Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals

Patent metadata

Field	Value
Publication number	US-2017239281-A1
Application number	US-201515512984-A
Country	US
Kind code	A1
Filing date	Sep 22, 2015
Priority date	Sep 25, 2014
Publication date	Aug 24, 2017
Grant date	—

Abstract

The present invention relates to combination of one or more SGLT2 inhibitors or pharmaceutically acceptable forms and/or salts thereof and one or more dopamine receptor agonists or pharmaceutically acceptable forms and/or salts thereof, preferably in the treatment and/or prevention of a metabolic disorder of an equine animal, wherein more preferably the metabolic disorder is one or more disorders selected from Equine Metabolic Syndrome (EMS), Equine Pituitary Pars Intermedia Dysfunction (PPID), also known as equine Cushing's syndrome, laminitis, vascular dysfunction, hypertension, hepatic lipidosis, hyperadreeocorticism, glucose intolerance, insulin resistance, hyperinsulinaemia, hirsutism, hyperhidrosis. polyuria, polydipsia, chronic infections, abnormal fat distribution, muscle wasting, abnormal weight loss and/or loss of appetite.

First claim

1 . A method for treating equines in need of treatment comprising one or more SGLT2 inhibitors, pharmaceutically acceptable forms or salts thereof in combination with one or more dopamine receptor agonists, pharmaceutically acceptable forms or salts thereof for use as a medicament.

2 . The method according to claim 1 , wherein said one or more SGLT2 inhibitors, pharmaceutically acceptable forms, or salts thereof in combination with the one or more dopamine receptor agonists, pharmaceutically acceptable forms, or salts thereof are used in the treatment or prevention of a metabolic disorder of an equine animal, wherein said metabolic disorder is one or more disorders selected from the group consisting of: Equine Metabolic Syndrome (EMS), Equine Pituitary Pars Intermedia Dysfunction (PPID), laminitis, vascular dysfunction, hypertension, hepatic lipidosis, hyperadrenocorticism, glucose intolerance, insulin resistance, hyperinsulinaemia, hirsutism, hyperhidrosis, polyuria, polydipsia, chronic infections, abnormal fat distribution, muscle wasting, abnormal weight loss, loss of appetite and combinations thereof.

3 . The method according to claim 2 , wherein the treatment or prevention of a metabolic disorder of an equine animal is treatment or prevention of clinical symptoms associated with Equine Pituitary Pars Intermedia Dysfunction (PPID), wherein such clinical symptoms are selected from the group consisting of: laminitis, vascular dysfunction, hypertension, hepatic lipidosis, chronic infections, hyperglycaemia, glucose intolerance, insulin resistance, hyperinsulinaemia, hirsutism, hyperhidrosis, polyuria, polydipsia, abnormal fat distribution, muscle wasting, abnormal weight loss, loss of appetite and combinations thereof.

4 . The method according to claim 1 , wherein the one or more SGLT2 inhibitors are glucopyranosyl-substituted benzene derivatives, wherein said one or more SGLT2 inhibitors are 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 hydroxyl; 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˜ -alkyl)carbonyl, (C 1-18 -alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C 1-3 -alkyl)-carbonyl;

(2) 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, represented by formula (2):

or a pharmaceutically acceptable salt and/or form thereof, wherein preferably the pharmaceutically acceptable form is a crystalline complex between the SGLT2 inhibitor and one or more amino acids, preferably wherein the one or more amino acids is proline, more preferably L-proline;

(3) Dapagliflozin, represented by formula (3):

(4) Canagliflozin, represented by formula (4):

(6) Luseogliflozin, represented by formula (5):

(7) Tofogliflozin, represented by formula (6):

(8) Ipragliflozin, represented by formula (7):

(9) Ertugliflozin, represented by formula (8):

(10) Atigliflozin, represented by formula (9):

(11) Remogliflozin, represented by formula (10):

(12) a thiophene derivative of the formula (11)

wherein R denotes methoxy or trifluoromethoxy;

(13) 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene;
represented by formula (12);

(14) a spiroketal derivative of the formula (13):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl;

(15) a pyrazole-O-glucoside derivative of the formula (14)

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) a compound of the formula (15):

(17) Sergliflozin, represented by formula (16):

(18) a compound represented by formula (17):

wherein
R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy;

preferably 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, represented by formula (2):

or a pharmaceutically acceptable salt and/or form thereof, wherein preferably the pharmaceutically acceptable form is a crystalline complex between the SGLT2 inhibitor and one or more amino acids, preferably wherein the one or more amino acids is proline, more preferably L-proline.

5 . The method according to claim 1 , wherein the one or more dopamine receptor agonists are selected from the group consisting of:
(1) an ergoline derivative of the formula (19)

wherein independently from each o

Assignees

• Boehringer Ingelheim Vetmedica Gmbh

Inventors

• Reiche Dania Birte
• Rahmel Daniela

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title