JPH03236376A - New isoquinolinequinone derivative and intermediate thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R1 is hydroxymethyl; R2 is H, acyl or R1 and R2 are bonded to form -CH2-O-CH2 bond), a steric isomer or a salt thereof. EXAMPLE:1-Hydroxymethyl-6-methoxy-3,7-dimethyl-5,8-dioxo-1,2,3,4,5,8- hexahydroisoquinoline. USE:An antitumor agent. PREPARATION:According to reaction formula, a compound shown by formula II-1 is dissolved in an inert solvent such as THF and then treated with 1-1.1 equivalent aluminum lithium hydride while stirring to give a compound shown by formula II-2. Then this compound is treated by catalytic hydrogenation method in an inert solvent to give a compound shown by formula II-5. Then this compound is oxidized with cerium [VIII] diammonium nitrate to give a compound shown by formula I-1.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to isoquinolinequinone derivatives, stereoisomers thereof, or salts thereof, methods for producing them, and synthetic intermediates thereof.

[Prior Art] The isoquinolinequinone derivative of the present invention is a novel compound that has not been described in any literature.

[Problems to be Solved by the Invention] The present invention provides novel isoquinoline quinone derivatives useful as medicines, particularly antitumor agents, or intermediates thereof, and synthetic intermediates useful for producing these compounds. The purpose is to

The following margin [Means for solving the problem] The isoquinoline quinone derivative according to the present invention has the formula (where R1 represents a hydroxymethyl group, R2 represents a hydrogen atom or an acyl group, or R□ and R2 are combined) isoquinolinequinone derivatives represented by -CH, -0-CH2- bonds, stereoisomers thereof, or salts thereof.

- An example of the acyl group for R2 in format (I) is an acetyl group.

The compound represented by the formula (I) of the present invention has the formula (wherein R1 is a hydroxymethyl group, R2 is a hydrogen atom and R3 is a hydrogen atom or a benzyl group, or R1 and R2 are taken together -CH, -0-CH, - The 0 dotted line indicating the - bond indicates the presence or absence of a double bond. However, if the carbon-phoneme bond indicates a double bond, the substituents are R, and R3). Compound (n-1) in which the carbon-nitrogen bonds at the 1st and 2nd positions are double bonds, R2 is -CO2Et and R3 is a benzyl group (n-1) (IF-2) can be obtained from.

More specifically, in the compound represented by the general formula (I), R8
Compound (I-1) in which is represented by a hydroxymethyl group and R2 is a hydrogen atom group can be obtained according to the following reaction formula.

Compound (n-2) is usually obtained by reducing compound (I[-1), that is, by dissolving it in an inert solvent such as tetrahydrofuran,
Then, 1 to 1.1 equivalents of lithium aluminum hydride was added to compound (II-1).

It is obtained by stirring for 30 minutes and then post-processing according to a conventional method.

Compound (n-5) is obtained by subjecting compound (I[-2) to catalytic hydrogenation in an inert solvent. That is, the compound (It-2
) in a solvent such as methanol or isopropyl alcohol and stirred in the presence of palladium/carbon.

Compound (I-1) can be obtained by oxidizing compound (II-5) using cerium ammonium nitrate [■] (hereinafter abbreviated as CAN). To oxidize the compound represented by compound (It-5) using CAN, it is dissolved in an inert solvent 9 such as acetonitrile, and then the compound (It-5) is oxidized using CAN.
Add 1 to 1.5 equivalents of CAN to II-5),
It is obtained by stirring for a period of time and then processing by a conventional method.

- Compound (■-2) of formula (I) in which R is a hydroxymethyl group and R2 is an acetyl group can be obtained by dissolving compound (I-1) in an inert solvent, such as acetyl chloride, acetic anhydride, etc. etc. and stirring.

Compound Cl-3, a compound represented by the general formula (I), in which R□ and R2 together represent a -CH2-0-CH2- group
) can be obtained by suspending compound (1-1)-paraformaldehyde and anhydrous sodium sulfate in an inert solvent and stirring at an appropriate temperature from 0°C to the boiling point of the solvent for 30 minutes to 5 hours.

This reaction is represented by the reaction formula below.

