Novel 4-(2-furoyl)aminopiperidines, intermediates in synthesizing the same, process for producing th

专利摘要:
Novel 4- (2-furoyl) aminopiperidine represented by the following formula (I), a synthetic intermediate thereof, a preparation method thereof, and a medicament using the same as an active ingredient are provided [Formula I] In the above formula, X is CH or N, Y is a group of the following general formula (II) or (II-a) or (III), [Formula II] [Formula II-a] [Formula III] Where a, b and c are integers from 0 to 6, Z is CH 2 or NH, W is O or S, T is O or NR 15 , R 15 is H, C 1 -C 6 alkyl group, benzyl group , Phenethyl group, R 1 is H, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group and the like. The 4- (2-furoyl) aminopiperidine derivative obtained by the present invention has an opioid μ-antagonist action and has side effects of opioid μ receptor agonists selected from constipation, nausea, vomiting or pruritus, sudden constipation, and postoperative ileus. It is useful for the prevention or treatment of Usus, Paralytic Ileus, Irritable Bowel Syndrome or Chronic Pruritus.
公开号:KR20040039495A
申请号:KR10-2004-7005180
申请日:2002-10-08
公开日:2004-05-10
发明作者:류따 후꾸또미；히또시 이노우에；고지 가와무라；다꾸야 기시모또；마사시 스즈끼；리에 시바야마；가즈꼬 고지마；고이찌로 하기하라
申请人:교린 세이야꾸 가부시키 가이샤；닛신 파마 가부시키가이샤；
IPC主号:

专利说明:

NOVEL 4- (2-FUROYL) AMINOPIPERIDINES, INTERMEDIATES IN SYNTHESIZING THE SAME, PROCESS FOR PRODUCING THE SAME AND MEDICINAL USE OF THE SAME}
[2] An opioid receptor is a receptor to which a drug having a morphine-like action specifically binds, and is present in the central and intestinal nerves. Three types of μ, δ, and κ are known for opioid receptors, and the primary structure of each receptor has been found by cloning of cDNA (Wang JB, FEBS Lett, 338: 217-222, 1994, Simonin F, Mol Pharmacol, 46: 1015-1021, 1994, Simonin F, Proc Natl Acad Sci USA, 92: 7006-7010, 1995). The pharmacological action of these opioid receptors depends on the receptor type (Martin WR, J Pharmacol Exp Ther, 197: 517-532, 1976). The microreceptor is involved in analgesic, respiratory depression, good feeling, mental and physical dependence, resistance, digestive tract locomotion, constipation, constipation and sympathetic action. On the other hand, the δ receptor is involved in analgesia, mental and physical dependence, affective action, and the like, and the κ receptor is involved in analgesia, sedation, bradycardia, diuresis, aversion and axial action.
[3] Morphine is a representative μreceptor agonist (Wood PL, Neuropharmacology, 20: 1215-1220, 1981) and is a potent analgesic used in patients with chronic or postoperative pain. However, morphine has an analgesic effect, and as a side effect, constipation, nausea, vomiting, drowsiness, hallucinations, confusion, respiratory depression, dry mouth, dry mouth, sweating, pruritus, urination disorder, drowsiness, dizziness, Causes myoclonus and the like. Among these, constipation, nausea and vomiting have a high incidence, and there is a high frequency of pruritus at the subarachnoid and epidural administration (Guide to Cancer Pain Treatment Guidelines, Committee for the Preparation of Cancer Pain Treatment Guidelines). Provisional Publications, 68-78, 2000).
[4] Opioid peptides are a generic term for a group of peptides that bind to opioid receptors with morphine-like actions. Those found in the central nervous system and peripheral tissues (intestinal tract, adrenal gland, etc.) are called endogenous opioid peptides. As endogenous opioid peptides, β-endorphins, enkephalins and dynorphins are known, among which β-endorphins and enkephalins have affinity for μ receptors (opioid peptides, Imurahiroo, and Sino Medical History, 240-250, 1985). In addition, the production and release of these endogenous opioid peptides have been reported to be promoted under many stress environments (in Enkephalins and Endorphins, ed. By Plotnikoff NP, Plenum, 1986). In this, endogenous opioid peptides have been pointed out as etiology such as idiopathic constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome and chronic pruritus (Orwoll ES, Endocrinology, 107: 438-442, 1980, Konturek) SJ, Am J Physiol, 238: G384-G389, 1980, Yamaguchi T, Jpn J Pharmacol, 78: 337-343, 1998).
[5] Therefore, the μ receptor antagonist is considered to be effective against the side effects of the μ receptor agonist such as constipation, nausea, vomiting and pruritus, diseases such as idiopathic constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome and chronic pruritus. .
[6] According to Japanese Patent Application Laid-Open No. 63-264460, a flexible compound based on fentanyl, an opioid μ receptor agonist, and a drug having an action of reversing respiratory inhibition, which is one of the side effects of morphine, in formula (XI), that is, opioid μ receptor antagonists have been found.
[7] Formula XI
[8]
[9] However, since opioid μ receptor antagonism of this drug is not sufficient as a therapeutic drug for digestive tract dysfunction such as constipation and irritable bowel syndrome, a stronger opioid μ receptor antagonist is required.
[1] The present invention provides novel 4- (2-furoyl) aminopiperidine and its preparation method, its synthetic intermediate and its preparation method, its in vivo metabolite, and its medicament, more specifically opioid μ Its use as an antagonist.
[10] MEANS TO SOLVE THE PROBLEM As a result of earnestly researching in order to solve such a subject, this inventor is following formula (XI) which is a fentanyl flexible compound disclosed by following Unexamined-Japanese-Patent No. 63-264460:
[11] Formula XI
[12]
[13] The 4-methylpyridin-2-yl group in the compound of the compound is structurally converted into a 5-methylpyridin-2-yl group or a p-toluyl group, and a cycloalkyl group is sandwiched between the appropriate spacer moieties bonded to one of the piperidine rings. A potent opioid μreceptor antagonist action was found for the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, which corresponds to the compound to which the is attached.
[14] [Formula I]
[15]
[16] [In the meal,
[17] X is CH or N,
[18] Y is formula (II), or formula (II-a), or formula (III),
[19] [Formula II]
[20]
[21] [Formula II-a]
[22]
[23] [Formula III]
[24]
[25] Where a, b and c are integers from 0 to 6, Z is CH ₂ or NH, W is O or S, T is O or NR ¹⁵ , R ¹⁵ is H, C 1 -C 6 alkyl group, benzyl group , Phenethyl group, R ¹ is H, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, 2-phenyl-1,3-dioxan-5-yl group, 2,2-dimethyl-1,3-dioxane- A 5-yl group or formula (IV), R ² is H or a formula (IV),
[26] [Formula IV]
[27]
[28] Wherein d is an integer of 0 to 6, R ³ , R ⁴ and R ⁵ are the same or different and are H, or-(CH ₂ ) _e R ⁶ , or-(CH ₂ ) _f CONR ⁷ R ⁸ ,
[29] E and f are integers of 0-6, R <^6> is a hydroxyl group, a C1-C6 alkanoyloxy group, a benzoyloxy group, a 2-furoyloxy group, a C1-C6 alkoxy C1-C6 alkoxy group, a C1-C6 alkoxycar Bonylphenoxy group, carboxyphenoxy group, dicarboxyphenoxy group, di C1-C6 alkoxycarbonylphenoxy group, dihydroxy C1-C6 alkylphenoxy group, amino group, C1-C6 alkoxycarbonylamino group, C1-C6 alkylsulfonamide group , Benzenesulfonamide group, p-toluenesulfonamide group, p-halobenzenesulfonamide group, carboxyl group, C1-C6 alkoxycarbonyl group, carbohydroxamic acid group, carbohydroxamic acid C1-C6 alkyl ester group, cyano group , 1H-tetrazol-5-yl group, 1-C1-C6 alkyl-1H-tetrazol-5-yl group, 2-C1-C6 alkyl-2H-tetrazol-5-yl group, N ² -hydroxycarbami Doyle group, N ¹ -C ^{1 to} C6 alkoxycarbonyl-N ² -hydroxycarbamididoyl group, 2H-5-thioxo-1,2,4-oxadiazol-3-yl group, 2H-5-oxo -1,2,4-oxa A diazol-3-yl group, a guanidino group, a di C1-C6 alkoxycarbonylguanidino group, a morpholinocarbonyl group, and R ⁷ and R ⁸ are the same or different, and are H, C1-C6 alkyl group, and C1-C6. C6 alkanoyloxy C1-C6 alkyl group, hydroxy C1-C6 alkyl group, bis (C1-C6 alkanoyloxy C1-C6 alkyl) methyl group, bis (hydroxy C1-C6 alkyl) methyl group, tris (C1-C6 alkanoyloxy C1-C6 alkyl) methyl group, tris (hydroxy C1-C6 alkyl) methyl group, carboxy C1-C6 alkyl group, C1-C6 alkoxycarbonyl C1-C6 alkyl group, N, N-bis (C1-C6 alkoxycarbonyl C1-C6 Alkyl) carbamoyl C1-C6 alkyl group, N, N-bis (carboxy C1-C6 alkyl) carbamoyl C1-C6 alkyl group, C1-C6 alkylsulfonyl group, carboxyphenyl group and pyrazinyl group.
[30] In addition, the group of compounds was a drug having high peripheral selectivity and little selectivity to the digestive tract with little peripheral action. Therefore, 4- (2-furoyl) aminopiperidine of the present invention has side effects caused by μ receptor agonists such as constipation, nausea, vomiting and pruritus, idiopathic constipation, postoperative ileus, paralytic ileus, and irritable bowel. It is considered to be effective against diseases such as syndrome and chronic pruritus.
[31] Substituent Y of the compound described in general formula (I) always has a group selected from a cycloalkyl group, a piperidinyl group, and a tetrahydropyranyl group, as described in the general formulas (II), (II-a) and (III). . B in general formula (II) and (III) is an integer of 0-6, Specifically, this cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and Cyclononyl group is mentioned.
[32] The cycloalkyl group, the piperidinyl group, the tetrahydropyranyl group and the piperidinyl group of the compound described in the formula (I) are bonded to each other via the structures described in the formulas (II), (II-a) and (III). have. In addition, a cycloalkyl group, a piperidinyl group, and a tetrahydropyranyl group have a substituent defined by R <^1> .
[33] Specific examples of R ¹ include hydrogen, a carboxyl group, a carboxymethyl group, a 3-carboxypropyl group, a 3,3-bis (carboxy) propyl group, a N, N-bis (carboxymethyl) carbamoylmethyl group, and N- (carboxy Methyl) carbamoylmethyl group, N- (2-carboxyethyl) carbamoylmethyl group, N, N-bis [N, N-bis (carboxymethyl) carbamoylmethyl] carbamoylmethyl, methoxycarbonyl group, meth Methoxycarbonylmethyl group, 3-methoxycarbonylpropyl group, 3,3-bis (methoxycarbonyl) propyl group, 3,3,3-tris (ethoxycarbonyl) propyl group, N, N-bis ( Ethoxycarbonylmethyl) carbamoylmethyl group, N- (ethoxycarbonylmethyl) carbamoylmethyl group, N- (2-ethoxycarbonylethyl) carbamoylmethyl group, N- (3-ethoxycarbonyl Propyl) carbamoylmethyl group, N, N-bis [N, N-bis (ethoxycarbonylmethyl) carbamoylmethyl] carbamoylmethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 3, 3-bis (hydroxymethyl) prop Lofil group, 5-hydroxy-3,3-bis (hydroxymethyl) pentyl group, 1,3-dihydroxy-2-propyl group, 6-carboxy-3,3-bis (hydroxymethyl) hexyl group , 6-methoxycarbonyl-3,3-bis (hydroxymethyl) hexyl group, tris (hydroxymethyl) methylcarbamoylmethyl group, N, N-bis [tris (hydroxymethyl) methylcarbamoylmethyl ] Carbamoylmethyl group, 3-acetoxypropyl group, 3,3-bis (acetoxymethyl) propyl group, 3,3-bis (methoxymethoxymethyl) propyl group, 5-acetoxy-3,3- Bis (acetoxymethyl) pentyl group, 2-phenyl-1,3-dioxan-5-yl group, 2,2-dimethyl-1,3-dioxan-5-yl group, 6-methoxycarbonyl-3, 3-bis (benzoyloxymethyl) hexyl group, 2- (2-furoyloxy) ethyl group, tris (acetoxymethyl) methylcarbamoylmethyl group, carbamoylmethyl group, cyanomethyl group, 2-cyanoethyl group, 2 -(Tetrazolyl) ethyl group, acethydroxysamic acid group, N- (t-butoxy) carbamoylmethyl group, 2-aminoethyl group, 2- (t-butoxycar Samide) ethyl group, 2- (methanesulfonamide) ethyl group, 2- (p-chlorobenzenesulfonamide) ethyl group, 2- (2-methoxycarbonylphenoxy) ethyl group, 2- (2-carboxyphenoxy) ethyl group , 2- (3,5-dicarboxyphenoxy) ethyl group, 2- (3,5-dimethoxycarbonylphenoxy) ethyl group, 2- (3,5-dihydroxymethylphenoxy) ethyl group, 2- ( 1-methyl-1H-tetrazol-5-yl) ethyl group, 2- (2-methyl-2H-tetrazol-5-yl) ethyl group, 2- (N ¹ -methoxycarbonyl-N ² -hydroxycar Bamidoyl) ethyl group, 2- (1,2-dimethoxycarbonylguanidino) ethyl group, methanesulfonylcarbamoylmethyl group, carboxyphenylcarbamoylmethyl group, pyrazinylcarbamoylmethyl group, etc. are mentioned. .
[34] In the group of the formula (Ⅱ) - a (CH ₂₎ Specific examples of the a- example, there may be mentioned a single bond, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group and hexamethylene group, etc. .
[35] Specific examples of the group of the formula (II-a) include a 2- [4- (2-hydroxyethyl) tetrahydropyran-4-yl] ethyl group, 2- [1-benzyl-4- (2-hydroxy Ethyl) piperidin-4-yl] ethyl group.
[36] As a specific example of group of general formula (III), 2- (cyclohexyl acetamide) benzyl group, 2- [2- (cyclohexyl acetamide) phenyl] ethyl group, 2- [2- [N- (cyclo) Hexylacetyl) carboxymethylamino] phenyl] ethyl group, 2- [2- [N- (cyclohexylacetyl) -tert-butoxycarbonylmethylamino] phenyl] ethyl group, 3- [2- (cyclohexylacetamide) Phenyl] propyl group, 3- [2- (3-cyclohexylpropionamide) phenyl] propyl group, 3- [2- [N- (3-cyclohexylpropionyl) carboxymethylamino] phenyl] propyl group, 3- [2- [N- (3-cyclohexylpropionyl) -tert-butoxycarbonylmethylamino] phenyl] propyl group, 3- [2- [N- (3-cyclohexylpropionyl) -3-carboxypropyl Amino] phenyl] propyl group, 2- [2- (3-cyclohexyl ureido) phenyl] ethyl group, 2- [2- [N- (N-cyclohexylcarbamoyl) carboxymethylamino] phenyl] ethyl group, 2 -[2- [N- (N-cyclohexylcarbamoyl) ethoxycarbonylmethylamino] phenyl] ethyl group, 3- [2- (4-cyclohexyl Tyramide) phenyl] propyl group, 2- [2- [N- [1- (carboxymethyl) cyclohexylacetyl] carboxymethylamino] phenyl] ethyl group, 2- [2- [N- [1- (carboxymethyl) Cyclohexylacetyl] ethoxycarbonylmethylamino] phenyl] ethyl group, 2- [2- [1- (carboxymethyl) cyclohexylacetamide] phenyl] ethyl group, 2- [2- [1- (methoxycarbonyl Methyl) cyclohexylacetamide] phenyl] ethyl group, 3- [2- (3-cyclohexyl ureido) phenyl] propyl group and 3- [2- [N- (3-cyclohexylthioureido) phenyl] A profile machine etc. are mentioned.
[37] The compound represented by the general formula (VIII) of the present invention can be obtained by, for example, reacting the compound represented by the general formula (V) with a reactive derivative such as 2-furancarboxylic acid or 2-furoyl chloride.
[38] [Formula Ⅹ]
[39]
[40] [In the meal,
[41] X is CH or N,
[42] Ya is formula (VI), or formula (VI-a), or formula (VII), or formula (VII),
[43] [Formula VI]
[44]
[45] [Formula VI-a]
[46]
[47] [Formula Ⅶ]
[48]
[49] [Formula Ⅷ]
[50]
[51] Wherein a, b and c are integers from 0 to 6, Z is CH ₂ or NH, W is O or S, T is O or NR ¹⁵ , R ¹⁵ is H, a C 1 to C 6 alkyl group, Benzyl group, phenethyl group, R ⁹ is H, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, 2-phenyl-1,3-dioxan-5-yl group, 2,2-dimethyl-1,3-di An oxan-5-yl group or formula (VII), R ¹⁰ is H or formula (VII),
[52] [Formula Ⅸ]
[53]
[54] Wherein d is an integer of 0 to 6, R ¹¹ , R ^12, and R ¹³ are the same or different and are H, or-(CH ₂ ) _e R ¹⁴ , e is an integer of 0 to 6, and R ¹⁴ is C1-C6 alkanoyloxy group, benzoyloxy group, 2-furoyloxy group, C1-C6 alkoxy C1-C6 alkoxy group, C1-C6 alkoxycarbonylphenoxy group, di C1-C6 alkoxycarbonylphenoxy group, dihydroxy C1-C6 alkylphenoxy group, carboxyl group, C1-C6 alkoxycarbonyl group, C1-C6 alkoxycarbonylamino group, benzyloxycarbonyl group, cyano group and C1-C6 alkylsulfonamide group.]
[55] [Formula Ⅴ]
[56]
[57] [Wherein X and Ya are the same as in general formula (X)].
[58] This reaction is carried out at an ice-cold to reflux temperature in an organic solvent such as dichloromethane, chloroform, diethyl ether and tetrahydrofuran.
[59] Specific examples of the base when the 2-furoyl chloride is reacted in the presence of a base include triethylamine and the like.
[60] Specific examples of the compound represented by the formula (X) include N- [1- (cyclohexylmethyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancar Copyamide, N- [1- (2-cyclohexylethyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- ( 3-cyclohexylpropyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- (4-cyclohexylbutyl) piperidine -4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- (2-cyclooctylethyl) piperidin-4-yl] -N- ( 5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- (3-cyclohexylpropyl) piperidin-4-yl] -N- (p-tolyl) -2-furancar Copyamide, N- (1-cyclohexylpiperidin-4-yl) -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [3- [2- (Cyclohexylacetamide) phenyl] propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [2 -(Cyclohexylacetamide) phenyl] ethyl] piperidin-4-yl] -N- (5- Methylpyridin-2-yl) -2-furancarboxamide, [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidine-1 -Yl] ethyl] cyclohexyl] methyl acetate, [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl ] Cyclopentyl] methyl acetate, 1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexanecarboxylate , 1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexanecarboxylic acid, 4- [1- [ 2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate, 3- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl, 3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1-propanedicarboxylic acid Dimethyl, [1- [2- [4- [N- (p-tol) ) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl acetate, acetic acid 3- [1- [4- [N- (5-methylpyridin-2-yl) -2- Furancarboxamide] piperidin-1-yl] methylcyclohexyl] propyl, 2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furan Carboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,3-diacetoxypropane, N- [1- [2- [1- (4-methoxymethoxy) -3 -(Methoxymethoxymethyl) butyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, 2- (acetoxymethyl ) -2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] Ethyl] -1,4-diacetoxybutane, N- [1- [2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperidine-4- Yl] -N-(-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1- (2,2-dimethyl-1,3-dioxan-5-yl ) Cyclohexyl] ethyl] piperidin-4] -yl] -N- (p-tolyl)) 2-furancarboxamide, 5,5-bis (benzoyl Dimethyl) -7- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] heptane Methyl acid, 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl ] Cyclohexyl] methyl heptanoate, 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl ] Ethyl] -1,3-diacetoxypropane, 2-furancarboxylic acid 2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] py Ferridin-1-yl] ethyl] cyclohexyl] ethyl, N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5 -Methylpyridin-2-yl) -2-furancarboxamide, [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] pi Ferridin-1-yl] ethyl] cyclohexyl] ethyl] carbamate tert-butyl, N- [1- [2- [1- (2-methanesulfonamideethyl) cyclohexyl] ethyl] piperidine-4 -Yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- (cyclohexyl Cetamide) benzyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [2- (cyclohexylaceta Mid) phenyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [3- [2- (3-cyclohexylpropionamide) phenyl ] Propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, [2- [3- [4- [N- (5-methylpyridin-2-yl)- 2-furancarboxamide] piperidin-1-yl] propyl] phenyl] carbamic acid tert-butyl, [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide ] Piperidin-1-yl] propyl] phenyl] carbamic acid tert-butyl, N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl ] -N- (p-tolyl) -2-furancarboxamide, 2- (acetoxymethyl) -2- [2- [1- [2- [4- [N- (p-tolyl) -2- Furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,4-diacetoxybutane, 2- [1- [2- [4- [N- (p-tolyl)- 2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethylcarbamate tert-butyl, 5- [2- [1- [2- [ 4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] dimethyl isophthalate, 2- [2- [1- [2- [ 4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] methyl benzoate, 2-furancarboxylic acid 2- [1- [2- [ 4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl, 4- [1- [2- [4- [N- (p- Tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate and 3- [1- [2- [4- [N- (p-tolyl) -2-furancar Copymid] piperidin-1-yl] ethyl] cyclohexyl] -1,1,1- propane tricarboxylic acid triethyl etc. are mentioned.
[61] The compound represented by the following general formula (XII) contained in the compound represented by the general formula (I) of the present invention includes a corresponding methyl ester, ethyl ester and the like as a base (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and Hydrolysis with potassium carbonate) or debenzylating a benzyl ester in the presence of a catalyst (for example, palladium-carbon, etc.) in a hydrogen atmosphere.
[62] [Formula XII]
[63]
[64] [In the meal,
[65] X is CH or N,
[66] Yb is formula (II)
[67] [Formula II]
[68]
[69] A and b are 0 to 6, R ¹ is a carboxyl group or formula (IV),
[70] [Formula IV]
[71]
[72] Wherein d is an integer from 0 to 6, R ³ is H or- (CH ₂ ) _e COOH, R ⁴ and R ⁵ are the same or different and are H, or-(CH ₂ ) _e R ⁶ , e Is an integer of 0 to ⁶ , and R ⁶ is a carboxyl group, a hydroxyl group, a carboxyphenoxy group, or a dicarboxyphenoxy group.].
[73] This reaction is carried out at room temperature to reflux temperature in water or an organic solvent such as methanol, ethanol, 1,4-dioxane, acetic acid and ethyl acetate.
[74] As a specific example of a compound represented by general formula (XII), [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidine-1- Il] ethyl] cyclohexyl] acetic acid, [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclo Pentyl] acetic acid, 4- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] butyric acid , 3- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1 Propanedicarboxylic acid, 3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1, 1-propanedicarboxylic acid, [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid, 5, 5-bis (hydroxymethyl) -7- [1- [2- [4- [N- (5-methylpyridin-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclo Hexyl] heptanoic acid, 5,5-bis (hydroxymethyl) -7- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] heptanoic acid, 5- [2- [1- [2- [4- [N- ( p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] isophthalic acid, 2- [2- [1- [2- [4- [N- (p -Tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzoic acid and 4- [1- [2- [4- [N- (p-tolyl) -2 -Furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] butyric acid, etc. are mentioned.
[75] Furthermore, after activating a compound represented by the formula (XII) with a carboxyl group activator, amino acid esters and amino alcohol acetate esters are reacted, or amino acid esters and amino alcohol acetate esters in the presence of a condensing agent. By reacting, the corresponding amino acid ester derivative and amino alcohol acetate ester derivative can be obtained. Moreover, corresponding amino acid and amino alcohol derivatives can be obtained by hydrolyzing these amino acid ester derivatives and amino alcohol acetate ester derivatives with an acid or a base. The compound obtained in this way is also contained in the compound represented by general formula (I) of this invention.
[76] Specific examples of the carboxyl group activator include oxalyl chloride and thionyl chloride. Specific examples of the condensing agent include dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl hydrochloride). Carbodiimide, Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, Benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate, O- (7-azabenzo Triazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, 2-bromo-1-ethylpyridiniumtetrafluoroborate and 2-fluoro-1-ethylpyridinium Tetrafluoroborate, and the like. Specific examples of the amino acid esters include ethyl acetate, ethyl 3-aminopropionate, ethyl 4-aminobutyrate, diethyl imino acetate, tris (acetoxymethyl) aminomethane, and the like. Used for hydrolysis. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and potassium carbonate, and acids include hydrochloric acid and trifluoroacetic acid.
[77] Specific examples of the obtained amino acid ester derivative, amino alcohol acetate ester derivative, amino acid derivative and amino alcohol derivative include N- [1- [2- [1- [N- [tris (hydroxymethyl) methyl] carbamoylmethyl ] Cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, 2-acetoxymethyl-2- [1- [2- [ 4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide-1,3-diacetoxypropane, 2 -[1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylimino diacetic acid diethyl , 2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetyliminodiacetic acid , 4- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] a Cetamide] ethyl butyrate, [2- [1- [2- [4- [N- (5-methylpyridine-) 2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] ethyl acetate, [2- [1- [2- [4- [N- (5- Methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] acetic acid, 3- [2- [1- [2- [4- [N -(5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] ethyl propionate, 3- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] propionic acid, 4- [2- [1 -[2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclopentyl] acetamide] ethyl butyrate, N- [1- [2- [1- [N, N-bis [N- [tris (acetoxymethyl) methyl] carbamoylmethyl] carbamoylmethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1- [N, N-bis [N- [tris (hydroxymethyl) methyl] Carbamoylmethyl] carbamoyl Methyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, [2- [1- [2- [4- [N -(p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] acetic acid, 4- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] butyric acid, 2- [1- [2- [4- [N- (p-tolyl) ) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetyliminodioacetic acid, 2- [1- [2- [4- [N- (p-tolyl) -2-furan Carboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylimino-N, N-bis (acetyliminodiisacetic acid) tetraethyl and 2- [1- [2- [4- [N- ( p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylimino-N, N-bis (acetylimino diacetic acid), etc. are mentioned.
[78] Carboxamide derivatives can be obtained by reacting a compound represented by the general formula (XII) with ammonia, ammonium salts, amines, amine salts, sulfonamides and the like in the presence of a condensing agent. Specific examples of the amines include morpholine, 2-methoxycarbonylaniline, pyrazinylamine, and the like. Methane sulfonamide etc. are mentioned as a specific example of sulfonamides. Moreover, the corresponding carboxylic acid can be obtained by hydrolyzing an ester derivative among these with an acid or a base. And this carboxamide derivative is also contained in the compound represented by general formula (I) of this invention.
[79] Specific examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro Phosphate, benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate, O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluroniumhexafluoro Rophosphate, 2-bromo-1-ethylpyridium tetramethyl tetrafluoroborate, 2-fluoro-1-ethylpyridium tetrafluoroborate, and the like.
[80] This reaction is carried out at room temperature to reflux temperature in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran and N, N-dimethylformamide.
[81] Examples of the base used for the hydrolysis include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate and the like, and acids include hydrochloric acid and trifluoroacetic acid.
[82] Specific examples of carboxamide derivatives include N- [1- [2- [1- (carbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine-2 -Yl) -2-furancarboxamide, N- [1- [2- [1- (1-methanesulfonylcarbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- ( p-tolyl) -2-furancarboxamide, N- [1- [2- [1- (1,1-dimethylcarbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- (2-morpholin-4-yl-2-oxoethyl) cyclohexyl] ethyl] piperidine-4- Yl] -N- (p-tolyl) -2-furancarboxamide, 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperi Din-1-yl] ethyl] cyclohexyl] acetylamino] benzoic acid, N- [1- [2- [1- [1- (pyrazin-2-yl) carbamoylmethyl] cyclohexyl] ethyl] piperidine -4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- (1,1-dimethylcarbamoylmethyl) cyclohexyl] ethyl] piperi Din-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1 -(2-morpholin-4-yl-2-oxoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, 2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylamino ] Benzoic acid and N- [1- [2- [1- (carbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, etc. Can be mentioned.
[83] Carboxamide derivatives may also be converted to nitrile derivatives in the presence of sulfonyl chloride (eg methanesulfonyl chloride, benzenesulfonyl chloride) and triethylamine. And this nitrile derivative is also contained in the compound represented by general formula (I) of this invention.
[84] This reaction takes place at room temperature to reflux in an organic solvent such as dichloromethane, chloroform, tetrahydrofuran and N, N-dimethylformamide.
[85] Specific examples of the nitrile derivatives include N- [1- [2- [1- (cyanomethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) 2-furancarboxamide and N- [1- [2- [1- (cyanomethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancar A copy mead etc. are mentioned.
[86] Nitrile derivatives can also be converted to tetrazole derivatives by reacting with trimethylsilylazide. And this tetrazole derivative is also contained in the compound represented by general formula (I) of this invention.
[87] This reaction takes place at ice-cold to reflux temperatures in organic solvents such as benzene, toluene, xylene, tetrahydroparan and 1,4-dioxane.
[88] By reacting the tetrazole derivative with trimethylsilyldiazomethane, it can be converted into a separate tetrazole derivative. And this tetrazole derivative is also contained in the compound represented by general formula (I) of this invention.
[89] This reaction is carried out at an ice-cold to reflux temperature in an organic solvent such as methanol, ethanol, benzene, toluene, xylene, tetrahydrofuran and 1,4-dioxane.
[90] Specific examples of the tetrazole derivatives include N- [1- [2- [1- (2-tetazolylethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine-2 -Yl) -2-furancarboxamide, N- [1- [2- [1- (2-tetrazolylethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) 2-furancarboxamide, N- [1- [2- [1- [2- (2-methyl-2H-tetrazol-5-yl) ethyl] cyclohexyl] ethyl] piperidin-4-yl ] -N- (5-methylpyridin-2-yl) -2-furancarboxamide and N- [1- [2- [1- [2- (1-methyl-1H-tetrazol-5-yl) Ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, and the like.
[91] The nitrile derivatives can also be converted to hydroxycarbamimidoyl derivatives by, for example, reacting with hydroxylamine in the presence of a base such as sodium hydrogen carbonate and potassium carbonate. And this hydroxycarbamimidoyl derivative is also contained in the compound represented by general formula (I) of this invention.
[92] This reaction takes place at ice-cold to reflux temperatures in organic solvents such as methanol, ethanol, benzene, toluene, xylene, tetrahydrofuran and 1,4-dioxane.
[93] Specific examples of the hydroxycarbamidoyl derivatives include N- [1- [2- [1- [2- (N ² -hydroxycarbamidoyl) ethyl] cyclohexyl] ethyl] piperidine 4-yl] -N- (p-tolyl) -2-furancarboxamide, etc. are mentioned.
[94] Hydroxycarbamimidoyl derivatives can be converted to thioxoxadiazole derivatives, for example by reacting with 1,1-thiocarbonyldiimidazole. And this thioxooxadiazole derivative is also contained in the compound represented by general formula (I) of this invention.
[95] This reaction is carried out at an ice-cold to reflux temperature in an organic solvent such as acetonitrile, benzene, toluene, xylene, tetrahydrofuran and 1,4-dioxane.
[96] Specific examples of thioxooxadiazole derivatives include N- [1- [2- [1- [2- (2H-5-thioxo-1,2,4-oxadiazol-3-yl) ethyl] Cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, and the like.
[97] The hydroxycarbamimidoyl derivatives can be converted to hydroxymethoxycarbonylcarbamidoyl derivatives by, for example, reacting with methyl chloroformate and the like in the presence of a base such as pyridine. And this hydroxymethoxycarbonylcarbamimidoyl derivative is also contained in the compound represented by general formula (I) of this invention.
[98] This reaction is carried out at an ice-cold to reflux temperature in an organic solvent such as N, N-dimethylformamide, acetonitrile, benzene, toluene, xylene, tetrahydrofuran and 1,4-dioxane.
[99] Specific examples of the hydroxymethoxycarbamimidoyl derivatives include 1- [1-hydroxyimino-3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxa Mid] piperidin-1-yl] ethyl] cyclohexyl] propyl] methyl carbamate etc. are mentioned.
[100] The hydroxymethoxycarbamimidoyl derivatives can be converted to oxooxadiazole derivatives by, for example, reacting with a base such as 1,8-diazabicyclo [5.4.0] -7-undecene. . And this oxooxadiazole derivative is also contained in the compound represented by general formula (I) of this invention.
[101] This reaction is carried out at an ice-cold to reflux temperature in an organic solvent such as acetonitrile, benzene, toluene, xylene, tetrahydrofuran and 1,4-dioxane.
[102] Specific examples of the oxooxadiazole derivatives include N- [1- [2- [1- [2- (2H-5-oxo-1,2,4-oxadiazol-3-yl) ethyl] cyclohexyl ] Ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, etc. are mentioned.
[103] The hydroxylsamic acid derivative can be obtained by reacting a compound represented by the formula (XII) with hydroxylamine hydrochloride, O- (tert-butyl) hydroxyamine hydrochloride and the like. The tert-butyl group can be deprotected with an acid (for example, hydrochloric acid, trifluoroacetic acid, etc.). And this hydroxamic acid derivative is also contained in the compound represented by general formula (I) of this invention.
[104] Specific examples of the hydroxamic acid derivative include [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] Cyclohexyl] acethydroxysamic acid tert-butyl, [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl ] Cyclohexyl] acethydroxysamic acid, [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxy Tert-butyl triacid and [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxysamic acid Can be.
[105] The compound represented by the following general formula (XIII) contained in the compound represented by the general formula (I) of the present invention includes a corresponding acetic acid ester, a benzoyl ester and a 2-furoyl ester as a base (for example, lithium hydroxide, Hydrolyzed by sodium hydroxide, potassium hydroxide and potassium carbonate, or the corresponding acetal bodies (eg 2-phenyl-1,3-dioxan-5-integer, 2,2-dimethyl-1,3-di Oxygen-5-one, methoxymethyl body) is hydrolyzed with an acid (for example hydrochloric acid, p-toluenesulfonic acid, etc.), or the corresponding silyl ether body is acid (for example hydrochloric acid, p-toluenesulfonic acid, etc.) It can be obtained by hydrolyzing with or treating with a fluorination agent (for example, tetra n-butylammonium fluoride or the like).
[106] [Formula XIII]
[107]
[108] [In the meal,
[109] X is CH or N,
[110] Yc is formula (II) or formula (II-a),
[111] [Formula II]
[112]
[113] [Formula II-a]
[114]
[115] Wherein a and b are integers of 0 to 6, T is O or NR ¹⁵ , R ¹⁵ is H, C ¹ to C 6 alkyl group, benzyl group and phenethyl group, R ¹ is of formula (IV),
[116] [Formula IV]
[117]
[118] Wherein d is an integer from 0 to 6, R ³ is-(CH ₂ ) _e OH, R ⁴ and R ⁵ are the same or different and are H, or-(CH ₂ ) _e R ⁶ , and e is 0 It is an integer of -6, R <^6> is a carboxyl group, a hydroxyl group, and dihydroxy C1-C6 alkyl phenoxy group.].
[119] This hydrolysis reaction takes place at room temperature to reflux temperature in water or an organic solvent such as methanol, ethanol and 2-propanol. The treatment with the fluorinating agent is performed at an ice-cold to reflux temperature in an organic solvent such as dichloromethane, chloroform, diethyl ether and tetrahydrofuran.
[120] As a specific example of a compound represented by general formula (XIII), N- [1- (1- (3-hydroxypropyl) cyclohexylmethyl) piperidin-4-yl] -N- (5-methylpyridine- 2-yl) -2-furancarboxamide, N- [1- [2- [1- (4-hydroxy-3-hydroxymethylbutyl) cyclohexyl] ethyl] piperidin-4-yl]- N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1- [5-hydroxy-3,3-bis (hydroxymethyl) pentyl] cyclo Hexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1- [1,3-di Hydroxypropan-2-yl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1- [1,3-dihydroxypropan-2-yl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1 -[2- [1- (4-hydroxy-3-hydroxymethylbutyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, 5 , 5-bis (hydroxymethyl) -7- [1- [2- [4- [N- (5-methylpyridin-2-yl)- 2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] heptanoic acid, 5,5-bis (hydroxymethyl) -7- [1- [2- [4- [N- (p -Tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] heptanoic acid, N- [1- [2- (1- (2-hydroxyethyl) cyclohexyl) ethyl] Piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [2- [1- [5-hydroxy-3,3- Bis (hydroxymethyl) pentyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- [2 -[3,5-bis (hydroxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1 -[2- [1- [2- [3,5-bis (hydroxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine-2- Yl) -2-furancarboxamide, N- [1- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl)- 2-furancarboxamide, N- [1- [2- [1- (2-hydroxyethyl) cyclobutyl] ethyl] piperidin-4-yl] -N- (p -Tolyl) -2-furancarboxamide, N- [1- [2- [1- (2-hydroxyethyl) cyclooctyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [4- (2-hydroxyethyl) tetrahydropyran-4-yl] ethyl] piperidin-4-yl] -N- (p- Tolyl) -2-furancarboxamide and N- [1- [2- [1-benzyl-4- (2-hydroxyethyl) piperidin-4-yl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, etc. are mentioned.
[121] The amine derivative represented by the following general formula (XIV) contained in the compound represented by the general formula (I) of the present invention desorbs the corresponding tert-butoxycarbonyl body in the presence of an acid (for example hydrochloric acid, trifluoroacetic acid). Can be obtained by protection.
[122] [Formula XIV]
[123]
[124] [In the meal,
[125] X is CH or N,
[126] Yd is formula (XV), or formula (XV-a), or formula (XVI)
[127] [Formula XV]
[128]
[129] [Formula XV-a]
[130]
[131] [Formula XVI]
[132]
[133] (Wherein a, b, c, and d are integers of 0 to 6).
[134] This reaction is carried out at room temperature to reflux temperature in water or an organic solvent such as methanol, ethanol, dichloromethane, 1,4-dioxane and ethyl acetate.
[135] As a specific example of the compound represented by general formula (XIV), N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5- Methylpyridin-2-yl) -2-furancarboxamide, N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (5-methylpyridine-2- Yl) -2-furancarboxamide, N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide and N- [1 -[2- [1- (2-guanidinoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, etc. Can be mentioned.
[136] Among the amine derivatives represented by the general formula (XIV), those having the general formula (XVI) as Yd can be alkyl derivatized and acyl derivatized by conventional methods. In addition, among the amine derivatives represented by the general formula (XIV), those having the general formula (XV) as Yd can be sulfonyl derivatized. As a specific example of the obtained compound, N- [2- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -N- (Cyclohexylacetyl) aminoacetic acid, N- [2- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -N- (Cyclohexylacetyl) amino acetic acid tert-butyl, N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] -N- (3-cyclohexylpropionyl) aminoacetic acid, N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl ] Phenyl] -N- (3-cyclohexylpropionyl) aminoacetic acid tert-butyl, N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidine -1-yl] propyl] phenyl] -N- (3-cyclohexylpropionyl) aminobutyric acid, 3- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2- Furancarboxamide] piperidin-1-yl] ethyl] phenyl] -5-cyclohexylhydantophosphate ethyl, 3- [2- [2- [4- [N- (5-methylpyridin-2-yl ) -2-furancarboxamide] piperi -1-yl] ethyl] phenyl] -5-cyclohexylhydantophosphoric acid, N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] Piperidin-1-yl] ethyl] phenyl] aminoacetate ethyl, N-[(1-methoxycarbonylmethylcyclohexyl) acetyl] -N- [2- [2- [4- [N- (5- Methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] aminoacetate ethyl, N-[(1-carboxymethylcyclohexyl) acetyl] -N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] aminoacetic acid, N- [1- [3- [2- (3-cyclohexylpropionamide) phenyl] propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1- [ 2- [2- (3-cyclohexylureido) phenyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, N- [1 -[3- [2- (4-cyclohexylbutyramid) phenyl] propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide, 1 -[N- [2- [2- [4- [N- (5-methylpyridine-] 2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] carbamoylmethyl] cyclohexyl acetate methyl, 1- [N- [2- [2- [4- [N -(5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] carbamoylmethyl] cyclohexylacetic acid, N- [1- [3- [2 -(3-cyclohexylureido) phenyl] propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [3- [2- (3 -Cyclohexylthioureido) phenyl] propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- (2- Methanesulfonylaminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- [2- ( p-toluenesulfonylamino) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, N- [1- [2- [1- [ 2- (4-chlorobenzenesulfonylamino) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide, and N- [1- [2 -[1- [2- (1,2-ditert-butoxycarbonylguadino) ] Cyclohexyl], and the like ethyl] piperidin-4-yl] -N- (5- methylpyridin-2-yl) furan-2-carboxamide.
