Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-27
2004-03-09
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C206S568000, C514S267000, C544S250000, C544S281000
Reexamination Certificate
active
06703393
ABSTRACT:
BACKGROUND OF THE INVENTION
This application claims priority from U.S. Provisional Application Ser. No. 60/279,147, filed Mar. 27, 2001, the disclosure of which is hereby incorporated by reference in its entirety.
1. Field of the Invention
This invention relates to (oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides that bind and more specifically to such components to the benzodiazepine site of GABA
A
receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases.
2. Description of the Related Art
The GABA
A
receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, &ggr;-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed throughout the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABA
A
receptor, which causes alteration in chloride conductance and membrane polarization. In addition to being the site of neurotransmitter action, a number of drugs including the anxiolytic and sedating benzodiazepines bind to this receptor. The GABA
A
receptor comprises a chloride channel that generally, but not invariably, opens in response to GABA, allowing chloride to enter the cell. This, in turn, effects a slowing of neuronal activity through hyperpolarization of the cell membrane potential.
GABA
A
receptors are composed of five protein subunits. A number of cDNAs for these GABA
A
receptor subunits have been cloned and their primary structures determined. While these subunits share a basic motif of 4 membrane-spanning helices, there is sufficient sequence diversity to classify them into several groups. To date at least 6&agr;, 3&bgr;, 3&ggr;, 1&egr;, 1&dgr; and 2&rgr; subunits have been identified. Native GABA
A
receptors are typically composed of 2&agr;, 2&bgr;, and 1&ggr; subunits (Pritchett & Seeburg
Science
1989; 245:1389-1392, and Knight et. al.,
Recept. Channels
1998; 6:1-18). Various lines of evidence (such as message distribution, genome localization and biochemical study results) suggest that the major naturally occurring receptor combinations are &agr;
1
&bgr;
2
&ggr;
2
, &agr;
2
&bgr;
3
&ggr;
2
, &agr;
3&bgr;
3
&ggr;
2
, and &agr;
5
&bgr;
3
&ggr;
2
(Mohler et al.
Neuroch. Res.
1995; 20 (5):631-36).
The GABA
A
receptor binding sites for GABA (2 per receptor complex) are formed by amino acids from the &agr; and &bgr; subunits. Amino acids from the &agr; and &ggr; subunits together form one benzodiazepine site per receptor. Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA
A
receptor. In addition to the benzodiazepine site (sometimes referred to as the benzodiazepine or BDZ receptor), the GABA
A
receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and a barbiturate site. The benzodiazepine site of the GABA
A
receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for other classes of drugs that bind to the receptor or for GABA (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6
th
ed., 1991, pp. 145-148, Oxford University Press, New York).
In a classic allosteric mechanism, the binding of a drug to the benzodiazepine site increases the affinity of the GABA receptor for GABA. Benzodiazepines and related drugs that enhance the ability of GABA to open GABA
A
receptor channels are known as agonists or partial agonists depending on the level of GABA enhancement. Other classes of drugs, such as &bgr;-carboline derivatives, that occupy the same site and negatively modulate the action of GABA are called inverse agonists. A third class of compounds exists which occupy the same site as both the agonists and inverse agonists and yet have little or no effect on GABA activity. These compounds will, however, block the action of agonists or inverse agonists and are thus referred to as GABA
A
receptor antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early, and the distribution of activities at different subtype receptors has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have enjoyed long pharmaceutical use as anxiolytics, these compounds are known to exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABA
A
selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABA
A
selective ligands than when used alone.
SUMMARY OF THE INVENTION
The invention provides (oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides and specifically to such compounds that interact with the benzodiazepine site of GABA
A
receptors, including human GABA
A
receptors. Preferred compounds of the invention interact with high selectivity and/or high affinity to GABA
A
receptors and act as agonists, antagonists or inverse agonists of such receptors. As such, they are useful in the treatment of a variety of CNS disorders.
In one aspect, the invention provides compounds of Formula I:
and pharmaceutically acceptable salts thereof, wherein:
n is 1, 2, or 3;
where R
1
and R
2
are independently chosen from hydrogen, halogen, hydroxy, amino, mono- and di(C
1
-C
6
)alkyl amino, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, C
1
-C
6
alkyl and C
1
-C
6
alkoxy; or R
1
and R
2
together with the atoms with which they are attached form a partially saturated or unsaturated carbocyclic ring of from 3 to 8 carbon atoms, wherein the ring is optionally substituted by up to 5 substituents independently chosen from halogen, hydroxy, amino, mono- and di(C
1
-C
6
)alkyl amino, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, C
1
-C
6
alkyl and C
1
-C
6
alkoxy;
R
3
, R
4
and R
5
are independently chosen from (i) hydrogen; and
(ii) C
1
-C
6
acyl and C
1
-C
6
alkyl, each of which is optionally substituted with up to three substituents independently chosen from halogen, hydroxy, halo(C
1
-C
2
)alkyl, halo(C
1
-C
2
)alkoxy, methoxy, ethoxy, C
3
-C
7
cycloalkyl, phenyl, pyridyl, and pyrimidyl, wherein each of phenyl, pyridyl, and pyrimidyl is optionally substituted with up to three groups selected independently from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, hydroxy and amino;
R
6
and R
6
′ are independently selected at each occurrence from hydrogen and C
1
-C
6
alkyl;
W is aryl or heteroaryl (such as phenyl, naphthyl, pyridyl, pyrimidinyl, pyridizinyl, pyrrolyl, imidazolyl, pyrazolyl or thiophenyl), each of which is optionally substituted with up to 5 groups independently selected from hydrogen, halogen, hydroxy, amino, mono- or di(C
1
-C
6
)alkyl amino, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy.
In another aspect, the invention provides compounds of formula Ia:
and pharmaceutically acceptable salts thereof, wherein:
n is 1, 2, or 3;
R
1
and R
2
are independently chosen from hydrogen, halogen, hydroxy, amino, mono- and di(C
1
-C
6
)alkyl amino, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy; or
R
1
and R
2
together with the atoms with which they are attached form a partially saturated or unsaturated carbocyclic ring of from 3 to 8 carbon atoms, wherein the ring is optionally substituted by up to 5 substituents independently chosen from halogen, hydroxy, amino, mono- and di(C
1
-C
6
)alkyl amino, halo
Albaugh Pamela
Li Guiying
Peterson John
Berch Mark L.
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
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