HK1115808B - Analgesic - Google Patents
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- HK1115808B HK1115808B HK08106279.1A HK08106279A HK1115808B HK 1115808 B HK1115808 B HK 1115808B HK 08106279 A HK08106279 A HK 08106279A HK 1115808 B HK1115808 B HK 1115808B
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Description
Technical Field
The present invention relates to an analgesic agent useful for the treatment of pain, which comprises, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof.
Background
In the onset of pain, it is known that pain is caused by local generation of a pain-causing substance by damaging a tissue due to a disease, a trauma, or the like; and pain caused by a direct factor such as non-invasive stimulation or a functional abnormality of the nervous system. If pain is classified according to its origin, it can be roughly classified into: (1) nociceptive pain; (2) neuropathic pain; (3) psychological pain is classified into three types. Nociceptive pain refers to pain caused by external stimulation applied to a living body such as trauma or pain caused by a lesion in an internal tissue or the like. This pain is most likely temporary, and the underlying condition disappears as soon as the pain is cured, often classified as acute pain. On the other hand, there are chronic pains that are caused by dysfunction in the central nervous system due to abnormality of peripheral tissues or peripheral nerve terminals or injury of peripheral nerves, and also caused by disorder of the central nervous system, psychological mechanism, and the like, and the above-mentioned neuropathic pain and psychological pain are among such chronic pains. Pain is caused by various factors, and the mechanism of generation thereof is not completely understood, but bradykinin, histamine, prostaglandin, 5-hydroxytryptamine, substance P, opioid peptide, and the like are reported as in vivo substances involved in pain and regulation thereof.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and acetaminophen, which act on the peripheral sites, are used as therapeutic agents for mild pain; opioid analgesics such as morphine, which have central points of action, are used for moderate or severe pain. However, when peripheral analgesics such as NSAIDs are used, there is a problem that side effects on the digestive system and the like are caused in addition to the insufficient analgesic effect in some cases. When opioid analgesics are used, side effects such as nausea, vomiting, constipation, and dependence are problematic. In addition, although these morphine-containing analgesics exhibit an effect on acute pain, they often do not exhibit a sufficient effect on neuropathic pain and psychological pain. Therefore, development of a novel analgesic agent which is effective not only for acute pain but also for chronic pain such as pain not acting on morphine and has few side effects has been desired.
However, morphinan compounds, which are represented by morphine, have been known to have analgesic effects for a long time. Even if the morphinan compound having a nitrogen-containing cyclic substituent at the 6-position is limited, it has been shown that a cyclic secondary amino compound or the like has an analgesic effect (see patent documents 1, 2, and 3). Some morphinan compounds having a cyclic imino group at the 6-position have not been directly shown to have analgesic activity, but compounds having a chemical structure have been disclosed (see non-patent documents 1, 2, and 3). On the other hand, it is disclosed that the compound of the present application has a therapeutic effect on pollakiuria and urinary incontinence (see patent document 4), and its use as an antipruritic is disclosed later than the priority date of the present application (patent document 5). However, all of the above disclosures do not suggest that the compounds of the present application have significant analgesic effects and are also applicable to chronic pain and useful as analgesics.
Patent document 1: japanese examined patent publication No. 41-18824
Patent document 2: japanese examined patent publication No. 41-18826
Patent document 3: international publication No. 95/03308 pamphlet
Patent document 4: international publication No. 2004/033457 pamphlet (European patent office publication No. EP 1555266)
Patent document 5: international publication No. 2005/094826 pamphlet
Non-patent document 1: CsAba Simon and 2 others, Tetrahedron, 1994 Vol.50, 32, 9757-9768
Non-patent document 2: sayre, and 3 others, Journal of Medicinal Chemistry, Vol.27, Vol.10, 1984, pp.1325-
Non-patent document 3: csaba Simon and 2 others Synthetic Communications, vol.22, 1992, pp.6, 913-
Non-patent document 4: chaplan SR and 4 additional people, Journal Neuroscience Methods (J. Neuroscience Methods), volume 53, pages 55-63, 1994
Disclosure of Invention
Problems to be solved by the invention
An analgesic agent comprising, as an active ingredient, a compound having a cyclic nitrogen-containing substituent at the 6-position, which has a very high analgesic effect and is effective for the treatment of various pains, including acute pain and chronic pain, or a pharmacologically acceptable acid addition salt thereof.
Means for solving the problems
As a result of intensive studies to achieve the above object, it was found that: among morphinan compounds having a nitrogen-containing cyclic substituent at the 6-position, the compounds of the present application having an acylamino moiety structure have a very high analgesic effect as compared with the compounds having a cyclic amino group. The compounds of the present invention have been found to be effective in the treatment of various pains ranging from acute pain to chronic pain, and thus the present invention has been completed.
Namely, the present invention provides an analgesic agent comprising, 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,
in the formula R1Represents hydrogen, an alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms, a cycloalkenylalkyl group having 5 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an alkenyl group having 3 to 7 carbon atoms, a furanylalkyl group (the carbon atom of the alkyl moiety is 1 to 5), a thienylalkyl group (the carbon atom of the alkyl moiety is 1 to 5) or a pyridylalkyl group(the number of carbon atoms in the alkyl moiety is 1 to 5); r2、R3Each independently represents hydrogen, hydroxyl, alkoxy having 1 to 5 carbon atoms, alkenyloxy having 3 to 7 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or alkanoyloxy having 1 to 5 carbon atoms; -X-represents an alkylene group, an alkenylene group or an alkynylene group having 2 to 7 carbon atoms (wherein 1 or more carbon atoms may be substituted by nitrogen, oxygen or sulfur atoms) which constitutes a part of the cyclic structure; y represents an atomic valence bond, -C (O) -, -C (S) -, -S (O)2)-、-N(-R4)-、-C(＝O)-N(-R4) -or-C (═ S) -N (-R)4)-；R4Represents hydrogen or an alkyl group having 1 to 5 carbon atoms; k represents an integer of 0 to 8; r5Each of k substituents on the cyclic structure independently represents fluorine, chlorine, bromine, iodine, nitro, an alkyl group having 1 to 5 carbon atoms, an alkylene group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 7 to 13 carbon atoms, a cycloalkylalkylene group having 7 to 13 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an aralkylene group having 7 to 13 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an isothiocyanate group, or a (CH) substituent group2)pSR7、(CH2)pS(O)R7、(CH2)pS(O2)R7、(CH2)pOR7、(CH2)pC(＝O)R7、(CH2)pOC(＝O)R7、(CH2)pCO2R7、(CH2)pS(O)NR8R9、(CH2)pS(O2)NR8R9、(CH2)pC(＝O)NR8R9、(CH2)pNR8R9、(CH2)pN(R8)C(＝O)R9、(CH2)pN(R8)S(O2)R9Or k R5In which 2R are bound to the same carbon or sulfur atom5To an oxygen atom, represents a carbonyl group or a sulfoxide group; 2R bound to the same carbon atom5To a sulfur atom, represents a thiocarbonyl group; 4R bound to the same sulfur atom52 oxygen atoms represent a sulfonic acid group; or k R5Wherein 2R are independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by more than 1 substituent R6Substituted benzo, pyrido, naphtho, cyclopropane, cyclobutane, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptane or cycloheptene; r6Each independently represents fluorine, chlorine, bromine, iodine, nitro, an alkyl group having 1 to 5 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, an aryl group having 6 to 12 carbon atoms, an isothiocyanate group, or (CH)2)pSR7、(CH2)pS(O)R7、(CH2)pS(O2)R7、(CH2)pOR7、(CH2)pC(＝O)R7、(CH2)pOC(＝O)R7、(CH2)pCO2R7、(CH2)pS(O)NR8R9、(CH2)pS(O2)NR8R9、(CH2)pC(＝O)NR8R9、(CH2)pNR8R9、(CH2)pN(R8)C(＝O)R9Or (CH)2)pN(R8)S(O2)R9(ii) a p represents an integer of 0 to 5; r7、R8、R9Each independently represents hydrogen, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 3 to 7 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms; r10Represents hydrogen, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, (CH)2)pOR7Or (CH)2)pCO2R7(p、R7Same as defined above); r11、R12Combined to represent-O-, -S-or-CH2-, or R11Represents hydrogen, R12Represents hydrogen, hydroxyl, alkoxy with 1-5 carbon atoms or alkanoyloxy with 1-5 carbon atoms; r13、R14Together represent oxo, or R13Represents hydrogen, R14Represents hydrogen, hydroxyl, alkoxy with 1-5 carbon atoms or alkanoyloxy with 1-5 carbon atoms; the general formula (I) comprises (+), (-) -, (+ -) -isomers.
The analgesic agent of the present invention is used for treating a subject including neuropathic pain, diabetic neuropathic pain, chronic pelvic visceral pain, or the like. Also, the present invention provides an analgesic method comprising administering to a patient an effective amount of one or more of the above morphinan derivatives having a nitrogen-containing cyclic substituent and pharmacologically acceptable acid addition salts thereof. The present invention also provides the use of the morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof of the present invention as described above for the preparation of an analgesic agent.
Effects of the invention
The morphinan derivative having a nitrogen-containing cyclic substituent according to the present application has a very high analgesic effect and is useful as an excellent analgesic agent effective for the treatment of various pains ranging from acute pain to chronic pain.
Brief Description of Drawings
Fig. 1 is a graph showing the results of morphine administration in the PGF2 α -induced allodynia model method as a comparative example.
Fig. 2 is a graph showing the results of confirmation of analgesic activity of compound 10 by PGF2 α -evoked allodynia model method.
Fig. 3 is a graph showing the results of confirmation of analgesic activity of compound 5 by PGF2 α -evoked allodynia model method.