[137] The compound represented by the following general formula (V) of the present invention, which is an intermediate compound for synthesizing the compound represented by the general formula (I) of the present invention, is a compound represented by the general formula (XVII), and a general formula (XVIII) or a general formula ( XIX) is reacted in the presence of a base, an aldehyde compound represented by formula (VII), formula (VII-a) or formula (XI), a ketone compound represented by formula (XIII), or a chemical formula It can be obtained by performing reductive amination in the presence of a reducing agent using a semiacetal compound represented by (XIII) or the general formula (XIII-a).
[138] [Formula V]
[139]
[140] [In the meal,
[141] X is CH or N,
[142] Ya is formula (VI), or formula (VI-a), or formula (VII), or formula (VII),
[143] [Formula VI]
[144]
[145] [Formula VI-a]
[146]
[147] (Wherein T is O or NR ¹⁵ , and R ¹⁵ is H, a C1-C6 alkyl group, a benzyl group, a phenethyl group)
[148] [Formula Ⅶ]
[149]
[150] [Formula Ⅷ]
[151]
[152] A, b and c are integers of 0 to 6, Z is CH ₂ or NH, W is O or S, R ⁹ is H, C ₁ to C ₆ alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, 2-phenyl -1,3-dioxane-5-yl group, 2,2-dimethyl-1,3-dioxan-5-yl group or formula (VII), R ¹⁰ is H or formula (VII),
[153] [Formula Ⅸ]
[154]
[155] Wherein d is an integer of 0 to 6, R ¹¹ , R ^12, and R ¹³ are the same or different and are H, or-(CH ₂ ) _e R ¹⁴ , e is an integer of 0 to 6, and R ¹⁴ is C1 to C6 alkanoyloxy group, benzoyloxy group, 2-furoyloxy group, C1 to C6 alkoxy C1 to C6 alkoxy group, C1 to C6 alkoxycarbonylphenoxy group, di C1 to C6 alkoxycarbonylphenoxy group, di C1 to C6 alkanoyloxy C1-C6 alkylphenoxy group, C1-C6 alkyldiarylsiloxy group, carboxyl group, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, cyano group and C1-C6 alkylsulfonamide group.]
[156] [Formula ⅩⅦ]
[157]
[158] [Wherein X is CH or N],
[159] [Formula ⅩⅧ]
[160]
[161] [Formula ⅩⅨ]
[162]
[163] [Wherein P is a derivative which activates a hydroxyl group represented by a halogen atom or a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a, b and c are integers from 0 to 6, and Z is CH ₂ or NH , W is O or S, R ⁹ is H, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, 2-phenyl-1,3-dioxan-5-yl group, 2,2-dimethyl-1,3 A dioxane-5-yl group or formula (IX),
[164] [Formula IX]
[165]
[166] Wherein d is an integer of 0 to 6, R ¹¹ , R ^12, and R ¹³ are the same or different and are H, or-(CH ₂ ) _e R ¹⁴ , e is an integer of 0 to 6, and R ¹⁴ is C1-C6 alkanoyloxy group, benzoyloxy group, 2-furoyloxy group, C1-C6 alkoxy C1-C6 alkoxy group, C1-C6 alkoxycarbonylphenoxy group, di C1-C6 alkoxycarbonylphenoxy group, di C1-- C6 alkanoyloxy C1-C6 alkylphenoxy group, C1-C6 alkyldiarylsiloxy group, carboxyl group, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, cyano group and C1-C6 alkylsulfonamide group.]
[167] [Formula ⅩⅩ]
[168]
[169] [Formula VII-a]
[170]
[171] [Where T is NR ¹⁵ , and R ¹⁵ is H, a C1-C6 alkyl group, a benzyl group, a phenethyl group]
[172] [Formula VIIⅠ]
[173]
[174] [Formula XII]
[175]
[176] [Formula XIII]
[177]
[178] [Formula XIII-a]
[179] .
[180] These reactions take place under ice-cooling to reflux in water or an organic solvent such as 1,2-dichloroethane, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane and methanol.
[181] Specific examples of the compound of formula (V) include 2- [1- (cyclohexylmethyl) piperidin-4-ylamino] -5-methylpyridine, 2- [1- (2-cyclohexylethyl) pi Ferridin-4-ylamino] -5-methylpyridine, 2- [1- (3-cyclohexylpropyl) piperidin-4-ylamino] -5-methylpyridine, 2- [1- (4-cyclo Hexylbutyl) piperidin-4-ylamino] -5-methylpyridine, 2- [1- (2-cyclooctylethyl) piperidin-4-ylamino] -5-methylpyridine, 1- (3- Cyclohexylpropyl) -4- (p-toluidino) piperidine, 2- (1-cyclohexylpiperidin-4-ylamino) -5-methylpyridine, 2- [1- [3- [2 -(Cyclohexylacetamide) phenyl] propyl] piperidin-4-ylamino] -5-methylpyridine, 2- [1- [2- [2- (cyclohexylacetamide) phenyl] ethyl] pi Ferridin-4-ylamino] -5-methylpyridine, [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] methyl acetate, [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclopentyl] methyl acetate, 1- [2 -[4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexanecarboxylate, 1- [2- [4- (5-methylpyridin-2-ylamino) pi Ferridin-1-yl] ethyl] cyclohexanecarboxylic acid, 4- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate , 3- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl, 3 -[1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] -1,1-propanedicarboxylic acid dimethyl, [1- [2- [4 -(p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] methyl acetate, acetic acid 3- [1- [4- (5-methylpyridin-2-ylamino) piperidine-1- Il] methylcyclohexyl] propyl, 2- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1 , 3-diacetoxypropane, 2- [1- [2- [1- (4-methoxymethoxy) -3- (methoxymethoxymethyl) butyl] cyclohexyl] ethyl] piperidine-4- Ooh No] -5-methylpyridine, 2- (acetoxymethyl) -2- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl ] Cyclohexyl] ethyl] -1,4-diacetoxybutane, 2- [1- [2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperi Din-4-ylamino] -5-methylpyridine, 1- [2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] -4- (p- Toluidino) piperidine, 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl ] Cyclohexyl] methyl heptanoate, 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] Methyl heptate, 2- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,3-diacetoxypropane, 2-furancarboxylic acid 2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl, 2- [1- [2- [ 1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-ylamino] -5-methylpyridine, [2- [1- [2- [4- (5-meth Pyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] carbamic acid tert-butyl, N- [2- [1- [2- [4- (5-methylpyridine-2 -Ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] methanesulfonamide, N- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-ylmethyl ] Phenyl] cyclohexylacetamide, N- [2- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] phenyl] cyclohexylacetamide, N- [2- [3- [4- (p-toluidino) piperidin-1-yl] propyl] phenyl] cyclohexylacetamide, [2- [3- [4- (5-methylpyridin-2-ylamino ) Piperidin-1-yl] propyl] phenyl] carbamic acid tert-butyl, [2- [3- [4- (p-toluidino) piperidin-1-yl] propyl] phenyl] carba Tert-butyl hydrochloride, 1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] -4- (p-toluidino) piperidine, 5- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] dimethyl isophthalate, 1,3-diacetoxymethyl-5- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl ] Ethyl] cyclohexyl] ethoxy] benzene, 1,3-diacetoxymethyl-5- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidine-1 -Yl] ethyl] cyclohexyl] ethoxy] benzene, 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethanol, 4- [1 -[2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate, 3- [1- [2- [4- (p-toluidino) piperi Din-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl, 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] Ethyl] cyclobutyl] ethanol, 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclooctyl] ethanol, 2- [1- [2- [4 -(p-toluidino) piperidin-1-yl] ethyl] tetrahydropyran-4-yl] ethanol and 1- [2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxane) C) ethyl] piperidin-4-yl] ethyl] -4-toluidino piperidine, etc. are mentioned.
[182] Specific examples of the compound of formula (XVII) include 2- (piperidin-4-ylamino) -5-methylpyridine, 4- (p-toluidino) piperidine and the like.
[183] Specific examples of the compound of the formula (VII) include (bromomethyl) cyclohexane, (2-bromoethyl) cyclohexane, (3-bromopropyl) cyclohexane, (4-bromobutyl) cyclohexane, 1- (2-bromoethyl) cyclohexyl acetate, 1- (2-bromoethyl) cyclopentylmethyl acetate, acetic acid 3- [1- (trifluoromethanesulfonyloxymethyl) cyclohexyl] propyl and 3 -[1- (2-bromoethyl) cyclohexyl] propionitrile, etc. are mentioned.
[184] Specific examples of the compound of formula (XIX) include N- [2- (2-bromoethyl) phenyl] cyclohexylacetamide, 2-nitrobenzylbromide, (2-bromoethyl) -2-nitro Benzene, (3-bromopropyl) -2-nitrobenzene, [2- (3-bromopropyl) phenyl] carbamic acid tert-butyl, etc. are mentioned.
[185] Specific examples of the compound of formula (VII) include cyclooctyl acetaldehyde, 1- (formylmethyl) cyclohexanemethyl carboxylate, 1- (formylmethyl) cyclohexanecarboxylic acid benzyl, 4- [1- (formylmethyl ) Cyclohexyl] methyl butyrate, 3- [1- (formylmethyl) cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl, 3- [1- (formylmethyl) cyclohexyl] -1,1 Dimethyl propanedicarboxylic acid, 2- [2- [1- (formylmethyl) cyclohexyl] ethyl] -1,3-diacetoxypropane, [1- (4-methoxymethoxy) -3- (Methoxymethoxymethyl) butyl] cyclohexylacetaldehyde, 1- (2-phenyl-1,3-dioxan-5-yl) cyclohexylacetaldehyde, 1- (2,2-dimethyl-1,3- Dioxane-5-yl) cyclohexylacetaldehyde, 2- (acetoxymethyl) -2- [2- [1- (formylmethyl) cyclohexyl] ethyl] -1,4-diacetoxybutane, 5, 5-Bis (benzoyloxymethyl) -7- [1- (formylmethyl) cyclohexyl] methylheptanate, N- [2- [1- (formylmethyl) cyclohexyl] ethyl] methane Von amide and 1- (2-phthalimide ethyl), and the like cyclohexyl acetaldehyde.
[186] Specific examples of the compound of the formula (VII-a) include [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] acetaldehyde and the like. .
[187] As a specific example of a compound of general formula (XI), N- [2- (2-formylethyl) phenyl] cyclohexylacetamide etc. are mentioned.
[188] Cyclohexanone etc. are mentioned as a specific example of a compound of general formula (XIII).
[189] Specific examples of the compound of formula (XIII) include 3-oxaspiro [5.5] undecane-2-ol, 3-oxaspiro [5.3] nonan-2-ol and 3-oxaspiro [5.7] tridecane-2 -All etc. are mentioned. Specific examples of the base include organic bases such as triethylamine, pyridine, diisopropylamine, diisopropylethylamine and 1,8-diazabicyclo [5.4.0] -7-undecene, sodium hydroxide and hydroxide Inorganic bases, such as potassium, potassium carbonate, and sodium hydrogencarbonate, are mentioned. Specific examples of the reducing agent include sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride and the like.
[190] The compound of general formula (V) can also be synthesize | combined via a phthalimide derivative (XIV) and a nitro derivative (XV), as shown in Reaction Scheme 1.
[191]
[192] The compound represented by general formula (XVIII) can be synthesized by the method shown in Scheme 2.
[193] [Formula XVIII]
[194]
[195] [Wherein X is CH or N.]
[196]
[197] The compounds of the present invention described above, as shown in the following examples, by inhibiting the opioid μ receptor, side effects of i receptor agonists such as constipation, nausea, vomiting and pruritus, idiopathic constipation, postoperative ileus, paralytic ile It is useful as a therapeutic agent and a prophylactic agent, such as Us.
[198] Some of the compounds represented by the formula (I) of the present invention are prodrugs and are metabolized in vivo and converted into novel opioid μ receptor antagonists. Main metabolic sites are shown on formulas (I) to (IV).
[199]
[200] 1) hydroxylation of methyl group
[201] 2) hydroxylation of aromatic rings
[202] 3) N-oxides of nitrogen atoms
[203] 4) hydroxylation of piperidine ring
[204] 5) Hydroxylation of Methylene Chain
[205] 6) Hydroxylation of Cycloalkyl Group
[206] 7) Hydrolysis of Ester Group, Hydroxylation of Alkyl Chain
[207] 8) Gluconic acid, sulfuric acid, glutathione conjugate of the said compound
[208] The compounds represented by the formula (I) of the present invention can be converted into addition salts with pharmacologically acceptable acids or bases, if desired, and those acid or base addition salts are also included in the scope of the present invention. As the acid addition salt, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, acetic acid, succinic acid, oxalic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, lactic acid, methanesulfonic acid, p Salts with organic acids such as toluenesulfonic acid, mandelic acid, suberic acid, phthalic acid and terephthalic acid. Examples of the base addition salts include salts with inorganic or organic bases such as sodium salts, potassium salts and various ammonium salts. Can be mentioned.
[209] When using the compound represented by this general formula (I) as a medicine, it can be set as the preparation of various dosage forms. In other words, the preparations can be administered orally in the form of tablets, dragees, hard capsules, soft capsules, enteric preparations, solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of a liquid such as injections, suppositories, antiseptics, solutions, emulsions or suspensions.
[210] In the preparation of these formulations, additives commonly used for formulating, such as excipients, stabilizers, preservatives, solubilizers, wetting agents, emulsifiers, lubricants, sweeteners, colorants, flavors, enteric preparations, buffers and antioxidants It may be formulated by the addition.
[211] Although the method and dosage of the opioid μ receptor of the present invention are appropriately selected depending on the various formulation forms, the sex of the patient and the extent of the disease, the daily dosage of the active ingredient is 1 to 1000 mg.
[212] Best Mode for Carrying Out the Invention
[213] A prescription example is shown below.
[214] Prescription Example 1
[215] Gelatin Hard Capsule
[216] Example 4D-8 based compounds20mg Corn starch200 mg Magnesium stearate10mg Sum230mg
[217] Each component is mixed uniformly and filled into gelatin hard capsules to obtain a gelatin hard capsule having a content of 460 mg.
[218] Prescription Example 2
[219] Gelatin Hard Capsules
[220] Example 4D-6 Base Compound20mg Corn starch89mg Crystalline cellulose89mg Magnesium stearate2mg Sum200 mg
[221] Each component is mixed uniformly and filled into gelatin hard capsules to obtain a gelatin hard capsule having a content of 200 mg.
[222] Prescription Example 3
[223] Gelatin soft capsule
[224] (Chemical)Example 3D-3 Based Compounds20mg Medium chain fatty acid trigrid160mg Polyoxyethylene Cured Castor Oil 6020mg sub Total200 mg(film)gelatin100mg glycerin30mg Methyl paraoxybenzoate0.2mg Paraoxybenzoic acid propyl0.05mg Purified waterA reasonable amount sub Total140mgSum340 mg
[225] A film is manufactured by the film solution melt | dissolved by heat-dissolving by the rotary type soft capsule maker, and it coats and shape | molds the chemical liquid component previously uniformly melt | dissolved by this, and it dries sufficiently.
[226] Prescription Example 4
[227] refine
[228] Example 3B-1 based compound10mg Corn starch45mg Crystalline cellulose35mg Polyvinylpyrrolidone (as a 10% aqueous solution)4mg Carboxymethyl Cellulose Sodium4.5mg Magnesium stearate0.5mg Talc1mg Sum100mg
[229] Main medicine, starch and cellulose were passed through a sieve and mixed thoroughly. A polyvinylpyrrolidone aqueous solution was mixed with this powder, and then passed through a No. 14 mesh sieve. The particulate matter thus prepared was dried at 50 to 60 ° C. and passed through a No. 18 mesh sieve. Subsequently, sodium carboxymethyl starch, magnesium stearate, and talc, which have been previously passed through a No. 60 mesh sieve, are added to the particulate matter, mixed, and then tablets each weight of 100 mg are produced in a tablet press.
[230] Prescription Example 5
[231] refine
[232] Example 2-33 Base Compound250 mg Crystalline cellulose400 mg Cyroid10mg Magnesium stearate5mg Sum665 mg
[233] After uniform mixing of each component, tablets each weighing 665 mg are prepared in a tablet press.
[234] A suspension containing 5 mg of active ingredient per 5 mL dose is prepared as follows.
[235] Suspension
[236] Example 2-34 Base Compound5mg Carboxymethyl Cellulose Sodium50 mg Single syrup1.25 mL Benzoic acid solution0.10 mL air freshenerA reasonable amount Purified waterQuantity to make whole quantity 5mL Sum5 mL
[237] The medicine is passed through a sieve of No. 45 mesh and mixed with sodium carboxymethylcellulose and a single syrup to prepare a paste. The aqueous benzoic acid solution and the perfume are diluted with some purified water and added to the paste obtained under stirring. Subsequently, purified water is added to make the required capacity.
[238] The μ antagonistic activity (pA ₂ value) of the compound of the present invention was measured by the electric field stimulation method of the mormot ileum longitudinal root sample.
[239] The lateral root sample was made by bleeding mormort (Hartley, male) and then extracting the ileum. The samples of 20ml youngyangaek - a Magnus equipment filled with (Krebs-Henselite _{solution, 37 ℃, 95% O 2} 5% CO 2 air passage), by suspending a load of O.5g recorded the contraction of the isometric. Samples were equilibrated in nutrient solution for at least 1 hour and then subjected to electric field stimulation (0.1 Hz, 1 msec duration) at the voltage at which maximum contraction was obtained. After shrinkage stability, morphine of the μ receptor agonist was added cumulatively and stopped for 1 hour after washing. The compound of the present invention was added after the electric field stimulation and shrinkage stability, and morphine was added cumulatively 15 minutes after the addition. From the chart recording the electric field stimulation shrinkage, the shrinkage height (mm) before and after the addition of morphine was measured, and the shrinkage suppression rate (%) was calculated from the equation (1).
[240] Equation 1
[241] Shrinkage inhibition rate (%) = [(a-b) / a] × 100
[242] a: contraction height before morphine addition (mm)
[243] b: Shrinkage height after morphine addition (mm)
[244] The logarithmic concentration of morphine was taken on the horizontal axis, and the shrinkage inhibition rate (%) was plotted on the vertical axis to prepare a morphine concentration response curve in the absence and presence of the compound of the present invention. At the point at which the shrinkage inhibition rate of the morphine concentration response curve was 50%, the distance (mm) of the morphine concentration response curve from the absence to the presence of the compound of the present invention was measured. Based on this distance, the value of Log (CR-1) of the equation (2) was obtained from the van Rossum simple table to calculate the pA ₂ value.
[245] Equation 2
[246] Log (CR-1) = Log [B] + pA ₂
[247] [B]: concentration of compound of the present invention
[248] Table 1 shows the antagonistic activity (pA ₂ value) for the μ receptor of the compound of the present invention.
[249] Antagonistic activity against μ receptors Example numberpA ₂Japanese Patent Application Laid-Open No. 63-264460 Base Compound 10 (Electrode Compound XI)-* Example 2-38.14 Example 2-68.15 Example 2-158.30 Example 2-178.38 Example 2-188.86 Example 2-268.01 Example 2-318.58 Example 2-338.67 Example 2-348.61 Example 3B-18.26 Example 3C-48.15 Example 3D-38.05 Example 3G-28.12 Example 4A-18.13 Example 4A-48.36 Example 4D-18.12 Example 4D-28.26 Example 4D-67.85 Example 4D-88.61 Example 5B-18.66 Example 5B-48.42 Example 5B-68.23
[250] * Receptor agonist activity was shown. EC ₅₀ = 2.2 × 10 ^-7 M
[251] Antagonistic activity against the central μ receptor of the compounds of the present invention was measured by analgesic assay by pressure stimulation in mice.
[252] This assay is a method for measuring the pain threshold value of a mouse (ddY system, 5 weeks old, male) by using a Randall-Selitto pressure device, and measuring the pain resistance of the mouse as an index. to be. The pseudo-pain reaction is looking back, bite, restlessness, and expulsion.
[253] Initially, the critical pressure was measured before administration of the compound of the present invention. Next, the compound of the present invention was administered subcutaneously, and 15 mg after the administration of 10 mg / kg of morphine hydrochloride subcutaneously. Critical pressure was measured 45 minutes after morphine administration. In order to prevent damage to the tissue, the maximum pressure was set at 750 g (cutoff pressure), and the critical pressure of the compound administration group of the present invention and the solvent administration control group were measured. Each morphine analgesic effect (%) was calculated from equation (3).
[254] Equation 3
[255] Analgesic effect (%) = [(Pt-Po) / (cutoff pressure 750g-Po)] × 100
[256] Po: Pain threshold (g) prior to compound or solvent administration of the present invention
[257] Pt: pain threshold after morphine administration (g)
[258] The inhibition rate (%) of the morphine analgesic effect of the compound of this invention was computed according to Formula (4) from the average value (the number of each case is 5-9 cases) of the analgesic effect of each administration group.
[259] Equation 4
[260] Inhibition Rate (%) = [(Ao-At) / Ao] × 100
[261] Ao: Average analgesic effect (%) of solvent administration control group
[262] At: mean (%) analgesic effect of the compound of the present invention
[263] Dose response curves were created by taking the logarithmic capacity of the compounds of the invention on the horizontal axis and plotting the percent inhibition on the vertical axis. Thereby, the dose (AD ₅₀ value) of the compound of this invention which suppresses the analgesic effect of morphine 50% was calculated.
[264] The antagonistic activity of peripheral compound of the present invention was measured by the horse's horse transport capacity.
[265] Compounds of the present invention were administered subcutaneously to mice fasted overnight (ddY system, 5 weeks old, males). Thirty minutes after administration, 10 mg / kg of morphine hydrochloride was administered subcutaneously. 5% carbon powder was orally administered 30 minutes after morphine administration. Mice were killed 30 minutes after the end of the carbon spray and immediately removed from the stomach to the cecum. The distance from the extracted secretary's pyloric ring to the tip of the bullet was measured and the total length of the small intestine (pylor to ring). The tandem migration rate of the compound administration group and the control group of the present invention was calculated from Equation 5.
[266] Equation 5
[267] % Movement = (Mt / Mo) × 100
[268] Mo: full length of the small intestine (cm)
[269] Mt: Distance from the pyloric wheel to the tip of the bullet (cm)
[270] The improvement rate (%) of the compound of the present invention with respect to the action of lowering the bullet transport capacity by morphine was calculated from the formula (6) from the average value of the percentage of movement (%) of each administration group (the number of each case was 3 to 6 cases).
[271] Equation 6
[272] % Improvement = [(Et-Em) / (En-Em)] × 100
[273] En: Mean value of% of solvent administration and% of morphine non-administered group
[274] Em: Average value of% migration of the solvent administration and the morphine administration control group
[275] Et: average value of% migration of the compound of the present invention and the morphine group
[276] The logarithmic capacity of the compound of the present invention was taken on the horizontal axis, and the improvement rate (%) was plotted on the vertical axis to prepare a dose response curve. From this, it was calculated the tanmal transporting capacity lowering effect of morphine dose the compounds of the present invention to improve _50% (ED 50 value).
[277] The degree of peripheral selectivity of the compound of the present invention can be evaluated from the ratio (AD ₅₀ / ED ₅₀ ) of the AD ₅₀ value of the antagonistic activity to the central μ receptor and the ED ₅₀ value of the antagonistic activity to the peripheral μ receptor. The higher this ratio, the higher the peripheral selectivity.
[278] The peripheral selectivity (AD ₅₀ / ED ₅₀ ) of the compounds of the present invention is shown in Table 2.
[279] Peripheral selectivity Example NumberAD ₅₀ (mg / kg)ED ₅₀ (mg / kg)AD ₅₀ / ED ₅₀Example 2-32.719.30.1 Example 3B-14.03.31.2 Example 3D-316.78.42.0 Example 3G-25.35.31.0 Example 4D-67.73.02.6 Example 4D-816.35.53.0
[280] Although an Example demonstrates this invention further in detail below, these only illustrate this invention and do not limit this invention.
[281] Preparation Example 1A-1
[282] Cyclooctylidene acetate ethyl ester
[283]
[284] To a tetrahydrofuran (50 mL) suspension of 60% sodium hydride / mineral oil (960 mg) was added diethylphosphono acetate (5.48 mL) under ice-cooling. After stirring this solution under ice-cooling for 30 minutes, the tetrahydrofuran (70 mL) solution of cyclooctanone (2.52g) was dripped under ice-cooling. The solution was stirred for 2 hours at room temperature under ice-cooling for 40 hours, and then water and 3N hydrochloric acid were added and extracted with diethyl ether. The oil layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 9: 1) to give the title compound (1.96 g).
[285]
[286] Preparation Example 1A-2
[287] 2-cyclooctylethanol
[288]
[289] 10% palladium carbon (60 mg) was added to the ethanol (40 mL) solution of cyclooctylidene acetate ethyl ester (960 mg). This solution was stirred at room temperature under hydrogen atmosphere for 64 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Lithium aluminum hydride (132 mg) was added under ice-cooling to a diethyl ether (40 mL) solution of the obtained residue (920 mg). The solution was stirred for 30 minutes under ice cooling, and then water (0.13 mL) and 15% aqueous sodium hydroxide solution (0.13 mL) were added sequentially. After stirring this solution for 15 minutes at room temperature, water (0.39 mL) was added, and after stirring for 30 minutes, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 2: 1) to give the title compound (680 mg).
[290]
[291] Preparation Example 1A-3
[292] Cyclooctylacetaldehyde
[293]
[294] Pyridine (0.25 mL) is added to a dichloromethane (3 mL) solution of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodeoxol-3 (1H) -one (490 mg). It was. A dichloromethane (3 mL) solution of 2-cyclooctylethanol (120 mg) was added to this solution under ice-cooling, and stirred at room temperature for 3 hours. Diethyl ether was added and washed sequentially with aqueous sodium thiosulfate solution, 1N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain the title compound. This product was provided to the next step without purification.
[295] Preparation Example 1B-1
[296] 1,1-cyclohexanediacetic anhydride
[297]
[298] An acetic anhydride (20 mL) solution of 1,1-cyclohexanediacetic acid (20.0 g) was heated to reflux for 5 hours. The solution was concentrated under reduced pressure, and the residue was further azeotropically concentrated three times with benzene. The obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate = 2: 1) to give the title compound (20.1 g).
[299]
[300] Preparation Example 1B-2
[301] 3-oxa-spiro [5.5] undecane-2-one
[302]
[303] To a THF (150 mL) solution of 1,1-cyclohexanediacetic anhydride (20.1 g) was added sodium borohydride (3.78 g, 100 mmol) under ice-cooling, and further stirred at room temperature for 3 hours. Water was added to the solution, which was made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (17.07 g). This product was provided to the next step without purification.
[304]
[305] Preparation Example 1B-3
[306] 1- (2-bromoethyl) cyclohexyl acetic acid
[307]
[308] 30% hydrogen bromide / acetic acid solution (75 mL) was added to 3-oxa-spiro [5.5] undecane-2-one (16.9 g), and the mixture was stirred at room temperature for 48 hours. Water was added to this solution, and the precipitated crystals were collected by filtration and washed with water. The obtained crystals were dissolved in ethyl acetate, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain a crude crystal. The resulting crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (20.0 g).
[309]
[310] Preparation Example 1B-4
[311] 1- (2-bromoethyl) cyclohexyl acetate
[312]
[313] To the methanol (50 mL) solution of 1- (2-bromoethyl) cyclohexyl acetic acid (4.98 g), thionyl chloride (1.76 mL) was added dropwise under ice-cooling. After dripping, it progressed as it was and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, the mixture was washed with saturated sodium bicarbonate water, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (5.41 g). This product was provided to the next step without purification.
[314]
[315] Preparation Example 1C-1
[316] 8-oxa-spiro [4.5] decane-7-one
[317]
[318] Using 8-oxa-spiro [4.5] decane-7,9-dione (10.8 g), the title compound was obtained in the same manner as in Preparation Example 1B-2 (12.6 g). This product was provided to the next step without purification.
[319] Preparation Example 1C-2
[320] 1- (2-bromoethyl) cyclopentylacetic acid
[321]
[322] Using 8-oxa-spiro [4.5] decan-7-one (3.57 g), the title compound was obtained in the same manner as in Preparation Example 1B-3 (0.87 g).
[323]
[324] Preparation Example 1C-3
[325] 1- (2-bromoethyl) cyclopentylmethylacetate
[326]
[327] Using 1- (2-bromoethyl) cyclopentylacetic acid (2.20 g), the title compound was obtained in the same manner as in Preparation Example 1B-4 (2.26 g).
[328]
[329] Preparation Example 1D-1
[330] 1-allylcyclohexanemethyl carboxylate
[331]
[332] Tert-butoxy potassium (1.68 g, 15.0 mmol) was added to an N, N-dimethylformamide (20 mL) solution of methyl cyclohexyl carboxylate (1.42 g) and allyl bromide (3.02 g). After stirring this solution for 16 hours at room temperature, 8 hours at 50 degreeC, and again 64 hours at room temperature, water and 3N hydrochloric acid were added, extracted with diethyl ether, washed with water and saturated brine, It dried with magnesium, and concentrated under reduced pressure.
[333] The obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate = 97: 3) to give the title compound (340 mg).
[334] Preparation Example 1D-2
[335] 1- (formylmethyl) cyclohexanemethyl carboxylate
[336]
[337] To a tetrahydrofuran (7 mL) solution of 1-allylcyclohexanecarboxylate (340 mg) under ice-cooling, a water (14 mL) solution of sodium periodate (3.4 g, 16.0 mmol) and osmium tetraoxide (100 mg) were added sequentially. It was. After stirring this solution at room temperature for 20 hours, water was added and the insolubles were filtered out. The filtrate was extracted with ethyl acetate and washed sequentially with water, sodium thiosulfate and saturated brine. After drying over anhydrous magnesium sulfate, the residue was concentrated under a reduced pressure to obtain the title compound (250 mg). This product was provided to the next step without purification.
[338] Preparation Example 1E-1
[339] Cyclohexanecarboxylic acid benzyl
[340]
[341] Oxalyl chloride (1.92 mL) under ice-cooling was added to a N, N-dimethylformamide (0.5 mL) solution of cyclohexanecarboxylic acid (2.56 g) and dichloromethane (50 mL). The solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The dichloromethane (30 mL) solution of the obtained residue was added to a dichloromethane (30 mL) solution of benzyl alcohol (2.4 g) and triethylamine (8.4 mL) under ice-cooling. The solution was stirred for 1 hour under ice-cooling, and then washed with water, saturated sodium bicarbonate and saturated brine sequentially. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate = 9: 1) to obtain the title compound (3.44 g).
[342]
[343] Preparation Example 1E-2
[344] 1-allylcyclohexanecarboxylic acid benzyl
[345]
[346] To a tetrahydrofuran (40 mL) solution of cyclohexanecarboxylic acid benzyl (1.44 g) was added 1M lithium hexamethyldisilazane tetrahydrofuran solution (9.9 mL) under ice-cooling. After stirring this solution under ice-cooling for 1 hour, hexamethylphosphoramide (2.3 mL) was added, and it stirred for 10 minutes again. Allyl bromide (1.4 mL) was added to this solution, and after stirring for 1 hour under ice cooling, allyl bromide (1.4 mL) was further added, followed by stirring at room temperature for 18 hours. Water and 3N hydrochloric acid were added, extracted with diethyl ether, and the organic layer was washed sequentially with water, saturated sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the residue obtained was purified by chromatography (silica gel, hexane: ethyl acetate = 99: 1) to give the title compound (550 mg). This product was provided to the next step without further purification.
[347] Preparation Example 1E-3
[348] 1- (formylmethyl) cyclohexanecarboxylic acid benzyl
[349]
[350] Using 1-allylcyclohexanecarboxylic acid benzyl (1.52 g), the title compound was obtained in the same manner as in Preparation Example 1D-2 (360 mg).
[351]
[352] Preparation Example 1F-1
[353] 3-oxaspiro [5.5] undecane-2-ol
[354]
[355] To a diethyl ether (50 mL) solution of 3-oxaspiro [5.5] undecane-2-one (1.68 g) was added a 1 mm hydrogenated diisobutyl aluminum diethyl ether solution (15.0 mL) under ice-cooling. After stirring this solution for 15 minutes under ice-cooling, diethyl ether (100 mL) was added, and water (0.6 mL) and 15% sodium hydroxide aqueous solution (0.6 mL) were added sequentially. After stirring this solution for 30 minutes at room temperature, water (1.8 mL) was added, and after stirring for 15 minutes again, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate = 1: 1) to give the title compound (1.36 g).
[356]
[357] Preparation Example 1F-2
[358] 4- [1- (2-hydroxyethyl) cyclohexyl] methyl butyrate
[359]
[360] To trichloromethane (15 mL) solution of 3-oxa-spiro [5.5] undecane-2-ol (460 mg) was added triphenylphosphoranylidene acetate (1.36 g). After stirring this solution under reflux for 3 hours, triphenylphosphoranylidene acetic acid methyl (1.36 g) was added again, and it stirred under reflux for 14 hours. Concentration under reduced pressure, the residue obtained was purified by chromatography (silica gel, hexane: ethyl acetate = 1: 1), and a mixture of unsaturated esters and 3-oxa-spiro [5.5] undecane-2-ol (520 mg). Got. 10% palladium carbon (60 mg) was added to the ethanol (30 mL) solution of the obtained mixture, and it stirred for 63 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off, concentrated under reduced pressure, and the residue was chromatographed (silica gel, hexane: ethyl acetate = 1: 1) to give the title compound (210 mg).
[361]
[362] Preparation Example 1F-3
[363] 4- [1- (formylmethyl) cyclohexyl] methyl butyrate
[364]
[365] Using the 4- [1- (2-hydroxyethyl) cyclohexyl] methyl butyrate (210 mg), the title compound was obtained in the same manner as in Preparation Example 1A-3 (220 mg). This product was provided to the next step without further purification.
[366]
[367] Preparation Example 1G-1
[368] (1-allylcyclohexyl) methanol
[369]
[370] To a N, N-dimethylformamide (30 mL) solution of cyclohexanecarboaldehyde (2.24 g) was added tert-butoxy potassium (2.70 g) and allyl bromide (4.33 mL) under ice-cooling. After stirring this solution for 30 minutes under ice-cooling, water and 1N hydrochloric acid were added, and it extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Sodium borohydride (567 mg) was added to the ethanol (60 mL) solution of the obtained residue under ice-cooling. After stirring this solution at room temperature for 16 hours, acetic acid was added and it concentrated under reduced pressure. Saturated sodium bicarbonate water was added to the obtained residue, followed by extraction with diethyl ether. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Column chromatography (silica gel, hexane: ethyl acetate = 4: 1) was performed on the obtained residue to obtain the title compound (1.47 g).
[371]
[372] Preparation Example 1G-2
[373] [(1-allylcyclohexyl) methoxy] triethylsilane
[374]
[375] To a N, N-dimethylformamide (7 mL) solution of (1-allylcyclohexyl) methanol (1.0 g), imidazole (661 mg) and triethylchlorosilane (1.41 mL) were added at room temperature. After stirring this solution at room temperature for 3 hours, N, N- dimethylformamide was added, and it extracted with hexane. The combined hexane layers were washed with acetonitrile and then concentrated under reduced pressure to give the title compound (1.70 g). This product was provided to the next step without purification.
[376] Preparation Example 1G-3
[377] 3- [1- (triethylsiloxymethyl) cyclohexyl] propan-1-ol
[378]
[379] To a tetrahydrofuran (35 mL) solution of [(1-allylcyclohexyl) methoxy] triethylsilane (1.70 g) under cooling with ice, 2M borane-methyl sulfide salt / tetrahydrofuran solution (6.48 mL, 12.96 mmol) was added. It was. After stirring this solution under ice-cooling for 2 hours, water, 3N sodium hydroxide aqueous solution (6.5 mL), and 30% hydrogen peroxide solution (6.5 mL) were added, and it stirred at room temperature for 16 hours. Water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Column chromatography (silica gel, hexane: ethyl acetate = 7: 3) was performed on the obtained residue to obtain the title compound (810 mg).
[380]
[381] Preparation Example 1G-4
[382] [1- (3-acetoxypropyl) cyclohexylmethoxy] triethylsilane
[383]
[384] Acetic anhydride (3 mL) and pyridine (3 mL) were added to 3- [1- (triethylsiloxymethyl) cyclohexyl] propan-1-ol (410 mg) at room temperature. The solution was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Azeotropy with toluene gave the title compound (480 mg). This product was provided to the next step without purification.
[385]
[386] Preparation Example 1G-5
[387] Acetic acid 3- (1-hydroxymethylcyclohexyl) propyl
[388]
[389] The title compound was obtained (310 mg) in the same manner as in Preparation Example 3B-2 using [1- (3-acetoxypropyl) cyclohexylmethoxy] triethylsilane (480 mg).
[390]
[391] Preparation Example 1H-1
[392] [N- (tert-butoxycarbonyl) -N-carboxymethylamino] acetic acid
[393]
[394] Iminoacetic acid (10.00 g) was dissolved in a mixed solution of 1,4-dioxane (160 mL) and water (80 mL), and 1N aqueous sodium hydroxide solution (160 mL) was added, followed by ditert-butyl-dicarbonate (18.04 g). It was added and stirred at room temperature for 22 hours. Concentrated under reduced pressure, added with 5% aqueous potassium hydrogen sulfate solution to pH 3, extracted with 25% ethanol / chloroform, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane. The title compound was obtained (4.25 g).
