WO2013146969A1 - Novel disubstituted cyclohexane derivative - Google Patents

Novel disubstituted cyclohexane derivative Download PDF

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WO2013146969A1
WO2013146969A1 PCT/JP2013/059169 JP2013059169W WO2013146969A1 WO 2013146969 A1 WO2013146969 A1 WO 2013146969A1 JP 2013059169 W JP2013059169 W JP 2013059169W WO 2013146969 A1 WO2013146969 A1 WO 2013146969A1
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piperidine
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勝浩 川上
俊宏 木方
厚 天花寺
清水　弘樹
佐藤　厚
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第一三共株式会社
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a prostaglandin E 2 production inhibitor containing a quinoline derivative having an anti-inflammatory action, a salt thereof, or a solvate thereof.
  • Arachidonic acid is released from cell membrane phospholipid by phospholipase A 2, and prostaglandin H 2 (PGH 2 ) is synthesized through prostaglandin G 2 (PGG 2 ) by cyclooxygenase (COX).
  • This PGH 2 can be converted into prostaglandin D 2 (PGD 2 ), prostaglandin E 2 (PGE 2 ), prostaglandin F 2 ⁇ (PGF 2 ⁇ ), prostaglandin I 2 (PGI 2 ), and thrombos by each converting enzyme.
  • Prostanoids are produced by conversion to xan A 2 (TXA 2 ).
  • PGE 2 which is considered to be the most abundant prostanoid in the body, has a variety of from the center to the periphery, including hyperalgesia, fever, vascular smooth muscle relaxation, gastric acid secretion suppression, bronchial smooth muscle relaxation, and uterine contraction. It is known to have physiological activity. The physiological activities of not only PGE 2 but also other prostanoids are being elucidated, and they play an important role in maintaining the homeostasis of living organisms. It is considered deeply involved.
  • COX has two isozymes, COX-1 and COX-2.
  • Non-steroidal anti-inflammatory drugs NSAIDs
  • NSAIDs currently used as typical anti-inflammatory analgesics inhibit both COX-1 and COX-2. Since NSAIDs inhibit the production of COX-1-derived prostanoids involved in the gastrointestinal protective action, causing gastrointestinal disorders at a high frequency is a problem (Non-patent Document 1).
  • COX-2 inhibitors that have a selective inhibitory action on COX-2 induced by inflammatory stimuli are drugs with few side effects of gastrointestinal disorders, but the risk of cardiovascular events is a problem. It has become.
  • COX-2 selective inhibitor suppresses the production of PGI 2 derived from COX-2, which plays a role in inhibiting platelet aggregation and cardioprotection, while producing TXA 2 derived from COX-1 which has a contradictory effect in the coagulation system It is considered that one of the causes is not to suppress (Non-patent Document 2).
  • anti-inflammatory drugs such as steroids have been used as symptomatic treatment, and the occurrence of side effects has become a problem.
  • non-steroidal anti-inflammatory drugs and new NSAIDs are being developed, but as mentioned above, they still suffer from side effects, and the development of fundamental therapies is desired. ing.
  • rheumatoid arthritis arthritis, osteoarthritis, arthritis-related inflammatory diseases, inflammatory bowel Nerves such as diseases, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, diabetic neuralgia , Pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, strong Dermatosis, atherosclerosis and accompanying myocardial infarction, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstruct
  • an object of the present invention is to provide a novel compound having an excellent anti-inflammatory action with few side effects and a pharmacologically acceptable salt thereof.
  • the present invention (1) A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • R 1, R 2, R 3, and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, C 1 -C 6 optionally substituted by an alkoxy group
  • C 1 -C 6 Represents an alkyl group, a C 1 -C 6 alkoxy group, an ethynyl group optionally substituted with a C 1 -C 6 alkyl group, or a phenyl group
  • X 1 and X 2 represent a carbon atom or a nitrogen atom
  • Y is a C 1 -C 6 alkyl group optionally substituted with 1 to 3 groups selected from the substituent group ⁇ , a carboxy group optionally substituted with a C 1 -C 6 alkyl group, or C Represents a carbamoyl group optionally substituted by a 1 -C 6 alkyl group, n is 0 or 1;
  • Ring A forms a 5-membered unsaturated hetero
  • Ring A forms a 6-membered unsaturated hydrocarbon ring or heterocyclic ring, and R 3 and R 4 together with the carbon or nitrogen atom of the ring to which they are attached are saturated or unsaturated
  • the 5-membered to 6-membered hydrocarbon ring or heterocyclic ring may be formed, and the formed hydrocarbon ring or heterocyclic ring may be substituted with a group selected from the substituent group ⁇ .
  • Substituent group ⁇ represents a hydroxyl, C 1 -C 6 alkyl group, C 1 -C 6 alkyl group optionally substituted carboxyl group, and C 1 -C 6 alkyl carbamoyl group which may be substituted with a group Represents.
  • the substituent group ⁇ represents a halogen atom and a C 1 -C 6 alkyl group which may be substituted with 1 to 3 halogen atoms.
  • the compound of the present invention or a pharmacologically acceptable salt thereof has an excellent anti-inflammatory action with few side effects, and is used as a prophylactic or therapeutic agent for inflammatory diseases or other inflammation-related diseases for warm-blooded animals (particularly humans). Useful.
  • the vertical axis shows the 2 production in inflamed tissue prostaglandin E. 3 shows a dose-dependent inhibitory action of Example Compound 31.
  • the 5-membered unsaturated heterocycle adjacent to X 1 and X 2 is specifically a pyrrole ring, a furan ring, or a thiophene ring, and preferably a pyrrole ring. .
  • n When n is 0, a saturated or unsaturated 5- to 6-membered hydrocarbon ring or heterocycle formed together with R 2 and R 4 and the carbon atom or nitrogen atom of the ring to which they are bonded
  • Specific examples of the ring include a benzene ring and a pyridine ring.
  • X 1 is a nitrogen atom
  • X 2 is preferably a carbon atom
  • R 2 and R 4 are preferably a carbon atom
  • n 1, specifically, it is a pyridine ring, a pyrazine ring, or a pyridazine ring, but the ring A is preferably a pyridine ring in which X 1 and X 2 are both carbon atoms.
  • the ring formed by R 3 and R 4 together with the carbon atom or nitrogen atom of the ring to which they are bonded is specifically a furan ring, a thiophene ring, a pyrrole ring, Or a dihydrofuran ring can be mentioned, but a furan ring or a pyrrole ring is preferred.
  • the halogen atom is specifically a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
  • the C 1 -C 6 alkyl group may be a straight chain, branched chain or ring structure, and is an aliphatic hydrocarbon group containing 1 to 6 carbon atoms in the chain.
  • Branching means that one or more lower alkyl groups (for example, a methyl group, an ethyl group, or a propyl group) are bonded to a linear alkyl chain.
  • Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • a methyl group, an ethyl group, a propyl group, a cyclopropyl group, an isopropyl group, or a tert-butyl group is preferable, and a methyl group, an ethyl group, or a cyclopropyl group is more preferable.
  • the C 1 -C 6 alkoxy group means an alkyl-O group in which an oxygen atom is bonded to the C 1 -C 6 alkyl group, and contains 1 to 6 carbon atoms in the chain. Preferably, it has 1 to 3 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy, preferably methoxy group, ethoxy group, propoxy group or isopropoxy group, More preferably, it is a methoxy group.
  • C 1 -C 6 alkyl group which may be substituted with a C 1 -C 6 alkoxy group
  • a C 1 -C 6 alkoxy group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxymethyl group, a 1-methoxyethyl group, 2-methoxyethyl group, 1-methoxypropyl group, 2-methoxypropyl group, 3-methoxypropyl group, 1-methoxybutyl group, 2-methoxybutyl group, 3-methoxybutyl group, 4-methoxybutyl group, 1- Methoxypentyl group, 2-methoxypentyl group, 3-methoxypentyl group, 4-methoxypentyl group, 5-methoxypentyl group, 1-methoxyhexyl group, 2-methoxyhexyl group, 3-methoxyhexyl group, 4-methoxyhexyl Group
  • ethynyl group optionally substituted with a C 1 -C 6 alkyl group include a methylethynyl group, an ethylethynyl group, a propylethynyl group, an isopropylethynyl group, a butylethynyl group, a pentylethynyl group, or a hexylethynyl group.
  • R 1 is a phenyl group
  • R 2 is a hydrogen atom
  • R 3 is a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a halogen group, a methylethynyl group, or a phenyl group
  • R 4 is a cyano group or a methoxy group.
  • n is preferably 1, and R 3 and R 4 are preferably taken together with the carbon or nitrogen atom of the ring to which they are attached to form a saturated or unsaturated 5- to 6-membered Form a hydrocarbon ring or a heterocyclic ring.
  • X 1 and X 2 are preferably both carbon atoms.
  • the ring formed by combining R 3 and R 4 is preferably a furan ring, a dihydrofuran ring, a thiophene ring, a pyrrole ring, a pyridine ring, or a benzene ring.
  • the group that substitutes these rings is preferably a chlorine atom, a methyl group, a dimethyl group, an ethyl group, or a trifluoromethyl group.
  • the C 1 -C 6 alkyl group optionally substituted by 1 to 3 groups selected from the substituent group ⁇ is preferably a hydroxymethyl group, a carbamoylmethyl group, an ethylcarboxymethyl group, a carboxymethyl group, An ethylcarboxy (dimethyl) methyl group, a 1-carboxycyclopropyl group, or a carboxy (dimethyl) methyl group;
  • carbamoyl group which may be substituted with a C 1 -C 6 alkyl group
  • carbamoyl group which may be substituted with a C 1 -C 6 alkyl group
  • a carbamoyl group a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a butylcarbamoyl group, a pentylcarbamoyl group, Or a hexylcarbamoyl group can be mentioned, and a carbamoyl group, a methylcarbamoyl group, or an ethylcarbamoyl group is preferable.
  • Y is preferably a hydroxymethyl group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, methylcarboxy group, ethylcarboxymethyl group, ethylcarboxy (dimethyl) methyl group, carbamoylmethyl group, carboxymethyl group, or carboxy ( Dimethyl) methyl group.
  • More preferable examples of the compound having the general formula (I) include the compounds described in Examples.
  • Treatment means curing or ameliorating a disease or symptom or suppressing a symptom.
  • the “disease mediated by prostaglandin E 2 ” is not particularly limited as long as it is thought that prostaglandin E 2 is involved in the onset of the disease.
  • migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, cancer metastasis and familial colorectal polyposis
  • Rheumatoid arthritis osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory Pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis,
  • the compound of the present invention is applied to gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, asthma, fever, or inflammatory anorexia, and more preferably rheumatoid arthritis, osteoarthritis, asthma, chronic Dermatitis including obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis.
  • the pharmacologically acceptable salt refers to a salt that can be used as a medicine.
  • the salt when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
  • the pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt.
  • Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates, and aspartates, and alkali metal salts are preferred.
  • the pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization.
  • the present invention also includes such various hydrates, solvates and polymorphic compounds.
  • the compound of the present invention, a salt thereof, or a solvate thereof may be converted into a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer depending on the type or combination of substituents.
  • a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer depending on the type or combination of substituents.
  • the compound of the present invention includes all isomers, stereoisomers, and any ratio of these isomers and stereoisomer mixtures unless otherwise specified. is there. A mixture of these isomers can be separated by a known resolution means.
  • the compound represented by the general formula (I) of the present invention may contain an unnatural ratio of atomic isotopes at one or more of the constituent atoms.
  • the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), and carbon-14 ( 14 C). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compounds represented by general formula (I) are included within the scope of the present invention, whether radioactive or not.
  • the present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention.
  • a pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions.
  • Drug-forming groups are described in Prog. Med., Volume 5, pages 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of.
  • the prodrug more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated).
  • hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like.
  • a carboxy group is present in the compound of the present invention
  • a compound in which the carboxy group is esterified or amidated for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation or methylamidation compound, etc.
  • the production method for the general formula (I) is exemplified below.
  • the compound of the present invention represented by the formula (I) can be produced by various methods. As preferred examples, typical production methods are shown in the following formulas, but are not limited thereto.
  • Production method A is a method for producing a substituted piperidinecarboxylic acid (A21) that can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
  • R 1 to R 4 and X 1 to X 2 are the same as defined for the substituent of the general formula (I).
  • R 5 to R 8 represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl group or the like.
  • X 3 represents a carbon atom or a sulfur atom.
  • Z 1 represents a hydrogen atom, a cyano group, an amino group, or an alkoxy group
  • Z 2 represents a hydrogen atom, a chlorine atom, or a nitro group.
  • Z 3 and Z 4 represent a halogen atom (for example, a bromine atom or an iodine atom).
  • Step (A-1) is a step for producing compounds (A2) and (A4) by allowing a piperidine derivative to act on compounds (A1) and (A6) to carry out a substitution reaction with Z 4. .
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but N-methylpyrrolidone and N, N-dimethylacetamide are preferable.
  • step (A-2) a condition in which boronic acid or a boronic acid ester is allowed to act on the substituent Z 3 in the compound (A2) in the presence of a palladium catalyst (Suzuki coupling) or a tin compound is allowed to act (Stille A step of introducing a substituent corresponding to R 1 or a substituent serving as a precursor thereof under conditions such as coupling) or conditions in which a terminal alkyne is allowed to act in the presence of a palladium and copper catalyst (Sonogashira reaction). A3) is a process of manufacturing.
  • Suzuki coupling examples include Journal of Organic Chemistry, 68, 20, 2003, 7733-7741, Journal of Organic Chemistry, 70, 6, 2005, 2191-2194, Journal of Organic Chemistry, 68, 24, 2003, 9412 -9415, Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718, Tetrahedron, 66, 49, 2010, 9552-9559, Synthetic Communications, 30, 19, 2000, 3501-3510, Chemistry A European Journal, 12, 19 , 2006, 5142-5148, and the like.
  • Stille coupling examples include the methods described in Angewandte Chemie, International Edition, 25, 6, 1986, 508-524, Tetrahedron Letters, 35, 19, 1994, 3195-3196, Synthesis, 1986, 7, 564-565 etc. It can be performed according to.
  • Sonogashira reaction examples include Chemical. Review, 107, 3, 2007, 874-922, Journal of Organic Chemistry, 68, 9, 2003, 3736-3738, Organic Letters, 2, 12, 2000, 1729-1731. It can carry out according to the method as described in.
  • Step (A3) if Z 2 is a hydrogen atom, is a step for preparing the introduced compound substituent Z 5 in the compound (A3) (A4).
  • Compound in dichloromethane (A3) was halogenated by reaction with an electrophilic halide, and Suzuki coupling loop ring condition, Stille coupling conditions for applying a tin compound, corresponding to Z 5 due Sonogashira reaction conditions
  • This is a step of introducing a substituent or a substituent to be a precursor thereof, and the same method as in step (A-2) can be used.
  • the electrophilic halide include N-bromosuccinimide and N-iodosuccinimide.
  • step (A-4) when X 2 is a carbon atom and Z 1 is a tert-butoxy group, the compound (A4) is deprotected by acting trifluoroacetic acid in dichloromethane. This is a process for manufacturing (A7).
  • Step (A-5) is a step of alkylating compound (A7) by reacting with alkyl halide in the presence of a base in dimethylformamide, and producing compound (A8).
  • a base include potassium carbonate and sodium hydride.
  • the alkyl halide include methyl iodide, allyl bromide, 3-bromo-2-methylpropene, crotyl bromide and the like.
  • Step (A-6) when Z 5 is an iodine atom, the compound (A8) is subjected to intramolecular cyclization using Heck reaction conditions in the presence of a palladium catalyst. A10). Examples of Heck reactions are Chemical. Review, 100, 8, 2000, 3009-3066, Tetrahedron Letters, 45, 33, 2004, 6235-6237, Tetrahedron, 29, 37, 1988, 4687-4690, Tetrahedron Letters, 48, 13, 2007, 2307-2310 and the like.
  • Step (A-7) is a step of intramolecular cyclization of compound (A4) when X 2 is a carbon atom and Z 1 is an amino group, and is a step of producing compound (A11). This is a step of deprotecting the protecting group and modifying the substituent in R 5 as necessary.
  • step (A-8) the compound (A12) is subjected to a substitution reaction with Z 4 by acting a piperidine derivative, and then the substituent corresponding to R 1 or a precursor thereof is substituted for the substituent Z 3 .
  • This is a step of introducing a substituent that becomes a body, and a step of producing compound (A11).
  • the reaction with the piperidine derivative can use the same method as in step (A-1), and the conversion of substituent Z 3 can use the same method as in step (A-2).
  • Step (A-9) is a step of adding a piperidine derivative after allowing an acid anhydride or the like to act on compounds (A13) and (A18), and producing compounds (A14) and (A19) It is.
  • the same reaction as in step (A-1) can be used.
  • Step (A-10) is a step of producing compound (A15) by introducing a substituent corresponding to substituent R 7 or a substituent serving as a precursor thereof into compound (A14).
  • a method similar to 3) can be used.
  • Step (A-11) is a step of reacting compound (A16) with compound (A17) in the presence of a base in dichloromethane, followed by cyclization condensation, and producing compound (A18).
  • a microwave reactor can be used if necessary.
  • the base include triethylamine and diisopropylethylamine.
  • Step (A-12) is a step of deprotecting protecting group P 1 in compound (A20), and is a step of producing compound (A21).
  • Compound (A20) represents the outline of the compound group (A3, A4, A8, A9, A10, A11, A14, A15, A19) in Production Method A
  • Compound (A21) represents the outline of the substituted piperidinecarboxylic acid in Production Method A. Represents. Although this reaction varies according to the kind of the protecting group P 1, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" can be carried out according to the method described in.
  • Production method B is a method for producing a substituted amine (B8) that can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
  • [P 1 are as defined above.
  • X a represents an oxygen atom or NH
  • Y 1 represents a precursor of the substituent Y or the substituent Y itself.
  • R 9 represents a hydrogen atom or an optionally substituted alkylalkenyl, alkynyl, cycloalkyl group or the like.
  • R 10 and R 11 represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, —CH 2 CH 2 — group or the like.
  • P 2 and P 3 each represent an amino protecting group or hydrogen, and specific protecting groups include Boc group (tert-butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), benzylidene group, diphenylmethylene group and the like. Can be mentioned.
  • P 2 is a benzylidene group or a diphenylmethylene group
  • P 3 represents the same protecting group as P 2 .
  • Each step includes a step of protecting the substituent and deprotecting the protecting group as necessary.
  • Step (B-1) is a step of condensing compound (B1) with a compound having an amino group or a compound having a hydroxyl group in the presence of an appropriate condensing agent and a base, and a step of producing compound (B2) It is. Add additives to accelerate the reaction if necessary.
  • condensing agent examples include WSC (ie, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), DCC (ie, 1,3-dicyclohexylcarbodiimide), DMT-MM (ie, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), CDI (ie 1,1′-carbonyldiimidazole), DEPC (ie diethyl phosphorocyanide) DPPA (that is, diphenylphosphoroazideate) and the like can be mentioned.
  • WSC ie, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC ie, 1,3-dicyclohexylcarbodiimide
  • DMT-MM ie, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methyl
  • Examples of the base include aromatic amines such as pyridine and lutidine, and tertiary amines such as triethylamine, diisopropylethylamine, and DMAP (4-dimethylaminopyridine).
  • Representative examples of additives include HOAt (3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol), HOBt (1H-benzotriazol-1-ol), HOSu (N -Hydroxysuccinimide) and the like.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but dichloromethane and N, N-dimethylformamide are preferable.
  • Step (B-2) is a step of producing compound (B3) by allowing a suitable reducing agent to act on compound (B1).
  • the reducing agent may be reacted directly, but it may be reduced after once converted to an acid anhydride by the action of an appropriate acylating agent.
  • the reducing agent include borane and sodium hydrogen borate.
  • Step (B-3) is a step of converting compound (B3) into a suitable leaving group and then substituting it with a cyano group, which is a step of producing compound (B4).
  • the leaving group include a methylsulfonyloxy group, a p-toluenesulfonyloxy group, and a halogen atom.
  • Step (B-4) is a step of hydrolyzing the cyano group under acidic conditions with respect to compound (B4) and then protecting the resulting carboxy group, which is a step of producing compound (B5). If necessary, it includes a step of protecting the amino group again.
  • This reaction varies depending on the type of the protecting groups P 1 to P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
  • the protecting group P 1 is an ethyl group
  • thionyl chloride or the like is used in ethanol.
  • the protecting group P 2 is a Boc group
  • di-tert-butyl dicarbonate or the like is used in the presence of a base.
  • sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
  • the protecting group P 2 is a Cbz group
  • benzyl chloroformate or N- (benzyloxycarbonyloxy) succinimide is used in the presence of a base.
  • a base sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
  • benzaldehyde is used in the presence of anhydrous sodium sulfate or anhydrous magnesium sulfate as a reactant.
  • the solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
  • Step (B-5) is a step of alkylating compound (B5) stepwise, and is a step of producing compound (B6).
  • Step (B-6) is a step of deprotecting protecting groups P 2 and P 3 from compound (B7), and is a step of producing compound (B8).
  • the compound (B7) represents the outline of the compound group (B2, B5, B6) in the production method B
  • the compound (B8) represents the outline of the substituted amine in the production method B.
  • This reaction varies depending on the types of protecting groups P 2 and P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
  • the protecting group P 2 is a Boc group
  • a dioxane solution or an ethyl acetate solution of hydrochloric acid can be used as a reactant. You may add methanol, ethanol, and tetrahydrofuran as needed.
  • Production method C is a step in which the compound (A21) obtained by production method A and the substituted amine (B8) obtained by production method B are condensed to produce the target compound represented by formula (I).
  • Step (C-1) is a step of producing compound (C1) by reacting compound (A21) with substituted amine (B8) in the presence of various condensing agents and bases. ) Can be used.
  • Step (C-2) is a step of modifying the substituent Y 1 in the compound (C1). Hydrolysis reaction, amidation reaction, known deprotection reaction, oxidation reaction, acylation reaction, sulfonylation reaction, heterozygote
  • compound (I) is produced by a ring formation reaction, a hydrogenation reaction, an alkylation reaction, a reduction reaction, a carbon chain extension reaction, or a substituent exchange reaction, either alone or in combination. If necessary, the protecting groups in R 1 to R 4 can be deprotected.
  • Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like.
  • the preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.
  • parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like.
  • the preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives.
  • Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
  • the dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, body weight, type of drug to be administered in combination, dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), or once or several times a day, orally or parenterally, in the equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.
  • composition of the present invention can be used in combination with other active ingredients as necessary within the range not impairing the effects of the present invention.
  • the present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof. Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.
  • [Formulation example] (Formulation Example 1) Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender.
  • (Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
  • the rats were sacrificed, the left paw tissue (untreated paw) was collected, snap-frozen with liquid nitrogen and then crushed, and PBS containing Indomethacin and EDTA was added and homogenized.
  • the amounts of PGE 2 , PGF 1a (stable metabolite of PGI 2 ) and TXB 2 (stable metabolite of TXA 2 ) in the homogenized supernatant were quantified using an EIA kit manufactured by Cayman Chemical.
  • Example 31 of the present application showed a dose-dependent inhibitory effect on PGE 2 production in inflamed tissues by oral administration of 0.1 to 30 mg / kg.
  • Test Example 2 Evaluation of inhibition of A549 cell prostanoid production The A549 cell prostanoid production inhibition assay was performed with reference to the report of Staffan ThoreAn et al. (European Journal of Biochemistry, (2000) 267, 6428-6434). A549 cells suspended in DMEM supplemented with 10% FBS were seeded at 25000 cells / 0.1 mL / well and cultured overnight at 37 ° C. and 5% CO 2 .
  • the compounds of the examples of the present application showed an excellent inhibitory effect on PGE 2 production from rat macrophages.
  • the IC 50 values for TXB 2 production of the compounds of the present invention were all 1000 ng / mL or more, indicating that PGE 2 production was selectively suppressed.
  • the first peak eluting first was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (56.7 g, optical purity> 98% ee) as a solid.
  • the second peak eluting later was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (55.4 g, optical purity> 98% ee) as a solid.
  • the absolute configuration of the second peak obtained in Reference Example 1 was determined to be (1S, 3S).
  • Reference Example 3 Benzyl [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] carbamate
  • commercially available 1,1′-carbonyldiimidazole (7.37 g, 45.5 mmol) was added and stirred for 2 hours.
  • Reference Example 28 Ethyl 1- (6-tert-butoxy-5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate
  • ethyl 1- (5-bromo-6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate and potassium ethenyl (trifluoro) borate obtained in Reference Example 27,
  • Reference Example A solid (yield 61%) was obtained according to the method of No. 11.
  • the title compound (yield 84%) was obtained as a solid according to the method of Reference Example 15.
  • Reference Example 33 Ethyl 1- ⁇ 6-amino-3-phenyl-5-[(triisopropylsilyl) ethynyl] pyridin-2-yl ⁇ piperidine-4-carboxylate Using ethyl 1- (6-amino-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 32, a solid (yield 95%) was obtained according to the method of Reference Example 12. Obtained. The title compound (yield 81%) was obtained according to the method of Reference Example 16 using the obtained solid and commercially available (triisopropylsilyl) acetylene.
  • Reference Example 50 1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid Using the ethyl 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 49, the title compound was prepared according to the method of Reference Example 13. Obtained.
  • Reference Example 52 1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid Using the 6-methyl-3-phenylquinoxalin-2 (1H) -one described in Farmaco (1996), 51 (8,9), 569-577, a triflate was obtained according to the method of Reference Example 42. . Using the obtained compound and commercially available ethyl 4-piperidinecarboxylate, a solid (yield 91%) was obtained according to the method of Reference Example 17. Using the obtained solid, the title compound (99% yield) was obtained as a solid according to the method of Reference Example 13.
  • Reference Example 56 1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid Using ethyl 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 55 according to the method of Reference Example 13, The compound (yield 100%) was obtained as a solid.
  • Reference Example 65 3-Chloro-6-ethyl-4-phenylpyridazine Using 3,6-dichloro-4-phenylpyridazine described in the specification of PCT WO2005 / 072740, a solid (yield 9.9%) was obtained according to the method of Reference Example 14. Using the obtained solid, the title compound (yield 97%) was obtained according to the method of Reference Example 15.
  • Reference Example 66 1- (6-Ethyl-4-phenylpyridazin-3-yl) piperidine-4-carboxylic acid Using 3-chloro-6-ethyl-4-phenylpyridazine obtained in Reference Example 65 and commercially available ethyl 4-piperidinecarboxylate, a solid (yield 61%) was obtained according to the method of Reference Example 17. . Using the resulting solid, the title compound was quantitatively obtained according to the method of Reference Example 13.
  • Example 1 5-Bromo-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
  • 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 13 in acetonitrile (4 mL)
  • (1S, 3S)- 3-Amino-N-ethylcyclohexanecarboxamide 92 mg, 0.45 mmol
  • 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride 140 mg, 0 .45 mmol
  • triethylamine 125 ⁇ L, 0.89 mmol
  • Example 2 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide Using the ethyl 1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 15, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 38%) was obtained according to the method of Example 1. Obtained as a solid.
