PATENT ABSTRACTS OF JAPAN

(11)Publication number : 2002-030084 (43)Date of publication of application : 29.01.2002 (51)Int.Cl.

C07D453/02 A61K 31/439 A61P 25/18 A61P 25/28 A61P 43/00

(21)Application number : 2000-217709 (71)Applicant : MITSUBISHI PHARMA CORP (22)Date of filing : 18.07.2000 (72)Inventor : FUJIO MASAKAZU HASHIMOTO KENJI KATAYAMA JIRO NUMATA ATSUSHI (54) 1-AZABICYCLOALKANE COMPOUND AND PHARMACEUTICAL USE THEREOF (57)Abstract: PROBLEM TO BE SOLVED: To provide a new compound having 7-nicotine receptor agonism or 7-nicotine receptor partial agonism, therefore useful as a therapeutic or prophylactic agent for such diseases as Alzheimer's disease, recognition dysfunction, attention-defective hyperkinesia, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease and Huntington's disease. SOLUTION: This new compound is an 1azabicycloalkane compound of the general formula (I) (wherein, the definitions of the respective symbols are such as to be described in the specification), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION [Detailed Description of the Invention] [0001]

[Field of the Invention]This invention relates to the new 1-azabicyclo alkane compound for providing the disease of a central nervous system with useful medicine. [0002] [Description of the Prior Art][Description of the Prior Art]. As for ** and the Ching receptor, many subtypes are existence ********. It is known and by the present, At least 11 subtypes (alpha2-9 and beta2-4) are identified (1991; Progress in total theory: Trends in Pharmacological Sciences, 12:3440). Neurobiology, 53:199-23. A nicotinic receptor exists as a pentamer of these subtypes, an ion channel is formed, and taking in calcium ion etc. to intracellular is known. In the brain, although it is known that two kinds of subtypes (alpha4beta2 and alpha 7) mainly exist, alpha4beta2 nicotinic receptor is formed as hetero oligomer of alpha4 subunit and beta2 subunit, and alpha7 nicotinic receptor is formed as gay oligomer of alpha7 subunit. These subtypes (alpha4beta2 nicotinic receptor and alpha7 nicotinic receptor) are distributed over the broad parts (the cerebral cortex, a hippocampus, etc.) within a brain. The nicotinic receptor (alpha4beta2 nicotinic receptor and alpha7 nicotinic receptor) in a central nervous system, Nervous generating and differentiation, study, and formation of memory, Remuneration. . Participating in said various physiological functions is known. (Total theory:.) Brain Research Reviews, 26:198-216, 1998; Trends in Neurosciences, 22:555-561, 1999; MolecularNeurobiology, 20:1-16, 1999 ). neurotransmitter (acetylcholine.) with various nicotinic receptors which exist in a presynapsis Dopamine, In discharge of glutamic acid etc. An important role. . It is known that it is sure enough. (Total theory:.) Trends in Pharmacological Sciences, 20:92-98, 1997; Annual Reviews of Neuroscience 22:443-485, 1999; Molecular Neurobiology 20:1-16, 1999. The nicotinic receptor which exists in a back synapse, In the Kolin system neural transmission. Having played the important role is known (total theory: Trends in Pharmacological Sciences, 22:555-561, 1999; Molecular Neurobiology, 20:1-16, 1999). [0003]On the other hand, an acetylcholine system is one of the neurotransmitter with a main central nervous system, having played the role important for regulation of nerve activity of the cerebral cortex or a hippocampus is known, and a possibility of participating in the symptoms of various kinds of central diseases is pointed out. For example, in the cerebral cortex and the hippocampus of an autopsy brain of an Alzheimer disease patient. Also in an acetylcholine system, a nicotinic receptor. (alpha4beta2 nicotinic receptor.) . And reduction of the receptor of alpha7 nicotinic receptor is reported. (Journal of Neurochemistry, 46:288-293, 1986; Alzheimer's Disease Reviews, 3:20-27, 1998; Alzheimer's Disease Reviews, 3:28) -34, 1998. The quantity of mRNA of alpha7 nicotinic receptor in an Alzheimer disease patient's lymphocyte, Increasing intentionally as compared with the quantity of mRNA of alpha7 nicotinic receptor a normal person's lymphocyte is reported (Alzheimer's Research, 3:29-36-1997). The quantity of mRNA of alpha7 nicotinic receptor in an Alzheimer disease patient's hippocampus, Increasing intentionally as compared with the quantity of mRNA of alpha7 nicotinic receptor a normal person's hippocampus is reported (Molecular Brain Research, 66:94-103, 1999). As for a difference, as for the quantity of mRNA of other subtypes (alpha3 and alpha4), in this report, it is suggested from not having accepted between a normal person's brain and the patient brain of an Alzheimer disease that alpha7 nicotinic receptor has played the important role in the symptoms of an Alzheimer disease. In the examination using the primary culture system of the rat cerebral cortex, it is reported in the neurotoxicity by amyloid beta peptide that nicotine shows a neuroprotective action via alpha7 nicotinic receptor (Annuals of Neurology,

