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3-alkyl)-carbonyl;

[0052] (2) Veragliflozin represented by formula (2): [ka]

[0053] (3) Dapagliflozin represented by formula (3): [ka]

[0054] (4) Canagliflozin represented by formula (4): [ka] (5) Empagliflozin represented by formula (5): [ka]

[0055] (6) Luseogliflozin represented by formula (6): [ka]

[0056] (7) Tofogliflozin represented by formula (7): [ka]

[0057] (8) Ipragliflozin represented by formula (8): [ka] (9) Ertugliflozin represented by formula (9): [ka]

[0058] (10) Atigliflozin represented by formula (10): [ka]

[0059] (11) Remogliflozin represented by formula (11): [ka] (11A) Remogliflozin etabonate represented by formula (11A): [ka]

[0060] (12) Thiophene derivative of formula (12) [ka] (wherein R represents methoxy or trifluoromethoxy);

[0061] (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13); [ka]

[0062] (14) Spiroketal derivative of formula (14): [ka] (wherein R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl)

[0063] (15) Pyrazole-O-glucoside derivatives of formula (15) [ka] (In the formula, R 1 represents C1-3-alkoxy; L1 and L2 each independently represent H or F; R 6 is H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

[0064] (16) Sotagliflozin represented by formula (16): [ka]

[0065] (17) Sergliflozin represented by formula (17): [ka]

[0066] (18) Compound represented by formula (18): [ka] (In the formula, R 3is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy -3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, R 3 is most preferably cyclopropyl), or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

[0067] (19) Bexagliflozin represented by formula (19): [ka]

[0068] (20) Janagliflozin represented by formula (20): [ka] (21) Remogliflozin represented by formula (21): [ka] (22) Wampagliflozin.

[0069] The term "velagliflozin," as used herein, refers to velagliflozin of the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound, its synthesis methods, and its cocrystals are described, for example, in WO2007 / 128749, WO2014 / 016381, and WO2019 / 121509. The term "dapagliflozin" as used herein refers to dapagliflozin of the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and its synthesis methods are described, for example, in WO03 / 099836. Preferred hydrates, solvates, and crystalline forms are described, for example, in patent applications WO2008 / 116179 and WO2008 / 002824. The term "canagliflozin," as used herein, refers to canagliflozin of the above structure, as well as its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and its synthesis methods are described, for example, in WO2005 / 012326 and WO2009 / 035969. Preferred hydrates, solvates, and crystalline forms are described, for example, in patent application WO2008 / 069327.

[0070] The term "empagliflozin," as used herein, refers to empagliflozin having the above structure, as well as its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and its synthetic methods are described, for example, in WO2005 / 092877, WO2006 / 120208, and WO2011 / 039108. Preferred crystalline forms are described, for example, in patent applications WO2006 / 117359 and WO2011 / 039107. The term "atigliflozin" as used herein refers to atigliflozin of the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and its synthesis methods are described, for example, in WO2004 / 007517.

[0071] The term "ipragliflozin," as used herein, refers to ipragliflozin of the above structure, as well as its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and methods for its synthesis are described, for example, in WO2004 / 080990, WO2005 / 012326, and WO2007 / 114475. The term "tofogliflozin," as used herein, refers to tofogliflozin of the above structure, as well as its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound and methods for its synthesis are described, for example, in WO2007 / 140191 and WO2008 / 013280. The term "luceogliflozin," as used herein, refers to luseogliflozin of the above structure, as well as its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms.

[0072] The term "ertugliflozin" as used herein refers to ertugliflozin having the above structure, as well as its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms. The compound is described, for example, in WO2010 / 023594. The term "remogliflozin" as used herein refers to remogliflozin having the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms, including prodrugs of remogliflozin, particularly remogliflozin etabonate.Methods for its synthesis are described, for example, in patent applications EP1213296 and EP1354888. The term "sergliflozin" as used herein refers to sergliflozin of the above structure and its pharmaceutically acceptable forms, including its hydrates and solvates, and its crystalline forms, including prodrugs of sergliflozin, particularly sergliflozin etabonate, the preparation of which is described, for example, in patent applications EP1344780 and EP1489089.

[0073] The compound of the above formula (16), i.e., sotagliflozin, and its preparation are described, for example, in WO2008 / 042688 or WO2009 / 014970. Preferred SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives. Optionally, one or more hydroxyl groups of the glucopyranosyl group may be substituted with (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl.

[0074] More preferred are glucopyranosyl-substituted benzonitrile derivatives of formula (1) as disclosed hereinabove. However, even more preferred are glucopyranosyl-substituted benzonitrile derivatives of formula (18): [ka] (In the formula, R 3is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy -3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, R 3 is most preferably cyclopropyl), or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl.

[0075] Preferably, such an SGLT-2 inhibitor is velagliflozin as shown in formula (2). Optionally, one or more hydroxyl groups of the β-D-glucopyranosyl group of velagliflozin may be selected from the group consisting of (C 1-18-alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl. Thus, in a preferred embodiment, the at least one SGLT-2 inhibitor according to the present invention is a glucopyranosyl-substituted benzene derivative SGLT-2 inhibitor, preferably an SGLT-2 inhibitor of formula (1), more preferably an SGLT-2 inhibitor of formula (18), or more preferably an SGLT-2 inhibitor of formula (2), i.e. velagliflozin, in each case as defined herein above.

