WO2015046405A1 - Analgésique - Google Patents

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WO2015046405A1
WO2015046405A1 PCT/JP2014/075571 JP2014075571W WO2015046405A1 WO 2015046405 A1 WO2015046405 A1 WO 2015046405A1 JP 2014075571 W JP2014075571 W JP 2014075571W WO 2015046405 A1 WO2015046405 A1 WO 2015046405A1
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mmol
cyano
piperidine
benzyl
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PCT/JP2014/075571
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Japanese (ja)
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建也 西
裕 西村
祐子 加藤
新之助 林
亜衣子 山崎
将史 山本
由次 浅岡
将輝 山田
光 長谷部
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東レ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an analgesic.
  • Pain is an experience with an unpleasant sensation or unpleasant emotion that occurs when tissue damage or potential damage is caused. Pain is mainly classified into nociceptive pain and neuropathic pain, depending on the cause. In the present specification, “pain” and “pain” are synonymous.
  • Nociceptive pain refers to pain caused by damage to a living tissue or the addition of a noxious stimulus having such a risk, and refers to pain via a nociceptor. For example, physiological pain and inflammatory pain are applicable.
  • Neuropathic pain is pathological pain caused by abnormal functioning of the peripheral or central nervous system itself, and is caused by direct damage or compression of nerve tissue even though nociceptors are not subjected to noxious stimulation. This refers to the pain that occurs.
  • Neuropathic pain is defined as “pain caused directly by damage or disease to the somatosensory system” at the International Society of Pain (IASP) (Non-Patent Document 1), along with nociceptive pain and the like. It is positioned as one, and is classified into peripheral and central depending on the causative disease (Non-patent Document 2).
  • Neuropathic pain is characterized by persistent spontaneous pain, allodynia (pain response to non-nociceptive stimuli) and hyperalgesia, and in patients with neuropathic pain, severe pain due to these is a long-term of several months to 10 years or more. Since QOL (Quality of life) is significantly reduced (Non-patent Document 3), active treatment is required.
  • Non-steroidal anti-inflammatory analgesics NSAIDs
  • narcotic analgesics opioid, etc.
  • anticonvulsants and antidepressants are used as analgesics for neuropathic pain.
  • Antiepileptic agents such as anti-anxiety agents, gabapentin and pregabalin are used.
  • EETs epoxyeicosatrienoic acids
  • sEH soluble epoxide hydrolase
  • DHETs dihydroxyeicosatrienoic acids
  • DHETs soluble epoxide hydrolase inhibitors
  • sEH inhibitors have been shown to increase the amount of EETs (Non-Patent Document 5).
  • compounds having sEH inhibitory activity have been reported, and these compounds have been shown to have analgesic effects on nociceptive pain and neuropathic pain (Non-Patent Documents 6 and 7).
  • Patent Document 1 a heteroaryl amide derivative in which a heteroarylamine is condensed with nipecotic acid as a compound having a nipecotic acid diamide structure
  • Patent Document 2 Amidine derivatives
  • Patent Document 3 hydroxamic acid derivatives
  • Non-steroidal anti-inflammatory analgesics used for nociceptive pain are associated with side effects such as gastrointestinal disorders and renal disorders, and narcotic analgesics are known to have side effects such as constipation, sleepiness, nausea and vomiting. And its use is known to be limited.
  • Anticonvulsants, antidepressants, anxiolytics and antiepileptics used for neuropathic pain frequently involve central side effects such as dizziness, nausea and vomiting, which are difficult to discontinue for a long time or are discontinued. It has been pointed out that there are cases in which these drugs do not provide sufficient analgesic effects with these drugs (Non-patent Document 4).
  • an object of the present invention is to provide a new analgesic effective for pain, particularly nociceptive pain and neuropathic pain.
  • a novel nipecotic acid derivative or a pharmacologically acceptable salt thereof exhibits sEH inhibitory activity, and pain based on its action, In particular, it has been found that it exhibits an excellent analgesic effect against nociceptive pain and neuropathic pain, and has completed the present invention.
  • the present invention provides an analgesic containing an nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms.
  • a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms, Each independently may be substituted with a halogen atom, a hydroxyl group, a cyano group, —SR 6 , —S ( ⁇ O) —R 6 or —S ( ⁇ O) 2 R 6 ), —N (R 6 ) C ( ⁇ O) R 7 , —N (R 6 ) S ( ⁇ O) 2 R 7 , —C ( ⁇ O) N (R 6 ) R 7 or a heteroaryl group having 5 ring atoms, R 2 and R 3 are Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent — (CH 2 ) 1 —.
  • R 4 represents a substituent at the 2-position on the benzene ring
  • R 5 represents a substituent at the 4-position on the benzene ring.
  • R 1 represents —N (R 6 ) C ( ⁇ O) R 7 or —N (R 6 ) S ( ⁇ O) 2 R 7
  • R 4 represents a halogen atom.
  • R 5 represents a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms
  • R 6 represents a hydrogen atom.
  • R 1 represents —N (H) C ( ⁇ O) CH 2 CH 3
  • R 2 and R 3 together represent — (CH 2 ) 3 —
  • R 4 represents It is particularly preferred that it represents —OCF 3 and R 5 represents a cyano group.
  • the above analgesic is preferably an analgesic for nociceptive pain and / or neuropathic pain.
  • the analgesic of the present invention exhibits a high therapeutic effect or preventive effect on nociceptive pain and neuropathic pain based on sEH inhibitory activity, so that it can be administered as a medicine for a wide range of pain symptoms. Become.
