Aryl substituted tetrahydroindazoles

Details Aryl substituted tetrahydroindazoles Aryl substituted tetrahydroindazoles

2001-09-06

2003-12-02

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S338000, C544S238000, C546S275700

Reexamination Certificate

active

06656941

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention provides aryl substituted tetrahydroindazoles, and more specifically to aryl substituted tetrahydroindazoles that bind 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 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 through 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.
A number of cDNAs for GABA
A
receptor subunits have been characterized. To date at least 6&agr;, 3&bgr;, 3&ggr;, 1&egr;, 1&dgr; and 2&rgr; subunits have been identified. It is generally accepted that 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). 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): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA
A
receptor. In addition to the benzodiazepine site, the GABA
A
receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the 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 GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6
th
ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABA
A
receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABA
A
receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes 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 a long history of pharmaceutical use as anxiolytics, these compounds often 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 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.
International Application WO 00/40565 discloses tetrahydroindazole derivatives.
SUMMARY OF THE INVENTION
This invention provides aryl substituted tetrahydroindazoles, that preferably bind with both high affinity and high selectivity to the benzodiazepine site of the GABA
A
receptor, including human GABA
A
receptors.
Thus, the invention provides compounds of Formula I, and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pet) or livestock animals suffering from CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABA
A
receptors in tissue sections.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, or 2;
R
1
and R
2
are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, nitro, cyano, amino, and mono- or dialkylamino;
R
3
is hydrogen or C
1-6
alkyl;
Ar is aryl or a saturated, unsaturated, or aromatic heterocyclic group, wherein each aryl of heterocyclic group is optionally substituted;
when n is 0 or 2, Ar is optionally substituted with G, when n is 1 Ar is substituted by at least one group G, where
G represents a group of the formula:
where
W is oxygen, NH, N-alkyl, N-acyl, sulfur, or CR
5
R
6
where R
5
and R
6
are the same or different and represent hydrogen, alkyl, or R
5
and R
6
may be taken together to form a saturated or partially unsaturated carbocyclic ring having 3-7 carbon atoms;
 independently represent straight or branched carbon chains which may be substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mono or dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, haloalkyl, and haloalkoxy;
x is 0, 1, 2, or 3;
y is 0, 1, 2, or 3;
Z is hydrogen, hydroxy, alkoxy, cycloalkyl, cycloalkyl(alkoxy), amino, mono or dialkylamino, or —NR
7
COR
8
where R
7
and R
8
are the same or different and represent hydrogen or alkyl, or R
7
and R8 and the atoms to which they are attached form a heterocycloalkyl ring, or
Z is aryl or a saturated, partially unsaturated, or aromatic heterocyclic group of from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms selected from the group consisting of N, O, and S, wherein each aryl or heterocyclic group optionally substituted.
The invention also provides intermediates and methods of making the compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of Formula I are those where R
1
and R
2
groups include hydrogen, methyl, and ethyl with hydrogen being particularly preferred, R
3
is preferably hydrogen or methyl, Ar is preferably phenyl or pyridyl.
Particular compounds of Formula I include compounds wherein:
R
1
and R
2
are independently chosen at each occurrence from: hydrogen, halogen, hydroxy, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy, C
1-6
haloalkyl, C
1-6
haloalkoxy, nitro, cyano, amino, mono- or di(C
1-6
)alkylamino;
Ar is phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, naphthyl, indolyl, quinolinyl, or isoquinolinyl, each of optionally mono-, di-, or trisubstituted with substituents independently chosen from halogen, cyano, nitro, C
1-6
haloalkoxy, hydroxy, amino, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-7
cycloalkyl, C
3-7
cycloalkyl(C

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