[0076] Reference herein to SGLT-2 inhibitors and / or their uses according to the present invention includes pharmaceutically acceptable forms of SGLT-2 inhibitors, unless otherwise stated. According to the present invention, any pharmaceutically acceptable form of the SGLT-2 inhibitor, such as that of formula (1), preferably formula (18), more preferably formula (2), can be used. For example, crystalline forms can be used. Prodrug forms are also encompassed by the present invention. Prodrug forms can include, for example, esters and / or hydrates. The term "prodrug" is also intended to include any covalently bonded carriers that release an active compound of the invention in vivo when the prodrug is administered to a mammalian subject. Functional groups present in the compounds of the invention can be modified to prepare prodrugs of the compounds of the invention such that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compounds of the invention.

[0077] Crystalline forms for use according to the present invention include complexes of an SGLT-2 inhibitor with one or more amino acids (see, for example, WO 2014 / 016381) - so-called co-crystals. Amino acids for such uses may be naturally occurring amino acids. Amino acids may be proteinogenic amino acids (including L-hydroxyproline) or non-proteinogenic amino acids. Amino acids may be D-amino acids or L-amino acids. In some preferred embodiments, the amino acid is proline (L-proline and / or D-proline, preferably L-proline). For example, crystalline complexes / co-crystals of velagliflozin with proline (e.g., L-proline) and water of crystallization are preferred. Thus, disclosed herein are crystalline complexes / co-crystals of one or more naturally occurring amino acids and an SGLT-2 inhibitor, such as a crystalline complex / co-crystal of one or more naturally occurring amino acids and a glucopyranosyl-substituted benzene derivative SGLT-2 inhibitor, preferably an SGLT-2 inhibitor of formula (1), more preferably an SGLT-2 inhibitor of formula (18), or more preferably an SGLT-2 inhibitor of formula (2) (velagliflozin).

[0078] A certain pharmaceutical activity is a basic requirement that must be met by a pharmaceutically active agent before it can be approved as a marketed drug. However, there are various additional requirements that a pharmaceutically active agent must comply with. These requirements are based on various parameters, which are related to the properties of the active agent itself. Non-limiting examples of these parameters include the stability of the active agent under various environmental conditions, its stability during the production of the pharmaceutical formulation, and the stability of the active agent in the final pharmaceutical composition. The active pharmaceutical agent used to prepare a pharmaceutical composition should be as pure as possible, and its stability during long-term storage under various environmental conditions must be guaranteed. This is essential to prevent the use of pharmaceutical compositions containing, for example, degradation products of the actual active agent. In such cases, the content of the active agent in the pharmaceutical may be less than specified. The uniform distribution of the drug in the formulation is a crucial factor, especially when the drug must be administered in a low dose.To ensure uniform distribution, the particle size of the active substance can be reduced to an appropriate level, for example, by milling.Although a hard state is required during the process, it is absolutely necessary that the active substance be extremely stable throughout the milling process, since the degradation of the active pharmaceutical substance as a side effect of milling (or micronization) must be avoided as much as possible.Only if the active substance is sufficiently stable during the milling process can it be possible to produce a homogeneous pharmaceutical formulation, which always contains a specified amount of active substance in a reproducible manner.

[0079] Another problem that may arise in the milling process for preparing the desired pharmaceutical formulation is the energy input and stress on the crystal surface caused by this process. This may, in certain circumstances, lead to a change in polymorphism to amorphous or to changes in the crystal lattice. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance always has the same crystalline form, the stability and properties of the crystalline active substance are also subject to strict requirements from this point of view. The stability of the active pharmaceutical ingredient is also important in pharmaceutical compositions to determine the shelf life of a particular drug; shelf life is the length of time during which the drug can be administered without any risk.Therefore, the high stability of the drug in the above pharmaceutical composition under various storage conditions is an additional benefit to both patients and manufacturers. Moisture absorption reduces the content of the active pharmaceutical ingredient due to the increase in mass caused by water uptake. Pharmaceutical compositions that tend to absorb moisture must be protected from moisture during storage, for example, by adding a suitable desiccant or by storing the drug in an environment that protects it from moisture. Therefore, preferably, the active pharmaceutical ingredient should be at most slightly hygroscopic.

[0080] Furthermore, the availability of well-defined crystalline forms allows for purification of the drug substance by recrystallization. Apart from the requirements set out above, it should generally be kept in mind that any change to the solid state of a pharmaceutical composition can improve its physical and chemical stability, providing a significant advantage over a less stable form of the same drug. The crystalline complexes / co-crystals of natural amino acids and SGLT-2 inhibitors (e.g. glucopyranosyl-substituted benzene derivatives, or SGLT-2 inhibitors of formula (1) or formula (18), or in particular SGLT-2 inhibitors of formula (2), i.e. velagliflozin) fulfil the important requirements described hereinbefore. The SGLT-2 inhibitors for use according to the present invention can be prepared as pharmaceutical compositions. They can be prepared as solid or liquid formulations. In either case, they are preferably prepared in liquid form for oral administration, preferably oral administration (e.g., WO2017 / 032799). However, SGLT-2 inhibitors can also be prepared, for example, for parenteral administration. Solid formulations include tablets, granular forms, and other solid forms, such as suppositories. Among solid formulations, tablets and granular forms are preferred.

[0081] Pharmaceutical compositions within the contemplation of the present invention may comprise an SGLT-2 inhibitor according to the present invention and one or more excipients. Any excipient that enables or supports the intended medical action can be used. Such excipients are available to those skilled in the art. Useful excipients are, for example, anti-adherents (used to reduce adhesion between the powder (granules) and the punch faces, thus preventing sticking to the tablet punch), binders (solution or dry binders that hold ingredients together), coatings (protect tablet ingredients from deterioration due to moisture in the air and make large or unpleasant-tasting tablets easier to swallow), disintegrants (allow tablets to break up upon dilution), fillers, diluents, flavors, colors, glidants (flow regulators - promote powder flow by reducing inter-particle friction and adhesion), lubricants (prevent ingredients from clumping together and sticking to the tablet punch or capsule filling machine), preservatives, adsorbents, sweeteners, etc. Formulations according to the invention, e.g. solid formulations, may comprise carriers and / or disintegrants selected from the group of sugars and sugar alcohols, e.g. mannitol, lactose, starch, cellulose, microcrystalline cellulose and cellulose derivatives, e.g. methylcellulose.

[0082] Manufacturing procedures for formulations suitable for canines are known to those skilled in the art and include, for example, direct compression, dry granulation, and wet granulation methods for solid formulations. In the direct compression process, the active ingredient and all other excipients are placed together in a compression device to which the compression device is directly applied, and this material can be pressed to obtain tablets. The resulting tablets may then be coated to protect them physically and / or chemically, for example, with materials known from the state of the art. A unit for administration, e.g., a single liquid dose, or unit of a solid formulation, e.g., a tablet, for use according to the present invention may contain from 0.1 mg to 10 mg, or e.g., 0.3 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg; or 5 to 2500 mg, or e.g., 5 to 2000 mg, 5 mg to 1500 mg, 10 mg to 1500 mg, 10 mg to 1000 mg, or 10 to 500 mg of an SGLT-2 inhibitor. As will be appreciated by those skilled in the art, the content of SGLT-2 inhibitor in the solid formulation or any formulation disclosed herein for administration to non-human mammals, e.g., carnivores, particularly cats and / or dogs, may, if necessary, be increased or decreased in proportion to the body weight of such non-human mammal to be treated. In one embodiment, the pharmaceutical composition for use according to the invention is designed for oral or parenteral administration, preferably for oral administration. In particular, oral administration is improved by excipients, which, for example, modify the odor and / or tactile properties of the pharmaceutical composition for the intended patient as described.

[0083] When the SGLT-2 inhibitor for use according to the present invention is formulated for oral administration, it is preferred that the excipients provide properties that render the formulation suitable for administration to canines, such as palatability and / or chewiness. Liquid formulations are also preferred. Liquid formulations may be, for example, solutions, syrups, or suspensions. These liquid formulations may be administered directly to non-human mammals, such as canines, or may be mixed with the feed and / or drink (e.g., drinking water) of non-human mammals, such as canines. One advantage of liquid formulations (similar to granular formulations) is that such dosage forms allow for accurate dosing. For example, SGLT-2 inhibitors can be accurately dosed in proportion to the body mass of non-human mammals, such as canines. Typical compositions of liquid formulations are known to those skilled in the art.

[0084] A physician skilled in the art can determine the appropriate dosage for use in the present invention. Preferred unit dosage units include mg / kg body weight, i.e. mg of SGLT-2 inhibitor per kg body mass of a non-human mammal. The SGLT-2 inhibitor of the present invention may be administered at a dose of, for example, 0.01 to 10 mg / kg body weight per day, for example, 0.01 to 5 mg / kg body weight per day, for example, 0.01 to 4 mg / kg body weight per day, for example, 0.01 to 3 mg / kg body weight per day, for example, 0.01 to 2 mg / kg body weight per day, for example, 0.01 to 1.5 mg / kg body weight per day, for example, 0.01 to 1 mg / kg body weight per day, for example, 0.01 to 0.75 mg / kg body weight per day, for example, 0.01 to 0.5 mg / kg body weight per day, for example, 0.01 to 0.4 mg / kg body weight per day, or 0.1 to 3.0 mg / kg body weight per day, preferably 0.2 to 2.0 mg / kg body weight per day, more preferably 0.1 to 1 mg / kg body weight per day or 0.5 to 1 mg / kg body weight per day. In another preferred embodiment, the dosage is 0.01 to 1 mg / kg body weight per day, preferably 0.01 to 0.5 mg / kg body weight per day, more preferably 0.02 to 0.4 mg / kg body weight per day, for example, 0.03 to 0.3 mg / kg body weight per day. A physician skilled in the art can prepare the SGLT-2 inhibitors of the present invention for administration in a desired dose. [Example]

