Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-09
2002-03-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211010, C514S217110, C514S218000, C514S227500, C514S237500, C514S237800, C514S252120, C514S330000, C514S423000, C514S620000, C540S467000, C540S470000, C540S483000, C540S544000, C540S574000, C540S607000, C544S059000, C544S168000, C544S390000, C544S391000, C546S245000, C564S164000, C564S165000, C548S540000
Reexamination Certificate
active
06362174
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compounds, pharmaceutical compositions thereof and methods of using them in the treatment of stroke, cerebral ischemia, pain, epilepsy, and head trauma. In particular, the present invention relates to reduced backbone dipeptide compounds that are potent antagonists of N-type calcium channels.
SUMMARY OF THE RELATED ART
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 initiate 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: the L, N, P, Q, R,,and T types. Each type possesses distinct structural features, functional properties, and cellular/subcellular distributions. N-type calcium channels are tissue specific, restricted to the central and peripheral neurons of the forebrain and areas rich in synaptic connections. They have well defined roles, e.g., regulation of calcium flux necessary for depolarization-evoked release of transmitter from synaptic endings; and they can be selectively blocked by high-affinity ligands, like &OHgr;-conotoxins and synthetic analogs. Bowersox S. S., et al.,
Drug News and Perspective,
1994;7:261-268.
SUMMARY OF THE INVENTION
The present invention provides novel compounds and compositions that are capable of blocking N-type calcium channels. The compounds are useful in a method for treating afflictions associated with increased calcium ion uptake through N-type calcium channels, including such systemic effects as stroke, cerebral ischemia resulting from cardiac arrest, head trauma, closed head injury, pain, and epilepsy. Further advantages of this invention will be clear to one skilled in the art from the reading of the description that follows.
The present invention comprises new compounds and, more particularly, novel reduced backbone dipeptide compounds that are useful as N-type calcium channel blockers in mammals. The novel compounds of the present invention are represented by the following structural Formula I:
wherein A, B, X, R
1
, R
2
, R
3
, and R
6
are defined in more detail below and generally form a reduced dipeptide backbone.
The invention also includes novel compositions of matter containing the above-defined compound that are useful as neuroprotective agents for the treatment of afflictions associated with increased calcium ion uptake through N-type calcium channels in mammals, as well as the methods of treatment using such compositions.
The foregoing merely summarizes certain aspects of the present invention and is not intended, nor should it be construed, as limiting the invention in any manner. All patents and other publications referenced herein are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises novel reduced backbone dipeptide compounds and pharmaceutical compositions thereof that are useful as N-type calcium channel antagonists.
The novel compounds of the present invention have the following generic structural Formula I:
wherein
R
1
is H or methyl,
R
2
is H, azepanylcarbonyl, C
1
-C
7
alkyl, —(CH
2
)n-phenyl, wherein the phenyl is unsubstituted or substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or halo,
R
3
is C
1
-C
5
alkyl,
X is —NR
4
R
5
or —OR
7
,
R
4
and R
5
are independently H, C
1
-C
5
alkyl, or
R
4
and R
5
together with the nitrogen to which they are both bound form:
R
6
is —(CH
2
)
n
-phenyl, wherein the phenyl is unsubstituted or substituted with C
1
-C
4
alkyl, C
1
-C
4
alkoxy, or halo,
A and B are independently —CO— or —CH
2
—, provided that A and B are not both —CO—,
R
7
is C
1
-C
5
alkyl,
Z is —CH
2
—, —O—, —S—, or —N(R
8
)—,
R
8
is H or C
1
-C
6
alkyl, and n is 1 or 2.
In a preferred embodiment of the compound of Formula I, R
4
and R
5
are independently H, C
1
-C
5
-alkyl, or R
4
and R
5
taken together with the nitrogen to which they are both bound form 1-pyrrolidinyl, 1-piperidinyl, or 1-azepanyl, or R
4
and R
5
taken together with the nitrogen to which they are both bound are:
and Z is —S— or —O—.
