JP2985322B2 - Isoquinoline derivatives and their pharmaceutical uses - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to compounds having affinity for the delta opioid receptor. Delta opioid receptors are involved in analgesia, immunity, and the circulatory system (especially blood pressure), and highly selective ligands for these receptors are analgesics, immunosuppressants,
It can be used as a drug such as an immunopotentiator or an antihypertensive.

[0002]

2. Description of the Related Art The delta opioid receptor has many pharmacological actions as described above, and compounds having high selectivity for this receptor are expected as analgesics, immunosuppressants, immunopotentiators, and hypotensives. Have been. However, ligands with high selectivity for delta receptors have not been discovered until recently, except for peptides. Peptide-based compounds have the drawback that they do not easily pass through the blood-brain barrier and are easily degraded by peptidases in the body, so that their development as the above drugs has been difficult. Recently, Portog
have discovered NTI, a highly selective antagonist for the delta opioid receptor (PSPortoghese et al.
al., J. Med. Chem., 31, 281, (1988)). This NTI is an alkaloid, and unlike the peptide, the problem of passage through the blood-brain barrier and the problem of decomposition by peptidase are solved. However, NTI has many problems such as high production cost because it is synthesized from naltrexone as a raw material, and naltrexone is difficult to obtain because it is synthesized from the drug, thebaine. On the other hand, peptides such as DADLE and DPDPE are known as delta receptor agonists, but alkaloids with high selectivity have not yet been developed.

[0003]

SUMMARY OF THE INVENTION The above-mentioned pharmacological action is expected to have high affinity and selectivity to the delta receptor, can be synthesized by a route using no narcotic drug, and can pass through the blood-brain barrier and prevent peptidase. There is a need for inexpensive ligands (agonists and antagonists) with high stability.

[0004]

To achieve the above object, the present invention has the following arrangement. That is, the present invention relates to general formula (1)

[0005]

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[Wherein R ₁ is hydrogen, alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, 5 carbons
To 7 cycloalkenylalkyl, aralkyl having 7 to 14 carbon atoms, transalkenyl having 4 to 5 carbon atoms, allyl, furanyl-2-ylalkyl, thienyl-2-ylalkyl, alkanoyl having 1 to 5 carbon atoms, benzoyl,
Represents vinyloxy carbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or aryl alkanoyl of 8-14 carbon atoms, R ₂ is hydrogen or OR ₅
Wherein R ₅ represents hydrogen or alkanoyl having 1 to 5 carbon atoms, and R ₃ and R ₃ ′ independently represent 1 to ₃ carbon atoms.
5 represents alkyl, hydrogen, chlorine, fluorine, bromine, iodine, alkoxy having 1 to 5 carbon atoms, nitro, amino or alkylamino, and R ₄ represents hydrogen, alkyl having 1 to 3 carbon atoms, benzyl or carbon atom Represents an alkanoyl of the formulas (1) to (5), and X represents CH or N], or a pharmaceutically acceptable salt thereof, and an immunosuppressant or analgesic containing the derivative as an active ingredient.

The pharmacologically preferred salts include inorganic salts such as hydrochloride, sulfate, hydrobromide and phosphate, or methanesulfonate, acetate, lactate and p-toluenesulfonate. Phthalate, fumarate, maleate, glutarate and the like, but of course,
It is not limited to these.

In the general formula (1), R ₁ is, for example, specifically hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropylmethyl, cyclobutylmethyl,
Cyclopentylmethyl, cyclohexylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, allyl,
2-furanylmethyl, 2-thienylmethyl, trans-
2-butenyl, cyclopropylcarbonyl, 2, 2, 2
-Trichloroethoxycarbonyl, vinyloxycarbonyl, benzyloxycarbonyl, wherein R ₂ is hydrogen, O
R ₅ (R ₅ is hydrogen, acetyl, propanoyl, butanoyl, pentanoyl), R _3, R ₃ 'is hydrogen, methyl, chlorine, bromine, fluorine, methoxy, nitro, R ₄ is hydrogen, methyl, ethyl, propyl, benzyl , Acetyl, propanoyl, butanoyl, pentanoyl, and X represents CH or N. Among them preferably R1 is methyl, cyclopropylmethyl, cyclobutylmethyl, allyl, 2-furanylmethyl, cyclopropylcarbonyl, 2,2,2-trichloroethoxycarbonyl, vinyloxy carbonyl, R ₂ is hydrogen, acetoxy, R _3, R ₃ ′ is hydrogen, methyl, chlorine, fluorine, and R ₄ is hydrogen, methyl, benzyl, acetyl.

In the compound of the general formula (1) of the present invention, R ₁
Is methyl, R ₂ is hydrogen, R ₃ and R ₃ ′ are hydrogen, R ₄ is hydrogen, and X is N (Formula 2). That is, it is named 2-methyl-4aα- (3-hydroxyphenyl) -1,2,3,4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline. R ₁ is methyl, R ₂ is hydrogen, R ₃ ,
A compound wherein R ₃ ′ is hydrogen, R ₄ is hydrogen and X is CH (formula 3)
Is named as follows. That is, 2-methyl-4aα-
(3-hydroxyphenyl) -1,2,3,4,4a,
5,12,12aα-octahydro-quinolino [2,3
-G] named isoquinoline.

[0010]

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According to the above-mentioned nomenclature, the compounds of the present invention are specifically exemplified by 2-methyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-methyl-1,2,3
4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4a
α- (3-hydroxyphenyl) -8-butyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-butyl-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-4aα- (3-hydroxyphenyl) -8-bromo-1,2,3,4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- ( 3-methoxyphenyl)-
8-bromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-methoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinoxalino [2,3-
g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-hydroxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3 , 4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-2-oxa-3-butenyl) -4aα
-(3-hydroxyphenyl) -8,9-dibromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-2-oxa-3-butenyl) -4aα- (3-
Methoxyphenyl) -8,9-dibromo-1,2,3,
4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4a
α- (3-hydroxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline,
-Methyl-4aα- (3-methoxyphenyl) -8,9
-Dimethoxy-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-chloro-9-bromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-4aα- (3-hydroxyphenyl) -1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-
4aα- (3-methoxyphenyl) -1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-hydroxyphenyl) -1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,1
2aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-cyclopropylmethyl-4aα-
(3-methoxyphenyl) -1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2-phenethyl-4aα- (3-hydroxyphenyl) -1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3 -G] isoquinoline, 2
-Phenethyl-4aα- (3-hydroxyphenyl)-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3 , 4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4a, 5,12 ,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4-aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-phenethyl-4aα
-(3-hydroxyphenyl) -8-methyl-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-phenethyl-
4aα- (3-methoxyphenyl) -8-methyl-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-
4aα- (3-hydroxyphenyl) -8-methyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-methyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-bromo-1,2,3 , 4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-bromo-1,2,3,4,4a, 5,12 ,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4-aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-bromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-phenethyl-4aα
-(3-hydroxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-phenethyl-
4aα- (3-methoxyphenyl) -8-bromo-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-
4aα- (3-hydroxyphenyl) -8-bromo-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-bromo-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-1,2 , 3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-methyl-4aα- (3-methoxyphenyl) -8,
9-dimethyl-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4-aα
-(3-methoxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-1,2,3 , 4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline,
-Benzyl-4aα- (3-methoxyphenyl) -8,
9-dimethyl-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-phenethyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-1,2,3,4,4a,
5,12,12a β-octahydro-quinolino [2,3
-G] isoquinoline, 2-phenethyl-4aα- (3-
Methoxyphenyl) -8,9-dimethyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-hydroxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-
4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, of course. It is not limited.

The compound of the general formula (1) of the present invention wherein X is nitrogen, R1 is a methyl group and R2 is hydrogen (general formula (13)) is specifically obtained under the following conditions ( Chart 1).

[0013]

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In the first step, first, a strong base is allowed to act on the compound represented by the general formula (4) to generate an anion, which is reacted with the dibromo compound (5), and then cyclized using sodium iodide. In this method, the reaction is carried out, and the obtained enamine is reduced to an amine (R4 is the same as defined above).
Among the general formulas (4) used as raw materials, those in which R ₄ is a methyl group are described in DMZimmerman (J. Med. Chem., 29 , 1517 (1986)).
) Can be synthesized. In the first reaction (4) between the anion and the dibromo compound, an alkyllithium such as n-butyllithium, s-butyllithium or t-butyllithium is used as a strong base, but n-butyllithium is usually sufficient. The result is obtained. As the solvent, an ether-based solvent such as ether, THF, and DME is used. Usually, THF is used.
Although workable in the range of 50 ° C, satisfactory results are obtained especially at -80 to 0 ° C. The next cyclization reaction can be carried out using sodium iodide, potassium iodide or calcium iodide in the presence of a base such as potassium carbonate or sodium carbonate, and particularly preferred are sodium iodide and potassium carbonate. As the solvent, acetonitrile or a dipolar aprotic solvent such as DMF or DMSO is used. Among them, DMF is preferable. The temperature is 0
It can be performed in the range of 300 ° C.
Satisfactory results are obtained at 00 ° C. When the obtained enamine is further reduced to an amine, a metal hydride compound such as sodium borohydride, sodium cyanoborohydride or a catalyst such as palladium-carbon is used as a reducing agent in the presence of an acid. Hydrogenate in the presence. Among them, when obtaining the amine (6) in trans configuration, sodium cyanoborohydride gives a preferable result. Usually, methanolic hydrogen chloride is used as the acid to be added. Solvents are methanol, ethanol, 2-
Alcohol solvents such as propanol are used,
Among them, methanol is preferred. Reaction temperature is -80 to 50
The range of ℃ is considered, and especially -40 to 20 ° C is a range usually used. The subsequent second step is a step of converting the methyl group on the nitrogen of the amine (6) to urethane using a chlorocarbonate represented by the general formula (7) in the presence of a base. In the formula (7), R6 represents a vinyl or 2,2,2-trichloroethyl group. As the base, an amine having a substituent having a large steric hindrance that does not react with the acid chloride or an inorganic salt such as potassium carbonate is used. Among them, proton sponge and Hunig's base are preferably used. As the solvent, a halogen-based solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane is preferably used, and among them, 1,2-dichloroethane is preferably used. Although the reaction temperature may range from -80 to 100 ° C, satisfactory results are usually obtained at 0 ° C to around room temperature. The third step is a step of removing the protecting group of the diol, and includes hydrochloric acid (including methanolic hydrogen chloride),
A protic solvent such as methanol, ethanol, or water is used in the presence of an acid such as acetic acid or p-toluenesulfonic acid. Among them, methanolic hydrogen chloride is used, and in this case, satisfactory results are usually obtained at 0 ° C. to room temperature. can get. The next fourth step is a step of oxidizing the diol to form a diketone,
There is a method using a combination of DMSO and various activators such as DCC, oxalyl chloride, acetic anhydride and the like as the oxidizing agent. Among them, good results are obtained when DMSO and oxalyl chloride are used. In that case, a chlorine-based solvent such as methylene chloride or chloroform is used as the solvent, and methylene chloride is particularly preferably used. In the fifth step, a condensation reaction is carried out using the diamine derivative represented by the general formula (11) to synthesize a quinoxaline derivative. In the formula (11), R ₃ and R ₃ ′ are the same as defined above. Examples of the solvent include alcohol solvents such as methanol, ethanol and butanol, fatty acid solvents such as acetic acid and propionic acid, and dipolar aprotic solvents such as DMF and DMSO. Among them, alcohol solvents are preferable, and ethanol is particularly preferable. Is preferred. The reaction temperature is 0
A range of 300 ° C is conceivable.
And usually preferably carried out at 60 to 120 ° C. The next sixth step is to reduce urethane to N
-A step of converting to a methyl form. Examples of the reducing agent to be used include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride (Red Al), and among them, diisobutylaluminum hydride is preferable. As the solvent when diisobutylaluminum hydride is used as the reducing agent, ether, cyclohexane, benzene and toluene are used, and among them, toluene is preferable. The reaction can be carried out at a temperature in the range of -100 to 100 ° C.,
Preferred results are obtained in the range of 80 to 0 ° C.

Among the compounds represented by the general formula (13),
Compounds in which R ₄ is hydrogen (general formula (2) ′) can be obtained by dissolving a compound represented by general formula (13) in which R ₄ is a methyl group in a solvent and reacting with a base in the presence of mercaptan, or a trivalent boron compound (Wherein R ₃ and R ₃ ′ are the same as defined above). When using mercaptan and a base, DMF, DMSO, H
A dipolar aprotic solvent such as MPA is preferably used, and DMF is particularly preferable. When using trivalent boron, a halogen-based solvent such as methylene chloride, chloroform and carbon tetrachloride is preferable, and methylene chloride is particularly preferable. The mercaptans include those having a chain of the side chain of C ₁ -C _10, usually n- propyl mercaptan is preferably used. The base is potassium t
-Butoxide, potassium ethoxide, potassium methoxide, sodium t-butoxide, sodium ethoxide, alkali metal salts of alcohols such as sodium methoxide, sodium hydride, metal hydride compounds such as potassium hydride, sodium amide and the like Metal salts of amide anions are used, but usually satisfactory results are obtained with potassium t-butoxide. Examples of the trivalent boron include boron triiodide, boron tribromide, and boron trichloride, and among them, boron tribromide is preferable. When mercaptan is used, the reaction temperature may be in the range of 0 to 300 ° C, preferably 50 to 200 ° C, particularly preferably 120 to 180 ° C. When trivalent boron is used, the temperature is preferably -80 to 50C, and particularly preferably 0 to 30C.

In the general formula (1), X is nitrogen, R
Compounds in which ₁ is other than a methyl group can be easily synthesized from (12) by a conversion method (chart 3) described later. Next, the compound of the general formula (1) in which X is CH can be obtained by using the following conditions (Charts 2, 3).

[0017]

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In the case where X is CH and R ₁ is a methyl group in the formula (1), the compound represented by the general formula (14) is reacted with an aminoaldehyde derivative represented by the general formula (15) in a solvent in the presence of an acid catalyst. (Chart 2). Here, R ₃ , R ₃ ′, and R ₄ are the same as defined above. Among the compounds of the general formula (14),
Compounds in which R ₄ is a methyl group can be prepared by the method of DMZimmerman et al.
(J. Org. Chem., 54, 1442, (1989)). Examples of the solvent include alcohol solvents such as methanol and ethanol, fatty acid solvents such as acetic acid and propionic acid, DMF, D
Examples thereof include a dipolar aprotic solvent such as MSO. Among them, an alcohol solvent is preferable, and ethanol is particularly preferable. Examples of the aminoaldehyde derivative represented by the general formula (15) include an o-aminobenzaldehyde derivative. Examples of the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, formic acid and propionic acid. Among them, hydrochloric acid, sulfuric acid and methanesulfonic acid are exemplified. It is preferably used, but is not limited to these. The reaction temperature may be in the range of 0 to 300 ° C., but the reaction can be carried out in the range of 25 to 150 ° C., and a preferable result is usually obtained at 60 to 120 ° C.

