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Hydroxybutyrate ester and medical use thereof

A technology of hydroxybutyrate and hydroxybutyl, applied in the field of hydroxybutyrate, can solve problems such as impracticality of direct administration, acidosis and danger

Active Publication Date: 2011-08-24
OXFORD UNIV INNOVATION LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, direct administration of this compound is impractical and potentially dangerous
For example, direct administration of (R)-3-hydroxybutyrate or ethyl acetate in their free acid form may result in significant acidosis following rapid gastrointestinal absorption
Administration of the sodium salts of these compounds in unadjusted amounts is also inappropriate due to the potentially dangerous sodium overload that may accompany administration of therapeutically relevant amounts of the compounds

Method used

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  • Hydroxybutyrate ester and medical use thereof
  • Hydroxybutyrate ester and medical use thereof
  • Hydroxybutyrate ester and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The synthesis of embodiment 1 (3R)-hydroxybutyl (3R)-hydroxybutyrate

[0062]

[0063] Ethyl(3R)-hydroxybutyrate (approximately 3kg), (R)-1,3-butanediol (approximately 1.5kg) and solid-supported Candida antarctica lipase B (approximately 300g) were dissolved in a 20L Mix in a rotary evaporator flask, then place in a large on the evaporator. The system was rotary evacuated to 8-10 Torr at 40-45 °C until the diol was depleted (e.g. by 1 H NMR spectroscopic analysis; about 3 days). The crude material was filtered (clean), the enzyme was isolated, and excess ethyl (3R)-hydroxybutyrate was removed by evaporation (2-3 Torr and final pressure and temperature of 80-85°C). Cooling water was circulated throughout [-5°C during reaction, +5°C during ethyl(3R)-hydroxybutyrate removal]. Activated charcoal (quantity of 8 spatulas) was added, the mixing on the rotary evaporator was continued for 15 minutes, and then the pure mixture was passed through Filter and pour the pr...

Embodiment 2

[0064] Example 2 : (3R)-Hydroxybutyl(3R)-hydroxybutyrate - in vivo testing of a calorie-controlled diet

[0065] Young adult male Wistar rats (starting body weight 70 g) (Harlan UK Limited) (n=50) were housed at approximately 20°C under a 12h:12h light:dark cycle. Feed with standard laboratory chow (Chow) (SDS, Essex, UK) before starting the experimental diet: (a) normal "Western" diet (Western) (n=20) with 34% caloric From added palmitate, (b) high carbohydrate (CHO) (n=10) with 70% of calories from added corn starch or (c) (3R)-hydroxybutyl(3R)-hydroxybutyric acid Ester diet (monoester) (n=20) with 30% of calories from (3R)-hydroxybutyl (3R)-hydroxybutyrate.

[0066] The macronutrient indicators for these three meals are shown below. All meals contained the same energy in kCal / g but had different macronutrients.

[0067] Table 1

[0068]

[0069] Meals and monoesters were prepared at Oxford University. Water was quoted ad libitum. The research project was approv...

Embodiment 3

[0076] Example 3 : (3R)-Hydroxybutyl (3R)-hydroxybutyrate-in vivo assay of a meal-feeding diet test

[0077] Example 2 was repeated using the same diet as shown in Table 1, except that the rats were meal-fed. Therefore, the rats in this example can freely choose how much food to eat at each meal, instead of controlling calories as in Example 2.

[0078] Daily body weight (in g per rat per day) was plotted over time for each rat in the three dietary groups during the first 6 days of testing. The resulting graph is shown in figure 1 middle. One-way analysis of variance using Tukey-Kramer multiple comparison test (n=8 per group, ** p<0.001). In rats fed the monoester diet, a significant reduction in body weight was observed from day 3 to day 6. Rats fed the carbohydrate diet maintained high body weight throughout the feeding period.

[0079] Rats fed the monoester diet ate less and lost more body weight than rats on the other two diets. Daily food intake (in g per ra...

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Abstract

A compound which is 3-hydroxybutyl 3-hydroxybutyrate enantiomerically enriched with respect to (3R) hydroxybutyl (3R)-hydroxybutyrate of formula (I): is an effective and palatable precursor to the ketone body (3R)-hydroxybutyrate and may therefore be used to treat a condition which is caused by, exacerbated by or associated with elevated plasma levels of free fatty acids in a human or animal subject, for instance a condition where weight loss or weight gain is implicated, or to promote alertness or improve cognitive function, or to treat, prevent or reduce the effects of, neuro degeneration, free radical toxicity, hypoxic conditions or hyperglycaemia.

Description

field of invention [0001] The present invention relates to hydroxybutyrates that increase blood levels of ketone bodies, and to the medical use of these esters. Background of the invention [0002] Ketone bodies are compounds produced by fatty acids released by the liver from adipose tissue. Ketone bodies themselves can be used as a source of energy in most body tissues. Ingestion of compounds that increase blood levels of ketone bodies can lead to a variety of clinical benefits, including enhancement of physical and cognitive performance and treatment of cardiovascular conditions, diabetes, neurodegenerative diseases and epilepsy. [0003] Ketone bodies include (R)-3-hydroxybutyrate and ethyl acetate. As discussed in WO 2004 / 108740, these compounds could theoretically be administered directly to obtain an increase in ketone body levels in a subject. However, direct administration of this compound is impractical and potentially dangerous. For example, direct administrati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/675A61K31/22A61P3/04A61P3/10A61P25/00A23L1/30
CPCC07C69/675A61K45/06A61K31/22A23L1/30A23L33/10A61P21/00A61P21/02A61P25/00A61P25/08A61P25/14A61P25/16A61P25/26A61P25/28A61P3/00A61P3/02A61P3/04A61P35/00A61P3/06A61P39/06A61P43/00A61P5/14A61P5/16A61P9/00A61P3/10A61K2300/00
Inventor K·克拉克R·L·韦奇
Owner OXFORD UNIV INNOVATION LTD
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