Proteasome inhibitors and methods of using the same

• US 8,283,367 B2
• Filed: 11/06/2008
• Issued: 10/09/2012
• Est. Priority Date: 02/11/2005
• Status: Expired due to Fees

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Bernardini, Raffaella, Bernareggi, Alberto, Cassara, Paolo G., D'Arasmo, Germano, Menta, Ernesto, Oliva, Ambrogio
• Primary Examiner(s): Fetterolf, Brandon
• Assistant Examiner(s): Pagonakis, Anna
• Application Number:
  US12/265,998
• Publication Number:
  US 20090075936A1
• Time in Patent Office: 1,433 Days
• Field of Search: None
• US Class Current: 514/357
• 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

1. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound of Formula (I)

2. The pharmaceutical composition of claim 1 wherein Q is boronic acid or a cyclic boronic ester wherein said cyclic boronic ester contains from 6 to 10 carbon atoms and contains at least one cycloalkyl moiety.

3. The pharmaceutical composition of claim 1 wherein Q is pinanediol boronic ester.

4. The pharmaceutical composition of claim 1 wherein Z is —

CH(OH)CH₃.

5. The pharmaceutical composition of claim 1 wherein Z is —

CH₂NHR¹.

6. The pharmaceutical composition of claim 1 wherein Z is —

CH₂NHR¹ and R¹ is carbocyclyl-C(═

O)—

or carbocyclyl-S(═

O)₂—

, each 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.

7. The pharmaceutical composition of claim 1 wherein Z is —

CH₂NHR¹ and R¹ is aryl-C(═

O)—

or aryl-S(═

O)₂—

, each optionally substituted with 1, 2 or 3 substituents selected from C_1-6 alkyl, F, Cl, Br, I, C_1-4 haloalkyl, carbocyclyl optionally substituted with 1, 2, 3, 4 or 5 R³ and heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 R³.

8. The pharmaceutical composition of claim 1 wherein Z is —

CH₂NHR¹ and R¹ is phenyl-C(═

O)—

or phenyl-S(═

O)₂—

, each optionally substituted with C_1-4 alkyl, F, Cl, Br, I, or aryl.

9. The pharmaceutical composition of claim 1 wherein Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1, 2 or 3 R⁴.

10. The pharmaceutical composition of claim 1 wherein Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1, 2 or 3 R⁴.

11. The pharmaceutical composition of claim 1 wherein Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 C_1-8 alkyl, carbocyclyl optionally substituted with 1, 2 or 3 R⁵, or heterocyclyl optionally substituted with 1, 2 or 3 R⁵.

12. The pharmaceutical composition of claim 1 wherein Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 methyl, ethyl, propyl, butyl, aryl optionally substituted with 1, 2 or 3 R⁵, or heteroaryl optionally substituted with 1, 2 or 3 R5.

13. The pharmaceutical composition of claim 1 wherein Hy is selected from:

14. The pharmaceutical composition of claim 1 wherein:

Z is —

CH(OH)CH₃; and

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.

15. The pharmaceutical composition of claim 1 wherein:

Z is —

CH(OH)CH₃; and

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1, 2 or 3 R⁴.

16. The pharmaceutical composition of claim 1 wherein:

Z is —

CH₂NHR¹;

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; and

R¹ is carbocyclyl-C(═

O)—

or carbocyclyl-S(═

O)₂—

, each 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.

17. The pharmaceutical composition of claim 1 wherein:

Z is —

CH₂NHR¹;

Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1, 2 or 3 R⁴; and

R¹ is carbocyclyl-C(═

O)—

or carbocyclyl-S(═

O)₂—

, each optionally substituted with 1, 2 or 3 substituents selected from C_1-6 alkyl, F, Cl, Br, I, C_1-4 haloalkyl, carbocyclyl optionally substituted with 1, 2, 3, 4 or 5 R³, and heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 R³.

18. The pharmaceutical composition of claim 1 wherein the compound of Formula (I) is selected from:

19. The pharmaceutical composition of claim 1 wherein the compound of Formula (I) is a boronic anhydride.

20. The pharmaceutical composition of claim 19 wherein said boronic anhydride is a cyclic boronic anhydride.

21. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound of Formula (I)