uses of sglt2 inhibitors or pharmaceutically acceptable forms of them for the treatment of metabolic

专利摘要:
TREATMENT OF METABOLIC DISORDERS IN FELINE ANIMALS The present invention relates to one or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use in the treatment and / or prevention of a metabolic disorder in a feline animal, preferably where the metabolic disorder is one or more disorders selected from the group consisting of: ketoacidosis, pre-diabetes, type 1 or type 2 diabetes mellitus, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinaemia, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and / or syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function and / or where remission of the metabolic disorder, preferably diabetic remission, is achieved and / or maintained.
公开号:BR112016011564B1
申请号:R112016011564-3
申请日:2014-12-15
公开日:2021-02-09
发明作者:Dania Birte Reiche；Silke HAAG-DIERGARTEN；Leah Jeanette Hennings；Saskia Kley；Anne M. Traas
申请人:Boehringer Ingelheim Vetmedica Gmbh；
IPC主号:

专利说明:

Field of the Invention
[0001] The present invention relates to veterinary medicine, in particular the treatment and / or prevention of metabolic disorders in feline animals. Background of the Invention
[0002] Feline animals, for example, cats, are affected by various metabolic disorders. Numerous metabolic disorders are known in feline animals, including hyperglycemia, insulin resistance, diabetes (such as type 1 or type 2 diabetes mellitus, or pre-diabetes), liver lipidosis, obesity, hyperinsulinemia, impaired glucose tolerance, ketosis (in particular ketoacidosis), dyslipidemia, dysadipokinaemia, obesity, subclinical inflammation or systemic inflammation, in particular low-grade systemic inflammation, which also comprises adipose tissue, syndrome X (metabolic syndrome), atherosclerosis and / or inflammation of the pancreas. There are several correlations between these disorders. Among these disorders, in cattle, diabetes, in particular pre-diabetes and type 2 diabetes mellitus, as well as hyperglycemia, insulin resistance, liver lipidosis, and obesity are gaining more and more importance. This can be attributed, at least in part, to the changing lifestyles and feeding behavior of pets in recent years.
[0003] Diabetes mellitus is characterized by changes in the metabolism of carbohydrates, proteins and triglycerides based on a relative or absolute lack of insulin. It is a relatively common endocrinopathy in feline animals like the cat. The incidence for cats has increased about 5 to 12 times in the past four decades to approximately 0.5 to 1.2%. Several risk factors have been identified: age, obesity, castration and sex. Male, neutered, obese and old cats (> 10 years old) are likely to have the highest risk of developing diabetes mellitus. The current classification divides diabetes mellitus into three classes: (1.) Type 1 that results from loss of insulin-secreting cell function, for example, by immune destruction of beta cells or autoantibodies to insulin (juvenile diabetes in humans); (2.) Type 2 that results from a failure of cells stimulated by insulin to respond appropriately to insulin stimuli; it is also associated, for example, with amyloid accumulation in beta cells; type 2 usually develops over a long period of the so-called pre-diabetes state; (3.) secondary diabetes mellitus which may be due to diabetogenic drugs (for example, long-acting glycosteroids, megestrol acetate, etc.) or to other primary diseases such as pancreatitis, pancreatic adenocarcinoma, Cushing's, hypothyroidism or hyperthyroidism, producing tumors of growth hormone resulting in acromegaly.
[0004] Type 2 diabetes mellitus in particular is a growing problem for cat populations across the developed world. The changes in cat owners' lifestyle reflect on their cats - they are increasingly kept indoors, with reduced activity levels, and eat a high-calorie diet, leading to obesity and predisposition to diabetes mellitus type 2. As these trends continue, it is certain that the incidence of diabetes mellitus in cats will increase proportionately.
[0005] For the treatment of diabetes in humans, especially type 2 diabetes mellitus, several oral anti-hyperglycemic drugs have already been approved. These drugs act, for example, by stimulating pancreatic insulin secretion independently of glucose or dependent on glucose (sulfonylurea / meglitinides, or DPP IV inhibitors, respectively), increasing tissue sensitivity to insulin (biguanides, thiazolidinediones), or slowing down absorption of postprandial intestinal glucose (alpha-glucosidase inhibitors).
[0006] Other approaches have already been considered to treat diabetes and reduce hyperglycemia in humans, including inhibition of the renal sodium-dependent glucose cotransporter SGLT2. SGLT2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following blood filtration. Inhibition of SGLT2 in this way induces glycosuria and can reduce blood glucose levels. For example, the compound 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene is described as an SGLT2 inhibitor in WO 2007/128749. A wide variety of other SGLT2 inhibitors are also known. In WO 2011/117295, which deals with the medication of predominantly carnivorous non-human animals with dipeptidyl peptidase IV (DPP-IV) inhibitors, several SGLT2 inhibitors are mentioned among numerous other types of compounds in the context of combined therapies with inhibitors of DPP-IV.
[0007] SGLT2 inhibition not yet contemplated for the treatment of metabolic disorders in feline animals, such as cats. For feline animals, medications for metabolic disorders are much less advanced than for humans. Unfortunately, even if a treatment or prophylaxis is effective in humans, for example, or in other non-feline animals, it is not possible to conclude that the same approach will also be effective, safe and somehow appropriate in a feline animal, such as a cat.
[0008] Feline animals differ significantly from humans or, for example, dogs in terms of their metabolisms.
[0009] Being strictly carnivorous, felines do not adapt well to carbohydrates in the diet. For example, the liver of felines does not show glycokinase activity (Tanaka et al., Vet Res Commun. 2005, 29 (6): 477-485). In most mammals, for example, dogs or humans, hepatic glycokinase acts as a "glucose sensor" that allows liver metabolism to respond appropriately to changes in plasma glucose concentrations. In addition, insulin release from a cat's pancreas appears to be less responsive to glucose as a stimulus compared to most other species (Curry et al., Comp Biochem Physiol. 1982. 72A (2): 333-338).
[00010] Another adaptation to a strictly carnivorous diet concerns the use of protein and fat for energy production - i.e., gluconeogenesis. In an omnivore, gluconeogenesis occurs mainly in situations of hunger. On the contrary, in a mandatory carnivore, such as the cat, gluconeogenesis appears to be constantly active in the liver, regardless of the state of nutrition and appears to be, in postprandial terms, even higher than in a fed state (Hoenig et al. Am J Physiol, 2011, 301 (6): R1798- 1807, Verbrugghe et al., Crit Rev Food Sci Nutr. 2012; 52 (2): 172-182).
[00011] Consequently, the pathophysiology of feline metabolic disorders, and therefore also their responses to medication for such disorders, differ from those of other species.
[00012] As a diabetic complication, for example, vision problems and cataracts are commonly seen with diabetes mellitus in dogs, but are rarely found in feline animals.
[00013] Oral diabetes medications that are known to human medicine such as glipizide (sulfonylurea) work in a small proportion of cats, but these drugs can be completely ineffective if the pancreas is not working. But the worst is that, in some studies, glipizide and other oral hypoglycemic drugs have been shown to produce side effects such as vomiting and ichthyroid and damage the pancreas even leading to a reduced chance of remission of diabetes for cats. They have also been shown to cause liver damage. Even lower efficacies have been reported for the other groups of compounds, i.e., meglitinides, biguanides, thiazolidinediones and α-glucosidase inhibitors (Palm CA et al., Vet Clin Small Anim 2013, 43: 407-415).
[00014] The gold standard treatment of diabetic cats is currently considered to be insulin injection. However, cats are notoriously unpredictable in their response to exogenous insulin. Not a single type of insulin is routinely effective in maintaining glycemic control, even with administration twice a day. Even with the strict complacency of the owner, control is often poor and secondary problems are common. Many owners find it impossible to achieve acceptable levels of compliance, since synchronization of food intake and insulin injection is impossible in most cases. Finally, many cats with diabetes mellitus are euthanized because of the disease.
[00015] The factors that influence patient and owner complacency are also very different. In cats, oral administration, for example, is even more highly desirable than in humans.
[00016] A treatment that would enable better compliance and, therefore, better glycemic control than current insulin-based treatments would help to mitigate the evolution of the disease and to delay or prevent the onset of complications in many animals.
[00017] Furthermore, even when diabetic cats are aggressively treated with insulin and clinical remission is achieved, this also does not necessarily normalize insulin secretion, pancreatic beta cell function and / or insulin resistance. Cats remain susceptible to a new form of diabetes. It would be desirable to have a treatment of diabetes in feline animals that best increases, for example, insulin resistance and pancreatic beta cell function (Reusch CE et al., Schweizer Archiv fuer Tierheilkunde 2011, 153811): 495-500).
[00018] Therefore, there remains a particular need for effective, safe and somehow appropriate treatments for metabolic disorders, including diabetes, in feline animals. Description of the Invention Summary of the Invention
[00019] The present inventors have surprisingly found that inhibition of SGLT2 is effective and safe in the treatment and / or prevention of metabolic disorders in feline animals.
[00020] The present invention, therefore, offers the use of one or more SGLT2 inhibitors or a pharmaceutically acceptable form of them in the treatment and / or prevention of a feline animal's metabolic disorder. In addition, the present invention offers the use of one or more SGLT2 inhibitors or a pharmaceutically acceptable form of them in the treatment and / or prevention of a metabolic disorder in a feline animal, where the one or more SGLT2 inhibitors is 1- cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene (hereinafter referred to as compound A) or a pharmaceutically acceptable form thereof.
[00021] Compound A has the following chemical formula:

