US00821 1907B2

(12) United States Patent (10) Patent No.: US 8,211,907 B2 Hayashibe et al. (45) Date of Patent: Jul. 3, 2012

(54) FUSED INDANE COMPOUND OTHER PUBLICATIONS (75) Inventors: Satoshi Hayashibe, Tokyo (JP); Shingo Finsinger et al. CAS: 145:292878, 2006.* Yamasaki, Tokyo (JP); Nobuyuki Bhattacharya, et al., “Synthesis and Stereochemical Studies on the Reduction of Some Pyrrole Derivatives”. J. Chem. Soc., Perkin Shiraishi, Tokyo (JP); Hiroaki Hoshii, Trans. 1 (1984) 5-13. Tokyo (JP): Takahiko Tobe, Tokyo (JP) DeWit, et al., “cis-Fused hexahydro-4aH-indenol 1.2-bipyridines: transformation of bridgehead ester group and conversion to tricyclic (73) Assignee: Astellas Pharma Inc., Tokyo (JP) analogues or NK-1 and dopamine receptor ligands'. Tetrahedron Letters, vol. 42, No. 29 (2001) 4919-22. (*) Notice: Subject to any disclaimer, the term of this Froimowitz, "Conformational Analysis of Cocaine, the Potent Ana patent is extended or adjusted under 35 log 2B-Carbomethoxy-3B-(4-Fluorophenyl) Tropane (CFT), and U.S.C. 154(b) by 116 days. Other Dopamine Reuptake Blockers', Journal of Computational Chemistry, vol. 14, No. 8 (1993) 934-43. (21) Appl. No.: 12/741,307 Mach, et al., “Development of Novel 1,2,3,4-Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective (22) PCT Filed: Nov. 26, 2008 Dopamine D3 Receptor Ligands', ChemBioChem, vol. 5, No. 4 (2004) 508-18. (86). PCT No.: PCT/UP2008/071370 Maiti, et al., “Role of Remote Heteroatoms and Nature of the Reduc S371 (c)(1), ing Agents on the Stereochemical Course of Reductions of the Car (2), (4) Date: May 4, 2010 bon-Nitrogen T-Bond of a New Class of Tetrohydropyridines”. J. Chem. Soc., Perkin Trans. 1 (1988) 611-21. (87) PCT Pub. No.: WO2009/069610 Parcell, et al., “The Preparation of Tetrahydropyridines from Enamines and Imines”. J. Org. Chem... vol. 28, No. 12 (1963)3468 PCT Pub. Date: Jun. 4, 2009 73. Terada, et al., “Comprehensive Analysis of Quantitative Structure (65) Prior Publication Data Activity Relationships of Catecholamine-Uptake Inhibitors'. Quant. US 2010/O267695A1 Oct. 21, 2010 Struc. Act. Relat., vol. 10, No. 2 (1991) 118-25. Van Emelen, et al., “Synthesis of cis-fused hexahydro-4aH (30) Foreign Application Priority Data indeno. 1.2-bipyridines via intramolecular Ritter reaction and their conversion into tricyclic analogues of NK-1 and dopamine receptor Nov. 28, 2007 (JP) ...... 2007-307753 ligands'. Tetrahedron, vol. 58, No. 21 (2002) 4225-36. * cited by examiner (51) Int. Cl. A6 IK3I/44 (2006.01) Primary Examiner — Rei-tsang Shiao CO7D 22/06 (2006.01) (74) Attorney, Agent, or Firm — Fitzpatrick, Cella, Harper & (52) U.S. Cl...... 514/290; 546/79 Scinto (58) Field of Classification Search ...... 514,290: 54.6/79 (57) ABSTRACT See application file for complete search history. To provide a compound which is useful as an NMDA receptor (56) References Cited antagonist. The present inventors have studied a compound having an NMDA receptor antagonistic action, and con U.S. PATENT DOCUMENTS firmed that the fused indane compound of the present inven 5,574,060 A * 1 1/1996 Rothman et al...... 514,411 tion has an excellent NMDA receptor antagonistic action, 2007/O197594 A1 8/2007 Hayashibe et al. thereby completed the present invention. The fused indane 2009.0118267 A1 5/2009 Finsinger et al. compound of the present invention has an excellent NMDA FOREIGN PATENT DOCUMENTS receptor antagonistic action and can be used as a prophylactic JP 9-504514 5, 1997 and/or therapeutic agent for Alzheimer's disease, cerebrovas RU 227988O T 2006 cular dementia, Parkinson's disease, intractable depression, WO OOf 11952 3, 2000 attention deficit hyperactivity disorder, migraines, or the like. WO 2006/033318 3, 2006 WO 2006/094602 9, 2006 17 Claims, No Drawings US 8,21 1907 B2 1. 2 FUSED INDANE COMPOUND safety margin is desired (Ditzler K., Arzneimittelforschung, 41 (1991) 773-780; Maier C., Pain, 103 (2003) 277-283; This application is a 371 of PCT Application No. PCT/ Riederer P. Lancet, 338 (1991) 1022-1023). It is expected JH2008/071370 filed Nov. 26, 2008. that creation of such an NMDA receptor antagonist Superior in terms of a broader safety margin may bring about new TECHNICAL FIELD clinical usefulness of the NMDA receptor antagonist. It is known that a cyclic amine derivative represented by the The present invention relates to a pharmaceutical, particu following formula has an NMDA receptor antagonistic action larly a fused indane compound which is useful as an NMDA and is useful for treating and preventing Alzheimer's disease, receptor antagonist. 10 cerebrovascular dementia, Parkinson's disease, ischemic apoplexy, or pain (Patent Document 1). However, this docu BACKGROUND ART ment neither discloses nor Suggests the fused indane com Glutamic acid acts as a neurotransmitter in the central pound according to the present invention. nervous system of mammals, and controls the activity of 15 neurocytes or the release of neurotransmitters via a glutamate Chem. 1 receptor existing in synapses. At present, a glutamate receptor A is classified into an ionotropic receptor and a metabotropic Yl x11 receptor from many pharmacological and physiological stud R3 ies (Hollmann M. and Heinemann S., Annu. Rev. Neurosci. RI 17 (1994) 31-108). An NMDA (N-methyl-D-aspartic acid) R4 G 2 receptor is an ionotropic glutamate receptor specifically sen R5 X2 R sitive to the NMDA as an agonist (Moriyoshi K., Nature, 354 R6 (1991)31-37; Meguro H., Nature,357 (1992)70-74); and has high Ca" ion permeability (Iino M., J. Physiol. 424 (1990) 25 (For the symbols in the formula, refer to this document). 151-165). The NMDA receptor is expressed with a specific Further, it is known that a compound represented by the pattern in the central nervous system (Ozawa S. Prog. Neu following formula has anticancer activities (Patent Document robiol., 54 (1998) 581-618). 2). However, there is neither disclosure nor Suggestion on its From many pharmacological and biological studies, it is NMDA receptor antagonistic action, nor its usefulness for believed that an NMDA receptor is involved in higher nerve 30 treating Alzheimer's disease, cerebrovascular dementia, Par activities such as memory, learning, and the like (Morris R. kinson's disease, ischemic apoplexy, pain, or the like accord G., Nature, 319 (1986) 774-776: Tsien J. Z., Cell, 87 (1996) ing to the present invention. 1327-1338). On the other hand, it is suggested that the acute or chronic enhancement or inhibition of the NMDA receptor 35 activity relates to various nervous system diseases, for Chem. 2 example, ischemic apoplexy, hemorrhagic brain disorder, traumatic brain disorder, neurodegenerative disorders (Alzheimer's disease, cerebrovascular dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral Sclerosis, and the like), glaucoma, AIDS encephalopathy, dependence, 40 Schizophrenia, depression, mania, stress-related diseases, epilepsy, pain, and the like (Beal M. F., FASEB.J., 6 (1992) 3338-3344; Heresco-Levy U. and Javitt D.C., Euro. Neurop sychopharmacol., 8 (1998) 141-152; Hewitt D. J., Clin. J. Pain, 16 (2000) S73-79). Accordingly, it is thought that drugs 45 capable of controlling the activity of an NMDA receptor would be extremely useful in clinical application. Furthermore, it is Suggested that a compound represented As drugs capable of controlling the activity of an NMDA by the following formula is a ligand for a dopamine D3 receptor, a large number of non-competitive NMDA receptor receptor and relates to the diseases regarding central nerves antagonists are reported, but many of them have not been used 50 (Non-Patent Document 1). However, this document neither in clinical application because of their side effects based on discloses nor Suggests the fused indane compound according the NMDA receptor-antagonizing effect thereof, for to the present invention. example, mental aberrations such as hallucinations and con fusion, giddiness and the like. It has been tried to apply some of the conventional NMDA receptor antagonists, for 55 example, ketamine and dextromethorphan, against pain or the like in clinical application (Fisher K. J. Pain Symptom Man age. 20 (2000) 358-373). However, their safety margin in treatments is narrow, and their clinical use is limited (Fide P. K. Pain, 58 (1994)347-354). Also, memantine is known as a 60 non-competitive NMDA receptor antagonist that has com paratively few side effects (Parsons C. G., Neuropharmacol., 38 (1999) 735-767); and recently, it has been reported that it is effective for Alzheimer's disease (Reisberg B., N. Engl. J. Med.,348 (2003) 1333-1341). However, the safety margin of 65 rO memantine as a medicine is still not satisfactory, and devel opment of an NMDA receptor antagonist having a broader US 8,21 1907 B2 3 4 Further, an indeno1.2-bipyridine compound in which a DISCLOSURE OF INVENTION phenyl group is Substituted at the 9b-position is known as a ligand for NK-1 and dopamine receptors (Non-Patent Docu Problem that the Invention is to Solve ment 2 and Non-Patent Document 3). However, this docu ment neither discloses nor Suggests the fused indane com 5 A pharmaceutical having an NMDA receptor antagonistic pound according to the present invention. action, in particular, a compound which is useful as a prophy In addition, an indeno1,2-bipyridine compound in which lactic and/or therapeutic agent for Alzheimer's disease, cere a phenyl group is Substituted at the 5-position is known (Non brovascular dementia, Parkinson's disease, ischemic apo plexy, pain, intractable depression, attention deficit Patent Document 4). However, this document neither dis 10 closes nor Suggests the fused indane compound according to hyperactivity disorder, migraines, schizophrenia, generalized the present invention. anxiety disorder, obsessive-compulsive disorder, autism, Also, it is suggested that a compound represented by the bulimia, drug addiction, or the like, is provided. following formula has a catecholamine uptake inhibitory Means for Solving the Problem action and can be used as an anti-depressant or an anti-Par 15 kinson's disease drug (Non-Patent Document 5). However, The present inventors have studied a compound having an this document neither discloses nor Suggests the fused indane NMDA receptor antagonistic action, and found that the fused compound according to the present invention. indane compound of the present invention has an NMDA receptor antagonistic action, thereby completed the present invention. Chem. 4 That is, the following is provided by the present invention. (1) A compound of the formula (I) or a pharmaceutically acceptable salt thereof: 25 OX Chem. 6 R3 (I) R2 NN (X), (R') f X2 (In the formula, R represents —H or methyl). XI R4 Furthermore, two compounds below are known on the database as CAS registry numbers 1220-39-9 and 97555-62 (wherein, 9. Ring A represents a benzene ring or a thiophene ring, R" represents C, alkyl which may be substituted with one 40 or more groups selected from the group consisting of —OH, Chem. 5 —O—C alkyl, amino which may be substituted with one or two C- alkyl, and oxo; —O—C alkyl; halogen; cyano; or cyclic amino, in represents an integer of 0 to 4 in the case where Ring A 45 represents a benzene ring, and represents an integer of 0 to 2 OS in the case where Ring. A represents a thiophene ring, R represents —H or C alkyl, R represents C, alkyl which may be substituted with phenyl, cycloalkyl, or —H. O R" represents C, alkyl which may be substituted with one or more groups selected from the group consisting of —OH, Patent Document 1 Pamphlet of International Patent Publi —O—C alkyl, amino which may be substituted with one or cation WO 2006/033318 two Ce alkyl, oxo, and cyclic amino; cycloalkyl, aryl; or - OH, Patent Document 2 Pamphlet of International Patent Publi X' represents cation WO 2006/094602 CH(R) , Non-Patent Document 1 ChemBioChem, 2004, Vol. 5, No. X represents –C(R)(R)- or -O-, 4, pp. 508-518 X represents –C(R)(RP) , Non-Patent Document 2 Tetrahedron, 2002, Vol. 58, No. 21, m represents an integer of 1 to 3. pp. 4225-4236 60 R" represents —H, or R' is combined with R" to represent Cs alkylene, and, Non-Patent Document 3 Tetrahedron Letters, 2001, Vol. 42, R", R. R. and RP are the same as or different from each No. 29, pp. 4919-4922 other, and represent —H or C. alkyl, Non-Patent Document 4 Journal of Computational Chem wherein, in the case where m represents 2 or 3, each of R istry, 1993, Vol. 14, No. 8, pp. 934-943 65 and RP may be the same as or different from each other, Non-Patent Document 5 Quantitative Structure-Activity provided that 1-methyl-4-a-phenyl-2,3,4,4a,5.9b-hexahy Relationships, 1991, Vol. 10, No. 2, pp. 118-125 dro-1H-indeno1,2-bipyridine, 4a-phenyl-2,3,4,4a,5.9b US 8,21 1907 B2 5 6 hexahydro-1H-indeno1,2-bipyridine, and 2-(1,2,3,4,5,9b pyridine, or (4aS.9bS)-4a,9b-dimethyl-2,3,4,4a,5.9b hexahydro-4aH-indeno1,2-bipyridin-4a-yl)-N,N- hexahydro-1H-indeno1.2-bipyridine, or a pharmaceutically dimethylethaneamine are excluded. acceptable salt thereof. The same shall apply hereinafter.) (12) A pharmaceutical composition comprising the com (2) The compound or a pharmaceutically acceptable salt pound or a pharmaceutically acceptable salt thereof of (1), thereof of (1), wherein Ring A is a benzene ring. and a pharmaceutically acceptable excipient. (3) The compound or a pharmaceutically acceptable salt (13) A pharmaceutical composition for treating Alzhe thereof of (1), wherein Ring A is a thiophene ring. imer's disease, cerebrovascular dementia, Parkinson's dis (4) The compound or a pharmaceutically acceptable salt ease, ischemic apoplexy, pain, intractable depression, atten thereof described in either of (2) or (3), wherein X" is 10 tion deficit hyperactivity disorder, migraines, Schizophrenia, CH2—, X is —CH2—, X is —CH2—, and m is 2. generalized anxiety disorder, obsessive-compulsive disorder, (5) The compound or a pharmaceutically acceptable salt autism, bulimia, or drug addiction, which comprises the com thereof of (4), wherein R is C, alkyl which may be substi pound or a pharmaceutically acceptable salt thereof of (1), or tuted with one or more groups selected from the group con 4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyri sisting of —OH, -O-C alkyl, amino which may be Sub 15 dine or a pharmaceutically acceptable salt thereof, and a stituted with one or two C- alkyl, oxo, and cyclic amino. pharmaceutically acceptable excipient. (6) The compound or a pharmaceutically acceptable salt (14) The pharmaceutical composition of (13), which is a thereof of (5), wherein R is methyl, ethyl, isopropyl, meth pharmaceutical composition for treating Alzheimer's dis oxymethyl, or ethoxymethyl. ease, cerebrovascular dementia, Parkinson's disease, intrac (7) The compound or a pharmaceutically acceptable salt table depression, attention deficit hyperactivity disorder, or thereof of (6), wherein R is H. methyl, or ethyl. migraines. (8) The compound or a pharmaceutically acceptable salt (15) Use of the compound or a pharmaceutically accept thereof of (7), wherein R is - H or methyl. able salt thereof of (1), or 4a-phenyl-2,3,4,4a,5.9b-hexahy (9) The compound or a pharmaceutically acceptable salt dro-1H-indeno1,2-bipyridine or a pharmaceutically accept thereof of (8), wherein n is 0. 25 able salt thereof, for the manufacture of a pharmaceutical (10) The compound or a pharmaceutically acceptable salt composition for treating Alzheimer's disease, cerebrovascu thereof of (1), which is (4aRS.9bRS)-4a-methyl-2,3,4,4a,5. lar dementia, Parkinson's disease, ischemic apoplexy, pain, 9b-hexahydro-1H-indeno1.2-bipyridine, (4aRS.9bRS)-1, intractable depression, attention deficit hyperactivity disor 4a-dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1.2-bpy der, migraines, Schizophrenia, generalized anxiety disorder, ridine, (4aRS.9bRS)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H 30 obsessive-compulsive disorder, autism, bulimia, or drug indeno1.2-bipyridine, (4aR.9bR)-4a-methyl-2,3,4,4a,5.9b addiction. hexahydro-1H-indeno1,2-bipyridine, (4aS.9bS)-4a-methyl (16) The use of (15), wherein the pharmaceutical compo 2.3.4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS, sition for treating Alzheimer's disease, cerebrovascular 9bSR)-4a-isopropyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1, dementia, Parkinson's disease, ischemic apoplexy, pain, 2-bipyridine, (4aR.9bR)-4a-ethyl-2,3,4,4a,5.9b-hexahydro 35 intractable depression, attention deficit hyperactivity disor 1H-indeno1,2-bipyridine, (4aS.9bS)-4a-ethyl-2,3,4,4a.5, der, migraines, Schizophrenia, generalized anxiety disorder, 9b-hexahydro-1H-indeno1.2-bipyridine, (4aRS.9bRS)-8- obsessive-compulsive disorder, autism, bulimia, or drug methoxy-1,4a-dimethyl-2,3,4,4a,5.9b-hexahydro-1H addiction is a pharmaceutical composition for treating Alzhe indeno1.2-bipyridine, (4aRS.9bRS)-4a,9b-dimethyl-2,3,4, imer's disease, cerebrovascular dementia, Parkinson's dis 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS, 40 ease, intractable depression, attention deficit hyperactivity 9bRS)-4a-(ethoxymethyl)-2,3,4,4a,5.9b-hexahydro-1H disorder, or migraines. indeno1.2-bipyridine, (3bRS,7aRS)-2,7a-dimethyl-4,5,6,7, (17) A method for treating Alzheimer's disease, cere 7a, 8-hexahydro-3bH-thieno 2',3':4.5 cyclopenta 1.2-b brovascular dementia, Parkinson's disease, ischemic apo pyridine, (4aRS.9bRS)-4a-(methoxymethyl)-9b-methyl-2,3, plexy, pain, intractable depression, attention deficit hyperac 4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS, 45 tivity disorder, migraines, Schizophrenia, generalized anxiety 10bSR)-4a-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzoh disorder, obsessive-compulsive disorder, autism, bulimia, or quinoline, (5aRS, 10bSR)-5a-methyl-1,2,3,4,5,5a,6,10b drug addiction, comprising administering to a patient an octahydroindeno 1.2-blazepine, (4aRS.9bRS)-4a-ethyl-2,3, effective amount of the compound or a pharmaceutically 4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridin-8-yl) acceptable salt thereof of (1), or 4a-phenyl-2,3,4,4a,5.9b methanol, (4aRS.9bRS)-4a-methyl-1,2,3,4,4a,9b-hexahydro 50 hexahydro-1H-indeno1,2-bipyridine or a pharmaceutically 1)benzothieno 3.2-bipyridine, (4aR.9bR)-4a,9b-dimethyl acceptable salt thereof. 