WO2011058933A1 - Dérivé cyclique d'ester d'acide amine-1-carboxylique et composition pharmaceutique le contenant - Google Patents

Dérivé cyclique d'ester d'acide amine-1-carboxylique et composition pharmaceutique le contenant Download PDF

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WO2011058933A1
WO2011058933A1 PCT/JP2010/069748 JP2010069748W WO2011058933A1 WO 2011058933 A1 WO2011058933 A1 WO 2011058933A1 JP 2010069748 W JP2010069748 W JP 2010069748W WO 2011058933 A1 WO2011058933 A1 WO 2011058933A1
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compound
pain
physiologically acceptable
acceptable salt
formula
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Japanese (ja)
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保知 筑木
裕貴 宮地
伸彦 堀内
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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
    • C07D211/18—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
    • C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D211/40—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
    • C07D211/36—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
    • C07D211/04—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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

  • the present invention relates to a cyclic amine-1-carboxylic acid ester derivative useful as a therapeutic agent for pain and inflammation, and more specifically, a cyclic amine-1-carboxylic acid ester having a substituent having a 3,4-disubstituted benzyl group on the ring.
  • the present invention relates to a derivative and a pharmaceutical composition containing it.
  • 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 in the treatment of pain such as diabetic neuropathy and rheumatoid arthritis, as a result of persistent TRPV1 cation channel opening by capsaicin. 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 having a capsaicin-like medicinal mechanism can be used for pruritus, allergic and non-allergic rhinitis, overactive bladder, stroke, irritable bowel, which are pathologies involving primary afferent sensory nerves (C fibers). It is also considered useful as a therapeutic agent for syndromes, 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. Further, since it has been reported that insulin resistance is improved by treating diabetic rats with capsaicin [Non-Patent Document 5], it is 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.
  • the inventors of the present invention have obtained a cyclic amine-1-carboxylic acid ester derivative having a substituent having a 3,4-disubstituted benzyl group on the ring, that is, represented by the following formula (I).
  • a cyclic amine-1-carboxylic acid ester derivative having a substituent having a 3,4-disubstituted benzyl group on the ring that is, represented by the following 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 3 is substituted, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 cycloalkenyl, aryl or heteroaryl (respective group, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, a C 3 ⁇ 8 cycloalkyl or halogen .
  • C 6 ⁇ 12 represent an alkyl or C 6 ⁇ 12 alkenyl
  • X represents —NH—C ( ⁇ O) —NH—, —C ( ⁇ O) —NH—, —NH—C ( ⁇ S) —NH—, —C ( ⁇ S) —NH—, —NH—.
  • R 3 is, C 3 ⁇ 8 cycloalkyl or aryl (respective groups are selected from C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl and C 3 ⁇ 8 group consisting cycloalkyl Or a physiologically acceptable salt thereof, which may be substituted with the same or different 1 to 5 substituents.
  • Item 4 In item 3, in formula (I), X is —NH—C ( ⁇ O) —NH—, —NH—C ( ⁇ S) —NH— or —NH—C ( ⁇ S) —. Or a physiologically acceptable salt thereof.
  • Item 5 The compound according to Item 1 or 2, or a physiologically acceptable salt thereof, wherein, in the formula (I), X is —NH—C ( ⁇ O) —NH—.
  • Item 6 The compound or a physiologically acceptable salt thereof according to Item 1 or 2, wherein in the formula (I), X is —NH—C ( ⁇ S) —.
  • Item 7 The compound according to Item 1 or 2, or a physiologically acceptable salt thereof, wherein, in the formula (I), X is —C ( ⁇ O) —NH—.
  • Item 8 The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 4, wherein in formula (I), n and m are the same or different and each is an integer of 1 or 2.
  • Item 9 The compound according to Item 8 or a physiologically acceptable salt thereof, wherein in the formula (I), n and m are both 2.
  • Item 10 The compound or a physiologically acceptable salt thereof according to any one of Items 1 to 9, wherein, in the formula (I), p is an integer of 1.
  • Item 11 The compound according to any one of Items 1 to 10, or a physiologically acceptable salt thereof, wherein in the formula (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), R 2 is a hydrogen atom.
  • Item 13 A pharmaceutical composition comprising the compound according to any one of Items 1 to 12 or a physiologically acceptable salt thereof as an active ingredient.
  • Item 14 A therapeutic or preventive agent for pain and / or inflammation comprising the compound according to any one of Items 1 to 12 or a physiologically acceptable salt thereof as an active ingredient.