  • Example 3 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-methyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide Using the ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 12 and 2,4,6-trimethylboroxine, the method of Reference Example 11 was performed. Accordingly, an oily substance (44% yield) was obtained. Using the obtained oil, an amorphous product was obtained according to the method of Reference Example 13.
  • Example 4 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-5-prop-1-in-1-ylpyridin-2-yl) piperidine-4- Carboxamide Using ethyl 1- (3-phenyl-5-prop-1-in-1-ylpyridin-2-yl) piperidin-4-carboxylate obtained in Reference Example 16, an oil was prepared according to the method of Reference Example 13. I got a thing.
  • Example 5 (5-Chloro-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Using ethyl 1- (3-bromo-5-chloropyridin-2-yl) piperidine-4-carboxylate and phenylboronic acid obtained in Reference Example 17, a solid (yield) according to the method of Reference Example 11 85%).
  • Example 6 (3,5-Diphenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Using the ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate and phenylboronic acid obtained in Reference Example 12, a solid (yield) according to the method of Reference Example 11 83%). Using the obtained solid, an amorphous material was obtained according to the method of Reference Example 13.
  • Example 7 (6-Cyano-5-methyl-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide According to the method of Reference Example 14, using ethyl 1- (5-bromo-6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate and tetramethyltin obtained in Reference Example 19 An oil (yield 96%) was obtained. Using the obtained oil, an amorphous product was obtained according to the method of Reference Example 13.
  • Example 8 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxamide Using the methyl 1- (5-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 21, an amorphous product was obtained according to the method of Reference Example 13.
  • Example 9 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-5-propylpyridin-2-yl) piperidine-4-carboxamide Using the ethyl 1- (3-phenyl-5-propylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 22, an amorphous product was obtained according to the method of Reference Example 13.
  • Example 10 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-isopropyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide Using the ethyl 1- (5-isopropyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 23, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 47%) was obtained according to the method of Example 1.
  • Example 11 1- (6-Cyano-5-ethyl-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
  • methyl 1- (6-cyano-5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 25
  • an amorphous product was prepared according to the method of Reference Example 13. Obtained.
  • Example 12 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-6-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxamide Using the ethyl 1- (5-ethyl-6-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 30, a solid was obtained according to the method of Reference Example 13. .
  • Example 13 Ethyl [cis-4-( ⁇ [1- (5-Ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetate Using the ethyl 1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 15, an amorphous product was obtained according to the method of Reference Example 13.
  • Example 14 N- [cis-4- (2-amino-oxoethyl) cyclohexyl] -1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide [Cis-4-( ⁇ [1- (5-ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] acetic acid obtained in Reference Example 31 and commercially available 7N ammonia- Using methanol, the title compound (yield 71%) was obtained as a solid according to the method of Example 1.
  • Example 16 2- [cis-4-( ⁇ [1- (5-Ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] -2-methylpropanoic acid
  • Ethyl 2- [cis-4-( ⁇ [1- (5-ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] -2-methyl obtained in Example 15
  • Example 17 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4- Carboxamide 1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 35 and (1S, 3S)-obtained in Reference Example 4 The title compound (52% yield) was obtained as a solid according to the method of Example 1 using 3-amino-N-ethylcyclohexanecarboxamide.
  • Example 18 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (1-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) Piperidine-4-carboxamide Using the ethyl 1- (1-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 36, the method of Reference Example 13 According to the above, an amorphous material was obtained.
  • Example 19 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine- 4-carboxamide According to the method of Reference Example 13, using ethyl 1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 40 To obtain a solid (yield 97%).
  • Example 20 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxamide 1- (5-Phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 43 and (1S, 3S) -3-amino obtained in Reference Example 4 The title compound (yield 80%) was obtained according to the method of Example 1 using -N-ethylcyclohexanecarboxamide.
  • Example 21 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (5-phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxamide 1- (5-Phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 43 and (1S, 3S) -3-amino obtained in Reference Example 6 The title compound (yield 80%) was obtained as a solid according to the method of Example 1 using cyclohexanecarboxamide hydrochloride.
  • Example 22 Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ Amino) cyclohexyl] propanoate 1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 35 and ethyl 2- (cis- Using 4-aminocyclohexyl) -2-methylpropanoate, the title compound (yield 77%) was obtained according to the method of Example 1.
  • Example 23 2-Methyl-2- [cis-4-( ⁇ [1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ Amino) cyclohexyl] propanoic acid
  • Carbonyl ⁇ amino) cyclohexyl] propanoate was used to give the title compound as a solid (yield 32%) according to the method of Example 16.
  • Example 24 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) Piperidine-4-carboxamide 1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 46 and Reference Example 4 (1S , 3S) -3-Amino-N-ethylcyclohexanecarboxamide was used to give the title compound (yield 80%) as a solid according to the method of Example 1.
  • Example 25 Methyl (1S, 3S) -3-( ⁇ [1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ amino) Cyclohexanecarboxylate 1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 35 and methyl (1S, 3S) obtained in Reference Example 7 -3-Aminocyclohexanecarboxylate The title compound (yield 99%) was obtained according to the method of Example 1 using hydrochloride.
  • Example 26 Methyl (1S, 3S) -3-( ⁇ [1- (3-Chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] Carbonyl ⁇ amino) cyclohexanecarboxylate
  • N-chlorosuccinimide 42 mg, 0.31 mmol
  • Example 27 1- (3-Chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] Piperidine-4-carboxamide Methyl (1S, 3S) -3-( ⁇ [1- (3-chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-] obtained in Example 26 [Il] carbonyl ⁇ amino) cyclohexanecarboxylate was used to obtain an amorphous product according to the method of Reference Example 31.
  • Example 28 Ethyl [cis-4-( ⁇ [1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ amino ) Cyclohexyl] acetate 1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 46 and Izvestia Akademii Nauk SSSR, SeriyaKimicheskaya (1980) , 10, 2374-2379.
  • Example 29 [cis-4-( ⁇ [1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ amino) Cyclohexyl] acetic acid
  • Ethyl [cis-4-( ⁇ [1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl obtained in Example 28 ⁇ Amino) cyclohexyl] acetate was used to obtain the title compound (64% yield) according to the method of Reference Example 31.
  • Example 30 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide Using the ethyl 1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 47, a solid was obtained according to the method of Reference Example 13. Using the obtained solid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 85%) was obtained according to the method of Example 1. .
  • Example 31 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 50 and (1S, 3S) -3- obtained in Reference Example 4 The title compound (yield 86%) was obtained according to the method of Example 1 using amino-N-ethylcyclohexanecarboxamide.
  • Example 32 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide Using ethyl 1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-carboxylate obtained in Reference Example 51, an amorphous product according to the method of Reference Example 13 Got.
  • Example 33 Methyl (1S, 3S) -3-( ⁇ [1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexanecarboxy rate 1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 50 and methyl (1S, 3S) -3 obtained in Reference Example 7 -Aminocyclohexanecarboxylate The title compound (yield 109%, purity 91%) was obtained according to the method of Example 1 using hydrochloride.
  • Example 34 N-[(1S, 3S) -3- (Methylcarbamoyl) cyclohexyl] -1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide Methyl (1S, 3S) -3-( ⁇ [1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) obtained in Example 33 Using cyclohexanecarboxylate, an amorphous substance (yield 95%) was obtained according to the method of Reference Example 31.
  • Example 35 Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino ) Cyclohexyl] propanoate 1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 50 and ethyl 2- (cis-4-) obtained in Reference Example 10
  • the title compound (yield 97%) was obtained according to the method of Example 1 using aminocyclohexyl) -2-methylpropanoate.
  • Example 36 2-Methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) Cyclohexyl] propanoic acid
  • Example 37 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 52 and (1S, 3S) -3-amino-N-ethyl obtained in Reference Example 4 The title compound (yield 83%) was obtained as a solid according to the method of Example 1 using cyclohexanecarboxamide.
  • Example 38 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (6-methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxamide 1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 52 and (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 6 In accordance with the method of Example 1, the title compound (yield 86%) was obtained.
  • Example 39 Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoate 1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 52 and ethyl 2- (cis-4-aminocyclohexyl) -2 obtained in Reference Example 10 Using the methylpropanoate, the title compound (yield 95%) was obtained according to the method of Example 1.
  • Example 40 2-Methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] propanoic acid Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl ⁇ amino) cyclohexyl] obtained in Example 39] The title compound (yield 77%) was obtained as a solid using propanoate according to the method of Example 16.
  • Example 41 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4- Carboxamide 1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 56 and (1S, 3S)-obtained in Reference Example 4 The title compound (yield 79%) was obtained as a solid according to the method of Example 1 using 3-amino-N-ethylcyclohexanecarboxamide.
  • Example 42 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide 1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 56 and (1S, 3S)-obtained in Reference Example 6 Using 3-aminocyclohexanecarboxamide hydrochloride according to the method of Example 1, the title compound (yield 56%) was obtained.
  • Example 43 Ethyl 2-methyl-2- [cis-4-( ⁇ [1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ Amino) cyclohexyl] propanoate 1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 56 and ethyl 2- (cis- The title compound (90% yield) was obtained using 4-aminocyclohexyl) -2-methylpropanoate according to the method of Example 1.
  • Example 44 2-Methyl-2- [cis-4-( ⁇ [1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl ⁇ Amino) cyclohexyl] propanoic acid
  • Carbonyl ⁇ amino) cyclohexyl] propanoate was used to obtain the title compound (yield 67%) as a solid according to the method of Example 16.
  • Example 45 (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) -N-[(1S, 3S) -3- (ethyl Carbamoyl) cyclohexyl] piperidine-4-carboxamide
  • 1- (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 58 and obtained in Reference Example 4
  • the title compound (yield 70%) was obtained according to the method of Example 1.
  • Example 46 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl ) Piperidine-4-carboxamide 1- (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 58 and obtained in Reference Example 6 Using the obtained (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride, the title compound (yield 47%) was obtained according to the method of Example 1.
  • Example 47 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4- Carboxamide 1- (3-Ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 60 and (1S, 3S)-obtained in Reference Example 4 The title compound (yield 75%) was obtained according to the method of Example 1 using 3-amino-N-ethylcyclohexanecarboxamide.
  • Example 48 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide 1- (3-Ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 60 and (1S, 3S)-obtained in Reference Example 6 The title compound (yield 83%) was obtained as a solid according to the method of Example 1 using 3-aminocyclohexanecarboxamide hydrochloride.
  • Example 49 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl ] Piperidine-4-carboxamide 1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid obtained in Reference Example 62 and Reference Example 4 ( The title compound (yield 83%) was obtained as a solid according to the method of Example 15 using 1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide.
  • Example 50 Ethyl ⁇ cis-4-[( ⁇ 1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl ⁇ carbonyl) Amino] cyclohexyl ⁇ acetate 1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid obtained in Reference Example 62 and Izvestia Akademii Nauk SSSR, SeriyaKimicheskaya (1980) ), 10, 2374-2379, and the title compound (yield 84%) was obtained according to the method of Example 1 using ethyl (cis-4-aminocyclohexyl) acetate hydrochloride.
  • Example 51 N- [cis-4- (2-amino-2-oxoethyl) cyclohexyl] -1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine-2- Yl] piperidine-4-carboxamide ⁇ Cis-4-[( ⁇ 1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl ⁇ carbonyl obtained in Reference Example 63 ) Amino] cyclohexyl ⁇ acetic acid and a commercially available 7N ammonia-methanol solution were used to obtain the title compound (yield 59%) as a solid according to the method of Example 1.
  • Example 52 1- (4,6-Diphenylpyridazin-3-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
  • 4-,6-Diphenylpyridazin-3-yl) piperidine-4-carboxylic acid obtained in Reference Example 64 and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4 was used to give the title compound (yield 64%) as a solid according to the method of Example 15.
  • Example 53 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-ethyl-4-phenylpyridazin-3-yl) piperidine-4-carboxamide 1- (6-Ethyl-4-phenylpyridazin-3-yl) piperidine-4-carboxylic acid obtained in Reference Example 66 and (1S, 3S) -3-amino-N-ethyl obtained in Reference Example 4 The title compound (yield 80%) was obtained according to the method of Example 15 using cyclohexanecarboxamide.

Abstract

Provided are: compounds having a preventive or therapeutic effect against chronic rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, dermatitis, including psoriasis, etc.; a pharmaceutical composition containing said compounds; and a method for preventing or treating inflammatory diseases, characterized in that an effective dose of the pharmaceutical composition is administered to mammals. The present invention involves the compounds represented by general formula (I) or pharmaceutically acceptable salts thereof.

Description

新規二置換シクロヘキサン誘導体New disubstituted cyclohexane derivatives
　本発明は、抗炎症作用を有するキノリン誘導体、その塩、またはそれらの溶媒和物を含有するプロスタグランジンE2産生抑制剤に関する。 The present invention relates to a prostaglandin E 2 production inhibitor containing a quinoline derivative having an anti-inflammatory action, a salt thereof, or a solvate thereof.
　ホスホリパーゼA2により細胞膜リン脂質からアラキドン酸（AA）が遊離し、それがシクロオキシゲナーゼ（COX）によりプロスタグランジンG2（PGG2）を経てプロスタグランジンH2（PGH2）が合成される。このPGH2がそれぞれの変換酵素によりプロスタグランジンD2（PGD2）、プロスタグランジンE2（PGE2）、プロスタグランジンF2α（PGF2α）、プロスタグランジンI2（PGI2）ならびにトロンボキサンA2（TXA2）に変換されることで、プロスタノイドは産生される。 Arachidonic acid (AA) is released from cell membrane phospholipid by phospholipase A 2, and prostaglandin H 2 (PGH 2 ) is synthesized through prostaglandin G 2 (PGG 2 ) by cyclooxygenase (COX). This PGH 2 can be converted into prostaglandin D 2 (PGD 2 ), prostaglandin E 2 (PGE 2 ), prostaglandin F 2α (PGF 2α ), prostaglandin I 2 (PGI 2 ), and thrombos by each converting enzyme. Prostanoids are produced by conversion to xan A 2 (TXA 2 ).
　中でも、生体内において最も豊富に存在するプロスタノイドと考えられているPGE2は、痛覚過敏、発熱、血管平滑筋弛緩、胃酸分泌抑制、気管支平滑筋弛緩、子宮収縮など、中枢から末梢にわたり多彩な生理活性を有していることが知られている。PGE2のみならず他のプロスタノイドの生理活性も解明されつつあり、これらは、生体の恒常性の維持に重要な役割を担っているが、一方で、様々な病態の形成、進行ならびに持続に深く関与していると考えられている。 Among them, PGE 2 , which is considered to be the most abundant prostanoid in the body, has a variety of from the center to the periphery, including hyperalgesia, fever, vascular smooth muscle relaxation, gastric acid secretion suppression, bronchial smooth muscle relaxation, and uterine contraction. It is known to have physiological activity. The physiological activities of not only PGE 2 but also other prostanoids are being elucidated, and they play an important role in maintaining the homeostasis of living organisms. It is considered deeply involved.
　COXにはCOX-1とCOX-2の２つのアイソザイムが存在する。現在、代表的な消炎鎮痛剤として使用されている非ステロイド性抗炎症薬（NSAIDs）は、COX-1とCOX-2の両方を阻害する。NSAIDsは胃腸保護作用に関与するCOX-1由来のプロスタノイドの産生を阻害するため、胃腸障害を高頻度で惹起することが問題となっている（非特許文献１）。
また、炎症刺激により発現誘導されるCOX-2に対して選択的な阻害作用を示すCOX-2阻害剤は、胃腸障害の副作用は少ない薬剤であるが、心血管系イベント発生のリスクが問題となっている。COX-2選択的阻害剤は血小板凝集抑制や心臓保護の役割を果たしているCOX-2由来のPGI2の産生を抑制する一方、凝固系において相反する作用を有するCOX-1由来のTXA2の産生を抑制しないことがその原因の1つと考えられている（非特許文献２）。 COX has two isozymes, COX-1 and COX-2. Non-steroidal anti-inflammatory drugs (NSAIDs) currently used as typical anti-inflammatory analgesics inhibit both COX-1 and COX-2. Since NSAIDs inhibit the production of COX-1-derived prostanoids involved in the gastrointestinal protective action, causing gastrointestinal disorders at a high frequency is a problem (Non-patent Document 1).
In addition, COX-2 inhibitors that have a selective inhibitory action on COX-2 induced by inflammatory stimuli are drugs with few side effects of gastrointestinal disorders, but the risk of cardiovascular events is a problem. It has become. COX-2 selective inhibitor suppresses the production of PGI 2 derived from COX-2, which plays a role in inhibiting platelet aggregation and cardioprotection, while producing TXA 2 derived from COX-1 which has a contradictory effect in the coagulation system It is considered that one of the causes is not to suppress (Non-patent Document 2).
　従来、炎症性疾患等の治療においては、対症療法としてステロイドなどの抗炎症薬が使用されており、その副作用の発現が問題となっている。また、そうした副作用を回避するために非ステロイド性抗炎症薬や新たなNSAIDsの開発も進められているが、上述のように依然として副作用の発現に苦しんでおり、根本的治療法の開発が望まれている。 Conventionally, in the treatment of inflammatory diseases and the like, anti-inflammatory drugs such as steroids have been used as symptomatic treatment, and the occurrence of side effects has become a problem. In addition, in order to avoid such side effects, non-steroidal anti-inflammatory drugs and new NSAIDs are being developed, but as mentioned above, they still suffer from side effects, and the development of fundamental therapies is desired. ing.
　このような背景から、副作用が少なく、優れた抗炎症作用を有する化合物を見出すことが試みられている。これまでに、本発明の背景技術として、以下に示す文献が知られている。 From such a background, an attempt has been made to find a compound having few side effects and an excellent anti-inflammatory action. So far, the following documents are known as background art of the present invention.
WO2006/063466WO2006 / 063466 WO2007/134434WO2007 / 134434 WO2011/023812WO2011 / 023812 WO2007/042816WO2007 / 042816 WO2008/071944WO2008 / 071944 WO2010/034796WO2010 / 034796 WO2012/022793WO2012 / 022793 WO2010/132016WO2010 / 132016 WO2011/077313WO2011 / 077313 WO2011/131975WO2011 / 131975
　本発明者らは、副作用が少なく優れた抗炎症作用を有する新規化合物に関して、長年に亘り鋭意検討を重ねた結果、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、またはアルツハイマー病等に有用である新規化合物を見出して、本発明を完成した。 As a result of intensive studies over many years on novel compounds having excellent anti-inflammatory activity with few side effects, the present inventors have found that rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory diseases, inflammatory bowel Nerves such as diseases, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, diabetic neuralgia , Pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, strong Dermatosis, atherosclerosis and accompanying myocardial infarction, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, frequent Sclerosis, or useful in Alzheimer's disease and the like found a novel compound, and completed the present invention.
　したがって、本発明の課題は、副作用が少なく優れた抗炎症作用を有する新規化合物、その薬理上許容される塩を提供することである。 Therefore, an object of the present invention is to provide a novel compound having an excellent anti-inflammatory action with few side effects and a pharmacologically acceptable salt thereof.
　すなわち本発明は、
（１）一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩。 That is, the present invention
(1) A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
｛式中、Ｒ１、Ｒ２，Ｒ３、およびＲ４は、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルコキシ基で置換されていてもよいＣ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６アルキル基で置換されていてもよいエチニル基、又はフェニル基を表わし、
Ｘ１およびＸ２は、炭素原子又は窒素原子を表わし、
Ｙは、置換基群αから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基、又はＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基を表わし、
ｎは、０又は１であり、
（ｉ）ｎが０の場合：
環Ａは、Ｘ１とＸ２が隣り合う５員の不飽和の複素環を形成し、Ｒ２およびＲ４は、それらが結合している環の炭素原子又は窒素原子と一緒になって、飽和又は不飽和の５員～６員の炭化水素環又は複素環を形成していてもよく、形成された炭化水素環又は複素環は、置換基群βから選択される基で置換されていてもよい。
（ｉｉ）ｎが１の場合：
環Ａは、６員の不飽和の炭化水素環又は複素環を形成し、Ｒ３およびＲ４は、それらが結合している環の炭素原子又は窒素原子と一緒になって、飽和又は不飽和の５員～６員の炭化水素環又は複素環を形成していてもよく、形成された炭化水素環又は複素環は、置換基群βから選択される基で置換されていてもよい。
置換基群αは、水酸基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基、およびＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基を表わす。
置換基群βはハロゲン原子、および１乃至３個のハロゲン原子で置換されていてもよいＣ１－Ｃ６アルキル基を表わす。｝、
好適には、
（２）Ｘ１が炭素原子でありＸ２が炭素原子である、上記（１）に記載の化合物又はその薬理上許容される塩、
（３）ｎが１である、上記（１）乃至（２）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（４）環Ａが、６員の不飽和の複素環である、上記（１）乃至（３）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（５）Ｒ３、Ｒ４およびそれらが結合している環の炭素原子又は窒素原子が一緒になって形成する環が、フラン環、ジヒドロフラン環、チオフェン環、ピロール環、ピリジン環、又はベンゼン環である、上記（１）乃至（４）のいずれか１項に記載の化合物又はその薬理上許容される塩、
（６）一般式（Ｉ）を有する化合物が以下の化合物群から選択される化合物である、上記（１）記載の化合物又はその薬理上許容される塩、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－エチル－６－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド、
１－（３－クロロ－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキサミド、
２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸、
Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド、
Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド、
２－メチル－２－［シス－４－（｛［１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸、Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド、および、
Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
（７）一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物、
（８）プロスタグランジンE2により介在される疾患を予防又は治療するために用いるための、上記（７）に記載された医薬組成物、
（９）プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、又はアルツハイマー病である、上記（８）に記載された医薬組成物、
（１０）プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、喘息、慢性閉塞性肺疾患、潰瘍性大腸炎、炎症性疼痛、自己免疫性肝炎、多発性硬化症、又は乾癬を含む皮膚炎である、上記（８）乃至（９）に記載された医薬組成物、又は、
（１１）一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物の有効量を哺乳動物に投与することを特徴とする、炎症性疾患の予防方法又は治療方法、
である。 {Wherein, R 1, R 2, R 3, and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, C 1 -C 6 optionally substituted by an alkoxy group C 1 -C 6 Represents an alkyl group, a C 1 -C 6 alkoxy group, an ethynyl group optionally substituted with a C 1 -C 6 alkyl group, or a phenyl group;
X 1 and X 2 represent a carbon atom or a nitrogen atom,
Y is a C 1 -C 6 alkyl group optionally substituted with 1 to 3 groups selected from the substituent group α, a carboxy group optionally substituted with a C 1 -C 6 alkyl group, or C Represents a carbamoyl group optionally substituted by a 1 -C 6 alkyl group,
n is 0 or 1;
(I) When n is 0:
Ring A forms a 5-membered unsaturated heterocycle where X 1 and X 2 are adjacent, and R 2 and R 4 together with the carbon or nitrogen atom of the ring to which they are attached, A saturated or unsaturated 5- to 6-membered hydrocarbon ring or heterocyclic ring may be formed, and the formed hydrocarbon ring or heterocyclic ring is substituted with a group selected from the substituent group β. Also good.
(Ii) When n is 1:
Ring A forms a 6-membered unsaturated hydrocarbon ring or heterocyclic ring, and R 3 and R 4 together with the carbon or nitrogen atom of the ring to which they are attached are saturated or unsaturated The 5-membered to 6-membered hydrocarbon ring or heterocyclic ring may be formed, and the formed hydrocarbon ring or heterocyclic ring may be substituted with a group selected from the substituent group β.
Substituent group α represents a hydroxyl, C 1 -C 6 alkyl group, C 1 -C 6 alkyl group optionally substituted carboxyl group, and C 1 -C 6 alkyl carbamoyl group which may be substituted with a group Represents.
The substituent group β represents a halogen atom and a C 1 -C 6 alkyl group which may be substituted with 1 to 3 halogen atoms. },
Preferably,
(2) The compound or pharmacologically acceptable salt thereof according to (1) above, wherein X 1 is a carbon atom and X 2 is a carbon atom,
(3) The compound according to any one of (1) to (2) above, wherein n is 1, or a pharmacologically acceptable salt thereof,
(4) The compound according to any one of the above (1) to (3) or a pharmacologically acceptable salt thereof, wherein ring A is a 6-membered unsaturated heterocyclic ring,
(5) The ring formed by combining R 3 , R 4 and the carbon atom or nitrogen atom of the ring to which they are bonded together is a furan ring, dihydrofuran ring, thiophene ring, pyrrole ring, pyridine ring, or benzene The compound according to any one of (1) to (4) above, which is a ring, or a pharmacologically acceptable salt thereof,
(6) The compound according to (1) or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) is a compound selected from the following compound group:
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-6-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxamide;
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxamide ,
1- (3-Chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide ,
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide;
2-methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid,
N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide;
N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide;
2-Methyl-2- [cis-4-({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propane Acid, N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine- 4-carboxamide, and
N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide (7) General formula (I Or a pharmacologically acceptable salt thereof as an active ingredient,
(8) The pharmaceutical composition described in (7) above for use in preventing or treating a disease mediated by prostaglandin E 2 ,
(9) Diseases mediated by prostaglandin E 2 include rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, Edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, self Immune hepatitis, gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, scleroderma, atherosclerosis, and associated myocardial infarction, (8) above, which is stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sclerosis, or Alzheimer's disease Listed Pharmaceutical compositions,
(10) diseases mediated by prostaglandin E 2 are, rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis Or the pharmaceutical composition described in (8) to (9) above, which is dermatitis including psoriasis, or
(11) A method for preventing inflammatory diseases, comprising administering to a mammal an effective amount of a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient Method of treatment,
It is.
　本発明の化合物又はその薬理上許容される塩は、副作用が少なく優れた抗炎症作用を有し、温血動物（特に、ヒト）に対する炎症性疾患又はその他炎症関連疾患の予防剤若しくは治療剤として有用である。 The compound of the present invention or a pharmacologically acceptable salt thereof has an excellent anti-inflammatory action with few side effects, and is used as a prophylactic or therapeutic agent for inflammatory diseases or other inflammation-related diseases for warm-blooded animals (particularly humans). Useful.
縦軸には炎症組織中プロスタグランジンＥ２産生を示す。実施例化合物３１の用量依存的な抑制作用を示したものである。The vertical axis shows the 2 production in inflamed tissue prostaglandin E. 3 shows a dose-dependent inhibitory action of Example Compound 31.
　ｎが０の場合に、Ｘ１とＸ２が隣り合う５員の不飽和の複素環は、具体的には、ピロール環、フラン環、又はチオフェン環であり、好適には、ピロール環である。 When n is 0, the 5-membered unsaturated heterocycle adjacent to X 1 and X 2 is specifically a pyrrole ring, a furan ring, or a thiophene ring, and preferably a pyrrole ring. .
