Use of SGLT-2 inhibitors in the drying-off of non-human mammals

Abstract

The present invention is directed to the use of at least one SGLT-2 inhibitor in a non-human mammal, preferably ruminant, preferably for drying-off of a non-human mammal, preferably ruminant, as well as corresponding methods, such as improving and/or facilitating the drying-off of a non-human mammal, preferably ruminant, comprising administering to such non-human mammal, preferably ruminant, at least one SGLT-2 inhibitor.

Claims

1. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal at least one SGLT2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1) ##STR00065## wherein R.sup.1 denotes cyano, Cl or methyl, R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2): ##STR00066## (3) Dapagliflozin, represented by formula (3): ##STR00067## (4) Canagliflozin, represented by formula (4): ##STR00068## (5) Empagliflozin, represented by formula (5): ##STR00069## (6) Luseogliflozin, represented by formula (6): ##STR00070## (7) Tofogliflozin, represented by formula (7): ##STR00071## (8) Ipragliflozin, represented by formula (8): ##STR00072## (9) Ertugliflozin, represented by formula (9): ##STR00073## (10) Atigliflozin, represented by formula (10): ##STR00074## (11) Remogliflozin, represented by formula (11): ##STR00075## (11A) Remogliflozin etabonate, represented by formula (11A): ##STR00076## (12) a thiophene derivative of the formula (12) ##STR00077## wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13); ##STR00078## (14) a spiroketal derivative of the formula (14): ##STR00079## wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15): ##STR00080## wherein R.sup.1 denotes C.sub.1-3-alkoxy, L.sup.1, L.sup.2 independently of each other denote H or F, R.sup.6 denotes H, (C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16): ##STR00081## (17) Sergliflozin, represented by formula (17): ##STR00082## (18) a compound represented by formula (18): ##STR00083## wherein R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19): ##STR00084## (20) Janagliflozin, represented by formula (20): ##STR00085## (21) Rongliflozin; and (22) Wanpagliflozin.

2. A method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any harmful and/or abortifacient effects on a pregnant non-human mammal, and/or wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any negative effects on the subsequent reproduction cycle/fertility and milk yield and/or milk quality in the next lactation.

3. The method according to claim 2, wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount that additionally or alternatively effects a reduction of the incidence of new intra-mammary infections (IMI) or mastitis in the first month after start of the next lactation.

4. The method according to claim 1, wherein the non-human mammal is selected from the group consisting of: bovine, canine, caprine, equine, feline, lagomorphs, ovine, porcine, and rodent.

5. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered orally, parenterally, rectally, intravaginally, intravenously, subcutaneously or intramuscularly.

6. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.

7. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered once, twice, three-times, four-times, five-times, six-times or daily for a week.

8. The method according to claim 1, wherein the at least one SGLT-2 inhibitor is administered once only at start of drying-off or twice as two treatments 24 hours or 48 hours apart after last milking.

9. The method according to claim 1, wherein the non-human mammal is a cow, a pregnant cow, and/or a lactating cow.

10. The method according to claim 1, wherein the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by formula: ##STR00086##

11. A method of reducing milk production in a pregnant and/or lactating non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1) ##STR00087## wherein R.sup.1 denotes cyano, Cl or methyl, R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2): ##STR00088## (3) Dapagliflozin, represented by formula (3): ##STR00089## (4) Canagliflozin, represented by formula (4): ##STR00090## (5) Empagliflozin, represented by formula (5): ##STR00091## (6) Luseogliflozin, represented by formula (6): ##STR00092## (7) Tofogliflozin, represented by formula (7): ##STR00093## (8) Ipragliflozin, represented by formula (8): ##STR00094## (9) Ertugliflozin, represented by formula (9): ##STR00095## (10) Atigliflozin, represented by formula (10): ##STR00096## (11) Remogliflozin, represented by formula (11): ##STR00097## (11A) Remogliflozin etabonate, represented by formula (11A): ##STR00098## (12) a thiophene derivative of the formula (12) ##STR00099## wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13); ##STR00100## (14) a spiroketal derivative of the formula (14): ##STR00101## wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15): ##STR00102## wherein R.sup.1 denotes C.sub.1-3-alkoxy, L.sup.1, L.sup.2 independently of each other denote H or F, R.sup.6 denotes H, (C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16): ##STR00103## (17) Sergliflozin, represented by formula (17): ##STR00104## (18) a compound represented by formula (18): ##STR00105## wherein R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19): ##STR00106## (20) Janagliflozin, represented by formula (20): ##STR00107## (21) Rongliflozin; and (22) Wanpagliflozin.

