Boronic ester and acid compounds, synthesis and uses

• US 20030199561A1
• Filed: 03/19/2003
• Published: 10/23/2003
• Est. Priority Date: 10/28/1994
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Ma, Yu-Ting, Baevsky, Matthew, Adams, Julian, Grenier, Louis, Plamondon, Louis, Stein, Ross
• Granted Patent: US 6,747,150 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 37/00 Drugs for immunological or allergic disorders
• 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: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06 Dipeptides
• CPC Class Codes: C07K 5/06043 Leu-amino acid
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0808 : the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/0827 : containing heteroatoms different from O, S, or N

Abstract

Disclosed herein is a method for reducing the rate of degradation of proteins in an animal comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed herein are novel boronic ester and acid compounds, their synthesis and uses.

Claims

1. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor of formula (1b)

2. The method of claim 1, wherein the ring portion of said aryl or heterocycle in R¹¹, R ¹², R¹³ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, and C_6-10 arylsulfonyl.

3. The method of claim 1, wherein the ring portion of said phenyl or aralkyl in R¹⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, and C_6-10 arylsulfonyl.

4. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor of formula (1b)

5. The method of claim 4, wherein the ring portion of said aryl or heterocycle in R¹¹, R¹², R¹³ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, and C_6-10 arylsulfonyl.

6. The method of claim 4, wherein the ring portion of said phenyl or aralkyl in R¹⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, and C_6-10 arylsulfonyl.

7. The method of claim 4, wherein A is zero and R¹³ is C_1-6 alkyl.

8. The method of claim 7, wherein R¹³ is C₄ alkyl.

9. The method of claim 7, wherein R¹³ is isobutyl.

10. The method of claim 7, wherein:

R¹¹, R¹² and R¹³ are each independently one of hydrogen, C_1-8 alkyl, C_3-8 cycloalkyl, C_6-10 aryl, or —

CH₂—

R¹⁵;

R¹⁵, in each instance, is one of phenyl, C_6-10 ar(C_1-6) alkyl, C_3-8 cycloalkyl, C_1-8 alkoxy, or C_1-8alkylthio;

where the ring portion of said aryl group of R¹¹, R¹², and R¹³, and the ring portion of said phenyl or aralkyl group of R¹⁵, each can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, and C_6-10 arylsulfonyl.

11. The method of claim 7, wherein R¹² is one of isobutyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, or phenethyl.

12. The method of claim 7, wherein Z¹ and Z² are independently one of hydroxy, C_1-6alkoxy, or C_6-10aryloxy.

13. The method of claim 12, wherein Z¹ and Z² are both hydroxy.

14. The method of claim 7, wherein Z¹ and Z²form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.

15. The method of claim 7, wherein P is R⁷—

C(O)—

or R⁷—

O—

C(O)— and

R⁷ is alkyl, cycloalkyl, aryl or aralkyl.

16. The method of claim 15, wherein P is acetyl, benzoyl, benzyloxycarbonyl or tert-butoxycarbonyl.

17. The method of claim 4, wherein A is 1 and R¹³ is C_1-6 alkyl.

18. The method of claim 17, wherein R¹³ is C₄ alkyl.

19. The method of claim 17, wherein R¹³ is isobutyl.

20. The method of claim 17, wherein:

R¹¹, R¹² and R¹³ are each independently one of hydrogen, C_1-8 alkyl, C_3-8 cycloalkyl, C_6-10 aryl, or —

CH₂—

R¹⁵;

R¹⁵, in each instance, is one of phenyl, C_6-10 ar(C_1-6) alkyl, C_3-8 cycloalkyl, C_1-8 alkoxy, or C_1-8alkylthio;

where the ring portion of said aryl group of R¹¹, R¹², and R¹³ and the ring portion of said phenyl or aralkyl group of R¹⁵, each can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-8 cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8 alkenyl, C_2-8 alkynyl, cyano, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6 alkoxy, C_6-10 aryl, C_6-10 aryl(C_1-6)alkyl, C_6-10 aryl(C_1-6)alkoxy, hydroxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_6-10 arylthio, C_6-10 arylsulfinyl, and C_6-10 arylsulfonyl.

21. The method of claim 17, wherein R¹² is one of isobutyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, or phenethyl.

22. The method of claim 17, wherein Z¹ and Z² are independently one of hydroxy, C_1-6alkoxy, or C_6-10aryloxy.

23. The method of claim 22, wherein Z¹ and Z² are both hydroxy.

24. The method of claim 17, wherein Z¹ and Z² form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.

25. The method of claim 17, wherein P is R⁷—

C(O)—

or R⁷—

O—

C(O)— and

R⁷ is alkyl, cycloalkyl, aryl or aralkyl.

26. The method of claim 25, wherein P is acetyl, benzoyl, benzyloxycarbonyl or tert-butoxycarbonyl.