Compounds, Methods and Formulations for the Oral Delivery of a Glucagon-Like Peptide (Glp)-1 Compound or a Melanocortin-4 Receptor (Mc4) Agonist Peptide

a technology of glucagon-like peptides and oral delivery methods, which is applied in the field of compoundes, methods and formulations for the oral delivery of glucagon-like peptides (glp)1 compounds or mc4 receptor agonist peptides, can solve the problems of ineffectiveness of agents, inability to effectively deliver active agents, and inability to rapidly render agents ineffective or destroyed in the gastrointestinal tra

Inactive Publication Date: 2007-12-20
EMISPHERE TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers.
Biologically or chemically active agents are particularly vulnerable to such barriers.
These agents are rapidly rendered ineffective or are destroyed in the gastrointestinal tract by acid hydrolysis, enzymes, or the like.
However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of excipients, enhancers or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) they exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.

Method used

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  • Compounds, Methods and Formulations for the Oral Delivery of a Glucagon-Like Peptide (Glp)-1 Compound or a Melanocortin-4 Receptor (Mc4) Agonist Peptide
  • Compounds, Methods and Formulations for the Oral Delivery of a Glucagon-Like Peptide (Glp)-1 Compound or a Melanocortin-4 Receptor (Mc4) Agonist Peptide
  • Compounds, Methods and Formulations for the Oral Delivery of a Glucagon-Like Peptide (Glp)-1 Compound or a Melanocortin-4 Receptor (Mc4) Agonist Peptide

Examples

Experimental program
Comparison scheme
Effect test

preparation 1

6-Oxo-6-[N′-(pyridine-2-carbonyl)hydrazino]hexanoic Acid Methyl Ester

[0048]

[0049] Stir a solution of 2-picolinylhydrazide (8.05 g, 58.8 mmol) and adipic acid monomethyl chloride (10.5 g, 58.8 mmol) in DMF (117 mL) at room temperature under nitrogen for 12 hours. Remove the solvent under reduced pressure. Triturate the residue with diethyl ether (300 mL), collect the solids by filtration, dissolve in water (200 mL), and wash with ethyl acetate (200 mL). Adjust the pH to 8 with a saturated NaHCO3 solution and extract with ethyl acetate (2×200 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure to provide 6-oxo-6-[N′-(pyridine-2-carbonyl)hydrazino]hexanoic acid methyl ester (3.85 g, 59%).

example 1

5-(5-Pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic Acid Methyl Ester

[0050]

[0051] Add triethylamine (14.4 mL, 104 mmol) to a mixture of 6-oxo-6-[N′-(pyridine-2-carbonyl)hydrazino]hexanoic octanoic acid methyl ester (9.63 g, 34 mmol), carbon tetrachloride (26.6 g, 172 mmol) and triphenylphosphine (20.3 g, 78 mmol) in acetonitrile (35 mL) at room temperature under nitrogen and stir for 30 minutes. Remove the solids by filtration and then remove the filtrate solvent under reduced pressure. Dilute the residue with water (500 mL) and extract with ethyl acetate (3×500 mL). Wash the combined organic extracts with brine (200 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with ethyl acetate and collect the solids by filtration to afford 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid methyl ester (8.15 g, 91%).

example 2

5-(5-Pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic Acid

[0052] Add 2 N sodium hydroxide (20 mL) to a solution of 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid methyl ester (8.16 g, 31 mmol) in THF (60 mL) and methanol (20 mL) at room temperature under nitrogen and heat the mixture at reflux for 12 hours. Remove the solvent under reduced pressure, dilute the residue with water (500 mL), and wash with ethyl acetate (200 mL). Adjust the pH of the aqueous layer to pH 3 with concentrated HCl and extract with ethyl acetate (3×200 mL). Wash the combined organic extracts with brine (200 mL), dry over sodium sulfate, and remove the solvent under reduced pressure to afford 5-(5-pyridin-2-yl[1,3,4]oxadiazol-2-yl)pentanoic acid (2.05 g, 27%). APCI mass spectrum m / z 246 [C12H13N3O3+H]+.

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Abstract

The present invention relates to novel compounds, methods, and formulations useful for the oral delivery of a GLP-1 compound or an MC4 agonist peptide.

Description

BACKGROUND OF THE INVENTION [0001] Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself. Biologically or chemically active agents are particularly vulnerable to such barriers. In the delivery to animals of biologically active or chemically active pharmacological and therapeutic agents, physical and chemical barriers are imposed by the body. Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target, and examples of chemical barriers include, but are not limited to, variations in pH, lipid bilayers, and degrading enzymes. [0002] These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically or chemically active agents would be the route of choice fo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/42A61K31/44A61K38/00A61P43/00C07D263/30C07D413/00A61K47/22C07D233/54C07D249/06C07D249/08C07D261/08C07D263/32C07D271/06C07D277/24C07D285/12C07D409/04C07D413/04
CPCA61K47/22C07D233/64C07D249/06C07D249/08C07D261/08C07D413/04C07D271/06C07D277/24C07D285/12C07D409/04C07D263/32A61P43/00
Inventor JUNGHEIM, LOUIS NICKOLAUSMCGILL, III, JOHN MCNEILLTHRASHER, KENNETH JEFFHERR, ROBERT JASONVALLURI, MURALIKRISHNA
Owner EMISPHERE TECH INC
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