Immunomodulators

A technology selected from, methyl, applied in the direction of antiviral agents, allergic diseases, extracellular fluid diseases, etc., can solve the lack of MYPPY motifs and other problems, and achieve the effect of enhancing the functional activity of T cells

Active Publication Date: 2017-12-01
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although structurally similar to CTLA-4, PD-1 la...

Method used

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preparation example Construction

[0349] Preparation of INT-1300Z

[0350]

[0351] The following peptides were synthesized according to the above procedure on a 0.4 mmol scale. Underlined steps employed a double coupling procedure, and a 30 min single coupling was used to couple residues in italics. ClAc- Tyr -[N-Me]Ala- Asn -Pro-Dap- Leu -Hyp-Trp-Dab-[(S)-2-Amino-3-(1-(carboxymethyl)-1H-indol-3-yl)propionic acid]-[ N-Me] Nle -[N-Me]Nle-Leu-Cys-Gly; wherein Gly is added to 2-chlorotrityl resin. Cleavage from the resin was achieved by shaking the resin in 20% hexafluoroisopropanol / DCM for 5 min followed by filtration. The filtrate was concentrated in vacuo to provide the desired product. HPLCRT=2.21min, column: Waters Aquity UPLC BEH C18 2.1×50mm 1.7-μm particles; mobile phase A: acetonitrile containing 0.05% TFA; mobile phase B: water containing 0.05% TFA; gradient: within 1.5 minutes 2- 98% B, then hold at 98% B for 1.55 minutes; flow rate: 0.8 mL / min.

[0352] Preparation of INT-130AA

[0353...

Embodiment 13080

[0363] Preparation of Example 13080

[0364]

[0365] Step 1: To a solution of intermediate 1300Z (61.8 mg, 0.021 mmol) in DMF (537 μl) was added HATU (12.25 mg, 0.032 mmol) followed by Huenig's base (11.25 μl, 0.064 mmol). Finally, benzylamine (3.52 μl, 0.032 mmol) was added, and the resulting solution was stirred at room temperature. Within 3h, product had formed as shown by LC / MS. Water was added, and the resulting mixture was filtered to afford a solid 3-((7R,10S,13S,16S,19S,22S,25S)-25-((2S,4R)-4-(tert-butoxy)-1-( (S)-2-((S)-2-((S)-1-((S)-2-((S)-2-((S)-3-(4-(tert-butoxy) Phenyl)-2-(2-chloroacetylamino)-N-methylpropionylamino)propionylamino)-4-oxo-4-(tritylamino)butyryl)pyrrolidine-2-methane Amino)-3-((tert-butoxycarbonyl)amino)propionylamino)-4-methylpentanoyl)pyrrolidine-2-carboxamido)-19-((1-(2-(tert-butyl Oxy)-2-oxoethyl)-1H-indol-3-yl)methyl)-22-(2-((tert-butoxycarbonyl)amino)ethyl)-13,16-dibutyl Base-10-isobutyl-14,17-dimethyl-3,6,9,12,15,18,21,24-octaoxo-1-p...

Embodiment 13081

[0370] Preparation of Example 13081

[0371]

[0372] 2-((6S,9S,12S,18R,21S,24S,27S,30S,33S,36S,38aS,40R,44S,47S,49aS)-30,36-bis(( 1H-indol-3-yl)methyl)-6-(2-amino-2-oxoethyl)-44-(3-amino-3-oxopropyl)-24,27-dibutyl -40-Hydroxy-12-(4-hydroxybenzyl)-33,47-bis(hydroxymethyl)-21-isobutyl-9,10,25,28-tetramethyl-5,8,11, 14, 20, 23, 26, 29, 32, 35, 38, 43, 46, 49-Tetradecyloxotetraoctahydrodipyrrolo[2,1-g 1 :2',1'-x][1,4,7,10,13,16,19,22,25,28,31,34,37,40,43]thiatetradetraazepine To a solution of alkane-18-carboxamido)acetic acid (21.2mg, 0.012mmol) was added HATU (5.72mg, 0.015mmol) followed by Huenig base (8.08μl, 0.046mmol) in DMF and 5- Mixture of azidopentan-1-amine (14.82 mg, 0.116 mmol). The mixture was stirred at room temperature. After about 1 h, a small amount of product was seen and most of the SM remained. After another hour, the LC / MS did not change much. Additional HATU and amine mixture were added sequentially, and the yellow solution was stirred at room temp...

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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 / 134,686, filed March 18, 2015, which is hereby incorporated by reference. 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., 8:765-772 (1996)). PD-...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K7/64A61K38/12A61P35/00A61P31/00
CPCC07K7/08C07K7/64A61K38/00A61K39/0005A61K45/06A61P31/00A61P31/04A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02A61P35/04A61P37/02A61P37/04A61P43/00A61P7/00
Inventor K·M·博伊孙力强赵倩E·马尔E·P·吉利斯P·M·斯科拉
Owner BRISTOL MYERS SQUIBB CO
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