Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
  • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
  • C07D489/08—Oxygen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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]

Definitions

• the present invention relates to an analgesic comprising, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof useful for the treatment of pain.
• Pain develops when tissue is damaged due to illness or trauma, and local pain-producing substances are produced, or because there is no direct factor such as noxious stimulation, due to abnormal functioning of the nervous system, etc. It is known when it is caused. Pain is classified into three types: (1) nociceptive pain, (2) neuropathic pain, and (3) psychogenic pain. Can be separated. Nociceptive pain is pain caused by external force stimulation applied to a living body, such as trauma, or pain caused by a disease in an internal tissue. Many of these pains are transient and disappear when the underlying disease is cured, and can often be classified as acute pain.
• NSAIDs non-steroidal anti-inflammatory drugs
• acetaminophen which have an action point in the periphery
• Opioid analgesics represented by certain morphine have been used.
• peripheral analgesics such as NS AIDs
• opioid analgesics Nausea side effects such as vomiting, constipation, addiction are problems.
• these analgesics, including morphine are effective for acute pain but often are not effective for neuropathic and psychogenic pain. Therefore, it is desired to create a new analgesic agent that is effective not only for acute pain but also for chronic pain including pain that does not work with morphine and has few side effects.
• Patent Document 1 Japanese Patent Publication No. 41 18824
• Patent Document 2 Japanese Patent Publication No. 41-18826
• Patent Document 3 International Publication No. 95Z03308 Pamphlet
• Patent Document 4 International Publication No. 2004Z033457 pamphlet (European Patent Office published EP155 5266)
• Patent Document 5 Pamphlet of International Publication No. 2005Z094826
• Non-Patent Document 1 Csaba Simon, 2 others, Tetrahedron, 1994, 50th, No. 32, p. 9757-9768
• Non-Patent Document 2 LM Sayre, three others, Journal of Medicinal Chemistry, 1984, Vol. 27, No. 10, p. 1325-1335
• Non-Patent Document 3 Csaba Simon, 2 others, Synthetic Communications, 1992, No. 22, No. 6, p. 913-921
• Non-Patent Document 4 Chiaplan SR ( Chaplan SR), 4 others, journal 'Neuroscience' Method (Journal Neuroscience Methods) ⁇ 1994, 53 ⁇ , p. 55- 63
• the object of the present invention is remarkably high and has an analgesic effect, and is also effective for the treatment of various pains such as acute pain and chronic pain. It is to provide an analgesic comprising an effective compound or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
• the present compound having an acylamino partial structure compared to a compound having a cyclic amino group, Remarkably high! It was found to have an analgesic effect.
• the present compound was found to be effective for treating various pains such as acute pain and chronic pain, and completed the present invention.
• R 1 is hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 4 to 7 carbon atoms, cycloalkyl alkyl having 5 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, carbon Aralkyl having 7 to 13 carbon atoms, alkyl having 3 to 7 carbon atoms, fulleralkyl (wherein the alkyl portion has 1 to 5 carbon atoms), chaelalkyl (wherein the alkyl portion has 1 to 5 carbon atoms), or pyridylalkyl (The carbon number of the alkyl part is 1 to 5), R 2 and R 3 are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbon, alkke-hydroxy having 3 to 7 carbon, carbon Represents an aralkyloxy having 7 to 13 carbon atoms or an alkanoyloxy having 1 to 5 carbon atoms, and -X- represents a cyclic structure Represents an alkylene, alkylene
• R 4 represents hydrogen, alkyl having 1 to 5 carbon atoms
• k represents 0 to 8
• R 5 is k substituents on the cyclic structure, each independently of fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbons, alkylidene having 1 to 5 carbons , Cycloalkyl alkyl having 7 to 13 carbon atoms, cycloalkylalkylidene having 7 to 13 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, aralkylidene having 7 to 13 carbon atoms, and 6 to 12 carbon atoms Of aryloxy, trifluoromethyl, trifluoromethoxy, succinated isothiocyanate, (CH) SR 7 , (CH) S (0) R 7 , (CH) S (0) R 7
• R 5 atoms become one oxygen atom and a carbo group or sulfoxide group, and two R 5 atoms bonded to the same carbon atom become one sulfur atom and a thiocarbonyl group.