42:159-163, 1997). As one of the mechanisms of the neurotoxicity by amyloid beta peptide, there is an oxidant stress theory by a radical reaction, and a possibility that the stimulus of a nicotinic receptor is adjusting intracellular oxidant stress is suggested. Therefore, alpha7 nicotinic receptor is considered that a possibility of being concerned with the cause of a disease of an Alzheimer disease or the site of action as a remedy is high. [0004]on the other hand, . The relation of people with schizophrenia and alpha7 nicotinic receptor attracts attention. (Total theory:.) Harvard Reviews of Psychiatry, 2:179-192, 1994; Schizophrenia Bulletin,22:431-445, 1996; Schizophrenia Bulletin, 24 :. 189-202, 1998; Trends in Neurosciences, 22:555-561, 1999. People's with schizophrenia autopsy brain. The numbers of alpha7 nicotinic receptors, such as (a hippocampus and a frontal cortex). It is decreasing. **. (Schizophrenia Bulletin, 22:431445, 1996; Schizophrenia Bulletin, 24:189-202,1998; NeuroReport, 10:1779-1782, 1999reported ). It is reported that the abnormalities of sensory gating observed by people with schizophrenia improve by administration of nicotine and that alpha7 nicotinic receptor is participating in this phenomenon further. Therefore, alpha7 nicotinic receptor is considered that a possibility of being concerned with the cause of a disease of schizophrenia is high. By the way, the mechanism of the symptoms of schizophrenia, Although it is not clear at present, The neurotransmission system of glutamic acid which is one of the excitatory amino acid. . The hypothesis which is falling is advocated broadly. (Total theory:.) Harvard Reviews of Psychiatry, 3:241-253, 1996; American Journal of Psychiatry, 148:1301-1308, 1991;Archives of General. Psychiatry, 52:998-1007, 1995. By emitting glutamic acid from a presynapsis, the agonist of alpha7 nicotinic receptor activates the neurotransmission system of glutamic acid which is falling, and is considered to improve the condition (a positive symptom, negative symptoms, cognitive dysfunction, etc.) seen by people with schizophrenia. Thus, alpha7 nicotinic receptor is considered that a possibility of being concerned with the site of action of the remedy of schizophrenia is high. [0005]From what alpha7 nicotinic receptor exists also in the reward system considered to participate in dependence of smoking. The agonist of alpha7 nicotinic receptor to control of smoking. It may ****** (Trends in Neurosciences, 22:555-561, 1999; NeuroReport, 10:697-702, 1999; Neurosciences, 85:1005-1009, 1998). From these things, alpha7 nicotinic-receptor agonist or alpha7 nicotinic-receptor partial agonist, An Alzheimer disease, cognitive dysfunction, attention deficit hyperactivity disorder, insecurity, depression, It is thought that it is useful as a remedy or preventive medicines, such as schizophrenia, epilepsy, a pain, a Tourette's syndrome, a Parkinson Mr. disease, and a Huntington disease, and has an advantage as compared with the compound which is alpha4beta2 nicotinic-receptor agonist. Therefore, agonist or partial agonist alternative to alpha7 nicotinic receptor is desirable. Since these drugs have a neuroprotective action, its cholinergic nerve transfer is useful also as the therapy or prevention of the neurodegenerative disease which has caused abnormalities. It can be used for urging control of smoking. EFFECT OF THE INVENTION [Effect of the Invention]It has alpha7 nicotinic-receptor operation operation alternative [ the salt which can be permitted on the compound of general formula (I) an optical isomer, or its medicine ], and powerful, or alpha7 nicotinic-receptor partial operation operation, An Alzheimer disease, cognitive dysfunction, attention deficit hyperactivity disorder, insecurity, depression, Remedies, such as schizophrenia, epilepsy, a pain, a

