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Isomers of inositol niacinate and uses thereof

A technology of inositol hexanicotinate and stereoisomers, applied in the field of isomers of inositol hexanicotinate

Inactive Publication Date: 2010-03-31
CONCOURSE HEALTH SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, they have little effect on Lp(a) and may even increase Lp(a)

Method used

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  • Isomers of inositol niacinate and uses thereof
  • Isomers of inositol niacinate and uses thereof
  • Isomers of inositol niacinate and uses thereof

Examples

Experimental program
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preparation example Construction

[0104] Scheme 4 - Preparation of Scyllo-inositol

[0105]

[0106] basically,

[0107] 1. Myo-inositol orthoformate is first generated from myo-inositol.

[0108] 2. The diol is then protected with tosyl chloride (tosylation) and oxidized with oxalyl chloride at -78°C. The use of particularly low temperatures in the oxidation step ensures the stability of the compound and avoids destruction of the formate moiety.

[0109] 3. Sodium borohydride reduction leads to generation of -OH with scyllo-configuration (alternating three up and three down).

[0110] 4. Deprotection of the tosylate moiety with acetate (acetic anhydride), followed by mild hydrolysis with isobutylamine to yield scyllo-orthoformate.

[0111] 5. The orthoformate is then hydrolyzed with trifluoroacetic acid (TFA) to give scyllo-inositol.

[0112] As an alternative, an acetonide-like group can be used instead of the tosylate to protect the inositol formate from destruction in subsequent reactions.

[0113]...

Embodiment 1

[0156] Synthesis of embodiment 1-allo-inositol hexanicotinate

[0157] allo-IHN was prepared by reacting allo-inositol with six equivalents of nicotinoyl chloride hydrochloride in anhydrous pyridine at reflux. allo-IHN was produced within 5 hours with a purity of 95%. Then another 1 equivalent of nicotinoyl chloride hydrochloride (-100 mg) was added and the reaction was continued overnight. Excess niacinyl chloride was converted to niacin by adding DI water to quench the reaction. The product was then purified using a C18 column. Niacin, pyridine and water soluble contaminants were removed from the C18 column by washing with DI water. The allo-IHN was then eluted from the column with acetonitrile, the acetonitrile fractions were collected, their contents verified by HPLC and combined. Allo-IHN was obtained with a purity of 98.5% after evaporation of the solvent. The purity and identity of allo-IHN were confirmed by HPLC and LC-MS (model: Q-TofMicro, serial number YB314). ...

Embodiment 2

[0158] Synthesis of embodiment 2-scyllo-inositol hexanicotinate

[0159] Scyllo-inositol was prepared from myo-inositol by a method based on a chemical scheme described in the literature. "Improved Synthesis of Scyllo-inositol and its Orthoformate from Myo-inositol", Carbohydrate Research, 338:999-1001 (2003). In summary, myo-inositol orthoformate is first generated from myo-inositol, and the hydroxyl group is esterified with benzoyl chloride. The diol is then protected with tosyl chloride (tosylation), the benzoyl group is removed and the hydroxyl group is oxidized with oxalyl chloride at -78°C. The use of particularly low temperatures in the oxidation step ensures the stability of the compound and avoids destruction of the formate moiety. Sodium borohydride reduction results in the generation of -OH in the scyllo-configuration (alternating three up and three down). Removal of the tosylate with acetic anhydride followed by mild hydrolysis with isobutylamine yields the scyl...

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Abstract

An ester formed from an inositol or an inositol derivative and niacin, wherein the inositol or the inositol derivatives comprises a stereoisomer selected from allo-inositol, cis-inositol, epi-inositol, muco-inositol, neo-inositol, scyllo-inositol, D-chiro-inositol and L-chiro-inositol, or pharmaceutically acceptable salts thereof. Examples of esters include inositol hexaniacinates such as allo-inositol hexaniacinate and cis-inositol hexaniacinate. The esters can be used to treat any disorder that is treatable with niacin therapy such as dyslipidemia, hypercholesterolemia, hyperlipidemia or cardiovascular disease. The esters can be administered with other agents such as HMG-CoA reductase inhibitors, statins, fibrates, activators of peroxisome proliferator activated receptors policosanol, phytosterols, tocotrienols, calcium, bile acid sequestrants, guar gum and free niacin. The invention includes pharmaceutical compositions containing these compounds.

Description

technical field [0001] The present invention relates to novel compounds and methods of use thereof in the treatment of a wide range of diseases including, but not limited to, hypercholesterolemia, hyperlipidemia, and cardiovascular disease. More specifically, the present invention relates to isomers of inositol hexanicotinate and uses thereof. Background technique [0002] Various forms of dyslipidemia, including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperlipoproteinemia, hypocholesterolemia, and cardiovascular disease are increasingly prevalent in Western industrial societies hyperlipidemia, hypolipoproteinemia, and lipid, lipoprotein, and / or triglyceride disorders). The reasons for this are not fully understood, but may be partly related to a genetic predisposition to these conditions, and partly to a diet high in saturated fat and an increasingly sedentary lifestyle as manual labor becomes less necessary. Hypercholesterolemia and hyperlipidemia are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04A61K31/70
CPCC07D401/14C07D213/80A61P15/08A61P25/22A61P25/24A61P3/10A61P3/06A61P39/00A61P5/50A61P7/00A61P7/02A61P9/00A61P9/12C07D401/12A61K31/444
Inventor 柯特·亨德里克斯
Owner CONCOURSE HEALTH SCI
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