Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-28
2002-04-09
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S169000, C546S156000, C546S160000, C546S161000, C546S144000, C546S019000, C514S313000, C514S307000, C514S235200, C514S228200, C514S278000, C544S128000, C544S062000
Reexamination Certificate
active
06369053
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 2-aminoquinolinecarboxamides, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of certain central nervous system and peripheral diseases. The compounds of this invention are also useful as probes for the localization of cell surface receptors.
2. Description of the Related Art
The tachykinins represent a family of structurally related peptides originally isolated based upon their smooth muscle contractile and sialogogic activity. These mammalian peptides include substance P (SP), neurokinin A (NKA) and neurokinin &bgr; (NKB). Tachykinins are synthesized in the central nervous system (CNS), as well as in peripheral tissues, where they exert a variety of biological activities. Substance P can be produced from three different mRNAs (&agr;-, &bgr;- and &ggr;-preprotachykinin mRNAs) that arise from a single gene as a result of alternative RNA splicing, whereas NKA can be generated from either the &bgr;- or the &ggr;-preprotachykinin mRNA through posttranslationally processed precursor polypeptides. These precursors can also be differentially processed so that amino terminally extended forms of NKA (known as neuropeptide K and neuropeptide &ggr;) are produced. NKB is produced from a separate mRNA arising from a second gene known as preprotachykinin B.
Three receptors for the tachykinin peptides have been moleculary characterized and are referred to as neurokinin-1 (NK-1), neurokinin-2 (NK-2) and neurokinin-3 (NK-3) receptors. The NK-1 receptor has a natural agonist potency profile of SP>NKA>NKB. The NK-2 receptor agonist potency profile is NKA>NKB>SP, and the NK-3 receptor agonist potency profile is NKB>NKA>SP. These receptors mediate the variety of tachykinin-stimulated biological effects that generally include 1) modulation of smooth muscle contractile activity, 2) transmission of (generally) excitatory neuronal signals in the CNS and periphery (e.g. pain signals), 3) modulation of immune and inflammatory responses, 4) induction of hypotensive effects via dilation of the peripheral vasculature, and 5) stimulation of endocrine and exocrine gland secretions. These receptors transduce intracellular signals via the activation of pertussis toxin-insensitive (G
&agr;q,11
) G proteins, resulting in the generation of the intracellular second messengers inositol 1,4,5-trisphosyphate and diacylglycerol. NK-1 receptors are expressed in a wide variety of peripheral tissues and in the CNS. NK-2 receptors are expressed primarily in the periphery, while NK-3 receptors are primarily (but not exclusively) expressed in the CNS. Recent work confirms the presence of NK-3 receptor binding sites in the human brain.
Studies measuring the localization of NKB and NK-3 receptor mRNAs and proteins, along with studies performed using peptide agonists and non-peptide NK-3 receptor antagonists, provide a rationale for using NK-3 receptor antagonists in treating a variety of disorders in both the CNS and the periphery. In the CNS, activation of NK-3 receptors has been shown to modulate dopamine and serotonin release, indicating therapeutic utility in the treatment of a variety of disorders including anxiety, depression, schizophrenia and obesity. Further, studies in primate brain detect the presence of NK-3 mRNA in a variety of regions relevant to these disorders. With regard to obesity, it has also been shown that NK-3 receptors are located on MCH-containing neurons in the rat lateral hypothalamus and zona incerta. In the periphery, administration of NKB into the airways is known to induce mucus secretion and bronchoconstriction, indicating therapeutic utility for NK-3 receptor antagonists in the treatment of patients suffering from airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Localization of NK-3 receptors in the gastrointestinal (GI) tract and the bladder indicates therapeutic utility for NK-3 receptor antagonists in the treatment of GI and bladder disorders including inflammatory bowel disease and urinary incontinence.
Both peptide and nonpeptide antagonists have been developed for each of the tachykinin receptors. The first generation of peptide antagonists for the tachykinin receptors had problems with low potency, partial agonism, poor metabolic stability and toxicity, whereas the current generation of non-peptide antagonists display more drug-like properties. Unfortunately, previous non-peptide NK-3 receptor antagonists suffer from a number of problems such as species selectivity (which limits the potential to evaluate these compounds in many appropriate disease models). New non-peptide NK-3 receptor antagonists are therefore being sought, both as therapeutic agents and as tools to further investigate the anatomical and ultrastructural distribution of NK-3 receptors, as well as the physiologic and pathophysiologic consequences of NK-3 receptor activation.
SUMMARY OF THE INVENTION
This invention relates to 2-aminoquinolinecarboxamides represented by structure Formula I:
or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein in R
1
, R
2
, R
3
, X, Q
1
and Q
2
are hereinafter defined.
The invention also relates to pharmaceutical compositions comprising such compounds and the use of such compounds and compositions in the treatment of certain central nervous system and peripheral diseases or disorders.
The compounds of this invention are ligands for neurokinin receptors, in particular NK-3 receptors, and are useful in the treatment of a wide range of diseases or disorders including, but not limited to depression, anxiety, psychosis, obesity, pain, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases, movement disorders, respiratory diseases, inflammatory diseases, neuropathy, immune disorders, migraine, biliary disfunction, and dermatitis.
The invention provides novel 2-aminoquinolinecarboxamides that bind selectively to neurokinin receptors, in particular NK-3 receptors. These compounds are therefore of use in the treatment of a broad array of diseases which are characterized by modulation of the neurokinin receptors, in particular NK-3 receptors.
In a separate aspect, the invention 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 neurokinin-3 receptors, in tissue sections.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to 2-aminoquinolinecarboxamides, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of certain central nervous system and peripheral diseases or disorders.
Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:
or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, wherein:
R
1
is:
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), —NHCO
2
(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(C
1-6
alkyl),
where each C
1-6
alkyl is a straight, branched or cyclic alkyl group optionally containing one or two double or triple bonds and optionally substituted with one or more of hydroxy, oxo, halogen, amino, or C
1-3
alkoxy;
R
2
and R
3
are independently selected from the groups consisting of:
hydrogen, halogen, hydroxy, C
1-8
alkyl, —O(C
1-8
alkyl),—NO
2
, —CN, —SO
2
NH
2
, —SO
2
NH(C
1-8
alkyl), —SO
2
N(C
1-8
alkyl) (C
1-8
alkyl), amino, —NH(C
1-8
alkyl), —N(C
1-8
alkyl) (C
1-8
alkyl),—N(C
1-8
alkyl)CO(C
1-8
alkyl), —NHCO
2
(C
1-6
alkyl), —N(C
1-8
Hutchison Alan
Maynard George D.
Yuan Jun
Liu Hong
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Raymond Richard L.
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