In the compound represented by the general formula (16), R
_The compound represented by the general formula (3) ′ wherein ₄ is hydrogen can be obtained under the same conditions as those shown in the seventh step of Chart 1.

In the general formula (1) of the present invention, a compound wherein X is CH and R ₁ is other than a methyl group (general formula (21))
Can be obtained by using the following conditions (Chart 3).

[0021]

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The first step is the same as the second step of the chart 1. The second step is a step of removing the protecting group of nitrogen and converting to a secondary amine (18). When R ₆ is a vinyl group, it can be easily solvolyzed using methanolic hydrogen chloride. The reaction is usually performed under reflux of methanol. When R ₆ is a 2,2,2-trichloroethyl group, it can be reductively removed with zinc in the presence of an acid catalyst. Examples of the acid include acetic acid, hydrochloric acid, sulfuric acid, nitric acid, and the like. Usually, by using acetic acid as both a solvent and an acid catalyst, sufficiently satisfactory results can be obtained. In that case, the reaction can usually be performed at room temperature. The third step is a step of reacting a secondary amine (18) with an acid chloride in the presence of a base to obtain an amide (20) (R ₇ is a C ₂ -C ₄ alkyl group, C ₃ -C ₆ It represents an alkenyl group, a vinyl group or a 2-furanyl group,) - cycloalkyl group, cycloalkenyl group C ₄ -C _6, phenyl group, an aralkyl group of C ₇ -C _13, trans C ₃ -C _4. Tertiary amines such as triethylamine, diisopropylethylamine, and proton sponge are used as the base, and generally satisfactory results can be obtained with trialelamine. Solvents are ether solvents such as ether, THF, DME, dioxane or DMF, DMSO
And the like, and a dipolar aprotic solvent such as THF is preferably used. Reaction is -80 to 100 ° C
, And particularly preferably in the range of 0 to 30 ° C. The fourth step is to convert the amide to an amine by reduction. As the reducing agent, lithium aluminum hydride, diisobutylaluminum hydride, bis (2
-Methoxyethoxy) aluminum sodium (Red
Al) and the like, among which diisobutylaluminum hydride is preferable. As the solvent, ether, cyclohexane, benzene, toluene and the like are preferably used.
Among them, toluene is preferable. Reaction temperature is -100 to 10
Although it can be carried out in the range of 0 ° C., particularly preferable results are obtained in the range of −80 to 0 ° C. Among the compounds represented by the general formula (21), the compound represented by the general formula (3) "wherein R4 is hydrogen can be obtained under the same conditions as those shown in the seventh step of Chart 1.

Among the compounds of the general formula (1), those in which R ₁ is a methyl group, R ₂ hydroxyl group and X is methine are specifically obtained under the following conditions (Chart 4).

[0024]

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The first step is D. M. Zimmerman et al. (J. Org. Chem. 1989, 54, 14).
In this step, the methyl group on the nitrogen of the enamine compound (22), which can be synthesized according to (42), is converted into a carbamate compound using a chlorocarbonate represented by the general formula (7) in the presence of a base. In the formula (23), R ₆ represents a benzyl or trichloroethyl group. As the base, a substance having a large steric hindrance that does not react with the acid chloride is used. For example, those such as proton sponge and Hunig base are preferably used. As the solvent, a halogen-based solvent such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane is preferably used, and usually 1,2-dichloroethane is preferably used. The reaction temperature is -80 to 100
C. and usually gives satisfactory results between 0.degree. C. and room temperature. The second step is a step of reacting the carbamate body (23) with a peracid to form an epoxy body. As the peracid used, m-chloroperbenzoic acid usually gives satisfactory results. As the solvent, a halogen-based solvent such as methylene chloride, chloroform and carbon tetrachloride is preferably used, and usually methylene chloride is used. The reaction temperature is
It can be carried out at -80 to 50 ° C and usually gives satisfactory results at 0 ° C to around room temperature. In the third step, the epoxy compound (2
4) is a step of reductively opening the ring to form a bridgehead hydroxyl substrate (25). As a reducing agent, sodium borohydride,
When a metal hydride compound such as sodium cyanoborohydride is used and reacted under acidic conditions such as acetic acid, hydrochloric acid, and methanesulfonic acid, preferable results are obtained. In particular, acetic acid is preferably used also as a solvent, and reduction with sodium borohydride is preferred. The reaction can be carried out at a temperature of -80 ° C to 50 ° C, but satisfactory results can be obtained from 0 ° C to around room temperature. The fourth step is a step of simultaneously reducing the carbamate portion and the acetate portion of the bridgehead hydroxyl substrate (25) to obtain a dihydroxyamine compound (26). The reducing agent used is
Examples thereof include lithium aluminum hydride, diisobutylaluminum hydride, and lithium borohydride. Of these, lithium aluminum hydride is preferable. Examples of the solvent include ethers such as ether, THF, DME, and dioxane.
Ter-based solvents are preferably used, and among them, THF is preferred. The reaction can be carried out at a temperature in the range of -40 ° C to 100 ° C, and preferably 0 ° C to around room temperature. The fifth step is a step of oxidizing the secondary hydroxyl group of the dihydroxyamine derivative (26) to give a hydroxyketone derivative (27). Oxidizing agents include chromic acid, potassium permanganate, DMSO-DC
C, DMSO-oxalyl chloride, etc., among which DMSO-oxalyl chloride is preferred. As the solvent, a halogen-based solvent such as dichloromethane or chloroform is used, and dichloromethane is particularly preferable. The reaction can be performed in the range of -100 ° C to 0 ° C,
Particularly, the temperature is preferably from -80C to -50C. Quinoline body (2
The sixth step for obtaining 8), and further, in the compound represented by the general formula (28), R ₄ is represented by the general formula (3) ″ ′ wherein R ₄ is hydrogen.
The seventh step of obtaining the compound R> can be obtained under the same conditions as those shown in the first step of Chart 2 and the seventh step of Chart 1, respectively. The compound (general formula (33)) in which R ₁ is other than a methyl group can be obtained by using the following conditions (Chart 5).

[0026]

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In the first step and the second step, the carbamate (24) obtained in steps 1 and 2 of Chart 4 is converted to the amide (30) via the secondary amine (29). This is the step of conversion. These steps can be performed according to the method of the second step and the third step of the chart 3, respectively. The third step is a step for converting the amide acetate compound (30) into the dihydroxyamine compound (31). This step can be performed in the same manner as in the fourth step of the chart 4.
The fourth step is a step of oxidizing the secondary hydroxyl substrate (31) to a ketone body (32) as in the fifth step of Chart 4. The fifth step of further obtaining a quinoline compound, general formula (33)
In the compound represented by the general formula (3) wherein R ₄ is hydrogen:
In the sixth step of obtaining the compound represented by the formula, the compounds can be obtained under the same conditions as those shown in the first step of Chart 2 and the seventh step of Chart 1, respectively.

The isoquinoline derivative of the present invention is a highly selective agonist for the δ-opioid receptor. The δ-opioid receptor is involved in analgesia, immunity, and the circulatory system (particularly blood pressure), and ligands highly selective for this receptor include analgesics, immunosuppressants [organ transplantation (kidney, liver, heart), skin transplantation, It is known that it can be used as an autoimmune disease (used for intractable diseases such as rheumatism, various allergies, collagen diseases, osteoporosis, etc.), and as a drug such as a hypotensive agent. In particular, it can be used as an excellent analgesic and immunosuppressant. When the compound of the present invention is used clinically as an analgesic or immunosuppressant, a free base or a salt thereof may be used, and excipients such as a stabilizer, a buffer, a diluent, an isotonic agent, a preservative, and the like. May be appropriately mixed. Various forms such as injections, capsules, suppositories, and oral preparations are used. The dose is appropriately determined depending on the administration subject, administration method and symptoms. In the case of an injection, the dosage is 0.001 to 1 g / day. The drug containing the compound of the present invention is 0.05
It is considered that the drug may be contained in the range of 0.5% to 99%. Usually, a drug containing 0.5% to 20% for an injection and 0.1% to 50% for an oral preparation is used.

[0029]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but it is needless to say that the present invention is not limited thereto.

Reference Example 1 2-methyl-4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,6,7,8,8aβ-Decahydro-2,2-dimethyl-1,3-dioxolo [4,5-
g] isoquinoline 1

[0031]

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In an argon stream, 10.09 g (49.65 mmol) of 1-methyl-4- (3-methoxyphenyl) -1,2,3,6-tetrahydropyridine was added with anhydrous TH.
F100ml, cooled to -10 ° C, and n-butyl lithium 30.3ml (1.637N, 49.65mm
ol) and the mixture was stirred for 30 minutes and then cooled to -78 ° C. Next, 28.60 g of 2,2-dimethyl-4,5-bis (bromomethyl) -1,3-dioxolane (99.3)
(mmol) was dissolved in 70 ml of anhydrous THF, and the solution was cooled to -78 ° C. Next, 50 ml of water was added, 50 ml of a saturated aqueous solution of sodium hydrogen carbonate was further added, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of a saturated saline solution,
After drying over anhydrous sodium sulfate, the solvent is distilled off to obtain 4
0.48 g of an oil was obtained. The above oil was dissolved in 80 ml of anhydrous DMF under a stream of argon, and 37.21 g (248.3 mmol) of sodium iodide and 34.31 g (248.3 mmol) of anhydrous potassium carbonate were added.
Heating was performed at 100 ° C. for 30 minutes, 130 ° C. for 30 minutes, and 150 ° C. for 1.5 hours. After allowing to cool, insoluble materials are filtered off, and D
The MF was distilled off at a temperature of 40 ° C. or lower under reduced pressure. Water 50 in the residue
Then, 50 ml of a saturated aqueous solution of sodium hydrogencarbonate was added thereto, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and dried to obtain 30.25 g of an oil. This oil was dissolved in 90 ml of methanol, and 13.47 g of sodium cyanoborohydride was dissolved.
(198.6 mmol) was added and cooled to -30 to -15 ° C. 18 ml (about 4N, about 72.0 mmol) of methanolic hydrogen chloride was slowly dropped into the reaction solution,
Stirred for minutes. 50 ml of saturated sodium bicarbonate aqueous solution
After adding methanol as a solvent, 50 ml of water was added, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layer was washed three times with 50 ml of water and 50 ml of saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent, the obtained oil was separated and purified by column chromatography (silica gel, 2-30% methanol-chloroform) to obtain 4.42 g of the title compound (yield 2).
6.9%).

IR (liquid film method) cm ^-1 : 3372,2940,1607,1582,1
460,1288,1236,1122,1050,847,785 NMR (CDCl3,500MHz) δ: 1.27,1.29 (3H, s in total), 1.3
9,1.40 (3H, s in total), 1.57 ~ 1.64 (0.5H, m), 1.79 ~ 2.1
7 (3H, m), 2.17 to 2.30 (1.5H, m), 2.33, 2.35 (3H,
s), 2.45, 2.51 (1H, m), 2.60 to 2.75 (2H, m), 2.78 to 2.86 (1
H, m), 2.88 to 3.03 (2H, m), 3.12 to 3.17 (0.5H, m), 3.52
~ 3.57 (0.5H, m), 3.74 ~ 3.85 (0.5H, m), 3.12 ~ 3.17 (0.5
H, m), 3.52 to 3.57 (0.5H, m), 3.74 to 3.85 (0.5H, m), 3.81
(3H, s), 3.92 to 3.98 (0.5H, m), 6.71 to 6.77 (1H, m), 6.89
7.07.03 (3H, m), 7.21 to 7.25 (1H, t, J = 7.94 Hz) Mass (EI method): 331 (M ⁺ ) High-resolution mass spectrum Calculated as C ₂₀ H ₂₉ NO ₃ 331.21474 Actual 331.21286 .

Reference Example 2 2- (1-oxo-2-oxa-3-butenyl) -6
7-dioxo-4aα- (3-methoxyphenyl)-
1,2,3,4,4a, 5,6,7,8,8a β-decahydroisoquinoline 2

[0035]

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In an argon stream, vinyl chloroformate 0.3
8 ml (4.53 mmol) and proton sponge 1.6
2 g (7.54 mmol) of anhydrous dichloromethane 8 ml
And ice-cooled. Next, 2-methyl-4aα- (3-
Methoxyphenyl) -1,2,3,4,4a, 5,6
7,8,8aβ-decahydro-2,2-dimethyl-1,
500 mg of 3-dioxolo [4,5-g] isoquinoline
(1.508 mmol) was azeotroped twice with 2 ml of anhydrous toluene, then dissolved in 3 ml of anhydrous dichloromethane, added to the above reaction solution, and stirred at room temperature for 1 hour. The solvent was distilled off, 10 ml of ether was added, and the insoluble matter was separated by filtration. The filtrate was washed three times with 30 ml of 1N hydrochloric acid, and further washed with a saturated saline solution 3
After washing with 0 ml, it was dried over anhydrous sodium sulfate.
The solvent was distilled off to obtain 502.5 mg of a yellow oily carbamic acid ester.

This oily substance was dissolved in 6 ml of methanol and cooled with ice, and then 0.9 ml of methanolic hydrogen chloride (about 4N,
(About 3.6 mmol), and the mixture was stirred for 2.5 hours. To the reaction mixture was added 10 ml of a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted twice with 50 ml and 30 ml of ethyl acetate. The organic layer was washed with 20 ml of saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 348.4 mg of a pale yellow amorphous diol (yield 77.
1%). Next, oxalyl chloride under a stream of argon.
7 mg (0.636 mmol) of anhydrous dichloromethane 1
and cooled to -78 ° C.
7 mg (0.751 mmol) were added. After stirring for 10 minutes, 100.3 mg of the above diol (0.289 m
mol) was dissolved in 1 ml of anhydrous dichloromethane, washed with anhydrous dichloromethane, and the washing solution was also added. After the reaction solution was stirred at -78 ° C for 20 minutes, 0.24 ml (1.734 mmol) of triethylamine was added, and the mixture was further stirred for 1 hour. 6 ml of a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with 15 ml of ethyl acetate. The organic layer was washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was subjected to column chromatography (silica gel, Merck Rover Column Type B, cyclohexane: ethyl acetate = 4:
Separation and purification in 1) yielded 46.4 mg of the title compound (46.8% yield).

Mp: 155 to 157 ° C. IR (KBr method) cm ^-1 : 3364, 2944, 1702, 1676, 1601, 1435, 1274,
1236,1203,1156,1042,884,787 NMR (CDCl3,500MHz) δ: 1.73 ~ 1.94 (1H, m), 2.25 ~ 2.35
(1H, m), 2.46 -2.68 (2H, m), 3.03 (1H, d, J = 16.18Hz), 3.1
2 to 3.19 (1H, m), 3.45 to 3.66 (1H, m), 3.77, 3.79 (3H, s in total), 3.96 to 4.10 (1H, m), 4.22 to 4.36 (1H, m), 4.43 to
4.51 (1H, m), 4.72 to 4.86 (1H, m), 5.87 to 6.00 (1H, m), 6.0
6 to 6.22 (1H, m), 6.69 to 6.75 (1H, m), 6.78 to 6.89 (2H,
m), 7.06 ~7.26 (2H, m) Mass (EI method): 343 (M ⁺⁾ Elemental _{analysis: C H N C 19 H 21} NO as ₅ Calculated 66.46 6.16 4.08 Found 66.57 6.32 4.22.

