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Novel glutamine antagonists and uses thereof

An amino acid, selected technology, applied in the fields of peptides, organic chemistry, chemical instruments and methods, etc., can solve problems such as failure and hinder clinical development, etc.

Pending Publication Date: 2020-08-21
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, and abdominal pain) that occurred when such glutamine antagonists were administered at therapeutic dose levels hampered their clinical development
[0004] Previous attempts to mitigate severe toxicities associated with glutamine antagonists such as DON have been unsuccessful

Method used

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  • Novel glutamine antagonists and uses thereof
  • Novel glutamine antagonists and uses thereof
  • Novel glutamine antagonists and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0274] Example 1 Isopropyl 2-(6-acetylamino-2-((tert-butoxycarbonyl)amino)-hexanoylamino)-6-diazo-5-oxohexanoate (compound 1).

[0275]

[0276] Boc-L-Lys(Ac)-OH (446 mg, 1.55 mmol, 1.1 equiv) and HBTU (641 mg, 1.69 mmol, 1.2 equiv) were suspended in anhydrous DCM (8 mL), and the suspension was cooled to 0 °C. DIEA (546 mg, 735 μL, 4.22 mmol, 3 equiv) was added. The reaction mixture was stirred for 5 min, then a solution of DONiPr (300 mg, 1.41 mmol, 1 eq) in anhydrous DCM (2 mL) was added via syringe over 5 min. Under an inert atmosphere, the reaction mixture was stirred at 0 °C for 0.5 h and at room temperature for 1 h. Then add DCM (30mL), wash with H 2 O (2×50mL), brine (50mL) washed the solution, and washed with MgSO 4 dry. The organic solvent was evaporated in vacuo. The residue was chromatographed on silica gel (DCM / MeOH, 25:1) to give the desired product 1 (535 mg, 79%) as a pale yellow amorphous solid.

[0277] 1 H NMR (400MHz, CDCl 3 ):1.22(3H,d,J=6.3),1.2...

Embodiment 2

[0283] Example 2 2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-acetamide hexanoylamino)-6-diazo-5-oxohexanoic acid iso Propyl ester (Compound 2).

[0284]

[0285] Fmoc-L-Lys(Ac)-OH (6.35 g, 15.5 mmol, 1.1 equiv) and HBTU (6.41 g, 16.9 mmol, 1.2 equiv) were suspended in anhydrous DCM (80 mL), and the suspension was cooled to 0 ℃. DIEA (5.46 g, 7.35 mL, 42.2 mmol, 3 equiv) was added. The reaction mixture was stirred for 5 minutes, then a solution of DONiPr (3.00 g, 14.1 mmol, 1 equiv) in anhydrous DCM (20 mL) was added via syringe over 10 minutes. Under an inert atmosphere, the reaction mixture was stirred at 0 °C for 0.5 h and at room temperature for 1 h. Add DCM (30mL), wash with H 2 O (2×50mL), brine (50mL) washed the solution, and washed with MgSO 4 dry. The organic solvent was evaporated in vacuo. The residue was chromatographed on silica gel (CHCl 3 / MeOH, 30:1), the desired product 2 (5.72 g, 67%) was obtained as a pale yellow amorphous solid.

[0286] ...

Embodiment 3

[0292] Example 3 Isopropyl 2-(6-acetylamino-2-aminocaproylamino)-6-diazo-5-oxohexanoate (Compound 3).

[0293]

[0294] Compound 2 (5.00 g, 8.26 mmol, 1 equiv) was dissolved in anhydrous DCM (150 ml), and diethylamine (3.51 g, 4.97 mL, 41.3 mmol, 5 equiv) was added. The reaction mixture was stirred overnight (20 hours) at room temperature. The solvent was evaporated and the crude product was purified on silica gel to afford 2.91 g (92%) of compound 3 as a yellow solid.

[0295] 1 H NMR (400MHz, CDCl 3):1.20(3H,d,J=6.0),1.21(3H,d,J=6.0),1.33–1.53(4H,m),1.56–1.68(1H,m),1.72–1.84(1H,m) ,1.92(3H,s),1.91–2.02(1H,m),2.09–2.21(1H,m),2.28–2.48(2H,m),3.10–3.25(2H,m),3.43–3.73(3H, m), 4.43 (1H, td, J = 8.1, 4.7), 4.97 (1H, septet, J = 6.0), 5.46 (1H, bs), 6.51 (1H, bs), 8.05 (1H, d, J = 7.7).

[0296] 13 C NMR (101MHz, CDCl 3 ):21.76,22.57,23.22,27.29,29.06,29.71,33.92,36.70,39.06,51.84,54.53,55.13,69.40,170.66,171.24,174.15,194.15.

[0297] IR (KBr): 3432, 2110, 1731, 1635,...

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Abstract

Glutamine antagonists and their use for treating oncological, immunological, and neurological diseases are disclosed. Also disclosed are methods for treating an oncological, immunological, infectiousor neurological disease or disorder, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the disclosure or thepharmaceutical composition thereof. Also disclosed are methods of enhancing the effects of an immune checkpoint inhibitor, enabling a subject to respond to an immune checkpoint inhibitor, or enablingthe toxicity or the dose or number of treatments with an immune checkpoint inhibitor to be reduced, comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof, and an immune checkpoint inhibitor. Also disclosed are methods for treating an oncological, immunological, infectious or neurological disease or disorder that is refractory to checkpoint inhibitor therapy, the method comprising administering to a subject in need thereof, and having the refractory disease or disorder, a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof.

Description

[0001] federally funded research or development [0002] This invention was made with government support under P30MH075673-S1 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. Background technique [0003] Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON) and aza-serine, have shown broad anti-inflammatory activity in many published preclinical and several clinical studies. Virus (Antiviral Res.1997; 33(3):165-75; Antiviral Res.1994; 25(3-4):269-79), anti-infection (J.Bacteriol.1965; 89:1348-53), anti- Carcinoma (see, for example, Yoshioka et al., 1992; Tokushima J. Exp. Med. 39(1-2):69-76), anti-inflammatory, and immunosuppressive activity (Kulcsar et al., 2014; 111:16053-58; Maciolek et al., 2014; Curr OpinImmunol.27:60-74; Carr et al., 2010; J Immunol.185:1037-1044; Colombo et al., 2010; ProcNatl Acad SciUSA.107:18868-73), and seizure suppression (Proc R Soc Lond B BiolSci.1984Apr 24; 221(1223):145-68), ...

Claims

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Application Information

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IPC IPC(8): C07C251/76C07D209/10C07K5/06
CPCC07C271/22C07C271/34C07C245/18C07C251/76C07C2603/18C07C2603/74C07K5/0812C07K5/06086C07D217/26C07D209/18C07D209/20A61P35/00
Inventor B·思路十R·赖斯P·马也L·特诺拉K·诺夫那J·阿尔特
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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