Use of SGLT-2 inhibitors in the drying-off of non-human mammals
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.
1. A method of drying-off a lactating non-human mammal, comprising administering to the non-human mammal an active ingredient that inhibits SGLT activity and comprises at least one SGLT-2 inhibitor.
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 comprises velagliflozin, and the at least one SGLT-2 inhibitor is administered orally, 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.
9. 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.
10. The method according to claim 1 , wherein the non-human mammal is a cow.
11. The method according to claim 6 , wherein the non-human mammal is selected from the group consisting of: bovine, canine, caprine, equine, feline, lagomorphs, ovine, porcine, and rodent.
12. The method of claim 1 , wherein the SGLT activity consists of SGLT-2 activity.
13. A method of reducing milk production in a pregnant and/or lactating non-human mammal, comprising administering to the non-human mammal an active ingredient that inhibits SGLT activity, the SGLT activity consisting of SGLT-2 activity, wherein the active ingredient comprises at least one SGLT-2 inhibitor.
14. The method according to claim 13 , wherein the non-human mammal is a cow.
15. The method according to claim 13 , wherein the at least one SGLT-2 inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.
16. The method according to claim 15 , 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)
wherein R 1 denotes cyano, Cl or methyl;
R 2 denotes H, methyl, methoxy or hydroxy and
R 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 1-18 -alkyl) carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;
(2) Velagliflozin, represented by formula (2):
(3) Dapagliflozin, represented by formula (3):
(4) Canagliflozin, represented by formula (4):
(5) Empagliflozin, represented by formula (5):
(6) Luseogliflozin, represented by formula (6):
(7) Tofogliflozin, represented by formula (7):
(8) Ipragliflozin, represented by formula (8):
(9) Ertugliflozin, represented by formula (9):
(10) Atigliflozin, represented by formula (10):
(11) Remogliflozin, represented by formula (11):
(11A) Remogliflozin etabonate, represented by formula (11A):
(12) a thiophene derivative of the formula (12)
wherein K denotes methoxy or trifluoromethoxy;
(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, represented by formula (13);
(14) a spiroketal derivative of the formula (14):
wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert.butyl;
(15) a pyrazole-O-glucoside derivative of the formula (15):
wherein
R 1 denotes C 1-3 -alkoxy,
L 1 , L 2 independently of each other denote H or F,
R 6 denotes H, (C 1-3 -alkyl) carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;
(16) Sotagliflozin, represented by formula (16):
(17) Sergliflozin, represented by formula (17):
(18) a compound represented by formula (18):
wherein
R 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 1-18 -alkyl) carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;
(19) Bexagliflozin, represented by formula (19):
(20) Janagliflozin, represented by formula (20):
(21) Rongliflozin; and
(22) Wanpagliflozin.
17. 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 an active ingredient that inhibits SGLT activity, the SGLT activity consisting of SGLT-2 activity, wherein the active ingredient comprises at least one SGLT-2 inhibitor.
18. The method according to claim 17 , wherein the non-human mammal is a cow.
19. The method according to claim 17 , wherein the at least one SGLT-2 inhibitor is administered at a dose of 0.01 mg/kg bodyweight to 10 mg/kg bodyweight.
20. The method according to claim 19 , 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)
wherein R 1 denotes cyano, Cl or methyl;
R 2 denotes H, methyl, methoxy or hydroxy and
R 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 1-18 -alkyl) carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;
(2) Velagliflozin, represented by formula (2):
(3) Dapagliflozin, represented by formula (3):
(4) Canagliflozin, represented by formula (4):
(5) Empagliflozin, represented by formula (5):
(6) Luseogliflozin, represented by formula (6):
(7) Tofogliflozin, represented by formula (7):
(8) Ipragliflozin, represented by formula (8):
(9) Ertugliflozin, represented by formula (9):
(10) Atigliflozin, represented by formula (10):
(11) Remogliflozin, represented by formula (11):
(11A) Remogliflozin etabonate, represented by formula (11A):
(12) a thiophene derivative of the formula (12)
wherein R denotes methoxy or trifluoromethoxy;
(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene represented by formula (13);
(14) a spiroketal derivative of the formula (14):
wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert.butyl;
(15) a pyrazole-O-glucoside derivative of the formula (15):
wherein
R 1 denotes C 1-3 -alkoxy,
L 1 , L 2 independently of each other denote H or F,
R 6 denotes H, (C 1-3 -alkyl) carbonyl, (C 1-6 -alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;
(16) Sotagliflozin, represented by formula (16):
(17) Sergliflozin, represented by formula (17):
(18) a compound represented by formula (18):
wherein
R 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 1-18 -alkyl) carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;
(19) Bexagliflozin, represented by formula (19):
(20) Janagliflozin, represented by formula (20):
(21) Rongliflozin; and
(22) Wanpagliflozin.
21. A method of improving and/or facilitating the drying-off of a non-human mammal, comprising administering to the non-human mammal an active ingredient that inhibits SGLT activity, wherein the SGLT activity consists of SGLT-2 activity and that active ingredient comprises at least one SGLT-2 inhibitor.