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  Indole derivative having piperidine ringUSPTO Application #: 20050256103Title: Indole derivative having piperidine ring Abstract: It is an object of the present invention to discover an agent for treating or preventing lower urinary tract symptoms, and particularly symptoms regarding urinary storage, which has a superior strength of binding to a 5-HT1A receptor and an antagonism to the receptor.
wherein R1 and R2 are substituents adjacent to each other, and together with two carbon atoms to each of which they attach, form a 5- to 7-membered non-aromatic carbocyclic group or the like, which may be substituted by 1 to 4 substituents selected from (1) an oxo group, (2) a hydroxyl group, and the like; R3 represents a hydrogen atom or the like; and R6 represents a hydrogen atom or the like.
The present invention relates to a compound represented by the following formula, a pharmacologically acceptable salt thereof, or a use thereof as a pharmaceutical: (end of abstract)
Agent: Birch Stewart Kolasch & Birch - Falls Church, VA, US Inventors: Yuichi Suzuki, Koichi Ito, Atsushi Sasaki, Koshi Ueno, Miyuki Sakai, Hiroki Ishihara, Atsuhiko Kubota USPTO Applicaton #: 20050256103 - Class: 514217040 (USPTO) Related 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 Seven-membered Consisting Of One Nitrogen And Six Carbons, Additional Hetero Ring Attached Directly Or Indirectly To The Seven-membered Hetero Ring By Nonionic Bonding, The Additional Hetero Ring Is Six-membered And Contains Nitrogen The Patent Description & Claims data below is from USPTO Patent Application 20050256103. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims priority date under the Paris Convention based on Japanese Patent Applications No. 2004-142437 filed in Japan on May 12, 2004, the contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to a compound having ability to bind to a serotonin 1A receptor, and a use thereof as a pharmaceutical. More specifically, it relates to an agent for treating or preventing lower urinary tract symptoms. [0004] 2. Description of the Related Art [0005] In the periphery system, serotonin exhibits effects of smooth muscle relaxation, platelet aggregation, and gastrointestinal tract function regulation. On the other hand, in the central nervous system, serotonin functions as a neurotransmitter and is deeply associated with the motor system, perceptive system, physiological functions such as body temperature regulation, sleep, feeding behavior, vomiting, sexual behavior, neuroendocrine system, cognition and memory, or biorhythm, and pathologic conditions such as anxiety, aggression, obsession, mood disorder, hallucination, schizophrenia, autism, or drug dependence (refer to Peroutka S. J., 5-Hydroxytryptamine receptor subtypes, Annu Rev Neurosci. 1988; 11: p.45-60; and H. Matsui, and three others, Neurotransmitter Today, 19(2), 1997, p.131-146, for example). [0006] Serotonin receptor is classified into 7 families ranging from 5-HT1 to 5-HT7. 5HT1 is composed of 5 subtypes (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F). [0007] 5-HT1A receptor is widely distributed in the central nervous system. In the brain, this receptor is distributed at a high density, particularly in the cerebral limbic system, mainly in the hippocampus, the septum, the amygdaloid complex, and the nuclei raphes. In the spinal cord, it is distributed at a high density in the posterior horn cortex which primary afferent fibers project (I and II laminae), the anterior horn inner portion where motoneurons are localized (VIII-IX laminae), and the intermediolateral nucleus where preganglionic sympathetic cells are present (VII lamina). In the nerve, a serotonin receptor exists as a presynaptic receptor in the cell bodies of the serotonin nerve (5-HT1A somatodendritic autoreceptor), and as a postsynaptic receptor, exists on the nerve in which the serotonin nerve innervates. Such a presynaptic receptor conducts negative feedback regulation to serotonin release. [0008] The action of a 5-HT1A receptor in a living body and diseases in which the receptor is involved have been clarified as a result of the discovery of agonists and antagonists that are selective for the 5-HT1A receptor. [0009] Depression and anxiety disorder are examples of such diseases. It