WO2011058932A1 - Dérivé du n-benzylamide et composition pharmaceutique le contenant - Google Patents

Dérivé du n-benzylamide et composition pharmaceutique le contenant Download PDF

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WO2011058932A1
WO2011058932A1 PCT/JP2010/069747 JP2010069747W WO2011058932A1 WO 2011058932 A1 WO2011058932 A1 WO 2011058932A1 JP 2010069747 W JP2010069747 W JP 2010069747W WO 2011058932 A1 WO2011058932 A1 WO 2011058932A1
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alkyl
cycloalkyl
alkenyl
formula
compound
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Japanese (ja)
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保知 筑木
裕貴 宮地
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大日本住友製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to an N-benzylamide derivative useful as a therapeutic agent for pain and inflammation and a pharmaceutical composition containing the same.
  • narcotic analgesics such as morphine and non-narcotic analgesics such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are mainly used as analgesics.
  • NSAIDs Non-Steroidal Anti-Inflammatory Drugs
  • NSAIDs are severely restricted in their use due to the development of tolerance, dependence or other serious side effects.
  • NSAIDs are not effective for severe pain, and have problems such as a high rate of upper gastrointestinal tract disorders and liver disorders after long-term administration. Therefore, analgesics with higher analgesic effects and fewer side effects are eagerly desired.
  • neuropathic pain neuropathic pain
  • diabetic neuropathic pain postherpetic neuralgia, trigeminal neuralgia, and HIV-polyneuropathy.
  • HIV-polyneuropathy the development of therapeutic agents effective for them is also expected.
  • Capsaicin; (E) -8-methyl-N-vanillyl-6-nonenamide is contained in the juice of Capsicum plants, and is not only used as a spice but also has analgesic and anti-inflammatory effects It has been known.
  • civamide a geometric isomer of capsaicin; (Z) -8-methyl-N-vanillyl-6-nonenamide is also known to have analgesic action.
  • Capsaicin exerts analgesic and anti-inflammatory effects by acting specifically on a special receptor present in primary afferent sensory nerves (mainly C fibers: capsaicin-sensitive nerves), but it exhibits intense irritation ( It is also well known to have (pain).
  • this receptor has been cloned and named vanilloid receptor subtype 1 (VR1) [Non-patent Document 1]. Thereafter, this receptor is classified into TRPV (transient receptor potential) superfamily TRPV and is called TRPV1 [Non-Patent Document 2].
  • TRPV transient receptor potential
  • TRPV1 is considered to be a Ca 2+ highly permeable cation channel having a transmembrane region 6 times from its amino acid sequence, and is activated not only by capsaicin-like compounds but also by stimulation with heat, acid, etc. It has been suggested that it may contribute to pain in the pathology.
  • capsaicin acts on TRPV1 on the primary afferent sensory nerve, its cation channel is opened, the membrane is depolarized, neuropeptides such as substance P are released, etc., and pain is induced.
  • Capsaicin which is such a pain stimulating substance, is actually used for the treatment of pain such as diabetic neuropathy and rheumatoid arthritis.
  • sensory nerves As a result of continuous TRPV1 cation channel opening by capsaicin, sensory nerves are used. It is understood that it becomes unresponsive (desensitization) to painful stimulation [Non-Patent Document 3].
  • capsaicin-like compounds can exert analgesic effects based on a completely different medicinal mechanism (capsaicin-sensitive sensory nerve desensitization) from existing analgesics. It is highly expected to be effective as a therapeutic drug for pain caused by various pathological conditions such as neuropathic pain not responding to rheumatoid arthritis and osteoarthritis.
  • capsaicin is sold as an analgesic in the form of cream.
  • this cream has a problem that initial irritation is strong. Therefore, it has a capsaicin-like medicinal mechanism as a therapeutic agent for pain caused by various pathological conditions such as neuropathic pain, rheumatoid arthritis, osteoarthritis, etc. Development is desired.
  • Compounds with capsaicin-like medicinal mechanisms include pruritus, allergic and non-allergic rhinitis, pathologies involving primary afferent sensory nerves (C fibers), overactive bladder, stroke, irritable bowel syndrome, It is also considered useful as a therapeutic agent for respiratory diseases such as asthma / chronic obstructive pulmonary disease, dermatitis, mucositis, gastric / duodenal ulcer and inflammatory bowel syndrome.
  • Non-patent Document 4 since it has been reported that capsaicin promotes the secretion of adrenaline and exhibits an anti-obesity effect [Non-patent Document 4], a compound having a medicinal mechanism of capsaicin is useful as a therapeutic agent for obesity. It is believed that. Since it has been reported that insulin resistance is improved by treating diabetic rats with capsaicin [Non-patent document 5], it is also considered useful as a therapeutic agent for diabetes.
  • An object of the present invention is to have sufficient analgesic action and low irritation useful as a therapeutic or preventive agent for pain and inflammation caused by various pathologies such as neuropathic pain, rheumatoid arthritis and osteoarthritis. It is to provide a compound.
  • N-benzylamide derivatives that is, compounds represented by the following formula (I 0 ) or (I) have a strong analgesic action but have low irritation.
  • the present invention was completed. That is, the present invention provides the following inventions.
  • Item 1 The following formula (I 0 ):
  • R 1 represents a methyl or hydrogen atom
  • R 2 represents a hydrogen atom
  • L represents —NH— (C ⁇ O) — or — (C ⁇ O) —NH—
  • Z is a group represented by the following formula (A), (B), (C) or (D) (wherein azacycloalkyl in (A) is 1 to 5 identical or different C 1 to Optionally substituted with 4 alkyls):
  • n and m are the same or different and each represents an integer of 1, 2 or 3;
  • R 1 represents a methyl or hydrogen atom
  • R 2 represents a hydrogen atom, C 1 ⁇ 4 alkyl, C 1 ⁇ 4 alkyl or arylcarbonyl
  • Z is a group represented by the following formula (A), (B), (C) or (D):
  • n and m are the same or different and each represents an integer of 1, 2 or 3;
  • Item 3 The compound or a physiologically acceptable salt thereof according to Item 1 or 2, wherein in formula (I 0 ) or (I), n and m are the same or different and each is an integer of 1 or 2.
  • Item 4 The compound or a physiologically acceptable salt thereof according to Item 1 or 2, wherein in formula (I 0 ) or (I), n and m are both 2.