Fig. 4 is a graph showing the results of confirmation of analgesic activity of compound 6 by PGF2 α -evoked allodynia model method.
FIG. 5 is a tableThe compounds were confirmed by the rat Chung model method10fGraph of the results of analgesic activity of (a). Each group n is 6,***：P<0.001，**：P<0.01，*：P<0.05 vs. dosing group for solvent (multiple sets of corresponding t-tests (correction according to Dunnett))
FIG. 6 is a graph showing the results of confirmation of the analgesic activity of gabapentin by the mouse Seltzer model method. Each group n is 5, # # #: p<0.001vs control-administration of solvent to the group (student's t test or Welch's test),***：P<0.001，*：P<0.05vs ligation-administration of solvent (multiple sets of corresponding t-tests (correction according to Dunnett))
FIG. 7 shows the confirmation of compounds by the Seltzer model method in mice10fGraph of the results of analgesic activity of (a). Each group n is 5, # # #: p<0.001vs control-administration of solvent to the group (student's t test or Welch's test),***：P<0.001，*：P<0.05vs ligation-administration of solvent (multiple sets of corresponding t-tests (correction according to Dunnett))
FIG. 8 shows the confirmation of compounds by model method for diabetic-induced neuropathic pain in rat10fGraph of the results of analgesic activity of (a). Each group n is 4,***：P<0.001，**：P<0.01，*：P<0.05 vs. dosing group for solvent (multiple sets of corresponding t-tests (correction according to Dunnett))
Best Mode for Carrying Out The Invention
As described above, the analgesic agent of the present invention contains, as an active ingredient, a morphinan derivative having a nitrogen-containing cyclic substituent represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof.
In the compound represented by the general formula (I), R1Preferably: hydrogen, cycloalkylalkyl group having 4 to 7 carbon atoms, cycloalkenylalkyl group having 5 to 8 carbon atoms, aryl group having 6 to 12 carbon atoms, and 3 to E7 alkenyl group; among them, preferred are: hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutenylmethyl, 2-cyclobutenylethyl, 3-cyclobutenylpropyl, phenyl, naphthyl, tolyl, allyl, isopentenyl. Among them, preferred are: hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, isopentenyl; particularly preferred are: hydrogen, cyclopropylmethyl, cyclobutylmethyl, allyl.
R2、R3Each independently preferably: hydrogen, hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, acetoxy or propionyloxy. Among them, preferred are: hydrogen, hydroxyl, methoxy, acetoxy.
-X-preferably: an alkylene group or alkenylene group having 2 to 4 carbon atoms constituting a part of the ring structure, wherein: ethylene (-CH)2-CH2-), vinylene (-CH-), propylene (-CH-), or mixtures thereof2-CH2-CH2-) propenylene (-CH)2-CH ═ CH —). Y is preferably: the valency bond or — C (═ O) -, Y is particularly preferably: -C (═ O) -.
k is preferably: an integer of 0 to 6, particularly 1 or 2, and preferably 2.
When k is 1, R5Preferably: an alkyl group having 1 to 5 carbon atoms, an alkylene group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 7 to 13 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an aralkylene group having 7 to 13 carbon atoms, a cycloalkylalkylene group having 7 to 13 carbon atoms, or an aryloxy group having 6 to 12 carbon atoms; among them, preferred are: methyl, ethyl, ethylene, propyl, propylene, butyl, butylene, benzyl, benzylidene, methylbenzyl, methylbenzylidene, fluorobenzyl, fluorobenzylidene, trifluoromethoxybenzyl, trifluoromethoxybenzylidene, phenylethyl, phenylethylidene, cyclohexylmethyl, cyclohexylmethylene, phenoxy, chlorophenoxy; when k is 2, R5Preferably: 2R independently substituted on adjacent carbon atoms5Together areRepresents unsubstituted or substituted by more than one substituent R6Substituted benzo, pyrido, naphtho, cyclopropane, cyclobutane, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptane or cycloheptene, of which benzo, cyclohexeno and, in particular, benzo are preferred.
Benzo or cyclohexeno is also preferably unsubstituted benzo or cyclohexeno, substituent R6Each independently preferably: fluorine, chlorine, bromine, iodine, nitro, an alkyl group having 1 to 5 carbon atoms (particularly, methyl, ethyl, propyl), an aralkyl group having 7 to 13 carbon atoms (particularly, benzyl), methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, an aryl group having 6 to 12 carbon atoms (particularly, phenyl), an isothiocyanate group, SR7、S(O)R7、S(O2)R7、(CH2)pOR7、(CH2)pC(＝O)R7、(CH2)pCO2R7、S(O)NR8R9、S(O2)NR8R9、C(＝O)NR8R9、(CH2)pNR8R9、(CH2)pN(R8)C(＝O)R9(wherein p represents an integer of 0 to 5; R7Represents hydrogen, an alkyl group having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), an alkenyl group having 3 to 7 carbon atoms, or an aryl group having 6 to 12 carbon atoms (particularly phenyl); r8、R9Each independently represents hydrogen, an alkyl group having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), or an aralkyl group having 7 to 13 carbon atoms (particularly benzyl)); particularly preferred are: unsubstituted, and fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanate, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, acetoxy, phenoxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoylDimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, amino, acetylamino or acetylaminomethyl.
R10Preferably: hydrogen, an alkyl group having 1 to 5 carbon atoms, an allyl group, and a benzyl group, and particularly preferably: hydrogen, methyl;
R11、R12preferably combined as-O-, or R11Preferably hydrogen, R12Preferably: hydrogen, hydroxy, methoxy, particularly preferably both are combined as-O-.
R13、R14Preferably together form oxo, or R13Preferably hydrogen, R14Preferably: hydrogen, hydroxy, particularly preferably R13、R14Are both hydrogen, i.e. unsubstituted.
Pharmacologically preferred acid addition salts include: inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate; organic carboxylates such as acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, etc.; organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and camphorsulfonate, etc., among which hydrochloride, tartrate, methanesulfonate, maleate, etc. are preferably used, but not limited thereto.
It is preferable to combine the compounds having the above-described preferred examples of the substituents and their acid addition salts.
The substituent in the general formula (I) preferably has the following substituents. That is to say that the first and second electrodes,
(1) a compound represented by the general formula (I) wherein-X-is an alkylene group, alkenylene group or alkynylene group having 2 to 7 carbon atoms, which constitutes a part of the cyclic structure; r5Are k substituents on-X-, each independently: fluorine, chlorine, bromine, iodine, nitro, carbon atom number of 1 to5 alkyl group, C1-5 alkylene group, C7-13 cycloalkylalkyl group, C7-13 cycloalkylalkylene group, C6-12 aryl group, C7-13 aralkyl group, C7-13 aralkylene group, trifluoromethyl group, trifluoromethoxy group, cyano group, isothiocyanate group, (CH)2)pOR7、(CH2)pC(＝O)R7、(CH2)pCO2R7、(CH2)pNR8R9Or (CH)2)pN(R8)C(＝O)R9Or k R5Wherein 2R are independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by more than 1 substituent R6Substituted benzo, pyrido, naphtho, cyclopropane, cyclobutane, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptane or cycloheptene; r6Each independently represents: fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, aryl having 6 to 12 carbon atoms, isothiocyanate, (CH)2)pOR7、(CH2)pC(＝O)R7、(CH2)pCO2R7、(CH2)pNR8R9Or (CH)2)pN(R8)C(＝O)R9；R8、R9Each independently represents: hydrogen, an alkyl group having 1 to 5 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms; r13、R14Are both hydrogen.
(2) The compound according to the above (1) wherein-X-is an alkylene or alkenylene group having 2 carbon atoms, and an acid addition salt thereof.
(3) A compound represented by the general formula (I) wherein-X-is an alkylene group or alkenylene group having 2 to 4 carbon atoms, which constitutes a part of a cyclic structure; y is an atomic valence bond or-C (═ O) -; k is 1 or 2; r5Is an alkyl group having 1 to 5 carbon atoms, an alkylene group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 7 to 13 carbon atoms, a cycloalkyl group having 7 to 13 carbon atomsA cycloalkylalkylene group having 7 to 13 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an aralkylene group having 7 to 13 carbon atoms, or k R5Wherein 2R are independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by more than 1 substituent R6Substituted benzo, pyrido, naphtho, cyclopropane, cyclobutane, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptane or cycloheptene; r7Is hydrogen, methyl, ethyl, propyl or phenyl; r8、R9Each independently hydrogen, methyl, ethyl, propyl or benzyl; r10Is hydrogen, alkyl with 1-5 carbon atoms, allyl or benzyl.
(4) The compound of the above (3) wherein R is1Hydrogen, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, or alkenyl having 3 to 7 carbon atoms; r5Is methyl, ethyl, ethylene, propyl, propylene, butyl, butylene, benzyl, benzylidene, methylbenzyl, methylbenzylidene, fluorobenzyl, fluorobenzylidene, trifluoromethoxybenzyl, trifluoromethoxybenzylidene, phenylethyl, phenylethylidene, cyclohexylmethyl, cyclohexylmethylene, phenoxy, chlorophenoxy, or k R' s5Wherein 2R are independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by more than 1 substituent R6Substituted benzo, pyrido, naphtho, cyclopropane, cyclobutane, cyclopentano, cyclopenteno, cyclohexano, cyclohexeno, cycloheptane or cycloheptene; r11、R12Is combined as-O-, or R11Is hydrogen, R12Is hydrogen, hydroxy or methoxy.
(5) The compound of the above (4) wherein R is1Is hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutenylmethyl, 2-cyclobutenylethyl, 3-cyclobutenylpropyl, phenyl, naphthyl, tolyl, allyl or iso-butenylA pentenyl group; k is 2; 2R independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by more than one substituent R6Substituted benzo, pyrido, naphtho, cyclopropane, cyclobutane, cyclopentano, cyclopenteno, cyclohexane-o, cyclohexeno, cycloheptane or cycloheptene-o.