is considered that a presynaptic 5-HT1A receptor is important for treating depression. It is considered that a selective serotonin reuptake inhibitor (SSRI) and a selective serotonin/noradrenalin reuptake inhibitor (SNRI) that are currently used as therapeutic agents. These agents inhibit the uptake of these transmitters in nerve cells, so as to increase the concentration of the transmitters in a synaptic cleft, and that as a result, desensitizes a receptor, thereby exhibiting efficacy. Recently, it has been reported that (-) pindolol (which exhibits affinity for adrenaline .beta. and 5-HT1A receptor and has an antagonistic effect against 5-HT1A receptor) promotes the onset of the pharmacological effects of SSRI, thereby increasing the effective rate thereof in patients with depression. This may be because the release of serotonin at the nerve terminals is increased by the blockage of a presynaptic 5-HT1A receptor, so that the desensitization of the receptor is advanced (refer to Farde L, and four others, PET-Determination of robalzotan (NAD-299) induced 5-HT(1A) receptor occupancy in the monkey brain, Neuropsychopharmacology, 2000 April; 22(4): p. 422-9, for example). [0010] The study of Barros M. et al. using marmosets is a report suggesting a possibility of the use of a 5-HT1A receptor antagonist for anxiety disorder. Using, as an index, the fear and anxiety behavior of a marmoset provoked by showing the stuffed specimen of a predaceous animal to the marmoset, the effect of a 5-HT1A receptor antagonist on anxiety was studied. As a result, it was shown that this agent has an anxiolytic effect (refer to Barros M, and seven others, Anxiolytic-like effects of the selective 5-HT1A receptor antagonist WAY 100635 in non-human primates, Eur J Pharmacol., Dec. 15, 2003; 482(1-3): p. 197-203, for example). These results suggested a possibility that the 5-HT1A receptor antagonist is useful as an agent for preventing or treating depression or anxiety disorder. [0011] It has also been strongly suggested that the 5-HT1A receptor is associated with cognition, memory, and learning. An NMDA-type glutamate receptor antagonist, or the fornix transection induce cognitive disorder. Such cognitive disorder was improved by a 5-HT1A receptor antagonist (refer to Harder J A, Ridley RM. The 5-HT1A antagonist, WAY 100 635, alleviates cognitive impairments induced by dizocilpine (MK-801) in monkeys.Neuropharmacology. Feb. 14, 2000; 39(4): p. 54.sup.7-52 and Harder J A, and four others, The 5-HT1A antagonist, WAY 100635, ameliorates the cognitive impairment induced by fornix transection in the marmoset. Psychopharmacology (Berl). 1996 October; 127(3): 245-54, for example). Yasuno F. et al. administered a 5-HT1A receptor antagonist labeled with .sup.11C ([.sup.11C]WAY-100635) to a human. Thereafter, they examined the relationship between memory and a portion shared by the 5-HT1A receptor by positron emission tomography (refer to Yasuno F, and nine others, Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory, Am J Psychiatry. 2003 February; 160(2): p. 334-40, for example). As a result, a negative correlation was found between the improvement of remembrance and the affinity of [.sup.11C]WAY-100635 to bind to a hippocampal postsynaptic 5-HT1A receptor. This result suggests that postsynaptic 5-HT1A receptors distributed over the hippocampus have a negative effect on the memory. These findings suggest a possibility that a 5-HT1A receptor antagonist is effective for cognitive disorder, or memory or learning disorder. [0012] Also, in recent years, the association of a 5-HT1A receptor with urinary reflex has been reported (refer to Lecci A, and three others, Involvement of 5-hydroxytryptamine1A receptors in the modulation of micturition reflexes in the anesthetized rat, J Pharmacol Exp Ther., 1992 July; 262(1): p. 181-9, for example). [0013] Various subjective symptoms provoked by urinary dysfunction are generically called lower urinary tract symptoms. Such lower urinary tract symptoms are broadly divided into symptoms regarding urinary storage such as increased urinary frequency, urinary urgency, or urinary incontinence, and voiding symptoms such as difficulty of urination or anuresis. Urinary incontinence is further classified into stress incontinence, urge incontinence, overflow incontinence, reflex urinary