# US 2003/0114390 A1 · C-aryl glucoside SGLT2 inhibitors and method

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- Number: US 2003/0114390 A1
- Document ID: US20030114390A1
- Status: Published application
- Kind: A1
- Application number: 10/264,410
- Filed: 2002-10-04
- Published: 2003-06-19
- Earliest claimed: 2001-03-13
- Assignees: Bristol-Myers Squibb Company
- Inventors: William N. Washburn; Bruce Ellsworth; Wei Meng; Gang Wu; Philip M. Sher
- Web page: https://patentgrep.com/patent/US20030114390A1

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

A method is provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of a compound of the formula 1 alone or in combination with one or more other antidiabetic agent(s) or other therapeutic agent(s).

## Claims

### Claim 1

A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound of formula I having the structure
115
wherein
R1, R2 and R2a are independently hydrogen, OH, OR5, alkyl, CF3, OCHF2, OCF3, SR5i or halogen, or two of R1, R2 and R2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2;
R and R are independently hydrogen, OH, OR5a, OAryl, OCH2Aryl, alkyl, cycloalkyl, CF3, —OCHF2, —OCF3, halogen, —CN, —CO2R5b, —CO2H, COR6b, —CH(OH)R6c, CH(OR5h)R6d, CONR6R6a, —NHCOR5c, —NHSO2R5d, —NHSO2Aryl, Aryl, —SR5e, —SOR5f, —SO2R5g, —SO2Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2, or R3 and R4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2;
R5, R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h and R5i are independently alkyl;
R6, R6a, R6b, R6c, and R are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R6 and R6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2; and
A is O, S, NH, or (CH2)n where n is 0-3, or a pharmaceutically acceptable salt, stereoisomer, or prodrug ester thereof.

### Claim 2 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I having the structure
116

### Claim 3 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I wherein A is (CH2)n.

### Claim 4 (depends on 2)

The method as defined in claim 2 comprising administering a therapeutically effective amount of a compound of formula I wherein A is CH2 or O or S.

### Claim 5 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I wherein A is CH2 or O or S;
R1, R2 and R2a are independently selected from H, lower alkyl, halogen, OR5, or OCHF2, or two of R1, R2 and R2a are H and the other is lower alkyl, halogen, OR5, or OCHF2;
R3 and R4 are independently selected from lower alkyl, OR5a, —OCHF2, —SR5e, OH, CO2R5b, -3,4-(O—CH2—O)—, —COR6b, CH(OH)R6c, CH(OR5h)R6d, CF3,
117
—SOR5f, SO2R5g, Aryl, —NHSO2Aryl, —NHSO2R5d, CO2H, thiadizole, tetrazole, OCH2Aryl, —OCF3, OAryl, or H.

### Claim 6 (depends on 5)

The method as defined in claim 5 comprising administering a therapeutically effective amount of a compound of formula I wherein A is CH2; R1 is hydrogen, halogen or lower alkyl; R2 and R2a are each H; R3 is H; R4 is lower alkyl, —COR6b, —CH(OH)R6c, CH(OR5h)R6d, R5aO, —OCHF2, —OCF3 or —SR5e.

### Claim 7 (depends on 6)

The method as defined in claim 6 comprising administering a therapeutically effective amount of a compound of formula I wherein A is CH2; R1 is hydrogen, halogen or lower alkyl; and R4 is lower alkyl, R5aO, —OCHF2, or —SR5e.

### Claim 8 (depends on 6)

The method as defined in claim 6 comprising administering a therapeutically effective amount of a compound of formula I wherein R4 is 4-C2H5.

### Claim 9 (depends on 2)

The method as defined in claim 2 comprising administering a therapeutically effective amount of a compound of formula I having the structure
118

### Claim 10 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I having the structure set out as follows:
119
where A is CH2 and meta to the glucoside, R1, R2 and R2a are each H, and R3 is as follows:
4-Me, 4-OH, 3-Me, H, 3-OMe, 4-CO2Me, 3,4-(OCH2O), 4-CF3, 4-NHAc, 4-SO2Me, 4-Ph, 4-NHSO2Ph-4′-Me, 4-NHSO2Me, 4-CO2H, 4-Thiadiazole, 4-Tetrazole, 4-OCH2Ph-4′-CN, 4-OCHF2, 4-isopropyl, 2-isopropyl, 4-O-n-propyl, 4-Tetrazole-2′-Me, 4-Tetrazole-1′-Me, 4-OPh, 4-n-propyl, 4-n-butyl, 4-SO2Et, 4-SO2-n-propyl, 4-SO2Ph or 4-SOMe.

