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Analogs of 4-hydroxyisoleucine and uses thereof

A technology of group and alkyl group, applied in the field of 4-hydroxyisoleucine analogs

Inactive Publication Date: 2008-06-04
INNODIA INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although methods for the preparation of (2S,3R,4S)-4-hydroxyisoleucine have been described (see, e.g., U.S. Patent Application Publication No. 2003 / 0219880; Rolland-Fulcrand et al., Eur. J. Org. Chem. 873-877, 2004; and Wang et al., Eur.J.Org.Chem.834-839, 2002), but no one has ever disclosed synthetic 4-hydroxyisoleucine analogues, let alone for prophylaxis and / or analogues for the treatment of metabolic diseases such as diabetes

Method used

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

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preparation example Construction

[0238] Acceptable methods of preparing pharmaceutical compositions in appropriate pharmaceutical forms are known to those skilled in the art. For example, pharmaceutical formulations can be prepared by conventional techniques of medicinal chemists involving steps such as mixing, granulation and compression (essential for tablets) to produce the desired product for each route of administration. ), or mix, fill and properly dissolve ingredients.

[0239] Toxicity and therapeutic efficacy of analogs according to the invention can be assessed by standard pharmaceutical procedures in cell culture or experimental animals. Therapeutic efficacy of analogs according to the invention can be evaluated in animal model systems, which is predictive of efficacy in human disease. For example, animal models for evaluating the efficacy of glucose uptake include animal models for diabetes or other related animal models in which glucose infusion rates can be measured. Animal models for evaluati...

Embodiment 1

[0267] Example 1: General Procedure for the Preparation of 4-Hydroxyisoleucine Analogs

[0268] A) General Experimental Procedures

[0269] Referring to Figures 1 to 14, there are shown synthetic schemes for exemplary linear and cyclic analogs of 4-hydroxyisoleucine.

[0270] Figure 1 shows the synthesis of various 4-hydroxyisoleucine analogs with SSS, SSR, SRS and SRR configurations. Imine intermediate 1 was prepared from p-anisidine and ethyl glyoxylate (Cordova et al., J. Am. Chem. Soc. 124:1842-43, 2002). Reaction of imine 1 with the appropriate ketone in the presence of L-proline (as catalyst) yields the 2S,3S isomer (2). Epimerization at C-3 is achieved using a base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) to give the 2S,3R isomer (3 ). The (2S, 3S, 4S), (2S, 3S, 4R), (2S, 3R, 4S) and (2S, 3R, 4R) analogs of 4-hydroxyisoleucine were obtained from 2 or 3, respectively, as follows:

[0271] Deprotection of the amine moiety of 2 (removal of the p-methoxyphenyl gr...

Embodiment 2

[0649] Example 2: Glucose uptake by 4-hydroxyisoleucine analogues in differentiated 3T3-L1 adipocytes stimulation

[0650] The analogs selected according to the present invention were tested for differentiating 3T3-L1 adipocytes 3 The role of H-deoxyglucose uptake. Briefly, 3T3-L1 adipocytes (ATCC; CI-173) were cultured in 12-well tissue culture plates for three days to reach confluence (Lakshmanan et al., Diabetes Mellitus: Methods and Protocols), Saire Ozena, Ed. , Humana Press Inc., Tonowa, New Jersey 97-103, 2003). The culture 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 then the cells were cultured for another 9 days. Differentiation status was determined by visual inspection. Cells were starved for 5 hours by replacing the differentiation medium with medium lacking fetal bovine serum. During the last 30 minutes of the starvation period, cells were exposed t...

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Abstract

The invention relates to analogs of 4-hydroxyisoleucine, and to lactones, pharmaceutically acceptable salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. The analogs of the invention stimulate both glucose uptake and insulin secretion, and might thus 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) Technical field [0002] The present invention relates to: 4-hydroxyisoleucine analogue; its lactone, pharmaceutically acceptable salt and prodrug; its preparation method; its pharmaceutical composition; and its prevention and treatment of carbohydrate metabolism diseases or lipid metabolism Use in diseases including diabetes (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 insulin secretion or utilization, 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. Diabetes is divided into two types, Type 1 and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/22C07C229/36C07C229/28C07D207/16C07D405/06C07D211/60C07D307/32C07C229/30C07D295/18C07C311/19C07C271/22C07C229/12C07C229/50C07C309/18C07D257/04
CPCC07C2101/18C07D295/185C07C229/28C07C229/50C07C2101/08C07D207/16C07C2103/74C07C309/18C07D491/08C07F9/3808C07D211/78C07D257/04C07D265/06C07D261/18C07D307/33C07D405/06C07D211/60C07B2200/07C07C229/30C07C271/22C07C229/22C07C229/36C07C2101/14C07C311/19A61P3/06A61P3/08A61P3/10A61P43/00C07C2601/08C07C2601/14C07C2601/18C07C2603/74
Inventor 查尔斯·密欧斯科维斯基桑德拉·迪-拉莫-马林马丁尼·马若阿尼曼吉恩德尔·吉尔
Owner INNODIA INC
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