incontinence, extraurthral incontinence, or the like. Urinary incontinence having both the symptom of stress incontinence and that of urge incontinence is called mixed urinary incontinence. In the International Continence Society (ICS) that took place in 2001, the following proposal was given: "The overactive bladder is a medical condition referring to the symptoms of frequency and urgency, with or without urge incontinence, when appearing in the absence of local pathologic or metabolic factors that would account for these symptoms." Thus, a pathologic condition determined mainly based on subjective symptoms was defined as overactive bladder. [0014] Examples of a cause of symptoms regarding urine pooling storage may include neuropathic bladder caused by encephalopathy (including cerebrovascular disorder, Parkinson's disease, brain tumor, multiple sclerosis, and the like), senile dementia, myelopathy, or spinal disease, unstable bladder, benign prostatic hyperplasia, prostatic cancer, bladder neurosis, interstitial bladder cystitis, bladder irritation caused by chronic cystitis or chronic prostatitis, cystospasm, enuresis (including nocturnal enuresis), nocturia, and psychogenic dysuria. [0015] In studies regarding urinary reflex in rats, a 5-HT1A receptor agonist promotes urinary reflex (refer to Lecci A, and three others, Involvement of 5-hydroxytryptamine1A receptors in the modulation of micturition reflexes in the anesthetized rat, J Pharmacol Exp Ther., 1992 July; 262(1): p. 181-9, for example), whereas a 5-HT1A receptor antagonist suppresses urinary reflex measured by rhythmical bladder contraction or cystometogram. In addition, in the case of a 5-HT1A receptor partial agonist, the effect to suppress urinary reflex is reduced depending on the degree of the agonistic action of the agent (refer to Testa R, and nine others, Effect of several 5-hydroxytryptamine(1A) receptor ligands on the micturition reflex in rats: comparison with WAY 100635, J Pharmacol Exp Ther., 1999 September; 290(3): p. 1258-69, for example). From these findings, a 5-HT1A receptor antagonist is anticipated as a novel agent for treating symptoms regarding urinary storage based on a novel action mechanism (including increased urinary frequency, urinary urgency, and urinary incontinence, etc.) (refer to Andersson K E, Pehrson R, CNS involvement in overactive bladder: pathophysiology and opportunities for pharmacological intervention, Drugs, 2003; 63(23): p. 2595-611, for example). [0016] Other than the aforementioned diseases, there is a wide range of diseases in which a 5-HT1A receptor would be involved. Examples of such a disease may include neuropsychiatic disorder (e.g. obsessive-compulsive disorder (refer to Bourin M, and another, The future of antidepressants, Biomed Pharmacother., 1996; 50(1): p. 7-12, for example), borderline personality disorder (refer to Hansenne M, and seven others, 5-HT1A dysfunction in borderline personality disorder, Psychol Med. 2002 July; 32(5): p. 935-41, for example), post-traumatic stress disorder (refer to Wilson MS, and another, Effects of fluoxetine on the 5-HT1A receptor and recovery of cognitive function after traumatic brain injury in rats, Am J Phys Med Rehabil., 2002 May; 81(5): p. 364-72, for example), panic disorder, schizophrenia (refer to Fletcher A, and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), genital insufficiency (refer to Fletcher A, and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), alcohol and/or cocaine dependence (refer to Zhou F C, and three others, Additive reduction of alcohol drinking by 5-HT1A antagonist WAY 100635 and serotonin uptake blocker fluoxetine in alcohol-preferring P rats, Alcohol Clin Exp Res., 1998 February; 22(1): p. 266-9 and Carey R J, and two others, 5-HT1A agonist/antagonist modification of cocaine stimulant effects: implications for cocaine mechanisms. Behav Brain Res., Apr. 15, 2002; 132(1): p. 37-46, for example), sleep disorder (refer to Fletcher A, and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), pain (refer to Fletcher A, and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), migraine (refer to Boers P M, and three others, Naratriptan has a selective inhibitory effect on trigeminovascular neurones at central 5-HT1A and 5-HT(1B/1D) receptors in the cat: implications for migraine