[395]
[396] Preparation Example 1H-2
[397] [({tert-butoxycarbonyl-[(diethoxycarbonylmethylcarbamoyl) methyl] amino} acetyl) ethoxycarbonylmethylamino] ethyl acetate
[398]
[399] [N- (tert-butoxycarbonyl) -N-carboxymethylamino] acetic acid (0.57 g) was dissolved in dichloromethane (5 mL), iminoacetic acid diethyl ester (1.40 g), N, N-diiso Propylethylamine (1.59g), then 2-bromo-1-ethylpyridinium tetrafluoroborate (1.95g) were added, and it stirred at room temperature for 1 hour. Ethyl acetate was added, washed sequentially with saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel, 5-10% methanol /). Dichloromethane) to give the title compound (0.79 g).
[400]
[401] Preparation Example 1H-3
[402] [({[(Diethoxycarbonylmethylcarbamoyl) methyl] amino} acetyl) ethoxycarbonylmethylamino] acetic acid ethyl ester trifluoroacetic acid salt
[403]
[404] [({tert-butoxycarbonyl-[(diethoxycarbonylmethylcarbamoyl) methyl] amino} acetyl) ethoxycarbonylmethylamino] ethyl acetate (0.79 g) is dissolved in dichloromethane (8 mL), Trifluoroacetic acid (8.0 mL) was added at room temperature, and it stirred for 2 hours. The solvent was distilled off under reduced pressure and then azeotropic with xylene to give the title compound (0.81 g). This product was provided to the next step without purification.
[405] Preparation Example 1I-1
[406] 2-acetoxymethyl-2-amino-1,3-diacetoxypropane
[407]
[408] To 2-amino-2-hydroxymethyl-1,3-propanediol (10.00 g) were added acetic acid (40.0 mL), 1N hydrochloric acid / diethyl ether solution (90.0 mL), acetic anhydride (30.0 mL) in sequence, It heated and stirred at 110 degreeC for 6 hours. The solvent was distilled off under reduced pressure and then azeotropically dried using xylene. The obtained residue was diluted with water, washed with ethyl acetate, the aqueous layer was adjusted to pH 8 with sodium hydrogen carbonate, and then extracted with 25% ethanol / chloroform. Drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resultant residue was subjected to column chromatography (silica gel, 3-4% ethanol / dichloromethane) to obtain the title compound (4.02 g).
[409]
[410] Preparation Example 1J-1
[411] Acetic acid 3-acetoxy-2- (2-{[(2-acetoxy-1,1-diacetoxymethyl-ethylcarbamoyl) methyl] amino} acetylamino) -2-acetoxymethylpropyl ester
[412]
[413] 2-acetoxymethyl-2-amino-1,3-diacetoxypropane (1.18 g) was dissolved in dichloromethane (8 mL) and [N- (tert-butoxycarbonyl) -N-carboxymethyl]) Acetic acid (0.56 g), N, N-diisopropylethylamine (1.54 g), followed by 2-bromo-1-ethylpyridinium tetrafluoroborate (1.96 g) were added and stirred at room temperature for 10 hours. After adding ethyl acetate, the mixture was washed sequentially with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography. Photography (silica gel, 5-10% methanol / dichloromethane) was performed. The obtained compound was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5.0 mL) was added at room temperature, and the mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure, and column chromatography [silica gel, dichloromethane-methanol-ammonia water (90: 10: 0.5)] was performed on the obtained residue to obtain the title compound (0.47 g). This product was provided to the next step without further purification.
[414]
[415] Preparation Example 1K-1
[416] 1-methoxycarbonylmethylcyclohexyl acetic acid
[417]
[418] The acetic anhydride (8.0 mL) solution of 1,1-cyclohexane diacetic acid (5.0 g) was stirred under reflux for 5 hours, concentrated under reduced pressure, and azeotropic toluene. To a methanol (15.2 mL) solution of the obtained residue, boron trifluoride diethyl ether complex (1.58 mL) was added at room temperature. After stirring this solution at room temperature for 2 hours, saturated sodium carbonate aqueous solution was added and it wash | cleaned with diethyl ether. After neutralizing with concentrated hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (4.21 g).
[419]
[420] Preparation Example 1K-2
[421] 1-methoxycarbonylmethylcyclohexyl acetic acid
[422]
[423] Oxalyl chloride (0.12 mL) was added to an aqueous solution of 1-methoxycarbonylmethylcyclohexyl acetic acid (265 mg) in methylene chloride (10 mL) and N, N-dimethylformamide (1 drop) under ice-cooling. The solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the title compound. This product was provided to the next step without purification.
[424] Preparation Example 2A-1
[425] 3- (2-nitrophenyl) ethyl acrylate
[426]
[427] To ethyl tetrahydrofuran (40 mL) suspension of 60% sodium hydride / mineral oil (1.11 g) was added dropwise with ethyl diethylphosphono acetate (6.29 mL) under ice cooling. After stirring this solution under ice-cooling and 30 minutes, the tetrahydrofuran (30 mL) solution of 2-nitrobenzaldehyde (3.0g) was added under ice-cooling. After stirring this solution at room temperature for 8 hours, water and 3N hydrochloric acid were added, and it extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate = 3: 2) to obtain the title compound (3.74 g).
[428]
[429] Preparation Example 2A-2
[430] 3- (2-aminophenyl) propan-1-ol
[431]
[432] To a diethyl ether (30 mL) solution of 3- (2-nitrophenyl) ethyl acrylate (1.11 g) was added 1M diisobutylaluminum hexane solution (15.0 mL) under ice-cooling. After this solution was stirred for 1 hour under ice cooling, diethyl ether, water (0.6 mL), and 15% aqueous sodium hydroxide solution (0.6 mL) were added thereto. After stirring this solution for 15 minutes at room temperature, water (1.8 mL) was added and it stirred at room temperature for 15 minutes. Anhydrous magnesium sulfate was added to this solution, and the filtrate was concentrated under reduced pressure. 10% palladium carbon (200 mg) was added to the ethanol (50 mL) solution of the obtained residue, and the solution was stirred for 89 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane: ethyl acetate = 1: 2) to give the title compound (660 mg).
[433]
[434] Preparation Example 2A-3
[435] 2-cyclohexyl-N- [2- (3-hydroxypropyl) phenyl] acetamide
[436]
[437] To a solution of 3- (2-aminophenyl) propan-1-ol (180 mg) and cyclohexyl acetic acid (203 mg) in dichloromethane (12 mL) under ice-cooling, 1-hydroxybenzotriazole (193 mg) and 1-ethyl hydrochloride 1- (1-dimethylaminopropyl) carbodiimide (274 mg) was added. After stirring this solution at room temperature for 113 hours, chloroform was added and it wash | cleaned sequentially with water and saturated sodium bicarbonate water. After drying over anhydrous sodium sulfate, the reaction mixture was concentrated under reduced pressure, and column chromatography (silica gel, hexane: ethyl acetate = 1: 1) was carried out to obtain the title compound (170 mg).
[438]
[439] Preparation Example 2A-4
[440] 2-cyclohexyl-N- [2- (2-formylethyl) phenyl] acetamide
[441]
[442] It synthesize | combined by the method similar to manufacture example 1A-3 from the compound obtained in manufacture example 2A-3.
[443] Preparation Example 2B-1
[444] 2-cyclohexyl-N- [2- (2-hydroxyethyl) phenyl] acetamide
[445]
[446] Using 2-aminophenethyl alcohol (500 mg), the title compound was obtained in the same manner as in Preparation Example 2A-3 (780 mg).
[447]
[448] Preparation Example 2B-2
[449] N- [2- (2-bromoethyl) phenyl] -2-cyclohexylacetamide
[450]
[451] To a dichloromethane (20 mL) solution of 2-cyclohexyl-N- [2- (2-hydroxyethyl) phenyl] acetamide (780 mg), triphenylphosphine (938 mg) and carbon tetrabromide (1.12 g) were added to room temperature. Was added. After stirring this solution at room temperature for 1 hour, chloroform was added and it wash | cleaned sequentially with water and saturated sodium bicarbonate water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and then subjected to column chromatography (silica gel, hexane: ethyl acetate = 7: 3) to give the title compound (450 mg).
[452]
[453] Preparation Example 2C-1
[454] 1- (2-bromoethyl) -2-nitrobenzene
[455]
[456] Using 1- (2-hydroxyethyl) -2-nitrobenzene (10.11 g), the title compound was obtained in the same manner as in Preparation Example 2B-2 (21.46 g). This product was provided to the next step without further purification.
[457]
[458] Preparation Example 2D-1
[459] 1- (3-hydroxy-1-propenyl) -2-nitrobenzene
[460]
[461] 2-trans-nitrocinnamaldehyde (10.00 g) was dissolved in ethanol (50 mL), sodium borohydride (2.14 g) was added under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was poured into saturated sodium bicarbonate water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 20-50% ethyl acetate / hexanes) to obtain the title compound (8.00 g).
[462]
[463] Preparation Example 2D-2
[464] 1- (3-bromo-1-propenyl) -2-nitrobenzene
[465]
[466] The title compound was obtained in the same manner as in Production Example 2B-2 using 1- (3-hydroxy-1-propenyl) -2-nitrobenzene (8.00 g) (17.1 g). This product was provided to the next step without further purification.
[467] Preparation Example 2E-1
[468] 2- (3-hydroxypropyl) phenylcarbamic acid-tert-butyl
[469]
[470] In tetrahydrofuran (10 mL) solution of 3- (2-aminophenyl) propan-1-ol (660 mg), triethylamine (1.52 mL) and di-tert-butyldicarbonate (1.91 g) were added under ice-cooling. . After stirring this solution at room temperature for 20 hours, ethyl acetate and water were added and extracted. The organic layer was washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure and column chromatography (silica gel, hexane: ethyl acetate = 60:40) were carried out to obtain the title compound (730 mg).
[471]
[472] Preparation Example 2E-2
[473] 2- (3-Bromopropyl) phenylcarbamic acid-tert-butyl
[474]
[475] Using the 2- (3-hydroxypropyl) phenylcarbamic acid-tert-butyl (730 mg), the title compound was obtained in the same manner as in Preparation Example 2B-2 (670 mg).
[476]
[477] Preparation Example 2F-1
[478] 2- (2-hydroxyethyl) phenylcarbamic acid-tert-butyl
[479]
[480] Using 2-aminophenethyl alcohol (1.0 g), the title compound was obtained in the same manner as in Preparation Example 2E-1 (1.14 g).
[481]
[482] Preparation Example 2F-2
[483] 2- (2-Bromoethyl) phenylcarbamic acid-tert-butyl
[484]
[485] The title compound was obtained in the same manner as in Preparation Example 2B-2 using 2- (2-hydroxyethyl) phenylcarbamic acid-tert (1.14g) (0.75g).
[486]
[487] Preparation Example 3A-1
[488] 2- [1- (2-hydroxyethyl) cyclohexyl] ethanol
[489]
[490] Lithium aluminum hydride (2.28 g) was added to a tetrahydrofuran (90 mL) solution of 1,1-cyclohexanediacetic acid (6.0 g) under ice-cooling. The solution was stirred under reflux for 4 hours, then ice-cooled and diethyl ether (200 mL), water (2.3 mL), and 15% aqueous sodium hydroxide solution (2.3 mL) were added. After stirring this solution for 30 minutes at room temperature, water (6.9 mL) was added and it stirred at room temperature again for 30 minutes. Anhydrous magnesium sulfate was added, it filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, ethyl acetate) to give the title compound (4.83 g).
[491]
[492] Preparation Example 3A-2
[493] 2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethanol
[494]
[495] Triethylamine (6.74 mL) and tert-butyldiphenylchlorosilane (11.1 mL) were added to a dichloromethane (170 mL) solution of 2- [1- (2-hydroxyethyl) cyclohexyl] ethanol (6.41 g) at room temperature. Was added. After stirring this solution for 18 hours at room temperature, chloroform was added, and it wash | cleaned sequentially with 1N hydrochloric acid, saturated sodium bicarbonate water, and brine. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 85:15) to give the title compound (10.97 g).
[496]
[497] Preparation Example 3A-3
[498] tert-butyl [2- [1- (2-iodineethyl) cyclohexyl] ethoxy] diphenylsilane
[499]
[500] To a tetrahydrofuran (60 mL) and acetonitrile (20 mL) solution of 2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethanol (4.0 g), triphenylphosphine (3.3 g) ), Imidazole (993 mg) and iodine (3.46 g) were added sequentially at room temperature. After stirring this solution at room temperature for 2 hours, diethyl ether was added and it wash | cleaned sequentially with the sodium thiosulfate aqueous solution, water, and brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was dissolved in acetonitrile. The solution was extracted with hexane, the combined hexane layers were washed with acetonitrile and concentrated under reduced pressure to give the title compound (4.83 g).
[501]
[502] Preparation Example 3A-4
[503] 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl
[504]
[505] To a N, N-dimethylformamide (5 mL) solution of tert-butyl [2- [1- (2-iodethyl) cyclohexyl] ethoxy] diphenylsilane (540 mg) and methanetricarboxylic acid ethyl ester (727 mg), Potassium carbonate (575 mg) was added at room temperature. The solution was stirred at 110 ° C. for 6 hours, and water and 3N hydrochloric acid were added. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with 1N aqueous sodium hydroxide solution, water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 85:15) to give the title compound (470 mg).
[506]
[507] Preparation Example 3A-5
[508] 3- [1- (2-hydroxyethyl) cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl
[509]
[510] Methanol (10 mL) / tetrahydrofuran (5 mL) solution of 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl (470 mg) 3N hydrochloric acid (2.5 mL) was added at room temperature. After stirring this solution at room temperature for 4 hours, water was added and it concentrated under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 1: 1) to give the title compound (230 mg).
[511]
[512] Preparation Example 3A-6
[513] 3- [1- (formylmethyl) cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl
[514]
[515] To a dichloromethane (6 mL) solution of 3- [1- (2-hydroxyethyl) cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl (230 mg) was mixed with iodine dibenzene (213 mg) and 2,2, 6,6-tetramethyl-1-piperidinyloxy free radical (9.3 mg) was added at room temperature. The solution was stirred at room temperature for 16 hours, and then diethyl ether was added thereto to give an aqueous sodium thiosulfate solution, 1N hydrochloric acid, It was washed sequentially with saturated sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure to obtain the title compound. This product was no longer purified and provided to the next process.
[516] Preparation Example 3B-1
[517] 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] -1,1-propanedicarboxylic acid dimethyl
[518]
[519] To a N, N-dimethylformamide (20 mL) solution of tert-butyl [2- [1- (2-iodethyl) cyclohexyl] ethoxy] diphenylsilane (1.5 g) and dimethyl malonate (1.90 g), tert-butoxypotassium (1.45 g) was added at room temperature. After stirring this solution at 60 degreeC for 4 hours, water and 3N hydrochloric acid were added, and it extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 9: 1) to give the title compound (1.32 g).
[520]
[521] Preparation Example 3B-2
[522] 3- [1- (2-hydroxyethyl) cyclohexyl] -1,1-propanedicarboxylic acid dimethyl
[523]
[524] 1M tetrabutylammonium fluoride / into a tetrahydrofuran (10 mL) solution of 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] -1,1-propanedicarboxylic acid dimethyl (500 mg) Tetrahydrofuran solution (1.9 mL) was added at room temperature. This solution was stirred for 3 hours at room temperature. Water was added, extraction was performed with ethyl acetate, and the organic layer was washed sequentially with an aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 1: 1) to obtain the title compound (180 mg).
[525]
[526] Preparation Example 3B-3
[527] 2- {2- [1- (formylmethyl) cyclohexyl] ethyl} dimethyl malonic acid
[528]
[529] A crude title compound was obtained in the same manner as in Production Example 3A-6 using 3- [1- (2-hydroxyethyl) cyclohexyl] -1,1-propanedicarboxylic acid dimethyl (180 mg). This product was provided to the next step without further purification.
[530] Preparation Example 3C-1
[531] 2- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethyl] propane-1,3-diol
[532]
[533] Lithium aluminum hydride (191 mg) in a diethyl ether (30 mL) solution of 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] -1,1-propanedicarboxylic acid dimethyl (1.32 g) ) Was added under ice-cooling. The solution was stirred under ice cooling for 2 hours, and then water (0.2 mL) and 15% aqueous sodium hydroxide solution (0.2 mL) were added sequentially. After stirring this solution for 15 minutes at room temperature, water (0.6 mL) was added and it stirred for 30 minutes. It was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed (silica gel, hexane: ethyl acetate = 1: 1) on the obtained residue to obtain the title compound (790 mg).
[534]
[535] Preparation Example 3C-2
[536] 2- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] -1,3-diacetoxypropane
[537]
[538] Acetic anhydride (3.0 mL) in a pyridine (3.0 mL) solution of 2- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethyl] propane-1,3-diol (190 mg) ) Was added at room temperature. The solution was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. To a tetrahydrofuran (8 mL) solution of the obtained residue, a 1M tetrabutylammonium fluoride / tetrahydrofuran solution (0.53 mL) was added at room temperature. After the solution was stirred at room temperature for 1 hour, a 1M tetrabutylammonium fluoride / tetrahydrofuran solution (0.53 mL) was further added at room temperature. After the solution was stirred at room temperature for 1 hour, a 1M tetrabutylammonium fluoride / tetrahydrofuran solution (0.53 mL) was further added at room temperature. The solution was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 1: 1) to obtain the title compound (140 mg).
[539]
[540] Preparation Example 3C-3
[541] 2- [2- [1- (formylmethyl) cyclohexyl] ethyl] -1,3-diacetoxypropane
[542]
[543] The title compound was obtained in the same manner as in Preparation Example 1A-3 using 2- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] -1,3-diacetoxypropane (140 mg) (117 mg ). This product was provided to the next step without purification.
[544] Preparation Example 3D-1
[545] 2- [1- (2-benzyloxyethyl) cyclohexyl] ethanol
[546]
[547] N, N- of 2- [1- (2-hydroxyethyl) cyclohexyl] ethanol (2.92 g) under ice-cooling in a suspension of N, N-dimethylformamide (20 mL) in 60% sodium hydride / mineral oil (881 mg). Dimethylformamide (40 mL) solution was added. Benzyl bromide (2.83 mL) was added to this solution under ice cooling again, and the mixture was stirred at room temperature for 63 hours. Water and 3N hydrochloric acid were added, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine. The mixture was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed (silica gel, hexane: ethyl acetate = 6: 4) to give the title compound (2.93 g).
[548]
[549] Preparation Example 3D-2
[550] {2- [1- (2-iodineethyl) cyclohexyl] ethoxymethyl} benzene
[551]
[552] The title compound was obtained in the same manner as in Production Example 3A-3 using 2- [1- (2-benzyloxyethyl) cyclohexyl] ethanol (1.63 g) (1.87 g).
[553]
[554] Preparation Example 3D-3
[555] 2- {2- [1- (2-benzyloxyethyl) cyclohexyl] ethyl} malonic acid dimethyl
[556]
[557] Dimethyl malonate (1.84 mL) was added to a N, N-dimethylformamide (15 mL) suspension of 60% sodium hydride / mineral oil (613 mg) at room temperature. After the solution was stirred at room temperature for 15 minutes, a solution of N, N-dimethylformamide (15 mL) of {2- [1- (2-iodineethyl) cyclohexyl] ethoxymethyl} benzene (1.5 g) was added. . After stirring this solution at 60 degreeC for 6 hours, water and 3N hydrochloric acid were added. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 85:15) to obtain the title compound (1.03 g). This product was no longer purified and provided to the next process.
[558] Preparation Example 3D-4
[559] 2- {2- [1- (2-benzyloxyethyl) cyclohexyl] ethyl} propane-1,3-diol
[560]
[561] Lithium aluminum hydride (207 mg) was added to a diethyl ether (40 mL) solution of 2- {2- [1- (2-benzyloxyethyl) cyclohexyl] ethyl} malonate (1.03 g) under ice-cooling. The solution was stirred under ice cooling for 2 hours, and then water (0.2 mL) and 15% aqueous sodium hydroxide solution (0.2 mL) were added sequentially. After stirring this solution for 15 minutes at room temperature, water (0.6 mL) was added, and after stirring for 30 minutes, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 2: 3) to give the title compound (320 mg).
[562]
[563] Preparation Example 3D-5
[564] 2- [1- (4-methoxymethoxy-3-methoxymethoxymethylbutyl) cyclohexyl] ethanol
[565]
[566] Diisopropylethylamine (0.69 mL) and chloro in a dichloromethane (10 mL) solution of 2- {2- [1- (2-benzyloxyethyl) cyclohexyl] ethyl} propane-1,3-diol (320 mg) Methyl methyl ether (0.23 mL) was added at room temperature. After stirring this solution for 3 hours at room temperature, chloroform was added, and it wash | cleaned sequentially with 1N hydrochloric acid, saturated sodium bicarbonate water, and brine. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. 10% palladium carbon (50 mg) was added to the ethanol (30 mL) solution of the obtained residue. The solution was stirred at room temperature under hydrogen atmosphere for 16 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 3: 2) to obtain the title compound (300 mg).
[567]
[568] Preparation Example 3D-6
[569] 1- [4-methoxymethoxy-3- (methoxymethoxymethyl) butyl] cyclohexylacetaldehyde
[570]
[571] The title compound was obtained in the same manner as in Production Example 1A-3 using 2- [1- (4-methoxymethoxy-3-methoxymethoxymethylbutyl) cyclohexyl] ethanol (300 mg). This product was provided to the next step without purification.
[572] Preparation Example 3E-1
[573] 1,1-cyclohexanediacetic acid dimethyl acetate
[574]
[575] The title compound was obtained in the same manner as in Production Example 1B-4 using 1,1-cyclohexanediacetic acid (4.0 g) (4.56 g).
[576]
[577] Preparation Example 3E-2
[578] 2- (1-methoxycarbonylmethylcyclohexyl) dimethyl malonic acid
[579]
[580] To a tetrahydrofuran (8 mL) solution of diisopropylamine (1.01 mL, 7.2 mmol) was added 1.5 M, n-butyllithium / hexane solution (4.4 mL) under -78 ° C cooling. After stirring this solution at -78 degreeC for 1 hour, the tetrahydrofuran (7 mL) solution of 1,1- cyclohexane diacetic acid (685 mg) was added. After stirring this solution at -78 degreeC for 1 hour, methyl chloroformate (0.93 mL) was added, and it stirred at -78 degreeC for 1 hour. Water and 3N hydrochloric acid were added, and it extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 85:15) to give the title compound (490 mg).
[581]
[582] Preparation Example 3E-3
[583] 2- [1- (2-hydroxyethyl) cyclohexyl] propane-1,3-diol
[584]
[585] Lithium aluminum hydride (195 mg) was added to a tetrahydrofuran (15 mL) solution of 2- (1-methoxycarbonylmethylcyclohexyl) dimethylonic acid (490 mg) under ice-cooling. The solution was stirred at reflux for 1 hour, then ice-cooled, diethyl ether was added, and water (0.2 mL) and 15% aqueous sodium hydroxide solution (0.2 mL) were added.
[586] After stirring this solution for 15 minutes at room temperature, water (0.6 mL) was added, and also it stirred at room temperature for 30 minutes. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, chloroform: methanol = 85:15) to give the title compound (200 mg).
[587]
[588] Preparation Example 3E-4
[589] 2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethanol
[590]
[591] To a N, N-dimethylformamide (8 mL) solution of 2- [1- (2-hydroxyethyl) cyclohexyl] propane-1,3-diol (200 mg), benzaldehyde dimethylacetal (752 mg) and p-toluenesulfonic acid Pyridinium salt (48 mg) was added at room temperature. After stirring this solution at room temperature for 16 hours, saturated sodium bicarbonate water was added, and it extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 4: 6) to give the title compound (100 mg).
[592]
[593] Preparation Example 3E-5
[594] [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] acetaldehyde
[595]
[596] The title compound was obtained in the same manner as in Production Example 1A-3 using 2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethanol (100 mg). This product was provided to the next step without purification.
[597] Preparation Example 3F-1
[598] 2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] ethanol
[599]
[600] To acetone (10 mL) solution of 2- [1- (2-hydroxyethyl) cyclohexyl] propane-1,3-diol (200 mg), 2,2-dimethoxypropane (206 mg) and p-toluenesulfonic acid (17 mg ) Was added at room temperature. After stirring this solution for 48 hours at room temperature, saturated sodium bicarbonate water was added and it concentrated under reduced pressure. Diethyl ether and water were added to the obtained residue, followed by extraction with diethyl ether. The organic layer was washed sequentially with 0.5N hydrochloric acid, water, and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 1: 1 to 1: 2) to give the title compound (190 mg).
[601]
[602] Preparation Example 3F-2
[603] 2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] acetaldehyde
[604]
[605] The title compound was obtained in the same manner as in Production Example 3A-6 using 2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] ethanol (190 mg). This product was provided to the next step without purification.
[606] Preparation Example 3G-1
[607] 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-ethoxycarbonylsuccinate diethyl
[608]
[609] Prepared using tert-butyl- {2- [1- (2-iodethyl) cyclohexyl] ethoxy} diphenylsilane (1.77 g) and 1,1,2-ethanetricarboxylic acid ethyl ester (2.51 g) The title compound was obtained in the same manner as Example 3B-1 (1.43 g). This product was no longer purified and provided to the next process.
[610] Preparation Example 3G-2
[611] 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-hydroxymethylbutane-1,4-diol
[612]
[613] To a diethyl ether (20 mL) solution of 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-ethoxycarbonylsuccinate diethyl (1.0 g) Lithium aluminum hydride (178 mg) was added under ice-cooling. The solution was stirred under ice cooling for 1.5 hours, and then water (0.18 mL) and 15% aqueous sodium hydroxide solution (0.18 mL) were added sequentially. After stirring this solution for 15 minutes at room temperature, water (0.54 mL) was added and it stirred for 30 minutes. Dry over anhydrous magnesium sulfate and filter. Chloroform was added to the solid, and the mixture was stirred at room temperature for 2 hours, and then filtered. The combined filtrates were concentrated under reduced pressure, and the residue thus obtained was chromatographed (silica gel, hexane: ethyl acetate = 1: 4) to obtain the title compound (230 mg).
[614]
[615] Preparation Example 3G-3
[616] 2- (acetoxymethyl) -2- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethyl] -1,4-diacetoxybutane
[617]
[618] Pyridine (5.0 mL) solution of 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-hydroxymethylbutane-1,4-diol (300mg) Acetic anhydride (5.0 mL) was added to the mixture at room temperature. The solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure to give the title compound (340 mg).
[619]
[620] Preparation Example 3G-4
[621] 2- (acetoxymethyl) -2- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] -1,4-diacetoxybutane
[622]
[623] Methanol of 2- (acetoxymethyl) -2- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethyl] -1,4-diacetoxybutane (340 mg) ( 5 mL) and tetrahydrofuran (3 mL) were added to 3N hydrochloric acid (2.0 mL) at room temperature. After stirring this solution at room temperature for 5.5 hours, water was added, it concentrated under reduced pressure, methanol and tetrahydrofuran were distilled off. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 4: 6) to give the title compound (110 mg).
[624]
[625] Preparation Example 3G-5
[626] 2- (acetoxymethyl) -2- [2- [1- (formylmethyl) cyclohexyl] ethyl] -1,4-diacetoxybutane
[627]
[628] Preparation Example 3A-6 using 2- (acetoxymethyl) -2- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] -1,4-diacetoxybutane (110 mg); In the same manner the title compound was obtained. This product was provided to the next step without purification.
[629] Preparation Example 3H-1
[630] 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-pent-4-enylmalonic acid dimethyl
[631]
[632] To a N, N-dimethylformamide (15 mL) solution of 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) dimethyl malonate (1.30 g), 5- Bromo-1-pentene (813 mg) and tert-butoxy potassium (334 mg) were added sequentially at room temperature. After stirring this solution at 60 degreeC for 2 hours, water and 3N hydrochloric acid were added, and it extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 92: 8) to give the title compound (910 mg).
[633]
[634] Preparation Example 3H-2
[635] 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-pent-4-enylpropane-1,3-diol
[636]
[637] To a diethyl ether (15 mL) solution of 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-pent-4-enylmalonic acid dimethyl (910 mg) Lithium aluminum hydride (117 mg) was added under ice-cooling. After the solution was stirred at room temperature for 1 hour, water (0.12 mL) and 15% aqueous sodium hydroxide solution (0.12 mL) were added sequentially. After stirring this solution for 15 minutes at room temperature, water (0.36 mL) was added and it stirred for another 15 minutes. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 6: 4) to give the title compound (640 mg).
[638]
[639] Preparation Example 3H-3
[640] {2- [1- [3,3-bis (benzyloxymethyl) octo-7-enyl] cyclohexyl] ethoxy} -tert-butyldiphenylsilane
[641]
[642] Dichloromethane (12 mL) of 2- (2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethyl) -2-pent-4-enylpropane-1,3-diol (640 mg) To the solution, pyridine (0.67 mL) and benzoyl chloride (0.55 mL) were added at room temperature. The solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, and extracted with diethyl ether and 1N sodium hydroxide. The organic layer was washed sequentially with water, 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 94: 6) to give the title compound (840 mg).
[643]
[644] Preparation Example 3H-4
[645] 5,5-bis (benzyloxymethyl) -7- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} methyl carbonate
[646]
[647] Carbon tetrachloride (3 mL), acetonitrile (3 mL) of {2- [1- [3,3-bis (benzyloxymethyl) octo-7-enyl] cyclohexyl] ethoxy} -tert-butyldiphenylsilane (840 mg) Sodium periodate (1.98 g) and ruthenium trichloride monohydrate (10.3 mg) were added to a water (4.5 mL) solution at room temperature. After stirring this solution at room temperature for 4 hours, water was added and it extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the methanol (1.5 mL) / benzene (7.5 mL) solution of the obtained residue, 2M trimethylsilyldiazomethane / hexane solution (1.0 mL) under ice cooling was added. The solution was stirred for 30 minutes under ice cooling, and concentrated under reduced pressure. The obtained residue was chromatographed (silica gel, hexane: ethyl acetate = 85:15) to give the title compound (520 mg).
[648]
[649] Preparation Example 3H-5
[650] 5,5-bis (benzyloxymethyl) -7- [1- (2-hydroxyethyl) cyclohexyl] heptanate
[651]
[652] 5,5-bis (benzyloxymethyl) -7- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} methylheptanate (520 mg) was used to obtain the same composition as in Production Example 3B-2. The title compound was obtained by the method (360 mg).
[653]
[654] Preparation Example 3H-6
[655] 5,5-bis (benzyloxymethyl) -7- [1- (formylmethyl) cyclohexyl] heptanate
[656]
[657] The title compound was obtained in the same manner as in Production Example 3A-6 using 5,5-bis (benzyloxymethyl) -7- [1- (2-hydroxyethyl) cyclohexyl] methylheptanate (170 mg). This product was provided to the next step without purification.
[658] Preparation Example 3I-1
[659] 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] propionitrile
[660]
[661] 2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethanol (1.25 g) was dissolved in benzene (15 mL), and acetone cyanohydrin (0.40 mL), tri-n- Butylphosphine (1.08 mL) and 1,1-azobis (N, N-dimethylformamide) (754 mg) were added, and it stirred at room temperature for 18 hours. After distilling off the solvent under reduced pressure, ethyl acetate was added and the insolubles were filtered off. The solvent was distilled off under reduced pressure, and column chromatography (silica gel, hexane: ethyl acetate = 5: 1) was performed on the obtained residue to obtain the title compound (1.07 g).
[662]
[663] Preparation Example 3I-2
[664] 3- [1- (2-hydroxyethyl) cyclohexyl] propionitrile
[665]
[666] Using the 3- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] propionitrile (260 mg), the title compound was obtained in the same manner as in Preparation Example 3B-2 (80 mg).
[667]
[668] Preparation Example 3I-3
[669] 3- [1- (2-bromoethyl) cyclohexyl] propionitrile
[670]
[671] Using 3- [1- (2-hydroxyethyl) cyclohexyl] propionitrile (80 mg), the title compound was obtained in the same manner as in Preparation Example 2B-2 (98 mg). This product was provided to the next step without purification.
[672] Preparation Example 3J-1
[673] N- [2- [1- [2- (tert-butyldiphenylsiloxy)] ethyl] cyclohexyl] ethylphthalimide
[674]
[675] 2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethanol (1.23 g), phthalimide (530 mg) and triphenylphosphine (1.10 g) were added to tetrahydrofuran (15 mL). It dissolved in, stirred for 20 minutes, diethyl azodicarboxylate (0.57 mL) was added, and stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and column chromatography (silica gel, 15-20% ethyl acetate / hexane) was performed on the obtained residue to obtain the title compound (1.08 g).
[676]
[677] Preparation Example 3J-2
[678] 2- {1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl} ethylamine
[679]
[680] N- [2- [1- [2- (tert-butyldiphenylsiloxy)] ethyl] cyclohexyl] ethylphthalimide (1.52 g) was dissolved in ethanol (30 mL), and hydrazine monohydrate (222 mg) was dissolved. It was added and heated to reflux for 4 hours. After diethyl ether was added to filter insolubles, the solvent was distilled off under reduced pressure. Chloroform was added, 1N aqueous sodium hydroxide solution and water were added thereto to make basic, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure to obtain the title compound (1.20 g).
[681]
[682] Preparation Example 3J-3
[683] N- (2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethyl) methanesulfonamide
[684]
[685] 2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethylamine (409 mg) was dissolved in dichloromethane (10 mL) and triethylamine (0.28 mL) was added. Under ice-cooling, methanesulfonyl chloride (0.12 mL) was added, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. Column chromatography (silica gel, hexane: ethyl acetate = 6: 1) was performed on the obtained residue to obtain the title compound (327 mg).
[686]
[687] Preparation Example 3J-4
[688] N- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] methanesulfonamide
[689]
[690] The title compound was obtained in the same manner as in Production Example 3B-2 using N- (2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethyl) methanesulfonamide (317 mg). (153 mg).
[691]
[692] Preparation Example 3J-5
[693] N- [2- [1- (formylmethyl) cyclohexyl] ethyl] methanesulfonamide
[694]
[695] The title compound was obtained in the same manner as in Production Example 1A-3 using N- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] methanesulfonamide (153 mg). This product was provided to the next step without purification.
[696] Preparation Example 3K-1
[697] N- [2- [1- (2-hydroxyethyl) cyclohexyl] ethylphthalimide
[698]
[699] The title compound was prepared in the same manner as in Production Example 3B-2 using N- [2- [1- [2- (tert-butyldiphenylsiloxy)] ethyl] cyclohexyl] ethylphthalimide (1.08 g). Obtained (340 mg).
[700]
[701] Preparation Example 3K-2
[702] N- [2- [1- (formylmethyl) cyclohexyl] ethyl] phthalimide
[703]
[704] The title compound was obtained in the same manner as in Production Example 1A-3 using N- [2- [1- (2-hydroxyethyl) cyclohexyl] ethylphthalimide (340 mg). This product was provided to the next step without purification.
[705] Preparation Example 4-1
[706] 2- (1-benzylpiperidin-4-ylamino) -5-methylpyridine
[707]
[708] 4-Amino-1-benzylpiperidine (68.5 g) was added to 2-bromo-5-methylpyridine (15.5 g). After stirring this solution at 180 degreeC for 9 hours and 150 degreeC for 6 hours, ethyl acetate and water were added and saturated sodium bicarbonate water was added. After separation, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was chromatographed [silica gel, ethyl acetate-methanol-ammonia water (90: 10: 0.1)] to give the title compound (11.5 g).
[709]
[710] Preparation Example 4-2
[711] 4- (5-methylpyridin-2-yl) piperidine-1-carboxylate
[712]
[713] 2-bromo-5-methylpyridine (8.56 g), 1,3-bis (diphenylphosphino) propane (4.10 g), and tert-butoxy sodium (6.69 g) are suspended in toluene (500 mL), 4-Amino-1-piperidine ethyl carboxylate (10.28 g) was added. Tris (dibenzylideneacetone) palladium (3.19 g) was added, and it stirred at 70 degreeC for 4 hours. Ethyl acetate was added to the reaction mixture, which was then washed with brine and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was chromatographed (silica gel, ethyl acetate), followed by crystallization (X: ethyl acetate / hexane) to obtain the title compound (10.13 g).
[714]
[715] Preparation Example 4-3
[716] 2- (piperidin-4-ylamino) -5-methylpyridine
[717]
[718] Synthesis Method 1
[719] To an ethanol (250 mL) solution of 2- (1-benzylpiperidin-4-ylamino) -5-methylpyridine (11.3 g) was added 20% palladium hydroxide (4 g). After stirring for 48 hours at room temperature under a hydrogen atmosphere, 20% palladium hydroxide (2 g) was further added. After stirring for 99 hours at room temperature under a hydrogen atmosphere, the catalyst was filtered off. After concentration under reduced pressure, the residue was chromatographed [NH silica gel, chloroform: methanol = 10: 1]. The obtained crude product was crystallized from ethyl acetate / hexanes to give the title compound (5.97 g).
[720] Synthesis 2
[721] 30% hydrobromic acid / acetic acid solution (150 mL) was added to 4- (5-methylpyridin-2-yl) piperidine-1-carboxylate (10.13 g), and the mixture was heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, and the obtained solid was washed with ethyl acetate to obtain the hydrogen bromide salt of the title compound as a pale violet solid. Saturated sodium bicarbonate was added thereto, followed by extraction with 25% ethanol / chloroform. After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure and recrystallized (ethanol-chloroform-ethyl acetate) to obtain the title compound (3.62 g).
[722]
[723] Preparation Example 4-4
[724] 4- (p-toluidino) piperidine-1-carboxylic acid tert-butyl
[725]
[726] 4-oxopiperidine-1-carboxylic acid tert-butyl (5.01 g) and p-toluidine (2.69 g) were dissolved in tetrahydrofuran (50 mL), followed by sodium triacetoxyborohydride (7.99 g), followed by acetic acid ( 3.0 mL) was added and stirred for 2 days. The reaction solution was poured into saturated sodium bicarbonate water, and extracted with ethyl acetate. The extract was washed sequentially with water and brine, and then dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the obtained residue was chromatographed (silica gel, 20% ethyl acetate / hexane) to give the title compound (6.49 g).
