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1,3,4-oxadiazole and thiadiazole compounds as immunomodulators

A compound, C1-C6 technology, applied in the direction of organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve problems such as the breakdown of immune tolerance

Inactive Publication Date: 2017-11-28
AURIGENE DISCOVERY TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, abrogation of the PD-1 pathway can lead to the breakdown of immune tolerance, which can ultimately lead to the development of pathogenic autoimmunity

Method used

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  • 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators
  • 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators
  • 1,3,4-oxadiazole and thiadiazole compounds as immunomodulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0367] Embodiment 1: the synthesis of compound 1

[0368] Step 1a:

[0369]

[0370] Potassium carbonate (1.8 g, 13.0 mmol) and methyl iodide (0.65 mL, 10.4 mmol) were added to a solution of compound 1a (3.0 g, 8.7 mmol) in DMF (25 mL) and stirred at room temperature for 2 hours. Reaction completion was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, washed with Na 2 SO 4 Drying and evaporation under reduced pressure gave 3.0 g of compound 1b. LCMS: 361.1(M+H) + .

[0371] Step 1b:

[0372]

[0373] Hydrazine hydrate (3.3 mL, 8.3 mmol) was added to a solution of compound 1b (3.0 g, 8.3 mmol) in methanol (20 mL) and stirred at room temperature for 5 hours. Reaction completion was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and the residue obtained was partitioned between water and ethyl acetate. The organic layer was washed with...

Embodiment 2

[0397] Embodiment 2: the synthesis of compound 32

[0398] Step 32a:

[0399]

[0400] 4-Nitrophenol (1.3 g, 9.99 mmol) and pyridine (0.8 mL, 9.99 mmol) were dissolved in Et at -78 °C under argon atmosphere 2 A solution in O (20 mL) was added dropwise to SO 2 Cl 2 (0.8mL, 9.99mmol) in Et 2 solution in O (20 mL). The reaction mixture was allowed to reach room temperature and stirred for 4 hours. Reaction completion was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure to obtain crude compound. The crude compound was purified by silica gel column chromatography (eluent: 0%-3% ethyl acetate in hexanes) to afford 1.2 g of compound 32a. 1 H NMR (400MHz: CDCl 3 ) 8.39-8.36 (m 2H), 7.61-7.57 (m 2H).

[0401] Step 32b:

[0402]

[0403] Compound 32b (0.6g, 2.59mmol), molecular sieves (1.0g), 4-nitrophenol (0.72g, 5.18mmol) and Et 3 N (1.1 mL, 7.77 mmol) in anhydrous CH 2 Cl 2 (25.0 mL) was added dropwise to compound 32a (1.2 g, 5....

Embodiment 3

[0416] Example 3: Rescue of mouse splenocyte proliferation in the presence of recombinant PD-L1

[0417] Recombinant mouse PD-L1 (rm-PDL-1, catalog number: 1019-B7-100; R&D Systems) was used as a source of PD-L1.

[0418] Require:

[0419] Mouse splenocytes were harvested from 6-8 week old C57BL6 mice; RPMI 1640 (GIBCO, Cat# 11875); DMEM with high glucose (GIBCO, Cat# D6429); fetal bovine serum [Hyclone, Cat# SH30071.03] ; penicillin (10,000 units / mL)-streptomycin (10,000 μg / mL) liquid (GIBCO, cat. no. 15140-122); MEM sodium pyruvate solution 100 mM (100x), liquid (GIBCO, cat. no. 11360); not essential Amino Acid (GIBCO, Cat. No. 11140); L-Glutamine (GIBCO, Cat. No. 25030); Anti-CD3 Antibody (eBiosciences–16-0032); Anti-CD28 Antibody (eBiosciences–16-0281); ACK Lysis Buffer (1 mL ) (GIBCO, catalog number - A10492); Histopaque (density - 1.083 gm / mL) (SIGMA 10831); Trypan blue solution (SIGMA-T8154); 2 mL Norm Ject Luer Lock syringe (Sigma 2014-12); 40 μm nylon cells Filter ...

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Abstract

The present invention relates to 1,3,4-oxadiazole and thiadiazole compounds of formula (I) and their use to inhibit the programmed cell death 1 (PD-1) signaling pathway and / or for treatment of disorders by inhibiting an immunosuppressive signal induced by PD-1, PD-L1 or PD-L2.

Description

[0001] This application claims the benefit of Indian Provisional Application No. 1179 / CHE / 2015 filed on March 10, 2015; the specification of said Provisional Application is hereby incorporated by reference in its entirety. technical field [0002] The present invention relates to 1,3,4-oxadiazole and thiadiazole compounds and derivatives thereof which are therapeutically useful as immunomodulators. The present invention also relates to pharmaceutical compositions comprising 1,3,4-oxadiazole and thiadiazole compounds and derivatives thereof. Background of the invention [0003] Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that transmits negative signals when interacting with its two ligands, PD-L1 or PD-L2. Compared with other CD28 members, PD-1 and its ligands are widely expressed and play a broader range of immune regulatory roles in T cell activation and tolerance. PD-1 and its ligands are involved in attenuating infectious and tumor immunity and pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/433C07D285/08
CPCC07D413/06A61P35/00C07D271/10A61K31/4245A61K31/454A61K45/06C07D413/04C07D413/12A61K31/433
Inventor 波塔伊尔·戈文丹·奈尔·萨斯库马穆拉利达拉·拉马钱德拉西塔拉马伊阿·塞提·苏达山·纳里马德帕里
Owner AURIGENE DISCOVERY TECH
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