Treatment of diabetes and diabetes induced CKD and the associated symptoms

Abstract

The present invention describes synergistic compositions and combinations comprising one or more prolyl hydroxylase inhibitors or pharmaceutically acceptable salts thereof and a SGLT2 inhibitors or pharmaceutically acceptable salts thereof for the treatment of diabetes and diabetes induced CKD and the associated symptoms like anemia. Specifically, the present invention provides synergistic composition and combination of compound of formula (Ia) or its pharmaceutically acceptable salts and a SGLT2 inhibitors or pharmaceutically acceptable salts thereof for the treatment of diabetes and diabetes induced CKD and the associated symptoms like anemia. The present invention also describes the preparation of such compositions and combinations.

Description

[0001] TREATMENT OF DIABETES AND DIABETES INDUCED CKD AND THE

[0002] ASSOCIATED SYMPTOMS

[0003] Field of the invention

[0004] The present invention describes synergistic compositions and combinations comprising one or more prolyl hydroxylase inhibitors or pharmaceutically acceptable salts thereof and a SGLT2 inhibitors or pharmaceutically acceptable salts thereof for the treatment of diabetes and diabetes induced CKD and the associated symptoms like anemia. Specifically, the present invention provides synergistic composition and combination of compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitors or pharmaceutically acceptable salts thereof for the treatment of diabetes and diabetes induced CKD and the associated symptoms like anemia. The present invention also describes the preparation of such compositions and combinations.

[0005] Background of the invention

[0006] Diabetes is metabolic disorder caused by many factors like genetic disorder, aging, stress, obesity, elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors and other environmental factors (1). The most common cause of diabetic chronic kidney diseases (CKD) is hyperglycemia, insulin deficiency, insulin resistance and other metabolic disorders. Chronic hyperglycemia causes oxidative stress and affects normal functioning of kidney (2). As per ADA diabetes is diagnosed with fasting glucose >126 mg / dl and % HbAlc values >6.5 (3). Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects ~40% of type 1 and type 2 diabetic patients (4). It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases (4). Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 pg / min and <199 pg / min) and macroalbuminuria (UAE >200 pg / min) (4). Urine albumin to creatinine ratio (UAE) is markers used for nephropathy (4). The cutoff value of UAE 17 mg / 1 in a random urine specimen had a sensitivity of 100% and a specificity of 80% for the diagnosis of microalbuminuria when 24-h timed urine collection was the reference standard (5). Clinical consequences of diabetic CKD reduced kidney function may leads to kidney failure and increases blood pressure, retinopathy or other organ failures (6).

[0007] The standard definitive therapy for treating diabetic CKD are Biguanides Sulfonylureas , Glinides, Thiazolidinediones, DPP -4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors and insulin therapies (6, 7)). Biguanides like Metformin works mainly by lowering glucose production in the liver and improving the body's sensitivity to insulin so it uses insulin more effectively (8). Sulfonylureas like glyburide, glipizide help the body secrete more insulin (9) but frequent monitoring required due to increased risk of hypoglycemia (9). Glinides, repaglinide and nateglinide, are short acting secretagogues. The short duration of their action means reduced risk of hypoglycemia compared to sulfonylureas (9). This is an advantage for diabetic subjects with CKD because they belong in the high risk for hypoglycemia. Thiazolidinediones like rosiglitazone and pioglitazone acts as insulin sensitizer but weight gain may occur. DPP-4 inhibitors like sitagliptin, saxagliptin and linagliptin help to reduce blood sugar levels but having very modest effect. GLP-1 receptor agonists exenatide, liraglutide and semaglutide are injectable medications that slow digestion and help lower blood sugar levels. SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin reduces reabsorption of glucose in kidney (10).

[0008] SGLT2 inhibitors Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are FDA-approved for managing adult patients with type 2 diabetes mellitus (DM) to improve blood sugar control adjunct to diet and exercise (10). Recent clinical trials have confirmed the renoprotective action of SGLT2 inhibitors in diabetic nephropathy (11, 12). Clinical data shows that dapagliflozin lowers the estimated glomerular filtration rate and then slows the progression of diabetic nephropathy

[0009] (13). Dapagliflozin is small-molecules SGLT2 inhibitor that has been shown to reduce hyperglycemia in genetically leptin receptor deficient diabetic db / db mice

[0010] (14). It is also reported that dapagliflozin improves diabetic nephropathy not only by lowering blood glucose but also by inhibiting inflammation and oxidative stress in db / db mice (14, 15). However, the albuminuria-lowering action of dapagliflozin is variable and dependent on renal function (16). The effectiveness of SGLT2 inhibitors is decreased with the increasing severity of renal impairment, requiring dosage adjustments or restrictions with moderate to-severe renal dysfunction (16). Dapagliflozin treatment reduced serum creatinine and urea in ischemia perfusion injury (AKI) in kidney in mice and CI-AKI-iohexol (3500 mg / kg) induced AKI in rats (17). Dapagliflozin alleviates renal fibrosis in a mouse model of adenine- induced renal injury (18). Canagliflozin has been reported to protect AKI in euglycemic rats (19). Canagliflozin has been also reported to reduce glycemia in HFSTZ induced diabetes in mice (20) and high-fat diet and streptozotocin (STZ)- induced diabetes in rats (21). Empagliflozin has been reported to protect against renal ischemia / reperfusion injury in mice (22). Empagliflozin has been reported to protect against diabetic nephropathy in STZ-induced diabetic rats (23).

