| Aryl fused 2,4-disubstituted pyridines: nk3 receptor ligands -> Monitor Keywords |
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Aryl fused 2,4-disubstituted pyridines: nk3 receptor ligandsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Plural Hetero Atoms In The Bicyclo Ring SystemAryl fused 2,4-disubstituted pyridines: nk3 receptor ligands description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060142324, Aryl fused 2,4-disubstituted pyridines: nk3 receptor ligands. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to aryl fused 2,4-disubstituted pyridines that bind to cell surface receptors, particularly neurokinin-3 (NK-3) receptors. More specifically, the invention relates to such compounds that selectively bind to such receptors. This invention also relates to pharmaceutical compositions comprising such compounds. These novel NK-3 receptor ligands are useful in the treatment of a broad array of disorders and diseases of the central nervous system (CNS) and peripheral nervous systems in mammals that are associated with pathogenic NK-3 receptor activation. [0003] 2. Description of the Related Art [0004] 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 .beta. (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 (.alpha.-, .beta.- and .gamma.-preprotachykinin mRNAs) that arise from a single gene as a result of alternative RNA splicing, whereas NKA can be generated from either the .beta.- or the .gamma.-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 .gamma.) are produced. NKB is produced from a separate mRNA arising from a second gene known as preprotachykinin B. [0005] 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.sub..alpha.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. [0006] 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. [0007] 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 [0008] This invention provides novel compounds of Formula I (below), which interact with the NK3 binding site (the NK-3 receptor). The invention provides pharmaceutical compositions containing compounds described by Formula I. These novel tachykinin NK-3 receptor ligands act as receptor antagonists. As such, they useful in the treatment of a broad array of disorders and diseases of the central nervous system (CNS) and periphery in mammals in which pathogenic activation of NK-3 receptors may occur. These include anxiety, panic disorder, depression, psychosis, obsessive compulsive disorder, dementia, Huntington's disease, schizophrenia, stress related somatic disorders, reflex sympathetic dystrophy, dysthmic disorders, Parkinson's disease, movement disorders, obesity, eating disorders, addiction, convulsive disorders such as epilepsy, neurodegenerative diseases such as Alzheimer's disease, Multiple sclerosis and other demyelinating diseases, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia, diabetic or peripheral neuropathy, neurogenic inflammation, inflammatory pain and other types of chronic or acute pain, migraine, Reynaud's disease, vasodilation, vasospasm, angina, asthma, chronic obstructive pulmonary diseases, airway hyperreactivity, cough, allergic rhinitis, bronchospasm, bronchopneumonia, ocular inflammation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, skin disorders and itch, hypersensitivity disorders, atopic dermatitis, contact dermatitis, cutaneous wheal and flare, psoriasis, renal disorders, urinary incontinence, immune system disorders and adverse immunological reactions, fibrositis, osteoarthritis, eosinophilic fascioliasis, and scleroderma. [0009] These compounds are also useful for the diagnosis of disorders involving activation of tachykinin NK-3 receptors and as probes for detecting NK-3 receptors in cultured cells and tissue samples. [0010] Accordingly, a broad embodiment of the invention is directed to compounds of Formula I: [0011] and the pharmaceutically acceptable non-toxic salts or pharmaceutically acceptable solvates thereof wherein: [0012] Y is [0013] hydrogen, straight or branched chain lower alkyl having 1-6 carbon atoms, halogen, amino, hydroxyl, or lower alkoxy having 1-6 carbon atoms; or [0014] Y is [0015] straight or branched chain lower alkyl having 1-6 carbon atoms or lower alkoxy having 1-6 carbon atoms which is substituted on the alkyl chain with an amino or mono or dialkylamino group; [0016] W is [0017] phenyl, thienyl, or pyridyl, each of which may be mono or disubstituted with halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or [0018] W is [0019] straight or branched chain lower alkyl having 1-6 carbon atoms, cycloalkyl containing 5 to 8 carbon atoms or phenyl, thienyl or pyridyl straight or branched chain lower alkyl having 1-6 carbon atoms with all aryl groups being either unsubstituted or mono or disubstituted with halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms, amino, mono or dialkylamino where each alkyl is straight or branched chain lower alkyl having 1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6 carbon atoms; or [0020] W is [0021] piperidino, morpholino, thiomorpholino, pyrrolindino, piperazino, homopiperazino, azabicyclo[3.2.2]nonano, isoindolino, as well as any other nitrogen-containing heterocycle attached on nitrogen so as to form a tertiary amine in structure I wherein the heterocycle is unsubstituted, mono or disubstituted with alkyl or aryl groups, or fused to an aromatic ring; or [0022] W is Continue reading about Aryl fused 2,4-disubstituted pyridines: nk3 receptor ligands... 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