Cyclohexane derivatives

Details Cyclohexane derivatives Cyclohexane derivatives

1996-07-15

1998-01-13

Conrad, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514647, 560 43, 564336, A61K 3124, A61K 31135, C07C22934, C07C21125

Patent

active

057080267

DESCRIPTION:

BRIEF SUMMARY
This invention relates to cyclohexane derivatives more particularly to substituted aminocyclohexanes, to processes for preparing them to pharmaceutical compositions containing them. The compounds have pharmaceutical uses conferred by their ability to block voltage gated potassium channels and they are also useful as intermediates to nitrogen heterocycles which are potassium channel blockers.
Voltage gated potassium ion (K.sup.+) channels which produce transient outward currents (TOC) are present in the cell membranes of neurones and serve to repolarise the cell following a depolarisation by opening and allowing potassium ions to flow from the inside of the cell to the outside. They are, therefore, one of the main regulating influences on the nerve cell firing and determine the amount of current reaching the terminal regions of the cells. This in turn regulates the amount of neurotransmitter substances released from the nerve terminals. In addition, they help to determine the refractory period of the nerve cell and hence the probability of the cell firing again within a certain time. This governs neuronal excitability and also the tendency of a cell to undergo repetitive firing. An ability to modify the functioning of these channels by chemical means is likely to produce therapeutically useful agents. So far the agents which are known to block the TOC channels are toxins such as the snake toxin dendrotoxin, or 4-aminopyridine and its derivatives. Blockade of the TOC channels leads to a change in the pattern of transmitter release and depending upon the pattern and type of neurone affected different therapeutic ends will result. For example TOC blockers which increase dopaminergic transmission in the substantia nigra will be of use in treatment of Parkinson's disease. Likewise, an increase in cholinergic function is of use in Alzheimer's disease and in cognition enhancement. Because of the complicated neural networks in the brain blockade of the TOC may also lead to increase in more than one transmitter substance at a time and this can act synergistically where a disease state is associated with more than one transmitter deficit as is often the case. It is evident, therefore that TOC blockers may be of use in areas of depression. pain, psychoses, cognition, memory and learning, anxiety, Parkinson's disease and Alzheimer's disease. In addition they can be used as a treatment for conditions where there is an impairment of nerve transmission such as multiple sclerosis.
Compounds which act to increase channel funciion may be termed channel openers and these serve to increase the braking action of the channels on the cells. In this respect they will also reduce the likelihood of the cells to undergo repetitive firing and may be used as anticonvulsants in the treatment of epilepsy. Also, their action to reduce neurotransmitter release means that they may be used as anaesthetics, analgesics, sedatives and anxiolytics.
This invention provides compounds of generic formula (I): ##STR3## or a pharmaceutically acceptable salt thereof, where the dotted line represents an optional bond, C.sub.7 -C.sub.16 alkyl, --(CHR.sup.6).sub.n CHR.sup.7 CN, --(CHR.sup.6).sub.n CHR.sup.7 CONH.sub.2, --(CHR.sup.6).sub.n CHR.sup.7 COOR.sup.8, --(CHR.sup.6).sub.n CHR.sup.7 CH.sub.2 OH wherein n is 0 or 1, R.sup.6 and R.sup.7 independently represent hydrogen, C.sub.1 -C.sub.6 alkyl- or C.sub.7 -C.sub.16 alkyl-, and R.sup.7 also represents hydroxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.2 -C.sub.7)alkanoyloxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6 alkoxy)carbonyl- and R.sup.8 is hydrogen or C.sub.1 -C.sub.6 akyl; C.sub.7 -C.sub.16 akyl; group; said heteroaryl group containing 5 to 10 ring atoms of which one or more (e.g up to 3) of said atoms are heteroatoms selected from oxygen, nitrogen and sulphur, the same or different; said aryl or heteroaryl radicals being optionally substituted by one or more substituents the same or different, eg substituents commonly used in pharmaceutical chemistry such as for example: C.sub.1 -C.sub.6 alkyl; C.sub.1

REFERENCES:
Egli et la, Helv. Chim. Acta. 58 (8), 2321-2346 (1975).

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