Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-23
2000-09-26
Vollano, Jean F
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540596, 564165, 564306, 544 56, 544106, 514 12, 51421712, A61K 3155
Patent
active
061242802
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel substituted bis-(4-hydroxyphenyl)methanes and derivatives thereof useful as pharmaceutical agents, to methods of their production, compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are useful in the treatment of neurological disorders such as traumatic brain injury, cerebral ischemia, stroke, migraine, acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer's disease, amyotropic lateral sclerosis, multiple sclerosis, and depression. The compounds may also be useful for the treatment of nonneurological disorders such as asthma.
The entry of excessive amounts of calcium ion 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 disrupt 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. In particular, the selective N-type calcium channel blocker, SNX-111, 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).
Therefore, compounds which block N-type calcium channels may be useful in the treatment of neurological disorders such as traumatic brain injury, stroke, migraine, acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and depression.
SUMMARY OF THE INVENTION
A compound of formula ##STR1## wherein R.sup.1 to R.sup.11, X, Y, m, n, and o are as defined below are useful in treating various neurological disorders and nonneurological disorders such as asthma.
Preferred compounds of the invention are those of formula ##STR2## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.6, R.sup.8, R.sup.9, R.sup.10, X, Y, m, n, and o are as defined below, and ##STR3## wherein R.sup.1, R.sup.2, R.sup.4, R.sup.6, R.sup.8, R.sup.9, R.sup.10, X, Y, and m are as defined below.
Still more preferred compounds are those of Formula III wherein R.sup.1, R.sup.2, R.sup.4, R.sup.6, R.sup.8, R.sup.9, R.sup.10, Y, and m are as defined below and X is --(CH.sub.2).sub.p -- or --(CH.sub.2).sub.p ##STR4##
The most preferred compounds are selected from bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol], l]phenol], zepin-1yl)methyl]phenol], e, and
Other aspects of the instant invention are methods of treating neurological disorders such as: traumatic brain injury, cerebral ischemia, acute and chronic pain, epilepsy, Parkinsonism, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, and depression. Other disorders such as asthma are also treated.
DETAILED DESCRIPTION
The compounds of the instant invention are those of Formula I ##STR5## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 and R.sup.2 are each independently hydrogen, alkyl, aryl or arylalkyl, or may be taken together with the nitrogen to which they are attached to form a ring of from 4 to 8 carbon atoms, --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 SCH.sub.2 CH.sub.2 --; arylalkyl, or may be taken together with the nitrogen to which they are attached to form a ring of from 4 to 8 carbon atoms, --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 SCH.sub.2 CH.sub.2 --; each independently hydrogen, alkyl, or halogen; R.sup.19 is each independently hydrogen or alkyl of from 1 to 4, hydrogen or alkyl; wherein R.sup.17 is hydrogen, hydroxy, or alkyl; arylalkyl, heteroaryl, or heteroarylalkyl;
In the compounds of the present invention, the term alkyl, in general and unless specifically limited, means a straight, branched, or cyclic alkyl group of from 1 to 7 carbon atoms including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, and cyclohexyl.
Aryl refers t
REFERENCES:
CA:77:101011, abs of Zh Obsch Khim 42(4), 940-4 by Kuliev, 1972.
CA:89;129609, abs of Izv Akad Nauk SSSR Ser Khim, (7), pp1621-4 by Ivanov, 1978.
Journal of Chemical society vol. 68, pp. 1894-1901, by Burckhalter, 1946.
Bowersox, "Neuronal Voltage-Sensitive Calcium Channels", DN&P, 1994, 7(5):261-268.
Malone Thomas C.
Schelkun Robert M.
Yuen Po-Wai
Anderson Elizabeth M.
Vollano Jean F
Warner-Lambert & Company
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