Proteasome inhibitors and methods of using the same

• US 20090075936A1
• Filed: 11/06/2008
• Published: 03/19/2009
• Est. Priority Date: 02/11/2005
• Status: Active Grant

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Oliva, Ambrogio, Bernareggi, Alberto, D'Arasmo, Germano, Cassara, Paolo G., Bernardini, Raffaella, Menta, Ernesto
• Granted Patent: US 8,283,367 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.

Claims

3-1. The method of claim 1, wherein the method is a method of treating accelerated or enhanced proteolysis.

10. A method of inhibiting the degradation of a protein comprising contacting proteasome capable of degrading said protein with a compound of Formula (I)

or pharmaceutically acceptable salt form thereof, wherein:

Q is —

B(OR^B)₂, boronic acid, attached via the boron atom, or a cyclic boronic ester attached via the boron atom, wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O;

R^B is, independently, H, C_1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;

Z is —

CH(OH)CH₃ or —

CH₂NR^1aR¹;

Hy is a 5- or 6-membered heterocyclic group optionally fused with an aryl or heteroaryl group, wherein said 5- or 6-membered heterocyclic group contains at least one ring-forming N atom, and wherein said Hy is optionally substituted by 1, 2 or 3 R⁴;

R¹ is H, C_1-10 alkyl, carbocyclyl, heterocyclyl, C_1-10 alkyl-C(═

O)—

, C_2-10 alkenyl-C(═

O)—

, C_2-10 alkynyl-C(═

O)—

, carbocyclyl-C(═

O)—

, heterocyclyl-C(═

O)—

, carbocyclylalkyl-C(═

O)—

, heterocyclylalkyl-C(═

O)—

, C_1-10 alkyl-S(═

O)₂—

, carbocyclyl-S(═

O)₂—

, heterocyclyl-S(═

O)₂—

, carbocyclylalkyl-S(═

O)₂—

, heterocyclylalkyl-S(═

O)₂—

, C₁-C₁₀ alkyl-NHC(═

O)—

, carbocyclyl-NHC(═

O)—

, heterocyclyl-NHC(═

O)—

, carbocyclylalkyl-NHC(═

O)—

, heterocyclylalkyl-NHC(═

O)—

, C₁-C₁₀ alkyl-OC(═

O)—

, carbocyclyl-OC(═

O)—

, heterocyclyl-OC(═

O)—

, carbocyclylalkyl-OC(═

O)—

, heterocyclylalkyl-OC(═

O)—

, C_1-10 alkyl-NH—

C(═

O)—

NHS(═

O)₂—

, carbocyclyl-NH—

C(═

O)—

NHS(═

O)₂—

, heterocyclyl-NH—

C(═

O)—

NHS(═

O)₂—

, C_1-10 alkyl-S(═

O)₂—

NH—

C(═

O)—

, carbocyclyl-S(═

O)₂—

NH—

C(═

O)—

, heterocyclyl-S(═

O)₂—

NH—

C(═

O)—

, or an amino protecting group;

wherein R¹ is optionally substituted with 1, 2 or 3 substituents selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, F, Cl, Br, I, C_1-4 haloalkyl, —

NH₂, —

NHR², —

N(R²)₂, —

N₃, —

NO₂, —

CN, —

CNO, —

CNS, —

C(═

O)OR², —

C(═

O)R², —

OC(═

O)R², —

N(R²)C(═

O)R², —

N(R²)C(═

O)OR², —

C(═

O)N(R²)₂, ureido, —

OR², —

SR², —

S(═

O)—

(C_1-6 alkyl), —

S(═

O)₂—

(C_1-6 alkyl), —

S(═

O)-aryl, —

S(═

O)₂-aryl, —

S(═

O)₂—

N(R²)₂;

carbocyclyl optionally substituted with 1, 2, 3, 4 or 5 R³; and

heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 R³;

R^1a is H. Alternatively, R^1a and R¹ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclyl group optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C_1-6 alkyl;

alternatively, two R² may be combined, together with the N atom to which they are attached, to form a 5-, 6- or 7-membered heterocyclic group;

R³ is, independently, selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═

O)—

, alkyl-C(═

O)—

, aryl-OC(═

O)—

, alkyl-OC(═

O)NH—

, aryl-OC(═

O)NH—

, alkyl-C(═

O)NH—

, alkyl-C(═

O)O—

, —

OH, —

SH, —

CN, —

N₃, —

CNO, —

CNS, alkyl-S(═

O)—

, alkyl-S(═

O)₂—

, H₂NS(═

O)—

, and H₂NS(═

O)₂—

;

R⁴ is, independently, selected from C_1-20 alkyl, C_2-20 alkenyl, C_2-20 alkynyl, —

OR^4a, SR^4a, —

CN, halo, haloalkyl, —

NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NHC(═

O)O-alkyl, —

NHC(═

O)alkyl, —

COOH, —

C(═

O)O-alkyl, —

C(═

O)alkyl, —

C(O)H, —

S(═

O)-alkyl, —

S(═

O)₂-alkyl, —

S(═

O)-aryl, —

S(═

O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, and heterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^4a is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclyl or heterocyclyl;

R⁵ is, independently, selected from C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═

O)—

, alkyl-C(═

O)—

, aryl-OC(═

O)—

, alkyl-OC(═

O)NH—

, aryl-OC(═

O)NH—

, alkyl-C(═

O)NH—

, alkyl-C(═

O)O—

, —

OH, —

SH, —

CN, —

N₃, —

CNO, —

CNS, alkyl-S(═

O)—

, alkyl-S(═

O)₂—

, H₂NS(═

O)—

, and H₂NS(═

O)₂—

;

with the proviso that when Z is —

CH(OH)CH₃ and Q is

then Hy is other than

13. A method of inhibiting activity of transcription factor NF-κ

B comprising contacting Iκ

B, the inhibitor of transcription factor NF-κ

B, with a compound of Formula (I)

or pharmaceutically acceptable salt form thereof, wherein;