　ｎが０の場合に、Ｒ２およびＲ４とそれらが結合している環の炭素原子又は窒素原子と一緒になって形成する、飽和又は不飽和の５員～６員の炭化水素環又は複素環は、具体的には、ベンゼン環、ピリジン環などである。 When n is 0, a saturated or unsaturated 5- to 6-membered hydrocarbon ring or heterocycle formed together with R 2 and R 4 and the carbon atom or nitrogen atom of the ring to which they are bonded Specific examples of the ring include a benzene ring and a pyridine ring.
　ｎが０の場合に、Ｘ１は、窒素原子であり、Ｘ２は、炭素原子であることが好ましく、Ｒ２およびＲ４とそれらが結合している環の炭素原子又は窒素原子と一緒になって、６員の環構造をとることが好ましい。 When n is 0, X 1 is a nitrogen atom, X 2 is preferably a carbon atom, and together with R 2 and R 4 and the carbon atom or nitrogen atom of the ring to which they are attached Therefore, it is preferable to take a 6-membered ring structure.
　ｎが１の場合に、具体的には、ピリジン環、ピラジン環、又はピリダジン環であるが、環Ａは、Ｘ１とＸ２がともに炭素原子である、ピリジン環が好ましい。 When n is 1, specifically, it is a pyridine ring, a pyrazine ring, or a pyridazine ring, but the ring A is preferably a pyridine ring in which X 1 and X 2 are both carbon atoms.
　ｎが１の場合に、Ｒ３およびＲ４がそれらが結合している環の炭素原子又は窒素原子と一緒になって形成する環は、具体的には、フラン環、チオフェン環、ピロール環、又はジヒドロフラン環を挙げることができるが、フラン環又はピロール環が好ましい。 When n is 1, the ring formed by R 3 and R 4 together with the carbon atom or nitrogen atom of the ring to which they are bonded is specifically a furan ring, a thiophene ring, a pyrrole ring, Or a dihydrofuran ring can be mentioned, but a furan ring or a pyrrole ring is preferred.
　以下に本明細書中の置換基について説明する。 The substituents in this specification will be described below.
　ハロゲン原子は、具体的には、フッ素原子、塩素原子、臭素原子、又は、ヨウ素原子であり、好適には、フッ素原子、又は、塩素原子であり、さらに好適にはフッ素原子である。 The halogen atom is specifically a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.
　Ｃ１－Ｃ６アルキル基とは、直鎖であっても分枝鎖であっても環構造であってもよく、鎖中に１乃至６個の炭素原子を含む、脂肪族炭化水素基を意味する。分枝とは、１個以上の低級アルキル基（例えば、メチル基、エチル基又はプロピル基）が、直鎖アルキル鎖に結合していることを意味する。具体的には、メチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基等である。好適には、メチル基、エチル基、プロピル基、シクロプロピル基、イソプロピル基、又は、ｔｅｒｔ－ブチル基であり、さらに好適には、メチル基、エチル基、又はシクロプロピル基である。 The C 1 -C 6 alkyl group may be a straight chain, branched chain or ring structure, and is an aliphatic hydrocarbon group containing 1 to 6 carbon atoms in the chain. means. Branching means that one or more lower alkyl groups (for example, a methyl group, an ethyl group, or a propyl group) are bonded to a linear alkyl chain. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a tert-butyl group, a pentyl group, and a hexyl group. A methyl group, an ethyl group, a propyl group, a cyclopropyl group, an isopropyl group, or a tert-butyl group is preferable, and a methyl group, an ethyl group, or a cyclopropyl group is more preferable.
　Ｃ１－Ｃ６アルコキシ基とは、上記Ｃ１－Ｃ６アルキル基に酸素原子が結合した、アルキル－Ｏ基を意味し、鎖中に１乃至６個の炭素原子を含む。好適には、炭素数１乃至３個である。具体例としては、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、ヘプトキシおよびメチルヒドロキシ等が挙げられ、好適には、メトキシ基、エトキシ基、プロポキシ基、又は、イソプロポキシ基であり、さらに好適には、メトキシ基である。 The C 1 -C 6 alkoxy group means an alkyl-O group in which an oxygen atom is bonded to the C 1 -C 6 alkyl group, and contains 1 to 6 carbon atoms in the chain. Preferably, it has 1 to 3 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy, preferably methoxy group, ethoxy group, propoxy group or isopropoxy group, More preferably, it is a methoxy group.
　Ｃ１－Ｃ６アルコキシ基で置換されていてもよいＣ１－Ｃ６アルキル基は、具体的には、メチル基、エチル基、プロピル基、イソプロピル基、メトキシメチル基、１－メトキシエチル基、２－メトキシエチル基、１－メトキシプロピル基、２－メトキシプロピル基、３－メトキシプロピル基、１－メトキシブチル基、２－メトキシブチル基、３－メトキシブチル基、４－メトキシブチル基、１－メトキシペンチル基、２－メトキシペンチル基、３－メトキシペンチル基、４－メトキシペンチル基、５－メトキシペンチル基、１－メトキシヘキシル基、２－メトキシヘキシル基、３－メトキシヘキシル基、４－メトキシヘキシル基、５－メトキシヘキシル基、又は６－メトキシヘキシル基等であり、好適には、メチル基、エチル基、プロピル基、又はイソプロピル基である。 Specific examples of the C 1 -C 6 alkyl group which may be substituted with a C 1 -C 6 alkoxy group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxymethyl group, a 1-methoxyethyl group, 2-methoxyethyl group, 1-methoxypropyl group, 2-methoxypropyl group, 3-methoxypropyl group, 1-methoxybutyl group, 2-methoxybutyl group, 3-methoxybutyl group, 4-methoxybutyl group, 1- Methoxypentyl group, 2-methoxypentyl group, 3-methoxypentyl group, 4-methoxypentyl group, 5-methoxypentyl group, 1-methoxyhexyl group, 2-methoxyhexyl group, 3-methoxyhexyl group, 4-methoxyhexyl Group, 5-methoxyhexyl group, 6-methoxyhexyl group, etc., preferably methyl group, ethyl group, propylene Group, or an isopropyl group.
　Ｃ１－Ｃ６アルキル基で置換されていてもよいエチニル基は、具体的には、メチルエチニル基、エチルエチニル基、プロピルエチニル基、イソプロピルエチニル基、ブチルエチニル基、ペンチルエチニル基、又はヘキシルエチニル基を挙げることができ、好適にはメチルエチニル基、エチルエチニル基、又はプロピルエチニル基であり、さらに好適には、メチルエチニル基である。 Specific examples of the ethynyl group optionally substituted with a C 1 -C 6 alkyl group include a methylethynyl group, an ethylethynyl group, a propylethynyl group, an isopropylethynyl group, a butylethynyl group, a pentylethynyl group, or a hexylethynyl group. A methylethynyl group, an ethylethynyl group, or a propylethynyl group, and more preferably a methylethynyl group.
　好適には、Ｒ１は、フェニル基であり、Ｒ２は、水素原子であり、Ｒ３は、メチル基、エチル基、プロピル基、イソプロピル基、メトキシ基、ハロゲン基、メチルエチニル基、又はフェニル基であり、Ｒ４は、シアノ基、又はメトキシ基である。 Preferably, R 1 is a phenyl group, R 2 is a hydrogen atom, and R 3 is a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a halogen group, a methylethynyl group, or a phenyl group R 4 is a cyano group or a methoxy group.
　ｎは、好適には１であり、Ｒ３およびＲ４は、好適には、それらが結合している環の炭素原子又は窒素原子と一緒になって、飽和又は不飽和の５員～６員の炭化水素環又は複素環を形成する。 n is preferably 1, and R 3 and R 4 are preferably taken together with the carbon or nitrogen atom of the ring to which they are attached to form a saturated or unsaturated 5- to 6-membered Form a hydrocarbon ring or a heterocyclic ring.
　Ｘ１およびＸ２は、好適には、ともに炭素原子である。 X 1 and X 2 are preferably both carbon atoms.
　Ｒ３およびＲ４が結合して形成する環は、好適には、フラン環、ジヒドロフラン環、チオフェン環、ピロール環、ピリジン環、又はベンゼン環である。これらの環を置換する基は、好適には、塩素原子、メチル基、ジメチル基、エチル基、又はトリフルオロメチル基である。 The ring formed by combining R 3 and R 4 is preferably a furan ring, a dihydrofuran ring, a thiophene ring, a pyrrole ring, a pyridine ring, or a benzene ring. The group that substitutes these rings is preferably a chlorine atom, a methyl group, a dimethyl group, an ethyl group, or a trifluoromethyl group.
　Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基は、具体的には、カルボキシ基、メチルカルボキシ基、エチルカルボキシ基、プロピルカルボキシ基、イソプロピルカルボキシ基、ブチルカルボキシ基、ペンチルカルボキシ基、又はヘキシルカルボキシ基であり、好適には、カルボキシ基、メチルカルボキシ基、又はエチルカルボキシ基である。 Specific examples of the carboxy group that may be substituted with a C 1 -C 6 alkyl group include a carboxy group, a methyl carboxy group, an ethyl carboxy group, a propyl carboxy group, an isopropyl carboxy group, a butyl carboxy group, a pentyl carboxy group, Or a hexylcarboxy group, and preferably a carboxy group, a methylcarboxy group, or an ethylcarboxy group.
　置換基群αから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基は、好適には、ヒドロキシメチル基、カルバモイルメチル基、エチルカルボキシメチル基、カルボキシメチル基、エチルカルボキシ（ジメチル）メチル基、１－カルボキシシクロプロピル基、又はカルボキシ（ジメチル）メチル基である。 The C 1 -C 6 alkyl group optionally substituted by 1 to 3 groups selected from the substituent group α is preferably a hydroxymethyl group, a carbamoylmethyl group, an ethylcarboxymethyl group, a carboxymethyl group, An ethylcarboxy (dimethyl) methyl group, a 1-carboxycyclopropyl group, or a carboxy (dimethyl) methyl group;
　Ｃ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基は、具体的には、カルバモイル基、メチルカルバモイル基、エチルカルバモイル基、プロピルカルバモイル基、イソプロピルカルバモイル基、ブチルカルバモイル基、ペンチルカルバモイル基、又はヘキシルカルバモイル基を挙げることができ、好適には、カルバモイル基、メチルカルバモイル基、又はエチルカルバモイル基である。 Specific examples of the carbamoyl group which may be substituted with a C 1 -C 6 alkyl group include a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a butylcarbamoyl group, a pentylcarbamoyl group, Or a hexylcarbamoyl group can be mentioned, and a carbamoyl group, a methylcarbamoyl group, or an ethylcarbamoyl group is preferable.
　Ｙは、好適には、ヒドロキシメチル基、カルバモイル基、メチルカルバモイル基、エチルカルバモイル基、メチルカルボキシ基、エチルカルボキシメチル基、エチルカルボキシ（ジメチル）メチル基、カルバモイルメチル基、カルボキシメチル基、又はカルボキシ（ジメチル）メチル基である。 Y is preferably a hydroxymethyl group, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, methylcarboxy group, ethylcarboxymethyl group, ethylcarboxy (dimethyl) methyl group, carbamoylmethyl group, carboxymethyl group, or carboxy ( Dimethyl) methyl group.
　一般式（Ｉ）を有する化合物として、さらに好適には、実施例に記載の化合物である。 More preferable examples of the compound having the general formula (I) include the compounds described in Examples.
　「治療」とは、病気又は症状を治癒させること又は改善させること或いは症状を抑制させることを意味する。 “Treatment” means curing or ameliorating a disease or symptom or suppressing a symptom.
　「プロスタグランジンE2により介在される疾患」とは、その疾患の発症にプロスタグランジンE2が関与していると考えられているものであれば特に限定されないが、具体的には、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、または又はアルツハイマー病等が挙げられる。好適には、炎症性疾患とされる、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、喘息、発熱、又は炎症性食欲不振に本願発明の化合物が適用され、より好適には、慢性関節リウマチ、変形性関節症、喘息、慢性閉塞性肺疾患、潰瘍性大腸炎、炎症性疼痛、自己免疫性肝炎、多発性硬化症、又は乾癬を含む皮膚炎である。 The “disease mediated by prostaglandin E 2 ” is not particularly limited as long as it is thought that prostaglandin E 2 is involved in the onset of the disease. Rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, menstruation For dysfunction, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, cancer metastasis and familial colorectal polyposis Accompanied pain, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, scleroderma, atherosclerosis, and accompanying myocardial infarction, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstruction Lung disease Sudden infant death syndrome, asthma, fever, inflammatory anorexia, and multiple sclerosis, or or Alzheimer's disease and the like. Rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammatory Pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, The compound of the present invention is applied to gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, asthma, fever, or inflammatory anorexia, and more preferably rheumatoid arthritis, osteoarthritis, asthma, chronic Dermatitis including obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis.
　「その薬理上許容される塩」とは、医薬として使用することができる塩を示す。本発明の化合物では、酸性基又は塩基性基を有する場合に、塩基又は酸と反応させることにより、塩基性塩又は酸性塩にすることができるので、その塩を示す。 “The pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
　本発明の化合物の薬理上許容される「塩基性塩」としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩；マグネシウム塩、カルシウム塩のようなアルカリ土類金属塩；Ｎ－メチルモルホリン塩、トリエチルアミン塩、トリブチルアミン塩、ジイソプロピルエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ－メチルピペリジン塩、ピリジン塩、４－ピロリジノピリジン塩、ピコリン塩のような有機塩基塩類又はグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、好適には、アルカリ金属塩である。 The pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt. Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamates, and aspartates, and alkali metal salts are preferred.
　本発明の化合物の薬理上許容される「酸性塩」としては、好適には、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、リンゴ酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、最も好適には、ハロゲン化水素酸塩である。 The pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably hydrohalide salt.
　本発明の化合物又はその薬理上許容される塩は、大気中に放置したり又は再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となったりする場合があり、本発明には、そのような各種の水和物、溶媒和物及び結晶多形の化合物も包含する。 The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization. The present invention also includes such various hydrates, solvates and polymorphic compounds.
　本発明化合物、その塩又はそれらの溶媒和物は、置換基の種類や組み合わせによって、シス体、トランス体等の幾何異性体、互変異性体又はｄ体、ｌ体等の光学異性体等の各種異性体が存在し得るが、本発明の化合物は、特に限定していない場合はそれら全ての異性体、立体異性体及びいずれの比率のこれら異性体及び立体異性体混合物をも包含するものである。これらの異性体の混合物は、公知の分割手段により分離することができる。 The compound of the present invention, a salt thereof, or a solvate thereof may be converted into a geometric isomer such as a cis isomer or a trans isomer, a tautomer, an optical isomer such as a d isomer, or an l isomer depending on the type or combination of substituents. Although various isomers may exist, the compound of the present invention includes all isomers, stereoisomers, and any ratio of these isomers and stereoisomer mixtures unless otherwise specified. is there. A mixture of these isomers can be separated by a known resolution means.
　本発明の一般式（Ｉ）で表される化合物は、構成する原子の一つ又は複数で非天然の比率の原子同位体を含むこともある。原子同位体としては、例えば、重水素（２Ｈ)、トリチウム（３Ｈ)、ヨウ素－１２５、（１２５Ｉ）又は炭素－１４（１４Ｃ）などが挙げられる。これらの化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。一般式（Ｉ）で表される化合物のすべての同位体変種は、放射性であるかどうかにかかわらず、本発明の範囲内に含まれる。 The compound represented by the general formula (I) of the present invention may contain an unnatural ratio of atomic isotopes at one or more of the constituent atoms. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), and carbon-14 ( 14 C). These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variations of the compounds represented by general formula (I) are included within the scope of the present invention, whether radioactive or not.
　また、本発明には、本発明の化合物の薬理上許容されるプロドラッグも包含される。 The present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention.
　薬理上許容されるプロドラッグとは、加水分解により、若しくは、生理学的条件下で、本発明の化合物のアミノ基、水酸基、カルボキシル基等に変換し得る基を有する化合物であり、このようなプロドラッグを形成する基としては、Prog. Med.、第5巻、2157-2161ページ、1985年や、「医薬品の開発」（廣川書店、1990年）第7巻、分子設計163－198ページに記載の基である。当該プロドラッグとして、より具体的には、本発明の化合物に、アミノ基が存在する場合には、そのアミノ基がアシル化、アルキル化、りん酸化された化合物（例えば、そのアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物等である）等を挙げることができ、本発明の化合物に、水酸基が存在する場合には、その水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例えば、その水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等である。）等を挙げることができる。 A pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions. Drug-forming groups are described in Prog. Med., Volume 5, pages 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of. As the prodrug, more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated). Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert- In the case where a hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like.
　また、本発明の化合物に、カルボキシ基が存在する場合には、そのカルボキシ基がエステル化、アミド化された化合物（例えば、そのカルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、アミド化又はメチルアミド化された化合物等である。）等が挙げられる。
（製造法）
　一般式（Ｉ）に関する製造法を以下に例示する。式（Ｉ）で表される本発明の化合物は種々の方法により製造されるが、その好ましい例として代表的な製造法を次式に示し説明するが、これらに限定されるものではない。なお、反応に際しては必要に応じて置換基を保護基で保護して実施し、各置換基（官能基）の変換順序は特に限定されない。また、式中の化合物は、塩を形成している場合も含む。式中の化合物が市販されている場合には市販品をそのまま用いることもできる。
（製造法Ａ）
　製造法Ａは一般式（Ｉ）で表される化合物を製造する際に合成中間体として用いることのできる置換ピペリジンカルボン酸（Ａ２１）を製造する方法である。 In addition, when a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation or methylamidation compound, etc.).
(Production method)
The production method for the general formula (I) is exemplified below. The compound of the present invention represented by the formula (I) can be produced by various methods. As preferred examples, typical production methods are shown in the following formulas, but are not limited thereto. In the reaction, the substituent is protected with a protecting group as necessary, and the conversion order of each substituent (functional group) is not particularly limited. Moreover, the compound in a formula includes the case where the salt is formed. When the compound in the formula is commercially available, a commercially available product can be used as it is.
(Production method A)
Production method A is a method for producing a substituted piperidinecarboxylic acid (A21) that can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
［式中のＲ１～Ｒ４およびＸ１～Ｘ２は一般式（Ｉ）の置換基の定義と同様である。Ｒ５～Ｒ８は、水素原子、又は置換されていても良いアルキル、アルケニル、アルキニル、シクロアルキル基等を表す。Ｘ３は炭素原子または硫黄原子を表す。Ｚ１は、水素原子、シアノ基、アミノ基、又はアルコキシ基を表し、Ｚ２は水素原子、塩素原子、又はニトロ基を表す。Ｚ３およびＺ４はハロゲン原子（例えば、臭素原子、ヨウ素原子）を表す。Ｚ５は、ハロゲン原子（例えば、臭素原子、ヨウ素原子）、又は置換されていても良いアルキル、アルケニル、アルキニル、シクロアルキル、アルコキシ基等を表す。Ｐ１は、水素原子又はカルボキシ基の保護基を示し、具体的な保護基としてはメチル基、エチル基、ベンジル基、ｔｅｒｔ－ブチル基等が挙げられる。］
　工程（Ａ－１）は化合物（Ａ１）および（Ａ６）に対して、ピペリジン誘導体を作用させてＺ４との置換反応を行うことにより、化合物（Ａ２）および（Ａ４）を製造する工程である。反応の溶媒は、反応が進行する限り特に限定はされないが、Ｎ－メチルピロリドン、Ｎ，Ｎ－ジメチルアセトアミドが好ましい。 [Wherein R 1 to R 4 and X 1 to X 2 are the same as defined for the substituent of the general formula (I). R 5 to R 8 represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl group or the like. X 3 represents a carbon atom or a sulfur atom. Z 1 represents a hydrogen atom, a cyano group, an amino group, or an alkoxy group, and Z 2 represents a hydrogen atom, a chlorine atom, or a nitro group. Z 3 and Z 4 represent a halogen atom (for example, a bromine atom or an iodine atom). Z 5 represents a halogen atom (for example, bromine atom or iodine atom), or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy group or the like. P 1 represents a protecting group for a hydrogen atom or a carboxy group, and specific examples of the protecting group include a methyl group, an ethyl group, a benzyl group, and a tert-butyl group. ]
Step (A-1) is a step for producing compounds (A2) and (A4) by allowing a piperidine derivative to act on compounds (A1) and (A6) to carry out a substitution reaction with Z 4. . The solvent for the reaction is not particularly limited as long as the reaction proceeds, but N-methylpyrrolidone and N, N-dimethylacetamide are preferable.
　工程（Ａ－２）は化合物（Ａ２）における置換基Ｚ３に対して、パラジウム触媒存在下、ボロン酸やボロン酸エステルを作用させる（鈴木カップリンング）条件や、スズ化合物を作用させる（Stilleカップリング）条件、またはパラジウムおよび銅触媒存在下、末端アルキンを作用させる（薗頭反応）条件などによりＲ１に相当する置換基もしくはその前駆体となる置換基を導入する工程であり、化合物（Ａ３）を製造する工程である。また、化合物（Ａ５）における置換基Ｚ２に対して、同様な条件を用いてＺ５に相当する置換基もしくはその前駆体となる置換基を導入する工程であり、化合物（Ａ６）を製造する工程である。必要に応じてＲ１およびＺ５における保護基の脱保護や置換基の修飾を行う工程である。 In the step (A-2), a condition in which boronic acid or a boronic acid ester is allowed to act on the substituent Z 3 in the compound (A2) in the presence of a palladium catalyst (Suzuki coupling) or a tin compound is allowed to act (Stille A step of introducing a substituent corresponding to R 1 or a substituent serving as a precursor thereof under conditions such as coupling) or conditions in which a terminal alkyne is allowed to act in the presence of a palladium and copper catalyst (Sonogashira reaction). A3) is a process of manufacturing. Further, with respect to the substituent Z 2 in the compound (A5), a step of introducing a substituent or substituents which is a precursor thereof corresponding to Z 5 using similar conditions to produce the compound (A6) It is a process. This is a step of deprotecting the protecting group and modifying the substituent in R 1 and Z 5 as necessary.
　鈴木カップリンングの例として、Journal of Organic Chemistry, 68, 20, 2003, 7733-7741、Journal of Organic Chemistry, 70, 6, 2005, 2191-2194、Journal of Organic Chemistry, 68, 24, 2003, 9412-9415、Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718、 Tetrahedron, 66, 49, 2010, 9552-9559、Synthetic Communications, 30, 19, 2000, 3501-3510、Chemistry A European Journal, 12, 19, 2006, 5142-5148等に記載の方法に準じて行うことができる。 Examples of Suzuki coupling include Journal of Organic Chemistry, 68, 20, 2003, 7733-7741, Journal of Organic Chemistry, 70, 6, 2005, 2191-2194, Journal of Organic Chemistry, 68, 24, 2003, 9412 -9415, Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718, Tetrahedron, 66, 49, 2010, 9552-9559, Synthetic Communications, 30, 19, 2000, 3501-3510, Chemistry A European Journal, 12, 19 , 2006, 5142-5148, and the like.
　Stilleカップリングの例として、Angewandte Chemie, International Edition, 25, 6, 1986, 508-524、Tetrahedron Letters, 35, 19, 1994, 3195-3196、Synthesis, 1986 , 7, 564-565　等に記載の方法に準じて行うことができる。 Examples of Stille coupling include the methods described in Angewandte Chemie, International Edition, 25, 6, 1986, 508-524, Tetrahedron Letters, 35, 19, 1994, 3195-3196, Synthesis, 1986, 7, 564-565 etc. It can be performed according to.
　薗頭反応の例として、Chemical. Review, 107, 3, 2007, 874-922、Journal of Organic Chemistry, 68 , 9, 2003, 3736-3738、Organic Letters, 2, 12, 2000, 1729-1731. 等に記載の方法に準じて行うことができる。 Examples of Sonogashira reaction include Chemical. Review, 107, 3, 2007, 874-922, Journal of Organic Chemistry, 68, 9, 2003, 3736-3738, Organic Letters, 2, 12, 2000, 1729-1731. It can carry out according to the method as described in.
　工程（Ａ－３）はＺ２が水素原子の場合、化合物（Ａ３）に置換基Ｚ５を導入し化合物（Ａ４）を製造する工程である。化合物（Ａ３）をジクロロメタン中、求電子ハロゲン化物と反応させることによりハロゲン化した後、鈴木カップリンング条件や、スズ化合物を作用させるStilleカップリング条件、薗頭反応条件などによりＺ５に相当する置換基もしくはその前駆体となる置換基を導入する工程であり、工程（Ａ－２）と同様な方法を用いることができる。求電子ハロゲン化物としては、例えばＮ－ブロモスクシイミド、Ｎ－ヨードスクシイミドなどが挙げられる。 Step (A3) if Z 2 is a hydrogen atom, is a step for preparing the introduced compound substituent Z 5 in the compound (A3) (A4). Compound in dichloromethane (A3), was halogenated by reaction with an electrophilic halide, and Suzuki coupling loop ring condition, Stille coupling conditions for applying a tin compound, corresponding to Z 5 due Sonogashira reaction conditions This is a step of introducing a substituent or a substituent to be a precursor thereof, and the same method as in step (A-2) can be used. Examples of the electrophilic halide include N-bromosuccinimide and N-iodosuccinimide.
　工程（Ａ－４）はＸ２が炭素原子、Ｚ１がｔｅｒｔ－ブトキシ基の場合、化合物（Ａ４）に対してジクロロメタン中、トリフルオロ酢酸を作用させることにより脱保護を行う工程であり、化合物（Ａ７）を製造する工程である。 In the step (A-4), when X 2 is a carbon atom and Z 1 is a tert-butoxy group, the compound (A4) is deprotected by acting trifluoroacetic acid in dichloromethane. This is a process for manufacturing (A7).
　工程（Ａ－５）は化合物（Ａ７）に対して、ジメチルホルムアミド中、塩基存在下、ハロゲン化アルキルと反応させることによりアルキル化を行う工程であり、化合物（Ａ８）を製造する工程である。塩基としては、例えば炭酸カリウム、水素化ナトリウムなどが挙げられる。ハロゲン化アルキルとしては、例えばヨウ化メチル、アリルブロミド、３－ブロモ－２－メチルプロペン、クロチルブロミドなどが挙げられる。 Step (A-5) is a step of alkylating compound (A7) by reacting with alkyl halide in the presence of a base in dimethylformamide, and producing compound (A8). Examples of the base include potassium carbonate and sodium hydride. Examples of the alkyl halide include methyl iodide, allyl bromide, 3-bromo-2-methylpropene, crotyl bromide and the like.
