JPS6247191B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel camptothecin derivatives and methods for producing the same. More specifically, the present invention relates to camptothecin-7-aldehyde represented by the following chemical structural formula () and a method for producing the same.

Camptothecin is produced by Yoshiki Ochiba (Camp to the
It is an alkaloid extracted and isolated from plants such as caacuminata Nyssaceae, and has a strong nucleic acid synthesis inhibitory effect.Its action is rapid and reversible, and is unique in that it does not show cross-resistance with existing anticancer drugs. It is an antitumor substance with a mechanism of action, and is recognized to have strong anticancer effects on experimentally transplanted cancers such as murine leukemia L1210 and rat Walker 256 sarcoma.
The current situation is that its usefulness as a medicine is naturally limited.

Therefore, attempts have been made to chemically convert camptothecin into other substances, that is, to convert it into camptothecin derivatives, in order to reduce toxicity while retaining anticancer activity.

However, camptothecin itself is poorly soluble in various organic solvents, and camptothecin has resistance to electrophilic substitution reactions due to the heterocycle it has in its chemical structure. However, there are various obstacles, and the reality is that it is not as easy to obtain new derivatives as planned on paper.

The present inventors previously discovered a method for efficiently introducing a hydroxymethyl group into the 7-position of camptothecin in one step, and started from the 7-hydroxymethyl camptothecin obtained by this method to demonstrate various anticancer activities. As a result of further experimental research, we succeeded in obtaining a novel camptothecin derivative, camptothecin-7-aldehyde, by treating 7-hydroxymethylcamptothecin with a cationoid reagent.

In other words, the present invention is based on the chemical structural formula () The present invention provides camptothecin-7-aldehyde, which is a novel camptothecin derivative represented by the following formula, and a method for producing the same. The present invention will be explained in detail below.

Camptothecin-7-aldehyde, a novel substance provided by the present invention, is an important intermediate for producing other novel camptothecin derivatives. As a result of various studies starting from 7-hydroxymethylcamptothecin, the present inventors found that camptothecin-7-aldehyde can be directly produced by treating 7-hydroxymethylcamptothecin with various cationoid reagents without using an oxidizing agent. I found out what I can get. In this case, examples of cationic reagents that can be used include various mineral acids (inorganic acids), organic acids, Lewis acids, organic acid chlorides, and chlorinating agents. As the mineral acid, sulfuric acid, hydrochloric acid, perchloric acid, hydrobromic acid, etc. can be used, but in this case, preferably 20 to 50
% aqueous solution, 7-hydroxymethylcamptothecin is dissolved therein, and the solution is preferably boiled and refluxed. Organic acids include acetic acid, propionic acid, benzoic acid,
Examples include various carboxylic acids such as monochloroacetic acid and trifluoroacetic acid, and sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. When these cationoid reagents are used, they are preferably used in a solvent such as water, dimethylformamide, dioxane, or the like. However, in the case of acetic acid etc., the operation can be carried out using acetic acid itself as a solvent without using these solvents. Furthermore, Lewis acids such as boron trifluoride/ether, aluminum chloride, and stannic chloride can be used as cationoid reagents. In this case, Lewis acid is used as a solvent using 5 to 10 times the mole in an aprotic solvent such as nitrobenzene, dioxane, tetrachloroethane, diglyme, etc.
Preferably, it is heated to 90-100°C. Examples of organic acid chlorides include p-toluenesulfonyl chloride,
Examples include phenylacetyl chloride. In this case, preferably 5 to 10 times the molar amount of the organic acid chloride is used and
It is best to heat it to 90-100℃. Further, as the cationoid reagent, reagents commonly used as chlorinating agents such as inorganic acid chlorides such as phosphorus oxychloride and thionyl chloride, and triphenylphosphine-carbon tetrachloride can also be used. In this case, it is preferable to use 5 to 10 times the molar amount of the reagent in a solvent such as pyridine or dioxane, and to heat it to around 100°C.

