PRODRUGS OF PEPTIDE EPOXY KETONE PROTEASE INHIBITORS

• US 20160263234A1
• Filed: 03/09/2016
• Published: 09/15/2016
• 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.
• Granted Patent: US 9,878,047 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 formula (I):

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

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

10. The compound according to 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.

11. The compound according to claim 1, wherein R^S1 and R^S3 are both isobutyl, R^S4 is phenylethyl, and R^S2 is phenylmethyl.

38. The compound of claim 1,

wherein

R¹⁴ is:

(i) —

CH₂OC(═

O)R¹⁸;

(ii) —

C(═

O)OCH₂OC(═

O)R¹⁸;

or

(iii) —

SR¹⁸;

wherein;

R¹⁸ is C_1-6alkyl, C_1-6alkoxyC_1-6alkyl, C_6-10aryl, C_7-12aralkyl, C_3-7cycloalkyl, heteroaryl including from 5-10 ring atoms wherein from 1-3 of the ring atoms are independently selected from N, NH, N—

C₁-C₆ alkyl, O, and S;

or heterocyclyl including from 3-7 ring atoms wherein from 1-2 of the ring atoms are independently selected from N, NH, N—

C₁-C₆ alkyl, and O;

each of which is optionally substituted;

or

R¹⁸ is —

Y′

″

_r—

Z′

″

;

wherein;

Y′

″

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

heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, cyclodextrin, human serum albumin, amino acid, amino acid mimetic, or hydrazine;

Z′

″

comprises one or more of the following moieties;

alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, cyclodextrin, alkylated cyclodextrin, human serum albumin, —

OC(═

O)—

, —

C(═

O)O—

, —

NHC(═

O)—

, —

C(═

O)NH—

, —

C(═

O)—

, monoclonal anti-body, quaternary ammonium ion, NH₂, docosahexenoic acid, hyaluronic acid, poly(L-glutamic acid), N-(2-hydroxypropyl) methacrylamide copolymer, or a dendrimer; and

r is 0 or 1.

51. 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) as defined in claim 1 and is attached to PEG; and

m is 2-10.

63. The compound of claim 51, wherein the compound has Formula (VI):

64. The compound of claim 63, wherein m is 2, 4, or 8.

65. The compound of claim 63, wherein one R^N1 and R^N4 is R¹⁴ (e.g., R^N1) and the other is hydrogen, and R^N2 and R^N3 are each hydrogen.

66. The compound of claim 63, wherein one R^N2 and R^N3 is R¹⁴, and the other is hydrogen, and R^N1 and R^N4 are each hydrogen.

67. The compound according to claim 63, 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.

68. The compound of claim 67, wherein when alkylene chain is present, the alkylene chain is linked to the backbone nitrogen.

69. The compound according to claim 63, wherein R^14′

is -alkylene chain-O—

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

70. The compound according to claim 63, wherein R²⁰ is present.

71. The compound according to claim 63, wherein PEG is PEG_20K.

96. The compound according to claim 63, wherein R^S1 and R^S3 are each independently C_1-6alkyl, and R^S2 and R^S4 are each independently C_7-12aralkyl.

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

99. A compound according to claim 51, wherein the compound is selected from group consisting of

108. A pharmaceutical composition comprising a compound as claimed in claim 51, and a pharmaceutically acceptable carrier.

109. A method for treating a disease or condition selected from the group consisting of cancer, autoimmune disease, graft or transplant-related condition, neurodegenerative disease, fibrotic-associated condition, ischemic-related conditions, infection (viral, parasitic or prokaryotic) and diseases associated with bone loss, the method comprising administering to a patient a therapeutically effective amount of a compound as claimed in claim 51.

110. The method of claim 109, wherein the disease or condition is cancer.

111. The method of claim 110, wherein the cancer is multiple myeloma.

2. (canceled)

5-9. -9. (canceled)

12-38. -38. (canceled)

39-50. -50. (canceled)

52-62. -62. (canceled)

72-95. -95. (canceled)

98. (canceled)

100-107. -107. (canceled)

112-113. -113. (canceled)