　工程（Ａ－６）はＺ５がヨウ素原子の場合、化合物（Ａ８）に対して、パラジウム触媒存在下、Ｈｅｃｋ反応条件などを用いて分子内環化する工程であり、化合物（Ａ９）および（Ａ１０）を製造する工程である。Ｈｅｃｋ反応の例として、Chemical. Review, 100, 8, 2000, 3009-3066、Tetrahedron Letters, 45, 33, 2004, 6235-6237、Tetrahedron, 29, 37, 1988, 4687-4690、Tetrahedron Letters, 48, 13, 2007, 2307-2310等に記載の方法に準じて行うことができる。
工程（Ａ－７）はＸ２が炭素原子、Ｚ１がアミノ基の場合、化合物（Ａ４）に対して、分子内環化する工程であり、化合物（Ａ１１）を製造する工程である。必要に応じてＲ５における保護基の脱保護や置換基の修飾を行う工程である。 In the step (A-6), when Z 5 is an iodine atom, the compound (A8) is subjected to intramolecular cyclization using Heck reaction conditions in the presence of a palladium catalyst. A10). Examples of Heck reactions are Chemical. Review, 100, 8, 2000, 3009-3066, Tetrahedron Letters, 45, 33, 2004, 6235-6237, Tetrahedron, 29, 37, 1988, 4687-4690, Tetrahedron Letters, 48, 13, 2007, 2307-2310 and the like.
Step (A-7) is a step of intramolecular cyclization of compound (A4) when X 2 is a carbon atom and Z 1 is an amino group, and is a step of producing compound (A11). This is a step of deprotecting the protecting group and modifying the substituent in R 5 as necessary.
　工程（Ａ－８）は化合物（Ａ１２）に対して、ピペリジン誘導体を作用させてＺ４との置換反応を行った後、置換基Ｚ３に対して、Ｒ１に相当する置換基もしくはその前駆体となる置換基を導入する工程であり、化合物（Ａ１１）を製造する工程である。必要に応じてＲ５における保護基の脱保護や置換基の修飾を行う工程である。ピペリジン誘導体との反応は工程（Ａ－１）と同様な方法を用いることができ、置換基Ｚ３の変換は工程（Ａ－２）と同様な方法を用いることができる。 In the step (A-8), the compound (A12) is subjected to a substitution reaction with Z 4 by acting a piperidine derivative, and then the substituent corresponding to R 1 or a precursor thereof is substituted for the substituent Z 3 . This is a step of introducing a substituent that becomes a body, and a step of producing compound (A11). This is a step of deprotecting the protecting group and modifying the substituent in R 5 as necessary. The reaction with the piperidine derivative can use the same method as in step (A-1), and the conversion of substituent Z 3 can use the same method as in step (A-2).
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
［式中のＲ１～Ｒ４およびＸ１～Ｘ２は一般式（Ｉ）の置換基の定義と同様である。ｎは、１又は２である。Ｘ３は、窒素原子又は硫黄原子である。Ｒ７は、水素原子、臭素原子、メチル基、エチル基、又はビニル基であり、Ｒ８は、トリフルオロメチル基である。］
　工程（Ａ－９）は化合物（Ａ１３）および（Ａ１８）に対して、酸無水物などを作用させた後、ピペリジン誘導体を付加する工程であり、化合物（Ａ１４）および（Ａ１９）を製造する工程である。ピペリジン誘導体の付加反応は工程（Ａ－１）と同様な反応を用いることができる。 [Wherein R 1 to R 4 and X 1 to X 2 are the same as defined for the substituent of the general formula (I). n is 1 or 2. X 3 is a nitrogen atom or a sulfur atom. R 7 is a hydrogen atom, a bromine atom, a methyl group, an ethyl group, or a vinyl group, and R 8 is a trifluoromethyl group. ]
Step (A-9) is a step of adding a piperidine derivative after allowing an acid anhydride or the like to act on compounds (A13) and (A18), and producing compounds (A14) and (A19) It is. For the addition reaction of the piperidine derivative, the same reaction as in step (A-1) can be used.
　工程（Ａ－１０）は化合物（Ａ１４）に対して、置換基Ｒ７に相当する置換基もしくはその前駆体となる置換基を導入し化合物（Ａ１５）を製造する工程であり、工程（Ａ－３）と同様な方法を用いることができる。 Step (A-10) is a step of producing compound (A15) by introducing a substituent corresponding to substituent R 7 or a substituent serving as a precursor thereof into compound (A14). A method similar to 3) can be used.
　工程（Ａ－１１）はジクロロメタン中、塩基存在下、化合物（Ａ１７）に化合物（Ａ１６）を反応させた後、環化縮合する工程であり、化合物（Ａ１８）を製造する工程である。必要に応じてマイクロウェーブ反応装置を用いることができる。塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。 Step (A-11) is a step of reacting compound (A16) with compound (A17) in the presence of a base in dichloromethane, followed by cyclization condensation, and producing compound (A18). A microwave reactor can be used if necessary. Examples of the base include triethylamine and diisopropylethylamine.
　工程（Ａ－１２）は化合物（Ａ２０）における保護基Ｐ１を脱保護する工程であり、化合物（Ａ２１）を製造する工程である。化合物（Ａ２０）は製造法Ａにおける化合物群（Ａ３、Ａ４、Ａ８、Ａ９，Ａ１０，Ａ１１、Ａ１４、Ａ１５、Ａ１９）の概略を表し、化合物（Ａ２１）は製造法Ａにおける置換ピペリジンカルボン酸の概略を表す。本反応は保護基Ｐ１の種類により変わるが、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。
（製造法Ｂ）
　製造法Ｂは式（Ｉ）で表される化合物を製造する際に合成中間体として用いることのできる置換アミン（Ｂ８）を製造する方法である。 Step (A-12) is a step of deprotecting protecting group P 1 in compound (A20), and is a step of producing compound (A21). Compound (A20) represents the outline of the compound group (A3, A4, A8, A9, A10, A11, A14, A15, A19) in Production Method A, and Compound (A21) represents the outline of the substituted piperidinecarboxylic acid in Production Method A. Represents. Although this reaction varies according to the kind of the protecting group P 1, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" can be carried out according to the method described in.
(Production method B)
Production method B is a method for producing a substituted amine (B8) that can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
［Ｐ１は上記の定義と同様である。Ｘａは酸素原子またはＮＨを表し、Ｙ１は置換基Ｙの前駆体または置換基Ｙそのものを表す。Ｒ９は、水素原子、または置換されていても良いアルキルアルケニル、アルキニル、シクロアルキル基等を表す。Ｒ１０、Ｒ１１は、水素原子、または置換されていてもよいアルキル、アルケニル、アルキニル、シクロアルキル、－ＣＨ２ＣＨ２－基等を表す。］
　Ｐ2およびＰ３はアミノ基の保護基あるいは水素を示し、具体的な保護基としてはＢｏｃ基（ｔｅｒｔ－ブトキシカルボニル基）、Ｃｂｚ基（ベンジルオキシカルボニル基）、ベンジリデン基、ジフェニルメチレン基等が挙げられる。Ｐ２がベンジルリデン基、ジフェニルメチレン基の場合にはＰ３はＰ２と同一保護基を示す。各工程は必要に応じて置換基の保護や保護基の脱保護を行う工程を含む。 [P 1 are as defined above. X a represents an oxygen atom or NH, and Y 1 represents a precursor of the substituent Y or the substituent Y itself. R 9 represents a hydrogen atom or an optionally substituted alkylalkenyl, alkynyl, cycloalkyl group or the like. R 10 and R 11 represent a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, —CH 2 CH 2 — group or the like. ]
P 2 and P 3 each represent an amino protecting group or hydrogen, and specific protecting groups include Boc group (tert-butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), benzylidene group, diphenylmethylene group and the like. Can be mentioned. When P 2 is a benzylidene group or a diphenylmethylene group, P 3 represents the same protecting group as P 2 . Each step includes a step of protecting the substituent and deprotecting the protecting group as necessary.
　工程（Ｂ－１）は化合物（Ｂ１）に対して、適当な縮合剤および塩基の存在下、アミノ基を有する化合物または水酸基を有する化合物と縮合する工程であり、化合物（Ｂ２）を製造する工程である。必要に応じて反応を促進する添加剤を加える。縮合剤としては、例えばＷＳＣ（すなわち、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド），ＤＣＣ（すなわち、１，３－ジシクロヘキシルカルボジイミド）、ＤＭＴ－ＭＭ（すなわち、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド）、ＣＤＩ（すなわち、１，１´－カルボニルジイミダゾール）、ＤＥＰＣ（すなわち、ジエチル　ホスホロシアニドエート）、ＤＰＰＡ（すなわち、ジフェニルホスホロアジドエート）などが挙げられる。塩基としては、ピリジン、ルチジンなどの芳香族アミン類やトリエチルアミン、ジイソプロピルエチルアミン、ＤＭＡＰ（４－ジメチルアミノピリジン）などの３級アミン類などが挙げられる。添加剤の代表的な例として、ＨＯＡｔ（３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－３－オール）、ＨＯＢｔ（１Ｈ－ベンゾトリアゾール－１－オール）、ＨＯＳｕ（Ｎ－ヒドロキシスクシイミド）などが挙げられる。反応の溶媒は、反応が進行する限り特に限定はされないが、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミドが好ましい。 Step (B-1) is a step of condensing compound (B1) with a compound having an amino group or a compound having a hydroxyl group in the presence of an appropriate condensing agent and a base, and a step of producing compound (B2) It is. Add additives to accelerate the reaction if necessary. Examples of the condensing agent include WSC (ie, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), DCC (ie, 1,3-dicyclohexylcarbodiimide), DMT-MM (ie, 4- (4,6 -Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), CDI ( ie 1,1′-carbonyldiimidazole), DEPC (ie diethyl phosphorocyanide) DPPA (that is, diphenylphosphoroazideate) and the like can be mentioned. Examples of the base include aromatic amines such as pyridine and lutidine, and tertiary amines such as triethylamine, diisopropylethylamine, and DMAP (4-dimethylaminopyridine). Representative examples of additives include HOAt (3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol), HOBt (1H-benzotriazol-1-ol), HOSu (N -Hydroxysuccinimide) and the like. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but dichloromethane and N, N-dimethylformamide are preferable.
　工程（Ｂ－２）は化合物（Ｂ１）に対して、適当な還元剤を作用させて、化合物（Ｂ３）を製造する工程である。この際、直接還元剤を反応させても良いが、一旦、適当なアシル化剤を作用させ酸無水物へと変換した後に還元しても良い。還元剤としては、ボラン、ホウ酸水素ナトリウムなどが挙げられる。 Step (B-2) is a step of producing compound (B3) by allowing a suitable reducing agent to act on compound (B1). At this time, the reducing agent may be reacted directly, but it may be reduced after once converted to an acid anhydride by the action of an appropriate acylating agent. Examples of the reducing agent include borane and sodium hydrogen borate.
　工程（Ｂ－３）は化合物（Ｂ３）に対して、水酸基を適当な脱離基へと変換した後、シアノ基へと置換する工程であり、化合物（Ｂ４）を製造する工程である。脱離基としては、例えばメチルスルホニルオキシ基、ｐ－トルエンスルホニルオキシ基、ハロゲン原子などが挙げられる。 Step (B-3) is a step of converting compound (B3) into a suitable leaving group and then substituting it with a cyano group, which is a step of producing compound (B4). Examples of the leaving group include a methylsulfonyloxy group, a p-toluenesulfonyloxy group, and a halogen atom.
　工程（Ｂ－４）は化合物（Ｂ４）に対して、酸性条件下シアノ基を加水分解した後、得られたカルボキシ基を保護する工程であり、化合物（Ｂ５）を製造する工程である。必要に応じて、アミノ基を再度保護する工程を含む。本反応は保護基Ｐ１～Ｐ３の種類により変わるが、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。 Step (B-4) is a step of hydrolyzing the cyano group under acidic conditions with respect to compound (B4) and then protecting the resulting carboxy group, which is a step of producing compound (B5). If necessary, it includes a step of protecting the amino group again. This reaction varies depending on the type of the protecting groups P 1 to P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
　保護基Ｐ１がエチル基の場合、エタノール中において塩化チオニルなどが用いられる。 When the protecting group P 1 is an ethyl group, thionyl chloride or the like is used in ethanol.
　保護基Ｐ２がＢｏｃ基の場合、塩基存在下においてジ－ｔｅｒｔ－ブチル　ジカーボネートなどが用いられる。塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸水素カリウム、トリエチルアミンなどが用いられる。 When the protecting group P 2 is a Boc group, di-tert-butyl dicarbonate or the like is used in the presence of a base. As the base, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
　保護基Ｐ２がＣｂｚ基の場合、塩基の存在下において、ベンジル　クロロホルメートまたはＮ－（ベンジルオキシカルボニルオキシ）スクシイミドが用いられる。塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸水素カリウム、トリエチルアミンなどが用いられる。 When the protecting group P 2 is a Cbz group, benzyl chloroformate or N- (benzyloxycarbonyloxy) succinimide is used in the presence of a base. As the base, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, triethylamine and the like are used.
　保護基Ｐ２、Ｐ３がベンジリデン基の場合、反応剤として無水硫酸ナトリウムまたは無水硫酸マグネシウム存在下、ベンズアルデヒドが用いられる。反応の溶媒は、反応が進行する限り特に限定はされないが、ベンゼン、トルエン、ジクロロメタンなどが用いられる。 When the protecting groups P 2 and P 3 are benzylidene groups, benzaldehyde is used in the presence of anhydrous sodium sulfate or anhydrous magnesium sulfate as a reactant. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
　保護基Ｐ２、Ｐ３がジフェニルメチレン基の場合、反応剤としてベンゾフェノンイミンが用いられる。必要に応じて塩基を用いることができる。反応の溶媒は、反応が進行する限り特に限定はされないが、ベンゼン、トルエン、ジクロロメタンなどが用いられる。
工程（Ｂ－５）は化合物（Ｂ５）に対して、段階的にアルキル化を行う工程であり、化合物（Ｂ６）を製造する工程である。 When the protecting groups P 2 and P 3 are diphenylmethylene groups, benzophenone imine is used as a reactant. A base can be used as necessary. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but benzene, toluene, dichloromethane and the like are used.
Step (B-5) is a step of alkylating compound (B5) stepwise, and is a step of producing compound (B6).
　工程（Ｂ－６）は化合物（Ｂ７）に対して、保護基Ｐ２およびＰ３を脱保護する工程であり、化合物（Ｂ８）を製造する工程である。化合物（Ｂ７）は製造法Ｂにおける化合物群（Ｂ２、Ｂ５、Ｂ６）の概略を表し、化合物（Ｂ８）は製造法Ｂにおける置換アミンの概略を表す。本反応は保護基Ｐ２およびＰ３の種類により変わるが、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の方法に準じて行うことができる。 Step (B-6) is a step of deprotecting protecting groups P 2 and P 3 from compound (B7), and is a step of producing compound (B8). The compound (B7) represents the outline of the compound group (B2, B5, B6) in the production method B, and the compound (B8) represents the outline of the substituted amine in the production method B. This reaction varies depending on the types of protecting groups P 2 and P 3 , and can be performed, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts. it can.
　保護基Ｐ２がＢｏｃ基の場合、反応剤としては塩酸のジオキサン溶液または酢酸エチル溶液を用いることができる。必要に応じて、メタノール、エタノール、テトラヒドロフランを加えても良い。 When the protecting group P 2 is a Boc group, a dioxane solution or an ethyl acetate solution of hydrochloric acid can be used as a reactant. You may add methanol, ethanol, and tetrahydrofuran as needed.
　保護基Ｐ２がＣｂｚ基およびジフェニルメチレン基の場合、水素雰囲気下、パラジウム炭素または水酸化パラジウムを用いることができる。反応の溶媒は、反応が進行する限り特に限定されないが、メタノール、エタノール、テトラヒドロフランが好ましい。
保護基Ｐ２、Ｐ３がベンジリデン基の場合、希塩酸を用いることができる。反応の溶媒は、反応が進行する限り特に限定されないが、メタノール、エタノールが好ましい。
（製造法Ｃ）
　製造法Ｃは製造法Ａで得た化合物（Ａ２１）と製造法Ｂで得た置換アミン（Ｂ８）を縮合し、式（Ｉ）で示される目的化合物を製造する工程である。 When the protective group P 2 is a Cbz group or a diphenylmethylene group, palladium carbon or palladium hydroxide can be used in a hydrogen atmosphere. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but methanol, ethanol, and tetrahydrofuran are preferable.
When the protecting groups P 2 and P 3 are benzylidene groups, dilute hydrochloric acid can be used. The solvent for the reaction is not particularly limited as long as the reaction proceeds, but methanol and ethanol are preferable.
(Production method C)
Production method C is a step in which the compound (A21) obtained by production method A and the substituted amine (B8) obtained by production method B are condensed to produce the target compound represented by formula (I).
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
［式中のＲ１～Ｒ４、Ｘ１～Ｘ２、Ｙ１およびＹは上記の置換基の定義と同様である。］
　工程（Ｃ－１）は化合物（Ａ２１）に対して、種々の縮合剤および塩基の存在下、置換アミン（Ｂ８）を作用させて化合物（Ｃ１）を製造する工程であり、工程（Ｂ－１）と同様の方法を用いることができる。 [Wherein R 1 to R 4 , X 1 to X 2 , Y 1 and Y are the same as defined above for the substituent. ]
Step (C-1) is a step of producing compound (C1) by reacting compound (A21) with substituted amine (B8) in the presence of various condensing agents and bases. ) Can be used.
　工程（Ｃ－２）は化合物（Ｃ１）における置換基Ｙ１の修飾を行う工程であり、加水分解反応、アミド化反応、公知の脱保護反応、酸化反応、アシル化反応、スルホニル化反応、ヘテロ環形成反応、水素添加反応、アルキル化反応、還元反応、炭素鎖延長反応、置換基交換反応を単独あるいはその二つ以上を組み合わせることにより、化合物（Ｉ）を製造する工程である。必要に応じてＲ１～Ｒ４における保護基の脱保護を行うことができる。 Step (C-2) is a step of modifying the substituent Y 1 in the compound (C1). Hydrolysis reaction, amidation reaction, known deprotection reaction, oxidation reaction, acylation reaction, sulfonylation reaction, heterozygote In this step, compound (I) is produced by a ring formation reaction, a hydrogenation reaction, an alkylation reaction, a reduction reaction, a carbon chain extension reaction, or a substituent exchange reaction, either alone or in combination. If necessary, the protecting groups in R 1 to R 4 can be deprotected.
　経口用の医薬組成物の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている賦形剤、結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、希釈剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.
　非経口用の医薬組成物の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤、吸入剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている安定化剤、防腐剤、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、溶解補助剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. The preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives. Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
　一般式（Ｉ）を有する化合物又はその薬理上許容される塩の投与量は、症状、年齢、体重、組み合わせて投与する薬剤の種類や投与量等によって異なるが、通常、一般式（Ｉ）を有する化合物の換算量で、成人一人（体重約６０ｋｇとして）一回につき０．００１ｍｇ～１０００ｍｇの範囲で、全身的又は局所的に、一日一回から数回、経口又は非経口投与されるか、或いは一日１時間～２４時間の範囲で静脈内に持続投与されるのが好ましい。 The dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, body weight, type of drug to be administered in combination, dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), or once or several times a day, orally or parenterally, in the equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.
　さらに、本発明の医薬組成物には、本発明の効果を損なわない範囲において、必要に応じ、その他の有効成分を併用して用いることができる。 Furthermore, the pharmaceutical composition of the present invention can be used in combination with other active ingredients as necessary within the range not impairing the effects of the present invention.
　本発明には、本発明化合物又はその薬理上許容される塩を投与することを特徴とする前記疾患の防止方法及び／又は治療方法も含まれる。
さらに、本発明には、前記医薬組成物を製造するための本発明化合物、その薬理上許容される塩の使用も含まれる。
［製剤例］
（製剤例１）散剤
本発明の化合物５ｇ、乳糖８９５ｇおよびトウモロコシデンプン１００ｇをブレンダーで混合することにより、散剤を得る。
（製剤例２）顆粒剤
本発明の化合物５ｇ、乳糖８６５ｇおよび低置換度ヒドロキシプロピルセルロース１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液３００ｇを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥して顆粒剤を得る。
（製剤例３）錠剤
本発明の化合物５ｇ、乳糖９０ｇ、トウモロコシデンプン３４ｇ、結晶セルロース２０ｇおよびステアリン酸マグネシウム１ｇをブレンダーで混合した後、錠剤機で打錠することにより、錠剤を得る。
［試験例１］炎症組織中プロスタグランジン類産生評価
Opasらの報告を参考に実施した ( Opas EE, Dallob A, Herold E, Luell S and Humes JL. Pharmacological modulation of eicosanoid levels and hyperalgesia in yeast-induced inflammation. Biochem Pharmacol. 1987.36:547-551)。流動パラフィンに懸濁したMycobacterium Butyricum死菌体を超音波処理した後に、5または6週齢の雄性Lewisラット右側後足蹠皮内に0.05 ml注射した(100 ug/paw)。処置後19日目にラットを屠殺し、左足組織（非処置足）を回収して液体窒素で瞬間冷凍した後に粉砕し、Indomethacin, EDTAを含んだPBSを加えホモジナイズした。ホモジナイズ上清中のPGE2, PGF1a (PGI2の安定代謝物)およびTXB2 (TXA2の安定代謝物)量をCayman Chemical製のEIAキットを用いて定量した。 The present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof.
Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.
[Formulation example]
(Formulation Example 1) Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender.
(Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
(Formulation Example 3) Tablet After mixing 5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate with a blender, the tablet is obtained by tableting with a tablet machine.
[Test Example 1] Evaluation of prostaglandin production in inflamed tissues
It was carried out with reference to the report of Opas et al. (Opas EE, Dallob A, Herold E, Luell S and Humes JL. Pharmacological modulation of eicosanoid levels and hyperalgesia in yeast-induced inflammation. Biochem Pharmacol. 1987.36: 547-551) After sonicating dead Mycobacterium Butyricum cells suspended in liquid paraffin, 0.05 ml was injected into the right hind footpad of male Lewis rats at 5 or 6 weeks of age (100 ug / paw). On the 19th day after the treatment, the rats were sacrificed, the left paw tissue (untreated paw) was collected, snap-frozen with liquid nitrogen and then crushed, and PBS containing Indomethacin and EDTA was added and homogenized. The amounts of PGE 2 , PGF 1a (stable metabolite of PGI 2 ) and TXB 2 (stable metabolite of TXA 2 ) in the homogenized supernatant were quantified using an EIA kit manufactured by Cayman Chemical.
　
　本願実施例３１の化合物は、図１に示すように、０．１～３０ｍｇ／ｋｇの経口投与により炎症組織中のPGE2産生に対し用量依存的な抑制効果を示した。
［試験例２］A549細胞プロスタノイド産生阻害評価
　A549細胞プロスタノイド産生阻害アッセイはStaffan ThoreAnらの報告を参考に実施した（European Journal of Biochemistry、（2000）267、6428-6434）。10%FBS添加DMEMで懸濁したA549細胞を25000細胞/0.1 mL/ウェル播種し、37°C、 5%CO2条件下で一晩培養した。血清無添加DMEMを用いて細胞を1回洗浄後、血清無添加DMEMで希釈した化合物を0.09 mL/ウェル添加後、1時間培養した。10 ng/mL ヒトIL-1betaを0.01 mL/ウェル添加後、一晩培養した（IL-1betaの終濃度 1 ng/mL）。回収した培養上清中のPGE2濃度は市販のELISAにて測定した。
As shown in FIG. 1, the compound of Example 31 of the present application showed a dose-dependent inhibitory effect on PGE 2 production in inflamed tissues by oral administration of 0.1 to 30 mg / kg.
[Test Example 2] Evaluation of inhibition of A549 cell prostanoid production The A549 cell prostanoid production inhibition assay was performed with reference to the report of Staffan ThoreAn et al. (European Journal of Biochemistry, (2000) 267, 6428-6434). A549 cells suspended in DMEM supplemented with 10% FBS were seeded at 25000 cells / 0.1 mL / well and cultured overnight at 37 ° C. and 5% CO 2 . After washing the cells once with serum-free DMEM, 0.09 mL / well of a compound diluted with serum-free DMEM was added, followed by incubation for 1 hour. After adding 10 ng / mL human IL-1beta to 0.01 mL / well, the cells were cultured overnight (final concentration of IL-1beta: 1 ng / mL). The PGE 2 concentration in the collected culture supernatant was measured by a commercially available ELISA.
　表１に示すように、本願実施例の化合物はA549細胞からのPGE2産生に対し、優れた抑制効果を示した。
［試験例３］ラットマクロファージプロスタノイド産生評価
　ラットマクロファージプロスタノイド産生アッセイは松本らの報告を参考に実施した（Biochemical and Biophysical Research Communications、（1996）230、110-114）。ラット腹腔に5% Peptone、5% Starchを投与して3-4日後に、腹腔内液に浸潤する細胞を10%FBS添加RPMI-1640で回収して腹腔マクロファージを調製した。調整したマクロファージにアスピリンを終濃度で0.1 mM添加後、96 well プレートに200000細胞/0.1 mL/well 添加し、37°C、5% CO2 条件下で2 時間培養後、RPMI-1640 で2 回洗浄して非付着細胞を除いた。10%FBS添加RPMI-1640 を0.15 mL、4 倍濃度化合物0.05 mL を添加して、37°C、5% CO2条件下で1 時間培養した。その後、LPSを0.005 mL（終濃度 0.01 mg/mL）添加し、37°C、5% CO2条件下で24 時間培養した。翌日に培養上清を200 μL 回収してPGE2 などのプロスタノイドを定量した。 As shown in Table 1, the compounds of the examples of the present application showed an excellent inhibitory effect on PGE 2 production from A549 cells.
[Test Example 3] Evaluation of rat macrophage prostanoid production The rat macrophage prostanoid production assay was performed with reference to a report by Matsumoto et al. (Biochemical and Biophysical Research Communications, (1996) 230, 110-114). 3-4 days after 5% Peptone and 5% Starch were administered to the rat abdominal cavity, cells infiltrating the intraperitoneal fluid were recovered with RPMI-1640 supplemented with 10% FBS to prepare peritoneal macrophages. After adding 0.1 mM of aspirin to the prepared macrophages at a final concentration, add 200,000 cells / 0.1 mL / well to a 96-well plate, incubate for 2 hours at 37 ° C and 5% CO 2 , and then twice with RPMI-1640 Wash to remove non-adherent cells. RPMI-1640 supplemented with 10% FBS was added at 0.15 mL and 0.05 mL of a 4-fold concentration compound, and cultured at 37 ° C. under 5% CO 2 for 1 hour. Thereafter, 0.005 mL (final concentration 0.01 mg / mL) of LPS was added, and the cells were cultured for 24 hours at 37 ° C. and 5% CO 2 . On the next day, 200 μL of the culture supernatant was collected, and prostanoids such as PGE 2 were quantified.