• R 6 represents Separately, fluorine, chlorine, bromine, iodine, -head, alkyl having 1 to 5 carbon atoms, aralkyl having 7 to 13 carbon atoms, trifluorine, chlorine, bromine, iodine, -head, alkyl having 1 to 5 carbon atoms, aralkyl having 7 to 13 carbon atoms, trifluorine, chlorine, bromine, iodine, -head, alkyl having 1 to 5 carbon atoms, aralkyl having 7 to
• Each represents hydrogen, alkyl having 1 to 5 carbon atoms, alkenyl having 3 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, or aralkyl having 7 to 13 carbon atoms
• R 1Q represents hydrogen, 1 to carbon atoms 5 alkyls, 2 to 5 carbons, 7 to 13 carbons, (C H) OR 7 , or (CH) CO R 7 (p and R 7 are as defined above), and R u and R 12 are
• R 11 is hydrogen and R 12 is hydrogen, hydroxy, carbon number 1
• An analgesic comprising a morphinan derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient is provided.
• the analgesic of the present invention includes neuropathic pain, diabetic neuropathy, chronic pelvic visceral pain and the like as treatment targets.
• the present invention provides an analgesic method comprising administering to a patient one or more effective amounts of the above-described morphinan derivative having a nitrogen-containing cyclic substituent and a pharmacologically acceptable acid addition salt thereof. I will provide a.
• the present invention provides the use of the above-described morphinan derivative having a nitrogen-containing cyclic substituent of the present invention or a pharmacologically acceptable acid addition salt thereof for the production of an analgesic.
• the morphinan derivative having a nitrogen-containing cyclic substituent according to the present application has a remarkably high analgesic effect and can be an excellent analgesic agent effective in treating various pains such as acute pain and chronic pain.
• FIG. 1 is a diagram showing the results when Morphine is administered as a comparative example according to the PGF2a-induced halodia model method.
• FIG. 2 is a diagram showing the results of confirming the analgesic activity of a compound by the PGF2 ⁇ -induced Alodya model method.
• FIG. 3 is a graph showing the results of confirming the analgesic activity of Compound S by the PGF2 ⁇ -induced Alodya model method.
• FIG. 4 is a graph showing the results of confirming the analgesic activity of compound ⁇ by the PGF2 ⁇ -induced Alodya model method.
• FIG. 5 is a graph showing the results of confirming the analgesic activity of a compound by the rat Chung model method. is there.
• Each group n 6, ***: P ⁇ 0.001, **: P ⁇ 0.01, *: P ⁇ 0.05 vs. solvent-administered group (multiple groups corresponding t-test (corrected by Dunnett))
• FIG. 6 shows the results of confirming the analgesic activity of Gabapentin by the mouse Seltzer model method.
• Each group n 5, leakage: P ⁇ 0.001 vs control administration solvent administration group (student's t test or Welch's test), ***: P 0.001, *: P 0.05 vs ligation-administration solvent administration group (multiple groups) T-test (corrected by Dunnett))
• FIG. 7 shows the results of confirming the analgesic activity of a compound by the mouse Seltzer model method.
• Each group n 5, leakage: P ⁇ 0.001 vs control administration solvent administration group (student's t test or Welch's test), ***: P 0.001, *: P 0.05 vs ligation-administration solvent administration group (multiple groups T-test (corrected by Dunnett))
• FIG. 8 shows the results of confirming the analgesic activity of compound Ifi_f by the rat diabetes-induced neuropathic pain model method.
• Each group n 4, ***: P ⁇ 0.001, **: P ⁇ 0.01, *: P ⁇ 0.05 vs administration Solvent administration group (multiple groups corresponding t-test (corrected by Dunnett))
• the analgesic of the present invention comprises, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof. contains.
• R 1 may be hydrogen, cycloalkyl alkyl having 4 to 7 carbon atoms, cycloalkyl alkyl having 5 to 8 carbon atoms, or aryl having 6 to 12 carbon atoms. Hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, among others, those having 3 to 7 carbon atoms are preferred.