[00022] Other aspects of the invention are defined below as well as in the claims.
[00023] The pharmaceutically acceptable form of one or more SGLT2 inhibitors, preferably compound A, can be a crystalline complex between the one or more SGLT2 inhibitors and one or more amino acids, such as proline.
[00024] According to the invention, the one or more SGLT2 inhibitors, preferably compound A, or a pharmaceutically acceptable form thereof, can be presented, for example, for oral or parenteral administration, preferably for oral administration.
[00025] The one or more SGLT2 inhibitors, preferably compound A, or a pharmaceutically acceptable form thereof can be administered in dosages of 0.1 to 3.0 mg / kg of body weight per day, preferably of 0.2 to 2.0 mg / body weight per day, more preferably from 0.1 to 1 g / body weight per day. Accordingly, the one or more SGLT2 inhibitors, preferably compound A, or a pharmaceutically acceptable form thereof can be prepared for administration of 0.1 to 3.0 mg / kg of body weight per day, preferably of 0.2 to 2.0 mg / kg. body weight per day, more preferably 0.1 to 1 mg / kg body weight per day.
[00026] The one or more SGLT2 inhibitors, preferably compound A, or a pharmaceutically acceptable form of it is preferably administered only once a day.
[00027] The present invention also offers a pharmaceutical composition comprising one or more SGLT2 inhibitors, preferably compound A, or a pharmaceutically acceptable form thereof, for use in accordance with the invention disclosed in this report.
[00028] In the examples offered in this report, the therapeutic and / or prophylactic benefits resulting from the inhibition of SGLT2 according to the present invention are demonstrated experimentally. The experimental data disclosed in this report are intended to illustrate the invention, but do not have any limiting effect on the scope of protection, which is defined later by the claims.
[00029] In particular, the present inventors have surprisingly found that the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention advantageously leads to a reduction in insulin resistance in treated insulin-resistant feline animals. That is, equivalently, the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention advantageously leads to increased insulin sensitivity in treated insulin-resistant feline animals. Insulin sensitivity can be calculated by a variety of substitute indices, for example, during a glucose challenge such as the modified Belfiore index (1 / log (DAUC-glucose * DAUC-insulin)).
[00030] The invention therefore enables improved treatment and / or prevention of diabetes, in particular type 2 diabetes mellitus, in feline animals.
[00031] The use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention advantageously leads to a reduced insulin excursion, for example, measured during an intravenous glucose tolerance test (ivGTT), or after any other form of glucose ingestion, for example, after a carbohydrate-rich meal (postprandial insulin excursion) or after a stress-induced rise in blood glucose. More specifically, the use of one or more SGLT2 inhibitors, preferably compound A, according to the invention also advantageously leads to reduced insulin secretion in the second stage, for example, measured during an ivGTT, or after any other form of glucose intake, for example, after a meal.
[00032] The use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention also advantageously leads to a reduction in plasma levels of non-esterified fatty acids, or to an increased elimination of non-esterified fatty acids from blood flow, for example, measured during an ivGTT, or after any other form of testing by raising blood insulin.
[00033] The use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention, therefore, generally leads to improved glucose tolerance, i.e., reduces glucose intolerance.
[00034] The glucose excursion in an intravenous insulin tolerance test (ivITT) of a feline animal treated according to the invention is also and, advantageously, increased compared to an untreated animal.
[00035] The use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention also advantageously leads to a reduction in body fat, blood leptin levels, and / or the respiratory exchange ratio ( RER). The invention is also associated with anti-obesity effects, and can in particular advantageously prevent weight gain and / or lead to a decrease in body mass in a feline animal. In one aspect, the invention therefore allows obesity and / or obesity-related metabolic disorders to be controlled in a feline animal.
[00036] The effects of the uses according to the present invention (ie, the beneficial effects mentioned above on insulin resistance / sensitivity, insulin excursion, second-stage insulin secretion, glucose tolerance, elimination of unesterified fatty acids , body fat, blood leptin levels, RER values and / or body mass) are also advantageous in the sense that they allow subclinical treatment, for example, treatment of pre-diabetes status in feline animals. They therefore allow the possibility of preventing or delaying the onset of diabetes mellitus in feline animals. More particularly, they allow the possibility of preventing or delaying the evolution of certain metabolic disorders, symptoms or conditions described in this report (such as hyperglycemia, impaired glucose tolerance, insulin resistance, abnormal insulin excursion or abnormal glucose excursion, high levels from non-esterified fatty acids or leptin in the blood, obesity and / or loss of pancreatic beta cells) for diabetes mellitus, in particular type 2 diabetes mellitus, in feline animals.
[00037] Another advantage of the present invention is that the use of one or more SGLT2 inhibitors, preferably compound A, is effective against metabolic disorders alone, ie, if the use of one or more SGLT2 inhibitors is desired, preferably the compound A, in a feline animal offers monotherapy (ie, a single therapy; ie, no other medication is administered to the feline animal for the treatment or prevention of the same metabolic disorder). The invention also allows for the possibility of a combination therapy with another drug (for example, another insulin sensitizing drug or insulin itself).
[00038] Another advantage of the present invention is that, surprisingly, the use of one or more SGLT2 inhibitors, preferably compound A, is effective against metabolic disorders alone, ie, if the use of one or more SGLT2 inhibitors is desired. , preferably compound A, in a feline animal provides monotherapy (ie, a single therapy; ie, no other medication is administered to the feline animal for the treatment or prevention of the same metabolic disorder). The invention also allows for the possibility of replacing insulin therapy in feline animals, or for a combination therapy with insulin or with another drug (for example a hypoglycemic drug). Such a combination advantageously leads to a decrease in the dose and / or the frequency at which insulin or another drug (for example, a hypoglycemic drug) is administered, as compared to the feline animal's monotherapy with insulin or the other drug. More advantageously, the feline animal may have insulin or the other drug suspended. Therefore, clinical remission is achieved.
[00039] Therefore, the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention, provides the improved treatment and / or prevention of the metabolic diseases described in this report, including diabetes and / or pre -diabetes, in feline animals.
[00040] The effects of using one or more SGLT2 inhibitors, preferably compound A, according to the present invention (for example, the beneficial effects mentioned above on insulin resistance / sensitivity, insulin excursion, insulin secretion in the second glucose tolerance, elimination of non-esterified fatty acids, body fat, blood leptin levels, RER values, body mass and / or hyperglycemia) may be related to the same feline animal or a comparable feline animal prior to administration of one or more SGLT2 inhibitors, preferably compound A, according to the present invention, and / or relating to a comparable feline animal that has not received said treatment (e.g., a placebo group). In either case, when a comparison is made, the comparison can be made after a certain period of treatment, for example, 1, 2, 3, 4, 5, 6 or 7 days; 10 days, 14 days; 2, 3, 4, 5, 6, 7 or 8 weeks; 1, 2, 3 or 4 months. Preferably the treatment period is 4 weeks. Alternatively, the treatment period can be 6 or 8 weeks. Alternatively, the treatment period can be 8 weeks or more, for example 8-16 weeks.
[00041] Another advantage of the present invention is that one or more SGLT2 inhibitors, preferably compound A, can be effectively administered to a feline animal orally. In addition, the one or more SGLT2 inhibitors, preferably compound A, according to the present invention can be administered only once a day. These advantages allow a better compliance of the treated feline animal and the owner. This leads to better glycemic control of the disorders (eg, diabetes) for which feline animals are currently treated with insulin. Generally, the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention therefore helps to attenuate (ie, delay or prevent) the evolution of metabolic disorders and delay or prevent the manifestation of metabolic disorders (e.g., diabetes) and its complications in feline animals.
[00042] Accordingly, the present invention also offers pharmaceutical compositions comprising one or more SGLT2 inhibitors, preferably compound A, according to the invention for use in the treatment and / or prevention of metabolic disorders in feline animals.
[00043] The invention also offers methods of treating and / or preventing metabolic disorders in feline animals, comprising administering to a feline animal in need of such treatment and / or preventing an effective dose of one or more SGLT2 inhibitors, preferably the compound A, described in this invention.
[00044] Advantageously, the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention does not cause hypoglycemia.
[00045] The effects of using one or more SGLT2 inhibitors, preferably compound A, according to the present invention (for example, the beneficial effects mentioned above on insulin resistance / sensitivity, insulin excursion, insulin secretion in the second phase, glucose tolerance, elimination of non-esterified fatty acids, body fat, leptin levels in the blood, RER values, body mass and / or hyperglycemia) may be related to the same feline animal or to a comparable feline animal prior to administration of the one or more SGLT2 inhibitors, preferably compound A, according to the present invention, and / or relating to a comparable feline animal that has received, for example, treatment with standard insulin (for example a control group) or that has not been treated.
[00046] Another advantage of the present invention is that the one or more SGLT2 inhibitors, preferably compound A, can be effectively administered to a feline animal orally, for example in liquid form. In addition, the one or more SGLT2 inhibitors, preferably compound A, according to the present invention can be administered only once a day. These advantages allow an optimal dosage and complacency of the treated feline animal and the owner.
[00047] Generally, the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention can thus attenuate, delay or prevent the evolution of a metabolic disorder, for example, of the metabolic disorders described in this report, or it can delay or prevent the onset of metabolic disorders and their complications in feline animals. Definitions
[00048] All values and concentrations presented in this report are subject to inherent variations acceptable in biological science with an error of ± 10%. The term “about” also refers to this acceptable variation.
[00049] The treatment effects described in this report (such as an improvement, reduction or delay in the manifestation of a disorder, disease or condition, or the improvement, reduction, increase or delay of any effect, index, marker level or other parameter referring to a disorder, disease or condition) can be observed with a statistical significance of p <0.05, preferably <0.01.
[00050] When a deviation is mentioned in this report (for example, an increase, increase, excess, prolongation, enlargement, reduction, decrease, improvement, delay, abnormal levels, or any other variation, change or deviation from a reference) , the deviation can be, for example, 5% or more, particularly 10% or more, more particularly 15% or more, more particularly 20% or more, more particularly 30% or more, more particularly 40% or more, or more particularly 50% or more, in relation to the relevant reference value, unless otherwise indicated. Typically, such a deviation will be at least 10%, i.e., 10% or more. The deviation can also be 20%. The deviation can also be 30%. The deviation can also be 40%. The relevant reference value can be generated from a group of reference animals that are treated with placebo in place of one or more SGLT2 inhibitors, preferably compound A, or that are not treated.
[00051] In this report, an excursion, for example, an insulin excursion or glucose excursion, designates a variation in concentration or level in the blood over time. The magnitude of the excursions, for example, insulin excursions or glucose excursions, can be expressed as values of the area under the curve (AUC).
[00052] In this report, the terms "active substance" or "active ingredient" encompass one or more SGLT2 inhibitors, preferably compound A, or any pharmaceutically acceptable form thereof (for example, a prodrug or a crystalline form), for use according to the invention In the case of a combination with one or more additional active compounds, the terms "active ingredient" or "active substance" can also include the additional active compound.
[00053] In this report, the expression “associated with” in particular covers the expression “caused by”.
[00054] In this report, ivGTT refers to an intravenous glucose tolerance test. In an ivGTT, 0.8 g of dextrose per kg of body weight can typically be employed.
[00055] In this report, ivITT refers to an intravenous insulin tolerance test. In an ivITT, 0.05 U of insulin per kg of body weight can typically be employed. SGLT2 inhibitors
[00056] SGLT2 inhibitors for use according to the invention include, but are not limited to, glucopyranosyl-substituted benzene derivatives, for example, such as those described in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940, WO 2009/022020 or WO 2009/022008.
[00057] In addition, the one or more SGLT2 inhibitors for use according to the invention can be selected from the group consisting of the following compounds or pharmaceutically acceptable forms thereof: (1) a glucopyranosyl-substituted benzene derivative of formula ( 1)
wherein R1 means cyano, Cl or methyl (even more preferably cyan); R2 means H, methyl, methoxy or hydroxy (even more preferably H) and R3 means cyclopropyl, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert- butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethynyl, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1- hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethyloxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy, 2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R) -tetrahydrofuran-3-yloxy or (R) 3-yloxy or cyano; where R3 is preferably selected from cyclopropyl, ethyl, ethynyl, ethoxy, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy; and even more preferably R3 is cyclopropyl, or a derivative thereof where one or more hydroxyl groups from the β-D-glucopyranosyl group are acylated with groups selected from (C1-18-alkyl) carbonyl, (C1-18-alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C1-3-alkyl) -carbonyl; (2) 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene, represented by the formula (2):
(3) Dapagliflozin, represented by formula (3):
(4) Canagliflozin, represented by the formula (4):
(5) Empagliflozin, represented by the formula (5):
(6) Luseogliflozina, represented by the formula (6):
(7) Tofogliflozina, represented by the formula (7):
(8) Ipragliflozin, represented by the formula (8):
(9) Ertugliflozin, represented by the formula (9):
(10) Atigliflozin, represented by the formula (10):
(11) Remogliflozin, represented by the formula (11):
(12) a thiophene derivative of formula (12)
wherein R means methoxy or trifluoromethoxy; (13) 1 - (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene described in WO 2005/012326, represented by formula (13);
(14) a spirocetal derivative of formula (14):
wherein R stands for methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert-butyl; (15) a pyrazole-O-glucoside derivative of formula (15)
wherein R1 means C1-3-alkoxy, L1, L2 independently of each other means H or F, R6 means H, (C1-3-alkyl) carbonyl, (C1-6-alkyl) oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl; (16) a compound of formula (16):
(17) and Sergliflozina, represented by the formula (17):