12. A method of decreasing milk accumulation and/or engorgement in the udder and/or mammary gland of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1) ##STR00108## wherein R.sup.1 denotes cyano, Cl or methyl, R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2): ##STR00109## (3) Dapagliflozin, represented by formula (3): ##STR00110## (4) Canagliflozin, represented by formula (4): ##STR00111## (5) Empagliflozin, represented by formula (5): ##STR00112## (6) Luseogliflozin, represented by formula (6): ##STR00113## (7) Tofogliflozin, represented by formula (7): ##STR00114## (8) Ipragliflozin, represented by formula (8): ##STR00115## (9) Ertugliflozin, represented by formula (9): ##STR00116## (10) Atigliflozin, represented by formula (10): ##STR00117## (11) Remogliflozin, represented by formula (11): ##STR00118## (11A) Remogliflozin etabonate, represented by formula (11A): ##STR00119## (12) a thiophene derivative of the formula (12) ##STR00120## wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13); ##STR00121## (14) a spiroketal derivative of the formula (14): ##STR00122## wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15): ##STR00123## wherein R.sup.1 denotes C.sub.1-3-alkoxy, L.sup.1, L.sup.2 independently of each other denote H or F, R.sup.6 denotes H, (C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl: (16) Sotagliflozin, represented by formula (16): ##STR00124## (17) Sergliflozin, represented by formula (17): ##STR00125## (18) a compound represented by formula (18): ##STR00126## wherein R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19): ##STR00127## (20) Janagliflozin, represented by formula (20): ##STR00128## (21) Rongliflozin; and (22) Wanpagliflozin.

13. The method according to claim 12, wherein the at least one SGLT-2 inhibitor comprises Velagliflozin, represented by formula: ##STR00129##

14. A method of decreasing the discomfort associated with udder engorgement of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.

15. A method of decreasing milk leakage after drying-off of a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.

16. A method of decreasing an incidence of intra-mammary infections (IMI) in a non-human mammal, comprising administering to the non-human mammal at least one SGLT-2 inhibitor.

17. The method according to any one of claims 14, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1) ##STR00130## wherein R.sup.1 denotes cyano, Cl or methyl; R.sup.2 denotes H, methyl, methoxy or hydroxy and R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2): ##STR00131## (3) Dapagliflozin, represented by formula (3): ##STR00132## (4) Canagliflozin, represented by formula (4): ##STR00133## (5) Empagliflozin, represented by formula (5): ##STR00134## (6) Luseogliflozin, represented by formula (6): ##STR00135## (7) Tofogliflozin represented by formula (7): ##STR00136## (8) Ipragliflozin, represented by formula (8): ##STR00137## (9) Ertugliflozin, represented by formula (9): ##STR00138## (10) Atigliflozin, represented by formula (10): ##STR00139## (11) Remogliflozin represented by formula (11): ##STR00140## (11A) Remogliflozin etabonate, represented by formula (11A): ##STR00141## (12) a thiophene derivative of the formula (12) ##STR00142## wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13); ##STR00143## (14) a spiroketal derivative of the formula (14): ##STR00144## wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of the formula (15): ##STR00145## wherein R.sup.1 denotes C.sub.1-3-alkoxy, L.sup.1, L.sup.2 independently of each other denote H or F, R.sup.6 denotes H, (C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16): ##STR00146## (17) Sergliflozin, represented by formula (17): ##STR00147## (18) a compound represented by formula (18): ##STR00148## wherein R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19): ##STR00149## (20) Janagliflozin, represented by formula (20): ##STR00150## (21) Rongliflozin; and (22) Wanpagliflozin.

18. The method according to claim 14, wherein the method of decreasing the discomfort associated with udder engorgement of a non-human mammal is increasing the daily lying time and/or reduction of stress.

19. The method according to claim 16, wherein the intra-mammary infections (IMI) are mastitis and/or metritis.

20. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal velagliflozin as a single SGLT-2 inhibitor, wherein velagliflozin is administered subcutaneously or intramuscularly, once only at start of drying-off or twice (24 h or 48 h apart) at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.

21. The method according to claim 20, wherein the at least one SGLT-2 inhibitor is administered before, after or concomitantly with administering at least one feed supplement to the non-human mammal and/or before, after or concomitantly with a reduction in feed offered to the non-human mammal.

22. The method according to claim 21, wherein the feed supplement comprises one or more acidifying agents selected from the group consisting of: ammonium chloride, calcium chloride and calcium sulfate.

23. The method according to claim 22, wherein the feed supplement comprises 5% (w/w) to 15% (w/w) ammonium chloride, 40% (w/w) to 60% (w/w) calcium chloride and 15% (w/w) to 25% (w/w) calcium sulfate.

24. The method according to claim 22, wherein the feed supplement comprises 10.4% (w/w) ammonium chloride, 51.9% (w/w) calcium chloride and 20.1% (w/w) calcium sulfate.