  • the analgesic of the present invention is characterized by containing a nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms.
  • a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms, Each independently may be substituted with a halogen atom, a hydroxyl group, a cyano group, —SR 6 , —S ( ⁇ O) —R 6 or —S ( ⁇ O) 2 R 6 ), —N (R 6 ) C ( ⁇ O) R 7 , —N (R 6 ) S ( ⁇ O) 2 R 7 , —C ( ⁇ O) N (R 6 ) R 7 or a heteroaryl group having 5 ring atoms, R 2 and R 3 are Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group
  • C1-C6 alkyl group means a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms, such as a methyl group, Ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-2-propyl group (tert-butyl group), 2-methyl-1-propyl group, 2,2 -Dimethyl-1-propyl group, 1-pentyl group, 2-pentyl group or 3-pentyl group.
  • C 1-6 alkyloxy group means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, -Propyloxy group, 1-butyloxy group or 2-butyloxy group.
  • C3-C6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • C3-C6 cycloalkyloxy group means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.
  • C2-C7 alkyloxyalkyl group means a group having 2 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with an alkyloxy group.
  • cycloalkyl alkyl group having 4 to 7 carbon atoms means a group having 4 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with a cycloalkyl group. Examples thereof include a methyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • heteroaryl group having 5 ring atoms means that the number of ring atoms is 5 including 1 to 4 identical or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And includes, for example, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, furanyl group and thiazolyl group.
  • R 1 may be —N (R 6 ) C ( ⁇ O) R 7 or —N (R 6 ) S ( ⁇ O) 2 R 7
  • R 1 is acetylamidyl, propionamidyl group or methanesulfonylamidyl group.
  • R 2 and R 3 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or are preferably taken together as — (CH 2 ) 1 —.
  • R 4 is preferably a substituent at the 2-position on the benzene ring.
  • R 4 is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, more preferably a halogen atom or an alkyloxy group, and further preferably an alkyloxy group.
  • R 5 is preferably a substituent at the 4-position on the benzene ring.
  • R 5 is preferably a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms, and more preferably a halogen atom or a cyano group.
  • R 6 is preferably a hydrogen atom
  • R 7 is preferably a methyl group or an ethyl group.
  • L is preferably 2 or 3
  • m is preferably 2
  • n is preferably 2.
  • nipecotic acid derivative (I) has at least one asymmetric carbon atom and has optical isomers and diastereomers.
  • the nipecotic acid derivative (I) includes not only a single isomer but also a racemate and a mixture of diastereomers.
  • all rotamers are included.
  • Examples of the pharmacologically acceptable salt of the nipecotic acid derivative (I) include, for example, hydrochloride, trifluoroacetate, sulfate, nitrate, hydrobromide, hydroiodide or methane as an acid addition salt.
  • Examples of the sulfonate include hydrochloride, sulfate, hydrobromide, hydroiodide, and methanesulfonate.
  • the starting materials and reagents used for the production of the nipecotic acid derivative (I) may be commercially available products or may be synthesized by known methods.
  • the nipecotic acid derivative (Ia) can be produced, for example, by a condensation reaction of an amine derivative (II) and a carboxylic acid derivative (III) in the presence of a base and a condensing agent as shown in the following scheme 1.
  • Scheme 1 [Wherein R 1 ′ represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxy group having 2 to 7 carbon atoms.
  • alkyl group, a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms)
  • R 2 to R 6 are the same as defined above. ]
  • condensing agent used in the condensation reaction examples include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 1- [ Bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate HATU), and HATU is preferred.
  • the equivalent of the condensing agent is preferably 1 to 10 equivalents, and more preferably 1 to 3 equivalents.
  • Examples of the solvent used in the condensation reaction include N, N-dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), dichloromethane, chloroform, diethyl ether or dimethyl ether, with DMF or THF being preferred, and DMF being More preferred.
  • DMF N, N-dimethylformamide
  • THF tetrahydrofuran
  • dichloromethane dichloromethane
  • chloroform chloroform
  • diethyl ether or dimethyl ether dimethyl ether
  • Examples of the base used in the condensation reaction include organic bases such as diisopropylethylamine (hereinafter DIPEA), triethylamine (hereinafter TEA), pyridine or N-methylmorpholine, or organic acid salts such as potassium carbonate, sodium carbonate or sodium bicarbonate. DIPEA or TEA is preferable.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (II).
  • the equivalent amount of the carboxylic acid derivative (III) used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.1 to 10 equivalents, and even more preferably 0.8 to 2 equivalents with respect to the amine derivative (II). .
  • the reaction temperature of the condensation reaction is preferably ⁇ 50 to 100 ° C., more preferably 0 to 50 ° C., and further preferably 0 to 30 ° C.
  • the reaction time for the condensation reaction is preferably 1 minute to 48 hours, more preferably 1 minute to 24 hours, and even more preferably 10 minutes to 24 hours.
  • the concentration of the amine derivative (II) at the start of the condensation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and even more preferably 0.1 to 10M.
  • nipecotic acid derivative (Ib) in which R 1 is —N (H) C ( ⁇ O) R 7 is represented by, for example, an amine derivative (IV) in the presence of a base as shown in Scheme 2 below.