  • R 3 is aryl (said group, C 1 ⁇ 6 alkyl, selected from C 2 ⁇ 6 alkenyl and C 3 ⁇ 6 group consisting of cycloalkyl, the same Or optionally substituted with 1 to 5 different substituents), or —C ( ⁇ O) —S—R 7 or —S ( ⁇ O) 2 —NR 8 R 88 Yes, R 4 is —C ( ⁇ O) —O—R 7 , R 5 is —C ( ⁇ O) —O—R 7 , R 6 is The compound or a physiologically acceptable salt thereof according to claim 1 or 2 is a C 3 ⁇ 10 alkyl or C 3 ⁇ 10 alkenyl.
  • R 7 is, C 3 ⁇ 8 cycloalkyl (said group, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, a C 3 ⁇ 8 cycloalkyl and halogen Which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: R 8 and R 88 are the same or different, or a C 1 ⁇ 6 alkyl or C 2 ⁇ 6 alkenyl, or, R 8 and R 88 together, C 3 ⁇ 5 azacycloalkyl (the The group may be substituted with 1 to 5 C 1-6 alkyl), R 9 is a compound or a physiologically acceptable salt thereof according to any one of claims 1 to 5, a C 7 ⁇ 9 alkyl or C 7 ⁇ 9 alkenyl.
  • Item 7 The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I 0 ) or (I), Z is a group represented by the formula (A).
  • Item 8 The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I 0 ) or (I), Z is a group represented by the formula (B).
  • Item 9 The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I 0 ) or (I), Z is a group represented by the formula (C).
  • Item 10 The compound according to any one of Items 1 to 6, or a physiologically acceptable salt thereof, wherein, in the formula (I 0 ) or (I), Z is a group represented by the formula (D).
  • Item 11 The compound according to any one of Items 1 to 10 or a physiologically acceptable salt thereof, wherein, in the formula (I 0 ) or (I), R 1 is methyl.
  • Item 12 The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 11, wherein in the formula (I 0 ) or (I), R 2 is a hydrogen atom.
  • Item 13 In the formula (I 0 ) or (I), R 1 is methyl; R 2 is a hydrogen atom, Z is a group represented by the formula (B), n and m are both 2; Item 3.
  • Item 14 In the formula (I 0 ) or (I), R 1 is methyl; R 2 is a hydrogen atom, Z is a group represented by the formula (A), n and m are the same or different and an integer of 1 or 2, Item 3.
  • Item 15 A pharmaceutical composition comprising the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
  • Item 16 A therapeutic or prophylactic agent for pain and / or inflammation comprising the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
  • Item 17 An analgesic or anti-inflammatory drug comprising the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof as an active ingredient.
  • Item 18 A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the compound or the physiologically acceptable salt thereof according to any one of Items 1 to 14 to a patient.
  • Item 19 Use of the compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof for producing a therapeutic or preventive agent for pain and / or inflammation.
  • Item 20 The compound according to any one of Items 1 to 14 or a physiologically acceptable salt thereof, Narcotic analgesics, neuropathic pain treatments, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antidepressants, antiepileptic drugs, anticonvulsants, anesthetics, antiarrhythmic drugs, local anesthetics and anxiolytics And at least one other drug selected from the group consisting of drugs.
  • Item 21 A pharmaceutical composition comprising the medicine according to Item 20 as an active ingredient.
  • Item 22 A therapeutic or prophylactic agent for pain and / or inflammation, comprising the medicament according to Item 20 as an active ingredient.
  • Item 23 A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the medicament according to Item 20 to a patient.
  • Item 24 Use of the medicament according to Item 20, for producing a therapeutic or preventive agent for pain and / or inflammation.
  • analgesics and anti-inflammatory drugs for example, neuropathic pain, inflammatory properties in which existing analgesics are not sufficiently effective
  • a therapeutic or preventive agent for pain and / or inflammation of pain, musculoskeletal pain, visceral pain, skeletal pain, cancer pain, and combinations thereof can be provided.
  • Pain and / or inflammation pathologies include, for example, diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy, postoperative pain, central or peripheral neuropathy, and neuropathic Various types of neuropathic pain including low back pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, Fascia facial pain, abdominal pain, neck pain, central pain, toothache, opioid resistant pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pains or inflammations that require treatment .
  • neuropathic pain including low back pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, Fascia facial pain, abdominal pain,
  • migraine or cluster headache pruritus, allergic or non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, asthma and chronic obstructive pulmonary disease
  • a therapeutic or preventive agent for respiratory diseases, dermatitis, mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome, diabetes, and obesity can be provided.
  • the physiologically acceptable salt of the compound represented by the formula (I 0 ) or the formula (I) is a compound of the formula (I 0 ) or the formula (I) having a group capable of forming an acid addition salt in the structure.
  • Physiologically acceptable acid addition salts of the compounds, or salts with physiologically acceptable bases of the compounds of the formula (I 0 ) or of the formula (I) having a group capable of forming a salt with a base in the structure Means.
  • the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, malonate, Maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfone
  • organic acid salts such as acid salts
  • amino acid salts such as glutamate and aspartate.
  • salts with bases include alkali metal or alkaline earth metal salts such as sodium salt, potassium salt and calcium salt, salts with organic bases such as pyridine salt and triethylamine salt, and lysine and arginine. And salts with amino acids.
  • the compounds of formula (I 0 ) or formula (I) and their salts may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also present. Included in the compounds of the invention. That is, the “compound of the present invention” includes, in addition to the compound represented by the above formula (I 0 ) or formula (I) and physiologically acceptable salts thereof, hydrates and / or solvents thereof. Japanese products are included.
  • the compounds of formula (I 0 ) or formula (I) may have one or more asymmetric carbon atoms and may give rise to geometric isomerism and axial chirality, so that some stereoisomers Can exist as In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compounds represented by formula (I 0 ) or formula (I) of the present invention.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 1-4 alkyl or “C 1-6 alkyl” means 1 to 4 carbon atoms or 1 to 6 groups are meant.
  • C 1-4 alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • Examples of “C 1-6 alkyl” include pentyl, isopentyl, neopentyl, hexyl and the like in addition to the above alkyl.
  • the "C 6 ⁇ 12 alkyl hexyl, isoheptyl, octyl, nonyl, and decyl, and the like.
  • the alkyl may be linear or branched.
  • Alkenyl means a straight or branched unsaturated hydrocarbon group having at least one double bond.
  • C 2-6 alkenyl at least one have a double bond, means a unsaturated hydrocarbon group having a carbon number of 2-6.
