Boronic ester and acid compounds, synthesis and uses

• US 6,297,217 B1
• Filed: 01/25/2000
• Issued: 10/02/2001
• Est. Priority Date: 10/28/1994
• Status: Expired due to Term

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Adams, Julian, Grenier, Louis, Plamondon, Louis, Ma, Yu-Ting, Baevsky, Matthew, Stein, Ross
• Primary Examiner(s): Ramsuer, Robert W.
• Application Number:
  US09/490,511
• Time in Patent Office: 616 Days
• Field of Search: 514/18, 514/19, 514/64
• US Class Current: 514/19.3
• 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 treating cancer in a patient, comprising administering to said patient

(a) a proteasome inhibitor of formula (1a)

 

or a pharmaceutically acceptable salt thereof;

wherein

P is R⁷—

C(O)—

or R⁷—

SO₂—

, where R⁷ is pyrazinyl;

X² is —

C(O)—

NH—

;

R is hydrogen or alkyl;

R² and R³ are independently hydrogen, alkyl, cycloalkyl, aryl, or —

CH₂—

R⁵;

R⁵, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl;

where the ring portion of any of said aryl, aralkyl, or alkaryl in R², R³ and R⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C_3-6 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_1-6 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, C_6-10 arylsulfonyl, C_6-10 aryl, C_1-6 alkyl(C_6-10)aryl, and halo(C_6-10)aryl;

Z¹ and Z² are independently one of hydroxy, alkoxy, or aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O; and

A is zero.

2. The method of claim 1, wherein:

A is zero;

X is —

C(O)—

NH—

,

R is hydrogen or C_1-8 alkyl; and

R³ is C_1-6 alkyl.

3. The method of claim 2, wherein R₃ is C₄ alkyl.

4. The method of claim 1, wherein P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl.

5. The method of claim 1, wherein R is hydrogen or C_1-8 alkyl.

6. The method of claim 1, wherein:

R² and R³ are each independently one of hydrogen, C_1-8 alkyl, C_3-10 cycloalkyl, or C_6-10 aryl, or —

CH₂—

R⁵;

R⁵, in each instance, is one of C_6-10 aryl, C_6-10 ar(C_1-6)alkyl, C_1-6alk (C_6-10)aryl, C_3-10 cycloalkyl, C_1-8 alkoxy, or C_1-8alkylthio;

where the ring portion of any of said aryl, aralkyl, or alkaryl groups of R², R³ and R⁵ 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_1-6 alkyl(C_3-8)cycloalkyl, C_2-8alkenyl, C_2-8alkynyl, cyano, amino, C_1-6alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6alkoxy, C_6-10aryl, C_6-10aryl(C_1-6)alkyl, C_6-10aryl(C_1-6)alkoxy, hydroxy, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, C_6-10arylthio, C_6-10arylsulfinyl, C_6-10arylsulfonyl, C_6-10aryl, C_1-6alkyl(C_6-10)aryl, and halo(C_6-10)aryl.

7. The method of claim 1, wherein R₃ is C_1-12alkyl.

8. The method of claim 1, wherein R₃ is C_1-6alkyl.

9. The method of claim 1, wherein R₃ is C₄alkyl.

10. The method of claim 1, wherein R³ is isobutyl.

11. The method of claim 1, wherein R² is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl.

12. The method of claim 1, 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 1, 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.

15. The method of claim 1, wherein:

P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl;

A is zero;

X² is —

C(O)—

NH—

;

R is hydrogen or C_1-8 alkyl;

R² and R³ are each independently one of hydrogen, C_1-8alkyl, C_3-10cycloalkyl, C_6-10aryl, C_6-10ar(C_1-6)alkyl, pyridylmethyl, or quinolinylmethyl; and

Z¹ and Z² are both hydroxy, C_1-6alkoxy, or C_6-10aryloxy, or together 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.

16. The method of claim 1, wherein:

P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl;

A is zero;

X² is —

C(O)—

NH—

;

R is hydrogen or C_1-8 alkyl;

R³ is isobutyl;

R² is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl; and

Z¹ and Z² are independently one of hydroxy, C_1-6alkoxy, C_6-10aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol and diethanolamine.

17. The method of claim 1, wherein said compound is one of:

N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid;

N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid,

N-(8-quinoline)sulfonyl-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid;

or an isostere, pharmaceutically acceptable salt or boronate ester thereof.

27. The method of any one of claims 1, 18, or 20, further comprising administering to said patient a tumoricidal agent selected from the group consisting of cytotoxic drugs and radiation.

18. A method for treating cancer in a patient, comprising administering to said patient the compound N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, or a pharmaceutically acceptable salt or boronate ester thereof.

19. The method for treating cancer in a patient, comprising administering to said patient a compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein

P is R⁷—

C(O)— and

R⁷ is pyrazinyl;

X² is —

C(O)—

NH—

;

R is hydrogen or alkyl;

R² and R³ are independently hydrogen, alkyl, cycloalkyl, aryl, or —

CH₂—

R⁵;

R⁵, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl;

where the ring portion of any of said aryl, aralkyl, or alkaryl in R², R³ and R⁵ can be optionally substituted by one or two substituents independently selected from the group consisting of C_1-6alkyl, C_3-8cycloalkyl, 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_6-10aryl, 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, C_6-10 arylsulfonyl, C_6-10aryl, C_1-6alkyl (C_6-10)aryl, and halo (C_6-10)aryl;

Z¹ and Z² are independently one of hydroxy, alkoxy, or aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O; and

A is zero.

20. A method for treating cancer in a patient, comprising administering to said patient a compound having the formula:

or a pharmaceutically acceptable salt thereof;

wherein

P is an amino protecting group;

A is 1;

B¹ is CH;

X¹ is —

C(O)—

NH—

;

X² is —

C(O)—

NH—

;

R is hydrogen or alkyl;

R¹ is hydrogen, C_1-8alkyl, C_3-10cycloalkyl, C_6-10aryl, or —

CH₂—

R⁵, where the ring portion of said aryl can be optionally substituted;

R² is naphthylmethyl, pyridylmethyl or quinolinylmethyl;

R³ is C₄alkyl;

R⁵ is one of C_6-10aryl, C_6-10ar(C_1-6)alkyl, C_1-6alk(C_6-10)aryl, C_3-10cycloalkyl, C_1-8alkoxy or —

W—

R⁶, where W is a chalcogen and R⁶ is alkyl, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted; and

Z¹ and Z² are independently one of hydroxy, alkoxy, or aryloxy, or together Z¹ and Z² form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O.

21. The method of claim 20, wherein P is R⁷—

C(O)—

or R⁷—

O—

C(O)— and

R⁷ is alkyl, cycloalkyl, aryl or aralkyl.

22. The method of claim 21, wherein P is acetyl, benzoyl, benzyloxycarbonyl or tert-butoxycarbonyl.

23. The method of claim 20, wherein P is R⁷—

C(O)—

, and R⁷ is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl.

24. The method of claim 20, wherein R³ is isobutyl.

25. The method of claim 20, wherein R² is naphthylmethyl.

26. A method for treating cancer in a patient, comprising administering to said patient N-acetyl-L-leucine-β

-(1-naphthyl)-L-alanine-L-leucine boronic acid or a pharmaceutically acceptable salt or boronate ester thereof.