Boronic ester and acid compositions

• US 6,617,317 B1
• Filed: 04/19/2002
• Issued: 09/09/2003
• 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:
  US10/125,997
• Time in Patent Office: 508 Days
• Field of Search: 514/64
• US Class Current: 514/64
• 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 composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular or subcutaneous administration to a patient, said solution comprising a compound of the 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, alky, cycloalkyl, aryl, or —

CH₂—

R³;

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_3-8 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, 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 both hydroxy; and

A is zero.

2. The composition of claim 1, wherein:

R is hydrogen or C_1-8 alkyl; and

R³ is C_1-6 alkyl.

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

4. The composition of claim 1, wherein R is hydrogen or C_1-8 alkyl.

5. The composition 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_1-6alkyl, C_3-8 cycloalkyl, C_1-6alkyl-(C_3-8)cycloalkyl, C_2-8alkynyl, 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.

6. The composition of claim 1, wherein R³ is C_1-12alkyl.

7. The composition of claim 1, wherein R³ is C_1-6alkyl.

8. The composition of claim 1, wherein R³ is C₄alkyl.

9. The composition of claim 1, wherein R³ is isobutyl.

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

11. The composition of claim 1, wherein:

R is hydrogen or C_1-8 alkyl;

R³ is isobutyl; and

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

12. A composition, which upon combination with a physiologically acceptable aqueous carrier forms a solution suitable for intravenous, intramuscular, or sub-cutaneous administration to a patient, said solution comprising N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

13. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular, or subcutaneous administration to a patient, said solution comprising a compound having the formula (1a):

or a pharmaceutically acceptable salt thereof;

wherein

P is R⁷—

C(O)—

or R⁷—

SO₂—

, where R⁷ is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl, furyl, pyrrolyl, or N-morpholinyl;

X² is —

C(O)—

NH—

;

R is hydrogen or alkyl;

R² and R³ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and —

CH₂—

R⁵,

where 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_3-8 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, 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 both hydroxy; and

A is zero.

14. The composition of claim 13, 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-(4morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid,

N-(4-morpholine)carbonyl-β

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

N-(8-quinoline)sulfonyl-β

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

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

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

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

15. The composition of claim 13, wherein R² and R³ are independently selected from the group consisting of alkyl and —

CH₂R⁵, wherein R⁵ is as defined in claim 13.

16. The composition of claim 13, wherein R² and R³ are independently selected from the group consisting of C_1-4 alkyl and —

CH₂R⁵, wherein R⁵ is selected from the group consisting of cycloalkyl, aryl, and heterocycle.

17. The composition of claim 13, wherein R³ is isobutyl and R² is —

CH₂R⁵, wherein R⁵ is C_5-10 aryl where one or more ring carbon atoms can be replaced by O, N or S.

18. The composition of claim 13, wherein R² is:

19. The composition of claim 13, wherein:

R is hydrogen or C_1-8 alkyl;

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

20. The composition of claim 13, wherein the compound is selected from the group consisting of:

N-(2-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(2-quinoline)carbonyl-L-phenylalanine-L-leucine boronic acid;

N-(3-furoyl)-L-phenylalanine-L-leucine boronic acid;

N-(2-pyrrolyl)carbonyl-L-phenylalanine-L-leucine boronic acid; and

N-(8-quinoline)sulfonyl-L-phenylalanine-L-leucine boronic acid.

21. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular, or subcutaneous administration to a patient, said solution comprising a compound having the formula (1a):

or a pharmaceutically acceptable salt thereof;

wherein

P is H or an amino-group-protecting moiety;

X² is —

C(O)—

NH—

;

R is hydrogen or alkyl;

R² is naphthylmethyl, pyridylmethyl, or quinolylmethyl;

R³ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and —

CH₂—

R⁵,

where R⁵ 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_3-8 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, 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 both hydroxy; and

A is zero.

22. The composition of claim 21, wherein R³ is isobutyl.