JP2003119196A - Pharmacologically acceptable salts of pyrazinoisoquinoline compounds - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutically acceptable salt of a pyrazinoisoquinoline compound useful as a PDE4 inhibitor. SOLUTION: General formula [I]: (Wherein, R ¹ and R ² are the same or different and each represents a hydroxyl group or a lower alkoxy group).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmacologically acceptable salt of a pyrazinoisoquinoline compound having an excellent PDE4 inhibitory activity.

[0002]

2. Description of the Related Art c is an intracellular second messenger
AMP and cGMP are phosphodiesterases (PDE)
Is decomposed and inactivated by. Inhibiting PDE increases the intracellular cAMP and cGMP concentrations. PDEs are classified into several isozymes, and substrates (cAMP, c
GMP) specificity, biodistribution, etc. differ from isozyme to isozyme, and 4 types of PDE isozymes (PDE) (PDE
4) is known to specifically decompose cAMP.

Inhibition of PDE4 activity can also inhibit the release of inflammatory mediators [Journal of Molecular and Cellular Cardiology (J. Mol. Cell. Card.
iol. ) 12 (Suppl.II), S61 (198
9)], a PDE4 inhibitor is a cytokine T that is released by mononuclear phagocytes in response to immune stimulation.
It is known that it suppresses the production of NF-α and is useful for the treatment of various inflammatory diseases in which TNF-α is involved [Table 2000-503678, Table 2000-50272].
No. 4, Special Table 2000-510105, Special Table 2000-
No. 514804, Tokuyo 2000-502350, Tokuyo 2000-501741].

Theophylline, which is a typical PDE inhibitor, has been conventionally used for the treatment of asthma.
Since the E inhibitory action is non-specific, it has a cardiotonic action and a central action in addition to the bronchial smooth muscle relaxing action, and therefore side effects must always be noted. Therefore, among various PDE isozymes, there is a demand for the development of a new drug having a specific inhibitory action against PDE4, which is present in many bronchial smooth muscles and inflammatory cells. It is considered that such drugs can be excellent prophylactic / therapeutic agents for asthma (or prophylactic / therapeutic agents for inflammatory diseases, etc.).

On the other hand, 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H
-Pyrazino [1,2-b] isoquinoline, it has been reported that the compound has a central depressant action and a blood pressure lowering action [Indian Journal of Chemistry (Indian J. Chem.) Vol.
-237 (1975)]. However, regarding whether or not the compound has PDE4 inhibitory activity,
Nothing is mentioned in this report, and no pharmacologically acceptable salt of the compound is mentioned.

[0006]

The present invention provides pharmaceutically acceptable salts of pyrazinoisoquinoline compounds which are useful as PDE4 inhibitors.

[0007]

The present invention has the general formula [I]:

[0008]

[Chemical 2]

(In the formula, R ¹ and R ² are the same or different and each represents a hydroxyl group or a lower alkoxy group), and relates to a pharmacologically acceptable salt of the compound.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Of the pharmacologically acceptable salts of the compound [I] according to the present invention, the pharmacological effect of the compound of the formula [I] in which R ¹ and R ² are the same or different and are lower alkoxy groups. Acceptable salts are preferred, and R ¹ and R
More preferred are pharmaceutically acceptable salts of compounds in which ² is a methoxy group or an ethoxy group. Of these, 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a
Especially preferred are the pharmacologically acceptable salts of hexahydro-2H-pyrazino [1,2-b] isoquinoline.

The compound [I] or a pharmacologically acceptable salt thereof has an excellent inhibitory effect on PDE4 and is useful for the prevention / treatment of various diseases associated with PDE4. Examples of such diseases include various inflammatory diseases and allergic diseases, and more specifically, for example, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, atopic dermatitis, urticaria, allergic diseases. Rhinitis, allergic conjunctivitis, spring catarrhal, eosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, Examples include osteoarthritis.