[00058] The term "dapagliflozin" as used in this report refers to the dapagliflozin of the above structure as well as the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods for its synthesis are described in WO 03/099836, for example. Preferred hydrates, solvates and crystalline forms are described in patent applications WO 2008/116179 and WO 2008/002824, for example.
[00059] The term "canagliflozin" as used in this report refers to the canagliflozin of the above structure as well as the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods for its synthesis are described in WO 2005/012326 and WO 2009/035969, for example. Preferred hydrates, solvates and crystalline forms are described in patent application WO 2008/069327, for example.
[00060] The term "empagliflozin" as used in this report refers to the empagliflozin of the above structure as well as the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods for its synthesis are described in WO 2005/092877, WO 2006/120208 and WO 2011/039108, for example. A preferred crystalline form is described in patent applications WO 2006/117359 and WO 2011/039107, for example.
[00061] The term "atigliflozin" as used in this report refers to the atigliflozin of the above structure as well as the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods for its synthesis are described in WO 2004/007517, for example.
[00062] The term "ipragliflozin" as used in this report refers to the ipragliflozin of the above structure as well as to the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods for its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475, for example.
[00063] The term "tofogliflozina" as used in this report refers to the tofogliflozina of the above structure as well as to the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound and methods for its synthesis are described in WO 2007/140191 and WO 2008/013280, for example.
[00064] The term "luseogliflozina" as used in this report refers to the luseogliflozin of the above structure as well as to the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof.
[00065] The term "ertugliflozin" as used in this report refers to the ertugliflozin of the above structure as well as the pharmaceutically acceptable forms thereof, including hydrates and solvates thereof, and crystalline forms thereof. The compound is described, for example, in WO 2010/023594.
[00066] The term "remogliflozin" as used in this report refers to the remogliflozin of the above structure as well as the pharmaceutically acceptable forms thereof, including remogliflozin prodrugs, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms of the same. Methods for their synthesis are described in patent applications EP 1 213 296 and EP 1 354 888, for example.
[00067] The term "sergliflozin" as used in this report refers to sergliflozin of the above structure as well as to pharmaceutically acceptable forms thereof, including sergliflozin prodrugs, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms of the same. Methods for their production are described in patent applications EP 1 344 780 and EP 1 489 089, for example.
[00068] The compound of formula (16) above and its production are described, for example, in WO 2008/042688 or WO 2009/014970.
[00069] Preferred SGLT2 inhibitors are derived from benzene substituted with glucopyranosyl. Optionally, one or more hydroxyl groups of the glucopyranosyl group in such one or more SGLT2 inhibitors can be acylated with groups selected from (C1-18-alkyl) carbonyl, (C1-18-alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C1- 3-alkyl) -carbonyl.
[00070] Most preferred are derivatives of the benzonitrile type substituted with glucopyranosyl of formula (1) already described above. Even more preferred are derivatives of the benzonitrile type substituted with glucopyranosyl of formula (18):
where R3 stands for 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, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydrofuran-3-yloxy or cyano (where R3 is preferably selected from cyclopropyl ethyl, ethynyl, ethoxy, (R) -tetrahydrofuran-3-yloxy or (S) -tetrahydro drofuran-3-yloxy; and R3 even more preferably is cyclopropyl, or a derivative thereof where one or more hydroxyl groups from the β-D-glucopyranosyl group are acylated with groups selected from (C1-18-alkyl) carbonyl, (C1-18-alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C1-3-alkyl) -carbonyl.
[00071] Preferably, such a SGLT2 inhibitor is 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene shown in formula (2) (in this report also called “Compound A”). Optionally, one or more hydroxyl groups of the β-D-glucopyranosyl group of compound A can be acylated with groups selected from (C1-18-alkyl) carbonyl, (C1-18-alkyl) oxycarbonyl, phenylcarbonyl and phenyl- (C1-3 -alkyl) -carbonyl.
[00072] Therefore, in preferred embodiments, an SGLT2 inhibitor according to the present invention is an SGLT2 inhibitor of the type derived from benzopyranyl substituted with glucopyranosyl, preferably an SGLT2 inhibitor of formula (1), more preferably of formula (18) ), or even more preferably of formula (2) (ie, compound A), in each case as already defined above. Metabolic disorders
[00073] The metabolic disorder can be diabetes, pre-diabetes, obesity and / or any disorder, disease, condition or symptom associated with one or more of these disorders. In particular, the metabolic disorder may be hyperglycemia, insulin resistance, diabetes and / or liver lipidosis. Other relevant metabolic disorders include hyperinsulinemia, impaired glucose tolerance, ketosis (in particular ketoacidosis), hyperlipidaemia, high blood levels of fatty acids and / or glycerol, syndrome X (metabolic syndrome), atherosclerosis, inflammation of the pancreas, inflammation of adipose tissue and / or loss of pancreatic beta cell function.
[00074] In some embodiments, the metabolic disorder is diabetes. In this report, diabetes can be pre-diabetes, type 1 diabetes mellitus or type 2 diabetes mellitus. In particular, diabetes can be type 2 diabetes mellitus. In some modalities, diabetes can be associated with obesity.
[00075] In some modalities, the metabolic disorder is hyperglycemia. In this report, hyperglycemia can be associated with diabetes, for example, type 2 diabetes mellitus. In some modalities, hyperglycemia can be associated with obesity. Hyperglycemia can be chronic.
[00076] In some modalities, the metabolic disorder is insulin resistance. In this report, insulin resistance may be associated with diabetes, for example, type 2 diabetes mellitus. In some modalities, insulin resistance may be associated with obesity.
[00077] In some modalities, the metabolic disorder is impaired glucose tolerance (IGT). In this report, impaired glucose tolerance may be associated with diabetes, for example, type 2 diabetes mellitus. In some modalities, impaired glucose tolerance may be associated with obesity.
[00078] In some modalities, the metabolic disorder is hyperinsulinemia. In this report, hyperinsulinemia may be associated with diabetes, for example, type 2 diabetes mellitus. In some modalities, hyperinsulinemia may be associated with obesity.
[00079] In some embodiments, the metabolic disorder is one or more of hyperglycemia, insulin resistance, and liver lipidosis. In some modalities, the metabolic disorder is selected from hyperglycemia and insulin resistance.
[00080] In some embodiments, the metabolic disorder is one or more of hyperinsulinemia, impaired glucose tolerance, hyperglycemia and insulin resistance.
[00081] In certain modalities, the feline animal is obese. For example, according to the invention, one or more metabolic disorders selected from hyperglycemia, insulin resistance and hepatic lipidosis can be treated and / or prevented in an obese feline animal. In addition, for example, impaired hyperinsulinemia and / or impaired glucose tolerance can be treated and / or prevented in an obese feline animal. In addition, one or more disorders selected from ketosis (in particular ketoacidosis), hyperlipidaemia, high blood levels of fatty acids and / or glycerol, syndrome X (metabolic syndrome), atherosclerosis, inflammation of the pancreas, inflammation of adipose tissue and loss of pancreatic beta cell function can be treated and / or prevented in an obese feline animal.
[00082] In certain embodiments, the feline animal suffers from diabetes, for example, type 2 diabetes mellitus. For example, according to the invention, one or more metabolic disorders selected from the group of hyperglycemia, insulin resistance and liver lipidosis can be treated and / or prevented in a feline animal suffering from diabetes, for example, type 2 diabetes mellitus. In addition, for example, hyperinsulinemia and / or impaired glucose tolerance can be treated and / or prevented in a feline animal that suffer from diabetes, for example, type 2 diabetes mellitus. In addition, one or more disorders selected from ketosis (in particular ketoacidosis), hyperlipidaemia, high blood levels of fatty acids and / or glycerol, syndrome X (metabolic syndrome), atherosclerosis, inflammation of the pancreas, inflammation of adipose tissue and loss of pancreatic beta cell function can be treated and / or prevented in a feline animal suffering from diabetes, for example diabetes m type 2 elite.
[00083] In some modalities, the feline animal is obese and suffers from diabetes, for example, type 2 diabetes mellitus. In some modalities, the feline animal suffers from diabetes, for example, type 2 diabetes mellitus but is not obese. In some modalities, the feline animal is obese and does not suffer from diabetes.
[00084] The present invention also offers the use of one or more SGLT2 inhibitors, preferably compound A, for the treatment and / or prevention of pancreatic beta cell degeneration. For example, increasing the mass of pancreatic beta cells, and / or improving and / or restoring the functionality (i.e., insulin secretion) of pancreatic beta cells in a feline animal.
[00085] Ketosis is a state of high levels of ketone bodies in the body. Ketoacidosis can be described as a type of metabolic acidosis that is caused by high concentrations of ketone bodies, formed by the decomposition of fatty acids and the deamination of amino acids. The two common ketones produced in humans are acetoacetic acid and β-hydroxybutyrate. In cats, predominantly three ketones are found: acetoacetic acid, beta-hydroxybutyrate and pyruvic acid. Ketoacidosis can be felt on an individual's breath. This is due to acetone, a direct by-product of spontaneous decomposition of acetoacetic acid.
[00086] Ketoacidosis is an extreme and uncontrolled form of ketosis. Ketosis is also a normal response to prolonged fasting. In ketoacidosis, the body fails to properly regulate ketone production, especially by producing Acetyl-CoA, causing an accumulation of keto acids so severe that the pH of the pH is substantially lowered, i.e., excess ketone bodies can significantly acidify the blood. In extreme cases, ketoacidosis can be fatal.
[00087] Ketoacidosis can occur when the body produces high levels of ketone bodies via fatty acid metabolism (ketosis) and insulin does not sufficiently slow down this production (for example, due to insulin resistance / reduced insulin sensitivity). The presence of high blood sugar levels (hyperglycemia) caused by a lack of insulin can lead to increased acidity in the blood. In healthy individuals this is usually not the case because the pancreas produces insulin in response to rising levels of ketone / blood sugar.
[00088] Ketoacidosis is more common in untreated diabetes mellitus, when the liver breaks down fat and proteins in response to a perceived need for a respiratory substrate.
[00089] Pre-diabetes in feline animals is characterized by hyperinsulinemia, insulin resistance in target organs, impaired glucose tolerance including, for example, an altered insulin response to a glycemic challenge, for example, also, for example, induced by stress. Pre-diabetes is also often associated with obesity. Pre-diabetes can also be associated with intermittent hyperglycemia.
[00090] Type 2 diabetes in feline animals is characterized by both reduced insulin production and insulin resistance in target organs. Reduced insulin production can, for example, be caused by accumulation of amyloid in β cells, glucose toxicity and / or infections in the pancreas. The defect in beta cell function is usually progressive, and in some feline animals it results in complete loss of insulin secretion. Genetic factors glycosteroids, progesterone, lack of exercise, and obesity are possible reasons for insulin resistance. For example, in healthy cats, insulin sensitivity decreases by 50% after a weight gain of> 40%. Diabetic cats are believed to have mainly type 2, based on the fact that most diabetic cats have amyloid in their islets, which has been called the type 2 diabetes brand.
[00091] Only a substantial minority of cats are believed to have a secondary form of diabetes mellitus.
[00092] Clinical signs of diabetes mellitus seen in feline animals include polydipsia, polyuria, weight loss, and / or polyphagia. In cats, anorexia is most often described as polyphagia. Pathognomonic for diabetes mellitus in cats is a plantigrade posture (weakness in the hind legs, hocks touch the ground when the cat walks). This is caused by diabetic neuropathy.
[00093] Other particularly relevant clinical signs of diabetes mellitus in feline animals within the context of the present invention are hyperglycemia and glucosuria. Hyperglycemia in a feline animal (for example, a cat) is caused by plasma glucose values above normal values (3.9 - 8.3 mmol / l or 70 - 150 mg / dl), for example 8 mmol / l or more or 150 mg / dl or more of plasma glucose. Glucosuria in a feline animal (for example, a cat) is defined as urine glucose levels above normal values (0 ~ 2 mmol / L, or 36 mg / dl). The renal threshold is reached with blood glucose concentrations of approximately 11 - 17 mmol / l or 200 to 300 mg / dl.
[00094] The diagnosis of diabetes mellitus in feline animals can alternatively be based on three criteria, for example, as follows: (1) Measurements of fasting blood glucose concentration> 250 mg / dl; (2) Glucosuria already defined above; and (3) One or more of the following: polyuria, polydipsia, polyphagia, weight loss despite good appetite, or ketonuria (without signs of severe ketoacidosis).
[00095] In addition to the diagnoses mentioned above and to support them, additional tests may include hematology, blood chemistry, X-rays and / or abdominal ultrasound.
[00096] Preferably, the use of one or more SGLT2 inhibitors, preferably compound A, according to the invention allows normal or near normal blood glucose concentrations to be maintained and / or established. However, - unlike human therapy - it is not believed that this is always necessary for diabetic animals and, therefore, is not always the aim of treatment according to the invention. According to the invention, blood glucose concentrations can also be maintained, for example, between 5.5 and 16.6 mmol / l or 100 and 300 mg / dl. For feline animals these will generally be satisfactory.
[00097] An objective of the treatment of pre-diabetes or diabetes in feline animals according to the invention can be the elimination of signs observed by the owner (for example, lethargy, polyuria, polydipsia, weight loss, polyphagia, etc.) that occur secondary to hyperglycemia in untreated animals. Other treatment goals or treatment effects may be one or more of any of the advantageous effects of the invention described in this report, including, but not limited to, any or more of improved glucose tolerance, increased insulin sensitivity, insulin resistance reduced glucose excursion in an ivITT, improved insulin excursion in an ivGTT or in an oral glucose tolerance test (OGTT), reduced insulin secretion in the second phase, reduced levels of body fat, body mass, and / or blood leptin, a reduced respiratory exchange ratio (RER), and / or the absence of weight gain in the case of an obese animal.
[00098] Diabetic remission is used in cats when normal (or almost normal) blood glucose concentrations are reached, clinical signs have improved and insulin administration can be suspended or not used for at least four consecutive weeks. However, the viability of pancreatic beta cells may not have been fully recovered. The use of one or more SGLT2 inhibitors, preferably compound A, and therefore the reduction of blood glucose levels and an improvement in insulin resistance and pancreatic beta cell function is putatively of crucial relevance to achieve and maintain the remission of diabetes in a feline animal.
[00099] Insulin resistance can be described as the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin resistance in fat cells reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides in the absence of measures that either increase insulin sensitivity or provide additional insulin. The increased mobilization of lipids stored in these cells elevates the free fatty acids in the blood plasma. Insulin resistance in muscle cells reduces glucose absorption (and thus local storage of glucose as glycogen), while insulin resistance in liver cells results in impaired glycogen synthesis and a failure to suppress the production of glucose. Elevated levels of fatty acids in the blood, reduced absorption of muscle glucose, and increased production of hepatic glucose can all contribute to elevated blood glucose levels (hyperglycemia).
[000100] Substitute insulin sensitivity indices can be calculated according to QUICKI (quantitative insulin sensitivity verification index: 1 / log (glucose * insulin)) for baseline blood level. For dynamic tests, for example, during a glucose challenge, a modified Belfiore index (1 / log (DAUC-glucose * DAUC-insulin)) can be used.
[000101] Insulin resistance may be present associated with obesity, visceral adiposity, hypertension and dyslipidemia involving high triglycerides, small and dense low-density lipoprotein (sdLDL) particles, and decreased levels of HDL cholesterol. With regard to visceral adiposity, a large amount of evidence in humans suggests two strong links to insulin resistance. First, unlike subcutaneous adipose tissue, visceral fat cells produce significant amounts of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), and interleukins-1 and -6, etc. In numerous experimental models, these proinflammatory cytokines deeply disrupt the normal action of insulin in fat and muscle cells, and can be an important factor in causing insulin resistance in the entire body seen in human patients with visceral adiposity. Similarly, in cats, excess fat deposits contribute to low-grade systemic inflammation. The cause of the vast majority of cases of insulin resistance remains unknown. There is clearly a hereditary component. However, there are some grounds for suspecting that insulin resistance is related to a high-carbohydrate diet. Inflammation also appears to be involved in causing insulin resistance.
[000102] Hyperinsulinemia can be described as a condition in which there are excessive levels, ie, more than about 35 pmol / L sub-basal ("under basal") or about 200 pmol / L during, for example, a glycemic challenge (eg ivGTT or stress) of insulin circulating in the blood. As mentioned, it is commonly present in cases of, and may be a consequence of, insulin resistance in feline animals.
[000103] Impaired glucose tolerance can be described as a condition in which the response to after a glycemic challenge, for example, after a meal or after a load test (glucose tolerance test) or after an elevation stress-induced blood glucose concentration, the glycemic peak of the glucose excursion / e higher and / or the duration of the glucose excursion is prolonged.
[000104] Dyslipidemia or hyperlipidemia is the presence of increased or abnormal levels of lipids and / or lipoproteins in the blood. Abnormalities in lipids and lipoproteins are considered to be a highly modifiable risk factor for cardiovascular disease due to the influence of cholesterol. Glycerol is a precursor for the synthesis of triacylglycerols (triglycerides) and phospholipids in the liver and adipose tissue. When the body uses stored fat as an energy source, glycerol and fatty acids are released into the bloodstream after triglyceride hydrolysis. The glycerol component can be converted to glucose by the liver and provides energy for cellular metabolism. Normal levels of free fatty acids in the blood of pets (such as felines) are concentrations of triglycerides from 50 to 100 mg / dl (0.6 to 1.2 mmol / l). Normal blood cholesterol levels are, for example, 70–150 mg / dl for cats.
[000105] Dysadipokinemia can be described as a condition in which circulating plasma levels of biologically active substances produced in adipose tissue that act in an autocrine / paracrine or endocrine manner are shifted, for example, an increase in leptin and / or a reduction in adiponectin .
[000106] Subclinical inflammation or systemic inflammation, in particular low-grade systemic inflammation, is characterized by increased expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha and / or alpha factor and / or expression and secretion lower anti-inflammatory cytokines, for example, interleukin-10 and / or their respective receptors.
[000107] Obesity can be described as a medical condition in which excess body fat has accumulated to the point where it can have an adverse effect on health, leading to reduced life expectancy. In obese cats, for example, a body condition score (BCS) greater than 6 (out of 9) is found.
[000108] Metabolic disorders to be treated and / or prevented according to the invention include syndrome X (metabolic syndrome). This disorder can be described as a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes. Metabolic syndrome is also known as metabolic syndrome X (metabolic syndrome), syndrome X (metabolic syndrome), insulin resistance syndrome, Reaven syndrome, and CHAOS (an abbreviation for coronary artery disease, hypertension, atherosclerosis, obesity, and stroke ).
[000109] The exact mechanisms of the complex pathways of the metabolic syndrome are not yet fully understood. Pathophysiology is extremely complex and has only been partially elucidated. Most patients are elderly, obese, sedentary, and have a degree of insulin resistance. The most important factors, in order, are: (1) overweight and obesity, (2) genetics, (3) old age, and (4) physical inactivity, i.e., little physical activity and excess caloric intake.
[000110] Another risk factor is diabetes mellitus. At least in humans, the vast majority (~ 75%) of patients with type 2 diabetes or impaired glucose tolerance (IGT) have metabolic syndrome.
[000111] Pathophysiology is commonly characterized by the development of visceral fat and thereafter the adipocytes (fat cells) of visceral fat increase the plasma levels of TNF-alpha and alter the levels of numerous other substances (for example, adiponectin, resistin , PAI-1). It has been shown that TNF-alpha not only causes the production of inflammatory cytokines, but possibly triggers cell signaling by interacting with a TNF-alpha receptor that can lead to insulin resistance.
[000112] The current first-line treatment is lifestyle change (i.e., calorie restriction and physical activity). However, drug treatment is often necessary. Individual disorders that contribute to the metabolic syndrome can be treated separately. Diuretics and ACE inhibitors can be used to treat hypertension. Cholesterol drugs can be used to lower levels of LDL cholesterol and triglycerides, if they are high, and to increase HDL levels if they are low. Such treatments can be combined with the use of one or more SGLT2 inhibitors, preferably compound A, according to the present invention.
[000113] Metabolic disorders to be treated and / or prevented according to the invention include inflammation of the pancreas (pancreatitis). This disorder occurs either as an acute form or as a chronic form. Chronic pancreatitis can occur with or without steatorrhea and / or diabetes mellitus.
[000114] Pancreatitis can be caused by hypertriglyceridemia (in particular when triglyceride values exceed 1500 mg / dl (16 mmol / l), hypercalcemia, viral infection, trauma, vasculitis (ie, inflammation of small blood vessels in the pancreas), and autoimmune pancreatitis.
[000115] Metabolic disorders, especially dyslipidemia and elevated serum triglyceride levels, are risk factors for the development of pancreatitis, and can therefore be treated according to the present invention in association with pancreatitis. Therefore, the present invention also offers the prevention of pancreatitis. Therefore, the present invention also offers pancreatitis.
[000116] Metabolic disorders to be treated and / or prevented according to the invention include an inflammation of the adipose tissue (panniculitis), which is a group of disorders characterized by inflammation of the subcutaneous adipose tissue.
[000117] Panniculitis can occur in any adipose tissue (cutaneous and / or visceral). It can be diagnosed by means of a deep skin biopsy, and it can be further classified by histological characteristics based on the location of inflammatory cells (within fat lobules or in the septum that separates them) and in the presence or absence of vasculitis. Panniculitis can also be classified based on the presence or absence of systemic symptoms.
[000118] Metabolic disorders, especially pancreatitis, are risk factors for the development of panniculitis and can therefore be treated according to the present invention in association with panniculitis. Therefore, the present invention also offers the prevention of panniculitis. Feline animals
[000119] In this report, a feline animal is a member of the Felidae family (i.e., a felid). It can, therefore, belong to the feline subfamily or to the pantherino subfamily. The term feline animal encompasses the term cat, for example, a domestic cat. The term domestic cat encompasses the terms Felis catus and Felis silvestris catus. Pharmaceutically acceptable forms
[000120] In this report, references made to SGLT2 inhibitors and / or their use according to the invention cover pharmaceutically acceptable forms of SGLT2 inhibitors, unless otherwise specified.
[000121] According to the invention, any pharmaceutically acceptable form of the SGLT2 inhibitor, for example, of formula (1), preferably of formula (18), more preferably of formula (2), can be used. For example, a crystalline form can be used. Forms of prodrugs are also encompassed by the present invention.
[000122] Forms of prodrugs can include, for example, esters and / or hydrates. The term prodrug is also intended to include any covalently linked vehicle that releases the compound of the invention in vivo when the prodrug is administered to a mammalian individual. Prodrugs of a compound of the invention can be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound of the invention.
[000123] Crystalline forms for use according to the invention include a complex of an SGLT2 inhibitor with one or more amino acids (see, for example, WO 2014/016381). An amino acid for such use can be a natural amino acid. The amino acid can be a proteogenic amino acid (including L-hydroxyproline), or a non-proteogenic amino acid. The amino acid can be a D-amino acid or an L-amino acid. In some preferred embodiments the amino acid is proline (L-proline and / or D-proline, preferably L-proline). For example, a crystalline complex of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) - benzene (formula (2); compound A) with proline (for example L-proline) is preferred.
[000124] Therefore, this report discloses a crystalline complex between one or more natural amino acids and an SGLT2 inhibitor, for example, a crystalline complex between one or more natural amino acids and an SGLT2 inhibitor of the benzene-derived type substituted with glucopyranosyl, preferably an SGLT2 inhibitor of formula (1), more preferably of formula (18) or even more preferably of formula (2) (compound A). Therefore, this report discloses a crystalline complex between one or more natural amino acids and 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene (compound A ).
[000125] Still disclosed in this report is the use of one or more crystalline complexes defined above or further for the preparation of a pharmaceutical composition that is suitable for the treatment and / or prevention of diseases or conditions that may be influenced by inhibition of the sodium-dependent glucose cotransporter SGLT, preferably SGLT2. Also disclosed in this report is the use of one or more crystalline complexes defined above or later for the preparation of a pharmaceutical composition for inhibitor of the sodium-dependent glucose cotransporter SGLT2.
[000126] A crystalline complex between one or more natural amino acids (e.g., proline, preferably L-proline) and an SGLT2 inhibitor, is a preferred pharmaceutically acceptable form of an SGLT2 inhibitor for use in accordance with the present invention. In particular, a crystalline complex between one or more natural amino acids (e.g., proline, preferably L-proline) and a glucopyranosyl-substituted benzene-substituted SGLT2 inhibitor, preferably a SGLT2 inhibitor of formula (1), more preferably of formula (18) or even more preferably of formula (2) (compound A) is a preferred pharmaceutically acceptable form of an SGLT2 inhibitor for use in accordance with the present invention. A crystalline complex between one or more natural amino acids (for example, proline, preferably L-proline) and 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene (compound A) is particularly preferred as a pharmaceutically acceptable form of an SGLT2 inhibitor for use in accordance with the present invention.
[000127] Also disclosed in this report is a method for making one or more crystalline complexes defined above and further, said method comprising the following steps: (a) preparing a solution of the SGLT2 inhibitor (for example, a derivative of benzene substituted with glucopyranosyl, or an SGLT2 inhibitor of formula (1), preferably of formula (18) or more preferably of formula (2), ie, compound A) and the one or more natural amino acids in a solvent or mixture of solvents; (b) storing the solution so that the crystalline complex precipitates out of the solution; (c) removing the precipitate from the solution; and (d) optionally drying the precipitate until all excess of said solvent or mixture of solvents has been removed.
[000128] A certain pharmaceutical activity is the basic prerequisite to be fulfilled by a pharmaceutically active agent before it is approved as a medicine on the market. However, there are several additional requirements that must be met by a pharmaceutically acceptable agent. These requirements are based on several parameters that are connected with the nature of the active substance itself. Without limitation, examples of these parameters are the stability of the active agent in various environmental conditions, its stability during the production of the pharmaceutical formulation and the stability of the active agent in the final drug compositions. The pharmaceutically active substance used to prepare the pharmaceutical compositions must be as pure as possible and its stability in prolonged storage must be guaranteed under various environmental conditions. This is essential to prevent the use of pharmaceutical compositions that contain, in addition to the effective active substance, its decomposition products, for example. In such cases the content of active substance in the medication is possibly less than specified.
[000129] The uniform distribution of the drug in the formulation is a critical factor, particularly when the drug needs to be given in low doses. To ensure uniform distribution, the particle size of the active substance can be reduced to a suitable level, for example, by grinding. Since the decomposition of the pharmaceutically active substance as a side effect of crushing (or micronisation) has to be avoided as much as possible, rather than the strict conditions required during the process, it is essential that the active substance is highly stable throughout the grinding process. Only if the active substance is sufficiently stable during the grinding process will it be possible to produce a homogeneous pharmaceutical formulation that always contains the specified amount of active substance in a reproducible way.
[000130] Another problem that may arise in the grinding process to prepare the desired pharmaceutical formulation is the energy input caused by this process and the stress on the surface of the crystals. This can, in certain circumstances, lead to polymorphic changes, amorphization or a change in the crystalline network. As the pharmaceutical quality of a pharmaceutical formulation requires that the active substance always have the same crystalline morphology, the stability and properties of the crystalline active substance are subject to strict requirements from this point of view as well.
[000131] The stability of a pharmaceutically active substance is also important in pharmaceutical compositions for determining the shelf life of the particular drug; shelf life is the length of time during which the drug can be administered without any risk. The high stability of a drug in the pharmaceutical compositions mentioned above under various storage conditions is therefore an additional advantage for both the patient and the manufacturer.
[000132] Moisture absorption reduces the content of pharmaceutically active substance as a result of the increased weight caused by water absorption. Pharmaceutical compositions with a tendency to absorb moisture need to be protected from moisture during storage, for example, by adding suitable drying agents or by storing the drug in an environment in which it is protected from moisture. Preferably, therefore, a pharmaceutically active substance should be, at best, slightly hygroscopic.
[000133] In addition, the availability of a well-defined crystalline form allows the purification of the drug substance by recrystallization.
[000134] In addition to the requirements indicated above, it should generally be borne in mind that any change in the solid state of a pharmaceutical composition that is capable of improving its physical and chemical stability provides a significant advantage over less stable forms of the same drug.
[000135] A crystalline complex between a natural amino acid and an SGLT2 inhibitor (for example, a benzopy derivative substituted with glucopyranosyl or an SGLT2 inhibitor of formula (1), or of formula (18) or, particularly, of formula ( 2), ie, compound A) fulfills important requirements mentioned above.
[000136] Preferably, the natural amino acid is present in its enantiomeric (D) or (L) form, even more preferably as the (L) enantiomer.
[000137] Furthermore, those crystalline complexes according to this invention which are formed between the SGLT2 inhibitor (for example, of formula (1), preferably of formula (18) or, particularly, of formula (2), are preferred, ie, compound A) and a natural amino acid, even more preferably between compound A and the enantiomer (L) of a natural amino acid.
[000138] Preferred amino acids according to this invention are selected from the group consisting of phenylalanine and proline, in particular (L) -proline and (L) -phenylalanine.
[000139] According to a preferred embodiment, the crystalline complex is characterized by the fact that the natural amino acid is proline, in particular (L) -proline.
[000140] Preferably, the molar ratio between the SGLT2 inhibitor (for example, of formula (1), preferably of formula (18) or, particularly, of formula (2), ie, compound A) and the natural amino acid varies in range from about 2: 1 to about 1: 3; more preferably from about 1.5: 1 to about 1: 1.5, even more preferably from about 1.2: 1 to about 1: 1.2, even more preferably about 1: 1. In the following, such an embodiment is called "complex ( 1: 1) "or" 1: 1 complex ".
[000141] Therefore, a preferred crystalline complex according to this invention is a complex (1: 1) between said SGLT2 inhibitor (for example of formula (1), preferably of formula (18) or, particularly, of formula ( 2), ie, compound A) and proline; in particular between said SGLT2 inhibitor and L-proline.
[000142] According to a preferred embodiment the crystalline complex, in particular the 1: 1 complex of said SGLT2 inhibitor with L-proline, is a hydrate.
[000143] Preferably the molar ratio of the crystalline complex to water ranges from about 1: 0 to 1: 3; more preferably about 1: 0 to 1: 2, even more preferably about 1: 0.5 to 1: 1.5, even more preferably about 1: 0.8 to 1: 1.2, in particular about 1: 1.
[000144] The crystalline complex of said SGLT2 inhibitor with proline, in particular with L-proline and water, can be identified and distinguished from other crystalline forms by means of its characteristic powder X-ray diffraction (XRPD) patterns.
[000145] For example, a crystalline complex of compound A with L-proline is preferably characterized by a powder X-ray diffraction pattern comprising peaks at 20.28, 21.14 and 21.64 degrees 2θ (± 0.1 degrees 2θ), where the said powder X-ray diffraction pattern is made using CuKa1 radiation.
[000146] In particular, said powder X-ray diffraction pattern comprises peaks at 4.99, 20.28, 21.14, 21.64 and 23.23 degrees 2θ (± 0.1 degree 2θ), where said powder X-ray diffraction pattern is done using CuKa1 radiation.
[000147] More specifically, said powder X-ray diffraction pattern comprises peaks at 4.99, 17.61, 17.77, 20.28, 21.14, 21.64, 23.23 and 27.66 degrees 2θ (± 0.1 degree 2θ), where said pattern of X-ray powder diffraction is done using CuKa1 radiation.
[000148] Even more specifically, said powder X-ray diffraction pattern comprises peaks at 4.99, 15.12, 17.61, 17.77,18.17, 20.28, 21.14, 21.64, 23.23 and 27.66 degrees 2θ (± 0.1 degree 2θ), where the said powder X-ray diffraction pattern is made using CuKa1 radiation.
[000149] Even more specifically, the crystalline complex of compound A and L-proline is characterized by a powder X-ray diffraction pattern, made using CuKa1 radiation, which comprises peaks at 2θ degrees (± 0.1 degree 2θ) such as those contained in Table 1. Table 1: Powder X-ray diffraction pattern of the crystalline complex of compound A and L-proline (only the peaks up to 30 ° in 2θ are listed):