• Cyclobutenylmethyl, 2-cyclobutenylethyl, 3-cyclobutenylpropyl, phenyl, naphthyl, tolyl, allyl, and prenyl are preferred.
• hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, and palladium are preferable, and hydrogen, cyclopropylmethyl, cyclobutylmethyl, and allyl are preferable.
• R 2 and R 3 hydrogen, hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, acetoxy or propionoxy is preferable separately. Among these, hydrogen , Hydroxy, methoxy and acetoxy are preferred.
• -X- is preferably an alkylene or alkylene having 2 to 4 carbon atoms, which becomes a part of the ring structure.
• ethylene -CH-CH-
• Propylene -CH-C
• H 2 —CH 2 — and proberene (—CH 2 —CH ⁇ CH_) are preferred.
• Y is
• k is preferably an integer of 0 to 6, particularly 1 or 2, and is preferably 2
• R 5 when k is 1, alkyl of 1 to 5 carbons, an alkylidene having 1 to 5 carbons, having a carbon number of 7 13 cycloalkylalkyl, Ariru a carbon number of 6 12 carbon atoms Methyl, ethyl, ethylidene, propyl, propylidene, butyl, among which 7 to 13 aralkyl, 7 to 13 aralkylidene, 7 to 13 cycloalkylalkylidene, or 6 to 12 aralkyloxy are preferred.
• R 7 is hydrogen, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), an alkyl having 3 to 7 carbon atoms, or 6 to 12 carbon atoms.
• the reel (especially R 8 and R 9 are each independently hydrogen, alkyl having 1 to 5 carbon atoms (especially methyl, ethyl, propyl), or aralkyl having 7 to 13 carbon atoms (especially benzyl)).
• R 1Q hydrogen, alkyl having 1 to 5 carbon atoms, aryl, and benzyl are preferable, and hydrogen and methyl are particularly preferable.
• R u and R 12 are preferably those bonded to -0-, or R 11 is hydrogen, and R 12 is preferably hydrogen, hydroxy, or methoxy. -0- is preferred.
• R 13 As R 13, R 14, together such connexion Okiso or by R 13 is hydrogen R 14 is hydrogen, hydroxy Oh shall particularly preferred instrument R 13, R 14 both hydrogen, i.e. with unsubstituted Some are preferred.
• Pharmacologically preferred acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, lactate, and ken , Oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, etc., organic carboxylates, methanesulfonate Organic sulfonates such as ethane sulfonate, benzene sulfonate, p-toluene sulfonate, camphor sulfonate, etc., among which hydrochloride, tartrate, methane sulfonate, maleate The force that is preferably used is not limited to these.
• a compound having a combination of preferred examples of each of the above-described substituents and an acid addition salt thereof are preferred.
• substituents in the general formula (I) those having the following substituents are preferred. That is, (1) In the above general formula (I), -X- is an alkylene, alkylene, or alkylene having 2 to 7 carbon atoms that forms part of the cyclic structure; R 5 force -X -The above k substituents, Fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbon atoms, alkylidene having 1 carbon atom, cycloalkylalkyl having 7 to 13 carbon atoms, and cycloalkylalkylidene having 7 to 13 carbon atoms.
• R 6 is independently fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbons, trifluoromethyl, trifluoromethoxy, cyano, having 6 to 12 carbons
• R 6 is independently fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbons, trifluoromethyl, trifluoromethoxy, cyano, having 6 to 12 carbons
• R 13 and R 14 are both hydrogen and acid addition salts thereof,
• -X- is a C2 alkylene or alkene, and an acid addition salt thereof,
• k is 1 or 2
• R 5 is alkyl having 1 to 5 carbons, alkylidene having 1 to 5 carbons, cycloalkylalkyl having 7 to 13 carbons, 7 to 13 carbons Cycloalkylalkylidene, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, aralkylidene having 7 to 13 carbon atoms, or two Rs each substituting for adjacent carbons out of k R 5 Benzo, pyrido, naphtho, cyclopropano, cyclobutane-cyclopentano, cyclopenteno, cyclohexane-cyclohexene-cyclopentane, or 5 substituted together
• R 5 Benzo, pyrido, naphtho, R 5 together, unsubstituted or substituted with one or more substituents R 6 , Cyclopropano, cyclobutano, cyclopentano, cyclopenteno, cyclohexene cyclohexene cycloheptano, or cyclohepteno, and R U , R 12 are bonded to each other as a force of -0- or R 11 is hydrogen, R 11 Compounds wherein 12 is hydrogen, hydroxy or methoxy, and acid addition salts thereof,
• R 1 is hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentinole.