[0085] The following examples serve to further illustrate the present invention, but should not be construed as limiting the scope of the invention disclosed herein. Example 1 Exploratory clinical field experiment - cats Client-owned patients diagnosed with CKD (IRiS stage 3), as diagnosed via physical examination and biomarker levels, are treated orally with velagliflozin 0.1 mg / kg body weight once daily. During the study period, body weight, body condition score, biomarker levels (creatinine and SDMA), the presence of coexisting conditions, and the need for additional medication are examined by investigators on a standardized basis during the study visits. Parameters examined include creatinine and SDMA levels, proteinuria, blood pressure, quality of life, and hydration status. Additionally, variables observed include delay in onset of renal failure, survival time of feline patients, progression of IRiS stage, and kidney-related mortality and / or morbidity. Experimental results confirm beneficial effects on renal function and delay in disease progression.

[0086] Example 2 Exploratory clinical field experiment - dogs Client-owned patients diagnosed with CKD (IRiS stage 3), as determined through physical examination and biomarker levels, are treated orally with velagliflozin 0.3 mg / kg body weight once daily. During the study period, body weight, body condition score, biomarker levels (creatinine and SDMA), proteinuria, the presence of coexisting conditions, and the need for additional medication are examined by investigators on a standardized basis during the study visits. Parameters examined include creatinine and SDMA levels, proteinuria, blood pressure, and hydration status. Additionally, variables observed include delayed onset of renal failure, survival time of the canine patients, progression of the IRiS stage, and kidney-related mortality and / or morbidity. Experimental results confirm beneficial effects on renal function and delayed disease progression.

[0087] Example 3 Exploratory clinical field study in cats with CKD The clinical trial was conducted in three animal clinics. Overall, nine cats with chronic kidney disease (CKD) were included in the study and treated with velagliflozin orally at 1 mg / kg body weight once daily for up to 150 days (depending on enrollment time).

[0088] As recommended by the International Veterinary Nephrology Study Group (IRIS 2019), the diagnosis of CKD was based on two measurements of serum creatinine concentration (previous value and screening, and screening value in fasted cats) taken at least 2 weeks apart. The serum creatinine level required for admission to the registry was ≥ 2.2 mg / dL and < 5.0 mg / dL. Disease staging was performed based on serum creatinine levels throughout the experiment, according to the IRIS CKD staging (IRIS 2019). At enrollment, five of the nine cats were in stage 2 (cases 200-001, 200-005, 200-006, 300-003, and 300-008), and four of the nine were in stage 3 (cases 200-003, 200-004, 200-007, and 400-004).

[0089] Case 400-004-Improvement: Case 400-004 was a 6.9 kg, 12-year-old, neutered European cat on a renal diet. At screening, the owner reported a normal appetite, excessive drinking, and a good overall quality of life. The cat was not receiving any medications at screening. One non-serious adverse event was reported (owner reported diarrhea), which resolved within 24 hours without treatment. The cat received no concomitant medications throughout the study. As a result of oral treatment with velagliflozin at 1 mg / kg body weight once daily, clinical signs and biochemical parameters demonstrated an improvement in the condition (Tables 1 and 2). This was based on a decrease in serum creatinine and BUN concentrations. Serum potassium and phosphate levels remained within the reference range. In addition, total urinary protein decreased, while the UPC ratio remained within the normal range. According to the owner, drinking behavior improved from excessive to normal. The expected antidiabetic effect of velagliflozin during treatment was confirmed. Case 400-004 has completed testing.

[0090] [Table 1]

[0091] [Table 2]

[0092] Case 300-008-Stable: Case 300-008 was a 12-year-old, 2.5 kg, neutered European cat fed a standard diet. The owner reported a normal appetite, excessive drinking, and a good overall quality of life at screening. The cat was not receiving any medications at screening. No adverse events were reported during the study. The cat received no concomitant treatments throughout the study.

[0093] Oral treatment with velagliflozin at 1 mg / kg body weight once daily resulted in clinical signs and biochemical parameters demonstrating stabilization of the condition. Serum creatinine concentration remained stable, and serum potassium and phosphate levels remained within the reference range (Table 3). Accordingly, total urinary protein and UPC ratio remained within the reference range. According to the owner's assessment, drinking behavior improved from excessive to normal (Table 4). The expected antidiabetic effect of velagliflozin during treatment was confirmed. Case 300-008 has completed testing.

[0094] [Table 3]

[0095] [Table 4]

[0096] Case 200-004-Improvement: Case 200-004 was a 14-year-old, 3.9 kg, neutered Persian cat diagnosed with chronic kidney disease, IRIS stage 3, and fed a renal diet. At the time of screening, the owner reported a normal appetite, normal drinking behavior, and an overall excellent quality of life. The cat was reported to have three pre-existing medical conditions that had been noted within the three months prior to screening: dental calculus, hematuria, and erythropenia, all of which were ongoing at the time of screening. Consequently, the cat received butylscopolamine and beta-glucan-methonin for 4 days (days 0-3) and 20 days (days 1-20), respectively. No adverse events were reported during the study.