Example 1 2- (1-oxo-2-oxa-3-butenyl) -4a
α- (3-methoxyphenyl) -1,2,3,4,4
a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline 3

[0040]

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2- (1-oxo-2-oxa-3-butenyl) -6,7-dioxo-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,6,7, 8,8
aβ-Decahydroisoquinoline 450 mg (1.31 m
mol) and 397.5 mg of o-phenylenediamine
Ethanol (8 ml) was added to (3.93 mmol), and the mixture was heated and refluxed for 2 hours under an argon stream. After allowing to cool, 20 ml of 1N hydrochloric acid was added, and the mixture was extracted twice with 30 ml of chloroform. The organic layer was washed with 1N hydrochloric acid (20 ml) and saturated saline (20 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure.
6.9 mg were obtained (108% yield).

Mp: 191 ° -193 ° C. IR (KBr method) cm-1: 2918,1717,1649,1609,1578,1491,1460,1
439,1408,1270,1253,1234,1152,1052,876,766,708 NMR (CDCl3,500MHz) δ: 1.87-1.96 (1H, m), 2.30-2.38
(1H, m), 2.62 to 2.70 (1H, m), 2.88 to 3.03 (1H, m), 3.16 (1
(H, d, J = 16.48Hz), 3.35-3.45 (2H, m), 3.55-3.64 (1H, m),
3.68 (3H, s), 3.78 (1H, d, J = 16.48Hz), 4.06-4.16 (1H, m),
4.27 to 4.41 (1H, m), 4.46 to 4.54 (1H, m), 4.77 to 4.90 (1
H, m), 6.62 (1H, dd, J = 7.93,2.45Hz), 6.95-7.07 (2H, m),
7.11 (1H, t, J = 7.93Hz), 7.22-7.30 (3H, m), 7.61-7.67 (2
H, m), 7.88 to 7.96 (2H, m) Mass (EI method): 415 (M ⁺ ) High-resolution mass spectrum Calculated as C ₂₅ H ₂₅ N ₃ O ₃ : 415.19173 Found: 415.19197.

Similarly, instead of o-phenylenediamine, 4-methyl-1,2-phenylenediamine, 4-butyl-1,2-phenylenediamine, 4-bromo-1,
2-phenylenediamine, 4-methoxy-1,2-phenylenediamine, 4,5-dimethyl-1,2-phenylenediamine, 4,5-dibromo-1,2-phenylenediamine, 4,5-dimethoxy-1, Using 2-phenylenediamine and 4-chloro-5-bromo-1,2-phenylenediamine, respectively, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl)
-8-methyl-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4 , 4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2
-(1-oxo-2-oxa-3-butenyl) -4aα
-(3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8 -Methoxy-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline is obtained.

Example 2 2-methyl-4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline 4

[0045]

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2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12 is added to 11 ml of anhydrous toluene.
aβ-Octahydro-quinoxalino [2,3-g] isoquinoline (174.9 mg, 0.421 mmol) was added, and the mixture was cooled to -78 ° C.
l) was added. After stirring at -78 ° C for 10 minutes, 2 ml of methanol was added. 2 ml of saturated sodium bicarbonate solution
And 20 ml of chloroform were added and stirred, and then insolubles were filtered using Hyflo Super Cell. 20 ml of saturated aqueous sodium hydrogen carbonate solution and 20 ml of chloroform are added to the filtrate.
Was added and the mixture was separated, and the aqueous layer was further extracted with 50 ml of chloroform. The organic layer was washed with 20 ml of saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated and purified by column chromatography (silica gel, 2 to 50% methanol-chloroform) to give 103.9 m.
g of the title compound were obtained (68.7% yield).

Decomposition point: 177-179 ° C. (recrystallized from chloroform-ether) IR (KBr method) cm ⁻¹ : 3384,2940,2798,1607,1578,1489,1462,
1437,1288,1245,1048,876,779,764,708 NMR (CDCl3,400MHz) δ: 2.03-2.18 (2H, m), 2.28-2.30
(1H, m), 2.41 (3H, s), 2.72 ~ 2.77 (1H, m), 2.77 ~ 2.89 (2H,
m), 3.02 to 3.07 (1H, m), 3.17 (1H, d, J = 16.79 Hz), 3.32 to 3.
41 (1H, m), 3.41 to 3.52 (1H, m), 3.69 (3H, s), 3.75 (1H, d, J =
16.82Hz), 6.56-6.61 (1H, m), 7.03-7.12 (3H, m), 7.58
~7.66 (2H, m), 7.87~7.93 (2H, m) Mass (EI method): 359 (M ⁺⁾ High resolution mass spectrum C ₂₃ H ₂₅ N ₃ calculated for O: 359.20092 Found: 359.20105.

Similarly, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl)
-1,2,3,4,4a, 5,12,12a Instead of β-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl)
-4aα- (3-methoxyphenyl) -8-methyl-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
(1-oxo-2-oxa-3-butenyl) -4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-bromo -1, 2, 3, 4, 4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinoxalino [2,3-
g] isoquinoline, 2- (1-oxo-2-oxa-3)
-Butenyl) -4aα- (3-methoxyphenyl)-
8,9-dimethyl-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinoxalino [2,3-g]
Isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9
-Dibromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3 , 4,4a, 5,12,12aβ
-Octahydro-quinoxalino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl)
-4aα- (3-methoxyphenyl) -8-chloro-9
-Bromo-1,2,3,4,4a, 5,12,12aβ
Using 2-octahydro-quinoxalino [2,3-g] isoquinoline to give 2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4a
α- (3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-
4aα- (3-methoxyphenyl) -8-methoxy-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-4aα- (3-methoxyphenyl) -8,9-
Dimethyl-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-2-oxa-3-butenyl) -4a
α- (3-methoxyphenyl) -8,9-dibromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-4aα- (3-methoxyphenyl) -8,9-
Dimethoxy-1,2,3,4,4a, 5,12,12a
β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline is obtained.

Example 3 2-methyl-4aα- (3-hydroxyphenyl)-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline 5

[0050]

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In 1 ml of anhydrous dichloromethane, 0.96 ml of a 1M boron tribromide solution in dichloromethane (0.96 mm
ol), and the mixture was cooled on ice and stirred vigorously while 2-methyl-4aα- (3-methoxyphenyl) -1,2,2
3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline 117.1 mg
(0.326 mmol) dissolved in 2 ml of anhydrous dichloromethane was slowly added. Further, the mixture was washed with 5 ml of anhydrous dichloromethane, and the washing solution was added to the reaction solution. After stirring at room temperature for 20 minutes, the reaction solution is
1 and ice were added with vigorous stirring. This was extracted three times with 50 ml of a mixed solvent of chloroform: methanol = 3: 1. The organic layer was washed with 10 ml of saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue is subjected to column chromatography (silica gel, 5 to 10
% Methanol-chloroform).
A solid containing 8.7 mg of the title compound was obtained. Methanol was added thereto, and a methanol solution of methanesulfonic acid was added to make a salt, which was then separated and purified by column chromatography (Sephadex LH-20, methanol) to give 32.8 mg of the pure methanesulfonate of the title compound. Was obtained (yield 22.8%).

Decomposition point of the title compound:> 220 ° C IR (KBr method) cm ^-1 : 3220,2966,1584,1491,1466,1263,1098,
1025,872,801,768,708 NMR (CD3OD, 500MHz) δ: 2.12-2.23 (1H, m), 2.54-2.7
1 (3H, m), 2.80 (3H, s), 2.90 ~ 3.00 (1H, m), 3.23 ~ 3.30 (1
H, m), 3.40 to 3.60 (4H, m), 3.68 (1H, d, J = 16.48Hz), 4.59 (1
H, brs), 6.52 (1H, dd, J = 7.94,1.23Hz), 6.93-7.01 (2H,
m), 7.04 (1H, t, J = 7.94Hz), 7.68-7.75 (2H, m), 7.85-7.
94 (2H, m) Mass ( FAB method): 346 (M ⁺ +1) High resolution mass spectrum C ₂₂ H ₂₄ N ₃ calculated for O: 346.1919 Found: 346.1905 methanesulfonate of the title compound mp: 160 163163 ° C. Elemental analysis Calculated for CH ₂₂ S as C ₂₂ H ₂₄ N ₃ O.CH ₃ SO ₃ H.0.3H ₂ O 61.81 6.22 9.40 7.17 Found 62.15 6.29 9.38 7.24.

Similarly, 2-methyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,
12aβ-octahydro-quinoxalino [2,3-g]
2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4 instead of isoquinoline
a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4a
α- (3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-
4aα- (3-methoxyphenyl) -8-methoxy-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-4aα- (3-methoxyphenyl) -8,9-
Dimethyl-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-2-oxa-3-butenyl) -4a
α- (3-methoxyphenyl) -8,9-dibromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-
Methyl-4aα- (3-methoxyphenyl) -8,9-
Dimethoxy-1,2,3,4,4a, 5,12,12a
β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12a Using β-octahydro-quinoxalino [2,3-g] isoquinoline, respectively, 2-methyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline,
-Methyl-4aα- (3-hydroxyphenyl) -8-
Butyl-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl)
-8-bromo-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-methoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinoxalino [2,3-
g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-1,2,3,4
4a, 5,12,12aβ-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-2-oxa-3-butenyl) -4aα- (3-hydroxyphenyl) -8,9-dibromo-1, 2,3,4,4a, 5
12,12aβ-octahydro-quinoxalino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12a β-octahydro-quinoxalino [2,3-g] isoquinoline, 2-methyl-4a
.alpha .- (3-hydroxyphenyl) -8-chloro-9-bromo-1,2,3,4,4a, 5,12,12a.beta.-octahydro-quinoxalino [2,3-g] isoquinoline is obtained.

Example 4 2-methyl-4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline 6

[0055]

Embedded image

2-methyl-4aα- (3-methoxyphenyl) -6-oxo-1,2,3,4,4a, 5,6
7,8,8aβ-octahydroisoquinoline 295.2
mg (1.08 mmol) and 399.8 mg (3.30 mmol) of 2-aminobenzaldehyde were added to 5 ml of absolute ethanol, and 0.18 ml of methanesulfonic acid was further added.
(2.75 mmol) was added and the mixture was heated under reflux for 17 hours.
After cooling, 10 ml of a saturated aqueous solution of sodium hydrogen carbonate and 1 ml of water
0 ml was added, and the mixture was extracted twice with 50 ml and 30 ml of ethyl acetate. The organic layer was washed with 20 ml of saturated saline, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was separated and purified by column chromatography (silica gel, ammonia-saturated chloroform: chloroform = 1: 2 to 1: 1), and the crystals were filtered while washing with ether.
306.0 mg of the title compound were obtained (yield
0%).

Mp: 178.5-179 ° C. (recrystallized from ethyl acetate) IR (KBr method) cm ⁻¹ : 3392,2940,2806,1605,1578,1493,1286,
1245,1044,777,770 NMR (CDCl3,400MHz) δ: 1.96 to 2.06 (1H, m), 2.12 to 2.20
(1H, m), 2.25 to 2.32 (1H, m), 2.38 (3H, s), 2.59 to 2.80 (3
H, m), 2.92 to 2.97 (1H, m), 3.09 to 3.18 (2H, m), 3.22 to 3.
32 (1H, m), 3.68 (3H, s), 3.76 (1H, d, J = 16.47Hz), 6.55--6.
61 (1H, m), 7.03-7.12 (3H, m), 7.37-7.42 (1H, m), 7.53
~ 7.58 (1H, m), 7.61 ~ 7.66 (1H, m), 7.77 (1H, s), 7.91 (1H, m
d, J = 8.54Hz) Mass (FAB method): 359 (M ⁺⁺ 1)

Similarly, instead of 2-aminobenzaldehyde, 2-amino-4-methylbenzaldehyde,
2-amino-4-butylbenzaldehyde, 2-amino-4-bromobenzaldehyde, 2-amino-4-methoxybenzaldehyde, 2-amino-4,5-dimethylbenzaldehyde, 2-amino-4,5-dibromobenzaldehyde, -Amino-4,5-dimethoxybenzaldehyde and 2-amino-4-chloro-5-bromobenzaldehyde give 2-methyl-4aα-
(3-methoxyphenyl) -8-methyl-1,2,3
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-bromo-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-methoxy-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4a
α- (3-methoxyphenyl) -8,9-dimethyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8,9-dibromo-1,2 , 3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2
-Methyl-4aα- (3-methoxyphenyl) -8,9
-Dimethoxy-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl)
-8-chloro-9-bromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline is obtained.

Example 5 2-methyl-4aα- (3-hydroxyphenyl)-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline 7

[0060]

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Under an argon stream, potassium t-butoxide 3
09.1 mg (2.75 mmol) in 6 ml of anhydrous DMF
In n-propanethiol 0.36 ml (3.8
6 mmol) and heated to reflux for several minutes. After cooling, 2-methyl-4aα- (3-methoxyphenyl)-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline 197.5
mg (0.551 mmol) dissolved in 3 ml of anhydrous DMF was added. After further washing with 1 ml of anhydrous DMF and adding the washing solution, the mixture was heated under reflux for 4 hours. The reaction solution was allowed to cool, and DMF was distilled off under reduced pressure. 10 ml of water was added to the residue, and a mixed solvent 3 of chloroform: methanol = 3: 1 was used.
Extracted three times with 0 ml. The organic layer was washed with 10 ml of saturated saline, dried over anhydrous magnesium sulfate, and concentrated. To the obtained residue, 20 ml of methanol was added and heated, and 24.3 mg of an insoluble amorphous title compound was separated by filtration. After the solvent was distilled off from the filtrate, methanol (4 ml) was added again, and the mixture was adjusted to pH 2 by adding a methanol solution of methanesulfonic acid while cooling with ice. The solvent is distilled off, and the residue is subjected to column chromatography (Sephadex LH).
-20, methanol).
g of the methanesulfonate of the title compound was obtained (73.7% yield).

