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Prodrugs of glutamine analogs

A technology of glutamine and analogs, applied in the field of prodrugs of glutamine analogs, can solve problems such as hindering clinical development

Active Publication Date: 2018-07-17
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, severe toxicities (e.g., dose-limiting GI toxicities such as oral mucositis, gastric bleeding, nausea and vomiting, abdominal pain, leukopenia, thrombocytopenia, etc.) ) occurrence hinders their clinical development
[0005] Previous attempts to mitigate the severe toxicities associated with glutamine antagonists such as DON have been unsuccessful

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0310] method

[0311] General procedure: Commercially available HPLC grade methanol, catalyst and reagent grade materials were used as received. TLC was carried out on a silica gel 60F254 coated aluminum plate (Merck), and the 4 ) 2 Solution detection spot. 4H 2 O (1%) and H 3 P(Mo 3 o 10 ) 4 (2%) in sulfuric acid (10%). Use Isolera One HPFC system (Biotage company) on silica gel 60 (0.040-0.063mm, Fluka) or on KP‐C18‐HS or KP‐ Flash chromatography was performed on a SNAP cartridge. All chemicals were purchased from Sigma-Aldrich and used without further purification. Measured at 400.1MHz, 500.1MHz or 600.1MHz 1 H NMR spectrum, measured at 100.8MHz, 125.7MHz or 150.9MHz 13 C NMR spectrum. for 1 Normalization of H NMR spectra using the internal signal of TMS (δ0.0, CDCl 3 ) or the residual signal of the solvent (for CDCl 3 is δ7.26, for CD 3 COCD 3 is δ2.05, for CD 3 OD is δ3.31). exist 13 In the case of the C spectrum, use the residual signal of the ...

Embodiment 2

[0328] Prodrug Strategies - Masking of Carboxylate Functional Groups

[0329] In one embodiment, DON prodrugs are designed by masking only the carboxylate functionality with an alkyl ester of DON with an unprotected α-amino group. However, some DON alkyl esters with unprotected α-amino functional groups were found to undergo cyclization to form 5-membered cyclic Schiff's bases. The observed cyclization is pH dependent and rapid at pH 5-7. At lower pH, which generally prevents or reverses cyclization, the diazo function becomes unstable. As a result, cyclization is virtually irreversible, making some N-α-free alkyl esters unsuitable as DON prodrugs ( figure 1 A).

Embodiment 3

[0331] Prodrug Strategies - Masking Amino Functional Groups

[0332] In another embodiment, DON prodrugs are designed by using N-protected derivatives of DON with unprotected carboxyl functionality to mask only the amino functionality. N-protected derivatives of DON with unprotected carboxyl functional groups ( figure 1 B and figure 1 C) is also unstable. More specifically, the acidic carboxyl functionality causes progressively slower decomposition of the diazo group. In some salt forms, the carboxylate anion destabilizes the N-alpha-protecting group. Going a step further, as in figure 1 D. figure 1 E. figure 1 F. figure 1 G and figure 1 As shown in H, many of the tested prodrugs (except 26) with free carboxylate had negligible exposure when administered orally compared to DON, further suggesting that derivatized carboxylate and amine functional groups are important for oral availability benefits.

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Abstract

Prodrugs of glutamine analogs, such as prodrugs of aza-serine, and 6-diazo-5-oxo-norleucine (DON), and 5-diazo-4-oxo-L-norvaline (L-DONV) are disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 62 / 199,566, filed July 31, 2015, the entire contents of which are incorporated herein by reference. Background technique [0003] The prodrug approach is a well-established strategy for improving the physicochemical, biopharmaceutical, and pharmacokinetic properties of potential drug molecules. Approximately 5-7% of globally approved drugs are prodrugs, with sales of $11.2 billion in 2013. Most prodrugs are simple chemical derivatives of the original molecule. Ester prodrugs are the most common prodrugs, accounting for 49% of all commercially available prodrugs. Reasons for the popularity of ester prodrugs include their often straightforward synthesis, their improved lipophilicity and membrane permeability, and the ubiquity of esterases. An example of a method of preparing ester prodrugs is with lipophilic alkyl or alkoxymethyl esters (i.e., pivaloylox...

Claims

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Application Information

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IPC IPC(8): C07C227/14C07D209/10C07F9/06C07D317/40A61K31/404A61K31/66A61K31/7076
CPCC07C281/20A61P35/00A61P35/02A61K31/404A61K31/66A61K31/7076C07C227/14C07C245/18C07C271/22C07D209/10C07D209/18C07D209/20C07D211/90C07D263/04C07D263/18C07D309/10C07D317/38C07D317/40C07D473/34C07F9/06C07F9/2458C07F9/65616C07H15/203C07H19/207C07K5/06026C07K5/06156C07K5/0808A61K38/00
Inventor 芭芭拉·斯卢谢尔拉娜·赖斯卢卡斯·特诺拉帕维尔·马耶尔安德烈·扬恰日克
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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