Diastereoisomers of 4-hydroxyisoleucine and uses thereof

A technology of uses, compounds, applied in the field of isomers and their lactones, pharmaceutically acceptable salts and prodrugs, capable of solving problems such as no one has proven

Inactive Publication Date: 2008-02-20
INNODIA INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the other hand, the (2R, 3R, 4S) isomer has been reported to have no or much less biological activity than the (2S, 3R, 4S) isomer (Broca et al., Eur. J. Pharmaco. 390: 339-345, 2000)
[0008] Despite growing evidence of the positive activity o...

Method used

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  • Diastereoisomers of 4-hydroxyisoleucine and uses thereof
  • Diastereoisomers of 4-hydroxyisoleucine and uses thereof
  • Diastereoisomers of 4-hydroxyisoleucine and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Example 1 : General procedure for the preparation of 4-hydroxyisoleucine isomers

[0119] A) General Experimental Procedures

[0120] Figure 1 shows the synthetic schemes of 8 different configurational isomers (SRS, SRR, SSS, SSR, RSR, RSS, RRR and RRS) of 4-hydroxyisoleucine. The imine intermediate 1 was prepared from p-anisidine and ethyl glyoxylate (Cordova et al., A highly enantioselective amino acid-catalyzed route to functionalized alpha-amino acids ), J. Am. Chem. Soc. 124:1842-43, 2002). Reaction of imine 1 with 2-butanone in the presence of L-proline as catalyst followed by silica gel chromatography gave 2S,3S isomer 2. Epimerization at C-3 was achieved using 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) to give 2S,3R isomer 3. The (2S, 3R, 4S), (2S, 3R, 4R), (2S, 3S, 4S) and (2S, 3S, 4R) isomers of 4-hydroxyisoleucine are obtained from 2 or 3 as follows:

[0121] Deprotection of the amine moiety of 3 (removal of p-methoxyphenyl) using ceric ammonium nitrate (...

Embodiment 2

[0154] Example 2: Effect of Conformational Isomers of (2S,3R,4S)-4-Hydroxyisoleucine on Differentiation of 3T3-L1 Fat Stimulation of glucose uptake by cells

[0155] 3T3-L1 adipocytes (ATCC; CI-173) were cultured in 12-well tissue culture plates for 3 days to reach confluency (Lakshmanan et al., Analysis of insulin-stimulated glucose uptake in differentiated 3T3-L1 adipocytes. glucose uptake in differentiated3T3-L1 adipocytes). Diabetes Mellitus: Methods and Protocols, Saire Ozena, ed., Humana Press Inc., Tonowa, New Jersey 97-103, 2003). The medium was removed and replaced with differentiation medium (Green and Meuth, Cell 3: 127-133, 1974; Madsen et al., Biochem. J. 375: 539-549, 2003), and the cells were cultured for an additional 9 days . The differentiation status was confirmed by visual inspection. Cell starvation was performed for 5 hours by replacing the differentiation medium with medium lacking fetal bovine serum. During the last 30 minutes of the starvation p...

Embodiment 3

[0157] Example 3: Conformational isomers of (2S, 3R, 4S)-4-hydroxyisoleucine on islets of INS-1 cells glucose-dependent stimulation of hormone secretion

[0158] The insulinotropic effect of 4-hydroxyisoleucine configurational isomers on INS-1 cells was tested in a blind manner. Briefly, cells were 2 × 10 5 were plated in 12-well plates and cultured for 2 days in RPMI containing 10% fetal bovine serum and 11 mM glucose. The medium was removed 3 days after plating and replaced with RPMI containing 3 mM glucose and 10% fetal bovine serum. Cells were cultured for an additional 24 hours. On day 4 after plating, the medium was removed and replaced with Krebs-Ringer bicarbonate buffer containing 2 mM glucose. Cells were incubated for 30 minutes and the buffer was removed and replaced with Krebs-Ringer bicarbonate buffer containing 4.5 mM glucose and the optical isomer at a concentration of 0.5 mM. Cells were incubated for 1 hour. Basal insulin secretion was determined by cu...

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Abstract

The invention relates to configurational isomers 4-hydroxyisoleucine, and to lactones, pharmaceutically acceptable salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. The isomers of the invention exhibit insulinotropic activity and thus may be useful for the prevention and treatment of disorders of carbohydrate or lipid metabolism, including diabetes mellitus (type 1 and type 2 diabetes), pre-diabetes, and Metabolic Syndrome.

Description

Background of the invention [0001] a) Field of invention [0002] The present invention relates to isomers of 4-hydroxyisoleucine and their lactones, pharmaceutically acceptable salts and prodrugs, to their preparation methods and pharmaceutical compositions containing them, and to their prevention and treatment of carbohydrate metabolism diseases or lipid metabolism disorders including diabetes mellitus (type 1 and type 2 diabetes), prediabetes and metabolic syndrome. [0003] b) Brief description of related technologies [0004] Diabetes is a disease of carbohydrate metabolism that occurs when the body cannot effectively control blood sugar levels. The disease is characterized by insufficient secretion or utilization of insulin, high blood and urine glucose levels, and excessive thirst, hunger, weight loss, and urine production. It can lead to a number of serious complications, including cardiovascular disease, kidney disease, blindness, nerve damage and limb ischemia....

Claims

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Application Information

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IPC IPC(8): C07C229/22C07D307/32A61P3/10A61K31/198
CPCC07C229/22C07D307/33A61P3/00A61P3/10
Inventor 克劳德·哥古尔立特查尔斯·密欧斯科维他斯基艾伦·瓦格纳
Owner INNODIA INC
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