Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-30
2004-08-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254090, C548S416000, C548S469000, C548S452000, C548S509000, C548S550000, C544S358000, C544S373000, C544S402000
Reexamination Certificate
active
06770638
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to compositions comprising tetrahydroindolone linked to arylpiperazines for the treatment of psychosis and psychosis related diseases including cognitive impairment.
2. Background
Psychiatric and neurologic disorders are among the most severe and chronic diseases and conditions. These disorders are also extremely difficult to treat effectively because of the multiplicity of the symptoms and etiologies. Although many alternative and combination drug therapies have been attempted and proposed, an effective treatment remains elusive. The current therapies have focused on either high selectivity for one pharmacological effect or broad non-selectivity to attempt multiple symptom relief. Drug therapies that have focused on high pharmacological selectivity have limited benefit for disorders with multiple causes and can worsen some symptoms. For example, selective antagonism of dopaminergic receptors for schizophrenia results in a worsening of negative symptoms and tardive dyskinesia. In contrast to selective drug therapy, drug therapies having broad non-selectivity can provide relief for more symptoms, yet they have more side effects. For instance, current antipyschotic drugs have adrenergic, cholinergic, and histaminergic receptor antagonist activity which are associated with deterioration of cognitive function and other side-effects such as orthostatic hypotension, dry mouth, blurred vision, constipation, and motor impairment. Regardless of drug therapy selectivity, cognitive decline is one main symptom that is not adequately treated in both current psychiatric and neurological therapies.
Therefore, there is a particular need for the development of compounds that have improved activity in treating psychiatric disorders having symptoms including reduced cognition and emotional control such as schizophrenia, schizoaffective disorders, anxiety and depression with agitation without the side-effects of the existing therapies. There is a further need for compounds that provide treatment or relief from symptoms associated with neurological diseases such as, Alzheimer's disease, movement disorders, (such as Huntington's disease and Parkinson's disease), stroke pain and other neurodegenerative disorders, which can be genetic, spontaneous or iatrogenic. Additionally, there is a need for compounds that are neuroprotective, stimulate neuronal function, neuronal regeneration, neurogenesis and have fewer side effects.
INVENTION SUMMARY
Generally, the present invention relates to novel composite compounds having the general schematic structure, A}-L-{B, where A is a bicyclic ring structure such as tetrahydroindolone or a purine derivative, L is a hydrocarbyl chain, and B is an arylpiperazine or arylpiperazine derivative that are useful as pharmaceutical compositions for treating a wide range of psychiatric and neurological disorders.
Furthermore, these psychiatric and neurological disorders can be effectively treated without causing a deterioration of cognitive function or other major side effects. More particularly, the composite compounds of the present invention comprise tetrahydroindolones or purine derivatives linked to arylpiperazine structures.
Moreover, the composite compounds of the present invention can have other beneficial effects such as, but not limited to neuroprotective and neuroregenerative properties.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, and as used herein, the following terms, when appearing alone or as part of a moiety including other atoms or groups, are defined with the following meanings, unless explicitly stated otherwise. In addition, all groups described herein can be optionally substituted unless such substitution is excluded. The term “alkyl,” as used herein at all occurrences, refers to saturated aliphatic groups including straight-chain, branched-chain, and cyclic groups, all of which can be optionally substituted. Preferred alkyl groups contain 1 to 10 carbon atoms. Suitable alkyl groups include methyl, ethyl, and the like, and can be optionally substituted. The term “heteroalkyl” as used herein at all occurrences refers to carbon-containing straight-chained, branch-chained and cyclic groups, all of which can be optionally substituted, containing at least one O, N or S heteroatoms. The term “heteroalkenyl” as used herein at all occurrences refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chained, branch-chained and cyclic groups, all of which can be optionally substituted, containing at least one O, N or S heteroatoms. The term “alkenyl,” as used herein at all occurrences, refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain, and cyclic groups, all of which can be optionally substituted. Preferable alkenyl groups have 2 to 10 carbon atoms. The term “alkoxy” refers to the ether —O-alkyl, where alkyl is defined as above. The term “aryl” refers to aromatic groups which have at least one ring having a conjugated &pgr;-electron system and includes carbocyclic aryl and biaryl, both of which can be optionally substituted. Preferred aryl groups have 6 to 10 carbon atoms. The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl and the like; these groups can be optionally substituted. The term “aralkenyl” refers to an alkenyl group substituted with an aryl group. The term “heteroaryl” refers to carbon-containing 5-14 membered cyclic unsaturated radicals containing one, two, three, or four O, N, or S heteroatoms and having 6, 10, or 14 &pgr;-electrons delocalized in one or more rings, e.g., pyridine, oxazole, indole, thiazole, isoxazole, pyrazole, pyrrole, each of which can be optionally substituted as discussed above. The term “sulfonyl” refers to the group —S(O
2
)—. The term “alkanoyl” refers to the group —C(O)Rg, where Rg is alkyl. The term “aroyl” refers to the group —C(O)Rg, where Rg is aryl. Similar compound radicals involving a carbonyl group and other groups are defined by analogy. The term “aminocarbonyl” refers to the group —NHC(O)—. The term “oxycarbonyl” refers to the group —OC(O)—. The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl group. Similarly, the term “heteroaralkenyl” refers to an alkenyl group substituted with a heteroaryl group. Where used herein, the term “lower,” in reference to an alkyl or the alkyl portion of an another group including alkyl, is defined as a group containing one to ten carbon atoms, more typically one to six carbon atoms. The term “optionally substituted” refers to one or more substituents that are typically lower alkyl, aryl, amino, hydroxy, lower alkoxy, aryloxy, lower alkylamino, arylamino, lower alkylthio, arylthio, or oxo, in some cases, other groups can be included, such as cyano, acetoxy, or halo. The term “halo” refers generally to fluoro, chloro, bromo, or iodo; more typically, “halo” refers to chloro.
In accordance with the present invention, and as used herein, the term “derivative” refers to a compound that is modified or partially substituted with another component. Additionally, the term “derivative” encompasses compounds that can be structurally similar but can have similar or different functions.
The composite compounds of the present invention have the general schematic structure, A}-L-{B, where A is a bicyclic ring structure such as tetrahydroindolone or a purine derivative, L is a hydrocarbyl chain, and B is an arylpiperazine or arylpiperazine derivative.
I. TETRAHYDROINDOLONE AND PURINE DERIVATIVES
In one embodiment of the present invention, A is an 8-10 atom bicyclic moiety in which the five-aromatic membered ring has 1 to 2 nitrogen atoms, the bicyclic moiety having the structure of formula (I):
where:
(a) formula I is bonded to a hydrocarbyl linker L;
(b) A
2
is C or N;
(c) R
3
is hydrogen, alkyl, aralky, heteroaralkyl,
Fick David B.
Foreman Mark M.
Glasky Alvin J.
Helton David R.
Cullman Louis C.
Patel Sudhaker B.
Raymond Richard L.
Spectrum Pharmaceuticals Inc.
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