AMIDE GLYCOSIDES

This application claims the benefit of Indian Provisional Patent Application No. 1933/CHE/2008, filed August 11, 2008, which is incorporated herein by reference. Field of the Invention

The invention relates to O-glucosylated amide derivatives, which are inhibitors of Sodium dependent glucose co transporter (SGLT), particularly SGLT2.

Background of the Invention Diabetes is one of lifestyle-related diseases with the background of change of eating habit and lack of exercise. Hence, diet and exercise therapies are perfoπned in patients with diabetes. Approximately 200 million people worldwide suffer from Type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes of which are as yet not clearly understood. Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder characterized by impaired insulin secretion in response to glucose, increased hepatic glucose production, and decreased insulin-dependent glucose uptake in the peripheral tissues or insulin resistance. The prevalence of T2DM is reaching epidemic proportion with more than 194 million cases reported in 2003, expected to increase to 333 million by 2025 (Phannacother.; 118(2): 181-

191; 2008). The prolonged hyperglycemia in combination with insulin resistance, causes microvascular and macrovascular damage, which is a cause of considerable morbidity and mortality. Although, diet and exercise are the cornerstones of treatment in order to correct obesity and hyperglycemia, about 40 to 60 % of newly treated patients do not respond adequately or fail to comply with diet.

In recent years, development of new type antidiabetic agents has been progressing, which promote urinary glucose excretion and lower blood glucose level by preventing excess glucose reabsorption at the kidney (J. Clin. Invest., Vol. 79, pp. 1510-1515 (1987)). Sodium dependent glucose transporter-2 (SGLT2) is present in the Sl segment of the lddney's proximal tubule, participates mainly in reabsorption of glucose filtrated through glomerular (J. Clin. Invest, Vol. 93, pp. 397-404 (1994)). Accordingly, inhibiting a human SGLT2 activity prevents reabsorption of excess glucose at the kidney, subsequently promotes excreting excess glucose though the urine, and normalizes blood glucose level. Therefore, fast development of antidiabetic agents, which have a potent inhibitory activity in human SGLT2 is desired. In addition, since such agents promote the excretion of excess glucose though the urine and consequently the glucose accumulation in the body is decreased, they are also expected to have a preventing or alleviating effect on obesity and a urinating effect. Furthermore, the agents are considered to be useful for various related diseases which occur accompanying the progress of diabetes or obesity due to hyperglycemia. Since SGLT-2 inhibitors do not stimulate insulin secretion; therefore, they would be expected to have a low hypoglycemia risk (Intl journal of clinical practice; 62 (8), 1279-1284, 2008). In the recent past, many articles were published in various journals on SGLT inhibitors {Diabetes, 2008, 57, 1723-24; Diabetes, obesity and metabolism, 11, 2009, 79-88; and Diabetes, 1999, 48, 1794-1800). European journal of Pharmacology, 391 (2000), 183-192, Nature protocols, 2007, 2(6), 1356-59 described some preliminary assay methods to evaluate the compounds potential such as inhibition of Na+-glucose co transporter activity in brush border membrane vesicles (BBMVs) and Isolation of renal proximal tubular brush-border membranes.

It is thus believed that SGLT2 inhibitors may be relevant with respect to diabetes, diabetic complications or obesity. PCT Publications Nos. WO 01//016147,

WO 01/074835, WO 02/068439, WO 02/083066, WO 03/020737, WO 03/080635, WO 04/063209, WO 04/089967, WO 06//034489, WO 08/072726, WO 08/116195,

WO 08/122014, WO 08/101939 and WO 08/144346; US patent application/patent Nos. US 7,476,671, US 7,439,232, US 2006/0194809 and US 2008/0132563; EP patent application/patent Nos. EP 150621 IBl, EP 1224195B1, EP 1268502B1, EP 1268503A1, EP 1581543A4 and EP 1685147A4 disclose SGLT2 inhibitors, for treatment of various diseases mediated by SGLT2.

Also some disclosures and publications on various aspects of SGLT are as follows: Biochem.Biophys Acta 1975 ,554,259-263; Diabetes, vol.48, (1999), 1794- 1800; IntJ.Med Sci.2007, (3)131-139; Biol. & Pharma.Bulletin, 2000, 23, 1434; British J.of pharmacology 2001, 32,578-586; AmJ.Physiol.Endocrinol.Metab.2000.280, 535; Clin. & Experi. Pharmacology & physiology 2002, 9, 86; J.Med.cheml999, 42(26) 5311-5324; J.Med.chem2008, 51, 145-1149; Nature protocols 2007, 2(5), 356-1359; US 6,555,519; Bioorganic & Medicinal chemistry Letters 2003, 3, 269 - 2272; US 6,414,126 Bl; US 6,683,056 B2; International Journal of medical Sciences 2006, 3(3), 84-91; J.Clin.Invest.1994, 93,397-404; The Journal of Pharmacology and Experimental Therapeutics 2007, 320(1), 323-330; The Journal of Biological Chemistry 1995, 270 (49), 29365-29371; Life Sciences 2005; 76, 2655-2668; Bioorganic & Medicinal chemistry Letters 2005, 15, 2655 - 2668; The Journal of Biological Chemistry 1993, 268 (3), 1509- 1512; Tetrahedron Letters 2000; 41, 9213-9217; Life Sciences 2005, 76, 1039-1050;

Biol. Pharm. Bull 2006, 29(1), 114-118; Bioorganic & Medicinal chemistry Letters

2003, 13, 2269 - 2272; Drags of the future 2001, 26(8), 750; Drags of the future

2004, 29, 461-466; Proc.Natl.Acad.Sci USA 2003, 100 (20); 11753-11758; Annu.Rev.Nutr. 1996, 16, 235; J.Bio.chem 1994, 219, 753; Diabetes 1997, 46, 1667; Trends in cell biogy 2001, 11, 173; Proc.Natl.Acad.Sci USA 1989, 86, 5748; Biol.

& Pharma. Bull. 2000, 23, 1434; British. J. Pharm 2001, 132, 578; AmJ.physiol.Endcri.Metab.2000, 278, E-53; AmJ.physiol.Endcri.Metab.2000, 278, E-816; Bio chem.Biophy.Res.Commun.1999, 266, 252; Clin. & Experi. Pharmacology & physiology 2002, 29, 386; Chem. Pharm.Bulll996, 44, 1174-1180; and Chem. Pharm. Bull 1998, 46, 22-33; or Chem. Pharm. Bull 1998, 46, 1545-

1555.

Inhibition of SGLT2 for treating diabetes is a new approach, and there still exists a need and scope to discover new drugs with novel chemical structures for therapeutic treatment of diseases, conditions and/or disorders by inhibiting SGLT2. Summary of the Invention

The present invention relates to O-glucosylated amide compounds of the formula (1):

wherein, n can be an integer 0 to 4 (wherein, one or two of the methylene groups are optionally substituted by identical are different groups which can be selected from methyl, ethyl, CO, SO ₂ , fluoro, or trifluoromethyl); R ₃ can be methyl or trifluoromethyl;

R ₁ , R ₂ , R ₄ , R ₅ , and R ₆ are independently can be selected from H, halogen, substituted or unsubstitutedunsubstituted alkyl, -OH, 0-substituted or unsubstitutedunsubstituted allcyl, O-substituted or unsubstituted aryl, O-α or β-D- glucopyranosyl group, α or β-D-glucopyranosyl group (wherein, one or more hydroxyl groups may be acylated) or β-D-glucouronyl group (wherein, one or more hydroxyl groups may be acylated or carboxyl group may be esterified), OCH ₂ - substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, CF ₃ , SCF ₃ ,

OCHF ₂ , OCF ₃ , CN, OR ₇ , CO ₂ R ₇ , CO ₂ H, CONR ₇ R ₈ , NR ₇ R ₈ , SO ₂ NH ₂ , NHCOR ₇ , NHSO ₂ R ₇ , NHSO ₂ -aryl, SR ₇ , SOR ₇ , substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted biaryl, or substituted or unsubstituted 9 or 10-membered fused bicyclyl or fused heterobicyclyl

(wherein each fused heterobicyclyl has 1 to 4 heteroatoms selected from N, O, and

S);

together also represents P, wherein P can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; further R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ groups can be in each occurrence independently either identical groups or different groups, and they can be present one or more than one time on the phenyl ring;

R ₇ and Rs are independently can be selected from, hydrogen, substituted or un substituted alkyl, substituted or un substituted aryl, substituted or unsubstituted arylalkyl or substituted or unsubstituted cycloalkyl groups.

Pharmaceutically acceptable salts of the compounds of the formula (1) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1) are contemplated.

It should be understood that the formula (1) structurally encompasses all isomers, stereoisomers, including enantiomers and diastereomers, that may be contemplated from the chemical structure of the genus described herein.

Also contemplated are prodrugs of the compounds of the formula (1), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (1), wherein R ₁ is hydrogen, or methoxy. According to one embodiment, there is provided a compound of formula (1), wherein R ₂ is hydrogen, O-α or β-D-glucopyranosyl group or α or β-D- glucopyranosyl group wherein, one or more hydroxyl groups may be acylated.

According to one embodiment, there is provided a compound of formula (1), wherein R ₃ is methyl.

According to one embodiment, there is provided a compound of formula (1), wherein R ₄ is hydrogen or halogen.

According to one embodiment, there is provided a compound of formula (1), wherein R ₅ is hydrogen or halogen methyl, ethyl, methoxy, trifluoromethyl or halogen.