Decomposition point of the title compound: 260-265 ° C. IR (KBr method) cm ⁻¹ : 3032,2930,2804,1618,1582,1493,1454,
1421,1352,1267,1249,1147,779,756 NMR (DMSO-d6,500MHz) δ: 1.91 ~ 2.00 (1H, m), 2.09 (1H,
t, J = 12.21Hz), 2.30 (1H, d, J = 13.43Hz), 2.60 to 2.67 (1H,
m), 2.68-2.75 (1H, d, J = 11.60Hz), 2.75-2.84 (1H, m),
2.94-3.02 (1H, m), 3.08 (1H, d, J = 16.48Hz), 3.20-3.42
(2H, m), 3.63 (1H, d, J = 16.48Hz), 6.42-6.48 (1H, m), 6.9
2 to 7.01 (3H, m), 7.47 (1H, t, J = 7.33Hz), 7.58 to 7.64 (1H,
m), 7.77 (1H, d, J = 8.54Hz), 7.82 (1H, d, J = 8.55Hz), 8.00 (1
H, s) Mass (FAB method): 345 (M ⁺ +1) High-resolution mass spectrum Calculated as C ₂₃ H ₂₄ N ₂ O: 345.19767 Observed: 345.11967 Methanesulfonic acid salt of the title compound mp: 154-157 ℃ elemental analysis _{C 23 H 24 N 2 O ·} 2CH 3 SO 3 C H N as H · H ₂ O S calculated 54.14 6.18 5.05 11.56 Found 53.94 6.22 5.05 11.62.

Similarly, 2-methyl-4aα- (3-
Methoxyphenyl) -1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4 instead of isoquinoline
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-bromo-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8-methoxy-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4a
α- (3-methoxyphenyl) -8,9-dimethyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8,9-dibromo-1,2 , 3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2
-Methyl-4aα- (3-methoxyphenyl) -8,9
-Dimethoxy-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl)
-8-chloro-9-bromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] When isoquinoline is used, 2-methyl-4
aα- (3-hydroxyphenyl) -8-methyl-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-
4aα- (3-hydroxyphenyl) -8-butyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-bromo-1,2,3 , 4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-methoxy-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
-Methyl-4aα- (3-hydroxyphenyl) -8,
9-dimethyl-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-Hydroxyphenyl) -8-chloro-9-bromo-1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Example 6 2- (1-oxo-2-oxa-3-butenyl) -4a
α- (3-methoxyphenyl) -1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline 8

[0065]

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Under an argon stream, 2-methyl-4aα-
(3-methoxyphenyl) -1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] 300 mg (0.837 mmol) of isoquinoline
And 179.4 mg of proton sponge (0.837 mmol
1) was dissolved in 4 ml of anhydrous dichloroethane and cooled with ice.
Next, 0.21 ml of vinyl chloroformate (2.47 mmol
l) was added dropwise and stirred at room temperature overnight. 50 ml of 1N hydrochloric acid was added to the reaction solution, and 15 ml and 10 ml of dichloromethane were added.
And extracted twice. The obtained organic layer was washed twice with 50 ml of 1N hydrochloric acid, 30 ml of water and 30 ml of saturated saline, and dried over anhydrous magnesium sulfate. After the magnesium sulfate was filtered, the filtrate was concentrated to give a pale yellow amorphous 336.5.
mg was obtained. The amorphous was filtered with washing with ether to obtain 261.5 mg of the title compound (yield: 75.4%).

Mp 160-163 ° C. (washed with ether, amorphous) IR (KBr method) cm ⁻¹ : 2922,1755,1437,1245,1151,756 NMR (CDCl3,400 MHz) δ: 1.85-1.98 (1H, m) , 2.30 -2.40
(1H, m), 2.50 to 2.62 (1H, m), 2.88 to 3.05 (1H, m), 3.12 to
3.40 (3H, m), 3.47-3.60 (2H, m), 3.74 (3H, s), 4.06-4.19
(1H, m), 4.24 to 4.40 (1H, m), 4.50 (1H, d, J = 5.86Hz), 4.82
(1H, d, J = 14.16Hz), 6.65 (1H, dd, J = 8.30, 1.96Hz), 7.00
~ 7.10 (2H, m), 7.10 ~ 7.19 (1H, m), 7.19 ~ 7.30 (2H, m),
7.58 to 7.70 (1H, m), 7.70 to 7.90 (2H, m), 8.10 to 8.30 (1
H, m) Mass (EI method): 414 (M ⁺ ) High-resolution mass spectrum Calculated for C ₂₆ H ₂₆ N ₂ O ₃ : 414.1943 Found: 414.1939.

Similarly, 2-methyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,
Instead of 12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-
4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- ( 3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl)-
8-chloro-9-bromo-1,2,3,4,4a, 5
12,12aβ-octahydro-quinolino [2,3-
g] When isoquinoline is used, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2- (1-oxo-2-oxa-
3-butenyl) -4aα- (3-methoxyphenyl)-
8-butyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl)-
4aα- (3-methoxyphenyl) -8-bromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2- (1-oxo-2-oxa-
3-butenyl) -4aα- (3-methoxyphenyl)-
8,9-dibromo-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3 , 4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-3-butenyl)-
4aα- (3-methoxyphenyl) -8-chloro-9-
Bromo-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Example 7 2- (1-oxo-2-oxa-4,4,4-trichlorobutyl) -4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline 9

[0070]

Embedded image

Under an argon stream, 2-methyl-4aα-
(3-methoxyphenyl) -1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] 64.0 mg of isoquinoline (0.179 mmol
l) and 57.5 mg of proton sponge (0.269 mm)
ol) was dissolved in 1 ml of anhydrous dichloroethane and cooled with water. Next, 2,2,2-trichloroethyl chloroformate 5
2.8 mg (0.249 mmol) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. 10 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted twice with 30 ml of ethyl acetate. The obtained organic layer was washed with 10 ml of 1N hydrochloric acid, 30 ml of water, and 20 m of saturated saline.
and dried over anhydrous magnesium sulfate. After filtration of magnesium sulfate, the filtrate was concentrated to obtain 111.5 mg of a pale yellow oil. The oily product was separated and purified by column chromatography (silica gel, Merck Rover column type B, cyclohexane: ethyl acetate = 3: 1 to 2: 1) to obtain 76.2 mg of the title compound as an oil. This was further recrystallized from 1.0 ml of ethyl acetate and 1.4 ml of n-hexane to obtain 50.6 mg of crystals and 13.2 mg of a filtrate (yield: 68.6).
%).

Mp 183 ° -184 ° C. (recrystallized from ethyl acetate / n-hexane) IR (KBr method) cm ⁻¹ : 2944,1719,1601,1493,1437,1423,1241,
1131,1040,803,756,710 NMR (CDCl3,400MHz) δ: 1.91 (1H, td, J = 13.19,4.40Hz), 2.
30 ~ 2.35 (1H, m), 2.48 ~ 2.60 (1H, m), 3.02 ~ 3.22 (4H, m),
3.48 to 3.67 (1H, m), 3.67 (3H, s), 3.73 to 3.81 (1H, m), 4.05
~ 4.16 (1H, m), 4.23 ~ 4.31 (1H, m), 4.73 ~ 4.84 (1H, m),
6.62 (1H, d, J = 8.30Hz), 6.98 ~ 7.07 (1H, m), 7.08 ~ 7.20
(2H, m), 7.39 ~ 7.44 (1H, m), 7.55 ~ 7.62 (1H, m), 7.66 (1
H, d, J = 7.82Hz), 7.79 (1H, d, J = 5.86Hz), 7.92 (1H, d, J = 8.30)
Hz) Mass (EI method): 518 (M ⁺⁾ calculated for elemental analysis _{C H N Cl C 26 H 25} N 2 O 3 Cl 3 60.07 4.85 5.39 20.46 Found 60.21 5.04 5.25 20.25.

Similarly, 2-methyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,
Instead of 12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-
4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- ( 3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl)-
8-chloro-9-bromo-1,2,3,4,4a, 5
12,12aβ-octahydro-quinolino [2,3-
g] When isoquinoline is used, 2- (1-oxo-2-oxa-4,4,4,4-trichlorobutyl) -4a
α- (3-methoxyphenyl) -8-methyl-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-4,4,4-trichlorobutyl) -4a
α- (3-methoxyphenyl) -8-butyl-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-4,4,4-trichlorobutyl) -4a
α- (3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-4,4,4-trichlorobutyl) -4a
α- (3-methoxyphenyl) -8-methoxy-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-4,4,4-trichlorobutyl)-
4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-
(1-oxo-2-oxa-4,4,4-trichlorobutyl) -4aα- (3-methoxyphenyl) -8,9-
Dibromo-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-oxa-4,4,4-trichlorobutyl) -4aα- (3-methoxyphenyl)-
8,9-dimethoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (1-oxo-2-oxa-4,
4,4-trichlorobutyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Example 8 2- (1-oxocyclopropylmethyl) -4aα-
(3-methoxyphenyl) -1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline 10

[0075]

Embedded image

Under an argon stream, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline 2
14.6 mg (0.518 mmol) of methanol 2m
and about 8N methanolic hydrogen chloride (2 ml).
Heated to ° C. After 30 minutes, the mixture was ice-cooled, 6 ml of a saturated aqueous sodium hydrogen carbonate solution and 10 ml of water were added, and
Extracted twice with 0 ml. The obtained organic layer was washed with saturated saline 1
The extract was washed with 0 ml, dried over anhydrous magnesium sulfate and concentrated. The residue was dried under reduced pressure to give 187.5 mg of 2
A secondary amine was obtained (yield 105%). The obtained residue was mixed with 5 ml of anhydrous THF and 122.9 m of triethylamine.
g (1.21 mmol) and ice-cooled, and then 133.3 mg (1.27 m) of cyclopropanecarbanoyl chloride.
mol) was added dropwise and stirred at room temperature for 3 hours. 6 ml of saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted twice with 10 ml of dichloromethane. The obtained organic layer was washed with 10 ml of saturated saline and dried over anhydrous magnesium sulfate.
Concentrated. The resulting residue (241.0 mg) was separated and purified by column chromatography (silica gel, Merck Rover column type B, cyclohexane: ethyl acetate = 1: 3 to 1: 4) to obtain 169.6 mg of the title compound (yield: 26%). Rate 79.4%).

Mp: 227-228 ° C. (recrystallized from dichloromethane-ether) IR (KBr method) cm ⁻¹ : 2944,1636,1439,1257,1232,1050,781,7
54 NMR (CDCl3, 400MHz) δ: 0.72 to 0.85 (2H, m), 0.95 to 1.10
(2H, m), 1.74 to 2.00 (2H, m), 2.30 to 2.63 (2H, m), 2.97 to
3.22 (3H, m), 3.22 to 3.40 (1.5H, m), 3.67 (3H, s), 3.73 to 3.
89 (1.5H, m), 4.05-4.14 (0.6H, m), 4.16-4.26 (0.4H,
m), 4.32 to 4.42 (0.4H, m), 4.62 to 4.72 (0.6H, m), 6.63 (1H,
d, J = 7.32), 6.96-7.15 (3H, m), 7.36-7.46 (1H, m), 7.53
7.70 (2H, m), 7.79 (1H, s), 7.88 to 7.97 (1H, m) Mass (EI method): 412 (M ⁺ ) High-resolution mass spectrum Calculated value as C ₂₇ H ₂₈ N ₂ O ₂ : 412.2151 found: 412.2164.

Similarly, instead of cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride were used,
Benzoyl-4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1
-Oxo-2-propenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Further, similarly, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride and acroyl chloride are used, respectively, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,5 12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-methyl-1,2,3
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-methyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride and acroyl chloride are used, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,5 12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-butyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride, and acroyl chloride are used, respectively, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,5 12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-bromo-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-bromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride and acroyl chloride are used, respectively, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a, 5,5 1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2- (phenylacetyl) -4a
α- (3-methoxyphenyl) -8-methoxy-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4aα- (3-methoxyphenyl) -8-methoxy -1, 2, 3, 4, 4a, 5, 1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3 instead of octahydro-quinolino [2,3-g] isoquinoline , 4,4a, 5,12,12aβ-
When octahydro-quinolino [2,3-g] isoquinoline is used and cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride are used as acid chlorides, 2- (1-
(Oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα
-(3-methoxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
8,9-dimethyl-1,2,3,4,4a, 5,12,
12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4a
α- (3-methoxyphenyl) -8,9-dimethyl-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Further, similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3 instead of octahydro-quinolino [2,3-g] isoquinoline , 4,4a, 5,12,12aβ-
When octahydro-quinolino [2,3-g] isoquinoline is used and cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride are used as acid chlorides, 2- (1-
(Oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα
-(3-methoxyphenyl) -8,9-dibromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
8,9-dibromo-1,2,3,4,4a, 5,12,
12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4a
α- (3-methoxyphenyl) -8,9-dibromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3 instead of octahydro-quinolino [2,3-g] isoquinoline , 4,4a, 5,12,12aβ
When using -octahydro-quinolino [2,3-g] isoquinoline and using cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride as acid chlorides, 2- (1-
(Oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα
-(3-methoxyphenyl) -8,9-dimethoxy-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)
-8,9-Dimethoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (1-oxo-2-propenyl)-
4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Further, similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2 instead of octahydro-quinolino [2,3-g] isoquinoline , 3,4,4a, 5,12,12
a Using β-octahydro-quinolino [2,3-g] isoquinoline and using cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride as acid chlorides, respectively.
(1-oxocyclopropylmethyl) -4aα- (3-
Methoxyphenyl) -8-chloro-9-bromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-chloro-
9-bromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,3
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-chloro-9-bromo-1,2,3,4,4a, 5
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline is obtained.

Example 9 2- (1-oxocyclopropylmethyl) -4aα-
(3-methoxyphenyl) -1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline 10

[0088]

Embedded image

2- (1-oxo-2-oxa-4,4,4
4-trichlorobutyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline 9
00 mg (1.73 mmol) was dissolved in 10 ml of acetic acid, 2.08 g (31.8 mmol) of zinc was added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered using Hyflo Super Cell while washing with methanol, and the filtrate was concentrated.
A saturated aqueous sodium hydrogen carbonate solution was added to the residue while cooling with ice, and the mixture was extracted three times with 50 ml of chloroform. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (30 ml) and water (30 ml).
The extract was washed with 30 ml of a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated. The obtained yellow-brown amorphous 615.8 mg was filtered while washing with ether to obtain 265.9 mg of an amorphous secondary amine. 1 ml of anhydrous THF and 0.32 ml of triethylamine
(2.32 mmol) and ice-cooled, then 0.18 ml (1.93 mmol) of cyclopropanecarbanoyl chloride
l) was added dropwise and stirred at room temperature for 30 minutes. The reaction solution was ice-cooled, 10 ml of a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted twice with 10 ml of dichloromethane. The obtained organic layer was washed with 10 ml of saturated saline, dried over anhydrous magnesium sulfate, and concentrated. 299.9 m obtained residue
g was separated and purified by column chromatography (silica gel, cyclohexane: ethyl acetate = 1: 4 to 1: 6) to obtain 189.5 mg of the title compound (yield: 59.5% based on the secondary amine). The physical properties of the obtained compound were the same as those in Example 8.

