Prodrugs of peptide epoxy ketone protease inhibitors

• US 9,878,047 B2
• Filed: 03/09/2016
• Issued: 01/30/2018
• Est. Priority Date: 07/09/2012
• Status: Active Grant

• Current Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Original Assignee: Onyx Therapeutics, Inc. (Amgen Inc.)
• Inventors: Phiasivongsa, Pasit, Luehr, Gary W., Peng, Ge, By, Kolbot, Anik, Shabbir T.
• Primary Examiner(s): YANG, KAIPEEN E
• Application Number:
  US15/065,347
• Publication Number:
  US 20160263234A1
• Time in Patent Office: 692 Days
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/08 : Tripeptides
• CPC Class Codes: C07K 5/0806 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/081 : the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0821 : with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/10 : Tetrapeptides
• CPC Class Codes: C07K 5/1008 : the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1016 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/1021 : with the first amino acid being acidic
• CPC Class Codes: C07K 5/1024 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 7/06 : having 5 to 11 amino acids

Abstract

This disclosure features compounds that are useful as pro-drugs of epoxy ketone protease inhibitors.

Claims

1. A compound having the formula (SM)_m-PEG, or a pharmaceutically acceptable salt thereof;

wherein each SM is an independently selected compound of formula (I);

2. The compound of claim 1, wherein the compound has Formula (VI):

3. The compound of claim 2, wherein m is 2, 4, or 8.

4. The compound of claim 2, wherein one R^N1 and R^N4 is R¹⁴ and the other is hydrogen, and R^N2 and R^N3 are each hydrogen.

5. The compound of claim 2, wherein one R^N2 and R^N3 is R¹⁴, and the other is hydrogen, and R^N1 and R^N4 are each hydrogen.

6. The compound according to claim 2, wherein R^14′

is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, —

C(═

O)—

, —

NHC(═

O)—

, —

C(═

O)NH—

, heteroalkylene chain, phenylene, indolylene, indolinylene, thiophenylene, or furanylene, wherein phenylene, indolylene, indolinylene, thiophenylene, and furanylene are optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, C_1-6 alkoxy, heteroalkyl, CF₃, and C_1-6 alkyl.

7. The compound of claim 6, wherein when alkylene chain is present, the alkylene chain is linked to the backbone nitrogen.

8. The compound according to claim 2, wherein R^14′

is -alkylene chain-O—

C(O)-phenylene-, wherein the alkylene chain is linked to the backbone nitrogen.

9. The compound according to claim 2, wherein R²⁰ is present.

10. The compound according to claim 2, wherein PEG is PEG_20K.

11. The compound according to claim 2, wherein R^S1 and R^S3 are each independently C_1-6alkyl, and R^S2 and R^S4 are each independently C_7-12aralkyl.

12. The compound according to claim 1, wherein the compound is selected from group consisting of

13. A pharmaceutical composition comprising a compound as claimed in claim 1, and a pharmaceutically acceptable carrier.