[0011] Prolyl hydroxylase domain (PHD) inhibitors, primarily developed to treat renal anemia, stimulate erythropoietin production through activation of hypoxiainducible factor (HIF) (24). It was reported that the administration of a PHD inhibitor, enarodustat, resulted in the amelioration of obesity and insulin intolerance, and improvement in lipid metabolism in BTBR ob / ob mice. It also reduced albuminuria and amelioration of glomerular epithelial and endothelial damage. Enarodustat showed suppressive effect on CCL2 / MCP-1 production in mesangial cells via HIF-1 activation. A similar improvement in metabolic dysfunction has been reported with another PHD inhibitor, FG-4497 (25). PHD2 inhibition has been reported to protect against ischemia perfusion injury in kidney (26). Desidustat has been shown to be protective against adenine induced kidney injury (27). Diabetes and high blood pressure are major contributors to CKD. Desidustat alone or combination with SGLT2 inhibitor can improve other comorbid conditions that are associated with CKD, for example, but not limited to glomerulonephritis, pyelonephritis, acute and chronic renal injury, lupus nephritis, complement-mediated renal diseases, Atypical Hemolytic Uremic Syndrome (AHUS), C3 glomerulopathy (C3G), IgA nephropathy, membrane associated nephropathy, renal and cardiac failure, cerebral and cardiac stroke, anemia, mineral and bone disorders, and metabolic acidosis (28). Other complications related to CKD can also be an increased risk of infections, nerve damage, especially neuropathy or axonal degeneration. Studies suggest that PHD2 inhibitors like desidustat can improve sensorimotor outcomes and reduce neuroinflammation after stroke, especially in the context of CKD (29). SGLT2 inhibitors have been shown to reduce the risk of heart attack, stroke, and hospitalization for heart failure, particularly in patients with CKD (30).

[0012] The small molecule hypoxia-inducible factor stabilizer compound Desidustat (compound of formula (la)), inhibits the prolyl hydroxylase and has demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization. It also enhances erythroid maturation by suppressing hepcidin-ferroportin axis. Desidustat also showed antidiabetic effects in db / db mice, Streptozotocin (STZ) induced diabetic rats. Desidustat also protect kidney from ischemia perfusion injury and adenine induced CKD.

[0013] Several other prolyl hydroxylase inhibitors have been disclosed in EP661269, W02007070359, W02008076425, WO2011007856, WO2012106472, and WO2013043621. Specifically, W02004108681 and W02008002576 covers the prolyl hydroxylase inhibitors named Roxadustat and Vadadustat respectively.

[0014] These compounds are reported to be useful for the treatment of anemia. It has surprisingly now been found that compound of formula (la) as given below: formula (la) and its pharmaceutically acceptable salts are effective in the treatment of diabetes and diabetic CKD when combine with suitable SGLT2 inhibitor improve diabetes and diabetic CKD for the benefit of patients.

[0015] Embodiments of the invention

[0016] The present invention describes a combination of prolyl hydroxylase inhibitors or pharmaceutically acceptable salts thereof and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof.

[0017] In an embodiment the present invention provides a combination of compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof.

[0018] In an embodiment the present invention provides an additive or synergistic composition comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salt thereof is suitable for the treatment of diabetes or diabetic CKD.

[0019] In a still further embodiment is provided a pharmaceutical composition comprising, compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof according to the present invention, along with at least one suitable pharmaceutically acceptable carrier, diluents, vehicle or excipient.

[0020] In another embodiment, present invention provides use of combination of the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof for the treatment of diabetes and diabetic CKD. In an embodiment, the present invention provides a method of treating diabetic CKD using the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof.

[0021] In yet another embodiment the present invention provides the preparation of such compositions.

[0022] In one embodiment the present invention provides an additive or synergistic composition and combination comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor is dapagliflozin and pharmaceutically acceptable salts thereof.

[0023] In one embodiment the present invention provides an additive or synergistic composition and combination comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor is canagliflozin and pharmaceutically acceptable salts thereof.

[0024] In one embodiment the present invention provides an additive or synergistic composition and combination comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor is empagliflozin and pharmaceutically acceptable salts thereof.

[0025] Summary of the invention

[0026] The present invention describes an additive or synergistic composition and combination comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof for the treatment of diabetes and diabetic CKD and the associated symptoms like anemia. The invention also describes the preparation of such compositions and combinations.

[0027] Brief description of the drawings

[0028] Figure 1. The effect of Desidustat (compound of formula (la) or dapagliflozin or canagliflozin or empagliflozin alone and combinations of dapagliflozin or canagliflozin or empagliflozin with Desidustat (compound of formula (la) in AKI models of rats. Figure 2. The effect of desidustat (compound of formula (la)) or dapagliflozin or canagliflozin or empagliflozin alone and combinations of dapagliflozin or canagliflozin or empagliflozin with desidustat (compound of formula (la) on STZ induced diabetic CKD in wistar rats.

[0029] Figure 3. The effect of desidustat (compound of formula (la) or dapagliflozin or canagliflozin or empagliflozin alone and combinations of dapagliflozin or canagliflozin or empagliflozin with desidustat (compound of formula (la) on HFSTZ induced diabetic CKD in C57 mice.

[0030] Figure 4. The effect of desidustat (compound of formula (la) or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat (compound of formula (la) in db / db mice.

[0031] Figure 5. The effect of desidustat (compound of formula (la) or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat in adenine induced diabetic CKD in db / db mice.

[0032] Description of the Invention

[0033] The term ‘treating’ or ‘treatment’ or condition as used herein means: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and also include treating or preventing the disease condition.

[0034] The term "preventing" refers to barring a subject from acquiring a disorder or disease in the first place.

[0035] The term “combination” in the present invention is used as known to person skilled in the art. The combination comprises or consists of compound of formula (la) or pharmaceutically acceptable salts thereof or a polymorph thereof and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof, or a polymorph thereof. “Combination” for the purposes of the invention comprises fixed combinations, combination packs, kit-of-parts, non-fixed combinations and / or components (compound of formula (la), a SGLT2 inhibitor), which are administered simultaneously or sequentially.

[0036] The term 'pharmaceutically acceptable' use embraces both human and veterinary use.

[0037] Combination of a suitable prolyl hydroxylase inhibitor with a SGLT2 inhibitor The present invention describes a combination of prolyl hydroxylase inhibitors and a SGLT2 inhibitor suitable for the treatment of diabetic and other forms of CKD. In one embodiment, the prolyl hydroxylase inhibitors are selected from roxadustat, vadadustat, daprodustat, molidustat, enardustat and desidustat (compound of formula (la)).

[0038] In one embodiment the combination according to the invention comprises two or more SGLT2 inhibitors.

[0039] In one embodiment the SGLT2 inhibitor used in the combination according to the invention is selected from dapagliflozin, Canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergiflozin and tofogliflozin or pharmaceutically acceptable salts thereof.

[0040] In one embodiment the SGLT2 inhibitor used in the combination according to the invention is selected from dapagliflozin or its pharmaceutically acceptable salts, canagliflozin or its pharmaceutically acceptable salts and empagliflozin or its pharmaceutically acceptable salts.