According to one embodiment, there is provided a compound of formula (1), wherein Re is hydrogen, or α or β-D-glucopyranosyl group wherein, one or more hydroxyl groups may be acylated.

According to one embodiment, there is provided a compound of formula (1), one of the R ₄ , R ₅ , or Re groups is presented more than one time on phenyl group. In this embodiment, such repeated group is halogen.

According to one embodiment, there is provided a compound of formula (1), wherein P is tertiary butyl, cyclopentyl, or cycloheptyl.

According to one embodiment, there is provided a compound of formula (1), wherein n is 0.

Another preferred embodiment of the present invention is a compound of Formula (IA),

wherein, R _1A can be H, OH, O- substituted or unsubstituted alkyl, O-α or β-D- glucopyranosyl α or β-D-glucopyranosyl group (wherein, one or more hydroxyl groups may be acylated) or β-D-glucouronyl group (wherein, one or more hydroxyl groups may be acylated or carboxyl group may be esterified);

R _2A can be H; R _3A can be methyl; n can be 0 or 1;

R _4A , R.5 _A and R _OA are independently can be selected from H ₅ -OMe, halogen, OH, -CF ₃ , phenyl, substituted or unsubstituted alkyl, 0-α or β-D-glucopyranosyl group, or α- or β-D-glucopyranosyl group (wherein, one or more hydroxyl groups may be acylated) or β-D-glucouronyl group (wherein, one or more hydroxyl groups may be acylated or carboxyl group may be esterified); further R _IA , R ₂ A _J PMA, R _S A, and R _6A groups can be in each occurrence independently either identical groups or different groups and they can be present one or more than one time on the phenyl ring. Pharmaceutically acceptable salts of the compounds of the formula (IA) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IA) are contemplated.

It should be understood that the formula (IA) structurally encompasses all stereoisomers, including enantiomers and diastereomers, which may be contemplated from the chemical structure of the genus described herein.

Also contemplated are prodrugs of the compounds of the formula (IA), including ester prodrugs.

Another preferred embodiment of the present invention is a compound of Formula (IB),

wherein, n can be an integer 0 to 4 (wherein, one or two of the methylene groups are optionally substituted by identical are different groups which can be selected from methyl, ethyl, CO, SO ₂ , fluoro, or trifiuoromethyl); Pi _B can be substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

R _4B , R _5B , and Rβ _B are independently can be selected from H, F, Cl, -OH, CF ₃ ,

SCF ₃ , OCHF ₂ , OCF ₃ , halogen, CN, CO ₂ R ₇ B, N(R _7B ) ₂ , NHSO ₂ R ₇ B, NHSO ₂ AIyI,

SR _7B , SOR _7B , 0-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (wherein, one or more hydroxyl groups may be acylated), β-D-glucouronyl group (wherein, one or more hydroxyl groups may be acylated or carboxyl group may be esterified), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, O- substituted or unsubstituted alkyl, O- substituted or unsubstituted aryl, OCH ₂ - substituted or unsubstituted aryl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl; each R _7B can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl or substituted or unsubstituted cycloalkyl.

Pharmaceutically acceptable salts of the compounds of the foπnula (IB) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IB) are contemplated.

It should be understood that the formula (IB) structurally encompasses all stereoisomers, including enantiomers and diastereomers that may be contemplated from the chemical structure of the genus described herein. Also contemplated are prodrugs of the compounds of the formula (IB), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (IB), wherein P _IB is tertiory butyl, cycloheptyl, or cyclopentyl.

According to one embodiment, there is provided a compound of formula (IB)) wherein R _4B is hydrogen, methyl, or halogen.

According to one embodiment, there is provided a compound of formula (IB), wherein R _SB is hydrogen or halogen.

According to one embodiment, there is provided a compound of formula (IB), wherein R _6B is α or β-D-glucopyranosyl or acylated α or β-D-glucopyranosyl. According to one embodiment, there is provided a compound of formula

(IB), wherein n is 0.

According to another embodiment, there is provided a pharmaceutical preparation, which comprises any one of the above O-glucosylated amide compounds or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.

According to another embodiment, there is provided such a pharmaceutical preparation which is an inhibitor of sodium-dependent glucose transporter 2 activity. According to another embodiment, there is provided such a pharmaceutical preparation which is a prophylactic or therapeutic agent for diabetes, diabetes- related diseases or diabetic complications.

Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.

2-(acetoxymethyl)-6-(5-methoxy-2-((S)-l-(4- methoxyphenyl)ethylcarbamoyl)phenoxy)tetrahydro-2H-pyran-3,4 ,5-triyl triacetate (Compound No. 1),

4-methoxy-N-((S)-l-(4-methoxyρhenyl)ethyl)-2-(3,4,5-trih ydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 2),

2-(acetoxymethyl)-6-(2,3,6-trifluoro-5-((S)-l-phenylethyl carbamoyl) phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 3),

2,4,5-trifluoro-N-((S)-l-phenylethyl)-3-(3,4,5-trihydroxy -6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 4), 2-(acetoxymethyl)-6-(2,3,6-trifluoro-5-((R)-l-phenylethylcar bamoyl) phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 5),

2,4,5-trifluoro-N~((R)-l-phenylethyl)-3-(3,4,5-trihydroxy ~6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 6),

2-(acetoxymethyl)-6-(4-((S)-l-phenylethylcarbamoyl)phenox y)tetrahydro- 2H-pyran-3 ,4,5-triyl triacetate (Compound No. 7),

N-((S)-l-phenylethyl)-4-(3,4,5-trihydroxy-6-(hydroxymethy l)tetrahydro-2H- pyran-2-yloxy)benzamide (Compound No. 8),

2-(acetoxymethyl)-6-(4-((R)- 1 -phenylethylcarbamoyl)phenoxy) tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 9), N-((R)-l-phenylethyl)-4-(3,4,5-trihydroxy-6-(hydroxymethyl)t etrahydro-2H- pyran-2-yloxy)benzamide (Compound No. 10),

2-(acetoxymethyl)-6-(4-fluoro-2-((S)- 1 -phenylethylcarbamoyl) phenoxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 11),

5-fluoro-N-((S)-l-phenylethyl)-2-(3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 12),

4-methyl-N-((S)-l-phenylethyl)-2-(3,4,5-trihydroxy-6-(hyd roxymethyl) tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 13), 2-(acetoxymethyl)-6-(4-cliloro-2-((S)- 1 - phenylethylcarbamoyl)phenoxy)tetrahydro-2H-ρyran-3,4,5-triy l triacetate

(Compound No. 14),

5-chloro-N-((S)-l-phenylethyl)-2-(3,4,5-trihydroxy-6-(hyd roxyniethyl) tetrahydro-2H-ρyran-2-yloxy)benzamide (Compound No. 15),

2-(acetoxymethyl)-6-(4-((S)-l-(4- fluorobenzamido)ethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triy l triacetate

(Compound No. 16),

4-fluoro-N-((lS)-l-(4-(3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H- pyran-2-yloxy)phenyl)ethyl)benzamide (Compound No. 17),

2-(acetoxymethyl)-6-(4-((S)- 1 -(4-methylbenzamido)ethyl)phenoxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 18),

4-methyl-N-((lS)-l-(4-(3,4,5-trihydroxy-6-(hydroxymethyl) tetraliydro-2H- pyran-2-yloxy)phenyl)ethyl)benzamide (Compound No. 19), 2-(acetoxymethyl)-6-(4-((S)~ 1 -benzamidoethyl)phenoxy)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 20),

N-((lS)-l-(4-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydr o-2H-pyran-2- yloxy)phenyl)ethyl)benzamide (Compound No. 21),

2-(acetoxymethyl)-6-(4-((S)- 1 -(4-(trifluoromethyl)benzamido) ethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 22),

4-(trifluoromethyl)-N-((lS)-l-(4-(3,4,5-trihydroxy-6-(hyd roxymethyl) tetrahydro-2H-pyran-2-yloxy)phenyl)ethyl)benzamide (Compound No. 23),

2-(acetoxymethyl)-6-(4-(l-(4-ethylbenzamido)ethyl)phenoxy )tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 24), 2-(acetoxymethyl)-6-(3-(tert-butylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 25),

2-(acetoxymethyl)-6-(3-(tert-butylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 26),

2-(acetoxymethyl)-6-(3-(cycloheptylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 27),

N-cycloheptyl-2,4,5-trifluoro-3-(3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 28),

2-(acetoxymethyl)-6-(3-(cyclopentylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahydiO-2H-pyran-3,4,5-triyl triacetate (Compound No. 29), N-cyclopentyl-2,4,5-trifluoro-3-(3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide (Compound No. 30),

2-(acetoxymethyl)-6-(2-(tert-butylcarbamoyl)-5-methylphen oxy)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 31), N-tert-butyl-4-methyl-2-(3,4,5-trihydroxy-6-(hydroxymethyl)t etraliydro-2H- pyran-2-yloxy)benzamide (Compound No. 32),

2-(acetoxymethyl)-6-(2-(tert-butylcarbamoyl)-4-chlorophen oxy)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 33),

N-tert-butyl-5-chloro-2-(3,4,5-trihydroxy-6-(hydroxymethy l)tetraliydro-2H- pyran-2-yloxy)benzamide (Compound No. 34),

2-(acetoxymethyl)-6~(4-chloro-2-

(cyclopentylcarbamoyl)phenoxy)tetrahydro-2H-pyran-3,4,5-t riyl triacetate

(Compound No. 35),

5-chloro-N-cyclopentyl-2-(3,4,5-trihydroxy-6-(hydroxymeth yl)tetrahydro- 2H-pyran-2-yloxy)benzamide (Compound No. 36) or pharmaceutically acceptable salts, solvates, including hydrates and prodrugs of compounds 1-36 are also contemplated.

