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|Title:||Boronic ester and acid compounds, synthesis and uses|
|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.|
|Inventor(s):||Adams; Julian (Brookline, MA), Ma; Yu-Ting (Needham, MA), Stein; Ross (Sudbury, MA), Baevsky; Matthew (Jamaica Plain, MA), Grenier; Louis (Belmont, MA), Plamondon; Louis (Belmont, MA)|
|Assignee:||ProScript, Inc. (N/A)|
|Filing Date:||May 26, 1998|
|Claims:||1. A compound having the formula: ##STR51## or a pharmaceutically acceptable salt thereof; wherein P is an amino protecting group; |
A is 1;
B.sup.1 is CH;
X.sup.1 is --C(O)--NH--;
X.sup.2 is --C(O)--NH--;
R is hydrogen or alkyl;
R.sup.1 is hydrogen, C.sub.1-8 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or --CH.sub.2 --R.sup.5, where the ring portion of said aryl can be optionally substituted;
R.sup.2 is naphthylmethyl, pyridylmethyl or quinolinylmethyl;
R.sup.3 is C.sub.4 alkyl;
R.sup.5 is one of C.sub.6-10 aryl, C.sub.6-10 ar(C.sub.1-6)alkyl, C.sub.1-6 alk(C.sub.6-10)aryl, C.sub.3-10 cycloalkyl, C.sub.1-8 alkoxy 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, or alkaryl can be optionally substituted; and
Z.sup.1 and Z.sup.2 are independently one of hydroxy, alkoxy, or aryloxy, or together Z.sup.1 and Z.sup.2 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.
2. A compound of claim 1, wherein P is R.sup.7 --(O)-- or R.sup.7 --O--C(O)-- and R.sup.7 is alkyl, cycloalkyl, aryl or aralkyl.
3. A compound of claim 2, wherein P is acetyl, benzoyl, benzyloxycarbonyl or tert-butoxycarbonyl.
4. A compound of claim 1, wherein P is R.sup.7 --C(O)--, and R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl.
5. A compound of claim 1, wherein R.sup.3 is isobutyl.
6. A compound of claim 1, wherein R.sup.2 is naphthylmethyl.
7. N-Acetyl-L-leucine-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid or a pharmaceutically acceptable salt or boronate ester therof.
8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or boronate ester thereof, and a pharmaceutically acceptable carrier or diluent.
9. A method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a compound of claim 1.
10. A method for reducing the activity of NF-.kappa.B in a cell comprising contacting said cell with a compound of claim 1.
11. A method for reducing the rate of intracellular protein breakdown comprising contacting cells with a compound of claim 1.
12. A method of preventing or treating an inflammatory condition in a patient in need thereof, said method comprising administering to said patient a compound of claim 1.