[0041] In an embodiment, present invention provides a combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable SGLT2 inhibitor or pharmaceutically acceptable salts thereof, wherein formula (la) is represented by:

[0042] Formula (la) The pharmaceutical acceptable salts of the compound of formula (la) may be selected from suitable inorganic metal salts or organic amines salts.

[0043] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.

[0044] Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N- methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (25)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, (5)- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (5)-4-chlorophenylethylamine, (S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

[0045] A suitable SGLT2 inhibitor is selected from dapagliflozin or its pharmaceutically acceptable salts, canagliflozin or its pharmaceutically acceptable salts and empagliflozin or its pharmaceutically acceptable salts. Combination of compound of formula (la) or its pharmaceutically acceptable salts with a SGLT2 inhibitor

[0046] In an embodiment, present invention provides a combination of compound of formula (la) or its pharmaceutically acceptable salts with a SGLT2 inhibitor or pharmaceutical acceptable salts thereof, wherein formula (la) is represented by:

[0047] Formula (la)

[0048] The pharmaceutical acceptable salts of the compound of formula (la) may be selected from suitable inorganic metal salts or organic amines salts.

[0049] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.

[0050] Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N- methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (25)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, fS')- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (5)-4-chlorophenylethylamine, (*S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

[0051] A SGLT2 inhibitor is dapagliflozin or its pharmaceutically acceptable salts, canagliflozin or its pharmaceutically acceptable salts and empagliflozin or its pharmaceutically acceptable salts.

[0052] Mode of Administration

[0053] Combination as described above can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

[0054] An effective amount, e.g., dose, of combination compound or drug can readily be determined by routine experimentation, as can an effective and convenient route of administration and an appropriate formulation. Various formulations and drug delivery systems are available in the art. (See, e.g., Gennaro, ed. (2000) Remington's Pharmaceutical Sciences,; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.)

[0055] Suitable routes of administration may, for example, include oral, rectal, topical, nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intraarterial, intra-articular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred. In an embodiment the present invention provides the combination of compound of formula (la) and a SGLT2 inhibitors is administrated orally, intravenously or parentally in the subject who is in need of treatment.

[0056] In certain embodiments, the present invention provides the combination of compound of formula (la) and one or more SGLT2 inhibitors is administrated orally.

[0057] The effective amount of the compound of formula ((la), desidustat), roxadustat, vadadustat and daprodustat is selected from 1 mg to 500 mg preferably 1 mg to 250 mg and more preferably 4 mg to 50 mg.

[0058] In certain embodiments, the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about Img to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject.

[0059] In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.

[0060] The amount of dose in the range of about 1 mg to about 500 mg according to present disclosure include each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.25 4.5, 4.75, 5 etc.).

[0061] In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1 to 100 mg. In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1 to 50 mg. In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1 to 25 mg. In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg.

[0062] In a further embodiment, Dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, Canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

[0063] In one embodiment, dapagliflozin is administered orally to a subject in an amount of 1 mg. In a further embodiment canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 3 mg.

[0064] In certain embodiments, combination of compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.

[0065] In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 1 to 100 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg. In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 10 to 40 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg.

[0066] In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a and a SGLT2 inhibitor are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered simultaneously. Method of treating diabetes and diabetic CKD in combination of compound of formula (la) or its pharmaceutically acceptable salts with a SGLT2 inhibitor In an embodiment, the present invention provides a method of treating diabetes and diabetic CKD in a subject, comprising administering a combination of compound of formula (la) or its pharmaceutically acceptable salts with a suitable SGLT2 inhibitor.

[0067] The pharmaceutical acceptable salts of the compound of formula (la) may be selected from a suitable inorganic metal salts or organic amines salts.

[0068] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.

[0069] Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N- methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (25)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, (5)- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (5)-4-chlorophenylethylamine, (*S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

[0070] A suitable SGLT2 inhibitor is selected from dapagliflozin or its pharmaceutically acceptable salts, canagliflozin or its pharmaceutically acceptable salts and empagliflozin its pharmaceutically acceptable salts.

[0071] Combination as described above can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

[0072] In certain embodiments, the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about Img to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject.

[0073] In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.

[0074] The amount of dose in the range of about 1 mg to about 500 mg according to present disclosure include each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.25 4.5, 4.75, 5, etc.).

[0075] In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1 to 100 mg. In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1 to 50 mg. In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1 to 25 mg.

[0076] In one embodiment the combination according to the invention comprises a SGLT2 inhibitor in an amount of 1, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 mg.

[0077] In a further embodiment, Dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, Canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

[0078] In certain embodiments, combination of compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.

[0079] In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 1 to 100 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg. In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 10 to 40 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg.

[0080] In one embodiment, dapagliflozin is administered orally to a subject in an amount of 1 mg, In a further embodiment canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 3 mg.

[0081] In certain embodiments, combination of compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.

[0082] In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a and a SGLT2 inhibitor are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered simultaneously.

[0083] Pharmaceutical composition of compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor for use in treating diabetes and diabetic CKD

[0084] In an embodiment, present invention provides a pharmaceutical composition comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor or pharmaceutically acceptable salts thereof optionally with one or more pharmaceutically acceptable excipients for use in treating diabetes and diabetic CKD.

[0085] The pharmaceutical acceptable salts of the compound of formula (la) may be selected from suitable inorganic metal salts or organic amines salts.

[0086] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.

[0087] Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N- methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (25)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, (5)- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (5)-4-chlorophenylethylamine, (S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

[0088] A suitable SGLT2 inhibitor is selected from dapagliflozin or its pharmaceutically acceptable salts, canagliflozin or its pharmaceutically acceptable salts and empagliflozin its pharmaceutically acceptable salts.

[0089] In an embodiment pharmaceutical composition according to present invention can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

[0090] The pharmaceutical composition according to the present invention is in oral form. The pharmaceutically oral composition as described above or anywhere in the specification may be in the form of tablet, capsule and oral liquids.

[0091] In one embodiment, pharmaceutical acceptable salts of the Dapagliflozin may be selected from propylene glycolate hydrate / Dapagliflozin compound with (2s)- 1,2- propanediol hydrate.