The compound (I) of the present invention has a plurality of asymmetric carbon atoms, and the present invention naturally includes compounds that are stereoisomers. These stereoisomers can be separated, if necessary, by conventional separation methods, such as thin layer or column chromatography.

Acid addition salts of these compounds of the form CI) can be prepared using physiologically available acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, or acid addition salts such as maleic acid, fumaric acid, tosylic acid, etc. etc. can be easily produced by reacting them in a conventional manner.

The compound of formula (II-1), which is the starting compound for the above reaction, is also a new compound, and the known compound represented by formula (IV) (
H, Rapoport/), J, ○rg.

Chem, vol. 47, pp. 2404-2413, 198
2) according to the following reaction formula.

Grignard compound (V) can be obtained by adding benzyl halide to compound (1'/) in the presence of a base and stirring the mixture. That is, it can be obtained by introducing a benzyl group into a hydroxyl group. Compound (III-1) can be obtained by oxidizing compound (v) with osmium oxide-sodium periodate. That is, in order to oxidize compound (V) with an aqueous solution of osmium oxide and sodium periodate, compound (V)
) is dissolved or suspended in an inert solvent, and the compound (V) is then treated with a catalytic amount of osmium oxide and 2.
Add 5 equivalents of an aqueous solution of sodium periodate to 1.5~
After stirring for 2 hours, oxidation is complete. Compound (■-1) is then obtained by post-treatment according to a conventional method.

Compound (II-2) can be obtained by subjecting compound (1-1) to a Grignard reaction with methylmagnesium iodide. That is, methylmagnesium iodide and the compound (I-
To carry out the Grignard reaction of 1), compound (I[-1)
is dissolved or suspended in an inert solvent, and then 1 to 1.3 equivalents of methylmagnesium iodide to compound (I[-1) are added and stirred for 30 minutes to complete the process. Thereafter, the compound (I[
-2) is obtained. Compound (I[-2> is compound (V)
Compound (III-1) can also be obtained without isolation.

Compound (I[-3) can be obtained by reacting compound (I[-2) with mesylic acid chloride in the presence of a base by a conventional method. Compound (III-4) is compound (III-3
) is treated with sodium azide, that is, compound (II
It is obtained by dissolving I-3) in acetone, adding an aqueous solution of sodium azide, and stirring at 0 to 60°C.

Compound (m-5) can be obtained by dissolving compound Cl-4) in an inert solvent such as methanol, isopropyl alcohol, etc. and reducing the solution by a catalytic hydrogenation method.

Margin (III-3) Compound (III-6) can be obtained by stirring compound (IE[-5) and diethyl oxalate in ethanol at an appropriate temperature from room temperature to the boiling point for 30 minutes to 3 hours.

Compound (II-7) can be obtained by adding benzyl halide to compound (I[-6) in the presence of a base and stirring the mixture.

Compound (n-1) is compound (III) obtained by the above method.
-7) is dissolved in an inert solvent (toluene-ethanol), phosphorus oxychloride is added thereto, and the mixture is stirred at 100°C for 7 hours.

(III-6) (III-7) Furthermore, the compound (II-2) represented by the -format (I[) in which R1 is a hydroxymethyl group, R2 is a hydrogen atom, and R3 is a benzyl group is the compound (II-2) It can be obtained by dissolving 1) in an inert solvent and reducing it with lithium aluminum hydride.

- Compound (II-5) represented by the formula (Ill) in which R2 is hydroxymethyl, R2 is a hydrogen atom, and R3 is a hydrogen atom group is a compound (II-5) in which compound (I[-2) is
For example, it can be obtained by dissolving it in methanol, isopropyl alcohol, etc. and reducing it by a catalytic hydrogenation method.

A compound represented by the general formula (n) in which R1 and R2 together represent a -CH2-0-CH2- group (If
-3) is a compound <ff-2), paraformaldehyde and anhydrous sodium sulfate are suspended in an inert solvent, and the temperature is 0°C.
to the boiling point of the solvent for 30 minutes to 5 hours.

This reaction is represented by the reaction formula below.