2.3.4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, or (4aS, (18) The method for treating of (17), which is a method for 9bS)-4a,9b-dimethyl-2.3.4.4a.5.9b-hexahydro-1H-indeno treating Alzheimer's disease, cerebrovascular dementia, Par 1.2-bipyridine, or a pharmaceutically acceptable salt kinson's disease, intractable depression, attention deficit thereof. 55 hyperactivity disorder, or migraines. (11) The compound or a pharmaceutically acceptable salt Further, the present invention relates to a pharmaceutical thereof of (1), which is (4aRS.9bRS)-4a-methyl-2,3,4,4a,5. composition for treating Alzheimer's disease, cerebrovascu 9b-hexahydro-1H-indeno1.2-bipyridine, (4aR.9bR)-4a-me lar dementia, Parkinson's disease, ischemic apoplexy, pain, thyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, intractable depression, attention deficit hyperactivity disor (4aS.9bS)-4a-methyl-2,3,4,4a,5.9b-hexahydro-1H-indeno 60 der, migraines, Schizophrenia, generalized anxiety disorder, 1.2-bipyridine, (4aRS.9bRS)-4a-ethyl-2,3,4,4a,5.9b obsessive-compulsive disorder, autism, bulimia, drug addic hexahydro-1H-indeno1,2-bipyridine, (4aR.9bR)-4a-ethyl tion, or the like, which contains the compound of the formula 2.3.4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aS, (I) or a pharmaceutically acceptable salt thereof. 1-methyl 9bS)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1.2-b 4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyri pyridine, (4aRS.9bRS)-4a,9b-dimethyl-2,3,4,4a,5.9b 65 dine or a pharmaceutically acceptable salt thereof, 4a-phenyl hexahydro-1H-indeno1,2-bipyridine, (4aR.9bR)-4a,9b 2.3.4.4a,5.9b-hexahydro-1H-indeno 1,2-bipyridine or a dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1.2-b pharmaceutically acceptable salt thereof, or 2-(1,2,3,4,5,9b US 8,21 1907 B2 7 8 hexahydro-4aH-indeno1,2-bipyridin-4a-yl)-N,N-dimethyl In the present specification, the “C. alkyl refers to a ethane amine or a pharmaceutically acceptable salt thereof. linear or branched alkyl having 1 to 6 carbon atoms, for Further, this pharmaceutical composition includes a thera example, methyl, ethyl, n-propyl, isopropyl. n-butyl, isobu peutic agent for Alzheimer's disease, cerebrovascular demen tyl, Sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. In tia, Parkinson's disease, ischemic apoplexy, pain, intractable another embodiment, it is C alkyl, in a further embodiment, depression, attention deficit hyperactivity disorder, methyl or ethyl, and in an even further embodiment, methyl. migraines, Schizophrenia, generalized anxiety disorder, The “Cs alkylene' refers to a linear or branched alkylene obsessive-compulsive disorder, autism, bulimia, drug addic having 3 to 5 carbon atoms, for example, trimethylene, tet tion, or the like, which contains the compound of the formula ramethylene, pentamethylene, 1-methylpropylene, 2-methyl (I) or a pharmaceutically acceptable salt thereof. 1-methyl 10 propylene, 1-methylbutylene, 2-methylbutylene, 1,1-dimeth 4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H-indeno 1,2-bipyri ylpropylene, 1.2-dimethylpropylene, 1,3- dine or a pharmaceutically acceptable salt thereof, 4a-phenyl dimethylpropylene, 1-ethylpropylene, and the like. In another 2.3.4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine or a embodiment, it is trimethylene, tetramethylene or pentameth pharmaceutically acceptable salt thereof, or 2-(1,2,3,4,5,9b 15 ylene, and in a further embodiment, tetramethylene. hexahydro-4aH-indeno1,2-bipyridin-4a-yl)-N,N-dimethyl The “cycloalkyl refers to a Cs saturated hydrocarbon ethane amine or a pharmaceutically acceptable Salt thereof. ring group, for example, cyclopropyl, cyclobutyl, cyclopen Further, the present invention relates to use of the com tyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. In pound of the formula (I) or a pharmaceutically acceptable salt another embodiment, it is Cs, cycloalkyl, in a further thereof. 1-methyl-4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H embodiment, cyclohexyl. indeno1.2-bipyridine or a pharmaceutically acceptable salt The “aryl is a C- a mono- to tricyclic aromatic hydrocar thereof, 4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2- bon ring group, for example, phenyl, naphthyl, and the like. In bipyridine or a pharmaceutically acceptable salt thereof, or another embodiment, it is phenyl. 2-(1,2,3,4,5,9b-hexahydro-4aH-indeno1,2-bipyridin-4a The “halogen' means —F. —Cl, —Br, or —I. yl)-N,N-dimethyl ethane amine or a pharmaceutically 25 The “cyclic amino' is a monovalent group having at least acceptable salt thereof for the manufacture of a therapeutic one nitrogenas a ring-constituting atom, wherein the nitrogen agent for Alzheimer's disease, cerebrovascular dementia, has a binding arm, or a monovalent group of 3- to 10-mem Parkinson's disease, ischemic apoplexy, pain, intractable bered cyclic amine, which may further have at least one depression, attention deficit hyperactivity disorder, ring-constituting atom selected from nitrogen, oxygen, and migraines, Schizophrenia, generalized anxiety disorder, 30 Sulfur, for example, 1-aZetidinyl, 1-pyrrolidinyl, 1-piperidi obsessive-compulsive disorder, autism, bulimia, drug addic nyl, 1-azepanyl, morpholino, thiomorpholino. 1-piperazinyl, tion, or the like, and a method for treating Alzheimer's dis or the like. In another embodiment, it is 1-pyrrolidinyl or ease, cerebrovascular dementia, Parkinson's disease, 1-piperidinyl. ischemic apoplexy, pain, intractable depression, attention In the present specification, the “which may be substituted deficit hyperactivity disorder, migraines, schizophrenia, gen 35 represents unsubstituted or having 1 to 5 substituents. Fur eralized anxiety disorder, obsessive-compulsive disorder, ther, if it has a plurality of substituents, the substituents may autism, bulimia, drug addiction, or the like, comprising be the same as or different from each other. administering to a patient an effective amount of the com Certain embodiments regarding the compound according pound of the formula (I) or a pharmaceutically acceptable salt to the present invention will be described below. thereof. 1-methyl-4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H 40 (1) The compound in which Ring A is a benzene ring. Or in indeno1.2-bipyridine or a pharmaceutically acceptable salt another embodiment, the compound in which Ring A is a thereof, 4a-phenyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2- thiophene ring. bipyridine or a pharmaceutically acceptable salt thereof, or (2) The compound in which n is 0. Or in another embodi 2-(1,2,3,4,5,9b-hexahydro-4aH-indeno1,2-bipyridin-4a ment, the compound in which n is 1, and R' is C. alkyl or yl)-N,N-dimethyl ethane amine or a pharmaceutically 45 —O—C alkyl. acceptable salt thereof. (3) The compound in which R is —H or methyl. Or in another embodiment, the compound in which Ris—H. Orin Effects of the Invention a further embodiment, the compound in which R is methyl. (4) The compound in which R is H. methyl, or ethyl. Or The compound of the formula (I) or a pharmaceutically 50 in another embodiment, the compound in which Ris-H or acceptable salt thereof, or 4a-phenyl-2,3,4,4a,5.9b-hexahy methyl. Or in a further embodiment, the compound in which dro-1H-indeno1.2-bipyridine or a pharmaceutically accept R is —H. Or in an even further embodiment, the compound able salt thereof (which may be hereinafter referred to as “the in which R is methyl. compound according to the present invention' in some cases) (5) The compound in which R is C alkyl which may be has an NMDA receptor antagonistic action and thus can be 55 substituted with —O Calkyl. Or in another embodiment, used as a prophylactic and/or therapeutic agent for Alzhe the compound in which R is C alkyl which may be sub imer's disease, cerebrovascular dementia, Parkinson's dis stituted with —O C. alkyl. Or in a further embodiment, ease, ischemic apoplexy, pain, intractable depression, atten the compound in which R is methyl. Or in an even further tion deficit hyperactivity disorder, migraines, Schizophrenia, embodiment, the compound in which R is ethyl. Or in a still generalized anxiety disorder, obsessive-compulsive disorder, 60 further embodiment, the compound in which R is isopropyl. autism, bulimia, drug addiction, or the like. Or in an still even further embodiment, the compound in which R is methoxymethyl or ethoxymethyl. BEST MODE FOR CARRYING OUT THE (6) The compound in which X* is —CH2—, INVENTION (7) The compound in which X* is C(R)(R)—, and R' 65 and Rare both - H. Hereinafter, the present invention will be described in more (8) The compound in which X is C(R)(RP) , and R' detail. and Rare both -H, and m is 2. US 8,21 1907 B2 9 10 (9) The compound which is a combination of at least two depending on the kind of the Substituents, and these salts are groups as described in (1) to (8) above. included in the present invention, as long as they are pharma Specific examples of the compound included in the present ceutically acceptable salts. Specifically, examples thereof invention include the following compounds: include acid addition salts with inorganic acids such as hydro (4aRS.9bRS)-4a-methyl-2,3,4,4a,5.9b-hexahydro-1H-in chloric acid, hydrobromic acid, hydroiodic acid, Sulfuric deno1,2-bipyridine, (4aRS.9bRS)-1,4-a-dimethyl-2,3,4,4a, acid, nitric acid, phosphoric acid, and the like, and with 5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS.9bRS)- organic acids such as formic acid, acetic acid, propionic acid, 4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno 1.2-b oxalic acid, malonic acid, Succinic acid, fumaric acid, maleic pyridine, (4aR.9bR)-4a-methyl-2,3,4,4a,5.9b-hexahydro acid, lactic acid, malic acid, mandelic acid, tartaric acid, 1H-indeno1,2-bipyridine, (4aS.9bS)-4a-methyl-2,3,4,4a.5, 10 dibenzoyl tartaric acid, ditolyl tartaric acid, citric acid, meth 9b-hexahydro-1H-indeno1.2-bipyridine, (4aRS.9bSR)-4a anesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, isopropyl-2,3,4,4a,5.9b-hexahydro-1H-indeno 1,2-b p-toluenesulfonic acid, aspartic acid, glutamic acid, and the pyridine, (4aR.9bR)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H like, and salts with inorganic bases such as Sodium, potas indeno1.2-bipyridine, (4aS.9bS)-4a-ethyl-2,3,4,4a,5.9b sium, magnesium, calcium, aluminum, and the like, and hexahydro-1H-indeno1,2-bipyridine, (4aRS.9bRS)-8- 15 organic bases such as methylamine, ethylamine, ethanola methoxy-1,4a-dimethyl-2,3,4,4a,5.9b-hexahydro-1H mine, lysine, ornithine, and the like, salts with various amino indeno1.2-bipyridine, (4aRS.9bRS)-4a,9b-dimethyl-2,3,4, acids, ammonium salts, and others. 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS, Additionally, the present invention also includes various 9bRS)-4a-(ethoxymethyl)-2,3,4,4a,5.9b-hexahydro-1H hydrates or Solvates, and polymorphism of the compound indeno1.2-bipyridine, (3bRS,7aRS)-2,7a-dimethyl-4,5,6,7, according to the present invention and a pharmaceutically 7a, 8-hexahydro-3bH-thieno 2',3':4.5 cyclopenta 1.2-b acceptable salt thereof. Furthermore, the present invention pyridine, (4aRS.9bRS)-4a-(methoxymethyl)-9b-methyl-2,3, also includes the compounds labeled with various radioactive 4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS, isotopes or non-radioactive isotopes. 10bSR)-4a-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzoh (Production Processes) quinoline, (5aRS, 10bSR)-5a-methyl-1,2,3,4,5,5a,6,10b 25 The compound according to the present invention and a octahydroindeno 1.2-blazepine.(4aRS.9bRS)-4a-ethyl-2,3, pharmaceutically acceptable salt thereof can be prepared by 4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridin-8-yl) applying various known synthetic methods, using the charac methanol, (4aRS.9bRS)-4a-methyl-1,2,3,4,4a,9b-hexahydro teristics based on their basic skeletons or the kinds of the 1)benzothieno 3.2-bipyridine, (4aR.9bR)-4a,9b-dimethyl Substituents. At this time, depending on the types of the func 2.3.4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, and 30 tional groups, it is in Some cases effective from the viewpoint (4aS.9bS)-4a,9b-dimethyl-2,3,4,4a,5.9b-hexahydro-1H-in of the preparation techniques to Substitute the functional deno1,2-bipyridine, and pharmaceutically acceptable salts group with an appropriate protecting group (a group which is of these compounds. capable of being easily converted into the functional group), The compound according to the present invention may in during the steps from starting materials to intermediates. Some cases exist in tautomers or geometrical isomers, 35 Examples of the protecting group include the protective depending on the kinds of the Substituents. In the present groups as described in “Protective Groups in Organic Syn specification, the compound according to the present inven thesis (3rd edition, 1999)', edited by Greene and Wuts, and tion may be described in only one form of isomers, but the the like, which may be appropriately selected and used present invention includes other isomers, isolated forms of depending on the reaction conditions. In these methods, a the isomers, or a mixture thereof. 40 desired compound can be obtained by introducing the pro Furthermore, the compound according to the present tecting group to carry out the reaction, and then, if desired, invention may have asymmetric carbon atoms or asymme removing the protecting group. tries in Some cases, and correspondingly, it may exist in the Furthermore, another compound according to the present isolated forms of optical isomers. The present invention invention can also be prepared by further carrying out a includes the isolated form of the optical isomer of the com 45 method well-known to a person skilled in the art, such as pound according to the present invention or a mixture thereof. common N-alkylation, reduction, oxidation, hydrolysis, and In addition, in the stereochemical expressions of a chemi the like for the compound according to the present invention. cal structure, the compound denoted as a racemic compound For example, another compound according to the present includes, in addition to the racemic compound itself isolated invention can also be prepared by carrying out a reaction forms of each optical isomer. For example, if it is denoted as 50 which can be employed for introduction of a group repre (4aRS.9bRS), in addition to the racemic having a relative sented by R other than —H onto nitrogen by a person configuration of (4aRS.9bRS), each of the optical active skilled in the art, Such as common N-alkylation reactions, products, a (4aR.9bR)-form and a (4aS.9bS)-form, and a reductive amination reactions, and the like, for the compound mixture thereof are included. (1c) or (1e) obtained in the first production process, the com Additionally, the pharmaceutically acceptable prodrugs of 55 pound (2d) obtained in the second production process, the the compound according to the present invention are also compound (3.c) obtained in third production process, or the included in the present invention. The pharmaceutically compound (4d) obtained in fourth production process. Fur acceptable prodrug refers to a compound having a group ther, the introduction of a group represented by Rother which can be converted into an amino group, a hydroxyl than —H onto nitrogen can be conducted at a step during group, a carboxyl group, or the like, by Solvolysis or under a 60 preparation of intermediates, or specifically, for example, the physiological condition. Examples of the groups for forming introduction can also be conducted at a step of the compound a prodrug include those as described in Prog. Med., 5, 2157 (3.b) or the compound (4c). 2161 (1985) or “Pharmaceutical Research and Development” Additionally, the prodrug of the compound according to (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design, the present invention can be prepared by introducing a spe 163-198. 65 cific group during the steps from starting materials to inter Furthermore, the compound according to the present mediates, in the same manner as for the above protecting invention may forman acid addition salt or a salt with a base, groups, or by carrying out the reaction using the obtained US 8,21 1907 B2 11 12 compound according to the present invention. The reaction be used herein is not particularly limited, but examples can be carried out by applying a method known by a person thereof include alcohols such as methanol, ethanol. 2-pro skilled in the art, Such as general N-alkylation, esterification, panol, and the like; water, aprotic polar solvents such as amidation, dehydration, and the like. N,N-dimethyl formamide, N,N-dimethylacetamide, N-meth Hereinbelow, typical production processes of the com- 5 ylpyrrolidone, dimethylsulfoxide, and the like; and a mixed pound according to the present invention will be described. solvent thereof. The reaction is carried out at a hydrogen Each of the production processes can also be carried out with atmosphere of 1 atm to 5 atm. reference to the documents appended to the description (Step 2-1) herein. Further, the production process of the present inven The present step is a step for preparing the compound tion is not limited to the examples as shown below. In addi 10 according to the present invention in which R is – H by tion, the compound according to the present invention having cyclizing the compound (1b) obtained in the step 1 by a a skeleton not included in the typical production processes reductive amination reaction. can be prepared based on the description in Preparative The reductive amination reaction is carried out by usually Examples and Examples as described later, or using a method stirring for 0.1 hour to 5 hours in a solventinert to the reaction in accordance with the description, or by a modified method 15 at-45° C. to heating under reflux, preferably at 0°C. to room thereof. temperature, in the presence of a reducing agent. The Solvent (First Production Process) to be used herein is not particularly limited, but examples

