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1,2,4-Oxadiazole Derivatives as Immunomodulators

Inactive Publication Date: 2015-03-12
AURIGENE DISCOVERY TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides compounds that can stop or prevent the PD1 signaling pathway from causing programmed cell death. These compounds are oxadiazole and thiadiazole compounds that can be used as pharmaceutical agents. They can be administered to patients to treat diseases that are influenced by the PD1 pathway.

Problems solved by technology

Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity.

Method used

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  • 1,2,4-Oxadiazole Derivatives as Immunomodulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compound 1

[0128]

[0129]FIG. 1A illustrates Steps 1a, 1b and 1c.

[0130]Step 1a: Ethylchloroformate (1.5 g, 13.78 mmol) and N-Methylmorpholine (1.4 g, 13.78 mmol) were added to a solution of compound 1a (3 g, 11.48 mmol) in THF (30 mL) and stirred at −20° C. After 20 min. liquid ammonia (0.77 g, 45.92 mmol) was added to the active mixed anhydride formed in-situ and stirred at 0-5° C. for 20 min. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCO3, citric acid, brine solution, dried over Na2SO4 and evaporated under reduced pressure to get 2.9 g of compound 1b (Yield: 96.3%). LCMS: 261.0 (M+H)+.

[0131]Step 1 b: Trifluroacetic anhydride (9.7 g, 46.0 mmol) was added to a solution of compound 1b (8 g, 30.7 mmol) in pyridine (24.3 g, 307.0 mmol) and stirred at room temperature for 3 h. The completeness of the reaction was conf...

example 2

Synthesis of Compound 2

[0136]

[0137]FIG. 2 illustrates Steps 2a and 2b.

[0138]Step 2a: The urea linkage was carried out by the coupling compound 1f (2.7 g, 4.39 mmol) in THF (30 mL) at room temperature with compound 2b (1.67 g, 4.39 mmol). The coupling was initiated by the addition of TEA (0.9 g, 8.78 mmol) in THF (10 m L) and the resultant mixture was stirred at room temperature. After completion of 20 h, THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get compound 2a, which was further purified by silica gel column chromatography (Eluent: 0-50% ethyl acetate in hexane) to afford 3.46 g of compound 2a (Yield: 92.10%). LCMS 857.4 (M+H)+.

[0139]Step 2b: To a solution of compound 2a (0.22 g, 0.25 mmol) in CH2Cl2 (5 m L), trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred for 3 h at room temperature. T...

example 3

Synthesis of Compound 3

[0141]

[0142]The compound was synthesised using similar procedure as depicted in Example 1 (compound 1) and D-amino acids are linked up in reverse order. Boc-D-Thr(tBu)-OH was used in place of Boc-Ser(tBu)-OH (compound 1a, Example 1) and Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt)-OH to yield 0.15 g crude material of the title compound 3. LCMS: 230.1 (M+H)+.

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Abstract

The present invention relates to 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signaling pathway. The invention also refers to derivatives of the therapeutic agents. The invention also encompasses the use of the said therapeutic agents and derivatives for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This nonprovisional application claims the benefit of priority under 35 U.S.C. §119(a) of Indian provisional application number 4011 / CHE / 2013, filed on Sep. 6, 2013, which is hereby incorporated by reference.BACKGROUND OF THE INVENTION[0002]1. Technical Field of the Invention[0003]The present invention relates to 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds and their derivatives therapeutically useful as immune modulators. The invention also relates to pharmaceutical compositions comprising the said 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds and their derivatives as therapeutic agents.[0004]2. Description of the Related Art[0005]Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed and exert a wider range of immunoregulatory roles in T cells activation and tolerance compared with other CD2...

Claims

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Application Information

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IPC IPC(8): C07D271/06A61K45/06A61K31/4245
CPCC07D271/06A61K45/06A61K31/4245A61K31/433C07D273/08A61K31/395C07D273/00A61P1/00A61P1/04A61P1/18A61P11/00A61P13/08A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P25/00A61P27/02A61P31/00A61P31/04A61P31/10A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P37/02A61P5/00A61P37/00C07D285/08A61K2300/00Y02A50/30
Inventor SASIKUMAR, POTTAYIL GOVINDAN NAIRRAMACHANDRA, MURALIDHARANAREMADDEPALLI, SEETHARAMAIAH SETTY SUDARSHAN
Owner AURIGENE DISCOVERY TECH
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