[0092] In one embodiment, pharmaceutically acceptable excipients are selected at least one from diluent, binders, disintegrating agents, lubricating agents, glidant agent, coating redimix and the like.

[0093] Diluents include, but are not limited to lactose monohydrate, lactose, microcrystalline cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and preferably sulfobutyl ether b-cyclodextrin combinations thereof and other such materials known to those of ordinary skill in the art.

[0094] Binders include, but are not limited to hypromellose 3 Cps, carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein combinations thereof and other such materials known to those of ordinary skill in the art.

[0095] Disintegrating agents include, but are not limited to, croscarmellose Sodium, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate Sodium combinations thereof and other such materials known to those of ordinary skill in the art.

[0096] Glidant agents include, but are not limited to, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

[0097] Lubricant agents include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic Acid suitable combinations thereof and other such materials known to those of ordinary skill in the art.

[0098] Coating ready-mix is selected from Opadry Pink all such materials known to those of ordinary skill in the art.

[0099] In certain embodiments, the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject.

[0100] In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about Img to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject.

[0101] In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.

[0102] The amount of dose in the range of about 1 mg to about 500 mg according to present disclosure include each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.25 4.5, 4.75, 5, etc.).

[0103] In a further embodiment, Dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, Canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

[0104] In one embodiment, dapagliflozin is administered orally to a subject in an amount of 1 mg, In a further embodiment canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 3 mg.

[0105] In certain embodiments, combination of compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor can be further characterized according to the dose of compound administered to a subject, where subject is animal or human.

[0106] In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 1 to 100 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg. In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 10 to 40 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg.

[0107] In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a and a SGLT2 inhibitor are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered simultaneously. Use of compound of formula (la) or its pharmaceutically acceptable salts in combination with a SGLT2 inhibitor for use in treating diabetes and diabetic CKD.

[0108] In an embodiment, present invention provides use of combination of compound of formula (la) or its pharmaceutically acceptable salts with a SGLT2 inhibitor for treating diabetes and diabetic CKD.

[0109] The pharmaceutical acceptable salts of the compound of formula (la) may be selected from a suitable inorganic metal salts or organic amines salts.

[0110] The pharmaceutical acceptable salts of the compound of formula (la) may be selected from suitable inorganic metal salts or organic amines salts.

[0111] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium and the like.

[0112] Organic amines salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N- methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (25)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, a-naphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, (5)- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (5)-4-chlorophenylethylamine, (*S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2-hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- 1 adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2-aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

[0113] A suitable SGLT2 inhibitor is selected from dapagliflozin or its pharmaceutically acceptable salts, canagliflozin or its pharmaceutically acceptable salts and empagliflozin its pharmaceutically acceptable salts.

[0114] The pharmaceutically oral composition as described above or anywhere in the specification may be in the form of tablet, capsule and oral liquids.

[0115] In one embodiment, pharmaceutical acceptable salts of the Dapagliflozin may be selected from propylene glycolate hydrate / Dapagliflozin compound with (2s)- 1,2- propanediol hydrate.

[0116] In certain embodiments, the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about Img to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 225 mg to about 250 mg on each day the compound is administered to the subject.

[0117] In certain other embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (I) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide compound of formula (la) or a pharmaceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject.

[0118] The amount of dose in the range of about 1 mg to about 500 mg according to present disclosure include each integer and non-integer number between a particular range. The recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.25, 1.5, 1.75, 2.0, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4.0, 4.25 4.5, 4.75, 5, etc.).

[0119] In certain embodiments, combination of compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor can be further characterized according to the dose of compound administered to a subject, where subject is animal or human. In certain embodiments, dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

[0120] In one embodiment, dapagliflozin is administered orally to a subject in an amount of 1 mg, In a further embodiment canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 3 mg.

[0121] In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 1 to 100 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg. In one embodiment the combination according to the invention comprises compound of formula (la) in an amount 10 to 40 mg and a SGLT2 inhibitor in an amount of 0.5 to 50 mg.

[0122] In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered as one composition. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a and a SGLT2 inhibitor are administered separately. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered consecutively. In some embodiments, compounds of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitor are administered simultaneously.

[0123] The compound of formula (la) is known as desidustat. The compound of formula (la) may be prepared by any of the methods known in the art including those processes disclosed in the prior art such as those mentioned elsewhere in the specification. Dapagliflozin may be prepared by any of the methods known in the art including those processes disclosed in the prior art such as those mentioned elsewhere in the specification. Example 1

[0124] Desidustat (compound of formula (la) (15 mg / kg) or dapagliflozin (1 mg / kg) or canagliflozin (3 mg / kg) or empagliflozin (3mg / kg) or their combination with desidustat or vehicle in AKI induced by ischemia induced perfusion injury in Sprague Dawley rats. Serum was collected after 24 h after AKI and used to assay creatinine.

[0125] Results of Example 1

[0126] Table 1. The effect of Desidustat (compound of formula (la)) or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat in AKI models of rats.

[0127] TablmlA

[0128] Twenty-four hours after AKI rats showed increased serum creatinine against normal control rats. Administration of formulated Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and combination decreased elevated serum creatinine in AKI rats by 33.3, 35.3 and 56.8 %, respectively against vehicle (Figure 1A). Administration of formulated canagliflozin 3 mg / kg and its combination with desidustat decreased elevated serum creatinine in AKI rats by 29.1 and 50.6 %, respectively against vehicle (Figure IB). Administration of formulated empagliflozin 3 mg / kg and its combination with desidustat decreased elevated serum creatinine in AKI rats by 27.2 and 48.6 % (Figure IB) respectively against vehicle.