Compound [I] or a pharmacologically acceptable salt thereof has an excellent bronchoconstriction inhibitory action, and is therefore useful as a bronchoconstriction inhibitor.

The applicant of the present invention has found that a compound having a PDE4 inhibitory action is also useful for promoting fracture healing and repairing and treating cartilage diseases (eg osteoarthritis), and separately filed a patent application (patent application). 2001-154064 and Japanese Patent Application No. 2001-154048). From this finding, compound [I] or a pharmacologically acceptable salt thereof is also useful for promoting fracture healing and repairing and treating cartilage diseases (eg osteoarthritis).

Compound [I] or a pharmaceutically acceptable salt thereof selectively inhibits PDE4.
There are few side effects. Furthermore, the compound [I] or a pharmacologically acceptable salt thereof has low toxicity and is highly safe as a medicine. For example, 100 mg / kg of 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline was added to mice (BDF1 strain, male, 3
Example) was subcutaneously administered once, and the course was observed for 1 day, but no death was observed.

The compound [I] can be used in a free form for pharmaceutical use, but it is preferably used in the form of a pharmacologically acceptable salt. Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate and methanesulfone. Examples thereof include acid salts, benzene sulfonates, organic acid salts such as tosylate salts and maleate salts, and the like. Of these, the hydrochloride salt is particularly preferred.

The pharmacologically acceptable salt of the compound [I] according to the present invention includes any of its inner salts, adducts, solvates or hydrates thereof.

Further, the compound [I] has a plurality of stereoisomers (diastereoisomers, optical isomers) based on an asymmetric atom, and the present invention includes any one of these stereoisomers. It includes both stereoisomers and mixtures thereof.

The compound [I] or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and tablets, granules, capsules, powders, injections, inhalants, etc. It can be used as a conventional pharmaceutical preparation.

The dose of the compound [I] or a pharmacologically acceptable salt thereof will vary depending on the administration method, age, weight and condition of the patient, but in the case of an injection, it is usually about 0. 01-10 mg / kg, especially about 0.03-3 m
g / kg, usually about 0.
1-30 mg / kg, especially about 0.3-10 mg / k
It is preferably about g.

<Production Method of Pharmacologically Acceptable Salt of Pyrazinoisoquinoline Compound> Compound [I] can be produced by the following method, but is not limited thereto.

[0021]

[Chemical 3]

(In the formula, R ³ represents a lower alkyl group, and other symbols have the same meanings as described above.) The reaction for producing the compound [IV] from the compound [II] is
It can be carried out using a conventional esterification reaction (for example, in the presence of ethanol / acetyl chloride, ethanol / thionyl chloride, ethanol / hydrogen chloride and the like).

The reaction for producing the compound [VI] from the compound [IV] and the compound [V] is carried out by a conventional condensing agent (for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide / hydrochloride /
It can be carried out in the presence of 1-hydroxybenzotriazole monohydrate, etc.).

The reaction for producing the compound [VII] from the compound [VI] is carried out by condensation using, for example, phosphorus oxychloride, phosphorus pentachloride, etc., and then a conventional reducing agent (eg platinum oxide / hydrogen, palladium (carbon ) / Hydrogen etc.).

The reaction for producing the compound [IX] from the compound [VII] and the compound [VIII] can be carried out in the presence of a conventional condensing agent (eg, carbonyldiimidazole and the like). Further, the compound [IX] is the compound [V]
III] is an activator (eg, isobutyl chlorocarbonate,
Alternatively, the compound [VII] may be reacted with a compound [VII] after treatment with ethyl chlorocarbonate or the like) and a base (eg, triethylamine, N-methylmorpholine or the like) to convert the mixed acid anhydride. .

The reaction for producing the compound [X] by ring-closing the compound [IX] in the molecule can be carried out by treating the compound [IX] with an acid (eg, trifluoroacetic acid, hydrochloric acid, etc.) and then heating. it can.