therapy, Cephalalgia., 2004 February; 24(2): p. 99-109, for example), visual attention disorder (refer to Balducci C, and four others, Reversal of visual attention dysfunction after AMPA lesions of the nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT1A receptor antagonist WAY 100635,Psychopharmacology (Berl)., 2003 April; 167(1): p. 28-36, for example), temperature instability (refer to Fletcher A, and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), vomiting (refer to Gupta Y K, and another, Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis in dogs, Indian J Physiol Pharmacol., 2002 October; 46(4): p. 463-7, for example), gastrointestinal disorder (refer to Fletcher A, and two others, Silent-5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), eating disorder (refer to Fletcher A, and two others, Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents, Trends Pharmacol Sci., 1993 December; 14(12): p. 441-8, for example), hypertension (refer to Dabire H, Central 5-hydroxytryptamine (5-HT) receptors in blood pressure regulation, Therapie., 1991 November-December; 46(6): p. 421-9, for example), neuro-degenerative disease (refer to Kruger H, and two others, Effects of ionotropic glutamate receptor blockade and 5-HT1A receptor activation on spreading depression in rat neocortical slices, Neuroreport., Aug. 20, 1999; 10(12): p. 2651-6 and Suchanek B, and two others, The 5-HT1A receptor agonist BAY x 3702 prevents staurosporine-induced apoptosis, Eur J Pharmacol., Aug. 14, 1998; 355(1): p. 95-101, for example) (e.g. cerebral ischemia, Alzheimer's disease, etc.), dyskinesia caused by Parkinson's disease (refer to Bibbiani F, and two others, Serotonin 5-HT1A agonist improves motor complications in rodent and primate parkinsonian models, Neurology., Nov. 27, 2001; 57(10): p. 1829-34, for example), and symptoms associated with withdrawal from nicotine ingestion or smoking (refer to Kurt Rasmussen, and sixteen others, The Novel 5-Hydroxytryptamine1A Antagonist LY426965: Effects on Nicotine Withdrawal and Interactions with Fluoxetine, J. of Pharmacol. Experimental Therapeutics., 294: 688-700: (2000), for example). [0017] Accordingly, a 5-HT1A receptor antagonist is expected as an agent for preventing or treating such a wide range of diseases. Although studies for developing such a 5-HT1A receptor antagonist have actively been conducted, the agent has not yet been on the market. Thus, the development of a superior 5-HT1A receptor antagonist has been desired. [0018] A large number of reports have previously been made regarding compounds having an antagonistic effect against a 5-HT1A receptor. However, for the use as an agent for treating lower urinary tract symptoms, only a few compounds described in International Publication WO99/06384 and JP-A-2002-114684 have been known. [0019] The compound described in International Publication WO99/06384 is a compound represented by the following formula or a pharmacologically acceptable salt thereof: 2 [0020] wherein R represents a hydrogen atom or the like; R.sup.1 represents a hydrogen atom or the like; R.sup.2 represents a halogen atom or the like; and B represents a monocyclic aryl group or the like. The structural characteristics of this compound are that it has an N-phenylaminoalkyl group as a piperazine side chain. [0021] Accordingly, in terms of chemical structure, the compound described in International Publication WO99/06384 completely differs from the compound represented by formula (I) of the present invention characterized in that "it has an unsubstituted or monosubstituted carbamoyl group at position 6 on an indole skeleton, and has a methoxy group on an aryl group of an aryl alkyl side chain extended from a nitrogen atom on a piperidine ring, at an ortho position to the alkyl side chain." [0022] JP-A-2002-114684 is a prior art that is closest to the present invention. This document discloses an agent for treating lower urinary tract symptoms containing a compound represented by the following formula, a salt thereof, or a hydrate thereof: 3 Continue reading... Full patent description for Indole derivative having piperidine ring Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Indole derivative having piperidine ring 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. 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