[727]
[728] Preparation Example 4-5
[729] 4- (p-toluidino) piperidine
[730]
[731] 4- (p-toluidino) piperidine-1-carboxylic acid tert-butyl (32.06 g) was dissolved in dichloromethane (200 mL), trifluoroacetic acid (100 mL) was added at room temperature, and the mixture was stirred for 1 day. . The solvent was distilled off under reduced pressure, and the obtained residue was solidified with isopropyl ether and washed to give trifluoroacetic acid salt (42.17 g) as the title compound. Desalting according to the conventional method gave the title compound (18.03 g).
[732]
[733] Example 1A-1
[734] 2- [1- (cyclohexylmethyl) piperidin-4-ylamino] -5-methylpyridine
[735]
[736] An ethanol (2 mL) solution of 2- (piperidin-4-ylamino) -5-methylpyridine (191 mg), diisopropylamine (202 mg) and cyclohexylmethylbromide (212 mg) was refluxed for 16 hours. Ethyl acetate was added to the reaction solution, the insolubles were filtered off, and the residue was concentrated under reduced pressure, and then subjected to silica gel chromatography (NH silica gel, hexane: ethyl acetate = 4: 1) to obtain the title compound (216 mg). .
[737]
[738] Example 1A-2
[739] 2- [1- (2-cyclohexylethyl) piperidin-4-ylamino] -5-methylpyridine
[740]
[741] It synthesize | combined by the method similar to Example 1A-1 from the compound obtained by the manufacture example 4-3, and (2-bromoethyl) cyclohexane.
[742]
[743] Example 1A-3
[744] 2- [1- (3-cyclohexylpropyl) piperidin-4-ylamino] -5-methylpyridine
[745]
[746] It synthesize | combined by the method similar to Example 1A-1 from the compound obtained by the manufacture example 4-3, and (3-bromopropyl) cyclohexane.
[747]
[748] Example 1A-4
[749] 2- [1- (4-cyclohexylbutyl) piperidin-4-ylamino] -5-methylpyridine
[750]
[751] It synthesize | combined by the method similar to Example 1A-1 from the compound obtained by the manufacture example 4-3, and (4-bromobutyl) cyclohexane.
[752]
[753] Example 1A-5
[754] 2- [1- [2- (2-cyclohexylacetamide) phenyl] ethyl] piperidin-4-ylamino] -5-methylpyridine
[755]
[756] It synthesize | combined by the method similar to Example 1A-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 2B-2.
[757]
[758] Example 1A-6
[759] [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] methyl acetate
[760]
[761] The compound obtained in Preparation Example 4-3 and the compound obtained in Preparation Example 1B-4 were synthesized in the same manner as in Example 1A-1.
[762]
[763] Example 1A-7
[764] [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclopentyl] methyl acetate
[765]
[766] The compound obtained in Preparation Example 4-3 and the compound obtained in Preparation Example 1C-3 were synthesized in the same manner as in Example 1A-1.
[767]
[768] Example 1A-8
[769] [2- [3- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] propyl] phenyl] carbamic acid tert-butyl
[770]
[771] It synthesize | combined by the method similar to Example 1A-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 2E-2.
[772]
[773] Example 1A-9
[774] [2- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] phenyl] carbamic acid tert-butyl
[775]
[776] It synthesize | combined by the method similar to Example 1A-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 2F-2.
[777]
[778] Example 1B-1
[779] 1- (3-cyclohexylpropyl) -4- (p-toluidino) piperidine
[780]
[781] 4- (p-toluidino) piperidinetrifluoroacetate (0.7726 g) is dissolved in N, N-dimethylformamide (10 mL) and (3-bromopropyl) cyclohexane (0.57 g) And potassium carbonate (1.02 g) were added and the mixture was heated and stirred at 80 ° C for 5 hours. Dichloromethane was added to the reaction solution, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was chromatographed (silica gel, dichloromethane-methanol-ammonia water (95: 5: 0.3)] to give the title compound as a white solid (0.4879 g).
[782]
[783] Example 1B-2
[784] [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] methyl acetate
[785]
[786] It synthesize | combined by the method similar to Example 1B-1 from the compound obtained by manufacture example 4-5, and the compound obtained by manufacture example 1B-4.
[787]
[788] Example 1B-3
[789] 2- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-ylamino] -5-methylpyridine
[790]
[791] The compound obtained in Preparation Example 4-3 and the compound obtained in Preparation Example 3I-3 were synthesized in the same manner as in Example 1B-1.
[792]
[793] Example 1B-4
[794] 1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] -4- (p-toluidino) piperidine
[795]
[796] It synthesize | combined by the method similar to Example 1B-1 from the compound obtained by manufacture example 4-5, and the compound obtained by manufacture example 3I-3.
[797]
[798] Example 1B-5
[799] [2- [3- [4- (p-toluidino) piperidin-1-yl] propyl] phenyl] carbamic acid tert-butyl
[800]
[801] It synthesize | combined by the method similar to Example 1B-1 from the compound obtained by manufacture example 4-5, and the compound obtained by manufacture example 2E-2.
[802]
[803] Example 1C-1
[804] Acetic acid 3- [1- [4- (5-methylpyridin-2-ylamino] piperidin-1-yl] methylcyclohexyl] propyl
[805]
[806] Pyridine (0.18 mL) and anhydrous trifluoromethanesulfonic acid (0.37 mL) were added under ice-cooling to a dichloromethane (15 mL) solution of acetic acid 3- (1-hydroxymethylcyclohexyl) propyl (310 mg). The solution was stirred for 10 minutes under ice-cooling, followed by addition of water and chloroform for separation. The organic layer was washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. 2- (piperidin-4-ylamino) -5-methylpyridine (416 mg) was added to the residue, and stirred at 60 ° C for 1.5 hours. After cooling to room temperature, chromatography (NH silica gel, hexane: ethyl acetate = 4: 1) was performed to obtain the title compound (190 mg).
[807]
[808] Example 1D-1
[809] 1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexanecarboxylate
[810]
[811] To a tetrahydrofuran (10 mL) solution of 2- (piperidin-4-ylamino) -5-methylpyridine (191 mg) and methyl 1- (2-oxoethyl) cyclohexanecarboxylic acid (250 mg), acetic acid (150 mg) And sodium triacetoxy boron hydroxide (424 mg) were added at room temperature, followed by stirring for 20 hours. Saturated sodium bicarbonate was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure, and chromatography (silica gel, ethyl acetate-methanol-ammonia water (90: 10: 0.1)) was carried out to obtain the title compound (30 mg).
[812]
[813] Example 1D-2
[814] 2- [1- [3- [2- (cyclohexylacetamide) phenyl] propyl] piperidin-4-ylamino] -5-methylpyridine
[815]
[816] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 2A-4.
[817] This product was provided to the next step without purification.
[818] Example 1D-3
[819] 2- [1- (2- (cyclooctylethyl) piperidin-4-ylamino] -5-methylpyridine
[820]
[821] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 1A-3.
[822]
[823] Example 1D-4
[824] 4- [1- [2- [4- (5-methylpyridin-2-ylamino] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate
[825]
[826] The compound obtained in Preparation Example 4-3 and the compound obtained in Preparation Example 1F-3 were synthesized in the same manner as in Example 1D-1.
[827]
[828] Example 1D-5
[829] 3- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl
[830]
[831] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 3A-6.
[832]
[833] Example 1D-6
[834] 3- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] -1,1-propanedicarboxylic acid dimethyl
[835]
[836] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-5, and the compound obtained by manufacture example 3B-3.
[837]
[838] Example 1D-7
[839] 2- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,3-acetoxypropane
[840]
[841] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 3C-3.
[842] This product was provided to the next step without purification.
[843] Example 1D-8
[844] 2- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,3-diacetoxypropane
[845]
[846] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-5, and the compound obtained by manufacture example 3C-3.
[847]
[848] Example 1D-9
[849] 2- [1- [2- [1- (4-methoxymethoxy) -3- (methoxymethoxymethyl) butyl) cyclohexyl] ethyl] piperidin-4-ylamino] -5-methylpyridine
[850]
[851] The compound obtained in Preparation Example 4-3 and the compound obtained in Preparation Example 3D-6 were synthesized in the same manner as in Example 1D-1.
[852]
[853] Example 1D-10
[854] 2- [1- [2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperidin-4-ylamino] -5-methylpyridine
[855]
[856] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by the manufacture example 4-3 and the compound obtained by the manufacture example 3E-5.
[857]
[858] Example 1D-11
[859] 1- [2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] -4- (p-toluidino) piperidine
[860]
[861] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by the manufacture example 4-5, and the compound obtained by the manufacture example 3F-2.
[862]
[863] Example 1D-12
[864] 2- (acetoxymethyl) -2- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1 , 4-diacetoxybutane
[865]
[866] The compound obtained in Preparation Example 4-3 and the compound obtained in Preparation Example 3G-5 were synthesized in the same manner as in Example 1D-1.
[867]
[868] Example 1D-13
[869] 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] methyl heptanoate
[870]
[871] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by the manufacture example 4-3, and the compound obtained by manufacture example 3H-6.
[872]
[873] Example 1D-14
[874] 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] methyl carbonate
[875]
[876] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-5, and the compound obtained by manufacture example 3H-6.
[877]
[878] Example 1D-15
[879] N- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] methanesulfonamide
[880]
[881] It synthesize | combined by the method similar to Example 1D-1 from the compound obtained by manufacture example 4-3, and the compound obtained by manufacture example 3J-5.
[882]
[883] Example 1E-1
[884] 2- (1-cyclohexylpiperidin-4-ylamino) -5-methylpyridine
[885]
[886] Sodium triacetoxyborohydride (636 mg) was added to a tetrahydrofuran (10 mL) solution of 2- (piperidin-4-ylamino) -5-methylpyridine (192 mg) and cyclohexanone (196 mg), and room temperature Stirred for 16 h. Saturated sodium bicarbonate was added, extraction was performed with chloroform, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Chromatography (NH silica gel, hexane: ethyl acetate = 2: 1) was carried out to obtain the title compound. (170 mg).
[887]
[888] Example 1F-1
[889] 2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethanol
[890]
[891] Triacetoxyhydrogenation in a tetrahydrofuran (10 mL) solution of 2- (piperidin-4-ylamino) -5-methylpyridine (191 mg) and 3-oxaspiro [5.5] undec-2-ol (255 mg) Sodium boron (636 mg) was added at room temperature. After stirring for 87 hours at room temperature, saturated sodium bicarbonate water was added, followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was chromatographed [silica gel, ethyl acetate-methanol-ammonia water (80: 20: 0.1)] to give the title compound (290 mg).
[892]
[893] Example 1G-1
[894] [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] carbamate tert-butyl
[895]
[896] N- [2- [1- (formylmethyl)] cyclohexyl] ethylphthalimide obtained in 4- (5-methylpyridin-2-yl) aminopiperidine (O.31 g) and Production Example 3K-2. Was dissolved in dichloromethane (10 mL), sodium triacetoxy borohydride (0.71 g) was added, and the mixture was stirred for 3 days. Saturated sodium bicarbonate water (20 mL) was added to the reaction solution, followed by extraction with 25% ethanol / chloroform (20 mL). After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the obtained residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (90: 10: 0.5)] to give a yellow oily substance ( 0.63 g). This was dissolved in ethanol (15 mL), hydrazine monohydrate (O.15 g) was added, and the mixture was heated to reflux for 2 hours. After distilling off the solvent under reduced pressure, the residue was again suspended in dichloromethane (20 mL), triethylamine (0.32 g) and di-tert-butyldicarbonate (0.52 g) were added thereto, and the mixture was stirred at room temperature. Stirred for time. The insolubles were filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to chromatography [silica gel, dichloromethane-methanol-ammonia water (97: 3: 0.2-95: 5: 0.3)] to give the title. Compound obtained (0.42 g).
[897]
[898] Example 1G-2
[899] N- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-ylmethyl] phenyl] cyclohexylacetamide
[900]
[901] Diisopropylamine (159 mg) was added to an ethanol (5 mL) solution of 2- (piperidin-4-ylamino) -5-methylpyridine (150 mg) and 2-nitrobenzylbromide (339 mg) at room temperature. After stirring this solution under reflux for 20 hours, ethyl acetate was added, the insolubles were filtered off and concentrated under reduced pressure. The residue was chromatographed [silica gel, ethyl acetate: methanol: ammonia water (90/10 / 0.1)]. The obtained residue was dissolved in ethanol (10 mL), and platinum oxide (10 mg) was added. The solution was stirred at room temperature under hydrogen atmosphere for 4 hours, and then the catalyst was filtered off and concentrated under reduced pressure. To the obtained residue and dichloromethane (5 mL) solution of cyclohexaneacetic acid (52 mg) under ice-cooling, 1-hydroxybenzotriazole (49 mg) and hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ( 69 mg) was added. After stirring this solution for 87 hours at room temperature, chloroform was added and it wash | cleaned sequentially with water and saturated sodium bicarbonate water. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was chromatographed (NH silica gel, hexane: ethyl acetate = 2: 1) to give the title compound (90 mg).
[902]
[903] Example 1G-3
[904] N- [2- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] phenyl] cyclohexylacetamide
[905]
[906] 4- (p-tolyl) aminopiperidinetrifluoroacetate (2.21 g) and (2-bromoethyl) -2-nitrobenzene (3.04 g) were added to N, N-dimethylformamide (20 mL). It melt | dissolved, potassium carbonate (2.92g) was added, and it stirred at 80 degreeC for 2 hours. Dichloromethane was added to the reaction solution, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (95: 5: 0.3)] to give a yellow oily substance (0.6906 g). This was dissolved in acetic acid (20 mL), 10% palladium carbon (0.20 g) was added, and the mixture was stirred vigorously at room temperature under hydrogen atmosphere for 1 hour. The solvent was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (90: 10: 0.5)] to give a brown oily substance (0.5041). g). This was followed by cyclohexaneacetic acid (0.35 g), 4-dimethylaminopyridine (0.50 g) and hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.62 g) in N, N-dimethylformamide ( 10 mL) and stirred at room temperature for 15 hours. After adding ethyl acetate, the mixture was washed sequentially with saturated sodium bicarbonate and saturated brine, dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was chromatographed [silica gel, dichloromethane-methanol]. -Ammonia water (95: 5: 0.3)] to give the title compound (0.4453 g).
[907]
[908] Example 1G-4
[909] 3-cyclohexyl-N- [2- [3- [4- (p-toluidino) piperidin-1-yl] propyl] phenyl] propionamide
[910]
[911] 4- (p-tolyl) aminopiperidinetrifluoroacetic acid salt (2.08 g) and (3-bromopropenyl) -2-nitrobenzene (3.01 g) in N, N-dimethylformamide (20 mL) It dissolved in, potassium carbonate (2.75 g) was added, and it stirred at 80 degreeC for 2 hours. Dichloromethane was added to the reaction solution, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (95: 5: 0.3)] to give a yellow oily substance (1.05 g). This was dissolved in acetic acid (25 mL), 10% palladium carbon (0.50 g) was added, and the mixture was stirred vigorously under hydrogen atmosphere at room temperature for 1 hour. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the obtained residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (90: 10: 0.5)] to give a brown solid (0.5443 g) . A portion of this (0.3870 g) and cyclohexaneacetic acid (0.28 g), 4-dimethylaminopyridine (0.50 g) and hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.46 g) were added to N, It dissolved in N-dimethylformamide (5 mL) and stirred at room temperature for 18 hours. After adding ethyl acetate, the mixture was washed sequentially with saturated sodium bicarbonate and saturated brine, dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was chromatographed [silica gel, dichloromethane-methanol- Ammonia water (97: 3: 0.2)] to give the title compound (0.4190 g).
[912]
[913] Example 1H-1
[914] 1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexanecarboxylic acid benzyl
[915]
[916] To a tetrahydrofuran (15 mL) solution of 2- (piperidin-4-ylamino) -5-methylpyridine (277 mg) and 1- (2-oxoethyl) cyclohexanecarboxylic acid benzyl (360 mg) was diluted with acetic acid (207 mg) and Sodium triacetoxy borohydride (731 mg) was added at room temperature. After stirring for 18 hours, saturated sodium bicarbonate water was added, followed by extraction with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was chromatographed (NH silica gel, hexane: ethyl acetate = 2: 1) to give the title compound (520 mg).
[917]
[918] Example 1H-2
[919] 1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexanecarboxylic acid
[920]
[921] To a ethanol (16 mL) solution of 1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexanecarboxylic acid benzyl (160 mg, 0.37 mmol), 10% palladium Carbon (80 mg) was added, and it stirred at room temperature under hydrogen atmosphere for 24 hours. Acetic acid was added, filtered through Celite, and concentrated under reduced pressure. Methanol and diethyl ether were added to the residue, the mixture was stirred for 1 hour under ice-cooling, and the crystals were collected by filtration to obtain the title compound (100 mg).
[922]
[923] Example 2-1
[924] N- [1- (cyclohexylmethyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[925]
[926] Dichloromethane (3 mL) solution of 2- [1- (cyclohexylmethyl) piperidin-4-ylamino] -5-methylpyridine (216 mg), triethylamine (152 mg), prepared in Example 1A-1 2-furoyl chloride (0.11 mL) was added dropwise under ice-cooling. Stir at room temperature for 18 hours. Silica gel (NH silica gel) was added to the reaction solution, and the resulting mixture was concentrated under reduced pressure. The residue was chromatographed (NH silica gel, hexane: ethyl acetate = 2: 1) to give the title compound as colorless crystals (271 mg).
[927] Freeche
[928]
[929] Hydrochloride
[930]
[931] Example 2-2
[932] N- [1- (2-cyclohexylethyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[933]
[934] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-2.
[935] Freeche
[936]
[937] Hydrochloride
[938]
[939] Example 2-3
[940] N- [1- (3-cyclohexylpropyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[941]
[942] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-3.
[943] Freeche
[944]
[945] Hydrochloride
[946]
[947] Example 2-4
[948] N- [1- (4-cyclohexylbutyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[949]
[950] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-4.
[951] Freeche
[952]
[953] Hydrochloride
[954]
[955] Example 2-5
[956] N- [1- [2- [2- (cyclohexylacetamide) phenyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[957]
[958] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-5.
[959] Freeche
[960]
[961] Hydrochloride
[962]
[963] Example 2-6
[964] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl acetate
[965]
[966] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-6.
[967] Hydrochloride
[968]
[969] Example 2-7
[970] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclopentyl] methyl acetate
[971]
[972] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-7.
[973] Hydrochloride
[974]
[975] Example 2-8
[976] [2- [3- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] carbamic acid tert-butyl
[977]
[978] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-8.
[979]
[980] Example 2-9
[981] N- [1- (3-cyclohexylpropyl) piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[982]
[983] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1B-1.
[984]
[985] Example 2-10
[986] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl acetate
[987]
[988] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1B-2.
[989] Hydrochloride
[990]
[991] Example 2-11
[992] N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[993]
[994] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1B-4.
[995]
[996] Example 2-12
[997] Acetic acid 3- [1- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] methylcyclohexyl] propyl
[998]
[999] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1C-1.
[1000]
[1001] Example 2-13
[1002] 1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexanecarboxylate
[1003]
[1004] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-1.
[1005] Freeche
[1006]
[1007] Hydrochloride
[1008]
[1009] Example 2-14
[1010] N- [1- [3- [2- (cyclohexylacetamide) phenyl] propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1011]
[1012] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-2.
[1013] Freeche
[1014]
[1015] Hydrochloride
[1016]
[1017] Example 2-15
[1018] N- [1- (2-cyclooctylethyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1019]
[1020] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-3.
[1021] Freeche
[1022]
[1023] Hydrochloride
[1024]
[1025] Example 2-16
[1026] 4- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate
[1027]
[1028] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-4.
[1029] Freeche
[1030]
[1031] Hydrochloride
[1032]
[1033] Example 2-17
[1034] 3- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1, 1-propanetricarboxylic acid triethyl
[1035]
[1036] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-5.
[1037] Freeche
[1038]
[1039] Hydrochloride
[1040]
[1041] Example 2-18
[1042] 3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1-propanedicarboxylic acid dimethyl
[1043]
[1044] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-6.
[1045] Freeche
[1046]
[1047] Example 2-19
[1048] 2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,3-diacetoxypropane
[1049]
[1050] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-7.
[1051] Freeche
[1052]
[1053] Hydrochloride
[1054]
[1055] Example 2-20
[1056] 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,3- Diacetoxypropane
[1057]
[1058] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-8.
[1059]
[1060] Example 2-21
[1061] N- [1- [2- [1- (4-methoxymethoxy) -3- (methoxymethoxymethyl) butyl] cyclohexyl] ethyl] piperidin-4-yl) -N- (5- Methylpyridin-2-yl) -2-furancarboxamide
[1062]
[1063] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-9.
[1064]
[1065] Example 2-22
[1066] N- [1- [2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine-2 -Yl) -2-furancarboxamide
[1067]
[1068] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-10.
[1069]
[1070] Example 2-23
[1071] N- [1- [2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) 2-furancarboxamide
[1072]
[1073] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-11.
[1074]
[1075] Example 2-24.
[1076] 2- (acetoxymethyl) -2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl ] Ethyl] cyclohexyl] ethyl] -1,4-diacetoxybutane
[1077]
[1078] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-12.
[1079]
[1080] Example 2-25
[1081] 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl ] Ethyl] cyclohexyl] methyl heptate
[1082]
[1083] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-13.
[1084]
[1085] Example 2-26
[1086] N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarbox mid
[1087]
[1088] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1B-3.
[1089] Hydrochloride
[1090]
[1091] Example 2-27
[1092] N- [1- [2- [1- (2-methanesulfonamideethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancar Copy mid
[1093]
[1094] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-15.
[1095] Hydrochloride
[1096]
[1097] Example 2-28
[1098] N- (1-cyclohexylpiperidin-4-yl) -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1099]
[1100] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1E-1.
[1101]
[1102] Hydrochloride
[1103]
[1104] Example 2-29
[1105] N- [1- [2- (cyclohexylacetamide) benzyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1106]
[1107] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1G-2.
[1108] Freeche
[1109]
[1110] Hydrochloride
[1111]
[1112] Example 2-30
[1113] 5,5-bis (benzoyloxymethyl) -7- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl ] Methyl Hepcarbonate
[1114]
[1115] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1D-14.
[1116]
[1117] Example 2-31
[1118] 2-furancarboxylic acid 2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl
[1119]
[1120] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1F-1.
[1121] Freeche
[1122]
[1123] Hydrochloride
[1124]
[1125] Example 2-32
[1126] [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl] carba Tert-Butyl Acid
[1127]
[1128] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1G-1.
[1129]
[1130] Example 2-33
[1131] N- [1- [2- [2- (cyclohexylacetamide) phenyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1132]
[1133] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1G-3.
[1134] Hydrochloride
[1135]
[1136] Example 2-34
[1137] N- [1- [3- [2- (3-cyclohexylpropionamide) phenyl] propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1138]
[1139] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1G-4.
[1140] Hydrochloride
[1141]
[1142] Example 2-35
[1143] 1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexanecarboxylic acid
[1144]
[1145] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1H-2.
[1146] Freeche
[1147]
[1148] Hydrochloride
[1149]
[1150] Example 2-36
[1151] [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] carbamate tert-butyl
[1152]
[1153] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1B-5.
[1154]
[1155] Example 2-37
[1156] [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] carbamate tert-butyl
[1157]
[1158] It synthesize | combined by the method similar to Example 2-1 from the compound obtained in Example 1A-9.
[1159]
[1160] Example 3A-1
[1161] [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] Acetic acid
[1162]
[1163] [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] Ethyl acetate (221 mg) was dissolved in methanol (5 mL), 2N aqueous sodium hydroxide solution (2.1 mL) was added, and the mixture was stirred at room temperature for 16 hours. Acetic acid (0.25 mL) was added to neutralize (near pH 6). The solvent was evaporated under reduced pressure, and the obtained residue was extracted with 20% ethanol / chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound (170 mg).
[1164] Hydrochloride
[1165]
[1166] Example 3A-2
[1167] 3- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] aceta Mead] propionic acid
[1168]
[1169] It synthesize | combined by the method similar to Example 3A-1 from the compound obtained in Example 4A-3.
[1170] Hydrochloride
[1171]
[1172] Example 3A-3
[1173] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid
[1174]
[1175] It synthesize | combined by the method similar to Example 3A-1 from the compound obtained in Example 2-6.
[1176] Freeche
[1177]
[1178] Hydrochloride
[1179]
[1180] Example 3A-4
[1181] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclopentyl] acetic acid
[1182]
[1183] It synthesize | combined by the method similar to Example 3A-1 from the compound obtained in Example 2-7.
[1184] Hydrochloride
[1185]
[1186] Example 3B-1
[1187] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid
[1188]
[1189] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl acetate (0.5241 g) and lithium hydroxide monohydrate ( 0.94 g) was added 1,4-dioxane (20 mL) and water (5 mL), and the obtained suspension was stirred for 3 days at room temperature. The reaction solution was dried and solidified, and the residue was diluted with water, then acetic acid (1.0 mL) was added, followed by extraction with 25% ethanol / chloroform. After drying this (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue thus obtained was chromatographed (silica gel, 10% methanol / chloroform) to obtain the title compound. Hydrochloration was carried out again to give the title compound as a white solid (0.3805 g) (0.36 g).
[1190] Hydrochloride
[1191]
[1192] Example 3B-2
[1193] 3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1-propanedicarboxylic acid
[1194]
[1195] It synthesize | combined by the method similar to Example 3B-1 from the compound obtained in Example 2-18.
[1196] Freeche
[1197]
[1198] Hydrochloride
[1199]
[1200] Example 3B-3
[1201] 4- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] butyric acid
[1202]
[1203] It synthesize | combined by the method similar to Example 3B-1 from the compound obtained in Example 4B-3.
[1204] Hydrochloride
[1205]
[1206] Example 3B-4
[1207] 2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetyliminodiacetic acid
[1208]
[1209] It synthesize | combined by the method similar to Example 3B-1 from the compound obtained in Example 4C-1.
[1210] Hydrochloride
[1211]
[1212] Example 3B-5
[1213] N- [1- [2- [1- [N- [tris (hydroxymethyl) methyl] carbamoylmethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine- 2-yl) -2-furancarboxamide
[1214]
[1215] It synthesize | combined by the method similar to Example 3B-1 from the compound obtained in Example 4B-5.
[1216] Hydrochloride
[1217]
[1218] Example 3B-6
[1219] N-[(1-carboxymethylcyclohexyl) acetyl] -N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidine- 1-yl] ethyl] phenyl] aminoacetic acid
[1220]
[1221] It synthesize | combined by the method similar to Example 3B-1 from the compound obtained in Example 5B-5.
[1222] Hydrochloride
[1223]
[1224] Example 3B-7
[1225] 3- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -5-cyclohexyloxy Dantophosphate
[1226]
[1227] It synthesize | combined by the method similar to Example 3B-1 from the compound obtained in Example 5B-8.
[1228] Hydrochloride
[1229]
[1230] Example 3C-1
[1231] 4- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] butyric acid
[1232]
[1233] 4- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate (210 mg) To a methanol (10 mL) solution of 3N aqueous potassium hydroxide solution (1.4 mL) was added at room temperature. After stirring this solution at room temperature for 3 hours, 3N potassium hydroxide aqueous solution (0.7 mL) was further added at room temperature. After stirring this solution at room temperature for 2 hours, water (5 mL) and acetic acid (0.36 mL) were added. Concentrated under reduced pressure, methanol was distilled off and extracted with 20% ethanol / chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (180 mg).
[1234] Freeche
[1235]
[1236] Hydrochloride
[1237]
[1238] Example 3C-2
[1239] 5,5-bis (hydroxymethyl) -7- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl ] Ethyl] cyclohexyl] heptanoic acid
[1240]
[1241] It synthesize | combined by the method similar to Example 3C-1 from the compound obtained in Example 2-25.
[1242]
[1243] Example 3C-3
[1244] 5,5-bis (hydroxymethyl) -7- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl ] Heptanoic acid
[1245]
[1246] It synthesize | combined by the method similar to Example 3C-1 from the compound obtained in Example 2-30.
[1247] Freeche
[1248]
[1249] Example 3C-4
[1250] N- [1- [2- (1- (2-hydroxyethyl) cyclohexyl) ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarbox mid
[1251]
[1252] It synthesize | combined by the method similar to Example 3C-1 from the compound obtained in Example 2-31.
[1253] Freeche
[1254]
[1255] Hydrochloride
[1256]
[1257] Example 3C-5
[1258] 1- [N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] carbamoyl Methyl] cyclohexyl acetic acid
[1259]
[1260] It synthesize | combined by the method similar to Example 3C-1 from the compound obtained in Example 5B-4.
[1261] Freeche
[1262]
[1263] Hydrochloride
[1264]
[1265] Example 3D-1
[1266] N- [1- (1- (3-hydroxypropyl) cyclohexylmethyl) piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1267]
[1268] Methanol (10 mL) of acetic acid 3- [1- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] methylcyclohexyl] propyl (180 mg) Potassium carbonate (10 mg) was added to the solution at room temperature. The solution was stirred at room temperature for 16 hours, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed (NH silica gel, hexane: ethyl acetate = 2: 8) to give the title compound (180 mg).
[1269] Freeche
[1270]
[1271] Hydrochloride
[1272]
[1273] Example 3D-2
[1274] N- [1- [2- [1- (4-hydroxy-3-hydroxymethylbutyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancar Copy mid
[1275]
[1276] It synthesize | combined by the method similar to Example 3D-1 from the compound obtained in Example 2-20.
[1277] Freeche
[1278]
[1279] Hydrochloride
[1280]
[1281] Example 3D-3
[1282] N- [1- [2- [1- [5-hydroxy-3,3-bis (hydroxymethyl) pentyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine -2-yl) -2-furancarboxamide
[1283]
[1284] It synthesize | combined by the method similar to Example 3D-1 from the compound obtained in Example 2-24.
[1285] Freeche
[1286]
[1287] Hydrochloride
[1288]
[1289] Example 3E-1
[1290] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylimino-N, N-bis ( Acetylimino diacetic acid)
[1291]
[1292] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylimino-N, N-bis ( Acetyl imino diacetic acid) tetraethyl (0.2597 g) was dissolved in 6N hydrochloric acid (20 mL), and the solvent was distilled off under reduced pressure. This operation was repeated twice. The residue was lyophilized to give the title compound hydrochloride (0.2322 g).
[1293] Hydrochloride
[1294]
[1295] Example 3E-2
[1296] N- [1- [2- [1- [N, N-bis [N- [tris (hydroxymethyl) methyl] carbamoylmethyl] carbamoylmethyl] cyclohexyl] ethyl] piperidine-4- Il] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1297]
[1298] It synthesize | combined by the method similar to Example 3E-1 from the compound obtained in Example 4B-6.
[1299] Hydrochloride
[1300]
[1301] Example 3E-3
[1302] N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] -N- (3-cyclohexylpropionyl) Aminobutyric acid
[1303]
[1304] It synthesize | combined by the method similar to Example 3E-1 from the compound obtained in Example 5B-3.
[1305] Hydrochloride
[1306]
[1307] Example 3F-1
[1308] N- [2- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -N- (cyclohexylacetyl) aminoacetic acid
[1309]
[1310] N- [2- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -N- (cyclohexylacetyl) aminoacetic acid tert -Butyl (0.1318 g) was dissolved in 4N hydrochloric acid / 1,4-dioxane solution (6.0 mL) and stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the residue was solidified in ethyl acetate to obtain the title compound hydrochloride (0.0871 g).
[1311] Hydrochloride
[1312]
[1313] Example 3F-2
[1314] N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] -N- (3-cyclohexylpropionyl) Aminoacetic acid
[1315]
[1316] It synthesize | combined by the method similar to Example 3F-1 from the compound obtained in Example 5C-2.
[1317] Hydrochloride
[1318]
[1319] Example 3F-3
[1320] [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] acetic acid
[1321]
[1322] It synthesize | combined by the method similar to Example 3F-1 from the compound obtained in Example 4B-2.
[1323] Hydrochloride
[1324]
[1325] Example 3F-4
[1326] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetyliminodiacetic acid
[1327]
[1328] It synthesize | combined by the method similar to Example 3F-1 from the compound obtained in Example 4B-1.
[1329] Hydrochloride
[1330]
[1331] Example 3F-5
[1332] N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1333]
[1334] [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl] carba Tert-butyl hydrochloride (0.4760 g) was dissolved in 4N hydrogen chloride / 1,4-dioxane solution (10 mL) and methanol (5 mL) and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give the title compound (0.5036 g).
[1335] Hydrochloride
[1336]
[1337] Example 3G-1
[1338] 3- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1- Propanedicarboxylic acid
[1339]
[1340] 3- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1, Lithium hydroxide (100 mg) was added to a 1,4-dioxane (9 mL) and water (3 mL) solution of 1-propanetricarboxylic acid triethyl (200 mg). After stirring this solution at room temperature for 7 hours, water was added and it concentrated under reduced pressure. Acetic acid (0.14 mL) was added to the residue, and the resultant was further concentrated under reduced pressure, and dried to dryness. The residue was chromatographed (Mitsubishi Chemical Corporation., DIAION HP20, methanol) to give the title compound (150 mg).
[1341] Freeche
[1342]
[1343] Hydrochloride
[1344]
[1345] Example 3G-2
[1346] N- [1- [2- [1- (4-hydroxy-3-hydroxymethylbutyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) 2-furancarboxamide
[1347]
[1348] N- [1- [2- [1- (4-methoxymethoxy) -3- (methoxymethoxymethyl) butyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5- Concentrated hydrochloric acid (0.34 mL) was added to a methanol (10 mL) solution of methylpyridin-2-yl) -2-furancarboxamide (300 mg) at room temperature. It stirred at room temperature for 16 hours, added concentrated hydrochloric acid (0.17 mL) again, and stirred at 50 degreeC for 6 hours. Concentrated under reduced pressure, saturated sodium bicarbonate water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was chromatographed [silica gel, chloroform-methanol-ammonia water (90: 10: 0.1)] to give the title compound (260 mg).
[1349] Freeche
[1350]
[1351] Hydrochloride
[1352]
[1353] Example 3G-3
[1354] N- [1- [2- [1- [1,3-dihydroxypropan-2-yl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl ) -2-furancarboxamide
[1355]
[1356] N- [1- [2- [1- (2-phenyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine-2 4N hydrochloric acid (0.5 mL) was added to a methanol (5 mL) solution of -yl) -2-furancarboxamide (110 mg), and the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Saturated sodium bicarbonate water was added to the residue, followed by extraction with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound. 4N hydrogen chloride / ethyl acetate solution (0.15 mL) was added to the ethyl acetate (10 mL) solution as a residue, and the mixture was stirred at room temperature for 1 hour, after which the precipitated crystals were filtered to obtain hydrochloride (60 mg).
[1357] Hydrochloride
[1358]
[1359] Example 3G-4
[1360] N- [1- [2- [1- [1,3-dihydroxypropan-2-yl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furan Carboxamide
[1361]
[1362] N- [1- [2- [1- (2,2-dimethyl-1,3-dioxan-5-yl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) 3N hydrochloric acid (1.1 mL) was added to the methanol (5 mL) solution of 2-furancarboxamide (340 mg) at room temperature, and it stirred under 1 hour, and concentrated under reduced pressure. The residue chloroform / diethyl ether solution was stirred for 1 hour under ice-cooling, and then the precipitated crystals were filtered to obtain the title compound hydrochloride (240 mg).
