Prodrugs of guanfacine

一种胍法辛、前药的技术，应用在胍法辛的各种前药领域，能够解决药物暴露的速率和程度差异性等问题

Inactive Publication Date: 2012-06-13
SHIRE PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Variations in dietary status may thus result in variability in the rate and extent of drug exposure

Method used

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  • Prodrugs of guanfacine
  • Prodrugs of guanfacine
  • Prodrugs of guanfacine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0296] Example 1. Preparation of Guanfacine-Glutaryl-Valine Amide (Compound 1)

[0297] The synthesis of guanfacine-[glutaryl-(S)-valine]amide trifluoroacetate was completed in four steps. Glutaryl-(S)-valine tert-butyl ester was obtained by reacting (S)-valine tert-butyl ester with glutaric anhydride. The 'activated ester' was prepared from glutaryl-(S)-valine tert-butyl ester by DCC coupling with N-hydroxysuccinimide. This ester is then reacted with guanfacine to give guanfacine-[glutaryl-(S)-valine]amide tert-butyl ester. Removal of the tert-butyl group was accomplished by treatment with trifluoroacetic acid to give guanfacine-[glutaryl-(S)-valine]amide trifluoroacetate. The synthetic route is shown in Scheme 1 below.

[0298] Process 1:

[0299]

[0300] LCMS: m / z = 457.00 for the deprotonated ion (M-H) - is consistent

[0301] of

[0302] 1 H NMR (DMSO-d 6): 9.72 (br s, 3H, 3×NH), 8.00 (d, J=8.5Hz, 1H,

[0303] NH), 7.51(d, J=7.8Hz, 2H,...

Embodiment 2

[0308] Example 2. Synthesis of Guanfacine-β-Alanine-Valine Amide (Compound 2)

[0309] The synthesis of guanfacine-β-alanine-(S)-valine amide di-trifluoroacetate was accomplished in six steps. N-Boc-(S)-valine was treated with DCC and N-hydroxysuccinimide to give the first 'activated ester', which was then coupled with β-alanine benzyl ester. Subsequent debenzylation affords N-Boc-(S)-valine-β-alanine, which is then converted to a second 'activated ester' via DCC coupling with N-hydroxysuccinimide. The activated ester is coupled with guanfacine to give N-Boc-(S)-valine-β-alanine-guanfacine. Removal of the Boc protecting group was accomplished by treatment with trifluoroacetic acid to give guanfacine-β-alanine-(S)-valine amide di-trifluoroacetate. The synthetic route is shown in Scheme 2 below.

[0310] Process 2:

[0311]

[0312] LCMS: m / z = 414.00 for the deprotonated ion (M-H) - is consistent

[0313] 1 H 9.67 (br, 2H, NH 2 ), 8.52 (m, 1 H, NH), 8.10 (br, 3 H,

...

Embodiment 3

[0319] Example 3. Synthesis of Guanfacine-γ-Glutamyl-(R)-Valine Amide (Compound 5)

[0320] The synthesis of guanfacine-γ-(S)-glutamate-(R)-valineamide di-trifluoroacetate was accomplished by a method involving six reaction steps. N-Boc-(R)-valine is first treated with DCC and N-hydroxysuccinimide to obtain the first 'activated ester'. This 'activated ester' is then coupled with H-Glu(OBn)-OtBu followed by debenzylation to give N-Boc-(R)-valine-(S)-glutamic acid tert-butyl ester.

[0321] It is converted to a second 'activated ester' by DCC coupling with N-hydroxysuccinimide and this ester is reacted with guanfacine to give N-Boc-(R)-valine-(S)-glutamic acid (Guanfacine) tert-butyl ester. Removal of the tert-butyl ester and the Boc protecting group was successfully achieved using trifluoroacetic acid to give guanfacine-γ-(S)-glutamate-(R)-valine amide di-trifluoroacetate. The synthetic route is shown in Scheme 3.

[0322] Process 3:

[0323]

[0324] LCMS: m / z = 473.96...

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Abstract

Prodrugs of guanfacine with amino acids or short peptides,pharmaceutical compositions containing such prodrugs and a method for providing therapeutic benefit in the treatment of ADHD / ODD (attention deficient hyperactivity disorder and oppositional defiance disorder) with guanfacine prodrugs are provided herein. Additionally, methods for minimizing or avoiding the adverse gastrointestinal side effects associated with guanfacine administration, as well as improving the pharmacokinetics of guanfacine are provided herein.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 242,507, filed September 15, 2009, the contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to various prodrugs of guanfacine. In particular, the present invention relates to amino acid and peptide prodrugs of guanfacine which provide improved pharmacokinetic properties over guanfacine itself. The present invention also relates to methods of reducing gastrointestinal (GI) side effects associated with guanfacine therapy. These combined advantages should improve patient compliance, thereby improving the therapeutic effectiveness of the drug and patient benefit. Background of the invention [0004] Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent mental disorders affecting children. Prevalence estimates vary, but according to data from the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C279/22
CPCC07C279/24C07B2200/07C07C279/22A61P1/00A61P1/10A61P25/00A61P25/04A61P25/14A61P25/18A61P25/22A61P25/28A61P25/30A61P29/00A61P9/00A61P9/12C07C279/04A61K31/155
Inventor 理查德·弗兰克林罗伯特·G·泰森贝纳德·T·戈尔丁里斯·沃姆斯利
Owner SHIRE PLC
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