Q is —

B(OR^B)₂, boronic acid, attached via the boron atom, or a cyclic boronic ester attached via the boron atom, wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O;

R^B is, independently, H, C_1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;

Z is —

CH(OH)CH₃ or —

CH₂NR^1aR¹;

Hy is a 5- or 6-membered heterocyclic group optionally fused with an aryl or heteroaryl group, wherein said 5- or 6-membered heterocyclic group contains at least one ring-forming N atom, and wherein said Hy is optionally substituted by 1, 2 or 3 R⁴;

R¹ is H, C_1-10 alkyl, carbocyclyl, heterocyclyl, C_1-10 alkyl-C(═

O)—

, C_2-10 alkenyl-C(═

O)—

, C_2-10 alkynyl-C(═

O)—

, carbocyclyl-C(═

O)—

, heterocyclyl-C(═

O)—

, carbocyclylalkyl-C(═

O)—

, heterocyclylalkyl-C(═

O)—

, C_1-10 alkyl-S(═

O)₂—

, carbocyclyl-S(═

O)₂—

, heterocyclyl-S(═

O)₂—

, carbocyclylalkyl-S(═

O)₂—

, heterocyclylalkyl-S(═

O)₂—

, C₁-C₁₀ alkyl-NHC(═

O)—

, carbocyclyl-NHC(═

O)—

, heterocyclyl-NHC(═

O)—

, carbocyclylalkyl-NHC(═

O)—

, heterocyclylalkyl-NHC(═

O)—

, C₁-C₁₀ alkyl-OC(═

O)—

, carbocyclyl-OC(═

O)—

, heterocyclyl-OC(═

O)—

, carbocyclylalkyl-OC(═

O)—

, heterocyclylalkyl-OC(═

O)—

, C_1-10 alkyl-NH—

C(═

O)—

NHS(═

O)₂—

, carbocyclyl-NH—

C(═

O)—

NHS(═

O)₂—

, heterocyclyl-NH—

C(═

O)—

NHS(═

O)₂—

, C_1-10 alkyl-S(═

O)₂—

NH—

C(═

O)—

, carbocyclyl-S(═

O)₂—

NH—

C(═

O)—

, heterocyclyl-S(═

O)₂—

NH—

C(═

O)—

, or an amino protecting group;

wherein R¹ is optionally substituted with 1, 2 or 3 substituents selected from C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, F, Cl, Br, I, C_1-4 haloalkyl, —

NH₂, —

NHR², —

N(R²)₂, —

N₃, —

NO₂, —

CN, —

CNO, —

CNS, —

C(═

O)OR², —

C(═

O)R², —

OC(═

O)R², —

N(R²)C(═

O)R², —

N(R²)C(═

O)OR², —

C(═

O)N(R²)₂, ureido, —

OR², —

SR², —

S(═

O)—

(C_1-6 alkyl), —

S(═

O)₂—

(C_1-6 alkyl), —

S(═

O)-aryl, —

S(═

O)₂-aryl, —

S(═

O)₂—

N(R²)₂;

carbocyclyl optionally substituted with 1, 2, 3, 4 or 5 R³; and

heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 R³;

R^1a is H. Alternatively, R^1a and R¹ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclyl group optionally substituted with 1, 2, or 3 R³;

R² is, independently, H or C_1-6 alkyl;

alternatively, two R² may be combined, together with the N atom to which they are attached, to form a 5-, 6- or 7-membered heterocyclic group;

R³ is, independently, selected from C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═

O)—

, alkyl-C(═

O)—

, aryl-OC(═

O)—

, alkyl-OC(═

O)NH—

, aryl-OC(═

O)NH—

, alkyl-C(═

O)NH—

, alkyl-C(═

O)O—

, —

OH, —

SH, —

CN, —

N₃, —

CNO, —

CNS, alkyl-S(═

O)—

, alkyl-S(═

O)₂—

, H₂NS(═

O)—

, and H₂NS(═

O)₂—

;

R⁴ is, independently, selected from C_1-20 alkyl, C_2-20 alkenyl, C_2-20 alkynyl, —

OR^4a, SR^4a, —

CN, halo, haloalkyl, —

NH₂, —

NH(alkyl), —

N(alkyl)₂, —

NHC(═

O)O-alkyl, —

NHC(═

O)alkyl, —

COOH, —

C(═

O)O-alkyl, —

C(═

O)alkyl, —

C(O)H, —

S(═

O)-alkyl, —

S(═

O)₂-alkyl, —

S(═

O)-aryl, —

S(═

O)₂-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, and heterocyclyl optionally substituted with 1, 2 or 3 R⁵;

R^4a is H, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, carbocyclyl or heterocyclyl;

R⁵ is, independently, selected from C_1-10 alkyl, C_2-10 alkenyl, C_2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═

O)—

, alkyl-C(═

O)—

, aryl-OC(═

O)—

, alkyl-OC(═

O)NH—

, aryl-OC(═

O)NH—

, alkyl-C(═

O)NH—

, alkyl-C(═

O)O—

, —

OH, —

SH, —

CN, —

N₃, —

CNO, —

CNS, alkyl-S(═

O)—

, alkyl-S(═

O)₂—

, H₂NS(═

O)—

, and H₂NS(═

O)₂—

;

with the proviso that when Z is —

CH(OH)CH₃ and Q is

then Hy is other than