Prodrugs of peptide epoxy ketone protease inhibitors

• US 10,682,419 B2
• Filed: 01/29/2018
• Issued: 06/16/2020
• 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): Alstrum-Acevedo, James H
• Assistant Examiner(s): Yang, Kaipeen E
• Application Number:
  US15/881,919
• Publication Number:
  US 20180147291A1
• Time in Patent Office: 869 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:

2. The compound of claim 1, wherein Het is:

3. The compound according to claim 1, wherein M is CH₂.

4. The compound according to claim 1, wherein R³ is an activated hydroxyl.

5. The compound according to claim 4 wherein R³ is:

—

OC(═

O)—

R²²—

R²⁰-PEG,

wherein;

R²² is a divalent spacer comprising one or more of the following moieties;

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, arylene having 6-10 ring atoms, heteroarylene having from 5-10 ring atoms, heterocycloalkylene having 3-9 ring atoms, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

N(C_1-6 alkyl)C(═

O), —

C(═

O)N(C_1-6 alkyl)-, —

C(═

O)—

, —

NHC(═

O)NH—

, cyclodextrin, human serum albumin, amino acid, or hydrazine, wherein arylene having 6-10 ring atoms, heteroarylene having from 5-10 ring atoms, and heterocycloalkylene having 3-9 ring atoms are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C_1-6 alkoxy, heteroalkyl, C_6-10 aryloxy, C_7-12 aralkoxy, CF₃, quaternary ammonium ion, sugar, C_1-6 alkyl, —

C(═

O)(C_1-6 alkyl), —

SO₂(C_1-6 alkyl), —

C(═

O)O(C_1-6 alkyl), —

C(═

O)O(heteroalkyl), —

C(═

O)NH(C_1-6 alkyl), —

C(═

O)NH(heteroalkyl),—

C(═

O)(phenyl), —

SO₂(phenyl), and phosphate;

R²⁰ is

6. The compound according to claim 1, wherein each of R^N1, R^N2, R^N3, and R^N4 is H.

7. The compound of claim 1, wherein Q is SO₂.

8. The compound of claim 1, wherein m is 2, 4, or 8.

9. The compound according to claim 1, wherein R³ is OH.

10. The compound according to claim 1, wherein R¹⁹ is a divalent spacer comprising one or more of the following moieties:

heteroatom, alkylene chain, —

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.

11. The compound of claim 10, wherein when R¹⁹ comprises either of —

NHC(═

O)—

or —

C(═

O)NH—

, the —

NHC(═

O)—

or —

C(═

O)NH—

of R¹⁹ is linked to PEG.

12. The compound according to claim 1, wherein R¹⁹ is

13. The compound according to claim 1, wherein PEG is PEG_20K.

14. The compound according to claim 1, wherein R^S5 is H.

15. The compound of claim 1, wherein R^S1 and R^S3 are each independently C_1-6alkyl, and R^S2 and R^S4 are each independently C_7-12aralkyl.

16. The compound of claim 1, wherein the compound is a prodrug of:

17. A compound according to claim 1, wherein the compound is selected from the group consisting of:

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

19. The compound according to claim 1, wherein the PEG has PEG architecture 2B or 2C;

and/or the PEG has a molecular weight selected from the group consisting of;

greater than 1 kDa, 1 kDa, greater than 2 kDa, 2 kDa, greater than 5 kDa, 5 kDa, greater than 10 kDa, 10 kDa, greater than 20 kDa, 20 kDa, greater than 30 kDa, 30 kDa, greater than 40 kDa, 40 kDa, and greater than 50 kDa.