25. The method according to claim 20, wherein the non-human mammal is a cow, a pregnant cow, and/or a lactating cow.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the correlation between velagliflozin plasma concentrations and urinary glucose excretion normalized to urinary creatinine (glucose/creatinine) in Holstein-Frisian cows.

(2) FIG. 2 depicts the delta values (kg) between mean afternoon (post meridian—PM) milking of two days before administration of velagliflozin and milk yield (individual values) about 8 hours after i.v. administration (PM milking) of three different doses of velagliflozin (0.03 mg/kg bodyweight; 0.3 mg/kg bodyweight and 3 mg/kg bodyweight) in dairy cows. It further depicts the correlation between reduction of milk yield and velagliflozin plasma concentrations 8 hours after treatment in Holstein-Frisian cows.

EXAMPLES

(3) The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

Example 1 Pharmacokinetics (PK)/Pharmacodynamics (PD) and Milk Reduction by a Single Velagliflozin Dosing in Lactating Cows

(4) Velagliflozin treatment is tested in n=4 lactating Holstein-Frisian cows. In weekly intervals, velagliflozin is administered intravenously (i.v.) in increasing doses (0.03 mg/kg bodyweight-0.3 mg/kg bodyweight-3 mg/kg bodyweight) in the morning after AM (ante meridian) milking into the right jugular vein in a volume of 2.5 ml of a propylene glycol based solution per 100 kg body weight. Blood samples for determination of velagliflozin plasma levels and urine samples for determination of glucose and creatinine levels are collected one day prior to treatment and ˜8 hours, ˜24 hours and ˜48 hours post treatment and stored frozen until being analysed. Blood glucose and ketone body (beta-hydroxy-butyrate) concentrations are determined immediately after blood collection at the same time points. The total urinary creatinine excreted per day is rather constant in mammals, thus, since urine volume was not determined, the glucose to creatinine ratio was calculated as a surrogate of the total glucose excretion. All animals are milked twice daily, in the morning (ante meridian—AM) and in the late afternoon (post meridian—PM). Throughout the study, milk yield is recorded as kg per animal per milking.

(5) Results: Velagliflozin plasma level show a linear dose to exposure relationship (see FIG. 1). The urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner (FIG. 1). After treatment, the milk yield of the subsequent milking (PM) decreases in a dose/exposure dependent manner (FIG. 2). Of safety relevance, blood glucose or ketone body level were within normal reference ranges after treatment with all dosages of velagliflozin.

(6) Clearly, these effects are dependent on the plasma velagliflozin level, indicating that also other parenteral administration routes—e.g. intramuscular or subcutaneous administrations are effective. It is thus concluded that a single (e.g. parenteral) dose of at least one SGLT-2 inhibitor, such as velagliflozin, can be safely employed in lactating cows to reduce milk yield.

Example 2 Reduction of Milk Production and Udder Engorgement

(7) In studies in lactating cows, SGLT-2 inhibitor, such as velaglifozin, treatment can be performed as a single parenteral administration, preferably s.c. or i.m. or also as two treatments e.g. ˜24 h or 48 h apart.

(8) The treatment is also performed in combination with or subsequently to treatment with feed supplements, e.g. Bovikalc® Dry, and/or a reduction in feed offered to the cow with the aim to reduce the milk production prior to dry-off.

(9) Reduction in milk yield is evaluated by weighing of the milk yield per animal and per milking (see e.g. Example 1).

(10) Udder engorgement is evaluated by measuring the teat distance, by direct pressure measurements and/or measuring udder firmness—indicative for engorgement using for instance a dynamometer (e.g. Penefel DFT 14; Agro Technologies, Forges-les-Eaux, France). These readings are compared between measurements before the last milking with those on the following days after dry-off. However, also treatment effects on reduction in milk yield and udder engorgement can be compared between cows treated with at least one SGLT-2 inhibitor with cows that receive no treatment or cows offered a reduced feed ration only.

Example 3 Effects on Milk Composition and Involution Marker

(11) In studies as described in Example 2, concurrent with the reduction in milk yield changes in the composition of the milk/secreted fluid, indicating the involution of the secretory cells and/or the disruption of cellular tight junctions are investigated. For instance, somatic cell counts, bovine serum albumin, lactose, potassium and sodium as well as total protein, whey protein, casein protein, protease peptone, lactoferrin level and/or the gelatinase activity are measured.

(12) To achieve this, small amounts of mammary secretions (5 to 50 mL) are collected from alternating quarters on several days after the last milking, i.e. dry-off.

(13) These readings are compared with measurements before the last milking compared with those on the following days after dry-off; but also treatment effects may be compared between cows treated with at least one SGLT-2 inhibitor, e.g. velagliflozin, with cows that receive no treatment or cows offered a reduced feed ration only.