The invention also provides a pharmaceutical composition that includes at least one compound of described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container.

The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and /or disorders mediated by SGLT2 inhibitors.

The invention further provides a method of treating a disease, condition and / or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor. Also provided are compounds of the formula (1), (IA) or (IB), which inhibit greater than or equal to 50% at 10 micro molar concentration of SGLT2 activity in isolated rat Brush Border Membrane Vesicles (BBMVs) or against rat SGLT2.

Also provided herein are processes for preparing compounds described herein.

The invention provides a method for preventing, ameliorating or treating a SGLT2 mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. The invention further provides a method, wherein the SGLT2 mediated disease, disorder or syndrome is diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as" Syndrome X" (also known as Metabolic Syndrome).

The invention provides a method of treating diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention. A number of assays have been published in the literature to assess the anti diabetes activity of the compounds. For example, in- vitro assays have been reported in Am J physiol Renal Physiol 286, F127-F133, 2004 or Nature protocols, 2007, 2(6), 1356-59. The invention provides a method of treating type I diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention

The invention provides a method of treating type II diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention.

The invention provides a process for the preparation of a compound of formula (I): wherein, n can be an integer 0 to 4 (wherein, one or two of the methylene groups are optionally substituted by identical are different groups which can be selected from methyl, ethyl, CO, SO ₂ , fluoro, or trifluoromethyl);

R ₃ can be methyl or trifluoromethyl;

R ₁ , R ₂ , R ₄ , R ₅ , and Re are independently can be selected from H, halogen, substituted or unsubstituted alkyl, -OH, O-substituted or unsubstituted alkyl, O- substituted or unsubstituted aryl, O-α or β-D-glucopyranosyl group, α or β-D- glucopyranosyl group (wherein, one or more hydroxyl groups may be acylated) or β-D-glucouronyl group (wherein, one or more hydroxyl groups may be acylated or carboxyl group may be esterified), OCH ₂ -substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, CF ₃ , SCF ₃ , OCHF ₂ , OCF ₃ , CN, OR ₇ , CO ₂ R ₇ ,

CO ₂ H, CONR ₇ R ₈ , NR ₇ R ₈ , SO ₂ NH ₂ , NHCOR ₇ , NHSO ₂ R ₇ , NHSO ₂ -aryl, SR ₇ , SOR ₇ , substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted biaryl, or substituted or unsubstituted 9 or 10-membered fused bicyclyl or fused heterobicyclyl (wherein each fused heterobicyclyl has 1 to 4 heteroatoms selected from N, O, and S);

group together also represents P, wherein P can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; further R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ groups can be in each occurrence independently either identical groups or different groups, and they can be present one or more than one time on the phenyl ring; R ₇ and R ₈ are independently can be selected from, hydrogen, substituted or un substituted alkyl, substituted or un substituted aryl, substituted or unsubstituted arylalkyl or substituted or unsubstituted cycloalkyl groups, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of:

(a) chlorinating the compounds of formula (1)

1 with chlorinating agent to form a compound of formula (2)

2 (b) reacting the compounds of formula (2) with the compounds of formula (3)

to form a compound of formula (4)

(c) demethylating the compounds of formula (4) to form a compound of formula (5)

(d) reacting the compounds of formula (5) with the compounds of formula (6) 6 to form a compound of formula (7)

7

Formula (1), when R ₂ is acylated D-glucuronyl and

(e) hydrolysing the compounds of formula (7) to form a compound of formula (8)

Formula (1), when R2 is D-glucuronyl

Alternatively, the invention provides another process for the preparation of a compound of formula (I):

wherein, n can be an integer 0 to 4 (wherein, one or two of the methylene groups are optionally substituted by identical are different groups which can be selected from methyl, ethyl, CO, SO ₂ , fluoro, or trifluoromethyl); R ₃ can be methyl or trifluoromethyl;

Ri, R ₂ , R ₄ , R ₅ , and R ₆ are independently can be selected from H, halogen, substituted or unsubstituted alkyl, -OH, O-substituted or unsubstituted alkyl, O- substituted or unsubstituted aryl, O-α or β-D-glucopyranosyl group, α or β-D- glucopyranosyl group (wherein, one or more hydroxyl groups may be acylated) or β-D-glucouronyl group (wherein, one or more hydroxy! groups may be acylated or carboxyl group may be esterified), OCH ₂ -substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, CF ₃ , SCF ₃ , OCHF ₂ , OCF ₃ , CN, OR _7, CO ₂ R ₇ , CO ₂ H, CONR ₇ R ₈ , NR ₇ R ₈ , SO ₂ NH ₂ , NHCOR ₇ , NHSO ₂ R ₇ , NHSO ₂ -aryl, SR ₇ , SOR ₇ , substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted biaryl, or substituted or unsubstituted 9 or 10-membered fused bicyclyl or fused heterobicyclyl (wherein each fused heterobicyclyl has 1 to 4 heteroatoms selected from N, O, and S);

group together also represents P, wherein P can be H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl; further Ri, R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ groups can be in each occurrence independently either identical groups or different groups, and they can be present one or more than one time on the phenyl ring; R ₇ and R ₈ are independently can be selected from, hydrogen, substituted or un substituted alkyl, substituted or un substituted aryl, substituted or unsubstituted arylalkyl or substituted or unsubstituted cycloalkyl groups, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of:

(a) chlorinating the compounds of formula (9)

9 with chlorinating agent to form a compound of formula (10)

(b) demethylating the compounds of formula (10) with the compounds of formula (11)

to form a compound of formula (12)

(c) hydrolysing the compounds of formula (12) to form a compound of formula (13)

(d) reacting the compounds of formula (13) with the compounds of formula (6) 6 to form a compound of formula (14)

14

Formula (1), when R ₆ is acylated D-glucopyranosyl _an J (e) hydrolysing the compounds of formula (14) to form a compound of formula (15)

Formula (1), when Re is D-glucopyranosyl

The invention provides a process for the preparation of a compound of formula (IB):

wherein, n can be an integer 0 to 4 (wherein, one or two of the methylene groups are optionally substituted by identical are different groups which can be selected from methyl, ethyl, CO, SO ₂ , fluoro, or trifluoromethyl);

Pi _B can be substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

R4B, R ₅ B ₅ and R ₆ B are independently can be selected from H, F, Cl, -OH, CF ₃ , SCF ₃ , OCHF ₂ , OCF ₃ , halogen, CN, CO ₂ R _7B , N(R _7B ) ₂ , NHSO ₂ R _7B , NHSO ₂ Aryl,

SR _7B , SOR _7B , 0-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group

(wherein, one or more hydroxyl groups may be acylated), β-D-glucouronyl group

(wherein, one or more hydroxyl groups may be acylated or carboxyl group may be esterified), substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, O- substituted or unsubstituted alkyl, O- substituted or unsubstituted aryl, OCH ₂ - substituted or unsubstituted aryl, substituted or unsubstituted aryl, or substituted or unsubstituted arylalkyl; each R _7B can be independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl or substituted or unsubstituted cycloalkyl, an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of:

(a) chlorinating the compounds of formula (16)

16 with chlorinating agent to form a compound of formula (17)

17 (b) reacting the compounds of formula (17) with the compounds of formula (18)

P _1B -NH ₂ 18 to form a compound of formula (19)

(c) demethylating the compounds of formula (19) to form a compound of formula (20)

(d) reacting the compounds of formula (20) with the compounds of formula (6) to form a compound of formula (21)

Formula (1B), when R ₆ B is acylated D-glucuronyl i

(e) hydrolysing the compounds of formula (21) to form a compound of formula (22)

22

Formula (1B), when R _6B is D-glucuronyl

The invention provides for use of a compound of the invention for the manufacture of a medicament for, for example, preventing, ameliorating or treating a SGLT2 mediated disease, disorder or syndrome in a subject in need thereof. The invention further provides for use wherein the SGLT2 mediated disease, disorder or syndrome is diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as "Syndrome X" (also known as Metabolic Syndrome).

Detailed Description of the Invention The invention provides O-glucosylated amide derivatives, which may be used as SGLT2 inhibitors and processes for the synthesis of these compounds.

Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs of these compounds that may have the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by SGLT2 inhibitors are further provided.

The following definitions apply to the terms as used herein: The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2 -methyl- 1-propenyl, 1-butenyl, and 2-butenyl.

The teπn "haloalkyl" is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl. The term "acyl group" is used to denote a linear or branched aliphatic acyl group (preferably a C _2-6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms. Examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred. The term "alkoxy group" is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are CM alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group and a tert-butoxy group.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl. The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.

The term "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH ₂ CeHs and -C ₂ HsCeHs.