(It-2) These compounds (I) and (■) obtained by the above method
, and -formal sulfonyloxy, azide, amino, substituted amino (-NH
-Co-CO2Et), R2 represents a hydrogen atom or a benzyl group> Details of the manufacturing method and physical and chemical properties of the compound are shown in the following examples.

1 The names of the compounds represented by formulas (l-3) and (I[-3) in the present invention are based on the structural formula of 3H-oxazolo[4,3-al isoquinoline] described in the chemical abstract. did.

The following margins (in the formula, R1 is formylmethyl or -CH2CH(-A
) CH, group, A is hydroxy, methane Example (Example 1) - Preparation of compound of form (III) (Rs is formylmethyl, R2 is benzyl group: compound l-1) 3.5-dimethoxy- 4-Methyl-2-phenylmethyloxy-1-(2-propenyl)benzene (compound (L
)) 2.14g of 1,4-dioxane-water (30ml-
0.2 osmium oxide dissolved in 20 ml) solution at room temperature.
0 g and 4.60 g of sodium periodate were added and stirred for 1 hour. Insoluble matters were removed by filtration, and 60 ml of benzene and 60 ml of water were added to the residue for partition. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (carbon tetrachloride to carbon tetrachloride/methylene chloride (1:1)).

4-Methyl-3,5-dimethoxy-2-phenylmethyloxyphenylacetaldehyde (compound 1-1) 0.
92g (42%) was obtained.

H-NMR (CDC13) δ 2.16 (3H,s, methyl proton), 3.53 (
2H, d (J=2.2Hz), -Cdan, -CHO)3
．． 77 (3H,8,-OCH), 3.85 (3
H,s, -QCdanx), 4.96 (2H,s, -C
! ILL C6H3), 6.35 (LH,s),
7.2-7.4 (5H, rn, phenyl proton),
9.53(IH,t (J=2.2Hz, -CHO)(
Example 2) - Production of compound of formula (I) (Rt is 2-hydroxypropyl group, R2 is benzyl group: Compound ■-2) 3.5-dimethoxy-4-methyl-2-phenylmethyloxy-1- (2-propenyl)benzene (compound (v)
)) 10.0 g was dissolved in 130 ml of dioxane, and 100 ml of water was added to this solution and stirred. Add 250 mg of osmium oxide and 17.0 mg of sodium periodate to this solution.
Added 92g. 1.75 hours later, add 30% benzene to the reaction solution.
0 ml and 300 ml of water were added and distributed. The obtained residue was dissolved in 30 ml of diethyl ether, and added to 100+nl of a previously prepared solution of 78.9 mmol of methylmagnesium iodide in diethyl ether with stirring while cooling with dry ice-isobrobyl alcohol, followed by stirring for 30 minutes. Water-saturated diethyl ether was added to the reaction solution to decompose excess methylmagnesium iodide, and 300% of benzene was added.
ml and 300 ml of water were added, neutralized with a dilute aqueous hydrochloric acid solution, and then distributed. The organic layer was washed with water and then dried (anhydrous sodium sulfate). The solvent was concentrated under reduced pressure and the resulting residue was separated and purified by silica gel column chromatography (carbon tetrachloride to carbon tetrachloride/chloroform (1:1)). -(4-Methyl-3,5dimethoxy-2-phenylmethyloxyphenyl)-2-hydroxypropane (compound 1[[-2)
5.40 g (50.3%: from compound (v)) was obtained.

H-NMR (CD, 00) δ 1.11 (3H, d (J = 6.1 Hz), -C(O
H)-CdanJL), 2.09 (38,s, methyl proton), 2.67 (2H,d (J=6.6Hz).

-(danxc (OH)-), 3.75 (3H, s.