• R 1 is hydrogen, cyclopropylmethyl, cyclobutylmethyl, allyl, or prenyl
• R 2 and R 3 are independently hydrogen, hydroxy, methoxy, , Ethoxy, aryloxy, benzyloxy, acetoxy or propionoxy
• -X- is ethylene, beylene, propylene or propylene, together with two R 5 s each replacing adjacent carbons Benzo or cyclohexeno which is unsubstituted or substituted with 1 to 4 substituents R 6 ,
• R 1Q is hydrogen or methyl
• R u , R 12 are bonded to -0 -And the acid addition salts thereof
• R 1 is hydrogen, cyclopropylmethyl, cyclobutyl Tilmethyl, or aryl
• R 2 and R 3 are each independently hydrogen, hydroxy, methoxy, or acetyloxy
• -X- is beylene
• R 6 is each independently, fluorine, Chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyanophenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio , Methylsulfur, methylsulfol, methoxymethyl, eth
• -X- is beylene
• k is 2, and two of the adjacent carbons are substituted.
• R 1Q , R 13 , R ′′ are hydrogen
• R U , R 12 are bonded and are —O— compounds It is shown in Table 1.
• CPM means cyclopropylmethyl
• “-” means unsubstituted
• the stereochemistry at the 6-position is a or j8.
• R 1 is cyclopropylmethyl
• R 2 and R 3 are hydroxy
• N- [l 7- (cyclopropylmethyl) -4,5 a -epoxy-3,14-dihydroxymorphinan-6 ⁇ -yl 4-fluorophthalimide is named.
• a Linole 0H 0H Me Me A Linole 0H 0H Me Me
• Aryl H 0H C 1 C1 Aryl H 0H C1 C1
• -X- is propylene or probene
• ⁇ is a valence bond
• R 1Q R 13 R 14 is hydrogen
• R U R 12 is bonded.
• -0- specific examples of the compound represented by the following general formula (Id) or (Id '), wherein two R 5 groups that substitute for each adjacent specific carbon are a specific fused ring together An example is shown in Table 4.
• -X- is unsubstituted or R 5a and / or R 5b (R ;
• R 5b is the same as the definition of R 5 above), and Y is a valence bond, R 1Q , R 13 and R 14 are hydrogen, R U and R 12 are bonded, and -O Specific examples of the compound represented by the following general formula (ID or (10), which is a compound of-are shown in Table 6.
• a morphinan derivative having a nitrogen-containing cyclic substituent at the 6-position used as an active ingredient of the analgesic agent of the present invention represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof.
• R 13 and R 14 are R 13 ′ and R 14 ′ (R 13 ′ and R 14 ′ are oxo together, or ′ is hydrogen and R 14 ′ is hydroxy, alkoxy having 1 to 5 carbon atoms, (Representing an alkanoyloxy having 1 to 5 carbon atoms) R 5 , R 1Q , R U , R 12 , k, X, and Y are as defined above), as shown in Scheme 1, International Publication WO 04/033457 (European Publication No.
• a hydroxy group or an oxo group can be directly introduced, but after the introduction of the oxo group, a reduction step can be performed. Depending on the type of the substituent, protection and deprotection steps may be added as necessary.
• oxidizing agents that can be used for the acidity of the benzyl position are generally applicable.
• a manganese (III) salt such as manganese acetate (III)
• Lead compounds such as lead tetraacetate, organic peroxides such as t-butyl hydroperoxide and benzoyl peroxide, cerium compounds such as cerium (IV) ammonium (CAN), oxygen, etc.