The reaction for reducing the compound [X] to produce the compound [I] is carried out using a suitable reducing agent (for example, borane-dimethyl sulfide complex, lithium aluminum hydride, bis (2-methoxyethoxy) aluminum hydride, etc.). It can be carried out in the presence.

The compound [I] is also prepared by converting the substituents on R ¹ , R ² and / or ring A of the compound obtained as described above into other desired substituents. be able to. Such a method of converting a substituent may be appropriately selected according to the kind of the desired substituent. For example, in the compound [I] in which R ¹ and / or R ² in the general formula [I] is lower alkoxy, the corresponding compound [I] in which R ¹ and / or R ² is a hydroxyl group and a lower alkylating agent (for example, Dimethylsulfate, methyl halide, etc.) and base (eg sodium hydroxide, sodium hydride, potassium carbonate, sodium methoxide, etc.)
It can also be produced by reacting in the presence of. The lower alkylating agent can be used in an amount of 1 to 8 equivalents, preferably 1.2 to 2.2 equivalents, relative to compound [I]. The present reaction suitably proceeds at 0 ° C to 50 ° C, especially 10 ° C to 40 ° C.

The compound [I] obtained by the above-mentioned production method can be converted into a pharmaceutically acceptable salt according to a method known to those skilled in the art.

In producing the above-mentioned compound [I], each of the intermediate compounds is not limited to those shown in the above-mentioned sentence or the chemical reaction formulas, and may be any one as long as it does not adversely affect the reaction.
Those salts or their reactive derivatives can also be used appropriately. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium and magnesium, salts with an organic base such as pyridine, triethylamine and diisopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like. Such as salts with inorganic acids, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, citric acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. Examples thereof include salts with organic acids.

Further, in the production of the compound [I] and the starting compound, when the starting compound or each intermediate has a functional group, a protecting group suitable for each functional group can be prepared by a conventional synthetic chemistry method other than the above-mentioned ones. May be introduced, and if necessary, those protecting groups may be appropriately removed.

Each of the above reactions can be carried out in a suitable solvent or without solvent, if necessary. The solvent is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoric triamide (HMP).
A), hexamethylphosphorus triamide (HMP
T), benzene, tetrahydrofuran, toluene, xylene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethyl ether, diisopropyl ether, dimethoxyethane, dimethyl. Sulfoxide, acetone, methyl ethyl ketone, acetonitrile,
Water or a mixed solvent thereof can be appropriately selected and used.

In the present invention, examples of the lower alkoxy group include linear or branched ones having 1 to 6 carbon atoms, and particularly ones having 1 to 4 carbon atoms.

[0034]

