Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-02
2003-10-28
Morris, Patricia L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S268400
Reexamination Certificate
active
06638954
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the drug potential of anticonvulsants in the treatment of stroke, particularly, several &Dgr;
2
-1,2,3-triazoline and aminoalkylpyridine (AAP) anticonvulsants that seem to work by impairing the excitatory amino acid (EAA) L-glutamate (L-Glu) neurotransmission, as antiischemic agents, useful in the treatment of stroke victims.
There is strong evidence that the “excitotoxic” action resulting from the excessive accumulation of L-Glu plays a prominent role in human epilepsy as well as brain ischemia/stroke, leading to neuronal dysfunction and cell death. The 1,2,3-triazolines and the aminoalkylpyridine (AAP) metabolite analogues are two groups of novel anticonvulsants discovered in the Applicant's laboratories. These are very effective in the kindling and in the maximal electroshock (MES) seizure models of epilepsy, the best analogies to human partial seizures, where EAA neurotransmission plays an important role. Thus it is logical to expect that the anticonvulsant triazolines and AAP metabolite analogues would evince beneficial therapeutic potential in cerebral ischemia.
The ability of the triazolines and AAP compounds to afford protection and reduce neuronal degeneration are assessed in animal models of stroke, by utilizing the bilateral carotid occlusion model in the gerbil and the middle cerebral artery occlusion (MCAO) model in the rat. Post-ischemic gerbils undergo a predictable pattern of behavioral changes and the effects of drugs in producing alterations in this pattern are monitored by determining the post ischemic changes in locomotor activity as well as by changes in radial arm maze performance, and corroborated by post reperfusion histopathological assessment. In the MCAO rat model, a focal stroke model, drug effects are evaluated from their ability to reduce the infarct volume following MCAO.
BACKGROUND ART
There is a desperate need for clinically effective chemotherapeutic agents for intervention in and management of cerebral ischemia resulting from stroke. In the U.S. alone, 1.1 million individuals suffer stroke annually; it is the most common, and devastating neurological condition that kills more than a quarter million Americans every year and the leading cause of long-term intellectual and physical disability. In the past decade, it has become increasingly evident from data from numerous laboratories that EAA neurotransmission plays an important role in ischemic brain injury occurring in stroke and other neurological disorders (McCulloch, J., et al., Ed., “Frontiers in Pharmacology and Therapeutics: Excitatory Amino Acid Antagonists.”, Oxford, UK; Blackwell Scientific Publishers, 287-326, 1991: Choi, D. W. & Rothman, S. M.,
Annu. Revs., Neurosci.,
13, 171-182, 1991; Takagi, K., et al.,
J. Cereb. Blood Flow Metab.,
13, 575-585, 1993; Graham, S. H., et al.,
J. Cereb. Blood Flow Metab.,
13, 88-97, 1993; Muir, K. W., & Lees, K. R.,
Stroke,
26, 503-515, 1995). The excessive accumulation of the excitatory neurotransmitter L-Glu, followed by its excitotoxic action, has been strongly implicated in the cascade of pathological mechanisms that cause neuronal dysfunction and cell death in cerebral hypoxia-ischemia resulting from stroke, cardiac arrest, or mechanical brain injury. Thus, the EAA neurotransmitter systems may be considered potential therapeutic targets and development of agents that are EAA antagonists may constitute novel and effective therapies, as cytoprotective agents, in stroke.
SUMMARY OF THE INVENTION
It is accordingly one object of the present invention to provide novel &Dgr;
2
-1,2,3-triazolines and AAP compounds and their method of preparation.
It is a further object of the present invention to provide antiischemic/antistroke agents which comprise triazolines and AAP compounds
A further object of the present invention is to provide a method for the treatment of cerebral ischemia resulting from stroke, by administration of an effective amount of the triazoline and AAP compounds of this invention.
A further object of the present invention is to provide triazolines and AAPs bearing three different pyridyl substituents and a pyrrolidinone group, and methods for their use in the treatment of neurological disorders such as cerebral ischemia resulting from stroke and also in the treatment of epilepsy.
A still further object of the present invention is to provide triazolines and AAP compounds, as inhibitors of the EAA neurotransmitter L-glutamate. The triazolines and AAPs of this invention afford pronounced protection in the maximal electroshock seizure (MES) model in both mice and rats, by the intraperitoneal, intravenous, and oral route, which is indicative of their action as glutamate antagonists.
A still further object of the present invention is to provide antiischemic compositions that contain as the essential ingredient certain triazolines and AAPs and that are highly effective by the intraperitoneal and intravenous routes, the preferred routes of administration, in stroke victims, and use of these triazolines and AAPs as effective antiischemic drugs in the treatment of cerebral ischemia resulting from stroke.
Other objects and advantages of the present invention include use of the triazolines and AAPs in the treatment of stroke and epilepsy and also other neurological disorders such as Parkinson's disease, by virtue of their action as EAA antagonists and inhibitors of L-glutamate neurotransmission.
In satisfaction of the foregoing objects and advantages, there are provided by this invention several triazolines and AAPs which are useful as antiischemic/antistroke drugs. The various groups of triazolines and AAPs substituted with the various pyridyl groups and also the pyrrolidinyl group, may be characterized by the following general formulae:
wherein R
1
is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.
Also provided by this invention are non-toxic antiischemic compositions that are intraperitoneally and intravenously active and comprise as the active ingredient, a compound selected from those of the formulae (I-VII), wherein R
1
is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.
Also provided are methods for the administration of the antiischemic compositions of this invention to mammals, including animals and humans, in the treatment of cerebral ischemia resulting from stroke, including both global ischemia and focal ischemia.
DESCRIPTION OF PREFERRED EMBODIMENTS
As indicated above, this invention relates to several groups of compounds belonging to the seven structures (I-VII) shown above, which are useful as antiischemic drugs in the treatment of cerebral ischemia resulting from stroke. In one group of triazolines (I) and AAPs (V), a 4-pyridyl substituent is present, in a second group of these compounds (II & VI), a 3-pyridyl substituent and in a third group (III & VII), a 2-pyridyl substituent is present. Also, in a fourth group of triazolines (IV), a 2-oxo-1-pyrrolidino group is present. In all three groups of AAP compounds, the R
2
group is methyl, ethyl or phenyl. The triazolines and AAPs of this invention are further substituted on the phenyl rings by 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen. The triazolines and AAPs of this invention have potent antiischemic activity and protect the brain from neuronal damage in both global and focal ischemia, and are useful as antiischemic/antistroke drugs in the treatment of cerebral ischemia resulting from stroke in humans.
In one aspect of the present invention, three groups of triazolines and two groups of AAPs, are provided which have potent antiischemic activity and which have the general formulae represented by structures I, II and IV, and V and VI, respectively. In the above formulae, in structures I and II, the 5-substituent
K and K Biosciences, Inc.
McDermott & Will & Emery
Morris Patricia L.
LandOfFree
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