Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1994-06-01
1996-07-23
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
558166, 562 11, A61K 3166, C07F 938, C07F 940
Patent
active
055389562
DESCRIPTION:
BRIEF SUMMARY
This application was filed under 35 U.S.C. .sctn. 371 and was based upon PCT International Application No. PCT/GB92/02229 which was filed on Dec. 1, 1992.
This invention relates to amines possessing a pharmacological activity, to processes for preparing them and to pharmaceutical compositions containing them. More particularly this invention relates to amines useful in the treatment of depression.
In the UK the annual referral rate for depression is around 300-400 per 10.sup.5 population of whom 10-15% require hospitalisation. At present the most effective and safe treatment for severe depression involves electroconvulsive therapy (ECT) where the patient receives a series of controlled electric shocks. However such treatment understandably engenders an atavistic fear and apprehension in many patients. It also has undesirable side-effects, notably disturbance of memory.
ECT is also expensive and time-consuming to administer, requiring the presence of specialist doctors such as psychiatrists and anaesthetists. As an alternative to ECT, drug therapy provides a more acceptable treatment for the patient but at the present time such therapy has not displaced ECT as the optimal treatment in severe cases because it is not always effective. There is therefore a need for new drugs for the treatment of depression, especially drugs having new modes of action mimicking ECT.
The mode of action of ECT remains unknown but in recent years much has been learnt about the biological effects of electroconvulsive shock (ECS) in animals. In particular, repeated ECS, given in ways closely mimicking those used to administer ECT clinically, elicits in rodents changes in monoamine functions. These include: increased 5-HT-mediated behaviour, increased dopaminergic behaviour and depressed beta-adrenoceptor binding and sensitivity of the coupled adenylate cyclase. The last is also seen following chronic treatment with a number of antidepressant drugs.
The effects of repeated ECS are presumably a response or adaptation to the acute effects of the seizures. Among these acute effects are a marked change in the release, synthesis and level of gamma aminobutyric acid (GABA) in the brain.--see Green A. R. et al, British J. Pharmacol., 92, 5-11 and 13-18 (1987) and Bowdler et al, ibid, 76, 291-298 (1982).
GABA is one of the most widespread and abundant transmitters in the mammaltan central nervous system and plays a major role in the control of brain excitability. It is similarly implicated in the benzodiazepine-mediated relief of anxiety. Recently, evidence has come to light which suggests that GABA transmission may also be involved in the therapeutic effects of some antidepressant treatments. In particular, new compounds designed as GABA agonists (e.g. fengabine and progabide) have been shown in preliminary clinical trials to have antidepressant activity (vide infra). Taken together, these findings suggest that interventions directed specifically at GABA transmission may provide the basis of novel therapies for the treatment of affective disorders.
At present three GABA receptors have been identified in the central nervous system. These are (1) a GABA.sub.A -receptor known to be mainly postsynaptic and mediating inhibition of neuronal firing--see for example Stephenson, F. A. Biochem, J., 249 pp 21-32 (1988); (2) a GABA.sub.B receptor located both postsynaptically and presynaptically, where it mediates the inhibition of release of a number of neuro-transmitters, e.g. noradrenaline and aspartic acid,--see for example Bowery, N. G. et al, Nature, 283, 92-94 (1980); and (3) a GABA autoreceptor which modulates the release of GABA from neurones--see for example Mitchell, P. R., and Martin, I. L. Nature, 274 904-905 (1978); Arbilla, S. Kanal, J. L and Langer, S. Z. Eur.J.Pharmac., 57, 211-217 (1979) and Brennan M. J. W. et al, Molec. Pharmac., 19, 27-30 (1981).
The pharmacological importance of these receptors is currently a subject of investigation with a major part of the work involving the search for anticonvulsant drugs with a mode of action
REFERENCES:
patent: 3812221 (1974-05-01), Braden et al.
patent: 4656298 (1987-04-01), Dingwall et al.
patent: 5190934 (1993-03-01), Mickel et al.
patent: 5229379 (1993-07-01), Marescaux et al.
patent: 5281747 (1994-01-01), Hall et al.
D. Brigot et al, Tetrahedron, vol. 35, No. 11, 1979 pp. 1345-1355.
Minchin Michael C.
White John F.
Ambrose Michael G.
John Wyeth & Brother Limited
Ramsuer Robert W.
Seifert Arthur G.
LandOfFree
Amine derivatives containing a phosphonic acid moiety does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Amine derivatives containing a phosphonic acid moiety, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amine derivatives containing a phosphonic acid moiety will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-713111