Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof

a technology of enzyme-cleavage amphetamine and amphetamine inhibitor, which is applied in the direction of biocide, amide active ingredients, peptide/protein ingredients, etc., can solve the problems of patients being denied treatment, amphetamines are susceptible to misuse, abuse or overdose, and the access to these types of drugs is expensive to administer, so as to improve patient compliance, reduce side effects of therapy, and improve patient compliance

Inactive Publication Date: 2013-03-07
SIGNATURE THERAPEUTICS
View PDF3 Cites 11 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028]The embodiments include methods for treating a patient comprising administering any of the compositions or dose units described herein to a patient in need thereof. The embodiments include methods to reduce side effects of a therapy comprising administering any of the compositions or dose units described herein to a patient in need thereof. The embodiments include methods of improving patient compliance with a therapy prescribed by a clinician comprising directing administration of any of the compositions or dose units described herein to a patient in need thereof. Such embodiments can provide for improved patient compliance with a prescribed therapy as compared to patient compliance with a prescribed therapy using drug and / or using prodrug without inhibitor as compared to prodrug with inhibitor.
[0029]The embodiments include methods of reducing risk of unintended overdose of amphetamine comprising directing administration of any of the pharmaceutical compositions or dose units described herein to a patient in need of treatment.

Problems solved by technology

Amphetamines are susceptible to misuse, abuse, or overdose.
The control of access to these types of drugs is expensive to administer and can result in denial of treatment for patients suffering from conditions such as Attention Deficit Hyperactivity Disorder (ADHD), Chronic Fatigue Syndrome (CFS), brain injury, narcolepsy, or obesity.
Furthermore, control of use is often ineffective, leading to substantial morbidity and deleterious social consequences.

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
  • Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof
  • Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof
  • Compositions Comprising Enzyme-Cleavable Amphetamine Prodrugs and Inhibitors Thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Amphetamine Prodrug Compounds

Synthesis of Amphetamine-arginine-acetate (Compound AM-1; also referred to as 2-acetylamino-5-guanidino-pentanoic acid ((R)-1-methyl-2-phenyl-ethyl)-amide) and Amphetamine-arginine-malonic acid (Compound AM-2; also referred to as N-[4-guanidino-1-((R)-1-methyl-2-phenyl-ethylcarbamoyl)-butyl]-malonic acid)

[0391]

Preparation of Compound A

[0392]D-Amphetamine sulfate (5.0 g, 27.1 mmol), Boc-Arg(Pbf)-OH (10.0 g, 19.0 mmol) and HATU (10.8 g, 28.5 mmol) were suspended in DMF (100 mL), brought to 5° C. and treated drop wise with DIEA (13.3 mL, 76.0 mmol) over 10 min. The reaction mixture was stirred at 5° C. for an additional 10 min, warmed to ambient temperature, followed by stirring for 30 min. The reaction was then diluted with EtOAc (400 mL) and poured into water (600 mL). The layers were separated, the aqueous layer extracted with EtOAc (3×300 mL) and the combined organic layers washed with 2% aq. H2SO4 (150 mL), water (2×600 mL) and brine (600 ...

example 2

Synthesis of Amphetamine-arginine-N-methyl (Compound AM-4)

[0398]

Preparation of Compound E

[0399]D-Amphetamine sulfate (496 mg, 2.68 mmol), Boc-N-Me-Arg(Mtr)-OH (940 mg, 1.88 mmol) and HATU (855 mg, 2.25 mmol) were suspended in DMF (20 mL), cooled to 5° C. and treated drop wise with DIEA (1.9 mL, 10.7 mmol) over 5 min. After addition, the reaction mixture was stirred at 5° C. for an additional 10 min. Next, the reaction was warmed to ambient temperature and stirred for 30 min. The reaction was then diluted with EtOAc (250 mL) and poured into water (200 mL). The layers were separated, the aqueous layer extracted with EtOAc (2×150 mL), and the combined organic layers washed with 2% aq. H2SO4 (50 mL), water (2×300 mL) and brine (200 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give compound E in quantitative yield (1.28 g, 1.88 mmol) as a colorless foamy solid. LC-MS [M+H] 618.6 (C31H47N5O6S+H, calc: 618.3). Compound E was used without further purifi...

example 3

Synthesis of Amphetamine-lysine-acetate (Compound AM-5)

[0401]

[0402]Compound AM-5 was prepared following the method described in Example 1 to prepare Amphetamine-arginine-acetate (Compound AM-1), but using Fmoc-Lys(Boc)-OH instead of Boc-Arg(Pbf)-OH, piperidine instead of HCl in dioxane (for deprotection of Fmoc group on α-nitrogen of Lys), and lastly HCl in dioxane for Boc deprotection of the Lys reside. LC-MS [M+H] 306.6 (C17H28N3O2+H, calc: 306.2).

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
weightaaaaaaaaaa
pHaaaaaaaaaa
body weightaaaaaaaaaa
Login to view more

Abstract

Pharmaceutical compositions and their methods of use are provided, where the pharmaceutical compositions comprise an amphetamine prodrug that provides enzymatically-controlled release of amphetamine or an amphetamine analog. The composition can further comprise an enzyme inhibitor that interacts with the enzyme(s) that mediates the enzymatically-controlled release of amphetamine or the amphetamine analog from the amphetamine prodrug so as to attenuate enzymatic cleavage of the amphetamine prodrug.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority benefit of the U.S. Provisional Application Ser. No. 61 / 326,609 filed on Apr. 21, 2010; the disclosure of which application is herein incorporated by reference in its entirety.INTRODUCTION[0002]Amphetamines are susceptible to misuse, abuse, or overdose. Use of and access to these drugs therefore needs to be controlled. The control of access to these types of drugs is expensive to administer and can result in denial of treatment for patients suffering from conditions such as Attention Deficit Hyperactivity Disorder (ADHD), Chronic Fatigue Syndrome (CFS), brain injury, narcolepsy, or obesity. Furthermore, control of use is often ineffective, leading to substantial morbidity and deleterious social consequences. Current existing amphetamine drug products provide no significant barriers to abuse and misuse by patients.SUMMARY[0003]The present disclosure provides pharmaceutical compositions, and their methods of...

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): A61K31/197C07C279/14C12Q1/02C07C237/22A61K31/165
CPCA61K31/16A61K45/06A61K47/48038A61K47/48046C07C279/14C07C237/22A61K2300/00A61K47/542A61K47/543A61K31/165A61K31/24A61K9/0019A61K9/0053
Inventor JENKINS, THOMAS E.HUSFELD, CRAIG O.SEROOGY, JULIE D.WRAY, JONATHAN W.
Owner SIGNATURE THERAPEUTICS
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