[1363] Hydrochloride
[1364]
[1365] Example 4A-1
[1366] 4- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] aceta Mid] ethyl butyrate
[1367]
[1368] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (133 mg), triethyl The amine (0.04 mL) was suspended in N, N-dimethylformamide (10 mL), and 4-aminobutyrate ethyl hydrochloride (69 mg) was added. Hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (78 mg, 0.41 mmol) and 1-hydroxybenzotriazole hydrate (63 mg) were added under ice cooling, and it stirred at the same temperature for 30 minutes. It heated up to room temperature and stirred for 15 hours. Water and saturated sodium hydrogen carbonate solution were added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was chromatographed (NH silica gel, chloroform: methanol = 10: 1) to give the title compound (142 mg).
[1369] Hydrochloride
[1370]
[1371] Example 4A-2
[1372] [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] Ethyl acetate
[1373]
[1374] The compound obtained in Example 3A-3 was synthesized in the same manner as in Example 4A-1, using ethyl amino acetate instead of 4-aminobutyrate.
[1375] Hydrochloride
[1376]
[1377] Example 4A-3
[1378] 3- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] aceta Mid] ethyl propionate
[1379]
[1380] The compound obtained in Example 3A-3 was synthesized in the same manner as in Example 4A-1, except that ethyl 3-aminopropionate was used instead of 4-aminobutyrate.
[1381] Hydrochloride
[1382]
[1383] Example 4A-4
[1384] 4- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclopentyl] aceta Mid] ethyl butyrate
[1385]
[1386] It synthesize | combined by the method similar to Example 4A-1 from the compound obtained in Example 3A-4.
[1387]
[1388] Example 4B-1
[1389] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetyliminodiisacetic acid ditert butyl
[1390]
[1391] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (0.2144 g) with imino diacetic acid di-tert -Butyl (0.2389 g) was dissolved in dichloromethane (5 mL), N, N-diisopropylethylamine (0.18 g) followed by 2-bromo-1-ethylpyridiniumtetrafluoroborate (0.26 g) at room temperature Was added and stirred for 20 hours. Ethyl acetate (60 mL) was added, washed sequentially with saturated sodium bicarbonate and saturated brine, dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was chromatographed [silica gel, dichloromethane- Methanol-ammonia water (97: 3: 0.2-95: 5: 0.3)] to give the title compound (0.2722 g).
[1392]
[1393] Example 4B-2
[1394] [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] acetic acid tert butyl
[1395]
[1396] It synthesize | combined by the method similar to Example 4B-1 from the compound obtained in Example 3B-1.
[1397] This product was provided to the next step without purification.
[1398] Example 4B-3
[1399] 4- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetamide] ethyl butyrate
[1400]
[1401] It synthesize | combined by the method similar to Example 4B-1 from the compound obtained in Example 3B-1.
[1402]
[1403] Example 4B-4
[1404] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylimino-N, N-bis ( Acetylimino diacetic acid) tetraethyl
[1405]
[1406] It synthesize | combined by the method similar to Example 4B-1 from the compound obtained in Example 3B-1.
[1407]
[1408] Example 4B-5
[1409] 2-acetoxymethyl-2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl Acetamide-1,3-diacetoxypropane
[1410]
[1411] It synthesize | combined by the method similar to Example 4A-1 from the compound obtained in Example 3A-3.
[1412] This product was provided to the next step without purification.
[1413] Example 4B-6
[1414] N- [1- [2- [1- [N, N-bis [N- [tris (acetoxymethyl) methyl] carbamoylmethyl] carbamoylmethyl] cyclohexyl] ethyl] piperidine-4- Il] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1415]
[1416] It synthesize | combined by the method similar to Example 4A-1 from the compound obtained in Example 3A-3.
[1417] This product was provided to the next step without purification.
[1418] Example 4C-1
[1419] 2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetyliminodiisacetic acid ethyl
[1420]
[1421] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (0.2527 g) was diluted with It melt | dissolved in methane (5 mL) and N, N- dimethylformamide (5 drops), oxalyl chloride (O.10 mL) was dripped under ice cooling, it returned to room temperature, and it stirred for 1 hour. After distilling off the solvent under reduced pressure, dichloromethane (3 mL) was added and dissolved under ice-cooling again, and a dichloromethane (2 mL) solution of imino diethyl acetate (0.21 g) and triethylamine (0.23 g) was added thereto. Stir at room temperature for 2 days. The reaction solution was chromatographed [silica gel, dichloromethane-methanol-ammonia water (95: 5: 0.3)] without pretreatment to obtain the title compound (0.1702 g).
[1422]
[1423] Example 4D-1
[1424] N- [1- [2- [1- (carbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1425]
[1426] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (909 mg), ammonium chloride (216 mg), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (1.56 g), 1-hydroxybenzotriazole hydrate (470 mg), N, N-diisopropylamine (1.4 mL ) Was dissolved in N, N-dimethylformamide (8 mL) and stirred at room temperature for 22 hours. Saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained residue was chromatographed (silica gel, chloroform: methanol = 1: 1) to give the title compound (652 mg).
[1427] Hydrochloride
[1428]
[1429] Example 4D-2
[1430] N- [1- [2- [1- (cyanomethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1431]
[1432] N- [1- [2- [1- (carbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide (154 mg) was dissolved in dichloromethane (3 mL), and triethylamine (0.10 mL) was added. Methanesulfonic acid chloride (0.038 mL) was added under ice-cooling, and it heated up to room temperature and stirred for 24 hours. Moreover, triethylamine (0.14 mL) and methanesulfonic acid chloride (0.063 mL) were added under ice cooling, and it stirred at room temperature for 24 hours. Water was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography (silica gel, chloroform: methanol = 20: 1) to give the title compound (133 mg).
[1433] Hydrochloride
[1434]
[1435] Example 4D-3
[1436] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxamic acid tert-butyl
[1437]
[1438] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (366 mg), O- (tert-butyl) hydroxyamine hydrochloride (304 mg), 1-hydroxybenzotriazole hydrate (187 mg) and triethylamine (0.56 mL) were dissolved in dichloromethane (15 mL). Under ice-cooling, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (239 mg) hydrochloride was added, and the mixture was stirred for 1 hour. The temperature was gradually raised to room temperature and stirred for 44 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography (silica gel, chloroform: methanol = 95: 5) to obtain the title compound (390 mg).
[1439] Freeche
[1440]
[1441] Example 4D-4
[1442] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid
[1443]
[1444] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxamic acid tert-butyl Trifluoroacetic acid (3.0 mL) was added to (266 mg), and it stirred at room temperature for 23 hours. Then, after stirring at 40 degreeC for 2 hours, trifluoroacetic acid (2.0 mL) was added and it stirred at 50 degreeC for 3 hours. Trifluoroacetic acid was distilled off under reduced pressure under azeotropic reaction with xylene. Water and chloroform were added, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with 20% ethanol / chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The obtained residue was purified by chromatography (silica gel, chloroform: methanol = 85:15) to give the title compound (75 mg).
[1445] Hydrochloride
[1446]
[1447] Example 4D-5
[1448] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxamic acid tert-butyl
[1449]
[1450] It synthesize | combined by the method similar to Example 4D-3 from the compound obtained in Example 3B-1.
[1451]
[1452] Example 4D-6
[1453] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxamic acid tert-butyl (7288), [ 1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acethydroxysamic acid
[1454]
[1455] It synthesize | combined by the method similar to Example 4D-4 from the compound obtained in Example 4D-5.
[1456]
[1457] Example 4D-7
[1458] N- [1- [2- [1- (2-tetrazolylethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarbox mid
[1459]
[1460] N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarbox Mid (355 mg) was dissolved in toluene (2 mL), trimethylsilylazide (0.21 mL) and di-n-butyltin oxide (19.7 mg) were added, and the mixture was heated to reflux for 11 hours. Moreover, trimethylsilyl azide (0.42 mL) and di-n-butyl tin oxide (98.0 mg) were added, and it heated and refluxed for 4 hours. The solvent was distilled off under reduced pressure (methanol azeotrope). The residue obtained was chromatographed (silica gel, chloroform: methanol = 80:20) to give the title compound (385 mg).
[1461] Hydrochloride
[1462]
[1463] Example 4D-8
[1464] N- [1- [2- [1- (2-tetrazolylethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1465]
[1466] It synthesize | combined by the method similar to Example 4D-7 from the compound obtained in Example 2-11.
[1467] Hydrochloride
[1468]
[1469] Example 5A-1
[1470] N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1471]
[1472] [2- [3- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] carbamate tert-butyl (790 mg 4N hydrogen chloride / ethyl acetate solution (2.3 mL) was added to a methanol (15 mL) solution in The solution was stirred at room temperature for 16 hours, concentrated under reduced pressure, saturated sodium bicarbonate water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give the title compound (700 mg).
[1473]
[1474] Example 5A-2
[1475] N- [1- [3- (2-aminophenyl) ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide
[1476]
[1477] It synthesize | combined by the method similar to Example 5A-1 from the compound obtained in Example 2-37.
[1478]
[1479] Example 5A-3
[1480] N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1481]
[1482] It synthesize | combined by the method similar to Example 5A-1 from the compound obtained in Example 2-36.
[1483]
[1484] Example 5B-1
[1485] N- [1- [3- [2- (3-cyclohexylpropionamide) phenyl] propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarbox mid
[1486]
[1487] N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide (100mg) and cyclohexyl To dichloromethane (3 mL) solution of propionic acid (49 mg) was added ice-cold 1-hydroxybenzotriazole (42 mg) and hydrochloric acid 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (60 mg). After stirring at room temperature for 64 hours, chloroform was added and the mixture was washed sequentially with water and saturated sodium bicarbonate water. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was chromatographed (NH silica gel, hexane: ethyl acetate = 1: 2) to give the title compound (120 mg).
[1488] Freeche
[1489]
[1490] Hydrochloride
[1491]
[1492] Example 5B-2
[1493] N- [1- [3- [2- (4-cyclohexylbutyramid) phenyl] propyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancar Copy mid
[1494]
[1495] It synthesize | combined by the method similar to Example 5B-1 from the compound obtained in Example 5A-1.
[1496] Freeche
[1497]
[1498] Hydrochloride
[1499]
[1500] Example 5B-3
[1501] N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] -N- (3-cyclohexylpropionyl) Ethyl aminobutyrate
[1502]
[1503] N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] ethyl butyrate (0.2552 g) was diluted with dichloromethane ( 10 mL), 3-cyclohexanepropionic acid (0.11 g), N, N-diisopropylethylamine (0.31 g), and 2-bromo-1-ethylpyridinium tetrafluoroborate (0.39 g) were sequentially added. Was added and stirred for 5 days at room temperature. Ethyl acetate (50 mL) was added, washed sequentially with saturated sodium bicarbonate and brine, dried (MgSO ₄ ), the solvent was distilled off under reduced pressure, and the residue was chromatographed [silica gel, dichloromethane]. -Methanol-ammonia water (97: 3: 0.2)] to give the title compound.
[1504] This product was provided to the next step without purification.
[1505] Example 5B-4
[1506] 1- [N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] carbamoyl Methyl] cyclohexyl acetate
[1507]
[1508] After adding N, N-dimethylformamide (one drop) to a dichloromethane (10 mL) solution of 1-methoxycarbonylmethylcyclohexyl acetic acid (265 mg), oxalyl chloride (0.12 mL) was added under ice cooling. Added. The solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. This dichloromethane (5 mL) solution was diluted with N- [1- [3- (2-aminophenyl) ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2- It was added to the dichloromethane (5 mL) solution of furancarboxamide (250 mg) under ice-cooling, after addition of triethylamine (0.29 mL). After stirring for 1 hour under ice-cooling, saturated sodium bicarbonate water and chloroform were added to separate the solution. The organic layer was washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was chromatographed (silica gel, hexane: ethyl acetate = 6: 4) to give the title compound (320 mg).
[1509] Freeche
[1510]
[1511] Hydrochloride
[1512]
[1513] Example 5B-5
[1514] N-[(1-methoxycarbonylmethylcyclohexyl) acetyl] -N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] py Ferridin-1-yl] ethyl] phenyl] amino acetate
[1515]
[1516] It synthesize | combined by the method similar to Example 5B-4 from the compound obtained in Example 5D-2.
[1517] Freeche
[1518]
[1519] Example 5B-6
[1520] N- [1- [2- [1- [5-hydroxy-3,3-bis (hydroxymethyl) pentyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine -2-yl) -2-furancarboxamide
[1521]
[1522] 1 of N- [1- [3- (2-aminophenyl) ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide (82 mg) Cyclohexyl isocyanate (38 mg) was added to a 2-dichloroethane (2 mL) solution at room temperature. After stirring this solution at 50 degreeC for 5 hours, it concentrated under reduced pressure. The residue was chromatographed (NH silica gel, ethyl acetate) to give the title compound (70 mg).
[1523] Freeche
[1524]
[1525] Hydrochloride
[1526]
[1527] Example 5B-7
[1528] N- [1- [3- [2- (3-cyclohexylureido) phenyl] propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1529]
[1530] It synthesize | combined by the method similar to Example 5B-6 from the compound obtained in Example 5A-1.
[1531] Hydrochloride
[1532]
[1533] Example 5B-8
[1534] 3- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -5-cyclohexyloxy Ethyl tomate
[1535]
[1536] It synthesize | combined by the method similar to Example 5B-6 from the compound obtained in Example 5D-2.
[1537] Freeche
[1538]
[1539] Example 5B-9
[1540] N- [1- [3- [2- (3-cyclohexylthioureido) phenyl] propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1541]
[1542] N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (0.42 g) to 1,2-dichloroethane It melt | dissolved in (5 mL) and added cycloisoxyl isothiocyanate (0.42g), and it heated and refluxed for 8 hours. The reaction solution was chromatographed [silica gel, dichloromethane-methanol-ammonia water (97: 3: 0.2-95: 5: 0.3)] to give the title compound (0.2458 g).
[1543]
[1544] Example 5C-1
[1545] N- [2- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] -N- (cyclohexylacetyl) aminoacetic acid tert -Butyl
[1546]
[1547] N- [1- [2- [2- (cyclohexylacetamide) phenyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (0.3464 g) with Bromoacetic acid tert-butyl (0.38 g) was dissolved in N, N-dimethylformamide (5 mL), 60% sodium hydride / mineral oil (0.0622 g) was added, and the mixture was stirred at room temperature for 17 hours. After dilution with ethyl acetate (50 mL), washing with saturated brine, drying (MgSO ₄ ), distilling off the solvent under reduced pressure, and performing chromatography (silica gel, ethyl acetate) on the obtained residue, Compound obtained (0.1318 g).
[1548]
[1549] Example 5C-2
[1550] N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] -N- (3-cyclohexylpropionyl) Aminoacetic acid tert-butyl
[1551]
[1552] It synthesize | combined by the method similar to Example 5C-1 from the compound obtained in Example 2-34.
[1553]
[1554] Example 5D-1
[1555] N- [2- [3- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] propyl] phenyl] ethyl butyrate
[1556]
[1557] N- [1- [3- (2-aminophenyl) propyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (03211 g) was dissolved in ethanol (3 mL) , 4-bromobutyrate (0.23 g) and then diisopropylamine (0.16 g) were added, and it heated and refluxed for 5 hours. After adding ethyl acetate (10 mL), washing with saturated brine, drying (MgSO ₄ ), and distilling off the solvent under reduced pressure, the obtained residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (97 : 3: 0.2)] to give the title compound (0.2552g).
[1558]
[1559] Example 5D-2
[1560] N- [2- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] phenyl] aminoacetate ethyl
[1561]
[1562] It synthesize | combined by the method similar to Example 5D-1 from the compound obtained in Example 5A-2.
[1563]
[1564] Example 6
[1565] N- [1- [2- [1- [2- (N ² -hydroxycarbamididoyl) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl)- 2-furancarboxamide
[1566]
[1567] N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (Example 2 Synthesis at -11) (1.75 g) is dissolved in ethanol (15 mL), an aqueous solution of hydroxylamine hydrochloride (0.82 g) (5 mL) is added followed by an aqueous solution of potassium carbonate (1.62 g) (10 mL) for 24 hours. Heated to 90 ° C. After adding silica gel (15 g) to the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water (0: 10: 0.5)] to give the title compound. Was obtained (1.4660 g).
[1568] Hydrochloride
[1569]
[1570] Example 7
[1571] 1- [1-hydroxyimino-3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] propyl ] Methyl Carbamate
[1572]
[1573] N- [1- [2- [1- [2- (N ² -hydroxycarbamididoyl) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl)- 2-furancarboxamide (synthesized in Example 6) (0.4740 g) was dissolved in N, N-dimethylformamide and pyridine (0.12 g), methyl chloroformate (0.092 g) was added under ice-cooling, and the mixture was stirred at room temperature. Stirred for 1 hour. After adding water to the reaction solution, the mixture was extracted with 25% ethanol-chloroform, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water ( 95: 5: 0.3)] to give the title compound (0.4535 g).
[1574] Hydrochloride
[1575]
[1576] Example 8
[1577] N- [1- [2- [1- [2- (2H-5-thioxo-1,2,4-oxadiazol-3-yl) ethyl] cyclohexyl] ethyl] piperidin-4-yl ] -N- (p-tolyl) -2-furancarboxamide
[1578]
[1579] N- [1- [2- [1- [2- (N ² -hydroxycarbamididoyl) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl)- 2-furancarboxamide (synthesized in Example 6) (0.3097 g) was dissolved in acetonitrile (10 mL), and 1,1'-thiocarbonyldiimidazole (0.17 g) was added. The reaction solution changed from an orange solution to a yellow suspension. 1, 8- diazabicyclo [5.4.0] -7-undecene (O.39g) was added here, and it heated and refluxed for 4 hours. After adding water to the reaction solution, the mixture was extracted with 25% ethanol-chloroform, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was chromatographed [silica gel, dichloromethane-methanol-ammonia water ( 90: 10: 0.5)] to give the title compound (0.2810 g).
[1580] Hydrochloride
[1581]
[1582] Example 9
[1583] N- [1- [2- [1- [2- (2H-5-oxo-1,2,4-oxadiazol-3-yl) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1584]
[1585] 1- [1-hydroxyimino-3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] propyl ] Carbamate Methyl Hydrochloride (Synthesis in Example 7) (0.3565 g) is dissolved in acetonitrile (10 mL) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.50 g) is added. And refluxed for 1 hour. Water (30 mL) was added to the reaction solution, followed by extraction with 25% ethanol-chloroform, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. The obtained residue was chromatographed [silica gel, dichloromethane-methanol- Ammonia water (90: 10: 0.5)] to obtain the title compound (0.2818 g).
[1586] Hydrochloride
[1587]
[1588] Example 10
[1589] N- [1- [2- [1- (1-methanesulfonylcarbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1590]
[1591] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (synthesized in Example 3B-1) (203 mg ), Methanesulfonamide (84 mg), 1,3-dicyclohexylcarbodiimide (101 mg), and 4-dimethylaminopyridine (59 mg) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to obtain the title compound (233 mg).
[1592] Freeche
[1593]
[1594] Hydrochloride
[1595]
[1596] Example 11
[1597] N- [1- [2- [1- (1,1-dimethylcarbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1598]
[1599] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (synthesized in Example 3B-1) (678 mg N, N-dimethylformamide (2 drops) was added dropwise to a dichloromethane (15 mL) solution, and then oxalyl chloride (0.16 mL) was added dropwise under ice-cooling. After stirring for 2 hours under ice-cooling, 5 mL of the reaction solution was taken and added dropwise to 50% dimethylamine aqueous solution (5 mL) under ice-cooling. The reaction solution was allowed to proceed and stirred at room temperature for 48 hours, followed by addition of NH silica gel and concentration under reduced pressure. The residue was purified by column chromatography [NH silica gel, hexane-ethyl acetate (1: 1)] to give the title compound (164 mg).
[1600] Hydrochloride
[1601]
[1602] Example 12
[1603] N- [1- [2- [1- (2-morpholin-4-yl-2-oxoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2- Furancarboxamide
[1604]
[1605] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (synthesized in Example 3B-1) (200 mg ) Was dissolved in dichloromethane (4 mL), and N, N-dimethylformamide (1 drop) was added. Oxalyl chloride (0.050 mL) was added dropwise under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain an acid chloride.
[1606] Morpholine (61 mg) was dissolved in dichloromethane (4 mL), and triethylamine (0.13 mL) was added dropwise. Under ice-cooling, a dichloromethane (3 mL) solution of an acid chloride was added dropwise, stirred for 1 hour, and then heated to room temperature, followed by stirring for 19 hours. Ethyl acetate was added, and it wash | cleaned sequentially by the 10% aqueous citric acid solution, the saturated aqueous sodium hydrogen carbonate solution, and the saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The aqueous layer was reextracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure together with the organic layer. The obtained residue was purified by column chromatography [NH silica gel, hexane-ethyl acetate (2: 1)] to give the title compound (116 mg).
[1607] Freeche
[1608]
[1609] Hydrochloride
[1610]
[1611] Example 13
[1612] 2- (acetoxymethyl) -2- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,4-dia Cetoxybutane
[1613]
[1614] 2- (acetoxymethyl) -2- [2- [1- (formylmethyl) cyclohexyl] ethyl] -1,4-diacetoxybutane (synthesized in Preparation Example 3G-5) (280 mg) and 4- (p-toluidino) piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) (356 mg) was suspended in 1,2-dichloroethane (5 mL). Triethylamine (0.23 mL) was added at room temperature to make a homogeneous solution, and then acetic acid (0.048 mL) was added and stirred for 15 minutes. Under ice-cooling, sodium triacetoxy borohydride (377 mg) was added, and then the temperature was raised to room temperature, followed by stirring for 16 hours. Saturated sodium bicarbonate was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, 33% ethyl acetate / hexanes] to obtain the title compound (334 mg).
[1615]
[1616] Example 14
[1617] 2- (acetoxymethyl) -2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl ] Ethyl] -1,4-diacetoxybutane
[1618]
[1619] 2- (acetoxymethyl) -2- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethyl] -1,4-dia Cetoxybutane (synthesized in Example 13) (324 mg) was dissolved in dichloromethane (4 mL) and triethylamine (0.16 mL) was added. 2-furoyl chloride (0.084 mL) was added under ice-cooling, and then it was raised to room temperature and stirred for 17 hours. 10% citric acid aqueous solution was added and extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1: 1)] to obtain the title compound (356 mg).
[1620]
[1621] Example 15
[1622] N- [1- [2- [1- [5-hydroxy-3,3-bis (hydroxymethyl) pentyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) 2-furancarboxamide
[1623]
[1624] 2- (acetoxymethyl) -2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl ] Ethyl] -1,4-diacetoxybutane (synthesis in Example 14) (313 mg) was dissolved in methanol (5 mL), potassium carbonate (39 mg) was added at room temperature, and the mixture was stirred for 20 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with a chloroform-ethanol (80:20) mixed solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (252 mg).
[1625] Hydrochloride
[1626]
[1627] Example 16
[1628] 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethylcarbamate tert-butyl
[1629]
[1630] 4- (p-toluidino) piperidine (synthesized in Preparation Example 4-5) (0.73 g), N- [2- [1- (formylmethyl) cyclohexyl] ethyl] phthalimide (Preparation Example Sodium triacetoxy borohydride (0.82 g) was added to the 1,2-dichloroethane (10 mL) solution of (0.77 g) and acetic acid (0.30 mL), and it stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with chloroform-ethanol (10: 1). After drying anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (20: 1)] to obtain a colorless oily substance (1.32 g).
[1631]
[1632] Hydrazine monohydrate (0.37 mL) was added to the ethanol (20 mL) solution of the obtained oily substance (1.32 g), and it heated and refluxed for 1 hour. The reaction solution was concentrated under reduced pressure (toluene azeotropy), and dichloromethane (20 mL), triethylamine (1.0 mL), and di-tert-butyldicarbonate (1.00 g) were sequentially added to the obtained residue, followed by 13 hours at room temperature. Stirred. The reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography [silica gel, chloroform-methanol (100: 1)] to obtain the title compound (1.08 g).
[1633]
[1634] Example 17
[1635] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethylcarbamate tert-butyl
[1636]
[1637] 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethylcarbamate tert-butyl (synthesized in Example 16) (1.08 g) Triethylamine (0.68 mL) and 2-furoyl chloride (0.31 mL) were added sequentially to the dichloromethane (5 mL) solution, and it stirred at room temperature for 1 hour. NH silica gel was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (4: 1)] to obtain the title compound (1.14 g).
[1638]
[1639] Example 18
[1640] N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1641]
[1642] 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethylcarbamate tert-butyl (Example Synthesis at 17) 4N hydrochloric acid / dioxane solution (3 mL) was added to a methanol (4 mL) solution of (1.14 g), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography [NH silica gel, chloroform-methanol (20: 1)] to obtain the title compound (1.01 g).
[1643] Freeche
[1644]
[1645] Hydrochloride
[1646]
[1647] Example 19
[1648] N- [1- [2- [1- (2-methanesulfonylaminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1649]
[1650] N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (in Example 18 Synthesis) Triethylamine (0.15 mL) and methanesulfonic acid chloride (56 mL) were sequentially added to a dichloromethane (3 mL) solution of (260 mg), followed by stirring at room temperature for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7: 3-1: 1: 1: 2)] to give the title compound (213 mg).
[1651] Freeche
[1652]
[1653] Hydrochloride
[1654]
[1655] Example 20
[1656] N- [1- [2- [1- [2- (p-toluenesulfonylamino) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancar Copy mid
[1657]
[1658] N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (in Example 18 Synthesis) 1,4-diazabicyclo [2.2.2] octane (108 mg) and p-toluenesulfonic acid chloride (120 mg) were sequentially added to a solution of (228 mg) of dichloromethane (3 mL) at room temperature for 6 hours. Stirred. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7: 3 to 1: 2)] to give the title compound (265 mg).
[1659] Freeche
[1660]
[1661] Hydrochloride
[1662]
[1663] Example 21
[1664] N- [1- [2- [1- [2- (4-chlorobenzenesulfonylamine) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furan Carboxamide
[1665]
[1666] N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (in Example 18 Synthesis) 1,4-diazabicyclo [2.2.2] octane (100 mg) and p-chlorobenzenesulfonate chloride (100 mg) were sequentially added to a dichloromethane (3 mL) solution of (199 mg), followed by 2 at room temperature. Stirred for time. The reaction solution was diluted with chloroform, washed sequentially with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7: 3)] to obtain the title compound (181 mg).
[1667] Freeche
[1668]
[1669] Hydrochloride
[1670]
[1671] Example 22
[1672] 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylamino] benzoic acid
[1673]
[1674] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (synthesized in Example 3B-1) (678 mg N, N-dimethylformamide (2 drops) was added to a solution of dichloromethane (15 mL). Under ice-cooling, oxalyl chloride (228 mg) was added dropwise. After stirring for 2 hours under ice-cooling, 5 mL of the reaction solution was taken and added dropwise to a dichloromethane (5 mL) solution of methyl anthranilate (99 mg) and triethylamine (182 mg) under ice-cooling. The reaction solution was proceeded as it was, stirred at room temperature for 18 hours, and then NH silica gel was added thereto, followed by concentration under reduced pressure. The obtained residue was purified by chromatography (silica gel, chloroform-ethanol (20: 1)], and 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancar Copyamide] piperidin-1-yl] ethyl] cyclohexyl] acetylamino] methyl benzoate was obtained (150 mg).
[1675] The aqueous solution (3 mL) of sodium hydroxide (51 mg) was dripped at this methanol (5 mL) solution, and it stirred at room temperature for 18 hours. After neutralizing with 2N hydrochloric acid, silica gel was added and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to obtain the title compound (148 mg).
[1676] Freeche
[1677]
[1678] Hydrochloride
[1679]
[1680] Example 23
[1681] N- [1- [2- [1- [1- (pyrazin-2-yl) carbamoylmethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2- Furancarboxamide
[1682]
[1683] [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (synthesized in Example 3B-1) (201 mg ) Was dissolved in dichloromethane (6 mL), and N, N-dimethylformamide (2 drops) was added. Oxalyl chloride (0.060 mL) was added dropwise under ice cooling, and the mixture was stirred for 1.5 hours. At the same temperature, triethylamine (0.12 mL) was added and stirred for 20 minutes, followed by 2-aminopyrazine (128 mg). After stirring for 1 hour at the same temperature, the temperature was raised to room temperature, followed by stirring for 16 hours. NH silica gel was added to the reaction solution, and the mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography [1st NH silica gel, hexane-ethyl acetate (2: 1) 2nd silica gel, chloroform-methanol (10: 1)], and the title compound was obtained (116 mg).
[1684] Freeche
[1685]
[1686] Hydrochloride
[1687]
[1688] Example 24
[1689] 5- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] isophthalic acid dimethyl
[1690]
[1691] 2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethanol (synthesis in Preparation Example 3A-2) (2.03 g) and 5-hydroxyisophthalic acid dimethyl (1.26 g) It dissolved in (50 mL) and added triphenylphosphine (1.56 g). Diethyl azo dicarboxylate (0.95 mL) was added dropwise thereto at room temperature, followed by stirring for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (4: 1)] to obtain the title compound (1.84 g).
[1692]
[1693] Example 25
[1694] 5- [2- [1- (2-hydroxyethyl) cyclohexyl] ethoxy] isophthalate dimethyl
[1695]
[1696] 5- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] dimethyl isophthalate (synthesized in Example 24) (0.53 g) was added to tetrahydrofuran (6 mL). It melt | dissolved, the 1M tetrabutylammonium fluoride / tetrahydrofuran solution (1.32 mL) was dripped at room temperature, and it stirred for 3 hours. Aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (1: 1)] to obtain the title compound (255 mg).
[1697]
[1698] Example 26
[1699] 5- [2- [1- (formylmethyl) cyclohexyl] ethoxy] dimethyl isophthalate
[1700]
[1701] 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (444 mg) was suspended in dichloromethane (4 mL). Pyridine (196 mg) was added there and it was set as the substantially uniform solution. It was added dropwise by dissolving 5- [2- [1- (2-hydroxyethyl) cyclohexyl] ethoxy] isophthalate (synthesis in Example 25) (253 mg) in dichloromethane (4 mL) under ice-cooling. Stirred for 1.5 h. After warming to room temperature, diethyl ether (50 mL) was added, followed by washing with 10% aqueous sodium thiosulfate solution (15 mL), 1N hydrochloric acid (20 mL), saturated sodium bicarbonate (20 mL), and brine (30 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (253 mg). This product was provided to the next step without further purification.
[1702] Example 27
[1703] 5- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] isophthalate dimethyl
[1704]
[1705] 5- [2- [1- (formylmethyl) cyclohexyl] ethoxy] isophthalic acid dimethyl (synthesized in Example 26) (253 mg) and 4- (p-toluidino) piperidineditrifluoroacetic acid Salt (synthesized in Preparation Example 4-5) (356 mg) was suspended in 1,2-dichloroethane (8 mL). Triethylamine (170 mg) was added at room temperature to make a homogeneous solution, and then acetic acid (51 mg) was added and stirred for 10 minutes. Under ice-cooling, sodium triacetoxy borohydride (371 mg) was added, and then the temperature was raised to room temperature, followed by stirring for 3 hours. Saturated sodium bicarbonate was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, chloroform-methanol (10: 1)] to obtain the title compound (296 mg).
[1706]
[1707] Example 28
[1708] 5- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] isophthalic acid dimethyl
[1709]
[1710] 5- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] dimethyl isophthalate (synthesized in Example 27) (280 mg) Was dissolved in dichloromethane (5 mL) and triethylamine (0.14 mL) was added. 2-furoyl chloride (0.077 mL) was added under ice-cooling, and then, the temperature was raised to room temperature, followed by stirring for 15 hours. Aqueous 10% citric acid solution was added and extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1: 1)] to obtain the title compound (288 mg).
[1711]
[1712] Example 29
[1713] 5- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] isophthalic acid
[1714]
[1715] 5- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] dimethyl isophthalate ( (255 mg) synthesize | combined in Example 28, was dissolved in methanol (5 mL), the 2N sodium hydroxide aqueous solution (2.0 mL) was added, and it stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, water was added, neutralized with acetic acid (0.23 mL), and extracted with chloroform-ethanol (80:20). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (243 mg).
[1716] Hydrochloride
[1717]
[1718] Example 30
[1719] 1- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] -3,5-dihydroxymethylbenzene
[1720]
[1721] Lithium aluminum hydride (172 mg) was suspended in tetrahydrofuran (10 mL), and dimethyl 5- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] isophthalate at room temperature (Synthesis in Example 24) A tetrahydrofuran (15 mL) solution of (1.30 g) was added dropwise and stirred for 3 hours. After adding water (0.16 mL) and stirring for 10 minutes, 15% aqueous sodium hydroxide solution (0.16 mL) was added, followed by stirring for 15 minutes. Diethyl ether was added, and water (0.48 mL) was added and stirred for 30 minutes. It was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, ethyl acetate] to obtain the title compound (1.04 g).
[1722]
[1723] Example 31
[1724] 2- [1- [2- (3,5-Diacetoxymethylphenoxy) ethyl] cyclohexyl] ethanol
[1725]
[1726] 1- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] -3,5-dihydroxymethylbenzene (synthesized in Example 30) (1.04 g) was prepared. It melt | dissolved in pyridine (5.0 mL), added acetic anhydride (5 mL) under ice cooling, stirred for 1 hour, heated up to room temperature, and stirred for 1 hour. The reaction solution was concentrated under reduced pressure (toluene azeotropy), thereby obtaining 1- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] -3,5-diacetoxymethylbenzene Obtained (1.13 g). This product was provided to the next step without purification.
[1727] 1- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] -3,5-diacetoxymethylbenzene (1.13 g) in tetrahydrofuran (7 mL) It melt | dissolved, the 1M tetrabutylammonium fluoride / tetrahydrofuran solution (2.8 mL) was dripped at room temperature, and it stirred for 15 hours. Aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (1: 1)] to obtain the title compound (439 mg).
[1728]
[1729] Example 32
[1730] 1,3-diacetoxymethyl-5- [2- [1- (formylmethyl) cyclohexyl] ethoxy] benzene
[1731]
[1732] 2- [1- [2- (3,5-Diacetoxymethylphenoxy) ethyl] cyclohexyl] ethanol (synthesis in Example 31) (430 mg) was dissolved in dichloromethane (5 mL) and diacetic acid at room temperature Iodinebenzene (388 mg) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (18.5 mg) were added sequentially. After stirring this solution for 15 hours, diethyl ether was added, and it wash | cleaned sequentially with 10% sodium thiosulfate aqueous solution, IN hydrochloric acid, saturated sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (479 mg). This product was provided to the next step without further purification.
[1733] Example 33
[1734] 1,3-Diacetoxymethyl-5- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzene
[1735]
[1736] 1,3-Diacetoxymethyl-5- [2- [1- (formylmethyl) cyclohexyl] ethoxy] benzene (synthesized in Example 32) (215 mg) and 4- (p-toluidino) pi Ferridine (synthesized in Preparation Example 4-5) (127 mg) was dissolved in 1,2-dichloroethane (5 mL). Acetic acid (0.04 mL) was added at room temperature and stirred for 45 minutes. Sodium triacetoxy borohydride (294 mg) was added at room temperature, and the mixture was stirred for 3 hours. Saturated sodium bicarbonate was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to give the title compound (334 mg). This product was provided to the next step without further purification.
[1737]
[1738] Example 34
[1739] N- [1- [2- [1- [2- [3,5-bis (hydroxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl ) -2-furancarboxamide
[1740]
[1741] 1,3-Diacetoxymethyl-5- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzene (Example Synthesis at 33) (222 mg) was dissolved in dichloromethane (4 mL), and triethylamine (0.11 mL) was added. 2-furoyl chloride (0.06 mL) was added under ice-cooling, and then, the temperature was raised to room temperature, followed by stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to give N- [1- [2- [1- [2- [3,5-bis (Acetoxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide was obtained (276 mg). This product was provided to the next step without further purification.