Also provided are pharmaceutically acceptable salts, esters, amides, and pro-drugs of the compounds of the Formula I.
The term “alkyl” means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, (CH
3
)
2
CHCH
2
CH
2
—, (CH
3
)
3
CCH
2
CH
2
—, and heptyl.
The term “alkoxy” means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
In a preferred embodiment, compounds of the invention are selected from the group consisting of:
2-((2-(Azaperhydroepinylcarbonylamino)-4-methylpentyl)amino)-N-(tert-butyl)-3-(4-(phenylmethoxy)phenyl)-(2S)-propanamide;
[S-(R*,R*)]-Azepane-1-carboxylic acid {1-[2-(4-benzyloxy-phenyl)-1-tert-butoxymethyl-ethylcarbamoyl]-3-methyl-butyl}-amide;
[S-(R*,R*)]Azepane-1-carboxylic acid (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-amide;
[S-(R*,R*)]-2-Dimethylamino-4-methyl-pentanoic acid [2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethyl]-amide;
[S-(R*,R*)]-Azepane-1-carboxylic acid {1-[2-(4-benzyloxy-phenyl)-1-morpholin-4-ylmethyl-ethylcarbamoyl]-3-methyl-butyl}-amide;
[S-(R*,R*)]Azepane-1-carboxylic acid {1-[2-(4-benzyloxy-phenyl)-1-(tert-butylamino-methyl)-ethylcarbamoyl]-3-methyl-butyl}-amide;
(S,S)-Azepane-1-carboxylic acid {1-[2-(4-benzyloxy-phenyl)-1-diethylaminomethyl-ethylcarbamoyl]-3-methyl-butyl}-amide;
(S)-2-(2-Amino-4-methyl-pentylamino)-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide dihydrochloride; and
2-(2-Amino-4-methyl-pentylamino)-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide dihydrochloride.
The compounds of the invention may be readily prepared as set forth in the following reaction scheme(s) which employ general synthetic methods well-known to those skilled in organic chemistry. The following definitions apply:
H
2
SO
4
Sulfuric acid
HBTU
O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium-
hexafluorophosphate
DMAP
4-(Dimethylamino)pyridine
DMF
N,N-Dimethylformamide
Et
2
O
Diethylether
HCl
Hydrochloric acid
NaBH
3
CN
Sodium cyanoborohydride
MeOH
Methanol
TFA
Trifluoroacetic acid
DMC
4,4′-Dichloro-&agr;-methylbenzhydrol
i-Pr
2
Net
Diisopropyl ethylamine
LAH
Lithium aluminum hydride
HNMeOMe
Methoxymethylamine
Pd/C
Palladium on carbon catalyst
wherein R
a
-R
g
are any chemical moiety consistent with the definitions of R
1
-R
7
.
The compounds of the invention are also useful research tools for studying the biological, cellular effects of blocking N-type calcium channels.
The invention further comprises a pharmaceutical composition for the treatment of illnesses induced by uncontrolled high concentrations of calcium in neurons, which composition comprises a compound of Formula I as defined above or, a pharmaceutically acceptable salt, solvent or pro-drug thereof, in an amount effective in the treatment of said illnesses, and a pharmaceutically acceptable carrier. The invention also comprises a pharmaceutical composition for the treatment of afflictions associated with increased calcium ion uptake through N-type calcium channels, including such systemic effects as stroke, pain, cerebral ischemia, head trauma, and epilepsy, which comprises a compound of Formula I as defined above in an amount effective in the treatment of said disorders, and a pharmaceutically acceptable carrier. Preferred compositions of the invention are those containing preferred compounds of Formula I as described above. Th
Rafferty Michael Francis
Song Yuntao
Ashbrook Charles W.
Kurlandsky David R.
Rao Deepak R.
Raymond Richard L.
Warner-Lambert & Company
LandOfFree
Reduced dipeptide analogues as calcium channel antagonitsts does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Reduced dipeptide analogues as calcium channel antagonitsts, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Reduced dipeptide analogues as calcium channel antagonitsts will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2859721