  • Specific examples of the "C 2 ⁇ 6 alkenyl” include vinyl, allyl, 1-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 1,3-butadienyl, 2-, 3- or 4- Pentenyl, 2-methyl-2-butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 4-methyl-1-pentenyl, 3,3-dimethyl-1-butenyl, and 5-hexenyl It is done.
  • the "C 6 ⁇ 12 alkenyl" 4-methyl-3-pentenyl, 3,3-dimethyl-1-butenyl, 5-hexenyl, 3-ethyl - include pentenyl, and 3-octenyl and the like.
  • the alkenyl may be linear or branched.
  • the number of double bonds contained in the alkenyl may be one or two.
  • Cycloalkyl means a monocyclic saturated hydrocarbon group.
  • C 3-8 cycloalkyl carbon atoms means a monocyclic saturated hydrocarbon group of 3 to 8.
  • Specific examples of the "C 3 ⁇ 8 cycloalkyl”, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl The same applies to “C 3-6 cycloalkyl”.
  • the "C 3-8 cycloalkenyl" number of carbon atoms having one or two double bonds means a monocyclic unsaturated hydrocarbon group having 3 to 8.
  • the number of double bonds contained in the cycloalkenyl is preferably one.
  • Aryl means phenyl or naphthyl. Phenyl is preferred. Similarly, “arylcarbonyl” means phenylcarbonyl or naphthylcarbonyl.
  • Heteroaryl means 1 to 3 heteroatoms of 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 12 carbon atoms. Meaning a group, each ring being a 3-8 membered ring.
  • halogen include fluorine, chlorine, bromine and iodine.
  • C 1 alkylcarbonyl corresponds to acetyl. Therefore, specific examples of the "C 1 ⁇ 4 alkyl-carbonyl” include acetyl, propionyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, iso-butylcarbonyl, and tert- butylcarbonyl and the like.
  • Alkyl-substituted cycloalkyl refers to a group in which one or more (for example, 1 to 5, preferably 1 to 4) hydrogen atoms of the above cycloalkyl are substituted with the above-described alkyl. means.
  • Specific examples of “cycloalkyl substituted with alkyl” include 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl, 4,4-dimethyl.
  • Cyclohexyl 3,5-dimethylcyclohexyl, 3,3,5,5-tetramethylcyclohexyl, 4,4-diethylcyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-butylcyclohexyl, 4-propylcyclohexyl, 4-isopropyl
  • Examples include cyclohexyl, and 4-t-butylcyclohexyl. The same applies to each of the following substituents substituted with alkyl: cycloalkenyl, aryl, heteroaryl.
  • Cycloalkyl substituted with alkenyl refers to one in which one or more (eg, 1 to 2, preferably 1) hydrogen atoms of the cycloalkyl are substituted with the alkenyl.
  • alkenyl-substituted cycloalkyl include 2-ethenylcyclohexyl, 3-ethenylcyclohexyl, 4-ethenylcyclohexyl, 2- (1-propenyl) cyclohexyl, and 3- (1-propenyl) cyclohexyl.
  • Aryl substituted with cycloalkyl means a group in which one or more (eg, 1 to 3, preferably 1) hydrogen atoms of the above aryl are substituted with cycloalkyl.
  • aryl substituted with cycloalkyl include 2-cyclopropylphenyl, 4-cyclopropylphenyl, 2-cyclobutylphenyl, 4-cyclobutylphenyl, 2-cyclopentylphenyl, 4-cyclopentylphenyl, 2 -Cyclohexylphenyl, and 4-cyclohexylphenyl. The same applies to each of the following substituents substituted with cycloalkyl: cycloalkyl, cycloalkenyl, and heteroaryl.
  • Aryl substituted with halogen means a group in which one or more (for example, 1 to 5, preferably 1 to 2) hydrogen atoms of the aryl are substituted with halogen.
  • Specific examples of “aryl substituted with halogen” include 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, and 4- And iodophenyl. The same applies to the following substituents substituted with halogen: cycloalkyl, cycloalkenyl, and heteroaryl.
  • the plurality of substituents may be the same or different. Specific examples of the plurality of substituents may be any combination of the substituents exemplified above.
  • C 3 ⁇ 8 cycloalkyl C 1 ⁇ 6 alkyl 4-cyclopropyl butyl, 3-cyclobutyl-propyl, cyclopentylmethyl, and cyclohexylmethyl and the like.
  • the "C 3 - 7 azacycloalkyl” includes one nitrogen atom, a group represented by the monocyclic saturated hydrocarbon group containing 3 to 7 carbon atoms, specifically, Examples thereof include azetidinyl, pyrrolidinyl and piperidinyl.
  • azetidinyl pyrrolidinyl
  • piperidinyl As the one to five C 1 - C 3 substituted by alkyl of 1-7 azacycloalkyl, 3-butyl azetidinyloxyimino, 4-propyl-piperidinylmethyl, 4-t-butyl-piperidinylmethyl and the like Can be illustrated.
  • Examples of the groups in the compound (I) and the formula (I 0 ) of the present invention include the following.
  • R 1 represents a methyl or hydrogen atom, preferably methyl.
  • R 2 is a hydrogen atom, C 1 ⁇ 4 alkyl, shows a C 1 ⁇ 4 alkyl or arylcarbonyl, preferably a hydrogen atom.
  • L represents —NH— (C ⁇ O) — or — (C ⁇ O) —NH—, and preferably —NH— (C ⁇ O) —.
  • N and m are the same or different and represent an integer of 1, 2 or 3, preferably 1 or 2.
  • n and m are more preferably both 1 or 2, or one is 1 and the other is 2, and particularly preferably both are 2.
  • R 3 in formula (A) represents aryl or heteroaryl, or —S ( ⁇ O) 2 —R 7 , —C ( ⁇ O) —R 7 , —C ( ⁇ O) —S—R 7 , —C ( ⁇ O) —NR 8 R 88 , —S ( ⁇ O) 2 —NR 8 R 88 , —C ( ⁇ O) —O—R 9 or —C ( ⁇ S) —NR 8 R 88 Indicates.
  • Aryl and heteroaryl as R 3 is, C 1 ⁇ 6 alkyl, by C 2 ⁇ 6 alkenyl or C 3 ⁇ 6 cycloalkyl, it may be substituted at a substitutable position, for example, the same or different It may be substituted with 1 to 5 of the above substituents.
