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  5-substituted-2-arylpyridinesUSPTO Application #: 20080107608Title: 5-substituted-2-arylpyridines Abstract: Novel 5-substituted-2-arylpyridine compounds are provided. Such compounds can act as selective modulators of CRP receptors. The 5-substituted-2-arylpyridine compounds provided herein are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds provided are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given. (end of abstract) Agent: Neurogen Corporation - Branford, CT, US Inventors: Ping Ge, Taeyoung Yoon, Luyan Zhang, Raymond F. Horvath USPTO Applicaton #: 20080107608 - Class: 424045000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Effervescent Or Pressurized Fluid Containing, Organic Pressurized Fluid The Patent Description & Claims data below is from USPTO Patent Application 20080107608. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60/292,703 filed May 22, 2001, the teachings of which are incorporated herein by reference. BACKGROUND [0002] 1. Field of the Invention [0003] The present invention relates to 5-substituted-2-arylpyridine compounds. Such compounds bind with high selectivity and/or high affinity to CRF1 receptors (Corticotropin Releasing Factor 1 Receptors). Preferred compounds block, inhibit, activate, or otherwise modulate the activity of the receptors to which they bind. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases, irritable bowel syndrome, and colonic hypersensitivity associated with psychopathological disturbance and stress. Additionally this invention relates to the use such compounds as probes for the localization of CRF1 receptors in cells and tissues. [0004] 2. Background of the Invention [0005] Corticotropin releasing factor (CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors. [0006] CRF acts by binding to and modulating the signal transduction activities of specific cell surface receptors, including CRF1 receptors and CRF2 receptors. These receptors are found at high concentrations in the central nervous system (CNS), particularly in certain regions of the brain. CRF1 receptors are also found outside the CNS. [0007] Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system. [0008] In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression. There is also preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain. [0009] The mechanisms and sites of action through which conventional anxiolytics and antidepressants produce their therapeutic effects remain to be fully elucidated. It has been hypothesized however, that they are involved in the suppression of CRF hypersecretion that is observed in these disorders. [0010] CRF has been implicated in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models. Preliminary studies using the putative CRF receptor antagonist .alpha.-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test and in the acoustic startle test in rats. The benzodiazepine receptor antagonist Ro 15-1788, which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner, while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF. [0011] CRF activity has also been implicated in the pathogenesis of certain cardiovascular or heart-related, digestive, degenerative, dermatological, and immunological, diseases and disorders such as hypertension, tachycardia and congestive heart failure, stroke, acne and osteoporosis, as well as in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity, e.g., associated with psychopathological disturbance and stress. SUMMARY OF THE INVENTION [0012] The invention provides novel compounds of Formula I (shown below). The invention also comprises pharmaceutical compositions comprising compounds of Formula I and at least one pharmaceutically acceptable carrier or excipient. Such 5-substituted-2-arylpyridines bind to cell surface receptors, preferably G-coupled protein receptors, especially CRF receptors and most preferably CRF1 receptors. Preferred compounds of Formula I exhibit high affinity for CRF1 receptors, i.e., they bind to, activate, inhibit, or otherwise modulate the activity of receptors other than CRF receptors with affinity constants of less than 1 micromolar, preferably less than 100 nanomolar, and most preferably less than 10 nanomolar. Additionally, preferred compounds of Formula I also exhibit high selectivity for CRF1 receptors. [0013] The invention further comprises methods of treating patients suffering from certain diseases or disorders by administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These diseases and disorders include CNS disorders, particularly affective disorders, anxiety, stress, depression, and eating disorders and also include certain digestive disorders, particularly irritable bowel syndrome and Crohn's disease. These diseases or disorders further include cardiovascular or heart-related, digestive, degenerative, dermatological, and immunological, diseases and disorders such as hypertension, tachycardia and congestive heart failure, stroke, acne and osteoporosis, as well as premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity. The patient suffering from such diseases or disorders may be a human or other animal (preferably a mammal), such as a domesticated companion animal (pet) or a livestock animal. [0014] According to yet another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I or pharmaceutically acceptable salts or solvates thereof together with at least one pharmaceutically acceptable carrier or excipient, which compositions are useful for the treatment of the disorders recited above. The invention further provides methods of treating patients suffering from any of these disorders with an effective amount of a compound or composition of Formula I. [0015] Additionally this invention relates to the use of labeled compounds of Formula I (particularly radiolabeled compounds of this invention) as probes for the localization of receptors in cells and tissues and as standards and reagents for use in determining the receptor-binding characteristics of test compounds. [0016] Thus, in a first aspect, the invention is directed to compounds of Formula I and the pharmaceutically acceptable salts thereof. [0017] Ar is phenyl, 1-naphthyl or 2-naphthyl, each of which is mono-, di-, or tri-substituted, or Ar is mono-, di-, or tri-substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring and from 1 to about 3 heteroatoms in at least one of said rings. [0018] R is oxygen or absent. [0019] R.sub.2 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted mono or dialkylamino, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted mono or dialkylcarboxamide, optionally substituted aryl or optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring and from 1 to about 3 heteroatoms in at least one of said rings. [0020] R.sub.1, R.sub.3, and R.sub.4 are independently chosen from hydrogen, halogen, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted mono- or di-alkylamino, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)oxy, optionally substituted (cycloalkyl)alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted mono- or dialkylcarboxamide. [0021] Not all of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 in Formula I are unsubstituted alkyl and not all of R.sub.1, R.sub.3, and R.sub.4 are hydrogen. DETAILED DESCRIPTION OF THE INVENTION Continue reading... Full patent description for 5-substituted-2-arylpyridines Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this 5-substituted-2-arylpyridines patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like 5-substituted-2-arylpyridines or other areas of interest. ### Previous Patent Application: Method for the prediction of the risk potential for cancerous diseases and inflammatory intestinal diseases and corresponding tests Next Patent Application: Pulmonary disease treatment Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the 5-substituted-2-arylpyridines patent info. 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