Macrocyclic peptides useful as immunomodulators

A medicinal salt and selected technology, applied in the field of macrocyclic peptides used as immunomodulators, can solve problems such as the lack of MYPPY motifs, and achieve the effect of improving various diseases

Active Publication Date: 2017-08-29
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • Macrocyclic peptides useful as immunomodulators
  • Macrocyclic peptides useful as immunomodulators
  • Macrocyclic peptides useful as immunomodulators

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 0001

[0794] Example 0001 - Solid Phase Peptide Synthesis and Cyclization of Peptides

[0795] The procedures described in the following examples, in whole or in part, were used to synthesize the macrocyclic peptides in Tables 1, 2, 3, 4 and 5.

[0796] Scheme 1 – General synthetic method for thioether-cyclized peptides

[0797]

[0798] General protocol for solid-phase peptide synthesis and macrocyclization. Sieber amide resin (0.71mmol / g, 0.100mmol, 141mg ) with DMF (7mLx4min) swelling, every 30 seconds with N 2The airflow stirred slightly. Drain off the solvent and couple the first amino acid using the following method: wash the resin twice with 20% piperidine / DMF (5 mL) for 2.5 min each to remove the Fmoc group from the resin-loaded binding block, and every 30 sec Agitate gently with nitrogen stream. The resin was washed three times with DMF (5-8 mL and 1.5 min per wash). Then 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetic acid (0.2 M in DMF, 0.5 mmol) was added, f...

preparation Embodiment 11001

[0854]

Embodiment 11001

[0855] The preparation of Example 11001 followed the general synthetic sequence described for the preparation of Example 0001 and consisted of the following general procedures: "Symphony Method A: Resin Swelling Procedure", "Symphony Method A: Standard Coupling Procedure", "Symphony Method A: Secondary Amine Coupling Protocol A", "Common Amino Acid Coupling Protocol", "Chloroacetyl Chloride Coupling Protocol", "Overall Deprotection Protocol A", and "Cyclization Protocol A". Modified Rink resin D was used in this synthesis. "

[0856] The crude material was purified by preparative LC / MS under the following conditions: Column: Waters XBridge C18, 30x100 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water + 10-mM ammonium acetate; Mobile phase B: 95:5 Acetonitrile: water + 10-mM ammonium acetate; gradient: 30-100% B over 25 minutes, then hold at 100% B for 5 minutes; flow rate: 30 mL / min. Fractions containing the desired product were combined and dried by centrifugal ev...

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Abstract

The present disclosure provides compounds which are immunomodulators 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 U.S. Provisional Patent Applications USSN 62 / 204,689, filed August 13, 2015, USSN 62 / 111,388, filed February 3, 2015, and USSN 62 / 079,944, filed November 14, 2014, at These applications are hereby incorporated by reference in their entirety. technical field [0003] The present application 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] The programmed death 1 (PD-1) protein is an inhibitory member of the CD28 receptor family, 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56C07K7/08A61K38/10A61K38/12A61P37/04A61P35/00A61P35/04A61P31/18A61P31/20A61P31/14A61P31/22A61P31/16A61P31/04
CPCC07K7/08C07K7/56A61K38/00A61K51/088A61K38/10A61K45/06A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/12A61P15/00A61P17/00A61P31/00A61P31/04A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/04A61P37/02A61P37/04A61P37/06A61P43/00A61P7/00C07D201/00Y02A50/30
Inventor K·W·吉尔曼J·古德里奇K·M·博伊Y·张C·马佩利M·A·帕斯L-Q·孙赵倩E·马尔E·P·吉利斯P·M·斯科拉D·R·兰勒
Owner BRISTOL MYERS SQUIBB CO
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