  • an acid chloride derivative (V), or a condensation reaction between an amine derivative (IV) and a carboxylic acid derivative (VI) in the presence of a base and a condensing agent. Scheme 2 [Wherein R 2 to R 5 and R 7 are the same as defined above]. ]
  • Examples of the solvent used for the condensation reaction with the acid chloride derivative (V) include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether or 1,2-dimethoxyethane. 1,2-dichloroethane, acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the acid chloride (V) used in the condensation reaction with the acid chloride derivative (V) is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the amine derivative (IV). 5 equivalents are more preferred.
  • Examples of the base used for the condensation reaction with the acid chloride derivative (V) include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (IV).
  • the reaction temperature of the condensation reaction with the acid chloride derivative (V) is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time for the condensation reaction with acid chloride (V) is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 8 hours.
  • the concentration at the start of the reaction of the amine derivative (IV) in the condensation reaction with the acid chloride derivative (V) is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.
  • nipecotic acid derivative (Ic) in which R 1 is —N (H) S ( ⁇ O) 2 R 7 can be synthesized, for example, with an amine derivative (IV) in the presence of a base as shown in Scheme 3 below. It can be produced by a sulfonamidation reaction with a sulfonic acid chloride derivative (VII). (Scheme 3) [Wherein R 2 to R 5 and R 7 are the same as defined above]. ]
  • Examples of the solvent used in the sulfonamidation reaction include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether, or 1,2-dimethoxyethane, but dichloromethane, 1,2-dichloroethane, Acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the sulfonic acid chloride derivative (VII) used in the sulfonamidation reaction is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, and further preferably 1 to 1.5 equivalents with respect to the amine derivative (IV). preferable.
  • Examples of the base used in the sulfonamidation reaction include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (IV).
  • the reaction temperature of the sulfonamidation reaction is preferably ⁇ 50 to 50 ° C., more preferably ⁇ 30 to 30 ° C., and further preferably ⁇ 20 to 20 ° C.
  • the reaction time of the sulfonamidation reaction is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and further preferably 30 minutes to 8 hours.
  • the concentration of the amine derivative (IV) at the start of the reaction in the sulfonamidation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.
  • the amine derivative (IV) which is the starting material in the above-mentioned schemes 2 and 3, is, for example, after the condensation reaction between the amine derivative (II) and the carboxylic acid derivative (VIII) in the presence of a base, as shown in the following scheme 4.
  • the deprotection reaction following the condensation reaction can be performed by a known method described in, for example, Protective Groups in Organic Synthesis 3rd Edition (Green et al., 1999, John Wiley & Sons, Inc.).
  • the protecting group is a tert-butoxycarbonyl group
  • the protecting group can be removed by treatment with a strong acid such as trifluoroacetic acid.
  • the amine derivative (II) which is the starting material in the above-mentioned schemes 1 and 4 is, for example, as shown in the following scheme 5, in the presence of a base and a condensing agent, benzylamine derivative (IX), nipecotic acid derivative (X) and After the condensation reaction, a deprotection reaction for removing the protecting group can be used.
  • Scheme 5 [Wherein R 4 , R 5 and R 8 are the same as defined above. ]
  • the deprotection reaction can be carried out under the same conditions as in the method described in Scheme 4.
  • the condensation reaction of Scheme 5 can also be performed in the presence of a base by converting the nipecotic acid derivative (X) into an acid chloride.
  • Examples of the reagent for converting the nipecotic acid derivative (X) into acid chloride include oxalyl chloride and thionyl chloride, with oxalyl chloride being preferred.
  • the equivalent amount of the reagent is preferably 1 to 10 equivalents, more preferably 1 to 1.5 equivalents, relative to the nipecotic acid derivative (X).
  • Examples of the solvent used for converting the nipecotic acid derivative (X) into the acid chloride include dichloromethane, chloroform, THF, 1,2-dichloroethane, acetonitrile, 1,4-dioxane, and DMF, and dichloromethane, THF, or DMF.
  • a mixed solvent thereof is preferable, and a mixed solvent of dichloromethane and DMF or a mixed solvent of THF and DMF is more preferable.
  • the reaction temperature for converting the nipecotic acid derivative (X) to acid chloride is preferably -50 to 100 ° C, more preferably -30 to 30 ° C, and further preferably -20 to 0 ° C.
  • the reaction time for converting the nipecotic acid derivative (X) to acid chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 2 hours.
  • the concentration of the nipecotic acid derivative (X) at the start of the reaction when converting the nipecotic acid derivative (X) to acid chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and more preferably 0.1 to 3M. Is more preferable.
  • nipecotic acid derivative (I) obtained as described above, a pharmacologically acceptable salt thereof, or an intermediate, a raw material compound or a reagent used for the production of the nipecotic acid derivative (I) is necessary. Depending on the method, it may be isolated and purified by a method such as extraction, distillation, chromatography or recrystallization.
  • the above analgesic is characterized by containing the above nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient, and is based on sEH inhibitory activity, and in particular, nociceptive pain In addition, it can exert a high analgesic effect on neuropathic pain.
  • SEH is an abbreviation for soluble epoxide hydrolase, which is a metabolic enzyme that catalyzes the hydrolysis of epoxide and converts it to the corresponding diol.
  • the most known substrate of sEH is EETs, which is one of endothelial cell-derived hyperpolarizing factors, and sEH has an action of metabolizing EETs to DHETs and inactivating them.
  • EETs is an abbreviation for Epoxyeicosatrienoic acids
  • DHETs is an abbreviation for Dihydroxyeicosatrienoic acids. Examples of the EETs include 14,15-epoxyeicosatrienoic acid (hereinafter, 14,15-EET). Examples of DHETs include 14,15-dihydroxyeicosatrienoic acid (14,15-DHET).
