Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-03
2001-06-12
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S333000, C514S339000, C514S416000, C546S277100, C548S471000
Reexamination Certificate
active
06245768
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to aminoisoindole derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to 1-(N′-(arylalkylaminoalkyl)) aminoisoindoles and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating various neuropsychochological disorders.
2. Description of the Related Art
Schizophrenia or psychosis is a term used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterized by a variety of symptoms which are classified as positive symptoms (disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and unresponsiveness). These disorders have an age of onset in adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patient's lifetime and can result in prolonged institutionalization. Within the United States of America, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.
During the 1950's physicians demonstrated that they could successfully treat psychotic (schizophrenic) patients with medications called neuroleptics. This classification of antipsychotic medication was based largely on the activating (neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain. This finding suggested that altered neuronal firing of the dopamine system contributed in some way to the aberrant behavior observed in schizophrenic patients. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus striatum, an effect reversed by neuroleptic agents. Thus, cumulative evidence from these and later experiments strongly suggested that the neurotransmitter dopamine was involved in schizophrenia
One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain. Several dopamine systems appear to exist in the brain and at least five classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity and were originally classified on the basis of their ability to bind various dopaminergic ligands.
The butyrophenones are a class of drugs containing many potent antipsychotic drugs. Perhaps the most prominent member of this class of compounds is the antipsychotic drug haloperidol (chemical name). Haloperidol binds relatively weakly at the major dopamine receptor subtype which activates adenylate cyclase (commonly classified as the D
1
dopamine receptor). In contrast, haloperidol displayed binding affinity at a dopamine receptor subtype which suppressed the activity of adenylate cyclase (commonly classified as D
2
receptors) in the subnanomolar range.
Recently, three additional dopamine receptor subtypes have been identified using the often congruent sciences of receptor pharmacology and molecular biology. These new dopamine receptors have been labeled as D3, D4, and D
5
. The D
3
and D
4
subtypes are pharmacologically related to the D
2
receptor via their ability to suppress the activity of adenylate cyclase. Conversely, the D
5
receptor is classified as a “D
1
-like” dopamine subtype through its ability to stimulate cyclase activity.
Recently, a new group of drugs (such as sulpiride and clozapine) have been developed with a lesser incidence of extrapyramidal side effects (EPS) than classical neuroleptics. In addition, there is some indication that they may be more beneficial in treating negative symptoms in some patients. Since all D
2
blockers do not possess a similar profile, hypotheses underlying the differences have been investigated. Major differences have been detected in the anticholinergic actions of these drugs. It has also been suggested that the dopamine receptors in motor areas may differ from those in the limbic areas which are thought to mediate the antipsychotic responses. The existence of the D
3
, D
4
and D5 and other as yet undiscovered dopamine receptors may contribute to this profile. Some of the atypical compounds possess similar activity at D
2
, D
3
and D
4
receptors. The examples of this patent fall into this general class of molecules.
Using molecular biological techniques it has been possible to clone cDNAs coding for each of the pharmacologically defined receptors There are at least two forms of D1 which have been identified as D
1
and D
5
, and two forms of D
2
, identified now as D2 and D
4
dopamine receptors. In addition, there is at least one form of D
3
dopamine receptor. The 1-(N′-(arylalkylaminoalkyl))aminoisoindoles of this invention possess differential affinities for each receptor subtype.
SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula 1 which interact with dopamine receptor subtypes.
The invention provides pharmaceutical compositions comprising compounds of Formula 1. The invention also provides compounds useful in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Furthermore, compounds of this invention are useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Since particularly dopamine D
3
and D
4
receptor subtypes are concentrated in the limbic system (Taubes,
Science
265 (1994) 1034), which controls cognition and emotion, compounds which interact with these receptors are useful in the treatment of cognitive disorders. Such disorders may be the cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorders can also be treated with some of the compounds of this invention that interact specifically with dopamine D
3
and/or D
4
receptor subtypes. Accordingly, a broad embodiment of the invention is directed to a compounds of Formula 1
where
the 6-membered A ring may be optionally substituted with up to four groups independently selected from halogen, hydroxy, lower alkyl, or lower alkoxy;
Ar represents optionally substituted aryl or heteroaryl
Z represents carbon or nitrogen provided that where Z is carbon. R
11
represents hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy, or phenyl optionally substituted with one or two groups selected from hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy; and where Z is nitrogen, R
11
represents an electron pair;
R
5
is hydrogen or lower alkyl;
L is an integer of from 1-4;
m is an integer of from 2-5;
n is 0, or an integer of from 1-4;
R
12
and R
13
independently represent lower alkyl; or together may represent (CR
x
R
y
)
s
where s is an integer of from 1-6 and R
x
and R
y
independently represent hydrogen or lower alkyl;
CR′R″ represents a methylene group optionally substituted with lower alkyl; and
k is 0 or an integer of from 1 to 3.
Thus, the compounds of Formula 1 can be used in the treatment of various neuropsychochological disorders including, for example, schizophrenia, dementia, depression, anxiety, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention can be described by general formula 1:
wherein:
R
1
, R
2
, R
3
, R
4
and R
7
, R
8
and R
9
are the same or different and represent hydrogen, halogen, hydroxy, lower alkyl, or lower alkoxy;
X represents carbon or nitrogen provided that where X carbon, R
6
represents hydrogen, halogen, hydroxy, lower alkyl having 1-6 carbon atoms, or lower alkoxy; and where X is nitrogen, R
6
represents an electron pair;
Y represents carbon or nitrogen provided that where Y is carbon, R
10
represents hydrogen, halogen,
de Costa Brian
He Xiao-Shu
Wasley Jan W. F.
Liu Hong
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Sarussi Steven J.
Shah Mukund J.
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