Combination therapy and / or prevention of kidney disease and / or hypertension in non-human mammals, including one or more SGLT-2 inhibitors and telmisartan.

Abstract

The present invention relates to the use of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof, particularly for the prevention and / or treatment of one or more kidney diseases and / or hypertension in non-human mammals / animals of other human origin, such as dogs or cats.

Claims

1. One or more SGLT-2 inhibitors, or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use as a pharmaceutical.

2. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to claim 1 in a method for preventing and / or treating one or more kidney diseases and / or hypertension in non-human mammals / patient non-human mammals, particularly in canids / patient canids or felines / patient felines.

3. A method for treating one or more kidney diseases and / or hypertension in non-human mammals / animals suffering from diseases of non-human mammals, particularly in canids / animals suffering from diseases of canids or felines / animals suffering from diseases of felines, for use according to claim 2, comprising one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof.

4. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for use according to claim 2 or 3, in combination with telmisartan or a pharmaceutically acceptable form thereof, wherein one or more kidney diseases are selected from the group consisting of renal dysplasia, glomerulosis, polycystic kidney disease, amyloidosis, tubulonephritis / tubulointerstitial nephritis (TIN), acute kidney disease, chronic kidney disease, and proteinuria.

5. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof for use as described in claim 4, wherein one or more kidney diseases are selected from the group consisting of acute kidney disease and chronic kidney disease, and the non-human mammal / non-human mammal suffering is a feline / feline suffering, preferably a feline suffering that requires such prevention and / or treatment, more preferably a cat that requires such prevention and / or treatment, one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof.

6. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to claim 2 or 3, wherein the hypertension is selected from the group consisting of systemic hypertension, glomerular hypertension, situational hypertension, secondary hypertension and idiopathic hypertension.

7. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to claim 6, wherein the secondary hypertension is selected from the group consisting of hypertension associated with chronic kidney disease (CKD), diabetes mellitus, obesity, heart disease, endocrine disorders such as Cushing's disease, hyperthyroidism, acromegaly, and pharmaceutically, preferably, an elevation of blood pressure (BP) induced by glucocorticoids, mineralocorticoids, erythrocyte production stimulants, ephedrine and / or high-dose sodium chloride.

8. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 7, wherein one or more SGLT-2 inhibitors are (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 This includes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methylbuta-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropane-1-yl, 3-hydroxy Represents 3-methylbuta-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 The is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, most preferably R 3 (It 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 Acylated with a group selected from -alkyl-carbonyl groups; (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) Erzggliflozin represented by formula (9): 【Chemistry 9】 (10) Atigliflozin represented by formula (10): 【Chemistry 10】 (11) Remogliflozin represented by formula (11): 【Chemistry 11】 (11A) Lemogliflozin etabonate represented by formula (11A): 【Chemistry 12】 (12) Thiophene derivatives of formula (12) 【Chemistry 13】 (In the formula, 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) Spirochetal 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 represents C 1-3 -alkoxy, and L 1 , L 2 These represent H or F independently of each other. R 6 H, (C 1-3 -Alkyl)carbonyl, (C 1-6 (- Represents alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, or benzylcarbonyl); (16) Sotagliflozin represented by formula (16): 【Chemistry 17】 (17) Cergliflozin represented by formula (17): [Chemistry 18] (18) Compounds represented by formula (18): 【Chemistry 19】 (In the formula, R 3 This includes cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, 3-methylbuta-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxycyclopropyl, 1-hydroxycyclobutyl, 1-hydroxycyclopentyl, 1-hydroxycyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropane-1-yl, 3-hydroxy 3-methylbuta-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 The is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy, most preferably R 3 (It 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 Acylated with a group selected from -alkyl-carbonyl groups; (19) Bexagliflozin represented by formula (19): 【Chemistry 20】 (20) Janagliflozin represented by formula (20): 【Chemistry 21】 (21) Long liflozin represented by formula (21): 【Chemistry 22】 (22) Wampagliflozin; (23) Enabogliflozin represented by formula (23): 【Chemistry 23】 (24) TFC-039 represented by formula (24): 【Chemistry 24】 One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, selected from the group consisting of the following.

9. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for use according to any one of claims 1 to 8, in combination with telmisartan or a pharmaceutically acceptable form thereof, wherein the pharmaceutically acceptable form is a crystalline complex of one or more SGLT-2 inhibitors and one or more amino acids, preferably proline, more preferably L-proline, and most preferably a cocrystal of one or more SGLT-2 inhibitors, L-proline, and water of crystallization.

10. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for use according to any one of claims 1 to 9, wherein veragliflozin or a pharmaceutically acceptable form thereof is administered as a single SGLT-2 inhibitor in combination with telmisartan or a pharmaceutically acceptable form thereof.

11. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 10, wherein veragliflozin or a pharmaceutically acceptable form thereof is used as a single SGLT-2 inhibitor, and the use is carried out in a method for preventing and / or treating CKD or hypertension in canids / canid animals.

12. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 10, wherein veragliflozin or a pharmaceutically acceptable form thereof is used as a single SGLT-2 inhibitor, and the use is carried out in a method for preventing and / or treating CKD or hypertension in felines / feline animals.

13. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 10, wherein veragliflozin or a pharmaceutically acceptable form thereof is used as a single SGLT-2 inhibitor, and the use is carried out in a method for treating CKD or hypertension in canids / canine animals.

14. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 10, wherein veragliflozin or a pharmaceutically acceptable form thereof is used as a single SGLT-2 inhibitor, and the use is carried out in a method for treating CKD or hypertension in felines / feline animals.

15. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 14, which are administered orally, parenterally, intravenously, subcutaneously, or intramuscularly, and preferably orally.

16. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 15, in a dose of 0.01 mg / kg body weight to 10 mg / kg body weight per day, preferably 0.01 mg / kg body weight to 5 mg / kg body weight per day, more preferably 0.01 mg / kg body weight to 4 mg / kg body weight per day, and even more preferably 0.01 mg / One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, administered in a dose of 3 mg / kg body weight to 3 mg / kg body weight per day, more preferably 0.01 mg / kg body weight to 2 mg / kg body weight per day, more preferably 0.01 mg / kg body weight to 1 mg / kg body weight per day, more preferably 0.01 mg / kg body weight to 0.5 mg / kg body weight per day, and most preferably 0.01 mg / kg body weight to 0.3 mg / kg body weight per day.

17. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof for use according to any one of claims 1 to 16, wherein one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof are administered once or twice daily, preferably once daily.

18. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 17, wherein telmisartan or a pharmaceutically acceptable form thereof is administered in a dose of about 0.01 to about 10 mg / kg body weight per day, preferably about 0.05 to about 8 mg / kg body weight, more preferably about 0.1 to about 5 mg / kg body weight, more preferably about 0.2 to about 4 mg / kg body weight, more preferably about 0.3 to about 3 mg / kg body weight, more preferably about 0.4 to about 2.5 mg / kg body weight, more preferably about 0.5 to about 2 mg / kg body weight, most preferably about 0.75 to about 1.5 mg / kg body weight per day.

19. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 18, wherein telmisartan or a pharmaceutically acceptable form thereof is administered once or twice daily, preferably once daily, one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof.

20. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for use according to any one of claims 1 to 19, in combination with telmisartan or a pharmaceutically acceptable form thereof, which are administered in combination with telmisartan or a pharmaceutically acceptable form thereof, preferably before, after, or concurrently with administration of telmisartan or a pharmaceutically acceptable form thereof.

21. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for use according to any one of claims 1 to 20, in combination with telmisartan or a pharmaceutically acceptable form thereof, wherein the prophylactic and / or therapeutic effect is one or more of the following clinical and / or biochemical parameters: - Improvement of renal function: reduction in proteinuria, and / or reduction and / or stabilization of blood parameters, such as serum SDMA, serum creatinine, FGF23, blood urea nitrogen (BUN), and / or hyperphosphatemia, and / or slowing of the decline in glomerular filtration rate (GFR); - Increased ketone body production in the liver: increased plasma levels of 3-hydroxybutyrate 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); - Delaying the onset of hypertension and / or preventing target organ damage and / or improving blood pressure; - Improvement of hydration state; - Preferably, a delay in the onset of renal failure by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer, or a delay and / or cessation of the progression of one or more kidney diseases, particularly chronic kidney disease, and / or improvement in the classification stage of one or more kidney diseases, particularly CKD (e.g., from stage 3 to stage 2); - Promoting diuresis to reduce renal failure with oliguria and / or hypertension; - In non-human mammals, preferably an extension of survival time of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer, and / or a reduction in kidney-related mortality and / or morbidity; - Improvement of clinical signs, e.g., polydipsia, polyuria, vomiting, lethargy, weight loss, and / or reduction of signs associated with dehydration; - Improving the quality of life One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, characterized by the above.

22. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, for use according to any one of claims 1 to 21, in combination with telmisartan or a pharmaceutically acceptable form thereof, wherein the systolic blood pressure (SBP) measured in non-human mammals / non-human mammals in need, particularly in canids / canids or felines / felines, is reduced by at least 5 mmHg, preferably at least 10 mmHg, more preferably at least 20 mmHg, particularly 5 to 100 mmHg, more preferably 5 to 50 mmHg, and most preferably 10 to 50 mmHg after the treatment period, compared to the baseline SBP measured before the treatment period, in non-human mammals / non-human mammals in need, particularly in canids / canids or felines / felines, more preferably in cats or dogs.

23. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 22, the method comprising measuring SBP, optionally identifying TOD, and subsequently administering a therapeutically effective dose of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof to a non-human mammal / a non-human mammal, particularly a canid / a canid or a feline / a feline, wherein the therapeutically effective dose of one or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof is administered in a daily dose that may vary over the course of treatment in response to subsequent measurements of SBP.

24. One or more SGLT-2 inhibitors or pharmaceutically acceptable forms thereof, in combination with telmisartan or a pharmaceutically acceptable form thereof, for use according to any one of claims 1 to 23, wherein hypertension is contraindicated to treatment with ACE inhibitors in non-human mammals / patient non-human mammals, particularly in canids / patient canids or felines / patient felines, particularly in cats or dogs to be treated, most preferably in dogs to be treated.

25. A pharmaceutical composition comprising one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof in combination with telmisartan or a pharmaceutically acceptable form thereof for use as defined in any one of claims 1 to 24, wherein such a pharmaceutical composition is a fixed-dose combination (FDC) of one or more SGLT-2 inhibitors or a pharmaceutically acceptable form thereof and telmisartan or a pharmaceutically acceptable form thereof, and more preferably such FDC is a solid formulation or a liquid formulation.

Images