[1742] N- [1- [2- [1- [2- [3,5-bis (acetoxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl ) -2-furancarboxamide (276 mg) was dissolved in methanol (4 mL), potassium carbonate (11 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate water was added, followed by extraction with chloroform-ethanol (80:20). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (228 mg).
[1743] Freeche
[1744]
[1745] Hydrochloride
[1746]
[1747] Example 35
[1748] 2- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] methyl benzoate
[1749]
[1750] Tert-butyl [2- [1- (2-iodineethyl) cyclohexyl] ethoxy] diphenylsilane (prepared in a solution of methyl salicylate (456 mg) and potassium carbonate (498 mg) in N, N-dimethylformamide (10 mL) (1.7 g) synthesize | combined in Example 3A-3, and it heated and stirred at 80 degreeC for 24 hours. Water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and brine. The ether layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography [silica gel, hexane-ethyl acetate (10: 1)] to give the title compound (547 mg).
[1751]
[1752] Example 36
[1753] Methyl 2- [2- [1- (2-hydroxyethyl) cyclohexyl] ethoxy] benzoate
[1754]
[1755] Methyl 2- [2- [1- [2- (tert-butyldiphenylsiloxy) ethyl] cyclohexyl] ethoxy] benzoate (synthesized in Example 35) (547 mg) in tetrahydrofuran (4 mL) solution of room temperature Then, 1M tetrabutylammonium fluoride / tetrahydrofuran solution (1 mL) was added, followed by further stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by chromatography [silica gel, hexane-ethyl acetate (2: 1)] to obtain the title compound (226 mg).
[1756]
[1757] Example 37
[1758] Methyl 2- [2- [1- (formylmethyl) cyclohexyl] ethoxy] benzoate
[1759]
[1760] Methyl 2- [2- [1- (2-hydroxyethyl) cyclohexyl] ethoxy] benzoate (synthesized in Example 36) (226 mg), 2,2,6,6-tetramethyl-1-piperidinyl To a dichloromethane (4 mL) solution of oxy free radicals (23 mg) was added iodine dibenzene benzene (261 mg) at room temperature and stirred at room temperature for 48 hours. Silica gel was added to the reaction solution and concentrated under reduced pressure. The residue was purified by chromatography [silica gel, hexane-ethyl acetate (5: 1)] to give the title compound (118 mg).
[1761]
[1762] Example 38
[1763] 2- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzoate
[1764]
[1765] Methyl 2- [2- [1- (formylmethyl) cyclohexyl] ethoxy] benzoate (synthesized in Example 37) (118 mg), 4- (p-toluidino) piperidineditrifluoroacetic acid salt (Synthesis in Production Example 4-5) In a solution of (194 mg), 1,2-dichloroethane (2 mL) and triethylamine (94 mg), acetic acid (28 mg) and sodium triacetoxy borohydride (115 mg) were added at room temperature. Added. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by chromatography [upper layer: NH silica gel, lower layer: silica gel, chloroform-ethanol (20: 1)] to obtain the title compound (205 mg).
[1766] Example 39
[1767] 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] methyl benzoate
[1768]
[1769] Methyl 2- [2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzoate (synthesized in Example 38) (186 mg), 2-furoyl chloride (0.046 mL) was added dropwise under ice-cooling to a dichloromethane (2 mL) solution of triethylamine (0.081 mL). After dripping, it progressed as it was and stirred at room temperature for 18 hours. NH silica gel was added to the reaction solution, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (3: 1)] to obtain the title compound (223 mg).
[1770]
[1771] Example 40
[1772] 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzoic acid
[1773]
[1774] 2- [2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethoxy] methylbenzoate (implemented To a methanol (5 mL) solution of Synthesis (221 mg) in Example 39, a water (3 mL) solution of sodium hydroxide (77 mg) was added dropwise at room temperature, followed by stirring at room temperature for 18 hours. After neutralizing with 2N hydrochloric acid, silica gel was added and concentrated under reduced pressure. The residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to give the title compound (172 mg).
[1775] Hydrochloride
[1776]
[1777] Example 41
[1778] N- [1- [2- [1- [2- (2-methyl-2H-tetrazol-5-yl) ethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methyl Pyridin-2-yl) -2-furancarboxamide
[1779]
[1780] N- [1- [2- [1- [2- (1-methyl-1H-tetrazol-5-yl) ethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methyl Pyridin-2-yl) -2-furancarboxamide
[1781]
[1782] N- [1- [2- [1- (2-tetrazolylethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarbox Mead (synthesized in Example 4D-7) (228 mg) was dissolved in methanol (0.65 mL) and benzene (3.25 mL), and trimethylsilyldiazomethane (0.30 mL) under ice-cooling was added thereto. After warming to room temperature, the mixture was stirred for 19 hours. Moreover, trimethylsilyl diazomethane (0.60 mL) was added at room temperature, and it stirred for 75 hours. Trimethylsilyl diazomethane (1.12 mL) was further added at room temperature, and the mixture was stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to chromatography [NH silica gel, hexane-ethyl acetate (1: 1) to ethyl acetate]]. Title compound (N- [1- [2- [1- [2- (2-methyl-2H-tetrazol-5-yl) ethyl) cyclohexyl] ethyl] piperidin-4-yl as a low polar effluent ] -N- (5-methylpyridin-2-yl) -2-furancarboxamide) was obtained (151 mg). Title compound (N- [1- [2- [1- [2- (1-methyl-1H-tetrazol-5-yl) ethyl] cyclohexyl] ethyl] piperidin-4-yl as a high polar effluent. ] -N- (5-methylpyridin-2-yl) -2-furancarboxamide) was obtained (55 mg).
[1783] N- [1- [2- [1- [2- (2-methyl-2H-tetrazol-5-yl) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methyl Pyridin-2-yl) -2-furancarboxamide
[1784]
[1785] N- [1- [2- [1- [2- (1-methyl-1H-tetrazol-5-yl) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methyl Pyridin-2-yl) -2-furancarboxamide
[1786]
[1787] Example 42
[1788] N- [1- [2- [1- (1,1-dimethylcarbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2 Furancarboxamide
[1789]
[1790] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (Example 3A-3 N, N-dimethylformamide (1 drop) was added dropwise to a solution of (300 mg) of dichloromethane (4 mL), and then oxalyl chloride (0.087 mL) was added dropwise under ice-cooling. After stirring for 2 hours under ice-cooling, the reaction solution (2 mL) was taken and added dropwise into a 50% aqueous dimethylamine solution (2 mL). After proceeding as it was and stirring at room temperature for 18 hours, NH silica gel was added to the reaction solution, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [NH silica gel, hexane-ethyl acetate (1: 1)] to give the title compound (90 mg).
[1791] Hydrochloride
[1792]
[1793] Example 43
[1794] N- [1- [2- [1- (2-morpholin-4-yl-2-oxoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine-2- I) -2-furancarboxamide
[1795]
[1796] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (Example 3A-3 N, N-dimethylformamide (1 drop) was added dropwise to a solution of (300 mg) dichloromethane (4 mL), followed by dropwise oxalyl chloride (0.087 mL) under ice-cooling. After stirring for 2 hours under ice-cooling, 2 mL of the reaction solution was taken and added dropwise to a dichloromethane (4 mL) solution of morpholine (288 mg) under ice-cooling. After stirring for 1.5 hours under ice cooling, NH silica gel was added to the reaction solution, and the resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1: 1)] to give the title compound (60 mg).
[1797] Hydrochloride
[1798]
[1799] Example 44
[1800] N- [1- [2- [1- [2- (1,2-di tert-butoxycarbonylguanidino) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5 -Methylpyridin-2-yl) -2-furancarboxamide
[1801]
[1802] N- [1- [2- [1- (2-aminoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide (Synthesis in Example 3F-5) (104 mg), N, N-dimethylformamide (5 mL) of 1,3-bis (tert-butoxycarbonyl) -2-methyl-2-thioshudorea (85 mg) To the solution, N, N-diisopropylethylamine (0.12 g) and then mercury chloride (II) (113 mg) were added at room temperature, and it stirred at room temperature for 3 days. Dichloromethane was added, the insolubles were filtered through celite, the solvent was distilled off under reduced pressure, and the obtained residue was purified by chromatography [silica gel, dichloromethane-methanol-ammonia water (97: 3: 0.2)] The title compound was obtained (0.1049 g).
[1803]
[1804] Example 45
[1805] N- [1- [2- [1- (2-guanidinoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancar Copy mid
[1806]
[1807] N- [1- [2- [1- [2- (1,2-di tert-butoxycarbonylguanidino) ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5 -Methylpyridin-2-yl) -2-furancarboxamide (synthesized in Example 44) (105 mg) was dissolved in 4N hydrochloric acid / 1,4-dioxane solution (12 mL) and methanol (5 mL) to allow room temperature. Stirred for 2 days. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized (methanol-ethyl acetate) to obtain the title compound (69 mg).
[1808] Hydrochloride
[1809]
[1810] Example 46
[1811] 2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylamino ] Benzoic acid
[1812]
[1813] [1- [2- [4- [N- (5-methylpyridin-2-yl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid (Example 3A-3 Synthesis) (210 mg) was added N, N-dimethylformamide (1 drop) to a dichloromethane (2 mL) solution. Under ice-cooling, oxalyl chloride (0.038 mL) was added dropwise. After stirring for 2 hours under ice-cooling, methyl anthranilate (242 mg) was added dropwise. The reaction solution was proceeded as it was, stirred at room temperature for 18 hours, and then NH silica gel was added thereto, followed by concentration under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-ethanol (20: 1)] to give 2- [2- [1- [2- [4- [N- (5-methylpyridin-2-yl) 2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetylamino] methyl benzoate was obtained (150 mg).
[1814] A water (3 mL) solution of sodium hydroxide (77 mg) was added dropwise to this methanol (5 mL) solution at room temperature, followed by stirring at room temperature for 18 hours. After neutralizing with 2N hydrochloric acid, silica gel was added and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (8: 1)] to give the title compound (60 mg).
[1815]
[1816] Example 47
[1817] 1,3-diacetoxymethyl-5- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] benzene
[1818]
[1819] 1,3-Diacetoxymethyl-5- [2- [1- (formylmethyl) cyclohexyl] ethoxy] benzene (synthesized in Example 32) (215 mg) and 2- (piperidin-4-yl Amino) -5-methylpyridine (synthesized in Preparation Example 4-3) (126 mg) was dissolved in 1,2-dichloroethane (5 mL). Acetic acid (0.04 mL) was added at room temperature and stirred for 45 minutes. Sodium triacetoxy borohydride (295 mg) was added at room temperature, and it stirred for 3 hours. Saturated sodium bicarbonate was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to give the title compound (258 mg).
[1820]
[1821] Example 48
[1822] N- [1- [2- [1- [2- [3,5-bis (hydroxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methyl Pyridin-2-yl) -2-furancarboxamide
[1823]
[1824] 1,3-diacetoxymethyl-5- [2- [1- [2- [4- (5-methylpyridin-2-ylamino) piperidin-1-yl] ethyl] cyclohexyl] ethoxy] Benzene (synthesized in Example 47) (249 mg) was dissolved in dichloromethane (4 mL) and triethylamine (0.13 mL) was added. 2-furoyl chloride (0.065 mL) was added under ice-cooling, and then it was raised to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by chromatography [silica gel, chloroform-methanol (10: 1)] to give N- [1- [2- [1- [2- [3,5-bis (Acetoxymethyl) phenoxy] ethyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furancarboxamide was obtained (303 mg).
[1825] This was dissolved in methanol (4 mL), potassium carbonate (12 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate water was added, and the mixture was extracted with chloroform-ethanol (80:20). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (248 mg).
[1826] Freeche
[1827]
[1828] Hydrochloride
[1829]
[1830] Example 49
[1831] N- [1- [2- [1- [5-hydroxy-3,3-bis (hydroxymethyl) pentyl] cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridine -2-yl) -2-furancarboxamide
[1832]
[1833]
[1834] Example 50
[1835] N- [1- [2- [1- (4-hydroxy-3-hydroxymethylbutyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) 2-furancarboxamide
[1836]
[1837]
[1838] Example 51
[1839] 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethanol
[1840]
[1841] It synthesize | combined by the method similar to Example 1F-1 from the compound obtained in Example 1F-1 and the compound obtained in Preparation Example 4-5.
[1842]
[1843] Example 52
[1844] 2-furancarboxylic acid 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl
[1845]
[1846] Synthesis from 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] ethanol (synthesis in Example 51) in the same manner as in Example 2-31 It was.
[1847] Hydrochloride
[1848]
[1849] Example 53
[1850] N- [1- [2- [1- (2-hydroxyethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1851]
[1852] 2-furancarboxylic acid 2- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] ethyl (in Example 52 Synthesis) was synthesized in the same manner as in Example 3C-4.
[1853]
[1854] Example 54
[1855] N- [1- [2- [1- (carbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1856]
[1857] It synthesize | combined by the method similar to Example 4D-1 from the compound synthesize | combined in Example 3B-1.
[1858]
[1859] Example 55
[1860] N- [1- [2- [1- (cyanomethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1861]
[1862] N- [1- [2- [1- (carbamoylmethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide (in Example 54 Synthesis) was synthesized in the same manner as in Example 4D-2.
[1863]
[1864] Example 56
[1865] 4- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate
[1866]
[1867] It synthesize | combined by the method similar to Example 1D-4 from the compound obtained by manufacture example 1F-3, and the compound obtained by manufacture example 4-5. This product was provided to the next step without further purification.
[1868] Example 57
[1869] 4- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate
[1870]
[1871] 4- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate (synthesized in Example 56) in the same manner as in Example 2-16 Synthesized.
[1872]
[1873] Example 58
[1874] 4- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] butyric acid
[1875]
[1876] 4- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] methyl butyrate (synthesized in Example 57) Synthesis was carried out in the same manner as in Example 3C-1.
[1877]
[1878] Example 59
[1879] 3- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl
[1880]
[1881] It synthesize | combined by the method similar to Example 1D-5 from the compound obtained by manufacture example 3A-6 and manufacture example 4-5. This product was provided to the next step without further purification.
[1882] Example 60
[1883] 3- [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid Triethyl
[1884]
[1885] 3- [1- [2- [4- (p-tolyl) piperidin-1-yl] ethyl] cyclohexyl] -1,1,1-propanetricarboxylic acid triethyl (synthesis in Example 59) Synthesis was carried out in the same manner as in Example 2-17.
[1886]
[1887] Example 61
[1888] Cyclobutylidene acetate ethyl ester
[1889]
[1890] Triethylphosphonoacetate (3.4 mL) was added dropwise over 5 minutes to an N, N-dimethylformamide (20 mL) suspension of ice-cooled sodium hydride (0.68 g). After stirring for 30 minutes under ice-cooling, cyclobutanone (1.1 mL) was dripped over 5 minutes, and also it stirred for 1 hour under ice-cooling. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (20: 1)] to obtain the title compound (1.27 g).
[1891]
[1892] Example 62
[1893] Acetic acid 2-cyclobutylideneethyl
[1894]
[1895] To a tetrahydrofuran (10 mL) solution of ice-cold cyclobutylidene acetic acid ethyl ester (1.27 g) was added dropwise 1 M hydrogen diisobutylaluminum / hexane (27 mL) over 10 minutes. After stirring for 1 hour under ice-cooling, 1N hydrochloric acid (30 mL) was added to the reaction solution, and the temperature was raised to room temperature, followed by stirring for 30 minutes. The reaction solution was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and dried under reduced pressure. Pyridine (2 mL), acetic anhydride (2 mL) and N, N-dimethylaminopyridine (110 mg) were sequentially added to the obtained residue, which was stirred for 14 hours at room temperature. The reaction solution was diluted with ethyl acetate and washed sequentially with 3N hydrochloric acid, saturated sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (50: 1)] to obtain the title compound (0.98 g).
[1896]
[1897] Example 63
[1898] (1-Vinylcyclobutyl) methyl acetate
[1899]
[1900] 1.57 Mn-butyllithium / hexane (4.47 mL) was added dropwise to a THF (10 mL) solution of ice-cooled diisopropylamine (1.07 mL) over 5 minutes. After stirring for 30 minutes under ice cooling, the reaction solution was cooled to -78 ° C, and a tetrahydrofuran (0.8 mL) solution of 2-cyclobutylideneethyl acetate (0.89 g) was added dropwise over 5 minutes. After stirring for 1 hour at the same temperature, chlorotrimethylsilane (0.97 mL) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for 1 hour and then heated to reflux for 4 hours and 30 minutes. The reaction solution was ice-cooled, methanol (2 mL) and 3N sodium hydroxide aqueous solution (5 mL) were added, stirred for 30 minutes, concentrated hydrochloric acid (2 mL) was added, and further stirred for 30 minutes. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue (1.77 g) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (2.82 g) and methyl iodide (0.62 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite, and the insoluble matter on Celite was washed with ethyl acetate. The filtrate and washing liquid were combined, and washed sequentially with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (20: 1)] to obtain the title compound (0.67 g).
[1901]
[1902] Example 64
[1903] 3-oxaspiro [5.3] nonan-2-one
[1904]
[1905] To a tetrahydrofuran (3 mL) solution of ice-cold (1-vinylcyclobutyl) acetate (0.67 g), 0.5 M9-borabicyclo [3.3.1] nonane / tetrahydrofuran (17.5 mL) was added over 10 minutes. After dripping, the reaction liquid was heated up to room temperature and stirred for 9 hours. The reaction solution was ice-cooled again, ethanol (4 mL), 6N aqueous sodium hydroxide solution (8 mL), and 30% hydrogen peroxide solution (8 mL) were added sequentially, and then the reaction solution was heated to room temperature and stirred for 30 minutes. The reaction solution was cooled again, and concentrated hydrochloric acid (5 mL) was added. Then, the reaction solution was heated to room temperature and stirred for another 1 hour. The reaction solution was extracted with tert-butyl methyl ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (9: 1)] to obtain the title compound (0.31 g).
[1906]
[1907] Example 65
[1908] 3-oxaspiro [5.3] nonan-2-ol
[1909]
[1910] To a tetrahydrofuran (3 mL) solution of 3-oxaspiro [5.3] nonan-2-one (0.67 g) cooled to −78 ° C., 1 M diisobutylaluminum / tetrahydrofuran (1.0 mL) was added for 5 minutes. After dripping over, it stirred at the same temperature for 1 hour 30 minutes. Water (40 µL) was added to the reaction solution, and the temperature was raised to room temperature, followed by 15% aqueous sodium hydroxide solution (40 µL) and water (120 µL). After stirring for 10 minutes at room temperature, diethyl ether (2 mL) and anhydrous magnesium sulfate (0.17 g) were added, and after stirring for 30 minutes, the reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (230 mg).
[1911]
[1912] Example 66
[1913] 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclobutyl] ethanol
[1914]
[1915] To a tetrahydrofuran (3 mL) suspension of 4- (p-toluidino) piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) (418 mg), triethylamine (0.28 mL) was added to After stirring for 5 minutes at room temperature, a tetrahydrofuran (3 mL) solution of 3-oxaspiro [5.3] nonan-2-ol (synthesized in Example 65) (104 mg) was added, followed by stirring at room temperature for 10 minutes. It was. The reaction solution was ice-cooled, and sodium triacetoxyborohydride (424 mg) was added, and then the reaction solution was heated to room temperature and stirred for another 4 hours and 30 minutes. An aqueous solution of 3N sodium hydroxide (5 mL) was added to the reaction solution, followed by extraction with tert-butylmethyl ether, and the obtained organic layer was extracted with 4N hydrochloric acid (6 mL). The aqueous layer was ice-cooled, 50% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (7: 3)] to obtain the title compound (175 mg).
[1916]
[1917] Example 67
[1918] N- [1- [2- [1- (2-hydroxyethyl) cyclobutyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1919]
[1920] Tetrahydrofuran (3 mL) solution of 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclobutyl] ethanol (synthesized in Example 66) (175 mg) Triethylamine (0.46 mL) and 2-furoyl chloride (0.16 mL) were added sequentially, and it stirred at room temperature for 40 minutes. Methanol (4 mL) and 3N potassium hydroxide aqueous solution (2 mL) were added to the reaction solution, and further stirred at room temperature for 30 minutes. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, hexane-ethyl acetate (1: 1)] to obtain the title compound (159 mg).
[1921]
[1922] Example 68
[1923] Cyclooctylidene acetate ethyl ester
[1924]
[1925] Triethylphosphonoacetate (4.8 mL) was added dropwise over 5 minutes to a tetrahydrofuran (40 mL) suspension of ice-cooled sodium hydride (0.88 g). After stirring for 1 hour under ice-cooling, cyclooctanone (2.52 g) was added, followed by stirring for 1 hour at room temperature and 87 hours at room temperature. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-isopropylether (97: 3)] to give the title compound (2.67 g).
[1926]
[1927] Example 69
[1928] Acetic acid 2-cyclooctylideneethyl
[1929]
[1930] To a tetrahydrofuran (25 mL) solution of ice-cold cyclooctylidene acetic acid ethyl ester (4.82 g) was added dropwise 1M hydrogen diisobutylaluminum / hexane (73.8 mL) over 15 minutes. After 30 minutes stirring under ice cooling, 2N hydrochloric acid (50 mL) was added to the reaction solution. It heated up to room temperature and stirred for 30 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and dried under reduced pressure. Pyridine (22 mL), acetic anhydride (10.1 mL) and N, N-dimethylaminopyridine (0.26 g) were sequentially added to the obtained residue, followed by stirring at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with 2N hydrochloric acid, saturated sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (97: 3)] to obtain the title compound (3.41 g).
[1931]
[1932] Example 70
[1933] (1-Vinylcyclooctyl) methyl acetate
[1934]
[1935] To a tetrahydrofuran (10 mL) solution of ice-cooled diisopropylamine (1.68 mL), 1.57 Mn-butyllithium / hexane (7.0 mL) was added dropwise over 10 minutes. After stirring for 30 minutes under ice cooling, the reaction solution was cooled to -78 ° C, and a tetrahydrofuran (2 mL) solution of 2-cyclooctylideneethyl acetate (1.96 g) was added dropwise over 10 minutes. After stirring for 1 hour at the same temperature, chlorotrimethylsilane (1.52 mL) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for 1 hour and then heated to reflux for 4 hours and 30 minutes. The reaction solution was ice-cooled, methanol (5 mL) and 3N aqueous sodium hydroxide solution (8 mL) were added and stirred for 30 minutes, followed by addition of concentrated hydrochloric acid (4 mL), followed by further stirring for 30 minutes. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (20 mL), potassium carbonate (8.29 g) and methyl iodide (1.87 mL) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was filtered through Celite, and the insoluble matter on Celite was washed with ethyl acetate. The filtrate and washings were combined, and washed sequentially with 2N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (97: 3)] to obtain a title compound (1.33 g).
[1936]
[1937] Example 71
[1938] 3-oxaspiro [5.7] tridecan-2-one
[1939]
[1940] To a tetrahydrofuran (6 mL) solution of ice-cold (1-vinylcyclooctyl) methyl acetate (1.33 g) was added 0.5 M9-borabicyclo [3.3.1] nonane / tetrahydrofuran (25.3 mL) over 15 minutes. After dripping, the reaction liquid was heated up to room temperature and stirred for another 2 hours. The reaction solution was ice-cooled again, ethanol (8 mL), 6N aqueous sodium hydroxide solution (11 mL) and 30% hydrogen peroxide solution (11 mL) were added sequentially, and then the reaction solution was allowed to warm up to room temperature and stirred for another 75 minutes. The reaction solution was cooled again, and concentrated hydrochloric acid (8 mL) was added. Then, the reaction solution was heated to room temperature and stirred for another 30 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (9: 1)] to obtain the title compound (0.74 g).
[1941]
[1942] Example 72
[1943] 3-oxaspiro [5.7] tridecan-2-ol
[1944]
[1945] To a tetrahydrofuran (9 mL) solution of 3-oxaspiro [5.7] tridecan-2-one (O.74 g) cooled to -78 ° C, 1M diisobutylaluminum / tetrahydrofuran (4.9 mL) was added 5 After dripping over minutes, it stirred at the same temperature for 30 minutes. Water (0.18 mL) was added to the reaction solution, and the temperature was raised to room temperature. Then, 15% aqueous sodium hydroxide solution (0.18 mL) and water (0.54 mL) were added sequentially. After stirring for 10 minutes at room temperature, diethyl ether (9 mL) and anhydrous magnesium sulfate (0.17 g) were added, and after stirring for 15 minutes, the reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (3: 1 → 2: 1 → 1: 1)] to obtain the title compound (0.62g).
[1946]
[1947] Example 73
[1948] 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclooctyl] ethanol
[1949]
[1950] To a 1,2-dichloroethane (6 mL) suspension of 4- (p-toluidino) piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) (1.31 g), triethylamine (0.96 mL ) Was added and stirred at room temperature for 5 minutes, followed by addition of a solution of 3-oxaspiro [5.7] tridecane-2-ol (synthesized in Example 72) (0.62 g) of 1,2-dichloroethane (3 mL). It stirred again at room temperature for 10 minutes. The reaction solution was cooled on ice and sodium triacetoxyborate sodium (O.70 g) was added. Then, the reaction solution was heated to room temperature and stirred for another 4 hours and 30 minutes. Saturated sodium bicarbonate water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, methanol-chloroform (3: 97 → 1: 9)] to obtain the title compound (0.53 g).
[1951]
[1952] Example 74
[1953] N- [1- [2- [1- (2-hydroxyethyl) cyclooctyl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[1954]
[1955] Tetrahydrofuran (7 mL) of 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] cyclooctyl] ethanol (synthesized in Example 73) (0.53 g) Triethylamine (0.79 mL) and 2-furoyl chloride (0.35 mL) were added sequentially to the solution, and the mixture was stirred at room temperature for 1 hour. Methanol (7 mL) and 3N potassium hydroxide aqueous solution (4.7 mL) were added to the reaction solution, and the mixture was further stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, methanol-chloroform (5:95)] to obtain the title compound (0.55 g).
[1956]
[1957] Example 75
[1958] (Tetrahydropyran-4-ylidene) acetic acid ethyl ester
[1959]
[1960] Triethylphosphonoacetate (3.6 mL) was added dropwise over 5 minutes to an N, N-dimethylformamide (30 mL) suspension of ice-cooled sodium hydride (0.72 g). After stirring for 45 minutes under ice-cooling, tetrahydro-4H-pyran-4-one (1.4 mL) was added dropwise over 3 minutes, and stirred for another 35 minutes under ice-cooling. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (3.31 g). This product was provided to the next step without further purification.
[1961]
[1962] Example 76
[1963] Acetic acid 2- (tetrahydropyran-4-ylidene) ethyl
[1964]
[1965] To a tetrahydrofuran (20 mL) solution of ice-cold (tetrahydropyran-4-ylidene) acetate ethyl ester (3.31 g) was added dropwise 1M diisobutylaluminum / hexane (45 mL) over 25 minutes. After stirring for 1 hour under ice-cooling, 1N hydrochloric acid (100 mL) was added to the reaction solution, and then the temperature was raised to room temperature, followed by further stirring for 30 minutes. The reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and dried under reduced pressure. Pyridine (3 mL), acetic anhydride (3 mL), and N, N-dimethylaminopyridine (0.18 g) were sequentially added to the obtained residue, followed by stirring at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (20: 1 → 7: 3)] to obtain a title compound (2.50 g).
[1966]
[1967] Example 77
[1968] (4-Vinyltetrahydropyran-4-yl) methyl acetate
[1969]
[1970] 1.57 Mn-butyllithium / hexane (4.17 mL) was added dropwise to a tetrahydropyran (10 mL) solution of ice-cooled diisopropylamine (1.00 mL) over 5 minutes.
[1971] After stirring again for 30 minutes under ice-cooling, the reaction solution was cooled to -78 ° C, and a tetrahydrofuran (1 mL) solution of acetic acid 2- (tetrahydropyran-4-ylidene) ethyl (1.00 g) was added over 5 minutes. It dripped. After stirring for 80 minutes at the same temperature, chlorotrimethylsilane (0.90 mL) was added dropwise over 5 minutes. The reaction solution was stirred at room temperature for 1 hour and then heated to reflux for 4 hours and 30 minutes. The reaction solution was ice-cooled, methanol (3 mL) and 3N sodium hydroxide aqueous solution (5 mL) were added, the mixture was stirred for 15 minutes, concentrated hydrochloric acid (2 mL) was added, and the mixture was further stirred for 5 minutes. The reaction solution was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue (1.27 g) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (1.38 g) and methyl iodide (0.37 mL) were added, and the mixture was stirred at room temperature for 1 hour 30 minutes. The reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (9: 1 → 7: 3)] to give the title compound (455 mg).
[1972]
[1973] Example 78
[1974] 3,9-dioxaspiro [5.5] undecane-2-one
[1975]
[1976] To a tetrahydrofuran (3 mL) solution of ice-cold (4-vinyltetrahydropyran-4-yl) methyl acetate (455 mg), 0.5M9-borabicyclo [3.3.1] nonane / tetrahydrofuran (10.0 mL) was added. After dripping over 10 minutes, the reaction liquid was heated up to room temperature and stirred for 17 hours. The reaction solution was ice-cooled again, ethanol (2 mL), 6N aqueous sodium hydroxide solution (4 mL), and 30% hydrogen peroxide solution (4 mL) were added sequentially, and then the reaction solution was raised to room temperature and stirred for another 30 minutes. The reaction solution was ice-cooled again, and concentrated hydrochloric acid (2.5 mL) was added. The reaction solution was then heated to room temperature and stirred for another 1 hour. The reaction solution was extracted with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, hexane-ethyl acetate (7: 3-&gt; 6: 4)] to give the title compound (271 mg).
[1977]
[1978] Example 79
[1979] 3,9-dioxaspiro [5.5] undecane-2-ol
[1980]
[1981] To a tetrahydrofuran (2 mL) solution of 3,9-dioxaspiro [5.5] undecane-2-one (134 mg) cooled to -78 ° C, 1M diisobutylaluminum hydride / tetrahydrofuran (1.0 mL) was added. After dripping over 5 minutes, it stirred at the same temperature for 1 hour. Water (40 µL) was added to the reaction solution, and the temperature was raised to room temperature, followed by 15% aqueous sodium hydroxide solution (40 µL) and water (120 µL). After stirring for 15 minutes at room temperature, diethyl ether (2 mL) and anhydrous magnesium sulfate (0.17 g) were added, and after stirring for 30 minutes again, the reaction liquid was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (136 mg). This product was provided to the next step without further purification.
[1982]
[1983] Example 80
[1984] 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] tetrahydropyran-4-yl] ethanol
[1985]
[1986] To a tetrahydrofuran (5 mL) suspension of 4- (p-toluidino) piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) (656 mg), triethylamine (0.44 mL) was added, and After stirring for 25 minutes at room temperature, a tetrahydrofuran (3 mL) solution of 3,9-dioxaspiro [5.5] undecane-2-ol (synthesized in Example 79) (135 mg) was added thereto, followed by further room temperature. Stir for 5 minutes at. The reaction solution was ice-cooled, and sodium triacetoxyborate sodium 333 mg (333 mg) was added. Then, the reaction solution was heated to room temperature and stirred for another 26 hours. 3N sodium hydroxide aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (20: 1)] to give the title compound (240 mg).
[1987]
[1988] Example 81
[1989] N- [1- [2- [4- (2-hydroxyethyl) tetrahydropyran-4-yl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarbox mid
[1990]
[1991] Tetrahydro of 2- [1- [2- [4- (p-toluidino) piperidin-1-yl] ethyl] tetrahydropyran-4-yl] ethanol (synthesized in Example 80) (239 mg) Triethylamine (0.29 mL) and 2-furoyl chloride (0.17 mL) were sequentially added to the furan (3 mL) solution, and the mixture was stirred at room temperature for 30 minutes. Methanol (4 mL) and 3N potassium hydroxide aqueous solution (2 mL) were added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (30: 1)] to give the title compound (210 mg).
[1992]
[1993] Example 82
[1994] 1-benzylpiperidine-4,4-diethyl acetate
[1995]
[1996] 1-benzyl-4-piperidone (9.27 mL) and ethyl cyanoacetate (10.6 mL) were added to ice-cold 7M ammonia / methanol (28 mL), and it was left to stand in a refrigerator (0 degreeC) for 5 days. The precipitated crystals were collected by filtration (9.14 g).
[1997] Water (8.81 mL) and concentrated sulfuric acid (10.3 mL) were added to the obtained crystals (8.64 g), and it heated for 2 days in 100 degreeC oil bath. The mixture was returned to room temperature, ethanol (100 mL) was added, concentrated by an evaporator, and the azeotroped water. This operation was performed 4 times. Ethanol (73 mL) was added and heated to reflux for 24 hours. It was ice-cooled, sodium carbonate (20 g) was added, and it concentrated under reduced pressure. Ethyl acetate was added, and the resultant was washed sequentially with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, methanol-chloroform (3:97)] to give the title compound (6.25 g).
[1998]
[1999] Example 83
[2000] 1-benzyl-4,4-bis (2-hydroxyethyl) piperidine
[2001]
[2002] A tetrahydrofuran (10 mL) solution of 1-benzylpiperidine-4,4-diethyl acetate (3.47 g) was added dropwise to a tetrahydrofuran (120 mL) solution of ice-cooled lithium aluminum hydride (0.76 g). The ice bath was removed and stirred at room temperature for 1 hour. It was ice-cooled again, and water (0.76 mL), 15% aqueous sodium hydroxide solution (0.76 mL) and water (2.28 mL) were added sequentially, and the precipitate was filtered off by Celite. The filtrate was concentrated under reduced pressure to give the title compound (about 2.63 g). This product was provided to the next step without further purification.
[2003]
[2004] Example 84
[2005] 2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] ethanol
[2006]
[2007] To a solution of 1-benzyl-4,4-bis (2-hydroxyethyl) piperidine (about 2.63 g) in dichloromethane (50 mL), triethylamine (1.81 mL), tert-butyldiphenylchlorosilane (2.86 mL) was added and stirred for 18 hours at room temperature. Chloroform was added to the reaction mixture, washed with saturated sodium bicarbonate water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, methanol-chloroform (3:97)] to obtain the title compound (2.61 g).
[2008]
[2009] Example 85
[2010] [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] acetaldehyde
[2011]
[2012] A dichloromethane (3 mL) solution of oxalyl chloride (0.26 mL) was cooled to -78 ° C, and a dichloromethane (1 mL) solution of dimethyl sulfoxide (0.43 mL) was added dropwise over 10 minutes. It stirred at -78 degreeC for 30 minutes. Dichloromethane (2 mL) of 2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] ethanol (O.75 g) was added dropwise over 10 minutes. The mixture was stirred at -78 ° C for 30 minutes. Triethylamine (2.1 mL) was added, the mixture was stirred for 10 minutes, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Dichloromethane was added, washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.75 g). This product was provided to the next process without further purification.
[2013]
[2014] Example 86
[2015] 1- [2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] ethyl] -4-toluidinopiperidine
[2016]
[2017] To a 1,2-dichloroethane (3 mL) suspension of 4- (p-toluidino) piperidineditrifluoroacetate (synthesized in Preparation Example 4-5) (0.63 g), triethylamine (0.42 mL ) Was added and stirred at room temperature for 25 minutes, followed by [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] acetaldehyde (synthesis in Example 85) ) (0.75 g) 1,2-dichloroethane (1.5 mL) solution was added, and it stirred at room temperature for 5 minutes again. The reaction solution was cooled on ice and sodium triacetoxyborate borohydride (0.50 g) was added, and then the reaction solution was heated to room temperature and stirred for 15 hours. Saturated sodium bicarbonate water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, ethyl acetate-chloroform (5:95)] to obtain the title compound (0.87 g).
[2018]
[2019] Example 87
[2020] N- [1- [2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2-furancarboxamide
[2021]
[2022] 1- [2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] ethyl] -4-toluidinopiperidine (in Example 86 Synthesis) Triethylamine (0.35 mL) and 2-furoyl chloride (0.19 mL) were sequentially added to a tetrahydrofuran (7 mL) solution of (0.87 g), followed by stirring at room temperature for 1 hour. Saturated sodium bicarbonate water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [silica gel, chloroform-methanol (95: 5)] to give the title compound (0.73 g).
[2023]
[2024] Example 88
[2025] N- [1- [2- [1-benzyl-4- (2-hydroxyethyl) piperidin-4-yl] ethyl] piperidin-4-yl] -N- (p-tolyl) -2 Furancarboxamide
[2026]
[2027] N- [1- [2- [1-benzyl-4- [2- (tert-butyldiphenylsiloxy) ethyl] piperidin-4-yl] ethyl] piperidin-4-yl] -N- To a tetrahydrofuran (3 mL) solution of (p-tolyl) -2-furancarboxamide (synthesized in Example 87) (O.73 g), 1M tetran-butylammonium chloride / tetrahydrofuran (1.9 mL) Was added and stirred at room temperature for 15 hours. Saturated sodium bicarbonate water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography [NH silica gel, chloroform-methanol (98: 2)] to obtain the title compound (0.32 g).
[2028]
[2029] The novel 4- (2-furoyl) aminopiperidine derivative obtained by the present invention has an opioid μ-antagonistic action and has the side effects of opioid μ receptor agonists selected from constipation, nausea, vomiting or pruritus, sudden constipation, and post-surgery. It is useful for the prevention or treatment of ileus, paralytic ileus, irritable bowel syndrome or chronic pruritus.

