WO2013146969A1 - Nouveau dérivé de cyclohexane disubstitué - Google Patents

Nouveau dérivé de cyclohexane disubstitué 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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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D471/00—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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—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
    • 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
    • C07D491/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
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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.

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Abstract

La présente invention concerne : des composés présentant un effet préventif ou thérapeutique sur la polyarthrite rhumatoïde chronique, l'arthrose, l'asthme, la bronchopneumopathie obstructive chronique, la rectocolite hémorragique, les douleurs inflammatoires, l'hépatite auto-immune, la sclérose en plaques, la dermatite, notamment le psoriasis, etc. ; une composition pharmaceutique contenant lesdits composés ; et une méthode de prévention ou de traitement des maladies inflammatoires, caractérisée en ce qu'une dose efficace de la composition pharmaceutique est administrée à des mammifères. La présente invention concerne les composés représentés par la formule générale (I) ou leurs sels de qualité pharmaceutique.
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US8933236B2 (en) 2012-05-22 2015-01-13 Xenon Pharmaceuticals Inc. N-substituted benzamides and methods of use thereof
US8952169B2 (en) 2012-05-22 2015-02-10 Xenon Pharmaceuticals Inc. N-substituted benzamides and methods of use thereof
US10071957B2 (en) 2012-07-06 2018-09-11 Genentech, Inc. N-substituted benzamides and methods of use thereof
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WO2014092100A1 (fr) * 2012-12-11 2014-06-19 武田薬品工業株式会社 Composé hétérocyclique
US9643957B2 (en) 2012-12-11 2017-05-09 Takeda Pharmaceutical Company Limited Heterocyclic compounds having cholesterol 24-hydroxylase activity
US9550775B2 (en) 2013-03-14 2017-01-24 Genentech, Inc. Substituted triazolopyridines and methods of use thereof
US9493429B2 (en) 2013-03-15 2016-11-15 Genentech, Inc. Substituted benzoxazoles and methods of use thereof
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US10526285B2 (en) 2014-07-07 2020-01-07 Genentech, Inc. Therapeutic compounds and methods of use thereof
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US10899732B2 (en) 2015-11-25 2021-01-26 Genentech, Inc. Substituted benzamides useful as sodium channel blockers
US10766858B2 (en) 2016-03-30 2020-09-08 Genentech, Inc. Substituted benzamides and methods of use thereof
US11203572B2 (en) 2016-03-30 2021-12-21 Genentech, Inc. Substituted benzamides and methods of use thereof
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US10793550B2 (en) 2017-03-24 2020-10-06 Genentech, Inc. 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors
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US10947251B2 (en) 2018-03-30 2021-03-16 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2023082145A1 (fr) * 2021-11-11 2023-05-19 4B Technologies (Suzhou) Limited Composé intermédiaire de quinoxaline et son procédé de préparation
WO2023083247A1 (fr) * 2021-11-11 2023-05-19 4B Technologies (Suzhou) Limited Composé intermédiaire de quinoxaline et son procédé de préparation

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