Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-31
2003-09-30
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S019000, C546S273400, C546S144000, C546S199000, C540S480000, C540S603000, C548S200000, C548S309700, C548S304700, C548S305100, C514S278000, C514S365000, C514S394000, C514S339000, C514S322000, C514S234500, C514S217090, C514S307000, C514S228200, C544S062000, C544S139000
Reexamination Certificate
active
06627624
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain aryl fused aminoalkylimidazole derivatives which when appropriately substituted selectively bind to GABA
A
receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazepine-type drugs, Down Syndrome, depression, sleep, seizure and cognitive disorders both in human as well as domestic pets and livestock.
The compounds of this invention are also useful as probes for the localization of cell surface receptors.
BACKGROUND
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 certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when when used in combination with GABA
A
selective ligands than when used alone.
SUMMARY OF THE INVENTION
This invention relates to aryl fused aminoalkyl-derivatives. Preferred compounds of the invention that bind with high affinity to the benzodiazepine site of the GABA
A
receptor, including human GABA
A
receptors. Preferred compounds of the invention also bind with high selectivity to the benzodiazepine site of the GABA
A
receptor.
The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from certain 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 (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated 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. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
Packaged pharmaceutical compositions including instructions for use of the composition are also included.
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.
The invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly GABA
A
receptors, in tissue sections. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans.
Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
or the pharmaceutically acceptable non-toxic salts thereof wherein:
W represents
where Z is O, or S:
R
1
represents phenyl, C
1
-C
6
alkyl, cyclopentyl, cyclohexyl, benzyl, 3-fluorobenzyl, or cyclopropylmethyl;
R
2
represents hydroxyl, C
1
-C
6
alkyl or C
1
-C
6
alkoxy, either of which could be substituted with amino or mono or di(C
1
-C
6
) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH
2
)
n
CO
2
R
8
where n=1,2,3,4, NR
8
COR
9
, COR
8
, CONR
8
R
9
or CO
2
R
8
where R
8
and R
9
are the same or different and represent hydrogen or C
1
-C
6
alkyl, additionally R
8
and R
9
can be a 5,6,7 member heterocyclic ring;
R
3
represents C
1
-C
6
alkyl, allyl, cyclopropylmethyl, cyclopentyl; or benzyl optionally mono-, di-, or trisubstituted independently with halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C
1
-C
6
alkyl or C
1
-C
6
alkoxy, either of which could be substituted with amino or mono or di(C
1
-C
6
) alkylamino, additionally the alkyl portion can form a 5,6,7 member ring; or O(CH
2
)
n
CO
2
R
8
where n=1,2,3,4, NR
8
COR
9
, COR
8
, CONR
8
R
9
or CO
2
R
8
where R
8
and R
9
are the same or different and represent hydrogen or C
1
-C
6
alkyl, additionally R
8
and R
9
can be a 5,6,7 member heterocyclic ring, additional substitution on the benzyl ring can be directly bound or O(CH
2
)
n
(where n=1,2,3,4) linked SO
2
R
8
, NHSO
2
R
8
, SO
2
NHR
8
, SO
2
NHCOR
8
, CONHSO
2
R
8
, as well as tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;
R
4
, R
5
and R
6
are the same or different and repre
DeSimone Robert W.
Hutchison Alan
Rosewater Daniel L.
Shaw Kenneth
Liu Hong
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Shah Mukund J.
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