Formulation of boronic acid compounds

• US 7,109,323 B2
• Filed: 12/23/2003
• Issued: 09/19/2006
• Est. Priority Date: 01/25/2001
• Status: Expired due to Term

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited), United States Department Of Health And Human Services
• Inventors: Grenier, Louis, Plamondon, Louis, Gupta, Shanker Lal, Adams, Julian
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Henry, Michael C.
• Application Number:
  US10/744,843
• Publication Number:
  US 20040138411A1
• Time in Patent Office: 1,001 Days
• Field of Search: 536/53, 536/17.1, 514/2, 514/18, 514/19, 514/64, 544/229, 530/320, 558/286
• US Class Current: 536/53
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The invention relates to the formulation of pharmaceutical compounds. More particularly, the invention provides stable, pharmaceutically acceptable compositions prepared from boronic acid compounds and methods for preparing the compositions. The invention also provides novel boronate ester compounds. The invention further provides boronic acid anhydride compounds useful in the methods of the invention.

Claims

1. A method for formulating a boronic acid compound, the method comprising:

(a) preparing an aqueous mixture comprising

(i) a boronic acid compound; and

(ii) a compound selected from the group consisting of pinanediol, pinacol, perfluoropinacol, ethylene glycol, diethylene glycol, catechol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, 1,2-butanediol, 1,4-butanediol, glycerol, and diethanolamine; and

(b) lyophilizing the mixture.

2. The method of claim 1, wherein the boronic acid compound has formula (3):

wherein;

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

R is hydrogen or alkyl;

A is 0, 1, or 2;

R¹, R², and R³ are independently hydrogen, alkyl, cycloalkyl, aryl, or —

CH₂—

R⁵;

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

W—

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

where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R¹, R², R³ or R⁵ can be optionally substituted; and

Z⁵ and Z⁶ are each OH.

3. The method of claim 2, wherein P is one of R⁷—

C(O)—

, R⁷—

S(O)₂, R⁷—

NH—

C(O)—

, or R⁷—

O—

C(O)—

;

where R⁷ is one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R⁷—

C(O)—

or R⁷—

S(O)₂—

, R⁷ can also be an optionally substituted 5- to 10-membered saturated, partially unsaturated, or aromatic heterocycle.

4. The method of claim 3, wherein P is R⁷—

C(O)—

or R⁷—

S(O), —

, and R⁷ is an aromatic heterocycle.

5. The method of claim 4, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

6. The method of claim 3, wherein:

A is zero;

R is hydrogen or C₁-C₈ alkyl; and

R³ is C₁-C₆ alkyl.

7. The method of claim 6, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.

8. The method of claim 3, wherein:

R¹, R² and R³ are each independently one of hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, or C₈-C₁₀ aryl, or —

CH₂—

R⁵;

R⁵, in each instance, is one of C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, (C₁-C₆)alk(C₆-C₁₀)aryl, C₃-C₁₀ cycloalkyl, C₁-C₈ alkoxy, or C₁-C₈ alkylthio;

where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R¹, R², R³ or R⁵ can be optionally substituted.

9. The method of claim 1, wherein the boronic acid compound is:

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;

or

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

10. The method of claim 1, wherein the boronic acid compound is N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid.

11. The method of claim 1, wherein the aqueous mixture further comprises a water-miscible co-solvent.

12. The method of claim 11, wherein the water-miscible co-solvent is an alcohol.