0 (Dan 1), 3.77 (3H, s, -QC Danyo), 3
．． 9 (m, LH, -CH(OH)), 4.90
(s, 2H, -CLL -C6H5>, 6.52 (
s, IH), 7.2-7.5 (m, 5H, phenyl proton) (Example 3) - Compound of format (I) (Rt is 2-methanesulfonyloxypropyl group, R2 is benzyl group: Compound ■ -3) 2-hydroxy-1-(4-methyl-3,5-dimethoxy-2-phenylmethyloxyphenyl)propane obtained in Example 2. Dissolve OOg in 30ml of pyridine, add 1.07g of methanesulfonyl chloride to 5ml of pyridine.
The solution was added to the solution while stirring under water cooling. The mixture was stirred at N temperature for 10 hours and the reaction solution was concentrated under reduced pressure. ! Benzene 10 in the residue
0 ml and 100 ml of water were added and distributed. The organic layer was dried and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (carbon tetrachloride to carbon tetrachloride/chloroform (1:1)) to obtain 2-methanesulfonyloxy-1-(4-methyl-3,5-dimethoxy-2). -phenylmethyloxyphenyl)propane (compound 11[
-3) 1.40g (56.2%) was obtained.

H-NMR (solvent CD So D ) δ1.32 (3
H, d, methyl proton), 2.10 (3H, s, methyl proton), 2.59 (3H.

s, -08O2CUi), 3.75 (3H,S,
0 (dan□), 3.78 (3H,s, QC danyu),
4゜93 (2H,8,-CjilC6H5), 6.5
0 (IH,S), 7.2-7.5 (58, m, phenyl proton) (Example 4) - Compound of format (III) (R□ is 2-azidopropyl group, R2 is benzyl group: compound ll-4)
2-methanesulfonyloxy-1- obtained in Production Example 3
(4-Methyl-3,5-dimethoxy-2-phenylmethyloxyphenyl)propane 23.1g was added to acetone 4
00ml and add 26.0ml of sodium azide to this solution.
7 g was dissolved in 240 ml of water and added. This solution was stirred at 40°C for 60 hours, and the reaction solution was concentrated under reduced pressure.
After adding 400 ml of benzene to the residue and shaking it, the aqueous layer was separated and discarded. After drying the organic layer, the solvent was distilled off under reduced pressure. 1jIi
The residue was separated and purified by silica gel column chromatography (carbon tetrachloride to carbon tetrachloride/chloroform (7:3)) to obtain 2-azido-1-(4-methyl-3,5-dimethoxy-2-phenylmethyloxyphenyl). ) 14.6 g (72°2%) of propane (compound ll-4) are obtained.

H-NMR (CD) OD) δ 1.11 (3H, d (J=6.6Hz), -C(-
N,)-Cdan1), 2.11 (s, 3H, methyl proton), 2.64 (d, 2H (J=6.4Hz).

methylene proton), 3.6 (m, IH, -Cri(N
))-), 3.73 (s, 3H, 0CULL).

3.77 (s, 3H, -QCdanx), 4.92 (s
.

2H, -〇danx-CsH5), 6.48 (s, IH)
.

7.2-7.5 (m, 5H, phenyl proton) (Example 5) - Production of compound of format (I[) (Rs is 2-aminopropyl group, R2 is hydrogen atom group: compound ■-5) 2-azido-1-(4-methyl-3 obtained in Example 4)
, 5-dimethoxy-2-phenylmethyloxyphenyl) propane (395 mg) was dissolved in 20 rnl of methanol, 100 mg of 10% palladium/carbon was added thereto, and the mixture was stirred for 3 hours under a hydrogen stream. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to give 2-amino-1-(2-hydroxy-4-methyl-3,5-dimethoxyphenyl)propane (compound IIll-5) 230 (89,2 %) was obtained.

H-NMR (CD30D) δ 1.10 (3H, d (J=6.6Hz), -CH(
-NH2)-Cdanyu), 2.08 (3H,s, methyl proton), 2.7 (2H,m, -(upperyuCH(-
NH2) CH3), 3.2 (IH, m, CH
2CH (NH2) CH3), 3.71 (S, 3H
, -O figure Danyu), 3.72 (s, 3H, QC Danyo),
6.41 (s, IH) (Example 6) - Compound of format (1) (where R1 is 2-(N-
2-Amino-1-(2-hydroxy-4-methyl-3,5-dimethoxyphenyl) obtained in Production Example 5 of Nidoxylylaminoprobyl group, R2 is a hydrogen atom group: Compound 1-6) Dissolve 7.33 g of propane in 50 ml of ethanol,
It was added to 1.83 g of diethyl oxalate heated to 0°C, and this solution was stirred at 100"C for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (carbon tetrachloride to carbon tetrachloride). carbon/chloroform (1:1))
2-(N-nidoxylylamino-1-
(2-hydroxy-4-methyl-3,5-dimethoxyphenyl)propane (compound m-6) 7.93 g (74,
9%).