Example 4 Reduction of Milk Leakage and Intra-Mammary Infections (IMI) During Dry Period

(14) In studies as described in Example 2, also in the first days after dry-off leakage of milk from the mammary gland, i.e. milk dropping or flowing from any teat is evaluated. In addition, the udder quarter can be closely monitored to detect symptoms of intra-mammary infections or mastitis, i.e. warm or hot, sensitive or swollen udder quarters. Besides, symptoms of systemic illness, e.g. signs of fever, rapid pulse, depression, weakness and loss of appetite may be present. Also, small amounts of mammary secretions (5 to 50 mL) are collected from alternating quarters on several days after the last milking, i.e. dry-off to investigate eventual subclinical intra-mammary infections/presence of microorganisms.

(15) These readings are compared between cows treated with at least one SGLT-2 inhibitor, such as velagliflozin, with cows that receive no treatment or cows offered a reduced feed ration only.

Example 5 Reduction of Discomfort and Stress Caused by Dry-Off

(16) In studies in pregnant, lactating cows, SGLT-2 inhibitor treatment, for instance by means of velagliflozin, is installed typically e.g. in the eighth month of gestation at dry-off. The treatment is also performed in combination with or subsequently to treatment with feed supplements, e.g. Bovikalc® Dry, and/or a reduction in feed offered to the cow with the aim to reduce the milk production prior to dry-off.

(17) Stress and/or other discomfort measurements after dry-off are evaluated recording the time spent lying and/or ruminating. In addition, the increase in the concentration of blood cortisol or faecal glucocorticoid metabolites is measured.

(18) An udder pain score can be employed, i.e. the behaviour of the cows may be classified into 4 categories (0=no udder pain; 1=light udder pain; 2=moderate udder pain and 3=severe udder pain) depending on their reaction at udder palpation (from no behavioural response to refusal of the palpation).

(19) These readings are compared between cows treated with at least one SGLT-2 inhibitor, such as velagliflozin, with cows that receive no treatment or cows offered a reduced feed ration only.

Example 6 Treatment in Ruminants at Dry-Off—Safety and Long Term Effects

(20) In studies in pregnant, lactating cows, treatment with at least one SGLT-2 inhibitor, such as velagliflozin, can be installed typically e.g. in the eighth month of gestation at dry-off. The treatment is performed as a single administration or also as two treatments ˜24 h or 48 h apart after last milking. The treatment is also performed in combination with or subsequently to treatment with feed supplements, e.g. Bovikalc® Dry, and/or a reduction in feed offered to the cow with the aim to reduce the milk production prior to dry-off.

(21) The safety of a for instance velagliflozin treatment can be assessed by evaluating the metabolic response of the negative energy balance induced, i.e. evaluating the blood glucose and ketone body, as well as the blood lipid concentrations (e.g. NEFAs). In addition, the electrolyte balance of the cows is monitored, with e.g. special emphasise on the calcium homeostasis.

(22) The administration of at least one SGLT-2 inhibitor, such as velagliflozin, even makes it possible to improve the immune status and/or liver function of dairy cows. This can be measured by markers of a systemic proinflammatory status, e.g. acute phase proteins like serum amyloid A (SAA) or haptoglobulin.

(23) Besides, the impact on the foetus or even abortive effects can be monitored.

(24) Severity and incidence of safety relevant observations are compared between SGLT-2 inhibitor (e.g. velagliflozin) treated cows with cows that receive no treatment or cows offered a reduced feed ration. In addition, a combined treatment with the SGLT-2 inhibitor, e.g. velagliflozin, and offering reduced feed ratios shows that there is no adverse influence of the SGLT-2 inhibitor, e.g. velagliflozin, treatment at dry-off on the safety of a pregnant cow and the foetus.

(25) In studies where the subsequent lactation is monitored it can be shown that treatment with at least one SGLT-2 inhibitor, such as velagliflozin, does not negatively affect reproduction/fertility and/or milk yield and/or quality of milk in the next lactation. In contrast, it can even reduce the incidence of new intra-mammary infections or mastitis in the first month after start of the next lactation.

(26) These readings are compared between cows treated with at least one SGLT-2 inhibitor, such as velagliflozin, with cows that receive no treatment or cows offered a reduced feed ration only prior to dry-off.

Example 7 Dose/Pharmacodynamics (PD) of Dapagliflozin after a Single Parenteral Injection in Lactating Ruminants

(27) In studies in pregnant or non-pregnant, lactating cows, treatment with dapagliflozin is performed as described in Example 1. I.e. employing a dose escalation design the cows receive a single parenteral injection containing dapagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. Pharmacodynamics data are evaluated as described in Example 1. Thus, it is investigated: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking (PM) decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(28) Thus, similar to what is described with velagliflozin, also for dapagliflozin it is anticipated that a parenteral treatment at a dose between 0.01 to 10 mg/kg bodyweight per injection has the potential to be safely employed in lactating cows to reduce milk yield and have beneficial effects if treatment is installed at dry-off in analogy to Examples 2 to 6 of the present invention.