  • Item 15 An analgesic or anti-inflammatory agent comprising the compound according to any one of Items 1 to 12 or a physiologically acceptable salt thereof as an active ingredient.
  • Item 16 A method for treating or preventing pain and / or inflammation, comprising administering an effective amount of the compound according to any one of Items 1 to 12 or a physiologically acceptable salt thereof to a patient.
  • Item 17 Use of the compound according to any one of claims 1 to 12 or a physiologically acceptable salt thereof for the manufacture of a therapeutic or preventive agent for pain and / or inflammation.
  • Item 18 The compound according to any one of Items 1 to 12 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 19 A pharmaceutical composition comprising the medicament according to claim 18 as an active ingredient.
  • Item 20 A therapeutic or prophylactic agent for pain and / or inflammation, comprising the medicament according to claim 18 as an active ingredient.
  • Item 21 A method for treating or preventing pain and / or inflammation, comprising administering to a patient an effective amount of the medicament according to Item 18.
  • Item 22 Use of the medicament according to claim 18 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 prophylactic agent for respiratory diseases, dermatitis, mucositis, gastric / duodenal ulcer, inflammatory bowel syndrome and diabetes, and obesity can be provided.
  • the physiologically acceptable salt of the compound represented by the formula (I) is a physiologically acceptable acid addition salt of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure, Or the salt with the physiologically acceptable base of the compound of the formula (I) which has a group which can form a salt with a base in a structure is meant.
  • 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, potassium and calcium salts, salts with organic bases such as pyridine salts and triethylamine salts, and lysine and arginine. And salts with amino acids such as
  • the compounds of formula (I) and their salts may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
  • the “compound of the present invention” includes these hydrates and / or solvates in addition to the compound represented by the above formula (I) and physiologically acceptable salts thereof.
  • the compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore may exist as several stereoisomers. .
  • these stereoisomers, mixtures thereof and racemates are included in the compound represented by the 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.
  • Yes at least one double bond and "C 2-6 alkenyl", carbon atoms means a unsaturated hydrocarbon group of 2 to 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. Further, the number of double bonds contained in the alkenyl may be one or two.
  • C 3-8 cycloalkyl carbon atoms means a monocyclic saturated hydrocarbon group of 3 to 8.
  • 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 (for example, 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.
  • substituents when the hydrogen atom of cycloalkyl, cycloalkenyl, aryl or heteroaryl is substituted with a plurality of substituents, these substituents may be the same or different. Specific examples of the plurality of substituents may be any combination of the substituents exemplified above.
  • Examples of each group in the compound (I) 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.
  • R 3 is, C 3 ⁇ 8 cycloalkyl, C 3 ⁇ 8 cycloalkenyl, aryl or heteroaryl (respective group, C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl, in C 3 ⁇ 8 cycloalkyl or halogen, may be substituted at a substitutable position, for example, it may be substituted by the same or different and one to five of the substituents) or show, or, C 6 - 12 alkyl or C show 6 to 12 alkenyl.
  • the cycloalkyl is preferably, C 4 ⁇ 8 cycloalkyl, more preferably, C 5 ⁇ 7 cycloalkyl. Further, the cycloalkyl is preferably unsubstituted or one to five identical or different C 1 - 6 alkyl, C 2 - 6 alkenyl, better to be substituted with C 3 ⁇ 8 cycloalkyl, more preferably, unsubstituted or one to five identical or different C 1 ⁇ 4 alkyl, it is to be substituted with C 2 ⁇ 4 alkenyl or C 3 ⁇ 6 cycloalkyl.
  • the cycloalkenyl is preferably C 4 ⁇ 8 cycloalkenyl, more preferably C 5 ⁇ 8 cycloalkenyl. Further, the cycloalkenyl is preferably unsubstituted or 1 to 5, preferably substituted with 1 to 2 identical or different C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl or C 3 ⁇ 8 cycloalkyl are the well, and more preferably, an unsubstituted or 1-2 same or different C 1 ⁇ 4 alkyl, it is to be substituted with C 2 ⁇ 4 alkenyl or C 3 ⁇ 6 cycloalkyl.
  • Aryl is preferably phenyl. Further, the aryl is preferably unsubstituted or one to five identical or different C 1 ⁇ 6 alkyl, good to be substituted with C 2 ⁇ 6 alkenyl or C 3 ⁇ 8 cycloalkyl, more preferably , it is to be substituted with an unsubstituted or 1-2 same or different C 1 ⁇ 5 alkyl, C 2 ⁇ 5 alkenyl or C 3 ⁇ 6 cycloalkyl.