The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxinyl benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

Unless otherwise specified, the term "substituted" as used herein refers to, for example, substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR ^X , -C(O)R ^X , -C(S)R*, -C(O)NR ^x R ^y , -C(O)ONR ^x R ^y , -NR ^x CONR ^y R ^z , - N(R ^x )SOR ^y , -N(R ^x )SO ₂ R ^y , -(=N-N(R ^x )R ^y ), -NR ^x C(O)OR ^y , -NR ^x R ^y , -NR ^x C(O)R ^y , -

NR ^x C(S)R ^y , -NR ^x C(S)NR ^y R ^z , -S0NR ^x R ^y , -SO ₂ NR ^x R ^y , -OR ^X , -OR ^x C(O)NR ^y R ^z , - OR ^x C(O)OR ^y , -OC(O)R ^X , -0C(0)NR ^x R ^y , -R ^x NR ^y C(O)R ^z , -R ^x OR ^y , -R ^x C(O)OR ^y , - R ^x C(O)NR ^y R ^z , -R ^x C(O)R ^y , -R ^x OC(O)R ^y , -SR ^X , -SOR ^X , -SO ₂ R ^X , and -ONO ₂ , wherein R ^x , R ^y and R ^z are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "prodrug" means a compound that is transformed in vivo to yield, for example, a compound of Formula (1), Formula (IA), or Formula (IB) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella,

"Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "treating" or "treatment" of a state, disease, disorder or condition includes, for example:

(1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or sub clinical symptoms of the state, disease, disorder or condition;

(2) inhibiting the state, disease, disorder or condition, e.g., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or sub clinical symptom thereof; or

(3) relieving the state, disease, disorder or condition, e.g., causing regression of the state, disease, disorder or condition or at least one of its clinical or sub clinical symptoms.

The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.

The term "subject" includes, for example, mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

A "therapeutically effective amount" means, for example, the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.

The term "diabetes" encompasses, for example, type I diabetes, type II diabetes, and other types of diabetes with specific etiology.

The term "diabetes-related diseases" includes, for example, adiposis, hyperinsulmemia, abnormal carbohydrate metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, congestive heart failure, edema, hyperuricemia and gout. The term "diabetic complications" can be classified into acute complications and chronic complications.

The term "acute complications" includes, for example, hyperglycemia (e.g., ketoacidosis), infections (e.g., skin, soft tissue, biliary system, respiratory system and urinary tract infections), etc. The term "chronic complications" includes, for example, microangiopathy

(e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion), neuropathy (e.g., sensory nerves, motor nerves, or autonomic nerves), foot gangrene, etc. Major complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.

The compound of theinvention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of invention are capable of existing in stereo isomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the invention may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

All stereoisomer of the compounds of this invention are contemplated, either admixture or substantially pure form or in pure form. The compounds of present invention have asymmetric centers at any of the carbon atoms including any one of the R substituents. Thus the compounds of formula 1, formula IA, or formula IB can exist in racemic, enantiomeric, or diasteriomeric forms, or in mixtures thereof. The process for preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

Pharmaceutically acceptable solvates includes, for example, hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

Pharmaceutical Compositions

The pharmaceutical compositions provided in the invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to inhibit SGLT2 in a subject.

The subjects contemplated include, for example, a living cell and a mammal, including human mammal. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 ^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.

The pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application. The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride. Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Methods of Treatment

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors. The connection between therapeutic effect and inhibition of SGLT2 is illustrated. For example in PCT publication Nos. WO

01//016147, WO 02/08306, or WO 03/020737; J. Clin. Invest. Vol. 79, pp. 1510-

1515 (1987); J.Clin. Invest., Vol. 93, pp. 397-404 (1994); Diabetes; 57, 1723-1729,

2008 and references cited therein, all of which are incorporated herein by reference in their entirety and for the purpose stated.

The invention further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention. Diseases, conditions, and/or disorders that are mediated by SGLT2 inhibitors are believed to include, but are not limited to, diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as "Syndrome X" (also known as Metabolic Syndrome) are detailed in Johannsson, J. Clin. Endrocrinol. Metab. , 82, 727-34 (1997) incorporated herein by reference.

The compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the existing drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than SGLT2 inhibitors can be avoided or declined.

Methods of Preparation

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme 1-3. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

Scheme 1

Formula (1), when Formula (1), when R ₂ R ₂ is D-glucuronyl is acylated D-giucuronyl

The compounds of Formula (1) (wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are as defined above) can be prepared by the above procedure as described in Scheme 1. The acid compounds of formula 1 can be treated with chlorinating agents such as, for example thionyl chloride or the like to give the acid chlorides of compounds of formula 2 in the solvents such as, for example dichloromethane or the like. The acid chlorides of compounds of formula 2 can be treated with the amine compounds of formula 3 to give the amide compounds of formula 4 in the presence of solvents such as, for example dichloromethane, triethylamine or the like. Methoxy group of the amide compounds of formula 4 can be demethylated in presence of demetylating agents such as, for example boron tri bromide to give the hydroxy compounds of formula 5 in the solvents such as, for example dichloromethane or the like. The hydroxy compounds of formula 5 can be treated with the acylated-bromo sugar compounds of formula 6 (as described in Organic Synthesis Collective volme 3, page 11, 1955) to give the acylated sugar compounds of formula 7 in presence of a base and phase transfer catalyst such as, for example benzyl tributyl ammonium chloride, or the like in the solvents such as, for example chloroform and a base like potassium or cesium carbonate or the like. The acylated sugar compounds of formula 7 can be hydrolyzed to give the sugar compounds of formula 8 in presence oh hydrolyzing agents such as, for example methanolic ammonia, or the like.

Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.

Scheme 2

Formula (1), when Formula (1), when R ₆

R ₆ is D-glucouronyl is acylated D-glucouronyl

The compounds of Formula (1) (wherein, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are as defined above) also can be prepared by the above procedure as described in Scheme

2. The acid compounds of formula 9 can be treated with chlorinating agents such as, for example thionyl chloride or the like to give the acid chlorides of compounds of formula 10 in the solvents such as, for example dichloromethane or the like. The acid chlorides of compounds of formula 10 can be treated with the amine compounds of formula 11 to give the amide compounds of formula 12 in the presence of solvents such as, for example dichloromethane, triethylamine or the like.

The amide compounds of formula 12 can be demethylated in presence of demethylating agents such as, for example boron tri bromide to give the hydroxy compounds of formula 13 in the solvents such as, for example dichloromethane or the like. The hydroxy compounds of formula 13 can be treated with the acylated- bromo sugar compounds of formula 6 to give the acylated sugar compounds of formula 14 in presence of a base and a phase transfer catalyst such as, for example benzyl tributyl ammonium chloride, or the like in the solvents such as, for example chloroform, base is selected from calcium carbonate or the like. The acylated sugar compounds of formula 14 can be deacylated to give the sugar compounds of formula

15 in presence of base such as, for example methanolic ammonia, or the like.

Scheme 3

Formula (IB), when ^FormuIa ( ^1B )> ^{when R} SB

R ₆₈ is D-glucouronyl ^{1S ac} y ^lated D-gh ⁱ couronyl

The compounds of Formula (IB) (wherein, Pm, R _4B , R ₅ B and R ₆ B are as defined above) can be prepared by the above procedure as described in Scheme 3. The acid compounds of formula 16 can be treated with chlorinating agents such as, for example thionyl chloride or the like to give the acid chlorides of compounds of formula 17 in the solvents such as, for example dichloromethane or the like. The acid chlorides of compounds of formula 17 can be treated with the amine compounds of formula 18 to give the amide compounds of formula 19 in the presence of solvents such as, for example dichloromethane, triethylamine or the like.

The amide compounds of formula 19 can be demethylated in presence of demethylating agents such as, for example boron bromide to give the hydroxy compounds of formula 20 in the solvents such as, for example dichloromethane or the like. The hydroxy compounds of formula 20 can be treated with the acylated- bromo sugar compounds of formula 6 to give the acylated sugar compounds of formula 21 in presence of base and phase transfer catalyst, for example potassium carbonate or cesium carbonate and benzyl tributyl ammonium chloride, or the like in the solvents such as, for example chloroform. The acylated sugar compounds of formula 21 can be deprotected to give the sugar compounds of formula 22 in presence of a base such as, for example methanolic ammonia, or the like.

Experimental

The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and Examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.

Examples

Example 1 : Preparation of 2-(acetoxymethyl)-6-(5-methoxy-2-((S)-l-(4- methoxyphenyl)ethylcarbamoyl)phenoxy)tetrahvdro-2H-pyran-3,4 ,5-triyl triacetate:

Step 1: Synthesis of(S)-2-hydroxy-4-methoxy-N-(l-(4- methoxyphenyl)ethyl)benzamide:

To a stirred solution of 2-hydroxy-4-methoxybenzoic acid (about 3.0 g,

17.85 mmol) in DCM (about 50 ml) thionyl chloride (about 4.36 ml, 53.5 mmol) was added at room temperature and refluxed for about 6 hours at about 40 C and completion of the reaction monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure and the residue, 2-hydroxy -4- methoxy benzoyl chloride was taken in DCM (15 ml) then kept under N ₂ atmosphere.

To a stirred solution of (R)-I -(4-methoxyphenyl)ethanamine (about 3.3 ml, 21.42 mmol) in DCM (about 50 ml) triethyl amine (about 7.45 ml, 53.5 mmol) was added at O ⁰ C and stirred for about 15 minutes followed by 2-hydroxy -4-methoxy benzoyl chloride, above prepared compound was taken in DCM (15 ml) then stirred at room temperature for about 8 hours and completion of the reaction monitored by thin layer chromatography. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with DCM, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (5 g) as a white solid. Mass: [M+l] ⁺ : 301 (100 %).