Chem. 7 O

(R) 2 pi XS (X)-CN3y - XI R (1a) cle O N 7 (R'), X2 (R'), (X)- 4 N?(X) v3 --CHNH2 X2W XI R X Y. (1b) (1d) Step 2. r 2-2

H H N- R24 N

2 2 XI X XI X R4 R4 (1c)

(The symbols in the formula represent the meanings as thereof include alcohols; ethers such as diethyl ether, tetrahy described above and R' represents C alkyl. The same shall drofuran, dioxane, dimethoxy ethane, diglyme, and the like; apply hereinafter.) 50 halogenated hydrocarbons such as dichloromethane, chloro The present production process is a method for preparing a form, carbon tetrachloride, dichloroethane, and the like; or compound (1c) or a compound (1e) by reducing a compound acetic acid; and a mixture thereof. Examples of the reducing (1a) and carrying out a reductive amination or alkyl addition agent include Sodium cyanoborohydride, Sodium triacetoxy reaction for the obtained compound (1b) or compound (1 d), borohydride, sodium borohydride, and the like. It is prefer respectively. 55 able in Some cases to carry out the reaction in the presence of (Step 1) a dehydrating agent such as molecular sieves, and the like or The present step is a step for Subjecting the compound (1a) an acid such as acetic acid, hydrochloric acid, a titanium (IV) to a reduction reaction, and either or both of two kinds of isopropoxide complex, and the like. Depending on the reac product, that is, the compound (1b) and the compound (1 d) tion, the compound may be isolated as an imine intermediate, may be obtained in Some cases. As a typical example of the 60 that is, as the compound (1 d) in some cases, and the com reduction reaction of the present step, a reduction reaction by pound (1 d) may be directly obtained in the step 1 in some hydrogenation with a Raney Nickel catalyst can be exempli cases. In Such a case, an imine product can be reduced by a fied. reducing agent such as sodium borohydride, lithium alumi The present reduction reaction is usually carried out by num hydride, and the like to obtain a desired compound (1c). stirring for 1 hour to 120 hours in a solventinert to the reaction 65 Further, instead of the treatment with a reducing agent, reduc from 0°C. to under heating, and preferably at 0°C. to room tion in accordance with the step 1 of the first production temperature, in the presence of a Raney nickel. The solvent to process, or a reduction reaction using palladium-Supported US 8,21 1907 B2 13 14 carbon instead of Raney nickel can be employed in a solvent addition reaction of ketone for the compound (1a), converting Such as alcohols, ethyl acetate, and the like in the presence or the hydroxyl group of the obtained compound (2a) into an absence of an acid such as acetic acid, hydrochloric acid and amino group, reducing the cyano group of the obtained com the like. pound (2b), and carrying out a reductive amination reaction (Step 2-2) 5 for the obtained compound (2c). The present step is a step for preparing the compound (Step 1) according to the present invention in which R is Coalkyl by The present step is a step for carrying out a reduction Subjecting the compound (1 d) obtained as an intermediate of reaction or alkyl addition reaction for the compound (1a). the step 1 or the step 2-1 to an alkyl addition reaction. The reduction reaction is carried out by allowing a reduc The alkyl addition reaction is carried out by allowing an o ing agent to undergo a reaction and usually stirring for 0.1 alkyladditive to undergo a reaction and usually stirring for 0.1 hour to 5 hours in a solventinert to the reaction from -78°C. hour to 5 hours in a solvent inert to the reaction from -78°C. to under heating, preferably at 0°C. to room temperature. to room temperature, preferably at -50° C. to 0°C., and if Examples of the solvent to be used herein include alcohols: necessary, in the presence of a Lewis acid. The solvent to be ethers; aromatic hydrocarbons; and a mixed solvent thereof. used herein is not particularly limited, but examples thereof is Examples of the reducing agent include Sodium borohydride, include ethers; Saturated hydrocarbons such as hexane, pen lithium borohydride, lithium aluminum hydride, and the like. tane, heptane, and the like; aromatic hydrocarbons such as The alkyl addition reaction can be carried out in the same benzene, toluene, Xylene, and the like; and a mixture thereof. manner as in the step 2-2 of the first production process. Examples of the alkylating agent include alkyl lithium (Step 2) reagents such as methyl lithium, butyl lithium, and the like; The present step is a step for converting the hydroxyl group Grignard reagents such as methyl magnesium bromide, ethyl of the compound (2a) obtained in the step 1 into an amino magnesium chloride, and the like, and examples of the Lewis group. Specifically, for example, an azidation reaction can be acid include a borontrifluoride diethyl ether complex, cerium carried out, and Subsequently a reduction reaction can be chloride, magnesium bromide, and the like. carried out for the compound (2a). (Second Production Process) 25 The azidation reaction is carried out by allowing anaZidat ing agent to undergo a reaction and usually stirring for 0.1 hour to 5 hours in a solvent inert to the reaction, in the Chem. 8 presence of an acid catalyst if necessary, and using an acid as O a solvent as occasion demands, from -45° C. to heating under 30 reflux, preferably at 0°C. to room temperature. The solvent to (R'), X2 be used herein is not particularly limited, but examples Y(x), CN Step 1 thereof include halogenated hydrocarbons: aprotic polar sol XI R4 vent; ethers; aromatic hydrocarbons; and a mixture thereof. Examples of the acid catalyst include trichloroacetic acid, (1a) 35 trifluoroacetic acid, a borontrifluoride diethyl ether complex, R2 OH and the like, and examples of the azidating agent include sodium azide, lithium azide, trimethylsilyl azide, and the like. (R) X2 Subsequently, the reduction reaction is carried out by Y(x)--CN Step 2 allowing a phosphine compound to undergo a reaction and X R4 40 usually stirring for 1 hour to 24 hours in a solvent inert to the reaction, from 0° C. to heating under reflux, preferably at (2a) room temperature. The solvent to be used herein is not par R NH ticularly limited, but examples thereof include alcohols; (R'), X2 ethers; and a mixed solvent thereof with water, and the like. YCX)--CN Step 3 45 Examples of the phosphine compound include triphenyl phosphine and tributyl phosphine. Further, this reduction XI R4 reaction can also be carried out by usually stirring for 1 hour (2b) to 24 hours in an inert solvent from 0° C. to heating under R NH reflux, preferably at room temperature, in the presence of a 50 catalytic reduction catalyst and a hydrogen Source. The Sol (R'), X2 vent to be used herein is not particularly limited, but examples YCX)-CHO SP'- thereof include alcohols; ethers; ethyl acetate, a mixed sol XI R4 vent thereof with water, and the like. Examples of the cata lytic reduction catalyst include palladium-Supported carbon, (2c) H 55 Raney nickel, platinum oxide, and the like, and examples of the hydrogen Source include hydrogen, ammonium formate, R2 s and the like, under ambient pressure to under pressure. Fur (R') X)- thermore, this reduction reaction can also be carried out by X2 allowing a reducing agent Such as lithium aluminum hydride, X Y. 60 and the like to undergo a reaction in ethers; aromatic hydro carbons as a solvent, from 0° C. to heating under reflux, (2d) preferably from room temperature to under warming. (Step 3) (The symbols in the formula represent the meanings as The present step is a step for Subjecting the compound (2b) described above. The same shall apply hereinafter.) 65 obtained in the step 2 to a reduction reaction. The present production process is a method for preparing a The reduction reaction is carried out by allowing a reduc compound (2d) by carrying out a reduction reaction or alkyl ing agent to undergo a reaction and usually stirring for 0.1 US 8,21 1907 B2 15 16 hour to 5 hours in a solvent inert to the reaction from -78°C. from 0°C. to heating under reflux in the presence of an acid. to room temperature, preferably at -50° C. to 0° C. The The solvent to be used herein is not particularly limited, but solvent to be used herein is not particularly limited, but examples thereof include acetic acid; acetic anhydride; examples thereof include ethers; aromatic hydrocarbons; and ethers; aliphatic hydrocarbons; halogenated hydrocarbons; a mixed solvent thereof. As the reducing agent, diisobutyla nitrobenzene; and a mixture thereof. Examples of the acid to luminum hydride is suitably used. be used include sulfonic acids or hydrates thereof such as (Step 4) methanesulfonic acid, p-toluenesulfonic acid, trifluo The present step is a step for preparing the compound romethanesulfonic acid, and the like; sulfuric acid; trifluoro according to the present invention by cyclizing the compound acetic acid; perchloric acid; phosphoric acid; polyphosphoric (2c) obtained in the step 3 by a reductive amination reaction. 10 acid; formic acid; and Lewis acids such as a borontrifluoride The reductive amination reaction can be carried out in the diethyl ether complex, trimethylsilyl triflate, and the like. same manner as in the step 2-1 of the first production process. (Step 3) (Third Production Process) The present step is a step for preparing the compound 15 according to the present invention by Subjecting the com pound (3.b) obtained in the step 2 to a reduction reaction. Chem.9) The reduction reaction is carried out by allowing a reduc O ing agent to undergo a reaction and usually stirring for 0.1 hour to 5 hours in a solventinert to the reaction from -20°C. (R'), X2 to heating under reflux, preferably from 0°C. to under heat Y(x),...-CN Step 1 ing. The solvent to be used herein is not particularly limited, XI R4 but examples thereof include ethers; aromatic hydrocarbons; (1a) and a mixed solvent thereof. Examples of the reducing agent R2 OH include lithium aluminum hydride, aborane/tetrahydrofuran 25 complex, Sodium bis(2-methoxyethoxy)aluminum hydride, (R'), X2 and the like. n (X)--CN Step'P 27 (Fourth Production Process) XI R4 30 Chem. 10 (3a) R2 H O Step 1 (R'), O SP (R'), R-(X)- Step 3 He XI R4 X2 35 X' Y4 (4a) 2 H O (3.b) R. S. Step 2 (R'), OH He v \ 40 Lw (R') X)- XI R4 X2 XI R4 (4b) 2 H O (3.c) R. S. 45 Step 3 (R'), He (The symbols in the formula represent the meanings as O described above. The same shall apply hereinafter.) X Y. The present production process is a method for preparing a (4c) compound (3.c) by reducing the compound (1a), carrying out 50 2 H a cyclization reaction under an acidic condition for the R. R. obtained compound (3a), and reducing the obtained com pound (3b). (R'), ) (Step 1) XI O The present step is a step for Subjecting the compound (1a) 55 R4 to a reduction reaction or an alkyl addition reaction. (4d) The reduction reaction or the alkyladdition reaction can be carried out in the same manner as in the step 1 of the second production process. (The symbols in the formula represent the meanings as (Step 2) 60 described above, and -LV represents a leaving group. The The present step is a step for carrying out a cyclization same shall apply hereinafter.) reaction under an acidic condition for the compound (3a) The present production process is a method for preparing obtained in the step 1. Specifically, a Ritter reaction can be the compound according to the present invention, in which X carried out for the compound (3a). is -O-, m is 2, X is C(R)(RP) , and R and RP are The Ritter reaction is carried out by usually stirring for 0.1 65 both—H, that is a compound (4d), by carrying out a coupling hour to 5 hours without a solvent or in a solvent inert to the reaction with a nitrile compound under an acidic condition for reaction from -45° C. to heating under reflux, preferably the compound (4a), Subjecting the obtained compound (4b) to US 8,21 1907 B2 17 18 a ring-closure reaction, and Subjecting the obtained com (Production Process 1 for Intermediate) pound (4c) to a reduction reaction. Further, examples of the leaving group include chloro, bromo, hydroxy, methanesulfonyloxy, p-toluenesulfonyloxy, Chem. 11 trifluoromethanesulfonyloxy, and the like. O Step 1 (Step 1) (R'), RC The present step is a step for carrying out a coupling reac R4 tion with a nitrile compound under an acidic condition for the X RS-2 compound (4a). Specifically, a Ritter reaction can be carried 10 (5a) CN out for the compound (4a). RB The Ritter reaction can be carried out in the same manner as (5b) in the step 2 of the third production process. Further, examples of the nitrile compound used herein 15 O include chloroacetonitrile, bromoacetonitrile, and hydroxy acetonitrile. (R) 2 pi XS (X)-CN3 - (Step 2) XI R The present step is a step for Subjecting the compound (4b) (1a) obtained in the step 1 to a ring-closure reaction. Further, in the case of using hydroxyacetonitrile in the step 1, according to the reaction to be carried out in the present (The symbols in the formula represent the meanings as step, the hydroxyl group of the compound (4b) may be con described above. The same shall apply hereinafter.) Verted into methanesulfonyloxy, p-toluenesulfonyloxy, trif 25 The present production process is a method for preparing luoromethanesulfonyloxy, or the like, and then subjected to the compound (1a) in which m is 1 and X is C(R)(R)— the reaction of the present step. by allowing the compound (5a) to undergo a reaction with a If the leaving group is chloro, bromo, methanesulfonyloxy, base, and Subjecting the compound (5b) to an addition reac p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, or the 30 tion. Further, in order to introduce R' which is other than like, specifically, for example, an O-alkylation reaction can be —H, the compound according to the present invention can be employed, whereas if the leaving group is hydroxy, specifi derived by reducing the carbonyl of the compound (1a), for cally, for example, a Mitsunobu reaction can be employed. example, by Substituting with methoxy by methylation and The O-alkylation reaction is carried out by usually stirring then introducing by alkylation into the C-position of nitrile, for 0.1 hour to 5 hours in a solvent inert to the reaction, from 35 Subjecting the product to a Ritter reaction according to the -20°C. to heating under reflux, preferably at 0°C. to room step 2 of the third production process, and following the step temperature in the presence of a base. The solvent to be used 3 of the third production process. herein is not particularly limited, but examples thereof include ethers; aromatic hydrocarbons; aprotic polar Sol (Step 1) vents: alcohols and a mixed solvent thereof. Examples of the 40 The present step is a step for allowing the compound (5a) to base include Sodium methoxide, potassium t-butoxide, undergo a reaction with a base and Subjecting the compound Sodium hydride, potassium hydroxide, cesium carbonate, and (5b) to an addition reaction. Specifically, a Michael addition the like. reaction can be carried out. The Mitsunobu reaction is carried out by usually stirring The Michael addition reaction is carried out by usually for 0.1 hour to 5 hours in a solvent inert to the reaction from 45 stirring with acrylonitriles for 0.1 hour to 5 hours in a solvent 0° C. to heating under reflux, preferably at 0° C. to room inert to the reaction from -20° C. to heating under reflux, temperature in the presence of a phosphorus compound and preferably at 0°C. to room temperature in the presence of a anaZodicarbonyl compound. The solvent to be used herein is base. The solvent to be used herein is not particularly limited, not particularly limited, but examples thereof include halo but examples thereof include ethers; aromatic hydrocarbons; genated hydrocarbons; ethers; aromatic hydrocarbons; and a 50 mixed solvent thereof. Examples of the phosphorus com aprotic polar solvents; alcohols and a mixed solvent thereof. pound include tributyl phosphine, triphenyl phosphine, and Examples of the base include sodium methoxide, potassium the like, and examples of the azodicarbonyl compound t-butoxide, Sodium hydride, potassium hydroxide, and the include diethylazodicarboxylate, 1,1'-(azodicarbonyl)dipip like. eridine, and the like. Instead of using an activator prepared 55 (Production Process 2 for Intermediate) from the phosphorus compound and the azodicarbonyl com pound, a reagent Such as cyanomethylenetributylphos phorane, and the like can also be used. Chem. 12 (Step 3) The present step is a step for preparing the compound 60 according to the present invention in which X is -O-, mis (R'), Step 1 2, X is C(R)(RP) , and R and RP are both – H by Subjecting the compound (4c) obtained in the step 2 to a reduction reaction. 65 The reduction reaction can be carried out in the same manner as in the step 3 of the third production process. US 8,21 1907 B2 19 20 -continued 7.5) added thereto, and centrifuged at 15000 g at 4°C. for 20 minutes. 50 mM Tris-HCl (pH 7.5) was again added to the pellets, and centrifuged in the same manner as before. The (R'), pellets were suspended in 20 ml of 50 mM Tris-HCl (pH 7.5) added thereto, and homogenized with the Teflon (registered trademark) homogenizer. The membrane specimen was dis pensed portionwise into tubes and stored in a deep freezer (1a) (-80° C.). For use, this was washed twice with 5 mM Tris (The symbols in the formula represent the meanings as HCl (pH 7.5) of five times the volume of the membrane described above. The same shall apply hereinafter.) 10 specimen. After controlling the concentration at 1 mg protein/ The present production process is a method for preparing ml with 5 mM Tris-HCl (pH 7.5), it was used for assay. the compound (1a) in which X is C(R)(R)—by allow 2) HMK-801 Binding Assay ing the compound (5a) to undergo a reaction with a base and 50 ul of the rat membrane specimen (1 mg protein/ml) was Subjecting the compound (5c) to an addition reaction. added to a solution of a test compound dissolved in 1 Jul of (Step 1) 15 dimethylsulfoxide. Then, 50 ul of a ligand solution (600 nM The present step is a step for allowing the compound (5a) to glutamate, 600 nM glycine, 8 nM H MK-801 (Perkin Elmer) was added thereto and well stirred, followed by the undergo a reaction with a base and Subjecting the compound reaction at room temperature for 45 minutes. Using Uni Filter (5c) to an addition reaction. Plate GF/B 96 (Perkin-Elmer) previously coated with 0.2% The addition reaction is carried out by usually stirring with polyethyleneimine, the membrane specimen was collected, halogenated alkyls having a cyano group or Sulfonyloxy and the filter was well washed with 5 mM Tris-HCl (pH 7.5). alkyls for 0.1 hour to 5 hours in a solvent inert to the reaction 30 ul of Microscinti 20 (Perkin-Elmer) was added to the filter, from -78°C. to heating under reflux, preferably from -78°C. and the radioactivity trapped on the filter was measured by a to room temperature in the presence of a base. The solvent to microplate scintillation counter (TopCountTM: Beckman). be used herein is not particularly limited, but examples Based on the MK-801 (final 1 uM) inhibition, 100%, of a thereof include ethers; aromatic hydrocarbons; aprotic polar 25 control case of dimethylsulfoxide alone, the concentration of solvents; alcohols and a mixed solvent thereof. Examples of the compound for 50% inhibition, ICso was computed. Inhi the base include Sodium methoxide, potassium t-butoxide, bition rate of MK-801 (final concentration: 1 uM) relative to Sodium hydride, potassium hydroxide, lithium diisopropyl the case in which dimethylsulfoxide alone was added was set amide, lithium hexamethyldisilazide, and the like. to 100%, the concentration in which the test compound The compound according to the present invention is iso 30 showed 50% inhibition rate was calculated as ICso. The H lated and purified as a free compound, pharmaceutically MK-801 binding affinity for the rat membrane specimen was acceptable salts thereof, hydrates, solvates, or polymorphism calculated to be Kd=1.6 nM through Scatchard analysis. The thereof. The pharmaceutically acceptable salt of the com Ki value of the compound was computed according to the pound according to the present invention can also be prepared calculation equation: Ki-ICso/(1+radioligand concentration in accordance with a conventional method for a salt formation 35 reaction. (4 nM) in assay)/Kd value (1.6 nM)). Isolation and purification are carried out by employing As a result, some of the compounds according to the general chemical operations such as extraction, fractional present invention exhibited binding affinity for an NMDA crystallization, various types of fractional chromatography, receptor with 10 uMorless of a Ki value in the test above. The and the like. results of some of Example compounds in the present test are Various isomers can be separated by selecting an appropri 40 shown in Table 1. ate starting compound or by making use of the difference in the physicochemical properties between isomers. For TABLE 1 example, the optical isomer can be obtained by general opti Example No. Ki?uM cal resolution methods of racemic compounds (for example, 45 1 O.9 fractional crystallization for inducing diastereomer salts with 3 1.2 optically active bases or acids, chromatography using a chiral 13 2.0 column and the like, and others) and can also be prepared 15 8.5 from an appropriate optically active starting compound. 17 2.0 22 S.1 The pharmacological activity of the compound according 50 32 6.8 to the present invention was confirmed by the following test. 38-1 O.S 38-2 6.3 Text Example 1 42 1.3 56 1.5 63 O.8 MK-801 Binding Test 55 68 O.6 69 1.3 1) Preparation of Specimens of Rat Meninges 73 7.1 The whole brain was taken out from 30 10-week SD rats 77 4.0 81 2.0 (Nippon SLC), and the cerebellum was removed. A 0.32 M 82 6.7 aqueous Sucrose solution was added to the part containing the 83-1 O.6 cerebrum, followed by cutting by a mixer and homogenizing 60 83-2 2.7 with a Teflon (registered trademark) homogenizer. After cen 84-1 O.S 84-2 1.1 trifugation at 2800 rpm at 4°C. for 15 minutes, the resulting Compound A 38 supernatant was again centrifuged at 15000 g at 4°C. for 20 Compound B 23 minutes. The pellets were suspended in 50 mM Tris-HCL (pH Compound C 2O 7.5) containing 0.08%TritonX-100, and kept statically on ice 65 Compound F 3.4 for 30 minutes, then centrifuged at 15000 g at 4°C. for 20 minutes. The pellets were suspended in 50 mM Tris-HCl (pH US 8,21 1907 B2 21 22 Further, in Table 1 and Text Examples below, Compound glucose, Ca", Mg"-free PBS), and treated at 37° C. for 15 A, Compound B, Compound C, and Compound F each rep minutes. This was centrifuged at 400 g for 5 minutes, and the resent (4aRS.9bRS)-2,3,4,4a,5.9b-hexahydro-1H-indeno1, Supernatant was removed by Suction. This was Suspended in 2-bipyridine, (4aRS.5RS.9bRS)-5-phenyl-2,3,4,4a,5.9b a neurocyte culture medium (Sumitomo Bakelite), and the hexahydro-1H-indeno1,2-bipyridine, (4aRS,5SR.9bRS)-5- cell masses were removed using a filter. The number of the phenyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, living cells was counted, and 100,000 cells/well were incu and (4aRS.9bRS)-1-methyl-4-a-phenyl-2,3,4,4a,5.9b bated on a 96-well plate (Biocoat PDL96W black/clear (Nip hexahydro-1H-indeno1,2-bipyridine, each of which is a pon Becton Dickinson)) (37°C., 5% CO). known compound having the following chemical structure. 2) Intracellular Calcium Concentration Determination by 10 FLIPR (Fluorometric Imaging Plate Reader) The culture medium of rat first-generation neurocytes Chem. 13 (DIV7-9) was removed by suction, and the cells were washed Compound A once with a 100 ul assay buffer (Hank's Balanced Salt Solu tion (Ca", Mg"-free), 20 mM Hepes-NaOH (pH 7.4), 1 mM 15 CaCl). 100 ul of the assay buffer containing Fluo3 (Dojin ... is ill) Chemical) was added thereto, and incubated for 1 hour (37° C., 5% CO). The cells were washed three times with 100 ul of the assay buffer, and thena compound Solution dissolved in Compound B 1 ul of dimethylsulfoxide, and 100 ul of the assay buffer containing 2.5 LLM (final concentration) tetrodotoxin were added thereto and incubated for 30 minutes (37°C., 5% CO). ').. The fluorescent intensity was measured at intervals of two seconds, and ten seconds after the measurement start, 50ll of a ligand solution (Hank's Balanced Salt Solution (Ca", 25 Mg"-free), 20 mM Hepes-NaOH (pH 7.4), 1 mM CaCl, 9 uMNMDA, 30 uM glycine) containing the compound solu tion dissolved in 0.5 ul of dimethylsulfoxide was added Compound C thereto, and the fluorescent intensity was measured for 120 seconds from the start of the measurement. The data mea 30 sured for total of 120 seconds (60 times in total) were aver aged. Inhibition rate of 10 uMMK-801 relative to the case in which dimethylsulfoxide alone was added was set to 100%, the concentration in which the compound showed 50% inhi bition rate was calculated as ICs. 35 As a result, some of the compounds according to the present invention exhibited an NMDA receptor antagonistic action with 100LM or less of IC values in the test above. The Compound F results of some of Example compounds in the present test are shown in Table 2. 40 TABLE 2 Example No. ICsom 1 S.1 45 3 6.8 22 34 63 3.0 81 21 82 94 83-1 3.1 50 83-2 12 84-1 1.8 Text Example 2 84-2 6.1 Intracellular Calcium Concentration Determination Test by FLIPR (Fluorometric Imaging Plate Reader) 55 Text Example 3 1) Preparation of Rat First-Generation Neurocytes MES (Maximal Electroshock Seizure) Inhibitory Anesthetized with ether, Wistar rats (Nippon SLC) at the Action 19th day of pregnancy were let die from blood loss by breast incision. The abdomen was cut open, and the womb was 60 A test compound was orally administered to a male ddy extracted, and the fetus was removed. The whole brain was mouse, an inhibitory action on the seizures caused by an removed, the hemicerebrum was then isolated in Neurobasal electroshock applied at 30 minutes later (Interval 10 ms. medium (Glu, Asp-free; Gibco), and the meninx was Duration 0.9 ms, Amplitude 50 mA, Gate 0.2s) was evalu removed. The hemicerebrum was recovered by centrifuga ated, and an NMDA receptor inhibitory action in vivo was tion, and Suspended in a cell-dispersing solution (0.36 mg/ml 65 measured (Palmer G. C. Harris E. W. Ray R. Stagnitto M L. papain, 150 U/ml DNase 1, 0.02% L-cysteine monohydro Schmiesing R J. Arch Int Pharmacodyn Ther. 1992 May chloride monohydrate, 0.02% bovine serum albumin, 0.5% June; 317: 16-34). US 8,21 1907 B2 23 24 As a result, some of the compounds according to the As the Solid composition for oral administration, tablets, present invention exhibited an anti-seizure action with an powders, granules, or the like are used. In Such a solid com EDso value of 50 mg/kg or less in the test above. The results position, one or two or more kinds of active ingredients are of Some of the Example compounds in the present test are mixed with at least one inert excipient such as lactose, man shown in Table 3. Further, known compounds Compound A nitol, glucose, hydroxypropylcellulose, microcrystalline cel and Compound F did not exhibit an anti-seizure action even at lulose, starch, polyvinyl pyrrolidone, and/or magnesium alu 80 mg/kg and 100 mg/kg, respectively. minometasilicate. According to a conventional method, the composition may contain inert additives such as a lubricant TABLE 3 Such as magnesium Stearate, a disintegrator Such as car 10 boxymethylstarch sodium, a stabilizing agent, and a solubi EDso Example No. mg/kg, po lizing agent. As occasion demands, the tablets or the pills may be coated with a Sugar coating, or a film of a gastric or enteric 1 6.8 material. 3 39 13 14 15 The liquid composition for oral administration includes 15 38 pharmaceutically acceptable emulsions, Solutions, Suspen 17 4.2 22 11 sions, syrups, elixirs, or the like, and contains a generally used 32 26 inert diluent such as purified water or ethanol. In addition to 42 31 the inert diluent, this liquid composition may contain an 63 5.8 auxiliary agent such as a solubilizing agent, a moistening 68 26 81 9.1 agent, and a Suspending agent, a Sweetener, a flavor, an 82 19 aroma, and an antiseptic. 83-1 6.2 The injections for parenteral administration include sterile 84-1 4.2 aqueous or non-aqueous liquid preparations, Suspensions and 84-2 28 Compound A >80 25 emulsions. The aqueous solvent includes, for example, dis Compound F >100 tilled water for injection and physiological Saline. Examples of the non-aqueous solvent include propylene glycol, poly ethylene glycol, plant oils such as olive oil, alcohols such as Text Example 4 ethanol, Polysorbate 80 (Japanese Pharmacopeia), and the 30 like. Such a composition may further contain atonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a Y-Maze Test Using Magnesium-Deficient Mouse dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized, for example, by filtration through a bac A learning disorder improvement action of a test com teria retaining filter, blending of a bactericide, or irradiation. pound on a learning disorder caused by magnesium defi 35 Additionally, these can also be used by preparing a sterile ciency (Bardgett ME, Schultheis PJ, McGill DL, Richmond Solid composition, and dissolving or Suspending it in Sterile R E. Wagge J. R. Magnesium deficiency impairs fear condi water or a sterile solvent for injection prior to its use. tioning in mice. Brain Res 2005: 1038:100-6.) can be evalu The agent for external use includes ointments, plasters, ated by a Y-maze test (Maurice T, Privat A. SA4503, a novel creams, jellies, cataplasms, sprays, lotions, eye drops, eye cognitive enhancer with al receptoragonist properties, facili 40 ointments, and the like. The agents contain generally used tates NMDA receptor-dependent learning in mice. EurJ Phar ointment bases, lotion bases, aqueous or non-aqueous liquid macol 1997; 328:9-18). preparations, Suspensions, emulsions, and the like. Examples As a result of the tests as described above, it was confirmed of the ointment bases or the lotion bases include polyethylene that the compound according to the present invention or a glycol, propylene glycol, white Vaseline, bleached bee wax, pharmaceutically acceptable salt thereof has an NMDA 45 polyoxyethylene hydrogenated castor oil, glyceryl receptor inhibitory action and thus can be used as a prophy monostearate, Stearyl alcohol, cetyl alcohol, lauromacrogol, lactic and/or therapeutic agent for Alzheimer's disease, cere Sorbitan Sesquioleate, and the like. brovascular dementia, Parkinson's disease, ischemic apo As the transmucosal agents such as an inhalation, a trans plexy, pain, intractable depression, attention deficit nasal agent, and the like, those in the form of a Solid, liquid, or hyperactivity disorder, migraines, Schizophrenia, generalized 50 semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known anxiety disorder, obsessive-compulsive disorder, autism, excipient, and also a pH adjusting agent, an antiseptic, a bulimia, drug addiction, or the like. Surfactant, a lubricant, a stabilizing agent, a thickening agent, A pharmaceutical composition containing one or two or or the like may be appropriately added thereto. For their more kinds of the compound according to the present inven 55 administration, an appropriate device for inhalation or blow tion as an active ingredient can be prepared in accordance ing can be used. For example, a compound may be adminis with a generally used method, using a pharmaceutical excipi tered alone or as a powder of formulated mixture, or as a ent, a pharmaceutical carrier, or the like, that is usually used Solution or Suspension in combination with a pharmaceuti in the art. cally acceptable carrier, using a conventionally known device The administration can be carried out in any form of oral 60 or sprayer, such as a measured administration inhalation administration via tablets, pills, capsules, granules, powders, device, and the like. A dry powder inhaler or the like may be liquid preparations, or the like; or parenteral administration for single or multiple administration use, and a dry powder or via injections such as intraarticular, intravenous, or intramus a powder-containing capsule may be used. Alternatively, this cular injections, Suppositories, eye drops, eye ointments, per may be in a form such as a pressurized aerosol spray which cutaneous liquid preparations, ointments, percutaneous 65 uses an appropriate propellant, for example, a Suitable gas patches, transmucosal liquid preparations, transmucosal Such as chlorofluoroalkane, hydrofluoroalkane, carbon diox patches, inhalations, and the like. ide, and the like, or other forms. US 8,21 1907 B2 25 26 In oral administration, the daily dose is generally from cooling, followed by stirring for 30 minutes, and acrylonitrile about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, (36.5 g) was then added dropwise thereto over 30 minutes. and more preferably 0.1 to 10 mg/kg, per body weight, The reaction liquid was further stirred for 30 minutes under administered in one portion or in 2 to 4 divided portions. In ice-cooling, and a saturated aqueous ammonium chloride the case of intravenous administration, the daily dose is Suit ably administered from about 0.0001 to 10 mg/kg per body solution was then added thereto. The mixture was extracted weight, once a day or two or more times a day. Additionally, with ethyl acetate, the organic layer was washed with water a transmucosal agent is administered at a dose from about and saturated brine, and dried over anhydrous magnesium 0.001 to 100 mg/kg per body weight, once a day or two or sulfate, and the solvent was then evaporated under reduced more times a day. The dose is appropriately decided in pressure to obtain the compound of Preparative Example 1 response to the individual case by taking the symptoms, the 10 (132 g) as a pale yellow oily Substance. age, and the gender, and the like into consideration. The compound according to the present invention can be Preparative Example 2 used in combination with various agents for treating or pre venting the diseases for which the compound according to the 2-Ethylindan-1-one (1.6 g) and potassium tert-butoxide present invention is considered to be effective. The combined 15 (560 mg) were dissolved in tert-butanol (20 ml), and acry preparation may be administered simultaneously, or sepa lonitrile (663 mg) was added thereto at room temperature. rately and continuously or at a desired time interval. The After stirring at the same temperature for 2 hours, 1 M hydro preparations to be co-administered may be a blend, or may be chloric acid was added thereto, followed by extraction with prepared individually. ethyl acetate. The organic layer was washed with Saturated brine and dried over anhydrous magnesium Sulfate, and the EXAMPLES solvent was then evaporated under reduced pressure. The Hereinbelow, the production processes for compounds residue was purified by silica gel column chromatography according to the present invention will be described in more (eluent; n-hexane:ethyl acetate-4:1) to obtain the compound detail with reference to Examples. Further, the present inven of Preparative Example 2 (1.92 g) as a pale yellow oily tion is not limited to the compounds described in the 25 Substance. Examples below. Furthermore, the production processes for the starting compounds will be described in Preparative Preparative Example 3 Examples. Further, the production processes for the com pound according to the present invention are not limited to the The compound of Preparative Example 109 (3.04 g) was production processes of the specific Examples as below, but 30 dissolved in tetrahydrofuran (30 ml) and tert-butanol (15 ml), the compound according to the present invention can also be and potassium tert-butoxide (300 mg) and acrylonitrile (1.5 prepared by a combination of the production processes or the ml) were added thereto under ice-cooling, followed by stir methods that are apparent to a person skilled in the art. ring at the same temperature for 1 hour and further at room In addition, the following abbreviations may be used some temperature for 15 hours. To the reaction liquid was added a times in Examples, Preparative Examples, and Tables to be 35 saturated aqueous ammonium chloride Solution, followed by described later. extraction with ethyl acetate, the organic layer was washed Px: Preparative Example number, Ex: Example number, with water and Saturated brine, dried over magnesium sulfate, STRUCTURE: Chemical structural formula (also, among the and the Solvent was then evaporated under reduced pressure. compounds shown in Stereochemistry, one denoted by The residue was purified by silica gel column chromatogra "chiral' represents a compound having Such a steric configu 40 phy (eluent; n-hexane:ethyl acetate-4:1) to obtain the com ration, and the other compounds represent racemic), Sal: Salt pound of Preparative Example 3 (1.45 g) as an oily substance. (representing the compound was isolated as the following salts. CL: hydrochloride, BR: bromohydride, MS: methane Preparative Example 19 sulfonate, OX: oxalate, FM: fumarate. Further, a blank or no description means that the compound was isolated as a free 45 To a solution of the compound of Preparative Example 1 form.), Syn: production process (the numeral shows that the (132 g) in methanol (700 ml) was added portionwise sodium compound was prepared in the same production process as in borohydride (12.6 g) under ice-cooling. After stirring at the the compound having its number as the Preparative Example same temperature for 1 hour, acetone was added thereto, number or Example number in the section), Data: physical followed by stirring for 1 hour further. The solvent was evapo data (which represents the analyzer data below of the com 50 rated under reduced pressure, and a saturated aqueous ammo pound. CI+: CIM+H", EI+: EIMI", FAB+: FAB-MSM-- nium chloride solution was then added thereto, followed by H*, ESI+: ESI-MSM-H, APCI+: APCI-MSM-H, extraction with ethyl acetate. The organic layer was Subse NMR-DMSOdó: 8 (ppm) of the peaks in "H-NMR in dim quently washed with a saturated aqueous ammonium chloride ethylsulfoxide-de, NMR-CDC13: 8 (ppm) of the peaks in solution (400 ml), twice with water (400 ml), and with satu H-NMR in CDC1, NMR-CD3OD: 8 (ppm) of the peaks in 55 rated brine (200 ml). After drying over anhydrous magnesium 'H-NMR in CDOD. In addition, for some compounds, char Sulfate, the solvent was evaporated under reduced pressure to acteristic peaks only are described). obtain the compound of Preparative Example 19 (131 g) as a Further, in Tables, for Example 79-1 and Example 79-2, colorless amorphous. Example 80-1 and Example 80-2, Example 83-1 and Example 83-2, and Example 84-1 and Example 84-2, abso 60 Preparative Example 20 lute arrangement is not determined, respectively, but each represents either different compounds. To a solution of the compound of Preparative Example 2 (1.92 g) in methanol (30 ml) was added sodium borohydride Preparative Example 1 (340mg), followed by stirring at room temperature for 1 hour. 65 Acetone was added thereto, the reaction Solution was concen To a solution of 2-methylindan-1-one (100 g) in 2-propanol trated under reduced pressure, and a saturated aqueous (1 L) was added potassium tert-butoxide (15.4 g) under ice ammonium chloride solution was then added thereto, fol US 8,21 1907 B2 27 28 lowed by extraction with ethyl acetate. The organic layer was Preparative Example 56 washed with Saturated brine and dried over anhydrous mag nesium sulfate, and the solvent was then evaporated under To a solution of cis-1,2,3,4,4a,9a-hexahydro-9H-fluoren reduced pressure and concentrated under reduced pressure to 9-one (1.4 g) and 2-bromoethylmethyl ether in tetrahydrofu obtain the compound of Preparative Example 20 (1.93 g) as a ran (20 ml) was added sodium iodide (1.1 g), and 55% oily sodium hydride (655 mg) was then added thereto, followed by colorless oily Substance. stirring at room temperature for 5 days. Water was added thereto, followed by extraction with ethyl acetate, the organic Preparative Example 21 layer was washed with saturated brine and washed with anhy drous magnesium Sulfate, and the solvent was then evapo The compound of Preparative Example 3 (258 mg) was 10 rated under reduced pressure. The residue was purified by dissolved in tetrahydrofuran (2.0 ml) and methanol (2.0 ml), silica gel column chromatography (eluent, n-hexane:ethyl and sodium borohydride (40 mg) was added thereto under acetate=20:1) to obtain the compound of Preparative ice-cooling, followed by stirring at the same temperature for Example 56 (808 mg) as a pale yellow oily substance. 2 hours. To the reaction solution were added water and a saturated aqueous ammonium chloride Solution, followed by 15 Preparative Example 59 extraction with ethyl acetate, and the organic layer was To a solution of the compound of Preparative Example 56 washed with saturated brine and then dried over anhydrous (808 mg) in methylene chloride (10 ml) was added a solution magnesium sulfate. The solvent was evaporated under of 1 M boron tribromide in methylene chloride (6.6 ml), reduced pressure to obtain the compound of Preparative followed by stirring at room temperature for 3 hours. Water Example 21 (260 mg) as a yellow oily substance. was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with water and Saturated brine, Preparative Example 38 and dried over anhydrous magnesium Sulfate, and the solvent was then evaporated under reduced pressure. The residue was A solution of methanesulfonic acid (23.5 g) in 1,2-dichlo 25 dissolved in N,N-dimethyl formamide (10 ml), and sodium roethane (640 ml) was warmed to 80°C., followed by stirring, azide (430 mg) was added thereto, followed by stirring at and a solution of the compound of Preparative Example 19 room temperature for 3 days. Water was added thereto, fol (32.8 g) in 1,2-dichloroethane (180 ml) was added dropwise lowed by extraction with ethyl acetate, the organic layer was thereto over 30 minutes. After stirring at the same tempera washed with Saturated brine and dried over anhydrous mag ture for further 1 hour, the reaction solution was ice-cooled, 30 nesium sulfate, and the solvent was then evaporated under and ice water (200 ml), a 1 M aqueous sodium hydroxide reduced pressure. The residue was purified by silica gel col solution (200 ml), and a saturated aqueous sodium hydrogen umn chromatography (eluent; n-hexane:ethyl acetate 20:1) carbonate solution were subsequently added thereto, fol to obtain the compound of Preparative Example 59 (844 mg) lowed by extraction with chloroform. The organic layer was as a colorless oily Substance. dried over anhydrous magnesium sulfate, the solvent was 35 evaporated under reduced pressure, and the residue was then Preparative Example 62-1 and Preparative solidified by adding diisopropyl ether to obtain the compound Example 62-2 of Preparative Example 38 (18.3 g) as a colorless powder. To a solution of the compound of Preparative Example 59 Preparative Example 39 40 (600 mg) in diethyl ether (3.6 ml) was added tri-n-butyl phosphine (476 mg), followed by stirring at room tempera To a solution of the compound of Preparative Example 20 ture for 1 hour. Under ice-cooling, a solution of 1 M methyl (1.93 g) in 1,2-dichloroethane (120 ml) was added methane lithium in diethyl ether (7.1 ml) and a solution of a boron sulfonic acid (870 mg), followed by stirring at 80° C. for 2 trifluoride diethyl ether complex (0.60 ml) in diethyl ether hours. After ice-cooling, a 1 M aqueous sodium hydroxide 45 (3.0 ml) were sequentially added thereto. After stirring at the solution was added thereto for neutralization, followed by same temperature for 3 hours, a saturated aqueous sodium extraction with chloroform. The organic layer was dried over hydrogen carbonate solution was added thereto, followed by anhydrous magnesium Sulfate, the solvent was evaporated extraction with chloroform. The organic layer was dried over under reduced pressure, and the residue was crystallized from anhydrous magnesium Sulfate, the solvent was then evapo diisopropyl ether to obtain the compound of Preparative 50 rated under reduced pressure, and the residue was purified by Example 39 (879 mg) as a colorless powder. silica gel column chromatography (eluent; chloroform: methanol: Saturated aqueous ammonia=10:1:0.1) to obtain an Preparative Example 40 oily Substance (212 mg). This was dissolved in pyridine (5 ml), and benzyl chloro To a solution of methanesulfonic acid (0.1 ml) in 1,2- 55 formate (400 mg) was added thereto, followed by stirring at dichloroethane (15 ml) were added dropwise a solution of the 50° C. overnight. The reaction solution was concentrated compound of Preparative Example 21 (255 mg) in 1,2-dichlo under reduced pressure and the residue was purified by silica roethane (5.0 ml) at 80°C. over 20 minutes. After stirring at gel column chromatography (eluent, n-hexane:ethyl the same temperature for 3 hours, the reaction solution was acetate-4:1) to obtain the compound of Preparative Example neutralized by adding a 1 Maqueous sodium hydroxide solu 60 62-1 (40 mg) and the compound of Preparative Example 62-2 tion under ice-cooling, and extracted with chloroform. The (30 mg), respectively, as a colorless oily Substance. organic layer was washed with Saturated brine and dried over anhydrous magnesium Sulfate, the solvent was then evapo Preparative Example 63-1 and Preparative rated under reduced pressure, and the residue was purified by Example 63-2 silica gel column chromatography (eluent; chloroform/ 65 methanol) to obtain the compound of Preparative Example 40 To a solution of the compound of Preparative Example 61 (170 mg) as a colorless amorphous. (630 mg) in diethyl ether (7 ml) was added tri-n-butyl phos US 8,21 1907 B2 29 30 phine, followed by stirring at room temperature for 1 hour. drous magnesium Sulfate, and the solvent was then evapo Then, a solution of 1 M methyl lithium in diethyl ether (6.8 rated under reduced pressure. The residue was purified by ml) and a borontrifluoride diethyl ether complex (0.576 ml) silica gel column chromatography (eluent, n-hexane:ethyl were added thereto under ice-cooling, followed by stirring at acetate-4:1) to obtain the compound of Preparative Example the same temperature for 3 hours. After completion of the 66 (1.12 g) as a colorless oily Substance. reaction, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chlo Preparative Example 67 roform, the organic layer was dried over anhydrous magne sium Sulfate, and the solvent was evaporated under reduced To a solution of diisopropylamine (0.97 ml) in tetrahydro pressure. The residue was purified by silica gel column chro 10 furan (10 ml) was added a solution of 1.58 Mn-butyl lithium matography (eluent; n-hexane:ethylacetate 2:1, chloroform: in tetrahydrofuran (4.38 ml) at 0°C., followed by stirring at methanol: Saturated aqueous ammonia=10:1:0.1) to obtain the same temperature for 30 minutes. Then, the compound of the compound of Preparative Example 63-2 (135 mg) and an Preparative Example 66 (1.06 g) was added thereto, followed oily substance (306 mg). by stirring for further 2 hours. Methyl iodide (0.862 ml) was Then, this oily substance was dissolved in pyridine (5 ml), 15 added thereto, followed by stirring at room temperature for and benzyl chloroformate (0.324 ml) was added thereto under further 2 hours. The reaction solution was added with a satu ice-cooling, followed by warming to 80°C. and stirring for 3 rated aqueous ammonium chloride solution, extracted with days. The reaction Solution was concentrated under reduced ethyl acetate, and then washed with saturated brine. After pressure and the residue was purified by silica gel column drying over anhydrous magnesium sulfate, the solvent was chromatography (eluent; n-hexane:ethyl acetate 4:1) to evaporated under reduced pressure. Then, the residue was obtain the compound of Preparative Example 63-1 (95 mg) as dissolved in 1,2-dichloroethane (100 ml), and methane a colorless oily Substance. sulfonic acid (0.30 ml) was added thereto under stirring under heating at 80° C. for 3 hours. The reaction solution was Preparative Example 64 cooled, added with a 1 Maqueous sodium hydroxide solu 25 tion, extracted with chloroform, and then dried over anhy To a solution of 2-methylindan-1-one (4.5 g) in N,N-dim drous magnesium sulfate, and the solvent was evaporated ethyl formamide (25 ml) was added 55% oily sodium hydride under reduced pressure. The residue was purified by silica gel (1.34 g) under ice-cooling, followed by stirring at the same column chromatography (eluent; chloroform:methanol 20: temperature for 30 minutes. On the other hand, 4-bromobu 1) to obtain the compound of Preparative Example 67 (718 tanenitrile (6.15 g) and sodium iodide (6.22 g) was stirred in 30 mg) as a yellow amorphous. N,N-dimethyl formamide (25 ml) at room temperature for 30 minutes. This reaction mixture was added to the above-de Preparative Example 68 scribed reaction solution under ice-cooling, followed by stir ring at the same temperature for 2 hours. To the reaction To a solution of the compound of Preparative Example 1 mixture was added a Saturated aqueous ammonium chloride 35 (35.8 g) in tetrahydrofuran (200 ml) was added a solution of solution, followed by extraction with ethyl acetate, and the a 1 M methyl magnesium bromide in tetrahydrofuran (215 organic layer was washed with water and saturated brine. ml) at -78° C., followed by stirring over 4 hours, slowly After drying over anhydrous magnesium sulfate, the Solvent warming to room temperature, and further stirring at room was evaporated under reduced pressure, and the residue was temperature overnight. A saturated ammonium chloride solu purified by Silica gel column chromatography (eluent; n-hex 40 tion was added thereto, followed by extraction with ethyl ane:ethyl acetate=4:1) to obtain the compound of Preparative acetate, the organic layer was washed with Saturated brine and Example 64 (3.31 g) as an oily Substance. then dried over anhydrous magnesium sulfate, and the Solvent was evaporated under reduced pressure. The residue was Preparative Example 65 purified by Silica gel column chromatography (eluent, n-hex 45 ane:ethyl acetate=4:1) to obtain the compound of Preparative To a Suspension of Raney nickel (440 mg) that had been Example 68 (29.0 g) as a yellow oily substance. sufficiently washed with water was added methanol (20 ml), and a solution of the compound of Preparative Example 64 Preparative Example 69 (1.6 g) in methanol (20 ml) was then added thereto. The mixture was stirred at room temperature for 3 days at normal 50 To a suspension of the compound of Preparative Example pressure under a hydrogen atmosphere. The reaction mixture 68 (9.3 g) and sodium azide (7.0 g) in chloroform (200 ml) was filtered through Celite, the filtrate was concentrated was added trifluoroacetic acid (8.4 ml) under ice-cooling. under reduced pressure, and the residue was purified by basic After stirring at the same temperature for 1 hour, to the reac silica gel column chromatography (eluent; ethyl acetate) to tion solution was added a 10% aqueous ammonia Solution, obtain the compound of Preparative Example 65 (494 mg) as 55 followed by extraction with ethyl acetate. The organic layer a colorless oily Substance. was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then evaporated Preparative Example 66 under reduced pressure. Then, the residue was dissolved in methanol (200 ml), and 10% palladium-supported carbon To a mixed solution of the compound of Preparative 60 (700mg) was added thereto, followed by stirring overnight at Example 26 (1.12 g) and methyl iodide (0.48 ml) in N.N- normal pressure under a hydrogen atmosphere. The reaction dimethyl formamide (20 ml) was added 55% oily sodium mixture was filtered through Celite and the filtrate was con hydride (269 mg) under ice-cooling, followed by stirring at centrated under reduced pressure. The residue was dissolved the same temperature for 1 hour. To the reaction solution was in ethyl acetate and extracted with 1 Mhydrochloric acid (100 added a saturated aqueous ammonium chloride solution, fol 65 ml). The aqueous layer was alkalified by adding a 1 Maque lowed by extraction with ethyl acetate, the organic layer was ous sodium hydroxide solution and then extracted with chlo washed with water and saturated brine, and dried over anhy roform. The organic layer was dried over anhydrous magne US 8,21 1907 B2 31 32 sium sulfate and then concentrated under reduced pressure. stirring at the same temperature for 1 hour and then stirring at The residue was purified by silica gel column chromatogra room temperature for 6 hours. The reaction mixture was phy (eluent; chloroform:methanol: Saturated aqueous ammo poured into ice water, followed by stirring for 30 minutes and nia=20:1:0.1) to obtain the compound of Preparative extraction with ethyl acetate, and the organic layer was Example 69 (2.15 g) as a colorless oily substance. washed with a saturated aqueous Sodium chloride solution, and then dried over magnesium Sulfate. The solvent was Preparative Example 70-1 and Preparative Example evaporated under reduced pressure and the residue was puri 70-2 fied by silica gel column chromatography (eluent; chloro form) to obtain the compound of Preparative Example 72-1 To a solution of the compound of Preparative Example 69 10 (2.73 g) as a colorless solid, and further the compound of (6.45 g) in toluene (100 ml) was added a solution of 0.99 M Preparative Example 72-2 (0.49 g) as a pale brown solid, disobutylaluminum hydride intoluene (76ml) at -78°C. The respectively. reaction liquid was slowly warmed to -35°C. over 3 hours, and methanol (10 ml) was then added thereto. In addition, a Preparative Example 73 saturated aqueous ammonium chloride solution was added 15 thereto under ice-cooling, followed by stirring at room tem To a suspension of 55% oily sodium hydride (500mg) in perature for 1 hour and filtering through Celite, the filtrate tetrahydrofuran (75 ml) was added dropwise a solution of the was concentrated under reduced pressure. The residue (6.0 g) compound of Preparative Example 72-1 (500mg) in tetrahy was dissolved in 1,2-dichloroethane (600 ml), and titanium drofuran (75 ml) at 80°C. over 2 hours, followed by stirring tetraisopropoxide (8.9 ml) was added thereto, followed by at the same temperature for 1 hour. The reaction solution was stirring at room temperature for 1 hour. Sodium triacetoxy cooled, water and a saturated aqueous ammonium chloride borohydride (12.7 g) was added thereto, followed by stirring solution were added thereto, followed by extraction with at room temperature overnight. The reaction liquid was ethyl acetate, and the organic layer was washed with a satu poured into a 4 Maqueous sodium hydroxide solution added rated aqueous sodium chloride solution. After drying over with ice, and then filtered through Celite, and the filtrate was 25 anhydrous magnesium sulfate, the solvent was evaporated extracted with chloroform. The organic layer was dried over under reduced pressure to obtain the compound of Prepara anhydrous magnesium Sulfate and the solvent was then tive Example 73. evaporated under reduced pressure. The residue was dis solved in chloroform (100 ml), and a saturated aqueous Preparative Example 75 Sodium hydrogen carbonate solution was added thereto and 30 then benzyl chloroformate (6.7 g) was added thereto, fol To a solution of 3-(1-oxo-2,3-dihydro-1H-inden-2-yl)pro lowed by stirring at room temperature for 3 hours. The reac panenitrile (724 mg) in methanol (10 ml) was added sodium tion solution was extracted with chloroform, the organic layer borohydride (148 mg) under ice-cooling, followed by stirring was dried over anhydrous magnesium sulfate, and the Solvent at the same temperature for 1 hour. To the reaction solution was then evaporated under reduced pressure. The residue was 35 was added a saturated aqueous ammonium chloride solution, purified by Silica gel column chromatography (eluent; n-hex followed by extraction with ethyl acetate. The organic layer ane:ethyl acetate=20:1) to obtain the compound of Prepara was washed with saturated brine and dried over anhydrous tive Example 70-1 (1.97g) and the compound of Preparative magnesium sulfate, and the solvent was evaporated under Example 70-2 (1.72 g), respectively, as a colorless oily sub reduced pressure. Then, the residue was dissolved in 1,4- Stance. 40 dioxane (20 ml), and pyridinium p-toluenesulfonate (500mg) was added thereto, followed by heating under stirring at 100° Preparative Example 71 C. for 3 days. The reaction solution was cooled, and a satu rated aqueous Sodium hydrogen carbonate Solution was then To a solution of 2-methylindan-1-one (1.02 g) in tetrahy added thereto, followed by extraction with ethyl acetate. The drofuran (15 ml) was added a solution of 1 M lithium hexam 45 organic layer was washed with 1 M hydrochloric acid and ethyl disilazide in tetrahydrofuran (8.4 ml) at -70° C., fol saturated brine. After drying over anhydrous magnesium Sul lowed by stirring at the same temperature for 30 minutes. fate, the solvent was evaporated under reduced pressure to Subsequently, 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-di obtain the compound of Preparative Example 75 (575 mg) as one (2.23 g) was added thereto, followed by further stirring at a colorless oily Substance. the same temperature for 1 hour. The reaction solution was 50 warmed to 0°C., and a saturated aqueous ammonium chlo Preparative Example 76 ride solution was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a To a solution of the compound of Preparative Example 75 saturated aqueous Sodium hydrogen carbonate solution and (575 mg) in chloroform (20 ml) were added sodium hydrogen saturated brine, and then, dried over anhydrous sodium Sul 55 carbonate (856 mg) and 75% 3-chloroperbenzoic acid (928 fate, and the solvent was evaporated under reduced pressure. mg) under ice-cooling, followed by stirring at room tempera The residue was purified by silica gel column chromatogra ture for 3 hours. To the reaction mixture was added a 1 M phy (eluent; n-hexane:ethyl acetate=10:1-1: 1) to obtain the aqueous sodium hydroxide Solution, followed by extraction compound of Preparative Example 71 (422 mg) as a pale with chloroform. The organic layer was dried over anhydrous yellow solid. 60 magnesium Sulfate and the solvent was evaporated under reduced pressure to obtain the compound of Preparative Preparative Example 72-1 and Preparative Example Example 76 (629 mg) as a colorless oily substance. 72-2 Preparative Example 77 To a solution of 6a-methyl-6,6a-dihydro-1ah-indeno1,2- 65 boxirene (5.5 g) and chloroacetonitrile (20 ml) was added To a solution of the compound of Preparative Example 76 methanesulfonic acid (5.0 ml) under ice-cooling, followed by (625 mg) in 1,2-dichloroethane (100 ml) was added methane US 8,21 1907 B2 33 34 Sulfonic acid (486 mg) under ice-cooling. After stirring at the evaporated under reduced pressure and the residue was puri same temperature for 6 hours, a 1 Maqueous sodium hydrox fied by silica gel column chromatography (eluent; chloro ide solution was added thereto, followed by extraction with form:methanol=100:0-90:10) to obtain the compound of Pre chloroform. The organic layer was dried over anhydrous parative Example 82 (114 mg) as a colorless oily Substance. magnesium sulfate, the solvent was then evaporated under 5 reduced pressure, and the residue was purified by Silica gel Preparative Example 83 column chromatography (eluent; chloroform:methanol=10: 1) to obtain the compound of Preparative Example 77 (100 To a solution of the compound of Preparative Example 82 mg) as a colorless amorphous. (53 mg) in tetrahydrofuran (1 ml) were added 55% oily 10 sodium hydride (8 mg) and methyl iodide (0.1 ml) under Preparative Example 78 ice-cooling, followed by stirring at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was To a solution of a free from of the compound of Example 66 added thereto, followed by extraction with ethyl acetate, (668 mg) in tetrahydrofuran (15 ml) was added di-tert-butyl washing with Saturated brine, and then drying over anhydrous dicarbonate (645 mg), followed by stirring at room tempera 15 Sodium sulfate, and the solvent was evaporated under reduced ture for 3 hours. Water was added thereto, followed by extrac pressure. The residue was purified by silica gel column chro tion with ethyl acetate, washing with Saturated brine, and then drying over anhydrous Sodium Sulfate, and the solvent was matography (eluent; n-hexane:ethyl acetate=100:0-80:20) to evaporated under reduced pressure. The residue was purified obtain the compound of Preparative Example 83 (40 mg) as a by silica gel chromatography (eluent, n-hexane:ethyl colorless oily Substance. acetate=100:0-60:40) to obtain the compound of Preparative Example 78 (829 mg) as a colorless oily substance. Preparative Example 84 Preparative Example 79 To a solution of a free from of the compound of Example 16 25 (1.17 g) in chloroform (20 ml) were added a saturated aque To a solution of the compound of Preparative Example 78 ous sodium hydrogen carbonate solution (20 ml) and benzyl (100 mg) in ethanol (3 ml) was added a 6 Maqueous sodium chloroformate (0.8 ml), followed by stirring at room tempera hydroxide solution, followed by heating under reflux for 5 ture for 17 hours. Chloroformand water were added thereto to hours. The reaction solution was concentrated under reduced carry out the liquid separation, and the organic layer was pressure, and to the residue was added 1 M hydrochloric acid 30 washed with saturated brine and then dried over anhydrous (30 ml), followed by extraction with ethyl acetate. The sodium sulfate. The solvent was evaporated under reduced organic layer was washed with saturated brine and dried over pressure and the residue was purified by silica gel column anhydrous Sodium sulfate, and the solvent was then evapo chromatography (eluent; n-hexane:ethyl acetate=100:0-60: rated under reduced pressure. The residue was dissolved in 40) to obtain the compound of Preparative Example 84 (1.72 N,N-dimethyl formamide (5 ml), and methyl amine hydro 35 g) as a colorless solid. chloride (103 mg), 1-hydroxybenzotriazole (83 mg), N-3- (dimethylamino)propyl)-N'-ethylcarbodiimide hydrochlo Preparative Example 86 ride (117 mg), and triethylamine (0.21 ml) were sequentially added, followed by stirring at room temperature overnight. To a solution of the compound of Preparative Example 85 The reaction mixture was added with a saturated aqueous 40 (250mg) in N,N-dimethyl formamide (3 ml) was added 55% Sodium hydrogen carbonate Solution, extracted with ethyl oily sodium hydride (39 mg) under ice-cooling, followed by acetate, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under stirring at the same temperature for 15 minutes. Methyl iodide reduced pressure and the residue was then purified by silica (0.069 ml) was added thereto, followed by stirring at room gel column chromatography (eluent; chloroform:metha 45 temperature for 2 hours. A saturated aqueous ammonium nol=100:0-90:10) to obtain the compound of Preparative chloride solution was added thereto, followed by extraction Example 79 (104 mg) as a colorless oily substance. with chloroform and drying over anhydrous magnesium Sul fate, and the solvent was then evaporated under reduced pres Preparative Example 82 Sure. The residue was purified by Silica gel column chroma 50 tography (eluent; n-hexane:ethyl acetate=3:1) to obtain the To a solution of the compound of Preparative Example 78 compound of Preparative Example 86 (219 mg) as a colorless (113 mg) in toluene (1.5 ml) was slowly added a solution of 1 oily Substance. Mdiisobutylaluminum hydride intoluene (0.8 ml) at -70°C., followed by stirring at the same temperature for 2 hours. To Preparative Example 88 the reaction solution was slowly added methanol, followed by 55 stirring for 20 minutes, and the reaction solution was then To a solution of the compound of Preparative Example 84 poured into 1 M hydrochloric acid under ice-cooling. This (1.14 g) in N-methyl pyrrolidone (20 ml) were added zinc was extracted with ethyl acetate, washed with saturated brine, cyanide (388 mg), calcium hydroxide (245 mg), and tetrakis and dried over anhydrous Sodium Sulfate, and the solvent was (triphenylphosphine)palladium (O) (960 mg), followed by then evaporated under reduced pressure. Subsequently, the 60 stirring at 100° C. for 3 hours. To the reaction solution were residue was dissolved in methanol, and sodium borohydride added chloroform and water, the insoluble materials were (14 mg) was added thereto under ice-cooling, followed by removed by filtration over Celite, and the liquid separation stirring for 30 minutes. A saturated aqueous ammonium chlo was carried out. The organic layer was washed with a 1 M ride solution was added thereto, followed by extraction with aqueous Sodium hydroxide Solution and Saturated brine, and ethyl acetate, washing with a saturated aqueous sodium 65 dried over anhydrous sodium sulfate, and the solvent was then hydrogen carbonate solution and Saturated brine, and then evaporated under reduced pressure. The residue was purified drying over anhydrous Sodium Sulfate. The solvent was by silica gel column chromatography (eluent; n-hexane:ethyl US 8,21 1907 B2 35 36 acetate=60:40-30:70) to obtain the compound of Preparative aqueous ammonium chloride solution was added thereto, fol Example 88 (988 mg) as a colorless oily substance. lowed by extraction with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was Preparative Example 89 then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chlo To a solution of the compound of Preparative Example 84 roform:methanol=10:1) to obtain the compound of Prepara (283 mg) in toluene (5 ml) were sequentially added pyrroli tive Example 92 (102 mg) as a colorless amorphous. dine (0.07 ml), sodium tert-butoxide (95 mg), tris(diben Zylideneacetone)dipalladium (O) (19 mg), and (2-biphenyl) Preparative Example 94 dicyclohexylphosphine (29 mg), followed by stirring at 85° 10 C. for 5 hours. To the reaction mixture were added ethyl To a solution of methyl (4aRS.9bRS)-2-oxo-1,2,3,4,5,9b acetate and water to carry out the liquid separation, the hexahydro-4aH-indeno1,2-bipyridine-4a-carboxylate (2.0 organic layer was washed with a Saturated aqueous sodium g) in methanol (10 ml) was added a 5 M aqueous Sodium chloride solution and dried over anhydrous sodium sulfate, hydroxide solution, followed by stirring at room temperature and the solvent was evaporated under reduced pressure. The 15 for 2 hours. Concentrated hydrochloric acid (12 ml) was residue was purified by basic silica gel column chromatogra added thereto under ice-cooling, and then followed by further phy (eluent; n-hexane:ethyl acetate=9:1) to obtain the com stirring for 30 minutes, and the resulting precipitate was col pound of Preparative Example 89 (102 mg) as a colorless oily lected by filtration to obtain the compound of Preparative Substance. Example 94 (1.68 g) as an off-white powder. Preparative Example 90 Preparative Example 95 To a mixture of methyl (4aRS.9bRS)-9b-methyl-2-oxo-1, To a solution of the compound of Preparative Example 94 2.3.4.5.9b-hexahydro-4-aH-indeno1,2-bipyridine-4a-car (400 mg) in N,N-dimethyl formamide (10 ml) were sequen boxylate (770 mg) in toluene (10 ml) was added a solution of 25 tially added N-3-(dimethylamino)propyl-N'-ethylcarbodi 70% sodium aluminum bis(2-methoxyethoxy)dihydride in imide hydrochloride (497 mg), 1-hydroxybenzotriazole (233 toluene (4.2 ml), followed by stirring at 80°C. for 4 hours. To mg), piperidine (295 mg), and triethylamine (350 mg). After the reaction Solution was added a 1 M aqueous sodium stirring the reaction liquid at room temperature for 6 hours, a hydroxide solution under ice-cooling, followed by extraction saturated aqueous sodium hydrogen carbonate Solution was with chloroform, the organic layer was dried over anhydrous 30 added thereto and the resulting precipitate was collected by magnesium sulfate, and the solvent was then evaporated filtration to obtain the compound of Preparative Example 95 under reduced pressure. The residue was dissolved in chlo (388 mg) as a colorless powder. roform (10 ml), and benzyl chloroformate (1.5 g) and a satu rated aqueous Sodium hydrogen carbonate Solution (10 ml) Preparative Example 99 were added thereto, followed by stirring at room temperature 35 for 1 hour. To the reaction solution was added saturated aque To a solution of the compound of Preparative Example 38 ous ammonia (4 ml), followed by extraction with chloroform, (510 mg) and methyl iodide (0.24 ml) in N,N-dimethyl for the organic layer was dried over anhydrous magnesium Sul mamide (10 ml) was added 55% oily sodium hydride (133 fate, and the solvent was then evaporated under reduced pres mg), followed by stirring at room temperature for 1 hour. To Sure. The residue was purified by Silica gel column chroma 40 the reaction solution was added a saturated aqueous ammo tography (eluent; n-hexane:ethyl acetate=1:1-0:1) to obtain nium chloride solution, followed by extraction with chloro the compound of Preparative Example 90 (361 mg) as a form, the organic layer was dried over anhydrous magnesium colorless oily Substance. sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chro Preparative Example 91 45 matography (chloroform:methanol-30:1) to obtain the com pound of Preparative Example 99 (536 mg) as a colorless To a solution of the compound of Preparative Example 90 Viscous Solid. (180 mg) in N,N-dimethyl formamide (3 ml) was added 55% oily sodium hydride (45 mg) under ice-cooling, followed by Preparative Example 100 stirring for 30 minutes under ice-cooling. Methyl iodide (0.06 50 ml) was added thereto, followed by stirring at the same tem To a solution of the compound of Preparative Example 40 perature for further 1 hour, and a saturated aqueous ammo (650mg) and triethylamine (363 ml) in methanol (50 ml) was nium chloride solution was then added thereto, followed by added 10% palladium-Supported carbon having a water con extraction with ethyl acetate. The organic layer was dried over tent of 50% (500 mg), followed by stirring at room tempera anhydrous magnesium Sulfate, the solvent was evaporated 55 ture for 22 hours at normal pressure under a hydrogen atmo under reduced pressure and the residue was then purified by sphere. The insoluble materials were removed by filtration silica gel column chromatography (eluent, n-hexane:ethyl through Celite, and the filtrate was subjected to liquid sepa acetate-4:1) to obtain the compound of Preparative Example ration with water and ethyl acetate, and the organic layer was 91 (167 mg) as a colorless oily substance. washed with saturated brine. After drying over anhydrous 60 magnesium sulfate, the solvent was evaporated under reduced Preparative Example 93 pressure to obtain the compound of Preparative Example 100 (395 mg) as a colorless solid. To a solution of methyl (4aRS.9bRS)-2-oxo-1,2,3,4,5,9b hexahydro-4aH-indeno1,2-bipyridine-4a-carboxylate (200 Preparative Example 101 mg) in tetrahydrofuran (4 ml) was added a solution of 1 M 65 methyl magnesium bromide in tetrahydrofuran (4 ml), fol To a suspension of methyl 3-(2-methoxy phenyl)-3-oxo lowed by stirring at room temperature for 2 days. A saturated propanoate (5.08 g) and potassium carbonate (5.0 g) in tet US 8,21 1907 B2 37 38 rahydrofuran (50 ml) was added ethyl iodide (2.5 ml), fol chloroform, and the organic layer was dried over anhydrous lowed by stirring at 80° C. for 13 hours. To the reaction magnesium Sulfate. The solvent was evaporated under mixture was added water, followed by extraction with ethyl reduced pressure and the residue was purified by Silica gel acetate, and the organic layer was washed with Saturated brine column chromatography (eluent; n-hexane:ethyl acetate) to and then dried over anhydrous magnesium sulfate. The Sol obtain the compound of Preparative Example 105 (2.37 g) as vent was evaporated under reduced pressure and the residue a colorless oily Substance. was purified by Silica gel column chromatography (eluent; n-hexane:ethyl acetate) to obtain the compound of Prepara Preparative Example 106 tive Example 101 (4.51 g) as a pale yellow oily substance. 10 To a solution of the compound of Preparative Example 105 Preparative Example 102 (1.24 g) in N,N-dimethyl formamide (20 ml) was added 1.8- diazabicyclo5.4.0]undecene (1.6 ml), followed by stirring at To a mixed solution of the compound of Preparative 80° C. for 2 hours. The reaction was cooled, and water and 1 Example 101 (4.51 g) in tetrahydrofuran (40 ml) and tert M hydrochloric acid were then added thereto, followed by butanol (20 ml) were added potassium tert-butoxide (500mg) 15 extraction with ethyl acetate, and the organic layer was and acrylonitrile (1.8 ml) under ice-cooling, followed by washed with water and saturated brine. After drying over stirring at the same temperature for 1 hour and further at room anhydrous magnesium sulfate, the solvent was evaporated temperature for 5 hours. To the reaction solution was added a under reduced pressure and the residue was purified by silica saturated aqueous ammonium chloride Solution, followed by gel column chromatography (eluent; n-hexane:ethyl acetate) extraction with ethyl acetate, and the organic layer was to obtain the compound of Preparative Example 106 (350mg) washed with water and saturated brine, and then dried over as a pale yellow solid. anhydrous magnesium Sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica Preparative Example 107 gel column chromatography (eluent; n-hexane:ethyl acetate) to obtain the compound of Preparative Example 102 (4.37g) 25 To a solution of 4-bromobenzenethiol (5.0 g) and ethyl as a colorless oily Substance. 2-bromopropionate (4.0 ml) in N,N-dimethyl formamide (50 ml) was added potassium carbonate (4.4 g), followed by Preparative Example 103 heating and stirring at 60° C. for 4 hours. The reaction was cooled, water was then added thereto, followed by extraction A solution of the compound of Preparative Example 102 30 with ethyl acetate, and the organic layer was washed with (4.36 g) in lithium chloride (2.0 g) in dimethylsulfoxide (40 saturated brine. After drying over anhydrous magnesium Sul ml) was stirred at 150° C. for 3 hours, and lithium chloride fate, the solvent was evaporated under reduced pressure to (2.0 g) was added thereto, followed by stirring at the same obtain the compound of Preparative Example 107 (8.2 g) as a temperature for 3 hours. The reaction solution was cooled, 1 yellow oily substance. M hydrochloric acid was then added thereto, followed by 35 stirring for a while and extraction with ethyl acetate, and the Preparative Example 108 organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the Solvent To a mixed solution of the compound of Preparative was then evaporated under reduced pressure, and the residue Example 107 (5.15g) in ethanol (25 ml)-tetrahydrofuran (25 was purified by Silica gel column chromatography (eluent; 40 ml) was added a 1 Maqueous sodium hydroxide solution (70 n-hexane:ethyl acetate) to obtain the compound of Prepara ml), followed by stirring at room temperature for 3 days. To tive Example 103 (3.1 g) as a pale yellow oily substance. the reaction solution was added 1 M hydrochloric acid (100 ml), followed by extraction with ethyl acetate, and the organic Preparative Example 104 layer was washed with saturated brine. After drying over 45 anhydrous magnesium sulfate, the solvent was evaporated To a solution of the compound of Preparative Example 103 under reduced pressure to obtain the compound of Prepara (3.1 g) in chloroform (50 ml) was added a solution of 1.0 M tive Example 108 (4.24 g) as a colorless solid. borontribromide in dichloromethane (15 ml) under ice-cool ing, followed by stirring at the same temperature for 1 hour. Preparative Example 109 To the reaction solution were added water and a saturated 50 aqueous ammonium chloride Solution, followed by extraction To the compound of Preparative Example 108 (2.17 g) was with chloroform, and the organic layer was dried over anhy added trifluoromethanesulfonic acid (50 g), followed by stir drous magnesium Sulfate. The solvent was evaporated under ring at 80° C. for 30 minutes. The reaction was cooled and reduced pressure and the residue was purified by Silica gel then poured into ice water, followed by extraction with chlo column chromatography (eluent; n-hexane:ethyl acetate) to 55 roform. The organic layer was washed with a saturated aque obtain the compound of Preparative Example 104 (1.52 g) as ous sodium hydrogen carbonate Solution and then dried over a pale yellow oily Substance. anhydrous magnesium Sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica Preparative Example 105 gel column chromatography (eluent; chloroform:methanol) 60 to obtain the compound of Preparative Example 109 (715 mg) To a solution of the compound of Preparative Example 104 as a red-brown oily Substance. (1.51 g) and pyridine (5 ml) in methylene chloride (30 ml) was added trifluoromethanesulfonic anhydride (0.15 ml) Example 1 under ice-cooling, followed by stirring at the same tempera ture for 1 hour and further at room temperature for 19 hours. 65 To a solution of the compound of Preparative Example 39 To the reaction solution were added water and 1 M hydro (879 mg) in tetrahydrofuran (15 ml) was added lithium alu chloric acid under ice-cooling, followed by extraction with minum hydride (400 mg), followed by heating and stirring at US 8,21 1907 B2 39 40 60° C. for 3 hours. After completion of the reaction, the thereto under ice-cooling, followed by stirring at 60° C. for Solution was ice-cooled, and water (0.4 ml), a 15% aqueous further 1 hour. A 1 Maqueous sodium hydroxide solution was sodium hydroxide solution (0.4 ml), and water (1.2 ml) were added thereto under ice-cooling, followed by extraction with sequentially added thereto. The mixture was stirred at room chloroform. After drying over anhydrous magnesium sulfate, temperature for 1 hour. Anhydrous magnesium Sulfate was the solvent was evaporated under reduced pressure, and the added thereto, followed by stirring and then filtering through residue was purified by basic silica gel column chromatogra Celite. The filtrate was concentrated under reduced pressure phy (eluent; n-hexane:ethyl acetate=10: 1-4:1) to obtain to obtain (4aRS.9bRS)-4a-ethyl-2,3,4,4a,5.9b-hexahydro (4aRS.9bSR)-4a-(piperidin-1-ylmethyl)-2,3,4,4a,5.9b 1H-indeno1,2-bipyridine (817 mg) as a colorless oily sub hexahydro-1H-indeno1,2-bipyridine (66 mg) and (4aRS, stance. This was made into a hydrochloride by a conventional 10 9bRS)-4a-(piperidin-1-ylcarbonyl)-2,3,4,4a,5.9b-hexahy method, washed with ethyl acetate, and collected by filtration dro-1H-indeno1,2-bipyridine (182 mg), respectively. These to obtain (4aRS.9bRS)-4a-ethyl-2,3,4,4a,5.9b-hexahydro were each made into a hydrochloride by a conventional 1H-indeno1,2-bipyridine hydrochloride as a colorless pow method, washed with 2-propanol/ethyl acetate, and collected der. by filtration to obtain (4aRS.9bSR)-4a-(piperidin-1-ylm 15 ethyl)-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine Example 13 hydrochloride Example 26-1 and (4aRS.9bRS)-4a-(piperi To a solution of the compound of Preparative Example 100 din-1-ylcarbonyl)-2,3,4,4a,5.9b-hexahydro-1H-indeno 1,2- (472 mg) in tetrahydrofuran (10 ml) was added a solution of bipyridine hydrochloride Example 26-2, respectively, as a a 1.02 Mborane tetrahydrofuran complex in tetrahydrofuran colorless powder. (6.6 ml), followed by stirring at 80° C. for 2 hours and then cooling to room temperature. To the reaction mixture was Example 30 added piperidine (2.0 ml), followed by stirring at 60°C. for 2 hours. Then, water was added thereto, followed by extraction To a solution of the compound of Preparative Example with ethyl acetate, and washing with a saturated aqueous 25 63-2 (135 mg) in tetrahydrofuran (5 ml) was added lithium Sodium hydrogen carbonate Solution, water, and Saturated aluminum hydride (100 mg) under ice-cooling, followed by brine. After drying over anhydrous sodium sulfate, the sol stirring at room temperature for 6 hours. To the reaction vent was evaporated under reduced pressure to obtain (4aRS, solution were sequentially added water (0.1 ml), a 15% aque 9bRS)-4a-methyl-1,2,3,4,4a,9b-hexahydro 1 benzothieno ous sodium hydroxide solution (0.1 ml), and water (0.3 ml), 3.2-bipyridine (396 mg) as an oily substance. This was made 30 and the mixture was stirred at room temperature for 3 days. into a hydrochloride by a conventional method, washed with Anhydrous magnesium sulfate was added thereto, followed ethyl acetate, and then collected by filtration to obtain (4aRS, by filtration through Celite, and the filtrate was concentrated 9bRS)-4a-methyl-1,2,3,4,4a,9b-hexahydro 1 benzothieno under reduced pressure. The residue was purified by silica gel 3.2-bipyridine hydrochloride as a colorless powder. column chromatography (eluent; chloroform: methanol:Satu 35 rated aqueous ammonia=20:1:0.1) to obtain a colorless oily Example 22 Substance (34 mg). This was made into a hydrochloride by a To a mixture of the compound of Preparative Example 38 conventional method, washed with ethyl acetate, and col (42.5 g) in toluene (600 ml) was slowly added dropwise a lected by filtration to obtain (3aRS,8bSR)-3a-phenyl-1,2,3, solution of a 70% sodium aluminum bis(2-methoxyethoxy) 40 3a.4.8b-hexahydroindeno1,2-bipyrrole hydrochloride (30 dihydride in toluene (182 g) under ice-cooling. After comple mg) as a colorless powder. tion of the dropwise addition, the mixture was heated and stirred at 60° C. for 4 hours. After completion of the reaction, Example 31 a 1 Maqueous sodium hydroxide solution was slowly added dropwise under ice-cooling. The mixture was extracted with 45 To a mixed suspension of Raney nickel that had been chloroform, the organic layer was dried over anhydrous mag sufficiently washed with water in water (20 ml)/methanol (45 nesium sulfate, and the solvent was then evaporated under ml) was added a solution of the compound of Preparative reduced pressure. The residue was dissolved in ethyl acetate, Example 2 (1.77 g) in methanol (45ml), followed by stirring followed by extraction twice with 2 Mhydrochloric acid (150 at room temperature overnight at normal pressure under a ml). The aqueous layer was basified by Sodium hydroxide, 50 hydrogen atmosphere. The reaction Suspension was filtered followed by extraction with toluene and drying over anhy through Celite, the filtrate was concentrated under reduced drous magnesium sulfate, and the solvent was evaporated pressure, and the residue was purified by silica gel column under reduced pressure to obtain (4aRS.9bRS)-4a-methyl-2, chromatography (eluent; chloroform:methanol:Saturated 3.4.4a.5.9b-hexahydro-1H-indeno1.2-bipyridine (34 g) as aqueous ammonia=10:1:0.1) to obtain an oily substance (415 an oily Substance. This was made into a hydrochloride by a 55 mg). This was dissolved in 1,2-dichloroethane (40 ml), and conventional method, washed with ethyl acetate, and col sodium triacetoxyborohydride (848 mg) was added thereto, lected by filtration to obtain (4aRS.9bRS)-4a-methyl-2,3,4, followed by stirring at room temperature for 2 days. To the 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine hydrochloride reaction mixture was added a 1 Maqueous Sodium hydroxide as a colorless