  • SEH inhibitory activity means an activity that inhibits the action of sEH. Therefore, the sEH inhibitory activity includes the activity of inhibiting the enzymatic reaction of sEH to catalyze the hydrolysis of EETs, which is one of sEH substrates.
  • SEH inhibitor means a compound showing sEH inhibitory activity or a composition containing the compound as an active ingredient.
  • the sEH inhibitory activity is, for example, that human sEH and its substrate EETs are reacted in the presence of an sEH inhibitor, and the amount of DHETs produced is compared with the amount of DHETs produced in the absence of the sEH inhibitor. Can be measured.
  • a commercially available measurement kit Soluable Epoxide Hydrose Inhibitor Screening Assay Kit; Cayman
  • the sEH inhibitory activity of the inhibitor can be measured.
  • racemic 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate was used as a substrate for sEH, and 4-nitrophenolate anion was used.
  • the appearance of 6-methoxy-2-naphthaldehyde is measured using cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate as a substrate for sEH.
  • the sEH inhibitory activity of the sEH inhibitor can also be measured by measuring the appearance.
  • Nociceptive pain refers to pain caused by damage to biological tissue or the addition of a noxious stimulus having such a risk, and refers to pain via nociceptors.
  • nociceptive pain examples include pain caused by injuries such as fractures and cuts, postoperative pain, sprain pain, bruise pain, joint pain, low back pain, muscle pain, post-extraction pain, toothache, appendicitis, rheumatoid arthritis. Pain due to inflammatory diseases such as rheumatic fever, osteoarthritis, ankylosing spondylitis, osteoarthritis, cervical shoulder arm syndrome, periarthritis, connective tissue inflammation, acute otitis media, prostatitis, alveolar periosteitis, vaginitis Can be mentioned.
  • the nociceptive pain includes deep pain and visceral pain (for example, headache, abdominal pain, back and back pain, chronic pelvic pain syndrome, pain associated with endometriosis, pain associated with urolithiasis and urethral stones, Pain associated with gastrointestinal lesions, pelvic pain, pain associated with urological disorders).
  • More preferable target diseases of the above analgesic include rheumatoid arthritis, osteoarthritis, postoperative pain, joint pain, low back pain, muscle pain or toothache.
  • Neuroopathic pain is pathological pain caused by abnormalities in the function of the peripheral or central nervous system itself, and direct damage or compression of nerve tissue even though nociceptors are not subjected to noxious stimuli. This refers to pain caused by the like.
  • neuropathic pain examples include cancer pain, herpes zoster pain, postherpetic neuralgia, painful diabetic neuropathic pain, AIDS-related neuralgia, neuropathic back pain, phantom limb pain, anticancer Neuropathic pain caused by administration of agents, pain after spinal cord injury, pain due to strangulated neuropathy such as carpal trunk syndrome and spinal canal stenosis, pain due to Guillain-Barre syndrome, or trigeminal neuralgia.
  • nipecotic acid derivative (I) which is an active ingredient of the above-mentioned analgesic agent, or a pharmacologically acceptable salt thereof should be evaluated using an appropriate animal model.
  • Suitable animal models for nociceptive pain include, for example, the mouse acetate rising model, the rat formalin test, the rat carrageenan-induced inflammation model, the mouse or rat hot plate test for acute pain, or the tail flick test.
  • suitable animal models of neuropathic pain include, for example, a mouse or rat partial sciatic nerve ligation model or a mouse or rat spinal nerve ligation model, or a mouse or rat streptozotocin-induced diabetic neuropathy model.
  • Acute pain is usually short-term, but includes acute postoperative pain, herpes zoster pain, post-extraction pain, or trigeminal neuralgia.
  • Chronic pain is usually defined as pain lasting for 3-6 months and includes somatic and psychogenic pain, such as rheumatoid arthritis, osteoarthritis, painful diabetic neuropathic pain Chronic postoperative neuropathic pain or postherpetic neuralgia.
  • analgesic is prepared by using a nipecotic acid derivative (I), which is an active ingredient, or a pharmacologically acceptable salt thereof as it is or as a pharmaceutical composition in an appropriate dosage form for mammals (eg, mice, rats, etc.). , Hamsters, rabbits, dogs, monkeys, cows, sheep or humans) orally or parenterally (eg, transdermal, intravenous, rectal, inhalation, nasal or ophthalmic) Can be administered.
  • mammals eg, mice, rats, etc.
  • mammals eg, mice, rats, etc.
  • parenterally eg, transdermal, intravenous, rectal, inhalation, nasal or ophthalmic
  • Examples of the dosage form for administration to mammals include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions or suppositories, or known continuous forms.
  • a formulation is mentioned.
  • These dosage forms can be produced by a known method and contain a carrier generally used in the pharmaceutical field. Examples of such carriers include excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizers, suspending agents, or soothing agents in liquid preparations.
  • excipient examples include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • lubricant examples include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • binder examples include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose or sodium carboxymethylcellulose.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil or corn oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, or sodium citrate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose. , Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.
  • Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the isotonic agent include glucose, sodium chloride, D-sorbitol, and D-mannitol.
  • buffer solutions such as phosphate, acetate, carbonate or citrate.
  • preservative examples include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidant examples include sulfite and ascorbic acid.
  • the analgesic preferably contains 0.001 to 99% by weight, more preferably 0.01 to 99% by weight, of the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof.
