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Chemically modified small molecules

a small molecule, chemical technology, applied in the direction of organic chemistry, nervous disorders, drug compositions, etc., can solve the problems of serious side effects, direct conflict with the properties required for optimal target affinity and administration, and impracticality of oral administration

Inactive Publication Date: 2006-08-17
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] The invention provides methods of modifying the rate of systemic absorption of a drug administered to a subject by a pulmonary route, the method comprising covalently conjugating a hydrophilic polymer to a drug, wherein the unconjugated drug has a half-life of elimination from the lung of less than about 180 minutes, to form a drug-polymer conjugate, wherein the drug-polymer conjugate has a net hydrophilic character and a weight average molecular weight of from abo...

Problems solved by technology

Unfortunately, many small molecule drugs possess properties (e.g., low oral bioavailability) that render oral administration impractical.
Often, the properties of small molecule drugs that are required for dissolution and selective diffusion through various biological membranes directly conflict with the properties required for optimal target affinity and administration.
For many orally administered drugs, permeation across certain biological membranes such as the blood-brain barrier or the blood-placental barrier is highly undesirable and can result in serious side-effects such as neurotoxicity, insomnia, headache, confusion, nightmares or teratogenicity.

Method used

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Examples

Experimental program
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example 1

Synthesis of CH3(OCH2CH2)3—NH-13-cis-retinamide (PEG3-13-cis-RA)

[0235] PEG3-13-cis-RA was prepared. The overview of the synthesis is provided below.

0.1085 grams of CH3(OCH2CH2)3—NH2 (0.6656mmoles), 0.044 grams of 1-hydroxybenzyltriazole (“HOBT,” 0.3328 mmoles), and 0.200 g of 13-cis-retinoic acid (“13-cis-RA,” 0.6656 mmoles) were dissolved in 10 mL of benzene. To this solution was added 0.192 grams of 1,3-dicyclohexylcarbodiimide (“DCC,” 0.9318mmoles) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the solvent was removed using rotary evaporation. The crude product was further dried under vacuum, dissolved in 20 mL of dichloromethane, and the organic phase was washed twice with 15 mL of deionized water. The organic phase was dried over Na2SO4, filtered, and the solvent removed by rotary evaporation. To the recovered product was added 2 drops of dichloromethane containing 50 ppm butylated hydroxytoluene and the product was...

example 2

Synthesis of CH3—(OCH2CH2)7—NH-13-cis-retinamide (PEG7-13-cis-RA)

[0236] 0.2257 grams of CH3(OCH2CH2)7—NH2 (0.6656 mmoles), 0.044 grams of 1-hydroxybenzyltriazole (0.3328 mmoles), and 0.200 grams of 13-cis-retinoic acid (0.6656 mmoles) were dissolved in 10 mL of benzene. To this solution was added 0.192 g 1,3-dicyclohexylcarbodiimide (0.9318 mmoles) and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, the solvent removed using rotary evaporation, and the product dried under vacuum. The product was dissolved in 20 mL dichloromethane and the solution was washed twice with 15 mL deionized water. The organic phase was dried over Na2SO4, filtered, and the solvent removed using rotary evaporation. To the recovered product was added 2 drops of dichloromethane containing 50 ppm butylated hydroxytoluene, and the product was dried under vacuum. Yield 0.426 g. 1H NMR (DMSO): δ 1.01 (s, 2 CH3), 1.68 (s, CH3), 3.5 (br m, PEG), 6.20 (m, ...

example 3

Synthesis of CH3—(OCH2CH2)11—NH-13-cis-retinamide (PEG11-13-cis-RA)

[0238] 0.349 grams of CH3(OCH2CH2)11—NH2 (0.6789 mmoles), 0.044grams of 1-hydroxybenzyltriazole (0.3328 mmoles), and 0.204 grams of 13-cis-retinoic acid (0.6789 mmoles) was dissolved in 10 mL of benzene. To this solution was added 0.192 g 1,3-dicyclohexylcarbodiimide (0.9318 mmoles) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the solvent distilled off using rotary evaporation. The product was dried under vacuum and dissolved in 20 mL dichloromethane. The solution was washed twice with 15 mL of deionized water and the organic phase dried over Na2SO4. The solution was filtered and the solvent was distilled off by rotary evaporation. To the recovered product was added 2 drops of dichloromethane containing 50 ppm butylated hydroxytoluene, and the product was dried under vacuum. Yield 0.541 g. 1H NMR (DMSO): δ 1.01 (s, 2 CH3), 1.68 (s, CH3), 3.5 (br m, PEG), 6...

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Abstract

Methods of modifying the rate of systemic absorption of a drug administered to a subject by a pulmonary route, the method comprising covalently conjugating a hydrophilic polymer to a drug, wherein the drug has a half-life of elimination from the lung of less than about 180 minutes, to form a drug-polymer conjugate, wherein the drug-polymer conjugate has a net hydrophilic character and a weight average molecular weight of from about 50 to about 20,000 Daltons, and wherein the half-life of elimination from the lung of the drug-polymer conjugate is at least about 1.5-fold greater than the half-life of elimination from the lung of the drug, wherein the half-life of elimination from the lung is measured by bronchoalveolar lavage followed by assaying residual lung material.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of U.S. Patent Application Ser. No. 11 / 015,196, filed Dec. 16, 2004, which claims priority to U.S. Provisional Patent Application No. 60 / 530,122, filed Dec. 16, 2003, both of which are incorporated herein by reference in their entireties.FIELD OF THE INVENTION [0002] This invention provides chemically modified small molecules and related methods that possess certain advantages over small molecules lacking the chemical modification. The chemically modified small molecules described herein relate to and / or have application(s) in the fields of drug discovery, pharmacotherapy, physiology, organic chemistry, polymer chemistry, and others. BACKGROUND OF THE INVENTION [0003] The use of proteins as active agents has expanded in recent years due to several factors: improved techniques for identifying, isolating, purifying and / or recombinantly producing proteins; increased understanding of the roles of p...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61L9/04A61K31/765A61K31/785A61K47/48
CPCC07C41/24A61K47/48215A61K47/60A61K31/167A61K31/485A61P25/36A61K9/007
Inventor FISHBURN, C. SIMONELECHUGA-BALLESTEROS, DAVIDVIEGAS, TACEYKUO, MEI-CHANGSONG, YUANGURSAHANI, HEMALEACH, CHESTER
Owner NEKTAR THERAPEUTICS INC
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