  • heteroaryl preferably thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, benzoisoxazolyl, benzoxiadiazolyl, benzothiadiazolyl
  • Examples include pyridazinyl, pyrazolopyridinyl, cinnolinyl, triazolyl, quinolyl, isoquinolyl, and naphthyridinyl, and more preferably thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrimidinyl, oxadiazolyl , Thiadiazolyl,
  • heteroaryl said are preferably substituted with an unsubstituted or same 1 to 5 at substitutable positions or different C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl or C 3 ⁇ 8 cycloalkyl good to have, more preferably, it is to be substituted with an unsubstituted or 1-2 same or different C 1 ⁇ 5 alkyl, C 2 ⁇ 5 alkenyl or C 3 ⁇ 6 cycloalkyl.
  • C 3 ⁇ 8 cycloalkyl or aryl (respective group is selected from C 1 ⁇ 6 alkyl, C 2 ⁇ 6 alkenyl and C 3 ⁇ 8 group consisting cycloalkyl may be substituted by the same or different and 1 to 5 substituents.), a more preferred group, one to four identical or different C 1 - 6 alkyl, C 2 - 6 alkenyl or C 3 - which may be substituted by 8 cycloalkyl C 5 - 7 cycloalkyl, or one to two may be substituted by the same or different C 1 - 6 alkyl or C 3 - 6 cycloalkyl Phenyl.
  • X represents —NH—C ( ⁇ O) —NH—, —C ( ⁇ O) —NH—, —NH—C ( ⁇ S) —NH—, —C ( ⁇ S) —NH—, —NH—.
  • n and m are the same or different and each represents an integer of 1, 2 or 3, preferably 1 or 2, more preferably an integer of 1 or 2, or one is 1 and the other is 2 It is. Particularly preferably, both are 2.
  • P represents an integer of 0, 1 or 2, preferably an integer of 1 or 2, more preferably an integer of 1.
  • Preferred compounds in the present invention are represented by the following formula (I ′)
  • R 3 ' is 1 to 4 identical or different C 1 - 6 alkyl, C 2 - 6 alkenyl or C 3 - which may be substituted by 8 cycloalkyl C 5 - 7 cycloalkyl
  • X represents —NH—C ( ⁇ O) —NH—, —C ( ⁇ O) —NH—, —NH—C ( ⁇ S) —NH—, —C ( ⁇ S) —NH— or —NH—.
  • C ( S) ⁇ , n and m both represent an integer of 1 or 2, or one represents 1 and the other represents 2.
  • the compound represented by the formula (I) or a physiologically acceptable salt thereof is a novel compound, and includes, for example, a method according to the method described below, examples described later or known methods. Can be manufactured by.
  • the compound used in the following production method may form a salt as long as the reaction is not hindered.
  • a functional group that may participate in the reaction when included in the structure of the starting material, for example, amino, carboxyl, hydroxyl group, and carbonyl, it is generally used for these groups. It may be protected by introducing a protective group, and in that case, the desired compound can be obtained by removing the protective group as appropriate after completion of the reaction.
  • 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 and propionyl.
  • alkylcarbonyl such as formyl, benzoyl, aralkyloxycarbonyl such as benzyloxycarbonyl, and silyl.
  • the carbonyl can be protected by converting the carbonyl to an acyclic ketal such as dimethyl ketal and diethyl ketal or a cyclic ketal such as 1,3-dioxolane and 1,3-dioxane.
  • acyclic ketal such as dimethyl ketal and diethyl ketal
  • a cyclic ketal such as 1,3-dioxolane and 1,3-dioxane.
  • R 1 , R 2 , R 3 , X, m, n and p are R 1 , R 2 , Defined similarly to R 3 , X, m, n and p.
  • Y represents a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, and imidazolyl).
  • a compound of formula (I) is prepared by converting a compound of formula (II) into a reactive derivative represented by formula (III) and then reacting it with a compound of formula (IV) under commonly used conditions. be able to.
  • the above reaction between the compound of formula (III) and the compound of formula (IV) 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 starting compound used, etc., 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.
  • compound (III) from compound (II) is, for example, J. Org. Chem., 27, 961 (1962), J. Chem. Soc., Perkin Trans. 1, 1205 (1996), Tetrahedron, 61, 7153 (2005) or the like, or a method based on these methods.