The production method of the present invention can convert the hydroxymethyl group of 7-hydroxymethylcamptothecin into an aldehyde in one step without using an oxidizing agent.
This is a novel method that has not been previously known even for heterocyclic compounds such as hydroxymethylquinoline.

Additionally, camptothecin-7 obtained according to the present invention
-Aldehyde can be easily converted into 7-dialkoxymethylcamptothecin by acetalization of aldehyde using a conventional method. The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Example 1 7-hydroxymethylcamptothecin (200
mg, 0.529 mmol.) was suspended in H ₂ O (20 ml), concentrated sulfuric acid (6 ml) was added little by little to make the whole solution, and the mixture was boiled under reflux for 30.5 hours. After cooling, the reaction mixture was diluted with ice water (500 ml) and extracted with CHCl ₃ (300 ml x 3). At this time, the solids that are insoluble in both the aqueous layer and the CHCl ₃ layer are removed and dried (7-hydroxy-methylcamptothecin, recovered). Combine ₃ layers of CHCl
Dry with MgSO ₄ , filter and dry in vacuo. The residue is purified by silica gel column chromatography (CHCl ₃ ) to obtain 39 mg (yield 29.7%) of camptothecin-7-aldehyde. At this time, a total of 68 mg of 7-hydroxymethylcamptothecin was recovered.

Analysis data for camptothecin-7-aldehyde.

Yellow prism crystal mp256-260゜(dec.) (from benzene) IRν ^KBr _nax cm ^-1 : 3350, 3080, 2960, 2925, 2860
,
1750 (lactone), 1690 (CHO), 1655 (lactam), 1600, 1460, 1225, 1155, 765.

NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.5Hz),
1.93 (2H, q, J = 7.5Hz), 5.31 (1H, d, J
= 16Hz, C ₁₇ -H), 5.63 (2H, s, C ₅ -H),
5.80 (1H, d, 16Hz, _C17 -H), 7.68 (1H,
s, _C14 -H), 7.90 (2H, m), 8.38 (1H,
m), 8.80 (1H, m, C ₉ −H), 11.20 (1H,
s, C H O).

MS: m/e376 [M ⁺ ] (C ₂₁ H ₁₆ N ₂ O ₅ = 376) Example 2 7-Hydroxymethylcamptothecin (200
mg, 0.529 mmol.) in acetic acid (100 ml),
Boil and reflux for 5.5 hours. The reaction mixture was dried under reduced pressure, and the residue was separated and purified by silica gel (30 g) column chromatography (CHCl ₃ ) to obtain 7-acetoxymethylcamptothecin (19
mg, yield 8.5%) and camptothecin-7-aldehyde (135 mg, yield 67.8%).

Example 3 7-Hydroxymethylcamptothecin (100
mg, 0.264 mmol.) was suspended in tetrachloroethane-dioxane (30 ml-20 ml), and boron trifluoride ether (500 μl, approximately 3.96 mmol.) was added.
Boil and reflux for 14.5 hours. The reaction mixture is dried under reduced pressure and the residue is suspended in water (100 ml) and extracted with chloroform (100 ml x 3). Combine the chloroform layers, dry with magnesium sulfate, filter,
After drying under reduced pressure and purifying the residue by silica gel column chromatography (chloroform), 26
mg (yield 26.1%) of camptothecin-7-aldehyde is obtained as yellow crystals.

Example 4 7-hydroxymethylcamptothecin (378
mg, 1 mmol.) was dissolved in warm pyridine (200 ml), p-toluenesulfonyl chloride (950 mg, 5 mmol.) was added thereto, and the mixture was stirred at 80-90°C for 4.5 hours. The reaction mixture is dried under reduced pressure, and the residue is separated and purified by silica gel column chromatography (CHCl ₃ ) to obtain 255 mg (yield 68.7%) of camptothecin-7-aldehyde as a yellow solid.

