Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen bonded directly to ring carbon of the purine ring...
Reexamination Certificate
1999-12-22
2002-07-02
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen bonded directly to ring carbon of the purine ring...
Reexamination Certificate
active
06414147
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel substituted 2-amino-9-alkylpurines which selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating anxiety, depression, Down's Syndrome, sleep and seizure disorders, and overdoses of benzodiazepine-type drugs, and enhancing memory. The interaction of certain substituted 2-amino-9-alkylpurines of the invention with a GABA binding site, the benzodiazepine (BDZ) receptor, is described. This interaction results in the pharmacological activities of these compounds.
2. Description of the Related Art
&ggr;-Aminobutyric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 40 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel,
J. Biol. Chem
187: 55-63, 1950; Udenfriend,
J. Biol. Chem.
187: 65-69, 1950). Since that time, an enormous effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety, and cognition (Tallman and Gallager,
Ann. Rev. Neuroscience
8: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. GABA mediates many of its actions through a complex of proteins localized both on cell bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to hyperpolarization of the cell. Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of GABA.
The 1,4-benzodiazepines, such as diazepam, continue to be among the most widely used drugs in the world as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors. Early electrophysiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse agonists, and the compounds blocking both types of activity have been termed antagonists.
The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cDNAs were identified as subunits of the GABAa receptor complex by cloning and expression. These are categorized into &agr;, &bgr;, &ggr;, &dgr;, &egr;, and provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The &ggr; subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profiles of subtype specific pharmacological action.
With the discovery of the “receptor” for the benzodiazepines and the subsequent definition of the nature of the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of a behavior. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety).
Various compounds have been prepared as benzodiazepine agonists and antagonists. For example
J. Med. Chem,
1989, 32, 1020 and
J. Med. Chem,
1990, 33, 196 disclose 6-substituted purines.
These compounds however lack any substitution at C-2. Substituted 2-amino-9-alkylpurines have been reported in the literature to be potential antiviral agents; see, e.g.,
Chem. Pharm. Bull,
1988, 36 1283.
J. Med. Chem.,
1987, 30, 109 discloses yet other purines as an inhibitor of DNA polymerase.
Also, Published International Application WO 9720843-A1 discloses purine derivatives as antineoplastic agents. cl SUMMARY OF THE INVENTION
This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.
The invention provides pharmaceutical compositions comprising the compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, depression, sleep and seizure disorders, Down's Syndrome, overdose with benzodiazepine drugs, and for the enhancement of memory. Accordingly, a broad embodiment of the invention is directed to compounds of general Formula I:
W is oxygen or sulfur;
X is lower alkyl
optionally mono-, di- or trisubstituted with C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, lower alkoxy, halogen, hydroxy, trifluoromethyl, aryl, heteroaryl, C
3
-C
7
cycloalkyl, tetrahydrofuranyl, CO
2
R where R is hydrogen or lower alkyl, or
aryl or heteroaryl, each of which is optionally substituted with halogen or lower alkoxy; or
X is aryl or heteroaryl
each of which is optionally substituted with up to three groups selected from halogen and lower alkoxy;
Y is hydrogen or lower alkyl;
Z is lower alkyl optionally substituted with alkenyl, alkynyl, aryl or hydroxy; and
T is aryl(C
1
-C
6
)alkyl, aryl, or heteroaryl each of which is optionally substituted on the aryl with up to 5 groups selected from halogen, lower alkyl, lower alkoxy, or C
1
-C
6
alkoxy(C
1
-C
6
)alkyl.
The compounds are highly selective agonists, antagonists, or inverse agonists for GABAa brain receptors, or prodrugs of agonists, antagonists, or inverse agonists for GABAa brain receptors. Thus these compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, depression, Down's Syndrome, overdose with benzodiazepine drugs, and for the enhancement of memory.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention can be described by the general Formula I set forth above or the pharmaceutically acceptable non-toxic salts thereof.
Preferred compounds of Formula I are those where Y is hydrogen and Z represents a straight or branched chain. lower alkyl having 1-6 carbon atoms.
In addition, the present invention encompasses compounds of Formulas IIa and IIb:
wherein
W, X, Y, and Z are as defined above for Formula I and
R
a
and R
b
are the same or different and represent hydrogen, lower alkyl, halogen, or OR′ where R′ is lower alkyl or lower alkoxy, or
R
a
and R
b
together with the carbon atom to which they are attached form a 5, 6, or 7 membered carbocyclic ring up to two of which members are optionally hetero atoms selected from oxygen, sulfur and nitrogen.
Preferred compounds of Formula IIa and IIb are where Y is hydrogen and Z is lower alkyl.
More preferred compounds of Formula IIa are where Y is hydrogen, Z is lower alkyl, R
a
is hydrogen, lower alkyl or lower alxoxy and R
b
is hydrogen, halogen, lower alkyl, or lower alkoxy.
More preferred compounds of Formula IIb are where Y is hydrogen, Z is lower alkyl, R
a
is hydrogen, and R
b
is halogen or lower alkoxy.
In addition, the present invention encompasses compounds of Formula III:
wherein
W, X, Y, and Z are as defined above for Formula I, m is 1, 2, or 3, and
R
a
is lower alkyl, lower alkoxy, or halogen.
Preferred compounds of Formula III are where Y is hydrogen and Z is lower alkyl.
More preferred compounds of Formula III are where R
a
is lower alkoxy.
Most preferred compounds of Formula III are where R
a
is 4-methoxy.
Preferred compounds of the invention are encompassed by the following formulae:
wherein
W, X,
Albaugh Pamela
Chen Paul
Currie Kevin S.
McDonnell & Boehnen Hulbert & Berghoff
McKenzie Thomas
Neurogen Corporation
Shah Mukund J.
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