  • the effective dosage and frequency of administration of the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof vary depending on the dosage form, patient age, body weight, or the nature or severity of the symptoms to be treated / prevented. However, usually 1 to 1000 mg, preferably 1 to 300 mg per day for an adult can be administered in one or several divided doses.
  • analgesics may be administered alone, but may be combined with other drugs or combined with other drugs to supplement or enhance the preventive or therapeutic effect of the disease or reduce the dose. It can also be used in combination.
  • Examples of other drugs that can be combined or used together include antitussives, expectorants, antitussive expectorants, bronchodilators, peptic ulcers, antibiotics, or narcotic analgesics.
  • the timing of administration of the analgesic and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, May be administered.
  • the concomitant drug may be a low molecular compound, a polymer such as a protein, polypeptide or antibody, or a vaccine.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the analgesic and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination of the above analgesic and concomitant drug, and the like. For example, when the administration subject is a human, the concomitant drug may be used in a mixing ratio of 0.01 to 99.99 with respect to the above analgesic.
  • Antitussives, expectorants and antitussive expectorants include, for example, dextromethorphan, benproperine, dimemorphan, clofedanol, ephedrine, decoben, minc ), Methylephedrine, acetylcysteine, ambroxol, carbocysteine, bromhexine, epradinone, incode, indehyde Ydrocodeine) or tipepidine (tipepidine) and the like.
  • bronchodilators examples include clenbuterol, cromoglycate, salbutamol, salmeterol, tulobuterol, and theophylline.
  • peptic ulcer agents examples include azulene, aldioxa, irsogladine, ecabet, omeprazole, ornoprostil, cimetidine, cimetidine, cimetidine. , Sulpiride, cetraxate or famotidine.
  • Antibiotics include, for example, amoxicillin, azithromycin, erythromycin, clarithromycin, tetracycline, and doxycycline (doxycycline).
  • narcotic analgesics examples include opium alkaloids, ethyl morphine, oxycodone, morphine, cocaine, fentanyl, and pethidine.
  • Step 2 Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanol: At ⁇ 10 ° C., sodium borohydride (2.4 g, 63 mmol) was added to a methanol (0.23 L) solution of Reference Example compound 1 (16 g, 59 mmol). After stirring at ⁇ 10 ° C. for 10 minutes, acetone (10 mL) and 1N hydrochloric acid (10 mL) were added to the reaction solution. The reaction solution was concentrated under reduced pressure, water was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 3 Synthesis of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate: Methanesulfonyl chloride (0.93 g, 8.1 mmol) was added to a solution of Reference Example Compound 2 (2.0 g, 7.4 mmol) and TEA (1.2 mL, 8.9 mmol) in dichloromethane (20 mL) under ice cooling. It was. After stirring at room temperature for 3 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 2.6 g of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate (hereinafter referred to as Reference Example Compound 3) ( (Quantitative).
  • Step 5 Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanamine: Hydrazine monohydrate (0.98 g, 19 mmol) was added to a methanol (40 mL) solution of Reference Example compound 4 (2.6 g, 6.5 mmol) at room temperature. After stirring at 60 ° C. for 2 hours, the solid precipitated at room temperature was filtered off. The filtrate was concentrated under reduced pressure, and the resulting crude product was dissolved in ethyl acetate and washed with water and a saturated aqueous sodium chloride solution.
  • Step 7 Synthesis of (R) -tert-butyl 3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carboxylate: At room temperature, a solution of Reference Compound 6 (0.050 g, 0.10 mmol) and zinc cyanide (0.012 g, 0.10 mmol) in DMF (2.0 mL) was added to tetrakistriphenylphosphine palladium (0) (0. 030 g, 0.026 mmol) was added. After stirring at 150 ° C. for 30 minutes, water was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether.
  • Step 8 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: Under ice-cooling, trifluoroacetic acid (hereinafter TFA) (35 mL, 0.45 mol) was added to a solution of Reference Example Compound 7 (6.9 g, 16 mmol) in dichloromethane (0.16 L). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane.
  • TFA trifluoroacetic acid
  • Example Compound 1 (1-propionamidocyclobutanecarbonyl) piperidine-3-carboxamide was obtained in an amount of 6.2 g (71%).
  • Example Compound 2 (2-Methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 2) was obtained in an amount of 2.4 g (87%).
  • Example Compound 3 (1- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 3) was obtained in an amount of 0.56 g (74%).
  • Example 4 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) piperidine-3-carboxamide: The same reaction as in Example 1 [Step 9] was carried out using 1- (trifluoromethyl) cyclopropanecarboxylic acid (0.054 g, 0.17 mmol) to give (R) -N- (4-cyano- 0.044 g (58%) of 2- (trifluoromethoxy) benzyl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 4) was obtained.
  • Example 5 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (methylsulfonamido) cyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 10 (0.020 g, 0.047 mmol). 0.017 g (71%) of benzyl) -1- (1- (methylsulfonamido) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 5) was obtained.
  • Example 6 Synthesis of (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using isobutyryl chloride (0.0055 g, 0.052 mmol). 0.022 g (95%) of (benzyl) -1- (1-isobutyramidecyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 6) was obtained.
  • Example 7 Synthesis of (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using pivaloyl chloride (0.0063 g, 0.052 mmol). 0.017 g (72%) of (benzyl) -1- (1-pivalamidocyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 7) was obtained.
