Peptidyl calcium channel blockers

Details Peptidyl calcium channel blockers Peptidyl calcium channel blockers

1998-12-16

2002-07-23

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C540S483000, C540S607000, C544S159000, C544S168000, C544S391000, C546S221000, C546S224000, C546S233000, C548S338100, C548S538000, C548S557000, C548S568000, C548S953000, C548S966000, C564S153000, C564S155000, C564S157000

Reexamination Certificate

active

06423689

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds that act to block calcium channels; methods of using the compounds to treat stroke, cerebral ischemia, pain, head trauma or epilepsy; and to pharmaceutical compositions that contain the compounds of the present invention.
BACKGROUND OF THE INVENTION
The entry of excessive amounts of calcium ions into neurons following an ischemic episode or other neuronal trauma has been well documented. Uncontrolled high concentrations of calcium in neurons initiates a cascade of biochemical events that disrupts normal cellular processes. Among these events are the activation of proteases and lipases, breakdown of neuronal membranes and the formation of free radicals, which may ultimately lead to cell death. Several types of calcium channels have been discovered and called the L, N, P, Q, R and T types. Each type possesses distinct structural features, functional properties and cellular/subcellular distributions. Type selective calcium channel blockers have been identified. For example, SNX-111 has been shown to be a selective N-type calcium channel blocker and has demonstrated activity in a number of models of ischemia and pain (Bowersox S. S., et al.,
Drug News and Perspective,
1994:7:261-268 and references cited therein). The compounds of the present invention are calcium channel blockers that can block N-type calcium channels and can be used to treat stroke, pain, cerebral ischemia, head trauma, and epilepsy.
SUMMARY OF THE INVENTION
The present invention provides compounds having the Formula I
wherein
each R′ is independently hydrogen, C
1
-C
6
alkyl, or R′ together with N to which R′ is attached and R
1
can form a mono or bicyclic structure;
R
1
is C
1
-C
6
alkyl, —CH
2
-phenyl, hydrogen, —CH
2
-indolyl, —(CH
2
)
n
—S—C
1
-C
6
alkyl, —(CH
2
)
n
-substituted phenyl, —(CH
2
)
n
cycloalkyl, —(CH
2
)
n
-heteroaryl, or
;R
2
is hydrogen or C
1
-C
6
alkyl;
R
3
is —O(C
1
-C
6
alkyl), —O(CH
2
)
n
phenyl,
 —NH(C
1
-C
6
alkyl), —N(C
1
-C
6
alkyl)
2
, —NH(CH
2
)
n
cycloalkyl, —NH(CH
2
)
n
NH cycloalkyl,
 —NH—(CH
2
)
n
-substituted phenyl, —NH—(CH
2
)
n
-phenyl—CH
2
NH
2
, —NH—(CH
2
)
n
pyridyl, —NH—(CH
2
)
n
imidazolyl, —NH—(CH
2
)
n
furyl,
 —NH—(CH
2
)
n
-indolyl, —NH—(CH
2
)
n
OH, —NH—(CH
2
)
n
—CN,
 —NH(CR′R′)
n
NH(C
1
-C
6
alkyl), —NH(CH
2
)
n
-piperidiny, —NH(CH
2
)
n
-substituted piperidinyl,
 
