Aryl boronate functionalized polymers for treating obesity

a functionalized polymer and aryl boronate technology, applied in the field of aryl boronate functionalized polymers for treating obesity, can solve the problems of reducing patient compliance and unpleasant side effects of oil spillage from stool, and achieve the effects of reducing fat absorption, potent inhibitors of lipase enzymes, and removing fa

Inactive Publication Date: 2006-06-15
GENZYME CORP
View PDF67 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The polymers disclosed herein are believed to release aryl boronic acids in the gastrointestinal tract. Aryl boronic acids are potent inhibitors of lipase enzymes. The polymers of the present invention are therefore effective in removing fat from the gastrointestinal tract of subjects for whom reduced fat absorbtion can be clinically beneificial. Thus, these polymers are useful in the treatment of obesity. Because many of the disclosed polymers bind the lipids, the unpleasant leakage of oil from the stools that often accompanies the administration of lipase inhibitors is reduced or eliminated compared with other lipase inhibiting drugs. The disclosed polymer drugs and many of the liberated boronic acid groups are largely unabsorbed by the intestines and therefore also have the advantage of causing minimal systemic side effects.

Problems solved by technology

Leakage of oil from the stool is an unpleasant side effect that often occurs when stools have a high fat or oil content.
However, the need to administer two drugs can reduce patient compliance because it is burdensome and inconvenient.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Aryl boronate functionalized polymers for treating obesity
  • Aryl boronate functionalized polymers for treating obesity
  • Aryl boronate functionalized polymers for treating obesity

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid chloride (6)

[0087] The synthesis of Compound (6) is shown out schematically in FIG. 1. A detailed description of the procedure is provided below.

Step 1. Synthesis of 4-acetyl-3-fluorophenylboronic acid (1)

[0088] An oven-dried, 3-liter, 3-necked, round-bottomed flask (fitted with a nitrogen inlet, addition funnel, and overhead stirrer) was charged with 50 grams (0.25 mole) of 4-cyano-3-fluorophenyl bromide. Anhydrous tetrahydrofuran (200 milliliters) was added to the flask resulting in a clear solution. The solution was cooled to 0° C. using an ice bath. At this temperature, 125 milliliters of 3.0 M solution of CH3MgBr in ether (1.5 equivalents, 0.375 mole) was added slowly to the reaction flask using an addition funnel. The reaction mixture was allowed to slowly warm up to room temperature and was stirred for 48 hours. Thin layer chromatography (TLC) indicated the starting material was consumed. After ...

example 2

Synthesis of 2,5-difluoro-4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid (11)

[0097] The synthesis of Compound (11) is shown out schematically in FIG. 2. A detailed description of the procedure is provided below.

Step 1—Synthesis of 4-bromo-2,5-difluoroacetophenone (7)

[0098] Anhydrous aluminum chloride was mixed (5 grams, 37.5 millimoles, 2.4 equivalents) with 1-bromo-2,5 difluorobenzene in a dry, round-bottom flask blanketed with nitrogen and fitted with a condenser. The mixture was heated to 60° C. and acetyl chloride (1.7 milliliters, 23.3 millimole, 1.5 equivalents) was added by syringe. The wet yellow solid changed then into a scarlet solution and was heated at 90° C. for 1 hour. The reaction mixture was poured onto 38 grams of ice, HCl was added (3 milliliters, 37% concentration) and the mixture was extracted with ether. The crude material was dried over magnesium sulfate and evaporated down. The crude material was purified by column chromatography or distilled. ...

example 3

Synthesis of 2,5-difluoro-4-(13′-trimethylamonium-3′-thia-1′-ketotridecyl)phenyl(neopentyl glycolato) boron chloride (14)

[0103] The synthesis of Compound (14) is shown schematically in FIG. 3. A detailed description of the procedure is provided below.

Step 1—Synthesis of 10-bromodecyltrimethylammonium bromide

[0104] 1,10-Dibromodecane (20 grams, 66.7 mmoles) and THF (100 milliliters) were placed in a 500-mL, three-necked flask. The solution was cooled to 0° C. with an ice-water bath. Anhydrous trimethylamine (3 grams, 50.8 mmoles) was added to the mixture by slowly bubbling trimethylamine gas for about 15 minutes. Then the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The solid material was filtered and washed with THF (5×30 milliliters). After drying in vacuo overnight, 12.5 grams (34.82 mmoles, 69% based on the amine used) of the product was obtained as a white solid.

Step 2—Synthesis of 10-mercaptodecyltrimethylammonium bromi...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
molecular weightaaaaaaaaaa
molecular weightaaaaaaaaaa
temperatureaaaaaaaaaa
Login to view more

Abstract

Disclosed are polymers comprising one or more phenyl boronate ester, boronamide or boronate thioester groups. The phenyl boronate ester, boronamide and boronate thioester groups are represented by one of the following structural formulas: Ar in Structural Formulas (I) and (II) is substituted or unsubstituted; and each Z is —O—, —NH— or —S— and is independently selected. Pharmaceutically acceptable salts of the polymer are also included. The aryl boronate ester, boronamide or boronate thioester can be cleaved to release the corresponding aryl boronic acid. Also disclosed are pharmaceutical compositions comprising the polymers of the present invention and a pharmaceutically acceptable carrier or diluent; and methods of treating a subject for obesity with the polymers of the present invention.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 302,221, filed Jun. 29, 2001, and U.S. Provisional Application No.60 / 359,473, filed Feb. 22, 2002, the entire teachings of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Human obesity is a recognized health problem with approximately ninety-seven million people considered clinically overweight in the United States. Various chemical approaches have been used for treating obesity. In one such approach, a medicament which inhibits lipases is administered to the obese patient. Lipases are key enzymes in the digestive system which break down diglycerides and triglycerides into monoglycerides and fatty acids. Diglycerides and triglycerides have a high caloric content but are not absorbed by the small intestine until broken down by the lipases. Therefore, inhibition of lipases within the digestive system results in a reduction in the absorption of fat and co...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/69C08G79/08A01N55/08A61K31/80A61K31/74A61K31/785A61P3/04C08F30/06
CPCA61K31/74A61K31/785A61K47/48176C08F8/42C08F8/44C08G65/331C08G73/0206C08G79/08C08F20/60C08F26/02A61K47/58A61P3/04
Inventor HOLMES-FARLEY, STEPHEN RANDALLMANDEVILLE, W. HARRY IIIDHAL, PRADEEP K.HUVAL, CHAD CORILI, XINHUAPOLOMOSCANIK, STEVEN CRAIG
Owner GENZYME CORP
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap