JPH0343261B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel optically active alkyloxynaphthacene derivative and a method for producing the same. More specifically, the present invention relates to a 7-alkyloxy-5,7,8,9,10,12-hexahydronaphthacene derivative represented by the following general formula [] and its acid addition salt.

[In the formula, A means a straight chain alkylene group having 2 to 8 carbon atoms, and R ¹ and R ² are the same or different and mean a hydrogen atom or a lower alkyl group. ] Inorganic acids and organic acids can be used as acids for forming acid addition salts.

Inorganic acids such as hydrochloric acid and hydrobromic acid, organic acids such as acetic acid, phosphoric acid, citric acid, and tartaric acid, can be selected as long as they do not adversely affect the human body.

Here, the meanings of terms representing substituents used in this specification will be mentioned.

"Lower alkyl group" refers to a linear or branched alkyl group having 1 to 4 carbon atoms, specifically methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group. group, t-butyl group, etc.

"Alkylene group" refers to a linear alkylene having 2 to 8 carbon atoms, more specifically -(CH ₂ ) _n -(m=
2 to 8).

The compound represented by the general formula [] is extremely effective as an anticancer agent. Adriamycin (hereinafter abbreviated as ADR) and daunomycin (hereinafter abbreviated as DMC) are currently used clinically.
Although it is highly effective, it also has strong side effects, including fatal cardiotoxicity. Furthermore, it is difficult to separate and purify these anthracycline antibiotics during production. For these reasons, research has been actively conducted on new analogues of ADR and DMC through chemical modification or total synthesis, particularly on analogues in which the sugar moiety has been changed in some way. However, to date, there have been no reports of analogues in which the sugar moiety of anthracycline is converted to a substituent other than sugar and exhibit strong anticancer effects. For example, Journal of Medicinal Chemistry, Volume 22, 8.
No., pages 922-926, the 7-O-β-alanine ester of daunomarecinone has shown only borderline efficacy against P388 leukemia in animal experiments using mice.

The compound [ ] according to the present invention inhibits P388 tumor cells.
In a survival test on mice in which 10 ⁶ cells were intraperitoneally transplanted (the drug was administered on the 1st and 5th days from the day of transplantation), the following significant effects were shown. That is,
ADR showed a 93% survival rate (ILS) at a single dose of 1 mg/Kg, whereas 9-acetyl-7-
β-dimethylaminoethyloxy-6,9,11-
Trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione is 50mg/Kg
The dose showed a 120% survival rate (ILS).

As described above, the present invention provides an anticancer agent with a strong action obtained by introducing an easily available aminoalkyloxy group into the 7-position of an anthracycline aglycone in place of a sugar substituent that is difficult to synthesize. It is something to do.

The compound [ ] according to the present invention is a known substance 9-acetyl-6,7,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione and the following general formula [] [In the formula, A, R ¹ and R ² have the same meanings as above. ] It can be easily synthesized by reacting the alcohol derivative or its active ester derivative represented by the following under suitable condensation reaction conditions.

The stereoisomers of the compound [] according to the present invention include the following formulas [], [] and [] [In the formula, A, R ¹ and R ² have the same meanings as above. ] are possible, but in addition to [ ], the present application also includes mixtures of all these isomers and all stereoisomers in arbitrary combinations in arbitrary proportions.

Hereinafter, some of the compound groups according to the present invention are more specifically listed below.

7(S)-(2-aminoethyl)oxy-9(S)
-acetyl-6,9,11-trihydroxy-5,
7,8,9,10,12-hexahydronaphthacene-
5,12-dione 7(S)-(2-methylaminoethyl)oxy-
9(S)-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione 7(S)-(2-dimethylaminoethyl) Oxy-9(S)-acetyl-6,9,11-trihydroxy-5,7,9,10,12-hexahydronaphthacene-5,12-dione 7(S)-(3-dimethylaminopropyl) Oxy-9(S)-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione 7(S)-(2-diethylaminoethyl ) Oxy-9(S)-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione The present invention will now be explained by way of example. The present invention will be explained in more detail below, but the present invention is not limited to the following examples.

Example 1 9-acetyl-6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (1.0 g) was dissolved in trifluoroacetic acid (45.5 ml). ). Under nitrogen flow 0-5
After dropping 2-dimethylaminoethanol (7.28 g) at 50-55°C, the mixture is reacted for 4 hours. Further 2-
Add dimethylaminoethanol (2.43 g) and react at the same temperature for an hour. Excess trifluoroacetic acid was distilled off under reduced pressure (azeotropic distillation was carried out three times with a mixed solvent of benzene-dichloromethane-methanol=10/8/2 ml), and the residue was extracted with concentrated hydrochloric acid (50 ml) and chloroform (100 ml). The organic layer is further extracted two to three times with concentrated hydrochloric acid (50 ml). Combine the hydrochloric acid aqueous layers and adjust the pH to 8.0 with caustic soda water at 5-10°C. Extract the organic matter with chloroform (200 ml). Washing with water (100
ml), drying (mirabilite), and removing the solvent. The resulting crude product was purified by silica gel chromatography (chloroform/methanol = 9/1) to yield 7-β-dimethylaminoethyloxy-9-acetyl-6,
9,11-trihydroxy-5,7,8,9,10,
Orange crystal of 12-hexahydronaphthacene-5,12-dione (mp244-248℃, IR (Nujol) νcm ^-1 ;
3500~3300, 1710, 1630, 1590, NMR ( _CDCl3 )
δ; 1.78-2.08 (1H, m), 2.33 (6H, s), 2.41
(3H, s), 2.1~3.4 (5H, m), 3.7~4.0 (3H,
m), 4.88-5.08 (1H, bs), 7.63-7.93 (2H, m),
8.18~8.48 (2H, m), 12.4~14.0 (1H, m, _D2O
mass spectrometry (based on field day soap mass spectrometry; the same applies hereinafter);
440 (M+1) ⁺ ) was obtained. Also, by the above procedure, 7-β-dimethylaminoethyloxy-9-acetyl-6,7,11-trihydroxy-5,7,
8,9,10,12-hexahydronaphthacene-5,
Red-orange crystals of 12-dione (mp235-240℃, IR
(Nujol) νcm ^-1 ; 3600~3200, 1720, 1620,
1580, NMR (CDCl ₃ ) δ; 1.99 (1H, s, D ₂ O disappearance), 2.33 (6H, s), 2.38 (3H, s), 2.0-2.5
(2H, m), 2.58-2.7 (2H, t), 3.0 (1H, s),
3.2 (1H, s), 3.72-3.84 (2H, t), 4.97-5.09
(1H, t), 7.62-7.92 (2H, m), 8.1-8.4 (2H,
m), 12.2-13.8 (1H, m, D ₂ O disappearance), mass spectrometry; 440 (M+1) ⁺ ) was also obtained.