　表１に示すように、本願実施例の化合物はラットマクロファージからのPGE2産生に対し、優れた抑制効果を示した。また、本願発明の化合物のTXB2産生に対するIC50値は、いずれも1000 ng/mL以上であり、PGE2産生を選択的に抑制していることが示された。 As shown in Table 1, the compounds of the examples of the present application showed an excellent inhibitory effect on PGE 2 production from rat macrophages. In addition, the IC 50 values for TXB 2 production of the compounds of the present invention were all 1000 ng / mL or more, indicating that PGE 2 production was selectively suppressed.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
（参考例１）
（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸　および
（１Ｒ，３Ｒ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸
　ＰＣＴ　ＷＯ２００８／０７５１９６出願明細書記載のトランス－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸（１２０ｇ）を用いて超臨海流体クロマトグラフィー（ダイセル　キラルパックＡＤ－Ｈ、二酸化炭素／メタノール＝７５：２５）にて光学分割を行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、標記化合物（５６．７ｇ，光学純度　＞９８％ｅｅ）を固体として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、標記化合物（５５．４ｇ，光学純度　＞９８％ｅｅ）を固体として得た。
（参考例２）ベンジル　［（１Ｒ，３Ｒ）－３－｛［（１Ｓ）－１－フェニルエチル］カルバモイル｝シクロヘキシル］カーバメート
　参考例１で得られた第一ピーク（３００ｍｇ，１．０８ｍｍｏｌ）のジクロロメタン（１１ｍＬ）溶液に、３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－３－オール（２９４ｍｇ，２．１６ｍｍｏｌ）、（１Ｓ）－１－フェニルエタンアミン（１３８μＬ，１．０８ｍｍｏｌ）、１－エチル－３－(３－ジメチルアミノプロピル) カルボジイミド　塩酸塩（４１４ｍｇ，２．１６ｍｍｏｌ）、およびトリエチルアミン（０．４５２ｍＬ，３．２４ｍｍｏｌ）を加え、室温にて２０時間攪拌した。反応混合物に水を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０－０／１００）にて精製し、標記化合物３９４ｍｇ（収率９６％）を固体として得た。得られた固体を用いてイソプロピルアルコール溶媒から結晶化を行った。得られた結晶を用いてＸ線結晶構造解析によって絶対立体構造を決定した。絶対立体配置は（１Ｓ）－１－フェニルエタンアミンの立体配置を基に（１Ｒ，３Ｒ）であると決定した。よって、参考例１で得られた第二ピークの絶対立体配置は（１Ｓ，３Ｓ）であると決定した。
（参考例３）ベンジル　［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］カーバメート
　参考例１で得られた第二ピーク（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸（１０．５ｇ，３７．９ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、氷冷下、市販の１，１’－カルボニルジイミダゾール（７．３７ｇ，４５．５ｍｍｏｌ）を加え、２時間攪拌した。氷冷下、反応混合物に市販のエチルアミン（２．０Ｍ　テトラヒドロフラン溶液，５０ｍＬ，１００ｍｍｏｌ）を加え、室温にて１５時間攪拌した。反応液を減圧濃縮した後、酢酸エチルにて希釈した。反応混合物を１Ｎ塩酸水溶液、水および飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物１１．９ｇを得た。
（参考例４）（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミド
　参考例３で得られたベンジル　［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］カーバメート（１１．９ｇ，３７．９ｍｍｏｌ相当）のエタノール（８０ｍＬ）溶液に、市販の１０％パラジウム炭素（１．９７ｇ）を加え、水素雰囲気下、室温にて５時間攪拌した。反応混合物をセライトろ過した後、減圧下にて溶媒を留去し、標記化合物６．７３ｇを定量的に固体として得た。
（参考例５）ベンジル　［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］カーバメート
　参考例１で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸および市販のアンモニア水を用いて、参考例３の方法に準じて標記化合物（収率１００％）を固体として得た。
（参考例６）（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩
　参考例５で得られたベンジル　［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］カーバメート（３．００ｇ，１０．９ｍｏｌ）のエタノール（１００ｍＬ）溶液に、市販の１０％パラジウム炭素（３００ｍｇ）を加え、水素雰囲気下、室温にて２．５時間攪拌した。反応混合物をセライトろ過した後、減圧下にて溶媒を留去した。得られた残渣に１Ｎ塩酸エタノール溶液を加えて懸濁させた後、減圧下にて溶媒を留去した。得られた残渣を乾燥し、標記化合物１．９５ｇ（収率９７％）を固体として得た。
（参考例７）メチル　（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキシレート　塩酸塩
　参考例１で得られた（１Ｓ，３Ｓ）－３－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロヘキサンカルボン酸およびメタノールを用いて、参考例３の方法に準じて固体（収率９２％）を得た。得られた固体を用いて、参考例４の方法に準じて標記化合物（収率７２％）を固体として得た。
（参考例８）エチル　（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）アセテート
　Ｉｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ（１９８０）， １０，２３７４－２３７９．記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩（５．６０ｇ，２５．３ｍｍｏｌ）に飽和炭酸水素ナトリウム水溶液を用いて中和し、クロロホルムにて抽出した。さらに水層に０．１Ｎ水酸化ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を合わせ飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣を乾燥し油状物３．５０ｇを得た。得られた油状物（１．８０ｇ，９．７２ｍｍｏｌ）のメタノール（４９ｍＬ）溶液に、無水硫酸ナトリウム（９．００ｇ）およびベンズアルデヒド（０．９８ｍＬ，９．７ｍｍｏｌ）を加えて室温にて１６時間攪拌した。反応混合物をろ過し、減圧下にて溶媒を留去し、標記化合物を得た。
（参考例９）エチル　２－メチル－２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエート
　窒素雰囲気下、１．１４Ｍリチウムジイソプロピルアミドのテトラヒドロフラン溶液（０．３５３ｍＬ，０．４０２ｍｍｏｌ）に、ドライアイス－メタノールで冷却下、参考例８で得られたエチル　（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）アセテート（５０．０ｍｇ，０.１８３ｍｍｏｌ）のテトラヒドロフラン溶液（０．９２ｍＬ）を加えた。氷冷下、２０分間撹拌した後、再びドライアイス－メタノールにて冷却した。ヨウ化メチル（３４μＬ，０.５５ｍｍｏｌ）およびヘキサメチルリン酸トリアミド（７０μＬ，０.４０ｍｍｏｌ）のテトラヒドロフラン溶液（０．９２ｍＬ）を加え、室温にて２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した後、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し得られた残渣に対して、同様な反応条件を用いて再度メチル化反応を行うことにより、標記化合物を定量的に得た。
（参考例１０）エチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエート
　参考例９で得られたエチル　２－メチル－２－（シス－４－｛［（１Ｅ）－フェニルメチレン］アミノ｝シクロヘキシル）プロパノエート（６．５１ｇ，２０．５ｍｍｏｌ相当）のジクロロメタン（６８ｍＬ）溶液に、氷冷下、トリフルオロ酢酸（２．３５ｍｌ，３０．７ｍｍｏｌ）を加えて室温で２時間攪拌した。減圧下にて溶媒を留去した後、市販の４Ｎ塩酸－酢酸エチル（１０ｍｌ）を加えて再び減圧下にて溶媒を留去した。水を加えてトルエンにて洗浄後、４Ｎ水酸化ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去し、標記化合物４．０２ｇ（収率９２％）を得た。
（参考例１１）エチル　１－（３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　ＰＣＴ　ＷＯ２００６／０２５７８３出願明細書記載のエチル　１－（３－ブロモピリジン－２－イル）ピペリジン－４－カルボキシレート（９８０ｍｇ，，３．１３ｍｍｏｌ）およびフェニルボロン酸（５６３ｍｇ，６．２６ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液に、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド　ジクロロメタン錯体（１：１）（１３０ｍｇ，０．１６ｍｍｏｌ）およびリン酸カリウム（２．１０ｇ，９．３９ｍｍｏｌ）を加え、アルゴン雰囲気下、２０時間加熱還流した。反応混合物に酢酸エチルを加え、不溶物をセライトろ過した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）により精製し、標記化合物９１１ｍｇ（収率９４％）を固体として得た。
（参考例１２）エチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１１で得られたエチル　１－（３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（２５０ｍｇ，０．８１ｍｍｏｌ）のジクロロメタン（６ｍＬ）溶液に、氷冷下、Ｎ－ブロモスクシンイミド（１４３ｍｇ，０．８１ｍｍｏｌ）を加えた後、室温にて３時間攪拌した。反応混合物に水を加え、ジクロロメタンにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）により精製し、標記化合物３００ｍｇ（収率９６％）を固体として得た。
（参考例１３）１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボン酸
　参考例１２で得られたエチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（８７ｍｇ，０．２２ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）およびエタノール（２ｍＬ）の混合溶液に、１Ｎ水酸化ナトリウム水溶液（１ｍＬ）を加え、室温にて１３時間攪拌した。反応混合物に１Ｎ塩酸水溶液を加えた後、減圧濃縮した。得られた残渣に水を加え、ジクロロメタンにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、標記化合物を得た。
参考例（１４）エチル　１－（３－フェニル－５－ビニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１２で得られたエチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（２３８ｍｇ，０．６１ｍｍｏｌ）のトルエン（６ｍＬ）溶液に、市販のトリ－ｎ－ブチル（ビニル）スズ（３６８μＬ，１．２２ｍｍｏｌ）およびテトラキス（トリフェニルホスフィン）パラジウム（０）（７１ｍｇ，０．０６ｍｍｏｌ）を加え、アルゴン雰囲気下、９０℃にて２３時間加熱攪拌した。反応混合物を減圧濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－１７／３）により精製し、標記化合物１４６ｍｇ（収率７１％）を得た。
（参考例１５）エチル　１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１４で得られたエチル　１－（３－フェニル－５－ビニルピリジン－２－イル）ピペリジン－４－カルボキシレート（１０８ｍｇ，０．３２ｍｍｏｌ）のエタノール（６ｍＬ）溶液に、１０％パラジウム炭素（５０％水分，５０ｍｇ）を加え、水素雰囲気下、室温にて１６時間攪拌した。１０％パラジウム炭素（５０％水分，３０ｍｇ）を追加し、さらに２６時間攪拌した。反応混合物をセライトろ過した後、エタノールにて洗浄した。減圧下にて溶媒を留去し、標記化合物１０６ｍｇ（収率９８％）を得た。
（参考例１６）エチル　１－（３－フェニル－５－プロプ－１－イン－１－イルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１２で得られたエチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（２５０ｍｇ，０．６４ｍｍｏｌ）のテトラヒドロフラン（３．２ｍＬ）溶液に、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（４５ｍｇ，０．０６ｍｍｏｌ）、ヨウ化銅（Ｉ）（２４ｍｇ，０．１３ｍｍｏｌ）、ジイソプロピルエチルアミン（４４３μＬ，２．５７ｍｍｏｌ）および１Ｍフッ化テトラ－ｎ－ブチルアンモニウムを加えた後、さらにトリメチル－プロプ－１－イニルシラン（２８５μＬ，１．９３ｍｍｏｌ）を滴下した。反応系内を窒素置換した後、９０℃にて３０分間マイクロウェーブ照射した。反応混合物に酢酸エチルを加え、不溶物をセライトろ過により除去した。ろ液を水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物１６０ｍｇ（収率７２％）を得た。
（参考例１７）エチル　１－（３－ブロモ－５－クロロピリジン－２－イル）ピペリジン－４－カルボキシレート
　市販の３－ブロモ－２，５－ジクロロピリジン（１．８７ｇ，８．２４ｍｍｏｌ）のＮ－メチルピロリドン（４ｍＬ）溶液に、氷冷下、市販のエチル　４－ピペリジンカルボキシレート（３．８１ｍＬ，２４．７ｍｍｏｌ）を滴下した後、１２０℃に昇温し、４時間加熱攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物２．４７ｇ（収率８６％）を得た。
（参考例１８）エチル　１－（６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　Ｔｅｔｒａｈｅｄｒｏｎ　（１９９０），４６（１６），５７１５－５７３２に記載の６－クロロ－５－フェニルピリジン－２－カルボニトリルおよび市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて標記化合物（収率８７％）を固体として得た。
（参考例１９）エチル　１－（５－ブロモ－６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１８で得られたエチル　１－（６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（３４４ｍｇ，１．０３ｍｍｏｌ）のジクロロメタン（５ｍＬ）およびエタノール（５ｍＬ）混合溶液に、氷冷下、テトラ－ｎ－ブチルアンモニウムトリブロミド（７４２ｍｇ，１．５４ｍｍｏｌ）を加えた後、室温にて６時間攪拌した。反応混合物にテトラ－ｎ－ブチルアンモニウムトリブロミド（７４２ｍｇ，１．５４ｍｍｏｌ）を追加し、室温にて１４時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液水を加え、ジクロロメタンにて抽出後した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物２１２ｍｇ（収率５０％）を得た。
（参考例２０）エチル　１－（５－ニトロ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　市販の３－ブロモ－２－クロロ－５－ニトロピリジンおよび市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて油状物（収率１００％）を得た。得られた油状物およびフェニルボロン酸を用いて、参考例１１の方法に準じて標記化合物（収率６７％）を得た。
（参考例２１）メチル　１－（５－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２０で得られたエチル　１－（５－ニトロ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（１．１１ｇ，３．１２ｍｍｏｌ）のテトラヒドロフラン（４０ｍＬ）、水（１０ｍＬ）およびエタノール（１０ｍＬ）の混合溶媒に、鉄粉（１．２２ｇ，２１．９ｍｍｏｌ）および塩化アンモニウム（５０１ｍｇ，９．３７ｍｍｏｌ）を加え、窒素雰囲気下、室温にて１７時間攪拌した。セライトろ過した後、減圧下にて溶媒を留去した。得られた残渣に水を加え、酢酸エチルにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１－２／３）により精製し、固体６９７ｍｇ（収率６９％）を得た。得られた固体（２５０ｍｇ，０．７７ｍｍｏｌ）および水（４ｍＬ）からなる混合物に、氷冷下、硫酸（０．４ｍＬ）を加えた後、亜硝酸ナトリウム（６０ｍｇ，１．００ｍｍｏｌ）の水（１ｍＬ）溶液を滴下した。０℃にて３０分間攪拌した後、窒素雰囲気下、９０℃にて２時間加熱攪拌した。反応混合物に水を加えた後、飽和炭酸水素ナトリウム水溶液を加えてｐＨ７付近とし、酢酸エチルにて抽出した。有機層を合わせ、硫酸マグネシウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣のメタノール（４ｍＬ）およびトルエン（４ｍＬ）からなる混合物に、氷冷下、市販の２Ｍトリメチルシリルジアゾメタンのｎ－ヘキサン溶液（４ｍＬ）を滴下した後、室温にて２時間攪拌した。反応混合物に、２Ｍトリメチルシリルジアゾメタンのｎ－ヘキサン溶液（１ｍＬ）を追加で滴下し、さらに２時間攪拌した。反応混合物を氷冷し、酢酸（８８０μＬ，１５．４ｍｍｏｌ）をゆっくり滴下した後、０℃にて１０分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－３／２）により精製し、標記化合物４２ｍｇ（収率１７％）を固体として得た。
（参考例２２）エチル　１－（３－フェニル－５－プロピルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１６で得られたエチル　１－（３－フェニル－５－プロプ－１－イン－１－イルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１５の方法に準じて標記化合物（収率８４％）を固体として得た。
（参考例２３）エチル　１－（５－イソプロピル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１２で得られたエチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよび４，４，５，５－テトラメチル－２－（プロプ－１－エン－２－イル）－１，３，２－ジオキサボロランを用いて、参考例１１の方法に準じて油状物（収率４４％）を得た。得られた油状物を用いて、参考例１５の方法に準じて標記化合物（収率４０％）を得た。
（参考例２４）メチル　１－（５－ブロモ－６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例１８で得られたエチル　１－（６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよびメタノール溶媒を用いて、参考例１９の方法に準じ、標記化合物（収率２７％）を得た。
（参考例２５）メチル　１－（６－シアノ－５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２４で得られたメチル　１－（５－ブロモ－６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（２０３ｍｇ，０．５１ｍｍｏｌ）のテトラヒドロフラン（６ｍＬ）溶液に、トリス（ジベンジリデンアセトン）ジパラジウム（０）（１４ｍｇ，０．０２ｍｍｏｌ）および１，２，３，４，５－ペンタフェニル－１’－（ジ－ｔｅｒｔ－ブチルホスフィノ）フェロセン（４８ｍｇ，０．０７ｍｍｏｌ）を加え、アルゴン置換した後、氷冷下、市販の１．１Ｍジエチル亜鉛のｎ－ヘキサン溶液（１ｍＬ）を５分間かけて滴下した。反応混合物を０℃にて３時間攪拌後、１Ｎ塩酸水溶液（６ｍＬ）を滴下した。反応混合物を室温に戻し、飽和炭酸水素ナトリウム水溶液を加えた。得られた混合物に対して、デカンテーションを行った後、分液し、水層を酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物１０３ｍｇ（収率５８％）を得た。
（参考例２６）エチル　１－（６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　市販の２－ブロモ－６－ｔｅｒｔ－ブトキシピリジン（７．１４ｇ，３１．０ｍｍｏｌ）のジメチルホルムアミド（４０ｍＬ）溶液に、氷冷下、Ｎ－ブロモスクシンイミド（６．６３ｇ，３７．２ｍｍｏｌ）を加え、５０℃にて９時間加熱攪拌した。反応混合物に水を加え、ｎ－ヘキサンにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－１９／１）により精製し、油状物６．０５ｇ（収率６３％）を得た。得られた油状物および市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて油状物（収率１０４％，純度９６％）を得た。得られた油状物およびフェニルボロン酸を用いて、参考例１１の方法に準じて標記化合物（収率８６％）を固体として得た。
（参考例２７）エチル　１－（５－ブロモ－６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２６で得られたエチル　１－（６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１２の方法に準じて標記化合物（収率９９％）を固体として得た。
（参考例２８）エチル　１－（６－ｔｅｒｔ－ブトキシ－５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２７で得られたエチル　１－（５－ブロモ－６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよびカリウム　エテニル（トリフルオロ）ボレートを用いて、参考例１１の方法に準じて固体（収率６１％）を得た。得られた固体を用いて、参考例１５の方法に準じて標記化合物（収率８４％）を固体として得た。
（参考例２９）エチル　１－（５－エチル－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２８で得られたエチル　１－（６－ｔｅｒｔ－ブトキシ－５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（８３０ｍｇ，２．０２ｍｍｏｌ）のジクロロメタン（１２ｍＬ）溶液に、トリフルオロ酢酸（３ｍＬ）を加え、室温にて７時間攪拌した。反応混合物を減圧濃縮した後、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣にｎ－ヘキサンを加えた。懸濁状態で攪拌した後、デカンテーションにより溶液を除去した。残渣を濃縮乾固し、標記化合物６９５ｍｇ（収率９７％）を固体として得た。
（参考例３０）エチル　１－（５－エチル－６－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２９で得られたエチル　１－（５－エチル－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル）ピペリジン－４－カルボキシレート（１５０ｍｇ，０．４２ｍｍｏｌ）のジメチルホルムアミド（２ｍＬ）溶液に、炭酸カリウム（８８ｍｇ，０．６３ｍｍｏｌ）およびヨウ化メチル（１０５ｍｇ，１．６９ｍｍｏｌ）を加え、６０℃にて１０時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１－１／１）により精製し、標記化合物１４０ｍｇ（収率９０％）を得た。
（参考例３１）［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸
　実施例１３で得られたエチル　［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート（１．０１ｇ，１．８５ｍｍｏｌ相当）のエタノール（９．３ｍＬ）懸濁液に、４Ｎ水酸化ナトリウム水溶液（１．４ｍＬ，５．６ｍｍｏｌ）を加え、６０℃にて１．５時間攪拌した。反応混合物に水を加え、減圧濃縮した。６Ｎ塩酸水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０－０／１００、クロロホルム／メタノール＝９５／５９０／１０）により精製し、標記化合物３３７ｍｇ（収率４１％）を固体として得た。
（参考例３２）エチル　１－（６－アミノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　市販の２－アミノ－５，６-ジブロモピリジンおよび市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて固体（収率５０％）を得た。得られた固体を用いて、参考例１１の方法に準じて標記化合物（収率３９％）を固体として得た。
（参考例３３）エチル　１－｛６－アミノ－３－フェニル－５－［（トリイソプロピルシリル）エチニル］ピリジン－２－イル｝ピペリジン－４－カルボキシレート
　参考例３２で得られたエチル　１－（６－アミノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１２の方法に準じて固体（収率９５％）を得た。得られた固体および市販の（トリイソプロピルシリル）アセチレンを用いて、参考例１６の方法に準じて標記化合物（収率８１％）を得た。
（参考例３４）エチル　１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート
　参考例３３で得られたエチル　１－｛６－アミノ－３－フェニル－５－［（トリイソプロピルシリル）エチニル］ピリジン－２－イル｝ピペリジン－４－カルボキシレート（１９８ｍｇ，０．３９ｍｍｏｌ）およびピリジン（１２６μＬ，１．５７ｍｍｏｌ）のジクロロメタン（４ｍＬ）溶液に、氷冷下、アセチルクロリド（３６μＬ，０．５１ｍｍｏｌ）を滴下し、０℃にて２０分間攪拌した後、室温にて７時間攪拌した。反応混合物に水を加え、ジクロロメタンにて洗浄した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をトルエンにて共沸した後、残渣をテトラヒドロフラン（３ｍＬ）溶解した。反応液にテトラ－ｎ－ブチルアンモニウムフルオリド（１Ｍテトラヒドロフラン溶液，１．２ｍＬ）を加え、８０℃にて５時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物９３ｍｇ（収率６８％）を得た。
（参考例３５）１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸
　参考例３４で得られたエチル　１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて標記化合物を得た。
（参考例３６）エチル　１－（１－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート
　参考例３４で得られたエチル　１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート（１０１ｍｇ，０．２９ｍｍｏｌ）の脱水ジメチルホルムアミド（２ｍＬ）溶液に、氷冷下、６０％水素化ナトリウム（１７ｍｇ，０．４３ｍｍｏｌ）を加えた後、室温にて２０分間攪拌した。反応混合物を再び氷冷し、ヨウ化メチル（５４μＬ，０．８７ｍｍｏｌ）を滴下後、室温にて２時間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。、減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）により精製し、標記化合物８４ｍｇ（収率８０％）を得た。
（参考例３７）エチル　１－（５－アリル－６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２７で得られたエチル　１－（５－ブロモ－６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよび市販の４，４，５，５－テトラメチル－２－（プロプ－２－エン－１－イル）－１，３，２－ジオキサボロランを用いて、参考例１１の方法に準じて標記化合物（収率８４％）を固体として得た。
（参考例３８）エチル　１－［６－ｔｅｒｔ－ブトキシ－５－（２－ヒドロキシエチル）－３－フェニルピリジン－２－イル］ピペリジン－４－カルボキシレート
　参考例３７で得られたエチル　１－（５－アリル－６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレート（５９１ｍｇ，１．４０ｍｍｏｌ）および５０％Ｎ－メチルモルホリン－Ｎ－オキシド水溶液（８７１μＬ）のアセトン（４ｍＬ）、テトラヒドロフラン（４ｍＬ）および水（３ｍＬ）の混合溶液に、氷冷下、４％四酸化オスミウム水溶液（２６７μＬ，０．０４ｍｍｏｌ）を加え、室温にて５時間攪拌した。反応混合物を再び氷冷後、飽和チオ硫酸ナトリウム（２０ｍＬ）を滴下し、５分間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し油状物を得た。得られた油状物のテトラヒドロフラン（６ｍＬ）、メタノール（６ｍＬ）および水（６ｍＬ）の混合溶液に、氷冷下、過ヨウ素酸ナトリウム（８９８ｍｇ，４．２０ｍｍｏｌ）を加えた後、室温にて１時間攪拌した。反応混合物に酢酸エチルを加えた後、不溶物をろ去した。ろ液を水にて洗浄した後、硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し油状物を得た。得られた油状物のメタノール（１２ｍＬ）溶液に、氷冷下、水素化ホウ素ナトリウム（１０６ｍｇ，２．８０ｍｍｏｌ）を加え、０℃にて３０分間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－１／１）により精製し、標記化合物４３８ｍｇ（収率７３％）を固体として得た。
（参考例３９）エチル　１－［５－（２－ヒドロキシエチル）－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル］ピペリジン－４－カルボキシレート
　参考例３８で得られたエチル　１－［６－ｔｅｒｔ－ブトキシ－５－（２－ヒドロキシエチル）－３－フェニルピリジン－２－イル］ピペリジン－４－カルボキシレートを用いて、参考例２９の方法に準じて標記化合物（収率８４％）を固体として得た。
（参考例４０）エチル　１－（５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート
　参考例３９で得られたエチル　１－［６－ｔｅｒｔ－ブトキシ－５－（２－ヒドロキシエチル）－３－フェニルピリジン－２－イル］ピペリジン－４－カルボキシレート（２５２ｍｇ，０．６８ｍｍｏｌ）、１，１'－（アゾジカルボニル）ジピペリジン（３４３ｍｇ，１．３６ｍｍｏｌ）および脱水テトラヒドロフラン（４ｍＬ）からなる混合物に、氷冷下、トリ－ｎ－ブチルホスフィン（３４０μＬ，１．３６ｍｍｏｌ）を加えた後、室温にて２時間攪拌した。反応混合物中の不溶物をろ去し、テトラヒドロフラン（４ｍＬ）にて洗浄した。ろ液および洗液を減圧濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－７／３）により精製した。さらに、シリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）にて再精製し、標記化合物１９０ｍｇ（収率７９％）を固体として得た。
（参考例４１）５－フェニルチエノ［２，３－ｂ］ピリジン－６（７Ｈ）－オン
　Ｊｏｕｒｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ　（２００３）， ６８（２４）,９５１３－９５１６記載の２－ブロモチオフェン－３－カルバルデヒド（２．１７ｇ，１１．４ｍｍｏｌ）、２-フェニルアセトアミド（２．００ｇ，１４．８ｍｍｏｌ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）（３１２ｍｇ，０．３４ｍｍｏｌ）、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（６３７ｍｇ，１．０２ｍｍｏｌ）、炭酸セシウム（６．２９ｇ，１９．３ｍｍｏｌ）およびトルエン（３０ｍＬ）からなる混合物をアルゴン雰囲気下、１００℃にて１５時間攪拌した。反応混合物を減圧濃縮し、不溶物をろ取した。得られた不溶物を酢酸エチルに溶解させ、水にて洗浄した。有機層を硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去し、標記化合物１．１１ｇ（収率４３％）を固体として得た。
（参考例４２）５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル　トリフルオロメタンスルホネート
　参考例４１で得られた５－フェニルチエノ［２，３－ｂ］ピリジン－６（７Ｈ）－オン（１．１１ｇ，４．８８ｍｍｏｌ）および２，６-ルチジン（１．１４ｍＬ，９．７７ｍｍｏｌ）の脱水ジクロロメタン（２０ｍＬ）溶液に、氷冷下、トリフルオロメタンスルホン酸無水物（９８４μＬ，５．８６ｍｍｏｌ）を滴下し、０℃にて１時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物６６１ｍｇ（収率３８％）を得た。
（参考例４３）１－（５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸
　参考例４２で得られた５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル　トリフルオロメタンスルホネートおよび市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて油状物（収率９１％）を得た。得られた油状物を用いて、参考例１３の方法に準じて標記化合物（収率６１％）を固体として得た。
（参考例４４）５－ブロモ－６－クロロ－３－メチル－１Ｈ－ピロロ［２，３－ｂ］ピリジン
　ジメチルアミン塩酸塩（３２６ｍｇ，３．８０ｍｍｏｌ）および酢酸（８ｍＬ）からなる混合物に、氷冷下、３０％ホルムアルデヒド水溶液（２６８μＬ，３．６３ｍｍｏｌ）を滴下した後、０℃にて２０分間攪拌した。反応混合物に、ＰＣＴ　ＷＯ２０１０／０１６４９０出願明細書記載の５－ブロモ－６－クロロ－１Ｈ－ピロロ［２，３－ｂ］ピリジン（８００ｍｇ，３．４６ｍｍｏｌ）を加えた後、６０℃にて１６時間攪拌した。反応混合物を減圧濃縮して得られた残渣に、飽和炭酸水素ナトリウム水溶液を加えて中和したところ、不溶物が生じた。この不溶物をろ取し、アセトニトリル（３０ｍＬ）に溶解させた後、水素化トリアセトキシホウ素ナトリウム（７．１１ｇ，３１．９ｍｍｏｌ）を加えた。混合物を室温にて２０分間攪拌した後、４時間加熱還流した。反応混合物を放冷した後、水素化トリアセトキシホウ素ナトリウム（７．１１ｇ，３１．９ｍｍｏｌ）を追加し、さらに５時間加熱還流した。反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した。硫酸ナトリウムにて乾燥し、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－４／１）により精製し、標記化合物２０１ｍｇ（収率２６％）を固体として得た。
（参考例４５）エチル　１－｛５－ブロモ－３－メチル－１－［（４－メチルフェニル）スルホニル］－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル｝ピペリジン－４－カルボキシレート
　参考例４４で得られた５－ブロモ－６－クロロ－３－メチル－１Ｈ－ピロロ［２，３－ｂ］ピリジン（１９８ｍｇ，０．８１ｍｍｏｌ）および脱水テトラヒドロフラン（４ｍＬ）からなる混合物に、氷冷下、６０％水素化ナトリウム（４８ｍｇ，１．２１ｍｍｏｌ）を少しずつ加えた後、室温にて１時間攪拌した。反応混合物を再び氷冷し、４－メチルベンゼンスルホニル　クロリド（１８５ｍｇ，０．９７ｍｍｏｌ）を加えた後、室温にて１５時間攪拌した。反応混合物に水（８０ｍＬ）を加え、酢酸エチルにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣にｎ－ヘキサン（１０ｍＬ）を加えた後、デカンテーションにより溶液を除去した。残渣を減圧濃縮し、固体３００ｍｇ（収率９３％）を得た。得られた固体および市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて標記化合物（収率８５％）を得た。
（参考例４６）１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸
　参考例４５で得られたエチル　１－｛５－ブロモ－３－メチル－１－［（４－メチルフェニル）スルホニル］－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル｝ピペリジン－４－カルボキシレートおよびフェニルボロン酸を用いて、参考例１１の方法に準じて固体（収率９６％）を得た。得られた固体を用いて、参考例１３の方法に準じて標記化合物（収率２５％）を固体として得た。
（参考例４７）エチル　１－（３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレート
　Ｏｒｇａｎｉｃ　Ｌｅｔｔｅｒｓ　（２００４），６（１４）， ２４３３－２４３５．記載の３－フェニル－１，８－ナフチリジン－２（１Ｈ）－オンを用いて参考例４２の方法に準じてトリフレート体を得た。得られた化合物および市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて標記化合物（収率６２％）を固体として得た。
（参考例４８）エチル　１－（６－ブロモ－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレート
　Ｏｒｇａｎｉｃ　Ｌｅｔｔｅｒｓ　（２００４），６（１４）， ２４３３－２４３５．記載の３－フェニル－１，８－ナフチリジン－２（１Ｈ）－オンを用いて、参考例１２の方法に準じて固体（収率８８％、純度約８０％）を得た。得られた固体を用いて、参考例４２の方法に準じてトリフレート体を得た。得られた化合物および市販のエチル　４－ピペリジンカルボキシレート用いて、参考例１７の方法に準じて標記化合物（収率７４％）を固体として得た。
（参考例４９）エチル　１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例４８で得られたエチル　１－（６－ブロモ－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレートおよび２，４，６－トリメチルボロキシンを用いて、参考例１１の方法に準じて標記化合物（収率７０％）を固体として得た。
（参考例５０）１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボン酸
　参考例４９で得られたエチル　１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて標記化合物を得た。
（参考例５１）エチル　１－（６－エチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例４８で得られたエチル　１－（６－ブロモ－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレートおよび市販のトリ－ｎ－ブチル（ビニル）スズを用いて、参考例１４の方法に準じて固体（収率６８％）を得た。得られた固体を用いて、参考例１５の方法に準じて標記化合物（収率７５％）を得た。
（参考例５２）１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－カルボン酸
　Ｆａｒｍａｃｏ　(１９９６)，５１(８，９)，５６９－５７７記載の６－メチル－３－フェニルキノキサリン－２（１Ｈ）－オンを用いて、参考例４２の方法に準じてトリフレート体を得た。得られた化合物および市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて固体（収率９１％）を得た。得られた固体を用いて、参考例１３の方法に準じて標記化合物（収率９９％）を固体として得た。
（参考例５３）エチル　１－（５－ヨード－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル）ピペリジン－４－カルボキシレート
　参考例２６で得られたエチル　１－（６－ｔｅｒｔ－ブトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよびＮ－ヨードスクシンイミドを用いて、参考例１２の方法に準じて固体（収率９６％）を得た。得られた固体を用いて、参考例２９の方法に準じて標記化合物（収率８１％）を固体として得た。
（参考例５４）エチル　１－［６－（アリルオキシ）－５－ヨード－３－フェニルピリジン－２－イル］ピペリジン－４－カルボキシレート
　参考例５３で得られたエチル　１－（５－ヨード－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル）ピペリジン－４－カルボキシレートおよびアリルブロミドを用いて、参考例３０の方法に準じて標記化合物（収率１００％）を得た。
（参考例５５）エチル　１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート
　参考例５４で得られたエチル　１－［６－（アリルオキシ）－５－ヨード－３－フェニルピリジン－２－イル］ピペリジン－４－カルボキシレート（６．０８ｇ，１２．４ｍｍｏｌ）の１，４－ジオキサン（１２０ｍＬ）溶液に、酢酸パラジウム（ＩＩ）（８３ｍｇ，０．３７ｍｏｌ）、炭酸セシウム（４．８３ｇ，１４．８ｍｍｏｌ）、ギ酸ナトリウム（１．０１ｇ，１４．８ｍｍｏｌ）およびテトラ－ｎ－ブチルアンモニウムブロミド（４．７８ｇ，１４．８ｍｍｏｌ）を加え、アルゴン雰囲気下、４時間加熱還流した。反応混合物を減圧濃縮し、得られた残渣に酢酸エチル（２００ｍＬ）を加えた。不溶物をセライトろ過により除去し、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１０／０－９／１）により精製し、標記化合物２．１１ｇ（収率４７％）を固体として得た。
（参考例５６）１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸
　参考例５５で得られたエチル　１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて標記化合物（収率１００％）を固体として得た。