HN M R (CD 3o D ) δ 1.22 (3H, d (J=6.6Hz), -CH(
-NH-)-C Danyo), 1.30 (3H,t (J=
7.1 Hz, CHzCUi), 2.08 (3H
,s.

methyl proton), 2.83 (2H, d (J=7°1Hz), -Ctan□CH(NH) CHs) -3,6
8 (3H,8,-OCH), 3.71 (3H.

s, -QC Dan, 3J, 4.2 (I H, m, methine proton), 4.25 (2H, q (J = 7.1
Hz).

-Indanyu CHs), 6, 47 (IH,
s ) (Examination P7I47) - Compounds (R
2-(N-nidoxylylamino-1 obtained in Production Example 6) where l is a 2-(N-nidoxylylaminopropyl group and R2 is a benzyl group: Compound ■-7)
10.38 g of -(2-hydroxy-4-methyl-3゜5-dimethoxyphenyl)propane was dissolved in 10 ml of dimethylformamide, and 7.10 g of benzyl bromide and 20.0 g of potassium carbonate were added thereto at 100°C with stirring. Warm for an hour. Insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was mixed with 300 ml of chloroform and 20 ml of diluted Shioshun aqueous solution.
Distribute at 0ml. The organic layer is dried and then concentrated under pressure. The obtained residue was separated and purified by silica gel column chromatography (carbon tetrachloride to carbon tetrachloride/chloroform (7:3)) to obtain 2-(N-nidoxylylamino-1-(4-
Methyl-3,5-dimethoxy-2-phenylmethyloxyphenyl)propane (compound 1-7) 11.3 g (
85.6%).

HN M R (CD so D ) δ 1.15 (3H, d (J=6.6Hz), -CH
(-NH-) -ζ0yo), 1.25 (3H,t
(J=7.1Hz, -CH2CH), 2.08 (
38, s.

methyl proton), 2.7 (2H,m, -Cdanyo-C
(NH)CHs), 3.73 (3H,a.

-OC Danx), 3.77 (3H,s, -QC Danyo)2
4.19 (2H, ct (J=7.1Hz), -
CHCHHz), 4.2 (I H,m, -CH(-NH
)).

4.87 (IH, d (J=11.0Hz), -CH
-HC5H5), 5.01 (IH, d (J=1
1.0Hz), -CHH-C6H5), 6.49
(IH,s)7.2-7.5 (m, 5H, phenyl proton) (Example 8) - Compound of the form (n) (R□ is an ethoxycarbonyl group, R1 is a benzyl group: Compound I [-
2-N-nidoxylylamino-1- obtained in Production Example 7 of 1)
(4-Methyl-3,5-dimethoxy-2-phenylmethyloxyphenyl)propane 204mg to toluene 3
ml and 0.1 ml of ethanol, and 0.28 ml of phosphorus oxychloride is added to this solution. Stir this solution 1
After stirring at 00°C for 7 hours, the solvent was distilled off under reduced pressure. The residue obtained is partitioned between 20 ml of benzene and 20 ml of 10% sodium hydrocarbonate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified with silica gel WII'! ! It was separated and purified by chromatography (chloroform-methanol (45:1)) to give 1-ethyloxycarbonyl-3゜4-dihydro-6,8-dimethoxy-3,7-dimethyl-5-phenylmethyloxyisoquinoline (Compound I [ -1)1
04 mg (53.3%) was obtained.

H-NMR (CD30D) δ 1.23 (3H, d (J = 6.8 Hz), methyl proton), 1.38 (3H, t (J = 7.1) 1z
.

-CH2 Toyotanyo), 2.09 (IH, dd CJ=1
6.3Hz, J=11.3Hz)), 2.20 (3H
.