[0129] Example 2

[0130] Diabetic nephropathy was induced in wistar rats with single dose streptozotocin (50 mg / kg, intraperitoneal). One week after streptozotocin administration, animals were dosed orally with Desidustat (compound of formula (la)) (15 mg / kg) or dapagliflozin (1 mg / kg) or canagliflozin (3 mg / kg) or empagliflozin (3 mg / kg) or their combination or vehicle daily once for 12 weeks. Fluorescein isothiocyanate- labeled inulin (FITC-Inulin) clearance was used to estimate glomerular filtration rate (GFR). Briefly, 5% (w / v) FITC-inulin dissolved in 0.9% (w / v) saline was dialyzed (1000 MWCO) overnight and sterilized by filtration (0.2 mm). Anesthetized rats received a bolus (25 mg / kg, BW) of FITC-inulin via tail-vein injections. Blood samples (<150 pL) were collected by the retroorbital puncture into heparinized tubes, and centrifuged for 10 minutes at 10,000 RPM. Blood sampling was carried out at 3, 7, 10, 15-, 35-, 55- and 75-minutes post injection. Samples were buffered in 500 mM HEPES pH 7.4 and plasma fluorescence was measured (Excitation 485 nm / Emission 528 nm). Data was analyzed to calculate GFR with appropriate software (e.g. GraphPad Prism) by using a two-phase exponential decay function. At the end of treatment urine were collected for a day to determine urinary albumin. Serum was used to assay biochemistry.

[0131] Results of Example 2

[0132] Table 2. The effect of desidustat (compound of formula (la)) or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat on STZ-induced diabetic CKD in wistar rats.

[0133]

[0134] Treatment with Desidustat at 15 mg / kg, Dapagliflozin 1 mg / kg and combination in STZ treated rats decreased microalbumin by 30.6, 35.4 and 61.4 % (Figure 2A) respectively against vehicle. Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and combination treatment decreased serum creatinine by 12.3, 16.5 and 27.7 % (Figure 2B) respectively against vehicle. Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and combination treatment decreased serum BUN by 28.7, 36.7 and 69.7 % (Figure 2C) respectively against vehicle. Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination treated rats increased creatinine clearance by 32.1, 44.0 and 77.6 % (Figure 2D) and BUN clearance by 80.1, 87.4 and 109.9 % (Figure 2E) respectively against vehicle. Desidustat 15 mg / kg, dapagliflozin 1 mg / kg and combination showed decreased hyperfiltration (GFR) by 38.2, 47.6 and 78.1 % (Figure 2F) and serum glucose by 25.5, 33.8 and 43.8 % (Figure 2G) respectively against vehicle.

[0135] Treatment with canagliflozin 3 mg / kg and its combination with desidustat in STZ treated rats decreased microalbumin by 28.8 and 54.7 % (Figure 2H), decreased serum creatinine by 7.7 and 21.1 % (Figure 21) and decreased serum BUN by 25.2 and 59.6 % (Figure 2J) respectively against vehicle. Canagliflozin 3 mg / kg and combination with desidustat treated rats increased creatinine clearance by 33.2 and 62.1 % (Figure 2K), and BUN clearance by 88.2 and 107.3 % (Figure 2L) respectively against vehicle. Canagliflozin 3 mg / kg and combination with desidustat showed decreased hyperfiltration (GFR) by 44.7 and 67.9 % (Figure 2M) and serum glucose by 33.6 and 42.1 % (Figure 2N) respectively against vehicle.

[0136] Treatment with empagliflozin 3 mg / kg and its combination with Desidustat in STZ treated rats decreased microalbumin by 27.2 and 48.6 % (Figure 20), serum creatinine by 15.4 and 25.5 % (Figure 2P) and serum BUN by 32.6 and 61.5 % (Figure 2Q) respectively against vehicle. Empagliflozin 3 mg / kg and combination with desidustat treated rats increased creatinine clearance by 44 and 77.6 % (Figure 2R), and BUN clearance by 87.4 and 109.9 % (Figure 2S) respectively against vehicle. Empagliflozin 3 mg / kg and combination with desidustat showed decreased hyperfiltration (GFR) by 49.1 and 73.8 %, respectively (Figure 2T) and serum glucose by 37.1 and 45.3 % (Figure 2U) respectively against vehicle.

[0137] Example 3

[0138] Diabetic nephropathy was induced in male C57 mice after 8 weeks high fat diet and multiple low dose streptozotocin (MLDS) 40 mg / kg, daily for 5 days by intraperitoneal route. Three weeks after streptozotocin administration, animals were dosed orally with Desidustat (15 mg / kg) or dapagliflozin (1 mg / kg) or canagliflozin (3 mg / kg) or empagliflozin (3 mg / kg) or their combination or vehicle daily once for 7 days. Whole blood samples were collected in EDTA containing tubes by the retro- orbital puncture for hemoglobin, % HCT and % HbAlc. Another set of blood were collected for serum biochemistry. Results of Example 3

[0139] Table 3. The effect of desidustat (compound of formula (la)) or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat on HFSTZ-induced diabetic

[0140] CKD in C57 mice. Treatment with Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and combination in STZ treated mice decreased serum glucose by 39.4, 45.3 and 55.1% (Figure 3 A) and % HbAlc by 14.3, 17.5 and 23.2 % (Figure 3B) respectively against vehicle. Treatment with Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination in STZ treated mice improved kidney function by decreasing serum creatinine by 30.8, 26.4 and 37.7% (Figure 3C) and decreased serum urea by 15.5, 22.4 and 26.0 % (Figure 3D) respectively against vehicle. Treatment with Desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination in STZ treated mice also improved hemoglobin by 20.8, 2.1 and 18.0 % (Figure 3E) and increased % HCT by 19.3, 0.8 and 18.1 % (Figure 3F) respectively against vehicle.

[0141] Treatment with Canagliflozin 3 mg / kg and its combination with desidustat in STZ treated mice decreased serum glucose by 33.2 and 55.1% (Figure 3G) and % HbAlc by 13.7 and 23.2 % (Figure 3H) respectively against vehicle. Treatment with canagliflozin 3 mg / kg and its combination with desidustat in STZ treated mice improved kidney function by decreasing serum creatinine by 21.1 and 40.3% (Figure 31) and serum urea by 17.5 and 29.7 % (Figure 3 J) respectively against vehicle. Treatment with canagliflozin 3 mg / kg and combination in STZ treated mice also improved hemoglobin by 4.8 and 20.8 % (Figure 3K) and % HCT by 4.3 and 19.9 % (Figure 3L) respectively against vehicle.

