JPH04338399A - Condensed quinoline derivative - Google Patents

Abstract

PURPOSE:To obtain a new condensed quinoline derivative having a specific structure containing a substituent group consisting of saccharide in a molecule, capable of suppressing proliferation of cancerous cell and exhibiting life- prolonging effect to a cancer-carried animal and expected in utilization as anticancer agent. CONSTITUTION:2, 3, 4, 6-Tetra-O-acetyl-alpha-galactopyranosylboromide expressed by formula I (Ac is acetyl) is dissolved in dried dimethylformamide and dried pyridine and stirred in argon stream at ambient temperature for 12hr and then an indoroquinoline based compound expressed by formula II is added thereto and the mixture is stirred at ambient temperature for 1 day to react both compounds and after reaction, reaction mixture is poured into ice water and extracted with chloroform and the solvent is distilled off by extraction liquid and the residue is recrystallized to give a compound expressed by formula III, which is then as necessary hydrolyzed by treating the compound in ammonia water and methanol to provide formula IV [R<1> is H or the formula CH2OR<3> (R is H or acetyl); R<2> is H or acetyl].

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel condensed quinoline compounds. More specifically, the present invention relates to novel indoquinoline compounds having excellent anticancer activity.

0002

[Prior Art] Kane, Auwell, Seeley (B.
F. Cain, G. J. Atwell, R.
N. Sealye et al. synthesized various acridine compounds having an alkylamino group at the 9-position and found that they had anti-leukemic activity [J. M
ed. Chem. vol. 15,611 (1972
)].

Furthermore, Kane, Auwell, and Seeley et al. carried out a molecular conversion of the alkylamino group at the 9-position of acridine, resulting in N-[4-(9-acridylamino)3
-methoxyphenyl)methanesulfonamide (Amsa
Crine) has been found to have the strongest anticancer effect [J. Med. Chem. vol. 17,
922 (1974)].

[0004] Furthermore, G. W. Rewcastle, Beagley, Awell, Denny
B. C. Bagley, G. J. Atw
ell, W. A. Denny et al. attempted molecular transformation of amsacrine, synthesized derivatives in which a methyl group or N-methylcarbamoyl group was introduced into the acridine ring, and found that these had strong anticancer effects [J.
Med. Chem. vol. 30,1576 (1
987)].

On the other hand, the present inventor has synthesized indenoquinoline compounds separately from these and found that they exhibit strong anticancer activity (Japanese Patent Application Laid-Open No. 101369/1983).

Furthermore, we synthesized new benzofloquinoline and benzothienoquinoline compounds and found that they also exhibited strong anticancer activity (Japanese Patent Laid-Open No. 63-238
No. 079).

The present inventors have also filed patent applications for condensed quinoline compounds such as indoquinoline compounds and benzacridine compounds (Japanese Patent Laid-Open No. 63-5688).
No. 3, Japanese Unexamined Patent Publication No. 2-256667).

[0008]

OBJECTS OF THE INVENTION An object of the present invention is to provide novel quinoline compounds having excellent anticancer activity.

[0009] Therefore, the present inventor has conducted further research on the various condensed quinoline compounds described above, and has discovered a new condensed quinoline compound.

0010

[Means for Solving the Problems] The present invention relates to the following general formula [I
].

[Case 2]

In the formula, R1 is a hydrogen atom or -CH2O
R3 (where R3 represents a hydrogen atom or an acetyl group)
shows. R2 represents a hydrogen atom or an acetyl group.

The present invention will be explained below based on Scheme 1 and Scheme 2. In addition, in the scheme, Ac represents an alkyl group.

[0013]

[C3]

[0014]

[C4]

In Scheme 1, R1 is -CH2OR3
A synthetic scheme of a compound is shown below. In Scheme 2, R
A synthetic scheme of a compound in which 1 is a hydrogen atom is shown.

In the scheme, the starting compound (1) is a known galactopyranosyl bromide derivative and is an easily available compound (H. Paulsen,
C. Kolar, Chem. Ber. , 112
, 3190 (1979)). In addition, raw material compound (5)
is also a known arabinopyranosyl bromide derivative and is an easily available compound (Humoller
, F. L. :Methods in Carboh
ydrate Chem. NY 1,83 (1962
)). On the other hand, the raw material compound (2) is also a known compound,
It can be synthesized according to Example 23 of JP-A-2-256667.

Compound (1) or (5) and compound (2)
) means 12 to 10% at room temperature in the presence of pyridine, in a solvent such as dimethylformamide, or in an inert atmosphere such as argon.
By reacting for about 48 hours, compound (3
) or (6) can be obtained.

Compounds (3) and (6) are deacetylated by the action of ammonia in a solvent such as methanol to form compounds (4) and (7), respectively.
can be obtained.

Compounds (4) and (7) of the present invention are
It is expected to be used as an anticancer agent because it suppresses the proliferation of cancerous cells and has a life-prolonging effect on cancer-bearing animals.

[0020]

[Examples] The present invention will be further explained by the following examples.

Example 1 7-(N-galactopyranosylamine) indolo[3.
2-b] Synthesis of quinoline derivative (4)

[0022]2
, 3,4,6-tetra-O-acetyl-α-galactopyranosyl bromide (560 mg, 1.5 mmol) was dissolved in dry DMF (30 ml) and dry pyridine (2 ml) and heated at room temperature for 12 hours under an argon atmosphere. After stirring in
Compound (2) (360 mg, 0.75 mmol) was added and stirred at room temperature for 1 day. After the reaction, pour into ice water and add C.
After extraction with HCl3, the CHCl3 layer was washed with water, dried, and the solvent was distilled off under reduced pressure. Reconsolidation of the residue with CH2Cl2 gave compound (3), melting point 181-185°C (decomposed).