（参考例５７）エチル　１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート
　参考例５３で得られたエチル　１－（５－ヨード－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル）ピペリジン－４－カルボキシレートおよび３－ブロモ－２－メチルプロペンを用いて、参考例３０の方法に準じて油状物（収率７２％）を得た。得られた油状物を用いて、参考例５５の方法に準じ、標記化合物（収率６９％）を固体として得た。
（参考例５８）１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸
　参考例５７で得られたエチル　１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて標記化合物（収率１００％）を固体として得た。
（参考例５９）エチル　１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレート
　参考例５３で得られたエチル　１－（５－ヨード－６－オキソ－３－フェニル－１，６－ジヒドロピリジン－２－イル）ピペリジン－４－カルボキシレートおよび市販の１－ブロモ－２―ブテンを用いて、参考例３０の方法に準じて油状物（収率７９％）を得た。得られた油状物を用いて、参考例５５の方法に準じ、標記化合物（収率６８％）を固体として得た。
（参考例６０）１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸
　参考例５９で得られたエチル　１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて標記化合物（収率９９％）を固体として得た。
（参考例６１）３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－オール
　窒素雰囲気下、市販の２－クロロ－２－フェニル酢酸クロリド（１８．８ｇ，１１６ｍｍｏｌ）のジクロロメタン溶液に、氷冷下、市販の５－トリフルオロ－２－アミノピリジン（２０．１ｍＬ，１２７ｍｍｏｌ）およびトリエチルアミン（１７．７ｍＬ，１２７ｍｍｏｌ）を加え、室温にて２０時間攪拌した。反応混合物に塩酸水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄し、無水硫酸ナトリウムにて乾燥した。減圧下にて溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１）により精製し、固体３２．０ｇ（収率８８％）を得た。得られた固体（３．００ｇ，９．５３ｍｍｏｌ）の２，６－ルチジン（１０ｍＬ）溶液に、１８０℃、１時間マイクロウェーブ照射を行った。室温に冷却後、反応混合物に水を加え、酢酸エチルにて抽出した。有機層を合わせ、飽和炭酸水素ナトリウム水溶液および飽和食塩水にて洗浄した。無水硫酸ナトリウムにて乾燥し、減圧下にて溶媒を留去した。得られた固体をエーテルにて洗浄し、標記化合物１．３４ｇ（収率５１％）を固体として得た。
（参考例６２）１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－カルボン酸
　参考例６１で得られた３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－オールを用いて、参考例４２の方法に準じて固体（収率９５％）を得た。得られた固体および市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて固体（収率２１％）を得た。得られた固体を用いて、参考例１３の方法に準じて標記化合物（収率８４％）を固体として得た。
（参考例６３）｛シス－４－［（｛１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－イル｝カルボニル）アミノ］シクロヘキシル｝酢酸
　実施例５０で得られたエチル　｛シス－４－［（｛１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－イル｝カルボニル）アミノ］シクロヘキシル｝アセテートを用いて、参考例３１の方法に準じて標記化合物（収率４６％）を固体として得た。
（参考例６４）１－（４，６－ジフェニルピリダジン－３－イル）ピペリジン－４－カルボン酸
　ＰＣＴ　ＷＯ２００７／１３０３８３出願明細書記載の３－クロロ－４，６－ジフェニルピリダジンおよび市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じてアモルファス状物（収率５３％）を得た。得られたアモルファス状物を用いて、参考例１３の方法に準じて標記化合物を定量的に得た。
（参考例６５）３－クロロ－６－エチル－４－フェニルピリダジン
　ＰＣＴ　ＷＯ２００５／０７２７４０出願明細書記載の３，６－ジクロロ－４－フェニルピリダジンを用いて、参考例１４の方法に準じて固体（収率９．９％）を得た。得られた固体を用いて、参考例１５の方法に準じて標記化合物（収率９７％）を得た。
（参考例６６）１－（６－エチル－４－フェニルピリダジン－３－イル）ピペリジン－４－カルボン酸
　参考例６５で得られた３－クロロ－６－エチル－４－フェニルピリダジンおよび市販のエチル　４－ピペリジンカルボキシレートを用いて、参考例１７の方法に準じて固体（収率６１％）を得た。得られた固体を用いて、参考例１３の方法に準じて標記化合物を定量的に得た。 (Reference Example 1)
(1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and
(1R, 3R) -3-{[(Benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid
Supercritical fluid chromatography (Daicel Chiralpak AD-H, carbon dioxide / methanol) using trans-3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid (120 g) described in PCT WO2008 / 075196 75:25). The first peak eluting first was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (56.7 g, optical purity> 98% ee) as a solid. The second peak eluting later was collected, and then the solvent was distilled off under reduced pressure to obtain the title compound (55.4 g, optical purity> 98% ee) as a solid.
Reference Example 2 Benzyl [(1R, 3R) -3-{[(1S) -1-phenylethyl] carbamoyl} cyclohexyl] carbamate
To a solution of the first peak (300 mg, 1.08 mmol) obtained in Reference Example 1 in dichloromethane (11 mL), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (294 mg, 2.16 mmol), (1S) -1-phenylethanamine (138 μL, 1.08 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (414 mg, 2.16 mmol), and triethylamine (0 .452 mL, 3.24 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-0 / 100) to obtain 394 mg (yield 96%) of the title compound as a solid. The obtained solid was crystallized from isopropyl alcohol solvent. The absolute steric structure was determined by X-ray crystal structure analysis using the obtained crystal. The absolute configuration was determined to be (1R, 3R) based on the configuration of (1S) -1-phenylethanamine. Therefore, the absolute configuration of the second peak obtained in Reference Example 1 was determined to be (1S, 3S).
Reference Example 3 Benzyl [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] carbamate
To a solution of the second peak (1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid (10.5 g, 37.9 mmol) obtained in Reference Example 1 in dichloromethane (10 mL), Then, commercially available 1,1′-carbonyldiimidazole (7.37 g, 45.5 mmol) was added and stirred for 2 hours. Under ice-cooling, commercially available ethylamine (2.0 M tetrahydrofuran solution, 50 mL, 100 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The reaction mixture was washed with 1N aqueous hydrochloric acid solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 11.9 g of the title compound.
Reference Example 4 (1S, 3S) -3-Amino-N-ethylcyclohexanecarboxamide
To a solution of benzyl [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] carbamate (11.9 g, equivalent to 37.9 mmol) obtained in Reference Example 3 in ethanol (80 mL), commercially available 10% palladium carbon (1 .97 g) was added and stirred at room temperature for 5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to obtain 6.73 g of the title compound as a solid quantitatively.
Reference Example 5 Benzyl [(1S, 3S) -3-carbamoylcyclohexyl] carbamate
Using the (1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid obtained in Reference Example 1 and commercially available aqueous ammonia, the title compound (yield) was obtained according to the method of Reference Example 3. 100%) as a solid.
Reference Example 6 (1S, 3S) -3-Aminocyclohexanecarboxamide hydrochloride
To a solution of benzyl [(1S, 3S) -3-carbamoylcyclohexyl] carbamate (3.00 g, 10.9 mol) obtained in Reference Example 5 in ethanol (100 mL) was added commercially available 10% palladium carbon (300 mg). The mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. A 1N hydrochloric acid ethanol solution was added to the obtained residue to suspend it, and then the solvent was distilled off under reduced pressure. The obtained residue was dried to obtain 1.95 g (yield 97%) of the title compound as a solid.
Reference Example 7 Methyl (1S, 3S) -3-aminocyclohexanecarboxylate hydrochloride
Using (1S, 3S) -3-{[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and methanol obtained in Reference Example 1, a solid (yield 92%) was obtained according to the method of Reference Example 3. Obtained. The title compound (yield 72%) was obtained as a solid according to the method of Reference Example 4 using the obtained solid.
Reference Example 8 Ethyl (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) acetate
Izvestiya Akademii Nauk SSSR, SeriyaKimicheskaya (1980), 10, 2374-2379. The described ethyl (cis-4-aminocyclohexyl) acetate hydrochloride (5.60 g, 25.3 mmol) was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. Further, a 0.1N aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dried to obtain 3.50 g of an oily substance. To a solution of the obtained oil (1.80 g, 9.72 mmol) in methanol (49 mL) was added anhydrous sodium sulfate (9.00 g) and benzaldehyde (0.98 mL, 9.7 mmol), and the mixture was stirred at room temperature for 16 hours. did. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound.
Reference Example 9 Ethyl 2-methyl-2- (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) propanoate
In a nitrogen atmosphere, a solution of 1.14M lithium diisopropylamide in tetrahydrofuran (0.353 mL, 0.402 mmol) was cooled with dry ice-methanol, and the ethyl (cis-4-{[(1E)) obtained in Reference Example 8 was used. -Phenylmethylene] amino} cyclohexyl) acetate (50.0 mg, 0.183 mmol) in tetrahydrofuran (0.92 mL) was added. The mixture was stirred for 20 minutes under ice cooling, and then cooled again with dry ice-methanol. A tetrahydrofuran solution (0.92 mL) of methyl iodide (34 μL, 0.55 mmol) and hexamethylphosphoric triamide (70 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. By subjecting the residue obtained by distilling off the solvent under reduced pressure to methylation reaction again under the same reaction conditions, the title compound was quantitatively obtained.
Reference Example 10 Ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate
To a solution of ethyl 2-methyl-2- (cis-4-{[(1E) -phenylmethylene] amino} cyclohexyl) propanoate (6.51 g, corresponding to 20.5 mmol) obtained in Reference Example 9 in dichloromethane (68 mL) Under ice cooling, trifluoroacetic acid (2.35 ml, 30.7 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, commercially available 4N hydrochloric acid-ethyl acetate (10 ml) was added, and the solvent was distilled off again under reduced pressure. Water was added and the mixture was washed with toluene, 4N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 4.02 g (yield 92%) of the title compound.
Reference Example 11 Ethyl 1- (3-phenylpyridin-2-yl) piperidine-4-carboxylate
Ethyl 1- (3-bromopyridin-2-yl) piperidine-4-carboxylate (980 mg, 3.13 mmol) and phenylboronic acid (563 mg, 6.26 mmol) in tetrahydrofuran (PCT WO 2006/025783 application specification) 20 mL) solution was added [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (130 mg, 0.16 mmol) and potassium phosphate (2.10 g, 9.39 mmol). ) And heated to reflux under an argon atmosphere for 20 hours. Ethyl acetate was added to the reaction mixture, the insoluble material was filtered through Celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to obtain 911 mg (yield 94%) of the title compound as a solid.
Reference Example 12 Ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate
To a solution of ethyl 1- (3-phenylpyridin-2-yl) piperidine-4-carboxylate (250 mg, 0.81 mmol) obtained in Reference Example 11 in dichloromethane (6 mL) was added N-bromosuccinimide ( (143 mg, 0.81 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to obtain 300 mg (yield 96%) of the title compound as a solid.
Reference Example 13 1- (5-Bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylic acid
A mixed solution of ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate (87 mg, 0.22 mmol) obtained in Reference Example 12 in tetrahydrofuran (2 mL) and ethanol (2 mL) To the mixture, 1N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 13 hours. A 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound.
Reference Example (14) Ethyl 1- (3-phenyl-5-vinylpyridin-2-yl) piperidine-4-carboxylate
To a solution of ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate (238 mg, 0.61 mmol) obtained in Reference Example 12 in toluene (6 mL), commercially available tri-n -Butyl (vinyl) tin (368 μL, 1.22 mmol) and tetrakis (triphenylphosphine) palladium (0) (71 mg, 0.06 mmol) were added, and the mixture was heated and stirred at 90 ° C. for 23 hours in an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-17 / 3) to obtain 146 mg (yield 71%) of the title compound.
Reference Example 15 Ethyl 1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate
To a solution of ethyl 1- (3-phenyl-5-vinylpyridin-2-yl) piperidine-4-carboxylate (108 mg, 0.32 mmol) obtained in Reference Example 14 in ethanol (6 mL) was added 10% palladium carbon ( 50% water, 50 mg) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. 10% palladium carbon (50% moisture, 30 mg) was added, and the mixture was further stirred for 26 hours. The reaction mixture was filtered through celite and washed with ethanol. The solvent was distilled off under reduced pressure to obtain 106 mg (yield 98%) of the title compound.
Reference Example 16 Ethyl 1- (3-phenyl-5-prop-1-in-1-ylpyridin-2-yl) piperidine-4-carboxylate
To a solution of ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate (250 mg, 0.64 mmol) obtained in Reference Example 12 in tetrahydrofuran (3.2 mL) was added dichlorobis (tri Phenylphosphine) palladium (II) (45 mg, 0.06 mmol), copper (I) iodide (24 mg, 0.13 mmol), diisopropylethylamine (443 μL, 2.57 mmol) and 1M tetra-n-butylammonium fluoride were added. Thereafter, trimethyl-prop-1-ynylsilane (285 μL, 1.93 mmol) was further added dropwise. After the atmosphere in the reaction system was replaced with nitrogen, microwave irradiation was performed at 90 ° C. for 30 minutes. Ethyl acetate was added to the reaction mixture, and the insoluble material was removed by Celite filtration. The filtrate was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to give 160 mg (yield 72%) of the title compound. Obtained.
Reference Example 17 Ethyl 1- (3-bromo-5-chloropyridin-2-yl) piperidine-4-carboxylate
Commercially available ethyl 4-piperidinecarboxylate (3.81 mL, 24 mL) was added to a solution of commercially available 3-bromo-2,5-dichloropyridine (1.87 g, 8.24 mmol) in N-methylpyrrolidone (4 mL) under ice cooling. 0.7 mmol) was added dropwise, and the mixture was heated to 120 ° C. and stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to give 2.47 g (yield 86%) of the title compound. Got.
Reference Example 18 Ethyl 1- (6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate
According to the method of Reference Example 17, using 6-chloro-5-phenylpyridine-2-carbonitrile described in Tetrahedron (1990), 46 (16), 5715-5732 and commercially available ethyl 4-piperidinecarboxylate. The title compound (yield 87%) was obtained as a solid.
Reference Example 19 Ethyl 1- (5-bromo-6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate
To a mixed solution of ethyl 1- (6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate (344 mg, 1.03 mmol) obtained in Reference Example 18 in dichloromethane (5 mL) and ethanol (5 mL). Under ice cooling, tetra-n-butylammonium tribromide (742 mg, 1.54 mmol) was added, followed by stirring at room temperature for 6 hours. Tetra-n-butylammonium tribromide (742 mg, 1.54 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to obtain 212 mg (yield 50%) of the title compound.
Reference Example 20 Ethyl 1- (5-nitro-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Using a commercially available 3-bromo-2-chloro-5-nitropyridine and a commercially available ethyl 4-piperidinecarboxylate, an oily substance (yield 100%) was obtained according to the method of Reference Example 17. The title compound (yield 67%) was obtained according to the method of Reference Example 11 using the obtained oil and phenylboronic acid.
Reference Example 21 Methyl 1- (5-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Ethyl 1- (5-nitro-3-phenylpyridin-2-yl) piperidine-4-carboxylate (1.11 g, 3.12 mmol) obtained in Reference Example 20 in tetrahydrofuran (40 mL), water (10 mL) and Iron powder (1.22 g, 21.9 mmol) and ammonium chloride (501 mg, 9.37 mmol) were added to a mixed solvent of ethanol (10 mL), and the mixture was stirred at room temperature for 17 hours under a nitrogen atmosphere. After filtration through celite, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1-2 / 3) to obtain 697 mg (yield 69%) of a solid. To a mixture of the obtained solid (250 mg, 0.77 mmol) and water (4 mL), sulfuric acid (0.4 mL) was added under ice cooling, and then sodium nitrite (60 mg, 1.00 mmol) in water (1 mL). ) The solution was added dropwise. After stirring at 0 ° C. for 30 minutes, the mixture was heated and stirred at 90 ° C. for 2 hours in a nitrogen atmosphere. After adding water to the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to around 7, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. A commercially available n-hexane solution (2 mL) of 2M trimethylsilyldiazomethane (4 mL) was added dropwise to a mixture of the resulting residue of methanol (4 mL) and toluene (4 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 2M trimethylsilyldiazomethane in n-hexane (1 mL) was added dropwise, and the mixture was further stirred for 2 hours. The reaction mixture was ice-cooled and acetic acid (880 μL, 15.4 mmol) was slowly added dropwise, followed by stirring at 0 ° C. for 10 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-3 / 2) to give 42 mg (yield 17%) of the title compound as a solid. Got as.
Reference Example 22 Ethyl 1- (3-phenyl-5-propylpyridin-2-yl) piperidine-4-carboxylate
Using ethyl 1- (3-phenyl-5-prop-1-in-1-ylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 16 according to the method of Reference Example 15, The compound (84% yield) was obtained as a solid.
Reference Example 23 Ethyl 1- (5-isopropyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate and 4,4,5,5-tetramethyl-2- (prop-1-ene) obtained in Reference Example 12 Using -2-yl) -1,3,2-dioxaborolane, an oil (44% yield) was obtained according to the method of Reference Example 11. Using the resulting oily matter, the title compound (yield 40%) was obtained according to the method of Reference Example 15.
Reference Example 24 Methyl 1- (5-bromo-6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Using the ethyl 1- (6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 18 and a methanol solvent, the title compound (yield) was obtained according to the method of Reference Example 19. 27%).
Reference Example 25 Methyl 1- (6-cyano-5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate
To a solution of methyl 1- (5-bromo-6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate (203 mg, 0.51 mmol) obtained in Reference Example 24 in tetrahydrofuran (6 mL) was added tris. (Dibenzylideneacetone) dipalladium (0) (14 mg, 0.02 mmol) and 1,2,3,4,5-pentaphenyl-1 ′-(di-tert-butylphosphino) ferrocene (48 mg, 0.07 mmol) The solution was purged with argon, and then a commercially available 1.1M diethylzinc n-hexane solution (1 mL) was added dropwise over 5 minutes under ice cooling. The reaction mixture was stirred at 0 ° C. for 3 hours, and 1N aqueous hydrochloric acid solution (6 mL) was added dropwise. The reaction mixture was returned to room temperature and saturated aqueous sodium hydrogen carbonate solution was added. The resulting mixture was decanted and then separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to obtain 103 mg of the title compound (yield 58%). It was.
Reference Example 26 Ethyl 1- (6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate
N-bromosuccinimide (6.63 g, 37.2 mmol) was added to a solution of commercially available 2-bromo-6-tert-butoxypyridine (7.14 g, 31.0 mmol) in dimethylformamide (40 mL) under ice cooling, The mixture was heated and stirred at 50 ° C. for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with n-hexane. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-19 / 1) to give 6.05 g of oil (63% yield). Got. Using the obtained oil and commercially available ethyl 4-piperidinecarboxylate, an oil (yield 104%, purity 96%) was obtained according to the method of Reference Example 17. The title compound (yield 86%) was obtained as a solid according to the method of Reference Example 11 using the obtained oil and phenylboronic acid.
Reference Example 27 Ethyl 1- (5-bromo-6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Using the ethyl 1- (6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 26 according to the method of Reference Example 12 (yield 99 %) As a solid.
Reference Example 28 Ethyl 1- (6-tert-butoxy-5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate
By using ethyl 1- (5-bromo-6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate and potassium ethenyl (trifluoro) borate obtained in Reference Example 27, Reference Example A solid (yield 61%) was obtained according to the method of No. 11. Using the resulting solid, the title compound (yield 84%) was obtained as a solid according to the method of Reference Example 15.
Reference Example 29 Ethyl 1- (5-ethyl-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate
To a solution of ethyl 1- (6-tert-butoxy-5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate (830 mg, 2.02 mmol) obtained in Reference Example 28 in dichloromethane (12 mL). , Trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was added to the resulting residue. After stirring in a suspended state, the solution was removed by decantation. The residue was concentrated to dryness to obtain 695 mg (yield 97%) of the title compound as a solid.