Example 2 Optically active 9(s)-acetyl-6,7,9,11-tetrahydroxy-5,7,8, with optical rotation [α] ²⁰ _D +81.4° (C = 0.1, CHCl ₃ ) 9,10,12-hexahydronaphthacene-5,12-dione (0.403g)
_were reacted and post-treated in the same molar ratio as in Example ¹ to obtain optically active 7-β-dimethylaminoethyloxy _- 9 (s )
-acetyl-6,9,11-trihydroxy-5,
7,8,9,10,12-hexahydronaphthacene-
Red-orange crystals of 5,12-dione (mp90-93℃, IR
(Nujol) νcm ^-1 3600~3300, 1720, 1620, 1585)
I got it.

Example 3 9-acetyl-6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (0.5 g) and 2-diethylaminoethanol The reaction was carried out in the same manner as in Example 1 at the same molar ratio, and 7-β-diethylaminoethyloxy-9-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene -5,12-dione orange crystal (mp252~
253.5゜, IR (Nujol) νcm ^-1 ; 3600~3100, 1700,
1625, 1590, NMR (CDCl ₃ ) δ; 1.0 (6H, t),
1.8~2.0 (1H, d), 2.2~2.8 (7H, m), 2.4 (3H,
s), 2.97 (1H, s), 3.15 (1H, s), 3.8 (2H,
t), 4.9-5.1 (1H, bs), 7.65-7.9 (2H, m),
8.2-8.4 (2H, m), mass spectrometry; 467M ⁺ ) and 7,9-trans form (mp141-143℃, IR
(Nujol) νcm ^-1 ; 1715, 1620, 1585, NMR
( _CDCl3 )δ; 1.0 (6H, t), 1.9-2.1 (1H, d),
2.38 (3H, s), 2.25-2.7 (7H, m), 3.0 (1H,
s), 3.2 (1H, s), 3.7 (2H, t), 4.95-5.1
(1H, t), 7.7-7.9 (2H, m), 8.15-8.4 (2H,
m), mass spectrometry; 467M ⁺ ) was obtained.

Example 4 9-acetyl-6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (0.5 g) and 3-dimethylamino- 1-propanol was reacted in the same molar ratio as in Example 1, and 7-γ-dimethylaminopropyloxy-9-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12 -Red-orange crystal of hexahydronaphthacene-5,12-dione (mp249~251℃, IR (Nujol) νcm ^-1 ; 3600~
3050, 1715, 1630, 1590, NMR (CDCl ₃ ) δ;
1.65-2.1 (4H, m), 2.2 (6H, s), 2.35 (3H,
s), 2.2-2.55 (6H, m), 3.0 (1H, s), 3.13
(1H, s), 3.8 (2H, t), 4.85~5.02 (1H, bs),
7.7-7.9 (2H, m), 8.2-8. (2H, m), mass spectrometry; 454 (M+1) ⁺ ) and 7,9-trans form (mp245-247°C, IR (Nujol) νcm ^-1 ; 1715 ,
1630, 1590 mass spectrometry; 454 (M+1) ⁺ ) was obtained.

Example 5 9-acetyl-6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (0.5 g) and N-methylethanolamine were reacted in the same molar ratio as in Example 1, and 7-β-methylaminoethyloxy-9-acetyl-6,9,11-trihydroxy-
Reddish brown crystals of 5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (mp259-262℃,
IR (Nujol) νcm ^-1 ; 3600~3300, 1700, 1620,
1590, NMR ( _CDCl3 ) δ; 1.8-2.1 (1H, d),
2.2-2.9 (7H, m), 2.4 (3H, s), 3.0 (1H, s),
3.13 (1H, s), 3.9 (2H, t), 4.9~5.08 (1H,
bs), 7.7-7.9 (2H, m), 8.2-8.4 (2H, m), mass spectrometry; 426 (M+1) ⁺ ) and 7,9 trans isomer (mp156-159°C, IR (Nujol) νcm ^-1 ; 3400〜
3000, 1720, 1630, 1590, mass spectrometry; 426 (M+
1) ⁺ ) was obtained.

Claims (1)

[Claims] 1. General formula [In the formula, A means a straight chain alkylene group having 2 to 8 carbon atoms, and R ¹ and R ² are the same or different and mean a hydrogen atom or a lower alkyl group. ] Novel optically active alkyloxynaphthacene derivatives and acid addition salts thereof.