Example 8 Dose/Pharmacodynamics (PD) of Canagliflozin after a Single Parenteral Injection in Lactating Ruminants

(29) In studies in pregnant or non-pregnant, lactating cows, treatment with canagliflozin is performed as described in Example 1. I.e. employing a dose escalation design the cows receive a single parenteral injection containing canagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. Pharmacodynamic data are evaluated as described in Example 1. Thus, it is investigated: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking (PM) decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(30) Thus, similar to what is described with velagliflozin, also for canagliflozin it is anticipated that a parenteral treatment at a dose between 0.01 to 10 mg/kg bodyweight per injection has the potential to be safely employed in lactating cows to reduce milk yield and have beneficial effects if treatment is installed at dry-off in analogy to Examples 2 to 6 of the present invention.

Example 9 Dose/Pharmacodynamics (PD) of Empagliflozin after a Single Parenteral Injection in Lactating Ruminants

(31) In studies in pregnant or non-pregnant, lactating cows, treatment with empagliflozin is performed as described in Example 1. I.e. employing a dose escalation design the cows receive a single parenteral injection containing empagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. Pharmacodynamic data are evaluated as described in Example 1. Thus, it is investigated: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking (PM) decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(32) Thus, similar to what is described with velagliflozin, also for empagliflozin it is anticipated that a parenteral treatment at a dose between 0.01 to 10 mg/kg bodyweight per injection has the potential to be safely employed in lactating cows to reduce milk yield and have beneficial effects if treatment is installed at dry-off in analogy to Examples 2 to 6 of the present invention.

Example 10 Dose/Pharmacodynamics (PD) of Ertugliflozin after a Single Parenteral Injection in Lactating Ruminants

(33) In studies in pregnant or non-pregnant, lactating cows, treatment with ertugliflozin is performed as described in Example 1. I.e. employing a dose escalation design the cows receive a single parenteral injection containing ertugliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. Pharmacodynamic data are evaluated as described in Example 1. Thus, it is investigated: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking (PM) decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(34) Thus, similar to what is described with velagliflozin, also for ertugliflozin it is anticipated that a parenteral treatment at a dose between 0.01 to 10 mg/kg bodyweight per injection has the potential to be safely employed in lactating cows to reduce milk yield and have beneficial effects if treatment is installed at dry-off in analogy to Examples 2 to 6 of the present invention.

Example 11 Effects on Milk Composition and Involution Marker—Ex Vivo/In Vitro Assessment

(35) The direct effects of SGLT2 inhibition on the bovine mammary gland are studied in isolated perfused bovine udders as well as in (primary) bovine mammary epithelial cells (MECs).

(36) The beneficial effects on the bovine mammary gland for dry-off are shown e.g. in the milk like secretion of perfused udders and/or the supernatant in MEC cultures—the reduction of lactose and/or triglycerides are measured. Also, the reduction of markers of milk production like beta-casein is quantified, e.g. by determining the protein content in western blots of cell lysates.

(37) In addition, the expression of involution marker are assessed. The exposure of perfused bovine udders and/or bovine MECs with at least one SGLT2 inhibitor according to the present invention influences apoptosis and/or autophagy. These effects are measured, e.g. by quantifying the expression of markers like transforming growth factor-beta1 and/or sequestosome-1 (also known as p62).

Example 12 Dose/Pharmacodynamics (PD) of Velagliflozin after a Single Administration in Lactating Laboratory Animals

(38) In studies in lactating laboratory animals, such as dogs, cats, rats, mice and/or rabbits, treatment with velagliflozin is performed similar as described in Example 1. I.e. employing a dose escalation design the animals receive a single parenteral injection or, alternatively, oral dosages containing velagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. In laboratory animals, the milk yield is measured using a weigh-suckle-weigh method. Briefly, the mother is separated from her pups for e.g. 3 h. Then the pups are weighed, allowed to suckle for e.g. 1 h, and are weighed again. This procedure may be repeated several times per day, e.g. the day before and the day of treatment with velagliflozin.

(39) Pharmacodynamic read outs investigated are e.g.: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(40) These readings are compared between, before, or after treatment with velagliflozin, or between animals that are treated with velagliflozin compared to others, that receive no treatment or placebo treatment.