Similarly, benzoyl chloride, phenylacetyl chloride and acroyl chloride were used in place of cyclopropanecarbanoyl chloride to give 2-
Benzoyl-4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1
-Oxo-2-propenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride and acroyl chloride are used, respectively, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,5 12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-methyl-1,2,3
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-methyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride and acroyl chloride are used, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,5 12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-butyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Further, similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride, and acroyl chloride are used, respectively, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,5 12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-bromo-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-bromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, 2- (1-oxo-2-)
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4 instead of octahydro-quinolino [2,3-g] isoquinoline , 4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
Cyclopropanecarbanoyl chloride as an acid chloride,
When benzoyl chloride, phenylacetyl chloride and acroyl chloride are used, respectively, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a, 5,5 1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2- (phenylacetyl) -4a
α- (3-methoxyphenyl) -8-methoxy-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4aα- (3-methoxyphenyl) -8-methoxy -1, 2, 3, 4, 4a, 5, 1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline is obtained.

Further, in the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3 instead of octahydro-quinolino [2,3-g] isoquinoline , 4,4a, 5,12,12aβ-
When octahydro-quinolino [2,3-g] isoquinoline is used and cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride are used as acid chlorides, 2- (1-
(Oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα
-(3-methoxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
8,9-dimethyl-1,2,3,4,4a, 5,12,
12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4a
α- (3-methoxyphenyl) -8,9-dimethyl-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3 instead of octahydro-quinolino [2,3-g] isoquinoline , 4,4a, 5,12,12aβ-
When octahydro-quinolino [2,3-g] isoquinoline is used and cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride are used as acid chlorides, 2- (1-
(Oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα
-(3-methoxyphenyl) -8,9-dibromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
8,9-dibromo-1,2,3,4,4a, 5,12,
12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4a
α- (3-methoxyphenyl) -8,9-dibromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3 instead of octahydro-quinolino [2,3-g] isoquinoline , 4,4a, 5,12,12aβ
When using -octahydro-quinolino [2,3-g] isoquinoline and using cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride as acid chlorides, 2- (1-
(Oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα
-(3-methoxyphenyl) -8,9-dimethoxy-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)
-8,9-Dimethoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (1-oxo-2-propenyl)-
4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline is obtained.

In the same manner, 2- (1-oxo-2-
Oxa-3-butenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
2- (1-oxo-2-oxa-3-butenyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2 instead of octahydro-quinolino [2,3-g] isoquinoline , 3,4,4a, 5,12,12
a Using β-octahydro-quinolino [2,3-g] isoquinoline and using cyclopropanecarbanoyl chloride, benzoyl chloride, phenylacetyl chloride, and acroyl chloride as acid chlorides, respectively.
(1-oxocyclopropylmethyl) -4aα- (3-
Methoxyphenyl) -8-chloro-9-bromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-chloro-
9-bromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,3
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-chloro-9-bromo-1,2,3,4,4a, 5
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline is obtained.

Example 10 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline
11

[0100]

Embedded image

2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) under a stream of argon
-1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline
2 mg of anhydrous toluene was added to 0 mg (0.330 mmol), cooled to -75 ° C, and then cooled to -78 ° C.
M diisobutylaluminum hydride-toluene solution 2m
1 (3 mmol) was added dropwise. 1. at -75 to -55 ° C.
After stirring for 5 hours, saturated aqueous sodium hydrogen carbonate solution 4m
1 was added. 20 ml of dichloromethane and 10 ml of water
After stirring at room temperature, insolubles were filtered using Hyflo Super Cell. The filtrate was separated, and the resulting aqueous layer was extracted twice with 20 ml of dichloromethane. The obtained organic layer was washed with 10 ml of saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 149.1 mg of a mixture of a white solid and an oil. The residue was separated and purified by column chromatography (silica gel, 5 to 10% methanol / chloroform) and recrystallized from ethyl acetate-n-hexane to give 46.4 mg of the title compound as crystals.
4.2 mg of the filtrate was obtained (yield 91.7%).

Mp: 208-212 ° C. (amorphous before recrystallization), 77-80 ° C. (recrystallized from ethyl acetate-n-hexane,
0.8 hydrate) IR (KBr method) cm ^-1 : 2912,1607,1582,1493,1238,1046,783,7
72,706 NMR (CDCl3,400MHz) δ: 0.10 to 0.20 (2H, m), 0.55 (2H, d, J
= 7.81Hz), 0.88-1.00 (1H, m), 2.02-2.21 (2H, m), 2.25
~ 2.43 (3H, m), 2.64 ~ 2.82 (2H, m), 2.93 ~ 3.00 (1H, m), 3.
11 to 3.32 (4H, m), 3.68 (3H, s), 3.75 (1H, d, J = 16.60Hz),
6.54 to 6.61 (1H, m), 7.02 to 7.10 (3H, m), 7.37 to 7.43 (1H,
m), 7.53 to 7.59 (1H, m), 7.64 (1H, d, J = 7.81Hz), 7.78 (1H,
s), 7.91 (1H, d, J = 8.79 Hz) Mass (EI method): 398 (M ⁺ ) High-resolution mass spectrum Calculated as C ₂₇ H ₃₀ N ₂ O: 398.2359 Found: 398.2354.

Similarly, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12a Instead of β-octahydro-quinolino [2,3-g] isoquinoline, 2-
Benzoyl-4aα- (3-methoxyphenyl) -1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl)-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1
-Oxo-2-propenyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxocyclopropylmethyl) -4aα
-(3-methoxyphenyl) -8-methyl-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-
4aα- (3-methoxyphenyl) -8-methyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8
-Methyl-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4aα-
(3-methoxyphenyl) -8-methyl-1,2,3
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,2 3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (phenylacetyl) -4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8-butyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxocyclopropylmethyl) -4aα
-(3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-
4aα- (3-methoxyphenyl) -8-bromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8
-Bromo-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4aα-
(3-methoxyphenyl) -8-bromo-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,2 3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2- (phenylacetyl) -4a
α- (3-methoxyphenyl) -8-methoxy-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4aα- (3-methoxyphenyl) -8-methoxy -1, 2, 3, 4, 4a, 5, 1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-benzoyl-4aα- (3-methoxyphenyl)-
8,9-dimethyl-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-
Methoxyphenyl) -8,9-dimethyl-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8,9-dimethyl-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxocyclopropylmethyl)-
4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- ( 3-methoxyphenyl) -8,9
-Dibromo-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-
Propenyl) -4aα- (3-methoxyphenyl)-
8,9-dibromo-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxocyclopropylmethyl)-
4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-
Benzoyl-4aα- (3-methoxyphenyl) -8,
9-dimethoxy-1,2,3,4,4a, 5,12,1
2aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2
-Propenyl) -4aα- (3-methoxyphenyl)-
8,9-dimethoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (1-oxocyclopropylmethyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzoyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (phenylacetyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,3 4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (1-oxo-2-propenyl) -4aα-
(3-methoxyphenyl) -8-chloro-9-bromo-
Using 1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline,
2-benzyl-4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
-(2-phenylethyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl)
-8-methyl-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3
-Methoxyphenyl) -8-methyl-1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-methoxyphenyl) -8-methyl-1,2,3
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a , 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,12, 12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-
(2-phenylethyl) -4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-butyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-cyclopropylmethyl-4aα-
(3-methoxyphenyl) -8-bromo-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα
-(3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-
Bromo-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-allyl-4aα- (3-methoxyphenyl) -8-
Bromo-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a, 5
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4 4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-
Allyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline,
-Cyclopropylmethyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8,9-
Dimethyl-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
8,9-dimethyl-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-
Methoxyphenyl) -8,9-dibromo-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα
-(3-methoxyphenyl) -8,9-dibromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl)-
8,9-dibromo-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,5
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline, 2-cyclopropylmethyl-4aα
-(3-methoxyphenyl) -8,9-dimethoxy-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2 , 3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-methoxyphenyl) -8,9-dimethoxy-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8
-Chloro-9-bromo-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1, 2,3,4,4a, 5,12,1
2aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Example 11 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline 12

[0105]

Embedded image

Under an argon stream, potassium t-butoxide 2
16.6 mg (1.93 mmol) of anhydrous DMF.
Dissolve in 5 ml and add 0.24 ml of n-propanethiol
(2.70 mmol) and heated to reflux for several minutes. After allowing to cool, 2-cyclopropylmethyl-4aα- (3-
Methoxyphenyl) -1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
A solution prepared by dissolving 154.0 mg (0.386 mmol) of isoquinoline in 1.5 ml of anhydrous DMF was added. After further washing with 2 ml of anhydrous DMF and adding the washing solution, the mixture was heated under reflux for 2 hours. The reaction solution was ice-cooled, and after adding 0.3 ml of acetic acid, DMF was distilled off under reduced pressure. 20 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted twice with 30 ml of a mixed solvent of chloroform: ethanol = 3: 1.
The organic layer was washed with 10 ml of water and 10 ml of saturated saline, dried over anhydrous magnesium sulfate, and concentrated. 6 ml of methanol was added to the obtained residue, and a methanol solution of 200 mg of methanesulfonic acid was added while cooling with ice. After filtering off the insoluble matter, concentrating the filtrate and separating and purifying the residue by column chromatography (Sephadex LH-20, methanol), the residue was washed twice with 4 ml of ether and twice with 4 ml of n-hexane. 178.5 mg of a pale brown amorphous which was a methanesulfonate of the title compound and 11.0 mg of a filtrate were obtained (yield: 85.1%).

Decomposition point of the title compound:> 250 ° C. IR (KBr method) cm ⁻¹ : 3400,2914,1580,1493,1423,1238,777,7
64 NMR (CD3OD, 400 MHz) δ: 0.26-0.38 (2H, m), 0.68 (2H, d, J
= 7.82Hz), 1.00-1.10 (1H, m), 2.02-2.15 (2H, m), 2.42
~ 2.58 (2H, m), 2.68 ~ 2.81 (3H, m), 3.10 ~ 3.42 (5H, m), 3.
42 to 3.55 (1H, m), 3.66 (1H, d, J = 16.11 Hz), 6.45 to 6.52 (1H
, m), 6.91-7.05 (3H, m), 7.43-7.50 (1H, m), 7.58-7.6
4 (1H, m), 7.70 (1H, d, J = 8.30Hz), 7.83 (1H, d, J = 8.30Hz), 8.
03 (1H, s) Mass (FAB method): 385 (M ⁺ +1) High-resolution mass spectrum (FAB method) Calculated value for C ₂₆ H ₂₉ N ₂ O: 385.2280 Found: 385.2328 Methanesulfonic acid of the title compound Salt mp: 140-143 ° C. Elemental analysis Calculated for CH ₂₆ S as C ₂₆ H ₂₈ N ₂ O.2CH ₃ SO ₃ H.1.6H ₂ O 55.53 6.53 4.63 10.59 found 55.50 6.32 4.60 10.73.

Similarly, 2-cyclopropylmethyl-4
aα- (3-methoxyphenyl) -1,2,3,4,4
a, 5,12,12aβ-Octahydro-quinolino [2,3-g] isoquinoline in place of 2-benzyl-
4aα- (3-methoxyphenyl) -1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4a
α- (3-methoxyphenyl) -1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-methyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3 , 4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-
(2-phenylethyl) -4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-methyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-cyclopropylmethyl-4aα-
(3-methoxyphenyl) -8-butyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα
-(3-methoxyphenyl) -8-butyl-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-
Butyl-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-allyl-4aα- (3-methoxyphenyl) -8-
Butyl-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-bromo-1,2,3,4,4a, 5,
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline, 2- (2-phenylethyl) -4a
α- (3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4a
α- (3-methoxyphenyl) -8-bromo-1,2,2
3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4 , 4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-benzyl-4aα- (3-methoxyphenyl) -8
-Methoxy-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-methoxy-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-methoxyphenyl) -8-methoxy-1,2,2
3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8,9
-Dimethyl-1,2,3,4,4a, 5,12,12a
β-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl)
-8,9-dimethyl-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2- (2-phenylethyl) -4aα-
(3-methoxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-
4aα- (3-methoxyphenyl) -8,9-dimethyl-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα -(3-methoxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8,9-dibromo-1,2,3 4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2-allyl-4aα- (3-methoxyphenyl) -8,
9-dibromo-1,2,3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα
-(3-methoxyphenyl) -8,9-dimethoxy-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2
-Phenylethyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3 , 4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-chloro-9-bromo-1,2,2 3,4,4a, 5,12,12
aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl)
-8-chloro-9-bromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] using isoquinoline to give 2-benzyl-
4aα- (3-hydroxyphenyl) -1,2,3
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -1,
2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-
4aα- (3-hydroxyphenyl) -1,2,3
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4a , 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-
Benzyl-4aα- (3-hydroxyphenyl) -8-
Methyl-1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline,
2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-methyl-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-butyl-1,2,3,4,4a, 5 , 12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-butyl-1,2,3,4,4a, 5,12,12aβ- Octahydro-quinolino [2,3-g] isoquinoline, 2
-(2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-butyl-1,2,3,4,4a, 5
12,12aβ-octahydro-quinolino [2,3-
g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-butyl-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-cyclopropylmethyl-4a
α- (3-hydroxyphenyl) -8-bromo-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-bromo-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2
-Phenylethyl) -4aα- (3-hydroxyphenyl) -8-bromo-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-bromo-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-cyclopropylmethyl-4aα-
(3-Hydroxyphenyl) -8-methoxy-1,2,2
3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4
aα- (3-hydroxyphenyl) -8-methoxy-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2
-Phenylethyl) -4aα- (3-hydroxyphenyl) -8-methoxy-1,2,3,4,4a, 5,1
2,12aβ-octahydro-quinolino [2,3-g]
Isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-methoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-cyclopropylmethyl-4a
α- (3-hydroxyphenyl) -8,9-dimethyl-
1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8,9-
Dimethyl-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8,9-dimethyl-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-hydroxyphenyl) -8,9-dimethyl-1,
2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl)-
8,9-dibromo-1,2,3,4,4a, 5,12,
12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8,9-dibromo-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2- (2-phenylethyl) -4
aα- (3-hydroxyphenyl) -8,9-dibromo-1,2,3,4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- ( 3-hydroxyphenyl) -8,9-
Dibromo-1,2,3,4,4a, 5,12,12aβ
-Octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα
-(3-hydroxyphenyl) -8,9-dimethoxy-
1,2,3,4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline, 2- (2
-Phenylethyl) -4aα- (3-hydroxyphenyl) -8,9-dimethoxy-1,2,3,4,4a,
5,12,12aβ-octahydro-quinolino [2,3
-G] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-1,2,3,
4,4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-1,2,3 , 4,4a, 5,12,1
2aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-1,2, 3,4,4a, 5,12,1
2aβ-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-1,2,3,4,4
a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline is obtained.

