Methods and systems for preparing irreversible inhibitors of protein tyrosine phosphatases

Patent metadata

Field	Value
Publication number	US-9399653-B2
Application number	US-201113582407-A
Country	US
Kind code	B2
Filing date	Mar 3, 2011
Priority date	Mar 3, 2010
Publication date	Jul 26, 2016
Grant date	Jul 26, 2016

Abstract

Described herein are the preparation and use of novel bromo-phosphonomethylphenylalanine amino acid derivatives (BrPmp) and BrPmp-containing peptides as specific, irreversible protein tyrosine phosphatase inhibitors, which are suitable for application in peptide synthesis. These derivatives are particularly advantageous since their synthesis is both easy and scalable, and they are suitable for peptide synthesis. The BrPmp derivatives described herein can be appropriately protected to allow for solid phase peptide synthesis (SPPS) and incorporation into peptides for preparation of protein tyrosine phosphatase inhibitors and inhibitor libraries. The peptides and peptide libraries can be used to identify new protein tyrosine phosphatase specific sequences and profile protein tyrosine phosphatase activity in cell lysates, diagnostic samples and biopsy samples.

First claim

What is claimed is:

1. A compound of Formula (I) or Formula (II):

or a salt thereof;
wherein R is Boc (butyloxycarbonyl), Fmoc (fluorenylmethyloxycarbonyl), Cbz (carboxybenzyl), or Alloc (allyloxycarbonyl);
each R 1 is independently methyl (—CH 3 ), ethyl (—CH 2 CH 3 ), tert-butyl (—C(CH 3 ) 3 ), benzyl (—CH 2 C 6 H 5 ), allyl (—CH 2 CH═CH 2 ), dimethylamino (—N(CH 3 ) 2 ), propylamino (—NHCH 2 CH 2 CH 3 ), isopropylamino (—NHCH(CH 3 ) 2 ), or acetate (—C(O)CH 3 );
each R 2 is independently methyl (—CH 3 ), ethyl (—CH 2 CH 3 ), tert-butyl (—C(CH 3 ) 3 ), benzyl (—CH 2 C 6 H 5 ), allyl (—CH 2 CH═CH 2 ), hydrogen (—H), dimethylamino (—N(CH 3 ) 2 ), propylamino (—NHCH 2 CH 2 CH 3 ), isopropylamino (—NHCH(CH 3 ) 2 ), or acetate (—C(O)CH 3 );
R 3 is hydrogen, acetyl, alkanoyl, alkyl, aryl, aralkyl, alkaryl, or polyethyleneoxy;
R 4 and R 5 are side chains of amino acids selected from the group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine;
R 6 is hydroxyl, NH 2 , O-alkyl, O-aryl, O-aralkyl, O-alkaryl, and N-polyethyleneoxy; and
each of n 1 and n 2 is independently zero or 1-50, wherein n 1 and n 2 are not zero at the same time, wherein alkyl groups of the compound of Formula (II) are optionally substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, alkoxy, haloalkoxy and alkoxyalkyl; and wherein the compound of Formula II is optionally substituted with a group selected from a fluorescent tag, a chemiluminescent tag, an affinity tag, an azide, an alkyne, an amino-oxy, or a hydrazine.

2. The compound of Formula (I) of claim 1 , wherein R is Fmoc and each R 1 is methyl.

3. The compound of Formula (I) of claim 1 , wherein R is Fmoc, Boc, or Cbz and R 1 is methyl, ethyl, benzyl, dimethylamino (—N(CH 3 ) 2 ), propylamino (—NHCH 2 CH 2 CH 3 ), isopropylamino (—NHCH(CH 3 ) 2 ) or allyl.

4. The compound of Formula (I) of claim 1 , which is an L-amino acid derivative.

5. The compound of Formula (I) of claim 1 , which is a D-amino acid derivative.

6. The compound of Formula (II) of claim 1 , wherein R 3 is hydrogen, R 4 is the side chain of aspartic acid, n 1 is 1, each R 2 is hydrogen, R 5 is the side chain of leucine, R 6 is hydroxyl, and n 2 is 1.

7. The compound of Formula (II) of claim 1 , wherein the amino acids are selected from the group consisting of L-amino acids, L-amino acid derivatives, D-amino acids, and D-amino acid derivatives.

8. The compound of claim 2 , which is an L-amino acid derivative.

9. The compound of claim 1 , wherein R is Fmoc, Boc, or Cbz.

Assignees

• Cairo Christopher Warren
• Tulsi Naresh Singh
• Downey Alan Michael
• Univ Alberta

Inventors

• Cairo Christopher Warren
• Tulsi Naresh Singh
• Downey Alan Michael

Classifications

• C12Q1/42

  involving phosphatase · CPC title

• C07F9/4056

  Esters of arylalkanephosphonic acids (C07F9/4025 takes precedence) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07F9/3882 Primary

  Arylalkanephosphonic acids (C07F9/3839 takes precedence) · CPC title

• C07K5/0827

  containing heteroatoms different from O, S, or N · CPC title