# US 9,040,713 B2 · Methods of managing blood sugar levels and compositions related thereto

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- Number: US 9,040,713 B2
- Document ID: US9040713B2
- Status: Granted
- Kind: B2
- Application number: 13/818,391
- Filed: 2011-09-27
- Published: 2013-06-20
- Granted: 2015-05-26
- Earliest claimed: 2010-09-27
- Assignees: Emory University
- Applicants: Keqiang Ye
- Inventors: Keqiang Ye
- Web page: https://patentgrep.com/patent/US9040713B2

## CPC

- A61K 31/122: having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07C 69/65: of unsaturated acids
- C07C 225/30: of condensed quinone ring systems formed by two rings
- C07C 321/22: Thiols, sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07D 277/84: Naphthothiazoles
- C07D 307/92: Naphthofurans; Hydrogenated naphthofurans
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The disclosure relates to methods of managing blood sugar levels and compositions related thereto. In certain embodiments, the disclosure relates to methods of treating or preventing diabetes, insulin resistance, or hyperglycemia comprising administering to a subject diagnosed with, at risk of or exhibiting symptoms of diabetes, insulin resistance, or hyperglycemia a pharmaceutical composition comprising a compound comprising formula I.

## Claims

### Claim 1

A method of treating diabetes, insulin resistance, or hyperglycemia comprising administering to a subject diagnosed with, or exhibiting symptoms of diabetes, insulin resistance, or hyperglycemia a pharmaceutical composition comprising a compound of formula I
or pharmaceutically acceptable salts thereof wherein, R2 and R5 are not hydroxy or alkoxy;
R2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R6;
R3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R6;
R4 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R6;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R7;
R7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
R8 and R9 are halogen;
R10 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11
R11 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12; and
R12 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

### Claim 2

A method of treating diabetes, insulin resistance, or hyperglycemia comprising administering to a subject diagnosed with, or exhibiting symptoms of diabetes, insulin resistance, or hyperglycemia a pharmaceutical composition comprising a compound of formula IA,
or pharmaceutically acceptable salts thereof wherein,
X is NH, O, or S;
R1 is alkyl, formyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R6;
R2 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R6;
R3 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R6;
R4 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R6;
R5 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R6;
R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R7; and
R7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

### Claim 3 (depends on 2)

The method of claim 2, wherein X is NH.

### Claim 4 (depends on 2)

The method of claim 2, wherein R1 is carbocyclyl, aryl, or heterocyclyl optionally substituted R6.

### Claim 5 (depends on 2)

The method of claim 2, wherein R6 is a halogen.

### Claim 6 (depends on 2)

The method of claim 2, wherein R2 and R5 are not unsubstituted hydroxy.

### Claim 7 (depends on 2)

The method of claim 2, wherein R2 and R5 are hydrogen.

### Claim 8 (depends on 2)

The method of claim 2, wherein the subject is diagnosed with Type 1 or Type 2 diabetes.

### Claim 9 (depends on 2)

The method of claim 2, wherein the compound is selected from 2-((4-chlorophenyl)amino)naphtho[2,3-d]thiazole-4,9-dione, and 2-((2,4-dichlorophenyl)amino)naphtho [2,3-d]thiazole-4,9-dione.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 and R5 are hydroxy substituted with formyl, wherein formyl is substituted with R7.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound selected from:
5,8-diacetyloxy-2,3- dichloro-1,4-naphthoquinone and
5-acetyloxy-2,3- dichloro-1,4-naphthoquinone.