powder. solution, followed by extraction with chloroform and drying 60 over anhydrous magnesium sulfate, and the solvent was then Example 26-1 and Example 26-2 evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: The compound of Preparative Example 95 (388 mg) was methanol:saturated aqueous ammonia=20:1:0.1-10:1:0.1) to suspended in tetrahydrofuran (5 ml), and a solution of a 1 M obtain (4aRS,9bSR)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H borane tetrahydrofuran complex in tetrahydrofuran (2 ml) 65 indeno1.2-bipyridine (183 mg) as an oily Substance. This was added thereto. After stirring at 60° C. for 5 hours, a was made into a hydrochloride by a conventional method, solution of 10% hydrogen chloride in methanol was added washed with ethyl acetate, and collected by filtration to obtain US 8,21 1907 B2 41 42 (4aRS.9bSR)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno pressure. The residue was purified by silica gel column chro 1,2-bipyridine hydrochloride as a colorless powder. matography (eluent; chloroform:methanol:Saturated aqueous ammonia=20:1:0.1) and then by basic silica gel column chro Example 34-1 and Example 34-2 matography (eluent; n-hexane:ethyl acetate-10:1-2: 1) to obtain (4aRS.9bSR)-4a,9b-dimethyl-2,3,4,4a,5.9b-hexahy To a solution of the compound of Preparative Example 59 dro-1H-indeno1,2-bipyridine (746 mg) as a colorless oily Substance. This was made into a hydrochloride by a conven (240 mg) in 1,2-dichloroethane (4 ml) was added tri-n-butyl tional method, washed with ethyl acetate, and collected by phosphine (190 mg), followed by stirring at room tempera filtration to obtain (4aRS.9bSR)-4a,9b-dimethyl-2.3.4.4a.5, ture for 1 hour. Acetic acid (0.27ml) and sodium triacetoxy 9b-hexahydro-1H-indeno1.2-bipyridine hydrochloride as a borohydride (299 mg) were added thereto, followed by stir 10 colorless powder. ring at 50° C. for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by Example 38-1 and Example 38-2 extraction with chloroform, drying over anhydrous magne sium sulfate, and then concentrating under reduced pressure. The compound of Preparative Example 65 (404 mg) was The residue was purified by basic silica gel column chroma 15 dissolved in 1,2-dichloroethane (20 ml), and titaniumtetrai tography (eluent; n-hexane:ethyl acetate 4:1-2: 1) to obtain sopropoxide (528 mg) was added thereto, followed by stirring (3aRS,7aSR.11bRS)-2,3,4,5,6,7,7a.11b-octahydro-1H-fluo at 60° C. for 3 hours. After cooling to room temperature, reno 9.8a-bipyrrole (24 mg), and (3aRS,7aSR.11bRS)-1- sodium triacetoxyborohydride (78.8 mg) was added thereto, ethyl-2,3,4,5,6,7,7a,11b-octahydro-1H-fluoreno 9.8a-bipyr followed by stirring at room temperature overnight. A 1 M role (52 mg). These were each made into a hydrochloride by aqueous Sodium hydroxide solution was added thereto, fol a conventional method, washed with ethyl acetate, and col lowed by filtration through Celite, and the filtrate was lected by filtration to obtain (3aRS,7aSR,11bRS)-2,3,4,5,6, extracted with chloroform, dried over anhydrous magnesium 7.7a, 11b-octahydro-1H-fluoreno 9,8a-bipyrrole hydrochlo Sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography ride (8 mg) Example 34-1 and (3aRS,7aSR.11bRS)-1- (eluent; chloroform: methanol:Saturated aqueous ammo ethyl-2,3,4,5,6,7,7a,11b-octahydro-1H-fluoreno 9.8a-b) 25 nia=10:1:0.1) to obtain (5aRS,10bRS)-5a-methyl-1,2,3,4,5, pyrrole hydrochloride (39 mg) Example 34-2, respectively, 5a,6,10b-octahydroindeno1,2-blazepine (27 mg) and as a colorless powder. (5aRS, 10bSR)-5a-methyl-1,2,3,4,5,5a,6,10b-octahydroin deno1,2-blazepine (185 mg). These were each made into a Example 36 hydrochloride by a conventional method, washed with ethyl 30 acetate, and collected by filtration to obtain (5aRS, 10bRS)- To a solution of the compound of Preparative Example 60 5a-methyl-1,2,3,4,5,5a,6,10b-octahydroindeno1.2-b (475 mg) in diethyl ether (5 ml) was added tri-n-butyl phos azepine hydrochloride Example 38-1 and (5aRS, 10bSR)- phine (0.545 ml) at room temperature, followed by stirring at 5a-methyl-1,2,3,4,5,5a,6,10b-octahydroindeno1.2-b the same temperature for 1 hour. A solution of a boron trif azepine hydrochloride Example 38-2, respectively, as a luoride diethyl ether complex (0.559 ml) and 1 M methyl 35 colorless powder. lithium in diethyl ether (6.62 ml) were added thereto under ice-cooling, followed by stirring at the same temperature for Example 39 3 hours. To the reaction Solution was added a saturated aque ous Sodium hydrogen carbonate solution, followed by extrac The compound of Preparative Example 71 (552 mg) was tion with chloroform and drying over anhydrous magnesium 40 dissolved in acetic acid (10 ml), and concentrated hydrochlo sulfate, and the solvent was then evaporated under reduced ric acid (2.5 ml) was added thereto, followed by heating under pressure. The residue was purified by silica gel column chro reflux. The reaction mixture was neutralized by adding an matography (eluent; n-hexane:ethyl acetate 4:1-2: 1) to excessive amount of a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate. After wash obtain (3aRS,8bSR)-3a.8b-dimethyl-1,2,3.3a.4.8b-hexahy ing with Saturated brine and drying over anhydrous Sodium droindeno1,2-bipyrrole as a colorless oily substance. This 45 Sulfate, the solvent was evaporated under reduced pressure. was made into a hydrochloride by a conventional method, The residue was dissolved in methanol, and sodium borohy washed with n-hexane/ethyl acetate, and then collected by dride was added thereto under ice-cooling, followed by stir filtration to obtain (3aRS.8bSR)-3a.8b-dimethyl-1,2,3.3a.4, ring at the same temperature for 30 minutes. A saturated 8b-hexahydroindeno1,2-bipyrrole hydrochloride (80 mg) as aqueous ammonium chloride Solution was added thereto to a colorless powder. 50 stop the reaction, and then a saturated aqueous sodium hydro gen carbonate solution was added thereto, followed by extrac Example 37 tion with ethyl acetate. After drying over anhydrous sodium Sulfate, the solvent was evaporated under reduced pressure, A Raney nickel Suspension (2 ml) was sufficiently washed and the residue was purified by basic silica gel column chro with water, and a solution of the compound of Preparative 55 matography (eluent; n-hexane:ethyl acetate-10:1-2: 1) to Example 1 (1.99 g) in methanol (50 ml) was added thereto. obtain (4aRS,9bSR)-4a-methyl-2,3,4,4a,5.9b-hexahydro The mixture was stirred at room temperature for 2 days under 1H-indene 1.2-bipyridine (164 mg) as an oily Substance. a hydrogen atmosphere and filtered through Celite, and the This was made into a hydrochloride by a conventional filtrate was concentrated under reduced pressure. The residue method, washed with ethyl acetate, and collected by filtration was dissolved in diethyl ether (50 ml), and a borontrifluoride 60 to obtain (4aRS,9bSR)-4a-methyl-2,3,4,4a,5.9b-hexahydro diethyl ether complex (1.85g) was added thereto under ice 1H-indeno1,2-bipyridine hydrochloride as a colorless pow cooling. A solution of 1 M methyl lithium in diethyl ether (30 der. ml) was further added at the same temperature, followed by stirring at room temperature for 3 hours. A 1 M aqueous Example 40-1 and Example 40-2 sodium hydroxide solution was added thereto, followed by 65 extraction with chloroform and drying over anhydrous mag To a solution of the compound of Preparative Example 57 nesium sulfate, and the solvent was evaporated under reduced (1.27 g) in methylene chloride (20 ml) was added a solution of US 8,21 1907 B2 43 44 1 Mboron tribromide in methylene chloride (12.4 ml) under temperature for 30 minutes, and a solution of 1.4 M methyl ice-cooling, followed by stirring at room temperature for 3 magnesium bromide in tetrahydrofuran/toluene was added hours. To the reaction solution was added water, followed by dropwise thereto. The reaction liquid was slowly warmed to extraction with ethyl acetate, the organic layer was washed room temperature over 2 hours, and then heated and stirred at with Saturated brine and then dried over anhydrous magne 60° C. overnight. To the reaction mixture was added a 30% sium Sulfate, and the solvent was evaporated under reduced aqueous Sodium hydroxide Solution, the mixture was then pressure. The residue was dissolved in N,N-dimethyl forma filtered through Celite, and the filtrate was extracted with mide (20 ml), and sodium azide (809 mg) was added thereto methylene chloride. The organic layer was dried over anhy at room temperature, followed by stirring for 3 days. To the drous magnesium sulfate, the solvent was then evaporated reaction solution was added water, followed by extraction 10 under reduced pressure, and the residue was purified by silica with ethyl acetate, the organic layer was washed with water gel column chromatography (eluent; chloroform: methanol: and Saturated brine, and then dried over anhydrous magne saturated aqueous ammonia=10:1:0.1) to obtain (4aRS, sium Sulfate, and the solvent was evaporated under reduced 9bRS)-1.2.2.4a-tetramethyl-2,3,4,4a,5.9b-hexahydro-1H pressure. Further, the residue was dissolved in methanol (20 indeno1.2-bipyridine (19 mg) as an oily Substance. This was ml), and tri-n-butyl phosphine (2.3 ml) was added thereto, 15 made into a salt using an equivalent amount of methane followed by stirring overnight. The reaction solution was sulfonic acid by a conventional method, washed with ethyl concentrated under reduced pressure, and the residue was acetate, and collected by filtration to obtain (4aRS.9bRS)-1, dissolved in ethyl acetate and extracted twice with 1 M hydro 2.2.4a-tetramethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2- chloric acid (20 ml). The aqueous layer was basified by the bipyridine methanesulfonate (15 mg) as an off-white powder. adding a 1 Maqueous sodium hydroxide solution, extracted with chloroform, and dried over anhydrous magnesium Sul Example 42 fate, and the solvent was evaporated under reduced pressure. Thereafter, the residue was dissolved in 1,2-dichloroethane To a solution of (4aRS.9bRS)-4a-methyl-2,3,4,4a,5.9b (20 ml), acetic acid (1.78 ml) was added thereto, followed by hexahydro-1H-indeno1,2-bipyridine (140 mg) in tetrahy stirring at room temperature for 30 minutes, and then sodium 25 drofuran (3 ml) were added a 35% formalin solution (0.55 ml) triacetoxyborohydride (2.64 g) was added thereto, followed and formic acid (0.3 ml), and the mixture was stirred at 80°C. by stirring at room temperature overnight. The reaction Solu for 1 hour. An excessive amount of a saturated aqueous tion was concentrated under reduced pressure, and the residue Sodium hydrogen carbonate Solution was added thereto for was dissolved in ethyl acetate and extracted twice with 1 M neutralization, followed by extraction with chloroform, the hydrochloric acid (20 ml). The aqueous layer was basified by 30 organic layer was dried over anhydrous magnesium sulfate, adding a 1 Maqueous sodium hydroxide solution, extracted and the solvent was evaporated under reduced pressure to with chloroform, and dried over anhydrous magnesium sul obtain an oily substance (150 mg). This was made into a fate, and the solvent was evaporated under reduced pressure. methanesulfonate using an equivalent amount of methane The residue was purified by basic silica gel column chroma sulfonic acid by a conventional method, washed with ethyl tography (eluent; n-hexane:ethyl acetate 2:1-1:1) to obtain 35 acetate, and collected by filtration to obtain (4aRS.9bRS)-1, (3aRS,8bSR)-3a-methyl-1,2,3.3a.4.8b-hexahydroindeno1, 4a-dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1.2-bpy 2-bipyrrole (172 mg) as a colorless oily substance and further ridine methanesulfonate (193 mg) as a colorless powder. a mixture of aminoketone products (242 mg) as an oily Sub stance. Further, the aminoketone mixture was dissolved in Example 59 1,2-dichloroethane (10 ml), acetic acid (0.36 ml) was added 40 thereto, followed by heating and stirring at 80° C. for 30 To a solution of (4aRS.9bRS)-4a-methyl-2,3,4,4a,5.9b minutes, and Sodium triacetoxyborohydride (2.64 g) was hexahydro-1H-indeno1,2-bipyridine (140 mg) and acetone added thereto, followed by heating and stirring at the same (217 mg) in 1,2-dichloroethane was added sodium triac temperature for 2 hours. The reaction solution was concen etoxyborohydride (792 mg), followed by stirring at room trated under reduced pressure, and the residue was dissolved 45 temperature for 3 days. A 1 M aqueous sodium hydroxide in ethyl acetate and extracted twice with 1 M hydrochloric solution was added thereto, followed by extraction with chlo acid (20 ml). The aqueous layer was basified by adding a 1 M roform, the organic layer was dried over anhydrous magne aqueous Sodium hydroxide Solution, extracted with chloro sium sulfate, and the solvent was then evaporated under form, and dried over anhydrous magnesium sulfate, and the reduced pressure to obtain (4aRS.9bRS)-1-isopropyl-4-a-me solvent was evaporated under reduced pressure. The residue 50 thyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine was purified by basic silica gel column chromatography (elu (138 mg) as an oily Substance. This was made into a salt using ent; n-hexane:ethyl acetate=2:1-1: 1) to obtain (3aRS,8bSR)- an equivalent amount of methanesulfonic acid by a conven 1-ethyl-3a-methyl-1,2,3,3a.4.8b-hexahydroindeno1,2-b tional method, washed with ethyl acetate, and collected by pyrrole (99 mg) as a colorless oily substance. The obtained filtration to obtain (4aRS.9bRS)-1-isopropyl-4a-methyl-2,3, product was each made into a hydrochloride by a conven 55 4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine methane tional method, washed with ethyl acetate, and collected by Sulfonate (95 mg) as a colorless powder. filtration to obtain (3aRS,8bSR)-3a-methyl-1,2,3.3a.4.8b hexahydroindeno1,2-bipyrrole hydrochloride Example Example 62 40-2 and (3aRS,8bSR)-1-ethyl-3a-methyl-1,2,3.3a.4.8b hexahydroindeno1,2-bipyrrole hydrochloride Example 60 To a solution of (4aRS.9bRS)-4a-methyl-2,3,4,4a,5.9b 40-1, respectively, as a colorless powder. hexahydro-1H-indeno1,2-bipyridine (140 mg) in 1,2- dichloroethane (3 ml) were added acetic acid (0.214 ml) and Example 41 sodium triacetoxyborohydride (1.1 g), followed by heating and stirring at 70° C. for 3 hours. The reaction solution was To a solution of the compound of Preparative Example 99 65 basified by adding a 1 Maqueous sodium hydroxide solution, (22.9 mg) in tetrahydrofuran (2 ml) was added titanium tetra extracted with chloroform, and dried over anhydrous magne chloride (201 mg) at -20°C., followed by stirring at the same sium sulfate, and the solvent was evaporated under reduced US 8,21 1907 B2 45 46 pressure to obtain (4aRS.9bRS)-1-ethyl-4-a-methyl-2,3,4,4a, amount of (+)-dibenzoyl-D-tartaric acid monohydrate, 5.9b-hexahydro-1H-indeno1,2-bipyridine (105 mg) as an recrystallization from ethyl acetate was repeated three times oily substance. This was made into a hydrochloride by a to carry out the optical resolution, and then the product was conventional method, washed with ethyl acetate, and col made into a free from by a conventional method to obtain lected by filtration to obtain (4aRS.9bRS)-1-ethyl-4a-me (-)-(4aR*.9bR)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-in thyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine deno1,2-bipyridine Example 79-1 as a colorless oily sub hydrochloride (108 mg) as a colorless powder. stance. (96% e.e.) Similarly, the optical resolution was carried out using (-)- Example 63 dibenzoyl-L-tartaric acid monohydrate to obtain an enanti 10 omer of the compound of Example 79-1, (+)-(4aR*.9bR)- To a solution of the compound of Preparative Example 4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno 1.2-b 70-1 (1.97g) in methanol (30 ml) was added 10% palladium pyridine Example 79-2). (97% e.e.) supported carbon (300 mg), followed by stirring at room The optical purity was measured by HPLC under the fol temperature for 4 hours at normal pressure under a hydrogen lowing condition. atmosphere. After filtration through Celite, the filtrate was 15 column: CHIRALCEL OD-RH (4.6x150 mm), eluent: concentrated to obtain (4aRS.9bRS)-4a,9b-dimethyl-2,3,4, acetonitrile/0.1 M aqueous KPF solution=35/65, flow rate: 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine (1.17 g) as an 0.5 ml/min. UV wavelength: 210 nm, retention time: 9.46 oily substance. This was made into a hydrochloride by a min. ((+) form), 12.29 min. ((-) form) conventional method, washed with ethyl acetate, and col lected by filtration to obtain (4aRS.9bRS)-4a,9b-dimethyl-2, Example 80-1 and Example 80-2 3.4.4a.5.9b-hexahydro-1H-indeno1.2-bipyridine hydro chloride as a colorless powder. (4aRS.9bRS)-4a,9b-dimethyl-2,3,4,4a,5.9b-hexahydro 1H-indeno1,2-bipyridine was made into a salt using an Example 73 equivalent amount of (-)-di-p-toluoyl-L-tartaric acid, recrys 25 tallization from ethyl acetate and then from methanol was To a solution of the compound of Preparative Example 83 conducted to carry out the optical resolution, and then the (40 mg) in ethyl acetate (3 ml) was added a solution of 4M product was made into a free from by a conventional method hydrogen chloride in ethyl acetate (1 ml), followed by stirring to obtain (-)-(4aR*.9bR*)-4a,9b-dimethyl-2,3,4,4a,5.9b for 3 days. The reaction solution was extracted with water, hexahydro-1H-indeno1,2-bipyridine Example 80-1 as a basified by adding carbonate, and extracted with ethyl 30 colorless oily substance (98% ee). acetate. After washing with Saturated brine and drying over Similarly, the optical resolution was carried out using (+)- anhydrous sodium sulfate, the solvent was evaporated under di-p-toluoyl-D-tartaric acid to obtain an enantiomer of the reduced pressure to obtain (4aRS.9bRS)-4a-ethyl-8-(meth compound of Example 80-1, (+)-(4aR*.9bR*)-4a,9b-dim oxymethyl)-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyri ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine dine (23 mg) as an oily Substance. This was made into fuma 35 Example 80-2 (98% ee). rate using an equivalent amount of fumaric acid by a The optical purity was measured by HPLC under the fol conventional method, washed with acetonitrile, and collected lowing condition. by filtration to obtain (4aRS.9bRS)-4a-ethyl-8-(methoxym column: CHIRALCEL OD-RH (4.6x150 mm), eluent: ethyl)-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine acetonitrile/0.1 M aqueous KPF solution=35/65, flow rate: hydrochloride as a colorless powder. 40 0.5 ml/min. UV wavelength: 210 nm, retention time: 7.92 min. ((+) form), 9.72 min. ((-) form) Example 78-1 and Example 78-2 Example 81 (4aRS.9bRS)-4a-Methyl-2,3,4,4a,5.9b-hexahydro-1H-in deno1.2-bipyridine was made into a salt using an equivalent 45 (-)-(4aR.9bR)-4a-Methyl-2,3,4,4a,5.9b-hexahydro-1H amount of (+)-dibenzoyl-D-tartaric acid monohydrate, crys indeno1.2-bipyridine was made into a hydrochloride by a tallization from acetone was repeated three times to carry out conventional method, and then recrystallized from ethyl the optical resolution, and then the product was made into a acetate/ethanol to obtain (4aR.9bR)-4a-methyl-2.3.4.4a.5, free from by a conventional method to obtain (-)-(4aR.9bR)- 9b-hexahydro-1H-indeno1.2-bipyridine hydrochloride as a 4a-methyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyri 50 colorless crystal. dine Example 78-1 as a colorless oily substance. (93% e.e.) Similarly, the optical resolution was carried out using (-)- Example 82 dibenzoyl-L-tartaric acid monohydrate to obtain an enanti omer of the compound of Example 78-1, (+)-(4aS.9bS)-4a (+)-(4aS.9bS)-4-a-Methyl-2,3,4,4a,5.9b-hexahydro-1H methyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine 55 indeno1.2-bipyridine was made into a hydrochloride by a Example 78-2). (97% e.e.) conventional method and then recrystallized from ethyl The optical purity was measured by HPLC under the fol acetate/ethanol to obtain (4aS.9bS)-4-a-methyl-2.3.4.4a.5, lowing condition. 9b-hexahydro-1H-indeno1.2-bipyridine hydrochloride as a column: CHIRALCEL OD-RH (4.6x150 mm), eluent: colorless crystal. acetonitrile/0.1 M aqueous KPF solution=35/65, flow rate: 60 0.5 ml/min. UV wavelength: 210 nm, retention time: 7.6 min. Example 83-1 and Example 83-2 ((+) form), 8.7 min. ((-) form) (-)-(4aR*.9bR)-4a-Ethyl-2,3,4,4a,5.9b-hexahydro-1H Example 79-1 and Example 79-2 indeno1.2-bipyridine and (+)-(4aR*.9bR)-4a-ethyl-2,3,4, 65 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine were each (4aRS.9bRS)-4a-Ethyl-2,3,4,4a,5.9b-hexahydro-1H-in made into a hydrochloride by a conventional method, washed deno1.2-bipyridine was made into a salt using an equivalent with ethyl acetate, and then collected by filtration to obtain US 8,21 1907 B2 47 48 (4aR*.9bR*)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno TABLE 4-continued 1,2-bipyridine hydrochloride and an enantiomer thereof, respectively, as a colorless powder. Px STRUCTURE