  • Example 9 Synthesis of (R) -1- (1-acetamidocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1- (1-acetamidocyclobutanecarbonyl) -N- (4) was prepared by performing the same reaction as in Example 8 [Step 3] using Reference compound 10 (0.020 g, 0.047 mmol). 0.013 g (60%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 9) was obtained.
  • Step 2 Synthesis of (R) -1-((R) -2-acetamido-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1-((R) -2-acetamido-3-methyl) was prepared by performing the same reaction as in Example 8 [Step 3] using Reference compound 23 (0.020 g, 0.047 mmol). 0.018 g (83%) of butanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 11) was obtained.
  • Example 12 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3- Synthesis of carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by conducting the same reaction as in Example 2 [Step 3] using Reference Example Compound 23 (0.020 g, 0.047 mmol). 0.020 g (83%) of benzyl) -1-((R) -3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 12) was obtained.
  • Example Compound 13 was obtained in an amount of 0.0080 g (13%).
  • Example Compound 14 (2-Methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide was obtained in an amount of 0.013 g (63%).
  • Example 15 (R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide Synthesis: (R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1 was prepared by carrying out the same reaction as in Example 14 using Example Compound 3 (0.025 g, 0.051 mmol). As a result, 0.020 g (77%) of — (2-methyl-2- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 15) was obtained.
  • Example 16 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-hydroxy-2-methylpropanoyl) piperidine-3-carboxamide: The same reaction as in Example 1 [Step 9] was performed using 2-hydroxy-2-methylpropanoic acid (0.15 g, 0.46 mmol) to give (R) -N- (4-cyano-2- 0.12 g (62%) of (trifluoromethoxy) benzyl) -1- (2-hydroxy-2-methylpropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 16) was obtained.
  • Example 17 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-pivaloylpiperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 8 (0.15 g, 0.46 mmol) and pivaloyl chloride (0.066 g, 0.55 mmol), (R) — 0.19 g (quantitative) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-pivaloylpiperidine-3-carboxamide (hereinafter, Example Compound 17) was obtained.
  • Step 2 Synthesis of ethyl 1- (N-methylmethylsulfonamido) cyclopropanecarboxylate: Sodium hydride (55 wt%, 0.51 g, 12 mmol) was added to a DMF (10 mL) solution of Reference Example Compound 24 (2.0 g, 9.7 mmol) under ice cooling. The mixture was stirred for 10 minutes under ice cooling, and then stirred for 30 minutes at room temperature. Methyl iodide (0.78 mL, 13 mmol) was added to the reaction solution under ice cooling.
  • Step 3 Synthesis of 1- (N-methylmethylsulfonamido) cyclopropanecarboxylic acid: A 1N aqueous sodium hydroxide solution (12 mL, 12 mmol) was added to a methanol (20 mL) solution of Reference Example Compound 25 (1.8 g, 7.9 mmol) at room temperature. After stirring at 50 ° C. for 3 hours, 1N hydrochloric acid was added to the reaction solution at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.88 g (58 %)Obtained.
  • HATU (0.35 g, 0.93 mmol) was added to a DMF (1.6 mL) solution of the obtained crude product (0.10 g) and DIPEA (0.30 mL, 1.7 mmol) under ice cooling. After stirring for 15 minutes under ice cooling, Reference Example Compound 8 (0.28 g, 0.85 mmol) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 Synthesis of (R) -1-((R) -2-aminobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1-((R) -2-aminobutanoyl)-was prepared by carrying out the same reaction as in Example 1 [Step 10] using Reference Example Compound 28 (0.47 g, 0.91 mmol). 0.38 g (quantitative) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 29) was obtained.
  • Step 4 Synthesis of (R) -1-((R) -2-acetamidobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1-((R) -2-acetamidobutanoyl)-was prepared by conducting the same reaction as in Example 8 [Step 3] using Reference compound 29 (0.091 g, 0.22 mmol). 0.085 g (85%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 21) was obtained.
  • Example 22 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 29 (0.096 g, 0.23 mmol). 0.090 g (79%) of (benzyl) -1-((R) -2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 22) was obtained.
  • Example 23 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-cyanocyclopropanecarbonyl) piperidine-3-carboxamide: The same reaction as in Example 1 [Step 9] was performed using 1-cyanocyclopropanecarboxylic acid (0.034 g, 0.31 mmol) to give (R) -N- (4-cyano-2- (tri 0.081 g (63%) of fluoromethoxy) benzyl) -1- (1-cyanocyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 23) was obtained.
  • Morpholine (0.36 mL, 4.1 mmol) was added to a solution of the obtained crude product (0.53 g) in DMF (4.0 mL) at room temperature. After stirring at room temperature for 6 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example Compound 24 The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 25 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 30 (0.10 g, 0.25 mmol). 0.099 g (83%) of benzyl) -1-((R) -2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 25) was obtained.
  • Example 26 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclopropanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and isobutyryl chloride (0.0062 g, 0.058 mmol), (R) — 0.017 g (71%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 26) was obtained. It was.
  • Example 27 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclopropanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and pivaloyl chloride (0.0064 g, 0.058 mmol), (R) — 0.018 g (73%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 27) Obtained.
  • Example 28 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (4- (methylsulfonamido) tetrahydro-2H-pyran-4-carbonyl) piperidine-3- Synthesis of carboxamide: [Step 1] Synthesis of 8-oxa-1,3-diazaspiro [4.5] decane-2,4-dione: Dihydro-2H-pyran 4 (3H) -one (2.0 g, 20 mmol), ammonium carbonate (9.6 g, 0.10 mol), TEA (2.8 mL, 20 mmol) in water: methanol (water: methanol) at room temperature.