each R
4
is independently —(CH
2
)
n
-phenyl, —(CH
2
)
n
-substituted phenyl, —(CH
2
)
n
—NH
2
, —(CH
2
)
n
N(C
1
-C
6
alkyl)
2
, —(CH
2
)
n
NH(C
1
-C
6
alkyl), —(CH
2
)
n
-pyridyl, C
1
-C
6
alkyl,
 —(CH
2
)
n
—C
3
-C
8
cycloalkyl, or —(CH
2
)
n
substituted C
3
-C
8
cycloalkyl;
 C
1
-C
6
perfluoroalkyl, C
1
-C
6
alkyl,
 —NH—C
3
-C
8
cycloalkyl, —NH(CH
2
)
n
C
2
-C
6
alkenyl, —NH—(CH
2
)
n
-phenyl, —NH—(CH
2
)
n
-substituted phenyl, —NH(C
1
-C
6
alkyl), —NH(C
1
-C
6
alkyl)
2
, —(CH
2
)
n
NH
2
, —(CH
2
)
n
NH(C
1
-C
6
alkyl), —(CH
2
)
n
N(C
1
-C
6
alkyl)
2,
—NH-naphthyl, —NH-phenyl-phenyl,
 —NHC
2
-C
8
alkenyl, —NH—(CH
2
)
n
-pyridyl, —NH-adamantyl, —NH(CH
2
)
n
-heteroaryl, -substituted phenyl, phenyl, —(CH
2
)
n
phenyl, —(CH
2
)
n
-substituted phenyl, —(CH
2
)
n
-indolyl, —(CH
2
)
n
-furyl, —(CH
2
)
n
-thienyl,
 heteroaryl, heterocycle, aryl, substituted aryl, substituted heteroaryl, substituted heterocycle, C
1
-C
6
perfluoroalkyl,
 —NH—(CH
2
)
n
NH(C
1
-C
6
alkyl), —NH—(CH
2
)
n
N(C
1
-C
6
alkyl)
2
,
R
6
is C
1
-C
6
alkyl, phenyl, substituted phenyl, —(CH
2
)
n
-phenyl, or —(CH
2
)
n
-substituted phenyl;
R
7
is hydrogen or C
1
-C
6
alkyl;
each n is independently 0 to 5; and
each m is independently 2 to 7;
each p is 0, 1, or 2, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of the compounds of Formula I,
, and each R′ is hydrogen.
In another preferred embodiment of the compounds of Formula I, R
3
is —OC
1
-C
6
alkyl, each R′ is hydrogen, and X is
.
In another preferred embodiment of the compounds of Formula I, R
3
is —NH(C
1
-C
6
alkyl), each R′ is hydrogen, and X is
.
In another preferred embodiment of the compounds of Formula I,
, Y is —O—, and R
4
is —CH
2
-phenyl or —CH
2
-substituted phenyl.
In another preferred embodiment of the compounds of Formula I,
, R
4
is —CH
2
-phenyl, and R
1
is isobutyl.
In another preferred embodiment of the compounds of Formula I,
, Y is —≡—, and R
4
is —(CH
2
)
n
phenyl or —(CH
2
)
n
substituted phenyl.
In another preferred embodiment of the compounds of Formula I,
, Y is absent, and R
4
is —(CH
2
)
n
phenyl or —(CH
2
)
n
substituted phenyl.
In another preferred embodiment of the compounds of Formula I, R
3
is —O-tert-butyl.
In another preferred embodiment of the compounds of Formula I, R
1
is —CH
2
-phenyl.
In another preferred embodiment of the compounds of Formula I,
, Y is O, and R
4
is —(CH
2
)
n
pyridyl.
In another preferred embodiment of the compounds of Formula I,
, Y is —≡—, and R
4
is —(CH
2
)
n
pyridyl.
In another preferred embodiment of the compounds of Formula I,
Y is absent, and R
4
is —(CH
2
)
n
pyridyl.
In another preferred embodiment of the compounds of Formula I, R
5
is —NH-phenyl, —NH-substituted phenyl, phenyl, or substituted phenyl.
In another preferred embodiment of the compounds of Formula I, R
5
is —NH-phenyl, —NH-substituted phenyl, phenyl, or substituted phenyl; R
1
is C
1
-C
6
alkyl; each R′ is hydrogen;
R
3
is —OC
1
-C
6
alkyl;
Y is O; and R
4
is —CH
2
-phenyl.
In another preferred embodiment of the compounds of Formula I,
Y is O; R
4
is —CH
2
-phenyl; each R′ is hydrogen;
R
1
is isopropyl; and R
3
is —O-tert-butyl.
In another preferred embodiment of the compounds of Formula I, R
5
is —NH-substituted phenyl.
In another preferred embodiment of the compounds of Formula I,
and R
5
is phenyl or substituted phenyl.
In another preferred embodiment of the compounds of Formula I,
and R
5
is —NH substituted phenyl,
In another preferred embodiment of the compounds of Formula I,
, each R′ is hydrogen, and R
5
is —NH-substituted phenyl.
Also provided are compounds having the Formula II
wherein
—NH-phenyl, or —NH-substituted phenyl;
R
b
is C
1
-C
6
alkyl, —(CH
2
)
n
-aryl, or —(CH
2
)
n
-heteroaryl;
R
c
is —CH
2
-phenyl, C
1
-C
6
alkyl, —CH
2
-substituted phenyl, or —CH
2
-heteroaryl;
R
d
is —OC
1
-C
6
alkyl, —N(C
1
-C
6
alkyl)
2
, —NH—C
1
-C
6
alkyl,
 —NHCH
2
CH
2
NCH
2
phenyl,
each n is independently 0 to 5; and
each m is independently 2 to 7, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
In a preferred embodiment of Formula II,
R
b
is —CH
2
CH(CH
3
)
2
;
R
c
is —CH
2
-phenyl or —CH
2
pyridyl; and
R
d
is O-tert-butyl or —NH-tert-butyl.
In a preferred embodiment, R
c
is —CH
2
pyridyl.
Also provided are compounds having the Formula III
wherein
—NH-phenyl, or —NH-substituted phenyl;
R
b
is C
1
-C
6
alkyl, —(CH
2
)
n
-aryl, or —(CH
2
)
n
-heteroaryl;
R
c
is phenyl, C
1
-C
6
alkyl, substituted phenyl, or heteroaryl;
R
d
is —OC
1
-C
6
alkyl, —N(C
1
-C
6
alkyl)
2
, —NH—C
1
-C
6
alkyl,
each n is independently 0 to 5; and
each m is independently 2 to 7, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided are compounds having the Formula IV
wherein
—NH-phenyl, —NH-substituted phenyl, C
1
-C
6
alkyl, aryl, heteroaryl, or substituted aryl;
R
b
is C
1
-C
6
alkyl, —(CH
2
)
n
-aryl, or —(CH
2
)
n
-heteroaryl;
R
c
is —CH
2
-phenyl, C
1
-C
6
alkyl, —CH
2
-substituted phenyl, or —CH
2
-heteroaryl;
R
d
is —OC
1
-C
6
alkyl, —N(C
1
-C
6
alkyl)
2
, —NH—C
1
-C
6
alkyl,
each n is independently 0 to 5; and
each m is independently 2 to 7, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Also provided are compounds having the Formula V
wherein
—NH-phenyl, —NH-substituted phenyl, C
1
-C
6
alkyl, aryl heteroaryl, or substituted aryl;
R
b
is C
1
-C
6
alkyl, —(CH
2
)
n
-aryl, o

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