[Experimental Example] Experimental Example 1 [PDE4 inhibitory action] (Preparation of partially purified PDE4 preparation) Hartley
The supernatant obtained by centrifuging the lung homogenate extracted from the male guinea pig of the (ley) system is fractionated by anion exchange column chromatography. ~ 4. The fractions satisfying the condition (1) were mixed to obtain a partially purified preparation of phosphodiesterase 4. 1. To selectively hydrolyze cAMP. 2. Its cAMP hydrolytic activity is not affected by cGMP. 3. Not be inhibited by the PDE3 selective inhibitor CI-930. 4. Rolipram (Roli), a PDE4 selective inhibitor
strongly inhibited by the pram). (Measurement of PDE4 activity) The method of Thompson et al. (Advance in cyclic nucleotide research [A
dvances in Cyclic Nucleoti
de Research], 10 volumes, Raven Press,
New York, pp. 69-92, 1979) with some modifications. That is, 50 mM Tris-HCl,
100 μl of partially purified PDE4 preparation diluted to hydrolyze about 10% of the total substrate at pH 8.0 was added to a glass test tube. Reaction buffer solution (50 mM Tris-HCl,
pH8.0,12.5mM MgCl _2, 10mM 2-
After adding 200 μl of mercaptoethanol), 5 μl of a test compound (compound described later) (100-fold concentration) dissolved in dimethyl sulfoxide was added. 2.5 μM [3H] cAM after preincubation at 30 ° C. for 5 minutes
200 μl of P (3.7 kBq / 200 μl) was added to start the reaction (final concentration 50 mM Tris-HCl, p.
H 8.0, 5 mM MgCl ₂ , 4 mM 2-mercaptoethanol). After 30 minutes of reaction at 30 ° C., the test tube was transferred to a boiling water bath to stop the reaction. After 90 seconds, the test tube was transferred into an ice water bath, and the temperature of the reaction solution was lowered. 30 ° C, 5
After pre-incubation for 1 minute, 100 μl of 1 mg / ml snake venom aqueous solution was added, and the mixture was reacted at 30 ° C. for 30 minutes. After stopping the reaction by adding 500 μl of methanol, Dowex resin (trade name: Dowex
1 ml of the reaction solution was applied to a column to which 200 μl (1 × 8, manufactured by Sigma) was added in advance. Then 1m of methanol
The Dowex resin was washed by adding 1.
The reaction solution passing through the column and the washing solution were combined, and the radioactivity thereof was measured. Calculate the inhibition rate of each sample as a control by adding only the buffer solution without adding the enzyme preparation as a blank, and adding the enzyme preparation but adding only dimethyl sulfoxide instead of the sample solution as a control. did. The IC ₅₀ value of each sample was calculated by determining the inhibition rate at a concentration of 3 or more points, and 4-parameter logistic estimation (4-parameter logistic) was performed.
It was performed by returning to ice que. (Sample) (Sample compound A): 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H
-Pyrazino [1,2-b] isoquinoline. (Sample compound B): 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H
-Pyrazino [1,2-b] isoquinoline dihydrochloride. (Sample compound C): (6S, 11aS) -8,9-dimethoxy-6-phenyl-dimethoxy-1,3,4,6,1
1,11a-hexahydro-2H-pyrazino [1,2-
b] Isoquinoline dihydrochloride. (Results) The PDE4 inhibitory activities (IC ₅₀ ) of the sample compounds were all 0.004 μM.

Experimental Example 2 (antigen-induced bronchoconstriction inhibitory action) (Procedure) Male Hartley guinea pigs (n = 2) were treated with rabbit anti-ovalbumin antiserum (0.2).
5 mL / kg, i. v. ) Was intravenously administered and passive sensitization was performed. The next day, α-chloralose (120 mg /
kg, i. v. ), Tracheal cannula was inserted, and under artificial respiration, galamine triethiodide (5 mg / k)
g, i. v. ). Specimen compound (8, 9
-Dimethoxy-6-phenyl-1,3,4,6,11,
11a-hexahydro-2H-pyrazino [1,2-b]
Isoquinoline dihydrochloride (1 mg / kg) was intravenously administered 2 minutes before the administration of the antigen (ovalbumin; 30 μg / kg, iv). The action of the test compound on the trachea (bronchoconstriction inhibitory action) is as described in Konzett-Roe.
The ssler method [Naunyn-Schmei, Arhuyf Heuer Experimentere Pathology und Pharmacology
deberg's Archiv fur Experi
mentelle Pathology und Pha
Rmakologie), 195, 71, 1940.
Year]. A group (n = 2) to which only the antigen was administered was used as a control. (Results) The bronchoconstriction inhibitory effect of the test compound (inhibition rate of bronchoconstriction due to antigen administration) was 84%.

[0036]