Physical properties of compound (3) IRνmax Nujol cm-1, 3600,
3380, 17501H-NMR (CDCl3+D
MSO-d6) δ: 2.08, 2.09, 2.1
3, 2.18 (12H, each s) 2.92 (3H
, s) 3.96 (3H, s) 4.14 (3H,
s) 5.18-5.52 (2H, m) 5.68-5
．． 91 (1H, m)6.38-6.46 (1H,
m) 6.58-6.71 (1H, m) 6.98-7
．． 82 (10H, m) 8.01-8.70 (3H
, m)

Compound (3) was dissolved in 28% aqueous ammonia (20 ml) and methanol (100 ml), and the mixture was stirred at room temperature for 3 days by occasionally introducing ammonia gas. After the reaction, methanol was distilled off and the residue was recrystallized from methanol to give 140 mg (yield 30%) of compound (4).
was gotten.

Compound (4) is poorly soluble in solvents, so NM
It was difficult to measure R. Therefore, compound (4) was converted into a tetraacetyl form having the same structure as compound (3) using acetic anhydride and pyridine, and then this tetraacetyl form was deacetylated with aqueous ammonia. That is, the melting point of compound (4) is 215-217
°C (decomposed) (recrystallized from methanol).

Further, the physical properties of the tetraacetyl compound are shown below. Melting point 193-195°C (decomposed) (recrystallized from dichloromethane) IRνmax Nujol cm-1, 3600,
3380, 1760, 17401H-NMR (6
0MHz, CDCl3+DMSO-d6+D2O)δ
: 1.96, 2.01, 2.08, 2.14
(3H each, s each, COCH3) 2.89 (3
H, s, SO2CH3)4.00 (3H, s,
OCH3) 3.81-4.36 (3H, m, 5'
'H and CH2) 5.12-5.49 (3H, m
, 2''H, 3''H and 4''H) 5.60
(1H, d, J=8Hz, 1''H)6.30
(1H, d, J=8Hz, 5'H)6.74(1
H, dd, J=2 and 8Hz, 6'H) 6.88
-7.75 (5H, m) 7.93 - 8.55 (3H
, m)

Example 2 7-(N-arabinopyranosylamino)indolo [3.
2-b] Synthesis of quinoline derivative (5)

Compound (6) was synthesized in the same manner as the synthesis of compound (4) in Example 1, except that compound (5) (560 mg, 1.5 mmol) and compound (2) (360 mg, 0.5 mmol) were used. This was further treated with ammonia to obtain compound (7) (120 mg, yield 25%).

Physical properties of compound (6) Melting point 160-167°C (decomposition) (recrystallization from CH2Cl2) IRνmax Nujol, 3600,
3380,17501H-NMR (CDCl3+DM
SO-d6) δ: 2.09, 2.10, 2.13
(9H, each s) 2.82 (3H, s) 3.9
1 (3H, s) 3.81-4.50 (3H, m
)5.01-5.42 (2H, m)6.13-6.
31 (1H, m)6.35-6.50 (1H,
m) 6.91-7.68 (10H, m) 7.94-
8.46 (3H, m)

Compound (7)
was difficult to measure by NMR because it was poorly soluble in solvents. Therefore, compound (7) was converted into a triacetyl form having the same structure as compound (6) using acetic anhydride and pyridine, and then this triacetyl form was deacetylated with aqueous ammonia. That is, the melting point of compound (7) was 205 to 207°C (decomposed) (recrystallized from methanol).

Further, the physical properties of the triacetyl compound are shown below. Melting point 160-167°C (decomposed) (recrystallized from dichloromethane) IRνmax Nujol cm-1, 3600,
3380, 17501H-NMR (CDCl3+D
MSO-d6) δ: 2.09, 2.10, 2.1
3 (each 3H, each s, COCH3) 2.82 (
3H, s, SO2CH3) 3.91 (3H, s,
OCH3) 3.81-4.50 (3H, m, C
H2 and 4'H) 5.01-5.42 (3H, m,
1'H, 2'H and 3'H) 6.13-6.31
(1H, m) 6.35-6.50 (1H, m)
6.91-7.68 (10H, m) 7.94-8.
46 (3H, m)

Test Example 1 Comparison was made between administering and not administering compound (4) or (7) in an in vivo system of p-388 tumor-bearing mice.

Experimental animals: CDF, mice (6 mice/group) Tumor: P-388 Number of transplanted cells: 106 cells/mouse Transplant site: i. p. Drug administration day; 1st and 5th day Drug administration amount; LD50 or 400mg/kg/
Day was set as the highest. Judgment criteria

[0034] The test was considered effective if the ratio of survival days in the treated group to survival days in the untreated group (T/C%) was 120% or more. Without treatment, survival was typically 10 days. The results are shown in Table 1.

[0035]

[Table 1]

Claims (1)

[Claims] [Claim 1] A compound represented by the following general formula [I]. [Formula 1] (wherein, R1 is a hydrogen atom or -CH2OR3(R3
represents a hydrogen atom or an acetyl group), and R2 represents a hydrogen atom or an acetyl group. )