Reference Example 3 2- (2,2,2-trichloroethoxycarbonyl)-
4a- (3-methoxyphenyl) -6-acetoxy-
2,3,4,4a, 5,6,7,8-octahydroisoquinoline 13

[0110]

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In an argon atmosphere, 2-methyl-4a-
(3-methoxyphenyl) -6-acetoxy-2,3,
4,4a, 5,6,7,8-octahydroisoquinoline (19.5 g) was added to 1,2-dichloroethane (100 m
l) into a proton sponge (6.6)
g) was added. At 0 ° C., 2,2,2-trichloroethylchloroformate (12.8 ml) was added dropwise, and the resulting suspension was heated to room temperature and stirred for 15 hours. After distilling off the solvent under reduced pressure, ether (400 ml) was added.
1N hydrochloric acid (150ml × 2), saturated saline (100m
Washed in l). After drying, the residue was purified by silica gel column chromatography (cyclohexane / ethyl acetate = 10: 1 → 5: 1) to give the title compound (6-position acetoxy mixture) 21.2.
g (72%).

The spectrum was measured for each of the partially separated 6-position acetoxy isomers.

Highly polar component (6α acetoxy compound) IR (liquid film method) cm ^-1 : 3024,1717,1415,1255,1216,758 NMR (CDCl3,400MHz) δ: 1.31 (3H, d, J = 4.8Hz) ), 1.57-1.65
(2H, m), 1.75-1.86 (2H, m), 1.98-2.06 (1H, m), 2.14-2.23 (1
H, m) 2.63-2.74 (1H, m), 2.77-2.88 (1H, m), 3.08 (1H, d, J = 1
5.1Hz), 3.80 (3H, s), 3.82-3.89 (1H, m), 4.67-4.85 (2H,
m), 4,98 (1H, s), 6.70 (1H, dd, J = 6.3,2.0Hz), 6.80 (1H, dd,
J = 2.5,1.9Hz), 6.85 (1H, d, J = 7.8Hz), 7.01 (1H, d, J = 7.8H
z), 7.22 (1H, t, J = 7.8 Hz) Mass (EI): 475 (M ⁺ ) High-resolution mass spectrum: Calculated value as C ₂₁ H ₂₄ O ₅ NCl ₃ 475.0720 Actual value 475.0716 Low polarity component (6β Acetoxy compound) IR (liquid film method) cm ^-1 : 2954,1725,1410,1251,1141,1046,754 NMR (CDCl3,400MHz) δ: 1.39-1.53 (2H, m), 1.83-2.09 (3H,
m), 2.02 (3H, s), 2.25-2.30 (2H, m), 2.83-3.07 (2H, m), 3.82
(3H, s), 3.85-3.95 (1H, m), 4.54-4.61 (1H, m), 4.70-4.88
(2H, m), 6.77 (1H, dd, J = 7.8,2.4Hz), 6.91-6.95 (2H, m), 6.9
8 (1H, d, J = 9.3Hz), 7.27 (1H, t, J = 7.8Hz) Mass (EI): 475 (M ⁺ ) High resolution mass spectrum: Calculated value as C ₂₁ H ₂₄ O ₅ NCl ₃ 475.0720 found 475.0718. Reference Example 4 2- (2,2,2-trichloroethoxycarbonyl)-
4aα- (3-methoxyphenyl) -6-acetoxy-
8aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline 14

[0114]

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Under an argon atmosphere, 2- (2,2,2-trichloroethoxycarbonyl) -4a- (3-methoxyphenyl) -6-acetoxy-2,3,4,4a, 5,
6,7,8-octahydroisoquinoline (16.5 g)
Was dissolved in methylene chloride (200 ml) and cooled to 0 ° C. m-Chloroperbenzoic acid (8.6 g) was added and reacted for 1.5 hours. The solvent was distilled off, and the obtained solid was directly used for the next reaction.

The above crude product was dissolved in acetic acid (150 ml), cooled to 0 ° C., and sodium borohydride was added little by little. The temperature was raised to room temperature and reacted for 15 minutes. The acetic acid was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (30
0 ml) and extracted with ethyl acetate (200 ml × 3). After drying over sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform) to obtain 10.8 g (63%) of the title compound (6-position acetoxy mixture). The spectrum was measured with the low-polarity component partially separated.

IR (liquid film method) cm ^-1 : 3462,2958,1715,1605,1
582,1437,1249,1033,758 NMR (CDCl3,90MHz) δ: 1.55-1.65 (2H, m), 1.65-1.85 (2H,
m), 1.92 (3H, s), 1.97-2.18 (2H, m), 2.20-2.57 (3H, m), 3.50
(1H, t, J = 7.8Hz), 3.79 (3H, s), 3.80-3.95 (2H, m), 4.78 (2H
H, d, J = 6.5 Hz), 6.68-6.84 (2H, m), 6.92-7.25 (2H, m) Mass (EI): 493 (M ⁺ ).

Reference Example 5 2-methyl-4aα- (3-methoxyphenyl) -6
8aβ-dihydroxy-1,2,3,4,4a, 5
6,7,8,8a-tetrahydroisoquinoline 15

[0119]

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Under an argon atmosphere, 2- (2,2,2-trichloroethoxycarbonyl) -4aα- (3-methoxyphenyl) -6-acetoxy-8aβ-hydroxy-
1,2,3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline (1.5 g) was added to anhydrous THF (20 m
l) and lithium aluminum hydride (0.35
g) was added. After reacting at room temperature for 30 minutes, it was cooled to 0 ° C. A saturated aqueous solution of Rossel's salt was slowly added dropwise, and when it became solid, chloroform (20 ml) was added, the mixture was stirred well, and filtered through celite. After washing well with chloroform, the collected filtrate and washings were concentrated under reduced pressure.
Purify by silica gel column chromatography (chloroform → ammonia-saturated chloroform → 5% methanol / ammonia-saturated chloroform) to obtain 0.63 g (71%) of the title compound.
%, 6-hydroxy mixture).

IR (KBr) cm ^-1 : 3412,1599,1493,1236,1071,
893,795,723,540 Mass (EI): 291 (M ⁺ ).

Reference Example 6 2-methyl-4aα- (3-methoxyphenyl) -6
Oxo-8aβ-hydroxy-1,2,3,4,4a,
5,6,7,8,8a-tetrahydroisoquinoline 1
6

[0123]

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Under an argon atmosphere, oxalyl chloride (0.19 ml) was dissolved in anhydrous methylene chloride (12 ml) and cooled to -55 ° C. A solution of DMSO dissolved in methylene chloride (1.5 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 2 minutes. 2-methyl-4aα- (3-methoxyphenyl) -6,8aβ-dihydroxy-1,2,2
A solution of 3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline (0.5 g) dissolved in methylene chloride (2 ml) was added dropwise, and a washing solution (methylene chloride, 2 ml) was also added. After stirring at −55 ° C. for 30 minutes, triethylamine (1.2 ml) was added, and the temperature was raised to room temperature. Distilled water (20 ml) was added for liquid separation, and the aqueous layer was further extracted with methylene chloride (12 ml × 2). The collected organic layer
The extract was washed with saturated saline (10 ml), dried and concentrated. Silica gel column chromatography (chloroform → 2% methano-
Then, the residue was purified with toluene / chloroform → 5% methanol / chloroform) to obtain 0.45 g (91%) of the title compound. n-
Recrystallized from hexane / ethyl acetate, 0.38 g of pure product (7
7%, mp 96-97 ° C).

IR (KBr) cm -1: 3406,2944,1711,1605,1578,
1452,1257,1114,1038,895,774,708 NMR (CDCl3,400MHz) δ: 1.85-1.93 (2H, m), 2.15-2.32 (3H,
m), 2.33 (3H, s), 2.39-2.46,2.55 (2H, t, J = 11.0Hz), 2.62-
2.66 (1H, m), 2.77 (1H, d, J = 11.0 Hz), 2.79-2.86 (2H, m),
3.13 (1H, d, J = 14.6Hz), 3.78 (3H, s), 6.72 (1H, dd, J = 7.4,3.
0 Hz), 6.96-6.97 (2H, m), 7.21 (1H, t, J = 8.5 Hz) Mass (EI): 289 (M ⁺ ).

Example 12 2-methyl-4aα- (3-methoxyphenyl) -12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline 17

[0127]

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Under an argon atmosphere, 2-methyl-4aα-
(3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5,6,7,8,8a
-Tetrahydroisoquinoline (100.9 mg) was dissolved in anhydrous ethanol (3 ml), and o-aminobenzaldehyde (170 mg) and methanesulfonic acid (56.6 µ) were dissolved.
l) was added. The reaction was carried out at 100 ° C. for 2 hours, and the mixture was allowed to cool to room temperature. Drain into saturated sodium bicarbonate (15 ml)
The organic layer was extracted with chloroform (10 ml × 2) and washed with a saturated saline solution (10 ml). After drying and concentration,
The residue was purified by silica gel column chromatography (chloroform → 5% methanol / chloroform) to give the title compound.
3 mg (89%) were obtained.

IR (liquid film method) cm ^- 1: 3,340,2941,1604,158
0,, 1430,1235,1039,874,750 NMR (CDCl3,400MHz) δ: 2.18 (1H, d, J = 14.1Hz), 2.30 (3H,
s), 2.33-2.41 (3H, m), 2.46-2.50 (1H, m), 2.85 (2H, q, J = 1
0.1Hz), 2.95-2.99 (2H, m), 3.33 (1H, d, J = 17.5Hz), 3.40 (1
H, d, J = 17.1Hz), 3.60 (3H, s), 3.70 (1H, d, J = 17.1Hz), 6.61
-6.63 (1H, m), 7.01-7.06 (3H, m), 7.41 (1H, t, J = 7.9Hz), 7.5
5 (1H, t, J = 6.6Hz), 7.66 (1H, d, J = 8.3Hz) 7.80 (1H, s), 7.93
(1H, d, J = 8.3Hz) Mass (EI): 374 (M ⁺ ).

Similarly, 2-amino-4-methylbenzaldehyde was used instead of 2-aminobenzaldehyde,
2-amino-4-butylbenzaldehyde, 2-amino-4-bromobenzaldehyde, 2-amino-4-methoxybenzaldehyde, 2-amino-4,5-dimethylbenzaldehyde, 2-amino-4,5-dibromobenzaldehyde, -Amino-4,5-dimethoxybenzaldehyde and 2-amino-4-chloro-5-bromobenzaldehyde give 2-methyl-4aα-
(3-methoxyphenyl) -8-methyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-methyl-4aα- (3-methoxyphenyl) -8-
Butyl-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-bromo-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methoxy-12aβ-hydroxy-1,2,3,4,4a, 5
12,12a-octahydro-quinolino [2,3-g]
Isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8,9-dibromo-12aβ-hydroxy -1, 2, 3, 4, 4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-
Methyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy-1,2,3
4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Example 13 2-methyl-4aα- (3-hydroxyphenyl) -1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline 18

[0132]

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Under an argon atmosphere, 2-methyl-4aα-
(3-methoxyphenyl) -12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline (86.1 m
g) with acetic acid (1 ml), 48% hydrogen bromide aqueous solution (1 m
1) and reacted at 100 ° C. for 5 hours. After cooling down,
The acetic acid is distilled off and a saturated aqueous sodium hydrogen carbonate solution (10 m
l) was added. Chloroform / ethanol (3/1, 1
5 ml × 2), and the collected organic layer was washed with saturated saline (1 ml).
0 ml). After drying, the mixture was concentrated and dissolved again in chloroform / ethanol (3/1, 20 ml). Methanesulfonic acid (31.3 μl) was added thereto, the solvent was distilled off, and the residue was purified by column chromatography (Sephadex LH20, methanol). Ether was added to the obtained oily substance to solidify it, and the solid was solidified with methanesulfonate of the title compound (55.2 m).
g (53%, mp> 250 ° C .; discolored to brown from 185 ° C.).

IR (KBr) cm ^-1 : 3040,2928,1615,1580,1492,
1420,1263,1150,783,742 NMR (DMSO-d6,400MHz) δ: 2.09-2.15 (1H, m), 2.24 (3H, s),
2.3-2.35 (3H, m), 2.40-2.45 (1H, m), 2.73-2.78 (2H, m), 2.9
0-2.94 (2H, m), 3.30 (1Hd, J = 17.3Hz), 3.35 (1H, d, J = 17.0H
z), 3.70 (1H, d, J = 17.0Hz), 6.41-6.47 (1H, m), 7.90-7.01 (3
H, m), 7.44 (1H, t, J = 7.5Hz), 7.59 (1H, t, J = 6.8Hz), 7.75 (1
H, d, J = 8.3Hz) 7.81 (1H, d, J = 8.3Hz), 7.98 (1H, s) Mass (FAB): 361 (M + + H) Elemental Analysis _{C 23 H 24 N 2 O 2} · C H N S calculated for _{2CH 3 SO 3 H · H 2} O 52.62 6.01 4.91 11.24 Found 52.48 6.22 5.08 11.53.

In the same manner, 2-methyl-4aα- (3-
Methoxyphenyl) -12aβ-hydroxy-1,2,2
Instead of 3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-methyl-1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-butyl-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα
-(3-methoxyphenyl) -8-bromo-12aβ-
Hydroxy-1,2,3,4,4a, 5,12,12a
-Octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl)-
8-methoxy-12aβ-hydroxy-1,2,3
4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-methoxyphenyl) -8,9-dimethyl-12a
β-hydroxy-1,2,3,4,4a, 5,12,1
2a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl)
-8,9-dibromo-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα
-(3-methoxyphenyl) -8,9-dimethoxy-1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy-1,2,3,4,4a , 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline yielded 2-methyl-4aα- (3-hydroxyphenyl) -8-methyl-12aβ-hydroxy-1,2,
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα
-(3-hydroxyphenyl) -8-butyl-12aβ
-Hydroxy-1,2,3,4,4a, 5,12,12
a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl)
-8-bromo-12aβ-hydroxy-1,2,3
4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα-
(3-hydroxyphenyl) -8-methoxy-12aβ
-Hydroxy-1,2,3,4,4a, 5,12,12
a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl)
-8,9-Dimethyl-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα
-(3-hydroxyphenyl) -8,9-dibromo-1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-1,2,3,4,4a, 5 , 12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2-methyl-4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy-1,2,3,
4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Reference Example 7 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline 19

[0137]

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Under an argon atmosphere, 2- (2,2,2-trichloroethoxycarbonyl) -4aα- (3-methoxyphenyl) -6-acetoxy-8aβ-hydroxy-
1,2,3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline (2.04 g) was added to acetic acid (50 ml).
And zinc powder (2.70 g) was added. The suspension was stirred at room temperature for 4 hours, and then filtered through celite to remove insolubles derived from zinc. The mixture was thoroughly washed with acetic acid and combined with the filtrate, and acetic acid was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added, and chloroform (50 ml) was added.
× 3) and washed with saturated saline (50 ml). After drying, the mixture was concentrated, and purified by silica gel column chromatography (chloroform → 5% methanol / ammonia-saturated chloroform) to give an N-nor compound (6-position acetoxy mixture) 0.95.
g (72%, Mass (EI): 319 (M +)).