[0142] Treatment with empagliflozin 3 mg / kg and its combination with Desidustat in STZ treated mice decreased serum glucose by 50.5 and 58.2% (Figure 3M) and % HbAlc by 18.5 and 24.5 % (Figure 3N) respectively against vehicle. Treatment with empagliflozin 3 mg / kg and its combination with desidustat in STZ treated mice improved kidney function by decreasing serum creatinine by 33.0 and 43.6% (Figure 30) and serum urea by 24.6 and 29.7 % (Figure 3P) respectively against vehicle. Treatment with empagliflozin 3 mg / kg and its combination with desidustat in STZ treated mice also improved hemoglobin by 4.9 and 21.3 % (Figure 3Q) and % HCT by 4.3 and 19.9 % (Figure 3R) respectively against vehicle. Example 4

[0143] Diabetic db / db mice treated with Desidustat (compound of Formula (la)) (15 mg / kg) or dapagliflozin (1 mg / kg) or canagliflozin (3 mg / kg) or empagliflozin (3 mg / kg) or their combination or vehicle daily once for 28 days. At the end of treatment urine were collected for a day to determine urinary albumin. Whole blood samples were collected in EDTA containing tubes by the retro-orbital puncture for hemoglobin. Another set of blood was collected and serum was used to assay biochemistry.

[0144] Results of Example 4

[0145] Table 4. The effect of desidustat (compound of formula (la)) or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat in db / db mice.

[0146]

[0147] Treatment with desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination in db / db mice decreased serum glucose by 22.6, 28.0 and 41.6 % respectively (Figure 4A), and increased hemoglobin by 7.8, -1.0 and 8.1 % (Figure 4B) respectively against vehicle. Treatment with desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination in db / db mice improved kidney function by decreasing serum creatinine by 44.7, 3 0.5 and 57.3 % (Figure 4C) and decreased serum urea by 33.3, 24.6 and 56.6 % (Figure 4D) respectively against vehicle. Treatment with desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination in db / db mice also decreased urine microalbumin by 32.5, 41.3 and 59.1 % (Figure 4E) respectively against vehicle.

[0148] Treatment with canagliflozin 3 mg / kg and its combination with desidustat in db / db mice decreased serum glucose by 22.6 and 45.9 % (Figure 4F), and increased hemoglobin by 1.1 and 8.9 % (Figure 4G) respectively against vehicle. Treatment with canagliflozin 3 mg / kg and its combination with desidustat in db / db mice improved kidney function by decreasing serum creatinine by 37.4 and 61.4 % (Figure 4H), and serum urea by 33.3 and 58.3 % (Figure 41) respectively against vehicle. Treatment with canagliflozin 3 mg / kg and its combination with desidustat in db / db mice also decreased urine microalbumin by 46.7 and 60.4 % respectively (Figure 4J) against vehicle.

[0149] Treatment with empagliflozin 3 mg / kg and its combination with Desidustat in db / db mice decreased serum glucose by 36.3 and 47.0 % (Figure 4K) and increased hemoglobin by 0.2 and 10.5 % (Figure 4L) respectively against vehicle. Treatment with empagliflozin 3 mg / kg and its combination with desidustat in db / db mice improved kidney function by decreasing serum creatinine by 35.4 and 59.4 % (Figure 4M), and serum urea by 34.9 and 59.4 % (Figure 4N) respectively against vehicle. Treatment with empagliflozin 3 mg / kg and its combination with desidustat in db / db mice also decreased urine microalbumin by 50.2 and 61.2 % (Figure 4J) respectively against vehicle.

[0150] Example 5

[0151] Diabetic CKD was induced in male db / db mice by oral administration of formulated adenine 50mg / kg for 7 days. After last dose adenine administration, animals were dosed orally with Desidustat (15 mg / kg) or dapagliflozin (1 mg / kg) or canagliflozin (3 mg / kg) or Empagliflozin (3 mg / kg) or their combination or vehicle daily once for 28 days. At the end of drug treatment blood were collected for serum biochemistry and 24h urine was collected for urine microalbumin.

[0152] Results of Example 5

[0153] Table 5. The effect of desidustat (compound of formula (la)), or dapagliflozin or canagliflozin or empagliflozin alone and combination of dapagliflozin or canagliflozin or empagliflozin with desidustat in adenine-induced diabetic CKD in db / db mice.

[0154] Adenine administered db / db mice showed increased serum creatinine, serum urea, urine microalbumin and decreased GFR against normal control non-diabetic mice. Administration of formulated desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and combination decreased elevated serum creatinine in adenine administered mice by 36.9, 41.6 and 55.1 % (Figure 5A) and reduced serum urea by 44.2, 42.2 and 52.4% (Figure 5B) respectively against vehicle. Treatment with desidustat at 15 mg / kg, dapagliflozin 1 mg / kg and its combination in db / db mice also decreased microalbumin by 37.9, 37.1 and 59.1 % (Figure 5C) and increased eGFR by 28.4, 33.0 and 69.7 % (Figure 5D) respectively against vehicle.

[0155] Canagliflozin 3 mg / kg and its combination with Desidustat decreased elevated serum creatinine in adenine administered mice by 31.3 and 48.9 % (Figure 5E) and serum urea by 36.0 and 50.9% (Figure 5F) respectively against vehicle. Treatment with canagliflozin 3 mg / kg and its combination with desidustat in db / db mice also decreased microalbumin by 29.9 and 56.2 % (Figure 5G) and increased eGFR by 40.2 and 77.9 % (Figure 5H) respectively against vehicle.

[0156] Empagliflozin 3 mg / kg and its combination with desidustat decreased elevated serum creatinine in adenine administered mice by 45.8 and 59.2 % (Figure 51), and serum urea by 45.3 and 58.7% (Figure 5J) respectively against vehicle. Treatment with empagliflozin 3 mg / kg and its combination with desidustat in db / db mice also decreased microalbumin by 46.9 and 67.2 % (Figure 5K) and increased eGFR by 57.0 and 67.8 % (Figure 5L) respectively against vehicle.

[0157] Conclusion: Combination of desidustat (compound of Formula (la)) with dapagliflozin or canagliflozin or empagliflozin showed additive effects on all the models we tested. Combination treatment was better effects than alone treated with Desidustat (compound of Formula (la)) or SGLT2 inhibitors dapagliflozin or canagliflozin or empagliflozin for improving acute AKI induced nephropathy and chronic models of diabetic nephropathy. References: Asiimwe D, Mauti GO, Kiconco R. Prevalence and risk factors associated with type 2 diabetes in elderly patients aged 45-80 years at Kanungu District. Journal of diabetes research. 2020 Jan 30;2020: l-5. Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nature reviews nephrology. 2020 Jul;16(7):377-90. American Diabetes Association Professional Practice Committee, American Diabetes Association Professional Practice Committee:. 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes — 2022. Diabetes care.