• cerium (IV) nitrate ammonium is useful because an ⁇ -hydroxy compound can be selectively obtained.
• an oxidizing agent containing an organic acid such as acetic acid
• an alkanoyloxy group such as acetoxy may be efficiently introduced in some cases.
• a permanganate such as potassium permanganate
• a manganese compound such as manganese dioxide
• a chromium compound such as chromium oxide or sodium chromate
• a selenium compound such as selenium dioxide
• Periodates such as sodium periodate
• quinones such as DDQ
• silver compounds such as silver oxide, cerium compounds such as cerium nitrate (IV) ammonium (CAN), halogens (chlorine, bromine, iodine), oxygen, Hydrogen peroxide or the like
• Reaction conditions such as reaction solvent, reaction temperature, reaction time, substrate concentration, and equivalent ratio of reactants are appropriately selected depending on the oxidizing agent used.
• the target compound can be obtained in high yield by reacting 4 equivalents of the oxidizing agent with respect to the substrate at room temperature in a mixed solvent system of acetonitrile and water.
• reducing agents used for reducing a normal carbonyl compound are applicable. Hydride reducing agents such as sodium borohydride and lithium aluminum hydride can be used. Preferably used.
• Reaction conditions such as reaction solvent, reaction temperature, reaction time, substrate concentration, and equivalent ratio of the reactants are appropriately selected depending on the reducing agent used. For example, when sodium borohydride is used, an alcohol system such as methanol is used. The target compound can be obtained in high yield by reacting in a solvent at room temperature. When a hydroxy group is synthesized through an oxo group reduction step, a ⁇ -isomer may be selectively obtained, contrary to the case of direct hydroxylation.
• the conversion of the hydroxy form to the alkoxy form or alkanoyloxy form can be carried out under ordinary etherification and alkali conditions, and chlorination is a pharmacologically acceptable acid in water or various organic solvents. And then concentrated, dried, reprecipitated, recrystallized, and the like.
• the morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof was obtained by the acetic acid rising method. showed significant analgesic effect was evaluated, PGF2 a induced Arodi - Amoderu, rat Chu n g model, mouse Seltzer model ,, rat diabetogenic neuropathic pain model, and an outer oblique muscle EMG activity associated with ⁇ extension
• bladder pain inhibitory action using as an index it was confirmed that it has analgesic action, so these derivatives can be widely applied to various pains ranging from acute pain to chronic pain. .
• the analgesic agent of the present invention can be used as acute pain, for example, pain due to injury such as fracture or cut, inflammatory pain such as appendicitis and postoperative pain, and chronic pain as neuropathic pain such as cancer pain, zonal pain. It is used for herpes pain, postherpetic neuralgia, trigeminal neuralgia, and pain caused by diabetic neuropathy, causalgia, and phantom limb pain.
• deep pain and internal pain such as headache, abdominal pain, back and back pain, chronic pelvic pain group, bladder pain, pain associated with vaginitis, pain associated with (chronic) prostatitis, associated with endometriosis Pain, pain associated with hysteromyoma, urolithiasis' pain associated with urethral stones, pain associated with cystitis, pain associated with urethritis, pain associated with urinary tract infection, pain associated with interstitial cystitis, digestion It can also be applied to cramps due to genital lesions, pelvic pain, pain associated with urological diseases, etc., and gynecological pain, such as pain due to dysmenorrhea, and psychological pain.
• the analgesic of the present invention can be used for mammals (eg, mouse, rat, wild, muster, usagi, cat, inu, ushi, hidge, monkey, human).
• the analgesic of the present invention comprises the compound contained in the present invention alone or in combination with one or more drugs used for treatment or prevention of disease, reduction or suppression of symptoms. Can be administered.
• each drug may be used in combination, or a combination may be used.
• examples of such drugs include non-steroidal anti-inflammatory drugs (NSAIDs), COX-1 and / or COX-2 inhibitors such as aspirin, indomethacin, diclofenac, ibuprofen, acetoaminophen, acetinoresari.