Step 2: Preparation of 2-(acetoxymethyl)-6-(5-methoxy-2-((S)-l-(4- methoxyphenyl)ethylcarbamoyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate :

To a stirred solution of (S)-2-hydroxy-4-methoxy-N-(l-(4-methoxyphenyl) ethyl) benzamide (about 2.0 g, 6.64 mmol) in chloroform, 2-(acetoxymethyi)~6- bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (about 4.37 g, 10.6 mmol) was added followed by potassium carbonate (about 2.75 g, 19.92 mmol) and benzyl tributyl ammonium chloride (about 4.13 g, 13.28 mmol) then stirred the reaction mass at room temperature for about 16 hours and completion of the reaction monitored by thin layer chromatography. The reaction mixture was neutralized with IN hydrogen chloride and extracted with chloroform, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound (1.0 g) as a white solid. ¹ HNMR 300 MHz in CDC1 _3: 1.12-1.14 (d, 3H, 6.9Hz); 2.03-2.06 (m, 12H);3.82-3.86 (m, IH); 4.17-4.26 (m, 3H); 5.07-5.29 (m, 4H); 6.40 (bd, IH); 6.96-6.98 (d, 2H, J=8.7Hz); 7.0-7.10 (m, 2H); 7.26 (s, IH); 7.30-7.33 (d, 2H, J=8.7); 7.74-7.79 (m, 2H); Mass: [M+l] ⁺ : 631(100%); IR (KBr)

Cm ^"1 : 3333; 2957; 2346; 1749; 1638; 1506; 1377; 1222; 1057; Purity: 98.7%.

Example 2: Preparation of 4-methoxy-N-((SV 1 -(4-methoxyphenyl)ethyl)-2-f 3,4,5- trihvdroxy-6-(hvdroxymethyl)tetrahvdro-2H-pyran-2-yloxy)benz amide:

2-(acetoxymethyl)-6-(5-methoxy-2-((S)-l-(4- methoxyphenyl)ethylcarbamoyl) phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Example 1, about 1.0 g, 1.58 mmol) was taken in methanolic ammonia (about 15 ml), then stirred at room temperature for about 6 hours and completion of the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.25 g) as a white solid. ¹ HNMR 300 MHz DMSOd ₆ : 1.43-1.45 (d, 3H, J-6.9Hz); 1.75 (s, IH); 3.21-3.28 (m, 7H); 3.64-3.66 (bd, IH, J=5.1Hz); 4.55 (m, IH), 4.79- 4.81 (d, IH, J=6.9Hz); 5.01-5.02 (d, IH, J=5.1); 5.08-5.10 (m, 2H); 5.28-5.30 (d,

IH ₃ J=4.2Hz); 6.95-6.98 (d, 2H, J=8.7Hz); 7.27-7.30 (m, 4H); 7.91-7.96 (m, 2H); 8.76-8.78 (d, IH, J=8.1Hz); Mass: [M+l] ⁺ : 463 (100%); HPLC Purity: 96.7%.

Similarly, the following compounds have been prepared by above procedure:

Example 3 : 2-(acetoxymethyl)-6-(2,3 ,6-trifluoro-5-((S V 1 -phenylethylcarbamovD phenoxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate:

¹ HNMR 300 MHz DMSO-O ₆ : 1.42-1.43(d, 3H, J=7.0); 1.95-1.98(m, 12H), 4.0- 4.23(m, 3H), 5.07-5.09(m, IH), 5.11-5.43(m, 4H); 7.22-7.23(d, IH, J=7Hz), 7.25-

7.38(m, 4H), 7.53-7.54(d, IH, J=5.3); 8.91-8.92(d, IH, J=7.5Hz); IR (KBr) Cm ^{" ]} :3371; 2984; 1748; 1505; 1229; 1089; MR: 143.1°-144.5°C. HPLC: Purity: 97.94%. Mass (M+Na):649.

Example 4: 2.4.5-trifluoro-N-rrSVl-phenylethylV3-(3.4.5-trihvdroxy-6-

(hvdroxymethyl)tetrahvdro-2H-pyran-2-yloxy ^' )benzamide:

¹ HNMR 300 MHz DMSO-O ₆ : 1.42-1.43(d, 3H, J=7.0); 3.15-3.32(m, 2H); 3.32- 3.60(m, 4H), 4.45(bs, IH); 4.91-4.92(d, IH, J=5.39Hz); 5.02-5.49(m, 5H); 6.67(s, 2H); 7.23-7.4.0(m, 6H); 8.89-8.91(d, IH, J=7.5Hz); IR (KBr) Cm ^"1 : 3347; 2931; 1660; 1505; 1074; 701; HPLC: Purity: 97.0%; Mass(M+l):458.

Example 5 : 2-facetoxyinethyl)-6-(2,3 ,6-trifluoro-5-(YR)- 1 -phenylethylcarbamovD phenoxy)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate :

¹ HNMR 300 MHz DMSO-O ₆ : 1.41-1.44(d, 3H, J=6.9Hz); 1.94-2.05(m, 12H); 3.96- 4.0(m, IH); 4.06-4.25(m, 2H); 5.0-5. l(m, 3H); 5.38-5.44(m, 2H); 7.24-7.39(m, 4H); 7.53-7.56(m, IH); 8.94-8.96(d, IH, J=7.8Hz); IR (KBr) Cm ^"1 : 3364; 2982; 1749; 1505; 1240; 1085; 699; MR: 145.8°-150.3° C; HPLC: Purity: 95.56%; Mass

(M+Na):648.

Example 6: 2.4.5-tri£luoro-N-( ^' (RVl-plienylethyl)-3-r3.4 _t 5-trihvdroxy-6- fhvdroxymethyl)tetrahvdro-2H-pyran-2-yloxy)benzamide:

¹ HNMR 300 MHz DMSO-O ₆ : 1.41-1.44 (d, 3H, J=7.2Hz); 4.50 (s, IH); 4.91-4.93 (m, IH); 5.06-5.11 (m, 2H); 5.52 (s, IH); 6.69 (s, 2H); 7.31-7.39 (m, 7H); 8.92-8.94 (d, IH, J=7.8); IR (KBr) Cm ^"1 : 3353; 2929; 1663; 1505; 1246; 1075; 565; Mass: 480 (M+Na) HPLC: Purity: 89.59%.

Example 7j 2-(acetoxymethylV6-(4-((SVl- phenylethylcarbamoyl)phenoxy)tetrarivdro-2H-pyran-3,4,5-triy l triacetate:

¹ HNMR 300 MHz ,CDCl ₃ : 1.44-1.46(d, 3H, J=7.0Hz); 2.04-2.07(m, 12H); 3.87- 3.90(m, IH); 4.15-4.18(dd, IH, J=11.7Hz, 1.9Hz); 4.26-4.30(m, IH); 5.13-5.19(m, 2H); 5.28-5.33(m, 2H); 6.21-6.22(4 IH, J=6.8Hz); 7.00-7.01(4 2H, 8.7Hz); 7.26- 7.29(m, IH); 7.34-7.39(m, 4H); 7.73-7.74(d, 2H, J=8.8Hz); HPLC: Purity: 99.27%.

Example 88:: N-CfS)- 1 -phenylethyl)-4-C3.4.5-trihydroxy-6- fhydroxymethyl)tetrahvdro-2H-pyran-2-yloxy)benzamide:

¹ HNMR 300 MHz DMSO-O ₆ : 1.44-1.46(4 3H, J=7Hz); 3.16-3.23(m, IH); 3.24- 3.37(m, 2H); 3.44-3.45(m, IH); 3.66-3.69(m, IH); 4.53-4.56(m, IH); 4.94-4.95(d, 2H, J=7Hz); 5.02-5. l(m, IH); 5.10-5.13(m, 2H); 5.33-5.34(1H, d, J==4.85Hz); 6.69(s, 2H); 7.05-7.07(d, 2H, J=8.6Hz), 7.20-7.30(m, IH); 7.31-7.37(m, 4H); 7.84- 7.85(4 2H, J=8.63); 8.65-8.66(d, IH, J=7.55Hz); HPLC: Purity: 99.4%.

Example 9 : 2-(acetoxymethyl)-6-(4-(f RV 1 -phenylethylcarbamoyQphenoxy) tetrahvdro-2H-pyran-3 ,4,5-triyl triacetate:

¹ HNMR 300 MHz in DMSO-d ₆ : 1.45-1.46(4 3H, J=7Hz); 2.04-2.08(m, 12H); 3.29- 3.31(d, IH, J=I 1.3Hz); 4.05-4.18(m, IH); 4.19-4.28(m, IH); 4.98-5.15Cm, 3H); 5.41-5.43(d, IH, J=9Hz); 5.65-5.67(4 IH, 7.5Hz); 7.03-7.05(4 2H, 8.6Hz); 7.20- 7.30(m, IH); 7.32-7.37(m, 4H); 7.86-7.88(d, 2H, J=8.6Hz); 8.69-8.71(4 IH, J=8Hz); IR (KBr) Cm ⁴ : 3353; 1748; 1637; 1534, 1505, 1370, 1242, 1226, 1074, 845; MR: 205.1°-207.2°C; HPLC: Purity: 97.32%.

