Lactacystin analogs

Details Lactacystin analogs Lactacystin analogs

2000-08-15

2002-10-01

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S444000, C514S470000

Reexamination Certificate

active

06458825

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates generally to lactacystin and analogues thereof.
Eukaryotic cells contain multiple proteolytic systems, including lysosomal proteases, calpains, ATP-ubiquitin-proteasome dependent pathway, and an ATP-independent nonlysosomal process. The major neutral proteolytic activity in the cytosol and nucleus is the proteasome, a 20S (700 kDa) particle with multiple peptidase activities. The 20S complex is the proteolytic core of a 26S (1500 kDa) complex that degrades or processes ubiquitin-conjugated proteins. Ubquitination marks a protein for hydrolysis by the 26S proteasome complex. Many abnormal or short-lived normal polypeptides are degraded by the ubiquitin-proteasome-dependent pathway. Abnormal peptides include oxidant-damaged proteins (e.g., those having oxidized disulfide bonds), products of premature translational termination (e.g., those having exposed hydrophobic groups which are recognized by the proteasome), and stress-induced denatured or damaged proteins (where stress is induced by, e.g., changes in pH or temperature, or exposure to metals). In addition, some proteins, such as casein, do not required ubquitination to be hydrolyzed by the proteasome.
The proteasome has chymotryptic, tryptic, and peptidyl-glutamyl peptide hydrolizing activities, i.e., the proteasome can cleave peptides on the carboxyl side of hydrophobic, basic, and acidic residues, respectively.
SUMMARY OF THE INVENTION
The invention relates to novel compounds structurally related to lactacystin and lactacystin &bgr;-lactone. The invention also relates to pharmaceutical compositions including lactacystin and lactacystin analogs.
One aspect of the invention is a pharmaceutical composition containing a compound having the formula
wherein Z
1
is O, S, SO
2
, NH, or NR
a
, R
a
being C
1-6
alkyl; X
1
is O, S, CH
2
, two singly bonded H, CH(R
b
) in the E or Z configuration, or C(R
b
) (R
c
) in the E or Z configuration, each of R
b
and R , independently, being C
1-6
alkyl, C
6-12
aryl, C
3-8
cycloalkyl, C
3-8
heteroaryl, C
3-8
heterocyclic radical, or halogen, X
1
being two singly bonded H when Z
1
is SO
2
; Z
2
is O, S, NH, NR
d
, or CHR
1
in the (R) or (S) configuration, wherein R
d
is C
1-6
alkyl and R
1
is H, halogen, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, NR
d
R
e
, or the side chain of any naturally occurring &agr;-amino acid, or R
1
and R
2
taken together are a bivalent moiety, provided that when R
1
and R
2
are taken together, Z
1
is NH or NR
a
and Z
2
is CHR
1
; R
e
being H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, or C
2-6
alkynyl, and the bivalent moiety forming a C
3-8
cycloalkyl, C
3-8
heteroaryl, C
3-8
heterocyclic radical, or C
6-12
aryl, where the H in CHR
1
is deleted when R
1
and R
2
taken together form a C
3-8
heteroaryl or C
6-12
aryl; R
2
is C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, azido, C
2-6
alkynyl, halogen, OR
f
, SR
f
, NR
f
R
g
, —ONR
f
R
g
, —NR
g
(OR
f
), or —NR
g
(SR
f
) (each of R
f
and R
g
, independently, being H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, or C
2-6
alkynyl), or R
1
and R
2
taken together are a bivalent moiety, the bivalent moiety forming a C
3-8
cycloalkyl, C
3-8
heteroaryl, C
3-8
heterocyclic radical, or C
6-12
aryl, where the H in CHR
1
is deleted when R
1
and R
2
taken together form a C
3-8
heteroaryl or C
6-12
aryl; A
1
is H, the side chain of any naturally occurring &agr;-amino acid, or is of the following formula,
—(CH
2
)
m
—Y—(CH
2
)
n
—R
3
X
3
wherein Y is O, S, C═O, C═S, —(CH═CH)—, vinylidene, —C═NOR
h
, —C═NNR
i
R
i′
, sulfonyl, methylene, CHX
4
in the (R) or (S) configuration, or deleted, X
4
being halogen, methyl, halomethyl, OR
h
, SR
h
, NR
i
R
i
, —NR
i
(OR
h
), or —NR
i
(NR
i
R
i′
), wherein R
h
is selected from H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, and C