  • R 3 is aryl or heteroaryl, or —S ( ⁇ O) 2 —R 7 , —C ( ⁇ O) —R 7 , In —C ( ⁇ O) —S—R 7 , —C ( ⁇ O) —NR 8 R 88 , —S ( ⁇ O) 2 —NR 8 R 88 , or —C ( ⁇ S) —NR 8 R 88 There may be.
  • R 3 is more preferably aryl (said group, C 1 - 6 alkyl is selected from C 2 - 6 alkenyl and C 3 - 6 the group consisting of cycloalkyl, the same or different and one to five Optionally substituted with a substituent), —C ( ⁇ O) —S—R 7 or —S ( ⁇ O) 2 —NR 8 R 88 .
  • R 4 in the formula (B) is —C ( ⁇ O) —O—R 7 , —S ( ⁇ O) 2 —R 7 , —C ( ⁇ O) —R 7 , —C ( ⁇ O) —S —R 7 , —C ( ⁇ O) —NR 8 R 88 or —S ( ⁇ O) 2 —NR 8 R 88 is shown.
  • R 4 is more preferably —C ( ⁇ O) —O—R 7 .
  • R 5 in the formula (C) represents —C ( ⁇ O) —O—R 7 or —O—C ( ⁇ O) —NR 8 R 88 .
  • R 5 is more preferably —C ( ⁇ O) —O—R 7 .
  • R 6 is more preferably C 3 ⁇ 10 alkyl or C 3 ⁇ 10 alkenyl.
  • R 7 in each of R 3 ⁇ R 6 is, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 cycloalkenyl, or an aryl or heteroaryl, or C 6 ⁇ 12 alkyl, C 6 ⁇ 12 alkenyl or, C 3 ⁇ shows the 8 cycloalkyl C 1 - 6 alkyl.
  • it may be substituted with 1 to 5 substituents which are the same or different.
  • R 7 is more preferably, C 3 ⁇ 8 cycloalkyl (said group, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, selected from the group consisting of C 3 ⁇ 8 cycloalkyl and halogen, the same or different Optionally substituted with 1 to 5 substituents).
  • R 8 and R 88 in each of R 3 ⁇ R 6 are the same or different, a hydrogen atom, C 1 ⁇ 8 alkyl, C 2 ⁇ 8 alkenyl, or may be substituted by C 1 ⁇ 6 alkyl C 3 ⁇ 6 cycloalkyl shows.
  • R 8 and R 88 together show a C 3 - 7 azacycloalkyl (which may be substituted with one to five C 1 - 6 alkyl).
  • R 8 and R 88 are more preferably either identical or different C 1 to 6 alkyl or C 2 - 6 alkenyl, or, C 3 ⁇ 5 to R 8 and R 88 are formed together Azacycloalkyl (the group may be substituted with 1 to 5 C 1-6 alkyl).
  • R 9 is, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 cycloalkenyl, or an aryl or heteroaryl, or shows a C 6 ⁇ 12 alkyl or C 6 ⁇ 12 alkenyl.
  • R 9 is more preferably C 7 ⁇ 9 alkyl or C 7 ⁇ 9 alkenyl.
  • R 10a and R 10b are the same or different and each represents a hydrogen atom or C 1-4 alkyl.
  • R 10a and R 10b are more preferably a hydrogen atom.
  • Preferred compounds in the present invention are represented by the following formula (I ′): Or a physiologically acceptable salt thereof.
  • Z ′ is a group represented by the following formula (A), (B) or (C): Indicates.
  • R 3 is aryl (said groups, substituted by C 1 - 6 alkyl is selected from C 2 - 6 alkenyl and C 3 - 6 the group consisting of cycloalkyl, the same or different and 1 to 5 substituents Or —C ( ⁇ O) —S—R 7 or —S ( ⁇ O) 2 —NR 8 R 88 , R 4 represents —C ( ⁇ O) —O—R 7 , R 5 represents —C ( ⁇ O) —O—R 7 , R 7 is, C 3 - 8 cycloalkyl (said groups, C 1 - 6 alkyl, C 2 - 6 alkenyl, selected from the group consisting of C 3 - 8 cycloalkyl and halogen, the same or different 1 was ⁇ Optionally substituted with 5 substituents), R 8 and R 88 are the
  • the compound represented by the formula (I 0 ) or the formula (I) or a physiologically acceptable salt thereof is a novel compound, and includes, for example, the methods described below, examples described later or publicly known It can manufacture by the method according to this method.
  • the compound used in the following production method may form a salt as long as the reaction is not hindered.
  • the structure of the starting material contains functional groups that may participate in the reaction, such as amino, carboxyl, hydroxyl group, and carbonyl, protection as commonly used for these groups It may be protected by introducing a group, and in that case, the desired compound can be obtained by removing the protecting group as appropriate after completion of the reaction.
  • functional groups such as amino, carboxyl, hydroxyl group, and carbonyl
  • amino protecting groups include alkylcarbonyl such as acetyl and propionyl; formyl; phenylcarbonyl; alkyloxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; aralkyl such as phenyloxycarbonyl; benzyloxycarbonyl and the like.
  • Oxycarbonyl; trityl; phthaloyl; tosyl are used.
  • carboxyl protecting group for example, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl; phenyl; benzyl; trityl;
  • hydroxyl-protecting group examples include methyl; tert-butyl; allyl; substituted methyl such as methoxymethyl and methoxyethoxymethyl; ethoxyethyl; tetrahydropyranyl; tetrahydrofuranyl; trityl; aralkyl such as benzyl; acetyl, propionyl and the like.
  • Aralkyloxycarbonyl such as alkylcarbonyl; formyl; benzoyl; benzyloxycarbonyl; silyl is used.
  • the carbonyl can be protected by converting the carbonyl to a cyclic ketal such as dimethyl ketal and diethyl ketal, or a cyclic ketal such as 1,3-dioxolane and 1,3-dioxane.
  • a cyclic ketal such as dimethyl ketal and diethyl ketal
  • a cyclic ketal such as 1,3-dioxolane and 1,3-dioxane.
  • R 1 , R 2 and Z are defined similarly to R 1 , R 2 and Z in formula (I), including preferred embodiments thereof.
  • the compound of the formula (I) can be produced by an amidation reaction of a compound of the formula (II) and a compound of the formula (III) under usually used reaction conditions.
  • the compound of formula (III) may be reacted with a compound of formula (II) after conversion to a reactive derivative at the carboxyl group.
  • Examples of the reactive derivative of the formula (III) include lower alkyl esters (particularly methyl esters), active esters, acid anhydrides, and acid halides (particularly acid chlorides).
  • Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, and pentafluorophenyl ester.
  • Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, and pivalic acid.
  • the compound of formula (III) may be reacted with the compound of formula (II) in the presence of a condensing agent.
  • a condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl-oxytris (Pyrrolidino) phosphonium, and hexafluorophosphate.
  • These condensing agents can be used alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide and N-hydroxybenzotriazole.
  • the above reaction between the compound of formula (III) or a reactive derivative thereof and the compound of formula (II) is usually carried out in a solvent or without solvent.
  • the solvent to be used should be selected according to the type of raw material compound and the like, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, and DMF. These solvents are used alone or as a mixed solvent of two or more.
  • the compound of the formula (II) may be used in the form of an acid addition salt such as hydrochloride to generate a free base in the reaction system.
  • This reaction is usually performed in the presence of a base.
  • a base include inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine.
  • the reaction temperature varies depending on the kind of starting compound used, etc., it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 70 ° C.
  • the reaction time is about 1 to 48 hours.
  • the compound of the formula (II) is a known compound, or can be produced according to a known compound production method.
  • Monatsh. Chem., 77, 54 (1947), Tetrahedron Lett., 43, 4281 (2002), J. Org. Chem., 53, 1064 (1988), J. Org. Chem., 54, 3477 ( 1989) or the like, or a method analogous thereto can be used to produce the compound of formula (II).
  • the compound of the formula (III) is commercially available, or can be produced by a known method or a method analogous thereto.
  • R 1 , R 2 and R 3 include formula (I) and Defined similarly to R 1 , R 2 and R 3 in formula (A).
  • P represents an amino protecting group
  • X represents a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, or imidazolyl).
  • the compound of the formula (IA) can be produced under the reaction conditions usually used for the compound of the formula (VI) and the compound of the formula (VII).
  • the above reaction between the compound of formula (VI) and the compound of formula (VII) is usually carried out in a solvent or in the absence of a solvent.
  • the solvent to be used should be selected according to the type of raw material compound, and examples thereof include toluene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, and DMF. These solvents can be used alone or as a mixed solvent of two or more. Moreover, this reaction is normally performed in presence of a base.
  • the base include inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine.
  • inorganic bases such as potassium carbonate and sodium bicarbonate
  • organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine.
  • the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 80 ° C.
  • the reaction time is about 1 to 48 hours.
  • the compound of the formula (VI) is produced by using the compound of the formula (II) and the compound of the formula (IV) in the same manner as the amidation reaction in the above-mentioned production method, It can be produced by deprotecting P).
  • the compound of the formula (IV) may be reacted with the compound of the formula (II) after being converted into a reactive derivative at carboxyl as described above.
  • the compound of the above formula (IV) is a known compound, or can be produced according to a known compound production method.
  • the compound of formula (IV) is produced according to the method described in J. Pharm. Sci., 71, 1214 (1982), J. Med. Chem., 31, 613 (1988) or the like, or a method analogous thereto. can do.
  • R 1 , R 2 and R 4 are represented by formula (I) And R 1 , R 2 and R 4 in the formula (B).
  • P represents an amino protecting group
  • X and Y represent a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, or imidazolyl).
  • the compound of formula (IB) can be prepared under the conditions described in the process for preparing the compound of formula (IA) described above under the reaction conditions usually used for the compound of formula (X) and the compound of formula (XI). Can be manufactured according to.
  • the compound of the formula (X) can be produced by deprotecting the protecting group (P) of the formula (IV).
  • the compound of the formula (IV) is prepared by converting the compound of the formula (II) into a reactive derivative represented by the formula (II ′) and then reacting with the compound of the formula (VIII) under usual conditions. can do.
  • the above reaction between the compound of formula (II ′) and the compound of formula (VIII) is usually carried out in a solvent or in the absence of a solvent.
  • the solvent to be used should be selected according to the type of raw material compound and the like, and examples thereof include toluene, THF, dioxane, ethylene glycol dimethyl ether, methylene chloride, chloroform, ethyl acetate, acetone, acetonitrile, and DMF. These solvents can be used alone or as a mixed solvent of two or more. Moreover, this reaction is normally performed in presence of a base.
  • the base include inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine.
  • inorganic bases such as potassium carbonate and sodium bicarbonate
  • organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine.
  • the reaction temperature varies depending on the kind of raw material compound used, it is generally about ⁇ 30 ° C. to about 150 ° C., preferably about ⁇ 10 ° C. to about 80 ° C.
  • the reaction time is about 1 to 48 hours.
  • the compound of the above formula (VIII) is a known compound, or can be produced according to a known compound production method.
  • the compound of formula (VIII) can be produced according to the method described in J. Heterocyclic Chem., 27, 1559 (1990), J. Chem. Soc., 3634 (1959), or a method analogous thereto. it can.
  • the production of the compound in which Z is a group represented by the formula (C) or the formula (D) is carried out by the method described in the following examples, or the group in which Z is represented by the formula (A) or the formula (B).
  • the compound can be synthesized by the same method as described above for a certain compound.
  • the compound represented by the formula (I 0 ) can also be synthesized by the method described in the following Examples or the same method as described above with respect to the compound of the formula (I).
  • the compounds of the present invention include compounds represented by the following formula (XII), that is, compounds represented by the formula (I 0 ) and L is — (C ⁇ O) —NH—, or physiologically acceptable compounds thereof. Salt is also included. This compound has similar utility as the compound of formula (I).
  • R 1 represents a methyl or hydrogen atom
  • R 2 represents a hydrogen atom, C 1 ⁇ 4 alkyl, C 1 ⁇ 4 alkyl or arylcarbonyl
  • R 10 is aryl (said group, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 3 - 8 cycloalkyl and a halogen selected from the group, the same or different and 1 to 5 substituents And may be substituted with n and m are the same or different and represent an integer of 1, 2 or 3.
  • the compound of the present invention obtained by the above production method can be isolated and purified according to a conventional method such as chromatography, recrystallization, reprecipitation and the like.
  • Optical isomers can be derived from asymmetric synthesis such as using a starting material having an asymmetric center, or can be derived by optical resolution such as use of a chiral column or fractional recrystallization.
  • Geometric isomers such as cis isomer and trans isomer can be derived synthetically and can be separated using a column.
  • the compound of the present invention may be obtained in the form of a salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. it can.
  • the compound of the present invention having a group capable of forming an acid addition salt in the structural formula can be converted into an acid addition salt by treating with various acids according to a conventional method.