权利要求:
Claims (12)
[1" claim-type="Currently amended] Compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
[Formula I]
[In the meal,
X is CH or N,
Y is a group of formula (II) or a group of formula (II-a) or formula (III),
[Formula II]
[Formula II-a]
[Formula III]
Where a, b and c are integers from 0 to 6, Z is CH ₂ or NH, W is O or S, T is O or NR ¹⁵ , R ¹⁵ is H, C 1 -C 6 alkyl group, benzyl group , Phenethyl group,
R ¹ is H, a C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, 2-phenyl-1,3-dioxan-5-yl group, 2,2-dimethyl-1,3-dioxan-5-yl group or A group of formula (IV),
[Formula IV]
Wherein d is an integer of 0 to 6, R ³ , R ⁴ and R ⁵ are the same or different and are H, or-(CH ₂ ) _e R ⁶ , or-(CH ₂ ) _f CONR ⁷ R ⁸ , e, f are integers of 0-6,
R ⁶ represents a hydroxyl group, a C1-C6 alkanoyloxy group, a benzoyloxy group, a 2-furoyloxy group, a C1-C6 alkoxy C1-C6 alkoxy group, a C1-C6 alkoxycarbonylphenoxy group, a carboxyphenoxy group, a dicarboxyphenoxy group , Di C1 to C6 alkoxycarbonylphenoxy group, dihydroxy C1 to C6 alkylphenoxy group, amino group, C1 to C6 alkoxycarbonylamino group, C1 to C6 alkylsulfonamide group, benzenesulfonamide group, p-toluenesulfonamide group , p-halobenzenesulfonamide group, carboxyl group, C1-C6 alkoxycarbonyl group, carbohydroxysamic acid group, carbohydroxysamic acid C1-C6 alkyl ester group, cyano group, 1H-tetrazol-5-yl group, 1- C1-C6 alkyl-1H-tetrazol-5-yl group, 2-C1-C6 alkyl-2H-tetrazol-5-yl group, N ² -hydroxycarbamididoyl group, N ¹ -C1-C6 alkoxycarbonyl -N ² -hydroxycarbamidoyl group, 2H-5-thioxo-1,2,4-oxadiazol-3-yl group, 2H-5-oxo-1,2,4-oxadiazole-3 Diary, guanidino, D. C1-C6 alkoxycarbonylguanidino group, morpholinocarbonyl group,
R ⁷ and R ⁸ are the same or different and are H, C 1 -C 6 alkyl group, C 1 -C 6 alkanoyloxy C 1 -C 6 alkyl group, hydroxy C 1 -C 6 alkyl group, bis (C 1 -C 6 alkanoyloxy C 1 -C 6 alkyl) methyl group , Bis (hydroxy C1-C6 alkyl) methyl group, tris (C1-C6 alkanoyloxy C1-C6 alkyl) methyl group, tris (hydroxy C1-C6 alkyl) methyl group, carboxy C1-C6 alkyl group, C1-C6 alkoxycarbonyl C1-C6 alkyl group, N, N-bis (C1-C6 alkoxycarbonyl C1-C6 alkyl) carbamoyl C1-C6 alkyl group, N, N-bis (carboxy C1-C6 alkyl) carbamoyl C1-C6 alkyl group, C1-C6 alkylsulfonyl group, carboxyphenyl group and pyrazinyl group,
R ² is H or a group of formula (IV).] [2" claim-type="Currently amended] The compound according to claim 1, wherein in formula (I),
X is CH or N,
Y is a group of formula (II), where a is an integer of 0 to 4, b is an integer of 2 to 5,
R ¹ is H, a methoxycarbonyl group, a carboxyl group, a 2-phenyl-1,3-dioxan-5-yl group, a 2,2-dimethyl-1,3-dioxan-5-yl group or a group of formula (IV) Where d is an integer of 0 to ² , R ³ , R ⁴ and R ⁵ are the same or different and are H, or-(CH ₂ ) _e R ⁶ , e is an integer of 0 to 3, and R ⁶ is Hydroxyl, acetoxy, benzoyloxy, 2-furoyloxy, methoxymethoxy, amino, tert-butoxycarbamoyl, methanesulfonamide, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbohydrock A compound which is a triacid group, a carbohydroxane tert-butylester group, a cyano group, and a 1H-tetrazol-5-yl group, or a pharmaceutically acceptable salt thereof.
[3" claim-type="Currently amended] The compound according to claim 1, wherein in formula (I),
X is CH or N,
Y is a group of formula (II), wherein a is 2, b is 2-3
R ¹ is a group of formula (IV) wherein d is 0, R ⁴ and R ⁵ are H, R ³ is — (CH ₂ ) _f CONR ⁷ R ⁸ , where f is 0, R ⁷ and R ⁸ is the same or different and is H, tris (acetoxymethyl) methyl group, tris (hydroxymethyl) methyl group, ethoxycarbonylmethyl group, carboxymethyl group, 2-ethoxycarbonylethyl group, 2-carboxyethyl group, 3- A compound which is an ethoxycarbonylpropyl group, 3-carboxypropyl group, N, N-bis (ethoxycarbonylmethyl) carbamoylmethyl group and N, N-bis (carboxymethyl) carbamoylmethyl group, or a pharmaceutically thereof Acceptable salts.
[4" claim-type="Currently amended] The compound according to claim 1, wherein in formula (I),
X is CH or N,
Y is a group of formula (III), wherein a is an integer from 0 to 2, b is 3, c is an integer from 1 to 3, Z is CH ₂ or NH, W is O or S,
R ¹ is H, methoxycarbonylmethyl group, carboxymethyl group,
R ² is H, a group of formula (IV), wherein d is an integer from 0 to 2, R ⁴ and R ⁵ are H, R ³ is — (CH ₂ ) _e R ⁶ , where e is 0 , R ⁶ is a carboxyl group, a C 1 to C ⁶ alkanoyloxy group, or a pharmaceutically acceptable salt thereof.
[5" claim-type="Currently amended] The compound of claim 2, wherein in formula (I), X is CH or N,
Y is a group of formula (II) wherein a is 2 and b is 3.
R ¹ is a carboxymethyl group, 3,3-bis (hydroxymethyl) propyl group, 5-hydroxy-3,3-bis (hydroxymethyl) pentyl group, acethydroxysamic acid group and 2- (1H-tetrazol -5-yl) ethyl group or a pharmaceutically acceptable salt thereof.
[6" claim-type="Currently amended] 6. A compound according to claim 5, wherein [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] ethyl] cyclohexyl] acetic acid, N- [1 -[2- [1- (4-hydroxy-3-hydroxymethylbutyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (5-methylpyridin-2-yl) -2-furan Carboxamide, N- [1- [2- [1- [5-hydroxy-3,3-bis (hydroxymethyl) pentyl] cyclohexyl] ethyl] piperidin-4-yl] -N- ( 5-methylpyridin-2-yl) -2-furancarboxamide, [1- [2- [4- [N- (p-tolyl) -2-furancarboxamide] piperidin-1-yl] Ethyl] cyclohexyl] acethydroxysamic acid and N- [1- [2- [1- (2-cyanoethyl) cyclohexyl] ethyl] piperidin-4-yl] -N- (p-tolyl)- A compound selected from 2-furancarboxamide or a pharmaceutically acceptable salt thereof.
[7" claim-type="Currently amended] Compound represented by the formula (V):
[Formula Ⅴ]
[In the meal,
X is CH or N,
Ya is a group of formula (VI) or a group of formula (VI-a) or a formula (VII), or a group of formula (VII),
[Formula VI]
[Formula VI-a]
[Formula Ⅶ]
[Formula Ⅷ]
Where a, b and c are integers from 0 to 6, Z is CH ₂ or NH, W is O or S, T is O or NR ¹⁵ , R ¹⁵ is H, C 1 -C 6 alkyl group, benzyl group , A phenethyl group, R ⁹ is H, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group, a carboxyl group, 2-phenyl-1,3-dioxan-5-yl group, 2,2-dimethyl-1,3-dioxane- A 5-yl group or formula (VII), R ¹⁰ is H or a formula (VII),
[Formula IX]
Wherein d is an integer of 0 to 6, R ¹¹ , R ¹² and R ¹³ are the same or different and are H, or-(CH ₂ ) _e R ¹⁴ , e is 0 to 6, and R ¹⁴ is C1 to C6 alkanoyloxy group, benzoyloxy group, 2-furoyloxy group, C1-C6 alkoxy C1-C6 alkoxy group, di C1-C6 alkanoyloxy C1-C6 alkylphenoxy group, C1-C6 alkyldiarylsiloxy group, C1 -C6 alkoxycarbamoyl group, carboxyl group, C1-C6 alkoxycarbonyl group, benzyloxycarbonyl group, cyano group, C1-C6 alkylsulfonamide group, C1-C6 alkoxycarbonylphenoxy group and di C1-C6 alkoxycarbonylphenoxy group. ] [8" claim-type="Currently amended] A method for producing a compound represented by the formula (VII), comprising reacting a compound represented by the formula (V) with 2-furancarboxylic acid or a reactive derivative thereof.
[Formula Ⅹ]
[Wherein X and Ya are the same as in formula (V)] [9" claim-type="Currently amended] A medicament formed by combining a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable pharmaceutical excipient as required.
[10" claim-type="Currently amended] The pharmaceutical according to claim 9, which is an opioid μ receptor antagonist or a prodrug thereof.
[11" claim-type="Currently amended] The method of claim 9, wherein the side effects of the μ receptor agonist selected from constipation, nausea, vomiting or pruritus, sudden constipation, postoperative ileus, paralytic ileus, irritable bowel syndrome or A drug that is a prophylactic and / or therapeutic drug for chronic pruritus.
[12" claim-type="Currently amended] In vivo metabolites having opioid receptor antagonistic activity of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-10-09|Priority to JP2001311828

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2001-10-09|Priority to JPJP-P-2001-00311828

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2002-10-08|Application filed by 교린 세이야꾸 가부시키 가이샤, 닛신 파마 가부시키가이샤

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2002-10-08|Priority to PCT/JP2002/010449

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2004-05-10|Publication of KR20040039495A

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2010-01-22|Application granted

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2010-01-22|Publication of KR100938369B1

优先权:

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申请号 | 申请日 | 专利标题

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JP2001311828|2001-10-09|

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JPJP-P-2001-00311828|2001-10-09|

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PCT/JP2002/010449|WO2003035645A1|2001-10-09|2002-10-08|Novel 4-aminopiperidines, intermediates in synthesizing the same, process for producing the same and medicinal use of the same|