• NSAIDs non-steroidal anti-inflammatory drugs
• COX-1 and / or COX-2 inhibitors such as aspirin, indomethacin, diclofenac, ibuprofen, acetoaminophen, acetinoresari.
• opioid analgesics such as codine, morphine, dihydrocodine, hydrocodone, hydromorphone, oxycodone, fentanyl, buprenorphine, butorphanol, nalbuphine, pentazocine, levorphanol, methadone, pethidine, tramadol, oxymorphone, etc .
• Other analgesics such as gabapentin, pregaparin, nocrophene; anesthetics such as norotan, lidocaine, etido in, oral viv
• the drug may be a free base or a salt thereof itself, or an excipient, stabilizer, preservative, buffer, solubilizer, emulsifier, diluent, Additives such as tonicity agents may be appropriately mixed.
• the drug can be produced by an ordinary method using these drug carriers as appropriate.
• the dosage form tablets or capsules, granules, powders, syrups and other oral preparations; injections, suppositories, liquids, parenterals; or ointments, creams, patches, topical administration, etc. I can list them.
• the analgesic of the present invention preferably contains 0.00001 to 90% by weight, more preferably 0.0001 to 70% by weight of the above active ingredient.
• the amount to be used is appropriately selected according to symptoms, age, body weight, administration method, etc. For adults, the amount of active ingredient is 0.1 ⁇ g to lg per day for injections, and 1 for oral agents. IX g to 10 g each and can be administered once or in several divided doses.
• the administration solvent or test compound was administered subcutaneously at a dose volume of 0.1 (mL / 10 g body weight). 15 minutes later, a 0.6% (v / v) acetic acid solution was administered intraperitoneally at a dose volume of 0.1 (mL / 10 g body weight), and after 10 minutes, the rising reaction (curved body) occurred within 10 minutes. Or the number of occurrences of twisting behavior) was measured, and this number was used as an index of pain.
• the amount of the test compound at which the number of rising reactions in the administration solvent group was 50% was defined as ED50, and analgesic activity was evaluated based on that value.
• Test compound IV 2, 3 ,, 5, 6, 7, 8, £, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21
• DMSO dimethylsulfoxide
• ddY male mice the administration solvent or test compound was administered subcutaneously at a dose volume of 0.1 (mL / 10 g body weight).
• PGF2a was administered into the spinal cord at a dose of 1 ⁇ g / mouse and a dose volume of 4 ⁇ L / mouse to induce arodia.
• Alodya is a paint brush The reaction of the animal when the left and right sides of the fish were stroked was determined by scoring with the following indices. Judgment result is 0 point; nothing reacts. 1 point; No way to escape. 2 points; Run away or run away quickly. Flicking. Measurements were carried out for 40 minutes at 5-minute intervals after PGF2 a dose. The results are shown in Figs.
• Rat Chung model animals were purchased from Japan SLC (Left hindlimb dominating nerve ligation treatment at 6 weeks of age). After one week of nerve ligation treatment Dixson's Up- using Filament (North Coast Medical, Inc. CA, USA) with a pressure of 0.407, 0.69 2, 1.202, 2.041, 3.630, 5.495, 8.511, or 15.136 g Evaluation was performed according to the Down method (Non-patent Document 4). A tactile stimulus was applied to the plantar of both hind limbs for 8 seconds (von Frey te st), and an avoidance reaction (lifting, flapping, licking) was shown during or immediately after the stimulation. In some cases, there was a response (X).
• ICR mice 5 weeks old, male were used. After anesthetizing the mouse with pentobarbital, the sciatic nerve in the right hind limb thigh was exposed, and the sciatic nerve was strengthened only half a circle using a silk suture (Natsume Seisakusho) of 8-0 (US Pharmacopeia) under a microscope. Triple ligation. On the other hand, only the sciatic nerve was exposed and the one with ligation strength was used as a control. Neural ligation treatment Using a filament (North Coast Medical, Inc. CA, USA) that applies 0.02g or 0.16g of pressure one week after the nerve ligation.