[000150] Even more specifically, said crystalline complex is characterized by a powder X-ray diffraction pattern, made using CuKαi radiation, which comprises peaks at 2θ degrees (± 0.1 degree 2θ shown in Figure 11).
[000151] Furthermore, said crystalline complex of compound A with L-proline is characterized by a melting point above 89 ° C, in particular in a range of about 89 ° C to about 115 ° C, more preferably in a range of about 89 ° C to about 110 ° C (determined via DSC; rated as initial temperature; heating rate 10 K / min). It can be seen that this crystalline complex melts with dehydration. The obtained DSC curve is shown in Figure 12.
[000152] Said crystalline complex of compound A with L-proline shows a weight loss by thermal gravimetry (TG). The observed weight loss indicates that the crystalline form contains water which can be linked by absorption and / or can be part of the crystalline network, i.e., the crystalline form can be present as a crystalline hydrate. The water content in crystalline form ranges from 0 to about 10% by weight, in particular 0 to about 5% by weight, even more preferably from about 1.5 to about 5% by weight. The dotted line in Figure 2 represents a weight loss of between 2.8 and 3.8% water. From the observed weight loss, it is possible to estimate a stoichiometry close to that of a monohydrate.
[000153] Said crystalline complex has advantageous physicochemical properties that are beneficial in the preparation of a pharmaceutical composition. In particular, the crystalline complex has a high physical and chemical stability under various environmental conditions and during the production of a medicine. For example, crystals can be obtained in a particle size and shape that are particularly suitable in a production method for solid pharmaceutical formulations. In addition, the crystals show a high mechanical stability that allows the crystals to be crushed. In addition, the crystalline complex does not show a great tendency to absorb moisture and is chemically stable, i.e., the crystalline complex allows the production of a solid pharmaceutical formulation with a long shelf life. On the other hand, the crystalline complex has a favorable high solubility over a wide pH range which is advantageous in solid pharmaceutical formulations for oral administration.
[000154] X-ray powder diffraction patterns can be recorded using a STOE - STADI P diffractometer in transmission mode equipped with a location-sensitive detector (OED) and a Cu anode as an X-ray source (CuK ai radiation , À = 1.54056 Â, 40 kV, 40 mA). In Table 1 the values of "20 [°]" denote the diffraction angle in degrees and the values "d [Â]" denote the specific distances in  between the planes of the network. The intensity shown in Figure 11 is given in units of cps (counts per second).
[000155] In order to admit experimental error, the values of 2 0 described above must be considered accurate up to ± 0.1 degrees 2 0, in particular ± 0.05 degrees 2 0. That is, when evaluating whether a given sample of crystals of compound A is the crystalline form according to the values of 2 Θ described above, a value of 2 Θ that is experimentally observed for the sample will be considered identical to a characteristic value described above if it resides within ± 0.1 degrees 2 θ of the characteristic value, in particular if reside within ± 0.05 degrees 2 θ of the characteristic value.
[000156] The melting point is determined by DSC (differential scanning calorimetry) using a DSC 821 (Mettler Toledo). Weight loss is determined by thermal gravimetry (TG) using a TGA 851 (Mettler Toledo).
[000157] Also disclosed in this report is a method for making a crystalline complex defined above and further, said method comprising the following steps: (a) preparing a solution of an SGLT2 inhibitor described in this invention (for example, compound A or another SGLT2 inhibitor described in this invention) and the one or more natural amino acids in a solvent or a mixture of solvents; (b) storing the solution to precipitate the crystalline complex in the solution; (c) removing the precipitate from the solution; and (d) optionally drying the precipitate until all excess of said solvent or mixture of solvents has been removed.
[000158] According to step (a), a solution of the SGLT2 inhibitor (for example, compound A or another SGLT2 inhibitor described in this report) and the one or more natural amino acids in a solvent or mixture are prepared of solvents. Preferably, the solution is saturated or at least almost saturated or even supersaturated with respect to the crystalline complex. In step (a) the SGLT2 inhibitor can be dissolved in a solution comprising the one or more natural amino acids or the one or more natural amino acids can be dissolved in a solution comprising the SGLT2 inhibitor. According to an alternative procedure the SGLT2 inhibitor is dissolved in a solvent or mixture of solvents to give a first solution and the one or more natural amino acids are dissolved in a solvent or mixture of solvents to give a second solution. Then said first solution and said second solution are combined to form the solution according to step (a).
[000159] Preferably the molar ratio of the natural amino acid and the SGLT2 inhibitor (for example, compound A or any other SGLT2 inhibitor described in this report) in the solution corresponds to a molar ratio of the natural amino acid and the SGLT2 inhibitor in the crystalline complex to be obtained. Therefore, a preferred molar ratio ranges from about 1: 2 to 3: 1; even more preferably about 1: 1.
[000160] Suitable solvents are preferably selected from the group consisting of C1-4-alkanols, water, ethyl acetate, acetonitrile, acetone, diethyl ether, tetrahydrofuran, and mixtures of two or more of these solvents.
[000161] Most preferred solvents are selected from the group consisting of methanol, ethanol, isopropanol, water and mixtures of two or more of these solvents, in particular mixtures of one or more of said organic solvents with water.
[000162] Particularly preferred solvents are selected from the group consisting of ethanol, isopropanol, water and mixtures of ethanol and / or isopropanol with water.
[000163] If a mixture of water and one or more C1-4-alkanols is used, in particular methanol, ethanol and / or isopropanol, even more preferably ethanol, a preferred volume ratio of water: the alkanol varies in the range of about 99: 1 to 1: 99; more preferably from about 50: 1 to 1: 80; even more preferably from about 10: 1 to 1: 60.
[000164] Preferably step (a) is carried out at approximately room temperature (about 20 ° C) or at an elevated temperature of up to approximately the boiling point of the solvent or mixture of solvents used.
[000165] According to a preferred embodiment, the starting material of the SGLT2 inhibitor (for example, compound A or any other SGLT2 inhibitor described in this report) and / or one or more natural amino acids and / or the solvent and mixtures of solvents contains an amount of H2O which is at least the amount needed to form a hydrate of the SGLT2 inhibitor; in particular at least 1 mol, preferably at least 1.5 mol of water per mol of SGLT2 inhibitor. Even more preferably, the amount of water is at least 2 moles of water per mole of SGLT2 inhibitor. This means that either the SGLT2 inhibitor (for example, compound A) as a starting material or the one or more natural amino acids or said solvent or mixture of solvents, or said compounds and / or solvents in combination contain an amount of H2O as specified above. For example, and the starting material of the SGLT2 inhibitor (for example, compound A) or the natural amino acid in step (a) contains sufficient water as specified above, a water content of the solvents will not be required.
[000166] In order to reduce the solubility of the crystalline complex according to this invention in the solution, in step (a) and / or in step (b) one or more antisolvents can be added, preferably during step (a) or in start of step (b). Water is an example of a suitable anti-solvent. The amount of antisolvent is preferably chosen in order to obtain a supersaturated or saturated solution in relation to the crystalline complex.
[000167] In step (b) the solution is stored long enough to obtain a precipitate, i.e., the crystalline complex. The temperature of the solution in step (b) is approximately the same or lower than that of step (a). During storage the temperature of the solution is preferably lowered, preferably to a temperature in the range of 20 ° C to 0 ° C or even lower. Step (b) can be carried out with or without agitation. As the person skilled in the art knows, the size, shape and quality of the crystals obtained can be controlled by the time period and the temperature difference in step (b). In addition, crystallization can be induced by methods known in the literature, for example, by mechanical means such as scraping or rubbing the contact surface of the reaction vessel, for example, with a glass rod. Optionally, the (almost) saturated or supersaturated solution can be inoculated with seed crystals.
[000168] In step (c) the solvents can be removed from the precipitate by known methods such as, for example, filtration, filtration with suction, decantation or centrifugation.
[000169] In step (d) the excess of solvents is removed from the precipitate by methods known to the person skilled in the art, for example, by reducing the partial pressure of the solvents, preferably under vacuum, and / or by heating above about 20 ° C. ° C, preferably in a temperature range below 100 ° C, even more preferably below 85 ° C.
[000170] Compound A can be synthesized by methods specifically and / or generically described or cited in international application WO 2007/128749, the whole of which is incorporated herein by reference, and / or in the Examples described below. The biological properties of compound A can also be investigated in the manner described in WO 2007/128749.
[000171] A crystalline complex described in this invention is preferably employed as an active drug substance in substantially pure form, that is, essentially free of other crystalline forms of the SGLT2 inhibitor (for example, compound A). However, the invention also encompasses a crystalline complex in admixture with another crystalline form or forms. If the active drug substance is a mixture of crystalline forms, it is preferable that the substance comprises at least 50% by weight, even more preferably at least 90% by weight, even more preferably at least 95% by weight of the crystalline complex described in this invention. .
[000172] In view of its ability to inhibit SGLT activity, a crystalline complex according to the invention is suitable for use in the treatment and / or preventive treatment of conditions or diseases that may be affected by the inhibition of SGLT activity, particularly of SGLT-2 activity, in particular the metabolic disorders described in this report. The crystalline complex according to the invention is also suitable for the preparation of pharmaceutical compositions for the treatment and / or preventive treatment of conditions or diseases that can be affected by the inhibition of SGLT activity, particularly SGLT-2 activity, in in particular the metabolic disorders described in this report. A crystalline complex described in this report (in particular compound A with a natural amino acid, for example, proline, particularly L-proline) is also suitable for use in the treatment of felines. Pharmaceutical compositions and formulations
[000173] SGLT2 inhibitors for use according to the invention can be prepared as pharmaceutical compositions. They can be prepared as formulations or as liquid formulations. In either case, they are preferably prepared for oral administration, preferably in liquid form for oral administration. However, SGLT2 inhibitors can also be prepared, for example, for parenteral administration.
[000174] Solid formulations include tablets, granular forms, and other solid forms such as suppositories. Among solid formulations, tablets and granular forms are preferred.
[000175] Pharmaceutical compositions in the context of the present invention can comprise a SGLT2 inhibitor according to the present invention and one or more excipients. Any excipient that enables, or supports, the intended medical effect can be used. Such excipients are available to the person skilled in the art. Useful excipients are, for example, non-stick (used to reduce the adhesion between the powder (granules) and the faces of the sack and thus prevent sticking to the sacks for tablets), binders (binders in solution or dry binders that hold the ingredients together ), coatings (to protect the tablet's ingredients from deteriorating by moisture in the air and to make large or unpleasant-tasting tablets easy to swallow), disintegrating (to allow the tablet to break when diluted), fillers, thinners, flavors , colors, glidants (flow regulators - to promote powder flow by reducing friction and interparticle cohesion), lubricants (to prevent ingredients from clumping together and sticking to pill capsules or capsule filling machines), condoms , adsorbents, sweeteners, etc.
[000176] The formulations according to the invention, for example, solid formulations, can comprise vehicles and / or disintegrants selected from the group of sugars and sugar alcohols, for example, mannitol, lactose, starch, cellulose, microcrystalline cellulose and derivatives of cellulose, for example, methyl cellulose, among others.
[000177] Manufacturing procedures for formulations suitable for feline animals are known in the literature, and for solid formulations they comprise, for example, direct compression, dry granulation and wet granulation. In the direct compression process, the active ingredient and all other excipients are placed together in a compression device that is applied directly to pressing tablets from this material. The resulting tablets can then be optionally coated in order to be physically and / or chemically protected, for example, by a material known in the art.
[000178] A unit for administration, for example, an individual liquid dose or a unit of a solid formulation, for example, a tablet, can comprise 0.1 mg to 10 mg, or for example 0.3 mg to 1 mg, 1 mg to 3 mg, 3 mg to 10 mg; or 5 to 2500 mg, or for example 5 to 2000 mg, 5 mg to 1500 mg, 10 mg to 1500 mg, 10 mg to 1000 mg, or 10-500 mg of an SGLT2 inhibitor for use according to the invention. As will be understood by the person skilled in the art, the content of the SGLT2 inhibitor in a solid formulation, or in any formulation disclosed in this report for administration to a feline animal, can be increased or decreased as appropriate in proportion to the body weight of the feline animal to be treated .
[000179] In one embodiment, a pharmaceutical composition for use according to the invention is designed for oral or parenteral administration, preferably for oral administration. Especially oral administration is improved by excipients that modify the smell and / or haptic properties of the pharmaceutical composition for the target patient, for example, as described.
[000180] When the SGLT2 inhibitor for use according to the invention is formulated for oral administration, it is preferable that the excipients confer properties, for example, palatability and / or chewability, that leave the formulation suitable for administration to a feline animal.
[000181] Also preferred are liquid formulations. Liquid formulations can be, for example, solutions, syrups or suspensions. They can be administered directly to the feline animal or can be mixed with the feline animal's food and / or drink (eg drinking water, or the like). An advantage of a liquid formulation (similar to a formulation in granular form), is that such a dosage form allows for precise dosing. For example, the SGLT2 inhibitor can be accurately dosed in proportion to the body mass of a feline animal. Typical compositions of liquid formulations are known to the person skilled in the art. Dosing and administration
[000182] The person skilled in the art can determine the appropriate doses for the uses of the present invention. Preferred dosage units include mg / kg, i.e., mg of SGLT2 inhibitor per body weight of the feline animal. An SGLT2 inhibitor of the invention can, for example, be administered in doses of 0.01-5 mg / kg per day, for example 0.01-4 mg / kg, for example 0.01-3 mg / kg, for example 0.01-2 mg / kg kg, for example 0.01-1.5 mg / kg, for example, 0.01-1 mg / kg, for example 0.01-0.75 mg / kg, for example 0.01-0.5 mg / kg, for example 0.01-0.4 mg / kg, for example 0.01-0.4 mg / kg daily; or 0.1 to 3.0 mg / kg per day, preferably from 0.2 to 2.0 mg / kg per day, more preferably from 0.1 to 1 mg / kg per day. In another preferred embodiment, the dose is 0.02-0.5 mg / kg per day, more preferably 0.03-0.4 mg / kg per day, for example 0.03-0.3 mg / kg per day.
[000183] The person skilled in the art is able to prepare an SGLT2 inhibitor of the invention for administration according to a desired dose.
[000184] Preferably, according to the invention, an SGLT2 inhibitor is administered at most three times a day, more preferably at most twice a day, even more preferably only once a day. The frequency of administration can be adapted to the typical feeding rate of the feline animal.
[000185] According to the invention, an SGLT2 inhibitor must be administered in such a way that an appropriate concentration of SGLT2 inhibitors in blood plasma is achieved (for example, a maximum concentration in blood plasma, or a concentration in blood plasma after a given period of time, for example, 4, 8, 12 or 24 hours after oral administration, preferably about 8 hours after oral administration). For example, for compound A, the concentration in blood plasma (for example, maximum concentration in blood plasma or concentration in blood plasma after the said period of time given after oral administration) can vary in the range of 2 to 4000 nM, for example example 20 to 3000, or for example 40 to 2000 nM.
[000186] Preferably, subsequent to the administration and the time required for an SGLT2 inhibitor to reach the bloodstream, such levels are maintained in the blood for a period of time of at least 12 hours, more preferably at least 18 hours, even more preferably at least 24 hours.
[000187] Preferably, according to the invention, an SGLT2 inhibitor is administered orally, in liquid or solid form. The SGLT2 inhibitor can be administered directly through the animals' mouths (for example, using a syringe, preferably a syringe graduated in body weight) or together with the animal's food or drink (for example, with its drinking water or similar), in each case preferably in liquid form. The SGLT2 inhibitor can, however, also be administered, for example, parenterally, or by any other route of administration, for example, rectally.
[000188] The SGLT2 inhibitor can be used alone or in combination with another drug. In some embodiments, one or more SGLT2 inhibitors, preferably compound A, is used in combination with one or more other oral anti-hyperglycemic drugs. When the SGLT2 inhibitor is used in combination with another drug, the SGLT2 inhibitor and any other drug can be administered simultaneously, in sequence (in any order), and / or according to a chronologically scaled dosing regimen. In such embodiments, when another drug for administration combined with an SGLT2 inhibitor or is not administered simultaneously with an SGLT2 inhibitor, the SGLT2 inhibitor and any other drug are preferably administered within a period of at least 2 weeks, 1 month. , 2 months, 4 months, 6 months or more, for example 12 months or more.
[000189] In some embodiments the SGLT2 inhibitor (whether used alone or in combination with another drug) is not used in combination with 1 - [(3-cyano-pyridin-2-yl) methyl] -3-methyl- 7- (2-butin-1-yl) -8- [3- (R) -amino-piperidin-1-yl] -xanthine or a pharmaceutically acceptable salt thereof, ie, the feline animal is not treated with said compound. In some embodiments the SGLT2 inhibitor is not used in combination with a DPP-IV inhibitor, i.e., the feline animal is not treated with a DPP-IV inhibitor.
[000190] In some embodiments, the SGLT2 inhibitor is used as a monotherapy, ie, a single therapy, ie, no other medication is administered to the feline animal for the treatment or prevention of the same metabolic disorder, ie, the metabolic disorder for which the SGLT2 inhibitor is administered. For example, no other medication is administered to the feline animal for the treatment or prevention of the same metabolic disorder within a period of at least 2, 3, or 4 weeks before and after the administration of the SGLT2 inhibitor. Brief Description of the Figures
[000191] Figure 1 shows the correlation between the plasma level of compound A and the excretion of glucose in the urine normalized to creatinine (gluc / crea). There is a clear logarithmic-linear relationship.
[000192] Figure 2 shows blood glucose profiles and insulin secretion in an intravenous glucose tolerance test (ivGTT) of normal lean cats according to Hoenig (Mol Cell Endocrinol 2002, 197 (1-2): 221-229 ) (iv GTT [1g / kg]) and insulin-resistant obese cats before (dotted line - pre-tests, “pre”) and after 4 weeks of treatment with compound A (solid line). The increased and prolonged second phase of the insulin-resistant obese cats used in the present study was significantly improved by treatment with compound A.