EXAMPLES Example 1 (1) 2-Amino-3- (3,4-dihydroxyphenyl) propanoic acid 98.6 g was dissolved in formic acid 900 ml,
300 ml of acetic anhydride is added thereto, and the mixture is stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, distilled water was added to the residue,
Concentrate again under reduced pressure. Dissolve the residue in 150 ml of distilled water,
Under ice cooling, 150 ml of 10 M aqueous sodium hydroxide solution and 95 ml of dimethylsulfate are added. Furthermore, dimethyl sulfate 2
85 ml was added in three portions every 30 minutes, and 290 ml of 10 M aqueous sodium hydroxide solution was added dropwise during this period to keep the reaction temperature at 40 ° C. or lower and the pH between 5-9. After stirring overnight at room temperature, 50 ml of 10 M aqueous sodium hydroxide solution is added and the mixture is stirred at room temperature for 30 minutes. The pH is adjusted to 2 with sulfuric acid, ethyl acetate is added, the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The residue is suspended in 1300 ml of ethanol, 280 ml of acetyl chloride is added dropwise under ice cooling, and the mixture is stirred at room temperature for 3 days. After evaporating the solvent under reduced pressure, methylene chloride was added, the organic layer was washed with an aqueous potassium carbonate solution, dried over magnesium sulfate, and then concentrated under reduced pressure to give 2-amino-3-.
Ethyl (3,4-dimethoxyphenyl) propanoate 11
1 g is obtained as an oil. MS (m / z): 253 (M
⁺ ). (2) 111 g of the compound obtained in (1) above and 73.6 ml of triethylamine are dissolved in 300 ml of methylene chloride, and 51.1 ml of benzoyl chloride is added dropwise under ice cooling. A saturated aqueous sodium hydrogen carbonate solution is added, the organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were collected by filtration with diethyl ether,
144 g of ethyl 3- (3,4-dimethoxyphenyl) -2- (phenylcarbonylamino) propanoate are obtained.
Melting point: 82-83 [deg.] C. MS (m / z): 357
(M ⁺ ). (3) 71.5 g of the compound obtained in (2) above is dissolved in 200 ml of phosphorus oxychloride and heated under reflux overnight. After the phosphorus oxychloride has been distilled off, the residue is diluted with methylene chloride.
The extract is washed with aqueous potassium carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in ethanol, 20 ml of concentrated hydrochloric acid is added, and the mixture is concentrated under reduced pressure. The residue is methanol 20
It is dissolved in 0 ml, 1 g of platinum dioxide is added, and the mixture is stirred under hydrogen pressure (3 atm) at room temperature for 4 hours. After filtering off the insoluble matter,
Concentrate under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were collected by filtration to give 6,7-dimethoxy-1-phenyl-1,2,
54.4 g of ethyl 3,4-tetrahydroisoquinoline-3-carboxylate are obtained. Melting point: 215-217 ° C (decomposition). MS (m / z): 341 (M ⁺ ). (4) 2-[(tert-Butoxy) carbonylamino] acetic acid (21.6 g) was dissolved in tetrahydrofuran (75 ml), triethylamine (18.7 ml) and isobutyl chloroformate (17.4 ml) were added dropwise at -20 ° C, and then at -10 ° C.
Stir for a minute. In addition to this, the compound 38.
A suspension of 2 g in 110 ml of tetrahydrofuran was added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure and then extracted with chloroform. Wash with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dry over magnesium sulfate,
Concentrate under reduced pressure. After crystallization with diethyl ether, the crystals were collected by filtration and used as 2- {2-[(tert-butoxy) carbonylamino] acetyl} -6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline- 31.7 g of ethyl 3-carboxylate is obtained. Melting point: 166-16
7 ° C. MS (m / z): 498 (M ⁺ ). (5) Under ice cooling, 31.7 g of the compound obtained in (4) above
60 ml of trifluoroacetic acid is added to and stirred for 1 hour.
The reaction solution is concentrated under reduced pressure, dissolved in chloroform, and neutralized with triethylamine. Saturated aqueous sodium hydrogen carbonate solution,
The extract is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in 350 ml of toluene and heated under reflux for 3 hours. After distilling off the solvent, the precipitate was collected by filtration with diethyl ether to obtain 8,9-dimethoxy-6-phenyl-
2,3,11,11a-Tetrahydro-6H-pyrazino [1,2-b] isoquinoline-1,4-dione 20.6
get g. Melting point: 265-267 [deg.] C. MS (m / z):
352 (M ⁺ ). (6) Under a nitrogen atmosphere, 22.7 ml of borane-dimethyl sulfide complex is ice-cooled, and 20 g of the compound obtained in the above (5) dissolved in 500 ml of tetrahydrofuran is added dropwise thereto. After heating under reflux overnight, 50 ml of 6M hydrochloric acid is added, and the solvent is distilled off. The residue is diluted with chloroform, washed with aqueous sodium hydroxide solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography using chloroform: methanol (9: 1) as an elution solvent, and the obtained crystals are dissolved in a chloroform-methanol mixed solvent. After adding a 4M hydrochloric acid / ethyl acetate solution to this, the solvent is distilled off. The precipitate was collected by filtration with ethanol to give 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride 7 0.6 g is obtained. Melting point: 220-224 ° C
(Disassembly). MS (m / z): 324 (M ⁺ ).