Tourette's syndrome, a Parkinson Mr. disease, and a Huntington disease, or a preventive medicine, and cholinergic nerve transfer are effective as the remedy or the preventive medicine, and also non-smoking medicine of the neurodegenerative disease which has caused abnormalities. this invention compound is excellent in oral absorbency and brain internal transmigration nature, and has the characteristic good as central nervous system medicine. 1.This document has been translated by computer. So the translation may not reflect the original precisely. 2.**** shows the word which can not be translated. 3.In the drawings, any words are not translated. TECHNICAL PROBLEM [Problem to be solved by the invention]This invention has powerful alpha7 nicotinicreceptor operation operation or alpha7 nicotinic-receptor partial operation operation, An Alzheimer disease, cognitive dysfunction, attention deficit hyperactivity disorder, insecurity, depression, It is in providing remedies, such as schizophrenia, epilepsy, a pain, a Tourette's syndrome, a Parkinson Mr. disease, and a Huntington disease, or a preventive medicine, the remedy of a neurodegenerative disease in which cholinergic nerve transfer has caused abnormalities or a preventive medicine, and the still more useful new molecular entity as a non-smoking medicine CLAIMS [Claim(s)] [Claim 1]General formula (I) [Chemical formula 1]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. A salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 2]A salt which a 2 cyclic aromatic heterocycle can permit on the 1-azabicyclo alkane compound according to claim 1 which is benzothiophene, benzofuran, benzothiazole, or benzimidazole, its optical isomer, or its medicine. [Claim 3]A salt which can be permitted on the 1-azabicyclo alkane compound according to claim 1 chosen from the following compounds, its optical isomer, or its medicine. (1) 3-. (.) (Benzo[b] thiophene 2-yl) Methoxy-1-azabicyclo [2.2.2] octane (2) (R)-3(benzo[b] thiophene 2-yl) (methoxy)-1-azabicyclo [2.2.2] octane (3) and (S)-3-. (.) (Benzo[b] thiophene 2-yl) methoxy-1-azabicyclo [2.2.2] octane (4)3-(benzo[b]

thiophene 3-yl) (methoxy)-1-azabicyclo [2.2.2] octane (5) 3-(2-naphthyl) (methoxy)-1azabicyclo [2.2. . 2] octane. (6) 3-. (.) (1-naphthyl) Methoxy-1-azabicyclo [2.2.2] octane (7)3-(2-(benzo[b] thiophene 2-yl) ethyl)-1-azabicyclo [2.2.2] octane (8) and (+)-3-(2(benzo[b] thiophene 2-yl) ethyl)-1-. Azabicyclo [2.2.2] octane. (9) (-)-3-(2-(benzo[b] thiophene 2-yl) ethyl)-1-azabicyclo [2.2.2] octane (10) 3-(2-(benzo[b] thiophene 2-yl)2-oxo ethyl)-1-azabicyclo [2.2.2] octane (one.) 1). (+)-3-. (2-.) (Benzo[b] thiophene 2yl)-2-oxo ethyl-1-azabicyclo [2.2.2] octane (12)(-)-3-(2-(benzo[b] thiophene 2-yl)-2-oxo ethyl)-1-azabicyclo [2.2.2] octane. (13) 3-. (2-.) (Benzothiazole 2-yl)-2-oxo ethyl-1azabicyclo [2.2.2] octane (14) 3-(2-(1-methylbenzimidazole 2-yl)-2-oxo ethyl)-1azabicyclo [2.2.2] octane. (15) 3-. (2-.) (Benzo[b] franc 2-yl)-2-Oxo ethyl-1-azabicyclo octane [ [2.2.2] ] (16) 3-(benzo[b] thiophene 2-yl) (methyl)-1-azabicyclo [2.2.2] octane (17) 3-. (.) (Benzo[b] thiophene 2-yl) Carbonyl-1-azabicyclo octane [ [2.2.2] ] (18) 3-(3(benzo[b] thiophene 2-yl) propyl)-1-azabicyclo [2.2.2] octane (19) 3-. (3-(benzo[b] thiophene 2-yl)-3-oxo propyl)-1-azabicyclo [2.2.2] octane [Claim 4]General formula (I) [Chemical formula 2]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. Ligand of alpha7 nicotinic receptor which consists of a salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 5]General formula (I) [Chemical formula 3]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. 1azabicyclo alkane compound expressed, alpha7 nicotinic-receptor agonist or alpha7 nicotinic-receptor partial agonist which consists of a salt which can be permitted on the optical isomer or its medicine. [Claim 6]General formula (I) [Chemical formula 4]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. Cognitive obstacle improvement medicine which consists of a salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 7]General formula (I) [Chemical formula 5]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. An antidementia drug which consists of a salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 8]General formula (I) [Chemical formula 6]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. A schizophrenia remedy which consists of a salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 9]General formula (I) [Chemical formula 7]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. Negative-symptoms improvement medicine for schizophrenia which consists of a salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 10]General formula (I) [Chemical formula 8]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. An attention deficit hyperactivity disorder remedy which consists of a salt which can be permitted on 1-azabicyclo alkane compound expressed, its optical isomer, or its medicine. [Claim 11]General formula (I) [Chemical formula 9]

(Among a formula, X do not exist or show O, S, or NH.) Y shows CH2 or C=O. m shows 1 or 2. n shows an integer of 0, or 1-3. Ar shows a naphthyl group which may have a 2 cyclic aromatic heterocycle which may have a substituent, or a substituent. A drug for Alzheimer's disease which consists of a salt which can be permitted on 1azabicyclo alkane compound expressed, its optical isomer, or its medicine.