  • Example 29 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (cyclopropanecarboxamido) cyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using cyclopropanecarbonyl chloride (0.0059 g, 0.057 mmol). 0.012 g (52%) of benzyl) -1- (1- (cyclopropanecarboxamide) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 29) was obtained.
  • Step 2 Synthesis of (S) -tert-butyl (1,3-dihydroxy-3-methylbutan-2-yl) carbamate: Methyl magnesium bromide diethyl ether solution (3N, 30 mL, 91 mmol) was added to a diethyl ether (0.12 L) solution of Reference Example compound 35 (4.0 g, 18 mmol) at ⁇ 78 ° C. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution and water were added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate.
  • Example Compound 30 ((R) -1-((R) -2-acetamido-3-hydroxy 0.029 g (66%) of -3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 30) was obtained.
  • Example 31 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine- Synthesis of 3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by conducting the same reaction as in Example 1 [Step 11] using Reference Example Compound 39 (0.0083 g, 0.019 mmol). As a result, 0.0065 g (70%) of benzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 31) was obtained.
  • Example Compound 32 0.038 g (81%) of (benzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 32) was obtained. .
  • Example 33 Synthesis of (R) -1- (1-butylamidocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1- (1-Butylamidocyclobutanecarbonyl) -N— (4) was prepared by performing the same reaction as in Example 1 [Step 11] using butyryl chloride (0.0060 g, 0.057 mmol). 0.018 g (79%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 33) was obtained.
  • Example 34 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclobutanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 9] using Reference Example Compound 10 (0.021 g, 0.049 mmol) and 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol), (R) 0.0065 g of —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 34) (26%) obtained.
  • Example 35 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclopropanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 9] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol), (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 35) 0083 g (35%) was obtained.
  • Step 2 Synthesis of sodium 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate: Under ice-cooling, 1N aqueous sodium hydroxide solution (3.9 mL, 3.9 mmol) was added to a solution of Reference Example Compound 40 (0.65 g, 3.6 mmol) in ethanol (18 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and sodium 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate (hereinafter referred to as Reference Example Compound 41) was reduced to 0. Obtained .67 g (quantitative).
  • Example 37 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (1H-pyrazol-1-yl) propanoyl) piperidine-3- Synthesis of carboxamide: [Step 1] Synthesis of ethyl 2-methyl-2- (1H-pyrazol-1-yl) propanoate: The same reaction as in Example 36 [Step 1] was performed using 1H-pyrazole (0.42 g, 6.2 mmol) to give ethyl 2-methyl-2- (1H-pyrazol-1-yl) propanoate ( In the following, 0.81 g (87%) of Reference Example Compound 42) was obtained.
  • Step 2 Synthesis of sodium 2-methyl-2- (1H-pyrazol-1-yl) propanoate: By performing the same reaction as in Example 36 [Step 2] using Reference Example Compound 42 (0.81 g, 4.5 mmol), sodium 2-methyl-2- (1H-pyrazol-1-yl) propanoate 0.80 g of Reference Example Compound 43 was obtained.
  • Step 3 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide: (R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexane) was prepared by performing the same reaction as in Example 20 using Reference Example Compound 45 (0.10 g, 0.35 mmol). 0.030 g (24%) of carbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 38) was obtained.
  • Example Compound 39 ((R) -1-((R) -2-acetamido-3-hydroxy 0.021 g (96%) of -3-methylbutanoyl) -N- (2,4-dichlorobenzyl) piperidine-3-carboxamide (hereinafter, Example Compound 39) was obtained.
  • Example 40 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Compound 47 (0.020 g, 0.050 mmol), (R) -N- (2,4-dichlorobenzyl) -1- ( 0.018 g (77%) of (R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 40) was obtained.
  • Example 41 (R) -N- (2,4-dichlorobenzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide Synthesis: The same reaction as in Example 2 [Step 3] was carried out using Reference Compound 47 (0.020 g, 0.050 mmol) to give (R) -N- (2,4-dichlorobenzyl) -1- ( 0.020 g (85%) of (R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 41) was obtained.
  • Example 42 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxypropanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2) was obtained by carrying out the same reaction as in Example 1 [Step 9] using (R) -2-hydroxypropanoic acid sodium salt (0.019 g, 0.17 mmol). 0.045 g (74%) of-(trifluoromethoxy) benzyl) -1-((R) -2-hydroxypropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 42) was obtained.
  • Example 43 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxybutanoyl) piperidine-3-carboxamide: (R) -2-N- (4-cyano-2-) is prepared by carrying out the same reaction as in Example 1 [Step 9] using (R) -2-hydroxybutanoic acid (0.017 g, 0.17 mmol). 0.056 g (89%) of (trifluoromethoxy) benzyl) -1-((R) -2-hydroxybutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 43) was obtained.
  • Example 44 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxy-3-methylbutanoyl) piperidine-3-carboxamide : (R) -2-Hydroxy-3-methylbutanoic acid (0.018 g, 0.15 mmol) was used for the same reaction as in Example 1 [Step 9] to give (R) -N- (4-cyano 0.042 g (64%) of 2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxy-3-methylbutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 44) was obtained. It was.
  • Tables 1-1 to 1-6 show physical property data of Example compounds 1 to 44, Table 2 shows physical property data of Comparative compounds 1 and 2, and Tables 3-1 to 3-5 The physical property data of Reference Example compounds 1 to 49 are shown in FIG. In the table, N.I. D. Represents “no data”.