  • the compound of formula (II) may be used in the form of an acid addition salt such as hydrochloride and the free base may be generated in the reaction system.
  • the compound of the formula (IV) is commercially available, or can be produced by a known method or a method analogous thereto.
  • R 1 , R 2 , R 3 , X, m, n and p are R 1 , R 2 , Defined similarly to R 3 , X, m, n and p.
  • Y represents a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, and imidazolyl).
  • the compound of the formula (I) can be produced by reacting the compound of the formula (II) with the compound of the formula (V) or the formula (VI) under usually used conditions.
  • the above reaction of the compound of formula (II) with the compound of formula (V) or formula (VI) 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 can be used alone or as a mixed solvent of two or more.
  • the compound of formula (II) may be used in the form of an acid addition salt such as hydrochloride and the free base may be generated in the reaction system. Moreover, this reaction is normally performed in presence of a base.
  • a base include inorganic bases such as potassium carbonate and sodium bicarbonate, or organic bases such as triethylamine, diisopropylethylamine, 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 80 ° C.
  • the reaction time is about 1 to 48 hours.
  • the compound of the formula (V) is commercially available, or a known method such as the method described in Synthesis, 103 (1993), J. Org. Chem., 53, 2340 (1988), or the like. Can be produced according to the methods described above.
  • the compound of formula (VI) can be obtained by known methods such as those described in J. Org. Chem., 27, 1901 (1962), Org. Synth., VI, 418 (1988), or the like. It can be produced according to a similar method.
  • R 1 , R 2 , m, n, and p are R 1 in formula (I) including preferred embodiments thereof. , R 2 , m, n and p.
  • Y represents a leaving group (for example, a halogen atom, lower alkoxy, phenoxy, and imidazolyl), and P 1 represents an amino-protecting group.
  • a compound of formula (II ′) can be prepared by deprotecting the protecting group (P 1 ) of formula (X).
  • a compound of formula (X) is prepared by converting a compound of formula (VII) into a reactive derivative represented by formula (VIII) and then reacting it with a compound of formula (IX) under commonly used conditions. be able to.
  • compound (X) from compound (VII) can be carried out, for example, according to the method described in Tetrahedron, 61, 7153 (2005), Synthesis, 423 (1989), or the like.
  • the compound of the formula (VII) is commercially available or can be produced by a known method or a method analogous thereto, and is used in the form of an acid addition salt such as hydrochloride, in the reaction system. A free base may be generated.
  • R 1 , R 2 , m, n and p including preferred embodiments thereof, R 1 , R 2 in formula (I) , M, n and p.
  • P 1 represents an amino protecting group.
  • a compound of formula (II ′′) can be prepared by deprotecting the protecting group (P 1 ) of formula (XIII).
  • the compound of the formula (XIII) can be produced by an amidation reaction between a compound of the formula (XI) and a compound of the formula (XII) under a commonly used reaction condition.
  • the compound of formula (XI) may be reacted with a compound of formula (XII) after conversion to a reactive derivative at the carboxyl group.
  • the compound of formula (XI) is commercially available, or can be produced by a known method or a method analogous thereto.
  • R 1 , R 2 , R 3 , m, n and p are R 1 , R 2 , R in the formula (I). 3 Defined similarly to m, n and p.
  • the production of the compound of the formula (I ′ ′′) from the compound of the formula (I ′′) can be carried out, for example, using the Lawson reagent, as described in Tetrahedron, 41, 2567 (1985), Synthesis, 152 (1988), etc. Or it can carry out according to the method according to these.
  • the compound of the formula (I ′′) can be produced according to the methods described in the production methods (1) and (2) of the compound of the formula (I) described above.
  • the compound of the formula (I) obtained by the above production method can be isolated and purified according to conventional methods such as chromatography, recrystallization, reprecipitation and the like.
  • the optical isomer can also be derived from asymmetric synthesis such as using a starting material having an asymmetric center, or by optical resolution such as using 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 formula (I) may be obtained in the form of a salt depending on the type of functional group present in the structural formula, selection of the raw material compound, and reaction treatment conditions. Can be converted.
  • the compound of the formula (I) 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.
  • the 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 and intracavitary injections, and infusions.
  • compositions are prepared according to conventional methods. That is, a pharmaceutical composition containing a compound represented by the formula (I) or a physiologically acceptable salt thereof includes an excipient, a binder, a lubricant, a stabilizer, a disintegrant, a base, and a buffer.