Example 10: N-((RVl-ρhenylethylV4-f3,4,5-trihydroxy-6-

(hydroxymethyl)tetrah.ydro-2H-pyran-2-yloxy)benzamide:

¹ HNMR 300 MHz DMSOd ₆ : 1.44-1.46(d, 3H, J=7Hz); 3.15-3.16(d, IH, 4.8Hz); 3.23-3.28(m, IH); 3.29-3.36(m, IH); 3.43-3.46(m, IH); 3.67(m, IH); 4.54-4.56(d, IH, J=5.9Hz); 4.93-4.95(d, IH, J=7Hz); 5.02-5.09(m, IH); 5.10-5.15(m, IH); 5.33- 5.34(1H, d, J=4.85Hz); 7.05-7.07(d, 2H, J=8.6Hz); 7.20-7.30(m, 2H); 7.32-7.37(m, 2H); 7.83-7.85(d, 2H, J=8.6Hz); 8.65-8.67(d, IH, J=8Hz); MR: 199.5-204.9;

IR:3382, 3313, 2860, 1629, 1609, 1542, 1506, 1300, 1245, 1078; HPLC: Purity: 99.4%;

Example 11 : 2-(acetoxymethyl)-6-f4-fluoro-2-((S)-l-phenylethylcarbamoyl) phenoxy) tetrahydr»2H-pyran-3 A5-triyl triacetate:

¹ H NMR (300 MHz, CD3OD): 1.59 - 1.61 (d, J=6Hz, 3H); 1.95 (s, 3H), 2.01 -2.02 (m, 9H), 3.99 - 4.03 (m, 2H), 4.31 - 4.37 (m, IH), 5.00 - 5. 21 (m, 3H), 5.36-5.39 (m, IH, J=9.3), 5.43-5.53 (m, IH), 7.25 - 7.27 (m, 3H), 7.30-7.46 (m, 5H); Mass: 612 (M+Na).

Example 12j 5-fluoro-N-rfSVl-phenylethyl)-2-(3,4.5-trihvdroxy-6-

(hvdroxymethyl)tetrahydro-2H-pyran-2-yloxy)benzamide:

1H NMR (300 MHz, DMSO-D6): 1.47 - 1.50 (d, J=9Hz, 3H); 1.75 (s, IH); 3.17 -

3.18 (m, IH); 3.73-3.76 (m, IH); 4.68 - 4.75 (m, IH); 4.95 -4.98 (m, IH), 5.10-5.16 (m, IH), 5.18-5.24 (m, 3H); 5.62 - 5.63 (d, J= 3Hz, IH); 7.21 - 7.50 (m, 8H); 8.78 - 8.81 (d, J=9Hz, IH); Mass: 444 (M+Na).

Example 13j 4-methyl-N-((SVl-phenylethyl)-2-(3.4.5-trilivdroxy-6-

(hydroxymethyl) tefaahydro-2H-pyran-2-yloxy)benzamide:

¹ H NMR (300 MHz, CD3OD ): 1.56 - 1.59 (d, J= 9 Hz ,3H); 2.00 (s, 3H); 3.13 - 3.35 (m, IH), 3.35-3.37 (m, 3H), 3.38-3.48 (m, IH), 3.49-3.52 (m, IH), 3.66 - 3.95 (m, IH), 5.04 -5.06 (m, IH), 5.19-5.49 (m, IH), 6.95 -6.98 (d, J=9Hz, IH), 7.21 - 7.23 (m, 2H), 7.23-7.28 (m, 2H), 7.30-7.33 (m, 2H), 7.40-7.67 (m, IH); Mass: 418 (M+l), 440(M+Na).

Example 14: 2-facetoxymethyl)-6-(4-chloro-2-r(S)-l- phenylethylcarbamoyl)phenoxy)tetrahvdro-2H-pyran-3,4.5-triyl triacetate:

¹ H NMR (300 MHz, CDC13): 1.61- 1.64 (d, J= 9Hz, 3H); 1.95 (s, 3H), 2.02 - 2.04 (m, 9H), 3.77 -3.83 (m, IH), 4.00 -4.05 (m, IH), 4.27 -4.32 (m, IH), 5.09-5.26 (m, 2H), 5.29-5.32 (m, 3H), 6.94 - 6.97 (d, J= 9Hz, IH), 7.25 -7.29 (m, IH), 7.30-7.37 (m, 4H), 7.39-7.45 (m, IH), 7.45- 7.63 (m, IH), 8.09 (s, IH); Mass: 628 (M+Na).

Example 15: 5-chloro-N-((S)-l-phenylethyl)-2-(3,4,5-trihydroxy-6-(;iiydr oxymethyl) tetrahydro-2H-pyran-2-yloxy)benzamide:

¹ H NMR (300 MHz, CD3OD): 1.57 -1.59 (d, J=6Hz, 3H); 3.30 -3.32 (m, IH), 3.47- 3.50 (m, 4H), 3.70-3.71 (m, IH), 3.89- 3.90 (m, IH), 5.19 - 5.22 (m, 2H); 7.22-7.24 (m, IH), 7.29-7.34 (m, 2H), 7.37- 7.45 (m, 5H), 7.73-7.74 (d, J=2.7, IH); Mass: 460 (M+Na).

Example 16: Preparation of 2-(acetoxymethyl)-6-(4-ffS)-l-f4- fluorobenzamido)ethyl)phenoxy)tetrahvdiO-2H-pyran-3.4,5-triy l triacetate:

Step 1: Synthesis of(S)-4-fluoro-N-(l-(4-methoxyphenyl)ethyl)benzamide:

To a stirred solution of 4-fluorobenzoic acid (about 5.0 g, 35.7 mmol) in DCM (50 ml), thionyl chloride (about 4.36 ml, 107.1, mmol) was added at room temperature and refluxed for about 6 hours at about 40 ⁰ C and completion of the reaction was monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure and the acid chloride residue was taken in DCM (15 ml) then kept under N ₂ atmosphere. To a stirred solution of (R)-l-(4-methoxyphenyl)ethanamine (about 6.45 ml,

42.8 mmol) in DCM (about 50 ml) triethyl amine (about 6.27 ml, 107.1 mmol) was added at O ⁰ C and stirred for about 15 minutes followed by above prepared acid chloride compound was taken in DCM (15 ml) then the reaction stirred at room temperature for about 8 hours then completion of the reaction was monitored by thin layer chromatography. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with DCM, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (5 g) as a white solid. Mass: [M+l] ⁺ : 273(100 % ).

Step 2: Synthesis of(S)-4-fluoro-N-(l-(4-hydroxyphenyl)ethyl)benzamide:

To a stirred solution of (S)-4-fluoro-N-(l-(4-methoxyphenyl)ethyl)benzamide

(about 5 g, 18.31 mmol) in DCM, boron tribromide (about 3.5 ml , 37 mmol) was added at about -2O ⁰ C and stirred for about 15 minutes. Stirring was continued at room temperature for about 20 hours. The reaction monitored by thin layer chromatography. The reaction mixture was neutralized on completion of the reaction, with saturated sodium bicarbonate and extracted with DCM, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (3 g) as a white solid. Mass: [MH-I] ⁺ : 259 (100%).

Step3: Preparation of 2-(acetoxymethyl)-6-(4-((S)-l-(4-fluorobenzamido)ethyl) phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate:

To a stirred solution of (S)-4~fluoro-N-(l-(4- hydroxyphenyl)ethyl)benzamide (about 2.Og, 7.72 mmol) in chloroform, 2-

(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (about 5.07 g, 12.3 mmol) was added followed by potassium carbonate (3.19 g, 23.16 mmol) and benzyl tributyl ammonium chloride (about 4.80 g, 15.44 mmol). The reaction mass was stirred at room temperature for about 16 hours and completion of the reaction monitored by thin layer chromatography. The reaction mixture was neutralized with

IN hydrogen chloride and extracted with CHCl _3, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound (0.8 g) as a white solid. 1HNMR 300 MHz in CDC1 _3; 1.12-1.14 (d, 3H, 6.9Hz), 2.03-2.06 (m, 12H), 3.82-

3.86 (m, IH), 4.17-4.26 (m, 3H), 5.07-5.29 (m, 4H), 6.96-6.98 (d, 2H, J=8.7Hz), 7.10 (m, 2H), 7.26-7.33 (m, 2H), 7.74-7.79 (m, 2H), IR (KBr) Cm ^"1 : 3333, 2957, 2346, 1749, 1638, 1506, 1377, 1222, 1057; MR: 140.1C°-144.5°C; HPLC: Purity: 97.6%.

Example 17: Preparation of 4-fluoro-N-((;iSVl-(;4-(3.4,5-trihvdroxy-6-

(hvdroxymethyl)tetrahvdro-2H-ρyran-2-yloxy)ϋhenyl)ethyl )benzamide:

2-(acetoxymethyl)-6-(4-((S)-l-(4- fluorobenzamido)ethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triy l triacetate (Example

16, about 1.0 g, 1.69 mmol) was taken in MeOH-NH ₃ (about 15 ml) then stirred at room temperature for about 6 hours and completion of reaction monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.25 g) as a white solid. 1HNMR 300 MHz DMSOd ₆ : 1.43-1.45(d,3H,J=6.9Hz);; 3.19-3.21 (m, 2H), 3.21-

3.28 (m, 3H), 3.64-3.66 (m, IH, J=5.1Hz), 4.55 (m, IH), 4.79-4.81 (d, IH, J=6.9Hz), 5.01-5.10 (m, 3H), 5.28-5.30 (d, IH, J=4.2Hz), 6.95-6.98 (d, 2H, J=8.7 Hz), 7.27-7.30 (m, 4H), 7.91-7.96 (m, 2H), 8.76-8.78 (d, IH, J=8.1Hz), IR (KBr) Cm ^"1 : 3280, 2936, 1632, 1505, 1237, 1076, 847; Mass: 444 (M+Na), MR: 187.1C ⁰ - 192.3 ⁰ C; HPLC: Purity: 97.29%; RT: 16.43.

