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1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Immunomodulators

a technology of oxadiazole and thiadiazole, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of immune tolerance breakdown and pathogenic autoimmunity, and achieve the effect of suppressing and/or inhibiting the programmed cell death 1 (pd1) signaling pathway

Inactive Publication Date: 2016-07-07
AURIGENE DISCOVERY TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent provides a new group of compounds (oxadiazole and thiadiazole) that can inhibit a specific protein called PD1. These compounds have potential to be used as drugs to treat diseases where PD1 is involved, such as cancer.

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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  • 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Immunomodulators
  • 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Immunomodulators
  • 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Immunomodulators

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Compound 1

Step 1a:

[0122]

[0123]Potassium carbonate (7.9 g, 57.39 mmol) and Methyl iodide (1.3 mL, 21.04 mmol) were added to a solution of compound 1a (5.0 g, 19.13 mmol) in DMF (35 mL) and stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get 5.0 g of compound 1b (Yield: 96.1%). LCMS: 176.1 (M-Boc)+.

Step 1b:

[0124]

[0125]Hydrazine hydrate (7.2 mL) was added to a solution of compound 1b (5.0 g, 18.16 mmol) in methanol (30 mL) and stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, the residue obtained was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure...

example 2

Synthesis of Compound 2

Step 2a:

[0138]

[0139]NMM (1.8 mL, 18.15 mmol) was slowly added to a stirred solution of 1c (2.0 g, 7.26 mmol), 2d (4.3 g, 7.26 mmol), HOBt (1.17 g, 8.7 mmol) and EDC.HCl (1.66 g, 8.7 mmol) in DMF (15 mL) at 0. The reaction mixture was stirred at room temperature for 12 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice, the solid precipitated was filtered and dried under vacuum to afford 3.7 g of pure product 2e (Yield: 59.6%). LCMS: 854.4 (M+H)+.

Step 2b:

[0140]

[0141]To a stirred solution of 2e (3.7 g, 4.33 mmol) dissolved in dry THF (25.0 mL) and DMF (10.0 mL), triphenylphosphine (2.28 g, 8.66 mmol) and iodine (2.2 g, 8.66 mmol) were added at 0. After the iodine was completely dissolved, Et3N (2.5 mL, 17.32 mmol) was added at same temperature. The reaction mixture was stirred at room temperature for 4 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice water and...

example 3

Synthesis of Compound 3

Step 3a:

[0148]

[0149]Lawesson's reagent (2.85 g, 7.03 mmol) was added to a solution of compound 2e (4 g, 4.68 mmol) in THF (40 mL) and stirred at 75° C. for 4 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and the obtained residue was partitioned between ice water and ethyl acetate. The organic layer was washed with NaHCO3 solution followed brine solution. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to get residue which was further purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in hexane) to afford 2.7 g of compound 3a (Yield: 67.66%). LCMS: 852.3 (M+H)+,

Step 3b:

[0150]

[0151]Fmoc group on compound 3a was deprotected by adding diethylamine (3.8 mL) to the solution of compound 3a (1 g, 1.17 mmol) in CH2Cl2 (3.8 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrate...

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Abstract

The present invention relates to 1,3,4-oxadiazole and 1,3,4-thiadiazole compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signalling 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

[0001]This application claims the benefit of Indian provisional application number 4012 / CHE / 2013, filed on Sep. 6, 2013; which hereby incorporated by reference.TECHNICAL FIELD[0002]The present invention relates to 1,3,4-oxadiazole and 1,3,4-thiadiazole compounds therapeutically useful as immune modulators. The invention also relates to pharmaceutical compositions comprising the said 1,3,4-oxadiazole and 1,3,4-thiadiazole compounds as therapeutic agents.BACKGROUND OF THE INVENTION[0003]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 CD28 members. PD-1 and its ligands are involved in attenuating infectious immunity and tumor immunity, and facilitating chronic infection and tumor progression. The biological significance of PD-1 and its ...

Claims

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Application Information

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IPC IPC(8): C07D285/12A61K31/4245A61K45/06C07D271/10A61K31/433
CPCC07D285/12C07D271/10A61K31/4245A61K45/06A61K31/433A61P31/00A61P35/00A61K2300/00
Inventor SASIKUMAR, POTTAYIL GOVINDAN NAIRRAMACHANDRA, MURALIDHARANAREMADDEPALLI, SEETHARAMAIAH SETTY SUDARSHAN
Owner AURIGENE DISCOVERY TECH
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