JP2008074853A - Remedy containing morphinan derivative or its pharmacologically permissible acid addition salt having n-containing heterocyclic substituent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel remedy or preventive for urinary frequency or urinary incontinence highly effective and improved in adverse effects. <P>SOLUTION: The remedy or the preventive for urinary frequency or urinary incontinence comprises a morphinan derivative expressed by general formula (I) [wherein R<SP>1</SP>expresses methyl or the like; R<SP>2</SP>and R<SP>3</SP>express each hydroxy, methoxy, acetoxy or the like; Y and Z together express a valent bond, -C(=O)- or the like; X expresses a 2-5C carbon chain constituting a part of a cyclic structure (wherein one of the carbon atoms may be substituted with O, S or N) or the like; (R<SP>4</SP>)<SB>k</SB>expresses an optionally substituted fused benzene ring, carbonyl or the like; R<SP>9</SP>expresses H or the like; R<SP>10</SP>and R<SP>11</SP>express -O- through bonding together; R<SP>6</SP>expresses H or the like] or its pharmacologically permissible acid addition salt as an effective ingredient. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel therapeutic or preventive agent for pollakiuria or urinary incontinence, and a morphinan derivative having a nitrogen-containing cyclic substituent or a pharmacologically acceptable acid addition salt thereof.

  In recent years, with the arrival of an aging society, the number of patients suffering from frequent urination and urinary incontinence is increasing. Currently, anticholinergics such as propiverine hydrochloride, oxybutynin hydrochloride and flavoxate hydrochloride are mainly used as therapeutic agents for frequent urination or urinary incontinence. However, these existing drugs have been reported as side effects such as dry mouth, digestive symptoms such as constipation, circulatory symptoms such as orthostatic hypotension, urinary retention and residual urine. In addition, prescribing existing drugs with anticholinergic action to treat frequent urinary or urinary incontinence associated with cerebrovascular disorders and dementia further suppresses the action of the acetylcholine system in the brain and adversely affects the symptoms of the underlying disease. There are concerns about the effects. On the other hand, frequent urination or urinary incontinence has been attracting attention as a symptom that should be actively treated from the viewpoint of improving the quality of life (QOL) of patients, which has been emphasized in recent years. There is a strong demand for the development of a treatment or prevention agent for incontinence.

  As the morphinan derivative having a nitrogen-containing cyclic substituent, the compounds described in JP-B-41-18824 and JP-B-41-18826 disclosed together with the analgesic and antitussive use, and the use is not particularly described Tetrahedron. 50, 9757 (1994), Synth. Commun. 22, 913 (1992), J. Med. Chem. 27, 1325 (1984), etc. There is no disclosure regarding the treatment or prevention of urinary incontinence. Further, although it does not contain a nitrogen-containing cyclic substituent, it is known that morphine, which is considered to be close to the present compound in that it has a morphinan structure, has an action of suppressing the micturition reflex (J. Pharm. Exp. Ther. 254 (1984) etc.), side effects such as drug dependence and constipation are strong, and it is not used as a therapeutic or preventive agent for frequent urination or incontinence.

Japanese Patent Publication No.41-18824 Japanese Patent Publication No.41-18826 Tetrahedron. 50, 9757 (1994) Synth. Commun. 22, 913 (1992) J. Med. Chem. 27, 1325 (1984)

  The present invention relates to a novel therapeutic or preventive agent for pollakiuria or urinary incontinence having a high therapeutic or preventive effect and improved side effects, a treatment or prevention method for the disease, use for the disease, and treatment of the disease Another object is to provide a novel compound useful as a prophylactic agent.

  As a result of diligent studies to achieve the above object, novel morphinan derivatives having nitrogen-containing cyclic substituents have been found, and including these morphinan derivatives, any of them can treat unexpectedly frequent pollakiuria or urinary incontinence. Or they have a preventive effect and can be administered orally, which is advantageous for long-term administration, and have been found that side effects such as drug dependence and constipation are separated, and the present invention has been completed.

  That is, the present invention relates to the general formula (I)

[Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 4 to 7 carbon atoms, cycloalkenyl alkyl having 6 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, or 7 to 13 carbon atoms. Aralkyl, alkenyl having 3 to 7 carbon atoms, furanyl alkyl (the alkyl part has 1 to 5 carbon atoms), thienyl alkyl (the alkyl part having 1 to 5 carbon atoms), or pyridylalkyl (the alkyl part having 1 carbon atom) To R), R ² and R ³ are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or 1 to 5 carbons Represents alkanoyloxy, Y and Z independently represent a valence bond, or -C (= O)-, and -X- represents a carbon chain having 2 to 7 carbon atoms that is part of the ring structure (but one or more of them) Carbon atoms are replaced by nitrogen, oxygen, or sulfur atoms May have I, the carbon chain represents may) be contained unsaturated bonds, k is an integer of 0 to 8, R ⁴ is an k-number of the substituents on the nitrogen-containing cyclic structure , Fluorine, chlorine, bromine, iodine, nitro, hydroxy, alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 7 to 13 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, Aralkyloxy having 7 to 13 carbon atoms, alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , (CH ₂ ) _p N (R ⁷ ) COR ⁸ or represents, among the k R ^4, the same two R ⁴ is is one of an oxygen atom a carbonyl group or a sulfoxide group attached to a carbon atom or a sulfur atom, the Two R ⁴ bonded to one carbon atom becomes one sulfur atom, a thiocarbonyl group, and four R ⁴ bonded to the same sulfur atom become two oxygen atoms, representing a sulfone group, Or a benzene fused ring, a pyridine fused ring, or a naphthalene fused ring in which two R ⁴ groups each substituting for adjacent carbon atoms in k R ⁴ groups are unsubstituted or substituted with one or more substituents R ⁵ , A cyclopropane condensed ring, a cyclobutane condensed ring, a cyclopentane condensed ring, a cyclopentene condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring, and R ⁵ each independently represents fluorine, chlorine, Bromine, iodine, nitro, hydroxy, alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, trifluoromethyl, trifluoromethoxy, cyano, from 6 carbons 12 aryls, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , _{^{CONR 7 R 8, (CH 2}} ) p NR 7 R 8, (CH 2) p N represents ^{(R 7) COR 8, R} 9 is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 1 to 5 carbon atoms , Aralkyl having 7 to 13 carbon atoms, hydroxyalkyl having 1 to 3 carbon atoms, (CH ₂ ) _p OR ⁶ , or (CH ₂ ) _p CO ₂ R ⁶ , wherein R ¹⁰ and R ¹¹ are bonded to each other to represent -O -, -S-, or -CH _2- , or R ¹⁰ is hydrogen, R ¹¹ is hydrogen, hydroxy, alkoxy having 1 to 5 carbons, or alkanoyloxy having 1 to 5 carbons, p Represents an integer of 0 to 5, R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, alkenyl having 3 to 7 carbons, aryl having 6 to 12 carbons, or aralkyl having 7 to 13 carbons, R ^7, R ⁸ are each independently hydrogen, alkyl of 1 to 5 carbon atoms or carbonitrides, A morphinan derivative having a nitrogen-containing cyclic substituent represented by formula (7) to (13), or a pharmacologically acceptable acid addition salt thereof as an active ingredient, or a therapeutic or preventive agent for pollakiuria or urinary incontinence Further provided are methods of treatment or prevention for the disease and their use for the disease.

  However, in the present specification, the substituent is used in the following meaning. Alkyl and the alkyl part of alkoxy, cycloalkylalkyl, aralkyl, aralkyloxy may be linear or branched, may be substituted with hydroxy, and may contain an unsaturated bond. The aromatic ring part of aryl, aralkyl, aralkyloxy, furanylalkyl, thienylalkyl, pyridylalkyl is alkyl having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine , Bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy may be substituted with at least one substituent.

  The present invention also provides a compound of the general formula (II)

[Wherein R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , R ¹¹ are the same as defined above, and R ^{4 ′} , X ′, Y ′, Z ′, k ′ are the same as R ⁴ , X Represents the same definition as Y, Z, and k, but Y 'and Z' are simultaneously valence bonds and X 'is-(CH ₂ ) ₄ -,-(CH ₂ ) ₅ -,-(CH ₂ ) ₂ In the case of —O— (CH ₂ ) ₂ —, k ′ must be 1 or more, and Y ′ and Z ′ are simultaneously —C (═O) — and X ′ is a ring structure composed of two carbons. In the case of a constituent chain, k ′ must be 1 or more, and in particular, when (R ^{4 ′} ) k ′ is a benzene condensed ring, the benzene ring must be substituted with R ⁵ ] , A novel morphinan derivative having a nitrogen-containing cyclic substituent, or a pharmacologically acceptable acid addition salt thereof, and a medicament or pharmaceutical composition comprising these compounds as active ingredients.

  In the practice of the present invention, the compound represented by formula (I) is preferably used. Particularly preferred substituents among the compounds of the general formula (I) are as follows. In the present specification, “therapeutic or preventive agent” may include not only those used for either treatment or prevention, but also those used for the purpose of simultaneously performing treatment and prevention.

  Y and Z are preferably both —C (═O) — or both having a valence bond.

When Y and Z are both —C (═O) —, R ¹ is hydrogen, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, C3-C7 alkenyl is preferred, among which hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclobutenyl Ethyl, 3-cyclobutenylpropyl, phenyl, naphthyl, tolyl, allyl and prenyl are preferred. Among these, hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, and prenyl are particularly preferable. R ² is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons, particularly hydrogen, Hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, acetoxy and propionoxy are preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. R ³ is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or alkanoyloxy having 1 to 5 carbon atoms. Among them, hydrogen, hydroxy, methoxy, ethoxy, benzyloxy, acetoxy Propionoxy is preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. -X- is preferably a carbon chain having 2 to 4 carbon atoms that becomes a part of the ring structure, and more preferably a carbon chain having 2 carbon atoms that becomes a part of the ring structure. k is preferably an integer of 0 to 6. As R ⁴ , alkyl having 1 to 5 carbon atoms, aralkyl having 7 to 13 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or R ⁴ substituted with two adjacent carbons together is unsubstituted or Benzene fused ring, pyridine fused ring, naphthalene fused ring, cyclopropane fused ring, cyclobutane fused ring, cyclopentane fused ring, cyclopentene fused ring, cyclohexane fused ring, cyclohexene fused ring, cyclohexane substituted with one or more substituents R ⁵ It is preferable to form a heptane condensed ring or a cycloheptene condensed ring. Among them, methyl, ethyl, ethylidene, propyl, propylidene, butyl, butylidene, benzyl, benzylidene, methylbenzyl, methylbenzylidene, fluorobenzyl, fluorobenzylidene, trifluoromethoxybenzyl, trifluoromethoxybenzylidene, phenethyl, phenethylidene, cyclohexylmethyl, cyclohexylmethyl Preferably it forms a redene, phenoxy, chlorophenoxy or benzene fused ring, especially benzene in which two R ⁴ together are unsubstituted or substituted with one or more, especially 1 to 4 substituents R ⁵ It is preferable to form a condensed ring. An unsubstituted benzene ring is also preferable, but each of the substituents R ⁵ is independently fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), carbon number 7 to 13 aralkyl (especially benzyl), hydroxy, alkoxy having 1 to 5 carbon atoms (especially methoxy, ethoxy), trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , ( CH ₂ ) _p N (R ⁷ ) COR ⁸ (wherein p represents an integer of 0 to 5, R ⁶ is hydrogen, alkyl having 1 to 5 carbons (particularly methyl, ethyl, propyl), C 3 represents 7 alkenyl or aryl having 6 to 12 carbon atoms (especially phenyl), R ^7, R ⁸ are each independently hydrogen, carbon atoms 1 5 alkyl (especially methyl, ethyl, propyl) or aralkyl having 7 to 13 carbon atoms (especially benzyl) is preferable, and in addition to unsubstituted, fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl Propyl, benzyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, acetoxy, Phenyloxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl , Dimethylaminoethyl, amino is preferable. R ⁹ is preferably hydrogen, alkyl having 1 to 5 carbon atoms, allyl or benzyl, and particularly preferably hydrogen or methyl. R ¹⁰ and R ¹¹ are preferably those bonded to —O—, or R ¹⁰ is hydrogen, and R ¹¹ is preferably hydrogen, hydroxy, or methoxy, and in particular, both are bonded to —O—. Those are preferred.

On the other hand, when Y and Z are both valence bonds, R ¹ includes hydrogen, alkyl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, and furanyl alkyl (the number of carbons in the alkyl part is 1 to 5). 5), thienylalkyl (the alkyl part has 1 to 5 carbon atoms) and pyridylalkyl (the alkyl part has 1 to 5 carbon atoms) are preferred, among them hydrogen, methyl, ethyl, propyl, benzyl, phenethyl, phenylpropyl, 2 -Or 3-furanylmethyl, 2- or 3-furanylethyl, 2- or 3-furanylpropyl, 2- or 3-thiophenylmethyl, 2- or 3-thiophenylethyl, 2- or 3-thiophenylpropyl, 2 -, 3- or 4-pyridinylmethyl, 2-, 3- or 4-pyridinylethyl, 2-, 3- or 4-pyridinylpropyl are preferred. Among these, hydrogen, methyl, phenethyl, furanylethyl, thiophenylethyl, and pyridinylethyl are particularly preferable. R ² is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons, particularly hydrogen, Hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, acetoxy and propionoxy are preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. R ³ is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons. Among them, hydrogen, hydroxy, methoxy, ethoxy, benzyloxy, Acetoxy and propionoxy are preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. -X- is preferably a carbon chain of 4 to 6 carbon atoms that becomes a part of the ring structure, or one in which one or two carbon atoms are replaced with oxygen, sulfur, or nitrogen atoms. Among them, a carbon chain having 5 carbon atoms that becomes a part of the ring structure, or one in which one carbon atom is replaced with an oxygen, sulfur, or nitrogen atom is preferable. k is preferably an integer of 0 to 6. R ⁴ may be CONR ⁷ R ⁸ (where R ⁷ and R ⁸ each independently represent hydrogen, methyl, ethyl, propyl, benzyl), or R ⁴ substituted with two adjacent carbons. A benzene fused ring, a pyridine fused ring, a naphthalene fused ring, a cyclopropane fused ring, a cyclobutane fused ring, a cyclopentane fused ring, a cyclopentene fused ring, which is unsubstituted or substituted with 1 or more, particularly 1 to 4 substituents R ⁵ , It is preferable to form a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring. Of these, dimethylamide and diethylamide are preferable, or a benzene condensed ring is preferably formed. Each independently other R ⁴ is to form methyl, ethyl, propyl, or benzyl are preferred, or the same two R ⁴ is is one of the oxygen atoms come together carbonyl group attached to a carbon atom In particular, it is preferable that the carbon atom adjacent to the carbonyl group is replaced with a nitrogen atom to form an amide bond. As the benzene condensed ring, an unsubstituted one is also preferable, but as the substituent R ⁵ , fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), carbon Aralkyl having 7 to 13 (especially benzyl), hydroxy, alkoxy having 1 to 5 carbons (especially methoxy, ethoxy), trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , (CH ₂ ) _p N (R ⁷ ) COR ⁸ (wherein p represents an integer of 0 to 5, R ⁶ is hydrogen, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), carbon number 3 represents 7 alkenyl or aryl having 6 to 12 carbon atoms (especially phenyl) from, R ^7, R ⁸ are each independently hydrogen, Preferred is an alkyl having 1 to 5 primes (particularly methyl, ethyl, propyl) or aralkyl having 7 to 13 carbons (particularly benzyl), and in particular, unsubstituted, fluorine, chlorine, bromine, iodine, nitro, methyl , Ethyl, propyl, benzyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, Acetoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylamino Methyl, dimethylaminoethyl, amino is preferable. R ⁹ is preferably hydrogen, alkyl having 1 to 5 carbon atoms, allyl, or benzyl, and particularly preferably hydrogen or methyl. R ¹⁰ and R ¹¹ are preferably bonded to —O—, or R ¹⁰ is hydrogen, and R ¹¹ is preferably hydrogen, hydroxy, or methoxy, particularly those having both bonded to —O—. Is preferred.

  The present invention also provides a morphinan derivative having a nitrogen-containing cyclic substituent represented by the above general formula (II), or a pharmacologically acceptable acid addition salt thereof.

  Y ′ and Z ′ are preferably both —C (═O) —, or both have a valence bond.

When both Y ′ and Z ′ are —C (═O) —, R ¹ is hydrogen, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 6 to 8 carbons, or 6 to 12 carbons. Aryl and alkenyl having 3 to 7 carbon atoms are preferable, among which hydrogen, cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropyl Butenylethyl, 3-cyclobutenylpropyl, phenyl, naphthyl, tolyl, allyl and prenyl are preferred. Among these, hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, and prenyl are particularly preferable. R ² is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons, particularly hydrogen, Hydroxy, methoxy, ethoxy, allyloxy, benzyloxy and acetoxy are preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. R ³ is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or alkanoyloxy having 1 to 5 carbon atoms. Among them, hydrogen, hydroxy, methoxy, ethoxy, benzyloxy, acetoxy Propionoxy is preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. k ′ is preferably an integer of 0 to 6. -X'- is preferably a carbon chain having 2 to 4 carbon atoms that becomes a part of the ring structure, and more preferably a carbon chain having 2 carbon atoms that becomes a part of the ring structure. R ^{4 ′} may be an alkyl group having 1 to 5 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an aralkyloxy group having 7 to 13 carbon atoms, or R ^{4 ′} substituted with two adjacent carbon atoms. Benzene fused ring, pyridine fused ring, naphthalene fused ring, cyclopropane fused ring, cyclobutane fused ring, cyclopentane fused ring, cyclopentene fused ring, cyclohexane fused with a substituted or one or more, especially 1 to 4 substituents R ⁵ It is preferable to form a ring, a cyclohexene fused ring, a cycloheptane fused ring, or a cycloheptene fused ring. Among them, ethyl, ethylidene, propyl, propylidene, butyl, butylidene, benzyl, benzylidene, methylbenzyl, methylbenzylidene, fluorobenzyl, fluorobenzylidene, trifluoromethoxybenzyl, trifluoromethoxybenzylidene, phenethyl, phenethylidene, cyclohexylmethyl, cyclohexylmethylidene, It is preferable to form a phenoxy, chlorophenoxy or benzene condensed ring, and particularly preferable to form a benzene condensed ring. An unsubstituted benzene ring is also preferable, but each of the substituents R ⁵ is independently fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), carbon number 7 to 13 aralkyl (especially benzyl), hydroxy, alkoxy having 1 to 5 carbon atoms (especially methoxy, ethoxy), trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , ( CH ₂ ) _p N (R ⁷ ) COR ⁸ (wherein p represents an integer of 0 to 5, R ⁶ is hydrogen, alkyl having 1 to 5 carbons (particularly methyl, ethyl, propyl), C 3 represents 7 alkenyl or aryl having 6 to 12 carbon atoms (especially phenyl), R ^7, R ⁸ are each independently hydrogen, carbon atoms 1 5 alkyl (especially methyl, ethyl, propyl) or aralkyl having 7 to 13 carbon atoms (especially benzyl) is preferable, and in addition to unsubstituted, fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl Propyl, benzyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, acetoxy, Phenyloxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl , Dimethylaminoethyl, amino is preferable. R ⁹ is preferably hydrogen, alkyl having 1 to 5 carbon atoms, allyl or benzyl, and particularly preferably hydrogen or methyl. R ¹⁰ and R ¹¹ are preferably those bonded to —O—, or R ¹⁰ is hydrogen, and R ¹¹ is preferably hydrogen, hydroxy, or methoxy, and in particular, both are bonded to —O—. Those are preferred.

On the other hand, when Y ′ and Z ′ are both valence bonds, R ¹ is hydrogen, alkyl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, or furanylalkyl (the carbon number of the alkyl part is 1 to 5), thienyl alkyl (the alkyl part has 1 to 5 carbon atoms), and pyridylalkyl (the alkyl part has 1 to 5 carbon atoms) are preferred, among which hydrogen, methyl, ethyl, propyl, benzyl, phenethyl, phenylpropyl 2-, 3-furanylmethyl, 2- or 3-furanylethyl, 2- or 3-furanylpropyl, 2- or 3-thiophenylmethyl, 2- or 3-thiophenylethyl, 2- or 3-thiophenylpropyl 2-, 3- or 4-pyridinylmethyl, 2-, 3- or 4-pyridinylethyl, 2-, 3- or 4-pyridinylpropyl are preferred. Among these, hydrogen, methyl, phenethyl, furanylethyl, thiophenylethyl, and pyridinylethyl are particularly preferable. R ² is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons, particularly hydrogen, Hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, acetoxy and propionoxy are preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. R ³ is preferably hydrogen, hydroxy, alkoxy having 1 to 5 carbons, aralkyloxy having 7 to 13 carbons, or alkanoyloxy having 1 to 5 carbons. Among them, hydrogen, hydroxy, methoxy, ethoxy, benzyloxy, Acetoxy and propionoxy are preferred. Among these, hydrogen, hydroxy, methoxy, and acetoxy are particularly preferable. -X'- is preferably a carbon chain of 4 to 6 carbon atoms that forms part of the ring structure, or one in which one or two carbon atoms are replaced with oxygen, sulfur, or nitrogen atoms. Among them, a carbon chain having 5 carbon atoms that becomes a part of the ring structure, or one in which one carbon atom is replaced with an oxygen, sulfur, or nitrogen atom is preferable. k ′ is preferably an integer of 0 to 6. R ^{4 ′} may be CONR ⁷ R ⁸ (where R ⁷ and R ⁸ each independently represent hydrogen, methyl, ethyl, propyl, benzyl), or R ^{4 ′} substituted with two adjacent carbons. A benzene fused ring, a pyridine fused ring, a naphthalene fused ring, a cyclopropane fused ring, a cyclobutane fused ring, a cyclopentane fused ring, a cyclopentene fused, which is unsubstituted or substituted with one or more, particularly 1 to 4 substituents R ^5. It is preferable to form a ring, a cyclohexane fused ring, a cyclohexene fused ring, a cycloheptane fused ring, or a cycloheptene fused ring. Of these, dimethylamide and diethylamide are preferable, or a benzene condensed ring is preferably formed. The other R ^{4 ′ s} are preferably each independently methyl, ethyl, propyl, or benzyl, or two R ^{4 ′} bonded to the same carbon atom are combined to form one oxygen atom to form a carbonyl group. In particular, it is preferable that the carbon atom adjacent to the carbonyl group is replaced with a nitrogen atom to form an amide bond. As the benzene condensed ring, an unsubstituted one is also preferable, but as the substituent R ⁵ , fluorine, chlorine, bromine, iodine, nitro, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), carbon Aralkyl having 7 to 13 (especially benzyl), hydroxy, alkoxy having 1 to 5 carbons (especially methoxy, ethoxy), trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , (CH ₂ ) _p N (R ⁷ ) COR ⁸ (wherein p represents an integer of 0 to 5, R ⁶ is hydrogen, alkyl having 1 to 5 carbon atoms (particularly methyl, ethyl, propyl), carbon number 3 represents 7 alkenyl or aryl having 6 to 12 carbon atoms (especially phenyl) from, R ^7, R ⁸ are each independently hydrogen, Preferred is an alkyl having 1 to 5 primes (particularly methyl, ethyl, propyl) or aralkyl having 7 to 13 carbons (particularly benzyl), and in particular, unsubstituted, fluorine, chlorine, bromine, iodine, nitro, methyl , Ethyl, propyl, benzyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, Acetoxy, phenyloxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylamino Methyl, dimethylaminoethyl, amino is preferable. R ⁹ is preferably hydrogen, alkyl having 1 to 5 carbon atoms, allyl, or benzyl, and particularly preferably hydrogen or methyl. R ¹⁰ and R ¹¹ are preferably bonded to —O—, or R ¹⁰ is hydrogen, and R ¹¹ is preferably hydrogen, hydroxy, or methoxy, particularly those having both bonded to —O—. Is preferred.

However, among the above compounds of the general formula (II), Y ′ and Z ′ are simultaneously valence bonds and X ′ is — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH ₂ ) ₂ —O— In the case of (CH ₂ ) ₂ —, k ′ must be 1 or more, and Y ′ and Z ′ are simultaneously —C (═O) — and X ′ is a cyclic structure chain consisting of two carbons. In case k ′ must be greater than or equal to 1, especially when (R ^{4 ′} ) k ′ is a benzene fused ring, the benzene ring must be substituted with R ⁵ .

  However, the present invention is not limited to these.

  Pharmacologically preferred acid addition salts include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates and other inorganic acid salts, acetates, lactates, citrates, Organic carboxylates such as oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, methanesulfonate, ethanesulfonate Organic sulfonates such as benzene sulfonate, p-toluene sulfonate, camphor sulfonate, etc., among which hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonic acid Although a salt etc. are used preferably, this is not restricted to these, either.

Among the compounds of the general formula (I) according to the present invention, -X- is a carbon chain having 2 carbon atoms that forms part of the ring structure, Y and Z are -C (= O)-, and two R ⁴ are Specific examples of the following general formula (Ia), which are unsubstituted or substituted benzene condensed rings substituted with one or more R ⁵ , R ⁹ is hydrogen, R ¹⁰ and R ¹¹ are combined and are —O— are shown in Table 1. Show. In the following tables, CPM means cyclopropylmethyl, and the 6-position bond is α or β.

Of the compounds of general formula (Ia), methyl R ¹ is cyclopropyl, R ^2, R ³ is hydroxy, R ⁵ is 4-fluoro, Compound 16 6-position of the three-dimensional is beta,

  It is named N- [17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl] -4-fluorophthalimide.

Of the compounds of the general formula (I) according to the present invention, -X- is a carbon chain having 3 carbon atoms that forms part of the ring structure, Y is -C (= O)-, Z is a valence bond, 2 Benzene condensed ring in which R ⁴ is unsubstituted or substituted with one or more R ⁵ , R ⁹ is hydrogen, and R ¹⁰ and R ¹¹ are combined to form a compound of —O—, a specific example of the following general formula (Ib) Is shown in Table 2.

Among the compounds of the general formula (Ib), R ¹ is cyclopropylmethyl, R ² and R ³ are hydroxy, no R ⁴ substituent other than the condensed benzene ring, R ⁵ is 6-fluoro, 6 Compound 82 in which the stereo of the position is β

It is named 2- [17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl] -6-fluoro-2,3-dihydro-isoindol-1-one.

Among the compounds of the general formula (I) according to the present invention, -X- is a carbon chain having 2 carbon atoms (single bond or unsaturated bond) that becomes a part of the ring structure, and Y and Z are -C (= O). Specific examples of the following general formula (Ic) in which —, R ⁹ are hydrogen, and R ¹⁰ , R ¹¹ are bonded to form —O— are shown in Table 3.

Also ,, R ¹ is cyclopropylmethyl Among the compounds of general formula (Ic), hydroxy R ^2, R ^3, R ⁴ is 2-ethylidene, Compound 22 is a 6-position of the three-dimensional is beta,

Named as N- [17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl] -2-ethylidene-succinimide.

Among the compounds of the general formula (I) according to the present invention, -X- is a carbon chain having 3 carbon atoms that forms part of the ring structure, Y is -C (= O)-, Z is a valence bond, R ⁹ Table 4 shows specific examples of the following general formula (Id), in which R is hydrogen, R ¹⁰ and R ¹¹ are combined to form a compound of —O—.

Further, among the compounds of the general formula (Id), a compound 47 in which R ¹ is cyclopropylmethyl, R ² , R ³ is hydroxy, R ⁴ is 3-benzyl, and the stereo at the 6-position is β,

It is named 3-benzyl-1- [17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl] -pyrrolidin-2-one.

Among the compounds of the general formula (I) according to the present invention, -X (R ⁴ ) _k-2 -is -A-, Y, Z is a valence bond, two R ⁴ are unsubstituted or one or more R Table 5 shows specific examples of the general formula (Ie) in which the benzene condensed ring substituted with ⁵ is substituted, R ⁹ is hydrogen, R ¹⁰ and R ¹¹ are combined and —O—.

Of the compounds of general formula (Ie), methyl R ^1, R ² are hydrogen, R ³ is hydroxy, -A- is - Compound 1 is a, - (CH _{2) 3}

It is named 4,5α-epoxy-6β-tetrahydroquinolin-17-methyl-morphinan-3-ol.

Among the compounds of general formula (Ie), methyl R ¹ is, R ² is hydrogen, R ³ is hydroxy, -A- is - a (CH _{2) 2} -O-, compound 4,

It is named 4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] oxazino) -17-methyl-morphinan-3-ol.

Among the compounds of general formula (Ie), R ¹ is methyl, R ^2, R ³ is hydroxy, -A- is a compound 8 is a -CH ₂ -CO-NMe-,

It is named 4- [4,5α-Epoxy-3,14-dihydroxy 17-methylmorphinan-6β-yl] -1-methyl-3,4-dihydro-1H-quinoxalin-2-one.

Among the compounds of general formula (Ie), methyl R ¹ is, R ² is hydrogen, R ³ is hydroxy, -A- is - compounds wherein _{10, - (CH 2) 2} -O-CH 2

It is designated 4,5α-epoxy-6β- (1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepino) -17-methyl-morphinan-3-ol.

  The morphinan derivative having a nitrogen-containing cyclic substituent, which is used as an active ingredient of the therapeutic or preventive agent for pollakiuria or urinary incontinence of the present invention represented by the above general formula (I), is specifically produced by the method shown below. can do.

Among the compounds represented by the general formula (I) of the present invention (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, k are the same as defined above) In the cyclic amine compound (Ia) in which Y and Z are both valence bonds, the general formula (IV) (R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , R ^{10 11} is the same as defined above, and is an iminium salt (Va) (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, and k are as defined above) The same as above) or enamine (Vb) (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, k are as defined above) It can be obtained by reaction.

  This reaction consists of two steps: (1) an iminium salt or enamine reaction using an acid catalyst, (2) a reduction with a metal hydride reducing agent, or a hydrogenation reaction in the presence of an acid or metal catalyst. The 6-oxo isomer represented by the general formula (IV) used as a starting material for this reaction is, for example, J. Org. Chem. 4, 220 (1939), J. Org. Chem. 15, 1103. (1950) and the like, and can be produced by the method described in the literature.

First, the iminium salt or enamine reaction of (1) is a reaction for obtaining an iminium salt (Va) or enamine (Vb) from an oxo compound (IV) and an amine (VI) (R ⁴ , X, and k are as defined above). It is. This reaction is carried out, for example, according to the method described in J. Org. Chem. 45, 3366 (1980), International Publication No. 93/15081, or the like, that is, the oxo form (IV) and amine (VI) in an appropriate reaction solvent. The reaction is allowed to proceed by heating under reflux and removing the water formed by azeotropic distillation with the reaction solvent or using a Dean-Stark type water separator or the like. In addition, addition of a suitable dehydrating agent to the reaction system is also a preferred method for producing iminium salt (Va) or enamine (Vb). At this time, the dehydrating agent to be used is not particularly limited, but inorganic dehydrating agents such as molecular sieve, anhydrous calcium sulfate, anhydrous copper sulfate, anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous calcium chloride, or orthoesters and acid anhydrides. And organic dehydrating agents such as dicyclohexylcarbodiimide, sulfur trioxide-pyridine complex, phosphorus oxychloride and thionyl chloride. Of these, organic dehydrating agents such as orthoesters, dicyclohexylcarbodiimide and sulfur trioxide-pyridine complex are preferable, and orthoesters are particularly preferable.

  The amount of amine (VI) used in this step is not particularly limited, but is usually 0.5 to 50 equivalents, preferably 1 to 30 equivalents, particularly preferably 1 to 10 equivalents.

  Examples of coexisting acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, carboxylic acids such as benzoic acid, acetic acid and oxalic acid, and usually amines. Any acid that forms a salt with the acid can be used, but hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, among them, p-toluenesulfonic acid, benzoic acid are preferably used. The amount of the coexisting acid is not particularly limited, but it can be carried out in the range of 0.5 to 50 equivalents. Usually, 1 to 30 equivalents, preferably 1 to 10 equivalents, gives satisfactory results.

  When orthoesters are used as a dehydrating agent, there is no particular limitation, but orthogi such as trimethyl orthoformate, triethyl orthoformate, tri-n-propyl orthoformate, triisopropyl orthoformate, diethylphenyl orthoformate, tri-n-butyl orthoformate, etc. Acid esters, trimethyl orthoacetate, triethyl orthoacetate, tri-n-propyl orthoacetate, triisopropyl orthoacetate, trimethyl orthopropionate, triethyl orthopropionate, tri-n-propyl orthopropionate, orthopropion Orthopropionates such as triisopropyl acid, trimethyl orthobutyrate, triethyl orthobutyrate, tri-n-propyl orthobutyrate, orthobutyric acid esters such as triisopropyl orthobutyrate, trimethyl orthobenzoate , Orthobenzoate such as triethyl orthobenzoate, tri-n-propyl orthobenzoate, triisopropyl orthobenzoate, etc., usually trimethyl orthoformate, triethyl orthoformate, tri-n-formate orthoformate Orthoformates such as -propyl and triisopropyl orthoformate, orthoacetic esters such as trimethyl orthoacetate, triethyl orthoacetate, tri-n-propyl orthoacetate, triisopropyl orthoacetate, among others trimethyl orthoformate, triethyl orthoformate, ortho Trimethyl acetate and triethyl orthoacetate are preferably used. The ortho ester can be used as a reaction solvent, but usually 0.5 to 10 equivalents, preferably 1 to 5 equivalents are used. In addition, the ortho ester may be coexistent at the start of the reaction, or a method of sequentially adding the ortho ester several times according to the progress of the reaction is also effective.

  The reaction solvent is not particularly limited, but ether solvents such as tetrahydrofuran (THF), ether, dimethoxyethane (DME) and dioxane, aromatic hydrocarbon solvents such as benzene, toluene, xylene and mesitylene, dimethylformamide (DMF) ), Polar solvents such as dimethyl sulfoxide (DMSO) can be used alone or in admixture of two or more of these solvents, among which THF, toluene, xylene, DMF, or a mixed solvent thereof is preferably used. .

  The concentration of the oxo compound (IV) in the reaction mixture is not particularly limited, but satisfactory results are usually obtained from 1 mmol / L to 1 mol / L. The reaction temperature is usually 0 to 250 ° C., preferably 0 to 200 ° C., but satisfactory results are obtained in the range of 20 to 150 ° C. The reaction time is appropriately selected according to the conditions such as the reaction temperature, but usually a satisfactory result is obtained in 3 hours to 100 hours.

  In the reduction reaction (2), the iminium salt (Va) or enamine (Vb) is generally reduced with a metal hydride reducing agent without isolation, or hydrogenated in the presence of an acid or a metal catalyst. Even if the iminium salt (Va) or enamine (Vb) is isolated, the desired cyclic amine (Ia) can be obtained.

  As the reaction solvent, the iminium salt or the solvent used in the enaminerization may be used as it is, but preferable results are obtained by mixing and reacting with an alcohol solvent such as methanol or ethanol, particularly methanol. Alternatively, the reaction solvent for iminium chloride or enamine may be distilled off under reduced pressure, and the reaction may be performed only with an alcohol solvent such as methanol or ethanol.

  Metal hydride reducing agents include sodium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, triacetoxyborohydride tetramethylammonium hydride, and borane-pyridine complexes. It is relatively stable and can be carried out. In particular, sodium cyanoborohydride, sodium triacetoxyborohydride, and borane-pyridine complex are preferably used. The metal hydride reducing agent can be used in an amount of 0.5 to 50 equivalents, but usually 1 to 20 equivalents, preferably 1 to 10 equivalents. Satisfactory results are obtained when the reaction temperature is usually -40 to 150 ° C, preferably -30 to 80 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but satisfactory results are usually obtained in about 30 minutes to 10 hours. The concentrations of the substrates (Va) and (Vb) in the reaction system are not particularly limited, but are usually preferably 1 mmol / L to 1 mol / L.

  When hydrogenation is performed in the presence of an acid or a metal catalyst, the reaction solvent may be the iminium salt or the solvent used in enamine, but alcohol solvents such as methanol and ethanol, or ethers such as THF and ether. Even if the system solvent is mixed, preferable results can be obtained. Alternatively, the reaction solvent for iminium chloride or enamine may be distilled off under reduced pressure, and the reaction may be carried out only with an alcohol solvent such as methanol or ethanol, or an ether solvent such as THF or ether. Examples of coexisting acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, carboxylic acids such as benzoic acid, acetic acid and oxalic acid, and usually amines. Any acid that forms a salt with the acid can be used, but hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, among them, p-toluenesulfonic acid, benzoic acid are preferably used. The amount of the coexisting acid is not particularly limited, but it can be carried out in the range of 0.5 to 50 equivalents. Usually, 1 to 30 equivalents, preferably 1 to 10 equivalents, gives satisfactory results.

  As the metal catalyst, any of the catalysts used in ordinary hydrogenation reactions such as platinum oxide, palladium hydroxide, palladium-carbon, etc. can be used, but platinum oxide and palladium-carbon are preferably used. The reaction temperature is −30 to 80 ° C., preferably 10 to 50 ° C., and the hydrogen pressure is 1 to 100 atm, preferably 1 to 30 atm. can get. The reaction time is appropriately selected depending on the reaction conditions, but satisfactory results are usually obtained in 0.5 to 30 hours. The concentrations of the substrates (Va) and (Vb) in the reaction system are not particularly limited, but are usually preferably 1 mmol / L to 1 mol / L.

  The cyclic amine form (Ia) can be produced by the reduction reaction to form an α form and a β form, but can be purified by ordinary column chromatography, recrystallization, slurry washing method or the like.

Among the compounds represented by the general formula (I) of the present invention (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, k are the same as defined above) Wherein Y is —C (═O) — and Z is a valence bond (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , k are as defined above) As shown in Scheme 2, the cyclic amide of the same formula (VIIa) (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , k is the same as defined above) And T is chlorine, bromine, iodine, or OTs, OMs) or (VIIb) [R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , k are as defined above, T ′ represents chlorine or OR ¹² (wherein R ¹² represents hydrogen, alkoxy having 1 to 5 carbon atoms, aralkyloxy having 7 to 13 carbon atoms, or alkanoyloxy having 1 to 5 carbon atoms)] Using an amino group alkylation or amidation reaction It is possible to elephants. The compounds represented by the general formulas (VIIa) and (VIIb) used as starting materials in Scheme 2 can be obtained by the method described in International Publication No. 93/15081 and the like.

  Alkylation or amidation can be generally performed by a method in which a base is present in a solvent.

  Examples of the base include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, metal hydrides such as sodium hydride and potassium hydride, metal alkoxides such as sodium ethoxide and potassium t-butoxide, triethylamine, Organic bases such as diisopropylethylamine, pyridine and 4-dimethylaminopyridine can be used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to the substrate. However, in the case of an amidation reaction, satisfactory results may be obtained without using a base.

  Solvents include aprotic polar solvents such as DMF, dimethylacetamide, DMSO, ether solvents such as diethyl ether, THF, DME, dioxane, hydrocarbon solvents such as benzene, toluene, dichloromethane, chloroform, 1,2- Halogen solvents such as dichloroethane can be used, among which DMF, THF, and toluene are preferably used.

  Satisfactory results are obtained when the reaction temperature is usually -20 to 200 ° C, preferably 0 to 150 ° C. The reaction time is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 30 minutes to 100 hours. The concentration of the substrates (VIIa) and (VIIb) in the reaction system is not particularly limited, but usually 1 mmol / L to 1 mol / L is preferable.

Among the compounds represented by the general formula (I) of the present invention (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, k are the same as defined above) And the cyclic imide derivative represented by the general formula (Ic) (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ and R ¹¹ are the same as defined above), The primary amine represented by the formula (VIII) (R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , R ¹¹ are the same as defined above) is represented by the general formula (IX) (R ⁴ is the same as defined above) It can manufacture by making the acid anhydride represented by this react. If necessary, the reaction can be carried out in the presence of an acid or a base in the reaction system.

  The acid anhydride (IX) can be used in an amount of 0.5 to 50 equivalents relative to the primary amine body (VIII), but preferably 1 to 20 equivalents, and particularly 1 to 10 equivalents gives good results. can get. Solvents include aprotic polar solvents such as DMF, dimethylacetamide, DMSO, ether solvents such as diethyl ether, THF, DME, dioxane, hydrocarbon solvents such as benzene, toluene, xylene, dichloromethane, chloroform, 1, Halogen solvents such as 2-dichloroethane, alcohol solvents such as methanol, ethanol, propanol and butanol, and acidic solvents such as acetic acid and propionic acid can be used, among which DMF, toluene and acetic acid are preferably used.

  As the base to coexist as necessary, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine can be used. Triethylamine, pyridine, potassium carbonate and sodium carbonate are preferably used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to the substrate. On the other hand, as the acid, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, carboxylic acids such as acetic acid, propionic acid and benzoic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid can be used. However, carboxylic acids such as acetic acid, propionic acid, and benzoic acid, among which acetic acid is preferably used. The amount of acid used is 1-30 equivalents, preferably 1-10 equivalents, relative to the substrate.

  The reaction temperature can usually be in the range of -20 to 200 ° C, and satisfactory results are preferably obtained in the range of 0 to 150 ° C. The reaction time is appropriately selected according to conditions such as the reaction temperature, but satisfactory results are usually obtained in about 30 minutes to 30 hours. The concentration of the substrate (VIII) in the reaction system is not particularly limited, but usually about 1 mmol / L to 1 mol / L is preferable.

  The primary amine compound represented by the general formula (VIII) used as the starting material in Scheme 3 is described in J. Med. Chem. 20, 1100 (1977), J. Org. Chem. 45, 3366 (1980), etc. It can be synthesized by the method described. Namely, (1) iminium salt or enamine reaction of oxo compound (IV) with a deprotectable primary or secondary amine, or (2) reduction with metal hydride reducing agent or in the presence of an acid or metal catalyst The primary amine compound (IX) can be obtained in good yield by using the three-step method of hydrogenation reaction in (3) and (3) removal of a deprotectable substituent.

  Here, as a deprotectable substituent, any protecting group for an amino group generally described in, for example, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (JHON WILEY & SONS, INC. 1991) can be used. Specifically, allyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-cyanobenzyl, dibenzosuberyl, diphenylmethyl, di (4-methoxyphenyl) Examples include methyl, triphenylmethyl, (4-methoxyphenyl), diphenylmethyl, fluorenyl, 9-phenylfluorenyl, ferrocenylmethyl, among them allyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl 2-nitrobenzyl and 4-nitrobenzyl are preferably used, and benzyl is particularly preferable.

  The iminium salt or enamine reaction of (1) can be carried out in the same manner as in the above-mentioned scheme 1, particularly when the oxo compound (IV) and amine are reacted in the presence of an acid catalyst and a dehydrating agent. . Preferred dehydrating agents in this case are orthoesters.

  Reduction (2) with a metal hydride reducing agent or hydrogenation reaction in the presence of an acid or a metal catalyst can also be carried out by the same method as in Scheme 1 described above.

  For example, when benzyl is used as a deprotectable substituent, the removal of the deprotectable substituent in (3) is performed by performing a hydrogenolysis reaction using hydrogen gas as a hydrogen source in the presence of a metal catalyst. Is possible. In this case, all catalysts used in ordinary hydrogenolysis reactions such as platinum catalysts such as platinum oxide and platinum hydroxide, palladium catalysts such as palladium hydroxide and palladium-carbon, nickel catalysts such as Raney nickel, etc. are used as metal catalysts. Although possible, palladium catalysts, particularly palladium-carbon, are particularly preferred.

  Reaction solvents are alcohol solvents such as methanol, ethanol and propanol, ether solvents such as THF, ether, DME and dioxane, and solvents inert under hydrogenation conditions such as aromatic hydrocarbons such as benzene, toluene and xylene. Can be used, but alcohol solvents, particularly methanol and ethanol are particularly preferably used.

  It is also possible to carry out the reaction in the presence of an acid in the reaction system. In this case, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid In addition, sulfonic acids such as camphorsulfonic acid, carboxylic acids such as benzoic acid, acetic acid, oxalic acid, and phthalic acid can be used as the acid catalyst. In particular, inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid, benzoic acid, Carboxylic acids such as phthalic acid, among which hydrochloric acid, acetic acid, benzoic acid and phthalic acid are preferably used. The reaction temperature is 0 to 150 ° C., preferably 10 to 100 ° C., and the hydrogen pressure is 1 to 100 atm, preferably 1 to 30 atm, but usually 20 to 80 ° C. and 1 to 10 atm are satisfactory. The result is very good. The reaction time is appropriately selected depending on the reaction conditions, but satisfactory results are usually obtained in 0.5 to 100 hours.

  It is also possible to use formic acid such as formic acid or ammonium formate instead of hydrogen gas as the hydrogen source, and the amount of formic acid used can be 0.5 to 100 equivalents, but usually 1 to 50 equivalents. 1-10 equivalents are preferably used. The conditions such as the metal catalyst, reaction solvent, and reaction temperature in this case are the same as those in the hydrogenolysis reaction using the hydrogen gas as a hydrogen source.

The cyclic imide derivative represented by the general formula (Ic) (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ and R ¹¹ are the same as defined above) is Tetrahedron. 50, 9757 (1994). It can also be produced by a method based on Mitsunobu reaction described in (1).

Of the compounds represented by the general formula (I) of the present invention (R ¹ , R ² , R ³ , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, k are the same as defined above) , Y is —C (═O) —, wherein general formulas (XIa) and (XIb) (R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , R ¹¹ , X, Z are the same as defined above; R ¹³ represents an alkyl having 1 to 5 carbon atoms and an aralkyl having 7 to 13 carbon atoms, and the compound represented by the general formula (X) (R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , R ¹¹ , X and Z are the same as defined above) and can be produced by alkylating or acylating in a solvent in the presence of a base. The compound represented by the general formula (X) used as the starting material in Scheme 4 can be obtained by the method shown in Scheme 2.

  The alkylating agent or acylating agent is preferably used in an amount of 1 to 20 equivalents, and satisfactory results are obtained with 1 to 10 equivalents.

  As the base, organolithium reactants such as methyl lithium, butyl lithium and LDA, metal hydrides such as sodium hydride and potassium hydride, metal alkoxides such as sodium ethoxide and potassium t-butoxide can be used. Of these, LDA and butyl lithium are preferably used. The base used is 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to the substrate.

  As the solvent, aprotic polar solvents such as DMF, dimethylacetamide and DMSO, ether solvents such as diethyl ether, THF, DME and dioxane, and hydrocarbon solvents such as pentane, hexane, benzene and toluene can be used. Of these, THF and DME are preferably used.

  Satisfactory results are obtained when the reaction temperature is usually from -100 to 200 ° C, preferably from -80 to 150 ° C. The reaction time is appropriately selected depending on the reaction temperature and other conditions, but satisfactory results are usually obtained in 30 minutes to 30 hours. Further, the concentration of the substrate (X) in the reaction system is not particularly limited, but usually 1 mmol / L to 1 mol / L is preferable.

Of the compounds represented by general formula (I), general formula (XIII) wherein R ³ is hydroxy (wherein R ¹ , R ² , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, When synthesizing a compound represented by k as defined above, R ³ is methoxy for the purpose of protecting the phenol moiety (wherein R ¹ , R ² , R ⁴ , R ⁹ , R ¹⁰ , R ¹¹ , X, Y, Z, and k are the same as defined above). In this case, as shown in the following scheme 5, the deprotection is a general demethylation reaction of phenolic methyl ether, specifically, (1) a method using boron tribromide, or (2) basic It can be performed by any of the methods using alkylthiol under conditions.

  In the method (1), the amount of boron tribromide used is preferably 1 to 20 equivalents, and satisfactory results are obtained with 1 to 7 equivalents. The reaction solvent is preferably a halogen-based solvent such as dichloromethane, chloroform, 1,2-dichloroethane, among which dichloromethane is preferred. The reaction temperature is preferably -70 to 50 ° C, and satisfactory results are obtained at -50 to 40 ° C. The reaction time is preferably 10 minutes to 10 hours, and satisfactory results are obtained in 30 minutes to 5 hours. Further, the concentration of the compound represented by the general formula (XII) in the reaction system is not particularly limited, but usually 1 mmol / L to 1 mol / L is preferable.

  In the method (2), alkylthiols such as ethanethiol, propanethiol and butanethiol are preferable as the reactant, and propanethiol is preferably used. The amount used is preferably 1 to 20 equivalents, with 1 to 7 equivalents giving satisfactory results. As the base, potassium t-butoxide, sodium hydride, potassium hydride and the like are preferable, and potassium t-butoxide is preferably used. The amount used is preferably from 1 to 20 equivalents, with 1 to 7 equivalents being particularly satisfactory. The reaction solvent is preferably an aprotic polar solvent such as DMF or dimethylacetamide, or an ether solvent such as THF or DME. Among them, DMF which is an aprotic solvent is preferably used. The reaction temperature is preferably 50 to 200 ° C, and satisfactory results are obtained at 80 to 150 ° C. The reaction time is preferably 1 hour to 15 hours, and satisfactory results can be obtained in 2 hours to 8 hours. Further, the concentration of the compound represented by the general formula (XII) in the reaction system is not particularly limited, but usually 1 mmol / L to 1 mol / L is preferable.

  The compound of the present invention can be used as a medicine or a pharmaceutical composition. Specifically, it can be used as a pharmaceutical useful for the treatment or prevention of frequent urination, urgency or urinary incontinence. In particular, neurogenic bladder disorder, nocturia, overactive bladder, unstable bladder, neurogenic urination, psychogenic urination, idiopathic urination, nocturia, bladder spasm, chronic cystitis, interstitial bladder It can be used for the treatment or prevention of urination disorders such as frequent urination or urinary incontinence caused by diseases such as inflammation, chronic prostatitis, prostatic hypertrophy, and prostate cancer. Neuropathic urinary bladder disorder as used here refers to a condition in which the urinary tract and urinary function of the lower urinary tract are abnormal as a result of some damage to the nerve that controls the lower urinary tract consisting of the bladder, urethra, and external urethral sphincter Say. Cerebrovascular disorders, brain tumors, brain trauma, encephalitis, brain tumors, normal pressure hydrocephalus, dementia, Parkinson's disease, depression, striatal nigra degeneration, progressive supranuclear palsy, Olive / bridge / cerebellar atrophy, Shy-Drager syndrome, spinal cord injury, spinal vascular disorder, spinal cord tumor, myelitis, cervical cord compression disease, syringomyelia, multiple sclerosis, spina bifida, spinal meningocele, spinal canal There are stenosis, Tethered cord syndrome, myelopathy, diabetes, pelvic surgery. However, the use of the therapeutic or preventive agent for pollakiuria or urinary incontinence of the present invention is not limited only to these disease cases.

  The morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) is not only used as a pharmaceutical useful for the treatment or prevention of frequent urine, urgency or urinary incontinence as described above, but also frequent urination, It can be used for treatment or prevention method for urinary urgency or urinary incontinence or use for frequent urination, urgency or urinary incontinence. Furthermore, for example, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc. are also useful as pharmaceuticals useful for the treatment or prevention of urinary urgency or urinary incontinence. It can also be used for treatment or prevention methods for incontinence or use for frequent urination, urgency or urinary incontinence.

  The therapeutic or preventive effect of frequent urinary or urinary incontinence of a morphinan derivative having a nitrogen-containing cyclic substituent represented by the general formula (I) is described in Brain. Res., Vol. 297, 191 (1984), or J. Pharmcol. Although it can be confirmed by the method described in Exp. Ther., Vol. 240, 978 (1987), it is not necessarily limited to this test method.

  When the compound of the present invention is used clinically as a therapeutic or preventive agent for pollakiuria or urinary incontinence, the drug may be a free base or a salt thereof, and excipients, stabilizers, preservatives, buffering agents. In addition, additives such as a solubilizer, an emulsifier, a diluent, and an isotonic agent may be appropriately mixed. The dosage form includes oral preparations such as tablets, capsules, granules, powders, and syrups, parenteral preparations such as injections, suppositories, and liquids, or topical administration such as ointments, creams, and patches. Can be mentioned. The therapeutic or preventive agent for pollakiuria or urinary incontinence of the present invention desirably contains the above-mentioned active ingredient in an amount of 0.01 to 90% by weight, more preferably 0.1 to 70% by weight. The amount used is appropriately selected according to symptoms, age, body weight, administration method, etc., but for adults, the amount of active ingredient is 0.1 μg to 10 g per day, preferably 1 μg to 1 g, particularly preferably 10 μg to 100 mg. Each can be administered once or in several divided doses.

  Compound (I) or a salt thereof of the present invention is a preventive or therapeutic agent for other dysuria, or a disease causing dysuria (for example, dementia including prostatic hypertrophy, prostate cancer, diabetes, cerebrovascular disorder, Alzheimer's disease, Depression, Parkinson's disease, multiple sclerosis, etc.) can also be used in combination with prophylactic or therapeutic agents.

  Other preventive or therapeutic agents for dysuria include, for example, propantheline, oxybutynin, propiverine, tolterodine, temiverine, trospium, darifenacin, solifenacin (Solifenacin), anticholinergic drugs such as KRP-197, smooth muscle relaxants such as Flavoxate, potassium channel openers such as NS-8, ZD-0947, KW-7158, ABT-598, WAY-151616, nifedipine Calcium channel antagonists such as (Nifedipine), flunarizine, skeletal muscle relaxants such as baclofen, diazepam, lanperisone, imipramine, desipramine, fluoxetine , Fluvoxamine, Milnacipran, Paroxetine, Duloxe Antidepressants such as Duloxetine, vasopressin agonists such as Desmopressin, tachykinin antagonists such as TAK-637, SR-48968 and Talnetant, beta agonists such as Clenbuterol and KUC-7748, capsaicin , Vanilloid agonists such as resiniferatoxin, PGE antagonists such as ONO-8711 and ONO-8992, COX inhibitors such as Flurbiprofen, α1 agonists such as R-450, doxazosin and indramin Terazosin (Terazosin), urapidil (Urapidil), alfuzosin (Alfuzosin), prazosin (Prazosin), naphthopidil (Naftopidil), tamsulosin (Tamsulosin), serodosin (Fiduxosin), KMD-3213, etc. Can be mentioned.

  Examples of diseases that cause dysuria include prostatic hypertrophy, prostate cancer, diabetes, cerebrovascular disorders, dementia including Alzheimer's disease, depression, Parkinson's disease, multiple sclerosis, etc. Examples of therapeutic agents include finasteride (Finasteride), dutasteride (Dutasteride), Izonsteride (Izonsteride), CS-891, 5α-reductase inhibitors such as MK-434, flutamide (Blututamide), nilutamide (Nilutamide) Androgen receptor antagonists such as Allylestrenol, Chlormadinone, Gestonorone, Cyproterone, Cyproterone, Osaterone, Nogestgestol, and other antiandrogens, SB-217242 , Endothelin antagonists such as TA-0201, plants such as shrimp prostat and sernirton And the above-mentioned α1 antagonists.

  Examples of preventive or therapeutic agents for prostate cancer include LH-RH agonists such as Leuprorelin, Goserelin, Buserelin, Nafarelin, Triptorelin, and Cetrorelix. ), LH-RH antagonists such as Ganirelix, Abarelix, 5α-reductase inhibitors described above, androgen receptor antagonists described above, antiandrogens described above, and the like.

  Examples of diabetes preventive or therapeutic agents include, for example, insulin resistance improvers such as pioglitazone, troglitazone, troglitazone, and rosiglitazone, tolbutamide, chlorpropamide, tolazamide, and acetohezamide. (Acetohezamide), Glyclopyramide, Glibenclamide, Gliclazide, Glimepiride, Repaglinide, Nateglinide, Neteglinide, Metformin, Metformin ) And other α-glucosidase inhibitors such as insulin, Acarbose, Voglibose, Miglitol, Emiglitate, AJ-9677, SR-58611-A, SB-226552, AZ40140 Β3 adrenergic receptor agonists, etc. Erogosetto (Erogoset), pramlintide (Pramlintide), leptin (Leptin), and the like BAY-27-9955.

  Examples of preventive or therapeutic agents for cerebrovascular disorders include aniracetam, ibudilast, tiapride, cardiochrome, citicoline, γ-aminobutyric acid, ifenprodil, nicergoline, vinpocetine, nizophenone, bencyclane, cinepazide and the like.

  Examples of the preventive or therapeutic agent for dementia including Alzheimer's disease include donepezil.

  Examples of the prophylactic or therapeutic agent for depression include the antidepressants described above.

  Examples of preventive or therapeutic agents for Parkinson's disease include amantadine, trihexyphenidyl, bromocriptine, levodopa, carbidopa, apomorphine and the like.

  Examples of preventive or therapeutic agents for multiple sclerosis include steroids and interferon-β-1b.

  Hereinafter, the present invention will be described in more detail based on examples.

Reference Example 1-1
Synthesis of 6β-dibenzylamino-17-cyclopropylmethyl-4,5α-epoxy-morphinan-3,14-diol

  Naltrexone 249.8 g (0.731 mol) was dissolved in a mixed solvent of THF 1700 mL and Toluene 1700 mL, and dibenzylamine 432.7 g (2.193 mol, 3.0 equivalents) was added. While stirring, the inside of the reaction vessel was depressurized and purged with argon. Next, 357.7 g (2.929 mol, 4.0 equivalents) of benzoic acid was weighed in a beaker and gradually added to the solution, whereby a white solid was precipitated. When the heating of the reaction apparatus was started using an oil bath, the precipitated crystals dissolved as the internal temperature increased, and became a uniform solution. Refluxing started at an internal temperature of 81.5 ° C., and the reaction was started. The reaction was carried out at an internal temperature of 81.5-87.4 ° C. 30 minutes after the start of the reaction, 53.9 g (0.363 mol, 0.50 equivalent) of triethyl orthoformate was added, and further 54.0 g (0.364 mol, 0.50 equivalent), 54.1 g of triethyl orthoformate were added after 2 hours 30 minutes and 4 hours 30 minutes, respectively. (0.365 mol, 0.50 equiv) was added. Six hours and 30 minutes after the start of the reaction, the oil bath was removed from the reaction apparatus, and the iminiumation reaction was completed.

  While the iminiumation reaction vessel was cooled in an ice bath, 54.0 g (0.859 mol, 1.17 equivalents) of sodium cyanoborohydride was weighed in another 1 L three-necked flask and dissolved by adding 532.3 g of methanol. This prepared solution was added dropwise to the iminiumization reaction solution over 10 minutes at an internal temperature of 2.5 to 10 ° C. The reaction was completed 30 minutes after the completion of the dropping, and post-treatment was performed.

  In a 5 L Erlenmeyer flask, 446.0 g (3.22 mol) of potassium carbonate and 3399.6 g of distilled water were weighed to prepare an aqueous potassium carbonate solution. This solution was added dropwise to the reaction mixture at an internal temperature of 5.0 to 18.0 ° C. over 12 minutes. After completion of the dropwise addition, the gel-like solid was dissolved by stirring for 10 minutes, and when the reaction solution became uniform, the solution was transferred to a 10 L separatory tank. To this, 599.8 g of THF and 615.5 g of ethyl acetate were added and stirred for 15 minutes. After the stirring was stopped, the mixture was allowed to stand for 20 minutes and separated to remove 5175.5 g of the extracted aqueous layer. Distilled water (1026.3 g) was added to the organic layer in the separation tank, and the mixture was stirred for 15 minutes and then allowed to stand overnight. On the next day, liquid separation was performed, and 1280.5 g of the aqueous layer was removed after washing with distilled water to obtain 4186.2 g of an organic layer after washing with distilled water. Thereafter, the organic layer was concentrated to obtain 2263.6 g of a concentrated residue. To this residue, 1340.1 g of ethyl acetate was added, and the solvent was replaced with ethyl acetate and water azeotroped. Thereafter, the same operation was performed 5 times in total to obtain 2189.7 g of the final concentrated residue. Next, 1221.7 g of methanol was added and concentrated, and the solvent was replaced with methanol. The subsequent operation was performed twice in total to obtain 2103.9 g of the final concentrated residue. To this residue, 528.3 g of methanol was added, and the vessel was immersed in an ice bath and stirred to perform slurry washing. The internal temperature at the start of stirring was 22.0 ° C., and stirring and washing were performed for 30 minutes. At the end of washing, the internal temperature was 8 ° C. The slurry washed with stirring was filtered through a 1 L funnel Millipore filter. The flask and the crystals were washed with 402.6 g of methanol. The crystals were transferred to a separable flask and dried under reduced pressure to obtain 329.2 g (yield 86%) of the title compound as white crystals.

Reference Example 1-2
Synthesis of 6β-naltrexamine

In a 5 L reaction vessel, 65.0-dibenzylamino-17-cyclopropylmethyl-4,5α-epoxy-morphinan-3,14-diol obtained in Reference Example 1-1 325.0 g (0.622 mol), 10% Pd A reactor was assembled by weighing 65.0 g (20 wt%) of / C (50% wet). Next, 2561.3 g of methanol (3.25 L, 10 mL / g-raw material) was added, stirring was started, and argon substitution was performed 3 times. Formic acid (88% sol.) 91.0 g (1.740 mol, 2.8 equivalents) was weighed in a beaker, and dropped at an internal temperature of 22.1 to 25.8 ° C. over 5 minutes using a dropping funnel. At this time, an increase in internal temperature was confirmed, and generation of gas was confirmed. After completion of the dropwise addition, heating was started, the reaction was started when the internal temperature reached 51.1 ° C., and analysis was performed by HPLC 2 hours after the start of the reaction. Although the reaction was completed at the point of 2 hours, stirring and heating were performed between 51.1-61.0 ° C. in order to carry out the reaction until the amount of residual formic acid was 0.03 equivalent or less. Sampling was performed 22 hours after the start of the reaction, and the reaction solution was analyzed by HPLC and ¹ H-NMR. From HPLC, no significantly increased impurities, decomposition products, etc. were confirmed. Further, it was confirmed that the amount of formic acid contained in the reaction solution was 0.090 equivalent. Since the determination of completion of the formic acid decomposition step is until the amount of residual formic acid becomes 0.03 equivalent or less, the reaction is continued at the same reaction temperature and stirring speed as it is. 28 hours after the start of the reaction, the amount of residual formic acid was measured by ¹ H-NMR and found to be 0.094 equivalent. Since the value confirmed at 22 hours was not changed, the reaction was continued by raising the internal temperature to 60.9-61.4 ° C. After 12 hours of raising the reaction temperature (40 hours after the start of the reaction), the amount of residual formic acid was confirmed by ¹ H-NMR. As a result, it was 0.037 equivalent. Although the end determination was 0.03 equivalent or less, the reaction was ended here and post-treatment was performed.

  The reaction mixture was immersed in an ice bath to an internal temperature of 20.7 ° C. and cooled, and Pd / C was filtered with a 1 L funnel Millipore filter. A 0.5 μm PTFE membrane filter was used as the filter, and the filtered Pd / C was washed with 227.5 g of methanol to obtain 3035.8 g of filtrate. The obtained filtrate was transferred to a 10 L evaporator flask, and the container was washed with 61.1 g of methanol. After the transfer, concentration was performed, and when the concentration residue reached 1624.9 g, concentration was temporarily stopped. To this, 1408.1 g of ethyl acetate was added and further concentrated, and the solvent was replaced from methanol to ethyl acetate. During the concentration, a white powder was precipitated, and the property changed from a solution to a slurry. Concentration was stopped when the solvent substitution residue reached 1455.4 g, and solvent substitution was performed twice in the same manner. After completion of solvent replacement, the powder was filtered, and the resulting white powder was washed with 178.6 g of ethyl acetate. This powder was transferred to a 1 L separable flask, immersed in a 50 ° C. water bath and dried under reduced pressure for 3 hours to obtain 185.5 g (yield 87.2%) of the title compound.

Example 1-1
Synthesis of 4,5α-epoxy-6β-tetrahydroquinolin-3-methoxy-17-methyl-morphinan (compound 201 )

  Dihydrocodeinone 304 mg (1.02 mmol) and methanesulfonic acid 0.12 ml (1.65 mmol) were dissolved in a mixed solvent of xylene 20 ml and dimethylformamide 10 ml, and 1,2,3,4-tetrahydroquinoline 0.2 ml (1.59 After addition of mmol), the mixture was heated to reflux for 12 hours while removing water azeotropically in an oil bath at 175 ° C. After allowing the reaction solution to cool to room temperature, 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 3 ml of aqueous ammonia were added to the reaction mixture, followed by extraction with chloroform (50 ml × 3 times). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 309 mg of a crude product. The obtained crude product was dissolved in 20 ml of methanol, 1.014 g (16.1 mmol) of sodium cyanoborohydride was added, and then 0.17 ml (2.62 mmol) of methanesulfonic acid was added, followed by stirring at room temperature for 24 hours. . To the reaction mixture, 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 3 ml of aqueous ammonia were added, followed by extraction with chloroform (50 ml × 3 times). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography [ChromatorexNH 40 g: cyclohexane-ethyl acetate (30: 1)] to obtain 103 mg of the title compound (yield 33%).

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.93-6.88 (2H, m), 6.77 (1H, d, J = 8.2 Hz), 6.67 (1H, d, J = 8.2 Hz), 6.52-6.45 (2H, m), 4.69 (1H, d, J = 8.2 Hz), 3.83 (3H, s), 3.66-3.56 (1H, m), 3.49-3.20 (2H, m), 3.11-3.09 (1H, m), 3.03 (1H, d, J = 18.2 Hz), 2.77-2.73 (2H, m), 2.56-2.50 (1H, m), 2.42 (3H, s), 2.40-2.34 (1H, m), 2.23-2.14 (2H, m), 2.05-1.82 (3H, m ), 1.77-1.73 (1H, m), 1.68-1.63 (3H, m), 1.15-1.00 (1H, m)
IR (cm ^-1 ) (KBr)
2926, 1600, 1570, 1499, 1438, 1373, 1341, 1277, 1256, 1190, 1148, 1104, 1079, 1050, 1016, 1000, 940, 910, 893, 855, 795, 743

Example 1-2
Synthesis of 4,5α-epoxy-6β-tetrahydroquinolin-17-methyl-morphinan-3-ol tartrate (compound 1 )

103 mg (0.25 mmol) of 4,5α-epoxy-6β-tetrahydroquinolino-3-methoxy-17-methyl-morphinan obtained in Example 1-1 was dissolved in DMF (5 mL), and n-propanethiol was dissolved. 0.12 ml (1.32 mmol) and potassium t-butoxide 142.6 mg (1.27 mmol) were added and reacted at 120 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, 20 ml of saturated aqueous sodium hydrogen carbonate solution and 3 ml of aqueous ammonia were added to the reaction mixture, and the mixture was extracted with chloroform (50 ml × 3 times). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (ChromatorexNH 5 g: ethyl acetate) to obtain a free form 75 mg (yield 75%) of the title compound. This was converted to the tartrate salt to give the title compound 1 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.93-6.87 (2H, m), 6.70 (1H, d, J = 8.2 Hz), 6.58 (1H, d, J = 8.2 Hz), 6.51-6.46 (1H, m), 6.37 (1H, d, J = 8.5 Hz), 4.62 (1H, d, J = 8.5 Hz), 3.19-3.11 (3H, m), 3.08-3.02 (1H, m), 2.96 (1H, d, J = 18.5 Hz), 2.74-2.70 ( 2H, m), 2.52-2.44 (1H, m), 2.35 (3H, s), 2.31-2.29 (1H, m), 2.20-1.48 (9H, m), 1.11-1.00 (1H, m) (free body )
IR (cm ^-1 ) (KBr)
3001, 2932, 2855, 1600, 1498, 1458, 1371, 1344, 1293, 1260, 1214, 1191, 1149, 1128, 1107, 1075, 1025, 1000
Elemental analysis value Composition formula: C ₂₆ H ₃₀ N ₂ O ₂・ 1.50C ₄ H ₆ O ₆・ 0.8H ₂ O
Calculated values: C: 59.86, H: 6.37, N: 4.36
Actual value: C: 59.77, H: 6.52, N: 4.38

Example 2-1
Synthesis of 4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] thiazino) -3-methoxy-17-methyl-morphinan (compound 202 )

  According to the method described in Example 1-1, using 3,4-dihydro-2H-benzo [1,4] thiazine instead of 1,2,3,4-tetrahydroquinoline, the title compound 239 mg 63%) was obtained.

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.98 (1H, dd, J = 1.8, 7.9 Hz), 6.86 (1H, ddd, J = 1.8, 7.3, 8.5 Hz), 6.78 (1H, d, J = 8.2 Hz), 6.69-6.65 (2H, m) , 6.61-6.55 (1H, ddd, J = 1.2, 7.6, 8.5 Hz), 4.61 (1H, d, J = 8.2 Hz), 3.85 (3H, s), 3.60-3.51 (3H, m), 3.14-2.96 (4H, m), 2.55-2.50 (1H, m), 2.41 (3H, s), 2.38-2.32 (1H, m), 2.23-2.12 (2H, m), 1.91-1.47 (5H, m), 1.12 -1.00 (1H, m)
IR (cm ^-1 ) (KBr)
2924, 1735, 1606, 1584, 1483, 1438, 1373, 1338, 1275, 1257, 1176, 1148, 1112, 1079, 1047, 1006, 937, 907, 891, 854, 793, 744

Example 2-2
Synthesis of 4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] thiazino) -17-methyl-morphinan-3-ol methanesulfonate (compound 2 )

According to the method described in Example 1-2, 4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] thiazino) -3-methoxy obtained in Example 2-1 Using 239 mg of 17-methyl-morphinane, 198 mg (yield 86%) of the free form of the title compound 2 was obtained. This was converted to methanesulfonate to give the title compound 2 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.00 (1H, dd, J = 1.8, 7.6 Hz), 6.92-6.87 (1H, m), 6.76 (1H, d, J = 8.2 Hz), 6.64 (1H, d, J = 8.2 Hz), 6.60-6.54 (2H, m), 4.58 (1H, d, J = 8.2 Hz), 3.63-3.51 (3H, m), 3.16-2.98 (4H, m), 2.57-2.52 (1H, m), 2.38 (3H, s ), 2.34-2.32 (1H, m), 2.22-2.14 (2H, m), 1.91-1.44 (5H, m), 1.16-1.02 (1H, m) (free body)
IR (cm ^-1 ) (KBr)
2925, 1609, 1584, 1484, 1440, 1373, 1337, 1280, 1253, 1175, 1146, 1112, 1069, 1045, 1025, 965, 925, 892, 855
Elemental analysis value Composition formula: C ₂₅ H ₂₈ N ₂ O ₂ S ・ 1.08MeSO ₃ H ・ 0.9H ₂ O
Calculated values: C: 57.95, H: 6.36, N: 5.18, O: 18.17, S: 12.34
Actual value: C: 57.77, H: 6.52, N: 5.18, O: 18.10, S: 12.43

Example 3
4- (4,5α-Epoxy-3-hydroxy-17-methyl-morphinan-6β-yl) -3,4-dihydro-2H-benzo [1,4] thiazine-1-oxide (mixture of diastereomers) Synthesis of methanesulfonate (compound 3 )

4,5α-Epoxy-6β- (3,4-dihydro-2H-benzo [1,4] thiazino) -17-methyl-morphinan-3-ol prepared by the method described in Example 2-2 164 mg (0.39 mmol) was dissolved in 5 mL of acetic acid, 63 mg (0.40 mmol) of sodium peroxoborohydride was added, and the mixture was stirred at room temperature for 1 hour. Then, 1 mL of concentrated hydrochloric acid was added to this reaction solution and stirred for 30 minutes. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 114 mg (yield 67%) of the free form of the title compound 3 . This was converted to methanesulfonate to give the title compound 3 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.54 (0.5H, t, J = 7.6 Hz), 7.53 (0.5H, t, J = 7.6 Hz), 7.2-7.25 (1H, m), 6.78 (0.5H, d, J = 8.2 Hz), 6.77 ( 0.5H, d, J = 8.2 Hz), 6.60-6.75 (3H, m), 4.74 (0.5H, d, J = 8.2 Hz), 4.67 (0.5H, d, J = 8.2 Hz), 3.90-4.05 ( 1H, m), 3.75-4.85 (1H, m), 3.50-3.60 (1H, m), 3.10-3.20 (2H, m), 3.04 (1H, d, J = 18.5 Hz), 2.50-2.75 (2H, m), 2.41 (3H, s), 2.3-2.4 (1H, m), 2.10-2.25 (2H, m), 1.6-1.9 (5H, m), 1.1-1.2 (1H, m) (free body)
Mass (ESI): 437 (M ⁺ +1)

Example 4-1
Synthesis of 4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] oxazino) -3-methoxy-17-methyl-morphinan (compound 204 )

  In accordance with the method described in Example 1-1, using 1,4-3,4-dihydro-2H-benzo [1,4] oxazine instead of 1,2,3,4-tetrahydroquinoline, the title compound 134 mg (yield) 29%).

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.79-6.67 (4H, m), 6.58-6.52 (2H, m), 4.63 (1H, d, J = 8.2 Hz), 4.32-4.14 (2H, m), 3.84 (3H, s), 3.60-3.51 ( 1H, m), 3.46-3.33 (2H, m), 3.12-3.10 (1H, m), 3.04 (1H, d, J = 18.2 Hz), 2.55-2.43 (1H, m), 2.42 (3H, s) , 2.38-2.34 (1H, m), 2.23-2.14 (2H, m), 1.91-1.45 (5H, m), 1.15-1.03 (1H, m)
IR (cm ^-1 ) (KBr)
2926, 2796, 1736, 1634, 1604, 1577, 1500, 1441, 1373, 1341, 1310, 1278, 1246, 1207, 1176, 1149, 1130, 1080, 1051, 1006, 974, 940, 913, 856, 823, 797, 741

Example 4-2
Synthesis of 4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] oxazino) -17-methyl-morphinan-3-ol methanesulfonate (compound 4 )

4,5α-epoxy-6β- (3,4-dihydro-2H-benzo [1,4] oxazino) -3-methoxy-17-methyl-morphinan obtained in Example 4-1 127 mg (0.30 mmol) Was dissolved in 6 mL of methylene chloride, cooled to 0 ° C., and 2.0 mL (2.0 mmol) of 1N boron tribromide methylene chloride solution was added while shielding from light, and then the mixture was warmed to room temperature and stirred for 30 minutes. Thereafter, 2 mL of an aqueous ammonia solution was added to the reaction solution and stirred for 1 hour. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 61 mg (yield 49%) of the free form of the title compound 4 . This was converted to methanesulfonate to give the title compound 4 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.80-6.73 (3H, m), 6.66 (1H, d, J = 8.2 Hz), 6.58 (1H, dt, J = 1.5, 7.6 Hz), 6.51-6.48 (1H, m), 4.62 (1H, d, J = 8.2 Hz), 4.31-4.11 (2H, m), 3.65-3.57 (1H, m), 3.45-3.31 (2H, m), 3.18-3.14 (1H, m), 3.02 (1H, d, J = 18.5 Hz), 2.61-2.56 (1H, m), 2.42 (3H, s), 2.39-2.36 (1H, m), 2.25-2.17 (2H, m), 1.94-1.84 (1H, m), 1.74-1.47 (4H, m), 1.16-1.04 (1H, m) (free body)
IR (cm ^-1 ) (KBr)
2927, 1736, 1604, 1501, 1448, 1375, 1341, 1310, 1278, 1242, 1208, 1179, 1148, 1128, 1059, 975, 925, 860, 823, 796, 735

Example 5-1
Synthesis of 4,5α-epoxy-6β-indolino-17-phenethyl-3-methoxy-morphinan-14-ol (compound 205 )

  In accordance with the method described in Example 1-1, indoline instead of 1,2,3,4-tetrahydroquinoline and 4,5α-epoxy-3-methoxy-6-oxo-17 instead of dihydrocodeinone 103 mg (yield 96%) of the title compound was obtained using -phenethyl-morphinan-14-ol.

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.34-7.18 (5H, m), 7.02-6.91 (2H, m), 6.76 (1H, d, J = 8.2 Hz), 6.64 (1H, d, J = 8.2 Hz), 6.57-6.52 (1H, m) , 6.29 (1H, d, J = 8.0 Hz), 4.79 (1H, d, J = 8.0 Hz), 3.84 (3H, s), 3.65-3.46 (2H, m), 3.40-3.31 (1H, m), 3.10 (1H, d, J = 18.1 Hz), 3.02-2.96 (2H, m), 2.86-2.61 (6H, m), 2.19-2.15 (3H, m), 1.59-1.42 (5H, m)
IR (cm ^-1 ) (KBr)
3387, 3024, 2926, 2832, 1759, 1605, 1496, 1438, 1397, 1368, 1327, 1279, 1257, 1187, 1154, 1128, 1049, 1024, 982, 937, 908, 852, 745, 700

Example 5-2
Synthesis of 4,5α-epoxy-6β-indolino-17-phenethyl-morphinan-3,14-diol methanesulfonate (compound 5 )

According to the method described in Example 4-2, using 103 mg of 4,5α-epoxy-6β-indolino-17-phenethyl-3-methoxy-morphinan-14-ol obtained in Example 5-1, 90 mg (90% yield) of the free form of the title compound 5 was obtained. This was obtained as the methanesulfonate salt to give the title compound 5 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.34-7.18 (5H, m), 7.05-6.96 (2H, m), 6.77 (1H, d, J = 8.2 Hz), 6.64-6.55 (2H, m), 6.25 (1H, d, J = 7.7 Hz) , 4.81 (1H, d, J = 8.2 Hz), 3.64-3.36 (3H, m), 3.09 (1H, d, J = 18.7 Hz), 3.05-2.99 (2H, m), 2.85-2.54 (7H, m ), 2.24-2.04 (3H, m), 1.65-1.44 (4H, m) (free body)
IR (cm ^-1 ) (KBr)
3376, 3025, 2926, 2831, 1736, 1605, 1489, 1455, 1398, 1325, 1242, 1187, 1152, 1125, 1036, 993, 941, 917, 854, 746, 700, 634, 583
Elemental analysis value Composition formula: C ₃₂ H ₃₄ N ₂ O ₃・ 1.94MeSO ₃ H ・ 0.40H ₂ O
Calculated values: C: 59.23, H: 6.23, N: 4.07, S: 9.26
Actual value: C: 59.14, H: 6.32, N: 4.05, S: 9.26
Mass (FAB): 495 (M ⁺ +1)

Example 6-1
Synthesis of 4,5α-epoxy-3-methoxy-17-methyl-6β-tetrahydroquinolino-morphinan-14-ol (compound 206 )

  According to the method described in Example 1-1, 325 mg (yield 75%) of the title compound was obtained using oxycodone instead of dihydrocodeinone.

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.98-6.89 (2H, m), 6.78 (1H, d, J = 8.2 Hz), 6.66 (1H, d, J = 8.2 Hz), 6.54-6.48 (2H, m), 4.78 (1H, d, J = 8.2 Hz), 3.84 (3H, s), 3.66 (1H, ddd, J = 12.6, 8.0, 4.1 Hz), 3.40-3.28 (2H, m), 3.16 (1H, d, J = 18.0 Hz), 2.82- 2.73 (3H, m), 2.60 (1H, dd, J = 18.0, 6.0 Hz), 2.44-2.39 (1H, m), 2.38 (3H, s), 2.33-2.10 (4H, m), 2.00-1.84 ( 3H, m), 1.66-1.60 (1H, m), 1.53-1.44 (1H, m)
IR (cm ^-1 ) (KBr)
3395, 3065, 3017, 2932, 2839, 1671, 1636, 1600, 1572, 1503, 1441, 1394, 1369, 1344, 1280, 1252, 1229, 1189, 1162, 1144, 1113, 1049, 1013, 976, 941, 910, 883, 851, 825, 802, 780, 762, 742, 689

Example 6-2
Synthesis of 4,5α-epoxy-17-methyl-6β-tetrahydroquinolino-morphinan-3,14-diol-tartrate (compound 6 )

According to the method described in Example 4-2, using 4,5α-epoxy-3-methoxy-17-methyl-6β-tetrahydroquinolino-morphinan-14-ol obtained in Example 6-1, 220 mg (yield 70%) of the free form of the title compound 6 was obtained. This was converted to the tartrate salt to give the title compound 6 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.99-6.91 (2H, m), 6.79 (1H, d, J = 8.2 Hz), 6.65 (1H, d, J = 8.2 Hz), 6.59-6.45 (2H, m), 4.78 (1H, d, J = 8.0 Hz), 3.73 (1H, ddd, J = 12.6, 8.0, 4.1 Hz), 3.38-3.27 (2H, m), 3.15 (1H, d, J = 18.0 Hz), 2.80-2.76 (3H, m), 2.60 (1H, dd, J = 18.0, 5.2 Hz), 2.44-2.40 (1H, m), 2.38 (3H, s), 2.29-2.11 (2H, m), 2.05-1.90 (2H, m), 2.16 ( 3H, s), 1.67-1.62 (1H, m), 1.52-1.41 (1H, m) (free body)
IR (cm ^-1 ) (KBr)
3200, 2929, 1736, 1638, 1601, 1572, 1499, 1458, 1372, 1341, 1307, 1241, 1189, 1161, 1125, 1110, 1061, 1034, 1016, 994, 979, 941
Elemental analysis value Composition formula: C ₂₆ H ₃₀ N ₂ O ₃・ 1.0 C ₄ H ₆ O ₆・ 1.0 H ₂ O
Calculated values: C: 61.42, H: 6.53, N: 4.78
Actual value: C: 61.41, H: 6.62, N: 4.74
Mass (EI): 418 (M ⁺ )

Example 7-1
Synthesis of 4- (4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6β-yl) -3,4-dihydro-1H-quinoxalino-2-one (compound 207 )

  According to the method described in Example 1-1, 3,4-dihydro-2-oxo-1H-quinoxaline was used instead of 1,2,3,4-tetrahydroquinoline, and oxycodone was used instead of dihydrocodeinone. Thus, 866 mg (yield 31%) of the title compound was obtained.

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.93-6.87 (1H, m), 6.78-6.67 (5H, m), 4.81 (1H, d, J = 8.0 Hz), 3.91 (2H, s), 3.82 (3H, s), 3.54-3.46 (1H, m), 3.16 (1H, d, J = 18.4 Hz), 2.79 (1H, d, J = 5.2 Hz), 2.61 (1H, dd, J = 18.4, 5.2 Hz), 2.38 (3H, s), 2.36- 2.10 (5H, m), 1.68-1.42 (3H, m)
IR (cm ^-1 ) (KBr)
3214, 2934, 1686, 1607, 1505, 1437, 1389, 1338, 1279, 1205, 1188, 1165, 1115, 1053, 1038, 1020, 981, 935, 909, 882, 851, 746, 687, 666

Example 7-2
Synthesis of 4- (4,5α-epoxy-3,14-dihydroxy-17-methyl-morphinan-6β-yl) -3,4-dihydro-1H-quinoxalino-2-one tartrate (compound 7 )

According to the method described in Example 1-2, 4- (4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6β-yl) -3 obtained in Example 7-1 , 4-Dihydro-1H-quinoxalino-2-one was used to give 158 mg (yield 19%) of the free form of the title compound 7 . This was converted to the tartrate salt to give the title compound 7 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.93-6.80 (3H, m), 6.75-6.70 (2H, m), 6.66 (1H, d, J = 8.2 Hz), 4.81 (1H, d, J = 8.0 Hz), 3.91 (1H, d, J = 12.2 Hz), 3.65 (1H, d, J = 12.2 Hz), 3.18-3.07 (2H, m), 2.72 (1H, d, J = 5.2 Hz), 2.51 (1H, dd, J = 18.4, 5.2 Hz) , 2.34 (3H, s), 2.36-2.10 (3H, m), 1.68-1.38 (5H, m) (free body)
Elemental analysis value Composition formula: C ₂₅ H ₂₇ N ₃ O ₄ · 1.02 C ₄ H ₆ O ₆ · 0.6 H ₂ O
Calculated values: C: 58.47, H: 5.79, N: 7.03
Actual value: C: 58.47, H: 5.63, N: 7.13
Mass (EI): 433 (M +)

Example 8-1
4- (4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6β-yl) -1-methyl-3,4-dihydro-1H-quinoxalino-2-one (compound 208 ) Composition

According to the method described in Example 1-1, 3,4-dihydro-1-methyl-2-oxo-1H-quinoxaline instead of 1,2,3,4-tetrahydroquinoline, and dihydrocodeinone Using oxycodone, the title compound (398 mg, yield 31%) was obtained.
Mass (ESI): 462 (M ⁺ +1)

Example 8-2
4- (4,5α-Epoxy-3,14-dihydroxy-17-methyl-morphinan-6β-yl) -1-methyl-3,4-dihydro-1H-quinoxalino-2-one tartrate (compound 8 ) Synthesis of

4- [4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6β-yl] -1 obtained in Example 8-1 according to the method described in Example 1-2 116 mg (yield 53%) of the free form of the title compound 8 was obtained using -methyl-3,4-dihydro-1H-quinoxalino-2-one. This was converted to the tartrate salt to give the title compound 8 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.01-6.93 (3H, m), 6.90-6.82 (1H, m), 6.72 (1H, d, J = 8.1 Hz), 6.58 (1H, d, J = 8.1 Hz), 5.26 (1H, s), 4.38 (1H, d, J = 8.1 Hz), 3.88 (1H, d, J = 15.9 Hz), 3.62 (1H, d, J = 15.9 Hz), 3.36 (3H, s), 3.14-3.00 (2H, m) , 2.73 (1H, d, J = 5.4 Hz), 2.53 (1H, dd, J = 18.9, 5.7 Hz), 2.40-2.28 (1H, m), 2.32 (3H, s), 2.20-2.02 (2H, m ), 1.74-1.56 (2H, m), 1.46-1.30 (2H, m) (free body)
Mass (ESI): 448 (M ⁺ +1)

Example 9-1
Synthesis of 4,5α-epoxy-6β- (3,4-dihydro-1-methyl-1H-quinoxalino) -3-methoxy-17-methyl-morphinan-14-ol (compound 209 )

4,5α-Epoxy-6β- (3,4-dihydro-1-methyl-2-oxo-1H-quinoxalino) -3-methoxy-17-methyl-morphinan-14-ol obtained in Example 8-1 144 mg (0.31 mmol) was dissolved in 10 mL of THF, 0.78 mL (1.56 mmol) of 2 N borane dimethyl sulfide THF solution was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, the temperature was raised to 50 ° C. and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 76 mg (yield 54%) of the title compound.
Mass (ESI): 448 (M ⁺ +1)

Example 9-2
Synthesis of 4,5α-epoxy-6β- (3,4-dihydro-1-methyl-1H-quinoxalino) -17-methyl-morphinan-3,14-diol tartrate (compound 9 )

4,5α-Epoxy-6β- (3,4-dihydro-1-methyl-1H-quinoxalino) -3-methoxy-17-methyl-morphinan-14-ol obtained in Example 9-2 42 mg (0.14 mmol) was dissolved in 5 mL of DMF, 0.06 ml (0.70 mmol) of n-propanethiol and 76 mg (0.67 mmol) of potassium t-butoxide were added and reacted at 120 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, 20 ml of saturated aqueous sodium hydrogen carbonate solution and 3 ml of aqueous ammonia were added to the reaction mixture, and the mixture was extracted with chloroform (50 ml × 3 times). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 25 mg (yield 34%) of the free form of the title compound 9 . This was converted to the tartrate salt to give the title compound 9 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.74 (1H, d, J = 8.1 Hz), 6.64-6.47 (4H, m), 6.44-6.36 (1H, m), 4.73 (1H, d, J = 7.6 Hz), 3.70-3.56 (1H, m) , 3.48-3.38 (2H, m), 3.31-3.20 (1H, m), 3.20-3.11 (1H, m), 3.09 (1H, d, J = 18.6 Hz), 2.82 (3H, s), 2.75 (1H , d, J = 3.0 Hz), 2.56 (1H, dd, J = 18.3, 5.4 Hz), 2.42-2.30 (1H, m), 2.33 (3H, s), 2.22-2.04 (3H, m), 1.66- 1.34 (4H, m) (free body)
Mass (ESI): 434 (M ⁺ +1)

Example 10-1
Synthesis of 4,5α-epoxy-6β- (1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepino) -3-methoxy-17-methyl-morphinan (compound 210 )

  According to the method described in Example 1-1, using 1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepine instead of 1,2,3,4-tetrahydroquinoline, the title Compound 34 mg (yield 24%) was obtained.

Example 10-2
Of 4,5α-epoxy-6β- (1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepino) -17-methyl-morphinan-3-ol methanesulfonate (compound 10 ) Composition

According to the method described in Example 1-2, 4,5α-epoxy-6β- (1,2,3,5-tetrahydro-benzo [e] [1,4] oxazepino obtained in Example 10-1 ) 33 mg (99% yield) of the free form of the title compound 10 was obtained using -3-methoxy-17-methyl-morphinan. This was converted to methanesulfonate to give the title compound 10 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
1.10-1.19 (1H, m), 1.51-1.62 (1H, m), 1.65-1.68 (2H, m), 1.83-1.96 (3H, m), 2.14-2.22 (2H, m), 2.31-2.34 (1H , m), 2.36 (3H, s), 2.38 (1H, dd, J = 4.7, 18.2 Hz), 3.08-3.12 (2H, m), 3.29-3.34 (2H, m), 3.75-3.89 (2H, m ), 4.49 (1H, d, J = 8.2 Hz), 4.57 (1H, d, J = 13.2 Hz), 4.65 (1H, d, J = 13.2 Hz), 6.59 (1H, d, J = 8.2 Hz), 6.67 (1H, d, J = 8.2 Hz), 6.78-6.87 (2H, m), 7.10-7.14 (2H, m) (free body)
Mass (ESI): 419 (M ⁺ +1)

Example 11
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide hydrochloride (compound 11 )

150 mg (0.44 mmol) of 6β-naltrexamine was dissolved in 7 mL of DMF, 71 mg (0.48 mmol) of phthalic anhydride and 0.92 mL (0.66 mmol) of triethylamine were added, and the mixture was stirred at 140 ° C. for 4 hours. The reaction solution was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 120 mg (11f: yield 58%) of the free form of the title compound 11 . This was converted to the hydrochloride salt to give the title compound 11 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.8-7.9 (2H, m), 7.7-7.8 (2H, m), 6.76 (1H, d, J = 7.9 Hz), 6.63 (1H, d, J = 8.2 Hz), 5.18 (1H, d, J = 8.5 Hz), 4.0-4.1 (1H, m), 3.11 (1H, d, J = 5.6 Hz), 3.05 (1H, d, J = 18.8 Hz), 2.6-2.9 (3H, m), 2.3-2.4 ( 3H, m), 2.15 (1H, dt, J = 12.0, 3.5 Hz), 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)
IR (cm ^-1 ) (KBr)
3320, 1769, 1708, 1626, 1504, 1466, 1428, 1379, 1323, 1271, 1240, 1190, 1173, 1075
Elemental analysis value Composition formula: C ₂₈ H ₂₈ N ₂ O ₅・ 1.0 HCl ・ 1.0 H ₂ O
Calculated value: C: 63.81, H: 5.93, N: 5.32, Cl: 6.73
Actual value: C: 63.72, H: 6.03, N: 5.40, Cl: 6.49
Mass (EI): 472 (M ⁺ )

Example 12
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-methylphthalimide hydrochloride (compound 12 )

According to the method described in Example 11, 4-methylphthalic anhydride was used in place of phthalic anhydride to obtain 219 mg (yield 77%) of the free form of title compound 12 . This was converted to the hydrochloride salt to give the title compound 12 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.67 (1H, d, J = 7.7 Hz), 7.61 (1H, s), 7.46 (1H, d, J = 7.7 Hz), 6.76 (1H, d, J = 7.9 Hz), 6.62 (1H, d, J = 7.9 Hz), 5.17 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H, m), 3.10 (1H, d, J = 5.8 Hz), 3.04 (1H, d, J = 18.4 Hz), 2.60-2.85 (3H, m), 2.49 (3H, s), 2.35-2.4 (3H, m), 2.13 (1H, dt, J = 12.0, 3.5 Hz), 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)
IR (cm ^-1 ) (KBr)
3401, 1769, 1707, 1618, 1504, 1464, 1429, 1376, 1324, 1240, 1188, 1100, 1074, 1032
Elemental analysis value Composition formula: C ₂₉ H ₃₀ N ₂ O ₅ · 1.0 HCl · 0.9 H ₂ O
Calculated values: C: 64.59, H: 6.13, N: 5.19, Cl: 6.57
Actual value: C: 64.88, H: 6.21, N: 5.28, Cl: 6.25
Mass (EI): 486 (M ⁺ )

Example 13
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide / tartrate (compound 13 )

According to the method described in Example 11, using 6β-naloxamine instead of 6β-naltrexamine, 24 mg (yield 34%) of the title compound 13 was obtained. This was converted to the tartrate salt to give the title compound 13 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.75-7.8 (2H, m), 7.6-7.7 (2H, m), 6.72 (1H, d, J = 8.2 Hz), 6.59 (1H, d, J = 8.2 Hz), 5.7-5.8 (1H, m) , 5.1-5.2 (3H, m), 4.0-4.05 (1H, m), 3.0-3.1 (3H, m), 2.45-2.9 (5H, m), 2.0-2.3 (2H, m), 1.6-1.7 ( 1H, m), 1.4-1.5 (2H, m) (free body)
Mass (ESI): 459 (M ⁺ +1)

Example 14
Synthesis of N- (4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide tartrate (compound 14 )

N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide 300 mg (0.65 mmol) prepared by the method described in Example 13 was added to 8 mL of acetonitrile, 1,2 -Dissolved in a mixed solution of 4 mL of dichloroethane and 2 mL of water, added (Ph ₃ P) ₃ RhCl 120 mg (0.13 mmol), and heated to reflux at 100 ° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 120 mg (44% yield) of the free form of the title compound 14 . This was converted to the tartrate salt to give the title compound 14 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.8-7.9 (2H, m), 7.7-7.8 (2H, m), 6.73 (1H, d, J = 8.2 Hz), 6.60 (1H, d, J = 8.2 Hz), 5.06 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H, m), 2.9-3.1 (3H, m), 2.2-2.7 (6H, m), 1.4-1.65 (4H, m) (free body)
Mass (ESI): 419 (M ⁺ +1)

Example 15
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-chlorophthalimide tartrate (compound 15 )

According to the method described in Example 11, 4-chlorophthalic anhydride was used in place of phthalic anhydride to obtain 91 mg (yield 77%) of the free form of title compound 15 . This was converted to the tartrate salt to give the title compound 15 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.75-7.8 (2H, m), 7.65-7.7 (1H, m), 6.76 (1H, d, J = 8.2 Hz), 6.62 (1H, d, J = 8.2 Hz), 5.14 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H, m), 3.11 (1H, d, J = 5.6 Hz), 3.05 (1H, d, J = 18.8 Hz), 2.6-2.8 (3H, m), 2.3-2.4 ( 3H, m), 2.14 (1H, dt, J = 12.0, 3.5 Hz), 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 (ESI): 507 (M ⁺ +1)

Example 16
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-fluorophthalimide tartrate (compound 16 )

According to the method described in Example 11, 4-fluorophthalic anhydride was used instead of phthalic anhydride to obtain 80 mg (yield 70%) of the free form of the title compound 16 . This was converted to the tartrate salt to give the title compound 16 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.75-7.85 (1H, m), 7.47 (1H, m), 7.3-7.4 (1H, m), 6.72 (1H, d, J = 7.9 Hz), 6.58 (1H, d, J = 8.2 Hz), 5.10 (1H, d, J = 8.2 Hz), 3.95-4.05 (1H, m), 3.07 (1H, d, J = 5.9 Hz), 3.02 (1H, d, J = 18.8 Hz), 2.55-2.8 (3H, m), 2.35-2.4 (3H, m), 2.10 (1H, dt, J = 12.0, 3.5 Hz), 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 (ESI): 491 (M ⁺ +1)

Example 17
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-fluorophthalimide tartrate (compound 17 )

According to the method described in Example 11, using 3-fluorophthalic anhydride instead of phthalic anhydride, 123 mg (yield 57%) of the free form of the title compound 17 was obtained. This was converted to the tartrate salt to give the title compound 17 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.65-7.75 (2H, m), 7.35-7.4 (1H, m), 6.76 (1H, d, J = 7.9 Hz), 6.62 (1H, d, J = 8.2 Hz), 5.15 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H, m), 3.11 (1H, d, J = 5.8 Hz), 3.05 (1H, d, J = 18.5 Hz), 2.60-2.85 (3H, m), 2.35-2.4 ( 3H, m), 2.13 (1H, dt, J = 12.0, 3.5 Hz), 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 (ESI): 491 (M ⁺ +1)

Example 18
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-methylphthalimide tartrate (compound 18 )

According to the method described in Example 11, 108 mg (yield 51%) of the free form of the title compound 18 was obtained using 3-methylphthalic anhydride instead of phthalic anhydride. This was converted to the tartrate salt to give the title compound 18 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.67 (1H, d, J = 7.3 Hz), 7.56 (1H, t, J = 7.3 Hz), 7.45 (1H, d, J = 7.3 Hz), 6.75 (1H, d, J = 8.2 Hz), 6.62 ( 1H, d, J = 7.9 Hz), 5.18 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H, m), 3.11 (1H, d, J = 5.6 Hz), 3.05 (1H, d, J = 18.5 Hz), 2.60-2.85 (3H, m), 2.69 (3H, s), 2.35-2.4 (3H, m), 2.14 (1H, dt, J = 12.0, 3.5 Hz), 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 (ESI): 487 (M ⁺ +1)

Example 19
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -naphthalenedicarboxylic acid imide hydrochloride (compound 19 )

According to the method described in Example 11, naphthalenedicarboxylic anhydride was used in place of phthalic anhydride to obtain 263 mg of free form of title compound 19 (yield 86%). This was converted to the hydrochloride salt to give the title compound 19 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
8.17 (2H, s), 7.95-8.00 (2H, m), 7.68-7.72 (2H, m), 6.78 (1H, d, J = 8.0 Hz), 6.63 (1H, d, J = 8.3 Hz), 5.28 (1H, d, J = 8.2 Hz), 4.1-4.2 (1H, m), 3.12 (1H, d, J = 5.8 Hz), 3.06 (1H, d, J = 18.4 Hz), 2.60-2.85 (3H, m), 2.35-2.4 (3H, m), 2.15 (1H, dt, J = 12.0, 3.5 Hz), 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)
IR (cm ^-1 ) (KBr)
3320, 1762, 1699, 1638, 1504, 1448, 1426, 1371, 1240, 1151, 1113, 1056, 1031, 1011
Elemental analysis value Composition formula: C ₃₂ H ₃₀ N ₂ O ₅ · 1.0 HCl · 0.6 H ₂ O
Calculated value: C: 67.45, H: 5.70, N: 4.92, Cl: 6.22
Actual value: C: 67.25, H: 5.92, N: 5.05, Cl: 6.42
Mass (EI): 522 (M ⁺ )

Example 20
Synthesis of N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -succinimide (compound 220 )

6β-Naltrexamine 300 mg (0.88 mmol) was dissolved in chloroform 10 mL, succinic anhydride 92 mg (0.92 mmmol) was added, and the mixture was stirred at room temperature for 2 hours. Then, after adding acetic anhydride 305 mg (2.82 mmol) and triethylamine 286 mg (2.82 mmol) to the reaction liquid, it heated and refluxed for 15 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 258 mg (yield 63%) of the title compound.
Mass (EI): 466 (M ⁺ )

Example 20-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -succinimide / tartrate (compound 20 )

N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -succinimide 221 mg (0.47 mmol) obtained in Example 20-1 was methanolized. Dissolved in 10 mL, 1 mL of 28% aqueous ammonia solution was added at 0 ° C. and stirred for 1 hour. Thereafter, chloroform was added to the reaction mixture for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 190 mg (yield 95%) of the free form of the title compound 20 . This was converted to the tartrate salt to give the title compound 20 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.72 (1H, d, J = 8.2 Hz), 6.59 (1H, d, J = 8.2 Hz), 5.16 (1H, d, J = 8.2 Hz), 3.9-4.0 (1H, m), 3.07 (1H, d , J = 5.8 Hz), 3.02 (1H, d, J = 18.7 Hz), 2.55-2.85 (6H, m), 2.25-2.40 (4H, m), 2.11 (1H, dt, J = 12.0, 3.5 Hz) , 1.6-1.7 (1H, m), 1.3-1.5 (3H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
IR (cm ^-1 ) (KBr)
3322, 1772, 1697, 1603, 1502, 1459, 1385, 1328, 1198, 1175, 1128, 1066, 1036, 1005
Elemental analysis composition formula: C ₂₄ H ₂₈ N ₂ O ₅・ 0.5 C ₄ H ₆ O ₆・ 1.6 H ₂ O
Calculated value: C: 59.10, H: 6.52, N: 5.30
Actual value: C: 59.03, H: 6.54, N: 5.29
Mass (EI): 424 (M ⁺ )

Example 21-1
Synthesis of N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -maleimide (compound 121 )

The title compound (200 mg, yield 75%) was obtained using maleic anhydride instead of succinic anhydride according to the method described in Example 20-1.
Mass (EI): 464 (M ⁺ )

Example 21-2
Synthesis of N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2-benzylidene-succinimide (Compound 221 )

N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -maleimide 200 mg (0.43 mmol) obtained in Example 21-1 was added to THF 5 mL. After adding nitromethylbenzene 85 mg (0.62 mmol) and DBU 66 mg (0.43 mmol), the mixture was stirred at room temperature for 1 hour. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 196 mg (yield 82%) of the title compound.
Mass (EI): 554 (M ⁺ )

Example 21-3
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2-benzylidene-succinimide / tartrate (compound 21 )

N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2-benzylidene-succinimide obtained in Example 21-2 195 mg (0.35 mmol) was dissolved in 10 mL of methanol, and 1 mL of 28% aqueous ammonia solution was added at 0 ° C. and stirred for 1 hour. Thereafter, chloroform was added to the reaction mixture for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 170 mg (yield 95%) of the free form of the title compound 21 . This was converted to the tartrate salt to give the title compound 21 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.40-7.45 (6H, m), 6.75 (1H, d, J = 8.0 Hz), 6.60 (1H, d, J = 8.2 Hz), 5.26 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H , m), 3.57 (2H, s), 3.08 (1H, d, J = 5.5 Hz), 3.03 (1H, d, J = 18.7 Hz), 2.55-2.80 (3H, m), 2.2-2.4 (3H, m), 2.10 (1H, dt, J = 12.0, 3.5 Hz), 1.6-1.7 (1H, m), 1.3-1.5 (3H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
IR (cm ^-1 ) (KBr)
3319, 1762, 1700, 1654, 1503, 1450, 1378, 1308, 1265, 1218, 1194, 1174, 1134, 1068
Mass (EI): 512 (M ⁺ )

Example 22-1
Synthesis of N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2-ethylidene-succinimide (compound 222 )

According to the method described in Example 21-2, nitroethane was used in place of nitromethylbenzene to obtain 192 mg (yield 45%) of the title compound.
Mass (EI): 492 (M ⁺ )

Example 22-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2-ethylidene-succinimide / tartrate (compound 22 )

N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) obtained in Example 22-1 according to the method described in Example 21-3 146 mg (yield 95%) of the free form of the title compound 22 was obtained using 160 mg of -2-ethylidene-succinimide. This gave the title compound 22 as the tartrate salt.

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.80-6.85 (1H, m), 6.74 (1H, d, J = 8.1 Hz), 6.60 (1H, d, J = 8.1 Hz), 5.18 (1H, d, J = 8.2 Hz), 3.98-4.03 (1H , m), 3.24 (2H, s), 3.08 (1H, d, J = 5.5 Hz), 3.03 (1H, d, J = 18.3 Hz), 2.55-2.80 (3H, m), 2.25-2.40 (3H, m), 2.12 (1H, dt, J = 12.0, 3.5 Hz), 1.87 (3H, d, J = 7.0 Hz), 1.6-1.7 (1H, m), 1.3-1.5 (3H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
IR (cm ^-1 ) (KBr)
3315, 1762, 1702, 1676, 1609, 1503, 1378, 1309, 1265, 1206, 1152, 1128, 1067, 1033
Mass (EI): 450 (M ⁺ )

Example 23-1
Synthesis of N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2-cyclohexylmethylidene-succinimide (compound 223 )

According to the method described in Example 21-2, using nitromethylcyclohexane instead of nitromethylbenzene, 120 mg (yield 50%) of the title compound was obtained.
Mass (EI): 560 (M ⁺ )

Example 23-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2-cyclohexylmethylidene-succinimide / tartrate (compound 23 )

N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) obtained in Example 23-1 according to the method described in Example 21-3 By using 120 mg of -2-cyclohexylmethylidene-succinimide, 107 mg (yield 96%) of the free form of the title compound 23 was obtained. This was converted to the tartrate salt to give the title compound 23 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.71 (1H, d, J = 8.2 Hz), 6.60-6.65 (1H, m), 6.58 (1H, d, J = 8.2 Hz), 5.16 (1H, d, J = 8.2 Hz), 3.95-4.05 (1H , m), 3.23 (2H, d, J = 1.9 Hz), 3.07 (1H, d, J = 5.8 Hz), 3.02 (1H, d, J = 18.7 Hz), 2.55-2.80 (3H, m), 2.25 -2.40 (3H, m), 2.05-2.20 (2H, m), 1.6-1.8 (6H, m), 1.1-1.5 (8H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
IR (cm ^-1 ) (KBr)
3319, 2927, 1763, 1701, 1671, 1617, 1507, 1377, 1309, 1266, 1197, 1132, 1067, 1032
Mass (EI): 518 (M ⁺ )

Example 24-1
Synthesis of N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2-butylidene-succinimide (compound 224 )

According to the method described in Example 21-2, using nitrobutane instead of nitromethylbenzene, 535 mg (yield 96%) of the title compound was obtained.
Mass (EI): 520 (M ⁺ )

Example 24-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2-butylidene-succinimide / tartrate (compound 24 )

N- (3-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) obtained in Example 24-1 according to the method described in Example 21-3 By using 535 mg of 2-butylidene-succinimide, 286 mg (yield 58%) of the free form of the title compound 24 was obtained. This was converted to the tartrate salt to give the title compound 24 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.77-6.85 (1H, m), 6.73 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 8.2 Hz), 5.16 (1H, d, J = 8.2 Hz), 3.95-4.05 (1H , m), 3.22 (2H, s), 3.08 (1H, d, J = 5.8 Hz), 3.03 (1H, d, J = 18.7 Hz), 2.55-2.80 (3H, m), 2.25-2.40 (3H, m), 2.05-2.20 (3H, m), 1.3-1.7 (6H, m), 0.96 (3H, t, J = 7.4 Hz), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m) , 0.1-0.2 (2H, m) (free body)
Mass (EI): 478 (M ⁺ )

Example 25
2- (17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-hydroxy-2,3-dihydro-isoindol-1-one (diastereomeric mixture)・ Synthesis of tartrate (compound 25 )

N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide 156 mg (0.33 mmol) prepared by the method described in Example 11 was added to 5 mL of methanol, chloroform It was made to melt | dissolve in a 5 mL mixed solution, 61 mg (1.61 mmol) of sodium borohydride was added at 0 degreeC, and it stirred for 2 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 130 mg (yield 83%) of the free form of the title compound 25 . This was converted to the tartrate salt to give the title compound 25 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.35-7.65 (4H, m), 6.68 (0.5H, d, J = 8.2 Hz), 6.63 (0.5H, d, J = 8.2 Hz), 6.56 (0.5H, d, J = 8.2 Hz), 6.51 ( 0.5H, d, J = 8.2 Hz), 6.07 (1.5H, s), 5.81 (1.5H, s), 5.39 (0.5H, d, J = 8.2 Hz), 5.22 (0.5H, d, J = 8.0 Hz), 4.70 (1H, dd, J = 6.0, 3.3 Hz), 4.0-4.1 (0.5H, m), 3.6-3.7 (0.5H, m), 2.95-3.05 (2H, m), 2.4-2.7 ( 3H, m), 2.2-2.4 (2H, m), 2.0-2.1 (2H, m), 1.6-1.7 (1H, m), 1.2-1.6 (3H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
Mass (EI): 474 (M ⁺ )

Example 26-1 (27-1)
2- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -3-hydroxy-2,3-dihydro-isoindol-1-one (diastereo Synthesis of compound 126 )

  2.00 g (4.23 mmol) of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide prepared by the method described in Example 11 was dissolved in 20 mL of DMF. After adding potassium carbonate 1.76 g (12.7 mmol) and benzyl bromide 0.5 mL (4.70 mmol), the mixture was stirred at room temperature for 18 hours. Thereafter, 40 mL of water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product.

Next, the obtained crude product was dissolved in a mixed solution of 30 mL of methanol and 10 mL of chloroform, and 161 mg (4.26 mmol) of sodium borohydride was added at 0 ° C. and stirred for 2 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 1.90 g (2 steps yield 80%) of the title compound.
Mass (EI): 564 (M ⁺ )

Examples 26-2, 27-2
2- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2,3-dihydro-3-methoxycarbonylmethyl-isoindol-1-one ( Synthesis of compounds 226 and 227 )

2- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -3-hydroxy-2,3-dihydro- obtained in Example 26-1 Isoindole-1-one 200 mg (0.35 mmol) was dissolved in toluene 10 mL, (carbomethoxymethylene) triphenylphosphorane 147 mg (0.43 mmol) was added, and the mixture was heated to reflux for 15 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain the title compound as a low-polar component 33 mg and a high-polar component 38 mg (15 and 17% yields, respectively).
Low polarity component: Mass (EI): 620 (M ⁺ )
High polarity component: Mass (EI): 620 (M ⁺ )

Examples 26-3, 27-3
2- (17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3-dihydro-3-methoxycarbonylmethyl-isoindol-1-one tartrate ( Synthesis of compounds 26 and 27 )

2- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2,3-dihydro-3-methoxycarbonyl obtained in Example 26-2 After dissolving 33 mg (0.05 mmol) of the low-polarity component of methyl-isoindol-1-one in 4 mL of methanol and adding 19 mg of Pd / C, the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. Thereafter, the reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 15 mg (yield 54%) of the free form of the title compound 26 . This was converted to the tartrate salt to give the title compound 26 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.84 (1H, d, J = 6.8 Hz), 7.53 (1H, d, J = 7.4 Hz), 7.46 (1H, t, J = 6.8 Hz), 7.36 (1H, d, J = 7.4 Hz), 6.75 ( 1H, d, J = 8.2 Hz), 6.60 (1H, d, J = 8.0 Hz), 5.43 (1H, d, J = 8.0 Hz), 4.70 (1H, dd, J = 6.0, 3.3 Hz), 3.57 ( 3H, s), 3.2-3.3 (1H, m), 3.05-3.15 (2H, m), 3.03 (1H, d, J = 18.8 Hz), 2.8-2.9 (2H, m), 2.63 (2H, dt, J = 18.6, 5.5 Hz), 2.3-2.4 (3H, m), 2.11 (1H, dt, J = 12.0, 3.5 Hz), 1.6-1.7 (1H, m), 1.4-1.5 (3H, m), 0.8 -0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
Mass (EI): 530 (M ⁺ )

On the other hand, 2- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -2,3-dihydro-3- obtained in Example 27-2 38 mg (0.06 mmol) of the highly polar component of methoxycarbonylmethyl-isoindol-1-one was dissolved in 4 mL of methanol, 20 mg of Pd / C was added, and the mixture was stirred at room temperature for 20 hours in a hydrogen atmosphere. Thereafter, the reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 17 mg (53% yield) of the free form of the title compound 27 . This was converted to the tartrate salt to give the title compound 27 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.83 (1H, d, J = 6.6 Hz), 7.4-7.5 (2H, m), 7.35 (1H, d, J = 7.4 Hz), 6.78 (1H, d, J = 8.2 Hz), 6.60 (1H, d , J = 8.0 Hz), 5.12 (1H, d, J = 8.0 Hz), 5.05 (1H, dd, J = 7.3, 5.5 Hz), 3.61 (3H, s), 3.4-3.5 (1H, m), 3.09 (1H, d, J = 5.5 Hz), 3.04 (1H, d, J = 18.7 Hz), 2.8-2.9 (2H, m), 2.5-2.7 (3H, m), 2.2-2.4 (3H, m), 2.11 (1H, dt, J = 12.0, 3.5 Hz), 1.6-1.7 (1H, m), 1.4-1.5 (3H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body)
Mass (EI): 530 (M ⁺ )

Example 28
Synthesis of 2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3-dihydro-isoindol-1-one tartrate (compound 28 )

2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-hydroxy-2,3-dihydro-isoindole-1 prepared by the method of Example 25 -On (diastereomeric mixture) 150 mg (0.32 mmol) is dissolved in a mixed solution of 7 mL of methylene chloride and 25 mL of chloroform, and boron trifluoride ether complex 0.22 mL (1.73 mmol), triethylsilane 0.28 mL (1.73 mmol) ) Was added at 0 ° C. and stirred for 22 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 55 mg (yield 38%) of the free form of the title compound 28 . This was converted to the tartrate salt to give the title compound 28 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.85 (d, J = 8.2 Hz, 1H), 7.58-7.45 (m, 3H), 6.79 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 4.68 (d, J = 8.2 Hz, 1H), 4.52 (d, J = 16.8 Hz, 1H), 4.44 (d, J = 16.8 Hz, 1H), 4.27 (ddd, J = 12.6, 8.2, 4.4 Hz, 1H), 3.11 (d , J = 5.5 Hz, 1H), 3.06 (d, J = 18.4 Hz, 1H), 2.70-2.59 (m, 2H), 2.39 (d, J = 6.6 Hz, 2H), 2.31-2.12 (m, 3H) , 1.72-1.49 (m, 4H), 0.93-0.79 (m, 1H), 0.58-0.50 (m, 2H), 0.17-0.11 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
3075, 3004, 2925, 2818, 1658, 1622, 1498, 1455, 1377, 1330, 1307, 1279, 1228, 1188, 1153, 1117, 1069, 1051, 1034, 981, 943, 919, 884, 859, 740
Mass (EI): 458 (M ⁺ )

Example 29
Synthesis of 1- (4,5α-epoxy-3,14-dihydroxy-17-methyl-morphinan-6β-yl) -pyrrolidine- (2S) -carboxylic acid diethylamide / tartrate (compound 29 )

Dissolve 300 mg (1.00 mmol) of oxymorphone and 244 mg (2.00 mmol) of benzoic acid in 15 ml of toluene, add 200 mg (1.17 mmol) of (S) -proline diethylamide, and then add water in a 145 ° C oil bath. Was refluxed for 12 hours while removing azeotropically. The reaction solution was allowed to cool to room temperature, 10 mL of a methanol solution of 188 mg (3.00 mmol) of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 202 mg (yield 44%) of the free form of the title compound 29 . This was converted to the tartrate salt to give the title compound 29 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.69 (1H, d, J = 8.2 Hz), 6.52 (1H, d, J = 8.2 Hz), 4.52 (1H, d, J = 8.0 Hz), 3.15-3.60 (6H, m), 3.09 (1H, d , J = 18.4 Hz), 2.6-2.7 (2H, m), 2.51 (1H, dd, J = 18.2, 5.9 Hz), 2.3-2.4 (2H, m), 2.34 (3H, s), 2.1-2.2 ( 2H, m), 1.7-2.0 (5H, m), 1.4-1.55 (3H, m), 1.1-1.3 (1H, m), 1.07 (3H, t, J = 7.0 Hz), 1.01 (3H, t, J = 7.0 Hz) (free body)
Mass (ESI): 456 (M ⁺ +1)

Example 30-1
Synthesis of 1- (4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6β-yl) -pyrrolidine- (2R) -carboxylic acid diethylamide (compound 230 )

According to the method described in Example 1-1, using oxycodone instead of dihydrocodeinone and (R) -proline diethylamide instead of 1,2,3,4-tetrahydroquinoline, the title compound 62 mg 26%).
Mass (ESI): 470 (M ⁺ +1)

Example 30-2
Synthesis of 1- (4,5α-epoxy-3,14-dihydroxy-17-methyl-morphinan-6β-yl) -pyrrolidine- (2R) -carboxylic acid diethylamide / tartrate (compound 30 )

In accordance with the method described in Example 1-2, 1-) 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-morphinan-6β-yl) -pyrrolidine obtained in Example 30-1 42 mg (yield 71%) of the free form of the title compound 30 was obtained using-(2R) -carboxylic acid diethylamide. This was converted to the tartrate salt to give the title compound 30 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.70 (1H, d, J = 8.2 Hz), 6.53 (1H, d, J = 7.9 Hz), 4.66 (1H, d, J = 7.9 Hz), 4.12 (1H, t, J = 8.2 Hz), 3.7- 3.8 (1H, m), 3.4-3.7 (2H, m), 3.10 (1H, d, J = 18.4 Hz), 3.0-3.1 (2H, m), 2.6-2.8 (3H, m), 2.53 (1H, dd, J = 18.4, 5.5 Hz), 2.4 (1H, m), 2.36 (3H, s), 2.1-2.2 (2H, m), 1.7-2.0 (5H, m), 1.45-1.65 (3H, m) , 1.3-1.4 (1H, m), 1.10 (3H, t, J = 7.0 Hz), 0.98 (3H, t, J = 7.0 Hz) (free body)
Mass (ESI): 456 (M ⁺ +1)

Examples 31, 32
1- (4,5α-epoxy-3-hydroxy-17-methyl-morphinan-6α-yl) -pyrrolidine- (2S) -carboxylic acid diethylamide tartrate (compound 31 ) and 1- (4,5α-epoxy Synthesis of 3-hydroxy-17-methyl-morphinan-6β-yl) -pyrrolidine- (2S) -carboxylic acid diethylamide tartrate (compound 32 )

  3-Benzyloxycarbonyloxy-4,5α-epoxy-17-methyl-6-oxo-morphinane 188 mg (0.45 mmol), benzoic acid 88 mg (0.72 mmol) were dissolved in toluene 20 ml, and (S)- After adding 115 mg (0.68 mmol) of proline diethylamide, the mixture was heated to reflux for 12 hours while removing water azeotropically in an oil bath at 145 ° C. The reaction solution was allowed to cool to room temperature, 10 mL of a methanol solution of sodium cyanoborohydride 99 mg (1.58 mmol) was added, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1- (3-benzyloxycarbonyloxy-4,5α-epoxy-17-methyl-morphinane as a crude product. -6-yl) -pyrrolidine- (2S) -carboxylic acid diethylamide (mixture of diastereomers) was obtained.

The crude product was dissolved in 10 mL of ethyl acetate, 15 mg of Pd / C was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 13 mg (2 steps yield, 6.6%) of the free form of the title compound 31 , and 9 mg (2 steps yield, 4.6%) of the free form of the title compound 32. Obtained. This was obtained as the tartrate salt to give the title compounds 31 and 32 , respectively.

Compound 31
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.74 (1H, d, J = 7.9 Hz), 6.53 (1H, d, J = 8.2 Hz), 4.58 (1H, dd, J = 13.0, 1.6 Hz), 3.7-3.8 (1H, m), 3.2-3.6 (5H, m), 3.0-3.1 (1H, m), 2.94 (1H, d, J = 18.5 Hz), 2.7-2.8 (2H, m), 2.4-2.5 (1H, m), 2.38 (3H, s ), 2.1-2.3 (4H, m), 1.7-1.9 (4H, m), 1.5-1.7 (2H, m), 1.2-1.3 (1H, m), 1.20 (3H, t, J = 7.0 Hz), 1.09 (3H, t, J = 7.0 Hz), 0.8-1.0 (2H, m) (free body)
Mass (ESI): 440 (M ⁺ +1)

Compound 32
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.69 (1H, d, J = 7.9 Hz), 6.53 (1H, d, J = 8.2 Hz), 4.45 (1H, d, J = 8.2 Hz), 3.55-3.65 (1H, m), 3.2-3.5 (5H , m), 3.05-3.10 (1H, m), 2.97 (1H, d, J = 18.5 Hz), 2.5-2.6 (2H, m), 2.1-2.5 (5H, m), 2.41 (3H, s), 1.9-2.1 (2H, m), 1.7-1.9 (2H, m), 1.5-1.7 (2H, m), 1.2-1.3 (2H, m), 1.09 (3H, t, J = 7.0 Hz), 1.02 ( 3H, t, J = 7.0 Hz), 0.8-0.9 (1H, m) (free body)
Mass (ESI): 440 (M ⁺ +1)

Example 33-1
Synthesis of 1- (4,5α-epoxy-14-hydroxy-17-methyl-3-methoxy-morphinan-6β-yl) -piperidine-3-carboxylic acid diethylamide (mixture of diastereomers) (compound 233 )

According to the method described in Example 1-1, using oxycodone instead of dihydrocodeinone and pipecolic acid diethylamide instead of 1,2,3,4-tetrahydroquinoline, the title compound 96 mg (yield 12% )
Mass (ESI): 484 (M ⁺ +1)

Example 33-2
Synthesis of 1- (4,5α-epoxy-3,14-dihydroxy-17-methyl-3-morphinan-6β-yl) -piperidine-3-carboxylic acid diethylamide (mixture of diastereomers) and tartrate (compound 33 )

1- (4,5α-Epoxy-14-hydroxy-17-methyl-3-methoxy-morphinan-6β-yl) -piperidine obtained in Example 33-1 according to the method described in Example 1-2. Using 3-carboxylic acid diethylamide (diastereomer mixture), 66 mg (yield 74%) of the free form of the title compound 33 was obtained. This was converted to the tartrate salt to give the title compound 33 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.70 (1H, d, J = 7.9 Hz), 6.56 (1H, d, J = 7.9 Hz), 4.70 (0.5H, d, J = 7.9 Hz), 4.63 (0.5H, d, J = 7.9 Hz), 3.2-3.4 (4H, m), 3.09 (1H, d, J = 18.5 Hz), 2.8-3.0 (3H, m), 2.60-2.75 (2H, m), 2.3-2.5 (4H, m), 2.35 ( 3H, s), 2.1-2.2 (2H, m), 1.7-2.0 (3H, m), 1.2-1.7 (6H, m), 1.18 (1.5H, t, J = 7.0 Hz), 1.17 (1.5H, t, J = 7.0 Hz), 1.10 (1.5H, t, J = 7.0 Hz), 1.08 (1.5H, t, J = 7.0 Hz) (free body)
Mass (ESI): 470 (M ⁺ +1)

Example 34
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -pyrrolidin-2-one hydrochloride (compound 34 )

  0.445 g (1.96 mmol) of platinum oxide was dissolved in 100 mL of methanol and stirred at room temperature for 2 hours under a hydrogen atmosphere. Thereafter, 150 mL of methanol containing 10.0 g (26.5 mmol) of naltrexone hydrochloride and 17.8 g (105.9 mmol) of ethyl 4-aminobutyrate was added to the reaction solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was filtered through celite, and the filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and 17-cyclopropylmethyl-4,5α-epoxy-6α- [4- (ethoxycarbonyl) butylamino] -morphinan-3,14-diol 5.46 g (Yield 45%) was obtained.

4.46 g (9.77 mmol) of this purified product was dissolved in 30 mL of toluene and heated to reflux for 72 hours. After allowing the reaction solution to cool to room temperature, the reaction solution was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 1.78 g (yield 44%) of the free form of the title compound 34 . This was converted to the hydrochloride salt to give the title compound 34 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.73 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.82 (d, J = 3.8 Hz, 1H), 4.67 (dt, J = 13.5, 3.8 Hz, 1H), 3.68 (td, J = 9.3, 5.8 Hz, 1H), 3.35 (td, J = 9.3, 5.5 Hz, 1H), 3.10 (d, J = 6.9 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H ), 2.66-1.70 (m, 11H), 1.57-1.24 (m, 4H), 0.90-0.75 (m, 1H), 0.56-0.50 (m, 2H), 0.16-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2959, 2823, 1655, 1499, 1463, 1310, 1160, 1116, 1070, 1040, 978, 951, 859, 802, 759
Mass (EI): 410 (M ⁺ )

Example 35
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3-benzyl-pyrrolidin-2-one (diastereomeric mixture) / tartrate (compound 35 ) Synthesis of

269 mg (0.65 mmol) of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -pyrrolidin-2-one prepared by the method described in Example 34 was added to THF. It melt | dissolved in 10 mL, 0.36 N LDA / THF solution 6.0 mL (2.16 mmol) was added at 0 degreeC, and it stirred for 30 minutes. Thereafter, 0.23 mL (1.96 mmol) of benzyl bromide was added and stirred for 100 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 49 mg (yield 15%) of the free form of the title compound 35 . This was converted to the tartrate salt to give the title compound 35 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.33-7.18 (m, 5H), 6.72 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.79 (d, J = 4.1 Hz, 1H), 4.67 (dt, J = 13.2, 4.1 Hz, 1H), 3.50-3.38 (m, 1H), 3.28 (q, J = 9.2 Hz, 1H), 3.21-3.10 (m, 2H), 3.03 (d, J = 18.7 Hz, 1H) , 2.75-2.55 (m, 4H), 2.42-2.18 (m, 4H), 2.05-1.93 (m, 1H), 1.87-1.68 (m, 2H), 1.58-1.22 (m. 4H), 0.93-0.77 ( m, 1H), 0.58-0.50 (m, 2H), 0.15-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2936, 2858, 1648, 1619, 1498, 1459, 1438, 1321, 1276, 1173, 1119, 1071, 1031, 918, 801, 748, 702
Mass (EI): 500 (M ⁺ )

Example 36-1
Synthesis of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -pyrrolidin-2-one (compound 136 )

  219 mg (0.53 mmol) of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -pyrrolidin-2-one prepared by the method described in Example 34 was added to DMF. It was made to melt | dissolve in 5 mL, potassium carbonate 738 mg (5.34 mmol) and benzyl bromide 0.19 mL (1.60 mmol) were added, and it stirred at room temperature for 96 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 265 mg (yield 99%) of the title compound.

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.43-7.29 (m, 5H), 6.77 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.18 (d, J = 11.8 Hz, 1H), 5.09 (d, J = 11.8 Hz, 1H), 4.79 (d, J = 3.8 Hz, 1H), 4.70 (dt, J = 13.4, 3.8 Hz, 1H), 3.76 (td, J = 8.2, 5.8 Hz, 1H), 3.28 (td , J = 8.5, 5.8 Hz, 1H), 3.10 (d, J = 6.9 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H), 2.67-1.20 (m, 15H), 0.87-0.81 (m, 1H), 0.56-0.49 (m, 2H), 0.13-0.08 (m, 2H).
IR (cm ^-1 ) (KBr)
2955, 2927, 2868, 1681, 1634, 1607, 1502, 1453, 1423, 1378, 1308, 1287, 1263, 1202, 1174, 1123, 1050, 941, 909, 854, 788, 764
Mass (EI): 500 (M ⁺ )

Example 36-2
1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -3-ethyl-pyrrolidin-2-one (mixture of diastereomers) (compound 236 ) Synthesis of

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -pyrrolidin-2-one obtained in Example 36-1 248 mg (0.50 mmol) ) Was dissolved in THF 5 mL, 0.36N LDA / THF solution 4.1 mL (1.48 mmol) was added at 0 ° C., and the mixture was stirred for 1 hour. Thereafter, 0.08 mL (0.99 mmol) of iodoethane was added and stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 176 mg (yield 67%).
Mass (EI): 528 (M ⁺ )

Example 36-3
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3-ethyl-pyrrolidin-2-one (diastereomer mixture) / tartrate (compound 36 ) Synthesis of

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -3-ethyl-pyrrolidin-2-one obtained in Example 36-2 ( Diastereomer mixture) 171 mg (0.32 mmol) and o-phthalic acid 108 mg (0.65 mmol) were dissolved in 10 mL of methanol, Pd / C 150 mg was added, and the mixture was stirred at room temperature for 19 hours under hydrogen atmosphere did. The reaction solution was filtered through celite, and the filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 68 mg (yield 48%) of the free form of the title compound 36 . This was converted to the tartrate salt to give the title compound 36 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.73 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 4.85 (d, J = 3.8 Hz, 1H), 4.65 (dt, J = 13.2, 3.8 Hz, 1H), 3.56 (q, J = 8.0 Hz, 1H), 3.30 (td, J = 5.9, 3.3 Hz, 1H), 3.10 (d, J = 6.6 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H), 2.65-2.50 (m, 2H), 2.49-2.10 (m, 5H), 1.95-1.70 (m, 3H), 1.65-1.25 (m, 6H), 0.95 (t, J = 7.1 Hz, 3H), 0.91- 0.81 (m, 1H), 0.56-0.49 (m, 2H), 0.14-0.09 (m, 2H) (free body)
Mass (EI): 438 (M ⁺ )

Examples 37-1, 38-1
1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -3-butyl-pyrrolidin-2-one (mixture of diastereomers) (compound 237 and 238 ) Synthesis

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 36-1 according to the method described in Example 36-2 ) -Pyrrolidin-2-one, iodobutane was used instead of iodoethane to give 203 mg (yield 62%) of the title compound as a mixture of diastereomers.
Mass (EI): 556 (M ⁺ )

Examples 37-2, 38-2
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3-butyl-pyrrolidin-2-one tartrate (compounds 37 and 38 )

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 37-1 according to the method described in Example 36-3 ) -3-Butyl-pyrrolidin-2-one was used to give 85 mg (yield 47%) of the free form of the title compound 37 (yield 47%) and 22 mg of the free form of the title compound 38 (low polarity) Yield 12%) was obtained. This was obtained as the tartrate salt to give the title compounds 37 and 38 , respectively.

Compound 37
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.73 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 4.1 Hz, 1H), 4.63 (dt, J = 12.9, 4.1 Hz, 1H), 3.55 (dt, J = 9.1, 7.7 Hz, 1H), 3.30 (td, J = 9.0, 3.0 Hz, 1H), 3.09 (d, J = 6.9 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H ), 2.67-2.13 (m, 8H), 1.94-1.74 (m, 2H), 1.65-1.24 (m, 10H), 0.96-0.78 (m, 4H), 0.57-0.49 (m, 2H), 0.15-0.08 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2928, 1656, 1499, 1459, 1377, 1324, 1262, 1164, 1118, 1070, 942, 859, 796, 752
Mass (EI): 466 (M ⁺ )
Elemental analysis value Composition formula: C ₂₈ H ₃₈ N ₂ O ₄・ 1.00C ₄ H ₆ O ₆・ 1.35H ₂ O
Calculated values: C, 60.00; H, 7.05; N, 4.35
Found: C, 59.96; H, 7.34; N, 4.37

Compound 38
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.72 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 4.78 (d, J = 4.1 Hz, 1H), 4.66 (dt, J = 13.5, 4.1 Hz, 1H), 3.58 (td, J = 9.1, 3.0 Hz, 1H), 3.23 (dt, J = 9.3, 8.0 Hz, 1H), 3.11 (d, J = 6.6 Hz, 1H), 3.04 (d, J = 18.7 Hz, 1H ), 2.68-2.54 (m, 2H), 2.42-2.06 (m, 5H), 1.98-1.24 (m, 13H), 0.96-0.78 (m, 4H), 0.57-0.49 (m, 2H), 0.15-0.08 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2929, 1656, 1501, 1459, 1377, 1324, 1262, 1164, 1119, 1071, 942, 859, 795, 750
Mass (EI): 466 (M ⁺ )
Elemental analysis value Composition formula: C ₂₈ H ₃₈ N ₂ O ₄・ 1.15C ₄ H ₆ O ₆・ 2.80H ₂ O
Calculated values: C, 57.01; H, 7.01; N, 4.15
Found: C, 56.78; H, 7.38; N, 4.06

Examples 39-1, 40-1
1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -3- (4-methyl-benzyl) -pyrrolidin-2-one (compound 239 and 240 ) Synthesis

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 36-1 according to the method described in Example 36-2 ) -Pyrrolidin-2-one (289 mg) and α-bromoxylene instead of iodoethane were used to give 224 mg (yield 64%) of the title compound as a mixture of diastereomers.
Mass (EI): 604 (M ⁺ )

Examples 39-2, 40-2
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3- (4-methyl-benzyl) -pyrrolidin-2-one tartrate (compound 39 and 40 ) Synthesis

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) obtained in Example 39-1 according to the method described in Example 36-3 Using 224 mg of -3- (4-methyl-benzyl) -pyrrolidin-2-one, 124 mg (yield 65%) of the free form of the title compound 39 (yield 65%) and the free form of the title compound 40 ( Low-polarity component) 31 mg (yield 16%) was obtained. This was obtained as the tartrate salt to give the title compounds 39 and 40 , respectively.

Compound 39
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.08 (s, 4H), 6.70 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 4.1 Hz, 1H), 4.64 (dt, J = 13.2 , 4.1 Hz, 1H), 3.44 (dt, J = 9.1, 8.2 Hz, 1H), 3.16 (dd, J = 13.5, 3.8 Hz, 1H), 3.12-2.98 (m, 3H), 2.77 (qd, J = 8.6, 3.8 Hz, 1H), 2.68-2.53 (m, 3H), 2.41-2.16 (m, 4H), 2.30 (s, 3H), 2.10-1.96 (m, 1H), 1.86-1.18 (m, 6H) , 0.90-0.78 (m, 1H), 0.57-0.50 (m, 2H), 0.16-0.10 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2925, 1657, 1500, 1459, 1439, 1313, 1263, 1162, 1116, 1069, 939, 858, 795, 751
Mass (EI): 514 (M ⁺ )
Elemental analysis value Composition formula: C ₃₂ H ₃₈ N ₂ O ₄・ 1.10C ₄ H ₆ O ₆・ 1.55H ₂ O
Calculated values: C, 61.58; H, 6.39; N, 3.96
Found: C, 61.78; H, 6.79; N, 3.96

Compound 40
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.14 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 4.80 ( d, J = 3.8 Hz, 1H), 4.66 (dt, J = 13.2, 3.8 Hz, 1H), 3.44 (td, J = 8.5, 3.5 Hz, 1H), 3.28-2.99 (m, 4H), 2.74-2.54 (m, 4H), 2.43-2.16 (m, 4H), 2.32 (s, 3H), 2.05-1.20 (m, 7H), 0.90-0.79 (m, 1H), 0.58-0.50 (m, 2H), 0.16 -0.10 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2927, 1656, 1502, 1459, 1439, 1376, 1323, 1271, 1163, 1118, 1070, 941, 858, 797, 754
Mass (EI): 514 (M ⁺ )
Elemental analysis value Composition formula: C ₃₂ H ₃₈ N ₂ O ₄ 2.30 C ₄ H ₆ O ₆ 0.30 H ₂ O
Calculated values: C, 57.23; H, 6.33; N, 3.45
Found: C, 57.19; H, 6.10; N, 3.24

Examples 41-1 and 42-1
1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -3- (4-fluoro-benzyl) -pyrrolidin-2-one (compound 241 and 242 ) Synthesis

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 36-1 according to the method described in Example 36-2 ) -Pyrrolidin-2-one 281 mg, and 4-fluorobenzyl bromide was used instead of iodoethane to give 205 mg (yield 67%) of the title compound as a diastereomeric mixture.
Mass (EI): 608 (M ⁺ )

Examples 41-2, 42-2
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3- (4-fluoro-benzyl) -pyrrolidin-2-one tartrate (compound 41 and 42 ) Synthesis

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 41-1 according to the method described in Example 36-3 ) -3- (4-Fluoro-benzyl) -pyrrolidin-2-one 195 mg, free form of title compound 41 (high polarity component) 105 mg (yield 63%), and free form of title compound 42 (Low polarity component) 33 mg (yield 20%) was obtained. This was obtained as the tartrate salt to give the title compounds 41 and 42 , respectively.

Compound 41
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.15 (dd, J = 8.8,5.4 Hz, 2H), 6.95 (t, J = 8.8 Hz, 2H), 6.70 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 4.84 (d, J = 4.1 Hz, 1H), 4.64 (dt, J = 12.9, 4.1 Hz, 1H), 3.45 (dt, J = 9.3, 8.0 Hz, 1H), 3.18-2.98 (m, 4H), 2.80 -2.53 (m, 4H), 2.42-2.16 (m, 4H), 2.10-1.96 (m, 1H), 1.86-1.14 (m, 6H), 0.89-0.78 (m, 1H), 0.58-0.49 (m, 2H), 0.15-0.08 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2929, 1657, 1509, 1459, 1439, 1313, 1271, 1221, 1159, 1117, 1069, 940, 859, 796, 757
Mass (EI): 518 (M ⁺ )
Elemental analysis value Composition formula: C ₃₁ H ₃₅ FN ₂ O ₄・ 1.10C ₄ H ₆ O ₆・ 2.20H ₂ O
Calculated value: C, 58.68; H, 6.05; N, 4.00; F, 2.62
Found: C, 58.73; H, 6.41; N, 3.87; F, 2.63

Compound 42
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.20 (dd, J = 8.5, 5.2 Hz, 2H), 6.98 (t, J = 8.5 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 4.77 (d, J = 4.1 Hz, 1H), 4.67 (dt, J = 13.5, 4.1 Hz, 1H), 3.46 (td, J = 9.3, 3.6 Hz, 1H), 3.29-2.99 (m, 4H), 2.74 -2.55 (m, 4H), 2.42-2.22 (m, 4H), 2.05-1.22 (m, 7H), 0.91-0.80 (m, 1H), 0.58-0.49 (m, 2H), 0.16-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2932, 1657, 1509, 1459, 1439, 1323, 1272, 1222, 1158, 1119, 1071, 941, 859, 795, 757
Mass (EI): 518 (M ⁺ )
Elemental analysis value Composition formula: C ₃₁ H ₃₅ FN ₂ O ₄・ 2.50C ₄ H ₆ O ₆・ 2.20H ₂ O
Calculated values: C, 52.81; H, 5.52; N, 3.09; F, 1.99
Found: C, 52.75; H, 5.87; N, 3.00; F, 2.04

Examples 43-1 and 44-1
1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -3- (4-trifluoromethoxy-benzyl) -pyrrolidin-2-one (compound 243 and 244 )

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 36-1 according to the method described in Example 36-2 ) -Pyrrolidin-2-one 281 mg, 4-trifluoromethoxybenzyl bromide was used instead of iodoethane, to give 383 mg (yield 100%) of the title compound as a diastereomeric mixture.
Mass (EI): 674 (M ⁺ )

Examples 43-2, 44-2
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3- (4-trifluoromethoxy-benzyl) -pyrrolidin-2-one tartrate (compound 43 and 44 ) synthesis

1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl obtained in Example 43-1 according to the method described in Example 36-3 ) -3- (4-trifluoromethoxy-benzyl) - - with a pyrrolidin-2-one 376 mg, free form of the title compound 43 (more polar component) 172 mg (53% yield), and the title compound 44 52 mg (yield 16%) of a free form (low polarity component) was obtained. This was obtained as the tartrate salt to give the title compounds 43 and 44 , respectively.

Compound 43
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.22 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 4.83 ( d, J = 4.1 Hz, 1H), 4.63 (dt, J = 12.4, 4.1 Hz, 1H), 3.46 (dt, J = 9.9, 7.7 Hz, 1H), 3.21-2.98 (m, 4H), 2.82-2.54 (m, 4H), 2.42-2.16 (m, 4H), 2.10-1.96 (m, 1H), 1.87-1.18 (m, 6H), 0.90-0.78 (m, 1H), 0.58-0.49 (m, 2H) , 0.16-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2933, 1656, 1613, 1508, 1460, 1439, 1381, 1261, 1224, 1159, 1117, 1070, 939, 859, 795, 764
Mass (EI): 584 (M ⁺ )
Elemental analysis value Composition formula: C ₃₂ H ₃₅ F ₃ N ₂ O ₅・ 1.00C ₄ H ₆ O ₆・ 2.80H ₂ O
Calculated values: C, 55.22; H, 5.76; N, 3.65; F, 7.07
Found: C, 55.07; H, 5.98; N, 3.57; F, 7.26

Compound 44
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.26 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 4.76 ( d, J = 4.1 Hz, 1H), 4.68 (dt, J = 13.2, 4.1 Hz, 1H), 3.50 (td, J = 9.6, 3.3 Hz, 1H), 3.34-2.98 (m, 4H), 2.76-2.54 (m, 4H), 2.42-2.18 (m, 4H), 2.08-1.94 (m, 1H), 1.88-1.60 (m, 2H), 1.58-1.20 (m, 4H), 0.92-0.78 (m, 1H) , 0.58-0.50 (m, 2H), 0.16-0.10 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2932, 1656, 1508, 1460, 1440, 1377, 1261, 1223, 1162, 1117, 1070, 940, 860, 795, 763
Mass (EI): 584 (M ⁺ )
Elemental analysis value Composition formula: C ₃₂ H ₃₅ F ₃ N ₂ O ₅・ 1.20C ₄ H ₆ O ₆・ 3.30H ₂ O
Calculated values: C, 53.97; H, 5.64; N, 3.36; F, 6.60
Found: C, 53.63; H, 5.97; N, 3.40; F, 6.92

Example 45
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-hydroxy-morphinan-6α-yl) -3-benzylidene-pyrrolidin-2-one tartrate (compound 45 )

  1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -pyrrolidin-2-one obtained in Example 36-1 482 mg (0.96 mmol) ) Was dissolved in THF 10 mL, 0.42 N LDA / THF solution 6.9 mL (2.89 mmol) was added at −78 ° C., and the mixture was stirred for 1 hour. Thereafter, 0.22 mL (1.92 mmol) of benzoyl chloride was added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy as a crude product. -Morhinan-6α-yl) -3-benzoyl-pyrrolidin-2-one was obtained.

  This crude product was dissolved in 15 mL of methanol, 158 mg (4.18 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy as a crude product. -Morhinan-6α-yl) -3- (hydroxy-phenyl-methyl) -pyrrolidin-2-one was obtained.

  The obtained crude product, o-phthalic acid 282 mg (1.70 mmol) was dissolved in methanol 40 mL, Pd / C 200 mg was added, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan- as a crude product. 6α-yl) -3- (hydroxy-phenyl-methyl) -pyrrolidin-2-one was obtained.

This crude product was dissolved in 60 mL of toluene, 323 mg (1.39 mmol) of camphorsulfonic acid was added, and the mixture was heated to reflux for 23 hours. The reaction solution was allowed to cool to room temperature, and then the reaction solution was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 153 mg of free form of the title compound 45 (4 steps yield: 32%). This was converted to the tartrate salt to give the title compound 45 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.50-7.26 (m, 6H), 6.74 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 4.94 (d, J = 4.1 Hz, 1H), 4.83 (dt, J = 13.2, 4.1 Hz, 1H), 3.82-3.72 (m, 1H), 3.51-3.40 (m, 1H), 3.13 (d, J = 6.9 Hz, 1H), 3.05 (d, J = 19.0 Hz, 1H) , 3.03-2.85 (m, 2H), 2.70-2.55 (m, 2H), 2.42-2.17 (m, 4H), 1.91-1.77 (m, 1H), 1.60-1.35 (m, 4H), 0.93-0.76 ( m, 1H), 0.58-0.47 (m, 2H), 0.19-0.08 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2927, 2824, 1665, 1636, 1493, 1444, 1370, 1309, 1284, 1157, 1117, 1068, 1034, 942, 858, 798, 748, 690
Mass (EI): 498 (M ⁺ )
Elemental analysis value Composition formula: C ₃₁ H ₃₄ N ₂ O ₄・ 1.00C ₄ H ₆ O ₆・ 2.60H ₂ O
Calculated values: C, 60.32; H, 6.41; N, 3.89
Found: C, 60.44; H, 6.55; N, 4.03

Example 46
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -pyrrolidin-2-one hydrochloride (compound 46 )

  6.70 g (19.6 mmol) of 6β-naltrexamine was dissolved in 250 mL of methylene chloride, 5.19 g (48.9 mmol) of sodium carbonate and 4.59 mL (41.1 mmol) of 4-chlorobutyric chloride were added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the residue obtained by concentrating the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 4.74 g of 6β- (4-chlorobutanamide) -17-cyclopropylmethyl-4,5α-epoxy-morphinan-3,14-diol (yield). 54%).

1.59 g (3.56 mmol) of this purified product was dissolved in 10 mL of DMF, 799 mg (7.12 mmol) of potassium t-butoxide was added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 577 mg (yield 40%) of the free form of the title compound 46 . This was converted to the hydrochloride salt to give the title compound 46 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.75 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 4.55 (d, J = 8.2 Hz, 1H), 4.00 (ddd, J = 13.1, 8.2, 4.7 Hz, 1H ), 3.59-3.40 (m, 2H), 3.07 (d, J = 5.8 Hz, 1H), 3.03 (d, J = 18.4 Hz, 1H), 2.66-2.02 (m, 11H), 1.65-1.36 (m, 4H), 0.90-0.78 (m, 1H), 0.57-0.49 (m, 2H), 0.16-0.08 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2925, 2849, 1685, 1663, 1499, 1450, 1425, 1375, 1329, 1291, 1239, 1189, 1155, 1128, 1038, 978, 927, 860, 74
Mass (EI): 410 (M ⁺ )

Example 47-1
Synthesis of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -pyrrolidin-2-one (Compound 247 )

  284 mg (0.69 mmol) of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -pyrrolidin-2-one prepared by the method described in Example 46 was added to DMF. It was made to melt | dissolve in 7 mL, potassium carbonate 958 mg (6.93 mmol) and benzyl bromide 0.25 mL (2.08 mmol) were added, and it stirred at room temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (281 mg, yield 81%).

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.46-7.24 (m, 5H), 6.72 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 5.21 (d, J = 12.1 Hz, 1H), 5.09 (d, J = 12.1 Hz, 1H), 4.64 (d, J = 8.2 Hz, 1H), 4.01 (ddd, J = 12.9, 8.2, 4.7 Hz, 1H), 3.61-3.41 (m, 2H), 3.06 (d, J = 5.5 Hz, 1H), 3.02 (d, J = 18.7 Hz, 1H), 2.70-2.55 (m, 2H), 2.47-1.99 (m, 9H), 1.66-1.39 (m, 4H), 0.86-0.78 (m , 1H), 0.55-0.49 (m, 2H), 0.14-0.09 (m, 2H)
IR (cm ^-1 ) (KBr)
2927, 2829, 1677, 1606, 1496, 1435, 1389, 1333, 1187, 1155, 1129, 1097, 1040, 1018, 979, 920, 883, 859, 749, 697
Mass (EI): 500 (M ⁺ )

Examples 47-2, 48-2
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-benzyl-pyrrolidin-2-one tartrate (compounds 47 and 48 )

  1- (3-Benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -pyrrolidin-2-one obtained in Example 47-1 145 mg (0.35 mmol) ) Was dissolved in THF 5 mL, 0.36 N LDA / THF solution 2.84 mL (1.02 mmol) was added at −78 ° C., and the mixture was stirred for 1 hour. Thereafter, 0.10 mL (0.87 mmol) of benzyl bromide was added and stirred for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy as a crude product. -Morhinan-6β-yl) -3-benzyl-pyrrolidin-2-one was obtained.

This crude product, 66 mg (0.40 mmol) of o-phthalic acid was dissolved in 10 mL of methanol, 100 mg of Pd / C was added, and the mixture was stirred at room temperature for 4.5 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to give 32 mg (2 steps yield 18%) of the free form of the title compound 47 (high polarity component) and 10 mg of the free form of the title compound 48 (low polarity component) 10 mg (2 steps yield 5.4%) was obtained. This was obtained as the tartrate salt to give the title compounds 47 and 48 , respectively.

Compound 47
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.29-7.16 (m, 5H), 6.76 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H), 4.51 (d, J = 8.2 Hz, 1H), 3.98 (ddd, J = 12.9, 8.2, 4.4 Hz, 1H), 3.38-3.30 (m, 1H), 3.17-2.99 (m, 4H), 2.87-2.55 (m, 4H), 2.36 (d, J = 6.6 Hz, 2H), 2.25-1.91 (m, 4H), 1.82-1.41 (m, 4H), 1.30-1.24 (m, 1H), 0.85-0.80 (m, 1H), 0.53-0.49 (m, 2H), 0.14-0.06 (m , 2H) (free body)
IR (cm ^-1 ) (KBr)
2928, 1663, 1498, 1456, 1376, 1325, 1292, 1236, 1185, 1153, 1127, 1037, 987, 918, 858, 802, 746, 700
Mass (EI): 500 (M ⁺ )

Compound 48
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.33-7.17 (m, 5H), 6.77 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.50 (d, J = 8.2 Hz, 1H), 3.98 (ddd, J = 12.9, 8.2, 4.7 Hz, 1H), 3.36-3.25 (m, 3H), 3.07-3.00 (m, 2H), 2.80-2.55 (m, 4H), 2.37 (d, J = 6.6 Hz, 2H), 2.26-1.38 (m, 9H), 0.90-0.75 (m, 1H), 0.57-0.48 (m, 2H), 0.15-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2926, 1655, 1498, 1458, 1377, 1330, 1240, 1187, 1155, 1128, 1037, 986, 921, 859, 750, 702
Mass (EI): 500 (M ⁺ )

Example 49
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-butyl-pyrrolidin-2-one (diastereomeric mixture) / tartrate (compound 49 ) Synthesis of

According to the method described in Examples 47-2 and 48-2, 16 mg (2 steps yield 7.3%) of the free form of the title compound 49 was obtained using iodobutane instead of benzyl bromide. This was converted to the tartrate salt to give the title compound 49 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.75 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 4.56 (d, J = 8.2 Hz, 1H), 3.97 (ddd, J = 13.2, 8.2, 4.7 Hz, 1H ), 3.48-3.24 (m, 2H), 3.07 (d, J = 6.9 Hz, 1H), 3.03 (d, J = 18.7 Hz, 1H), 2.68-2.41 (m, 3H), 2.37 (d, J = 6.6 Hz, 2H), 2.35-2.03 (m, 4H), 1.86-1.23 (m, 11H), 0.94-0.78 (m, 4H), 0.56-0.46 (m, 2H), 0.16-0.08 (m, 2H) (Free body)
IR (cm ^-1 ) (KBr)
2927, 2855, 1656, 1499, 1458, 1377, 1330, 1237, 1187, 1152, 1127, 1038, 986, 921, 859, 800, 747, 703
Mass (EI): 466 (M ⁺ )

Example 50
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-benzylidene-pyrrolidin-2-one tartrate (compound 50 )

According to the method described in Example 45, instead of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -pyrrolidin-2-one Using 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -pyrrolidin-2-one obtained in Example 47-1, the title compound 50 mg of free 50 mg (4 steps yield 10%) was obtained. This was converted to the tartrate salt to give the title compound 50 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.49-7.28 (m, 6H), 6.76 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 4.65 (d, J = 8.2 Hz, 1H), 4.16 (ddd, J = 13.2, 8.2, 4.7 Hz, 1H), 3.70-3.52 (m, 2H), 3.12-2.98 (m, 4H), 2.66-2.58 (m, 2H), 2.38 (d, J = 6.3 Hz, 2H), 2.30-2.08 (m, 3H), 1.71-1.44 (m, 4H), 0.91-0.77 (m, 1H), 0.58-0.49 (m, 2H), 0.16-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2935, 2822, 1671, 1642, 1496, 1461, 1376, 1323, 1295, 1156, 1116, 1035, 989, 923, 860, 760, 694
Mass (EI): 498 (M ⁺ )

Example 51
Synthesis of 1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-butylidene-pyrrolidin-2-one tartrate (Compound 51 )

According to the method described in Example 45, instead of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -pyrrolidin-2-one Instead of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -pyrrolidin-2-one obtained in Example 47-1, benzoyl chloride 29 mg (4 steps yield 11%) of the free form of the title compound 51 was obtained using butyric acid chloride. This was obtained as the tartrate salt to give the title compound 51 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.75 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 6.49-6.40 (m, 1H), 4.61 (d, J = 8.2 Hz, 1H), 4.09 (ddd, J = 13.7, 8.2, 4.7 Hz, 1H), 3.61-3.30 (m, 2H), 3.10-2.95 (m, 2H), 2.76-2.55 (m, 3H), 2.38 (d, J = 6.3 Hz, 2H), 2.30-2.04 (m, 4H), 1.75-1.37 (m, 8H), 1.00-0.77 (m, 4H), 0.59-0.50 (m, 2H), 0.18-0.09 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2926, 1656, 1499, 1450, 1376, 1331, 1289, 1238, 1187, 1152, 1127, 1036, 989, 921, 859, 747
Mass (EI): 464 (M ⁺ )

Example 52
Synthesis of 1- [17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl] -3-phenethylidene-pyrrolidin-2-one tartrate (Compound 52 )

According to the method described in Example 45, instead of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6α-yl) -pyrrolidin-2-one Instead of 1- (3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl) -pyrrolidin-2-one obtained in Example 47-1, benzoyl chloride 19 mg (4 steps yield 6.2%) of the free form of the title compound 52 was obtained using phenylacetyl chloride. This was converted to the tartrate salt to give the title compound 52 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.38-7.16 (m, 5H), 6.75 (d, J = 8.0 Hz, 1H), 6.70-6.60 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 8.0 Hz , 1H), 4.10 (ddd, J = 13.5, 8.0, 4.7 Hz, 1H), 3.65-3.44 (m, 3H), 3.31-2.96 (m, 2H), 2.83-2.74 (m, 1H), 2.68-2.43 (m, 2H), 2.37 (d, J = 6.3 Hz, 2H), 2.30-2.02 (m, 4H), 1.68-1.38 (m, 5H), 0.90-0.76 (m, 1H), 0.58-0.45 (m , 2H), 0.18-0.08 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2925, 1656, 1493, 1451, 1376, 1331, 1292, 1236, 1152, 1128, 1036, 990, 921, 859, 746, 700
Mass (EI): 512 (M ⁺ )

Examples 53, 54
1- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3- (4-chloro-phenoxy) -pyrrolidin-2-one tartrate (compound 53 and 54 ) Synthesis

  Dissolve 6β-naltrexamine 1.06 g (3.09 mmol) in 30 mL of methylene chloride, add sodium carbonate 820 mg (7.73 mmol), 4-chloro-2- (4-chlorophenoxy) butyric acid chloride 1.73 g (6.49 mmol). Stir at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 6β- (4-chloro-2- (4-chlorophenoxy) butanamide) -17-cyclopropylmethyl-4,5α-epoxy-morphinan-3, 116 mg of 14-diol (yield 6.5%) was obtained.

This purified product 96 mg (0.18 mmol) was dissolved in DMF 10 mL, potassium t-butoxide 100 mg (0.89 mmol) was added, and the mixture was stirred at room temperature for 70 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to give 25 mg (yield 27%) of the free form of the title compound 53 (high polarity component) and 19 mg of the free form (low polarity component) of the title compound 54 ( Yield 20%). This was obtained as the tartrate salt to give the title compounds 53 and 54 , respectively.

Compound 53
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.22 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 4.90 ( dd, J = 7.9, 6.3 Hz, 1H), 4.59 (d, J = 8.2 Hz, 1H), 3.99 (ddd, J = 12.9, 8.2, 4.4 Hz, 1H), 3.63-3.46 (m, 2H), 3.08 (d, J = 5.8 Hz, 1H), 3.04 (d, J = 18.4 Hz, 1H), 2.68-2.52 (m, 3H), 2.38 (d, J = 6.6 Hz, 2H), 2.30-2.06 (m, 4H), 1.71-1.62 (m, 1H), 1.55-1.42 (m, 3H), 0.90-0.77 (m, 1H), 0.57-0.48 (m, 2H), 0.17-0.08 (m, 2H) (free body )
IR (cm ^-1 ) (KBr)
2926, 1686, 1490, 1451, 1331, 1299, 1240, 1187, 1152, 1128, 1091, 1037, 989, 922, 859, 825, 748
Mass (EI): 536 (M ⁺ )

Compound 54
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.24 (d, J = 9.1 Hz, 2H), 7.00 (d, J = 9.1 Hz, 2H), 6.76 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 4.85 ( t, J = 7.6 Hz, 1H), 4.60 (d, J = 8.2 Hz, 1H), 4.00 (ddd, J = 13.7, 8.2, 4.1 Hz, 1H), 3.63 (td, J = 9.3, 3.3 Hz, 1H ), 3.43 (dt, J = 9.3, 7.1 Hz, 1H), 3.08 (d, J = 5.5 Hz, 1H), 3.04 (d, J = 18.3 Hz, 1H), 2.69-2.52 (m, 3H), 2.38 (d, J = 6.6 Hz, 2H), 2.30-2.06 (m, 4H), 1.76-1.40 (m, 4H), 0.90-0.78 (m, 1H), 0.58-0.50 (m, 2H), 0.18-0.10 (m, 2H) (free body)
IR (cm ^-1 ) (KBr)
2927, 1687, 1490, 1452, 1332, 1298, 1241, 1151, 1128, 1092, 1037, 989, 921, 859, 826, 749
Mass (EI): 536 (M ⁺ )

Example 55
Synthesis of N- [17- (cyclopropylmethyl) -4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl] -4,5-dichlorophthalimide tartrate (compound 55 )

According to the method described in Example 11, using 4,5-dichlorophthalic anhydride instead of phthalic anhydride, 130 mg (yield 83%) of the free form of title compound 55 was obtained. This was converted to the tartrate salt to give the title compound 55 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.92 (2H, s), 6.76 (1H, d, J = 7.8Hz), 6.63 (1H, d, J = 7.8Hz), 5.11 (1H, d, J = 8.7 Hz), 4.05-4.08 (1H, m ), 3.11 (2H, t, J = 5.7Hz), 3.03 (1H, s), 2.59-2.71 (3H, m), 2.29-2.39 (3H, m), 2.09-2.17 (2H, m), 1.69- 1.73 (2H, m), 1.44-1.48 (2H, m), 0.86-0.88 (1H, m), 0.53-0.55 (2H, m), 0.13-0.14 (2H, m) (free body)
Mass (ESI): 541 (M ⁺ +1)

Example 56
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -4-methylphthalimide tartrate (Compound 56 )

In accordance with the method described in Example 11, using 6β-naloxamine instead of 6β-naltrexamine and 4-methylphthalic anhydride instead of phthalic anhydride, 46 mg (yield: 32%) of the title compound 56 ) This was converted to the tartrate salt to give the title compound 56 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.69 (1H, d, J = 7.6 Hz), 7.63 (1H, s), 7.48 (1H, d, J = 7.8 Hz), 6.78 (1H, d, J = 8.1 Hz), 6.64 (1H, d, J = 8.1 Hz), 5.76-5.86 (1H, m), 5.16-5.24 (3H, m), 4.05 (1H, ddd, J = 13.2, 8.5, 4.4 Hz), 3.15 (2H, d, J = 6.4 Hz) , 3.10 (1H, d, J = 18.3 Hz), 2.51 (3H, s), 2.54-2.96 (4H, m), 2.32 (1H, dt, J = 12.4, 4.9 Hz), 2.15 (1H, dt, J = 12.1, 3.7 Hz), 1.67-1.70 (1H, m), 1.43-1.53 (3H, m) (free body)
Mass (ESI): 473 (M ⁺ +1)

Example 57
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -4-chlorophthalimide tartrate (Compound 57 )

In accordance with the method described in Example 11, using 6β-naloxamine instead of 6β-naltrexamine and 4-chlorophthalic anhydride instead of phthalic anhydride, 66 mg (yield 44%) of the free form of title compound 57 ) This was converted to the tartrate salt to give the title compound 57 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.81 (1H, s), 7.78 (1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 7.8 Hz)
6.78 (1H, d, J = 8.4 Hz), 6.65 (1H, d, J = 8.4 Hz), 5.75-5.86 (1H, m), 5.13-5.25 (3H, m), 4.06 (1H, ddd, J = 13.1, 8.3, 4.5 Hz), 3.15 (2H, d, J = 6.6 Hz), 3.11 (1H, d, J = 19.8 Hz), 2.95 (1H, d, J = 5.4 Hz), 2.54-2.80 (3H, m), 2.32 (1H, dt, J = 11.7, 3.6Hz), 2.14 (1H, dt, J = 11.7, 3.6 Hz), 1.68-1.72 (1H, m), 1.26-1.53 (3H, m) (Free body)
Mass (ESI): 493 (M ⁺ +1)

Example 58
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -4-fluorophthalimide tartrate (Compound 58 )

According to the method described in Example 11, 6 beta naltrexamine instead of 6 beta Narokisamin, using 4-fluoro-phthalic acid anhydride in place of phthalic anhydride, free form 43 mg (yield 30 the title compound 58 %). This was converted to the tartrate salt to give the title compound 58 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.84 (1H, dd, J = 8.0, 4.4 Hz), 7.51 (1H, dd, J = 6.8, 2.2, Hz), 7.37 (1H, dt, J = 8.4, 2.4 Hz), 6.76 (1H, d, J = 8.3 Hz), 6.64 (1H, d, J = 8.3 Hz), 5.75-5.85 (1H, m), 5.13-5.23 (3H, m), 4.05 (1H, ddd, J = 13.2, 8.5, 4.4 Hz) , 3.14 (2H, d, J = 6.4 Hz), 3.11 (1H, d, J = 18.3 Hz), 2.94 (1H, d, J = 5.6 Hz), 2.53-2.82 (3H, m), 2.23 (1H, dt, J = 12.0, 4.9 Hz), 2.21 (1H, dt, J = 12.0, 4.9 Hz), 1.67-1.71 (1H, m), 1.43-1.51 (3H, m) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 59
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -4,5-dichlorophthalimide tartrate (Compound 59 )

In accordance with the method described in Example 11, using 6β-naloxamine instead of 6β-naltrexamine and 4,5-dichlorophthalic anhydride instead of phthalic anhydride, 120 mg of the free compound of title compound 59 (concentration) Rate 75%). This was converted to the tartrate salt to give the title compound 59 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.91 (2H, s,) 6.77 (1H, d, J = 8.7 Hz), 6.65 (1H, d, J = 8.7 Hz), 5.74-5.86 (1H, m), 5.16-5.25 (2H, m), 5.12 (1H, d, J = 8.4Hz), 4.05 (1H, ddd, J = 13.1, 8.3, 4.5Hz), 3.15 (2H, d, J = 6.6 Hz), 3.11 (1H, d, J = 19.8 Hz) , 2.95 (1H, d, J = 5.4 Hz), 2.54-2.78 (3H, m), 2.31 (1H, dt, J = 11.7, 3.6 Hz), 2.13 (1H, dt, J = 11.7, 3.6 Hz), 1.68-1.72 (1H, m), 1.43-1.53 (3H, m) (free body)
Mass (ESI): 527 (M ⁺ +1)

Examples 60, 61
N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -3-methylphthalimide tartrate (compound 60 ), and N- (17-allyl-4,5α- Synthesis of epoxy-3,14-dihydroxymorphinan-6α-yl) -3-methylphthalimide tartrate (compound 61 )

In accordance with the method described in Example 11, using 6-naloxamine (diastereomer mixture) instead of 6β-naltrexamine and 3-methylphthalic anhydride instead of phthalic anhydride, heating to reflux for 20 hours, 38 mg (yield 26%) of the free form of the title compound 60 and 16 mg (yield 11%) of the free form of the title compound 61 were obtained. These were obtained as the tartrate salts to give the title compounds 60 and 61 , respectively.

Compound 60
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.67 (1H, d, J = 7.3 Hz), 7.56 (1H, t, J = 7.4 Hz), 7.45 (1H, d, J = 7.5 Hz), 6.76 (1H, d, J = 8.1 Hz), 6.64 ( 1H, d, J = 8.1 Hz), 5.75-5.85 (1H, m), 5.16-5.23 (3H, m), 4.05 (1H, ddd, J = 13.2, 8.5, 4.4 Hz), 3.14 (2H, d, J = 6.3 Hz), 3.11 (1H, d, J = 18.6 Hz), 2.69 (3H, s), 2.54-2.96 (4H, m), 2.31 (1H, dt, J = 12.4, 4.9 Hz), 2.15 ( 1H, dt, J = 12.0, 3.6 Hz), 1.67-1.70 (1H, m), 1.43-1.51 (3H, m) (free body)
Mass (ESI): 473 (M ⁺ +1)

Compound 61
¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.68 (d, 1H, J = 7.4 Hz), 7.56 (t, 1H, J = 7.4 Hz), 7.45 (d, 1H, J = 7.4 Hz), 6.83 (d, 1H, J = 8.4 Hz), 6.61 ( d, 1H, J = 8.4 Hz), 5.79-5.88 (m, 1H), 5.17-5.25 (m, 2H), 4.82 (dt, 1H, J = 4.1 Hz, J = 14.0 Hz), 4.65 (d, 1H , J = 4.1 Hz), 3.12 (d, 2H, J = 6.3 Hz), 3.11 (d, 1H, J = 15.6 Hz), 2.98 (d, 1H, J = 6.6 Hz), 2.57-2.71 (m, 1H ), 2.69 (s, 3H), 2.20-2.30 (m, 3H), 1.77-1.89 (m, 2H), 1.49-1.66 (m, 3H) (free body)
Mass (ESI): 473 (M ⁺ +1)

Example 62
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -3-fluorophthalimide tartrate (Compound 62 )

In accordance with the method described in Example 11, using 6β-naloxamine instead of 6β-naltrexamine and 3-fluorophthalic anhydride instead of phthalic anhydride, 42 mg of the free form of title compound 62 (yield 29 %). This was converted to the tartrate salt to give the title compound 62 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.74 (1H, dt, J = 7.7, 4.0 Hz), 7.68 (1H, d, J = 6.8 Hz), 7.38 (1H, t, J = 8.3 Hz), 6.77 (1H, d, J = 8.1 Hz), 6.65 (1H, d, J = 8.1 Hz), 5.76-5.86 (1H, m), 5.15-5.24 (3H, m), 4.06 (1H, ddd, J = 13.2, 8.5, 4.4 Hz), 3.14 (2H, d, J = 6.3 Hz), 3.10 (1H, d, J = 18.5 Hz), 2.94 (1H, d, J = 5.6 Hz), 2.78-2.85 (1H, m), 2.63 (1H, dd, J = 18.4 , 5.7 Hz), 2.56 (1H, dd, J = 11.6, 4.5 Hz), 2.31 (1H, dt, J = 12.5, 5.0 Hz), 2.15 (1H, dt, J = 12.0, 4.0 Hz), 1.68-1.72 (1H, m), 1.45-1.52 (3H, m) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 63
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -3-fluorophthalimide tartrate (Compound 63 )

According to the method described in Example 11, 6 beta instead 6α- Narokisamin of naltrexamine, using 3-fluoro-phthalic acid anhydride in place of phthalic anhydride, and heated to reflux for 20 hours, free of the title compound 63 70 mg (yield 32%) of the product was obtained. This was converted to the tartrate salt to give the title compound 63 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.82-7.92 (m, 2H), 7.54 (t, 1H, J = 7.4 Hz), 6.98 (d, 1H, J = 8.2 Hz), 6.77 (d, 1H, J = 8.2 Hz), 5.95-6.04 (m , 1H), 5.33-5.42 (m, 2H), 4.99 (dt, 1H, J = 4.1, 14.0 Hz), 4.81 (d, 1H, J = 4.1 Hz), 3.28 (d, 2H, J = 6.3 Hz) , 3.19 (d, 1H, J = 15.6 Hz), 2.98 (d, 1H, J = 6.9 Hz), 2.83 (1H, dd, J = 7.1, 18.5 Hz), 2.73-2.76 (m, 1H), 2.36- 2.46 (m, 3H), 1.39-2.00 (m, 4H) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 64
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -phthalimide / tartrate (Compound 64 )

In accordance with the method described in Example 11, 6α-naloxamine was used instead of 6β-naltrexamine, and the mixture was heated to reflux for 20 hours to obtain 24 mg (yield 26%) of the free form of the title compound 64 . This was converted to the tartrate salt to give the title compound 64 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.81-7.85 (m, 2H), 7.69-7.73 (m, 2H), 6.82 (d, 1H, J = 8.2 Hz), 6.59 (d, 1H, J = 8.2 Hz), 5.75-5.90 (m, 1H) , 5.16-5.24 (m, 2H), 4.83 (dt, 1H, J = 4.0, 14.2 Hz), 4.65 (d, 1H, J = 4.0 Hz), 3.12 (d, 2H, J = 6.3 Hz), 3.11 ( d, 1H, J = 15.2 Hz), 2.97 (d, 1H, J = 6.9 Hz), 2.52-2.71 (m, 2H), 2.17-2.34 (m, 3H), 1.50-1.89 (m, 4H) (free body)
Mass (ESI): 459 (M ⁺ +1)

Example 65
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -4-fluorophthalimide tartrate (compound 65 )

According to the method described in Example 11, 6 beta instead 6α- Narokisamin of naltrexamine, using 4-fluoro phthalic anhydride in place of phthalic anhydride, and 20 hours heating under reflux, free of the title compound 65 70 mg (yield 32%) of the product was obtained. This was obtained as the tartrate salt to give the title compound 65 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.84 (dd, 1H, J = 4.4, 8.2 Hz), 7.51 (dd, 1H, J = 2.2, 4.4 Hz), 7.37 (dt, 1H, J = 2.2, 8.2 Hz), 6.81 (d, 1H, J = 8.3Hz), 6.61 (d, 1H, J = 8.3 Hz), 5.86-5.77 (m, 1H), 5.24-5.17 (m, 2H), 4.85-4.79 (m, 2H), 4.64-4.63 (m, 1H ), 3.09-3.13 (m, 1H), 2.97 (d, 1H, J = 6.6Hz), 2.67 (dd, 1H, J = 6.8, 18.4, Hz), 2.57 (m, 1H), 2.20-2.30 (m , 3H), 1.79-1.87 (m, 1H), 1.51-1.65 (m, 4H) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 66
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -phthalimide / tartrate (Compound 66 )

According to the method described in Example 11, using 6α-naltrexamine instead of 6β-naltrexamine, the mixture was heated to reflux for 20 hours to obtain 46 mg (yield 22%) of the free form of the title compound 66 . This was converted to the tartrate salt to give the title compound 66 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.81-7.87 (m, 2H), 7.68-7.74 (m, 2H), 6.81 (d, 1H, J = 7.9 Hz), 6.59 (d, 1H, J = 7.9 Hz), 5.08 (bs, 1H), 4.83 (dt, 1H, J = 3.9, 14.1 Hz), 4.65 (d, 1H J = 3.9 Hz), 3.15 (d, 1H, J = 6.8 Hz), 3.07 (d, 1H, J = 18.4 Hz), 2.69 ( d, 1H, J = 6.6 Hz), 2.63 (d, 1H, J = 6.9 Hz), 2.43-2.19 (m, 5H), 1.79-1.91 (m, 1H), 1.49-1.69 (m, 3H), 0.83 -0.92 (m, 1H), 0.54-0.59 (m, 2H), 0.12-0.17 (m, 2H) (free body)
Mass (ESI): 473 (M ⁺ +1)

Example 67
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -3-fluorophthalimide tartrate (compound 67 )

In accordance with the method described in Example 11, using 6α-naltrexamine in place of 6β-naltrexamine and 3-fluorophthalic anhydride in place of phthalic anhydride, the mixture was heated to reflux for 20 hours to free the title compound 67 . 5 mg (yield 4%) was obtained. This was converted to the tartrate salt to give the title compound 67 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.74-7.67 (m, 2H), 7.39 (t, 1H, J = 7.9 Hz), 6.82 (d, 1H, J = 7.8 Hz), 6.60 (d, 1H, J = 7.8 Hz), 4.82 (dt, 1H , J = 3.9, 14.1 Hz), 4.65 (d, 1H, J = 4.2 Hz), 3.16 (d, 1H, J = 6.6 Hz), 3.08 (d, 1H, J = 18.3 Hz), 2.70 (d, 1H , J = 7.2 Hz), 2.64 (d, 1H, J = 7.2 Hz), 2.21-2.42 (m, 5H), 1.91-1.53 (m, 4H), 0.86-0.88 (m, 1H), 0.54-0.59 ( m, 2H), 0.14-0.18 (m, 2H) (free body)
Mass (ESI): 491 (M ⁺ +1)

Example 68
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -4-fluorophthalimide tartrate (Compound 68 )

In accordance with the method described in Example 11, using 6α-naltrexamine in place of 6β-naltrexamine and 4-fluorophthalic anhydride in place of phthalic anhydride, the mixture was heated at reflux for 20 hours to give the free compound of title compound 68 . 102 mg (yield 34%) of the product was obtained. This was converted to the tartrate salt to give the title compound 68 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.14 (dd, 2H, J = 9.6, 5.2 Hz), 0.55 (m, 2H), 0.87 (m, 1H), 1.59 (m, 4H), 1.84 (dt, 1H, J = 14.4, 10.0 Hz), 2.24 (tt, 2H, J = 14.4, 9.6 Hz), 2.31 (d, 1H, J = 7.2 Hz), 2.38 (ddd, 2H, J = 26.0, 12.8, 6.4 Hz), 2.64 (d, 1H, J = 6.8 Hz), 2.68 (d, 1H, J = 7.2 Hz), 3.07 (d, 1H, J = 18.8 Hz), 3.15 (d, 1H, J = 6.8 Hz), 4.65 (d, 1H, J = 4.0 Hz) , 4.82 (brdt, 2H, J = 14.4, 4.0 Hz), 6.60 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.4 Hz), 7.38 (td, 1H, J = 8.0, 2.4 Hz), 7.52 (dd, 1H, J = 7.2, 2.4 Hz), 7.85 (dd, 1H, J = 8.0, 4.0 Hz) (free body)
Mass (ESI): 491 (M ⁺ +1)

Example 69
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -hexahydrophthalimide tartrate (Compound 69 )

According to the method described in Example 11, hexahydrophthalic anhydride was used in place of phthalic anhydride to obtain 34 mg (yield 47%) of the free form of title compound 69 . This was converted to the tartrate salt to give the title compound 69 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.75 (d, 1H, J = 8.2 Hz), 6.61 (d, 1H, J = 8.2 Hz), 5.10 (d, 1H, J = 8.2 Hz), 3.98 (ddd, 1H, J = 4.5, 8.3, 13.1 Hz ), 3.10 (d, 1H, J = 5.1 Hz), 3.04 (d, 1H, J = 18.4 Hz), 2.84-2.90 (m, 2H), 2.58-2.77 (m, 3H), 2.28-2.39 (m, 3H), 2.10-2.18 (m, 1H), 1.23-1.94 (m, 14H), 0.83-0.85 (m, 1H), 0.51-0.57 (m, 2H), 0.13-0.14 (m, 2H) (free body )
Mass (ESI): 479 (M ⁺ +1)

Example 70
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -2,3-diphenylmaleimide tartrate (compound 70 )

In accordance with the method described in Example 11, 98 mg (yield 58) of the free form of the title compound 70 was obtained using 2,3-diphenylmaleic anhydride in place of phthalic anhydride and toluene in place of DMF as a solvent. %). This was converted to the tartrate salt to give the title compound 70 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.49 (d, 4H, J = 7.2 Hz), 7.33-7.39 (m, 6H), 6.74 (d, 1H, J = 8.0 Hz), 6.61 (d, 1H, J = 8.0 Hz), 5.20 (d, 1H , J = 8.0 Hz), 4.08 (ddd, 1H, J = 4.4, 8.2, 13.0 Hz), 3.13 (d, 1H, J = 5.2 Hz), 3.06 (d, 1H, J = 18.4 Hz), 2.61-2.94 (m, 3H), 2.31-2.40 (m, 3H), 2.14 (dt, 1H, J = 3.2, 10.3 Hz), 1.71 (d, 1H, J = 12.8 Hz), 1.47-1.53 (m, 3H), 0.82-0.89 (m, 1H), 0.53-0.55 (m, 2H), 0.13-0.14 (m, 2H) (free body)
Mass (ESI): 574 (M ⁺ )

Example 71
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -2-phenyl-succinimide (mixture of diastereomers) and tartrate (compound 71 )

In accordance with the method described in Example 11, using 2-phenyl-succinic anhydride in place of phthalic anhydride and toluene in place of DMF as a solvent, free form of title compound 71 (mixture of diastereomers) 113 mg (yield 78%) was obtained. This was converted to the tartrate salt to give the title compound 71 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.23-7.37 (m, 5H), 6.73 (d, 1H, J = 8.0 Hz), 6.60 (d, 1H, J = 8.0 Hz), 5.17 (d, 1H, J = 8.0 Hz), 4.08 (m, 2H ), 3.10-3.27 (m, 2H), 3.03 (d, 1H, J = 18.8 Hz), 2.58-2.87 (m, 4H), 2.31-2.38 (m, 3H), 2.12 (dt, 1H, J = 3.2 , 10.3 Hz), 1.68 (d, 1H, J = 12.8 Hz), 1.37-1.50 (m, 3H), 0.82-0.89 (m, 1H), 0.53-0.55 (m, 2H), 0.13-0.14 (m, 2H) (free body)
Mass (ESI): 500 (M ⁺ )

Example 72
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -3,4,5,6-tetrahydrophthalimide methanesulfonate (compound 72 )

In accordance with the method described in Example 11, 6α-naltrexamine instead of 6β-naltrexamine, 3,4,5,6-tetrahydrophthalic anhydride instead of phthalic anhydride, and toluene instead of DMF as the solvent The mixture was heated to reflux for 22 hours to give 18 mg (yield 13%) of the free form of the title compound 72 . This was converted to methanesulfonate to give the title compound 72 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
6.79 (1H, d, J = 8.3 Hz), 6.57 (1H, d, J = 8.3 Hz), 4.61 (1H, dt, J = 14.2, 4.0 Hz), 4.55 (1H, m), 3.12 (1H, d , J = 6.6 Hz), 3.05 (1H, d, J = 18.5 Hz), 2.6-2.7 (2H, m), 2.2-2.4 (8H, m), 2.05-2.10 (1H, m), 1.7-1.8 ( 5H, m), 1.6 (1H, m), 1.40-1.55 (2H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m), 0.1-0.2 (2H, m) (free body )
Mass (ESI): 476 (M ⁺ )

Example 73
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl) -3,4,5,6-tetrahydrophthalimide methanesulfonate (compound 73 )

In accordance with the method described in Example 11, 6β-naloxamine was used instead of 6β-naltrexamine, 3,4,5,6-tetrahydrophthalic anhydride was used instead of phthalic anhydride, and toluene was used instead of DMF as a solvent. As a result, 216 mg (yield 71%) of the free form of the title compound 73 was obtained. This was converted to methanesulfonate to give the title compound 73 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
1.35-1.46 (3H, m), 1.64 (1H, m), 1.76 (4H, br), 2.26 (1H, dd, J = 12.4, 4.8 Hz), 2.33 (5H, br), 2.54-2.65 (3H, m), 2.92 (1H, br), 3.07 (1H, d, J = 18.4 Hz), 3.13 (3H, brd, J = 6.0 Hz), 3.82 (1H, ddd, J = 12.8, 8.4, 4.8 Hz), 5.04 (1H, d, J = 8.4 Hz), 5.16 (2H, brd, J = 20.4 Hz), 5.20 (1H, d, J = 10.8 Hz), 5.80 (1H, ddt, J = 16.8, 10.0, 6.8 Hz ), 6.62 (1H, d, J = 8.0 Hz), 6.75 (1H, d, J = 8.0 Hz) (free body)
Mass (ESI): 463 (M ⁺ +1)

Example 74
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl) -3,4,5,6-tetrahydrophthalimide methanesulfonate (compound 74 )

In accordance with the method described in Example 11, 6α-naloxamine was used instead of 6β-naltrexamine, 3,4,5,6-tetrahydrophthalic anhydride was used instead of phthalic anhydride, and toluene was used instead of DMF as a solvent. The mixture was heated to reflux for 20 hours to give 30 mg (yield 21%) of the free form of the title compound 74 . This was converted to methanesulfonate to give the title compound 74 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
6.81 (d, 1H, J = 8.1 Hz), 6.60 (d, 1H, J = 8.3 Hz), 5.83 (m, 1H), 5.22 (d, 1H, J = 17.3 Hz), 5.19 (d, 1H, J = 10.0 Hz), 4.60-4.64 (m, 1H), 4.56 (d, 1H, J = 3.2 Hz), 3.09-3.13 (m, 3H), 2.97 (d, 1H, J = 6.6 Hz), 2.65 (dd , 1H, J = 6.6, 16.8 Hz), 2.58 (d, 1H, J = 7.8 Hz), 2.25-2.34 (m, 5H), 2.06-2.13 (m, 1H), 1.77-1.82 (m, 4H), 1.64 (d, 1H, J = 9.5 Hz), 1.43-1.54 (m, 2H) (free body)
Mass (ESI): 463 (M ⁺ +1)

Example 75
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3-dimethyl-maleimide tartrate (compound 75 )

6β-Naltrexamine 100 mg (0.29 mmol) was dissolved in 10 mL of acetic acid, 110 mg (0.88 mmol) of 2,3-dimethylmaleic anhydride was added, and the mixture was stirred at 125 ° C. for 20 hours. The reaction solution was allowed to cool to room temperature, the reaction mixture was concentrated with an evaporator, saturated aqueous sodium hydrogen carbonate solution was added to the reaction residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 36 mg (yield 27%) of the free form of the title compound 75 . This was obtained as the tartrate salt to give the title compound 75 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.73 (brs, 1H), 6.60 (brs, 1H), 5.02 (brd, 1H, J = 7.1 Hz), 3.81-3.87 (m, 1H), 3.47 (brd, 1H, J = 5.4 Hz), 3.01-3.09 (brm, 2H), 2.64 (brs, 2H), 2.59 (brs, 1H), 2.37 (brd, 2H, J = 6.4 Hz), 2.12 (brt, 1H, J = 12.2 Hz), 1.96 (s, 6H) , 1.65 (brd, 1H, J = 13.2 Hz), 1.36-1.47 (brm, 3H), 0.84 (brs, 1H), 0.52-0.54 (brm, 2H), 0.13 (brs, 2H) (free body)
Mass (ESI): 451 (M ⁺ +1)

Example 76
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -2,3-dimethyl-maleimide tartrate (compound 76 )

According to the method described in Example 75, 6α-naltrexamine was used instead of 6β-naltrexamine to obtain 8 mg (yield 7.5%) of the free form of title compound 76 . This was converted to the tartrate salt to give the title compound 76 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.78 (d, 1H, J = 8.1 Hz), 6.56 (d, 1H, J = 8.1 Hz), 4.61 (dt, 1H, J = 3.9, 14.2 Hz), 4.54 (d, 1H, J = 3.9 Hz), 3.12 (d, 1H, J = 6.6 Hz), 3.04 (d, 1H, J = 18.3 Hz), 2.60-2.78 (brm, 2H), 2.22-2.41 (m, 4H), 1.99-2.12 (m, 1H) , 1.95 (s, 6H), 1.74-1.83 (m, 1H), 1.58-1.66 (brm, 1H), 1.50 (dd, 1H, J = 9.3, 14.9 Hz), 1.37-1.44 (m, 1H), 0.81 -0.90 (m, 1H), 0.53-0.57 (m, 2H), 0.11-0.15 (m, 2H) (free body)
Mass (ESI): 451 (M ⁺ +1)

Example 77
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3,4,5,6-tetrahydrophthalimide tartrate (compound 77 )

Dissolve 113 mg (0.33 mmol) of 6β-naltrexamine in 3.3 mL of chloroform and add 58 mg (0.38 mmol) of 3,4,5,6-tetrahydrophthalic anhydride and 114 μL (0.82 mmol) of triethylamine to room temperature. And stirred for 50 minutes. Thereafter, 234 μL (1.68 mmol) of triethylamine and 158 μL (1.68 mmol) of acetic anhydride were added to the reaction solution, and the mixture was heated to reflux for 1 hour. Thereafter, the mixture was allowed to cool to room temperature, and the reaction mixture was concentrated with an evaporator. Then, 3 mL of methanol and 300 μL of 28% aqueous ammonia were added, and the mixture was stirred at room temperature for 4 hours. Then, water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 121 mg (77% yield) of the free form of the title compound 77 . This was converted to methanesulfonate to give the title compound 77 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.12 (2H, m), 0.52 (2H, m), 0.84 (1H, m), 1.43 (3H, m), 1.65 (1H, m), 1.76 (4H, br), 2.12 (3H, td, J = 12.0, 3.6 Hz), 2.26-2.38 (7H, m), 2.63 (3H, m), 3.03 (1H, d, J = 18.4 Hz), 3.08 (1H, d, J = 5.6 Hz), 3.83 (1H, ddd, J = 13.2, 8.4, 3.6 Hz), 5.05 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 8.4 Hz) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 78
N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -cis-1,2,3,6-tetrahydrophthalimide methanesulfonate (compound 78 ) Composition

According to the method of Example 77 described, 3,4,5,6 using cis-1,2,3,6-tetrahydrophthalic anhydride in place of tetrahydrophthalic anhydride, free of the title compound 78 13 mg (yield 11%) of the product was obtained. This was converted to methanesulfonate to give the title compound 78 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.10 (2H, m), 0.51 (2H, m), 0.83 (1H, m), 1.12 (1H, t, J = 7.2 Hz), 1.18 (1H, t, J = 7.2 Hz), 1.25 (1H, m ), 1.42 (2H, dd, J = 13.2, 3.0 Hz), 1.62 (2H, brdt, J = 13.2, 3.3 Hz), 2.07-2.24 (3H, m), 2.28 (1H, dd, J = 12.3, 4.8 Hz), 2.35 (2H, d, J = 6.3 Hz), 2.55-2.69 (4H, m), 3.05-3.09 (3H, m), 3.88 (1H, ddd, J = 13.2, 8.1, 4.8 Hz), 5.06 (2H, brd, J = 8.1 Hz), 5.91 (2H, t, J = 3.0 Hz), 6.59 (1H, d, J = 8.4 Hz), 6.73 (1H, d, J = 8.4 Hz) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 79
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -1,2-cyclopropanedicarbimide methanesulfonate (compound 79 )

According to the method of Example 77, wherein 3,4,5,6 instead of tetrahydrophthalic anhydride with 1,2-cyclopropane dicarboxylic acid anhydrides, free form 5 mg (yield of the title compound 79 Rate 5%). This was converted to methanesulfonate to give the title compound 79 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.18 (2H, m), 0.57 (2H, m), 0.89 (3H, m), 1.25-1.45 (8H, m), 1.53 (1H, ddd, J = 12.9, 7.8, 4.5 Hz), 1.69 (1H, brd, J = 13.5 Hz), 2.19 (1H, m), 2.32-2.45 (2H, m), 2.48 (2H, dd, J = 7.8, 3.6 Hz), 2.61-2.70 (2H, m), 3.70 (1H , m), 4.99 (1H, d, J = 8.1 Hz), 6.60 (1H, d, J = 8.1 Hz), 6.75 (1H, d, J = 8.1 Hz) (free body)
Mass (ESI): 437 (M ⁺ +1)

Example 80
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3-pyridinedicarbimide methanesulfonate (compound 80 )

  Dissolve 6β-naltrexamine 113 mg (0.33 mmol) in 3.3 mL of chloroform, add 57 mg (0.38 mmol) of 2,3-pyridinedicarboxylic anhydride and 136 μL (0.96 mmol) of triethylamine, and stir at room temperature for 2 hours. did. Thereafter, 227 μL (1.63 mmol) of triethylamine and 154 μL (1.63 mmol) of acetic anhydride were added to the reaction solution, and the mixture was heated to reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude reaction product.

This reaction product was dissolved in 3 mL of acetone, 1.5 mL of 3N hydrochloric acid was added, and the mixture was heated to reflux for 27 hours. Then, water was added to the reaction solution and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 13 mg (yield 8%) of the free form of the title compound 80 . This was converted to methanesulfonate to give the title compound 80 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.13 (2H, m), 0.54 (2H, m), 0.87 (1H, m), 1.49 (3H, m), 1.73 (2H, brd, J = 13.2 Hz), 1.99 (1H, d, J = 16.1 Hz ), 2.38 (5H, m), 2.67 (2H, d, J = 6.1Hz), 3.07 (1H, d, J = 9.8 Hz), 3.15 (1H, br), 4.15 (1H, ddd, J = 12.7, 8.8, 4.8 Hz), 5.17 (1H, d, J = 7.3 Hz), 6.62 (1H, d, J = 8.3 Hz), 6.78 (1H, d, J = 8.3 Hz), 7.63 (1H, dd, J = 7.6, 5.1 Hz), 8.17 (1H, dd, J = 7.6, 1.2 Hz), 8.98 (1H, dd, J = 4.8, 1.2 Hz) (free body)
Mass (ESI): 474 (M ⁺ +1)

Example 81
2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-fluoro-2,3-dihydro-isoindol-1-one methanesulfonate ( Synthesis of compound 81 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 17. 11 mg (yield) of the title compound 81 using the obtained N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-fluoro-phthalimide 13%: 2steps) was obtained. This was converted to methanesulfonate to give the title compound 81 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.14 (2H, m), 0.54 (2H, m), 0.85 (1H, m), 1.47-1.73 (4H, m), 2.13-2.29 (4H, m), 2.38 (2H, d, J = 6.3 Hz) , 2.59-2.67 (2H, m), 3.05 (1H, d, J = 18.9 Hz), 3.10 (1H, d, J = 5.4 Hz), 4.25 (1H, ddd, J = 13.5, 8.1, 4.8 Hz), 4.53 (3H, m), 4.68 (1H, d, J = 7.8 Hz), 6.62 (1H, d, J = 8.1 Hz), 6.76 (1H, d, J = 8.1 Hz), 7.22 (1H, t, J = 8.7 Hz), 7.42-7.49 (1H, m), 7.64 (1H, d, J = 7.8 Hz) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 82
2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -6-fluoro-2,3-dihydro-isoindol-1-one methanesulfonate ( Synthesis of compound 82 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 16. 19-mg (yield) of the title compound 82 using the obtained N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-fluoro-phthalimide 25%: 2 steps). This was converted to methanesulfonate to give the title compound 82 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
0.13 (2H, m), 0.53 (2H, m), 0.85 (1H, m), 1.47-1.72 (4H, m), 2.15-2.27 (4H, m), 2.39 (2H, d, J = 6.3 Hz) , 2.59-2.67 (2H, m), 3.06 (1H, d, J = 18.6 Hz), 3.12 (1H, d, J = 5.4 Hz), 4.23 (1H, ddd, J = 12.9, 8.4, 3.6 Hz), 4.46 (3H, m), 4.66 (1H, d, J = 8.4 Hz), 6.60 (1H, d, J = 8.1 Hz), 6.77 (1H, dd, J = 8.1, 1.5 Hz), 7.11-7.82 (3H , m) (free body)
Mass (ESI): 477 (M ⁺ +1)

Example 83
2- (17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3,4,5,6,7-hexahydro-isoindol-1-one tartaric acid Synthesis of salt (compound 83 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, Of the title compound 83 using the obtained N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3,4,5,6-tetrahydrophthalimide 16 mg (yield 43%: 2steps) was obtained. This was converted to methanesulfonate to give the title compound 83 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
6.75 (d, 1H, J = 8.3 Hz), 6.58 (d, 1H, J = 8.3 Hz) 4.54 (d, 1H, J = 8.1 Hz), 4.06 (ddd, J = 4.5, 8.3, 13.1 Hz), 3.93 (d, 1H, J = 18.8 Hz), 3.85 (d, 1H, J = 18.8 Hz), 3.09 (bs, 1H), 3.03 (d, 1H, J = 18.3 Hz), 2.65-2.59 (m, 2H) , 2.06-2.39 (m, 9H), 1.47-1.74 (m, 8H), 0.83-0.85 (m, 1H), 0.52-0.54 (m, 2H), 0.13-0.14 (m, 2H) (free body)
Mass (ESI): 463 (M ⁺ +1)

Example 84
2- (17-Allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3,4,5,6,7-hexahydro-isoindol-1-one methanesulfonic acid Synthesis of salt (compound 84 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, Of the title compound 84 using the obtained N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3,4,5,6-tetrahydrophthalimide 77 mg (Yield 52%: 2steps) was obtained. This was converted to methanesulfonate to give the title compound 84 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
1.41-1.80 (8H, m), 2.07-2.29 (7H, m), 2.51 (1H, br), 2.60 (1H, dd, J = 18.0, 5.6 Hz), 2.90 (1H, d, J = 5.6 Hz) , 3.07 (1H, d, J = 18.0 Hz), 3.12 (3H, brd, J = 6.0 Hz), 3.88 (1H, d, J = 18.8 Hz), 3.96 (1H, d, J = 18.8 Hz), 4.15 (1H, ddd, J = 12.8, 7.6, 4.4 Hz), 4.45 (1H, d, J = 8.0 Hz), 5.15 (2H, brd, J = 10.0 Hz), 5.21 (1H, d, J = 16.8 Hz) , 5.79 (1H, ddt, J = 16.8, 10.0, 6.4 Hz), 6.59 (1H, d, J = 8.0 Hz), 6.76 (1H, d, J = 8.0 Hz) (free body)
Mass (ESI): 449 (M ⁺ +1)

Example 85
2- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -2,3,4,5,6,7-hexahydro-isoindol-1-one tartrate ( Synthesis of compound 85 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 74. The obtained free form of the title compound 85 using N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -3,4,5,6-tetrahydrophthalimide 8 mg (Yield 40%: 2steps) was obtained. This was converted to the tartrate salt to give the title compound 85 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
6.74 (d, 1H, J = 8.3 Hz), 6.57 (d, 1H, J = 8.3 Hz), 5.80-5.84 (m, 1H), 5.18-5.25 (m, 2H), 4.86 (d, 1H, J = 2.0 Hz), 4.78-4.82 (m, 1H), 3.70-3.77 (m, 2H), 3.09-3.15 (m, 3H), 2.96 (d, 1H, J = 7.0 Hz), 2.57-2.67 (m, 2H ), 2.25-2.30 (m, 5H), 1.73-1.87 (m, 5H), 1.48-1.57 (m, 2H), 1.25-1.29 (m, 3H) (free body)
Mass (ESI): 449 (M ⁺ +1)

Example 86
Synthesis of 2- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3-dihydro-isoindol-1-one tartrate (compound 86 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 13. Using the obtained N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, 10 mg (yield 6.9%: 2steps) of the title compound 86 was obtained. Obtained. This was converted to the tartrate salt to give the title compound 86 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.85 (1H, m), 7.5-7.6 (1H, m), 7.4-7.5 (2H, m), 6.79 (1H, d, J = 8.2 Hz), 6.64 (1H, d, J = 8.2 Hz), 5.75 -5.85 (1H, m), 5.15-5.25 (2H, m), 4.66 (1H, d, J = 8.0 Hz), 4.54 (1H, d, J = 16.6 Hz), 4.46 (1H, d, J = 16.6 Hz), 4.25-4.30 (1H, m), 3.15 (1H, d, J = 6.6 Hz), 3.10 (1H, d, J = 18.3 Hz), 2.94 (1H, d, J = 5.6 Hz), 2.5- 2.7 (2H, m), 2.2-2.3 (3H, m), 1.5-1.7 (5H, m) (free body)
Mass (ESI): 445 (M ⁺ +1)

Example 87
Synthesis of 2- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -2,3-dihydro-isoindol-1-one tartrate (compound 87 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 64. Using the obtained N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6α-yl) -phthalimide, 7 mg (yield 13%: 2steps) of the title compound 87 was obtained. Obtained. This was converted to the tartrate salt to give the title compound 87 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.90 (d, 1H, J = 7.1 Hz), 7.51 (t, 1H, J = 7.1 Hz), 7.46 (t, 1H, J = 7.1 Hz), 7.37 (d, 1H, J = 7.1 Hz), 6.78 ( d, 1H, J = 8.1 Hz), 6.60 (d, 1H, J = 8.1 Hz), 5.80-5.87 (m, 1H), 5.18-5.25 (m, 2H), 4.95-5.02 (m, 2H), 4.69 (d, 1H, J = 17.3 Hz), 4.33 (d, 1H, J = 17.3 Hz), 3.10-3.15 (m, 3H), 2.98 (d, 1H, J = 6.6 Hz), 2.65 (dd, 1H, J = 7.6, 18.4 Hz), 2.56 (d, 1H, J = 6.6 Hz), 2.26-2.28 (m, 2H), 1.85-1.91 (m, 1H), 1.49-1.60 (m, 5H) (free body)
Mass (ESI): 445 (M ⁺ +1)

Examples 88, 89
2- (17-Allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -7-fluoro-2,3-dihydro-isoindol-1-one methanesulfonate (compound 88 ), And 2- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-fluoro-2,3-dihydro-isoindol-1-one methanesulfonate Synthesis of (Compound 89 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 62. The obtained N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-fluoro-phthalimide was used to give 23 mg of the title compound 88 free form (yield: 8% : 2steps), and 52 mg (yield 15%: 2steps) of the free form of the title compound 89 . These were obtained as methanesulfonates to give the title compound 88 and the title compound 89 , respectively.

Compound 88
¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
1.45-1.68 (3H, m), 2.12-2.33 (4H, m), 2.55 (1H, m), 2.64 (1H, dd, J = 18.6, 5.8 Hz), 2.94 (1H, d, J = 5.8 Hz) , 3.09 (1H, d, J = 18.6 Hz), 3.14 (3H, brd, J = 6.4 Hz), 4.25 (1H, ddd, J = 13.2, 8.6, 4.6 Hz), 4.48 (1H, d, J = 17.1 Hz), 4.52 (1H, d, J = 17.1 Hz), 4.67 (1H, d, J = 8.3 Hz), 5.13-5.26 (3H, m), 5.81 (1H, m), 6.63 (1H, d, J = 8.3 Hz), 6.79 (1H, d, J = 8.3 Hz), 7.20-7.68 (3H, m) (free body)
Mass (ESI): 463 (M ⁺ +1)

Compound 89
¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
1.45-1.72 (3H, m), 2.20-2.32 (4H, m), 2.54 (1H, br), 2.64 (1H, dd, J = 18.6, 5.8 Hz), 2.93 (1H, d, J = 5.8 Hz) , 3.10 (1H, d, J = 18.6 Hz), 3.15 (3H, brd, J = 6.4 Hz), 4.27 (1H, m), 4.44-4.68 (3H, m), 5.19 (3H, m), 5.81 ( 1H, m), 6.63 (1H, d, J = 8.3 Hz), 6.78 (1H, d, J = 8.3 Hz), 7.06-7.55 (3H, m) (free body)
Mass (ESI): 463 (M ⁺ +1)

Example 90
2- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -6-fluoro-2,3-dihydro-isoindol-1-one methanesulfonate (compound 90 )

According to the method described in Examples 25 and 28, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide, it was obtained in Example 58. The obtained N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-fluoro-phthalimide was used to give 86 mg of the free compound of the title compound 90 (yield 48% : 2steps). This was converted to methanesulfonate to give the title compound 90 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
1.48 (1H, m), 1.56 (1H, m), 1.67 (1H, m), 2.08-2.29 (4H, m), 2.53 (1H, d, J = 7.2 Hz), 2.63 (1H, dd, J = 18.4, 5.6 Hz), 2.93 (1H, d, J = 5.2 Hz), 3.10 (1H, d, J = 18.4 Hz), 3.14 (3H, brd, J = 6.8 Hz), 4.23 (1H, m), 4.40 -4.51 (2H, m), 4.66 (1H, d, J = 8.4 Hz), 5.15-5.24 (3H, m), 5.81 (1H, ddt, J = 23.2, 16.8, 6.4 Hz), 6.62 (1H, d , J = 8.4 Hz), 6.77 (1H, d, J = 8.4 Hz) 7.03-7.75 (3H, m) (free body)
Mass (ESI): 463 (M ⁺ +1)

Example 91
Synthesis of N- (14-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-3-hydroxymorphinan-6β-yl) -phthalimide tartrate (compound 91 )

  N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide 100 mg (0.21 mmol) obtained in Example 11 was dissolved in 2.5 mL of pyridine, Acetic anhydride (5.0 mL) was added, and the mixture was stirred at 80 ° C. for 24 hours. After concentrating the reaction solution, adding 5 mL of toluene and concentrating was repeated 5 times to obtain N- (3,14-diacetoxy-17-cyclopropylmethyl-4,5α-epoxy-morphinan-6β as a crude product. -Ill) -phthalimide was obtained.

This crude product was dissolved in 10 mL of ethanol, 1 mL of 28% aqueous ammonia solution was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 50 mg of the title compound 91 free form (yield 46%: 2steps). This was converted to the tartrate salt to give the title compound 91 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.8-7.9 (2H, m), 7.7-7.8 (2H, m), 6.77 (1H, d, J = 8.0 Hz), 6.63 (1H, d, J = 8.0 Hz), 5.15 (1H, d, J = 8.1 Hz), 4.39 (1H, d, J = 5.2 Hz), 4.0-4.1 (1H, m), 3.08 (1H, d, J = 18.3 Hz), 2.65-2.70 (2H, m), 2.4-2.6 ( 3H, m), 2.25-2.35 (2H, m), 2.22 (3H, s), 2.14 (1H, dt, J = 11.9, 3.9 Hz), 1.4-1.5 (3H, m), 0.7-0.8 (1H, m), 0.5 (2H, m), 0.05-0.10 (2H, m) (free body)
Mass (ESI): 514 (M ⁺ )

Example 92
Synthesis of N- (14-acetoxy-17-allyl-4,5α-epoxy-3-hydroxymorphinan-6β-yl) -phthalimide tartrate (compound 92 )

In accordance with the method described in Example 91 and obtained in Example 13 instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide. 66 mg (yield 30%: 2steps) of the title compound 92 was obtained using N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide. . This was converted to the tartrate salt to give the title compound 92 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.8-7.9 (2H, m), 7.7-7.8 (2H, m), 6.78 (1H, d, J = 8.1 Hz), 6.66 (1H, d, J = 8.1 Hz), 5.7-5.8 (1H, m) , 5.1-5.2 (2H, m), 5.15 (1H, d, J = 8.0 Hz), 4.23 (1H, d, J = 5.1 Hz), 4.05-4.15 (1H, m), 3.05-3.15 (2H, m ), 2.4-2.7 (5H, m), 2.22 (3H, s), 2.1-2.2 (2H, m), 1.7 (1H, m), 1.4-1.5 (2H, m) (free body)
Mass (ESI): 500 (M ⁺ )

Example 93
N- (14-acetoxy-17-cyclopropylmethyl-4,5α-epoxy-3-hydroxymorphinan-6β-yl) -2,3,4,5,6,7-hexahydro-isoindol-1-one・ Synthesis of tartrate (compound 93 )

In accordance with the method described in Example 91 and obtained in Example 83 instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide. Using 2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3,4,5,6,7-hexahydro-isoindol-1-one Thus, 38 mg (yield 58%: 2steps) of the free form of the title compound 93 was obtained. This was converted to the tartrate salt to give the title compound 93 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
6.76 (d, 1H, J = 8.2 Hz), 6.59 (d, 1H, J = 8.2 Hz), 4.69 (d, 1H, J = 8.1 Hz), 4.35 (m, 1H), 3.91 (s, 2H), 3.03-3.08 (m, 2H), 2.49-2.74 (m, 3H), 2.16-2.35 (m, 11H), 1.95-2.04 (m, 1H), 1.71-1.73 (m, 3H), 1.35-1.49 (m , 4H), 0.73-0.80 (m, 1H), 0.46-0.58 (m, 2H), 0.08-0.09 (m, 2H) (free body)
Mass (ESI): 504 (M ⁺ )

Example 94
Synthesis of N- (4,5α-epoxy-3,14-dihydroxy-17-propyl-morphinan-6β-yl) -phthalimide / tartrate (compound 94 )

50% (0.11 mmol) of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -phthalimide obtained in Example 13 was dissolved in 10 mL of dichloromethane and 10% Pd / C 10 mg was added, and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 49 mg (100% yield) of the free form of the title compound 94 . This was obtained as the tartrate salt to give the title compound 94 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.8-7.9 (2H, m), 7.7-7.8 (2H, m), 6.77 (1H, d, J = 8.2 Hz), 6.63 (1H, d, J = 8.2 Hz), 5.17 (1H, d, J = 8.2 Hz), 4.0-4.1 (1H, m), 3.10 (1H, d, J = 18.5 Hz), 2.7-2.9 (2H, m), 2.54 (1H, dd, J = 12.0, 4.0 Hz), 2.3- 2.5 (4H, m), 2.15 (1H, m), 1.4-1.7 (6H, m), 0.93 (3H, t, J = 7.3 Hz) (free body)
Mass (ESI): 461 (M ⁺ +1)

Example 95-1
Synthesis of N- (4,5α-epoxy-3-methoxy-17-methyl-morphinan-6β-yl) -phthalimide (compound 295 )

Toluene-4-sulfonic acid- (4,5α-epoxy-3-methoxy-17-methyl-morphinan-6β-yl) -ester 321 mg (0.70 mmol) was dissolved in DMF 15 mL, and phthalimide potassium 196 mg was added. The mixture was stirred at 80 ° C. for 15 hours and further stirred at 140 ° C. for 20 hours. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 116 mg (yield 38%) of the title compound.
Mass (ESI): 431 (M ⁺ +1)

Example 95-2
Synthesis of N- (4,5α-epoxy-3-hydroxy-17-methyl-morphinan-6β-yl) -phthalimide tartrate (compound 95 )

44 mg (0.10 mmol) of N- (4,5α-epoxy-3-methoxy-17-methyl-morphinan-6β-yl) -phthalimide obtained in Example 95-1 was dissolved in 5 mL of methylene chloride, Boron tribromide (0.32 mL) was added at 30 ° C, and the mixture was stirred at 0 ° C for 3 hours. Thereafter, 2 mL of an aqueous ammonia solution was added to the reaction solution and stirred for 1 hour. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 16 mg (yield 37%) of the free form of the title compound 95 . This was obtained as the tartrate salt to give the title compound 95 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.97-8.03 (m, 2H), 7.86-7.92 (m, 2H), 6.78 (d, 1H, J = 8.2Hz), 6.63 (d, 1H, J = 8.2 Hz), 5.07 (d, 1H, J = 8.2 Hz), 4.12-4.20 (ddd, 1H, J = 4.1, 8.2, 13.2 Hz), 3.33-3.75 (m, 1H), 3.18 (d, 1H, J = 18.5 Hz), 2.77 (dd, 1H, J = 3.2, 11.7 Hz), 2.52-2.53 (m, 5H), 2.31-2.45 (m, 2H), 2.16 (dt, 1H, J = 4.7, 12.3 Hz), 1.71-1.87 (m, 3H), 1.21- 1.34 (m, 1H) (free body)
Mass (ESI): 417 (M ⁺ +1)

Example 96
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-hydroxy-phthalimide tartrate (Compound 96 )

In accordance with the method described in Example 11, using 3-hydroxyphthalic anhydride instead of phthalic anhydride, 23 mg (yield 16%) of the free form of the title compound 96 was obtained. This was converted to the tartrate salt to give the title compound 96 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
9.03 (brs, 1H), 7.62 (t, 1H, J = 7.9 Hz), 7.25 (dd, 2H, J = 7.3, 16.4 Hz), 6.60 (dd, 2H, J = 7.8, 14.4 Hz), 5.04 (d , 1H, J = 8.2 Hz), 3.77-3.85 (m, 1H), 3.34 (brs, 1H), 2.98-3.07 (m, 2H), 2.31-2.64 (m, 4H), 1.96-2.02 (m, 1H ), 1.57 (d, 1H, J = 12.5 Hz), 1.41-1.43 (m, 2H), 1.25 (d, 1H, J = 10.3 Hz), 0.79-0.93 (m, 1H), 0.48 (d, 2H, J = 7.9 Hz), 0.14 (d, 2H, J = 4.4 Hz) (free body)
Mass (ESI): 489 (M ⁺ +1)

Example 97-1
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-nitro-phthalimide (Compound 297 )

According to the method described in Example 11, 3-nitrophthalic anhydride was used in place of phthalic anhydride to obtain 151 mg of the title compound as a crude product.
Mass (ESI): 518 (M ⁺ +1)

Example 97-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-amino-phthalimide methanesulfonate (compound 97 )

150 mg of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-nitro-phthalimide obtained as a crude product in Example 97-1 After dissolving in 10 mL, 10% Pd / C 20 mg was added, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 22 mg (yield 10%: 2steps) of the free form of the title compound 97 . This was converted to methanesulfonate to give the title compound 97 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.92 (s, 2H), 6.76 (d, 1H, J = 7.8 Hz), 6.63 (d, 1H, J = 7.8 Hz), 5.11 (d, 1H, J = 8.7 Hz), 4.05-4.08 (m, 1H ), 3.11 (t, 2H, J = 5.7 Hz), 3.03 (s, 1H), 2.59-2.71 (m, 3H), 2.29-2.39 (m, 3H), 2.09-2.17 (m, 2H), 1.69- 1.73 (m, 2H), 1.44-1.48 (m, 2H), 0.86-0.88 (m, 1H), 0.53-0.55 (m, 2H), 0.13-0.14 (m, 2H) (free body)
Mass (ESI): 488 (M ⁺ +1)

Example 98-1
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-nitro-phthalimide (compound 298 )

According to the method described in Example 11, 4-nitrophthalic anhydride was used in place of phthalic anhydride to obtain the title compound as a crude product.
Mass (ESI): 518 (M ⁺ +1)

Example 98-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-amino-phthalimide tartrate (compound 98 )

In accordance with the method described in Example 97-2, instead of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-nitro-phthalimide, Example The title compound was obtained using N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-nitro-phthalimide obtained as a crude product in 98-1. 98 mg of free form 10 mg (yield 15%: 2steps) was obtained. This was converted to the tartrate salt to give the title compound 98 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.56 (brs, 1H), 7.00 (brs, 1H), 6.72-6.80 (brm, 2H), 6.60 (brs, 1H), 5.12 (d, 1H, J = 8.2 Hz), 4.40-4.58 (m, 2H) , 4.00 (brs, 1H), 3.70 (brs, 1H), 2.86-3.07 (m, 3H), 2.63-2.95 (m, 2H), 2.34 (brs, 1H), 1.23-2.11 (m, 4H), 0.86 (brs, 1H), 0.50 (brs, 2H), 0.11 (brs, 2H) (free body)
Mass (ESI): 488 (M ⁺ +1)

Example 99-1
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-nitro-phthalimide (compound 299 )

According to the method described in Example 11, 6β-naloxamine was used in place of 6β-naltrexamine, and 4-nitrophthalic anhydride was used in place of phthalic anhydride to obtain the title compound as a crude product.
Mass (ESI): 504 (M ⁺ +1)

Example 99-2
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-amino-phthalimide tartrate (compound 99 )

N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-nitro-phthalimide obtained as a crude product in Example 99-1 was dissolved in ethanol to produce tin chloride. Dihydrate was added and stirred at 80 ° C. for 8 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 15 mg (yield: 8%: 2steps) of the free form of the title compound 99 . This was converted to the tartrate salt to give the title compound 99 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.55 (d, 1H, J = 7.6 Hz), 6.99 (s, 1H), 6.75-6.79 (m, 2H), 6.62 (d, 1H, J = 8.2 Hz), 5.73-5.87 (m, 1H), 5.15 -5.23 (brs, 3H), 4.50 (brs, 2H), 3.95-4.04 (m, 1H), 3.13 (d, 2H, J = 6.2 Hz), 3.05 (s, 1H), 2.93 (d, 1H, J = 5.3 Hz), 2.52-2.75 (m, 2H), 2.11-2.30 (m, 2H), 1.64-1.67 (m, 1H), 1.37-1.50 (m, 3H), 1.21-1.26 (m, 1H) ( Free body)
Mass (ESI): 474

Example 100-1 (M ⁺ +1)
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-nitro-phthalimide (compound 300 )

According to the method described in Example 11, 6β-naloxamine was used in place of 6β-naltrexamine, and 3-nitrophthalic anhydride was used in place of phthalic anhydride to obtain the title compound as a crude product.
Mass (ESI): 504 (M ⁺ +1)

Example 100-2
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-amino-phthalimide tartrate (compound 100 )

In accordance with the method described in Example 99-2, instead of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4-nitro-phthalimide, Example 100- The free form of the title compound 100 using N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-nitro-phthalimide obtained as a crude product in 1 12 mg (yield 25%: 2steps) was obtained. This was converted to the tartrate salt to give the title compound 100 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.33 (dd, 1H, J = 7.3, 8.2 Hz), 7.09 (d, 1H, J = 7.0 Hz), 6.76 (d, 2H, J = 8.2 Hz), 6.64 (d, 1H, J = 8.2 Hz), 5.74-5.87 (m, 1H), 5.32 (s, 1H), 5.20 (dd, 2H, J = 1.5, 17.2 Hz), 5.13 (d, 1H, J = 8.2 Hz), 3.95-4.03 (m, 1H) , 3.13 (d, 2H, J = 6.4 Hz), 3.06 (s, 1H), 2.93 (d, 1H, J = 5.6 Hz), 2.52-2.79 (m, 2H), 2.10-2.35 (m, 2H), 1.63-1.69 (m, 1H), 1.41-1.53 (m, 3H), 1.23 (t, 1H, J = 7.0 Hz) (free body)
Mass (ESI): 474 (M ⁺ +1)

Example 101
Synthesis of N- (4,5α-epoxy-3,14-dihydroxy-17-propyl-morphinan-6β-yl) -3-amino-phthalimide tartrate (Compound 101 )

N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-nitro-phthalimide obtained as a crude product in Example 100-1 was dissolved in methanol, 10% Pd / C was added and stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 10 mg of free form of the title compound 101 (yield 53%: 2steps). This was converted to the tartrate salt to give the title compound 101 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.33 (t, 1H, J = 7.8 Hz), 7.09 (d, 1H, J = 7.2 Hz), 6.77 (d, 2H, J = 8.1 Hz), 6.64 (d, 1H, J = 7.8 Hz), 5.33 ( bs, 2H), 5.14 (d, 1H, J = 7.8 Hz), 4.00 (ddd, 1H, J = 4.5, 8.3, 13.1 Hz), 3.10 (d, 1H, J = 18.0 Hz), 2.90 (d, 1H , J = 5.5 Hz), 2.15-2.79 (m, 8H), 1.26-1.70 (m, 8H) (free body)
Mass (ESI): 476 (M ⁺ +1)

Example 102-1
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -3-hydroxy-phthalimide (Compound 302 )

In accordance with the method described in Example 11, instead of 6β-naltrexamine, 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol 166 mg (0.44 mmol), phthalate Using 3-hydroxyphthalic anhydride instead of acid anhydride and toluene instead of DMF as a solvent, the mixture was heated to reflux for 20 hours to give 119 mg of the title compound 302 (yield 52%).
Mass (ESI): 533 (M ⁺ +1)

Example 102-2
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -3-methoxy-phthalimide tartrate (compound 102 )

  N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -3-hydroxy-phthalimide obtained in Example 102-1 119 mg (0.22 mmol) ) Was dissolved in 5 mL of DMF, 93 mg of potassium carbonate and 0.02 mL of methyl iodide were added, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxy as a crude product. 112 mg of methoxy-morphinan-6β-yl) -3-methoxy-phthalimide were obtained.

112 mg of the obtained N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -3-methoxy-phthalimide was added to 10 mL of methanol and 4 mL of chloroform. After dissolving, 0.1 mL of concentrated hydrochloric acid was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 9.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 115 mg (yield 100%: 2steps) of the free form of the title compound 102 . This was converted to the tartrate salt to give the title compound 102 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.64 (dd, 1H, J = 7.3, 8.2 Hz), 7.42 (d, 1H, J = 7.3 Hz), 7.18 (d, 1H, J = 8.5 Hz), 6.74 (d, 1H, J = 7.9 Hz), 6.60 (d, 1H, J = 8.2 Hz), 5.18 (d, 1H, J = 8.2 Hz), 3.98-4.07 (m, 4H), 2.58-3.10 (m, 5H), 2.26-2.38 (m, 3H) , 2.12 (dt, 1H, J = 3.5, 12.0 Hz), 1.64-1.70 (m, 1H), 1.42-1.53 (m, 3H), 0.78-0.91 (m, 1H), 0.49-0.55 (m, 2H) , 0.10-0.14 (m, 2H) (free body)
Mass (ESI): 503 (M ⁺ +1)

Example 103
Synthesis of 2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -1,2-dihydro-indazol-3-one tartrate (compound 103 )

6β-Naltrexamine 100 mg (0.29 mmol) was dissolved in THF 10 mL, sodium carbonate 132 mg and 2-nitrobenzoyl chloride 108 mg were added, and the mixture was stirred at room temperature for 1 hour. After concentrating the solvent under reduced pressure, 5 mL of ethanol and 4 mL of 1N NaOH aqueous solution were added, and the mixture was stirred at room temperature for 30 minutes. Then, 96 mg of Zn powder was added and heated to reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 29 mg (yield 22%) of the free form of the title compound 103 . This was obtained as the tartrate salt to give the title compound 103 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.82 (d, 1H, J = 8.0 Hz), 7.49 (t, 1H, J = 8.0 Hz), 7.24 (d, 1H, J = 8.0 Hz), 7.17 (t, 1H, J = 8.0 Hz), 6.79 ( d, 1H, J = 8.0 Hz), 6.60 (d, 1H, J = 8.0 Hz), 4.89 (d, 1H, J = 7.7 Hz), 4.44 (ddd, 1H, J = 4.5, 8.3, 13.1 Hz), 3.16 (d, 1H, J = 5.5 Hz), 2.98-3.09 (m, 3H), 2.61-2.69 (m, 2H), 2.43-2.50 (m, 2H), 2.15-2.12 (m, 2H), 1.27- 1.76 (m, 4H), 0.83-0.85 (m, 1H), 0.51-0.57 (m, 2H), 0.13-0.14 (m, 2H) (free body)
Mass (ESI): 460 (M ⁺ +1)

Example 104
Synthesis of 3- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -1H-quinazoline-2,4-dione tartrate (compound 104 )

  100 mg (0.29 mmol) of 6β-naltrexamine was dissolved in 10 mL of THF, 132 mg of sodium carbonate and 108 mg of 2-nitrobenzoyl chloride were added, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, 5 mL of methanol and 4 mL of 1N NaOH aqueous solution were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a residue.

  The obtained residue was dissolved in 5 mL of methanol, 20% of 10% Pd / C was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and 2-amino-N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -benzamide 90 mg (Yield 67%) was obtained.

80 mg of the obtained 2-amino-N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -benzamide was dissolved in dichloromethane, and 1,1′-carbonyl 42 mg of diimidazole was added and stirred at room temperature for 12 hours. After evaporating the solvent under reduced pressure, 4 mL of THF and 4 mL of 1N HCl aqueous solution were added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 27 mg (yield 32%) of the free form of the title compound 104 . This was converted to the tartrate salt to give the title compound 104 .

¹ H-NMR (ppm) (400 MHz, CDCl ₃ )
7.55 (d, 1H, J = 7.7 Hz), 7.45 (t, 1H, J = 7.7 Hz), 6.91 (t, 1H, J = 7.7 Hz), 6.84 (d, 1H, J = 8.2 Hz), 6.75 ( d, 1H, J = 8.2 Hz), 6.70 (d, 1H, J = 8.2 Hz), 5.62 (d, 1H, J = 8.2 Hz), 4.92 (ddd, 1H, J = 4.5, 8.3, 13.1 Hz), 2.99-3.18 (m, 3H), 2.21-2.75 (m, 5H), 1.45-1.98 (m, 6H), 0.83-0.85 (m, 1H), 0.55-0.58 (m, 2H), 0.16-0.18 (m , 2H) (free body)
Mass (ESI): 488 (M ⁺ +1)

Example 105
3- (17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2-thiooxo-2,3-dihydro-1H-quinazolin-4-one tartrate (compound 105 ) Synthesis

In accordance with the method described in Example 104, using 1,1′-thiocarbonyldiimidazole instead of 1,1′-carbonyldiimidazole, free form 10 mg of the title compound 105 (yield 13%: 2steps) Got. This was converted to the tartrate salt to give the title compound 105 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.91 (d, 1H, J = 7.4 Hz), 7.63 (t, 1H, J = 7.4 Hz), 7.23 (t, 1H, J = 7.4 Hz), 7.08 (d, 1H, J = 8.2 Hz), 6.79 ( d, 1H, J = 8.0 Hz), 6.66 (d, 1H, J = 8.2 Hz), 5.85 (ddd, 1H, J = 4.5, 8.3, 13.1 Hz), 5.55 (d, 1H, J = 8.2 Hz), 2.98-3.16 (m, 3H), 2.63-2.71 (m, 2H), 2.17-2.47 (m, 4H), 1.52-1.74 (m, 5H), 0.86-0.90 (m, 1H), 0.53-0.58 (m , 2H), 0.15-0.18 (m, 2H) (free body)
Mass (ESI): 504 (M ⁺ +1)

Example 106
Synthesis of 2- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -4H-isoquinoline-1,3-dione tartrate (compound 106 )

In accordance with the method described in Example 11, using homophthalic anhydride instead of phthalic anhydride, pyridine instead of triethylamine, and toluene instead of DMF as a solvent, the mixture was heated to reflux for 10 hours to give the title compound 106 . A free form 12 mg (yield 17%) was obtained. This was obtained as the tartrate salt to give the title compound 106 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
8.21 (d, 1H, J = 7.4 Hz), 7.58 (t, 1H, J = 7.4 Hz), 7.44 (t, 1H, J = 7.4 Hz), 7.25 (d, 1H, J = 7.4 Hz), 6.72 ( d, 1H, J = 8.2 Hz), 6.65 (d, 1H, J = 8.2 Hz), 5.32 (d, 1H, J = 8.2 Hz), 4.80 (ddd, 1H, J = 4.5, 8.3, 13.1 Hz), 4.06 (s, 2H), 2.89-3.12 (m, 3H), 2.59-2.69 (m, 3H), 2.10-2.40 (m, 4H), 1.24-1.70 (m, 4H), 0.84-0.90 (m, 1H ), 0.51-0.57 (m, 2H), 0.13-0.16 (m, 2H) (free body)
Mass (ESI): 487 (M ⁺ +1)

Example 107
2- (17-Cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -benzo [1,3,2] dithiazole-1,1,3,3-tetraoxide methane Synthesis of sulfonate (compound 107 )

  117 mg (0.30 mmol) of 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol was dissolved in 5 mL of dichloromethane, 0.04 mL (0.29 mmol) of triethylamine, benzene- 1,2-Disulfonyl-dichloride 79 mg (0.31 mmol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxy as a crude product. 192 mg of methoxy-morphinan-6β-yl) -benzo [1,3,2] dithiazole-1,1,3,3-tetraoxide was obtained.

192 mg of the obtained crude product was dissolved in 3 mL of 1,4-dioxane, 0.3 mL of concentrated hydrochloric acid and 1 mL of 2-propanol were added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography to obtain 76 mg (yield 46%: 2steps) of the free form of the title compound 107 . This was converted to the tartrate salt to give the title compound 107 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
8.03-8.00 (m, 2H), 7.94-7.90 (m, 2H), 6.79 (d, 1H, J = 8.2 Hz), 6.65 (d, 1H, J = 8.2 Hz), 5.25 (d, 1H, J = 8.5 Hz), 3.95 (ddd, 1H, J = 4.1, 8.5, 13.8 Hz), 3.10 (d, 1H, J = 7.6 Hz), 3.06 (d, 1H, J = 19.0 Hz), 2.86-2.56 (m, 3H), 2.38 (d, 2H, J = 6.4 Hz), 2.33 (m, 1H), 2.15 (ddd, 1H, J = 3.8, 12.0, 12.0), 2.01 (m, 1H), 1.78 (m, 1H) , 1.57-1.43 (m, 3H), 0.85 (m, 1H), 0.57-0.51 (m, 2H), 0.16-0.11 (m, 2H) (free body)
Mass (ESI): 545 (M ⁺ +1)

Example 108
Synthesis of N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -O-sulfonebenzoic acid imide tartrate (compound 108 )

  203 mg (0.53 mmol) of 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol was dissolved in 10 mL of chloroform, and 0.15 mL of triethylamine and methyl- 136 mg of (2-chlorosulfonyl) -benzoate was added, stirred at room temperature for 8 hours, and then heated to reflux for 30 minutes. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 2-[(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -sulfamoyl]- 219 mg (yield 71%) of methyl benzoate was obtained.

  Obtained 2-[(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -sulfamoyl] -benzoic acid methyl ester 91 mg (0.16 mmol) in DMF After dissolving in 10 mL, 352 mg of potassium carbonate was added, and the mixture was stirred at 80 ° C. for 3 hours. After allowing the reaction solution to cool to room temperature, the reaction solution is filtered through Celite, and the filtrate is concentrated to give N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy as a crude product. -Morhinan-6β-yl) -O-sulfonebenzoic imide was obtained.

The obtained crude product was dissolved in 2 mL of 2-propanol and 2 mL of chloroform, 0.2 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 67 mg (yield 85%: 2steps) of the free form of the title compound 108 . This was converted to the tartrate salt to give the title compound 108 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
8.06-8.08 (m, 1H), 7.82-7.97 (m, 3H), 6.80 (d, 1H, J = 8.1 Hz), 6.65 (d, 1H, J = 8.1 Hz), 5.28 (d, 1H, J = 8.3 Hz), 3.92 (ddd, 1H, J = 3.9, 8.3, 13.1 Hz), 3.11 (d, 1H, J = 5.6 Hz), 3.06 (d, 1H, J = 18.3 Hz), 2.78-2.87 (m, 1H), 2.60-2.70 (m, 2H), 2.32-2.39 (m, 3H), 2.13-2.20 (m, 1H), 1.46-1.76 (m, 4H), 0.82-0.88 (m, 1H), 0.52- 0.57 (m, 2H), 0.12-0.15 (m, 2H) (free body)
Mass (ESI): 509 (M ⁺ +1)

Example 109
Synthesis of N- (17-allyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -O-sulfonebenzoic acid imide / tartrate (compound 109 )

In accordance with the method described in Example 108, instead of 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol, 17-allyl-6β-amino-4,5α 8.7 mg of the free form of the title compound 109 was obtained using -epoxy-3-methoxymethoxy-morphinan-14-ol. This was converted to the tartrate salt to give the title compound 109 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.99-8.08 (m, 2H), 7.50-7.92 (m, 4H), 6.61-6.81 (m, 2H), 5.74-5.85 (m, 1H), 5.27 (d, 1H, J = 8.3 Hz), 3.89- 3.96 (m, 1H), 3.08-3.15 (m, 3H), 2.94-3.03 (m, 3H), 2.48-2.66 (m, 1H), 2.29-2.36 (m, 1H), 2.13-2.20 (m, 2H ), 1.45-1.75 (m, 3H) (free body)
Mass (ESI): 495 (M ⁺ +1)

Example 110
N- (17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxy-morphinan-6β-yl) -2,3-dihydro-benzo [d] isothiazole-1,1-dioxide / tartrate Synthesis of (compound 110 )

  N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl) -O-sulfone benzoic acid imide 37 mg (as intermediate of Example 108) 0.07 mmol) was dissolved in 5 mL of THF, 1.03 M borane / THF complex 2.0 mL was added, and the mixture was heated to reflux for 3 days. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give N- (17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxy as a crude product. Methoxy-morphinan-6β-yl) -2,3-dihydro-benzo [d] isothiazole-1,1-dioxide was obtained.

The obtained crude product was dissolved in 3 mL of 2-propanol and 1 mL of chloroform, 0.3 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 22 mg (yield 67%: 2steps) of the free form of the title compound 110 . This was converted to the tartrate salt to give the title compound 110 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
7.79 (d, 1H, J = 7.8 Hz), 7.61 (m, 1H), 7.53 (m, 1H), 7.44 (d, 1H, J = 7.8 Hz), 6.77 (d, 1H, J = 7.8 Hz), 6.62 (d, 1H, J = 8.3 Hz), 4.65 (d, 1H, J = 8.3 Hz), 4.59 (s, 2H), 3.64-3.70 (m, 1H), 3.10 (d, 1H, J = 5.6 Hz ), 3.04 (d, 1H, J = 18.3 Hz), 2.60-2.67 (m, 2H), 2.38 (d, 2H, J = 6.6 Hz), 2.21-2.33 (m, 2H), 2.13-2.19 (m, 1H), 1.78-1.83 (m, 1H), 1.68-1.72 (m, 1H), 1.50-1.59 (m, 2H), 0.81-0.86 (m, 1H), 0.51-0.56 (m, 2H), 0.10- 0.14 (m, 2H) (free body)
Mass (ESI): 495 (M ⁺ +1)

Example 111
Synthesis of 17-cyclopropylmethyl-4,5α-epoxy-6β- (pyrrolidin-1-yl) -morphinan-3,14-diol tartrate (compound 111 )

Naltrexone benzoate (200 mg, 0.43 mmol) was dissolved in benzene (20 ml), pyrrolidine (2 mL) was added, and the mixture was heated to reflux for 16 hours while azeotropically removing water in an oil bath at 100 ° C. The reaction solution was allowed to cool to room temperature, 10 mL of a methanol solution of 81 mg (1.29 mmol) of sodium cyanoborohydride was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain 142 mg (yield 83%) of the free form of the title compound 111 . This was converted to the tartrate salt to give the title compound 111 .

¹ H-NMR (ppm) (300 MHz, CDCl ₃ )
6.73 (1H, d, J = 8.1 Hz), 6.58 (1H, d, J = 8.1 Hz), 4.66 (1H, d, J = 6.9 Hz), 3.10 (1H, d, J = 5.6 Hz), 3.04 ( 1H, d, J = 18.3 Hz), 2.5-2.8 (6H, m), 2.38 (2H, d, J = 6.6 Hz), 2.1-2.4 (5H, m), 1.90-2.05 (1H, m), 1.8 (2H, m), 1.7 (1H, m), 1.65 (1H, m), 1.5 (1H, m), 1.4 (1H, m), 0.8-0.9 (1H, m), 0.5-0.6 (2H, m ), 0.1-0.2 (2H, m) (free body)
Mass (ESI): 397 (M ⁺ +1)

Example 112
Inhibitory effect on rat rhythmic bladder contraction
SD female rats were anesthetized by intraperitoneal administration of urethane (1.0 g / kg). A polyethylene tube is inserted into the bladder through the urethral orifice of the animal and fixed by ligation, and then physiological saline is injected through the tube as appropriate (injection rate: approx. 0.2 ml / min, max. Approx. 1.5 ml / animal). Was expressed. The rhythmic contraction movement of the bladder was monitored by measuring the intravesical pressure through a polyethylene tube inserted into the bladder. After confirming that stable rhythmic contraction movement was observed at least 10 times, each dose solution of the test compound was intravenously administered at a dose of 1 ml / kg. If the intravesical pressure is 50% or less of the intravesical pressure shown immediately after administration within 10 minutes after administration of the test compound, it is determined that there is a bladder contraction suppressing action, and the time until the intravesical pressure of 50% or more is shown again. It was set as the rhythmic bladder contraction suppression time. As test compound administration solvent, test compounds 4 , 7 , 8 , 9 , 10 , 13 , 29 , 30 , 31 , 33 , 34 , 75 , 76 , 79 , 80 , 81 , 82 , 84 , 89 , 90 , 91 93 , 94 , 95 , 110 and 111 , saline, and test compounds 11 , 12 , 14 , 15 , 16 , 17 , 18 , 20 , 21 , 21 , 23 , 28 , 46 , 47 , 50 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 77 , 78 , 83 , 85 , 86 , 87 , 88 , 92 , 96 , 97 , 98 , 99 , 100 , 102 , 103 , 104 , 105 , 106 , 107 , 108 and 109 are treated with 10% dimethyl sulfoxide (DMSO) aqueous solution and test compounds 1 , 2 , 67 and 101 Used 20% dimethyl sulfoxide (DMSO) aqueous solution, and 5% Xylitol aqueous solution was used for test compounds 5 and 35 . In addition, 10% DMSO aqueous solution, 20% DMSO aqueous solution, and 5% xylitol aqueous solution affecting rhythmic bladder contraction suppression time were also examined at a dose of 1 ml / kg. The results are shown in Table 6. In any of the compounds, the rhythmic bladder contraction suppression time was prolonged as compared with the administration group of only the solvent used.

  From the above, it was revealed that the compounds of the present invention have an excellent therapeutic or preventive effect on frequent urination or urinary incontinence.

  The compound of the present invention is useful as a novel therapeutic or preventive agent for pollakiuria or urinary incontinence with isolated side effects.

Claims (20)

Formula (I)

[Wherein R ¹ is hydrogen, alkyl having 1 to 5 carbon atoms, cycloalkyl alkyl having 4 to 7 carbon atoms, cycloalkenyl alkyl having 6 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, or 7 to 13 carbon atoms. Aralkyl, alkenyl having 3 to 7 carbon atoms, furanyl alkyl (the alkyl part has 1 to 5 carbon atoms), thienyl alkyl (the alkyl part having 1 to 5 carbon atoms), or pyridylalkyl (the alkyl part having 1 carbon atom) To R), R ² and R ³ are each independently hydrogen, hydroxy, alkoxy having 1 to 5 carbons, alkenyloxy having 3 to 7 carbons, aralkyloxy having 7 to 13 carbons, or 1 to 5 carbons Represents alkanoyloxy, Y and Z independently represent a valence bond, or -C (= O)-, and -X- represents a carbon chain having 2 to 7 carbon atoms that is part of the ring structure (but one or more of them) Carbon atoms are replaced by nitrogen, oxygen, or sulfur atoms May have I, the carbon chain represents may) be contained unsaturated bonds, k is an integer of 0 to 8, R ⁴ is an k-number of the substituents on the nitrogen-containing cyclic structure , Fluorine, chlorine, bromine, iodine, nitro, hydroxy, C1-C5 alkyl, C7-C13 cycloalkylalkyl, C6-C12 aryl, C7-C13 aralkyl, carbon Aralkyloxy having 7 to 13 carbon atoms, alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , (CH ₂ ) _p N (R ⁷ ) COR ⁸ carded, among the k R ^4, the same two carbonyl R ⁴ is is one of an oxygen atom group or sulfoxide group attached to a carbon atom or a sulfur atom, the same 2 R ⁴ bonded to the carbon atom of 1 is a sulfur atom to form a thiocarbonyl group, 4 R ⁴ bonded to the same sulfur atom is a 2 oxygen atom to represent a sulfone group, or a benzene fused ring, a pyridine fused ring, a naphthalene fused ring in which two R ⁴ groups each substituting for adjacent carbons out of k R ⁴ groups are unsubstituted or substituted with one or more substituents R ⁵ ; Represents a cyclopropane condensed ring, a cyclobutane condensed ring, a cyclopentane condensed ring, a cyclopentene condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring, and R ⁵ each independently represents fluorine, chlorine, bromine , Iodine, nitro, hydroxy, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, trifluoromethyl, trifluoromethoxy, cyano, 6 to 12 carbon atoms Aryl, ^{isothiocyanato, SR 6, SOR 6, SO} 2 R 6, (CH 2) p OR 6, (CH 2) p COR 6, (CH 2) p CO 2 R 6, SO 2 NR 7 R 8, CONR 7 R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , (CH ₂ ) _p N (R ⁷ ) represents COR ⁸ , R ⁹ is hydrogen, alkyl having 1 to 5 carbons, alkenyl having 1 to 5 carbons, carbon Represents an aralkyl having 7 to 13 carbon atoms, a hydroxyalkyl having 1 to 3 carbon atoms, (CH ₂ ) _p OR ⁶ , or (CH ₂ ) _p CO ₂ R ⁶ , and R ¹⁰ and R ¹¹ are bonded to each other by -O-, -S-, or -CH _2- , or R ¹⁰ is hydrogen, R ¹¹ is hydrogen, hydroxy, alkoxy having 1 to 5 carbons, or alkanoyloxy having 1 to 5 carbons, and p is 0 And R ⁶ represents hydrogen, alkyl having 1 to 5 carbons, alkenyl having 3 to 7 carbons, aryl having 6 to 12 carbons, or aralkyl having 7 to 13 carbons, R ⁷ , R ⁸ are each independently hydrogen, alkyl of 1 to 5 carbon atoms or carbon, Therapeutic or prophylactic agent for pollakiuria or urinary incontinence containing morphinan derivative or its pharmacologically acceptable acid addition salt thereof, as an active ingredient having a nitrogen-containing heterocyclic group represented by 7 of the 13 aralkyl.   2. The therapeutic or preventive agent for pollakiuria or urinary incontinence according to claim 1, wherein in general formula (I), only one of Y and Z is —C (═O) — and the other is a valence bond.   The therapeutic or prophylactic agent for pollakiuria or urinary incontinence according to claim 1, wherein Y and Z are both -C (= O)-in the general formula (I). In the general formula (I), R ¹ is hydrogen, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 6 to 8 carbons, aryl having 6 to 12 carbons, or alkenyl having 3 to 7 carbons , A benzene fused ring, a pyridine fused ring, a naphthalene fused ring, a cyclopropane fused ring, a cyclobutane in which two R ⁴ groups each substituted on adjacent carbons are unsubstituted or substituted with one or more substituents R ⁵ 4. The therapeutic or preventive agent for pollakiuria or urinary incontinence according to claim 3, which forms a condensed ring, a cyclopentane condensed ring, a cyclopentene condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring. In the general formula (I), R ¹ is hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, or prenyl, and R ² is hydrogen, hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, Acetoxy or propionoxy, R ³ is hydrogen, hydroxy, methoxy, ethoxy, benzyloxy, acetoxy or propionoxy,
k is an integer from 0 to 6, a two R ⁴ together unsubstituted or benzene fused ring substituted by 1 to 4 substituents R ^5, independently R ⁵ are each fluorine , chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, ^{isothiocyanato, SR 6, SOR 6, SO} 2 R 6, (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ⁸ , or (CH ₂ ) _p N (R ⁷ ) COR ⁸ , p is an integer from 0 to 5, R ⁶ is hydrogen, methyl, ethyl, propyl, or phenyl, and R ⁷ and R ⁸ are independently hydrogen, methyl , Ethyl, propyl, or benzyl, R ⁹ is hydrogen, or methyl, R ¹⁰ , R ¹¹ are bonded to —O—, or R ¹⁰ is hydrogen, R 4. The therapeutic or prophylactic agent for pollakiuria or urinary incontinence according to claim 3, wherein ¹¹ is hydrogen, hydroxy, or methoxy.   2. The therapeutic or prophylactic agent for pollakiuria or urinary incontinence according to claim 1, wherein Y and Z are both valence bonds in general formula (I). In general formula (I), R ¹ is hydrogen, alkyl having 1 to 5 carbon atoms, aralkyl having 7 to 13 carbon atoms, furanyl alkyl (wherein the alkyl portion has 1 to 5 carbon atoms), thienyl alkyl (wherein the alkyl portion) Is 1 to 5 carbon atoms, or pyridylalkyl (wherein the alkyl portion has 1 to 5 carbon atoms), and two adjacent R ⁴ substituents are substituted together to form an unsubstituted or 1 or more Benzene fused ring, pyridine fused ring, naphthalene fused ring, cyclopropane fused ring, cyclobutane fused ring, cyclopentane fused ring, cyclopentene fused ring, cyclohexane fused ring, cyclohexene fused ring, cycloheptane fused ring substituted with substituent R ⁵ Or a therapeutic or preventive agent for pollakiuria or urinary incontinence according to claim 6, which forms a cycloheptene fused ring. In the general formula (I), R ¹ is hydrogen, methyl, ethyl, propyl, benzyl, phenethyl, phenylpropyl, 2-furanylmethyl, 2-furanylethyl, 2-furanylpropyl, 3-furanylmethyl, 3-furanylethyl, 3-furanyl Nylpropyl, 2-thiophenylmethyl, 2-thiophenylethyl, 2-thiophenylpropyl, 3-thiophenylmethyl, 3-thiophenylethyl, 3-thiophenylpropyl, 2-pyridinylmethyl, 2-pyridinylethyl, 2-pyridinyl Dinylpropyl, 3-pyridinylmethyl, 3-pyridinylethyl, 3-pyridinylpropyl, 4-pyridinylmethyl, 4-pyridinylethyl, or 4-pyridinylpropyl, and R ² is hydrogen, hydroxy, methoxy, ethoxy, allyloxy , Benzyloxy, acetoxy or propionoxy and R ³ is hydrogen, hydroxy, Benzene which is toxi, ethoxy, benzyloxy, acetoxy or propionoxy, k is an integer from 0 to 6 and 2 R ⁴ together are unsubstituted or substituted by 1 to 4 substituents R ⁵ A fused ring, and each other R ⁴ is independently methyl, ethyl, propyl, or benzyl, or a carbonyl group in which two R ⁴ bonded to the same carbon atom become one oxygen atom. , R ⁵ are each independently fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , (CH ₂ ) _p NR ⁷ R ^8, or _{(CH 2) p N (R} 7) a COR ^8, an integer from p is 0 5 There, R ⁶ is hydrogen, methyl, ethyl, propyl or phenyl, R ^7, R ⁸ are each a independently hydrogen, methyl, ethyl, propyl or benzyl, are R ⁹ is hydrogen or methyl, 7. The therapeutic or prophylactic agent for pollakiuria or urinary incontinence according to claim 6, wherein R ¹⁰ and R ¹¹ are combined to form —O—, or R ¹⁰ is hydrogen, and R ¹¹ is hydrogen, hydroxy, or methoxy.   Treatment for frequent urination, urgency or urinary incontinence using the morphinan derivative having a nitrogen-containing cyclic substituent according to any one of claims 1 to 8, or a pharmacologically acceptable acid addition salt thereof Or prevention methods.   Use for urinary frequency, urgency or urinary incontinence using the morphinan derivative having a nitrogen-containing cyclic substituent according to any one of claims 1 to 8, or a pharmacologically acceptable acid addition salt thereof . Formula (II)

[Wherein R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ , R ¹¹ are the same as defined above, and R ^{4 ′} , X ′, Y ′, Z ′, k ′ are the same as R ⁴ , X Represents the same definition as Y, Z, and k, but Y 'and Z' are simultaneously valence bonds and X 'is-(CH ₂ ) ₄ -,-(CH ₂ ) ₅ -,-(CH ₂ ) ₂ In the case of —O— (CH ₂ ) ₂ —, k ′ must be 1 or more, and Y ′ and Z ′ are simultaneously —C (═O) — and X ′ is a ring structure composed of two carbons. In the case of a constituent chain, k ′ must be 1 or more, and in particular, when (R ^{4 ′} ) k ′ is a benzene condensed ring, the benzene ring must be substituted with R ⁵ ]. A morphinan derivative having a nitrogen cyclic substituent, or a pharmaceutically acceptable acid addition salt thereof.   12. In the general formula (II), only one of Y ′ and Z ′ is —C (═O) —, and the other is a valence bond. Acid addition salts.   12. The morphinan derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 11, wherein Y ′ and Z ′ are both —C (═O) — in the general formula (II). In the general formula (II), R ¹ represents hydrogen, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 6 to 8 carbon atoms, aryl having 6 to 12 carbon atoms, or alkenyl having 3 to 7 carbon atoms. A benzene fused ring, a pyridine fused ring, a naphthalene fused ring, a cyclopropane fused ring, in which two R ^{4 ′s} each substituted on adjacent carbons are unsubstituted or substituted with one or more substituents R ⁵ , The morphinan derivative according to claim 13, which forms a cyclobutane condensed ring, a cyclopentane condensed ring, a cyclopentene condensed ring, a cyclohexane condensed ring, a cyclohexene condensed ring, a cycloheptane condensed ring, or a cycloheptene condensed ring, or a pharmaceutically acceptable salt thereof. Acid addition salt. In the general formula (II), R ¹ is hydrogen, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, allyl, or prenyl, and R ² is hydrogen, hydroxy, methoxy, ethoxy, allyloxy, benzyloxy, Acetoxy or propionoxy, R ³ is hydrogen, hydroxy, methoxy, ethoxy, benzyloxy, acetoxy or propionoxy, k ′ is an integer from 0 to 6 and two R ^{4 ′} are not taken together a benzene fused ring which is substituted by substituted or 1 to 4 substituents R ^5, independently R ⁵ are each fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, Ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato _{^{SR 6, SOR 6, SO 2}} R 6, (CH 2) p OR 6, (CH 2) p COR 6, (CH 2) p CO 2 R 6, SO 2 NR 7 R 8, CONR 7 R 8, ( CH _{2) p} NR ⁷ R ⁸ or _{(CH 2) p N (R} 7,) a COR ^8, p is an integer from 5 to 0, R ⁶ is hydrogen, methyl, ethyl, propyl or phenyl, , R ⁷ and R ⁸ are each independently hydrogen, methyl, ethyl, propyl, or benzyl, R ⁹ is hydrogen or methyl, and R ¹⁰ , R ¹¹ are combined to be -O-, or 14. The morphinan derivative or a pharmacologically acceptable acid addition salt thereof according to claim 13, wherein R ¹⁰ is hydrogen and R ¹¹ is hydrogen, hydroxy, or methoxy.   12. The morphinan derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 11, wherein Y ′ and Z ′ in the general formula (II) are valence bonds. In general formula (II), R ¹ is hydrogen, alkyl having 1 to 5 carbons, aralkyl having 7 to 13 carbons, furanylalkyl (wherein the alkyl part has 1 to 5 carbons), thienylalkyl (wherein the alkyl part) Is 1 to 5 carbon atoms, or pyridylalkyl (wherein the alkyl moiety has 1 to 5 carbon atoms), and two R ^{4 ′s} each substituting for adjacent carbons are unsubstituted or 1 or more together benzene fused ring which is substituted with a substituent R ^5, pyridine fused ring, naphthalene fused ring, cyclopropane fused ring, cyclobutane fused ring, cyclopentane fused ring, cyclopentene fused ring, cyclohexane fused ring, cyclohexene fused ring, cycloheptane fused 17. The morphinan derivative according to claim 16, or a pharmacologically acceptable acid addition salt thereof, which forms a ring or a cycloheptene condensed ring. In the general formula (II), R ¹ is hydrogen, methyl, ethyl, propyl, benzyl, phenethyl, phenylpropyl, 2-furanylmethyl, 2-furanylethyl, 2-furanylpropyl, 3-furanylmethyl, 3-furanylethyl, 3-furanyl Nylpropyl, 2-thiophenylmethyl, 2-thiophenylethyl, 2-thiophenylpropyl, 3-thiophenylmethyl, 3-thiophenylethyl, 3-thiophenylpropyl, 2-pyridinylmethyl, 2-pyridinylethyl, 2-pyridinyl Dinylpropyl, 3-pyridinylmethyl, 3-pyridinylethyl, 3-pyridinylpropyl, 4-pyridinylmethyl, 4-pyridinylethyl, or 4-pyridinylpropyl, and R ² is hydrogen, hydroxy, methoxy, ethoxy, allyloxy , benzyloxy, and acetoxy or propionoxy, it is R ^3, hydrogen, hydroxy, Butoxy, ethoxy, benzyloxy, an acetoxy or propionoxy, k 'is an integer from 0 to 6, two R ^4' is replaced together from unsubstituted or 1 to 4 substituents R ⁵ Benzene condensed ring, and each other R ^{4 ′} is independently methyl, ethyl, propyl, or benzyl, or two R ^{4 ′} bonded to the same carbon atom become one oxygen atom A carbonyl group, and each R ⁵ is independently fluorine, chlorine, bromine, iodine, nitro, methyl, ethyl, propyl, benzyl, hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR ⁶ , SOR ⁶ , SO ₂ R ⁶ , (CH ₂ ) _p OR ⁶ , (CH ₂ ) _p COR ⁶ , (CH ₂ ) _p CO ₂ R ⁶ , SO ₂ NR ⁷ R ⁸ , CONR ⁷ R ⁸ , ( CH ₂ ) _p NR ⁷ R ⁸ , or (CH ₂ ) _p N (R ⁷ ) COR ⁸ and p is an integer from 0 to 5. R ⁶ is hydrogen, methyl, ethyl, propyl or phenyl; R ⁷ and R ⁸ are each independently hydrogen, methyl, ethyl, propyl or benzyl; R ⁹ is hydrogen or methyl; 17. The morphinan derivative according to claim 16, or R ¹⁰ , R ¹¹ bonded to -O-, or R ¹⁰ is hydrogen, and R ¹¹ is hydrogen, hydroxy, or methoxy, or a pharmacologically thereof Acceptable acid addition salt.   A medicament comprising the morphinan derivative according to any one of claims 11 to 18 or a pharmaceutically acceptable acid addition salt thereof.   19. A pharmaceutical composition comprising the morphinan derivative according to any one of claims 11 to 18 or a pharmaceutically acceptable acid addition salt thereof.