(41) The dose depended reduction of milk secretion of velagliflozin in cows (see Example 1) and laboratory animals indicate that SGLT2 inhibitors, like velagliflozin, but also others can successfully treat any condition of an animal (preferably ruminants, dogs, cats, horses, pigs) that is associated with an unwanted lactation—e.g. dry-off in dairy ruminants (Example 1), pseudopregnancy/galactorrhea in animals (Example 17). But also, if for other reasons it is required that whelping is to be discontinued abruptly, the treatment with at least one SGLT2 inhibitor according to the present invention is anticipated to reduce the milk secretion and in addition successfully reduce and/or prevent associated clinical signs—e.g. mammary engorgement, pain, milk leakage and/or mastitis.

Example 13 Dose/Pharmacodynamics (PD) of Dapagliflozin after a Single Administration in Lactating Laboratory Animals

(42) In studies in lactating laboratory animals, such as dogs, cats, rats, mice and/or rabbits, treatment with dapagliflozin is performed similar as described in Example 1. I.e. employing a dose escalation design the animals receive a single parenteral injection or, alternatively, oral dosages containing dapagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. In laboratory animals, the milk yield is measured using a weigh-suckle-weigh method. Briefly, the mother is separated from her pups for e.g. 3 h. Then the pups are weighed, allowed to suckle for e.g. 1 h, and are weighed again. This procedure may be repeated several times per day, e.g. the day before and the day of treatment with dapagliflozin. Pharmacodynamic read outs investigated are e.g.: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(43) These readings are compared between, before, or after treatment with dapagliflozin, or between animals that are treated with dapagliflozin compared to others, that receive no treatment or placebo treatment.

Example 14 Dose/Pharmacodynamics (PD) of Canagliflozin after a Single Administration in Lactating Laboratory Animals

(44) In studies in lactating laboratory animals, such as dogs, cats, rats, mice and/or rabbits, treatment with canagliflozin is performed similar as described in Example 1. I.e. employing a dose escalation design the animals receive a single parenteral injection or, alternatively, oral dosages containing canagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. In laboratory animals, the milk yield is measured using a weigh-suckle-weigh method. Briefly, the mother is separated from her pups for e.g. 3 h. Then the pups are weighed, allowed to suckle for e.g. 1 h, and are weighed again. This procedure may be repeated several times per day, e.g. the day before and the day of treatment with canagliflozin. Pharmacodynamic read outs investigated are e.g.: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(45) These readings are compared between, before, or after treatment with canagliflozin, or between animals that are treated with canagliflozin compared to others, that receive no treatment or placebo treatment.

Example 15 Dose/Pharmacodynamics (PD) of Empagliflozin after a Single Administration in Lactating Laboratory Animals

(46) In studies in lactating laboratory animals, such as dogs, cats, rats, mice and/or rabbits, treatment with empagliflozin is performed similar as described in Example 1. I.e. employing a dose escalation design the animals receive a single parenteral injection or, alternatively, oral dosages containing empagliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. In laboratory animals, the milk yield is measured using a weigh-suckle-weigh method. Briefly, the mother is separated from her pups for e.g. 3 h. Then the pups are weighed, allowed to suckle for e.g. 1 h, and are weighed again. This procedure may be repeated several times per day, e.g. the day before and the day of treatment with empagliflozin. Pharmacodynamic read outs investigated are e.g.: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(47) These readings are compared between, before, or after treatment with empagliflozin, or between animals that are treated with empagliflozin compared to others, that receive no treatment or placebo treatment.

Example 16 Dose/Pharmacodynamics (PD) of Ertugliflozin after a Single Administration in Lactating Laboratory Animals

(48) In studies in lactating laboratory animals, such as dogs, cats, rats, mice and/or rabbits, treatment with ertugliflozin is performed similar as described in Example 1. I.e. employing a dose escalation design the animals receive a single parenteral injection or, alternatively, oral dosages containing ertugliflozin in weekly intervals. Urinary glucose and creatinine, blood glucose and ketone body concentration and milk yield are measured. In laboratory animals, the milk yield is measured using a weigh-suckle-weigh method. Briefly, the mother is separated from her pups for e.g. 3 h. Then the pups are weighed, allowed to suckle for e.g. 1 h, and are weighed again. This procedure may be repeated several times per day, e.g. the day before and the day of treatment with ertugliflozin. Pharmacodynamic read outs investigated are e.g.: If the urinary glucose excretion normalized to urinary creatinine increases in a dose/exposure dependent manner. That, after treatment, the milk yield of the subsequent milking decreases in a dose/exposure dependent manner. And also, if blood glucose or ketone body level stay within normal reference ranges after treatment with all dosages.

(49) These readings are compared between, before, or after treatment with ertugliflozin, or between animals that are treated with ertugliflozin compared to others, that receive no treatment or placebo treatment.