[0097] Oral treatment with velagliflozin at 1 mg / kg body weight once daily resulted in an improvement in biochemical parameters, while clinical signs remained normal: serum creatinine decreased by a clinically relevant amount, resulting in an improvement in IRIS disease stage (from 3 to 2 (Table 5)). According to the owners, quality of life remained very good. The cats' appetite and drinking behavior remained normal throughout the study (Table 6). Case 200-004 has completed testing.

[0098] [Table 5]

[0099] [Table 6]

[0100] Case 200-005-Stable: Case 200-005 was an 8-year-old, 7.0 kg, neutered Savannah cat on a standard diet diagnosed with chronic kidney disease, IRIS stage 2. At screening, the owner reported normal appetite and drinking behavior, and an overall quality of life that was excellent. One pre-existing medical condition (previous 3 months) was reported at screening: loose teeth. The cat received no concomitant treatment throughout the study. No adverse events were reported after study participation.

[0101] Oral treatment with velagliflozin at 1 mg / kg body weight once daily resulted in clinical signs and biochemical parameters demonstrating stabilization of the condition. Serum creatinine decreased, while BUN remained stable (Table 7). Serum potassium levels remained stable. The owner classified the quality of life as good. The cat's appetite and drinking behavior remained normal throughout the experiment (Table 8). The expected antidiabetic effect of velagliflozin during treatment was confirmed. Accordingly, total urinary protein decreased, while the UPC ratio remained at 0.1.

[0102] Case 200-005 has completed testing.

[0103] [Table 7]

[0104] [Table 8]

[0105] Case 200-001-Stable: Case 200-001 was a 14-year-old, 2.8 kg, neutered Persian cat on a renal diet diagnosed with chronic kidney disease, IRIS stage 2. At screening, the owner reported normal appetite and drinking behavior, and an overall excellent quality of life. Three pre-existing medical conditions (past 3 months) were reported at screening: cataracts, dental calculus, and vomiting. Two adverse events were reported for this patient: one day of pectin-responsive diarrhea and pancreatitis. The pancreatitis was treated with amoxicillin, prednisolone, and a phosphate blocker. The patient was removed from the study early due to pancreatitis, a known co-occurring condition in older cats.

[0106] Oral treatment with velagliflozin at 1 mg / kg body weight once daily resulted in clinical signs and biochemical parameters demonstrating stabilization of the condition. Serum creatinine remained stable and increased in one single measurement on day 90, while BUN remained stable (Table 9). Serum potassium levels decreased within the reference range. The expected antidiabetic effect of velagliflozin was confirmed. Total urinary protein decreased accordingly. UPC improved from 0.4 to 0.2. According to the owners, the quality of life remained very good. The cats' appetite and drinking behavior remained normal throughout the study (Table 10).

[0107] [Table 9]

[0108] [Table 10]

[0109] Case 200-006-Stable: Case 200-006 was a 16-year-old, 3.7 kg, neutered European cat on a standard diet diagnosed with chronic kidney disease, IRIS stage 2. At screening, the owner reported poor appetite, excessive drinking, and a good overall quality of life. Regarding preexisting medical conditions (past 3 months), the following were reported at screening: weight loss, slow feeding, cataracts, and gingivitis. Three adverse events were reported: diarrhea, vomiting, and cystitis. Diarrhea was treated with pectin and resolved within 24 hours. Vomiting was treated with barium sulfate and a single injection of glucose, saline, vitamin complex, and maropitant. Cystitis was diagnosed just before Visit 2 and treated with amoxicillin and metamizole. Diarrhea resolved after 3 days, and cystitis resolved after 2 days.

[0110] Oral treatment with velagliflozin at 1 mg / kg body weight once daily resulted in clinical signs and biochemical parameters demonstrating a stable state. Serum creatinine and BUN remained stable (Table 11). Serum potassium levels remained within the reference range. The expected antidiabetic effect of velagliflozin during treatment was confirmed. Total urinary protein and UPC remained within the reference range. According to the owner, the quality of life remained good. The cat's appetite improved to normal, and drinking behavior improved to normal, but deteriorated again to excessive drinking (potentially due to cystitis) (Table 12). Overall, the cat's condition remains stable. During treatment with velagliflozin, at visits 2 and 3, the worsening parameters, proteinuria and water intake, may be related to cystitis. Case 200-006 has completed testing.

[0111] [Table 11]

[0112] [Table 12]

[0113] Case 200-007-Stable: Case 200-007 was an 18-year-old, 4.1 kg neutered European cat on a standard diet diagnosed with chronic kidney disease, IRIS stage 3. At screening, the owner reported a normal appetite, excessive drinking, and an overall excellent quality of life. The following pre-existing medical conditions (over the past 3 months) were reported at screening: weight loss, increased pigmentation around the tip of the left ear, cataracts, lymphopenia, and leukopenia. Adverse events reported for this patient included three episodes of vomiting, two episodes of anorexia, and one episode of mild anemia and leukopenia. Treatment for vomiting and anorexia included single doses of saline, glucose, maropitant, prednisolone, butylscopolamine, cyproheptadine hydrochloride, omeprazole, and amoxicillin-clavulanate.