Reference Example 30 Ethyl 1- (5-ethyl-6-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Ethyl 1- (5-ethyl-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate (150 mg, 0.42 mmol) dimethylformamide obtained in Reference Example 29 ( 2 mL) solution was added potassium carbonate (88 mg, 0.63 mmol) and methyl iodide (105 mg, 1.69 mmol), and the mixture was stirred at 60 ° C. for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1-1 / 1) to obtain 140 mg of the title compound (yield 90%). Obtained.
Reference Example 31 [cis-4-({[1- (5-ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid
Ethyl [cis-4-({[1- (5-ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate (1.01 g, obtained in Example 13) To a suspension of ethanol (9.3 mL) in 1.85 mmol) was added 4N aqueous sodium hydroxide solution (1.4 mL, 5.6 mmol), and the mixture was stirred at 60 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. A 6N aqueous hydrochloric acid solution was added, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-0 / 100, chloroform / methanol = 95/590/10) to obtain 337 mg (yield 41%) of the title compound as a solid. .
Reference Example 32 Ethyl 1- (6-amino-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Using a commercially available 2-amino-5,6-dibromopyridine and a commercially available ethyl 4-piperidinecarboxylate, a solid (yield 50%) was obtained according to the method of Reference Example 17. Using the resulting solid, the title compound (39% yield) was obtained as a solid according to the method of Reference Example 11.
Reference Example 33 Ethyl 1- {6-amino-3-phenyl-5-[(triisopropylsilyl) ethynyl] pyridin-2-yl} piperidine-4-carboxylate
Using ethyl 1- (6-amino-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 32, a solid (yield 95%) was obtained according to the method of Reference Example 12. Obtained. The title compound (yield 81%) was obtained according to the method of Reference Example 16 using the obtained solid and commercially available (triisopropylsilyl) acetylene.
Reference Example 34 Ethyl 1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate
Ethyl 1- {6-amino-3-phenyl-5-[(triisopropylsilyl) ethynyl] pyridin-2-yl} piperidine-4-carboxylate (198 mg, 0.39 mmol) and pyridine obtained in Reference Example 33 Acetyl chloride (36 μL, 0.51 mmol) was added dropwise to a solution of (126 μL, 1.57 mmol) in dichloromethane (4 mL) under ice cooling, and the mixture was stirred at 0 ° C. for 20 minutes and then stirred at room temperature for 7 hours. Water was added to the reaction mixture and washed with dichloromethane. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. After the obtained residue was azeotroped with toluene, the residue was dissolved in tetrahydrofuran (3 mL). Tetra-n-butylammonium fluoride (1M tetrahydrofuran solution, 1.2 mL) was added to the reaction mixture, and the mixture was stirred at 80 ° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to give 93 mg (yield 68%) of the title compound. Obtained.
Reference Example 35 1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid
Using ethyl 1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 34, the title was prepared according to the method of Reference Example 13. A compound was obtained.
Reference Example 36 Ethyl 1- (1-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate
Dehydrated dimethylformamide (2 mL) of ethyl 1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate (101 mg, 0.29 mmol) obtained in Reference Example 34 ) 60% sodium hydride (17 mg, 0.43 mmol) was added to the solution under ice cooling, followed by stirring at room temperature for 20 minutes. The reaction mixture was ice-cooled again, methyl iodide (54 μL, 0.87 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to obtain 84 mg (yield 80%) of the title compound. Obtained.
Reference Example 37 Ethyl 1- (5-allyl-6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate
Ethyl 1- (5-bromo-6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 27 and commercially available 4,4,5,5-tetramethyl- The title compound (yield 84%) was obtained as a solid according to the method of Reference Example 11 using 2- (prop-2-en-1-yl) -1,3,2-dioxaborolane.
Reference Example 38 Ethyl 1- [6-tert-butoxy-5- (2-hydroxyethyl) -3-phenylpyridin-2-yl] piperidine-4-carboxylate
Ethyl 1- (5-allyl-6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate (591 mg, 1.40 mmol) and 50% N-methylmorpholine obtained in Reference Example 37 To a mixed solution of —N-oxide aqueous solution (871 μL) in acetone (4 mL), tetrahydrofuran (4 mL) and water (3 mL) was added 4% osmium tetroxide aqueous solution (267 μL, 0.04 mmol) under ice cooling, and the mixture was brought to room temperature. And stirred for 5 hours. The reaction mixture was ice-cooled again, saturated sodium thiosulfate (20 mL) was added dropwise, and the mixture was stirred for 5 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil. To a mixed solution of the obtained oily substance in tetrahydrofuran (6 mL), methanol (6 mL) and water (6 mL) was added sodium periodate (898 mg, 4.20 mmol) under ice cooling, and then at room temperature for 1 hour. Stir. Ethyl acetate was added to the reaction mixture, and the insoluble material was removed by filtration. The filtrate was washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil. To a solution of the obtained oily substance in methanol (12 mL), sodium borohydride (106 mg, 2.80 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-1 / 1) to obtain 438 mg (yield 73%) of the title compound as a solid.
Reference Example 39 Ethyl 1- [5- (2-hydroxyethyl) -6-oxo-3-phenyl-1,6-dihydropyridin-2-yl] piperidine-4-carboxylate
Using the ethyl 1- [6-tert-butoxy-5- (2-hydroxyethyl) -3-phenylpyridin-2-yl] piperidine-4-carboxylate obtained in Reference Example 38, the method of Reference Example 29 The title compound (yield 84%) was obtained as a solid.
Reference Example 40 Ethyl 1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate
Ethyl 1- [6-tert-butoxy-5- (2-hydroxyethyl) -3-phenylpyridin-2-yl] piperidine-4-carboxylate obtained in Reference Example 39 (252 mg, 0.68 mmol), 1 , 1 ′-(azodicarbonyl) dipiperidine (343 mg, 1.36 mmol) and dehydrated tetrahydrofuran (4 mL) were added with tri-n-butylphosphine (340 μL, 1.36 mmol) under ice-cooling, Stir at room temperature for 2 hours. The insoluble material in the reaction mixture was filtered off and washed with tetrahydrofuran (4 mL). The filtrate and washings were concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-7 / 3). The product was further purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to obtain 190 mg (yield 79%) of the title compound as a solid.
Reference Example 41 5-Phenylthieno [2,3-b] pyridin-6 (7H) -one
2-Bromothiophene-3-carbaldehyde (2.17 g, 11.4 mmol), 2-phenylacetamide (2.00 g, 14.8 mmol) described in Journal of Organic Chemistry (2003), 68 (24), 9513-9516. , Tris (dibenzylideneacetone) dipalladium (0) (312 mg, 0.34 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (637 mg, 1.02 mmol), cesium carbonate (6. 29 g, 19.3 mmol) and toluene (30 mL) were stirred at 100 ° C. for 15 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the insoluble material was collected by filtration. The obtained insoluble material was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.11 g (43% yield) of the title compound as a solid.
Reference Example 42 5-Phenylthieno [2,3-b] pyridin-6-yl trifluoromethanesulfonate
5-phenylthieno [2,3-b] pyridin-6 (7H) -one (1.11 g, 4.88 mmol) and 2,6-lutidine (1.14 mL, 9.77 mmol) obtained in Reference Example 41 To a dehydrated dichloromethane (20 mL) solution, trifluoromethanesulfonic anhydride (984 μL, 5.86 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to obtain 661 mg (yield 38%) of the title compound.
Reference Example 43 1- (5-Phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid
Using 5-phenylthieno [2,3-b] pyridin-6-yl trifluoromethanesulfonate obtained in Reference Example 42 and commercially available ethyl 4-piperidinecarboxylate, an oil ( Yield 91%) was obtained. Using the resulting oily matter, the title compound (61% yield) was obtained as a solid according to the method of Reference Example 13.
Reference Example 44 5-Bromo-6-chloro-3-methyl-1H-pyrrolo [2,3-b] pyridine
To a mixture consisting of dimethylamine hydrochloride (326 mg, 3.80 mmol) and acetic acid (8 mL) was added dropwise a 30% aqueous formaldehyde solution (268 μL, 3.63 mmol) under ice cooling, followed by stirring at 0 ° C. for 20 minutes. To the reaction mixture, 5-bromo-6-chloro-1H-pyrrolo [2,3-b] pyridine (800 mg, 3.46 mmol) described in the specification of PCT WO2010 / 016490 was added, and then at 60 ° C. for 16 hours. Stir. The residue obtained by concentrating the reaction mixture under reduced pressure was neutralized with a saturated aqueous sodium hydrogen carbonate solution, resulting in insoluble matter. The insoluble material was collected by filtration and dissolved in acetonitrile (30 mL), and sodium triacetoxyborohydride (7.11 g, 31.9 mmol) was added. The mixture was stirred at room temperature for 20 minutes and then heated to reflux for 4 hours. After allowing the reaction mixture to cool, sodium triacetoxyborohydride (7.11 g, 31.9 mmol) was added, and the mixture was further heated to reflux for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. It dried with sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-4 / 1) to obtain 201 mg (yield 26%) of the title compound as a solid.
Reference Example 45 Ethyl 1- {5-bromo-3-methyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-6-yl} piperidine-4-carboxy rate
To a mixture of 5-bromo-6-chloro-3-methyl-1H-pyrrolo [2,3-b] pyridine (198 mg, 0.81 mmol) and dehydrated tetrahydrofuran (4 mL) obtained in Reference Example 44, Then, 60% sodium hydride (48 mg, 1.21 mmol) was added little by little, followed by stirring at room temperature for 1 hour. The reaction mixture was ice-cooled again, 4-methylbenzenesulfonyl chloride (185 mg, 0.97 mmol) was added, and the mixture was stirred at room temperature for 15 hr. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. After adding n-hexane (10 mL) to the obtained residue, the solution was removed by decantation. The residue was concentrated under reduced pressure to obtain 300 mg of solid (yield 93%). The title compound (yield 85%) was obtained according to the method of Reference Example 17 using the obtained solid and commercially available ethyl 4-piperidinecarboxylate.
Reference Example 46 1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid
Ethyl 1- {5-bromo-3-methyl-1-[(4-methylphenyl) sulfonyl] -1H-pyrrolo [2,3-b] pyridin-6-yl} piperidine-4 obtained in Reference Example 45 Using carboxylate and phenylboronic acid, a solid (yield 96%) was obtained according to the method of Reference Example 11. The title compound (yield 25%) was obtained as a solid according to the method of Reference Example 13 using the obtained solid.
Reference Example 47 Ethyl 1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate
Organic Letters (2004), 6 (14), 2433-2435. Using the described 3-phenyl-1,8-naphthyridin-2 (1H) -one, a triflate was obtained according to the method of Reference Example 42. The title compound (yield 62%) was obtained as a solid according to the method of Reference Example 17 using the obtained compound and commercially available ethyl 4-piperidinecarboxylate.
Reference Example 48 Ethyl 1- (6-bromo-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate
Organic Letters (2004), 6 (14), 2433-2435. Using the described 3-phenyl-1,8-naphthyridin-2 (1H) -one, a solid (yield 88%, purity about 80%) was obtained according to the method of Reference Example 12. Using the obtained solid, a triflate was obtained according to the method of Reference Example 42. The title compound (74% yield) was obtained as a solid according to the method of Reference Example 17 using the obtained compound and commercially available ethyl 4-piperidinecarboxylate.
Reference Example 49 Ethyl 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate
Using ethyl 1- (6-bromo-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate and 2,4,6-trimethylboroxine obtained in Reference Example 48, The title compound (yield 70%) was obtained as a solid according to the method of Example 11.
Reference Example 50 1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid
Using the ethyl 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 49, the title compound was prepared according to the method of Reference Example 13. Obtained.
Reference Example 51 Ethyl 1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate
Using ethyl 1- (6-bromo-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 48 and commercially available tri-n-butyl (vinyl) tin According to the method of Reference Example 14, a solid (yield 68%) was obtained. Using the obtained solid, the title compound (yield 75%) was obtained according to the method of Reference Example 15.
Reference Example 52 1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid
Using the 6-methyl-3-phenylquinoxalin-2 (1H) -one described in Farmaco (1996), 51 (8,9), 569-577, a triflate was obtained according to the method of Reference Example 42. . Using the obtained compound and commercially available ethyl 4-piperidinecarboxylate, a solid (yield 91%) was obtained according to the method of Reference Example 17. Using the obtained solid, the title compound (99% yield) was obtained as a solid according to the method of Reference Example 13.
Reference Example 53 Ethyl 1- (5-iodo-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate
Using ethyl 1- (6-tert-butoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate and N-iodosuccinimide obtained in Reference Example 26, a solid was prepared according to the method of Reference Example 12. (Yield 96%) was obtained. Using the obtained solid, the title compound (yield 81%) was obtained as a solid according to the method of Reference Example 29.
Reference Example 54 Ethyl 1- [6- (allyloxy) -5-iodo-3-phenylpyridin-2-yl] piperidine-4-carboxylate
Using ethyl 1- (5-iodo-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate and allyl bromide obtained in Reference Example 53, The title compound (yield 100%) was obtained according to the method.
Reference Example 55 Ethyl 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate
Ethyl 1- [6- (allyloxy) -5-iodo-3-phenylpyridin-2-yl] piperidine-4-carboxylate (6.08 g, 12.4 mmol) obtained in Reference Example 54 To a dioxane (120 mL) solution was added palladium (II) acetate (83 mg, 0.37 mol), cesium carbonate (4.83 g, 14.8 mmol), sodium formate (1.01 g, 14.8 mmol) and tetra-n-butylammonium. Bromide (4.78 g, 14.8 mmol) was added, and the mixture was heated to reflux for 4 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (200 mL) was added to the resulting residue. Insolubles were removed by celite filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10 / 0-9 / 1) to obtain 2.11 g (yield 47%) of the title compound as a solid.
Reference Example 56 1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid
Using ethyl 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 55 according to the method of Reference Example 13, The compound (yield 100%) was obtained as a solid.
Reference Example 57 Ethyl 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate
Using ethyl 1- (5-iodo-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate and 3-bromo-2-methylpropene obtained in Reference Example 53 According to the method of Reference Example 30, an oily substance (yield 72%) was obtained. Using the obtained oil, the title compound (yield 69%) was obtained as a solid according to the method of Reference Example 55.
Reference Example 58 1- (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid
Using ethyl 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 57, The title compound (yield 100%) was obtained as a solid according to the method of Example 13.
Reference Example 59 Ethyl 1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate
Ethyl 1- (5-iodo-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 53 and commercially available 1-bromo-2-butene And an oily substance (79% yield) was obtained according to the method of Reference Example 30. Using the obtained oil, the title compound (yield 68%) was obtained as a solid according to the method of Reference Example 55.
Reference Example 60 1- (3-Ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid
Using ethyl 1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 59, the title was prepared according to the method of Reference Example 13. The compound (99% yield) was obtained as a solid.
Reference Example 61 3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-ol
Under a nitrogen atmosphere, commercially available 2-chloro-2-phenylacetic acid chloride (18.8 g, 116 mmol) in dichloromethane solution was added with commercial 5-trifluoro-2-aminopyridine (20.1 mL, 127 mmol) and ice-cooled solution. Triethylamine (17.7 mL, 127 mmol) was added and stirred at room temperature for 20 hours. An aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9/1) to obtain 32.0 g (yield 88%) of a solid. A solution of the obtained solid (3.00 g, 9.53 mmol) in 2,6-lutidine (10 mL) was subjected to microwave irradiation at 180 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained solid was washed with ether to obtain 1.34 g (yield 51%) of the title compound as a solid.
Reference Example 62 1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid
Using 3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-ol obtained in Reference Example 61, a solid (yield 95%) according to the method of Reference Example 42 Got. Using the obtained solid and commercially available ethyl 4-piperidinecarboxylate, a solid (21% yield) was obtained according to the method of Reference Example 17. The title compound (yield 84%) was obtained as a solid according to the method of Reference Example 13 using the obtained solid.
Reference Example 63 {cis-4-[({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} carbonyl) amino ] Cyclohexyl} acetic acid
Ethyl {cis-4-[({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} obtained in Example 50} The title compound (yield 46%) was obtained as a solid according to the method of Reference Example 31 using carbonyl) amino] cyclohexyl} acetate.
Reference Example 64 1- (4,6-Diphenylpyridazin-3-yl) piperidine-4-carboxylic acid
Using 3-chloro-4,6-diphenylpyridazine described in the specification of PCT WO2007 / 130383 and commercially available ethyl 4-piperidinecarboxylate, an amorphous product (yield 53%) was obtained according to the method of Reference Example 17. Obtained. The title compound was quantitatively obtained according to the method of Reference Example 13 using the obtained amorphous material.
Reference Example 65 3-Chloro-6-ethyl-4-phenylpyridazine
Using 3,6-dichloro-4-phenylpyridazine described in the specification of PCT WO2005 / 072740, a solid (yield 9.9%) was obtained according to the method of Reference Example 14. Using the obtained solid, the title compound (yield 97%) was obtained according to the method of Reference Example 15.
Reference Example 66 1- (6-Ethyl-4-phenylpyridazin-3-yl) piperidine-4-carboxylic acid
Using 3-chloro-6-ethyl-4-phenylpyridazine obtained in Reference Example 65 and commercially available ethyl 4-piperidinecarboxylate, a solid (yield 61%) was obtained according to the method of Reference Example 17. . Using the resulting solid, the title compound was quantitatively obtained according to the method of Reference Example 13.
　参考例に記載の化合物の構造式および物理化学データを以下に示す。 The structural formula and physicochemical data of the compounds described in Reference Examples are shown below.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
（実施例１）１－（５－ブロモ－３－フェニルピリジン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例１３で得られた１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボン酸のアセトニトリル（４ｍＬ）溶液に、参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミド（９２ｍｇ，０．４５ｍｍｏｌ）、４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロリド（１４０ｍｇ，０．４５ｍｍｏｌ）、トリエチルアミン（１２５μＬ，０．８９ｍｍｏｌ）を加え、室温にて１４時間攪拌した。反応混合物に水（２０ｍＬ）を加え、ジクロロメタンにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣に酢酸エチルを加えて粉末化した。固体をろ取し、標記化合物１０３ｍｇ（収率９０％）を固体として得た。
（実施例２）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例１５で得られたエチル　１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率３８％）を固体として得た。
（実施例３）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－メチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例１２で得られたエチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよび２，４，６－トリメチルボロキシンを用いて、参考例１１の方法に準じて油状物（収率４４％）を得た。得られた油状物を用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率５８％）を固体として得た。
（実施例４）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－フェニル－５－プロプ－１－イン－１－イルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例１６で得られたエチル　１－（３－フェニル－５－プロプ－１－イン－１－イルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて油状物を得た。得られた油状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率５５％）を固体として得た。
（実施例５）１－（５－クロロ－３－フェニルピリジン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例１７で得られたエチル　１－（３－ブロモ－５－クロロピリジン－２－イル）ピペリジン－４－カルボキシレートおよびフェニルボロン酸を用いて、参考例１１の方法に準じて固体（収率８５％）を得た。得られた固体を用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８１％）を固体として得た。
（実施例６）１－（３，５－ジフェニルピリジン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例１２で得られたエチル　１－（５－ブロモ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよびフェニルボロン酸を用いて、参考例１１の方法に準じて固体（収率８３％）を得た。得られた固体を用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８９％）を固体として得た。
（実施例７）１－（６－シアノ－５－メチル－３－フェニルピリジン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例１９で得られたエチル　１－（５－ブロモ－６－シアノ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートおよびテトラメチルスズを用いて、参考例１４の方法に準じて油状物（収率９６％）を得た。得られた油状物を用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率９０％）を固体として得た。
（実施例８）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例２１で得られたメチル　１－（５－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率５１％）を固体として得た。
（実施例９）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－フェニル－５－プロピルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例２２で得られたエチル　１－（３－フェニル－５－プロピルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率５９％）を固体として得た。
（実施例１０）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－イソプロピル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例２３で得られたエチル　１－（５－イソプロピル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率４７％）を固体として得た。
（実施例１１）１－（６－シアノ－５－エチル－３－フェニルピリジン－２－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例２５で得られたメチル　１－（６－シアノ－５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率６２％）を固体として得た。
（実施例１２）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－エチル－６－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例３０で得られたエチル　１－（５－エチル－６－メトキシ－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて固体を得た。得られた固体および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率７１％）を固体として得た。
（実施例１３）エチル　［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート
　参考例１５で得られたエチル　１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物およびＩｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ　（１９８０）， １０，　２３７４－２３７９．記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩を用いて、実施例１の方法に準じて標記化合物を定量的に固体として得た。
（実施例１４）Ｎ－［シス－４－（２－アミノ－オキソエチル）シクロヘキシル］－１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例３１で得られた［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸および市販の７Ｎアンモニア－メタノールを用いて、実施例１の方法に準じて標記化合物（収率７１％）を固体として得た。
（実施例１５）エチル　２－［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパノエート
　参考例１５で得られたエチル　１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物（４５０ｍｇ，１．４５ｍｍｏｌ）および参考例１０で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエート（３０９ｍｇ，１．４５ｍｍｏｌ）のジクロロメタン（１４．５ｍＬ）懸濁液に、トリエチルアミン（６０７μＬ，４．３５ｍｍｏｌ）、３Ｈ－［１，２，３］トリアゾロ［４，５－ｂ］ピリジン－３－オール（３９５ｍｇ，２．９０ｍｍｏｌ）および１－エチル－３－(３－ジメチルアミノプロピル) カルボジイミド　塩酸塩（５５７ｍｇ，２．９１ｍｍｏｌ）を加え、室温にて１９時間攪拌した。反応混合物に水を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０－０／１００）により精製し、標記化合物５２６ｍｇ（収率７２％）を固体として得た。
（実施例１６）２－［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパン酸
　実施例１５で得られたエチル　２－［シス－４－（｛［１－（５－エチル－３－フェニルピリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］－２－メチルプロパノエート（３７５ｍｇ，０．７４２ｍｍｏｌ）のエタノール（４．１ｍＬ）溶液に、４Ｎ水酸化ナトリウム水溶液（１．６９ｍＬ，６．７６ｍｍｏｌ）を加え、１６０℃にて３０分間マイクロウェーブ照射を行った。反応混合物に６Ｎ塩酸水溶液を加え、クロロホルムにて抽出した。有機層を合わせ、無水硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／０－９／１）により精製し、標記化合物３１９ｍｇ（収率９０％）を固体として得た。
（実施例１７）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例３５で得られた１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率５２％）を固体として得た。
（実施例１８）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（１－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例３６で得られたエチル　１－（１－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率６３％）を固体として得た。
（実施例１９）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例４０で得られたエチル　１－（５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて固体（収率９７％）を得た。得られた固体および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミド用いて、実施例１の方法に準じて標記化合物（収率８４％）を固体として得た。
（実施例２０）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例４３で得られた１－（５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８０％）を得た。
（実施例２１）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例４３で得られた１－（５－フェニルチエノ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例６で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８０％）を固体として得た。
（実施例２２）エチル　２－メチル－２－［シス－４－（｛［１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例３５で得られた１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例１０で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて標記化合物（収率７７％）を得た。
（実施例２３）２－メチル－２－［シス－４－（｛［１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例２２で得られたエチル　２－メチル－２－［シス－４－（｛［１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例１６の方法に準じて標記化合物（収率３２％）を固体として得た。
（実施例２４）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例４６で得られた１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８０％）を固体として得た。
（実施例２５）メチル　（１Ｓ，３Ｓ）－３－（｛［１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレート
　参考例３５で得られた１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例７で得られたメチル　（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキシレート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率９９％）を得た。
（実施例２６）メチル　（１Ｓ，３Ｓ）－３－（｛［１－（３－クロロ－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレート
　実施例２５で得られたメチル　（１Ｓ，３Ｓ）－３－（｛［１－（５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレート（１２０ｍｇ，０．２６ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液に、氷冷下、Ｎ－クロロスクシンイミド（４２ｍｇ，０．３１ｍｍｏｌ）を加えた後、室温にて５時間攪拌した。反応混合物に水を加え、ジクロロメタンにて抽出した。有機層を合わせ、硫酸ナトリウムにて乾燥した後、減圧下にて溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９／１－１／４）により精製し、標記化合物３３ｍｇ（収率２６％）を得た。
（実施例２７）１－（３－クロロ－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　実施例２６で得られたメチル　（１Ｓ，３Ｓ）－３－（｛［１－（３－クロロ－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレートを用いて、参考例３１の方法に準じてアモルファス状物を得た。得られたアモルファス状物および市販のエチルアミン（２．０Ｍ　テトラヒドロフラン）を用いて、実施例１の方法に準じて標記化合物（収率１２％）を得た。
（実施例２８）エチル　［シス－４－（｛［１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテート
　参考例４６で得られた１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸およびＩｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ　（１９８０）， １０，　２３７４－２３７９．記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩を用いて、実施例１の方法に準じて標記化合物を定量的に得た。
（実施例２９）［シス－４－（｛［１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］酢酸
　実施例２８で得られたエチル　［シス－４－（｛［１－（３－メチル－５－フェニル－１Ｈ－ピロロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］アセテートを用いて、参考例３１の方法に準じて標記化合物（収率６４％）を得た。
（実施例３０）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例４７で得られたエチル　１－（３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じて固体を得た。得られた固体および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８５％）を得た。
（実施例３１）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例５０で得られた１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８６％）を得た。
（実施例３２）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－エチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキサミド
　参考例５１で得られたエチル　１－（６－エチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキシレートを用いて、参考例１３の方法に準じてアモルファス状物を得た。得られたアモルファス状物および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率６２％）を得た。
（実施例３３）メチル　（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレート
　参考例５０で得られた１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボン酸および参考例７で得られたメチル　（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキシレート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率１０９％、純度９１％）を得た。
（実施例３４）Ｎ－［（１Ｓ，３Ｓ）－３－（メチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボキサミド
　実施例３３で得られたメチル　（１Ｓ，３Ｓ）－３－（｛［１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキサンカルボキシレートを用いて、参考例３１の方法に準じてアモルファス状物（収率９５％）を得た。得られたアモルファス状物および市販のメチルアミン（２．０Ｍ　テトラヒドロフラン溶液）を用いて、実施例１の方法に準じて標記化合物（収率７９％）を得た。
（実施例３５）エチル　２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例５０で得られた１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－カルボン酸および参考例１０で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて標記化合物（収率９７％）を得た。
（実施例３６）２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例３５で得られたエチル　２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニル－１，８－ナフチリジン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例１６の方法に準じて標記化合物（収率７５％）を固体として得た。
（実施例３７）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－カルボキサミド
　参考例５２で得られた１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じて標記化合物（収率８３％）を固体として得た。
（実施例３８）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－カルボキサミド
　参考例５２で得られた１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－カルボン酸および参考例６で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８６％）を得た。
（実施例３９）エチル　２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例５２で得られた１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－カルボン酸および参考例１０で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて標記化合物（収率９５％）を得た。
（実施例４０）２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例３９で得られたエチル　２－メチル－２－［シス－４－（｛［１－（６－メチル－３－フェニルキノキサリン－２－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例１６の方法に準じて標記化合物（収率７７％）を固体として得た。
（実施例４１）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例５６で得られた１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じ、標記化合物（収率７９％）を固体として得た。
（実施例４２）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例５６で得られた１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例６で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例１の方法に準じ、標記化合物（収率５６％）を得た。
（実施例４３）エチル　２－メチル－２－［シス－４－（｛［１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエート
　参考例５６で得られた１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例１０で得られたエチル　２－（シス－４－アミノシクロヘキシル）－２－メチルプロパノエートを用いて、実施例１の方法に準じて標記化合物（収率９０％）を得た。
（実施例４４）２－メチル－２－［シス－４－（｛［１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパン酸
　実施例４３で得られたエチル　２－メチル－２－［シス－４－（｛［１－（３－メチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－イル］カルボニル｝アミノ）シクロヘキシル］プロパノエートを用いて、実施例１６の方法に準じて標記化合物（収率６７％）を固体として得た。
（実施例４５）１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例５８で得られた１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じ、標記化合物（収率７０％）を得た。
（実施例４６）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例５８で得られた１－（３，３－ジメチル－５－フェニル－２，３－ジヒドロフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例６で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例１の方法に準じ、標記化合物（収率４７％）を得た。
（実施例４７）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例６０で得られた１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１の方法に準じ、標記化合物（収率７５％）を得た。
（実施例４８）Ｎ－［（１Ｓ，３Ｓ）－３－カルバモイルシクロヘキシル］－１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボキサミド
　参考例６０で得られた１－（３－エチル－５－フェニルフロ［２，３－ｂ］ピリジン－６－イル）ピペリジン－４－カルボン酸および参考例６で得られた（１Ｓ，３Ｓ）－３－アミノシクロヘキサンカルボキサミド　塩酸塩を用いて、実施例１の方法に準じ、標記化合物（収率８３％）を固体として得た。
（実施例４９）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－カルボキサミド
　参考例６２で得られた１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１５の方法に準じて標記化合物（収率８３％）を固体として得た。
（実施例５０）エチル　｛シス－４－［（｛１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－イル｝カルボニル）アミノ］シクロヘキシル｝アセテート
　参考例６２で得られた１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－カルボン酸およびＩｚｖｅｓｔｉｙａ Ａｋａｄｅｍｉｉ Ｎａｕｋ ＳＳＳＲ， ＳｅｒｉｙａＫｈｉｍｉｃｈｅｓｋａｙａ（１９８０），１０，２３７４－２３７９記載のエチル　（シス－４－アミノシクロヘキシル）アセテート　塩酸塩を用いて、実施例１の方法に準じて標記化合物（収率８４％）を得た。
（実施例５１）Ｎ－［シス－４－（２－アミノ－２－オキソエチル）シクロヘキシル］－１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－カルボキサミド
　参考例６３で得られた｛シス－４－［（｛１－［３－フェニル－６－（トリフルオロメチル）イミダゾ［１，２－ａ］ピリジン－２－イル］ピペリジン－４－イル｝カルボニル）アミノ］シクロヘキシル｝酢酸および市販の７Ｎアンモニア－メタノール溶液を用いて、実施例１の方法に準じて標記化合物（収率５９％）を固体として得た。
（実施例５２）１－（４，６－ジフェニルピリダジン－３－イル）－Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］ピペリジン－４－カルボキサミド
　参考例６４で得られた１－（４，６－ジフェニルピリダジン－３－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１５の方法に準じて標記化合物（収率６４％）を固体として得た。
（実施例５３）Ｎ－［（１Ｓ，３Ｓ）－３－（エチルカルバモイル）シクロヘキシル］－１－（６－エチル－４－フェニルピリダジン－３－イル）ピペリジン－４－カルボキサミド
　参考例６６で得られた１－（６－エチル－４－フェニルピリダジン－３－イル）ピペリジン－４－カルボン酸および参考例４で得られた（１Ｓ，３Ｓ）－３－アミノ－Ｎ－エチルシクロヘキサンカルボキサミドを用いて、実施例１５の方法に準じて標記化合物（収率８０％）を得た。 Example 1 1- (5-Bromo-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
To the solution of 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 13 in acetonitrile (4 mL), (1S, 3S)- 3-Amino-N-ethylcyclohexanecarboxamide (92 mg, 0.45 mmol), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride (140 mg, 0 .45 mmol) and triethylamine (125 μL, 0.89 mmol) were added, and the mixture was stirred at room temperature for 14 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was pulverized by adding ethyl acetate. The solid was collected by filtration to give 103 mg (yield 90%) of the title compound as a solid.