Example 17 Treatment with SGLT2 Inhibitors for the Reduction of Milk Secretion in Cases of Unwanted Lactation Incl. e.g. Galactorrhea and/or Pseudopregnancy

(50) The previous examples have described, that the administration of at least one SGLT2 inhibitor according to the present invention can successfully treat any condition of an animal (preferably ruminant, dog, cat, horse, and/or pig) that is associated with an unwanted lactation—e.g. dry-off in dairy ruminants (Example 1). Also, other clinical conditions are often associated with an unwanted lactation, mammary engorgement and/or milk leakage. E.g. this is encountered in dogs affected by pseudopregnancy and/or galactorrhea.

(51) In affected dogs, SGLT-2 inhibitor, such as velaglifozin, treatment can be performed as a parenteral administration, preferably s.c. or i.m. or also by oral administration. The treatment may be a single treatment or repeated daily treatments e.g. ˜24 h or 48 h apart until the symptoms resolve.

(52) Responses to treatment are evaluated by visual inspection of the mammary gland area—i.e. engorgement and/or milk leakage—and/or manual palpation to evaluate pain and/or evolving intra mammary inflammation. Also, the resolution of additional behavioural symptoms (e.g. depression, weight gain, vomiting, or appetite loss) may be evaluated. The read outs may be reported on owner questionnaires.

REFERENCES

(53) (1) Bertulat S et al., J Dairy Sci 2017, 100(4): 3220-3232 (2) EP 2 349 272 (3) EP 2 675 527 (4) Gross J J et al., J Anim Physiol Anim Nutr 2015, 99: 747-756 (5) Lanctôt S et al., J Dairy Sci 2017, 100(3): 2269-2281 (6) Maynou G et al., J Dairy Sci 2018, 101(12): 1-12 (7) US 2004/0258778 (8) US 2011/0245261 (9) US 2014/0024670 (10) U.S. Pat. No. 4,412,993 (11) U.S. Pat. No. 6,391,849 (12) U.S. Pat. No. 8,133,916 (13) U.S. Pat. No. 9,487,557 (14) U.S. Pat. No. 9,744,158 (15) WO 2004/113378 (16) WO 2007/128749 (17) WO 2009/143020 (18) WO2014/016381 (19) WO 2015/173584 (20) WO 2016/104643 (21) WO 2017/156632 (22) WO 2019/121509 (23) Zhao F Q et al., J. Dairy Sci., 2005, 88: 2738-2748 (24) Zhao F Q, J Mammary Gland Biol Neoplasia 2014, 19: 3-17

(54) The following clauses are also comprised by the present invention: 1. Use of at least one SGLT-2 inhibitor in ruminants, preferably for drying-off of ruminants. 2. Method of improving and/or facilitating the drying-off of ruminants comprising administering to such ruminants at least one SGLT-2 inhibitor. 3. Method of reducing the milk production in pregnant and/or lactating ruminants comprising administering to such ruminants at least one SGLT-2 inhibitor. 4. Method of decreasing milk accumulation and/or engorgement in the udder of ruminants comprising administering to such ruminants at least one SGLT-2 inhibitor. 5. Method of decreasing the discomfort associated with udder engorgement, such as increasing the daily lying time and/or reduction of stress, of ruminants comprising administering to such ruminants at least one SGLT-2 inhibitor. 6. Method of decreasing milk leakage after drying-off of ruminants comprising administering to such ruminants at least one SGLT-2 inhibitor. 7. Method of decreasing the incidence of intra-mammary infections (IMI), preferably mastitis and/or metritis, in ruminants comprising administering to such ruminants at least one SGLT-2 inhibitor. 8. The use or method according to any one of clauses 1 to 7, wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any harmful and/or abortifacient effects on pregnant ruminants and/or wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount without exerting any negative effects on the subsequent reproduction cycle/fertility and milk yield and/or milk quality in the next lactation. 9. The use or method according to clause 8, wherein the at least one SGLT-2 inhibitor is administered in a therapeutically effective amount that additionally or alternatively effects a reduction of the incidence of new intra-mammary infections (IMI) or mastitis in the first month after start of the next lactation. 10. The use or method according to any one of clauses 1 to 9, wherein the at least one SGLT-2 inhibitor is selected from the group consisting of: (1) a glucopyranosyl-substituted benzene derivative of the formula (1)

(55) ##STR00044## wherein R.sup.1 denotes cyano, Cl or methyl (most preferably cyano); R.sup.2 denotes H, methyl, methoxy or hydroxy (most preferably H) and R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano; wherein R.sup.3 is preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and most preferably R.sup.3 is cyclopropyl, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1-3-alkyl)-carbonyl; (2) Velagliflozin, represented by formula (2):

(56) ##STR00045## (3) Dapagliflozin, represented by formula (3):