[0114] Oral treatment with velagliflozin at 1 mg / kg body weight once daily resulted in improved drinking behavior to normal, while quality of life changed from very good to good (Table 14). Serum creatinine levels increased moderately (Table 13). Serum potassium levels remained stable within the reference range. The expected antidiabetic effects of velagliflozin during treatment were confirmed. Total urinary protein and UPC increased moderately. Based on the more advanced stage of CKD, the cat's condition can be considered stable and within the expected range for the disease assessed. Case 200-007 has completed testing.

[0115] [Table 13]

[0116] [Table 14]

[0117] Summary: Chronic kidney disease is a progressive condition characterized by declining renal function. Affected cats exhibit an unpredictable disease course, with periods of stable renal function before decompensation. Disease-related azotemia and clinical signs become evident only in the later stages, when 75% or more of the kidney tissue is affected. Improvement in renal function is not predictable. Improvement in clinical signs is not expected due to disease progression, unless renal treatment is initiated.

[0118] Complications associated with CKD include systemic hypertension, secondary renal hyperparathyroidism, hypokalemia, anemia, and metabolic acidosis. Identified risk factors for reduced survival time in CKD patients include elevated UPC, plasma creatinine, phosphate (measured as correlated phosphorus) or urea, high blood white blood cell count, and signs of anemia (low hemoglobin and hematocrit). To date, the treatment goals for CKD patients are as follows: Slow disease progression (correcting the underlying cause, stabilizing identified risk factors, treating associated complications) Ensuring quality of life (minimizing clinical signs)

[0119] Nine cats with mild to moderate azotemia were enrolled in the study (advanced IRIS stage 2 and IRIS stage 3). The expected antidiabetic effects of velagliflozin were confirmed during treatment for all cats except for cat 200-004 (for which no data on total protein or UPC were recorded after treatment initiation). No cats received any concomitant renal therapy except for a renal diet or phosphate binders (patients had to be stabilized on diet / phosphate binders before screening).

[0120] Two cats were already prematurely withdrawn from the study on day 30. These cats were not further evaluated because they were only treated for a short period of time and only had one of the two recommended measurements of relevant clinical laboratory parameters during treatment with the available velagliflozin. Case 200-003 was a 15-year-old, 3.9 kg, neutered European cat on a renal diet diagnosed with a significantly more advanced stage of chronic kidney disease (CKD) (IRIS stage 3) at enrollment. Quality of life and appetite and drinking behavior improved to normal during treatment with velagliflozin, but unfortunately, the cat was excluded early based on a deterioration in a single measurement of a clinical laboratory parameter (expected in a cat with IRIS stage 3). Case 300-003 was a 13-year-old, 4.3 kg, neutered European cat on a renal diet diagnosed with chronic kidney disease, IRIS stage 2. At screening, the owner reported normal appetite and drinking behavior, and an overall quality of life was excellent. Toothache, feeding problems, and feline odontoclastic resorption lesions (FORL) were reported in the cat, which was treated with anesthesia (administration of anesthesia, antibiotics, and analgesics) and tooth extraction / cleaning. Following this, the patient was ruled out early, despite stable laboratory parameters and no deterioration in assessed clinical signs.

[0121] All other cats treated for >90 days had data for at least two time points under treatment available and were therefore evaluated. Disease progression, as well as IRIS staging in this study, was based on the most reliable biomarker: serum creatinine. Of the remaining seven cats, three unexpectedly demonstrated a ≥10% reduction in serum creatinine within the observation period. The improvement in serum creatinine in these cats was accompanied by improvement or stability of most other renal-related laboratory parameters and / or clinical signs. One of these cats had an improvement in IRIS staging by one category, which was highly unexpected, as disease progression is expected at a fairly advanced stage of disease (stage 3 to stage 2). This confirms the positive effect of oral treatment with velagliflozin, specifically at 1 mg / kg body weight once daily, since the cat did not receive any renal standard of care treatment.

[0122] The other cats (4 cats) showed stable laboratory parameters related to CKD (serum creatinine) and clinical signs. No CKD complications were observed under treatment with oral velagliflozin at 1 mg / kg body weight once daily. CKD-related clinical signs either remained well / stable or improved in the majority of cats. Improvement in clinical signs, in particular, is not expected in CKD patients unless renal treatment is administered.