[000193] Figure 3 shows values of the area under the curve (AUC) of insulin in the blood and a substitute insulin sensitivity index (insulin-to-blood ratio for glucose expressed by the modified Belfiore index) in insulin-resistant cats during a test of intravenous glucose tolerance (ivGTT) before (“pre”) and after (“post”) 4 weeks of treatment with compound A or its vehicle (“control”). Treatment with compound A leads to a significant reduction in insulin AUC (panel A), and significantly improved insulin sensitivity (panel B).
[000194] Figure 4 shows time periods of blood glucose concentrations [mmol / L] after insulin challenge in insulin resistant cats during an intravenous insulin tolerance test (ivITT) before (dotted line - pretest) , “Pre”) and after 4 weeks of treatment (full line) with compound A or its vehicle (“control”). In untreated animals (controls), insulin sensitivity (IS) decreased throughout the study (panel A). In comparison, treatment with compound A was associated with a significant improvement in SI (panel B).
[000195] Figure 5 shows time periods of non-esterified fatty acid (NEFA) levels in the blood [mEq / L] after insulin challenge in insulin-resistant cats during an ivITT before (dotted line - pre-tests, “ pre ”) and after 4 weeks of treatment (full line) with compound A or its vehicle (“ control ”). In untreated animals (controls), NEFA elimination significantly worsened throughout the study period (panel A), while it was significantly improved by treatment with compound A (panel B).
[000196] Figure 6 shows that leptin concentrations in the blood decreased significantly during the study period in the treated cats.
[000197] Figure 7 shows a reduction in the respiratory exchange ratio (RER) (indicating increased use of lipids) in the treated animals, measured by indirect calorimetry.
[000198] Figure 8 shows that the levels of β-hydroxybutyrate in the blood (β-HB / BHB) increased after 4 weeks of treatment with compound A.
[000199] Figure 9 shows the positive correlation between the variation in leptin concentration in the blood and the variation in RER before and after 4 weeks of treatment with compound A or vehicle (control).
[000200] Figure 10 shows the negative correlation between the levels of β-hydroxybutyrate in the blood (β-HB / BHB) and RER after 4 weeks of treatment with compound A.
[000201] Figure 11 shows a powder X-ray diffraction pattern of a representative batch of a crystalline complex of compound A with L-proline (1: 1).
[000202] Figure 12 shows a DSC / TG diagram of a representative batch of a crystalline complex of compound A with L-proline (1: 1).
[000203] Figure 13 shows the average blood glucose of the 9-hour glucose curve on the day of the visit.
[000204] Figure 14 shows serum fructosamine on the day of the visit.
[000205] Figure 15 Preliminary data from four cats demonstrate that fasting insulin concentrations increased compared to a simultaneous reduction in mean glucose values (from a 9-hour blood glucose curve) on day 7 compared to day 1 After that, insulin concentrations reached a plateau that can be explained by the glucose concentration already almost normalized. This reflects the normal physiological situation in fasting animals: when glucose is within the normal range (fasting state) it is expected that no increase in insulin concentrations will be present. These preliminary data of the fasting insulin values of four cats support the claimed indications “loss of pancreatic beta cell function” and “remission of metabolic disorder, preferably diabetic remission” as they demonstrate an increase in insulin concentrations and a decrease in insulin concentrations. glucose concentrations return to normalized values and therefore reflect the return to a normal physiological response. EXAMPLES
[000206] The following examples show the beneficial therapeutic effects on glycemic control and / or insulin resistance, etc., of using one or more SGLT2 inhibitors in feline animals, in accordance with the present invention. These examples are intended to illustrate the invention in more detail without any limitation on the scope of the claims. Example 1 Pharmacokinetics (PK) / pharmacodynamics (PD) of single oral administration of compound A in cats
[000207] Compound A was administered to cats that were fasting for one night. The groups (n = 3 per group) received a single oral administration either of vehicle alone (water) or of vehicle containing the SGLT2 inhibitor Compound A at a dose of 0.01 mg / kg, 0.1 mg / kg and 1 mg / kg. PK / PD measurements were made until day 4 after a single administration of compound A or its vehicle.
Pharmacodynamic data:
[000208] A prominent increase in the concentration of glucose in the urine was evident at doses> 0.01 mg / kg already 8 hours after administration (mean values of the groups: controls 1.4 mmol / L; 0.01 mg / kg - 1.4 mmol / L; 0.1 mg / kg - 46.1 mmol / L; 1 mg / kg - 239.3 mmol / L) and persisted for more than 24 hours.
[000209] None of the three doses of compound A changed the blood glucose level in cats compared to normal reference values.
[000210] None of the three doses of compound A altered the renal function of cats.
[000211] The increase in the excretion of glucose in the urine is clearly dependent on the dose and exposure of the compound in plasma (logarithmic-linear correlation), as shown in Figure 1. Example 2 The effect of compound A on glucose in urine and blood after repeated doses in cats
[000212] Compound A was administered to cats that were fasting for one night. The groups (n = 3 per group) received an oral administration once a day either from vehicle alone (PillPocketR) or from vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg / kg and 3 mg / kg per 3 consecutive days. Glucose in the urine and glucose in the blood were measured.
[000213] A prominent increase in the concentration of glucose in the urine was evident in both doses as early as 8 hours after administration. The maximum urinary concentration was not higher after repeated doses and was similar at doses of 1 mg / kg and 3 mg / kg (mean values - 281 mmol / L and 209 mmol / L, respectively).
[000214] None of the doses of compound A changed the blood glucose level in cats compared to normal reference values.
[000215] As for the excretion of glucose in the urine, it was thus estimated that the ED50 is <1mg / kg. Example 3 The effect of compound A on glucose in urine and blood after repeated doses in cats
[000216] Compound A was administered to normoglycemic obese cats that had a free diet. The groups (n = 6 per group) received an oral administration once a day, either by vehicle alone (gelatin capsules) or by vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg / kg for 4 weeks. Glucose in the urine and glucose in the blood were measured.
[000217] Urine glucose concentrations were significantly elevated at the end of the study - controls 0.6 mmol / L; 1 mg / kg - 489 mmol / L.
[000218] No changes in blood glucose levels have been observed. Example 4 Treatment of pre-diabetes: Prevention of type 2 diabetes manifested in cats
[000219] The effectiveness of SGLT2 inhibition according to the invention in the treatment of pre-diabetes characterized by pathological fasting glucose and / or impaired glucose tolerance and / or insulin resistance can be tested using clinical studies. In studies over a shorter or longer period (for example, 2-4 weeks or 1-2 years), treatment success is examined by determining fasting glucose values and / or glucose values afterwards after a meal or after a load test (oral glucose tolerance test or food tolerance test after a defined meal) after the end of the therapy period for the study and comparing them with the values before the start study and / or with those in a placebo group. In addition, the value of fructosamine can be determined before and after therapy and compared to the initial value and / or the value of the placebo. A significant drop in fasting or non-fasting glucose levels and / or fructosamine levels demonstrates the effectiveness of pre-diabetes treatment. In addition, a significant reduction in the number of patients who develop overt type 2 diabetes when treated with a pharmaceutical composition according to this invention compared to another form of treatment, demonstrates the effectiveness in preventing a transition from prediabetes to overt diabetes. . Example 5 Treatment of pre-diabetes: Improving insulin resistance in cats
[000220] The following example shows the beneficial effect of compound A in insulin-resistant obese cats. Compound A was administered to normoglycemic obese cats, resistant to insulin, which had a free diet. The groups (n = 6 per group) received an oral administration once a day, either by vehicle alone (gelatin capsules) or by vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg / kg for 4 weeks. The following experiments were performed before treatment and at the end of the 4-week treatment period approximately 24 hours after the last compound / vehicle administration.
[000221] An intravenous glucose tolerance test (ivGTT, 0.8 g / kg dextrose) was performed on cats that were fasted for one night. Blood was collected via catheters in the jugular vein. Blood samples were collected at -5, 0, 5, 10, 15, 30, 45, 60, 90, 120, 180 minutes in relation to the application of glucose.
[000222] Glucose and insulin excursion were quantified by calculating the corrected glucose AUC at baseline. An intravenous insulin tolerance test (ivITT, 0.05 U / kg of regular insulin) was performed on cats that were fasted for one night. Blood was collected via catheters in the jugular vein. Blood samples were collected at -5, 0, 15, 30, 60, 90, 120, 180 minutes in relation to insulin application.
[000223] The excursion of glucose and non-esterified fatty acids (NEFA) was quantified by calculating the glucose AUC and NEFA corrected at baseline.
[000224] The significance of the differences in means between the groups is assessed by two-way ANOVA (time and treatment) of repeated measures and by multiple post hoc comparisons versus the control or the respective baseline readings.
[000225] Glucose excursion during ivGTT did not change during the study period or due to treatment. Insulin excursion was not altered throughout the study period in control cats, but was significantly reduced in treated cats compared to baseline (p <0.05).
[000226] As shown in Figure 2, in comparison with lean cats, in the obese cats used in the present study, the insulin secretion profile exhibited a reduced first phase, and an increased and prolonged second phase. As shown in panel B of Figure 2, treatment with compound A led to a significant improvement in the insulin secretion profile in the second phase.
[000227] Insulin sensitivity was significantly increased in treated cats compared to baseline (p <0.05). This was demonstrated by calculating the relationship between glucose and insulin in terms of the modified Belfiore index (1 / log (ΔDAUCgluc * ΔDAUCins).
[000228] The values of the area under the blood insulin curve and the blood insulin-to-glucose ratio represented by the modified Belfiore index for insulin sensitivity in insulin-resistant cats during an iv glucose tolerance test (ivGTT) before ( “Pre”) and after (“post”) 4 weeks of treatment with compound A or its vehicle (“control”) are shown in Figure 3.
[000229] Glucose excursion during ivITT worsened significantly throughout the study period in control animals (p <0.05) (see Figure 4, panel A). This was similar for the elimination of NEFAs (see Figure 5, panel A). In contrast, in cats treated with compound A, the glucose curve did not change throughout the study period (see Figure 4, panel B), and NEFA elimination was significantly improved by treatment with compound A (p <0.01 ; see Figure 5, panel B).
[000230] These data indicate that in obese cats insulin resistance is significantly improved after a 4-week treatment with compound A. Since insulin resistance is a characteristic feature of pre-diabetes, the data strongly indicate that the compound A is able to treat pre-diabetes in feline animals.
[000231] In clinical studies in diabetic cats running for different periods of time (for example, 2 weeks to 12 months) the success of the improvement in insulin resistance can be verified by measuring baseline blood glucose, fructosamine in the blood and insulin in the blood and then monitoring the development of these levels in individual cats throughout the study period. Also, the glucose and insulin values after a meal or after a load test (glucose tolerance test or insulin tolerance test) after the end of the study therapy period can be compared with the values before the beginning of the study and / or with those of diabetic cats who were treated with other medications. Example 6 Treatment of type 2 diabetes in cats
[000232] Treatment of cats with type 2 diabetes with the pharmaceutical composition according to the invention, in addition to producing an acute improvement in the metabolic situation of glucose, prevents deterioration of the metabolic situation in the long term. This can be seen when cats are treated for a shorter or longer period, for example, 2-4 weeks or 3 months to 1 year, with the composition according to the invention and are compared with the metabolic situation before treatment or with cats that have been treated with insulin or other anti-diabetic medication. There is evidence of therapeutic success if the average daily level of glucose and fructosamine in the blood is reduced compared to the level before treatment. Additional evidence of therapeutic success is obtained if a significantly lower percentage of cats treated with a pharmaceutical composition according to the invention, compared to cats that have been treated with other medications, experience transient deterioration in the metabolic position of glucose (eg, hyperglycemia or hypoglycemia). Example 7 Improved pancreatic beta cell function
[000233] In clinical studies in diabetic cats running for different periods of time (eg, 4 weeks to 12 months) the success of treatment is verified by measuring baseline blood glucose, blood fructosamine and blood insulin levels and the corresponding relationship between the parameter in the individual cat. In addition, for example, arginine stimulation can be employed to test the ability of pancreatic beta cells to secrete insulin.
[000234] A significant increase in the level of insulin in the blood (either at baseline or after arginine stimulation) during or at the end of the study, compared with the baseline value or compared with a placebo group, or with a group that received a different therapy, proves the effectiveness of a pharmaceutical composition according to the invention in improving the function of pancreatic beta cells in diabetic cats. Example 8 Diabetic remission
[000235] In clinical studies in diabetic cats running for different periods of time (for example, 3 months to 1 year) the success of treatment is verified by measuring baseline blood glucose, blood fructosamine and blood insulin levels and the corresponding relationship between the parameter in the individual cat. There is evidence of therapeutic success when laboratory values are reduced compared to the level before treatment without the need for insulin injections.
[000236] If compound A has been used in a combination with, for example, insulin or other drugs that effectively reduce hyperglycemia, the feline animal may have insulin or the other drug suspended and still maintain glycemic control within the normal range .
[000237] More advantageously, the feline animal has compound A suspended. Example 9 Reduction of hyperglycemia
[000238] In clinical studies in diabetic cats running for different periods of time (for example, 1 day to 12 months) the success of treatment in cats with hyperglycemia is verified by determining the level of blood glucose or fructosamine in the blood. A significant drop in these values during or at the end of the study, compared to the initial value or compared to a placebo group, or to a group that had received a different therapy, proves the effectiveness of a pharmaceutical composition according to the invention in reducing of hyperglycemia in cats. Example 10 Body composition and reduction of body fat
[000239] The following example shows the beneficial effect of compound A in obese cats. Compound A was administered to obese cats that had a free diet. The groups (n = 6 per group) received an oral administration once a day, either by vehicle alone (gelatin capsules) or by vehicle containing the SGLT2 inhibitor (dry compound) at a dose of 1 mg / kg for 4 weeks. The following experiments were performed before treatment and at the end of the 4-week treatment period approximately 24 hours after the last administration of the compound / vehicle. As shown in Figure 6, leptin concentrations in the blood decreased significantly during the study period in the treated cats (mean values: pre: 2482 pmol / L, post: 2213 pmol / L, p <0.05).
[000240] Indirect calorimetry shows the influence of treatment on energy metabolism. The respiratory exchange ratios (RER; ratio between the amount of exhaled CO2 and inhaled O2; see Figure 7) indicated a significantly increased fatty acid metabolism (use of lipids) in the treated animals (mean RER values: 0.749 pre-treatment, 0.728 post-treatment; p <0.01).
[000241] The increased use of lipids was also mirrored in the increased concentrations of β-hydroxybutyrate (β-HB / BHB) in the blood, as shown in Figure 8. The increase in the concentrations of β-hydroxybutyrate in the blood did not exceed the reference values normal.
[000242] These variations in the relevant data throughout the study show a significant correlation and indicate that the treatment shows a beneficial effect on the composition of the body.
[000243] Therefore, the data show a positive correlation between the variation in leptin concentration in the blood and the variation in RER before and after 4 weeks of treatment with compound A (Figure 9), and a negative correlation between β levels. -hydroxybutyrate (β-HB / BHB) in the blood and the RER (Figure 10).
[000244] Liver parameters remained unchanged, and no ketones were detected in the urine. Consequently, the change in lipid and carbohydrate metabolism fell within normal physiological ranges.
[000245] Consequently, a 4-week treatment in obese cats clearly shows that dysadipokinemia has been improved and additionally the switch from the use of metabolic substrate from glucose to lipid represents a clear benefit in the treatment of obese cats. The data strongly indicate that compound A is capable of treating pre-diabetes in feline animals. Example 11 Pilot test of compound A in diabetic client cats
[000246] The following data are from 4 diabetic cats that had been prospectively treated orally with 1 mg / kg of compound A once daily for 28 days. The diagnosis of diabetes mellitus was made based on blood glucose> 250 mg / dl (13.9 mmol / L) at screening, or serum glucosuria or fructosamine> 400 μmol / L, and the persistence of at least one condition / clinical sign consistent with diabetes mellitus [lethargy, polyuria, polydipsia, polyphagia, weight loss, and / or plantigrade posture of the hind legs (DM polyneuropathy)].
[000247] The results revealed that the mean blood glucose values (Figure 13) of the 9-hour blood glucose curve were substantially decreased in all 4 cats compared to the baseline at the end of the study. The decrease was already present on day 7 and unexpectedly to an extent comparable to prolonged insulin therapy. For comparison, a comparable reduction in mean blood glucose was not observed in the 14 cats treated with Vetsulin® until day 14 (NADA 141-236, Freedom of Information Summary, Vetsulin). Serum fructosamine confirmed this satisfactory glycemic control and was also decreased to less than 350 μmol / L (excellent control according to laboratory interpretation standards) in all cats before day 28 (Figure 14). In contrast, the average serum fructosamine for cats treated with Vetsulin was 546 before day 30, and was still high at 462 on day 60 (NADA 141-236, Freedom of Information Summary, Vetsulin).
[000248] All cats showed improvement in at least one condition / clinical sign, and 3 of the 4 cats showed improvement in at least 3 conditions / clinical signs as assessed by the owner. All cats showed improvement in general diabetes control as assessed by the investigator. Excretion of glucose in the urine was decreased in all cats prior to the end of the study. Hypoglycemia (defined as blood glucose below 70 mg / dL) has not been reported.
[000249] In conclusion, these data demonstrate that compound A represents, can be used to treat diabetic cats with oral therapy once a day comparable to prolonged therapy with insulin twice a day. Example 12 Preparation of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene (compound A)
[000250] The following synthetic example serves to illustrate a method of preparing 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene (compound A) . A method for preparing your crystalline complex with L-proline is also described. It should be considered only as a possible method described by way of example, without restricting the scope of the invention. The terms "room temperature" and "room temperature" are used interchangeably and indicate temperatures of around 20 ° C. The following abbreviations are used:

[000251] Oxalyl chloride (13.0 ml) is added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid (49.5 g) in CH2Cl2 (200 ml). DMF (0.2 mL) is added and the solution is stirred at room temperature for 6 hours. Then, the solution is concentrated under reduced pressure and the residue is dissolved in THF (100 ml). The resulting solution is cooled in an ice bath and LiBH4 (3.4 g) is added gradually. The cooling bath is removed and the mixture is stirred at room temperature for 1 hour. The resulting mixture is diluted with THF and treated with 0.1 M hydrochloric acid. Then, the organic layer is separated and the aqueous phase is extracted with ethyl acetate. The organic layers are dried (Na2SO4) and the solvent is evaporated under reduced pressure to give the crude product. Yield: 47.0 g (99% of theory)

[000252] Thionyl chloride (13 ml) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 ml) containing DMF (0.1 ml). The mixture is stirred at room temperature for 3 hours. Then, the solvent and excess reagent are removed under reduced pressure. The residue is triturated with methanol and dried. Yield: 41.0 g (82% of theory)

[000253] Phenol (13 g) dissolved in a 4 M solution of KOH (60 ml) is added to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in acetone (50 ml). NaI (0.5 g) is added and the resulting mixture is stirred at 50 ° C overnight. Then, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (19: 1 cyclohexane / ethyl acetate). Yield: 38.0 g (79% of theory)

[000254] A 2 M solution of iPrMgCl in THF (11 mL) is added to dry LiCl (0.47 g) suspended in THF (11 mL). The mixture is stirred at room temperature until the whole LiCl dissolves. This solution is added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) in tetrahydrofuran (40 ml) cooled to -60 ° C in an argon atmosphere. The solution is heated to - 40 ° C and then 2,3,4,6-tetracis-O- (trimethylsilyl) -D-glucopyranone (10.7 g, 90% pure) in tetrahydrofuran (5 ml) is added. The resulting solution is heated to -5 ° C in the cooling bath and stirred for another 30 minutes at this temperature. An aqueous solution of NH4Cl is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in methanol (80 ml) and treated with methanesulphonic acid (0.6 ml) to produce only the most stable anomer. After stirring the reaction solution at 35-40 ° C for one night, the solution is neutralized with NaHCO3 and solid and the methanol is removed under reduced pressure. The remainder is diluted with an aqueous solution of NaHCO3 and the resulting mixture is extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is evaporated to give the crude product which is subjected to reduction without further purification. Yield: 7.8 g (93% of theory)