(57) ##STR00046## (4) Canagliflozin, represented by formula (4):

(58) ##STR00047## (5) Empagliflozin, represented by formula (6):

(59) ##STR00048## (6) Luseogliflozin, represented by formula (6):

(60) ##STR00049## (7) Tofogliflozin, represented by formula (7):

(61) ##STR00050## (8) Ipragliflozin, represented by formula (8):

(62) ##STR00051## (9) Ertugliflozin, represented by formula (9):

(63) ##STR00052## (10) Atigliflozin, represented by formula (10):

(64) ##STR00053## (11) Remogliflozin, represented by formula (11):

(65) ##STR00054## (11A) Remogliflozin etabonate, represented by formula (11A):

(66) ##STR00055## (12) a thiophene derivative of the formula (12)

(67) ##STR00056## wherein R denotes methoxy or trifluoromethoxy; (13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);

(68) ##STR00057## (14) a spiroketal derivative of the formula (14):

(69) ##STR00058## wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl; (15) a pyrazole-O-glucoside derivative of the formula (15)

(70) ##STR00059## wherein R.sup.1 denotes C.sub.1-3-alkoxy, L.sup.1, L.sup.2 independently of each other denote H or F, R.sup.6 denotes H, (C.sub.1-3-alkyl)carbonyl, (C.sub.1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) Sotagliflozin, represented by formula (16):

(71) ##STR00060## (17) Sergliflozin, represented by formula (17):

(72) ##STR00061## (18) a compound represented by formula (18):

(73) ##STR00062## wherein R.sup.3 denotes 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, ethinyl, 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, methlysulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano, and wherein R.sup.3 is preferably selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; and R.sup.3 most preferably is cyclopropyl, or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C.sub.1-18-alkyl)carbonyl, (C.sub.1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C.sub.1--alkyl)-carbonyl; (19) Bexagliflozin, represented by formula (19):

(74) ##STR00063## (20) Janagliflozin, represented by formula (20):

(75) ##STR00064## 11. The use or method according to any one of clauses 1 to 10, wherein the ruminants are selected from the group consisting of: bovine, caprine, ovine; more preferably selected from the group consisting of: cattle, cows, goats, sheep; even more preferably selected from the group consisting of: dairy cattle, pregnant and/or lactating dairy cattle; most preferably selected from the group consisting of: cows, pregnant and/or lactating cows. 12. The use or method according to any one of clauses 1 to 11, wherein the at least one SGLT-2 inhibitor is administered orally, parenterally, rectally, intravaginally, intravenously, subcutaneously or intramuscularly, preferably subcutaneously, intramuscularly or intravenously. 13. The use or method according to any one of clauses 1 to 12, wherein the at least one SGLT-2 inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight, preferably at a dose of 0.01 mg/kg bodyweight to 5 mg/kg bodyweight, more preferably at a dose of 0.01 mg/kg bodyweight to 3 mg/kg bodyweight, even more preferably at a dose of 0.03 mg/kg bodyweight to 3 mg/kg bodyweight, most preferably at a dose of 0.03 mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg bodyweight. 14. The use or method according to any one of clauses 1 to 13, wherein the at least one SGLT-2 inhibitor is administered once, twice, three-times, four-times, five-times, six-times or daily for a week, preferably once only at start of drying-off or twice as two treatments 24 hours or 48 hours apart after last milking. 15. The use or method according to any one of clauses 1 to 14, wherein the at least one SGLT-2 inhibitor is velagliflozin and velagliflozin is administered as single SGLT-2 inhibitor, preferably subcutaneously or intramuscularly, once only at start of drying-off or twice (24 h or 48 h apart) at a dose of 0.03 mg/kg bodyweight to 3 mg/kg bodyweight, preferably at a dose of 0.03 mg/kg bodyweight or 0.3 mg/kg bodyweight or 3 mg/kg bodyweight. 16. The use or method according to any one of clauses 1 to 15, wherein the at least one SGLT-2 inhibitor is administered before, after or concomitantly with administering at least one feed supplement, such as Bovikalc® Dry, to the ruminant and/or before, after or concomitantly with a reduction in feed offered to the ruminant. 17. The use or method according to clause 16, wherein the feed supplement comprises one or more acidifying agents selected from the group consisting of: ammonium chloride, calcium chloride and/or calcium sulfate, more preferably comprises ammonium chloride and calcium chloride and calcium sulfate, even more preferably comprises 5% (w/w) to 15% (w/w) ammonium chloride and 40% (w/w) to 60% (w/w) calcium chloride and 15% (w/w) to 25% (w/w) calcium sulfate, most preferably comprises 10.4% (w/w) ammonium chloride and 51.9% (w/w) calcium chloride and 20.1% (w/w) calcium sulfate.