  • the compounds of the present invention and physiologically acceptable salts thereof and hydrates or solvates thereof have a strong analgesic action and are weakly irritating, so that not only oral administration but also parenteral, for example, transdermal Administration, topical administration, nasal administration and intravesical injection are also effective. Therefore, the compounds of the present invention are used as analgesics and anti-inflammatory drugs, for example, neuropathic pain, inflammatory pain, musculoskeletal pain, visceral pain, skeletal pain, cancer in which existing analgesics do not sufficiently respond It is useful as a therapeutic or prophylactic agent for sexual pain, and pain and / or inflammation of a combination thereof.
  • Pain and / or inflammation pathologies include, for example, diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy, postoperative pain, central and peripheral neuropathy, neuropathic lumbar back Various types of neuropathic pain including pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, fascia Facial pain, abdominal pain, neck pain, central pain, toothache, opioid resistance pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pain and / or inflammation treatments that require treatment Or it is useful as a preventive agent.
  • neuropathic pain including pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain
  • Neuroopathic pain is chronic pain caused by damage to or pathological changes in the peripheral or central nervous system and can be related to or form the basis for neuropathic pain. obtain.
  • neuropathic pain include: diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, amputation posttraumatic pain (peripheral and / or central sensitization (eg, phantom limb pain) Cause nerve damage due to injury), neuropathic back pain, cancer, chemical injury, toxins, other major surgery, peripheral nerve damage caused by traumatic injury pressure, lumbar or cervical radiculopathy, fiber Myalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causal gear, thalamic syndrome, nerve root detachment or post-thoracotomy pain, malnutrition, or viral or bacterial infection (eg, herpes zoster or human immunodeficiency virus (HIV ) -Multiple neuropathic pain), or combinations thereof, metastatic infiltration
  • the administration route of the compound of the present invention oral administration or parenteral administration is possible, and transdermal administration which is one of parenteral administration is preferable.
  • the dose of the compound of the present invention varies depending on the type of compound, administration form, administration method, patient symptom, age, etc., but is usually 0.005 mg / kg / day to 150 mg / kg / day, preferably 0.05 mg / day. kg / day to 20 mg / kg / day, which can be administered once or in several divided doses.
  • the compound of the present invention can be combined with other drugs to form a medicine. Thereby, additive and synergistic pharmacological effects can be obtained.
  • the compounds of the present invention include, for example, narcotic analgesics, neuropathic pain therapeutics, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, antidepressants, antiepileptic drugs, anticonvulsants, anesthetics, antiarrhythmic drugs It can be used as a medicament in combination with at least one other drug selected from the group consisting of drugs, local anesthetics and anxiolytics.
  • At least one other drug selected from the group consisting of narcotic analgesics, therapeutic agents for neuropathic pain, nonsteroidal anti-inflammatory drugs, antiepileptic drugs, antiarrhythmic drugs and local anesthetics is preferable.
  • narcotic analgesics include morphine, codeine, oxycodone, pethidine, fentanyl, pentazocine, tramadol, butorphanol and buprenorphine.
  • therapeutic agents for neuropathic pain include various types such as pregabalin, gabapentin, carbamazepine, lidocaine, duloxetine and mexiletine.
  • non-steroidal anti-inflammatory drugs include acetylsalicylic acid, ibuprofen, loxoprofen sodium, diclofenac sodium, acetaminophen, etodolac, meloxicam, celecoxib and rofecoxib.
  • steroidal anti-inflammatory drugs include methylprezonidolone, prezonidolone and dexamethasone.
  • antidepressants include amitriptyline, nortriptyline, amoxapine, paroxetine, fluvoxamine, milnacipran and duloxetine.
  • antiepileptic drugs are carbamazepine, lamotrigine, gabapentin and pregabalin.
  • a specific example of an anticonvulsant is baclofen.
  • anesthetics include mepivacaine, bupivacaine, tetracaine, dibucaine and ketamine hydrochloride.
  • antiarrhythmic and local anesthetics include lidocaine, procaine, mexiletine and flecainide.
  • anxiolytic drugs are diazepam and etizolam.
  • agents combined with the compounds of the present invention are morphine, codeine, fentanyl, pentazocine, carbamazepine, lamotrigine, pregabalin, gabapentin, lidocaine, loxoprofen sodium, diclofenac sodium, acetaminophen, etodolac, meloxicam, celecoxib and rofecoxib At least one selected from the group consisting of
  • the medicament composed of the combination of the compound of the present invention and the above-mentioned other drugs, particularly as an analgesic and an anti-inflammatory drug, for example, neuropathic pain, inflammatory pain in which existing analgesics are not sufficiently effective, It can be provided as a therapeutic or prophylactic agent for pain and / or inflammation of musculoskeletal pain, visceral pain, bone pain, cancer pain, and combinations thereof.
  • Pain and / or inflammation pathologies include, for example, diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-polyneuropathy, postoperative pain, central and peripheral neuropathy, neuropathic lumbar back Various types of neuropathic pain including pain, rheumatoid arthritis, osteoarthritis, low back pain, fibromyalgia, atypical chest pain, herpes neuralgia, phantom limb pain, pelvic pain, fascia Facial pain, abdominal pain, neck pain, central pain, toothache, opioid resistant pain, visceral pain, surgical pain, bone injury pain, angina pain, and various pains and inflammations that require treatment.
  • a pharmaceutical comprising a combination of the pharmaceutical compound of the present invention and another drug can be provided as a therapeutic or prophylactic agent for pain and / or inflammation of these pathological conditions.
  • a medicament comprising the compound of the present invention or a combination thereof with the above other drugs is usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
  • a pharmaceutical carrier include tablets, capsules, granules, powders, syrups, fine granules, solutions, sublinguals, suspensions and other oral preparations, ointments, suppositories (rectal administration), intravesical Injections, patches (tapes, transdermal patch preparations, poultices, etc.), lotions, emulsions, creams, jellies, gels, external powders, inhalants, and nasal preparations, skin
  • injections such as internal injections, subcutaneous injections, intraperitoneal injections, intrabody injections such as joint cavities, and infusions.
  • compositions are prepared according to conventional methods. That is, a pharmaceutical composition containing a compound represented by formula (I 0 ) or formula (I) or a physiologically acceptable salt thereof is an excipient, a binder, a lubricant, a stabilizer, a disintegrant.