Example 2 (2S) -2-Amino-3- (3,4-dihydroxyphenyl) propanoic acid (L-DOPA) was used, and thereafter the same operation as in Example 1 was performed to obtain (6S, 11aS)
-8,9-dimethoxy-6-phenyl-1,3,4
6,11,11a-Hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride is obtained. Melting point:
225-229 ° C (decomposition). MS (m / z): 324
(M ⁺ ).

[0038]

INDUSTRIAL APPLICABILITY The pharmacologically acceptable salt of the compound [I] according to the present invention has an excellent inhibitory effect on PDE4, and various diseases related to PDE4 (asthma, chronic obstructive property) Lung disease (COPD), chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, spring catarrhal, eosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, various inflammatory diseases such as osteoarthritis,
It is useful for the prevention and treatment of allergic diseases.

Further, the pharmacologically acceptable salt of the compound [I] according to the present invention has an excellent bronchoconstriction inhibitory action and is therefore useful as a bronchoconstriction inhibitor.

Furthermore, the pharmacologically acceptable salt of the compound [I] according to the present invention is also useful for promoting fracture healing and repairing and treating cartilage diseases (eg osteoarthritis).

The pharmacologically acceptable salt of the compound [I] of the present invention selectively inhibits PDE4.
There are few side effects.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 11/00 A61P 11/00 11/02 11/02 11/06 11/06 13/12 13/12 17 / 00 17/00 17/06 17/06 19/02 19/02 27/02 27/02 29/00 29/00 101 101 31/04 31/04 37/00 37/00 37/08 37/08 39 / 02 39/02 43/00 111 43/00 111 (72) Inventor Aya Nakata 3-20-5-201 Kamijujo, Kita-ku, Tokyo (72) Inventor Atsuko Sakai 1-8 Suwahara Complex, Wako City, Saitama Prefecture 201 F Term (reference) 4C065 AA03 AA18 BB12 CC01 DD02 EE02 HH01 JJ01 KK02 LL03 PP01 4C086 AA02 AA03 CB09 MA01 MA04 NA14 ZA33 ZA34 ZA36 ZA51 ZA59 ZA68 ZA81 ZA89 ZA96 ZB11 ZB13 ZB15 ZB13 ZB15

Claims (5)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R ¹ and R ² are the same or different and each represents a hydroxyl group or a lower alkoxy group.) A pharmacologically acceptable salt of the pyrazinoisoquinoline compound. 2. A pharmacologically acceptable salt of a pyrazinoisoquinoline compound according to claim 1, wherein R ¹ and R ² are the same or different and each is a lower alkoxy group. 3. 8,9-Dimethoxy-6-phenyl-
1,3,4,6,11,11a-hexahydro-2H-
A pharmacologically acceptable salt of pyrazino [1,2-b] isoquinoline. 4. The pharmacologically acceptable salt of the pyrazinoisoquinoline compound according to claim 1, wherein the pharmacologically acceptable salt is a hydrochloride. 5. 8,9-Dimethoxy-6-phenyl-
1,3,4,6,11,11a-hexahydro-2H-
Pyrazino [1,2-b] isoquinoline dihydrochloride.