S, methyl proton), 2.72 (IH, dd (J
=16.3Hz, J=5.1Hz), 3.3 (IH.

m), 3.62 (3H,s, -QCdan,), 3.91
(3H,s, -QCdan,), 4.32 (2H,q(J
=7.1Hz, -Cdan, CH,), 4.96 (2H.

s, -CXLC6H5), 7.35 (5H, s, phenyl proton) Elemental analysis (C23827N O) C (%) H
(%) N (%) Analytical value 69.83 6.92 3.49 Theoretical value 6
9.50 6.85 3.52 (Example 9) - Production of a compound of format (II) (Rt is a hydroxymethyl group, R2 is a hydrogen atom group, and R3 is a benzyl group: compound ■-2) In Example 8 The obtained 1-ethyloxycarbonyl-3,
490 mg of 4-dihydro-6,8-dimethoxy-3゜7-dimethyl-5-phenylmethyloxyisoquinoline was dissolved in 30 ml of tetrahydrofuran and stirred under water cooling, and 200 mg of lithium aluminum hydride was added to this solution.
Add. After 30 minutes, water was added to decompose excess lithium aluminum hydride, and the mixture was partitioned between 300 ml of chloroform and 200 ml of saturated saline. The organic layer is dried and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel thin layer chromatography (chloroform-methanol (10=1)) to obtain 1,2,3.4-tetrahydro-1-hydroxymethyl-6,8-dimethoxy-3,7- Dimethyl-5-phenylmethyloxyisoquinoline (Compound IIl
l-2) 367 (83.3%) was obtained.

H-NMR (CD, 00) δ 1.20 (3H, d (J=6.1 Hz), methyl proton), 2.18 (3H, s, methyl proton).

1.8-2.3 (IH, m, -'CHHCH(-CH
3) -NH-), 2.4-3.0 (2H,m, -CH
HCH(CH3)-NH-), 3.66 (IH.

dd (J=10.7Hz, J=4.6Hz, =CH-
CHH-OH), 3.66 (3H,s, -0CHL)
, 3.81 (3H,8,-0CR), 4.03 (IH
, dd (J=10.7Hz, J=2.9Hz.

=CH-CHH-OH), 4.2 (IH, bm.

=CH-CHHOH), 7.1-7.5 (5H, m.

(Phenyl proton) (Example N10)-fi Compound of formula (It) (R is a hydroxymethyl group, R2 and R3 are hydrogen atom groups: metal compound ■
-5) 1,2,3.4-tetrahydro-1 obtained in Production Example 9
-Hydroxymethyl-6,8-dimethoxy-3,7-dimethyl-5-phenylmethyloxyisoquinoline 322
Dissolve 10 mg in 20 ml of isopropyl alcohol.
Add 67 mg of % palladium/carbon and 2 hours under a hydrogen stream.
Stir for hours.

Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to 1°2.3
．． 240 of 4-tetrahydro-5-hydroxy-1-hydroxymethyl-6,8-dimethoxy-3°7-dimethylisoquinoline (compound n-n-5) was obtained.

H-NMR (CD30D) δ 1.28, 1.32 (3H, d, d (J=6.1H
z.

methyl proton), 1.9-2.4 (IH, m).

2.16 (3H,s, methyl proton), 2.7-3
．． 4 (2H, m), 3.5-4.5 (3H, m.

Fumio-Nintan You OH), 3.63, 3.67 (3H.

s, s, -0dandanyu), 3.69 (3H,s, -〇(dandanyu) (Example 11) - Compound of formula (n) (when Rl and R2 are together -CH20-CH2 - group, R3 is benzyl group: Compound (1)-3) Compound obtained in Production Example 9, 1,2,3.4-tetrahydro-1-hydroxymethyl-628-dimethoxy-3
, 130 mg of 7-dimethyl-5-phenylmethyloxyisoquinoline, 300 mg of paraformaldehyde and 4 g of anhydrous sodium sulfate were added to 20 ml of benzene and stirred at room temperature for 48 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure.

The residue was separated and purified by silica gel thin layer chromatography (chloroform-methanol (30:1)), and 1,5,
6,10b-tetrahydro-8,10-dimethoxy-5
,9-dimethyl-7-phenylmethyloxy-3H-oxazolo[4,3-a]isoquinoline, (Compound I[-
3) 98 mg (73%) obtained.

This compound I[-3 is a mixture of stereoisomers and can be separated by silica gel thin layer chromatography (chloroform-methanol (30:1)).

