Immunomodulators

A technology selected from medicine and medicine, applied in antiviral agents, allergic diseases, peptide/protein components, etc., can solve the lack of MYPPY motifs and other problems

Active Publication Date: 2017-09-26
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif critical for CD80CD86(B7-2) binding

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1001

[0683] Example 1001, Isomer 1. The crude material was purified via preparative LC / MS using the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 20-60% B in 25 minutes, then 100% B for 5 minutes; flow rate: 20 mL / min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of product was 2.1 mg and its estimated purity by LCMS analysis was 95%.

[0684] Analytical LCMS condition D: retention time = 1.57min; ESI-MS (+) m / z 932.15 (M+2H)

[0685] Analytical LCMS Conditions E: retention time = 1.44 min; ESI-MS (+) m / z 932.35 (M+2H).

[0686]

Embodiment 1002

[0687] Example 1002, Isomer 2. The crude material was purified via preparative LC / MS using the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 20-60% B in 25 minutes, then 60% B for 5 minutes; flow rate: 20 mL / min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of product was 1.5 mg and its estimated purity by LCMS analysis was 99%.

[0688] Analytical LCMS condition D: retention time = 1.79 min; ESI-MS (+) m / z 932.15 (M+2H).

[0689] Analytical LCMS Conditions E: retention time = 1.66 min; ESI-MS (+) m / z 931.85 (M+2H).

[0690] Preparation of Example 1003 and Example 1004

[0691]

[0692] Start with Intermediate Resin A. The resulting resin was worked up using the following operations in sequence:

[0693] For (S)-2-(5-((S)-1-((((9...

Embodiment 1003

[0698] Example 1003, Isomer 1. The crude material was purified via preparative LC / MS using the following conditions: Column: WatersXBridge C18, 19×250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water, containing 10-mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; gradient: 20-65% B in 25 minutes, then 65% B for 5 minutes; flow rate: 20 mL / min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of product was 0.9 mg and its estimated purity by LCMS analysis was 100%.

[0699] Analytical LCMS condition D: retention time = 1.54min; ESI-MS (+) m / z 931.85 (M+2H)

[0700] Analytical LCMS Conditions E: retention time = 1.41 min; ESI-MS (+) m / z 931.90 (M+2H).

[0701]

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Abstract

The present disclosure provides novel macrocyclic peptides which inhibit the PD-1/PD-L1 and PD-L1/CD80 protein/protein interaction, and thus are useful for the amelioration of various diseases, including cancer and infectious diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 62 / 111,900, filed February 4, 2015, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention provides novel macrocyclic peptides that inhibit PD-1 / PD-L1 and CD80 / PD-L1 protein / protein interactions and are therefore useful for ameliorating various diseases, including cancer and infectious diseases. Background technique [0004] Programmed death protein 1 (PD-1) is an inhibitory member of the CD28 family of receptors, which also includes CD28, CTLA-4, ICOS and BTLA. PD-1 is expressed on activated B cells, T cells, and myeloid cells (Agata et al., supra; Okazaki et al., Curr. Opin. Immunol., 14:779-782 (2002); Bennett et al., J. Immunol., 170:711-718 (2003)). [0005] The PD-1 protein is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al., Int. Immunol., 8:765...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/54C07K7/56A61K38/12A61P37/02
CPCC07K7/54C07K7/56A61K38/00A61K38/12A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/12A61P31/04A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P37/02A61P43/00Y02A50/30A61K45/06
Inventor M·M·米勒M·P·艾伦L·李C·马佩里M·A·普瓦里埃L-Q·孙赵倩E·马尔E·P·吉利斯P·M·斯科拉
Owner BRISTOL MYERS SQUIBB CO
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