  • Solubilizer, tonicity agent, solubilizer, pH adjuster, surfactant, emulsifier, suspending agent, dispersant, suspending agent, thickener, viscosity modifier, gelling agent, soothing Can contain pharmaceutical carriers such as agents, preservatives, plasticizers, absorption promoters, anti-aging agents, moisturizers, preservatives, and perfumes, and can select two or more pharmaceutical carrier additives as appropriate It can also be used.
  • 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 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 layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. did.
  • N, N′-carbonyldiimidazole (1.67 g) was added to a mixture of cis-4-ethylcyclohexanol (1.02 g) and dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 14 hours, water was added, 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 1.71 g of cis-4-ethylcyclohexyl 1H-imidazole-1-carboxylate.
  • Cyclohexanol is used instead of cis-4-ethylcyclohexanol in Example 1 as 1- (4-benzyloxy-3-methoxybenzyl) -3- (piperidin-4-yl) urea hydrochloride
  • the product of 2) was used in the same manner as in Example 1 (3) and (4) and treated to give cyclohexyl 4- [2- (4-benzyloxy-3-methoxyphenyl) acetoxy] piperidine-1-carboxylate.
  • the reaction mixture was diluted with ethyl acetate, filtered through celite, and washed with 1 mol / l hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine in this order.
  • the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 14-22 Table 1 and Table 2 show the same reactions and treatments as in Example 13 except that various chloroformates were used instead of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl chloroformate in Example 13. The compound shown was obtained.
  • Example 19 The product of Example 19 was used instead of cyclohexyl 4- (4-hydroxy-3-methoxybenzylcarbamoyl) piperidine-1-carboxylate in Example 5, and the reaction and treatment were carried out in the same manner as in Example 5 (5). The desired product was obtained.
  • Example 5 From Example 5 (1) using 2- [1- (t-butoxycarbonyl) piperidin-4-yl] acetic acid instead of 1- (t-butoxycarbonyl) -piperidine-4-carboxylic acid in Example 5
  • the target product was obtained by reacting and treating in the same manner as in (4).
  • Example 5 From Example 5 (1) using 3- [1- (t-butoxycarbonyl) piperidin-4-yl] propion instead of 1- (t-butoxycarbonyl) -piperidine-4-carboxylic acid in Example 5
  • the target product was obtained by reacting and treating in the same manner as in (4).
  • 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-day-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 3 below.
  • the compound of the present invention caused an increase in intracellular calcium concentration similar to that of capsaicin, which is 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 (I) ou son sel. (Dans la formule, R1 représente un groupe méthyle ou analogue ; R2 représente H ou analogue ; R3 représente un groupe cycloalkyle, un groupe cycloalcényle, un groupe aryle ou un groupe hétéroaryle (chaque groupe étant facultativement substitué par un groupe alkyle, un groupe alcényle, un groupe cycloalkyle ou un atome d'halogène), ou représente un groupe alkyle ou un groupe alcényle ; X représente -NH-C(=O)-NH-, -C(=O)-NH-, -NH-C(=S)-NH-, -C(=S)-NH-, -NH-C(=S)-, -NH-C(=O)-CH2-, -NH-C(=O)-CH2-CH2-, -NH-C(=O)-O-, -O-C(=O)-NH-, -C(=O)-O-, -O-C(=O)- ou -C(=O)- ; n et m représentent chacun un nombre de 1 à 3 ; et p représente un nombre de 0 à 2.)
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JP2005504074A (ja) * 2001-09-13 2005-02-10 スミスクライン　ビーチャム　パブリック　リミテッド　カンパニー 新規化合物
JP2006519805A (ja) * 2003-03-08 2006-08-31 グラクソ　グループ　リミテッド バニロイド受容体拮抗活性を有する尿素誘導体
JP2007502258A (ja) * 2003-08-14 2007-02-08 グラクソ　グループ　リミテッド バニロイド受容体モジュレーターとして用いるためのピペリジン／シクロヘキサンカルボキサミド誘導体
JP2007509915A (ja) * 2003-10-29 2007-04-19 メルク シャープ エンド ドーム リミテッド 疼痛の治療のためにバニロイド１受容体（ｖｒ１）の機能を調節する４−フルオロ−４−（ピリジン−２−イル）ピペリジン−１−カルボキサミド誘導体及び関連化合物
WO2009136625A1 (fr) * 2008-05-07 2009-11-12 大日本住友製薬株式会社 Dérivé d’ester d’acide (amine cyclique)-1-carboxylique et composition pharmaceutique le contenant

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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