• Diabetes-induced rats were purchased from Japan SLC (Streptozotocin (STZ) 50 mg / kg, single intraperitoneal administration at 6 weeks of age). At 3 weeks after STZ administration, the blood glucose level was measured with a precision Q ⁇ I ⁇ D blood glucose meter, and those with a value of 200 mg / dL or more were judged to induce diabetes. Diabetes-induced animals are Dixson using 0.407, 0.692, 1.202, 2.041, 3.630, 5.495, 8.511, or 15.136 g of pressure-applying filament (North Coast Medical, Inc. CA, USA) after 4 weeks of STZ administration. This was evaluated according to the Up-Down method (Non-Patent Document 4).
• a polyethylene force tape (PE-50) for intravesical pressure measurement was inserted into the bladder transurethrally, and a polyethylene force tape for filling physiological saline from the top of the bladder. (PE-100) was inserted into the bladder.
• PE-50 polyethylene force tape
• PE-100 polyethylene force tape for filling physiological saline from the top of the bladder.
• Each catheter was tightly ligated so that physiological saline did not leak from the insertion site.
• a drug administration catheter was placed in the femoral vein. The skin on the flank was incised, and a bipolar electrode for electromyography was inserted into the lateral oblique muscle and placed. Connect a reservoir pre-filled with saline to an indwelling catheter Then, the bladder was extended by fixing at a specific height.
• the extension stimulation was 20 seconds, and the interval between repeated stimulations was 3 minutes.
• Bipolar electrode electroencephalogram needle, Nihon Kohden
• EMG100C EMG amplifier
• High cut filter 5 kHz
• low cut filter 100 Hz
• AD The device (MP-150WSW, Biopac systems) and computer were loaded at 1 kHz, and myoelectric activity was recorded using dedicated software (AcqKnowledge 3.8.1, Biopac systems).
• Intravesical pressure was measured using a pressure transducer (AP641G, Nippon Koden) and a general-purpose amplifier (DA100C, Biopac systems). After adjusting the halothane concentration and obtaining stable myoelectric activity by stretching 50 cmH 0, the drug is administered intravenously.
• the drug was dissolved in 5% xylitol-0.02% citrate aqueous solution, and the administration volume was 0.5 mL / kg.
• the change in the number of spikes after drug administration was standardized with the average value of the number of spikes due to bladder extension twice before drug administration as the pre-drug value and the pre-dose value as 100%.
• the mean value of the three spike count changes between 15 minutes after drug administration was calculated, and the drug effect was judged by Williams test.
• Drug dose Number of cases Myoelectric activity in the external oblique muscle (number of spikes) Inhibition rate (mg / kg, i v) (vs. pre-dose, 3 ⁇ 4)
• the analgesic of the present invention has a remarkably high analgesic action, and has various acute pain and chronic pain. It can be applied to pain.

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• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2005
  • 2005-11-03 TW TW094138512A patent/TW200621785A/zh not_active IP Right Cessation
  • 2005-11-03 AR ARP050104603A patent/AR053098A1/es not_active Application Discontinuation
  • 2005-11-03 PE PE2005001291A patent/PE20060723A1/es not_active Application Discontinuation
  • 2005-11-04 MX MX2007005336A patent/MX2007005336A/es active IP Right Grant
  • 2005-11-04 CN CN200580045038XA patent/CN101090722B/zh not_active Expired - Fee Related
  • 2005-11-04 EP EP05799891A patent/EP1820505A4/en not_active Withdrawn
  • 2005-11-04 CA CA2586181A patent/CA2586181C/en not_active Expired - Fee Related
  • 2005-11-04 US US11/667,136 patent/US8470845B2/en not_active Expired - Fee Related
  • 2005-11-04 JP JP2006542444A patent/JP4706636B2/ja not_active Expired - Fee Related
  • 2005-11-04 WO PCT/JP2005/020297 patent/WO2006049248A1/ja not_active Ceased
  • 2005-11-04 KR KR1020077011752A patent/KR101285645B1/ko not_active Expired - Fee Related
• 2007
  • 2007-06-04 NO NO20072832A patent/NO20072832L/no not_active Application Discontinuation

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