Example 2 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide
Using the ethyl 1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 15, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 38%) was obtained according to the method of Example 1. Obtained as a solid.
Example 3 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-methyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide
Using the ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 12 and 2,4,6-trimethylboroxine, the method of Reference Example 11 was performed. Accordingly, an oily substance (44% yield) was obtained. Using the obtained oil, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 58%) was obtained according to the method of Example 1. Obtained as a solid.
Example 4 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-5-prop-1-in-1-ylpyridin-2-yl) piperidine-4- Carboxamide
Using ethyl 1- (3-phenyl-5-prop-1-in-1-ylpyridin-2-yl) piperidin-4-carboxylate obtained in Reference Example 16, an oil was prepared according to the method of Reference Example 13. I got a thing. Using the obtained oil and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 55%) was solidified according to the method of Example 1 Got as.
Example 5 1- (5-Chloro-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
Using ethyl 1- (3-bromo-5-chloropyridin-2-yl) piperidine-4-carboxylate and phenylboronic acid obtained in Reference Example 17, a solid (yield) according to the method of Reference Example 11 85%). Using the obtained solid, an amorphous material was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 81%) was obtained according to the method of Example 1. Obtained as a solid.
Example 6 1- (3,5-Diphenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
Using the ethyl 1- (5-bromo-3-phenylpyridin-2-yl) piperidine-4-carboxylate and phenylboronic acid obtained in Reference Example 12, a solid (yield) according to the method of Reference Example 11 83%). Using the obtained solid, an amorphous material was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 89%) was obtained according to the method of Example 1. Obtained as a solid.
Example 7 1- (6-Cyano-5-methyl-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
According to the method of Reference Example 14, using ethyl 1- (5-bromo-6-cyano-3-phenylpyridin-2-yl) piperidine-4-carboxylate and tetramethyltin obtained in Reference Example 19 An oil (yield 96%) was obtained. Using the obtained oil, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 90%) was obtained according to the method of Example 1. Obtained as a solid.
Example 8 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxamide
Using the methyl 1- (5-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 21, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 51%) was obtained according to the method of Example 1. Obtained as a solid.
Example 9 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-5-propylpyridin-2-yl) piperidine-4-carboxamide
Using the ethyl 1- (3-phenyl-5-propylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 22, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 59%) was obtained according to the method of Example 1. Obtained as a solid.
Example 10 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-isopropyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide
Using the ethyl 1- (5-isopropyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 23, an amorphous product was obtained according to the method of Reference Example 13. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 47%) was obtained according to the method of Example 1. Obtained as a solid.
Example 11 1- (6-Cyano-5-ethyl-3-phenylpyridin-2-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
Using the methyl 1- (6-cyano-5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 25, an amorphous product was prepared according to the method of Reference Example 13. Obtained. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 62%) was obtained according to the method of Example 1. Obtained as a solid.
Example 12 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-6-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxamide
Using the ethyl 1- (5-ethyl-6-methoxy-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 30, a solid was obtained according to the method of Reference Example 13. . Using the obtained solid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 71%) as a solid was obtained according to the method of Example 1. Obtained.
Example 13 Ethyl [cis-4-({[1- (5-Ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetate
Using the ethyl 1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 15, an amorphous product was obtained according to the method of Reference Example 13. The obtained amorphous material and Izvestiya Akademii Nauk SSSR, SeriyaKimicheskaya (1980), 10, 2374-2379. The title compound was quantitatively obtained as a solid according to the method of Example 1 using the described ethyl (cis-4-aminocyclohexyl) acetate hydrochloride.
Example 14 N- [cis-4- (2-amino-oxoethyl) cyclohexyl] -1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxamide
[Cis-4-({[1- (5-ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid obtained in Reference Example 31 and commercially available 7N ammonia- Using methanol, the title compound (yield 71%) was obtained as a solid according to the method of Example 1.
Example 15 Ethyl 2- [cis-4-({[1- (5-Ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] -2-methylpropano Eate
Using the ethyl 1- (5-ethyl-3-phenylpyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 15, an amorphous product was obtained according to the method of Reference Example 13. The obtained amorphous product (450 mg, 1.45 mmol) and ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate (309 mg, 1.45 mmol) obtained in Reference Example 10 in dichloromethane (14 0.5 mL) suspension was triethylamine (607 μL, 4.35 mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (395 mg, 2.90 mmol) and 1-ethyl. -3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (557 mg, 2.91 mmol) was added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 0-0 / 100) to obtain 526 mg (yield 72%) of the title compound as a solid.
Example 16 2- [cis-4-({[1- (5-Ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] -2-methylpropanoic acid
Ethyl 2- [cis-4-({[1- (5-ethyl-3-phenylpyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] -2-methyl obtained in Example 15 To a solution of propanoate (375 mg, 0.742 mmol) in ethanol (4.1 mL) was added 4N aqueous sodium hydroxide solution (1.69 mL, 6.76 mmol), and microwave irradiation was performed at 160 ° C. for 30 minutes. A 6N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 10 / 0-9 / 1) to obtain 319 mg (yield 90%) of the title compound as a solid.
Example 17 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4- Carboxamide
1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 35 and (1S, 3S)-obtained in Reference Example 4 The title compound (52% yield) was obtained as a solid according to the method of Example 1 using 3-amino-N-ethylcyclohexanecarboxamide.
Example 18 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (1-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) Piperidine-4-carboxamide
Using the ethyl 1- (1-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 36, the method of Reference Example 13 According to the above, an amorphous material was obtained. Using the obtained amorphous product and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 63%) was obtained according to the method of Example 1. Obtained as a solid.
Example 19 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine- 4-carboxamide
According to the method of Reference Example 13, using ethyl 1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate obtained in Reference Example 40 To obtain a solid (yield 97%). Using the obtained solid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 84%) was obtained as a solid according to the method of Example 1. It was.
Example 20 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (5-phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxamide
1- (5-Phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 43 and (1S, 3S) -3-amino obtained in Reference Example 4 The title compound (yield 80%) was obtained according to the method of Example 1 using -N-ethylcyclohexanecarboxamide.
Example 21 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (5-phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxamide
1- (5-Phenylthieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 43 and (1S, 3S) -3-amino obtained in Reference Example 6 The title compound (yield 80%) was obtained as a solid according to the method of Example 1 using cyclohexanecarboxamide hydrochloride.
Example 22 Ethyl 2-methyl-2- [cis-4-({[1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl } Amino) cyclohexyl] propanoate
1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 35 and ethyl 2- (cis- Using 4-aminocyclohexyl) -2-methylpropanoate, the title compound (yield 77%) was obtained according to the method of Example 1.
Example 23 2-Methyl-2- [cis-4-({[1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} Amino) cyclohexyl] propanoic acid
Ethyl 2-methyl-2- [cis-4-({[1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] obtained in Example 22 ] Carbonyl} amino) cyclohexyl] propanoate was used to give the title compound as a solid (yield 32%) according to the method of Example 16.
Example 24 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) Piperidine-4-carboxamide
1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 46 and Reference Example 4 (1S , 3S) -3-Amino-N-ethylcyclohexanecarboxamide was used to give the title compound (yield 80%) as a solid according to the method of Example 1.
Example 25 Methyl (1S, 3S) -3-({[1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) Cyclohexanecarboxylate
1- (5-Phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 35 and methyl (1S, 3S) obtained in Reference Example 7 -3-Aminocyclohexanecarboxylate The title compound (yield 99%) was obtained according to the method of Example 1 using hydrochloride.
Example 26 Methyl (1S, 3S) -3-({[1- (3-Chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] Carbonyl} amino) cyclohexanecarboxylate
Methyl (1S, 3S) -3-({[1- (5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} obtained in Example 25 N-chlorosuccinimide (42 mg, 0.31 mmol) was added to a solution of (amino) cyclohexanecarboxylate (120 mg, 0.26 mmol) in dichloromethane (2 mL) under ice cooling, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1-1 / 4) to obtain 33 mg (yield 26%) of the title compound.
Example 27 1- (3-Chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] Piperidine-4-carboxamide
Methyl (1S, 3S) -3-({[1- (3-chloro-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-] obtained in Example 26 [Il] carbonyl} amino) cyclohexanecarboxylate was used to obtain an amorphous product according to the method of Reference Example 31. Using the resulting amorphous product and commercially available ethylamine (2.0 M tetrahydrofuran), the title compound (yield 12%) was obtained according to the method of Example 1.
Example 28 Ethyl [cis-4-({[1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino ) Cyclohexyl] acetate
1- (3-Methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 46 and Izvestia Akademii Nauk SSSR, SeriyaKimicheskaya (1980) , 10, 2374-2379. The title compound was quantitatively obtained according to the method of Example 1 using the described ethyl (cis-4-aminocyclohexyl) acetate hydrochloride.
Example 29 [cis-4-({[1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) Cyclohexyl] acetic acid
Ethyl [cis-4-({[1- (3-methyl-5-phenyl-1H-pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl obtained in Example 28 } Amino) cyclohexyl] acetate was used to obtain the title compound (64% yield) according to the method of Reference Example 31.
Example 30 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide
Using the ethyl 1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate obtained in Reference Example 47, a solid was obtained according to the method of Reference Example 13. Using the obtained solid and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 85%) was obtained according to the method of Example 1. .
Example 31 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide
1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 50 and (1S, 3S) -3- obtained in Reference Example 4 The title compound (yield 86%) was obtained according to the method of Example 1 using amino-N-ethylcyclohexanecarboxamide.
Example 32 N-[(1S, 3S) -3- (Ethylcarbamoyl) cyclohexyl] -1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide
Using ethyl 1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-carboxylate obtained in Reference Example 51, an amorphous product according to the method of Reference Example 13 Got. Using the obtained amorphous substance and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4, the title compound (yield 62%) was obtained according to the method of Example 1. Obtained.
Example 33 Methyl (1S, 3S) -3-({[1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxy rate
1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 50 and methyl (1S, 3S) -3 obtained in Reference Example 7 -Aminocyclohexanecarboxylate The title compound (yield 109%, purity 91%) was obtained according to the method of Example 1 using hydrochloride.
Example 34 N-[(1S, 3S) -3- (Methylcarbamoyl) cyclohexyl] -1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide
Methyl (1S, 3S) -3-({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino) obtained in Example 33 Using cyclohexanecarboxylate, an amorphous substance (yield 95%) was obtained according to the method of Reference Example 31. The title compound (yield 79%) was obtained according to the method of Example 1 using the obtained amorphous product and commercially available methylamine (2.0 M tetrahydrofuran solution).
Example 35 Ethyl 2-methyl-2- [cis-4-({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino ) Cyclohexyl] propanoate
1- (6-Methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 50 and ethyl 2- (cis-4-) obtained in Reference Example 10 The title compound (yield 97%) was obtained according to the method of Example 1 using aminocyclohexyl) -2-methylpropanoate.
Example 36 2-Methyl-2- [cis-4-({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino) Cyclohexyl] propanoic acid
Ethyl 2-methyl-2- [cis-4-({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl obtained in Example 35 } Amino) cyclohexyl] propanoate was used to give the title compound (yield 75%) as a solid according to the method of Example 16.
Example 37 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxamide
1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 52 and (1S, 3S) -3-amino-N-ethyl obtained in Reference Example 4 The title compound (yield 83%) was obtained as a solid according to the method of Example 1 using cyclohexanecarboxamide.
Example 38 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (6-methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxamide
1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 52 and (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride obtained in Reference Example 6 In accordance with the method of Example 1, the title compound (yield 86%) was obtained.
Example 39 Ethyl 2-methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate
1- (6-Methyl-3-phenylquinoxalin-2-yl) piperidine-4-carboxylic acid obtained in Reference Example 52 and ethyl 2- (cis-4-aminocyclohexyl) -2 obtained in Reference Example 10 Using the methylpropanoate, the title compound (yield 95%) was obtained according to the method of Example 1.
Example 40 2-Methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid
Ethyl 2-methyl-2- [cis-4-({[1- (6-methyl-3-phenylquinoxalin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] obtained in Example 39] The title compound (yield 77%) was obtained as a solid using propanoate according to the method of Example 16.
Example 41 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4- Carboxamide
1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 56 and (1S, 3S)-obtained in Reference Example 4 The title compound (yield 79%) was obtained as a solid according to the method of Example 1 using 3-amino-N-ethylcyclohexanecarboxamide.
Example 42 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide
1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 56 and (1S, 3S)-obtained in Reference Example 6 Using 3-aminocyclohexanecarboxamide hydrochloride according to the method of Example 1, the title compound (yield 56%) was obtained.
Example 43 Ethyl 2-methyl-2- [cis-4-({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl } Amino) cyclohexyl] propanoate
1- (3-Methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 56 and ethyl 2- (cis- The title compound (90% yield) was obtained using 4-aminocyclohexyl) -2-methylpropanoate according to the method of Example 1.
Example 44 2-Methyl-2- [cis-4-({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} Amino) cyclohexyl] propanoic acid
Ethyl 2-methyl-2- [cis-4-({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] obtained in Example 43 ] Carbonyl} amino) cyclohexyl] propanoate was used to obtain the title compound (yield 67%) as a solid according to the method of Example 16.
Example 45 1- (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) -N-[(1S, 3S) -3- (ethyl Carbamoyl) cyclohexyl] piperidine-4-carboxamide
1- (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 58 and obtained in Reference Example 4 Using the obtained (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide, the title compound (yield 70%) was obtained according to the method of Example 1.
Example 46 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl ) Piperidine-4-carboxamide
1- (3,3-Dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 58 and obtained in Reference Example 6 Using the obtained (1S, 3S) -3-aminocyclohexanecarboxamide hydrochloride, the title compound (yield 47%) was obtained according to the method of Example 1.
Example 47 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4- Carboxamide
1- (3-Ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 60 and (1S, 3S)-obtained in Reference Example 4 The title compound (yield 75%) was obtained according to the method of Example 1 using 3-amino-N-ethylcyclohexanecarboxamide.
Example 48 N-[(1S, 3S) -3-carbamoylcyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide
1- (3-Ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid obtained in Reference Example 60 and (1S, 3S)-obtained in Reference Example 6 The title compound (yield 83%) was obtained as a solid according to the method of Example 1 using 3-aminocyclohexanecarboxamide hydrochloride.
Example 49 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl ] Piperidine-4-carboxamide
1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid obtained in Reference Example 62 and Reference Example 4 ( The title compound (yield 83%) was obtained as a solid according to the method of Example 15 using 1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide.
Example 50 Ethyl {cis-4-[({1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} carbonyl) Amino] cyclohexyl} acetate
1- [3-Phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid obtained in Reference Example 62 and Izvestia Akademii Nauk SSSR, SeriyaKimicheskaya (1980) ), 10, 2374-2379, and the title compound (yield 84%) was obtained according to the method of Example 1 using ethyl (cis-4-aminocyclohexyl) acetate hydrochloride.
Example 51 N- [cis-4- (2-amino-2-oxoethyl) cyclohexyl] -1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine-2- Yl] piperidine-4-carboxamide
{Cis-4-[({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} carbonyl obtained in Reference Example 63 ) Amino] cyclohexyl} acetic acid and a commercially available 7N ammonia-methanol solution were used to obtain the title compound (yield 59%) as a solid according to the method of Example 1.
Example 52 1- (4,6-Diphenylpyridazin-3-yl) -N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide
1- (4,6-Diphenylpyridazin-3-yl) piperidine-4-carboxylic acid obtained in Reference Example 64 and (1S, 3S) -3-amino-N-ethylcyclohexanecarboxamide obtained in Reference Example 4 Was used to give the title compound (yield 64%) as a solid according to the method of Example 15.
Example 53 N-[(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-ethyl-4-phenylpyridazin-3-yl) piperidine-4-carboxamide
1- (6-Ethyl-4-phenylpyridazin-3-yl) piperidine-4-carboxylic acid obtained in Reference Example 66 and (1S, 3S) -3-amino-N-ethyl obtained in Reference Example 4 The title compound (yield 80%) was obtained according to the method of Example 15 using cyclohexanecarboxamide.
　実施例に記載の化合物の構造式および物理化学データを以下に示す。 The structural formulas and physicochemical data of the compounds described in the examples are shown below.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024

Claims (10)

  1. 一般式（Ｉ）で表わされる化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000001
    ｛式中、Ｒ１、Ｒ２，Ｒ３、およびＲ４は、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルコキシ基で置換されていてもよいＣ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ１－Ｃ６アルキル基で置換されていてもよいエチニル基、又はフェニル基を表わし、
    Ｘ１およびＸ２は、炭素原子又は窒素原子を表わし、
    Ｙは、置換基群αから選択される１乃至３の基で置換されていてもよいＣ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基、又はＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基を表わし、
    ｎは、０又は１であり、
    （ｉ）ｎが０の場合：
    環Ａは、Ｘ１とＸ２が隣り合う５員の不飽和の複素環を形成し、Ｒ２およびＲ４は、それらが結合している環の炭素原子又は窒素原子と一緒になって、飽和又は不飽和の５員～６員の炭化水素環又は複素環を形成していてもよく、形成された炭化水素環又は複素環は、置換基群βから選択される基で置換されていてもよい。
    （ｉｉ）ｎが１の場合：
    環Ａは、６員の不飽和の炭化水素環又は複素環を形成し、Ｒ３およびＲ４は、それらが結合している環の炭素原子又は窒素原子と一緒になって、飽和又は不飽和の５員～６員の炭化水素環又は複素環を形成していてもよく、形成された炭化水素環又は複素環は、置換基群βから選択される基で置換されていてもよい。
    置換基群αは、水酸基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルキル基で置換されていてもよいカルボキシ基、およびＣ１－Ｃ６アルキル基で置換されていてもよいカルバモイル基を表わす。
    置換基群βはハロゲン原子、および１乃至３個のハロゲン原子で置換されていてもよいＣ１－Ｃ６アルキル基を表わす。｝     A compound represented by formula (I) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
    {Wherein, R 1, R 2, R 3, and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, C 1 -C 6 optionally substituted by an alkoxy group C 1 -C 6 Represents an alkyl group, a C 1 -C 6 alkoxy group, an ethynyl group optionally substituted with a C 1 -C 6 alkyl group, or a phenyl group;
    X 1 and X 2 represent a carbon atom or a nitrogen atom,
    Y is a C 1 -C 6 alkyl group optionally substituted with 1 to 3 groups selected from the substituent group α, a carboxy group optionally substituted with a C 1 -C 6 alkyl group, or C Represents a carbamoyl group optionally substituted by a 1 -C 6 alkyl group,
    n is 0 or 1;
    (I) When n is 0:
    Ring A forms a 5-membered unsaturated heterocycle where X 1 and X 2 are adjacent, and R 2 and R 4 together with the carbon or nitrogen atom of the ring to which they are attached, A saturated or unsaturated 5- to 6-membered hydrocarbon ring or heterocyclic ring may be formed, and the formed hydrocarbon ring or heterocyclic ring is substituted with a group selected from the substituent group β. Also good.
    (Ii) When n is 1:
    Ring A forms a 6-membered unsaturated hydrocarbon ring or heterocyclic ring, and R 3 and R 4 together with the carbon or nitrogen atom of the ring to which they are attached are saturated or unsaturated The 5-membered to 6-membered hydrocarbon ring or heterocyclic ring may be formed, and the formed hydrocarbon ring or heterocyclic ring may be substituted with a group selected from the substituent group β.
    Substituent group α represents a hydroxyl, C 1 -C 6 alkyl group, C 1 -C 6 alkyl group optionally substituted carboxyl group, and C 1 -C 6 alkyl carbamoyl group which may be substituted with a group Represents.
    The substituent group β represents a halogen atom and a C 1 -C 6 alkyl group which may be substituted with 1 to 3 halogen atoms. }
  2. Ｘ１が炭素原子でありＸ２が炭素原子である、請求項１に記載の化合物又はその薬理上許容される塩。 The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein X 1 is a carbon atom and X 2 is a carbon atom.
  3. ｎが１である、請求項１乃至請求項２のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 2, wherein n is 1.
  4. 環Ａが、６員の不飽和の複素環である、請求項１乃至請求項３のいずれか１項に記載の化合物又はその薬理上許容される塩。 The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 3, wherein Ring A is a 6-membered unsaturated heterocyclic ring.
  5. Ｒ３、Ｒ４およびそれらが結合している環の炭素原子又は水素原子が一緒になって形成する環が、フラン環、ジヒドロフラン環、チオフェン環、ピロール環、ピリジン環、又はベンゼン環である、請求項１乃至請求項４のいずれか１項に記載の化合物又はその薬理上許容される塩。 The ring formed by combining R 3 , R 4 and the carbon atom or hydrogen atom of the ring to which they are bonded together is a furan ring, a dihydrofuran ring, a thiophene ring, a pyrrole ring, a pyridine ring, or a benzene ring. The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof.
  6. 一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  7. プロスタグランジンE2により介在される疾患を予防又は治療するために用いるための、請求項６に記載された医薬組成物。 For use for preventing or treating a disease mediated by prostaglandin E 2, the pharmaceutical composition according to claim 6.
  8. プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、月経困難症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、変形性関節症に伴う疼痛、頭痛、自己免疫性肝炎、胆石性疼痛、癌転移や家族性大腸ポリポーシスに伴う疼痛、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、強皮症、アテローム性動脈硬化症、およびそれに伴う心筋梗塞、脳卒中、腹部大動脈瘤、無呼吸症候群、呼吸窮迫症候群、慢性閉塞性肺疾患、乳幼児突然死症候群、喘息、発熱、炎症性食欲不振、多発性硬化症、又はアルツハイマー病である、請求項７に記載された医薬組成物。 Diseases mediated by prostaglandin E 2 include rheumatoid arthritis, osteoarthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis including psoriasis, eczema, edema, inflammation Pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis Gallstone pain, pain associated with cancer metastasis and familial colorectal polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, scleroderma, atherosclerosis, and associated myocardial infarction, stroke, abdomen The medicament according to claim 7, which is aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sclerosis, or Alzheimer's disease. Narubutsu.
  9. プロスタグランジンE2により介在される疾患が、慢性関節リウマチ、変形性関節症、喘息、慢性閉塞性肺疾患、潰瘍性大腸炎、炎症性疼痛、自己免疫性肝炎、多発性硬化症、又は乾癬を含む皮膚炎である、請求項７乃至請求項８に記載された医薬組成物。 Diseases mediated by prostaglandin E 2 are rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis The pharmaceutical composition according to claim 7, wherein the composition is dermatitis comprising
  10. 一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物の有効量を哺乳動物に投与することを特徴とする、炎症性疾患の予防方法又は治療方法。 A method for preventing or treating an inflammatory disease, comprising administering to a mammal an effective amount of a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
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