(6) The compound of the above (5) wherein R is1Is hydrogen, cyclopropylmethyl, cyclobutylmethyl, allyl or isopentenyl; r2、R3Each independently is hydrogen, hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, acetoxy, or propionyloxy; -X-is ethylene, vinylene, propylene or propenylene; 2R independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by 1 to 4 substituents R6Substituted benzo or cyclohexeno; r10Is hydrogen or methyl; r11、R12Are combined to be-O-.
(7) The compound of the above (6) wherein R in the formula (I) is1Is hydrogen, cyclopropylmethyl, cyclobutylmethyl or allyl; r2、R3Each independently is hydrogen, hydroxy, methoxy or acetoxy; -X-is vinylidene; y is-C (═ O) -; 2R independently substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by 1 to 4 substituents R6Substituted benzenes; r6Each independently is: fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanate, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, acetoxy, phenoxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, amino, acetylamino, acetamidomethyl, or methanesulfonamide; r10Is hydrogen; r13、R14Are both hydrogen.
Specific examples of the compounds represented by the general formula (Ia) among the compounds of the general formula (I) of the present invention are shown in Table 1, wherein-X-is a vinylidene group; y is-C (═ O) -; k is 2; 2R independently substituted on adjacent carbon atoms5Together form an unsubstituted or substituted R6a、R6b、R6cOr R6d(R6a、R6b、R6c、R6dAnd the above-mentioned R6Same as defined above) benzo substituted individually or in any combination; r10、R13、R14Is hydrogen; r11、R12To combine into-O-. Note that CPM in the following table represents a cyclopropylmethyl group, and "-" means that the stereochemistry at the 6-position bonded is α or β, which is unsubstituted.
In addition, in the compound of the general formula (Ia), R is1Is cyclopropylmethyl, R2、R3Is hydroxy, R6bThe compound which is fluorine and the spatial configuration of the 6-position is beta-configuration is named as: n- [17- (cyclopropylmethyl) -4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl]-4-fluorophthalimide.
[ tables 1-1]
| R1 | R2 | R3 | R6a | R6b | R6c | R6d |
| CPM | OH | OH | - | - | - | - |
| CPM | OH | OH | F | - | - | - |
| CPM | OH | OH | - | F | - | - |
| CPM | OH | OH | F | - | - | F |
| CPM | OH | OH | - | F | F | - |
| CPM | OH | OH | F | F | F | F |
| CPM | OH | OH | Cl | - | - | - |
| CPM | OH | OH | - | Cl | - | - |
| CPM | OH | OH | Cl | - | - | Cl |
| CPM | OH | OH | - | Cl | Cl | - |
| CPM | OH | OH | Br | - | - | - |
| CPM | OH | OH | - | Br | - | - |
| CPM | OH | OH | Br | - | - | Br |
| CPM | OH | OH | - | Br | Br | - |
| CPM | OH | OH | Me | - | - | - |
| CPM | OH | OH | - | Me | - | - |
| CPM | OH | OH | Me | - | - | Me |
| CPM | OH | OH | - | Me | Me | - |
| CPM | OH | OH | OMe | - | - | - |
| CPM | OH | OH | - | OMe | - | - |
| CPM | OH | OH | OMe | - | - | OMe |
| CPM | OH | OH | - | OMe | OMe | - |
| CPM | OH | OH | OH | - | - | - |
| CPM | OH | OH | - | OH | - | - |
| CPM | OH | OH | OH | - | - | OH |
| CPM | OH | OH | - | OH | OH | - |
| CPM | OH | OH | NO2 | - | - | - |
| CPM | OH | OH | - | NO2 | - | - |
| CPM | OH | OH | NO2 | - | - | NO2 |
| CPM | OH | OH | - | NO2 | NO2 | - |
| CPM | OH | OH | NH2 | - | - | - |
| CPM | OH | OH | - | NH2 | - | - |
| CPM | OH | OH | NH2 | - | - | NH2 |
| CPM | OH | OH | - | NH2 | NH2 | - |
| Allyl radical | OH | OH | - | - | - | - |
| Allyl radical | OH | OH | F | - | - | - |
| Allyl radical | OH | OH | - | F | - | - |
[ tables 1-2]
| R1 | R2 | R3 | R8a | R8b | R8c | R8d |
| Allyl radical | OH | OH | F | - | - | F |
| Allyl radical | OH | OH | - | F | F | - |
| Allyl radical | OH | OH | F | F | F | F |
| Allyl radical | OH | OH | Cl | - | - | - |
| Allyl radical | OH | OH | - | C1 | - | - |
| Allyl radical | OH | OH | Cl | - | - | Cl |
| Allyl radical | OH | OH | - | C1 | Cl | - |
| Allyl radical | OH | OH | Br | - | - | - |
| Allyl radical | OH | OH | - | Br | - | - |
| Allyl radical | OH | OH | Br | - | - | Br |
| Allyl radical | OH | OH | - | Br | Br | - |
| Allyl radical | OH | OH | Me | - | - | - |
| Allyl radical | OH | OH | - | Me | - | - |
| Allyl radical | OH | OH | Me | - | - | Me |
| Allyl radical | OH | OH | - | Me | Me | - |
| Allyl radical | OH | OH | OMe | - | - | - |
| Allyl radical | OH | OH | - | OMe | - | - |
| Allyl radical | OH | OH | OMe | - | - | OMe |
| Allyl radical | OH | OH | - | OMe | OMe | - |
| Allyl radical | OH | OH | OH | - | - | - |
| Allyl radical | OH | OH | - | OH | - | - |
| Allyl radical | OH | OH | OH | - | - | OH |
| Allyl radical | OH | OH | - | OH | OH | - |
| Allyl radical | OH | OH | NO2 | - | - | - |
| Allyl radical | OH | OH | - | NO2 | - | - |
| Allyl radical | OH | OH | NO2 | - | - | NO2 |
| Allyl radical | OH | OH | - | NO2 | NO2 | - |
| Allyl radical | OH | OH | NH2 | - | - | - |
| Allyl radical | OH | OH | - | NH2 | - | - |
| Allyl radical | OH | OH | NH2 | - | - | NH2 |
| Allyl radical | OH | OH | - | NH2 | NH2 | - |
| CPM | H | OH | - | - | - | - |
| CPM | H | OH | F | - | - | - |
| CPM | H | OH | - | F | - | - |
| CPM | H | OH | F | - | - | F |
| CPM | H | OH | - | F | F | - |
| CPM | H | OH | F | F | F | F |
| CPM | H | OH | Cl | - | - | - |
| CPM | H | OH | - | Cl | - | - |
[ tables 1 to 3]
| R1 | R2 | R3 | R8a | R8b | R8c | R8d |
| CPM | H | OH | Cl | - | - | Cl |
| CPM | H | OH | - | Cl | Cl | - |
| CPM | H | OH | Br | - | - | - |
| CPM | H | OH | - | Br | - | - |
| CPM | H | OH | Br | - | - | Br |
| CPM | H | OH | - | Br | Br | - |
| CPM | H | OH | Me | - | - | - |
| CPM | H | OH | - | Me | - | - |
| CPM | H | OH | Me | - | - | Me |
| CPM | H | OH | - | Me | Me | - |
| CPM | H | OH | OMe | - | - | - |
| CPM | H | OH | - | OMe | - | - |
| CPM | H | OH | OMe | - | - | OMe |
| CPM | H | OH | - | OMe | OMe | - |
| CPM | H | OH | OH | - | - | - |
| CPM | H | OH | - | OH | - | - |
| CPM | H | OH | OH | - | - | OH |
| CPM | H | OH | - | OH | OH | - |
| CPM | H | OH | NO2 | - | - | - |
| CPM | H | OH | - | NO2 | - | - |
| CPM | H | OH | NO2 | - | - | NO2 |
| CPM | H | OH | - | NO2 | NO2 | - |
| CPM | H | OH | NH2 | - | - | - |
| CPM | H | OH | - | NH2 | - | - |
| CPM | H | OH | NH2 | - | - | NH2 |
| CPM | H | OH | - | NH2 | NH2 | - |
| Allyl radical | H | OH | - | - | - | - |
| Allyl radical | H | OH | F | - | - | - |
| Allyl radical | H | OH | - | F | - | - |
| Allyl radical | H | OH | F | - | - | F |
| Allyl radical | H | OH | - | F | F | - |
| Allyl radical | H | OH | F | F | F | F |
| Allyl radical | H | OH | Cl | - | - | - |
| Allyl radical | H | OH | - | Cl | - | - |
| Allyl radical | H | OH | Cl | - | - | Cl |
| Allyl radical | H | OH | - | Cl | Cl | - |
| Allyl radical | H | OH | Br | - | - | - |
| Allyl radical | H | OH | - | Br | - | - |
| Allyl radical | H | OH | Br | - | - | Br |
[ tables 1 to 4]
| R1 | R2 | R3 | R8a | R8b | R8c | R8d |
| Allyl radical | H | OH | - | Br | Br | - |
| Allyl radical | H | OH | Me | - | - | - |
| Allyl radical | H | OH | - | Me | - | - |
| Allyl radical | H | OH | Me | - | - | Me |
| Allyl radical | H | OH | - | Me | Me | - |
| Allyl radical | H | OH | OMe | - | - | - |
| Allyl radical | H | OH | - | OMe | - | - |
| Allyl radical | H | OH | OMe | - | - | OMe |
| Allyl radical | H | OH | - | OMe | OMe | - |
| Allyl radical | H | OH | OH | - | - | - |
| Allyl radical | H | OH | - | OH | - | - |
| Allyl radical | H | OH | OH | - | - | OH |
| Allyl radical | H | OH | - | OH | OH | - |
| Allyl radical | H | OH | NO2 | - | - | - |
| Allyl radical | H | OH | - | NO2 | - | - |
| Allyl radical | H | OH | NO2 | - | - | NO2 |
| Allyl radical | H | OH | - | NO2 | NO2 | - |
| Allyl radical | H | OH | NH2 | - | - | - |
| Allyl radical | H | OH | - | NH2 | - | - |
| Allyl radical | H | OH | NH2 | - | - | NH2 |
| Allyl radical | H | OH | - | NH2 | NH2 | - |
| CPM | OAc | OH | - | - | - | - |
| CPM | OAc | OH | F | - | - | - |
| CPM | OAc | OH | - | F | - | - |
| CPM | OAc | OH | F | - | - | F |
| CPM | OAc | OH | - | F | F | - |
| CPM | OAc | OH | F | F | F | F |
| CPM | OAc | OH | Cl | - | - | - |
| CPM | OAc | OH | - | Cl | - | - |
| CPM | OAc | OH | Cl | - | - | Cl |
| CPM | OAc | OH | - | Cl | Cl | - |
| CPM | OAc | OH | Br | - | - | - |
| CPM | OAc | OH | - | Br | - | - |
| CPM | OAc | OH | Br | - | - | Br |
| CPM | OAc | OH | - | Br | Br | - |
| CPM | OAc | OH | Me | - | - | - |
| CPM | OAc | OH | - | Me | - | - |
| CPM | OAc | OH | Me | - | - | Me |
| CPM | OAc | OH | - | Me | Me | - |
[ tables 1 to 5]
| R1 | R2 | R3 | R6a | R8b | R8c | R8d |
| CPM | OAc | OH | OMe | - | - | - |
| CPM | OAc | OH | - | OMe | - | - |
| CPM | OAc | OH | OMe | - | - | OMe |
| CPM | OAc | OH | - | OMe | OMe | - |
| CPM | OAc | OH | OH | - | - | - |
| CPM | OAc | OH | - | OH | - | - |
| CPM | OAc | OH | OH | - | - | OH |
| CPM | OAc | OH | - | OH | OH | - |
| CPM | OAc | OH | NO2 | - | - | - |
| CPM | OAc | OH | - | NO2 | - | - |
| CPM | OAc | OH | NO2 | - | - | NO2 |
| CPM | OAc | OH | - | NO2 | NO2 | - |
| CPM | OAc | OH | NH2 | - | - | - |
| CPM | OAc | OH | - | NH2 | - | - |
| CPM | OAc | OH | NH2 | - | - | NH2 |
| CPM | OAc | OH | - | NH2 | NH2 | - |
| Allyl radical | OAc | OH | - | - | - | - |
| Allyl radical | OAc | OH | F | - | - | - |
| Allyl radical | OAc | OH | - | F | - | - |
| Allyl radical | OAc | OH | F | - | - | F |
| Allyl radical | OAc | OH | - | F | F | - |
| Allyl alcoholBase of | OAc | OH | F | F | F | F |
| Allyl radical | OAc | OH | Cl | - | - | - |
| Allyl radical | OAc | OH | - | Cl | - | - |
| Allyl radical | OAc | OH | Cl | - | - | Cl |
| Allyl radical | OAc | OH | - | Cl | Cl | - |
| Allyl radical | OAc | OH | Br | - | - | - |
| Allyl radical | OAc | OH | - | Br | - | - |
| Allyl radical | OAc | OH | Br | - | - | Br |
| Allyl radical | OAc | OH | - | Br | Br | - |
| Allyl radical | OAc | OH | Me | - | - | - |
| Allyl radical | OAc | OH | - | Me | - | - |
| Allyl radical | OAc | OH | Me | - | - | Me |
| Allyl radical | OAc | OH | - | Me | Me | - |
| Allyl radical | OAc | OH | OMe | - | - | - |
| Allyl radical | OAc | OH | - | OMe | - | - |
| Allyl radical | OAc | OH | OMe | - | - | OMe |
| Allyl radical | OAc | OH | - | OMe | OMe | - |
| Allyl radical | OAc | OH | OH | - | - | - |
[ tables 1 to 6]
| R1 | R2 | R3 | R8a | R8b | R8c | R8d |
| Allyl radical | OAc | OH | - | OH | - | - |
| Allyl radical | OAc | OH | OH | - | - | OH |
| Allyl radical | OAc | OH | - | OH | OH | - |
| Allyl radical | OAc | OH | NO2 | - | - | - |
| Allyl radical | OAc | OH | - | NO2 | - | - |
| Allyl radical | OAc | OH | NO2 | - | - | NO2 |
| Allyl radical | OAc | OH | - | NO2 | NO2 | - |
| Allyl radical | OAc | OH | NH2 | - | - | - |
| Allyl radical | OAc | OH | - | NH2 | - | - |
| Allyl radical | OAc | OH | NH2 | - | - | NH2 |
| Allyl radical | OAc | OH | - | NH2 | NH2 | - |
Specific examples of the compounds represented by the following general formula (Ib) among the compounds of the general formula (I) of the present invention are shown in Table 2, wherein-X-is an allylene group (-CH)2-CH ═ CH-); y is an atomic valence bond; 2R independently substituted on adjacent carbon atoms5Together form an unsubstituted or substituted R6a、R6b、R6cOr R6d(R6a、R6b、R6c、R6dAnd the above-mentioned R6Same as defined above) benzo substituted individually or in any combination; r10、R13、R14Is hydrogen; r11、R12A compound which binds to-O-.
In addition, in the compounds of the general formula (Ib), R is1Is cyclopropylmethyl, R2、R3Is hydroxy, R6cThe compound which is fluorine and the spatial configuration of the 6-position is beta-configuration is named as: 2- [17- (cyclopropylmethyl) -4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl]-6-fluoro-2, 3-dihydro-isoindol-1-one.
[ Table 2-1]
| R1 | R2 | R3 | R6a | R6b | R6c | R6d |
| CPM | OH | OH | - | - | - | - |
| CPM | OH | OH | F | - | - | - |
| CPM | OH | OH | - | F | - | - |
| CPM | OH | OH | - | - | F | - |
| CPM | OH | OH | - | - | - | F |
| CPM | OH | OH | - | F | F | - |
| CPM | OH | OH | F | F | F | F |
| CPM | OH | OH | Cl | - | - | - |
| CPM | OH | OH | - | Cl | - | - |
| CPM | OH | OH | - | - | Cl | - |
| CPM | OH | OH | - | - | - | Cl |
| CPM | OH | OH | - | Cl | Cl | - |
| CPM | OH | OH | Me | - | - | - |
| CPM | OH | OH | - | Me | - | - |
| CPM | OH | OH | - | - | Me | - |
| CPM | OH | OH | - | - | - | Me |
| CPM | OH | OH | - | Me | Me | - |
| CPM | OH | OH | OMe | - | - | - |
| CPM | OH | OH | - | OMe | - | - |
| CPM | OH | OH | - | - | OMe | - |
| CPM | OH | OH | - | - | - | OMe |
| CPM | OH | OH | - | OMe | OMe | - |
| Allyl radical | OH | OH | - | - | - | - |
| Allyl radical | OH | OH | F | - | - | - |
| Allyl radical | OH | OH | - | F | - | - |
| Allyl radical | OH | OH | - | - | F | - |
| Allyl radical | OH | OH | - | - | - | F |
| Allyl radical | OH | OH | - | F | F | - |
| Allyl radical | OH | OH | F | F | F | F |
| Allyl radical | OH | OH | C1 | - | - | - |
| Allyl radical | OH | OH | - | Cl | - | - |
| Allyl radical | OH | OH | - | - | Cl | - |
| Allyl radical | OH | OH | - | - | - | Cl |
| Allyl radical | OH | OH | - | Cl | Cl | - |
| Allyl radical | OH | OH | Me | - | - | - |
| Allyl radical | OH | OH | - | Me | - | - |
| Allyl radical | OH | OH | - | - | Me | - |
| Allyl radical | OH | OH | - | - | - | Me |
[ tables 2-2]
| R1 | R2 | R3 | R6a | R6b | R6c | R6d |
| Allyl radical | OH | OH | - | Me | Me | - |
| Allyl radical | OH | OH | OMe | - | - | - |
| Allyl radical | OH | OH | - | OMe | - | - |
| Allyl radical | OH | OH | - | - | OMe | - |
| Allyl radical | OH | OH | - | - | - | OMe |
| Allyl radical | OH | OH | - | OMe | OMe | - |
| CPM | H | OH | - | - | - | - |
| CPM | H | OH | F | - | - | - |
| CPM | H | OH | - | F | - | - |
| CPM | H | OH | - | - | F | - |
| CPM | H | OH | - | - | - | F |
| CPM | H | OH | - | F | F | - |
| CPM | H | OH | F | F | F | F |
| CPM | H | OH | Cl | - | - | - |
| CPM | H | OH | - | Cl | - | - |
| CPM | H | OH | - | - | Cl | - |
| CPM | H | OH | - | - | - | Cl |
| CPM | H | OH | - | Cl | Cl | - |
| CPM | H | OH | Me | - | - | - |
| CPM | H | OH | - | Me | - | - |
| CPM | H | OH | - | - | Me | - |
| CPM | H | OH | - | - | - | Me |
| CPM | H | OH | - | Me | Me | - |
| CPM | H | OH | OMe | - | - | - |
| CPM | H | OH | - | OMe | - | - |
| CPM | H | OH | - | - | OMe | - |
| CPM | H | OH | - | - | - | OMe |
| CPM | H | OH | - | OMe | OMe | - |
| Allyl radical | H | OH | - | - | - | - |
| Allyl radical | H | OH | F | - | - | - |
| Allyl radical | H | OH | - | F | - | - |
| Allyl radical | H | OH | - | - | F | - |
| Allyl radical | H | OH | - | - | - | F |
| Allyl radical | H | OH | - | F | F | - |
| Allyl radical | H | OH | F | F | F | F |
| Allyl radical | H | OH | Cl | - | - | - |
| Allyl radical | H | OH | - | Cl | - | - |
| Allyl radical | H | OH | - | - | Cl | - |
| Allyl radical | H | OH | - | - | - | Cl |
[ tables 2 to 3]
| R1 | R2 | R3 | R6a | R6b | R6c | R6d |
| Allyl radical | H | OH | - | Cl | CL | - |
| Allyl radical | H | OH | Me | - | - | - |
| Allyl radical | H | OH | - | Me | - | - |
| Allyl radical | H | OH | - | - | Me | - |
| Allyl radical | H | OH | - | - | - | Me |
| Allyl radical | H | OH | - | Me | Me | - |
| Allyl radical | H | OH | OMe | - | - | - |
| Allyl radical | H | OH | - | OMe | - | - |
| Allyl radical | H | OH | - | - | OMe | - |
| Allyl radical | H | OH | - | - | - | OMe |
| Allyl radical | H | OH | - | OMe | OMe | - |
Specific examples of the compounds represented by the following general formula (Ic) or (Ic') among the compounds of the general formula (I) of the present invention are shown in Table 3, wherein-X-is ethylene or vinylene; y is-C (═ O) -; r10、R13、R14Is hydrogen; r11、R12Combine to form-O-; 2R independently substituted on adjacent carbon atoms5Together form a particular fused ring.
In addition, in the compounds of the formula (Ic'), R is1Is cyclopropylmethyl, R2、R3Is hydroxy, 2R being independently substituted on adjacent carbon atoms5The compounds which together form a cyclohexeno, with the stereoconfiguration at position 6 being in the β -configuration, are named: n- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl) -3, 4, 5, 6-tetrahydrophthalimide.
[ Table 3]
Specific examples of the compounds represented by the following general formula (Id) or (Id') among the compounds of the general formula (I) of the present invention are shown in Table 4, wherein-X-is propylene or propylenylene; y is an atomic valence bond; r10、R13、R14Is hydrogen; r11、R12Combine to form-O-; 2R's each substituted on adjacent specific carbon atoms5Together form a particular fused ring.
In addition, in the compounds of the formula (Id'), R is1Is cyclopropylmethyl, R2、R3Is hydroxy, 2R being independently substituted on adjacent carbon atoms5The compounds which together form a cyclohexeno, with the stereoconfiguration at position 6 being in the β -configuration, are named: 2- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl) -2, 3, 4, 5, 6, 7-hexahydro-isoindol-1-one.
[ Table 4]
Specific examples of the compounds represented by the following general formula (Ie) or (Ie') among the compounds of the general formula (I) according to the present invention are shown in Table 5, wherein-X-is unsubstituted or substituted by R5aAnd/or R5b(R5a、R5bAnd the above-mentioned R5Same as defined above) substituted ethylene or vinylene; y is-C (═ O) -; r10、R13、R14Is hydrogen; r11、R12To combine into-O-.
In addition, in the compounds of the general formula (Ie), R is1Is cyclopropylmethyl, R2、R3Is hydroxy, R5aThe compound with the ethylene and the beta-configuration of the 6-position is named as: n- [17- (cyclopropylmethyl) -4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl) -2-ethylidenesuccinimide.
[ Table 5-1]
| General formula (VII) | R1 | R2 | R3 | R5a | R5b |
| Ie | CPM | OH | OH | - | - |
| Ie | CPM | OH | OH | Methylene group | - |
| Ie | CPM | OH | OH | Ethylene radical | - |
| Ie | CPM | OH | OH | Propylene radical | - |
| Ie | CPM | OH | OH | Butylene group | - |
| Ie | CPM | OH | OH | Cyclohexyl methylene | - |
| Ie | CPM | OH | OH | Benzylidene group | - |
| Ie | CPM | OH | OH | Phenylene ethyl radical | - |
| Ie | CPM | OH | OH | Methyl radical | - |
| Ie | CPM | OH | OH | Ethyl radical | - |
| Ie | CPM | OH | OH | Propyl radical | - |
| Ie | CPM | OH | OH | Butyl radical | - |
| Ie | CPM | OH | OH | Cyclohexyl methyl radical | - |
| Ie | CPM | OH | OH | Benzyl radical | - |
| Ie | CPM | OH | OH | Para-methylbenzyl radical | - |
| Ie | CPM | OH | OH | P-fluorobenzyl radical | - |
| Ie | CPM | OH | OH | P-chlorobenzyl | - |
| Ie | CPM | OH | OH | Para-trifluoromethoxybenzyl | - |
| Ie | CPM | OH | OH | Phenylethyl group | - |
| Ie | CPM | OH | OH | Phenoxy radical | - |
| Ie | CPM | OH | OH | P-methylphenoxy | - |
| Ie | CPM | OH | OH | P-fluorophenoxy group | - |
| Ie | CPM | OH | OH | P-chlorophenoxy radical | - |
| Ie | CPM | OH | OH | Phenyl radical | - |
| Ie | CPM | OH | OH | Phenyl radical | Phenyl radical |
| Ie’ | CPM | OH | OH | - | - |
| Ie’ | CPM | OH | OH | Phenyl radical | - |
| Ie’ | CPM | OH | OH | Phenyl radical | Phenyl radical |
| Ie’ | CPM | OH | OH | Methyl radical | - |
| Ie’ | CPM | OH | OH | Methyl radical | Methyl radical |
| Ie | Allyl radical | OH | OH | - | - |
| Ie | Allyl radical | OH | OH | Methylene group | - |
| Ie | Allyl radical | OH | OH | Ethylene radical | - |
| Ie | Allyl radical | OH | OH | Propylene radical | - |
| Ie | Allyl radical | OH | OH | Butylene group | - |
| Ie | Allyl radical | OH | OH | Cyclohexyl methylene | - |
| Ie | Allyl radical | OH | OH | Benzylidene group | - |
[ tables 5-2]
| General formula (VII) | R1 | R2 | R3 | R5a | R5b |
| Ie | Allyl radical | OH | OH | Phenylene ethyl radical | - |
| Ie | Allyl radical | OH | OH | Methyl radical | - |
| Ie | Allyl radical | OH | OH | Ethyl radical | - |
| Ie | Allyl radical | OH | OH | Propyl radical | - |
| Ie | Allyl radical | OH | OH | Butyl radical | - |
| Ie | Allyl radical | OH | OH | Cyclohexyl methyl radical | - |
| Ie | Allyl radical | OH | OH | Benzyl radical | - |
| Ie | Allyl radical | OH | OH | Para-methylbenzyl radical | - |
| Ie | Allyl radical | OH | OH | P-fluorobenzyl radical | - |
| Ie | Allyl radical | OH | OH | P-chlorobenzyl | - |
| Ie | Allyl radical | OH | OH | Para-trifluoromethoxybenzyl | - |
| Ie | Allyl radical | OH | OH | Phenylethyl group | - |
| Ie | Allyl radical | OH | OH | Phenoxy radical | - |
| Ie | Allyl radical | OH | OH | P-methylphenoxy | - |
| Ie | Allyl radical | OH | OH | P-fluorophenoxy group | - |
| Ie | Allyl radical | OH | OH | P-chlorophenoxy radical | - |
| Ie | Allyl radical | OH | OH | Phenyl radical | - |
| Ie | Allyl radical | OH | OH | Phenyl radical | Phenyl radical |
| Ie’ | Allyl radical | OH | OH | - | - |
| Ie’ | Allyl radical | OH | OH | Phenyl radical | - |
| Ie’ | Allyl radical | OH | OH | Phenyl radical | Phenyl radical |
| Ie’ | Allyl radical | OH | OH | Methyl radical | - |
| Ie’ | Allyl radical | OH | OH | Methyl radical | Methyl radical |
Specific examples of the compounds represented by the following general formula (If) or (If') among the compounds of the general formula (I) according to the present invention are shown in Table 6, wherein-X-is unsubstituted or substituted by R5aAnd/or R5b(R5a、R5bAnd the above-mentioned R5Same as defined above) substituted propylene or propylene group; y is an atomic valence bond; r10、R13、R14Is hydrogen; r11、R12Are combined to be-O-.
In addition, in the compounds of the general formula (If), R is1Is cyclopropylmethyl, R2、R3Is hydroxy, R5aThe compound which is benzyl and has the spatial configuration of 6 position as beta-configuration is named as: 3-benzyl-1- [17- (cyclopropylmethyl) -4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl]Pyrrolidin-2-one.
[ Table 6-1]
| General formula (VII) | R1 | R2 | R3 | R5a | R5b |
| If | CPM | OH | OH | - | - |
| If | CPM | OH | OH | Methylene group | - |
| If | CPM | OH | OH | Ethylene radical | - |
| If | CPM | OH | OH | Propylene radical | - |
| If | CPM | OH | OH | Butylene group | - |
| If | CPM | OH | OH | Cyclohexyl methylene | - |
| If | CPM | OH | OH | Benzylidene group | - |
| If | CPM | OH | OH | Phenylene ethyl radical | - |
| If | CPM | OH | OH | Methyl radical | - |
| If | CPM | OH | OH | Ethyl radical | - |
| If | CPM | OH | OH | Propyl radical | - |
| If | CPM | OH | OH | Butyl radical | - |
| If | CPM | OH | OH | Cyclohexyl methyl radical | - |
| If | CPM | OH | OH | Benzyl radical | - |
| If | CPM | OH | OH | Para-methylbenzyl radical | - |
| If | CPM | OH | OH | P-fluorobenzyl radical | - |
| If | CPM | OH | OH | P-chlorobenzyl | - |
| If | CPM | OH | OH | Para-trifluoromethoxybenzyl | - |
| If | CPM | OH | OH | Phenylethyl group | - |
| If | CPM | OH | OH | Phenoxy radical | - |
| If | CPM | OH | OH | P-methylphenoxy | - |
| If | CPM | OH | OH | P-fluorophenoxy group | - |
| If | CPM | OH | OH | P-chlorophenoxy radical | - |
| If | CPM | OH | OH | Phenyl radical | - |
| If | CPM | OH | OH | Phenyl radical | Phenyl radical |
| If’ | CPM | OH | OH | - | - |
| If’ | CPM | OH | OH | Phenyl radical | - |
| If’ | CPM | OH | OH | Phenyl radical | Phenyl radical |
| If’ | CPM | OH | OH | Methyl radical | - |
| If’ | CPM | OH | OH | Methyl radical | Methyl radical |
| If | Allyl radical | OH | OH | - | - |
| If | Allyl radical | OH | OH | Methylene group | - |
| If | Allyl radical | OH | OH | Ethylene radical | - |
| If | Allyl radical | OH | OH | Propylene radical | - |
| If | Allyl radical | OH | OH | Butylene group | - |
| If | Allyl radical | OH | OH | Cyclohexyl methylene | - |
| If | Allyl radical | OH | OH | Benzylidene group | - |
| If | Allyl radical | OH | OH | Phenylene ethyl radical | - |
[ tables 6-2]
| General formula (VII) | R1 | R2 | R3 | R5a | R5b |
| If | Allyl radical | OH | OH | Methyl radical | - |
| If | Allyl radical | OH | OH | Ethyl radical | - |
| If | Allyl radical | OH | OH | Propyl radical | - |
| If | Allyl radical | OH | OH | Butyl radical | - |
| If | Allyl radical | OH | OH | Cyclohexyl methyl radical | - |
| If | Allyl radical | OH | OH | Benzyl radical | - |
| If | Allyl radical | OH | OH | Para-methylbenzyl radical | - |
| If | Allyl radical | OH | OH | P-fluorobenzyl radical | - |
| If | Allyl radical | OH | OH | P-chlorobenzyl | - |
| If | Allyl radical | OH | OH | Para-trifluoromethoxybenzyl | - |
| If | Allyl radical | OH | OH | Phenylethyl group | - |
| If | Allyl radical | OH | OH | Phenoxy radical | - |
| If | Allyl radical | OH | OH | P-methylphenoxy | - |
| If | Allyl radical | OH | OH | P-fluorophenoxy group | - |
| If | Allyl radical | OH | OH | P-chlorophenoxy radical | - |
| If | Allyl radical | OH | OH | Phenyl radical | - |
| If | Allyl radical | OH | OH | Phenyl radical | Phenyl radical |
| If’ | Allyl radical | OH | OH | - | - |
| If’ | Allyl radical | OH | OH | Phenyl radical | - |
| If’ | Allyl radical | OH | OH | Phenyl radical | Phenyl radical |
| If’ | Allyl radical | OH | OH | Methyl radical | - |
| If’ | Allyl radical | OH | OH | Methyl radical | Methyl radical |
The above-mentioned morphinan derivatives and pharmacologically acceptable acid addition salts thereof may be used alone or in combination of two or more as the active ingredient of the analgesic agent of the present invention, and the above-mentioned cases are included in the scope of the present invention.
In a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof, which is represented by the general formula (I) above and is used as an active ingredient of an analgesic agent of the present invention, R13And R14Both hydrogen are of formula (Ig) (R)1、R2、R3、R5、R10、R11、R12K, X and Y are as defined above) or a pharmacologically acceptable acid addition salt thereof, and specifically can be produced by the method described in International publication WO2004/033457 (European publication EP 1555266) Tetrahedron, 50, 9757(1994) and the like.
In addition, in the morphinan derivative having a nitrogen-containing cyclic substituent at the 6-position, which is represented by the general formula (I) and used as an active ingredient of the analgesic agent of the present invention, or a pharmacologically acceptable acid addition salt thereof, R13And R14Are each R13’And R14’(R13’And R14’Together represent oxo, or R13’Represents hydrogen, R14’A hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, an alkanoyloxy group having 1 to 5 carbon atoms) is represented by the general formula (Ih) (R)1、R2、R3、R5、R10、R11、R12K, X and Y are as defined above) as shown in scheme 1, by a method shown in International publication WO04/033457 (European publication EP 1555266) to obtain a compound of the general formula (Ig) (R)1、R2、R3、R5、R10、R11、R12K, X and Y are as defined above) or a method described in International publication WO2004/033457 (European publication EP 1555266) for the use of a morphinan derivative having a nitrogen-containing cyclic substituent of the formula (IIa) (R)1、R2、R3、R10、R11、R12In the same manner as defined above, the above-mentioned,…q represents an oxo group or a dibenzylamino group), and a morphinan derivative represented by the general formula (IIb) (R)1、R2、R3、R10、R11、R12、R13’、R14’、…Q is the same as defined above). In the oxidation of the benzyl position, a hydroxyl group or an oxo group may be directly introduced, or a step of reducing the hydroxyl group after the introduction of the oxo group may be performed. Further, depending on the kind of the substituent, a protecting or deprotecting step may be added as necessary.
Scheme 1
Any oxidizing agent that can be generally used for the oxidation of the benzyl position in the oxidation step may be used, but when a hydroxyl group is introduced, for example: manganese (III) salts such as manganese (III) acetate, lead compounds such as lead tetraacetate; organic peroxides such as t-butyl hydroperoxide and benzoyl peroxide; cerium compounds such as cerium (IV) ammonium nitrate (CAN), oxygen, and the like. Among them, when cerium (IV) ammonium nitrate is used, an α -hydroxy compound can be selectively obtained in some cases, which is useful. When an oxidizing agent containing an organic acid such as acetic acid in the compound structure is used, an alkanoyloxy group such as an acetoxy group may be efficiently introduced in some cases.
When an oxo group is introduced, for example: permanganate such as potassium permanganate; manganese compounds such as manganese dioxide; chromium compounds such as chromium oxide and sodium chromate; selenium compounds such as selenium dioxide; periodates such as sodium periodate; quinones such as DDQ; silver compounds such as silver oxide; cerium compounds such as cerium (IV) ammonium nitrate (CAN); halogen (chlorine, bromine, iodine), oxygen, hydrogen peroxide, and the like.
Reaction conditions such as the reaction solvent, the reaction temperature, the reaction time, the substrate concentration, and the equivalent ratio of the reaction reagent are appropriately selected depending on the oxidizing agent used, and when a cerium compound such as cerium (IV) ammonium nitrate (CAN) is used, for example, the target compound CAN be obtained in a good yield by reacting 4 equivalents of the oxidizing agent to the substrate in a mixed solvent system of acetonitrile/water at room temperature.
When the oxo group is reduced to a hydroxy group, a reducing agent generally used for reducing a carbonyl compound can be used, but a hydride reducing agent such as sodium borohydride or lithium aluminum hydride is preferably used.
Reaction conditions such as the reaction solvent, the reaction temperature, the reaction time, the substrate concentration, and the equivalent ratio of the reaction reagent are appropriately selected depending on the reducing agent used, and when sodium borohydride is used, for example, the reaction is carried out in an alcohol solvent such as methanol at room temperature, whereby the target compound can be obtained in a good yield. When a hydroxyl group is synthesized through a step of reducing an oxo group, a β -isomer may be selectively obtained, contrary to the case of directly hydroxylating the hydroxyl group.
The conversion of the hydroxyl compound into an alkoxy compound or an alkanoyloxy compound can be carried out under ordinary etherification or acylation conditions, and the chlorination can be carried out by mixing with a pharmacologically acceptable acid in water or various organic solvents, followed by concentration, drying, reprecipitation, recrystallization, or the like.
Morphinan derivatives having a nitrogen-containing cyclic substituent represented by the general formula (I) or pharmacologically acceptable acid addition salts thereof are effective for the treatment of pain, and this can be confirmed by exhibiting an effect of inhibiting the action induced by pain in an animal model. For example, as a test method utilizing pain-induced behavior in an animal model, there have been reported a mouse writhing acetate (writing) method [ Life Sci, 65, 1685-93(1996) ] as an acute pain test method, a PGF2 a-induced allodynia model method [ pain.50, 223-229(1992) ] as a test method for inducing morphine-non-onset pain, a rat Chung model method [ pain.50, 355-363(1992) ] as a chronic pain test method, a mouse Seltzer method [ pain.76, 215-222(1998) ], a rat diabetic-induced neuropathic pain model method [ pain.80, 391-398(1999) ], and the like. In addition, PGF2 α -evoked allodynia model was reported as an animal model for the induction of allodynia characterized by symptoms in patients afflicted with chronic pain [ PAINRESEARCH., Vol.7, 129-134(1992), pain.50, 223-229(1992) ].
As shown in examples 1 to 5, the morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof showed a significant analgesic effect when evaluated by the acetate writhing method, and was confirmed to have an analgesic effect in the evaluation of the bladder pain-suppressing effect using PGF2 α -induced allodynia model, rat Chung model, mouse Seltzer model, rat diabetes-induced neuropathic pain model, and lateral abdominal oblique myoelectric activity accompanied by bladder hyperextension as an index, and therefore, the above derivative can be widely used for various pains ranging from acute pain to chronic pain. The analgesic agents of the invention can be used for: acute pain, for example, pain caused by injury such as fracture or cut, inflammatory pain such as appendicitis, and postoperative pain; and neuropathic pain belonging to chronic pain, such as cancer pain, herpes zoster pain, postherpetic neuralgia, trigeminal neuralgia and pain accompanying diabetic neuropathy, causalgia, phantom limb pain and the like. Further, it can be used for deep pain and visceral pain, such as headache, abdominal pain, low back pain, chronic pelvic pain syndrome, bladder pain, pain associated with vaginitis, (chronic) pain associated with prostatitis, pain associated with endometriosis, pain associated with hysteromyoma, pain associated with urinary calculus and urinary stone, pain associated with cystitis, pain associated with urethritis, pain associated with urinary tract infection, pain associated with interstitial cystitis, colic caused by pathological changes in the digestive system, pelvic pain, and pain associated with urinary system diseases; and pain in the gynecological field, such as pain caused by menstrual difficulty, etc., and psychological pain, etc. The analgesic agent of the present invention can be used for mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human).
The analgesic agent of the present invention may be administered alone or in combination with one or more agents for the treatment or prevention of diseases, reduction or suppression of symptoms, or both of the compounds contained in the present invention. The combination method can be combined by various medicaments, and can also be prepared into a mixture. Examples of the above-mentioned agents include: COX-1 and/or COX-2 inhibitors as non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin, indomethacin, diclofenac, ibuprofen, acetaminophen, acetylsalicylic acid, ketoprofen, piroxicam, mefenamic acid, tiaramide, naproxen, leprosy, oxaprozin, zaltoprofen, etodolac, meloxicam, lornoxicam, ampiroxicam, celecoxib, rofecoxib, valdecoxib, lumiracoxib (lumiracoxib), lincomone (licorone), and the like; opioid analgesics such as codeine, morphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone, fentanyl, buprenorphine, butorphanol, nalbuphine, pentazocine, levorphanol, methadone, meperidine, tramadol, oxymorphone and the like; other analgesics such as gabapentin, pregabalin, baclofen, and the like; anesthetics such as halothane, lidocaine, etidocaine, ropivacaine, chloroprocaine, bupivacaine, propofol, and the like; benzodiazepinesQuasi-drugs, e.g. diazepam, chlordiazepoxideAlprazolam, lorazepam, and the like; skeletal muscle relaxants such as carisoprodol, methocarbamol and aspirin tablets, dantrolene sodium, and the like; migraine remedies such as ergotamine, eletriptan, sumatriptan, rizatriptan, zolmitriptan, naratriptan, and the like; antispasmodics, e.g. カルマバゼピン, clonazepam, topiramate, phenytoin, propanValeric acid, zonisamide, oxcarbazepine, and the like; antidepressants such as amitriptyline, nortriptyline, amitriptyline (tryptanol), amoxapine, imipramine, paroxetine, fluvoxamine, milnacipran, duloxetine, and the like; corticosteroids such as prednisolone, dexamethasone, betamethasone, and the like; NMDA antagonists such as dextromethorphan, ketamine, memantine, amantadine, eliprodil, ifenprodil, and the like; capsaicin (vanilloid) agonists or antagonists, such as capsaicin, resiniferatoxin, and the like; calcium channel blockers such as ziconotide and the like; potassium channel openers such as flupirtine, retigabine, and the like; a serotonin receptor antagonist; a sodium channel blocker; cannabinoids; toxins such as botulinum toxin, tetrodotoxin and the like, but the above drugs are given as examples and should not be construed as limiting the invention in any sense.
When the analgesic agent of the present invention is clinically used, the agent may be a free base or a salt thereof itself, or an additive such as an excipient, a stabilizer, a preservative, a buffer, a solubilizing agent, an emulsifier, a diluent, and an isotonic agent may be appropriately mixed. The pharmaceutical agent can be prepared by a usual method using the above-mentioned pharmaceutical carrier as appropriate. The administration form includes: gastrointestinal tract administration in the form of tablet, capsule, granule, powder, syrup, etc.; parenteral administration in the form of injection, suppository, liquid preparation, etc.; or topically administered in the form of ointment, cream, patch, etc.
The analgesic agent of the present invention preferably contains the above active ingredient in an amount of 0.00001 to 90% by weight, more preferably 0.0001 to 70% by weight. The dosage is suitably selected according to symptoms, age, body weight, administration method, etc., and in the case of injection for adults, the amount of the active ingredient is 0.1 μ g to 1g per 1 day; in the case of an oral preparation, 1. mu.g to 10g of the active ingredient per day can be administered once or in several divided doses.
The present invention will be specifically described below with reference to examples.
Compounds used in examples 1 to 51[1- (17-cyclopropylmethyl-4, 5. alpha. -epoxy-3,14-dihydroxy-morphinan-6 beta-yl) pyrrolidin-2-one hydrochloride]A compound of2[1- (17-Cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 alpha-yl) pyrrolidin-2-one hydrochloride]A compound of3[1- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-morphinan-6 β -yl) -3-benzyl-pyrrolidin-2-one tartrate]A compound of4[1- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-morphinan-6 α -yl) -3-benzyl-pyrrolidin-2-one (mixture of diastereomers) tartrate]A compound of5[2- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-morphinan-6 β -yl) -2, 3-dihydro-isoindol-1-one tartrate]A compound of6[ N- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-morphinan-6 β -yl) -2-butylidenesuccinimide tartrate]A compound of7[ N- (17-allyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -4-fluorophthalimide tartrate]A compound of8[ N- (17-allyl-4, 5 alpha-epoxy-3, 14-dihydroxymorphinan-6 alpha-yl) -3-fluorophthalimide tartrate]A compound of9[ N- (17-allyl-4, 5 alpha-epoxy-3, 14-dihydroxymorphinan-6 alpha-yl) phthalimide tartrate]A compound of10[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -phthalimide hydrochloride]A compound of10f[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) phthalimide]A compound of11[ N- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-morphinan-6 β -yl) -4-methylphthalimide hydrochloride]A compound of12[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -4-chlorophthalimide tartrate]A compound of13[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -4-fluorophthalimide tartrate]A compound of14[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -3-fluorophthalimide tartrate]A compound of15[ N- (17-Cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -3-methylphthalimide tartrate]A compound of16[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -naphthalenedicarboxylic acid imide hydrochloride]A compound of17[ N- [17- (cyclopropylmethyl) -4, 5 α -epoxy-3, 14-dihydroxymorphinan-6 β -yl]-4, 5-dichlorophthalimide tartrate]A compound of18[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxymorphinan-6 alpha-yl) -phthalimide tartrate]A compound of19[ N- (17-cyclopropylmethyl-4, 5 α -epoxy-3, 14-dihydroxy-morphinan-6 β -yl) -3, 4, 5, 6-tetrahydrophthalimide tartrate]A compound of20[ 17-Cyclopropylmethyl-4, 5 alpha-epoxy-6 beta- (pyrrolidin-1-yl) -morphinan-3, 14-diol tartrate]And compounds21[ N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -succinimide tartrate]Synthesized by the method described in examples 46, 34, 48-2, 35, 28, 24-2, 58, 63, 64, 11, 12, 15, 16, 17, 18, 19, 55, 66, 77, 111 and 20-2 of International publication WO2004/033457 (European publication EP 1555266).
Hydrochloride salt of
Hydrochloride salt of
Tartrate salt
Tartrate salt
WineLithospermate salt
Tartrate salt
Tartrate salt
Tartrate salt
Tartrate salt
Hydrochloride salt of
Hydrochloride salt of
Tartrate salt
Tartrate salt
Tartrate salt
Tartrate salt
Hydrochloride salt of
Tartrate salt
Tartrate salt
Tartrate salt
Tartrate salt
Tartrate salt
Reference example 1
N- (17-cyclopropylmethyl-4, 5 alpha-epoxy-3, 14-dihydroxy-morphinan-6 beta-yl) -maleimide tartrate (compound)22) Synthesis of (2)
Tartrate salt
800mg (2.34mmol) of 6. beta. - ナルトレキサミン was dissolved in DMF (30mL), and 252mg (2.57mmol) of maleic anhydride and 0.48mL (3.50mmol) of triethylamine were added thereto, followed by stirring at room temperature for 1.5 hours. Then 0.53mL (8.18mmol) of methanesulfonic acid was added, followed by stirring at 120 ℃ for 8 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and washed with brineAfter drying over magnesium sulfate, concentration gave a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 141mg of the title compound22Free form of (1) (yield 14%). Making it into tartrate to obtain the title compound22。
1H-NMR(ppm)(400MHz，CDCl3)6.70-6.75(3H, m), 6.61(1H, d, J ═ 8.0Hz), 5.02(1H, d, J ═ 8.3Hz), 3.8-3.9(1H, m), 3.08(1H, d, J ═ 5.6Hz), 3.04(1H, d, J ═ 18.3Hz), 2.6-2.7(3H, m), 2.3-2.4(3H, m), 2.12(1H, dt, J ═ 12.0, 3.6Hz), 1.4-1.7(4H, m), 0.8-0.9(1H, m), 0.5-0.6(2H, m), 0.1-0.2(2H, m) (free body)
Mass spectrum (ESI): 423(M +1)
Example 1
Analgesic activity test by mouse acetic acid writhing method
The solvent or test compound was subcutaneously administered in an amount of 0.1(mL/10g body weight) using ddY male mice. After 15 minutes, the administration amount of 0.1(mL/10g body weight) of 0.6% (v/v) acetic acid solution was intraperitoneally administered, and after 10 minutes, the number of writhing reactions (behaviors of body bending and twisting) occurring within 10 minutes was measured, and this number was used as an index of pain. The amount of the test compound at 50% of the number of writhing responses given to the solvent group was used as ED50, and this value was used to evaluate analgesic activity. As a solvent for administration of the test compound, the test compound1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21And22the test compound was applied using a 10% Dimethylsulfoxide (DMSO) solution10f0.1% citric acid-5% xylitol aqueous solution was used. The results are shown in Table 7.
