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Quinoline 3-amino chroman derivativesRelated 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, Tricyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Plural Hetero Atoms In The Tricyclo Ring SystemQuinoline 3-amino chroman derivatives description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070191417, Quinoline 3-amino chroman derivatives. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims benefit of Provisional Application Ser. No. 60/466,583, filed Apr. 30, 2003, the disclosure of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to novel quinoline 3-amino chroman derivatives, processes for preparing such derivatives, and the use of such derivatives to treat a variety of psychological disorders. Preferred compounds of this invention display activity both as serotonin reuptake inhibitors and as 5-HT.sub.1A receptor agonists, and are useful in the treatment of serotonin-related disorders. BACKGROUND OF THE INVENTION [0003] Major depressive disorder affects an estimated 340 million people worldwide. Depression is the most frequently diagnosed psychiatric disorder and, according to the World Health Organization, is the fourth greatest public health problem. If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some cases, leading to suicide. Symptoms of the disorder include feelings of sadness or emptiness, lack of interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate guilt. In addition to the personal costs of depression, the disorder also has been estimated to result in more than $40 billion in annual costs in the United States alone, due to premature death, lost productivity, and absenteeism. [0004] Selective serotonin reuptake inhibitors (SSRIs) have had significant success in treating depression and related illnesses and have become among the most prescribed drugs since the 1980s. Some of the most widely known SSRIs are fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram. Although they have a favorable side effect profile compared to tricyclic antidepressants (TCAs), they have their own particular set of side effects due to the non-selective stimulation of serotonergic sites. They typically have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they have generally been found to be effective in less than two-thirds of patients. [0005] SSRIs are believed to work by blocking the neuronal reuptake of serotonin, increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors. Although a single dose of a SSRI can inhibit the neuronal serotonin transporter, and thus would be expected to increase synaptic serotonin, clinical improvement has generally been observed only after long-term treatment. It has been suggested that the delay in onset of antidepressant action of the SSRIs is the result of an increase in serotonin levels in the vicinity of the serotonergic cell bodies. This excess serotonin is believed to activate somatodendritic autoreceptors, i.e., 5-HT.sub.1A receptors, reduce cell firing activity and, in turn, decrease serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants acutely. Over time, the somatodendritic autoreceptors become desensitized, allowing the full effect of the SSRIs to be expressed in the forebrain. This time period has been found to correspond to the latency for the onset of antidepressant activity [Perez, V., et al., The Lancet, 1997, 349: 1594-1597]. [0006] In contrast to the SSRIs, a 5-HT.sub.1A agonist or partial agonist acts directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the latency period for the SSRI effect. Accordingly, the 5-HT.sub.1A partial agonists buspirone and gepirone [Feiger, A., Psychopharmacol. Bull., 1996, 32(4): 659-665; Wilcox, C., Psychopharmacol. Bull., 1996, 32(93): 335-342] and the 5-HT.sub.1A agonist flesinoxan [Grof, P., International Clinical Psychopharmacology, 1993, 8(3): 167-172] have shown efficacy in clinical trials for the treatment of depression. Furthermore, such agents are believed to stimulate the somatodendritic autoreceptors, thus hastening their desensitization and decreasing the SSRI latency period. An agent with a dual mechanism of antidepressant action would be expected to have greater efficacy and thus reduce the number of patients refractory to treatment. Indeed, buspirone augmentation to standard SSRI therapy has been shown to produce marked clinical improvement in patients initially unresponsive to standard antidepressant therapy [Dimitriou, E., J. Clinical Psychopharmacol., 1998, 18(6): 465-469]. [0007] Lacking from the current therapy regime, however, is a single compound that effectively displays the dual mechanism of antidepressant action. SUMMARY OF THE INVENTION [0008] This invention provides novel quinoline 3-amino chroman derivatives. In preferred embodiments, the compounds of this invention inhibit serotonin reuptake and/or are agonists or partial agonists at the 5-HT.sub.1A receptor. Such preferred compounds are thus useful in the treatment of diseases affected by disorders of serotonin-affected neurological systems, such as depression, anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine addiction, alcohol addiction, and sexual dysfunction. [0009] In one aspect, the present invention provides, quinoline 3-amino chroman derivatives having formula I or II: [0010] or a pharmaceutically acceptable salt thereof; [0011] wherein R.sup.1 is hydrogen, alkyl having 1 to 6 carbon atoms, cyclopropyl, cyclolbutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, or methylcyclobutyl; [0012] R.sup.2 is hydrogen or alkyl having 1 to 6 carbon atoms; [0013] R.sup.3 is hydrogen, fluoro, chloro, bromo, iodo, cyano at either the 5- or 6-position; and [0014] n is an integer from 2 to 4. [0015] In another aspect, the present invention is directed to compositions comprising a compound of formula I or II and one or more pharmaceutically acceptable carriers. [0016] Also provided methods for blocking the neuronal reuptake of serotonin and/or modulating the activity of 5-HT.sub.1A receptors through in vitro or in vivo administration of an effective amount of one or more compound according to the invention. In this respect, such compounds preferably function as 5-HT.sub.1A agonists. [0017] The present invention also provides methods of treating a patient suspected of suffering from a serotonin-related disorder, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula I or II. [0018] In yet another aspect, the present invention is also directed to methods of inhibiting the uptake of serotonin in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula I or II. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [0019] The term "alkyl", as used herein, refers to an aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains containing from 1-12 carbon atoms, preferably 1-6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term alkyl. 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