[000255] Boron trifluoride diethyl etherate (4.9 mL) is added to a solution of 1-bromo-4- (1-methoxy-D-glucopyran-1-yl) -2- (phenoxymethyl) -benzene (8.7 g) and triethylsilane (9.1 ml) in dichloromethane (35 ml) and acetonitrile (50 ml) cooled to -20 ° C at such a rate that the temperature remains below -10 ° C. The resulting solution is heated to 0 ° C for a period of 1.5 hours and then treated with an aqueous solution of sodium hydrogen carbonate. The resulting mixture is stirred for 0.5 hour, the organic solvent is removed and the residue is extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and the solvent is removed. The residue is recovered in dichloromethane (50 ml) and pyridine (9.4 ml), and acetic anhydride (9.3 ml) and 4-dimethylaminopyridine (0.5 g) are successively added to the solution. The solution is stirred for 1.5 hours at room temperature and then diluted with dichloromethane. This solution is washed twice with 1 M hydrochloric acid and dried over sodium sulfate. After the solvent is removed, the residue is recrystallized from ethanol to give the product as a colorless solid. Yield: 6.78 g (60% of theory) Mass spectrum (ESI +): m / z = 610/612 (Br) [M + NH4] + Preparation of 2- (phenoxymethyl) -4- (2,3,4,6-tetra-O-acetyl-D-glucopyran-1-yl) -benzonitrile

[000256] A flask loaded with zinc cyanide (1.0 g), zinc (30 mg), Pd2 (dibenzylidenoacetone) 3 * CHCl3 (141 mg) and tri-tert-butylphosphonium tetrafluoroborate (111 mg) is purged with argon. Then a solution of 1-bromo-4- (2,3,4,6-tetra-O-acetyl-D-glucopyran-1-yl) -2- (phenoxymethyl) -benzene (5.4 g) in NMP (12 mL) is added and the resulting mixture is stirred at room temperature for 18 hours. After dilution with ethyl acetate, the mixture is filtered and the filtrate is washed with an aqueous solution of sodium hydrogen carbonate. The organic phase is dried (sodium sulfate) and the solvent is removed. The residue is recrystallized from ethanol. Yield: 4.10 g (84% of theory) Mass spectrum (ESI +): m / z = 557 [M + NH4] +
[000257] Alternatively, the compound described above is synthesized starting from 1-bromo-4- (2,3,4,6-tetra-O-acetyl-D-glucopyranes-1-yl) -2- (phenoxymethyl) -benzene using copper (I) cyanide (2 equivalents) in NMP at 210 ° C.Preparation of 2-bromomethyl-4- (2,3,4,6-tetra-O-acetyl-D-glucopyran-1-yl) - benzonitrile

[000258] A 33% hydrobromic acid solution in acetic acid (15 mL) is added to a solution of 2-phenyloxymethyl-4- (2,3,4,6-tetra-O-acetyl-D-glucopyran-1 -il) -benzonitrile (0.71 g) and acetic anhydride (0.12 ml) in acetic acid (10 ml). The resulting solution is stirred at 55 ° C for 6 hours and then cooled in an ice bath. The reaction mixture is neutralized with a cooled aqueous solution of potassium carbonate, and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate / cyclohexane (1: 5), and the precipitate is filtered off and dried at 50 ° C to give the pure product. Yield: 0.52 g (75% of theory) Mass spectrum (ESI +): m / z = 543/545 (Br) [M + NH4] + Preparation of 4-cyclopropyl-phenylboronic acid

[000259] A 2.5 M solution of n-butyl lithium in hexane (14.5 mL) is added dropwise to 1-bromo-4-cyclopropyl-benzene (5.92 g) dissolved in THF (14 mL) and toluene (50 mL) and cooled to -70 ° C. The resulting solution is stirred at -70 ° C for 30 minutes before the addition of triisopropyl borate (8.5 mL). The solution is heated to -20 ° C and then treated with 4 M aqueous hydrochloric acid (15.5 ml). The reaction mixture is further warmed to room temperature and then the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (sodium sulfate). The solvent is evaporated and the residue is washed with a mixture of ether and cyclohexane to give the product as a colorless solid. Yield: 2.92 g (60% of theory) Mass spectrum (ESI-): m / z = 207 (Cl) [M + HCOO] -Preparation of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene

[000260] An air-filled flask is charged with 2-bromomethyl-4- (2,3,4,6-tetra-O-acetyl-D-glucopyran-1-yl) -benzonitrile (1.60 g), 4- cyclopropyl-phenylboronic (1.0 g), potassium carbonate (1.85 g) and a 3: 1 degassed mixture of acetone and water (22 mL). The mixture is stirred at room temperature for 5 minutes, before being cooled in an ice bath. Then palladium dichloride (30 mg) is added and the reaction mixture is stirred for 16 hours at room temperature. The mixture is then diluted with brine and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in methanol (20 ml) and treated with a 4 M aqueous solution of potassium hydroxide (4 ml). The resulting solution is stirred at room temperature for 1 hour and then neutralized with 1 M hydrochloric acid. Methanol is evaporated, and the residue is diluted with brine and extract with ethyl acetate. The collected organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel (dichloromethane / methanol 1: 0 -> 8: 1). Yield: 0.91 g (76% of theory) Mass spectrum (ESI +): m / z = 413 [M + NH4] + Preparation of a crystalline complex (1: 1) of compound A with L-proline
[000261] L-proline (0.34 g) dissolved in 2.1 mL of a mixture of ethanol and water (10: 1 volume ratio) is added to a solution of 1-cyano-2- (4-cyclopropyl-benzyl) -4 - (β-D-glucopyran-1-yl) - benzene (1.17 g, obtained as described above) dissolved in 2 ml of ethanol. The resulting solution is left to stand at room temperature. After about 16 hours, the crystalline complex is isolated as white crystals by filtration. If necessary, crystallization can be initiated by scratching with a glass rod or with a metal spatula, for example, or by inoculation with seed crystals. The residual solvent is removed by storing the crystals at a slightly elevated temperature (30 to 50 ° C) under vacuum for about 4 hours to give 1.27 g of the 1: 1 crystalline complex of L-proline and 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyran-1-yl) -benzene.
[000262] Several batches of the crystalline complex are obtained according to the above preparation. The patterns of powder X-ray diffraction coincide. Melting points are determined via DSC and evaluated as an initial temperature. Examples of melting points are approximately 89 ° C, 90 ° C, 92 ° C, 101 ° C and 110 ° C. The powder X-ray diffraction pattern contained in Table 1 and represented in Figure 11 and the DSC and TG diagrams in Figure 12 correspond to a batch with a melting point of approximately 90 ° C.
[000263] The powder X-ray diffraction pattern of the crystalline complex of compound A and L-proline (peaks up to 30 ° at 2 Q) is given above in Table 1. Example 13 Formulations
[000264] Some examples of formulations are described in which the term "active substance" means an SGLT2 inhibitor or a pharmaceutically acceptable form thereof, for example, a prodrug or crystalline form, for use according to the invention. In the case of a combination with one or more additional active substances, the term "active substance" can also include the additional active substance.
Preparation Method:
[000265] The active substance, lactose and starch are mixed and moistened evenly with an aqueous solution of polyvinylpyrrolidone. After the moistened composition has been sieved (sieve size 2.0 mm) and dried in a rack-type dryer at 50 ° C it is sieved again (sieve size 1.5 mm) and the lubricant is added. The finished mixture is compressed to form tablets. Tablet weight: 220 mg
[000266] Diameter: 10 mm, biplane, faceted on both sides and grooved on one side.

[000267] The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve with a sieve size of 1.5 mm. The granules, dried at 45 ° C, are passed through the same sieve again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture.

[000268] The active substance is mixed with the excipients, passed through a sieve with a sieve size of 0.75 mm and homogeneously mixed using a suitable device. The finished mixture is packed in size 1 hard gelatin capsules.

[000269] After the suppository mass has melted, the active substance is homogeneously distributed in it and the fondant is poured into chilled molds.

[000270] The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred to 2 ml ampoules.

[000271] The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred to 10 ml ampoules. REFERENCES 1) Curry et al., Comp Biochem Physiol. 1982. 72A (2): 333-338 2) EP 1 213 296 3) EP 1 354 888 4) EP 1 344 780 5) EP 1 489 089 6) Hoenig, Mol Cell Endocrinol 2002, 197 (1-2): 221-229 7) Hoenig et al., 2011, 301 (6): R1798-1807 8) NOTHING 141-236 Freedom of Information Vetsulin 9) Palm CA et al., Vet Clin Small Anim 2013, 43: 407-415 10 ) Reusch CE et al., Schweizer Archiv fuer Tierheilkunde 2011, 153811): 495-500 11) Tanaka et al., Vet Res Commun. 2005, 29 (6): 477-485 12) Verbrugghe et al., Crit Rev Food Sci Nutr. 2012; 52 (2): 172-182 13) WO 01/27128 14) WO 03/099836 15) WO 2004/007517 16) WO 2004/080990 17) WO 2005/012326 18) WO 2005/092877 19) WO 2006 / 034489 20) WO 2006/064033 21) WO 2006/117359 22) WO 2006/117360 23) WO 2006/120208 24) WO 2007/025943 25) WO 2007/028814 26) WO 2007/031548 27) WO 2007/093610 28) WO 2007/114475 29) WO 2007/128749 30) WO 2007/140191 31) WO 2008/002824 32) WO 2008/013280 33) WO 2008/042688 34) WO 2008/049923 35) WO 2008/055870 36) WO 2008/055940 37) WO 2008/069327 38) WO 2008/116179 39) WO 2009/014970 40) WO 2009/022008 41) WO 2009/022020 42) WO 2009/035969 43) WO 2010/023594 44) WO 2011 / 039107 45) WO 2011/039108 46) WO 2011/117295 47) WO 2014/016381

权利要求:
Claims (18)
[0001]
1. Use of SGLT2 inhibitor or pharmaceutically acceptable form thereof, wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof consists of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyranes -1-yl) -benzene, represented by the following formula:
[0002]
2. Use according to claim 1, characterized by the fact that the metabolic disorder is selected from the group consisting of prediabetes, type 1 diabetes mellitus, type 2 diabetes mellitus, and clinical conditions associated with prediabetes, type diabetes mellitus 1 or type 2 diabetes mellitus.
[0003]
Use according to claim 2, characterized by the fact that said metabolic disorder is pre-diabetes, type 2 diabetes mellitus or a clinical condition associated with pre-diabetes or type 2 diabetes mellitus.
[0004]
4. Use according to claim 2, characterized by the fact that said clinical condition is a condition selected from the group consisting of ketoacidosis, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinaemia, subclinical inflammation , systemic inflammation, low-grade systemic inflammation, liver lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy, syndrome X (metabolic syndrome), loss of pancreatic beta cell function, diabetic remission, and combination thereof.
[0005]
5. Use according to claim 1, characterized by the fact that said ketoacidosis, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinaemia, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and / or syndrome X (metabolic syndrome), pancreatic beta cell function and / or diabetic remission is associated with diabetes.
[0006]
6. Use according to claim 5, characterized by the fact that said diabetes is pre-diabetes or type 2 diabetes mellitus.
[0007]
7. Use according to claim 1, characterized by the fact that the feline animal is obese.
[0008]
8. Use according to claim 1, characterized by the fact that the feline animal suffers from diabetes.
[0009]
Use according to claim 8, characterized by the fact that said diabetes is pre-diabetes or type 2 diabetes mellitus.
[0010]
10. Use according to claim 1, characterized by the fact that the feline animal is a cat.
[0011]
Use according to claim 1, characterized in that the composition comprising said inhibitor or pharmaceutically acceptable form of it is administered only once a day.
[0012]
Use according to claim 1, characterized in that it further comprises administering to the feline animal a combination of insulin and SGLT2 inhibitor or pharmaceutically acceptable form thereof.
[0013]
Use according to claim 12, characterized in that the composition comprises a crystalline SGLT2 inhibitor complex (1: 1) or pharmaceutically acceptable form thereof and an amino acid, and the crystalline complex is a crystalline hydrate.
[0014]
Use according to claim 13, characterized in that said amino acid comprises proline.
[0015]
Use according to claim 14, characterized in that said amino acid comprises L-proline.
[0016]
16. Use of SGLT2 inhibitor or pharmaceutically acceptable form thereof, wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereof consists of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyranes -1-yl) -benzene, represented by the following formula:
[0017]
17. Use according to claim 16, characterized by the fact that the 1: 1: 1 crystalline complex is characterized by a powder X-ray diffraction (XRPD) pattern comprising peaks of 20.28, 21.14 and 21.64 degrees 2θ (± 0.1 degrees 2θ), where the aforementioned powder X-ray diffraction pattern is made using CuKa1 radiation.
[0018]
18. Use of SGLT2 inhibitor or pharmaceutically acceptable form thereof where the SGLT2 inhibitor or pharmaceutically acceptable form thereof consists of 1-cyano-2- (4-cyclopropyl-benzyl) -4- (β-D-glucopyranes- 1-yl) -benzene, represented by the following formula: characterized by the fact that it is for the preparation of a composition for the treatment or prevention of a metabolic disorder and a feline animal, in which the metabolic disorder is selected from the group consisting of ketoacidosis, pre-diabetes, type 1 or type 2 diabetes mellitus, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinaemia, subclinical inflammation, systemic inflammation, low-grade systemic inflammation, liver lipidosis, atherosclerosis, pancreatic inflammation, neuropathy, syndrome X (metabolic syndrome), loss pancreatic beta cell function, diabetic remission, and combinations thereof; wherein the composition comprises SGLT2 inhibitors or pharmaceutically acceptable forms thereof which is administered at a dose of 0.01 to 5.0 mg / kg of body weight daily, and where the composition comprises a crystalline complex of the SGLT2 inhibitor 1: 1: 1 or pharmaceutically acceptable form thereof, and an amino acid, and the crystalline complex is a crystalline hydrate.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112016011564B1|2021-02-09|uses of sglt2 inhibitors or pharmaceutically acceptable forms of them for the treatment of metabolic disorders in feline animals

---

AU2020201168B2|2021-03-25|Treatment of metabolic disorders in canine animals

---

KR20160132120A|2016-11-16|Treatment of metabolic disorders in equine animals

---

JP7022106B2|2022-02-17|Treatment of metabolic disorders in canines

同族专利:

---

公开号 | 公开日

---

CN105828815B|2020-03-27|

---

EA034837B1|2020-03-26|

---

PL3082829T3|2021-09-06|

---

EP3082829B1|2021-02-17|

---

JP6293897B2|2018-03-14|

---

DK3082829T3|2021-05-03|

---

AU2014364999A1|2016-05-19|

---

EP3082829A1|2016-10-26|

---

HUE053906T2|2021-07-28|

---

US10617666B2|2020-04-14|

---

KR20160096196A|2016-08-12|

---

CA2930034A1|2015-06-25|

---

JP2018090606A|2018-06-14|

---

EA201600467A1|2016-12-30|

---

EP3862003A1|2021-08-11|

---

CN105828815A|2016-08-03|

---

AU2021269354A1|2021-12-16|

---

JP2016540790A|2016-12-28|

---

AU2020201551B2|2021-09-23|

---

WO2015091313A1|2015-06-25|

---

JP6774449B2|2020-10-21|

---

US20200197352A1|2020-06-25|

---

ES2859905T3|2021-10-04|

---

CN111494357A|2020-08-07|

---

US20150164856A1|2015-06-18|

---

MX2016007856A|2016-10-07|

---

AU2014364999B2|2019-12-12|

---

AU2020201551A1|2020-03-19|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

AU782330B2|1999-08-31|2005-07-21|Kissei Pharmaceutical Co. Ltd.|Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof|