The H-NMR data of the isomer evolving upward (Compound I[-3a) and the downward isomer (Compound 11-3b) on the thin layer are shown below.

(Compound n 3a) HNMR (CD, OD) δ1.1
8 (3H, d (J=5.9Hz), methyl proton), 1.9-3.0 (3H, m, methylene proton,
Methine proton), 2.19 (3H,s.

methyl proton), 3.70 (3H,s, -0CHL
), 3.82 (3H,s, -QCdan, ), 4.0-
4.65 (3H, m), 4.94 (2H, s, -C
iLLC6H5), 7.1-7.5 (5H, m, phenyl proton) (Compound n-n-3b) H-N (CD30D) δ1.
03 (3H,d (J=6.6Hz), methyl proton), 2.18 (3H,s, methyl proton).

2.4-3.2 (38, m, methylene proton, methine proton), 3.47 (IH, dd (J = 7°8
Hz, J=7.1Hz), 3.80 (3H, s.

-0CR), 4.0-4.75 (4H, m'), 4°92 (2H, S, -Ci, C6Hs), 7.1-7.
5 (5H, m, phenyl proton) (Example 12) - Compound of formula (1) (Rt and R2 together are -CH2-0-CH, - group: Compound ■-1)
1,2,3,4-tetrahydro- obtained in Production Example 10
Dissolve 170 mg of 5-hydroxy-1-hydroxymethyl-6,8-dimethoxy-3,7-dimethylisoquinoline in a mixture of 10 ml of acetonitrile and 3 ml of water,
360 mg of CAN was added to this solution while stirring. After stirring for 1 hour, 100 ml of chloroform and 50 ml of a 5% aqueous sodium hydrogen carbonate solution were added to the reaction mixture for partition. After drying the organic layer, the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel thin layer chromatography (chloroform-methanol (
8:1)) to separate and purify 1-hydroxymethyl-6-
Medoxy 3,7-dimethyl-5,8 dioxo-1,2
, 3,4,5,8-hexahydroisoquinoline (compound I-1) (7l-1) 70%) was obtained.

H-NMR (CDsOD) δ 1.27 (3H,d (J=6.3Hz), methyl proton), 1.90 (3H,s, methyl proton).

1.7-2.9 (2H, m, methylene proton).

3.5-4.2 (2H, m, methylene proton).

3.96 (3H, s, -〇C Danyo) (Execution fN13
) - Compound of formula (1) (R□ is hydroxymethyl, R
2-acetyl group: 1-hydroxymethyl-6-medoxy-3,7-dimethyl-5,8-dioxo-1,2,3 obtained in Production Example 12 of compound l-2)
, 40 mg of 4,5,8-hexahydroisoquinoline was dissolved in 4 ml of methanol.

1125 mg of acid anhydride was added. After 30 minutes, the bath medium was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel thin layer chromatography (chloroform-methanol (10:1)) to obtain N-acetyl-1-hydroxymethyl-6-medoxy 3,7 -Simethyl-5.8dioxo-1,2,3,
4,5,8-hexahydroisoquinoline (compound I-l
-2) 19 was obtained.

HN M R (CD 30 D ) δ1.32 (
3H,d (J=6.6Hz), methyl proton), 1
．． 92 (38,s, methyl proton).

2.25 (3H,s, -NCOC Danyo), 3.98 (
3H,s, methyl proton) (Example g7I414) - compound of formula (I) (Rs and R
2 together to form -CH2-0-CH2- group: Compound ■
-3) 1-Hydroxymethyl-6-medoxy3,7-dimethyl-5,8dioxo-1,2,3 obtained in Production Example 12
,4,5,8-hexahydroisoquinoline (compound 1-
1-1) Add 70 to 30 ml of benzene and add 620 mg of rose formaldehyde and 5 g of anhydrous sodium sulfate at room temperature.
The reaction solution was stirred for 3 hours, and then insoluble matter in the reaction solution was removed by filtration.

The filtrate was concentrated under reduced pressure to give 8-methoxy-5,9-dimethyl-
7,10-dioxo1,5,6,7,10°10b-hexahydro-3H-oxazolo(4°3-a]isoquinoline (compound 1-3) was quantitatively obtained.