  • Base buffer, solubilizer, tonicity agent, solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier
  • pharmaceutical carriers such as gelling agents, soothing agents, preservatives, plasticizers, absorption enhancers, anti-aging agents, moisturizers, preservatives, and fragrances. Addition of two or more kinds of pharmaceutical carriers A thing can also be selected and used suitably.
  • the pharmaceutical carrier a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • Specific examples of the pharmaceutical carrier include lactose, corn starch, sucrose, mannitol, calcium sulfate, crystalline cellulose, croscarmellose sodium, modified starch, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose, methylcellulose, gelatin, Arabic gum, ethyl cellulose, hydroxypropyl cellulose, povidone, light anhydrous silicic acid, magnesium stearate, talc, sucrose fatty acid ester, sorbitan fatty acid ester, hydrogenated oil, carnauba wax, hydroxypropyl methylcellulose, macrogol, cellulose acetate phthalate, hydroxypropyl methylcellulose Acetate phthalate, titanium oxide, calcium phosphate, olive oil, refined lanolin, squalane, silico Oil, castor oil, soybean oil, cottonseed oil,
  • CFCs CFC-12, CFC-12, CFC-22, CFC-22, CFC-113, CFC-114, CFC-123, CFC-142c, CFC-134a, CFC-227, CFC-318 , 1,1,2-tetrafluoroethane, etc.
  • alternative CFCs HFA-227, HFA-134a, etc.
  • examples thereof include sodium acid, sodium acetate, sodium chloride, concentrated glycerin, benzalkonium chloride, paraben, a salt of stearic acid, starch, and cellulose.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, but is usually 0.0025% by mass to 20% by mass in the total composition.
  • These pharmaceutical compositions may also contain other therapeutically effective substances.
  • a pharmaceutical that employs a combination of the compound of the present invention and the above-mentioned other drug can constitute a single pharmaceutical composition containing the above-mentioned other drug together with the compound of the present invention.
  • a first pharmaceutical composition containing the compound of the present invention and a second pharmaceutical composition containing the other drug are provided separately and administered separately or simultaneously over a period of time. May be. More specifically, it may be a single preparation (compound) containing these active ingredients together, or may be a plurality of preparations in which each of these active ingredients is separately formulated. . When formulated separately, the formulations can be administered separately or simultaneously. Moreover, when it formulates separately, those formulations can be mixed using a diluent etc. at the time of use, and can be administered simultaneously.
  • the compounding ratio of the drugs can be appropriately selected depending on the age, sex, weight, symptoms, administration time, dosage form, administration method, combination of drugs and the like of the patient.
  • the administration route of the medicine oral administration and parenteral administration are possible.
  • the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate solution (4 times), saturated aqueous ammonium chloride solution and saturated brine in this order.
  • the organic phase was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. did.
  • Example 2 In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (1) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
  • Example 7 Using cis-4-ethylcyclohexaneamine p-toluenesulfonate in place of 4-t-butylpiperidine in Example 7, the reaction and treatment were conducted in the same manner as in Example 7 to obtain the desired product.
  • N-methyl-1-butanamine (306 mg) was added to a mixture of N, N′-thiocarbonyldiimidazole (754 mg) and methylene chloride (3.5 ml), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in acetonitrile (5 ml), and iodomethane (1.98 g) was added.
  • N, N′-carbonyldiimidazole (689 mg) and methylene chloride (4 ml) were added to a mixture of cyclohexanethiol (380 mg) and tetrahydrofuran (4 ml), and the mixture was stirred at room temperature for 12 hours.
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and then saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 674 mg of S-cyclohexyl 1H-imidazole-1-thiocarboxylate.
  • Triethylamine (188 mg) and 4-dimethylaminopyridine (14 mg) were added to a mixture of the above product (1) (157 mg), the product of Example 9 (3) (186 mg) and dimethyl sulfoxide (3 ml).
  • the mixture was heated and stirred at 70 ° C. for 6 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with water (twice) and saturated brine in that order and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • N, N′-carbonyldiimidazole (111 mg) was added to a mixture of 5-methylhexanol (69 mg) and methylene chloride (3 ml), and the mixture was stirred at room temperature for 20 hours.
  • the reaction solution was diluted with ethyl acetate, washed with water (twice) and saturated brine, and then the organic layer was dried over magnesium sulfate, and the solvent was distilled off.
  • the product of Example 1 (2) 200 mg
  • triethylamine 164 mg
  • 4-dimethylaminopyridine (10 mg) were added to a mixture of the obtained residue and dimethyl sulfoxide (3 ml), and heated at 70 ° C. for 7 hours.
  • the reaction solution was diluted with ethyl acetate, and washed with water, a saturated aqueous ammonium chloride solution, water (twice), a saturated aqueous sodium bicarbonate solution, and saturated brine in this order.
  • the organic layer was dried over magnesium sulfate and the solvent was distilled off.
  • Example 2 In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (1) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
  • N, N′-carbonyldiimidazole 100 mg was added to a mixture of 2-cyclohexylacetic acid (87 mg) and N, N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 1 hour.
  • the product of Example 1 (2) 200 mg
  • triethylamine 155 mg
  • N, N-dimethylformamide (1 ml) were added and stirred for 5 hours.
  • the reaction solution was diluted with ethyl acetate, and washed with water, a saturated aqueous ammonium chloride solution, water (twice), a saturated aqueous sodium bicarbonate solution, and saturated brine in this order.
  • Example 2 In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (1) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
  • the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate solution (4 times), saturated aqueous ammonium chloride solution and saturated brine in this order.
  • the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. did.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate / chloroform / ethanol, and then washed with water (twice), a saturated aqueous sodium bicarbonate solution, and saturated brine in this order. After the organic layer was washed with magnesium sulfate, the solvent was distilled off under reduced pressure. A mixed solvent of ethyl acetate / hexane was added to the residue and the precipitated crystals were collected by filtration to obtain 928 mg of cis-N- (4-benzyloxy-3-methoxybenzyl) -4-hydroxycyclohexanecarboxamide.
  • Example 2 In place of N- (4-benzyloxy-3-methoxybenzyl) -1- (N, N-dibutylsulfamoyl) piperidine-4-carboxamide in Example 1, the product of (2) above was used. Using and reacting in the same manner as in Example 1 (4), the desired product was obtained.
  • reaction solution was stirred at room temperature for 2 days, then washed in order with an aqueous citric acid solution, a saturated aqueous ammonium chloride solution, and saturated brine, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized with ethyl acetate to obtain 7.42 g of product.