### Claim 11 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I having the structure:
3 120 where A: R3: Bond H Bond 3-Me Bond 4-MeO (CH2)2 H (CH2)2 4-Me (CH2)3 H (CH2)3 4-Me (CH2)3 3-Me Bond (para link) H CH2 (ortho link) H CH2 (ortho link) 4-Et O 4-Me S 4-Me.

### Claim 12 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I having the structure:
4 121 where A: R1: R2: R3: CH2 2-Me H 4-Et CH2 4-Me H 4-Et CH2 4-Me H 4-SO2Me CH2 4-Me H 4-OH CH2 4-Me H 4-S(O)Me CH2 4-Me H 4-F CH2 4-Me H 4-Cl CH2 4-Me H 4-Me CH2 4-Me H H CH2 4-Me 6-Me 4-OMe CH2 4-F H 4-OMe CH2 4-Cl H 4-SOMe CH2 4-Cl H 4-SO2Me CH2 4-Cl H 4-OCHF2 CH2 4-Et H 4-OMe CH2 4-iPr H 4-OMe CH2 4-iPr H 4-SMe CH2 4-iPr H 4-SO2Me CH2 4,5-OCH2O H 4-Et CH2 5-Me H 4-Et CH2 5-Me 6-Me 4-OMe CH2 6-Me H 4-Et.

### Claim 13 (depends on 1)

The method as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I having the structure
122

### Claim 14 (depends on 1)

The mehtod as defined in claim 1 comprising administering a therapeutically effective amount of a compound of formula I and an antidiabetic agent other than an SGLT2 inhibitor, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, and/or a lipid-lowering agent.

### Claim 15 (depends on 14)

The method as defined in claim 14 comprising administering a therapeutically effective amount of a compound of formula I and an antidiabetic agent.

### Claim 16 (depends on 15)

The method as defined in claim 15 wherein the antidiabetic agent is 1, 2, 3 or more of a biguamide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a PPAR α/γ dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a meglitinide, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, and/or a glucos-6-phosphatase inhibitor.

### Claim 17 (depends on 16)

The method as defined in claim 16 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-H039242, GW-409544, KRP297, AC2993, LY315902, and/or NVP-DPP-728A.

### Claim 18 (depends on 15)

The method as defined in claim 15 wherein the compound of formula I is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 300:1.

### Claim 19 (depends on 14)

The method as defined in claim 14 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, and/or an anorectic agent.

### Claim 20 (depends on 19)

The method as defined in claim 19 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.

### Claim 21 (depends on 14)

The method as defined in claim 14 wherein the lipid lowering agent is an MTP inhibitor, an HMG COA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

### Claim 22 (depends on 21)

The method as defined in claim 21 wherein the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, atavastatin, rosuvastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, and/or LY295427.

### Claim 23 (depends on 21)

The method as defined in claim 21 wherein the compound of formula I is present in a weight ratio to the lipid-lowering agent within the range from about 0.01 to about 300:1.

### Claim 24

A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound of formula I having the structure
123
wherein
R1, R2 and R2a are independently hydrogen, OH, OR5, alkyl, CF3, OCHF2, OCF3, SR5i or halogen, or two of R1, R2 and R2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2;
R3 and R4 are independently hydrogen, OH, OR5a, OAryl, OCH2Aryl, alkyl, cycloalkyl, CF3, —OCHF2, —OCF3, halogen, —CN, CO2R5b, —CO2H, COR6b, CH(OH)R6c, —CH(OR5h)R6d, —CONR6R6a, —NHCOR5c, —NHSO2R5d, —NHSO2Aryl, Aryl, —SR5, —SOR5f, —SO2R5g, —SO2Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2, or R3 and R4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2;
R5, R5a, R5b, R5c, R5d, R5e, R5f, R5g, R5h and R5i are independently alkyl;
R6, R6a, R6b, R6c, and R6d are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R6 and R6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2; and
A is O, S, NH, or (CH2)n where n is 0-3, or a pharmaceutically acceptable salt, stereoisomer, or prodrug ester thereof alone or in combination with another antidiabetic agent, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a hypolipidemic agent.