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Non-Standard Amino Acid Conjugates of Amphetamine and Processes for Making and Using the Same

a technology of amino acid conjugates and amphetamine, which is applied in the field of non-standard amino acid conjugates of amphetamine and processes for making and using the same, can solve the problems of increased blood pressure and heart rate, euphoric drug “, and cardiovascular effects, and reduce abuse liability. , to achieve the effect of preventing the rebound effect, reducing or eliminating the pharmacological activity of amphetamine, and preventing cardiovascular stress and euphoria

Inactive Publication Date: 2009-09-17
SHIRE PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present technology describes a new way to deliver amphetamine as a treatment for certain disorders of the CNS (Central Nervous System) such as ADHD, ADD, obesity, narcolepsy, appetite suppressant, depression, anxiety, and wakefulness. The technology involves using non-standard amino acids to create prodrugs of amphetamine that can be controlled to release the drug over time in a safe and effective way. These prodrugs are resistant to abuse and can be used to treat stimulant addiction. The technology also provides a method for oral administration of the prodrugs, which results in gradual blood level increases and prevents the rebound effect that can occur with other stimulants. The non-standard amino acids used in the technology are covalently attached to amphetamine through the C-terminus of the non-standard amino acid. The patent text also describes the use of the technology to treat stimulant abuse and addiction."

Problems solved by technology

Again not wanting to be bound by any particular theory, it is also believed that such spikes in blood levels can lead to a euphoric drug “high” and cardiovascular effects like increased blood pressure and heart rate.
Although not wanting to be bound by any particular theory, it is believed that the treatment of such CNS conditions as noted above with compositions of the present technology results in substantially decreased abuse liability as compared to existing stimulant treatment modalities and dosage forms.

Method used

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  • Non-Standard Amino Acid Conjugates of Amphetamine and Processes for Making and Using the Same
  • Non-Standard Amino Acid Conjugates of Amphetamine and Processes for Making and Using the Same
  • Non-Standard Amino Acid Conjugates of Amphetamine and Processes for Making and Using the Same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Comparative Study of Pharmacokinetic Parameters of Released D-Amphetamine Following Administration of a Non-Standard Amino Acid Conjugate (hArg-Amp) and a Standard Amino Acid Conjugate (Vyvanse™, Lys-Amp)

[0120]The Pharmacokinetic Parameters of D-Amphetamine Following Oral Administration of a non-standard amino acid conjugate of the present technology and a standard amino acid conjugate, Vyvanse™ (Lys-Amp), commercially available from Shire, Incorporated of Wayne, Pa. are studied in this example. The non-standard amino acid conjugate used in this example is the hydrochloride salt of hArg-Amp. The results are recorded in the table below:

TABLE 1Non-standard amino acidParameter% amp1Vyvanse ™ % total Amp2AUC0-8 h94%100%AUC0-4 h77%100%AUCinf95%100%Cmax76%100%Tmax400% 100%1Percent amphetamine released relative to Vyvanse ™ (at an equimolar concentration of amphetamine contained in the non-standard amino acid prodrug compared to the total amphetamine contained in Vyvanse ™)2Percent ampheta...

example 2

Preparation of Boc-Orn(Boc)-Amp

[0123]Boc-Orn(Boc)-OH (1.5 g, 4.518 mmol) was dissolved in DMF (15 ml). EDCI (1.299 g, 6.777 mmol), NHS (0.572 g, 4.969 mmol), d-amphetamine (0.732 g, 5.422 mmol) and DIEA (0.87 ml, 4.969 mmol) were then added sequentially. The clear reaction mixture was stirred at room temperature for 16 hours (hrs). The reaction mixture was quenched with pH 3 water (40 ml), and the product was extracted with EtOAc (3×70 ml). The combined extracts were washed with pH 3 water, saturated NaHCO3 followed by water. The EtOAc layer was dried over anhydrous Na2SO4. Solvent was removed to obtain 1.82 g of protected amide as a white solid.

[0124]The white solid was analyzed by 1H NMR (CDCl3) δ. The results show 1.1-1.2 (m, 3H, Amp α-CH3), 1.3-1.5 (m, 18H, Boc CH3), 1.6-1.8 (m, 4H, Orn δ CH2), 2.75 (m, 2H, Amp β CH2), 3.05-3.1 (m, 2H, Orn δ CH2), 3.2 (m, 1H, Amp a CH), 4.1 (m, 1H, Orn α CH), 7.1-7.4 (m, 5H, Amp Ar—H). These NMR shifts are consistant with the structure of Orn-Am...

example 3

Preparation Of Orn-Amp

[0125]Boc-Orn(Boc)-Amp (1.35 g, 3 mmol) was dissolved in EtOAc (200 ml) and to the slightly cloudy solution was added MsOH (0.43 ml, 6.6 mmol) drop wise. The reaction mixture became a clear solution which was stirred at room temperature for approximately 20 hrs. Solvent was removed and the residue was triturated in hexanes. Off-white solid product was formed which was filtered under vacuum and washed with hexanes. The solid was dried in vacuum oven for 20 hrs to obtain 0.88 g of Orn-Amp.2MsOH (1-ornithine-d-amphetamine dimesylate).

[0126]The product obtained was tested by 1H NMR (DMSO-d6) δ. The result shows 1.1 (m, 3H, Amp α-CH3), 1.4-1.6 (m, 4H, Orn β, γ CH2), 2.35 (s, 6H, CH3SO3H CH3), 2.6-2.8 (m, 4H, Amp β and Orn δ), 3.75 (m, 1H, Amp α), 4.05 (m, 1H, Orn α), 7.1-7.3 (m, 5H, Amp Ar—H), 7.6-8.5 (br peaks, amide and amine); 13C NMR (DMSO-d6) δ 18.45 (Orn γ), 21.49 (Orn β), 27.30 (Amp β), 37.38 (Amp CH3), 37.77 (Amp α), 41.20 (Orn δ), 51.54 (Orn α), 125.29 (p-A...

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Abstract

Disclosed are amphetamine prodrug compositions comprising at least one non-standard amino acid conjugate of amphetamine, a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.

Description

RELATED APPLICATIONS[0001]This application is a continuation of PCT / US07 / 87028, Publication No. 1008 / 073918, filed on Dec. 10, 2007, which claims priority to and benefit from U.S. provisional patent application No. 60 / 869,375, filed on Dec. 11, 2006, which are incorporated hereby in their entireties.FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002][Not Applicable]MICROFICHE / COPYRIGHT REFERENCE[0003][Not Applicable]BACKGROUND OF THE INVENTION[0004]The present technology describes, in general, novel prodrugs / compositions of the stimulant amphetamine (i.e., 1-phenylpropan-2-amine) as well as non-standard amino acid conjugates of amphetamine, salts thereof, other derivatives thereof, and combinations thereof. Additionally, the presently described technology also relates generally to the methods of making and using these new prodrugs / compositions.[0005]The presently described technology in at least one aspect is focused on a slow / sustained controlled release composition of amphetamine, i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/165A61P3/04
CPCA61K31/135A61K31/198A61K47/48038A61K2300/00A61K47/542A61P25/00A61P25/22A61P25/24A61P25/28A61P3/04
Inventor MICKLE, TRAVIS C.
Owner SHIRE PLC
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