Similarly, the following compounds have been prepared by above procedure:

Example 18: 2-(acetoxymethyl)-6-f4-(fS)-l-f4-methylbenzamido)ethyl)pheno xy) tetrahvdro-2H-Oyran-3,4,5-triyl triacetate:

¹ HNMR 300 MHz in CDCl ₃ : 1.56-1.58 (d, 3H, J=7.2Hz), 2.03-2.07 (m, 12H), 2.39 (s, 3H), 3.80-3.90 (m, IH), 4.17-4.18 (d, IH, J=2.4z), 4.25-4.27 (d, IH, J=5.4), 5.26- 5.28 (m, 5H), 6.24-6.27 (d, IH, J=7.8Hz), 6.95-6.98 (d, 2H, J=8.7Hz), 7.26-7.31 (m, 4H), 7.64 (d, 2H, J=1.8Hz), IR (KBr) Cm ^"1 : 3339; 2957; 1749; 1634; 1377; 1219;

1034; 822; MP: 152.3°-160.4° C; HPLC: Purity: 99.3%.

Example 19: 4-methyl-N-((lS ^' )-l-('4-r3,4.5-trihvdroxy-6-( ^' hvdroxymethvDtetrahvdro- 2H-pyran-2-yloxy')phenyI)ethyl)benzamide:

¹ HNMR 300 MHz: CDCl ₃ : 1.39-1.42 (d, 3H), 1.83 (s,3 H), 2.23 (s, 3H), 2.43-2.45 (m, 2H), 3.42 (s, 2H), 3.69-3.72 (m, 2H), 4.23-4.26 (d, 2H, J=8.1Hz), 4.37 (s, IH), 4.77-4.79 (d, IH, J=7.2Hz), 5.1 (s, IH), 6.86-6.89 (d, 2H, J=8.7Hz), 7.05-7.10 (m, 3H), 7.16-7.27 (m, 2H), 7.56-7.59 (d, 2H, J=8.1Hz); IR (KBr) Cm ^"1 : 3281; 2940;1630; 1510; 1237; 1077; 832; MR: 199.7°-201.1° C; HPLC: Purity: 98.58%; Mass :456(M+Na).

Example 20 : 2-( acetoxymethyl)-6-f4-(Y S)- 1 -benzamidoethyl)phenoxy)tetrahydro- 2H-pyran-3,4,5-triyl triacetate:

¹ HNMR 300 MHz in CDCl ₃ : 1.57-1.59 (d, 3H, J=6.8Hz), 2.03-2.06 (s, 12H), 3.83- 3.85 (bd, IH, J=7.8Hz), 4.14-4.17 (d, IH, J=11.7Hz), 4.25-4.26 (dd, IH, J=4.8Hz and 7.8Hz), 5.05-5.06 (d, IH, J=6.8Hz), 5.14-5.30 (m, 4H), 6.26-6.27 (d, IH, 6.8Hz), 6.96-698 (d, 2H, J=8.79), 7.26-7.51 (m, 5H), 7.74-7.76 (d, 2H, J=7.8Hz), IR

(KBr) Cm ⁴ : 3369; 1750; 1634; 1224; 1046; MR: 158.8°-161.4°C; HPLC: Purity: 97.5%; Mass: 572 (M+l) ; 594(M+Na).

Example 21: N-f ( 1 S)- 1 -(4-( 3 A5 -faihvdroxy-6-fhvdroxymethyl)tetrahvdro-2H- τ>yran-2-yloxy)phenyl)etriyl)benzamide:

¹ HNMR 300 MHz DMSO-d ₆ : 1.44-1.46 (d, 3H, J=6.9); 3.22-3.23 (m, 6H); 3.65- 3.66 (m, IH); 4.55-4..82 (m, 2H); 5.0-5.29 (m, 4H); 6.96-6.99 (d, 2H, J=8.7Hz); 7.28-7.31 (d, 2H, J=8.7Hz); 7.45-7.52 (m, 3H); 7.85-7.88 (m, 2H); 8.73-8.75 (d, IH, J=8.1Hz); IR (KBr) Cm ⁴ : 3278; 2937; 1633; 1510; 1238; 1076; MR: 163.2°-

171.2 ⁰ C; Mass(M+Na):426; HPLC: Purity: 99.78%.

Example 22 : 2-(acetoxymethyl)-6-f4-(f S)- 1 -(4-(trifluoromethyl)benzamido) ethyl)phenoxy)tetrahvdro-2H-pyran-3 ,4,5-triyl triacetate:

¹ HNMR(CDCl ₃ ): 1.25 (s, 3H), 2.05-2.06 (m, 12H), 3.86-3.90 (m, IH), 4.14-4.31 (m, 2H), 4.81 (m, IH), 5.06-5.08 (m, 2H), 5.17-5.20 (m, 3H), 6.31 (m, IH), 6.97-7.00 (d, 2H, J= 7.8 Hz), 7.34 (m, 3H), 7.68-7.71 (d, 2H,J=7.8 Hz), 7.86-7.88 (d, 2H, J=7.8 Hz); Mass: (M +Na): 661.

Example 23: 4-(1τifluoromethyl)-N-((lS)-l-(4-f3,4,5--trihvdroxy-6-fhydr oxymethvD tetrahvdro-2H-pyran-2-yloxy)phenyl)ethyl)benzaniide:

¹ HNMR (CDCl ₃ ): 1.54-1.56 (d, 3H, J=6.9Hz), 3.07-3.08 (m, IH), 3.23-3.43 (m, IH), 3.86-3.90 (m, IH), 4.65-4.87 (m, 3H), 4.88-5.22 (m, 3H), 7.06-7.09 (d, 2H,

J=9Hz), 7.33-7.35 (d, 2H, J=8.7Hz), 7.75-7.78 (d, 2H, J=8.1Hz), 7.96-7.99 (d, 2H, J=8.1Hz); Mass: (M+Na): 494.

Example 24j 2-(acetoxymethyl)-6-(4-(l-( ^" 4- ethylbenzamido)ethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate:

¹ HNMR (CDCl ₃ ): 1.21-1.26 (m, 3H), 1.54 (d, 3H, J=6.9Hz), 2.05-2.10 (m,12H), 2.70-2.72 (m, 2H), 4.21-4.25 (m, IH), 4.40-4.44 (m, 2H), 5.22-5.23 (m, IH), 5.24- 5.25 (m, IH), 5.56-5.57 (m, IH), 6.26-6.28 (m, IH), 7.05-7.06 (d, 2H, J=2.1Hz), 7.07-7.08 (m, 3H), 7.24-7.26 (d, 2H, J=8.1Hz), 7.68-7.70 (d, 2H, J=8.1Hz); Mass:

(M+Na): 623.

Example 25: Preparation of 2-facetoxymethyl)-6-(3-ftert-butylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahydro-2H-pyran-3.4.5-triyl triacetate:

Step 1: Synthesis of N-Tert -butyl -2,4 ,5 trifluoro 3methoxy benzamide:

To a stirred solution of 2,4,5-trifiuoro-3-methoxybenzoic acid (about 5.0 g, 24.27 mmol) in dichloromethane, thionyl chloride (about 25 ml, 180 mmol) was added at room temperature and refluxed for about 6 hours at about 40 ⁰ C.

Completion of the reaction was monitored by thin-layer chromatography then the reaction mixture was concentrated under reduced pressure and the residue was taken in 15 ml dichloromethane and kept under N ₂ atmosphere.

To a stirred solution of tertiary-butyl amine (5.0 g, 24.27 mmol) in dichloromethane (25 ml, 180 mmol), triethyl amine (2 ml) was added at about O ⁰ C and stirred for about 15 minutes followed by above prepared compound (about 15 ml) and the reaction was stirred at room temperature for about 8 hours and completion of the reaction monitored by thin layer chromatography. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (7 g) as a white solid. ¹ H NMR (300 MHz, CDC13): 1.45 (s, 9H); 4.03 (s, 3H); 6.45 -6.49 (d, J = 12.3, IH); 7.52 - 7.60 (m, IH); Mass: [M+l] ⁺ : 261 (100 %).

Step 2: Synthesis ofN-Tert-butyl -2,4 ,5 trifluoro 3-hydroxyl benzamide:

To a stirred solution of N-Tert —butyl -2,4 ,5 trifluoro 3methoxy benzamide (about 5 g, 19.15 mmol) in dichloromethane, Boron tribromide (about 3.5 ml, 37 mmol) was added at about -2O ⁰ C and stirred for about 15 minutes then the reaction again stirred at room temperature for about 20 hours and completion of the reaction monitored by thin layer chromatography. The reaction mixture was neutralized with saturated sodium bicarbonate and extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (3 g) as a white solid. ¹ H NMR (300 MHz, DMSO-D6): 1.32 (s, 9H); 6.92 - 7.03 (m, IH); 7.91 (s, IH); Mass: [M+l] ⁺ : 247(100%).