Under an argon atmosphere, the N-nor derivative (0.
68 g) was dissolved in anhydrous 1,2-dichloroethane (15 ml), and proton sponge (0.46 g) and cyclopropanecarbonyl chloride (0.29 ml) were added. The solvent was distilled off under reduced pressure, ether (20 ml) was added, and the mixture was washed with 1N hydrochloric acid (20 ml) and saturated saline (10 ml).
After drying, the resulting oil was concentrated and subjected to the next reaction as it was (crude yield 91%, Mass (EI): 387 (M ⁺ )).

Under an argon atmosphere, the above oily product was treated with anhydrous T
Dissolved in HF (20 ml) and added lithium aluminum hydride (0.24 g) at 0 ° C. After reacting at 0 ° C. for 2 hours and at room temperature for 1 hour, a saturated aqueous solution of Rossel salt (5 ml) was used.
Was slowly added. Chloroform (50 ml) was added, filtered through celite and washed with chloroform.
The oil obtained by concentration was directly used for the next reaction (crude yield 85%, Mass (EI): 331 (M ⁺ )).

Under an argon atmosphere, oxalyl chloride (0.15 ml) was dissolved in anhydrous methylene chloride (10 ml) and cooled to -55 ° C. DMSO (0.24 ml)
Was dissolved in anhydrous methylene chloride (1 ml), and the mixture was slowly added dropwise to react at -55 ° C for 2 minutes. A solution obtained by dissolving the above oil in anhydrous methylene chloride (2 ml) was added thereto.
A washing solution (2 ml) was also added. After reacting at −55 ° C. for 30 minutes, triethylamine (1.09 ml) was added, and the temperature was raised to room temperature. Distilled water (15 ml) was added for liquid separation, and the aqueous layer was further extracted with methylene chloride (10 ml). The collected organic layer was washed with saturated saline (10 ml), dried, concentrated, and purified by silica gel column chromatography (chloroform → 2% methanol / chloroform) to give the title compound 0.48.
g (3 steps 68%).

IR (liquid film method) cm-1: 3404, 2940, 1711, 1605, 1
582,1493,1429,1241,1038,897,756 NMR (CDCl3,400MHz) δ: 0.11 (2H, d, J = 5.9Hz), 0.50-0.55
(2H, m), 0.81-0.89 (1H, m), 1.86-1.90 (2H, m), 2.25-2.28 (2
H, m), 2.32-2.37 (3H, m), 2.39-2.46 (1H, m), 2.53 (1H, d, J = 1
4.3Hz), 2.75-2.87 (4H, m), 3.14 (1H, d, J = 14.3Hz), 3.77 (3
H, s), 6.70-6.72 (1H, m), 6.97-6.98 (2H, m), 7.20 (1H, t, J =
8.8 Hz) Mass (EI): 329 (M ⁺ ) High-resolution mass spectrum: Calculated as C ₂₁ H ₂₇ O ₃ N 329.1991 Found 329.1955.

Similarly, benzoyl chloride, phenylacetyl chloride and acroyl chloride were used instead of cyclopropanecarbonyl chloride to give 2-
Benzyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a,
5,6,7,8,8a-tetrahydroisoquinoline, 2
-(2-phenylethyl) -4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline is obtained.

Example 14 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline 20

[0145]

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Under an argon atmosphere, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5,5
6,7,8,8a-tetrahydroisoquinoline (14
7.2 mg) in anhydrous ethanol (5 ml).
-Aminobenzaldehyde (212.4 mg), methanesulfonic acid (73.5 [mu] l) were added. The reaction was carried out at 100 ° C. for 5 hours and allowed to cool to room temperature. Pour into saturated sodium bicarbonate (15 ml) and add chloroform (15 ml x 2)
And the combined organic layer was washed with saturated saline (15 ml). After drying and concentration, the residue was purified by silica gel column chromatography (chloroform → 2% methanol / chloroform → 5% methanol / chloroform) to give the title compound 16
9.2 mg (91%) were obtained.

IR (liquid film method) cm ^-1 : 3388,2938,1605,1580,1
493,1433,1241,1042,878,758 NMR (CDCl3,400MHz) δ: 0.12 (2H, d, J = 6.1Hz), 0.53-0.57
(2H, m), 0.85-0.92 (1H, m), 2.18 (1H, d, J = 14.1Hz), 2.33-2.
41 (2H, m), 2.40 (1H, d, J = 6.7 Hz), 2.49-2.55 (1H, m), 2.86
(2H, q, J = 9.7Hz), 2.97-3.01 (2H, m), 3.35 (1H, d, J = 17.7Hz)
3.42 (1H, d, J = 17.1Hz), 3.63 (3H, s) 3.71 (1H, d, J = 17.1Hz),
6.61-6.64 (1H, m), 7.03-7.08 (3H, m), 7.41 (1H, t, J = 8.0H
z), 7.57 (1H, t, J = 6.7Hz), 7.67 (1H, d, J = 8.5Hz), 7.81 (1H,
s), 7.95 (1H, d, J = 8.5 Hz) Mass (EI): 414 (M ⁺ ).

In the same manner, 2-cyclopropylmethyl-4
aα- (3-methoxyphenyl) -6-oxo-8aβ
-Hydroxy-1,2,3,4,4a, 5,6,7,
Instead of 8,8a-tetrahydroisoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5,5
6,7,8,8a-tetrahydroisoquinoline, 2-
(2-phenylethyl) -4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
When 3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-benzyl-4aα-
(3-methoxyphenyl) -12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-12aβ-hydroxy-1,2,3,4,4a, 5
12,12a-octahydro-quinolino [2,3-g]
Isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline is obtained.

Similarly, 2-amino-4-methylbenzaldehyde was used in place of 2-aminobenzaldehyde, and 2-cyclopropylmethyl-4aα- (3-
(Methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-benzyl-4aα- (3-
Methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2- (2-phenylethyl)-
4aα- (3-methoxyphenyl) -6-oxo-8a
β-hydroxy-1,2,3,4,4a, 5,6,7,
8,8a-tetrahydroisoquinoline, 2-allyl-4
aα- (3-methoxyphenyl) -6-oxo-8aβ
-Hydroxy-1,2,3,4,4a, 5,6,7,
When 8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-methyl-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-methyl-
12aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα-
(3-methoxyphenyl) -8-methyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-allyl-4aα- (3-methoxyphenyl) -8-
Methyl-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline is obtained.

Similarly, using 2-amino-4-butylbenzaldehyde, 2-cyclopropylmethyl-4a
α- (3-methoxyphenyl) -6-oxo-8aβ-
Hydroxy-1,2,3,4,4a, 5,6,7,8,
8a-tetrahydroisoquinoline, 2-benzyl-4a
α- (3-methoxyphenyl) -6-oxo-8aβ-
Hydroxy-1,2,3,4,4a, 5,6,7,8,
8a-tetrahydroisoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a,
5,6,7,8,8a-tetrahydroisoquinoline, 2
-Allyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a,
When 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4aα-
(3-methoxyphenyl) -8-butyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-benzyl-4aα- (3-methoxyphenyl) -8
-Butyl-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2- (2-phenylethyl)-
4aα- (3-methoxyphenyl) -8-butyl-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-butyl-12aβ-hydroxy-1,2,2,
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, using 2-amino-4-bromobenzaldehyde, 2-cyclopropylmethyl-4a
α- (3-methoxyphenyl) -6-oxo-8aβ-
Hydroxy-1,2,3,4,4a, 5,6,7,8,
8a-tetrahydroisoquinoline, 2-benzyl-4a
α- (3-methoxyphenyl) -6-oxo-8aβ-
Hydroxy-1,2,3,4,4a, 5,6,7,8,
8a-tetrahydroisoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a,
5,6,7,8,8a-tetrahydroisoquinoline, 2
-Allyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a,
When 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4aα-
(3-methoxyphenyl) -8-bromo-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-benzyl-4aα- (3-methoxyphenyl) -8
-Bromo-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2- (2-phenylethyl)-
4aα- (3-methoxyphenyl) -8-bromo-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-bromo-12aβ-hydroxy-1,2,2,
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, using 2-amino-4-methoxybenzaldehyde, 2-cyclopropylmethyl-4
aα- (3-methoxyphenyl) -6-oxo-8aβ
-Hydroxy-1,2,3,4,4a, 5,6,7,
8,8a-tetrahydroisoquinoline, 2-benzyl-
4aα- (3-methoxyphenyl) -6-oxo-8a
β-hydroxy-1,2,3,4,4a, 5,6,7,
8,8a-tetrahydroisoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -6
-Oxo-8aβ-hydroxy-1,2,3,4,4
a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
6-oxo-8aβ-hydroxy-1,2,3,4,4
When a, 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4a
α- (3-methoxyphenyl) -8-methoxy-12a
β-hydroxy-1,2,3,4,4a, 5,12,1
2a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-methoxy-12aβ-hydroxy-1,2,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8-methoxy-12aβ-hydroxy- 1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-methoxy-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline is obtained.

Similarly, using 2-amino-4,5-dimethylbenzaldehyde, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -6-oxo-8
aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -6-oxo-
8aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-6-oxo-8aβ-hydroxy-1,2,3,4
4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
6-oxo-8aβ-hydroxy-1,2,3,4,4
When a, 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4a
α- (3-methoxyphenyl) -8,9-dimethyl-1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-8,9-dimethyl-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα
-(3-methoxyphenyl) -8,9-dimethyl-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, using 2-amino-4,5-dibromobenzaldehyde, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -6-oxo-8
aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -6-oxo-
8aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-6-oxo-8aβ-hydroxy-1,2,3,4
4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
6-oxo-8aβ-hydroxy-1,2,3,4,4
When a, 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4a
α- (3-methoxyphenyl) -8,9-dibromo-1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dibromo-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-8,9-dibromo-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα
-(3-methoxyphenyl) -8,9-dibromo-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Similarly, using 2-amino-4,5-dimethoxybenzaldehyde, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -6-oxo-
8aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -6-oxo-
8aβ-hydroxy-1,2,3,4,4a, 5,6
7,8,8a-tetrahydroisoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-6-oxo-8aβ-hydroxy-1,2,3,4
4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
6-oxo-8aβ-hydroxy-1,2,3,4,4
When a, 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4a
α- (3-methoxyphenyl) -8,9-dimethoxy-
12aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-1,2,3,4,4a, 5 , 12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2
-Phenylethyl) -4aα- (3-methoxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-12aβ-hydroxy -1, 2, 3, 4, 4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline is obtained.

Similarly, 2-amino-4-chloro-5
-Bromobenzaldehyde, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5,5
6,7,8,8a-tetrahydroisoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,3,4,4a, 5
6,7,8,8a-tetrahydroisoquinoline, 2-
(2-phenylethyl) -4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -6-oxo-8aβ-hydroxy-1,2,2
When 3,4,4a, 5,6,7,8,8a-tetrahydroisoquinoline is used, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy- 1,2,3,
4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα-
(3-methoxyphenyl) -8-chloro-9-bromo-
12aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα-
(3-methoxyphenyl) -8-chloro-9-bromo-
12aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy-1,2,3,4,4a , 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline is obtained.

Example 15 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -12aβ-hydroxy-1,2,3,4
4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline 21

[0158]

Embedded image

Under an argon atmosphere, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -12aβ-
Hydroxy-1,2,3,4,4a, 5,12,12a
-Octahydro-quinolino [2,3-g] isoquinoline (141.5 mg) was dissolved in acetic acid (1 ml) and a 48% aqueous hydrogen bromide solution (1 ml) and reacted at 100 ° C for 5 hours. After cooling, acetic acid was distilled off, and a saturated aqueous solution of sodium hydrogen carbonate (10 ml) was added. The mixture was extracted with chloroform / ethanol (3/1, 15 ml × 2), and the collected organic layer was washed with saturated saline (10 ml). After drying, the mixture was concentrated and dissolved again in chloroform / ethanol (3/1, 20 ml). Methanesulfonic acid (31.3 μl) was added thereto, the solvent was distilled off, and column chromatography (Sephadex L) was performed.
H20, methanol). Ether was added to the obtained oil to solidify, and the solid was solidified, and 62.5 mg (38%, mp> 250 ° C; discolored to brown from 170 ° C) of the title compound was filtered off.

IR (KBr) cm ^-1 : 3300,2920,1603,1579,1490,
1420,1240,773,755 NMR (DMSO-d6,400MHz) δ: 0.23-0.35 (2H, m) 0.60-0.64 (2
H, m), 1.01-1.09 (1H, m), 2.15-2.20 (1H, m), 2.39-2.55 (2H,
m), 2.60-2.79 (3H, m), 3.05-3.18 (2H, m), 3.32-3.45 (2H,
m), 3.63 (1H, d, J = 16.5Hz), 6.44-6.50 (1H, m), 6.94-7.08 (3
H, m), 7.39-7.43 (1H, m), 7.57-7.63 (1H, m), 7.64 (1H, d, J =
8.1Hz), 7.79 (1H, s ), 7.92 (1H, d, J = 8.1Hz) Mass (FAB): 401 (M + + H) Elemental Analysis _{C 26 H 28 N 2 O 2} · 2CH 3 SO 3 H · 0.5H C H N S calculated for ₂ O 55.89 6.20 4.65 10.66 Found 55.81 6.25 4.65 10.79.