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An update on SGLT2 inhibitors for the treatment of diabetes mellitus. Current opinion in endocrinology, diabetes, and obesity. 2017 Feb;24(l):73. Bessho R, Takiyama Y, Takiyama T, Kitsunai H, Takeda Y, Sakagami H, Ota T. Hypoxia-inducible factor- la is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Scientific reports. 2019 Oct 14;9(1): 14754. Packer M. Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney: modulation by SGLT2 inhibitors and hypoxia mimetics. American Journal of Kidney Diseases. 2021 Feb l;77(2):280-6. Heerspink HJ, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JF, McMurray JJ, Lindberg M, Rossing P, Sjbstrbm CD. Dapagliflozin in patients with chronic kidney disease. New England Journal of Medicine. 2020 Oct 8;383(15): 1436-46. Chang DY, Li XQ, Chen M, Zhao MH. 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Scientific reports. 2022 Nov 11; 12(1): 19323. Lee KA, Jin HY, Lee NY, Kim YJ, Park TS. Effect of empagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, on kidney and peripheral nerves in streptozotocin-induced diabetic rats. Diabetes & metabolism journal. 2018 Apr 25;42(4):338. Sugahara M, Tanaka S, Tanaka T, Saito H, Ishimoto Y, Wakashima T, Ueda M, Fukui K, Shimizu A, Inagi R, Yamauchi T. Prolyl hydroxylase domain inhibitor protects against metabolic disorders and associated kidney disease in obese type 2 diabetic mice. Journal of the American Society of Nephrology: JASN. 2020 Mar;31(3):560. Rahtu-Korpela L, Karsikas S, Hbrkkb S, Blanco Sequeiros R, Lammentausta E, Makela KA, Herzig KH, Walkinshaw G, Kivirikko KI, Myllyharju J, Serpi R. HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. Diabetes. 2014 Oct l;63(10):3324-33. 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Claims

We claim:

1. A combination comprising a prolyl hydroxylase inhibitors or pharmaceutically acceptable salt thereof and a SGLT2 inhibitors or pharmaceutically acceptable thereof.

2. A combination as claimed in claim 1, wherein a prolyl hydroxylase inhibitor is selected from roxadustat, vadadustat, daprodustat, Molidustat, enarudustat and desidustat (compound of formula (la)) or its pharmaceutically acceptable salts.

3. A combination as claimed in claim 1, wherein the SGLT2 inhibitors is selected from dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergiflozin and topogliflozin or pharmaceutically acceptable salts thereof.

4. A combination as claimed in claim 1 to 3, wherein the SGLT2 inhibitors is selected from dapagliflozin or its pharmaceutically acceptable salts, empagliflozin or its pharmaceutically acceptable salts, and canagliflozin or its pharmaceutically acceptable salts.

5. A combination comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT2 inhibitors or pharmaceutically acceptable salts thereof, wherein formula (la) is represented by:formula (la)6. A combination as claimed in claim 5, wherein the pharmaceutically acceptable salts of the compound of formula (la) is selected from a suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropylamine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N- methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, anaphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, (S)- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (S)-4- chlorophenylethylamine, (S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)- quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2- hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2- aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

7. A combination as claimed in claim 5, wherein the SGLT2 inhibitors is selected from dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergiflozin and topogliflozin or pharmaceutically acceptable salts thereof.

8. A combination as claimed in claim 5, wherein the SGLT2 inhibitors is selected from dapagliflozin or its pharmaceutically acceptable salts, empagliflozin or its pharmaceutically acceptable salts, and canagliflozin or its pharmaceutically acceptable salts.

9. A combination as claimed in claim 5 can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

10. A combination as claimed in claim 5, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT 2 inhibitor is administered orally as one composition, separately, consecutively or simultaneously.

11. A combination as claimed in claim 5, wherein the compound of formula (la) or its pharmaceutically acceptable salts administered orally to a subject in an amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject.

12. A combination as claimed in claim 5, wherein dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, Canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

13. A combination as claimed in claim 5, wherein dapagliflozin is administered orally to a subject in an amount of 1 mg. In a further embodiment, Canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, Empagliflozin is administered orally to a subject in an amount of about 3 mg.

14. A method of treating diabetes and diabetic CKD in a subject, comprising administering a combination of compound of formula (la) or its pharmaceutically acceptable salts with a SGLT2 inhibitor or pharmaceutically acceptable salt.

15. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein the pharmaceutically acceptable salts of the compound of formula (la) is selected from a suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t- butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N- trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene methanamine, ethanolamine, diethanolamine, tris- (hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N- methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3- dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, anaphthylamine, O- phenylenediamine, 1,3-Diaminopropane, (S)-a-naphthylethylamine, (S)-3- methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4- chlorophenylethylamine, (S)-4-methylphenylethylamine, cinchonine, cinchonidine, (-)- quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2- hydroxyethyl), N-N-diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L-adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2- aminoethoxy)ethanamine, N-methylmorpholine, and N-ethylmorpholine.

16. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein the SGLT2 inhibitors is selected from dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergiflozin and topogliflozin or pharmaceutically acceptable salts thereof.

17. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein the SGLT2 inhibitors is selected from dapagliflozin or its pharmaceutically acceptable salts, empagliflozin or its pharmaceutically acceptable salts, and canagliflozin or its pharmaceutically acceptable salts.

18. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14 can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

19. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT 2 inhibitor is administered orally as one composition, separately, consecutively or simultaneously.

20. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein the compound of formula (la) or its pharmaceutically acceptable salts administered orally to a subject in an amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject.

21. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

22. A method of treating diabetes and diabetic CKD in a subject as claimed in claim 14, wherein dapagliflozin is administered orally to a subject in an amount of 1 mg. In a further embodiment, canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, empagliflozin is administered orally to a subject in an amount of about 3 mg.

23. A pharmaceutical composition comprising compound of formula (la) or its pharmaceutically acceptable salts and a SGLT 2 inhibitor or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients for use in treating diabetes and diabetic CKD.