> Step 3: preparation of 2-(acetoxymethyl)-6-(3~(tert-butylcarbamoyl)-2,5,6~ trifluorophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate:

To a stirred solution of N -tert— butyl -2,4 ,5 trifluoro 3-hydroxyl benzamide (about 2.0 g, 8.09 mmol) in chloroform, 2-(acetoxymethyl)-6-bromotetrahydro-2H- pyran-3,4,5-triyl triacetate (about 5.3 g, 12.8 mmol) was added followed by potassium carbonate (about 3.35 g, 24.29 mmol) and benzyl tributyl ammonium chloride (about 5.03 g, 16.17 mmol) then stirred the reaction mass at room temperature for about 16 hours and completion of reaction monitored by thin layer chromatography. The reaction mixture was neutralized with IN hydrogen chloride, extracted with chloroform, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound (0.8 g) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): 1.45 (s, 9H); 2.02 - 2.06 (m, 12H ); 3.75- 3.81 (m, IH ); 4.15 - 4.40 (m, 2H); 5.02 - 5.56 (m, 5H ); 6.52 - 6.56 (d, J= 12Hz, IH); 7.62 -7.71 (m, IH); Mass: [MH]: 578 [M+Na] 600(100%); IR Cm^(KBr):

3682, 2966, 2638, 1758, 1743, 1666, 1540, 1508; Purity: 98.7%.

Example 26: Preparation of 2-(acetoxymethyl ^' )-6-(3-(tert-butylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahvdro-2H-pyran-3A5-triyl triacetate:

2-(acetoxymethyl)-6-(3-(tert-butylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Example 25, about 1.0 g, 1.73 mmol) was taken in methanolic ammonia (about 15 ml) and stirred the reaction mixture for about 6 hours at room temperature and completion of the reaction monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.25 g) as a white solid. ¹ H NMR (300 MHz, CD30D ) ; 1.43 (s ,9H ); 1.93 - 2.01 ( m , 5H ); 3.37 - 3.83 ( m , 5H ); 5.00 -5.03 ( d, J= 9Hz IH ) ; 7.24 -730 (m , IH ) ;7.94 ( s, IH ); Mass: [M+l] 409, [M+Na] 432 (100%); IR crn^KBr ); 3673, 3471 ,

3325 , 2971 , 2908 ,2358 , 1675 , 1536; Purity ; 96.7%.

Similarly, the following compounds have been prepared by above procedure: Example 27j 2-facetoxymethylV6-(3-fcycloheptylcarbamoyl)-2,5,6- trifluorophenoxy)tetrahvdro-2H-υyran-3A5-triyl triacetate:

¹ H NMR (300 MHz, CDC13): 1.53 - 1.59 (m, 13H); 2.03 - 2.12 (s, 12H); 3.69 -3.72 (m, IH); 4.15 - 4.22 (m, 2H); 5.02 -5.31 (m, 4H); 6.69 - 6.75 (m, IH); 7.65 - 7.75 (m, IH); Mass: 618 (M+l), (M+Na) 640.

Example 28j N-cvcloheptyl-2,4,5-trifluoro-3-(3,4,5-trihydroxy-6-

(hydiOxymethyl)tetrahvdro-2H-T3yran-2-yloxy)benzamide:

1H NMR (300 MHz, CD3OD): 1.56- 2.00 (m, 13H); 3.37-4.03 (m, 6H); 5.0 -5.03

(d, J=6Hz, IH); 7.26-7.34 (m, IH); Mass: 450 (M+1),(M+Na) 472.

Example 29j 2-(acetoxymethylV6-f3-(cvclopentylcarbamoyl)-2,5.6- trifluoroτjhenoxy)tetrahvdro-2H-ϋyran-3,4.5-triyl triacetate:

¹ H NMR (300 MHz, CDC13): 1.60 - 1.81 (m, 9H); 2.03 - 2.11 (m, 12H); 3.64 - 3.72 (m, IH); 4.20 - 4.22 (m, 2H); 4.38 - 4.40 (m, IH); 5.02 -5.31 (m, 4H); 6.71 - 6.77 (m, IH); 7.68 - 7.74 (m, IH); Mass: 590 (M+l), 612(M+Na)

Example 30j N-cyclopentyl-2,4,5-trifluoro-3-f3,4,5-trihγdroxy-6- fhvdroxymethvDtetrahvdro-2H-υyran-2~yloxy)benzamide:

¹ H NMR (300 MHz, CD3OD): 1.56- 2.02 (m, 9H); 3.40 - 3.79 (m, 5H); 4.26 -4.30 (m, IH); 5.01 - 5.03 (d, J=6Hz, IH); 7.26 - 7.34 (m, IH); Mass: 444 (M+Na).

Example 3Jj 2-facetoxymethyl)-6-f2-(tert-butylcarbamoyl)-5- methylphenoxy)tetrahydro-2H-pyran-3 A5-triyl triacetate:

1H NMR (300 MHz, CDC13): 1.45 (s, 9H); 2.05 - 2.07 (m, 12 H); 2.38 (s, 3H); 3.84

- 3.88 (m, IH); 4.08 - 4.13 (m, IH); 4.30 - 4.36 (m, IH); 5.16 - 5. 34 (m, 3H); 6.79 - 7.15 (m, 3H); 7.94 - 7.97 (d, J= 7.8, IH); Mass: 560 (M+Na).

Example 32j N-tert-butyl-4-methyl-2-f3A5-trihvdroxy-6- (hydroxymethyl)tetrahvdro-2H-pyran-2-yloxy)ben2amide:

¹ H NMR (300 MHz, CD3OD): 1.28 (s, 9H); 2.05 - 2.07 (m, 5 H); 2.35 (s, 3H); 3.34 - 3.45 (m, IH); 3.47 - 3.92 (m, 5 H); 5.04 - 5.07 (m, IH); 6. 94-7.14 (m, 2H); 7.68 -7.70(d, J= 7.8, IH); 8.08 (s, IH); Mass: 392 (M+Na).

Example 33: 2-(acetoxymethylV6-( ^' 2-( ^' tert-butylcarbamoyl)-4- chlorophenoxy)tetiahvdiO-2H-ρyran-3A5-triyl triacetate:

¹ H NMR (300 MHz, CDC13): 1.44 (s, 9H); 2.04-2.07 (m, 12H); 3.81-3.87 (m, IH); 4.06 -4.11 (m, IH); 4.32 - 4.34 (m, IH); 5.19 -5.32 (m, 5H); 6.94 -7.03 (m, 2H); 7.33 -7.36 (m, IH); 8.01-8.02 (d, J= 2.7, IH); Mass: 580 (M+Na).

Example 34: N-tert-butyl-5-chloro-2~(3A5-trihvdroxy-6-

(hydroxymethyl)tetrahydro-2H-pyran-2-yloxyTbenzamide:

¹ H NMR (300 MHz, CD3OD): 1.45 (s, 9H); 2.05 - 2.07 (m, 3H); 2.35 (s, 3H); 3.34 - 3.48 (m, 2H); 3.49 - 3.91 (m, 5H); 5.02 - 5.07 (m, 2H); 7.30 -7.45 (m, 2H); 7.73 - 7.74 (d, J= 2.7, IH); Mass: 412 (M+Na).

Example 35: 2-(acetoxymethyl)-6-f4-chloro-2-(cvclopentylcarbamoyl) phenoxy)tetrahvdro-2H-pyran-3 ,4.5-triyl triacetate:

¹ H NMR (300 MHz ₃ CDC13): 1.68 -1.69 (m, 9H); 2.03-2.11 (m, 12H); 3.64-3.72 (m, IH); 4.20-4.40 (m, 3H); 5.02- 5.31 (m, 3H); 6.71 - 6.77 (m IH); 7.68 -7.74 (m, IH); Mass: 592 (M+Na).

Example 36j 5-chloro-N-cyclopentyl-2-(3,4.5-trihvdroxy-6- fhvdroxymethyl)tetτahvdro-2H-pyran-2-yloxy ^' )benzaniide:

¹ H NMR (300 MHz, CD3OD ): 1.56 -2.02 (m, 9H ); 3.40 - 3.79 (m, 5H ) ; 4.26 4.30 (m, IH ); 5.01 - 5.03 (m, IH ); 7.26 - 7.34 (m,lH ); Mass: 424 (M+Na).

Pharmacological activity The compounds described herein can be tested for their SGLT2 inhibitory activity following procedures known in the art. For example, the following protocols may be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.

Example 37: Screening the activity of SGLT inhibitor in the rat renal BBMVs

(Brush border membrane vesicles):

Brush border membrane vesicles were prepared from renal tissues of normal rats by the MgCl ₂ precipitation method (Jurg Biber et al., 2007). Na+-glucose co transporter activity (SGLT) was determined by the rapid filtration method (Biochem.

Biophys. Acta, 554: 259-273, 1979). Glucose uptake was initiated by mixing 10 μL

(100 μg) of the BBMV membrane with 50 μL of buffer (100 mmol mannitol, 100 mmol NaCl and 10 mmol HEPES-Tris) containing D-[6 — ³ H(N)] glucose (1 μCi, NEN, Boston, MA, USA) and test compounds. Then the reaction was terminated after ten seconds by diluting the 60 μL reaction mixture with 1 mL of ice-cold stop solution (300 mmol mannitol, 80 mmol Na2SO4, 10 mmol Tris H2SO4 and 0.3 mmol phlorizin pH 7.4), which was then filtered through wet Millipore filters (0.45 μm pore size) and kept under suction. The filters were washed twice with 1 mL of ice-cold stop solution and dissolved in 5 mL of scintillation fluid, and the experiments were performed in triplicate. The radioactivity on the membrane was measured with a liquid scintillation counter (Tricarb).

The above described examples were tested in this biological assay described above and were found following results as shown in table 2 at two different concentrations like 10 μm and 3 μm.

Table-2

References:

1. Am Jphysiol Renal Physiol 286, Fl 27-F133, 2004

2. Nature protocols, 2007, 2(6), 1356-59.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

AU publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.