In the same manner, 2-cyclopropylmethyl-
Instead of 4aα- (3-methoxyphenyl) -12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2- (2-phenylethyl) -4a
α- (3-methoxyphenyl) -12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3- Methoxyphenyl) -12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-methyl-12aβ-hydroxy-1,
2,3,4,4a, 5,12,12a-octahydro-
Quinolino [2,3-g] isoquinoline, 2-benzyl-
4aα- (3-methoxyphenyl) -8-methyl-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-
Methoxyphenyl) -8-methyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxy Phenyl) -8-methyl-12aβ-hydroxy-1,2,3,4,4a, 5
12,12a-octahydro-quinolino [2,3-g]
Isoquinoline, 2-cyclopropylmethyl-4aα-
(3-methoxyphenyl) -8-butyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-benzyl-4aα- (3-methoxyphenyl) -8
-Butyl-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2- (2-phenylethyl)-
4aα- (3-methoxyphenyl) -8-butyl-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-butyl-12aβ-hydroxy-1,2,2,
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-bromo-12aβ-hydroxy-1,2 , 3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8-bromo-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-8-bromo-12aβ-hydroxy-1,2,3
4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-methoxyphenyl) -8-bromo-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-methoxy-12aβ-hydroxy-1,
2,3,4,4a, 5,12,12a-octahydro-
Quinolino [2,3-g] isoquinoline, 2-benzyl-
4aα- (3-methoxyphenyl) -8-methoxy-1
2aβ-hydroxy-1,2,3,4,4a, 5,1
2,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα-
(3-methoxyphenyl) -8-methoxy-12aβ-
Hydroxy-1,2,3,4,4a, 5,12,12a
-Octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl)-
8-methoxy-12aβ-hydroxy-1,2,3
4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-12aβ-hydroxy-1,2 , 3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-
(2-phenylethyl) -4aα- (3-methoxyphenyl) -8,9-dimethyl-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8,9-dimethyl-12aβ-hydroxy -1, 2, 3, 4, 4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-cyclopropylmethyl-4aα
-(3-methoxyphenyl) -8,9-dibromo-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl) -8,9-dibromo-12aβ-hydroxy-1,
2,3,4,4a, 5,12,12a-octahydro-
Quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl)-
8,9-dibromo-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα
-(3-methoxyphenyl) -8,9-dibromo-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-1,2,3,4,4a, 5 , 12,12a-
Octahydro-quinolino [2,3-g] isoquinoline,
2-benzyl-4aα- (3-methoxyphenyl)-
8,9-dimethoxy-12aβ-hydroxy-1,2,2,9
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-methoxyphenyl) -8,9
-Dimethoxy-12aβ-hydroxy-1,2,3
4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα-
(3-methoxyphenyl) -8,9-dimethoxy-12
aβ-hydroxy-1,2,3,4,4a, 5,12,
12a-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3-methoxyphenyl) -8-chloro-9-bromo-12aβ
-Hydroxy-1,2,3,4,4a, 5,12,12
a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-methoxyphenyl)
-8-chloro-9-bromo-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-
Phenylethyl) -4aα- (3-methoxyphenyl)
-8-chloro-9-bromo-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-methoxyphenyl) -8-chloro-9
-Bromo-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] When isoquinoline is used, 2-benzyl-4aα- (3-hydroxyphenyl) -12aβ-
Hydroxy-1,2,3,4,4a, 5,12,12a
-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα
-(3-hydroxyphenyl) -12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-cyclopropylmethyl-4aα- (3 -Hydroxyphenyl) -8-methyl-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4a
α- (3-hydroxyphenyl) -8-methyl-12a
β-hydroxy-1,2,3,4,4a, 5,12,1
2a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-methyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-methyl-12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-cyclopropylmethyl-4aα
-(3-hydroxyphenyl) -8-butyl-12aβ
-Hydroxy-1,2,3,4,4a, 5,12,12
a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-butyl-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-
Butyl-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-butyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-bromo-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4a
α- (3-hydroxyphenyl) -8-bromo-12a
β-hydroxy-1,2,3,4,4a, 5,12,1
2a-octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-bromo-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-bromo-12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-cyclopropylmethyl-4aα
-(3-hydroxyphenyl) -8-methoxy-12a
β-hydroxy-1,2,3,4,4a, 5,12,1
2a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8-methoxy-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-
Methoxy-12aβ-hydroxy-1,2,3,4,4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8-methoxy-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-
Cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-12aβ-hydroxy -1, 2, 3, 4, 4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2- (2-phenylethyl)-
4aα- (3-hydroxyphenyl) -8,9-dimethyl-12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8,9-dimethyl-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-
Cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8,9-dibromo-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8,9-dibromo-12aβ-hydroxy -1, 2, 3, 4, 4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2- (2-phenylethyl)-
4aα- (3-hydroxyphenyl) -8,9-dibromo-12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8,9-dibromo-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2-
Cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-
1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-benzyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-12aβ-hydroxy -1, 2, 3, 4, 4
a, 5,12,12a-Octahydro-quinolino [2,
3-g] isoquinoline, 2- (2-phenylethyl)-
4aα- (3-hydroxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline, 2-allyl-4aα- (3-hydroxyphenyl) -8,9-dimethoxy-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3 -G] isoquinoline, 2
-Cyclopropylmethyl-4aα- (3-hydroxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy-1,2,3,4,4a, 5,12,12a-octahydro-quinolino [2,3- g] isoquinoline, 2-
Benzyl-4aα- (3-hydroxyphenyl) -8-
Chloro-9-bromo-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-Octahydro-quinolino [2,3-g] isoquinoline, 2- (2-phenylethyl) -4aα- (3-hydroxyphenyl) -8-
Chloro-9-bromo-12aβ-hydroxy-1,2,2
3,4,4a, 5,12,12a-octahydro-quinolino [2,3-g] isoquinoline, 2-allyl-4aα
-(3-hydroxyphenyl) -8-chloro-9-bromo-12aβ-hydroxy-1,2,3,4,4a,
5,12,12a-octahydro-quinolino [2,3-
g] isoquinoline is obtained.

Example 16 4aα- (3-Methoxyphenyl) -1,2,3,4
4a, 5,12,12aβ-octahydro-quinolino [2,3-g] isoquinoline 22

[0163]

Embedded image

2- (1-oxo-2-oxa-4,4,4
4-trichlorobutyl) -4aα- (3-methoxyphenyl) -1,2,3,4,4a, 5,12,12aβ-
Octahydro-quinolino [2,3-g] isoquinoline 1
46.8 mg (0.282 mmol) of acetic acid 1.5 ml
, And zinc (184.6 mg, 2.82 mmol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was filtered using Hyflo Super Cell while washing with methanol, and the filtrate was concentrated. 4m saturated sodium bicarbonate aqueous solution
l was added while cooling with ice, and extracted twice with 10 ml of chloroform / methanol = 3/1. The obtained organic layer was washed with 10 ml of saturated saline, dried over anhydrous magnesium sulfate, and concentrated. 127. Yellowish brown amorphous obtained.
3 mg was dissolved in 0.5 ml of chloroform, and a solution of 85 mg (0.884 mmol) of methanesulfonic acid in chloroform was added while cooling with ice. The solvent was distilled off, and the obtained residue was subjected to column chromatography (Sephadex LH-
20, methanol).
Methanesulfonate of the title compound was obtained (yield
82.8%).

Methane sulfonate of the title compound mp: 137-143 ° C. IR (KBr method) cm-1: 3400, 2940, 2776, 1599, 1454, 1199, 1044, 7
74,561,536 NMR (CDCl3,500MHz) δ: 1.60 to 2.30 (1H, brs), 2.37 to 2.
48 (2H, m), 2.78 to 2.92 (7H, m), 3.10 to 3.23 (1H, m), 3.35
~ 3.52 (4H, m), 3.65 ~ 3.79 (5H, m), 4.55 (1H, d, J = 17.7H
z), 3.68 (3H, s), 6.50 (1H, dd, J = 7.9,2.1Hz), 7.02 (1H, s),
7.08 (1H, d, J = 7.9Hz), 7.17 (1H, t, J = 7.9Hz), 7.71 (1H, m, J =
7.93 Hz), 7.88 (1H, t, J = 7.9Hz), 7.93 (1H, d, J = 8.6Hz), 8.4
2 (1H, d, J = 8.6 Hz), 8.52 (1H, s), 8.91 (1H, brs), 9.35 (1H, b
rs) Mass (FAB method): 345 (M ⁺ +1) High-resolution mass spectrum (FAB method) Calculated value for C ₂₃ H ₂₅ N ₂ O: 345.1967 Found: 345.1993.

Example 17 4aα- (3-Hydroxyphenyl) -1,2,3
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline 23

[0167]

Embedded image

Under an argon stream, potassium t-butoxide 1
22.7 mg (0.915 mmol) in 2 ml of anhydrous DMF
in 0.15 ml of n-propanethiol (1.
28 mmol) and heated to reflux for several minutes. After cooling, 4aα- (3-methoxyphenyl) -1,2,3,
4,4a, 5,12,12a β-octahydro-quinolino [2,3-g] isoquinoline 62.9 mg (0.18
(3 mmol) dissolved in 2 ml of anhydrous DMF was added. After further washing with 2 ml of anhydrous DMF and adding the washing solution, the mixture was heated under reflux for 3 hours. The reaction solution was allowed to cool and acetic acid 1m
After adding 1, DMF was distilled off under reduced pressure. To the residue were added 4 ml of a saturated aqueous solution of sodium hydrogen carbonate, 4 ml of water and 6 ml of saturated saline, and warmed chloroform: methanol = 5:
The mixture was extracted twice with 20 ml of the mixed solvent of No. 2. The organic layer was dried over anhydrous magnesium sulfate and concentrated. 4 ml of a mixed solvent of chloroform: methanol = 5: 2 is added to the obtained residue.
And 88.8 mg of methanesulfonic acid while cooling with ice.
(0.924 mmol) methanol solution
And 2. The solvent was distilled off, and the residue was separated and purified by column chromatography (Sephadex LH-20, methanol) to obtain 54.5 mg of the methanesulfonate of the title compound (yield: 57.0%).

Methanesulfonic acid salt of the title compound Melting point: 163-169 ° C IR (KBr method) cm-1: 3400, 2934, 2798, 1599, 1466, 1197, 1052, 7
85,561,536 NMR (DMSO-d6 + CD3OD, 500MHz) δ: 2.08 (1H, td, J = 13.9,3.7
Hz), 2.46 (6H, s), 2.45 to 2.53 (1H, m), 2.59 to 2.68 (1H,
m), 2.75-2.85 (1H, m), 3.30 (1H, d, J = 13.2Hz), 3.36-3.
48 (3H, m), 3.48 to 3.56 (2H, m), 3.75 (1H, d, J = 17.2 Hz), 6.
56 (1H, dd, J = 7.9,1.6Hz), 6.91 ~ 6.94 (1H, m), 6.98 (1H, d, J
= 7.9Hz), 7.07 (1H, t, J = 7.9Hz), 7.78 (1H, t, J = 7.3Hz), 7.9
5 (1H, t, J = 7.3Hz), 8.03 (1H, d, J = 8.2Hz), 8.12 (1H, d, J = 8.
2Hz), 8.71 (1H, s ) Mass (FAB method): 331 (M ⁺ +1) Elemental Analysis _{C 22 H 22 N 2 O ·} 2CH 3 SO 3 C H N S calculated for H · H ₂ O 53.32 5.97 5.18 11.86 Found 53.04 5.65 5.10 11.48.

Example 18 (a) Binding assay with opioid receptor and analgesic activity (suppressing action on guinea pig ileal contraction and mouse vas deferens contraction) (Experimental method) Binding experiment was performed using 0.7 mg prot / tube of guinea pig cerebral homogenate. Tris to be in quantity
buffer, add to the reaction solution, and use it.
t. al., Naunyn-Schmiedeberg's Arch Pharmacol., 319,
197 (1982)). For the ligand,
Hot is 3H-DAGO (μ), DPDPE (δ), E
KC (κ) was used, cold was naloxone (μ), DA
DLE (δ) and naloxone (κ) were used. The agonist and antagonist activities of the compound of the present invention were determined by the method of Takemori et al. (Takemori, AEet. Al., Eur. J. Pharmacol., 85 , 163 (198) using ileum of guinea pig and vas deferens of mouse.
2)). Tables 1 to 3 list the opioid activities of the main compounds.

[0171]

[Table 1]

[0172]

[Table 2]

[0173]

[Table 3]

(B) Inhibition of mouse T cell proliferation by stimulation with ConA (Experimental method) The spleen was aseptically removed from the mouse, and a single cell suspension was passed through a mesh. 5 × 10
6 / ml, and 100 μl thereof was spread on each well of a 96-well plate. Put mitogen on a plate with spleen cells
ConA (1 μg / ml) was added to 50 μl / well and each concentration of compound (0.1, 0.5, 0.75, 1.0, 2.5, 5.0, 7.5, 10, 12.5, 1).
5, 17.5, 20μg / ml) at 50 ℃ / well
The cells were cultured for 48 hours in an O2 incubator. 8 after culture
Time before [3H] thymidine (2μCi / 10μl / well)
Was added. Eight hours after the addition, the cells were collected on a filter paper with a cell harvester, dried, added with a toluene scintillator, and the radioactivity of [3H] thymidine incorporated into the cells was measured with a scintillation counter.

The T cell proliferation inhibition rate was calculated according to the following equation.

[0176]

(Equation 1)

Table 4 shows the T cell proliferation inhibitory rates of the main compounds.

[0178]

[Table 4]

Pharmacological Test Results Tables 1 to 3 show that the compounds of the present invention are highly selective agonists for opioid δ-receptors.
In particular, 2-methyl-4aα- (3-hydroxyphenyl)
-1,2,3,4,4a, 5,12,12a α-Octahydro-quinolino [2,3-g] isoquinoline 7 shows very high selectivity for the δ receptor (μ / δ = 207
0). Further, the shrinkage suppression effect of the guinea-pig ileum in 7 (mu, has many κ receptor) is weak, mu chromatography antagonist naloxone, whereas hardly affects the κ chromatography antagonist nor-BNI, the shrinkage suppression effects of mouse vas deferens ( (having many δ and μ receptors) is strong and is shifted 92 times by the δ-antagonist NTI. In addition, the effect of 12 having a cyclopropylmethyl group as a nitrogen substituent on the contraction of mouse vas deferens is even stronger and shifts by 56 times by NTI. As described above, the compound of the present invention is a highly selective agonist for the δ-receptor and is a non-peptidic compound, so that it can cross the blood-brain barrier and has high stability against peptidase. Also, from Table 4, compounds 7 and 12 clearly show an immunosuppressive effect. Generally, since an agonist of an opioid receptor has an analgesic effect,
Its subtypes 7 , 12 having agonist activity at the δ-receptor can be used as analgesics.

[0180]

The isoquinoline derivative of the present invention represented by the general formula (1) is an agonist having high selectivity for δ-receptor and can be used as an immunosuppressant or an analgesic.

──────────────────────────────────────────────────続 き Continuing on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 605 A61K 31/495 605 (72) Inventor Osamu Matsumoto 1111 Tehiro, Kamakura-shi, Kanagawa Pref. Tanemura Yoshiki (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07D 471/04 A61K 31/47 610 A61K 31/495 605 CAPLUS (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula (1) [Wherein R ₁ is hydrogen, alkyl having 1 to 5 carbons, 4 carbons
Cycloalkylalkyl having 7 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 14 carbon atoms, transalkenyl having 4 to 5 carbon atoms, allyl, furanyl-
2-ylalkyl, thienyl-2-ylalkyl, alkanoyl having 1 to 5 carbon atoms, benzoyl, vinyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl or arylalkanoyl having 8 to 14 carbon atoms, wherein R ₂ is hydrogen or OR ₅ (where R ₅ represents hydrogen or alkanoyl having 1 to 5 carbon atoms), and R ₃ and R ₃ ′ independently represent alkyl having 1 to 5 carbons;
R ₄ represents hydrogen, alkyl having 1 to 3 carbons, benzyl, hydrogen, chlorine, fluorine, bromine, iodine, alkoxy having 1 to 5 carbons, nitro, amino, or alkylamino;
Or an alkanoyl having 1 to 5 carbon atoms, and X represents CH or N], or a pharmaceutically acceptable salt thereof. 2. An immunosuppressant comprising the isoquinoline derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. An analgesic comprising the isoquinoline derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.