Generated: May 26, 2017
|Title:||Formulation of boronic acid compounds|
|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.|
|Inventor(s):||Plamondon; Louis (Watertown, MA), Grenier; Louis (Cambridge, MA), Adams; Julian (Brookline, MA), Gupta; Shanker Lal (Rockville, MD)|
|Assignee:||The United States of America as represented by the Department of Health and Human Services (Washington, DC) N/A (Cambridge, MA) Millennium Pharmaceutical, Inc. (N/A)|
|Filing Date:||Dec 23, 2003|
|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): ##STR00016## wherein: P is hydrogen or an amino-group-protecting moiety; R is hydrogen or alkyl; A is 0, 1, or 2; R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2--R.sup.5; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R.sup.1, R.sup.2, R.sup.3 or R.sup.5 can be optionally substituted; and Z.sup.5 and Z.sup.6 are each OH.
3. The method of claim 2, wherein P is one of R.sup.7--C(O)--, R.sup.7--S(O).sub.2, R.sup.7--NH--C(O)--, or R.sup.7--O--C(O)--; where R.sup.7 is one of alkyl, aryl, alkaryl, or aralkyl, any of which can be optionally substituted, or when P is R.sup.7--C(O)-- or R.sup.7--S(O).sub.2--, R.sup.7 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 R.sup.7--C(O)-- or R.sup.7--S(O), --, and R.sup.7 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 C.sub.1-C.sub.8 alkyl; and R.sup.3 is C.sub.1-C.sub.6 alkyl.
7. The method of claim 6, wherein P is (2-pyrazine)carbonyl or (2-pyrazine)sulfonyl.
8. The method of claim 3, wherein: R.sup.1, R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.10 cycloalkyl, or C.sub.8-C.sub.10 aryl, or --CH.sub.2--R.sup.5; R.sup.5, in each instance, is one of C.sub.6-C.sub.10 aryl, (C.sub.6-C.sub.10)ar(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alk(C.sub.6-C.sub.10)aryl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.8 alkoxy, or C.sub.1-C.sub.8 alkylthio; where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl groups of R.sup.1, R.sup.2, R.sup.3 or R.sup.5 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-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid; N-(8-quinoline)sulfonyl-.beta.-(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-leu- cine 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.
Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.