Example 5 7-Hydroxymethylcamptothecin (100
mg, 0.264 mmol.) was dissolved in pyridine (50 ml)-dimethylformamide (50 ml), to which was added phenylacetyl chloride (200 mg, 1.29 mmol.), and the mixture was stirred at 90-100°C for 6 hours. The reaction mixture was dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (CHCl ₃ ) to yield 7-phenylacetoxymethylcamptothecin (74 mg, yield 56.5%) and camptothecin-7-
The aldehyde (19 mg, yield 19.1%) is obtained.

Example 6 7-hydroxymethylcamptothecin (100
mg, 0.268 mmol.) was suspended in dioxane-chloroform (15 ml-7 ml), and phosphorus oxychloride (0.5 ml, 5.37 mmol.) was added thereto and boiled under reflux for 2 hours. The reaction mixture was dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (CHCl ₃ ) to obtain 34 mg (yield 34.2%) of camptothecin-7-aldehyde as a yellow solid.

Example 7 7-Hydroxymethylcamptothecin (100
mg, 0.264 mmol.) was suspended in dioxane-chloroform (75 ml-25 ml), thionyl chloride (680 mg, 5.71 mmol.) was added thereto, and the mixture was boiled and refluxed for 14 hours. The reaction mixture is dried under reduced pressure and the residue is purified by silica gel column chromatography (chloroform) to obtain 57 mg (yield 57.2%) of camptothecin-7-aldehyde as a yellow solid.

Example 8 7-Hydroxymethylcamptothecin (200
mg, 0.529 mmol.) in dimethylformamide (150
ml), and to this was added triphenylphosphine (700 mg, 2.67 mmol.) and carbon tetrachloride (300 mg, 2.67 mmol.).
μl, about 3.11 mmol.) and stirred at 95-100°C for 10 hours. The reaction mixture was dried under reduced pressure, and the residue was separated and purified by silica gel column chromatography (CHCl ₃ ) to give 101 mg (yield:
56.4%) of camptothecin-7-aldehyde is obtained as a yellow solid. A small amount (about 20mg) of 7-
Hydroxymethylcamptothecin is recovered.

Reference example Camptothecin-7-aldehyde (200mg,
0.532 mmol.) in ethanol (50 ml),
Add boron trifluoride/ether (1 ml) and boil under reflux for 3.5 hours. The reaction mixture was dried under reduced pressure, water (100 ml) and chloroform (100 ml) were added to the residue, shaken, and hydrogen was further extracted with chloroform (100 ml). The combined chloroform layers are dried over magnesium sulfate, filtered, and dried under reduced pressure. The residue was purified by silica gel column chromatography (10%
-n-hexane-chloroform) to obtain 209 mg (yield 87.3%) of 7-diethoxymethyl-camptothecin as yellow-white crystals.

The analytical data for 7-diethoxymethylcamptothecin is as follows.

mp223～224゜(dec.) [Ethanol] IRν ^KBr _nax cm ^-1 : 3400, 2960, 2920, 2880, 1740
,
1655, 1600, 1155, 1050, 765.

NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.3Hz),
1.26 (3H, t, J = 6.8Hz), 1.28 (3H, t, J
= 6.8Hz), 1.90 (2H, q, J = 7.3Hz, 3.70
(4H, m), 5.29 (1H, d, J=16Hz), 5.50
(2H, s), 5.76 (1H, d, J=16Hz), 6.36
(1H, s), 7.66 (1H, s), 7.64−7.87 (2H,
m), 8.19−8.39 (2H, m).

MS: m/e450 [M ⁺ ] (C ₂₅ H ₂₆ N ₂ O ₆ = 450)

Claims (1)

[Claims] 1. Camptothecin-7-aldehyde represented by the chemical structural formula (). 2 Chemical structural formula () characterized by treating 7-hydroxymethylcamptothecin with a cationic reagent A method for producing camptothecin-7-aldehyde represented by