[0123] Risk factors for progression of CKD should be prevented, and include serum phosphate level, serum potassium level, hematocrit, UPC, and blood pressure. The following observations were made in this study: Serum phosphorus concentration: There is strong evidence in the literature that maintaining plasma phosphorus levels within the International Veterinary Nephrology Group targets for CKD patients improves survival. In this study, five cats were fed a low-phosphate diet, while four cats were fed a standard diet. In all evaluated cases in this clinical trial, serum phosphate levels remained within the laboratory reference range throughout the study (with the exception of one measurement for case 200-001 at day 90), regardless of the administration of a low-phosphate diet and / or phosphorus binders. This suggests a beneficial effect of velagliflozin on phosphorus homeostasis and, therefore, benefit in CKD cats. Serum potassium levels remained within the reference range in all treated cats, suggesting that oral treatment with velagliflozin at 1 mg / kg body weight once daily prevents hypokalemia, a known complication in CKD cats. Hematocrit was monitored to detect anemia in renal disease. Hematocrit remained within the reference range in all cats treated with oral velagliflozin at 1 mg / kg body weight, suggesting a protective effect against anemia. In all patients, proteinuria remained within the reference range of ≤0.33, suggesting that oral velagliflozin treatment at 1 mg / kg body weight once daily prevented the progression of proteinuria. Systolic blood pressure remained <160 mmHg throughout the course of the experiment in all cats.

[0124] Conclusion: Veragliflozin, administered orally to feline CKD patients at a dose of 1 mg / kg body weight once daily, stabilized or even improved renal parameters and clinical signs in cats with IRIS stages 2 and 3 CKD (e.g., improved UPC in case 200-001, normalized appetite in case 200-006, and normalized drinking behavior in cases 200-007, 400-004, and 300-008). Serum creatinine was reduced in three cats, and IRIS stage improved, even improving from IRIS stage 3 to 2 in one case. Improvement of disease-related clinical signs or renal laboratory parameters, and even a reduction in IRIS stage, in CKD cats is highly unexpected. Deterioration over time is expected, especially in untreated cats and cats with advanced disease stages, due to the progressive pathology of the disease. None of the cats evaluated in this study received any renal standard care (in the case of administration of a renal diet or phosphate binders, patients had to be already stable at screening), and we confirmed the beneficial effects of oral treatment with velagliflozin at 1 mg / kg body weight once daily in feline CKD patients. In addition, risk factors for disease progression remained stable and within reference ranges (e.g., UPC, blood pressure, potassium, phosphorus, etc.). This suggests a preventive effect of velagliflozin treatment against disease progression and possible target organ damage.

[0125] Example 4 Exploratory clinical field study in client-owned dogs with CKD Client-owned patients diagnosed with CKD, as determined through physical examination and biomarker levels, were treated orally with velagliflozin 0.05 mg / kg body weight once daily. During the study period, body weight, body condition score, biomarker levels (creatinine and SDMA), proteinuria, the presence of coexisting conditions, and the need for additional medication were examined by investigators on a standardized basis during and after the study visits. Parameters examined included creatinine and SDMA levels, proteinuria, blood pressure, and hydration status. Additionally, the canine patients' survival time, progression of IriS stages, and kidney-related mortality and / or morbidity were monitored as variables for delaying the onset of renal failure. The study results confirmed beneficial effects on renal function and delaying disease progression.

[0126] reference TIFF2026034464000060.tif54125

Claims

1. 1. One or more SGLT-2 inhibitors, or pharmaceutically acceptable forms thereof, for use in a method for the prevention and / or treatment of one or more kidney diseases in a non-human mammal, preferably a carnivore, more preferably a cat or a dog.

2. 2. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to claim 1, wherein the one or more renal diseases are selected from the group consisting of renal dysplasia, glomerulopathy, polycystic kidney disease, amyloidosis, tubulonephritis / tubulointerstitial nephritis (TIN), acute kidney disease, and chronic kidney disease.

3. 3. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to claim 2, wherein the one or more renal diseases are selected from the group consisting of acute renal disease and chronic renal disease.

4. 4. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to claim 3, wherein the one or more renal diseases are selected from the group consisting of chronic kidney diseases.

5. 5. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 4, wherein the one or more SGLT-2 inhibitors are glucopyranosyl-substituted benzene derivatives.

6. one or more SGLT-2 inhibitors (1) Glucopyranosyl-substituted benzene derivative of formula (1) 【Chemistry 1】 (In the formula, R 1 represents cyano, Cl or methyl (most preferably cyano); R 2 represents H, methyl, methoxy or hydroxy (most preferably H), R 3 is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy -3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, R 3 is most preferably cyclopropyl) or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1 - 18 -alkyl)carbonyl, (C 1 - 18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1 - 3 -alkyl)-carbonyl; (2) Veragliflozin represented by formula (2): 【Chemistry 2】 (3) Dapagliflozin represented by formula (3): 【Transformation 3】 (4) Canagliflozin represented by formula (4): 【Chemistry 4】 (5) Empagliflozin represented by formula (5): 【Transformation 5】 (6) Luseogliflozin represented by formula (6): 【Transformation 6】 (7) Tofogliflozin represented by formula (7): 【Transformation 7】 (8) Ipragliflozin represented by formula (8): 【Transformation 8】 (9) Ertugliflozin represented by formula (9): 【Chemistry 9】 (10) Atigliflozin represented by formula (10): 【Chemistry 10】 (11) Remogliflozin represented by formula (11): 【Chemistry 11】 (11A) Remogliflozin etabonate represented by formula (11A): 【Chemistry 12】 (12) Thiophene derivative of formula (12) 【Chemistry 13】 wherein R represents methoxy or trifluoromethoxy. (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13); 【Chemistry 14】 (14) Spiroketal derivative of formula (14): 【Chemistry 15】 wherein R represents methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl, or tert-butyl; (15) Pyrazole-O-glucoside derivative of formula (15) 【Chemistry 16】 (In the formula, R 1 is C 1-3 represents alkoxy, L 1 , L 2 are each independently H or F, R 6 is H, (C 1-3 -alkyl)carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzyl); (16) Sotagliflozin represented by formula (16): 【Chemistry 17】 (17) Sergliflozin represented by formula (17): [Chemistry 18] (18) Compound represented by formula (18): 【Chemistry 19】 (In the ceremony R 3 is cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy -3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, R 3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, R 3 is most preferably cyclopropyl), or a derivative thereof, wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are (C 1-18 -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl; (19) Bexagliflozin represented by formula (19): 【Chemistry 20】 (20) Janagliflozin represented by formula (20): 【Chemistry 21】 (21) Remogliflozin represented by formula (21): 【Chemistry 22】 (22) Wampagliflozin 6. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 5, selected from the group consisting of:

7. 7. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 6, wherein the pharmaceutically acceptable form is a crystalline complex of the one or more SGLT2 inhibitors with one or more amino acids, preferably proline, more preferably L-proline, and most preferably a co-crystal of the one or more SGLT2 inhibitors, L-proline and water of crystallization.

8. 8. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 7, wherein the non-human animal, preferably a carnivore, more preferably a feline or canine, is a non-human animal patient in need of such prevention and / or treatment, preferably a carnivore patient in need of such prevention and / or treatment, more preferably a feline or canine patient in need of such prevention and / or treatment, even more preferably a non-diabetic feline or canine patient in need of such prevention and / or treatment.

9. 9. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 8, wherein the one or more SGLT-2 inhibitors are administered orally, parenterally, intravenously, subcutaneously, or intramuscularly, preferably orally.

10. 10. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 9, wherein the one or more SGLT-2 inhibitors are to be administered at a dose of 0.01 mg / kg to 10 mg / kg body weight, preferably at a dose of 0.01 mg / kg to 5 mg / kg body weight, more preferably at a dose of 0.01 mg / kg to 4 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 3 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 2 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 1 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.5 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.3 mg / kg body weight, and most preferably at a dose of 0.05 mg / kg body weight or 1.0 mg / kg body weight.

11. 11. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 10, wherein such one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof are to be administered once per day or twice per day.

12. 12. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 11, wherein the one or more SGLT-2 inhibitors is velagliflozin, and velagliflozin is to be administered as the sole SGLT-2 inhibitor, preferably orally, more preferably once or twice per day at a dose of 0.01 mg / kg to 1 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.5 mg / kg body weight, even more preferably at a dose of 0.01 mg / kg to 0.3 mg / kg body weight, and most preferably at a once daily dose of 0.05 mg / kg or 1.0 mg / kg body weight.

13. 13. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use according to claim 12, wherein velagliflozin as the single SGLT-2 inhibitor is to be orally administered once daily at a dose of 0.01 mg / kg body weight to 1.0 mg / kg body weight, preferably at a dose of 0.05 mg / kg body weight or 1.0 mg / kg body weight.

14. 14. The one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 13, wherein the one or more SGLT-2 inhibitors are to be administered before, after or simultaneously with the administration of one or more other active pharmaceutical ingredients, preferably selected from the group consisting of another SGLT-2 inhibitor or a pharmaceutically acceptable form thereof; one or more ACE inhibitors, such as benazepril, ramipril or enalapril; one or more calcium channel blockers, such as diltiazem or amlodipine; one or more angiotensin receptor blockers, such as telmisartan; one or more calcium channel sensitizers and / or positive inotropes, such as pimobendan and / or digitalis alkaloids; and / or one or more phosphate binders, such as chitosan.

15. The prophylactic and / or therapeutic effect is measured by one or more of the following clinical and / or biochemical parameters: - improved renal efficiency, characterized by a reduction in proteinuria and a reduction and / or stabilization of serum SDMA and / or serum creatinine; - increased hepatic ketone body production, characterized by increased plasma levels of 3-hydroxybutyric acid and / or the corresponding acylcarnitine, i.e., hydroxybutyrylcarnitine, and increased plasma levels of one or more branched-chain amino acids (e.g., valine, leucine, and isoleucine); - Improved blood pressure; - Improved hydration status; - delaying the onset of renal failure, preferably by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more, or slowing and / or halting the progression of one or more kidney diseases, in particular chronic kidney disease, and / or improving the classification stage of one or more kidney diseases, in particular CKD (e.g. improving from phase 3 to phase 2); - increased survival time of non-human mammalian patients, preferably at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more, and / or lower kidney-related mortality and / or morbidity; - Improved clinical signs, e.g., reduction in polydipsia, polyuria, vomiting and / or lethargy; - Higher quality of life 15. The one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use according to any one of claims 1 to 14, characterized in that:

16. A pharmaceutical composition comprising one or more SGLT2 inhibitors according to any one of claims 1 to 15 or a pharmaceutically acceptable form thereof for the use according to any one of claims 1 to 15.

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