HNMR (CDsoD) δ 1.14 (38,d (J=6.6Hz), methyl proton), 1.89 (3H,s, methyl proton).

1.9-2.9 (2H, m, methylene proton).

3.4-3.7 (IH, m), 3.98 (3H, s
.

-0CR), 4.1-4.6 (3H, m) elemental analysis (
C14817N (as Os) C (%) H (%)
N (%) Analytical value 63.98 6.70 5.21 Theoretical value
63.87 6.51 5.32 or below margin
It was found that it has antitumor activity against tumor Im cells such as 1210.

The antitumor activity test of the compound of the present invention was conducted by the following method.

(Test Example 1) Cultured Co1on261IIIiL on CoIon26 at 10% CV/V)
ME containing fetal bovine serum and 60μ/ml kanamycin
I.
After making 100ml, culture dish (Coster No. 351
2) and cultured at 37°C in a carbon dioxide incubator (5% carbon dioxide, 95% air).

After 24 hours, compounds dissolved or suspended in ethanol or dimethyl sulfoxide were added at various concentrations. After adding m, incubate at 37℃ in a carbon dioxide incubator (5% carbon dioxide, 95%
The cells were incubated for 1 hour in air).

Suction and remove the culture solution in the multi-hole with an aspirator and add 1 ml of P.
BS was added and the mu surface was gently washed and removed by suction. After treatment with HBSS containing 0.05% trypsin and 0.02% EDTA and bivetting, diluted with Mysotone solution and washed with a Coulter Counter (manufactured by Coulter).
The number of mm in ml suspension was counted. The effect of drugs is T/C
It was shown in

T/C (%) = (Number of viable cells in test example/Number of viable m cells in control) x 100 The results are shown in Table 1.

(Test g42) Add culture medium 11L121011Jll to L1210 at 10% (v/v)
RPM116 containing fetal bovine serum and 20 μM (2-mercaptoethanol and 100 μg/ml kanamycin)
A 10'l'li/1 ml floating *knit m solution was prepared with 40 medium solution. Culture test tube (Falcon No, 2054
) and cultured at 37°C in a carbon dioxide incubator (5% carbon dioxide, 95% air).

After 5 hours, compounds dissolved or suspended in ethanol or dimethyl sulfoxide were added at various concentrations. After addition, the llI cell suspension was incubated at 37°C for 1 hour in a carbon dioxide gas incubator (5% carbon dioxide, 95% air), and the number of llI cells in each wm suspension was counted using a Coulter counter. did. The effect of the drug was shown in TiC.

The results are shown in Table 2.

D50 Cytotoxicity is the ED50 value (ml! with the non-additive group as a control).
The data are shown in triplicate (concentration that inhibits 50% growth) at each concentration.
) was calculated from the value of

The respective results are shown in Table 1.2.

Blank space below [Effects of the Invention] The novel isoquinoline quinone derivative compound represented by formula (I), which is the object compound of the present invention, exhibits antitumor activity.The present invention provides a novel chemical substance having properties as an antitumor agent. I was able to do that.

Furthermore, the compounds represented by formulas (It) and (11[) are useful as intermediates for producing the compound represented by formula CI).

Claims (3)

[Claims] (1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 represents a hydroxymethyl group, R_2 represents a hydrogen atom or an acyl group. Or R_1 and R_2 together represent -CH_2-O An isoquinolinequinone derivative represented by -CH_2- bond, a stereoisomer thereof, or a salt thereof. (2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 is a hydroxymethyl group, R_2 is a hydrogen atom, and R_3 is a hydrogen atom or a benzyl group. Or R_1 and R_2 are combined. -CH_2-O-CH_
2 - Indicates a bond. Dotted lines indicate the presence or absence of double bonds, respectively. However, when the carbon-nitrogen bond is a double bond, the substituents are R_1 and R_3), or a stereoisomer thereof, or a salt thereof. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R_1 is formylmethyl or -CH(-A)C
H_3 group, A is hydroxy, methanesulfonyloxy, azide, amino, substituted amino (-NH-CO-C
O_2Et) group, and R_2 represents a hydrogen atom or a benzyl group).