  • Test Example 1 TRPV1 agonist activity measurement using intracellular calcium concentration as a biological activity index: fluorescence image plate reader (FLIPR) method This test was performed using rat dorsal root ganglion culture cells rich in TRPV1 expression. BrJ Anaesth measures the agonist activity of TRPV1 of the test compound using the increase in calcium concentration as an indicator.
  • the method of Jerman et al. Jerman, JC, et al., Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors. , 2002. 89 (6): p.882-7).
  • dorsal root ganglia were excised from 7 days old Wistar rats, and cells were isolated by collagenase-trypsin treatment. Thereafter, primary culture was performed for 2 days in a CO 2 incubator set at 37 ° C. with 5% CO 2 .
  • the culture solution used was Neurobasal TM medium supplemented with L-glutamine, nerve growth factor, N-2 Supplement, Penicillin-Streptomycin, 5-Fluoro-2'-deoxyuridine (only on the first day of culture).
  • the FLIPR TETRA system (Molecular Device) was used for intracellular calcium concentration measurement. By measuring the fluorescence intensity rising when the test compound was applied to the rat dorsal root ganglion primary cells into which the calcium fluorescent reagent was incorporated, it was used as an index of TRPV1 agonist activity. The results are shown in Table 1 below.
  • the compound of the present invention caused an increase in intracellular calcium concentration similar to that of capsaicin, a TRPV1 agonist.
  • Test Example 2 Examination of irritation (eye-wiping test) This test examines the degree of irritation of the compounds of the present invention. The method of Jancso et al. [Acta. Physiol. Acad. Sci. Hung., 19, 113-131 (1961)] and This was carried out according to the method of Szallasi et al. [Brit. J. Pharmacol., 119, 283-290 (1996)]. Specifically, a test compound is dissolved in physiological saline containing 5% Tween 80 and 5% ethanol so as to have each concentration (10 ⁇ g / ml or 30 ⁇ g / ml), and the resulting solution is Std: ddy.
  • the compounds of the present invention and physiologically acceptable salts thereof have a strong analgesic action and are less irritating than capsaicin, and as an analgesic and anti-inflammatory drug, existing analgesics are sufficiently effective.
  • neuropathic pain such as diabetic neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, HIV-multiple neuropathic pain, and pain caused by rheumatoid arthritis and osteoarthritis Useful as.
  • these include migraine and cluster headaches, pruritus, allergic and non-allergic rhinitis, overactive bladder, stroke, irritable bowel syndrome, respiratory diseases such as asthma and chronic obstructive pulmonary disease, skin It is also useful as a preventive and / or therapeutic agent for inflammation, mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome and diabetes, and obesity.

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Abstract

La présente invention a pour objet un composé représenté par la formule (I0) ou son sel. Dans la formule, R1 représente un groupe méthyle ou analogue ; R2 représente H ou analogue ; L représente -NH-(C=O)- ou analogue ; et Z représente un groupe qui est représenté par la formule (A), (B), (C) ou (D).
PCT/JP2010/069747 2009-11-11 2010-11-05 Dérivé du n-benzylamide et composition pharmaceutique le contenant WO2011058932A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018172251A1 (fr) * 2017-03-20 2018-09-27 Eternygen Gmbh Inhibiteurs d'un transporteur de citrate et leur utilisation en thérapie
WO2020017569A1 (fr) * 2018-07-17 2020-01-23 日本ケミファ株式会社 Inhibiteur du canal calcique de type t
WO2020203609A1 (fr) * 2019-03-29 2020-10-08 日本ケミファ株式会社 Utilisation de bloqueur des canaux calciques de type t servant au traitement du prurit
WO2020203610A1 (fr) * 2019-03-29 2020-10-08 日本ケミファ株式会社 Utilisation d'un bloqueur des canaux calciques de type t servant au traitement de la polyarthrite rhumatoïde
WO2022050385A1 (fr) 2020-09-07 2022-03-10 大日本住友製薬株式会社 Dérivé de phénol

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE041652T2 (hu) * 2013-10-11 2019-05-28 Hoffmann La Roche TRPA1-modulátorokként hasznos szubsztituált heterociklusos szulfonamid-vegyületek

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047868A1 (fr) * 1999-12-28 2001-07-05 Ajinomoto Co., Inc. Nouveaux derives de phenylalanine
WO2006115168A1 (fr) * 2005-04-21 2006-11-02 Dainippon Sumitomo Pharma Co., Ltd. Derive de phenylacetamide n-substitue et composition pharmaceutique le contenant
JP2008120797A (ja) * 2006-10-19 2008-05-29 Dainippon Sumitomo Pharma Co Ltd Ｎ−置換フェニルアセトアミド誘導体からなる医薬

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047868A1 (fr) * 1999-12-28 2001-07-05 Ajinomoto Co., Inc. Nouveaux derives de phenylalanine
WO2006115168A1 (fr) * 2005-04-21 2006-11-02 Dainippon Sumitomo Pharma Co., Ltd. Derive de phenylacetamide n-substitue et composition pharmaceutique le contenant
JP2008120797A (ja) * 2006-10-19 2008-05-29 Dainippon Sumitomo Pharma Co Ltd Ｎ−置換フェニルアセトアミド誘導体からなる医薬

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARTINEZ-TEIPEL BLANCA ET AL., QSAR & COMBINATORIAL SCIENCE, vol. 23, 2004, pages 854 - 858 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018172251A1 (fr) * 2017-03-20 2018-09-27 Eternygen Gmbh Inhibiteurs d'un transporteur de citrate et leur utilisation en thérapie
WO2020017569A1 (fr) * 2018-07-17 2020-01-23 日本ケミファ株式会社 Inhibiteur du canal calcique de type t
JPWO2020017569A1 (ja) * 2018-07-17 2021-12-02 日本ケミファ株式会社 Ｔ型カルシウムチャネル阻害剤
WO2020203609A1 (fr) * 2019-03-29 2020-10-08 日本ケミファ株式会社 Utilisation de bloqueur des canaux calciques de type t servant au traitement du prurit
WO2020203610A1 (fr) * 2019-03-29 2020-10-08 日本ケミファ株式会社 Utilisation d'un bloqueur des canaux calciques de type t servant au traitement de la polyarthrite rhumatoïde
WO2022050385A1 (fr) 2020-09-07 2022-03-10 大日本住友製薬株式会社 Dérivé de phénol
KR20230066016A (ko) 2020-09-07 2023-05-12 스미토모 파마 가부시키가이샤 페놀 유도체

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