4-substituted quinoline derivatives

Details 4-substituted quinoline derivatives 4-substituted quinoline derivatives

2000-03-28

2001-10-30

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S218000, C514S256000, C514S314000, C514S312000, C514S313000, C546S157000, C546S159000, C546S167000, C544S333000, C540S553000

Reexamination Certificate

active

06310212

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field Of The Invention
This invention relates to quinoline derivatives, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of certain central nervous system and peripheral diseases or disorders. This invention also relates to the use of such compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. The compounds of this invention are also useful as probes for the localization of cell surface receptors.
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 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
Disclosed are compounds, particulary quinoline derivatives that bind to cell surface receptors. Preferred compounds of the invention bind to neurokinin and/or GABA receptors, in particular these compounds possess affinity for GABA
A
receptors. These compounds are therefore considered to be of use in the treatment of a broad array of diseases or disorders in patients which are characterized by modulation of GABA
A
receptors.
This invention provides compounds of general Formula I:
or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof,
wherein in R
1
, R
2
, R
3
, R
4
, X, Y
1
and Y
2
are hereinafter defined.
Preferred compounds of this invention are ligands for GABA receptors, GABA
A
receptors, and are useful in the treatment of a wide range of diseases or disorders including, but not limited to depression, anxiety, sleep disorders, cognitive disorders, low alertness, psychosis, obesity, pain, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases, movement disorders, Down's syndrome, and benzodiazepine overdoses.
The invention also provides pharmaceutical compositions comprising compounds of Formula I. The invention further comprises a method of treating a patient suffering from certain central nervous system and peripheral diseases or disorders with effective concentration of a compound of the invention. 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.
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.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to quinoline derivatives, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of central nervous system and peripheral diseases or disorders.
Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
and the pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, wherein:
R
1
is selected from:
hydrogen, halogen, hydroxy, C
1-6
alkyl, —O(C
1-6
alkyl), —NO
2
, —CN, —SO
2
NH
2
, —SO
2
NH(C
1-6
alkyl), —SO
2
N(C
1-6
alkyl)(C
1-6
alkyl), amino, —NH(C
1-6
alkyl), —N(C
1-6
alkyl)(C
1-6
alkyl), —N(C
1-6
alkyl)CO(C
1-6
alkyl), —N(C
1-6
alkyl)CO
2
(C
1-6
alkyl), —NHSO
2
(C
1-6
alkyl), —N(C
1-6
alkyl)SO
2
(C
1-6
alkyl), —SO
2
NHCO(C
1-6
alkyl), —CONHSO
2
(C
1-6
alkyl), —CON(C
1-6
alkyl)(C
1-6
alkyl), —CO
2
(C
1-6
alkyl), —S(C
1-6
alkyl), —SO(C
1-6
alkyl), or —SO
2
(C
1-6
alkyl),
wherein said C
1-6
alkyl is straight, branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, fluoro, amino, C
1-3
alkoxy;
R
2
and R
3
are independently selected from the groups consisting of:
(1) C
1-8
alkyl, wherein said C
1-8
alkyl is straight, branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more of the substituents selected from:
(i) hydroxy,
(ii) oxo,
(iii) fluoro,
(iv) amino,
(v) Ar
1
, wherein Ar
1
is independently selected at each occurrence from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,

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