24. A pharmaceutical composition for use as claimed in claim 23, wherein the pharmaceutically acceptable salts of the compound of formula (la) is selected from a suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N-methyl isopropyl amine, n-butyl amine, t-butyl amine, 2- butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine,hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2- butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, anaphthylamine, O-phenylenediamine, 1,3- Diaminopropane, (S)-a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)- 4-methoxyphenylethylamine, (S)-4- chlorophenylethylamine, (S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)- quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2- hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2- aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

25. The pharmaceutical composition for use as claimed in claim 23, wherein the SGLT2 inhibitors is selected from dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergiflozin and topogliflozin or pharmaceutically acceptable salts thereof.

26. The pharmaceutical composition for use as claimed in claim 25, wherein the SGLT 2 inhibitor is selected from Dapagliflozin or its pharmaceutically acceptable salts, Empagliflozin or its pharmaceutically acceptable salts and Canagliflozin or its pharmaceutically acceptable salts.

27. The pharmaceutical composition for use as claimed in claim 23 is in the form of oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

28. The pharmaceutical composition for use as claimed in claim 23 is in oral form.

29. The pharmaceutical composition for use as claimed in claim 23, wherein the pharmaceutically acceptable excipient is selected from diluent, binders, disintegrating agents, lubricating agents, glidant agent, coating redimix; wherein diluent is selected from lactose monohydrate, lactose, microcrystalline cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride, spray dried lactose, and preferably sulfobutyl ether b-cyclodextrin; binder is selected from hypromellose 3 Cps, carbomers selected from carbopol, gellan, gum Arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein; Disintegrate is selected from croscarmellose Sodium, bicarbonate salt, chitin, gellan gum, polacrillin potassium and docusate Sodium; Glidant is selected from colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc; lubricant agent is selected from calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic Acid; Coating ready-mix is selected from Opadry Pink.

30. The pharmaceutical composition for use as claimed in claim 23, wherein the compound of formula (la) or its pharmaceutically acceptable salts is administered orally to a subject in amount of 1 mg to 500 mg or 50 mg to 450 mg or 100 mg to 400 mg or 150 mg to 350 mg or 200 mg to 300 mg or 1 mg to 50 mg or 1 mg to 25 mg to the subject.

31. The pharmaceutical composition for use as claimed in claim 23, wherein the SGLT 2 inhibitor is selected from Dapagliflozin or its pharmaceutically acceptable salts, Empagliflozin or its pharmaceutically acceptable salts and Canagliflozin or its pharmaceutically acceptable salts.

32. The pharmaceutical composition for use as claimed in claim 23, wherein combination of the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT 2 inhibitor is administered orally to a subject, where subject is animal or human.

33. The pharmaceutical composition for use as claimed in claim 23, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT 2 inhibitor is administered orally as one composition, separately, consecutively or simultaneously.

34. Use of combination of compound of formula (la) or its pharmaceutically acceptable salts with a SGLT2 inhibitor or pharmaceutically acceptable salt for treating diabetes and diabetic CKD.

35. Use of combination as claimed in claim 34, wherein the pharmaceutically acceptable salts of the compound of formula (la) is selected from a suitable inorganic metal salts or organic amines salts; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, N- methyl isopropyl amine, n-butyl amine, t-butyl amine, 2-butamine, 1,2-ethane diamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4- aminobutyl) guanidine, dicyclohexylamine, benzene methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4- methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2- aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, cycloheptanamine, meglumine, benethamine, dibenzylamine, diphenylamine, anaphthylamine, O-phenylenediamine, 1,3 -Diaminopropane, (S)- a-naphthylethylamine, (S)-3 -methoxyphenylethylamine, (S)-4- methoxyphenylethylamine, (S)-4- chlorophenylethylamine, (S)-4- methylphenylethylamine, cinchonine, cinchonidine, (-)- quinine, triethanolamine, imidazole, ethylenediamine, epolamine, morpholine 4-(2- hydroxyethyl), N-N- diethylethanolamine, deanol, hydrabamine, betaine, adamantanamine, L- adamantanmethylamine, tritylamine, glucamine, N-methyl pyrrolidine, urea, procaine, metformin, hexane- 1-6-diamine, 2-(2- aminoethoxy)ethanamine, N- methylmorpholine, and N-ethylmorpholine.

36. Use of combination as claimed in claim 34, wherein the SGLT2 inhibitors is selected from dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin, sergiflozin and topogliflozin or pharmaceutically acceptable salts thereof.

37. Use of combination as claimed in claim 34, wherein the SGLT2 inhibitors is selected from dapagliflozin or its pharmaceutically acceptable salts, empagliflozin or its pharmaceutically acceptable salts, and canagliflozin or its pharmaceutically acceptable salts.

38. Use of combination as claimed in claim 34 can be administered as oral, rectal, topical, nasal, pulmonary, ocular, intestinal or parenteral.

39. Use of combination as claimed in claim 34, wherein the compound of formula (la) or its pharmaceutically acceptable salts and a SGLT 2 inhibitor is administered orally as one composition, separately, consecutively or simultaneously.

40. Use of combination as claimed in claim 34, wherein the compound of formula (la) or its pharmaceutically acceptable salts administered orally to a subject in an amount of 1 mg to 500 mg or, 1 mg to 250 mg or 1 mg to 150 mg or 1 mg to 100 mg or 1 mg to 50 mg or 1 mg to 25 mg or 25 mg to 50 mg or 100 mg to 150 mg or 200 mg to 350 mg to the subject.

41. Use of combination as claimed in claim 34, wherein dapagliflozin is administered orally to a subject in an amount of 0.5 to 50 mg. In a further embodiment, canagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, empagliflozin is administered orally to a subject in an amount of about 1 mg to 100 mg.

42. Use of a combination as claimed in claim 34, wherein dapagliflozin is administered orally to a subject in an amount of 1 mg. In a further embodiment, canagliflozin is administered orally to a subject in an amount of about 3 mg. In a further embodiment, empagliflozin is administered orally to a subject in an amount of about 3 mg.

43. A method of treatment for preventing and / or treatment of diseases in a subject in need thereof using the combination according to any one of claims 1 to 42.

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