2-6
alkynyl, and each of R
i
and R
i
, independently is selected from H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, and C
1-10
acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R
3
is straight chain or branched C
1-8
alkylidene, straight chain or branched C
1-8
alkylene, C
3-10
cycloalkylidene, C
3-10
cycloalkylene, phenylene, C
6-14
arylalkylidene, C
6-14
arylalkylene, or deleted, and X
3
is H, hydroxyl, thiol, carboxyl, amino, halogen, (C
1-6
alkyl)oxycarbonyl, (C
7-14
arylalkyl)-oxycarbonyl, or C
6-14
aryl; or R
3
and X
3
taken together are the side chain of any naturally occurring &agr;-amino acid; X
2
is O or S; and L
O
is an organic moiety having 1 to 25 carbon atoms, 0 to 10 heteroatoms, and 0 to 6 halogen atoms; and a pharmaceutically acceptable carrier.
A second aspect is a pharmaceutical composition comprising a compound having the following formula
wherein Z
1
is O, S, SO
2
, NH, or NR
a
, R
a
being C
1-6
alkyl; X
1
is O, S, CH
21
two singly bonded H, CH(R
b
) in the E or Z configuration, or C(R
b
) (R
c
) in the E or Z configuration, each of R
b
and R
c
, independently, being C
1-6
alkyl, C
6-12
aryl, C
3-8
cycloalkyl, C
3-8
heteroaryl, C
3-8
heterocyclic radical, or halogen, provided that when Z
1
is SO
2
, X
1
is two singly bonded H; Z
2
is CHR
1
in the (R) or (S) configuration, R
1
being H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, hydroxyl, halogen, a side chain of a naturally occuring &agr;-amino acid, OR
d
, SR
d
, or NR
d
R
e
(each of R
d
and R
e
, independently, being H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, or C
2-5
alkynyl); Z
3
is O, S, NH, or NR
j
, wherein R
j
is C
1-6
alkyl; X
2
is O or S; and A
1
is H, the side chain of any naturally occurring &agr;-amino acid, or is of the following formula,
—(CH
2
)
m
—Y—(CH
2
)
n
—R
3
X
3
wherein Y is O, S, C═O, C═S, —(CH═CH)—, vinylidene, —C═NOR
h
, —C═NNR
i
R
i′
, sulfonyl, methylene, CHX
4
in the (R) or (S) configuration, or deleted, X
4
being halogen, methyl, halomethyl, OR
h
, SR
h
, NR
i
R
i′
, —NR
i
(OR
h
), or —NR
i
(NR
i
R
i′
), wherein R
h
is selected from H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, and C
2-6
alkynyl, and each of R
i
and R
i′
, independently is selected from H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, and C
1-10
acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R
3
is straight chain or branched C
1-8
alkylidene, straight chain or branched C
1-8
alkylene, C
3-10
cycloalkylidene, C
3-10
cycloalkylene, phenylene, C
6-14
arylalkylidene, C
6-14
arylalkylene, or deleted, and X
3
is H, hydroxyl, thiol, carboxyl, amino, halogen, (C
1-6
alkyl)oxycarbonyl, (C
7-14
arylalkyl)-oxycarbonyl, or C
6-14
aryl; or R
3
and X
3
taken together are the side chain of any naturally occurring &agr;-amino acid; and a pharmaceutically acceptable carrier.
A third aspect is a pharmaceutical composition comprising a compound having one of the following formulae
wherein Z
1
is NH or NR
a
, R
a
being C
1-6
alkyl; X
1
is O, S, CH
2
, two singly bonded H, CH(R
b
) in the E or Z configuration, or C(R
b
) (R
c
) in the E or Z configuration, each of R
b
and R
c
, independently, being C
1-6
alkyl, C
6-2
aryl, C
3-8
cycloalkyl, C
3-8
heteroaryl, C
3-8
heterocyclic radical, or halogen; Z
2
is O, S, NH, or NR
j
, wherein R
j
is C
1-6
alkyl; R
1
is in the (R) or (S) configuration, and is H, C
1-6
alkyl, C
1-6
haloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, hydroxyl, halogen, a side chain of a naturally occuring &agr;-amino acid, OR
d
, SR
d
, or NR
d
R
e
(each of R
d
and R
e
, independently, being H, C
1-6
alkyl, C
1-6
haloalkyl, C
6-12
aryl, C
3-8
cycloalkyl, C
3-8
heteroaryl, C
3-8
heterocyclic radical, or halogen); X
2
is O or S; and A
1
is H, the side chain of any naturally occurring &agr;-amino acid, or is of the following formula,
—(CH
2
)
m
—Y—(CH
2
)
n
—R
3
X
3
wherein Y is O, S, C═O, C═S, —(CH═CH)—, vinylidene, —C═NOR
h
, —C═NNR
i
R
i′
, sulfonyl, methylene, CHX
4
in the (R) or (S) configur

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