  • the solvent name in the 1H-NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by ⁇ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), m ( Multiple line), brs (wide), dd (double double line), dt (double triple line), ddd (double double line), dq (double quadruple line), td (triple double line) (Multiple line) or tt (triple triple line). All solvents were commercially available.
  • the ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technology).
  • Example 45 Evaluation test of sEH inhibitory activity in vitro: Inhibition of sEH of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof using human sEH based on the method described in known literature (Analytical Biochemistry, 2005, 343, p. 66-75) Activity was evaluated.
  • Example compounds 1 to 44 showed a very strong inhibitory activity against the enzymatic reaction of human sEH, as compared with Comparative compounds 1 and 2.
  • nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof exhibits a very strong inhibitory activity on the enzyme reaction of human sEH.
  • Example 46 Drug efficacy evaluation test in mouse acetate rising model: The analgesic action of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was examined using a mouse acetate rising method capable of evaluating nociceptive pain.
  • mice The mouse acetate rising method was performed according to an existing method (Endoh et al., Life Science, 1999, Vol. 65, p. 1685-1694).
  • ddY male mice 5-6 weeks old (Japan SLC) were bred under free drinking, and the test compound solution or its solvent (Vehicle) was orally administered (10 mL / kg).
  • Tween 80 methyl cellulose (hereinafter referred to as MC): distilled water (0.5: 0.5: 99) was used as a solvent for the test compound solution.
  • the * mark in the figure indicates that it is statistically significant in comparison with the solvent administration group (Student's t test, p ⁇ 0.05).
  • Example Compound 1 When the Example Compound 1 was orally administered at 30 mg / kg, a significant decrease in the number of rising reactions was observed as compared with the solvent administration group. On the other hand, when 30 mg / kg of Comparative Example Compound 1 or Comparative Example Compound 2 was orally administered, no significant reduction in the number of rising reactions was observed compared to the solvent administration group. From the above results, Example Compound 1 was shown to have an analgesic effect on nociceptive pain, and nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was effective against nociceptive pain. It was shown to have analgesic action.
  • nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was effective against nociceptive pain. It was shown to have analgesic action.
  • the mouse partial sciatic nerve ligation model was prepared according to the method of Seltzer et al. (Malberg et al., Pain, 1998, Vol. 76, p. 215-222).
  • a group that was ligated three times in half-strength was called a “ligation group”, and a group that only exposed the sciatic nerve but did not ligate was called a “sham surgery group”.
  • neuropathic pain (hereinafter referred to as von Frey test) was performed by acclimating a mouse for at least 1 hour in a measurement acrylic cage (Natsume Seisakusho) installed on a wire mesh and then applying a filament (0.16 g pressure) Using North Coast Medical, Inc.
  • the pre value was measured before oral administration of the test compound 7 days after the sciatic nerve ligation operation, and the mice in the ligation group were divided into the solvent administration group and the test compound administration group so that the total score of the von Frey test was uniform. Divided.
  • the test compound solution or its solvent (Vehicle) was orally administered (10 mL / kg) to mice in the ligation group, and von Frey tests were performed 1 hour and 2 hours after oral administration, respectively. The value was used as an index of analgesic action. Tween 80: MC: distilled water (0.5: 0.5: 99) was used as a solvent for the test compound solution.
  • the results are shown in FIGS. It should be noted that the group administered with the solvent was the “solvent administered group”, the group administered with Example Compound 1 at a dose of 30 mg / kg was the “Example Compound 1 administered group”, and the comparative compound 1 was administered at a dose of 30 mg / kg. The group administered in 1) was designated as “Comparative Example Compound 1 Administration Group”, and the group administered with Comparative Compound 2 at a dose of 30 mg / kg was designated as “Comparative Example Compound 2 Administration Group”.
  • the * mark in the figure indicates that it is statistically significant in comparison with the solvent administration group (Student's t test, p ⁇ 0.05).
  • Example Compound 1 was shown to have an analgesic effect on neuropathic pain, and nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was effective against neuropathic pain. It was shown to have analgesic action.
  • the analgesic of the present invention comprises a nipecotic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient, and exhibits a medicinal effect based on sEH inhibitory activity, in particular nociceptive pain and / or neuropathy. It can be used as an analgesic for pain.

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Abstract

　L'objectif de l'invention est de mettre au point un nouvel analgésique efficace contre la douleur, notamment la douleur nociceptive et douleur neuropathique. La présente invention concerne un analgésique contenant, comme principe actif, un dérivé d'acide nipécotique représenté par la formule chimique ou un sel pharmaceutiquement acceptable de celui-ci.
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CN111909067A (zh) * 2020-08-28 2020-11-10 浙江凯普化工有限公司 一种d-青霉胺的有机全合成方法
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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WO2009070497A1 (fr) * 2007-11-28 2009-06-04 Smithkline Beecham Corporation Inhibiteurs de ehs et de 11β-hsd1 et leur utilisation
JP2011016742A (ja) * 2009-07-07 2011-01-27 Astellas Pharma Inc 環状アミノ化合物又はその塩
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909067A (zh) * 2020-08-28 2020-11-10 浙江凯普化工有限公司 一种d-青霉胺的有机全合成方法
CN111909067B (zh) * 2020-08-28 2022-03-15 浙江凯普化工有限公司 一种d-青霉胺的有机全合成方法
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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