Antidiabetic oxazolidinediones and thiazolidinediones

A technology of alkyl and compound, which is applied in the field of anti-diabetic oxazolidinedione and thiazolidinedione, which can solve the problems of limited curative effect, adverse effect on blood lipid profile, and inability to significantly improve lipid metabolism, etc.

Inactive Publication Date: 2007-02-07
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Another disadvantage of currently marketed PPAR agonists is their limited efficacy in treating type 2 diabetes alone - reducing mean plasma glucose by ≈20% and reducing hemoglobin A1C from ≈9% to ≈8%
Current compounds also do not significantly improve lipid metabolism and may in fact adversely affect lipid profile

Method used

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  • Antidiabetic oxazolidinediones and thiazolidinediones
  • Antidiabetic oxazolidinediones and thiazolidinediones
  • Antidiabetic oxazolidinediones and thiazolidinediones

Examples

Experimental program
Comparison scheme
Effect test

example 20

[0153] For binding to PPARδ, an aliquot of the receptor was treated with 0.1% nonfat dry milk and 2.5 nM [ 3 h 2 ] L-783483 (17Ci / mmole) in TEGM (10mM Tris, pH7.2, 1mM EDTA, 10% glycerol, 7μL / 100mL β-mercaptoethanol, 10mM sodium molybdate, 1mM dithiothreitol, 5μg / mL pH Peptidase, 2 μg / mL leupeptin, 2 μg / mL benzamidine, and 0.5 mM PMSF), and according to Berger et al. in Novel peroxisome proliferator-activated receptor (PPARγ) and PPARδligands product distinct biological effects.J.Biol.Chem (1999), 274:6718-6725 to increase or decrease the test compound. L-783483 is Example 20 in WO97 / 28137: 3-Chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benzene-[4,5]-isoxazolyloxy base) propylthio) phenylacetic acid. Assay samples were incubated at 4°C for approximately 16 hr in a final volume of 150 μL. Unbound ligand was removed by incubating 100 μL of dextran / gelatin-coated activated charcoal for about 10 min under ice-cold conditions. After centrifugation at 3000 rpm for 10 min at 4°C, 5...

Embodiment 1

[0253] (5R)-5-{3-[4-(4-Chlorophenoxy)-2-propylphenoxy]phenyl}-5-methyl-1,3-oxazolidine-2,4 - dione

[0254]

[0255] Step 1. Preparation of methyl (2R)-2-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]phenyl}-2-hydroxypropionate

[0256] For intermediate 1 (2.6g, 10mmol), intermediate 9 (3.9g, 15mmol), palladium acetate (90mg, 0.04mmol), bis(tert-butyl)(2-diphenyl)phosphine (179mg, 0,06mmol ) and potassium phosphate (4.2 g, 20 mmol) in toluene (30 mL) were degassed and 2 heated at 100°C for 16 hours. The reaction mixture was diluted with ether (50 mL) and filtered through a short pad of silica gel to afford the crude title product which was used directly in the next step.

[0257] Step 2. Preparation of (2R)-2-{3-[4-(4-chlorophenoxy)-2-propylphenoxy]phenyl}-2-hydroxypropionamide

[0258] A solution of the crude product from step 1 in methanol (35 mL) was cooled to 0°C and saturated with ammonia gas. The solution was concentrated after storage at 25°C for 2 days. The residue ...

Embodiment 2

[0264] (5R)-5-{3-[4-(4-Methoxyphenoxy)-2-propylphenoxy]phenyl}-5-methyl-1,3-oxazolidine-2, 4-diketone

[0265]

[0266] The preparation method of the title compound is the same as that of step 1-3 of Example 1, except that intermediate 9 is replaced by intermediate 10 in the first step.

[0267] 1 HNMR (600MHz, CD 3 OD) δ7.26(t, J=7.8Hz, 1H), 7.19(d, J=7.8Hz, 1H), 7.07(t, J=1.8Hz, 1H), 6.94(dd, J=8.4Hz, 2.4 Hz, 1H), 6.93(d, J=12.0Hz, 2H), 6.91(dd, J=7.2Hz, 2.4Hz, 1H), 6.83(d, J=3.6Hz, 1H), 6.82(d, J= 1.8Hz, 1H), 6.74(dd, J=8.4Hz, 2.4Hz, 1H), 6.72(dd, J=8.0Hz, 3.0Hz, 1H), 3.77(s, 3H), 2.47(t, J=7.8 Hz, 2H), 1.69 (s, 3H), 1.54 (m, 2H), 0.87 (t, J = 7.8 Hz, 3H).

[0268] MS (ESI, m / z): 447.9 (M+1).

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Abstract

Phenoxyphenyl and phenoxybenzyl oxazolidine-2,4-diones and thiazolidine-2,4-diones of formula (I) are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity that are often associated with type 2 diabetes.

Description

technical field [0001] The present invention relates to phenoxyphenyl and phenoxybenzyl oxazolidine-2,4-diones and thiazolidine-2,4-diones, including pharmaceutically acceptable salts and prodrugs thereof, which can be Useful as a therapeutic compound, especially for the treatment of type 2 diabetes and diseases generally associated with type 2 diabetes, including obesity and lipid disorders. Background technique [0002] Diabetes mellitus is a multifactorial disease manifested by increased plasma glucose levels (hyperglycemia) in the fasted state or after administration of glucose during an oral glucose tolerance test. It is generally recognized that there are two types of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), the body still produces insulin. Patients with type 2 diabetes ofte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/44C07D277/34A61K31/421A61K31/426A61P3/10
CPCC07D277/34C07D263/44C07D263/64A61K38/26A61K38/55A61K38/28A61P3/04A61P3/06A61P3/10A61K2300/00
Inventor 施国强P·T·梅因克J·F·德罗平斯基张勇
Owner MERCK & CO INC
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