Example 84-1 and Example 84-2 O 2 (-)-(4aR*.9bR)-4a,9b-Dimethyl-2,3,4,4a,5.9b-hexahy dro-1H-indeno 1.2-bipyridine and (+)-(4aR*.9bR*)-4a,9b- CH3 dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyri- 10 HC CH dine were each made into a hydrochloride by a conventional 3 3 method, washed with ethyl acetate, and then collected by filtration to obtain (4aR*.9bR*)-4a,9b-dimethyl-2,3,4,4a,5. O 9b-hexahydro-1H-indeno1.2-bipyridine hydrochloride and 2N an enantiomer thereof, respectively, as a colorless powder. 15 The chemical structural formulae of the Preparative Example compounds are shown in Table 4 to Table 12 below. Further, the chemical structural formulae of the Example compounds are shown in Table 13 to Table 25 below. 2O Further, the production processes and the physical data of 8 O z the Preparative Example compounds are shown in Table 26 to C 2 Table 29 below. Further, the production processes and the physical data of the Example compounds are shown in Table CH 30 to Table 38 below. 25 CH3 3

TABLE 4 9 CH3 O Px STRUCTURE 2N 30 2 1 O N CH3 2.2 CH 10 O 35 2. N 2 O 2N CH3 2 HC 40 11 O H3C H3C C2.N

3 N CH3 M. 45 O C Br 12 O 2N CH3 c2 S 50 CH3 4 O 2N CH3 X^- 55 13 O F N

CH 5 O 60 2N 14 O 2 O N / 2.2 CH H3C CH3 US 8,21 1907 B2

TABLE 4-continued TABLE 5-continued

Px STRUCTURE Px STRUCTURE 5 23 OH 15 N N M 2. O C CH3 HC-( 10 HC S CH3 24 OH N 16 O 2. Br %N 15 CH CH3 H3C CH3

2O 25 N TABLE 5 2.

Px STRUCTURE

17 O 25 CH

26 CEN 30 18 /W CH3 CH O C X-C’s 27 OH 35 CH O 3 2 CH3 19 OH HC aN 40 c2 28 CH OH CH3 2 OH N 45 CH 22 29 OH H3C C2.N

CH3 21 N M OH C 30 OH Br 55 2

CH CH3 S 3

22 OH CH3 2N 60 c2 31 OH F C2.N

65 CH US 8,21 1907 B2

TABLE 5-continued TABLE 6-continued

Px STRUCTURE Px STRUCTURE 5 40 O 32 OH & NH C HC1 O Br CH3 10 S CH

41 TABLE 6 15 Px STRUCTURE

33 N M OH C ic-( 2O S CH 3 42

34 OH 25 Br 22 N CH3

35 OH 30 CH3 43

CEN 35 36 2.N C OH

40

O 44 CH

37 N M 45 OH C

O CH 50 45 38

55

39 46 O 60 US 8,21 1907 B2

TABLE 7 TABLE 7-continued

Px STRUCTURE Px STRUCTURE

47 5 S4 O H N

10 O CH3 48 55 O H N 15

O CH 2O 56 O 49 O s-N/ CH3

25

57 O 50 30 'Neil, CH

s 58 O

35 On 51-1 O CH NH O 40

HC-6 59 O S CH N s-N/ 51-2 O NH 45

50 TABLE 8 52 Px STRUCTURE

60 O

N OXCH 53 61 O 60 N

65 US 8,21 1907 B2 55 TABLE 8-continued TABLE 8-continued

Px STRUCTURE Px STRUCTURE

62-1 66 O- CH 3 z %2

10 CH3 CH3

67 O

15 CH3 CH3

62-2

2O

O 68 HC OH 2.2N 25 CH

69 HC NH 2N 30 2 63-1 CH

O-/ 35 TABLE 9

Px STRUCTURE

70-1 40

O 45 63-2 HC-, N

50 CH3

70-2

64 55

CH O 60 o 65 H3C N

CH 65 CH US 8,21 1907 B2 57 58 TABLE 9-continued TABLE 9-continued

Px STRUCTURE Px STRUCTURE

71 O O CH3

N

O

72-1 O H

- Cl OH CH

72-2 O H

N - Cl OH CH

30 73 O TABLE 10 H N Px STRUCTURE

O CH3

74 O H N

O CH

75

CEN

76 O

CEN

77 O H N

HO

OH 65 CH3 US 8,21 1907 B2 59 60 TABLE 10-continued TABLE 10-continued

Px STRUCTURE Px STRUCTURE

83

10

15

84 TABLE 11

Px STRUCTURE

85

86 US 8,21 1907 B2 61 62 TABLE 11-continued TABLE 12

Px STRUCTURE Px STRUCTURE

96 91 H N

10 - O N 97 15

CH

92

98

25

30

99

35

93

40 100 O H N

45 S CH 94 101 O O 50 CH

c O CH3 55 CH

102

95 HC No O O 60 o1 CH

CH3 65 s US 8,21 1907 B2 63 64 TABLE 12-continued TABLE 13

Px STRUCTURE Ex STRUCTURE Sal

103

104

105

106

107

108 O S 55 HO CH HC CH Br 60 7 CH3 H CL 109 O N Br CH % S 65 CH US 8,21 1907 B2 6 5 66 TABLE 1.4 TABLE 1.5

Ex STRUCTURE Sal Ex STRUCTURE Sal

CL 16 © –

10

CL

CH

CL

CH3

CL

CL

O

CL

O 50 CH

14 |IZ CL 22 Q –

55

15 CL 60 23 CL

65 US 8,21 1907 B2 67 68 TABLE 16 TABLE 17

Ex STRUCTURE Sal Ex STRUCTURE Sal

24 CL 29-1 CL

10 OH NH

25

CL

OH CH

26-1 CL

26-2 CL

CL 27-1

CH M N V CH3

CL 27-2

CH3 M N V CH

28 CL

|IZ V CH US 8,21 1907 B2 69 70 TABLE 18 TABLE 19

Ex STRUCTURE Sal Ex STRUCTURE Sal

34-2 CL 40-1 CL

10

15 40-2 MS

35 CL

41 MS

25

36 CL 30 42 MS

CH3 35

37 CL

43 BR 40

38-1 CL 45

44 MS

50

38-2 CL

55 CH 45 MS

39 CL 60

65 US 8,21 1907 B2 71 72 TABLE 20 TABLE 21

Ex STRUCTURE Sal Ex STRUCTURE Sal 53 HC MS N

46 HC MS N N N

MS

47

CL

48

BR

49

BR

50

MS

51

55 TABLE 22

CH3 Ex STRUCTURE Sal 59 CH3 MS 52 MS 60 N

65 CH3 US 8,21 1907 B2 73 74 TABLE 22-continued TABLE 23-continued

Ex STRUCTURE Sal Ex STRUCTURE Sal 5 60 MS 66 N N CL & s

10 CH3

61 MS

62 CL

63 H CL H3C N

CH

64 H CL N

V CH

TABLE 23 55 TABLE 24 STRUCTURE Sal Ex STRUCTURE Sal H CL N 72 H CL

w

65

US 8,21 1907 B2 89 90 TABLE 40 TABLE 40-continued

No STRUCTURE No STRUCTURE 19

11 H N

10

12 15

2O INDUSTRIAL APPLICABILITY

13 H The compound according to the present invention has an H3C N NMDA receptor inhibitory action and can be used as a pro phylactic and/or therapeutic agent for Alzheimer's disease, cerebrovascular dementia, Parkinson's disease, ischemic Cy) 25 apoplexy, pain, intractable depression, attention deficit CH hyperactivity disorder, migraines, schizophrenia, generalized anxiety disorder, obsessive-compulsive disorder, autism, 14 30 bulimia, drug addiction, or the like.

The invention claimed is: 1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: 3 35

15 (I) R3 R2 40 n 3 (R'), X m X2 XI R4 16 45 wherein Ring. A represents a benzene ring, R" represents Calkyl which may be substituted with one or more groups selected from the group consisting of —OH, -O-C alkyl, amino which may be substi 50 tuted with one or two C- alkyl, and oxo; —O—C. alkyl; halogen; cyano; or cyclic amino, in represents an integer of 0 to 4. 17 R represents —H or C, alkyl, R represents C alkyl which may be substituted with 55 phenyl, cycloalkyl, or —H. R" represents Calkyl which may be substituted with one or more groups selected from the group consisting of —OH, -O-C alkyl, amino which may be substi tuted with one or two Ce alkyl, oxo, and cyclic amino, 18 60 X' represents —CH2— or -CH(R') , X represents –C(R)(R)- X represents –C(R)(RP) , m represents an integer of 1 to 3. R" represents —H, or R' is combined with R" to represent 65 Cs alkylene, and, R. R. R. and RP independently represent —H or C. alkyl, US 8,21 1907 B2 91 92 wherein, in the case where m represents 2 or 3, each of R dine, (4aS.9bS)-4-a-methyl-2,3,4,4a,5.9b-hexahydro-1H and RP may be the same as or different from each other, indeno1.2-bipyridine, (4aRS.9bRS)-4-a-ethyl-2.3.4.4a.5, and provided that 2-(1,2,3,4,5,9b-hexahydro-4aH-in 9b-hexahydro-1H-indeno1.2-bipyridine, (4aR.9bR)-4-a- deno1,2-bipyridin-4a-yl)-N,N-dimethylethaneamine ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, is excluded. 5 (4aS.9bS)-4-a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1, 2. The compound or a pharmaceutically acceptable salt 2-bipyridine, (4aRS.9bRS)-4-a,9b-dimethyl-2,3,4,4a,5.9b thereof of claim 1, wherein X is —CH. , X is —CH2—, hexahydro-1H-indeno1,2-bipyridine, (4aR.9bR)-4-a,9b X is —CH2—, and m is 2. dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1.2-b 3. The compound or a pharmaceutically acceptable salt pyridine, or (4aS.9bS)-4-a,9b-dimethyl-2,3,4,4a,5.9b thereof of claim 2, wherein R is methyl, ethyl, isopropyl, 10 hexahydro-1H-indeno1.2-bipyridine, or a pharmaceutically methoxymethyl, or ethoxymethyl. acceptable salt thereof. 4. The compound or a pharmaceutically acceptable salt 9. A pharmaceutical composition comprising the com thereof of claim3, wherein R is -H, methyl, or ethyl. pound or a pharmaceutically acceptable salt thereof of claim 5. The compound or a pharmaceutically acceptable salt 1, and a pharmaceutically acceptable excipient. thereof of claim 4, wherein R is -H or methyl. 15 10. A method for treating Alzheimer's disease, cerebrovas 6. The compound or a pharmaceutically acceptable salt cular dementia, Parkinson's disease, ischemic apoplexy, thereof of claim 5, wherein n is 0. pain, intractable depression, attention deficit hyperactivity 7. The compound or a pharmaceutically acceptable salt disorder, migraines, schizophrenia, generalized anxiety dis thereof of claim 1, which is (4aRS.9bRS)-4-a-methyl-2,3,4, order, obsessive-compulsive disorder, autism, bulimia, or 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS, drug addiction, comprising administering to a patient an 9bRS)-1,4-a-dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno effective amount of the compound of claim 1 or a pharma 1.2-bipyridine, (4aRS.9bRS)-4-a-ethyl-2,3,4,4a,5.9b ceutically acceptable salt thereof. hexahydro-1H-indeno1,2-bipyridine, (4aR.9bR)-4-a- 11. The method for treating of claim 10, which is a method methyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, for treating Alzheimer's disease, cerebrovascular dementia, (4aS.9bS)-4-a-methyl-2,3,4,4a,5.9b-hexahydro-1H-indeno 25 Parkinson's disease, intractable depression, attention deficit 1,2-bipyridine, (4aRS.9bSR)-4-a-isopropyl-2,3,4,4a,5.9b hyperactivity disorder, or migraines. hexahydro-1H-indeno1,2-bipyridine, (4aR.9bR)-4-a-ethyl 12. (4aR.9bR)-4a-methyl-2,3,4,4a,5.9b-hexahydro-1H 2.3.4.4a.5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aS, indeno1.2-bipyridine or a pharmaceutically acceptable salt 9bS)-4-a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-b thereofas a single optical isomer. pyridine, (4aRS.9bRS)-8-methoxy-1,4-a-dimethyl-2,3,4,4a, 30 13. (4aS.9bS)-4a-methyl-2,3,4,4a,5.9b-hexahydro-1H-in 5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aRS.9bRS)-4- deno1.2-bipyridine or a pharmaceutically acceptable salt a.9b-dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-b thereof as a single optical isomer. pyridine, (4aRS.9bRS)-4-a-(ethoxymethyl)-2,3,4,4a,5.9b 14. (4aR.9bR)-4a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-in hexahydro-1H-indeno1,2-bipyridine, (4aRS.9bRS)-4-a- deno1.2-bipyridine or a pharmaceutically acceptable salt (methoxymethyl)-9b-methyl-2,3,4,4a,5.9b-hexahydro-1H 35 thereofas a single optical isomer. indeno1.2-bipyridine, (5aRS, 10bSR)-5a-methyl-1,2,3,4,5, 15. (4aS.9bS)-4-a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-in 5a,6,10b-octahydroindeno1,2-blazepine, (4aRS.9bRS)-4- deno1.2-bipyridine or a pharmaceutically acceptable salt a-ethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyridin thereofas a single optical isomer. 8-yl)methanol, (4aR.9bR)-4-a,9b-dimethyl-2,3,4,4a,5.9b 16. (4aR.9bR)-4a,9b-dimethyl-2,3,4,4a,5.9b-hexahydro hexahydro-1H-indeno1,2-bipyridine, or (4aS.9bS)-4-a,9b 40 1H-indeno1,2-bipyridine or a pharmaceutically acceptable dimethyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1.2-b salt thereof as a single optical isomer. pyridine, or a pharmaceutically acceptable salt thereof. 17. (4aS.9bS)-4a,9b-dimethyl-2,3,4,4a,5.9b-hexahydro 8. The compound or a pharmaceutically acceptable salt 1H-indeno1,2-bipyridine or a pharmaceutically acceptable thereof of claim 1, which is (4aRS.9bRS)-4-a-methyl-2,3,4, salt thereof as a single optical isomer. 4a,5.9b-hexahydro-1H-indeno1,2-bipyridine, (4aR.9bR)-4- 45 a-methyl-2,3,4,4a,5.9b-hexahydro-1H-indeno1,2-bipyri k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8,211,907 B2 Page 1 of 4 APPLICATIONNO. : 12/741307 DATED : July 3, 2012 INVENTOR(S) : Satoshi Hayashibe et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

TITLE PAGE AT ABSTRACT ITEM (57): Line 6, “completed should read --completing--.

IN THE SPECIFICATIONS:

COLUMN 1: Line 4, “JH2008/071370 should read --JP2008/071370--.

COLUMN 4: Line 20, “completed should read-completing--.

COLUMN 8: Line 61, “an should read -a-.

COLUMN 21: Line 3, “resent should read --resents--.

COLUMN 25: Line 54, “NMR-CDCl3: should read --NMR-CDCl3:--, and Line 55, “NMR-CD3OD:” should read --NMR-CDOD:--.

COLUMN 26: Line58, “amorphous.' should read-amorphous substance.--.

Signed and Sealed this Sixteenth Day of April, 2013 2 2-Y xx 26-e-s? 2.*é-...sé -13 . . Teresa Stanek Rea Acting Director of the United States Patent and Trademark Office CERTIFICATE OF CORRECTION (continued) Page 2 of 4 U.S. Pat. No. 8,211.907 B2

COLUMN 27: Line 67, “amorphous.' should read-amorphous substance.--.

COLUMN 29: Line 66, "acetate, should read -acetate.--.

COLUMN 30: Line 30, “amorphous.' should read-amorphous substance.--.

COLUMN 33: Line 9, “amorphous.' should read-amorphous substance.--.

COLUMN 34: Line 24, “from should read --form--.

COLUMN 35: Line 12, "Separation, should read --Separation:--, and Line 24, “-4-ah-should read ---4aH---.

COLUMN 36: Line 7, "amorphous.' should read -amorphous Substance.--, and Line 42, “form, should read --form:--.

COLUMN 41: Line 36, “were should read --was--.

COLUMN 45: Line 49, “from should read --form--.

COLUMN 46: Line 4, “from should read --form-- Line 27, “from should read --form-- Line 54, “(+)-(4aS.9bS)-4-a-should read --(+)-(4aS.9bS)-4a---, and Line 57, “(4aS.9bS)-4-a- should read --(4aS.9bS)-4a---.