[ Table 7]
| Test compounds | ED50(mg/kg) |
| Compound 1 Compound 2 Compound 34Compound (I)5Compound (I)6Compound (I)7Compound (I)8Compound (I)9Compound (I)10Compound (I)10fCompound (I)11Compound (I)12Compound (I)13Compound (I)14Compound (I)15Compound 16 compound 17 compound 18 compound 19 | 2.620.950.280.260.0710.480.0330.030.140.0310.0370.0450.290.0370.0340.030.310.270.0190.032 |
| Compound 20 (control Compound) Compound21Compound (I)22 | >103.372.18 |
Example 2
Analgesic Activity test Using PGF2 alpha-evoked allodynia model method
The solvent or test compound was subcutaneously administered in an amount of 0.1(mL/10g body weight) using ddY male mice. After 30 minutes, PGF2 α was administered intraspinally at a dose of 1 μ g per mouse and at a dose of 4 μ L per mouse, to induce allodynia. Allodynia was determined by scoring the response of the animals when the left and right body sides of the mice were touched with a brush as follows. The judgment result is as follows: 0 min, no reaction. 1 minute, sound gently. Escaping bored. 2 minutes, screaming, boring around to flee or escaping swiftly. Flicking (Flicking). Measurements were taken at 5 minute intervals for 40 minutes from the start of PGF2 α dosing. The results are shown in FIGS. 1 to 4.
Example 3
Analgesic Activity assay Using the rat Chung model method
SD line 7-week-old male rats were used. Rat Chung model animals were purchased from japan SLC (ligation of left hind limb innervation at 6 weeks of age). Evaluation was performed according to the Up-Down method of Dixson (non-patent document 4) using a filament to which a pressure of 0.407, 0.692, 1.202, 2.041, 3.630, 5.495, 8.511 or 15.136g was applied (North coast Medical, Inc.CA, USA) 1 week after the nerve ligation treatment. The filament was placed on the soles of both hind limbs and a contact stimulus (von Frey test) was applied for 8 seconds, and the case where an escape response (lifting, not stomping, licking) occurred during the application of the stimulus or immediately after the stimulus was completed was a response, and was denoted as (×); when the escape reaction did not occur, no reaction was observed and the result was designated as (O). The von frey test was administered as a Pre (Pre) value prior to administration, followed by gastrointestinal administration of the agent. After gastrointestinal administration for 30 minutes, 60 minutes, and 180 minutes, von Frey test was performed, and% MPE (% maximum possible effect ═ weight threshold after administration-preset ÷ (cutoff (15.00g) -preset) was determined, and each value was calculated by the method described in document 4. This value was used as an index of analgesic effect. The results are shown in FIG. 5.
Example 4
Analgesic Activity test Using a mouse Seltzer model method
ICR line 5-week-old male mice were used. After anesthetizing the mouse with pentobarbital, the sciatic nerve of the hind leg thigh on the right side was exposed, and only half-cycle force of the sciatic nerve was triple ligated under a microscope using 8-0 (united states pharmacopeia) silk suture silk (manufactured by charles). In contrast, mice with only sciatic nerve exposed and no ligation were used as controls. 1 week after the nerve ligation treatment, the filaments were placed on the soles of both hind limbs using a 0.02g or 0.16g pressure-applied filament (North Coast Medical, Inc.CA, USA), and 3-second contact stimulation was applied thereto, and 3 repetitions were carried out at 3-second intervals (von Frey test) to score the escape behavior at that time (0: no response; 1: slow and slight escape behavior to stimulation; 2: rapid escape without fear or licking; 3: rapid escape with fear or licking), and the total value of the 3 scores was used as an index of pain. Von Frey test was administered as a pre-set prior to administration, after which the agent was given gastrointestinal. Analgesic effects were evaluated by administering von Frey test 30 minutes, 60 minutes, and 180 minutes after gastrointestinal administration, and the results are shown in fig. 6 and 7.
Example 5
Analgesic Activity test Using diabetic-induced neuropathic pain model method in rats
Male rats aged 10 weeks of SD line were used. Diabetes-inducing rats were purchased from Japanese SLC (streptozotocin (STZ) at 50mg/kg for a single intraperitoneal administration at 6 weeks of age). Blood glucose levels were measured with a Precision Q.I.D blood glucose meter at week 3 of STZ administration, and rats with blood glucose levels of 200mg/dL or more were determined to be diabetes-induced rats. The diabetes-inducing animals were evaluated according to the Up-Down method by Dixson (non-patent document 4) using a filament to which a pressure of 0.407, 0.692, 1.202, 2.041, 3.630, 5.495, 8.511 or 15.136g was applied after the 4 th week of STZ administration (North Coast Medical, Inc.CA, USA). The filament was placed on the soles of both hind limbs and a contact stimulus (von Frey test) was applied for 8 seconds, and the case where an escape response (lifting, not stomping, licking) occurred during the application of the stimulus or immediately after the stimulus was completed was a response, and was denoted as (×); when the escape reaction did not occur, no reaction was observed and the result was designated as (O). Von Frey test was administered as a pre-dose prior to administration, after which the agent was administered parenterally. After gastrointestinal administration for 30 minutes, 60 minutes, and 180 minutes, von Frey test was performed to determine% MPE. This value was used as an index of analgesic effect. The results are shown in FIG. 8.
Example 6
Bladder pain suppression using lateral oblique abdominal myoelectrical activity associated with hyperextension of bladder as an indicator
Evaluation of use
Evaluation of Compound Using myoelectric Activity of lateral oblique Abdominal muscle in hyperextension of bladder of anesthetized rat as an index for bladder pain10fInhibiting bladder pain. Sprague-Dawle with the age of 14-15 weeks and the weight of 300-360 g is used in the experimenty line female rats (Japanese クレア).
Under halothane (2.5-4%) anesthesia, a polyethylene tube (PE-50) for measuring intravesical pressure was inserted into the bladder through the urethra, and a polyethylene tube (PE-100) for filling with physiological saline was inserted into the bladder from the bladder apex. Each tube was tightly ligated so that the physiological saline did not leak from the insertion portion. The administration tube was placed in the femoral vein. The skin of the lateral abdomen was incised, and a bipolar electrode for electromyogram measurement was inserted into the lateral oblique abdominal muscle and left therein. A reservoir filled with a physiological saline in advance is connected to a tube indwelling in the bladder and fixed at a specific height, thereby stretching the bladder. The stretching stimulation was performed for 20 seconds with 3 minutes intervals between repeated stimulations. A bipolar electrode (needle electrode for brain wave measurement, japanese photoelectricity) was connected to an electromyogram amplifier (EMG100C, Biopac systems), a high-impedance filter (5kHz) and a low-impedance filter (100Hz) were added, and then the signals were input to an AD converter (MP-150WSW, Biopac systems) and a computer at 1kHz, and electromyogram activity was recorded using dedicated software (acqknowledge3.8.1, Biopac systems). Intravesical pressure was measured using a pressure sensor (AP641G, japan photovoltaics) and a general purpose amplifier (DA100C, biopascasyss). Adjusting the concentration of halothane to 50cm H2Stretching of O results in stable myoelectrical activity, after which the drug is administered intravenously and further repeated for bladder stretching over at least 20 minutes.
The medicine is dissolved in 5% xylitol-0.02% citric acid water solution, and the dosage is 0.5 mL/kg. The mean value of the number of peaks produced by bladder stretching 2 times immediately before administration was taken as the pre-administration value, and the change in the number of peaks after administration was normalized with the pre-administration value as 100%. The mean of the 3 peak changes within 15 minutes after administration was calculated and the effect of the drug was judged by Williams test.
As shown in table 7, compound 10f significantly inhibited myoelectrical activity depending on the amount used. The minimum effective dosage is 0.01 mg/kg.
[ Table 8]
Compound (I)10fEffect on lateral oblique abdominal myoelectrical activity by bladder stretching
Data are expressed as mean ± standard error.
*P<0.025 (significance given to control group relative to solvent, Williams test)
Industrial applicability
The analgesic agent of the present invention has a very high analgesic effect and is applicable to various pains ranging from acute pain to chronic pain.
Claims (4)
1. Use of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) below or a pharmacologically acceptable acid addition salt thereof for the preparation of an analgesic agent:
in the formula, R1Represents a cycloalkylalkyl group having 4 to 7 carbon atoms;
R2、R3represents a hydroxyl group;
-X-represents an alkenylene group having 2 carbon atoms constituting a part of the cyclic structure;
y represents-C (═ O) -;
k represents 2;
R5is k substituents on a cyclic structure, 2R substituted on adjacent carbon atoms5Together represent unsubstituted or substituted by more than one substituent R6Substituted benzo or cyclohexeno;
R6each independently represents fluorine or an alkyl group having 1 to 5 carbon atoms;
R10represents hydrogen;
R11、R12represents binding to form-O-;
R13、R14represents hydrogen.
2. The use according to claim 1, wherein in the formula (I), R1Is cyclopropylmethyl.
3. The use of any one of claims 1 or 2, wherein the pain in the subject treated is neuropathic pain or bladder pain.
4. The use of any one of claims 1 or 2, wherein the pain in the subject treated is diabetic neuropathy pain.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP320583/2004 | 2004-11-04 | ||
| JP2004320583 | 2004-11-04 | ||
| PCT/JP2005/020297 WO2006049248A1 (en) | 2004-11-04 | 2005-11-04 | Analgesic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1115808A1 HK1115808A1 (en) | 2008-12-12 |
| HK1115808B true HK1115808B (en) | 2012-10-12 |
Family
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