---

US6515117B2|1999-10-12|2003-02-04|Bristol-Myers Squibb Company|C-aryl glucoside SGLT2 inhibitors and method|

---

PH12000002657B1|1999-10-12|2006-02-21|Squibb Bristol Myers Co|C-aryl glucoside SGLT2 inhibitors|

---

CA2429833A1|2000-11-30|2002-06-06|Kissei Pharmaceutical Co., Ltd.|Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof|

---

KR100701437B1|2000-12-28|2007-03-30|깃세이 야쿠힌 고교 가부시키가이샤|Glucopyranosyloxypyrazole derivatives and use thereof in medicines|

---

CA2444481A1|2001-04-11|2002-10-24|Bristol-Myers Squibb Company|Amino acid complexes of c-aryl glucosides for treatment of diabetes and method|

---

BR0308653A|2002-03-22|2005-02-15|Kissei Pharmaceutical|Glycopyranosyloxybenzyl benzene derivative crystals|

---

DE10231370B4|2002-07-11|2006-04-06|Sanofi-Aventis Deutschland Gmbh|Thiophene glycoside derivatives, medicaments containing these compounds and methods of making these medicaments|

---

EP1581543A4|2003-01-03|2008-03-19|Squibb Bristol Myers Co|Methods of producing c-aryl glucoside sglt2 inhibitors|

---

ZA200507754B|2003-03-14|2007-01-31|Astellas Pharma Inc|C-glycoside derivatives and salts thereof|

---

DE10312809A1|2003-03-21|2004-09-30|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Pramipexole to reduce excessive food intake in children|

---

ES2402098T5|2003-08-01|2021-06-09|Mitsubishi Tanabe Pharma Corp|Novel compounds that have inhibitory activity against the sodium-dependent transporter|

---

US7375090B2|2003-08-26|2008-05-20|Boehringer Ingelheim International Gmbh|Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processed for the preparation thereof|

---

US7371732B2|2003-12-22|2008-05-13|Boehringer Ingelheim International Gmbh|Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture|

---

PL1730131T3|2004-03-16|2012-10-31|Boehringer Ingelheim Int|Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof|

---

US7393836B2|2004-07-06|2008-07-01|Boehringer Ingelheim International Gmbh|D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

EP1773800A1|2004-07-27|2007-04-18|Boehringer Ingelheim International GmbH|D-glucopyranosyl phenyl-substituted cyclene, medicaments containing these compounds, their use, and method for the production thereof|

---

AR051446A1|2004-09-23|2007-01-17|Squibb Bristol Myers Co|C-ARYL GLUCOSIDS AS SELECTIVE INHIBITORS OF GLUCOSE CONVEYORS |

---

DE102004048388A1|2004-10-01|2006-04-06|Boehringer Ingelheim Pharma Gmbh & Co. Kg|D-pyranosyl-substituted phenyls, pharmaceutical compositions containing them, their use and processes for their preparation|

---

EP1828216B1|2004-12-16|2008-09-10|Boehringer Ingelheim International GmbH|Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

CA2595257A1|2005-02-23|2006-08-31|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted arylethynyl-benzyl)-benzene derivatives and use thereof as sodium-dependent glucose cotransporter 2 inhibitors|

---

US7723309B2|2005-05-03|2010-05-25|Boehringer Ingelheim International Gmbh|Crystalline forms of 1-chloro-4--2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

US7713938B2|2005-05-03|2010-05-11|Boehringer Ingelheim International Gmbh|Crystalline form of 1-chloro-4--2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

US7772191B2|2005-05-10|2010-08-10|Boehringer Ingelheim International Gmbh|Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein|

---

WO2007014894A2|2005-07-27|2007-02-08|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted cycloalyklethynyl-benzyl) -benzene derivatives and use thereof as sodium-dependent glucose cotransporter inhibitors|

---

WO2007025943A2|2005-08-30|2007-03-08|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

US8507450B2|2005-09-08|2013-08-13|Boehringer Ingelheim International Gmbh|Crystalline forms of 1-chloro-4--2-[4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments|

---

AR056195A1|2005-09-15|2007-09-26|Boehringer Ingelheim Int|PROCEDURES TO PREPARE DERIVATIVES OF -BENZENE REPLACED GLUCOPYRANOSIL AND INTERMEDIATE COMPOUNDS OF THE SAME|

---

UY30082A1|2006-01-11|2007-08-31|Boehringer Ingelheim Int|CRYSTAL FORM OF 1- -4` - METHYL) -5`- METHYL-1H-PIRAZOL-3`-OBD-GLUCOPYRANOSIDE, A METHOD FOR PREPARATION AND USE OF THE SAME TO PREPARE MEDICATIONS|

---

TW200801029A|2006-02-15|2008-01-01|Boehringer Ingelheim Int|Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture|

---

PE20080697A1|2006-05-03|2008-08-05|Boehringer Ingelheim Int|BENZONITRILE DERIVATIVES SUBSTITUTED WITH GLUCOPYRANOSIL, PHARMACEUTICAL COMPOSITIONS CONTAINING COMPOUNDS OF THIS TYPE, THEIR USE AND PROCEDURE FOR THEIR MANUFACTURE|

---

TWI370818B|2006-04-05|2012-08-21|Astellas Pharma Inc|Cocrystal of c-glycoside derivative and l-proline|

---

GB0608647D0|2006-05-02|2006-06-14|Haritou Susan J A|Methods of diagnosis and treatment|

---

EP2019679B1|2006-05-23|2018-06-20|Theracos, Inc.|Glucose transport inhibitors and methods of use|

---

US7919598B2|2006-06-28|2011-04-05|Bristol-Myers Squibb Company|Crystal structures of SGLT2 inhibitors and processes for preparing same|

---

TWI403516B|2006-07-27|2013-08-01|Chugai Pharmaceutical Co Ltd|To replace spirocyclic alcohol derivatives, and its use as a therapeutic agent for diabetes|

---

TW200817424A|2006-08-04|2008-04-16|Daiichi Sankyo Co Ltd|Benzylphenyl glucopyranoside derivatives|

---

CA2656847A1|2006-08-15|2008-02-21|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as sglt inhibitors and process for their manufacture|

---

CA2664095A1|2006-09-21|2008-03-27|Boehringer Ingelheim International Gmbh|Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

TWI499414B|2006-09-29|2015-09-11|Lexicon Pharmaceuticals Inc|Inhibitors of sodium glucose co-transporter 2 and methods of their use|

---

US8283326B2|2006-10-27|2012-10-09|Boehringer Ingelheim International Gmbh|Crystalline form of 4--1-methyl-2-[4--tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments|

---

EP2079753A1|2006-11-06|2009-07-22|Boehringer Ingelheim International GmbH|Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

CN101534815A|2006-11-09|2009-09-16|贝林格尔.英格海姆国际有限公司|Combination therapy with SGLT-2 inhibitors and their pharmaceutical compositions|

---

UY30730A1|2006-12-04|2008-07-03|Mitsubishi Tanabe Pharma Corp|CRYSTAL FORM OF HEMIHYDRATE 1- -D-GLUCOPYRANOSIL) -4-METHYL-3- [5- -2-TIENYLMETHYL] BENZENE|

---

WO2008101939A1|2007-02-21|2008-08-28|Boehringer Ingelheim International Gmbh|Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture|

---

AR065809A1|2007-03-22|2009-07-01|Squibb Bristol Myers Co|PHARMACEUTICAL FORMULATIONS CONTAINING AN SGLT2 INHIBITOR|

---

AU2008279424B2|2007-07-26|2013-06-13|Lexicon Pharmaceuticals, Inc.|Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors|

---

FR2920045B1|2007-08-16|2010-03-12|Valeo Systemes Thermiques|MULTI-FLAP EVAPORATOR, ESPECIALLY FOR A MOTOR VEHICLE AIR CONDITIONING CIRCUIT|

---

UY31291A1|2007-08-16|2009-03-31|PHARMACEUTICAL COMPOSITION THAT INCLUDES A DERIVATIVE OF PIRAZOL-0-GLUCOSIDO|

---

PE20090938A1|2007-08-16|2009-08-08|Boehringer Ingelheim Int|PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL|

---

DK2200606T3|2007-09-10|2017-12-04|Janssen Pharmaceutica Nv|PROCEDURE FOR THE PREPARATION OF RELATIONSHIP USED AS INHIBITORS OF SGLT|

---

WO2009124755A1|2008-04-08|2009-10-15|European Molecular Biology Laboratory |Compounds with novel medical uses and method of identifying such compounds|

---

CN102105153B|2008-05-22|2014-03-05|百时美施贵宝公司|Method for treating hyperuricemia employing SGLT2 inhibitor and composition containing same|

---

CN103910702A|2008-08-22|2014-07-09|泰拉科斯有限公司|Processes For The Preparation Of Sglt2 Inhibitors|

---

DK2334687T5|2008-08-28|2012-09-10|Pfizer|Dioxa-bicyclo [3.2.1.] Octane-2,3,4-triol derivatives|

---

WO2010048358A2|2008-10-22|2010-04-29|Auspex Pharmaceutical, Inc.|Ethoxyphenylmethyl inhibitors of sglt2|

---

US20100167989A1|2008-10-23|2010-07-01|Auspex Pharmaceuticals, Inc.|Isopropoxyphenylmethyl inhibitors of sglt2|

---

HUE050287T2|2009-02-13|2020-11-30|Boehringer Ingelheim Int|Pharmaceutical composition comprisng a sglt2 inhibitor, a dpp-iv inhibitor and optionally a further antidiabetic agent and uses thereof|

---

SG10201600204YA|2009-02-13|2016-02-26|Boehringer Ingelheim Int|SGLT-2 Inhibitor For Treating Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Impaired Glucose Tolerance Or Hyperglycemia|

---

HUE029381T2|2009-09-30|2017-02-28|Boehringer Ingelheim Int|Method for the preparation of a crystalline form of 1-chloro-4--2--tetrahydrofuran-3-yloxy)benzyl)benzene|

---

BR112012007085B8|2009-09-30|2021-05-25|Boehringer Ingelheim Int|processes for the preparation of glycopyranosyl substituted benzyl-benzene derivatives|

---

BRPI0904365A2|2009-11-05|2011-11-16|Ouro Fino Participacoes E Empreendimentos S A|pharmaceutical associations, pharmaceutical compositions, medicament and method of treating animals|

---

EP2368552A1|2010-03-25|2011-09-28|Boehringer Ingelheim Vetmedica GmbH|1-[methyl]-3-methyl-7--8-[3--amino-piperidin-1-yl]-xanthine for the treatment of a metabolic disorder of a predominantly carnivorous non-human animal|

---

WO2011153712A1|2010-06-12|2011-12-15|Theracos, Inc.|Crystalline form of benzylbenzene sglt2 inhibitor|

---

US9616097B2|2010-09-15|2017-04-11|Synergy Pharmaceuticals, Inc.|Formulations of guanylate cyclase C agonists and methods of use|

---

US20120283169A1|2010-11-08|2012-11-08|Boehringer Ingelheim International Gmbh|Pharmaceutical composition, methods for treating and uses thereof|

---

US8614195B2|2011-04-14|2013-12-24|Novartis Ag|Glycoside derivatives and uses thereof|

---

EP2755651A1|2011-09-13|2014-07-23|Biomed Valley Discoveries, Inc.|Compositions and methods for treating metabolic disorders|

---

US9145434B2|2012-07-26|2015-09-29|Boehringer Ingelheim International Gmbh|Crystalline complex of 1-cyano-2--4--benzene, methods for its preparation and the use thereof for preparing medicaments|

---

EP2727587A1|2012-10-30|2014-05-07|Pharnext|Compositions, methods and uses for the treatment of diabetes and related conditions by controlling blood glucose level|

---

WO2014161836A1|2013-04-04|2014-10-09|Boehringer Ingelheim Vetmedica Gmbh|Treatment of metabolic disorders in equine animals|

---

CA2930034A1|2013-12-17|2015-06-25|Boehringer Ingelheim Vetmedica Gmbh|Treatment of metabolic disorders in feline animals|

---

EP3485890A1|2014-01-23|2019-05-22|Boehringer Ingelheim Vetmedica GmbH|Treatment of metabolic disorders in canine animals|

---

DK3125882T3|2014-04-01|2020-06-29|Boehringer Ingelheim Vetmedica Gmbh|TREATMENT OF METABOLIC DISORDERS IN ANIMAL ANIMALS|

---

MX2017003716A|2014-09-25|2017-06-30|Boehringer Ingelheim Vetmedica Gmbh|Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals.|

---

AU2016310535B2|2015-08-27|2021-08-19|Boehringer Ingelheim Vetmedica Gmbh|Liquid pharmaceutical compositions comprising SGLT-2 inhibitors|JP3217277B2|1996-10-08|2001-10-09|花王株式会社|Detergent composition|

---

WO2014161836A1|2013-04-04|2014-10-09|Boehringer Ingelheim Vetmedica Gmbh|Treatment of metabolic disorders in equine animals|

---

CA2930034A1|2013-12-17|2015-06-25|Boehringer Ingelheim Vetmedica Gmbh|Treatment of metabolic disorders in feline animals|

---

EP3485890A1|2014-01-23|2019-05-22|Boehringer Ingelheim Vetmedica GmbH|Treatment of metabolic disorders in canine animals|

---

DK3125882T3|2014-04-01|2020-06-29|Boehringer Ingelheim Vetmedica Gmbh|TREATMENT OF METABOLIC DISORDERS IN ANIMAL ANIMALS|

---

MX2017003716A|2014-09-25|2017-06-30|Boehringer Ingelheim Vetmedica Gmbh|Combination treatment of sglt2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals.|

---

AU2016310535B2|2015-08-27|2021-08-19|Boehringer Ingelheim Vetmedica Gmbh|Liquid pharmaceutical compositions comprising SGLT-2 inhibitors|

---

CN110141566A|2018-02-11|2019-08-20|清华大学深圳研究生院|Application of the SGLT2 inhibitor in regulation inflammation|

---

WO2020186142A1|2019-03-14|2020-09-17|Increvet, Inc.|A compound for the management of feline diabetes|

---

EP3958855A2|2019-04-26|2022-03-02|Increvet, Inc.|Methods for reducing the weight loss or increasing the weight of a feline in need thereof|

---

WO2021092341A1|2019-11-07|2021-05-14|Increvet, Inc.|Sodium-glucose linked transporter inhibitors for the management of chronic kidney disease, hypertension, and heart failure in companion animals|

---

WO2021165177A1|2020-02-17|2021-08-26|Boehringer Ingelheim Vetmedica Gmbh|Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in felines|

法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2019-07-02| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO POR NAO SE ENQUADRAR NO ART. 229-C DA LPI. |

---

2020-02-11| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-06-23| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

---

2020-11-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-02-09| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/12/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

EP13197821.5|2013-12-17|

---

EP13197821|2013-12-17|

---

EP14187228|2014-10-01|

---

EP14187228.3|2014-10-01|

---

PCT/EP2014/077677|WO2015091313A1|2013-12-17|2014-12-15|Treatment of metabolic disorders in feline animals|

---