Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1999-01-19
2000-09-12
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530334, 530343, A61K 3805, C07K 1600
Patent
active
061178411
DESCRIPTION:
BRIEF SUMMARY
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 ##STR2## wherein * denotes a first chiral center when R.sup.3 and R.sup.4 are different; C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.6 heterocycloalkyl, C.sub.3 -C.sub.7 substituted C.sub.2 -C.sub.8 alkenyl, ##STR3## C.sub.2 -C.sub.8 substituted alkenyl, --CH.sub.2 --COC.sub.1 -C.sub.6 alkyl, --CH.sub.2 --COH, -substituted C.sub.3 -C.sub.7 heterocycle, or R.sup.1 and R.sup.2 may be taken together to form a 5- to 7-membered ring which may contain heteroatoms, provided that R.sup.1 and R.sup.2 are not both hydrogen; -C.sub.8 alkyl; --N(R.sup.3)(CH.sub.2).sub.n --, --(CH.sub.2).sub.n N(R.sup.3)--, --C.tbd.C--; -C.sub.7 cycloalkyl, substituted C.sub.3 -C.sub.7 cycloalkyl, or C.sub.1 -C.sub.8 alkyl; ##STR4## --NH(CH.sub.2).sub.n -heterocycloalkyl, --OC.sub.1 -C.sub.6 alkyl, ##STR5## --NH(CH.sub.2).sub.n heterocycle, --NH(CH.sub.2).sub.n substituted heterocycle; definitions of R.sup.3 and R.sup.5 above, R.sup.3 and R.sup.5 can together with the nitrogen atom form a ring having from 3 to 7 atoms; and prodrugs thereof.
In a preferred embodiment of the compound of Formula I, R.sup.1 is methyl.
In another preferred embodiment of the compounds of Formula I, R.sup.3, R.sup.5, and R.sup.6 are hydrogen.
In another preferred embodiment of the compounds of Formula I, ##STR6## or --O-tert-butyl.
In another preferred embodiment of the compounds of Formula I, ##STR7##
In another preferred embodiment of the compounds of Formula I, Z is phenyl.
In another preferred embodiment of the compounds of Formula I, R.sup.1 is methyl, R.sup.3, R.sup.5, and R.sup.6 are hydrogen, R.sup.4 is isobutyl, ##STR8## Y is --OCH.sub.2 --, and Z is phenyl.
In another preferred embodiment of the compounds of Formula I, R.sup.3 is hydrogen and R.sup.2 is C.sub.1 -C.sub.8 alkyl, substituted cyclohexyl, cyclohexyl, cyclohexenyl, --CH.sub.2 -phenyl, --CH.sub.2 -substituted phenyl, --CH.sub.2 -cyclohexyl, ##STR9## R.sup.2 and R.sup.3 taken together along with the nitrogen atom form a ring having the structure ##STR10##
In another preferred embodiment of the compounds of Formula I, R.sup.3 is isobutyl, and R.sup.4 is hydrogen.
In another preferred embodiment of the compounds of Formula I, R.sup.5 and R.sup.6 are hydrogen.
In another preferred embodiment of the compounds of Formula I, R.sup.2 is C.sub.1 -C.sub.8 alkyl, cyclohexyl, substituted cyclohexyl, --CH.sub.2 -phenyl, or --CH.sub.2 -substituted phenyl.
In another preferred embodiment of the compounds of Formula I, ##STR11## --O-tert-butyl, ##STR12##
REFERENCES:
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Hu Lain-Yen
Malone Thomas Charles
Nadasdi Laszlo
Rafferty Michael Francis
Ryder Todd Robert
Ashbrook Charles W.
Patel Sudhaker B.
Raymond Richard L.
Warner-Lambert & Company
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